THE

CHEMICAL

PHARMACOLOGY

OF

BASIS

INTRODUCTION

AN

TO

PHARMACODYNAMICS
STUDY

BASED

THE

OF

CARBON

ON

THE

COMPOUNDS

BY

FRANCIS
PROFESSOB

FRANCIS,
UKIVERSITY

CHEMISTRY,

OF

D.Sc., PH.D.
COLLEGE,

BRISTOL

AND

J. M. FORTESCUE-BRICKDALE,
PHYSICIAN,
MEDICAL

DEMONSTRATOR

BRISTOL

M.A., M.D.(OxoN)
HOSPITAL

ROYAL

BRISTOL

REGISTRAR,
OF

PHYSIOLOGY,

FOR
ROYAL

UNIVERSITY

SICK
INFIRMARY

COLLEGE,

LONDON
EDWARD

CHILDREN

ARNOLD

1908

[AllMights Reserved]

BRISTOL

'

Did

rhubarb,

file,

of

will

sleep;
laid

well

as

the

on

go

file,
no

the

as

balance

removed;
a

purge,

or

that,

machine

it

performs

watchmaker

the

keep
small

some

would

and

quite

watch

lose

and

make

being

its motion

and

Book

359279

Human

IV,

of

paper

till

it

rubbed
the

iii, " 25.

be

by
watch

Understanding:
chap,

any

man

more.'

LOCKE,

of

that

beforehand

going

it

of

figure

little piece

from
of

part

the

opium

that

does

operations,

tell

to

can

watchmaker

alter

able

Ml,

of the particles of
a

its

will

be

hemlock

will

as

man,

them

on

should

we

affections

and

whereby

by rubbing

wheels,

rhubarb

mechanical

opium,

watch,

which

the

the

hemlock,

of

those

know

we

PREFACE:

IN
of

the

writing

adding

Organic Chemistry
the

sufficient

by

way

not

to

clearness
of

Since

the

Lectures,
in the
with

but

Hopkins,

of

drugs

admirable

Sir

far

subject as
far

at

the

headings
found

in

has

are

aware,

of

Hale

appeared
dealing
logical
physio-

and

Pharmacology

White,

there

F.

Dr.

subject by

chemical
of

the

of the
on

theory

has

of

subject

authors
into

chapters

is

Gowland

action

viii and

of

On

the

is

organic chemistry,
been

introduced
clear

to

as

those

feel,indeed, that
the

teaching

of

book

will

be

on

lines

seen

by

resembling

will

suffice

this

been

have

of

much
to

planned

it has

subject

to

of

are

relationship,
the

ment
arrangefound

those

this

Medical

portion

studied

might

in

chemical

general

render

modifications

as

reference

recently

not

for

of the

which

whole, however,

so

some

has

chemical

close

no

and

who

outline

an

bodies

together

but

xv.

readers

found

be

might

use

occasionally, however,

group

subject-matter

works

The

lines, as

to

physiological

some

English

understood.

necessary

chapters

the

book

Textbook

readers

Croonian

structure

Dr.

this

on

no

chemical

by

that

more

their

Brunton's

of

with

somewhat

say

authors

in the

before

lay

present

possible on

similar

1889,

possible that

should

as

been

in

the

chapter

seemed

which

book

Lauder

the

they hope

introduce

T.

as

though

either

F.R.S., of Cambridge.

It therefore

The

of

Therapeutics (1901), edited

short

as

book.

relationshipsbetween

the

and

to

the

so

intention

no

succinctly but
to

to

serve

delivered

were

English language,

action

to

publication

which

indicated

been

shall

had

While

title,they desire

which

but

authors

existing textbooks,

many

has

work

preface

the

Pharmacology.

in the

subject

the

of

or

of their

purport

the

to

more

one

volume

present

be

it.

duced
intro-

Students,

PREFACE

vi
which

would

enable

them

to

realize its connexion

present day Pharmacology. It is,however, in

Materia

Medica

radical

changes

Medical

Students

that

the authors

introduced.

would

This

wish

with

the
to

the

teachingof
the

see

subject is placed

most

before

if,on

their first duty

becoming qualified,
would
be to go out and gather simpleson the mountain-side ;
in actual fact,what
whereas
they have to do is to gauge the
relative merits or demerits of a host of synthetic
remedies, the
literature of which is so plenteouslyshowered
upon them as
as

'

their

as

soon

of
recognition

The

doctor ; and of the

commits

wearilyto
small

very

pointthe
to

of

be

way

rational

remembered

in

small

some

of
appreciation

both

use

for examination

memory

daily brought

to

in

preparations,and
hoped,enable the

with

book

reference,in which

may

in

used

as

to be used

to

be found

The

index

the

and

it seems

been

introduced
how

the older
To

had

now

medical

on

prima facieevidence

for

chemical

the
the

only

materia

test

in

littlelikelihood there

was

would

the

often be
chemical

never

of
have

able to appreciate

generalbeen
of their

of

largenumber

the market

men

is

of

highlyprobablethat

syntheticremedies

is

work

as

may

will, it

action may
drug,the probablephysiological
fairlyaccuratelyestimated by a consideration of its
structure

may

introduction

an

extent

some

the

actual

who
practitioner
of new
drugs,new

the claims

against classes and individuals in

medica.
Though clinical experienceis
of

and

to the

or

value

only

aspect of Pharmacology it

Trade-Names.

new

the student

degree the present work

the student, and

contact

knowledge

purposes,

that meanwhile
one

tory.
Direc-

purity in

for

which
preparations

numerous

reform,and

to

in the Medical

crude

proportion are

practice.
It is hoped that

appear

drugs and the tests

no
longernecessary
certainly

preparedproductsare
for

addresses

and

names

provingsuperiorto

preparations.

those

who

chemistry,it
to

is

are

hoped

engaged solelyin
that this volume

the
will

study
serve

branch
fascinating
particularly

as

of
an

of the

organic
duction
intro-

applied

PREFACE
The

science.
work

would

authors

contribute, even
of

feel

the

to

vii

sincerelygratifiedshould

smallest

manufacture

the

extent, towards

of

of such

economic

is

regulationsas
and

purposes,

be

now

may
at

the

home

on

recent

scale

their

Lauder

Dixon,
Otto

for

to

the

have

subject in
the

to

Fraser, Crum

and

from

hand.

acknowledge

exhaustive

Finally, they
F.

would
H.

most

Cash,

the

passage

new

may

articles.

original

would

in any

others, of
man,
Stock-

Dunstan,

and

of the book

Fischer,

the

Kast,

assistance
of

S.

Professor
valuable

through the

Mer-

They

they

have

Fraenkel, whose

subject with

other

v.

Curci.

.and

wealth

volume.

sincerelythank

much

here

their friend

of Medicine
advice

and

at

and
versity
Uni-

assistance

press.

F. F.
J.

UNIVEKSITY

COLLEGE,

BKISTOL,
Jan.

1908,

it

Hildebrandt, Hinsberg,

the entire

Edgeworth,

College,Bristol,for
during

on

that

the

writings, among

treatise

example quite unapproached

colleague,Dr.

Britain

They

Filehne, I?aal, Baumann

the

the

manufacturing

consulted

Brown,

illustrates
Arzneimittelsynthese
of

the

Marshall, Schmiedeberg, Ehrlich, Emil

particularly to

received

that

replacethe imported

ing, Ladenberg, Sahli, Dujardin Beaumetz,

wish

in

patent laws

in Great

Fischer, Nencki, Einhorn, Loew,

Heinz, Knorr

tion
applica-

development

hoped

the

this

profitableto produce synthetic drugs

indebtedness

Brunton,

in

conditions

largeenough

with

be

of alcohol

use

possible,the authors

dealing

express

; it is to

the

on

couragement
en-

in

discussed

are

its successful

alterations

these

possible and

Whenever
papers

the

to

favourably affect

so

for

dependent

fiscal conditions

and

Excise

it is

as

general scientific principlesas

present work,

the

synthetic drugs

country. This important industry,based

their

M.

F.-B.

CONTENTS

CHAPTER
CHEMICAL

A.

INTRODUCTION
PAGES

of

Theory

Structural

Valency,
Methods

systems.
formulae

B.
Rational

General
of

the

and

between

Their

THE

methods

of

synthesis of their
B.

or

Ethyl

Isomeric

groups,

and

Methods

used

in

the
2^44

of

....

CHARACTERISTICS

reactivity

OF

of

the

ORGANIC

HYDROCARBONS

THE

introduction

condition

saturated

un

Stereoisomeric

IN

activity
Re-

HYDROCARBONS

properties.

of

the

of

molecule,

Methyl
and

of
45-54

relationships

CHAPTER
CHANGES

theory of

action.

"

AROMATIC

Physiological

on

Loew's

derivatives

PHYSIOLOGICAL

Effect

and

in

II

AND

preparation

Difficulties

13-23

bioplasm

ALIPHATIC

and

structure

CHAPTER
A.

INTRODUCTION

physiological properties.

and

drug

Therapeutics.

of

methods

relationships

the

Carbon

constitutional

of

PHYSIOLOGICAL

Empiric

correlating chemical
poisons.

.....

GENERAL

and

of

1-13

determination

for

adopted

Inertia

Isomerism,

formulae,

III

SUBSTANCES

PRODUCED

BY

METABOLIC

PROCESSES

Syntheses

"

of Amido-acetic
and

Methyl

and

Reduction

Sulphuric

and

acid, Urea.
radicals.

Glycuronic

acid

Sulphocyanides.

Cystein

derivatives.

derivatives, Compounds
Introduction
Processes

of
of

Acetyl

Oxidation
55-80

CONTENTS

CHAPTER
THE
The

ALCOHOLS

Main

IV

AND

THEIR

DERIVATIVES

Group of Anaesthetics

and

Hypnotics
PAGES

I. General

of

physiologicalaction
Overton-Meyer Theory. Traube.
theory
Baglioni's
II. Methods

anaesthetics

Moore

and

Roaf

and

Chloroform.

on

["".

hypnotics.
81-87

preparationand chemical and physiological

properties
phurous
Esters of Halogen acids,Nitrous
and Nitric,Sul.'
87-104
Sulphuricacids. The Ethers
of

of the Alcohols.
and

'

ALCOHOLS
The

AND

(CONTINUED)

DERIVATIVES

THEIR

Oxidation

CHAPTER
THE

productsof the

Alcohols

physiologicalcharacteristics of the Aldehydes,

Ketones, Sulphones,Acids. The derivatives of the Acids.
Halogen
substitution products,
Esters,Amides, Nitriles. Sulphur derivatives

The

chemical

and

105-127

CHAPTER
AROMATIC
Main

VI

HYDROXYL

DERIVATIVES

Antiseptics

Group of Aromatic

propertiesof Phenols, Cresols,Di- and

physiological
of the antiseptic
of
Recent
investigations
Tri-oxybenzenes.
power
Phenol and its derivatives,
Creosote,Guaiacol,and their derivatives 128-148

Chemical

and

CHAPTER
AROMATIC

HYDROXYL
The

Classification of
Tannic

and

acid
Salicylic

VII

Hydroxy Acids
derivatives.

Nencki's

Salol

Principle.

Gallic acids

149-160

CHAPTER
ANTISEPTIC

AND

VIII
SUBSTANCES

OTHER

IODINE
lodoform.

(CONTINUED)

DERIVATIVES

AND

SULPHUR

Classification of substances introduced

and the Alkali Iodides.

Derivatives

CONTAINING

in

placeof lodoform
containingSulphur Ichthyol 161-170
"

CONTENTS

xi

CHAPTER

IX

DERIVATIVES

AMMONIA

OP

Antipyretics
Group of Synthetic

The Main

PAGES

discussion

derivatives
of^ara-Amido-phenol

GROUP

MAIN

Hydrazineand

171-197

....

(CONTINUED)

ANTIPYRETICS

SYNTHETIC

OF

Classification

CHAPTER
THE

Aromatic

Aliphatic and

of

allied substances.

and

Aniline, Acetanilide

Amines.
and

character
physiological

and

Chemical

its derivatives

Physiologicalaction of Phenylhydrazine and its derivatives.

Summary
Pyrazolon group" Antipyrine,Pyramidon. General

THE

GROUP

Hedonal.

Urethane.
Thiosinamine.

Veronal

II.

UREA

URETHANES,

OF

from

Hypnotics derived
hypnotics

THE

PURINE

Diuretics and Cardiac tonics.

GROUP

UREIDES

AND

Thio-urea.

Urea.

AND

PILOCARPINE

of substances

of Xanthine

type. Diaphoretics.Pilocarpine

221-232

XII

CHAPTER

Chemical
General

and

ALKALOIDS

introduction.
physiological

of Alkaloidal
principles

action.

Method

The

of classification.

Coniine,

Pyridinegroup"

233-257

Nicotine,and allied substances

CHAPTER
THE

198-212

213-220

Modification

THE

of

XI

CHAPTER
I.

derivatives

of the Ammonia

characteristics
Physiological

The

ALKALOIDS

XIII

(CONTINUED)

Cocaine, Atropine, Hyoscyamine. Quinoline

Pyrrolidinegroup
Quinine,Cinchonine, and their substitutes. Strychnineand
group"
"

Bmcine

258-283

xii

CONTENTS

CHAPTER
THE

XIV

ALKALOIDS

(CONTINUED)
PAGES

iso-quinoline'group

Hydrastine, Cotarnine, Berberine.

"

Phenanthrene

Codeine,

Morphine,

group.

and

Morpholine

(?)-

Alkaloids

Opium

"

Hordenine

284-303

CHAPTER
PRODUCTS

SYNTHETIC

of

Derivatives

PHYSIOLOGICAL

WITH

COCAINE,

TO

Guanidine,

Halogen

derivatives.

other

and

Amido-

Piperidine, Pyrrolidine,

SIMILAR

ACTION

HYDRASTIS

ATROPINE,

acid, jpara-Amido-phenol,

Benzoic

XV

Oxy-amido-

and

Tertiary Amyl-alcohol.

Substitutes

and

Atropine

for

304^319

Hydrastis

CHAPTER

XVI
GLUCOSIDES

THE

Jalapin, Amygdalin,

Sinigrin, Sinalbin,

phanthin, Saponarin,

Coniferin, Phlorizin, Stro-

Purgatives derived

"c.

from

Anthraquinone

320-330

CHAPTER
DEPENDENCE

TASTE

OP

XVII

ODOUR

AND

ORGANIC
I.

Saccharin

Sternberg's views.

II.

Physical

Odour.

III.

Organic dyes.

Picric

Curare

Action

Stereoisomerism

of

its derivatives.

and

Chemical

and

Ehrlich's

factors.

criticism

Dulcin

331-340

Typical perfumes

of

Loew's

Bismarck

Chrysoidin,

action

Antipyrine
on

"

DYES

Theory

brown,

of

341-346
.

Poisons.

violet,

Methyl

blue, Phosphine

APPENDIX.
rule.

CONSTITUTION.

acid, Aurantia,

Methylene

CHEMICAL

ON

taste.

347-355

of Ammonium
derivatives.
Action

of

Bases, exceptions

Hydroberberine.
Rosaniline

to

general

Influence

derivatives

on

of

Try356-358

panosomes
INDEX

359-372
.

ERRATA

p.
p.

line

4,
7,

in

line
p.

for

21, for

p.

21, line

6, for

p.

27,

line

7 from

coniine

read

zso-butane

18,for proteid

line

19,

conine

3, for

formula

bottom,

p.

39,
40,

line

12

p.

42,

line

11, for alkyl read

p.

50,

line

12

p.

52,

in

65,

line

p.

formula

double

omit

p.

for CH5

for

bromtoluene/or-

first formula

in

NO2

CH.COH

71, line

p.

75,

in

p.

77,

formula

79,

line

10

line

6 from

p.

18

formula

for CH

for
for

"c.,

OH2
acid

for

ethyl

formula

for

dimethyl-ethyl

p.

90,

p.

92,

in

p.

104,

line

9 from

p.

109,

line

18,for CC13COH

line

21, for CC13

p.

112,

last

but

p.

113,

second

p.

117,

in

equation,

formula

for

p.

123,

last

equation

p.

126,

line

17, for

but

127,

line

8, for alkyl

p.

131,

line

2, for pinacol

p.

144,

in

p.

149,

line

p.

156.

The

two

9,

formula

of

14

from

second

read

trichlorbutyric

for CaC03

add

+H2O

read

(CH3)2

(OCH3)a

read

acids.

one,

for CH5COOC2H5
FerrS
should

in

each

CH8COOC3H5

read

read

case

CH3

allyl

read

for

guaiacol
hydroquinone/or

bottom, for C7H5

not

as

read

C6H4

-guaiacol for O.C6H4

read

O.COC6H4

C6H5

read

derivative

C6H5
C6H5OCH3

read

should

for p-acetamido-benzoyl

and

(C2H3)

2CaCO3

read

read

resorcin

ONO

CH3CHC1CC12CHO

read

C6H4.OCH3

salicylic acid

read

CC1S.CH2OH

one,

read

formula

first formula.

142,

CH3.CHC1.CC12CHO

read

carbinol/or

CHO

CH2

C2H5

p.

p.

read

read

Ferre

formula

in

C6H5.CH2CO.NH.CH2.COOH

be

for ON02

o-Xylene/or

p. 119, last line, for acid

line

nitrite

bottom, for (OC2H3)2

equation

last

CH2

read

should

bottom, for CC13.CH2.CHO

formula

CHO

CH3CHC1.CC13.

read

bottom, for /3-trichlorpropionicread

in

in

"e.

CH

read

tyrosin/or

CH.COH

II

II

phenaceturic

from

CH"CH

CH

bottom, for CC13.CH2.CHO

from

CH,

CH3

read

Y
p.

read

produce

insert

II

66,

CH

(acrolein),for

CH"

p.

syntheses

read

halogen

bottom

2, after to

CH3

read

for synthesis

bottom,

from

McKendrick

read

in

from

cerebral

read

Kendrick

first formula

protein

read

central

Cl

omit

contains

stated

two

salicylic acid.

(i)

one

molecules

molecule
of

of

resorcin

and

resorcin

and

one

of

ERRATA

(ii)

174,

sixth

equation,

add

p.

181,

for

formula

HaO

after

oxycarbanile

CH3NH2

should

C6H4

read

p.

189,

line

from

bottom,

Propyl

for

Propionyl

read

p.

200,

last

line,

ethyl

for

ene-phenylhydrazine

ethylene-diphenylhydrazine

read

p.

226,

12,

line

for

Theophyllin

dioxypurin

and

read

Theophylline

and

p.

last

227,

formula,

line

omit

from

bottom,

CH3

in

for

position

6-dihydropurine

p.

three

read

dihydropurine

232,

line

308,

in

3,

for

glyoxolin

read

glyoxalin

p.

formula

for

triacetone-alkamine-carboxyl

p.

323,
p.

in

formula

for

aceto-chlorhydrose/or

(C3H30)4

read

(CH80)4

dioxypurine

THE

CHEMICAL

BASIS

PHARMACOLOGY

OF

CHAPTEE

CHEMICAL

A.

INTRODUCTION.

Inertia

Isomerism,

of constitutional

Rational

and

chemical

and

GENERAL
of

between

and

structure

Loew's

action.

INTRODUCTION.

Difficulties

therapeutics.

formulae,

determination

for

adopted

PHYSIOLOGICAL

physiological properties.

relationships

Structural

Valency,

Methods

systems.
B.

methods

empiric

of

Theory

of carbon
formulae.

of

theory

in

General

poisons.

of the

Reactivity

correlating
and

drug

the

bioplasm.
CHEMICAL

A.
Historical.

laid

was

which

The

"

in

that

stated

similar

conditions

number

of molecules

has

been

The

could

atomic
a

be

and

through

always
The

the

to

that

pressure,

contain

1840
so

Theory

and

important
of

the

striking results

most

in

1828,

supposed
the

same

of this

that

of the

individual

"

reactions

Gay

Lussac,

that

This

atom.

retained

many

theory

rupture

of

their existence

realization

the

to

the

the

compound, behaving

to

which
led

to

substances

organic

1840, showed

and

of atoms

fatal

was

of life.

agency

compound

changes

organic

least

substances, under

from

groups

"

hypothesis,

Organic Chemistry.

1830

pass

chemical
in

Avogadro's

Theory

gaseous

of

the

of

the

molecule

possible.

investigationsof Laurent, Dumas,

between

played

of

Chemical

Berzelius, Liebig, Wohler,

could

Radicals

principle that
was

of

similar

various

the

Wohler,

by

urea

others, between

manner

and

of

one

produced through

complexes

Compound

volumes

Vitalism, which

researches

Bunsen,

and

of
of

temperature

of

of

theory

The

in

of

synthesis
alone

equal

general

enunciation

the

rapid development

the

current

of

commencement

by

1811

INTRODUCTION.

1860, led
a

Valency.

to

the

theory

part in the science

"

The

outcome

Gerhardt

of

of

of

and

valency,

Frankland,
which

has

Organic Chemistry.

the

molecular

hypothesis

INTRODUCTION

CHEMICAL

the

was

of assigning
formulae
possibility

to the

stances
followingsub-

acid
Hydrochloric

HC1

Water
Ammonia
Marsh

Since
combines

gas

has
experience
with

more

,.

....

shown

than

that
atom

one

atom
single
of another

of

H2O
H3N
H4C
hydrogennever

element,it

appears
that this substance possesses the faculty
for combination in as low
elements ; a fact that is expressed
in
a degree
as
any of the known

the

conceptionthat hydrogen has only one power of combining

with other atoms
shown by one
stroke.
one
graphically
valency,
Since oxygen combines with two atoms of hydrogenits valencyis
reason
two, and for the same
nitrogenis trivalent and carbon
"

tetravalent.
that could be
the simplest
examplesgiven are of course
of different
taken,but they clearlyshow the varying powers
elements of unitingwith the same
substance,
hydrogen.
The
Variation
of Valency.
if
question the valency of an
element is constant
or
not, led to a long discussion. Kekule
and others regardedit as invariable as the atomic weightsthemselves,
but the upholdersof this view were
drawn into many
of which the following
contradictions,
may be taken as an example.
acid to form ammonium
Ammonia, NH3, combines with hydrochloric
chloride,
NH4C1 ; since the valencyof hydrogen and chlorine are
the same, it follows that nitrogen
from beingtrivalent in ammonia
has become pentavalent
in ammonium
chloride. Those who regarded
valencyas invariable had to look upon this latter substance as
and HC1, and it was
a molecular compound of NH3
as
represented
NH3 HC1, and but littleattention was paidto the forces that kept
these halves together.
various organic
Now
groups may take the placeof hydrogenin
be replaced,
for instance,
ammonia, it may
by the monovalent
in the substance
radicals methyl (CH3)'or ethyl(C2H5)'.Now
and the characis stilltrivalent,
teristic
triethylamine,
N(C2H5)3,nitrogen
still present; it combines with
of ammonia
are
properties
acid or methyl chloride,
hydrochloric
CH3 Cl, and the resulting
to the old hypothesis
compound N(C2H5)3CH3C1 should,according
of valency,be different from the substance
of the invariability
from the addition of ethylchloride,
resulting
C2H5C1,to methyldiethylamine,
(C2H5)2C2H6C1" but since these
e.g. (CH3) N

The

"

CHEMICAL

INTRODUCTION

have been obtained

such lineshave amply justified

on
by proceeding
the working hypothesis,for example,,
the determination of the
followed by
structural formulae of indigoblue and eonrne, was
soon
the synthetic
formation of these substances,
and in the case of the
articleof commerce.
as an
former,by its production
But the studyof OrganicChemistry
with the relatively
commences
of the changes producedin hydrocarbons,
simpleinvestigations
the compoundsof carbon and hydrogen,
by the entrance of certain
atoms
of one
or
Methane, CH4, on the replacement
groups.
hydrogen atom by chlorine givesmethyl chloride,
CH3C1, and the
characteristics producedby the entrance
of the chlorine atom
are
those that generally
follow the replacement
of hydrogenby that
element.
When
one
hydrogen atom in water is replaced
by an
the simplest
member
of the
organicradical such as methyl (CH3)',
the introduction
CH3 OH ; and again,
group of alcohols is produced,
of the hydroxylgroup, (OH)',into methane, causes
number
of
a
which are generally
and physiological
chemical,
differences,
physical,
characteristicof the presence of that grouping.
The organicacids all contain the complex (COOH)', which
confers definite properties
the hydrocarboninto which it
upon
.enters.It is the knowledgeof the characteristicsof such groups and
their combinations that is required
to solve the difficultproblemof
the constitution of substances of unknown
structure.
determining
But
is further complicated
the question
Isomerism.
by the
of differing
possibility
arrangementsof the atoms in the molecule.
itis at
ethane,CH3
Supposingthe hydrocarbon
CH3, is considered;
obvious that the hydrogen atoms are symmetrically
once
arranged
"

"

"

in the

molecule,and that

it is a matter

of indifference for instance

replaced
by the hydroxylgroup ; that is,OH.CH2 CH3 is
the same
then,the theory
as CH3
Theoretically,
clearly
CH2 OH.
and
that only one ethylalcohol should exist,
of valencydemands
But with the next higher
known.
hydrocarbon,
onlyone is actually
is
different;onlythe two end
propane, CH3. CH2. CH3, the case
their hydrogen atoms, are symmethyl groups, and consequently
metrical,
but the hydrogen of the central CH2 group is different;
the theoryof valencypointsto the existence of
and consequently
OH
two alcohols derivable from this substance,
one
CH2. CH2.CH3,
two
Now
known
are
and the other CH3. CH.OH.CH3.
actually
and consequently
this theory
normal- and eso-propyl
alcohol,
givesthe
of the existence of two substances of the
most satisfactory
explanation
molecular magnitudeand
formula C8H8O,havingthe same
empirical
which

is

ISOMERISM

same

vapour

bodies

These two
different

but
density,
are

different chemical and

has

Chemistry;

physical
properties.
differ
owing to the
they
This theory
in the molecule.
important part in Organic

said to be isomeric ;

arrangement of the

of isomerism

played

atoms

most

the existence of such isomeric bodies

was

realizedabout

followed the introduction of the theory

explanation
terpreta
inThis theoryoffered a most satisfactory
of valencyin 1860.
of observed phenomenauntil about 1876,when evidence
For
in certain cases
of its insufficiency
began to accumulate.
shown
example,in the case of lactic acid it had been conclusively
scheme
that itsstructuralformula was represented
by the following
1823

the

and

"

CH,"

OH

C"
COOH

and

yet three

isomeric modifications

were

known, whose

chemical

able.
considerdifferenceswere
but whose physical
sligtot,
the other
One rotated the planeof polarized
lightto the right,
the theoryof
to the left,
and the third had no action at all. Now
for the existence of such isomers,
valencycould offerno explanation
and Le Bel and van 3i Hoff in 1877 broughtforward the hypothesis
that,were such systemsconsidered in three dimensions a satisfactory
could be obtained. The central carbon was
as
regarded
explanation
solid
its valencies in three dimensions towards the
angles
exerting
is investigated,
and when such a configuration
of a regular
tetrahedron,
becomes evident that it is onlywhen four different
it at once
that the existence of
attached to that carbon,
are
groups or atoms
the mirrored,non-superposable
two
forms becomes
one
possible,
light
imageof the other. If one form rotates the planeof polarized
to the right,
the other will rotate it to the left. In the case of that
it
modification of lacticacid which has no action on polarized
light,
to effect a resolution into its active components,
should be possible
carried out. This theoryof the Asymmetric
and this was
actually
Carbon Atom, whose four valencies are saturated by differentgroups
and it may
confirmation,
or atoms, has received the fullest possible
of carbon
be stated that,with very few exceptions,
the vast majority
such groups, act on the plane of polarized
compounds,containing
and exist in three or more
isomeric forms,depending
light,
optically
differenceswere

on
case

the number
of

an

of such groups

organicsubstance

presentin the molecule.

is known

which

Further,no

rotates

polarized

lightwhen

CHEMICAL

INTRODUCTION

in solution and

does not contain

one

or

more

metric
asym-

carbon atoms.
The

example of
in which

tartaric acids is

classicalillustrationof the

this

theoryhas been employed,for the older

of explaining
the existence of
theoryof isomerism was incapable
dextro- and laevo-rot"toTy
meso-tartaric and racemic acids,
tartaric,
since it had been conclusively
shown
that all these forms are
identical and represented
by the formula
manner

Now

COOH"

C"

OH

COOH"

C"

OH

in this molecule there

asymmetriccarbon atoms,and
in the same
it is clear that these may both rotate lightto the right,
rotate
way as ^-lactic acid,and the mirrored image of this would
lightto the left. Now supposingthat one rotates to the rightand
the other to the
which has

the
left,

action

two

are

net resultis an
and
light,

acid,i.e. meso-tartaric acid,

which isfurther

of being
incapable
resolved into its active components, since it is intra-molecularly
obtained in the
compensated. Then the acid that is synthetically
forces,i.e. racemic
laboratory,
by the employment of symmetrical
acid,would be a mixture of equalmolecules of dextro- and laevobut be capableof
rotatory,and hence have no action on light,
vestigat
being decomposedinto its active components. Pasteur had inno

on

this acid

in 1853

and

determined

the methods

that

could be

employedfor this separation

; but as this line of research
has, as yet, proved of but small value in the problemsto be
discussed,those desirous of obtainingfurther information on
referred to E. Werner, Lehrluch der Stereochemie,
the question
are
Stewart's Stereochemistry
of Physical
or A. W.
Chemistry
(Textbooks
edited by Sir W. Ramsay), where the vast amount
of work that
to other
has been carried out on this theory,and its application
elements,is described.
will eventually
investigations
play an importantpart
than
in the preparation
of physiologically
active drugs is more
that have been made with optical
Several of the experiments
likely.
That these

isomerides will be described

glaucum is capableof

but
later,

one
destroying

the

mere

form in

fact that

penicillium
another,

to
preference

ISOMERISM

for instance,
^-lactic,
compared with /-lacticacid,is an indication
that molecules of one type have a closer connexion with the cells
than the other. Stillmore
form of life,
of that particular
clearly
of /-mandelic acid,which is broken down
is this shown in the case
tion
glaucum and bacterium termo,whereas the ^-modificaby penicillium
is similarly
Then.
ellipsoideus.
decomposedby saccharomyces
is sweet, whereas the /-modification is not.
J-asparagine
It will be readily
that considerations such as those just
seen
the problem of determining
sketched further complicate
the constitution
the molecular magnitude
of organic substances;as
number
of isomers. Butane, C4H10"
so does the possible
increases,
of the paraffin
is the firstmember
series in which the possibility
of isomerism appears, e. g. ra-butane,
CH34 CH2.CH2. CH3, and,
?"0*butane
or
trimethylmethane

CH3
CH3"

hydrocarbonC13H28 is considered,the possible

is 802, and the difficultiesof assigningconstitutional
number
formulae to complex substances becomes at once
apparent. Take
their molecular magnitude,
for example the proteitfX
group;
is enormous
comparedwith the majorityof organicsubstances^
it is,perhaps,
whether it is accurately
known for any
questionable
Their decomposition
and
singlemember.
productsare numerous,
certainly
yet the ruptureof the molecule
many of these are simple,
has been so deep,that we
of
are, up to the present,incapable
and in consequence
in ignoranceof
are
piecingthem together,
the structure of the original
substance. But E. Fischer's method
of dealingwith this problem,by the syntheses
of the so-called
makes
it appear
polypeptides,
quite likelythat this extremely
solved. As far as can
importantquestionmay be eventually
at present,there appears
be seen
to be no
limit to the possible
number
of combinations and permutations
the relatively
among
few elements found in organicsubstances;this is to be traced
to the fact that carbon possesses the peculiar
firstly
property
of forming,
with other carbon atoms,open and closed rings. This
of
in the case
marked
tendencyto self-combination is much more
carbon,than in that of any other element : not onlyare molecules
But

when

the

"

known

containing
up

to 30

carbon

atoms

linked to

each

other,

CHEMICAL

but this accumulation

INTRODUCTION

does not

indication of
slightest
is the resistancetowards
operating
cause

the

And the other cause

instability.
due to the peculiar
disruption,
propertycarbon confers on molecules
for instance,
breaks
into which it enters. Althoughnitro-glycerine,
up with a largeevolution of heat,showingthat strong forces are
tendingto decomposeit,yet within fairlywide limits it is a
stable substance.
It is due to this property,often
strikingly
alluded to

as

the inertia of the carbon

observable among
than in the case

system,that isomerism is
carbon compoundsto a very much greaterdegree
of any of the other elements,for it implies
the

continued existence of the less stable form

"

OrganicChemistryand

is the regionof isomerism.

It is further in consequence
Inorganic
that OrganicChemistryis the region
of this inertia,
of slow
of measurements
of velocity
reactions and consequently
; and from
that in determining
the constitution
it follows the important
principle
of an organicsubstance the least possible
number
of carbon
linkagesare broken in any reaction that it undergoes.

not

Determination

formulae.

to fully
possible
investigate
any organicsubstance
it is necessary either to obtain it pure or to be able to purifyone
of its derivatives. The usual criterion of purityin the
more
or
of a solid is constancy and sharpness
of melting-point
on
case
from different solvents,
and althoughthis is not
recrystallization
the exceptions
The effectsof
but rarely
met with.
invariable,
are
ally
occasionminute traces of impurityon the melting-point
are
even
and may be comparedwith the differing
physiological
very great,
reactions of,say, natural and artificialsalicylic
acid,which only
differ by the presence of minute traces of impurityin the latter
In this connexion it may
that the
be mentioned
preparation.
of so many
of the solid aromatic
great power of crystallizability
substances has playeda very considerable part in the investigation
of bodies belongingto that class.
is the most
In the case of liquids,
constancyof boiling-point
importantcriterion; but again,constant boilingmixtures are not
and if this be suspected,
the best method is,if possible,
uncommon,
and carry out the
to convert the liquid
into a solid derivative,
investigations
upon this.
all that are
Althoughthese standards of purityare by no means
of the Organicchemist,
at the disposal
theyare the most important
and most generally
adopted.

Before

it is

of Constitutional

FORMULAE

CONSTITUTIONAL

have

obtainingthis purityare limited,

of substances which

up to the present
resistedall attemptsat investigation,
owing to the impossibility

there

and

available for

the methods

But

of either

largegroups

are

purifyingthem

or

convertingthem

into

crystallizable

derivatives.
It will be

from
clear,

has been

what

that
stated,
previously

the

first factors necessary for the elucidation of the constitutional

formula will be the quantitative
and molecular weight
composition
of the

in

substance

detail the methods

employedfor

these constants

oxidation of

known

water
products,

question.It

is not

the determination

the data for the firstare

and

describe in

proposedto
obtained

by

of either of
the

complete

weight of the substance to its final oxidation

carbon

the
dioxide,

amount

of the former

being

determined

by absorption
by a known weightof calcium chloride ; of
the latterby absorption
in caustic potashsolution,
and from the results
of this combustion the percentageamounts
of carbon and hydrogen
calculated. If nitrogen
is present,
the operation
is carried out in
are
and under these conditions free
an
atmosphereof carbon dioxide,
isevolved and itsvolume measured. Oxygen isalwaysdetermined
nitrogen
and other elements are
estimated by special
by difference,
methods,of which
on

fullaccount

OrganicChemistry.

ratio of the atoms

is to be found in any of the textbooks

the percentagecomposition
the least

From

calculated and the empirical

presentis readily
This may represent
the true molecular weight,or

formula obtained.
the latter may be a
determined from a

of it. This magnitudemay be

simplemultiple
based on Avogadro's
knowledgeof the density,
of the loweringof the freezingor by the determination
hypothesis,
of a pure solvent, the latter
of the boiling-point
point or raising
methods possessing
in the case of those substances
greatimportance
which cannot be volatilized without decomposition.
The molecular
with a high degreeof probability,
weightmay also be determined,
from purelychemical considerations,
and the identity
of the constants
obtained by both methods
is of the greatestvalue to the
molecular hypothesis.
"

Two

cases

will

now

be taken

as

of what
illustrations

has been

stated.
previously
I. On

acetic acid givesthe following

results :
analysis,
"

H=
O

40-0%
6-6%
53-3 "/o

CHEMICAL

10

The

ratio of
simplest

INTRODUCTION
the atoms

0-3?
H=

presentis then

-"

6-6

or[CH20]

The

formula for this substance is consequently

empirical
CH2O,
is 30, the molecular weightis 60, and therebut since the density
fore
the molecular formula is [CH2O]2 or C2H4O.2. This same
formula can
be arrived at by purelychemical considerations such
the action of phosphoruspentachloride,
which
as, for instance,
results in the formation of a substance of the formula C2H3OC1.
Since one of the general
reactions of this reagentis to replace
the
the deduction follows that the
hydroxylgroup (OH) by chlorine,
The
simplestformula for acetic acid must be C2H3O .OH.
in which the atoms
are
questionthen arises as to the manner
has
pentachloride
groupedin this molecule ; the action of phosphorus
shown the presence of an hydroxyl
group (OH),and this isalso borne
out by the formation of a series of salts in which the hydrogenof
silveracetate,
this groupingis replaced
C2H3O OAg.
; for instance,
The next problemis the nature of the atomic arrangementof the
residue [C2H3O]',
line of argument may be
when the following
employed. The acid chloride,acted upon by ammonia, gives
acid and an
amide, a reaction represented
by the
hydrochloric
:
equation
HC1 + [C2H30]'NH2.
+ NH3
[C2H30]'C1
.

The

amide

thus

obtained

of
dehydratedby means
substance of the empiricaland
be

can

phosphoruspentoxide,and a
molecular formula C2H3N results:

[C2H3OyNH2-H20
The

by

the

C2H3N.

derivative is methylnitrileand may

resulting
action of potassium
cyanideon methyliodide

CH3I

+ KCN

KI +

be

synthesized

CH3CN.

for methyl iodide,

possible
it follows that C2H3N also contains this methyl group, which was
in acetic
presentthroughoutthe seriesof reactions and consequently
with dilute acids,
warmed
acid itself. Moreover,methyl nitrile,
of water, into acetic acid.
passes back,by the absorption
Since but

one

molecular structure is

CHEMICAL

12

than the
in

the

Without
of

are

INTRODUCTION

and here the theoryof valency

discussed,
previously
of Kekule
hands
gained one of its greatest victories.
the proof that the hydrogen atoms
going into details,
equal value has been shown on the followinggeneral
one

argument.
the
Kepresenting

molecule

as

C6
it has been

by

provedthat

the radical

if

(OH),say

2345

H,

of the

one

hydrogen atoms be replaced

resulting
compound phenol

No. 1, the
1

23456

C6 (OH)

is identicalwith those obtained

has been further
those numbered

either 2, 3, or 4
by replacing
with respectto position
numbered

provedthat

2 and

and
identical,

are

also 3 and

; it

1,

quently,
Conse-

5.

hydrogenatoms, and therefore the carbons to which

placedtowards each other.
they are joined,are symmetrically
this in the following
Kekule aptlyexpressed
constitutional formula :
all the

CH=CH

\CH

CH^
CH"

CH

as
Here, the latent valencies,
termed,
they have been previously
cussed
are
by double bonds, a point which will be disrepresented
in a later chapter,
and may for the presentbe disregarded.
This structural arrangement,whilst clearly
showing the existence

of but

one

mono-substitution

product,givesfurther

existence of three di-substitution

of the
explanation
of
alwaysprovided,
substituting
group.

course, that isomerism

is not

complete

derivatives,

in
possible

the

for instance,
existsin three isomeric modifications,
Dichlorbenzene,
and

the
representing

benzene nucleus

as

hexagon,the

structural

formulae for these will be

-'Cl

(1)
The

first is termed

01

(2)
the ortho

or

(3)

the
2-dichlorbenzene,

second

FORMULAE

CONSTITUTIONAL
the meta

or

most

extended

more

than

must

be the

as

same

1:4, and since the

or

that in such

shown

cases

never

it follows that position

1 :2
obtained,
1 : 5.
: 6, and 1 : 3 as
Ladenburg,however,

three isomers

the

was

3, and the fourth the para

observations have

this
subjected
such

13

are

and conclusively
proved that
investigation

to close

case.

characteristics of this

closed-ring
system are pronounced
; the nucleus
open -chain hydrocarbons

The

and very different from the

to be present in
has been shown
benzene

resins that

so

many
its derivatives are

and

aromatic

oils and

termed

Aromatic,

open-chainhydrocarbonswhich

in distinction to the

called

are

Aliphatic.Now, more
perhapsfor the sake of convenience than
of benzene derivatives is so
anything else,since the number
from the aliphatic
enormous, these are usuallystudied separately
derivatives ; but
in this work

the

even

less

fraction of those discussed in any of

carbons
moderatelysized textbooks on Chemistry,the hydrotheir

seven

of both series,
will be studied
derivatives,

when
together,

carbon atoms

replaced
by

mere

similaritiesand many
Not onlyare such
to

it is

Practical

hoped

been

and
isolated,

of these

some

or

inductive

may, that
in their turn
;

is to say, be based on some

which
generalprinciples
held as to diseased processes
depend on the conceptions

more

or

atoms

INTRODUCTION.

be deductive

therapeutics
may

the result of

three

following
chapters.

PHYSIOLOGICAL

of
pharmaco-dynamics

more

of their

from
substances containing
ring-shaped
carbon
known, but many containing

other elements have

GENERAL

that

better grasp
dissimilaritieswill be obtained.

will be described in the

B.

of substances of both seriesdescribed

the number

is but

and
or

as

certain

or
substances,
they may

less discrete observations

as

to

and
be

the

merely

the curative

value of such substances in certain diseased conditions. The former

method
In

one

is often

spoken of

of his lectures on

out
pointing

'

as

rational ',and the latteras

Pharmacologythe

this distinction,
warned

late Dr.

his hearers

'

'.
empiric

Moxon, after

against reasonings
in medical therapeutics
Inductions
\
he continued,are commonly
in harmonywith the teachings
of Physiology,
but I advise
and do
you to hold them a good deal distinctfrom those teachings,
not be too readyto allow them to rest,even
in appearance, on those
'

'

'

'

PHYSIOLOGICAL

14

teachings/

The

INTRODUCTION

lecture from

which

this passage

is taken

was

of Crum
delivered in 1874, six years after the publication
Brown
and Fraser's work on the curariform action of the ammonium

bases,which appearedto be the beginningof

action
pharmacology.Physiological

studyof

determined

system of
ciples
generalprin-

rational
on

chemical

of
exact adaptation
an
composition,
of empirical
the disappearance
to ends, and
medication
means
achievements after a beginninghad once
seemed not impossible
been made
by this importantand far-reaching
generalization.
determined
not
a
was
Moxon, however,
empiric,
owing to any

by

aversion to scientificmethod, but because he

knowledgeof

facts was

saw

that

our

mental
funda-

sufficiently
largeto supportany
of a generalor theoretical character.
superstructure
Although
remarkable advances in Pharmacologyhave been made during the
is not greatly
last half century,the practical
now
position
changed
lecture.
since Moxon's
Schmiedeberg,
writingin 1902, said : The
to Pharmacologyis obvious,
relation of Therapeutics
in so far as
not

'

the former

is based

on

scientificfoundation.

This,however,is

is
being the case.
Everywhere,pristine
empiricism
unconfined by any scientificbarriers.' There are
master, entirely
must
not wanting, however, signsthat althoughempiricism
for
treatment of diseased conditions,
years longerdominate our
many
of rational therapeutics,
yet there is a growinginterestin the subject
of the advantageswhich an
extended
and a wider appreciation
Not only has a vast
knowledge of the matter would ensure.
of research been devoted to elucidating
such relationships
amount
exist between the chemical structure of a drug and its
as
may
action,
but,in addition,
some
physiological
space is devoted to these
topicsin textbooks and in the medical press; moreover, there is
though not indeed in this
alreadya largeindustryestablished,
of synthetic
drugs,
country,which has for its objectthe production
the action of which is more
less
f
rom
their
or
predicted
accurately
very

far from

chemical constitution.
allude to the obstacles which have prevented
therefore,
and a more
stillgreaterexpansionof the domain of rationalism,
We

may,

abandonment
of the therapy
of empiricism.
The difficulties
complete
chemical and physiological
fall into two
in correlating
properties
main divisions,
the firsthas reference to the drug itself,
and the
second to the organismon which it is intended to act.
and volatility,
Various physical
such as solubility
characteristics,
markedlyinfluence and alter the action of a drug,and interfere

RATIONALISM

TO

OBSTACLES

15

of its action. Upon these depend,in part at

development
and excretion ; a decrease in the former or
least,
speedof absorption
a decrease in physiomean
increase in the latter will generally
an
logical
in the hypnotics
is seen
The effect of solubility
activity.
chloral hydrateand sulphonal.The former is soluble and rapidly
effect;
and consequently
producesits physiological
rapidly
absorbed,
absorbed and hence
is slowly
the latter,
owing to its slightsolubility,
and drowsiness
but also prolonged,
action is delayed,
the physiological
hours after the administration of that
for many
persist
may
with the

substance.
of
inactivity
physiological

The

the

highermembers

of many
is attributable to
acids,

such as the alcohols or

homologousseries,
of beingabsorbed.
which renders them incapable
their insolubility,
of solubility
in fattysubstances will be
The important
question
Narcotics.
dealt with in the chapter
on
tion
soluThe degreeof dissociation which a substance undergoes
on
in water can
play an importantpart in its action on the
with which alone this work
organism. But organicsubstances,
of certain groups such as the acids,
deals,
are, with the exception
undissociated on solution. The case of the mercury salts
generally
may, however,be given as an illustrationof this phenomenon.
the disinfectant power of mercuric
Paul and Kronig investigated
chloride,
HgCl2, bromide,HgBr2, and cyanide,
Hg(CN)2,usingthe
solutions
Anthracis,and found that in equimolecular
spores of B
then the bromide,
the chloride was
the most
powerfulantiseptic,
and that the cyanidehad least action. This corresponds
to the
degreeof dissociationwhich takes placein the three solutions. The
character of the metallic ion is,of course, of primaryimportance,
as
.

salts of other bases which

not

the

An

are

stillmore

disinfectant action

same

as

dissociated in solution have

those of mercury.

instructive insight
into the difficulties
of the

afforded

by

same

authors into the disinfectant

of mercury and common

salt.
perchloride
of
when advisingintravenous injections
Many years ago, Bacelli,
mercurial salts in cases of syphilis,
employeda solution of the perchloride
to
mixed with sodium chloride in the proportion
of one
effectivein actual practice.Paul
three,which he stated was more
and Kronig have shown that the actual process is as follows :
A double salt (Na2HgCl4)is formed,which dissociatesinto positive
sodium ions and negativecomplex ions of mercury
and chlorine.
The latter are inactive from an antiseptic
pointof view,but a cerpowers

of

the researches of the

problemis further

solution of

"

PHYSIOLOGICAL

16
tain amount

INTRODUCTION

of

dissociation of the complex negative

ion
secondary
in the formation of the active mercury ions,
though
occurs, resulting
to a smaller extent than when an equimolecular
solution of mercuric
chloride alone is employed. The action is thus hindered,
but in
which is obtained by the addition
the increased solubility
practice
of saltmore

than counterbalances the decreased ionicdissociation. On

the other hand, salicylic

acid,which
solution and

is

dissociated
onlyvery slightly

is a
consequently

its bactericidal
very weak acid,owes
action to the entire molecule and not to the ions. Sodium salicylate,
on

is

when
dissolved in water shows no
largelydissociated,
antiseptic
properties.
of diffusion of a substance will playan important
That the velocity
and to this factor may
is clear,
reactivity
part in its physiological
which

be

for instance,
the differences observed
ascribed,

in the group

of

The most powerfulmember

of this group is
glucosides.
digitalis
substance.
Cloetta has introduced
a
digitoxin,
very insoluble crystalline
which has been
an
amorphousand soluble form of digitoxin
in all probability,
named digalen
increased solubility
: following,
on
and to this is attributed the absence
there is increased diffusibility,
disturbances when it is administered by the mouth.
of digestive
Two further points
importance,
may be mentioned as of practical
which render the issues of pharmacological
experimentdifficultto
determine.
The first of these is the erroneous
to the
as
impression
main action of a drug which may be producedby certain bye effects.
An extreme
instance of this is alcohol,
which is commonly known as
taken to producea feeling
of warmth,
a stimulant and is frequently
whereas its chief physiological
actions are those of a narcotic and
The second is the effectof dosage.Many bodies produce
antipyretic.
varied effectsaccordingto the doses in which theyare administered.
This,of course, does not dependon any real alteration in the physiological
character of the drug,but is merelya matter of distribution.
A narcotic drug, for example,when
given in doses largeenough
to produce sleep,
actions
fail to exhibit certain secondary
may
the central
of the effect on
which
are
producedindependently
nervous
system. On the other hand, a substance with a specific
action on particular
cause
organs, if given in toxic doses,may
and characteristic
mask the particular
generalsymptoms which entirely
effect.
Thus
which

chloroform

might

be

in narcotic doses

merelythe

causes

fall of

result of muscular

with vasodilatation and increased heat loss. But

temperature,

relaxation

coupled

it has been shown

OF

THEORY

LOEWS

POISONS

17

dependenton a direct action

temperatureis partly
of the drug,which,apartfrom itsnarcotic powers, has an inhibiting
effecton oxidation processes. In this it differsfrom ether,
though
ether
in
fall
narcosis.
there is also a
temperatureduring
of
The
main
however, to a rational appreciation
obstacle,
that this fallof

actions
pharmaceutical

lies in

of the livingcells.
reactivity
of

chemical

of the

to

done when

To

is

made

and
chemistry

the constitution of

an
known, is obviously

of

measure
onlya partial

attemptsare

the

attempt to calculate the result

interaction in which

bodies concerned

destined

ignoranceof

our

success

only one
undertaking

but this is what

to set forth the chemical

is

basis of

the action of

drugs.
in the proper sense
of the word,are not
Completeexplanations,
but starting
from the better-known factor,
at presentpossible,
chemical variations
that is,the drug,it is possible
by introducing
of a definite character to modifythe pharmacological
and
results,
thus in some
instances to gain an insight
into the chemical influences
which can be broughtto bear on living
cells.
will now
We
proceedto consider in detail the two variants
in any pharmacological
process, namely (A) the cell protoplasm,
and (B) the drug.
the theoryof Oscar Loew is
(A) With respectto the protoplasm,
of considerable interest. He
divides the generalpoisonsinto
and
These
oxidizing/
'catalytic/
'salt-forming/
substituting/
in sufficientconcentration,
act on all living
and depend
protoplasm,
for their activity
the chemical character of the substances of
on
which living
cellsare composed.
The special
poisons,
formingthe second main group, comprise
those which onlyact on certain classes of organisms.Under this
1

head

'

are

included the

the action of which

and
toxins,the antitoxins,

similar

bodies,

is

for certain kinds of protoplasm;

specific
the alkaloids)
act by
which probably
(including

the

organicbases
the structural character of certain cells; and the indirect
disturbing
which make respiration
"c.
poisons
impossible,
Now
as
the firstthree classes are
regardsthe generalpoisons,
not important
for our present purpose.
The firstincludes bodies
such as ozone, peroxide
of hydrogen,
chromic acid,permanganates,
i.e. those
"c. Among the catalytic,
hypochlorites,
phosphorus,
which influence chemical action without undergoing
any apparent
the aliphatic
changethemselves,
which will be dealt
are
narcotics,
with

later

on

in the present work.

c

The

third group

owes

its

INTRODUCTION

PHYSIOLOGICAL

18

existence to the

character
amphoteric

the soluble bases

saltsof the

as

and
protein,

alkalies and

alkaline

includes

acids,

earths,and

the

heavy metals.
class includes

fourth

The

such

of

number

of bodies which

even

in

aldehydesand amines, forming

The more
the name.
substitution products whence
readilythis
reaction takes placethe more
powerfulwill be the toxic effect.
in hydrazineand phenylhydrazine,
Examples may be found, firstly
and are consequently
combine with aldehydes
which most readily
aniline and
free
similarly,
hydroxylamine,
powerful poisons
;
the phenolsand their derivatives,
ammonia.
especially
Secondly,
the amidophenols
acid,sulphuretted
hydrogen,
prussic
; and thirdly,
and the acid sulphitesall substances capableof reactingwith
aldehydegroups.
As a general
are
series)
rule,primaryamines (notof the aliphatic
than
and these more
reactive than secondary,
so
tertiary.
more
with a tertiary
nitrogenatom, is much less toxic than
Pyridine,
which contains an NH
Xanthine,with three
piperidine,
group.
dilutions

extreme

react

can

with

"

"

NH

groups, is

toxic than theobromine

more

Methyl aniline has

The amido group

with two

different but weaker action than

attacked
is readily

by nitrous

or

such radicals.
aniline.
nitric acids,
by

ketones,"c.
aldehydes,
Loew
givesmany examplesselected from among those bodies
that toxicity
and shows generally
which are protoplasmic
poisons,
increasesparipassu with reactivity.
the very various chemical structures of these
Thus Loew explains
protoplasmic
poisons,
by showingthat theywill allreact with
general
one

or

two

very labile groups

which

he believes

are

presentin the

but undergo a chemical change and

molecule,
livingprotoplasmic
these
the protoplasmdies. Consequently,
become
stable when
from
so
differing
generalpoisonshave no action on dead protein,
destructive to living
which are equally
bodies likethe mineral acids,
dead

or

tissues.

Though considerations of this sort may helptowards elucidating

fail to account for what
certain generalreactions,
they completely
the selective action of drugs.1 From
known
our
is generally
as
stated as
should perhapsbe more
correctly
presentpointof view,-it
1

Drugs having

selective action

are

classed

by

Loew

under

'special

dealt
them, the
important group among
will
with in detail in a subsequentchapter,and Loew's theory in general
be criticized in the chapteron organicdyes.

poisons'. An

Alkaloids,will be

INTRODUCTION

PHYSIOLOGICAL

20

which we can onlysay

of the protein
concerningportion,
integrity
condition.1
that it is too labile to admit of examination in a living
tions,
reac(B) When we turn to the second factor in pharmacological
namely,the drugs,our survey of the subject
may conveniently
In
first
the
be divided into two
place,we may notice
parts.
which
connected with physiological
certain generalities
activity
have been arrived at by the experimental
method, and then we

the

may

go

to

on

as
expressed

to

theoretical views which

consider the
the

drugs exhibit

in which

way

been

have

their

particular

actions in the animal

body.
with their comparatively
I. In correspondence
slightchemical
seriesof bodies do not on the whole possess
the aliphatic
reactivity,
and Cash state that
actions. Brunton
powerfulpharmacological
of the fattyseries is
the predominantfeature of the lower members
centres (frogs).
their stimulant and anaesthetic action on the nerve
Schmiedeberg collects in a generalclass the narcotics of the
This
Chloroform
series as (1)the Alcohol and
aliphatic
group.
the monatomic
alcohols
includes the gaseous and fluid hydrocarbons,
and their halogen derivatives.
and their ethers,
ketones,aldehydes,
These are
mainly characterized by their action on the cerebrum
narcosis. They will be considered in detail in subsequent
producing
the other hand, are
on
derivatives,
chapters. (2) The Ammonia
characterized by a convulsant action on the cellsof the spinalcord.
the triad nitrogen,by the addition of another alkyl
When
remarkable change in
is converted into pentadnitrogen,
a
group
first pointedout by
action occurs, which was
the physiological
confirmed
Brown
and Eraser in 1868, subsequently
Crum
by
observers.
Brunton
and Cash, and very fullyillustrated by many
All

the

the motor
paralysing
will be
this principle
II. The

aromatic

more
physiologically

that the members

the

bases have

quaternary ammonium

nervous

than sensory,

nerve

endings. Numerous

found in the
bodies

course

of the

effective.

illustrations of

reactive

are

Experimentswith frogs showed

of the aromatic

that instead of

action,

presentwork.

being chemicallymore

system, but they appear

so

curare-like

like the aliphatic,

affect
series,
to affect motor

centres

more

like members
producinganaesthesia,

they tend rather to give rise to tremor, convulsions,

fattyseries,
and paralysis
(Brunton and Cash). The activityis, however,
increased by the substitution of hydrogen. In this case, alterations
of

1902.
Pharmacologie,

REACTIVITY

OF

THE

DRUG

21

be

producednot onlyby alterations in

the molecule as a whole, but by variations in the group which
substitutes hydrogen. Examples of this will be considered in the
bases with
chapteron the Alkaloids,which are all heterocyclic
various side chains.
Especially
importantin this connexion is the
in

action
physiological

rule enunciated

and Dewar, that

by^Kendrick

the introduction of

logical
cyclicbases in all cases increases their physioaction,and thus their toxicity.
ceptions
generalsense, also,Dujardin-Beaumetzand Bardel's con-

hydrogen into
In

may

the

of the influence of various side groups

on

the benzene

compounds may be taken as accurate :

hydroxylare antiseptic,
(i)Those containing
acid amide are
amido
an
(ii)Those containing
group or an
hypnotic.
both an amine group and an alkylgroup
Those containing
(iii)
are
analgesic.
to variation and
These few generalrules will be found subject
factors which have
of those disturbing
due to one or more
exception,
alreadybeen noted; but they show by their very existence that
within certain limits it is possible
to modifythe physiological
action
rules of lessgeneral
of a drug at will in a givendirection. Other
will be noted under the various groups of compounds
applicability
which will be discussed in subsequent
chapters.
of interaction between
We have already
dealt with the mechanism
the living
celland the drug from the pointof view of the cell,
far
as
stated about the matter ; a littlemore
as
anythingcan be definitely
be said regarding
the drug.
may now
The action of a drug appears to dependupon its possessing,
firstly,
some
effect on the
capableof exertinga specific
group of atoms
and secondly,
another group or side chain capableof entering
cell,
kind of chemico-physical
into some
with certain cells,
relationship
wherebythe first is enabled to produceits action. This second is
commonly known as the anchoringgroup. The term 'chemicoit cannot
be said to be definitely
as
physicalwas used advisedly,
settled whether a chemical reaction in the ordinarysense
really
takes place. P. Ehrlich has compared the reaction which is
posed
supto take
place with those postulated
by Witt for the
of a substance are dependent
organicdyes. The dyeingproperties
the presence of certain atomic groupingswhich are termed
on
colour groups or chromophores.The entrance of the chromophore
"

'

'

group

into

molecule

results in

derivative

more

or

less coloured,

22

PHYSIOLOGICAL

INTRODUCTION

but

lackingthe characteristicsof a dye,and it is onlywhen basic

radicals (auxochrome)
further introduced,
that the
or hydroxyl
are
dyes result. For example, in azo-benzene C6H5 N : N.C6H5 the
group N2 is the chromophore.The substance which is coloured (red)
Witt termed the chromogene; it is not a dye,but becomes one on
the introduction of a basic group, e. g. C6H5 N : N.C6H4(NH2).
Anthraquinone
.

but
is colourless (chromogene),
groups,

the

the introduction of two

on

hydroxyl

dye alizarin results

consequently
necessary to confer on a substance
the colour itselfis dependenton the
its dyeingproperties
; further,
Two

number

are

groups

of the

and nature

benzene, CgH5

N
.

is orange,

say

"

"

basic radicals ;

N.C6H4(NH2), is yellow,the

thus,amido-azodi-amido

vative
deri-

the tri-amido brown.

and
Many drugs can be extracted unchanged from the tissues,
from solution and
Ehrlich regards
them as havingbeen withdrawn
there in a state of, possibly,
solid solution in a corresponding
existing
to a dye. A dye is also withdrawn
from solution
manner
by a cellular material,and Witt regardsit as forming a solid
be again withdrawn
solution from which it may
by the use of
Freudas
a more
powerfulsolvent. But it is much more probable,
lich and Losev have shown,that since Henry'slaw does not hold for
of adsorption,
and with
the phenomenon of dyeingis one
dyestuffs,
in the chapteron
be compared the views expressed
this may
in which the drug enters the cell.
Narcotics as to the manner
of acidic substances is traced to the fact that
The non-toxicity
of beingabsorbed by the tissues. Ehrlich
theyare no longercapable
that those dyeswhich stain the brain tissue cease
to do
has shown
substances
conversion into sulphonicacids,as neurotropic
on
so
"

lose their characteristicson

He

suggeststhat

also

action of substances

dyes,may

and

the entrance

the

the

of such

analogy between

theorythat

has

groups.

the

physiological

been sketched of the

stances
of drugs. Subsynthetic
production
actingon definite cells may be found

be of value in the

with

the power

of

neurotropic,
"c.),and the character of their action
(myotropic,
of varied
controlled by the introduction of groups (chromophore)
effect.
pharmaco-dynamic

OF

REACTIVITY

selective

The
from

to

in full in

be discussed

outline

much

details

been

rather

of

The

become

and

The

correlation

of

intimate
determinable

by

combination

NOTE.

of

the

action

is

known,

which

possible
the

to

drug

suppose

has

postulates

now

These

toxin

and

for

and

being

thrown
doses

off

any

the

to

has

he

groups

or

haptophoric

of

capable

as

drug

will be

of

territories

actual

to the

with

with

those

the

of

the

constitution

be

indistinguishable

an

or

nature

time

differences

the

on

of

drug

was

the

inclined

of

an

to

which

chemical

formula
it

that

deny

by which

exist

the

toxin

was

and

cell.
somewhat

modified

side-chains

called

of the

groups

supposed

are

anti-bodies,
are

their

that

similarity in the mechanism

chemio-receptors

less

and

present be

at

concerned

merely

whether

that

some

being less intimately analogous

in

no

the

defined

details

cannot

get

we

insisted

always

of

Recently, however,

corresponding

yet

as

though

to be

divide

chemistry,

or

ways

practical medicine.

these

physiology

matter,

physics

anchored

are

of

phenomena

is

all, only aggregates

which

is

there

both.

Ehrlich

"

between

of

after

nearer

various

yet

are

the

to

as

many

in

character

are,

the

by

Whether

physical

of

will

will at least

remains, and

its limits

boundaries

constitution

be

question

question

exist,

more

pharmacologist

the

This

empiricism

much

sciences

the

and
to

delineated.

less distinct

less and

things.

of

done

or

various

convenience,

shown

demonstrated

chemical

stated.

of

be

its action

referred

instances

some

pharmaco-dynamics,

instances

many

been

has

of

and

abandonment

the

principlehas
the

in

relationship may

Though

in

may

present position of the

chemistry

that, whereas

possibilityof

view,

been

already

chapter (see p. 83).

later

the

of

relationshipsbetween
close

has

23

solubilityin lipoid substances.

its

explained by

show

of

DRUG

which

drug,

opposite point

the

This

of

action

THE

to

to

administered

are
over

united

are

differ from

in

the

matter

the

to

increased

long period

and

which
cell

the

body.

ordinary receptors
of the

apparatus

existence

they

views

chemio-receptors by

drug

nutritive

the

independent
nor

his

; hence
in

they

number

of time.

cell,and

cannot

when

in

be
small

CHAPTER
A.
of

THE

A.LIPHATIC

preparation

derivatives.

and

Ethyl

and

Stereo-isomeric

THE
and

properties.

AND

hydrocarbons
hydrogen which

between

are

simplest series
of

number

have

been

of

classified
that

what

have

owing

to

is termed

what

member

differs from

with

its

carbon

various

been

have

groups

found

exist

to

their

great stability,the

the

by

next

Methane

CH4

Ethane

C0H,

Propane

C3H8

Butane

C4H10

B.

P.

1"

C6H14

B.

p.

71"

C14H13

M.

p.

5-5"

M.

p.

102"

Hexane

to

gaseous

of

increases

magnitude
the

high,

or

from

melting-point as

singly linked

carbon

the

liquids of
case

atoms,

may
and

in

which

each

gases.

of

the

liquid phase, from

carbons,
hydro-

paraffins. They

one

"

limit

or

large

quantity, viz. CH2.

constant

general physical property

molecular

methane

series

homologous

an

related

and

CH4,

general characteristics,are

Di-myricyl C60H122
One

methane,

termed

Tetradecane

low

into

been

the

n.

those

of

compounds

Hydrocarbons.

commences

possessing

or,

form

Methyl

of Isomeric

and

them.

this, and

to

of

HYDROCARBONS.

number

Paraffin

The

introduction

molecule,

AROMATIC

striking differences

the

to

CARBONS.
HYDRO-

THE

relationships.

ALIPHATIC

owing

OF

of the

methods

synthesis of their

the

reactivity of the

condition

of unsaturated

groups,

in

used

CHARACTERISTICS

Physiological

on

Their

HYDROCARBONS.

Methods

PHYSIOLOGICAL

B.

Effect

A.

AROMATIC

AND

and

II

such

is that

group

members

of

liquidsof

low

it pass

as

from

the

the

boiling-pointto
high boiling-pointto solids of
be.

since

This
the

series

limit

of

only

contains

saturation

by

HYDROCARBONS

PARAFFIN

25

called the limit

hydrogen has been reached,they are frequently
hydrocarbons.Isomerism first appears in butane,C4H10,and the
accounts
for the existence of two
theoryof valencysatisfactorily
substances of that formula,having the same
densityand
vapour
and chemical properties,
molecular weight,but differing
physical
w-butane,CH3 CH2 CH2 CH3, and iw-butane,
viz.,
.

CH3
CH"

The

n-

normal

or

derivations

those

are

of
consisting

chain of

carbon atoms, whilst the iso- have a branched structure. But since
such hydrothis latternomenclature may not be sufficiently
precise,
carbons

regardedas derivatives of methane ; thus,w0-butane

This is,
clearer in the
perhaps,
may be termed tri-methyl-methane.
of pentane. ^-Pentane is CH3 CH2 CH2 CH2 CH3, two
case
exist; if the first
2"0-pentanes
may

be

CH3

CH3"

CH3

C"
CH"

and
tetra-methyl-methane,

is termed

the second

ethyl-di-methyl-

C2H5

CH3"

CH,
structures
methane, their respective

are

at

once

evident.

of these

hydrocarbonsoccur
in nature. Methane, or marsh gas, formed by the decayof organic
is found in the coal measures,
and in regionslike
substances,
Baku in the Caucasus,and in the petroleumdistrictsof America.
of mixtures of members
of petroleum,
of
Largedeposits
consisting
Occurrence

this

in

are
series,

That

from

The

fractions
and

90"-120"

found

America

Many

Nature.

in

America, Russia,Alsace

and

Hanover.

of normal paraffins.
exclusively
of pen50"-60" consist chiefly
tane

consists almost

boilingbetween

hexane, between

heptaneand

octane.

70"-80"

hexane

Refined

and

heptane,between

petroleumor

kerosene

boils

ALIPHATIC

26

at 150"-300".

AROMATIC

AND
The

solid

HYDROCARBONS

are
high-boiling
paraffins

more

abundant

petroleumfrom Baku than in that from America, and are

and
obtained by the distillationof the tar from turf lignite,

in the

also

bituminous

shales.

Paraffins that

known

as

and
liquefy
readily
vaselines and employedas

the lower

diminishes

by

as

30" and

40", are

salves.

of this group
insoluble in
are
but the solubility
soluble in alcohol and ether,

All the members

Properties.
water

fuse between

are

the molecular

their

terized
weight increases. They are characand consequentslightreactivity.
great stability

Fuming nitric or even chromic acid does not affectthem in the cold,
and on heatingthe action is but slow. Chlorine and bromine give
rise to substitution products,
rated
characteristic propertyof the satua
gives firstly
methyl
hydrocarbons. Methane, for instance,
chloride,
CH3C1, then CH2C12,CHC13, and finally
CC14,in which
all the hydrogen atoms have been replaced
by chlorine;in such
for
reactions,
atom

e.g.

atom

every

hydrogen is
CH4 + C12 HC1
of

removed
+

the molecule

of chlorine that enters

in the form

CH3C1, and

so

of

an

acid,
hydrochloric

on.

Olefines.

The next group of hydrocarbons

contains two hydrogenatoms less
than those justconsidered,
and forms an homologousseries,
with
similar to the paraffins.
the structure of,
When
physical
properties
that
is considered,
it is seen
member, ethylene,
say, the simplest
carbon is actingas a trivalent element,thus CH2 CH2.
apparently
But all the members
of this series,
are
quiteunlike the paraffins,
and
reactive
:
They absorb
properties
very
possess the following
.

molecule of

chlorine,
bromine,and iodine,without the formation

of the

cules
halogenhydride. In a similar manner, molecorresponding
of hydrogen or the haloid acids are
readilyadded, and
The
these reactions usuallytake placewith considerable ease.
that is offered of these phenomena is the assumption
explanation
that the fourth valencies of each carbon atom
mutuallysaturate
described by a double bond,e. g. H2C
each other,
graphically
CH2,
and
substance
said
to
is
unsaturated.
the
be
The
or
CH2:CH2
reactions alluded to beingexpressed
:
by the following
equations
=

"

CH2

CH2

C12

CH2C1 CH2C1.
.

CH2:CH2+H2=CH3.CH3.
CH2 : CH2

+ HI

CH3 CH2I.
.

ALIPHATIC

28

The

AND

reaction with

AROMATIC

the

and
givesdichlorethylene

HYDROCARBONS

chlorine
halogensis similar,
then

for instance

tetrachlorethane,

CH

CHC1

CHCL

CH

CHC1

CHC12
Tetrachlorethane.

Acetyleneand
formation

of its derivatives

many

of solid silverand copper

are

characterized

compounds, which when

by the
dry are

extremelyexplosive.These may be employed for the detection and

isolation of the acetylenes,
since on treatment
with hydrochloric
acid the pure
hydrocarbon is liberated. Acetyleneitself is at
present prepared in large quantityby the action of water
on
calcium carbide and is used for illuminating
purposes.

Benzene

last series of

be regardedas derived from

hydrocarbons
may
of the replacement
of one or
member, benzene,by means
simplest
of the hydrogen atoms
series.
by the residues of the aliphatic
constitutional formula assignedto the parent hydrocarbonby

The
the
more

The

hydrocarbons.

Kekule, viz.

is in

agreement with

most

of its properties
and those of its derivatives,

indicated. But when the nature of the alternate

previously
and
double
single bonds is investigatedit becomes at once
apparent that phenomena of a different order appear with the
formation of this closed-ringsystem. In this case, the double bond
discussed.
For instance,
the
to that previously
bears no similarity
action of chlorine on benzene
gives rise to substitution products
such as C6H6C1 or C6H4C12, and not to addition derivatives,
as
cule
might have been expectedhad the unsaturated nature of the molebeen akin to that of ethylene. Moreover, had this double
union been analogousto that previously
the compounds
discussed,
whereas they are identical,
1 : 2 and 1 : 6 should be different,
e. g.
as

Cl

Cl

I
=

Cl"

"'

HYDROCARBONS

BENZENE

for,in the first case, between

exists

there

chlorine atoms

in the second.

absent

In

have been
It

may

CH3

two

the
carrying-

bonds, which is
in the open-chain

chlorine substitution products

would

the two

CH2

atoms

of these double

one

i.e. isomeric.
different,
be put in a different way

littledifference between

and

carbon

the two

case
corresponding

these
derivatives,
ethylene

29

follows

as

There

is but

rc-hexane,
hydrocarbons

CH2

CH2

CH2

CH3

hexamethylene,
or, hexahydrobenzene,
xCH2

"

CH

CH2.
CH

CH2"

derivative
Further,the unsaturated ethylene

CH3
has the

CH2

CH2

CH

CH

CH3

generalcharacteristicsas tetrahydrobenzene,

same

/CH2

CH

"

CH2"

"CH

CH2" CH/
is,the behaviour of the two towards the halogens,
halogen
described. Then with
"c.,is similar to that previously
hydrides,
that

the

di-ethylene,
CH3

and

CH

CH

CH

CH
.

CH3

dihydrobenzene,
CH2-CH

CH2"
XCH=

CH

holds true,both have the general

relationship
derivatives. But when the third double
of di-ethylene
properties
becomes benzene,
these
linkageis introduced and dihydrobenzene
and are replaced
different
generalproperties
disappear
by entirely
of the radical of this hydrocarbon,
characteristics. The entrance
termed phenyl,into various molecules,
results in changesin the
chemical and physiological
of quitea different
physical,
properties
order from those producedby the corresponding
entrance of aliphatic
much

about the

radicals :

same

result appear what are termed the negativecharacteristics

of the benzene nucleus,
phenomena which will be studied
as

in relation to physiologically
active substances,
in
detail,
following
chapter.
in

the

ALIPHATIC

30

AND

AROMATIC

HYDROCARBONS

other derivatives are

only benzene but numerous
obtained by the dry distillationof coal. They are presentin coal
in the manufacture of
tar,which is producedin enormous
quantities
coal gas.
Among the homologuesfound are toluene or methyl
benzene, C6H6.CH3, the three dimethyl benzenes or xylenes,
C6H4(CH3)2 and the three trimethyl
benzenes,C6H3(CH3)3.
Among the higherboilingfractions of coal tar, many more
highly condensed aromatic hydrocarbonsare found; of these,
naphthalene,
C10H8,and anthracene,
C14H10,are the onlytwo that
will be discussed. The former shows great similarity
to benzene,
from which it differs by C4H2. Its deportmentis satisfactorily
explained
by the constitutional formula suggested
by Erlenmeyer,
Sources.

Not

It consists of two

nuclei,
having in

benzene

occupyingthe

common

two

carbon

ortho

position.
Anthracene is the parent hydrocarbonof a series of vegetable
compoundsof which the most importantis the dye alizarine. The
to benzene and itsvarious
formula expresses its relationship
following
syntheses,
atoms

/CH\XCH\/CH\
CH

I
CH

Oxidation

and

Reduction.

II
C

C
CH

A,,
The chief characteristicof the benzene

is the great stability

of the ring complex; in the vast
hydrocarbons
majorityof reactions undergone by its derivatives the nucleus itself
the aromatic substances
is not destroyed.This feature distinguishes
from the derivatives of the methane and other open-chain
series.
As a very generalrule,oxidation or reduction can
be carried
without
on
tearingthis ring asunder. In the former process the
benzene homologues have their side chains oxidized to (COOH)
This conwhich occupies
the position
of the substituting
group.

AND

OXIDATION

sequentlyaffords
derivatives.

method

31

of

between
distinguishing
xylenes,

the three

Thus

REDUCTION

isomeric

1:3 and 1:4,

C6H4"Ji{J"l:2,
1 :
ethylbenzene,C6H5 C2H5; on oxidation,

isomeric with

are

2-

acid,
xylenegivesphthalic
l

,COOH

2"

1 : 3 di-carboxylic
acid,
givesthe corresponding
acid
the
and the para, 1 : 4 di-carboxylic
other
or
terephthalic ; on
Of the
hand, ethyl benzene gives benzoic acid C6H5 COOH.
acids mentioned above,onlythe ortho givesan
three di-carboxylic
anhydride,

the meta

isomer

/C0\0S^J

r
IT
V^tfXl

iX

/^i/^"

this beingdue to the

Similar

interaction of

the

another

such

two

substance to form

proofthat theyoccupy

reacting
groups.

two

noticed

be

among

much
so
derivatives,

of ortho substituted benzene

number

as

proximityof the
to this will
peculiarities

with

a
so

large
that

each

other,or with
be generally
taken
closed chain,can
e. ortho)in the
adjacentpositions
(i.
groups

nucleus.
reduction of benzene

The

is much

difficultthan

more

that of

heated
Benzene itself,
open-chainhydrocarbons.
acid,giveshexamethylene,
high temperaturewith hydriodic

the unsaturated
to

/CH2 CH2X
"

CH2"

"CH2.

\CH2" CH/
acid reduced
Salicylic
acid,
fl-pimelic

by

sodium

in

amyl

COOH

CH

CH

CH

alcohol solution

gives

COOH

OH

CH2
CH;

CH.Lg

NCH,
Such
case,

breakdown

in
resulting

of the benzene

the final substance

nucleus,as
the
possessing

in this latter
same

carbon

AND

ALIPHATIC

32

HYDROCARBONS

AROMATIC

speaking,
is, relatively
original,
extremelyrare.
of
effect
Powerful oxidizing
completedecomposition,
agents, course,
the invariable rule in carbonaceous compounds; but in those cases
where
derivative has
the nucleus itself is attacked,the resulting
content than that of the benzene derivative
a less carbon
generally
experimented
upon.
content

the

as

GENERAL

METHODS

USED

IN

PREPARATION

THE

OF

THE

HYDROCARBONS.
Since

the

hydrocarbonsare the parent substances of all other

and although
their syntheses
of especial
are
interest,
organicbodies,
the methods that may be used for their preparation
are
many, the
can
followingare the more important.A few, such as acetylene,
but the majority
be obtained by the direct union of their elements,
formed by the union of simpler
are
hydrocarbonnuclei.
1. Hydrocarbons

obtained

of

by heatinga

Paraffin

the

mixture

and

Benzene

of the sodium

series

can

be

salt of the acid with

caustic soda.

CH8!COONa

NaOjH

Na2CO3

Methane.

Sodic acetate.

C6H5:COONa4-NaOjH Na2CO3 + C6H6

=

Sodium

2. The

Wiirtz

derivatives

bromo

Benzene.

benzoate.

the iodo or
consists in actingupon
synthesis
in etherial solution,
with
of the hydrocarbons,

metallic sodium
2NaI

C2H5jI+ Na2 + IjC2H6

=

C2H5 C2H5
.

w-Butane.

Ethyl iodide.

rule,the iodine derivatives react best,and the reaction proceeds

those
derivatives
with
better
e.
(i.
containing
primaryhalogen

As

CH2X group)than with secondary(:CHX), and seldom

tertiary
(jC" X).
i.e.
Mixtures of halogenderivatives may also be employed,
the.

CH3

CH2:I+ Na2 + I;CHa CH2

.

CH2

CH3

with

M-Iodo-butane.

2NaI

CH3.CH2.CH2.CH2.CH2.CH3
w-Hexane.

SYNTHESIS

HYDROCARBONS

OF

further showed that

Fittig
of Benzene
for the preparation

similar reaction could be

C6H6jBr+ Na2 + IiC2H5

33

employed

homologues.
NaBr

+ Nal

-f

C6H5 C2H5
.

Ethyl-benzene.

Brom-benzene.

2NaBr

C6H5jBr+ Na^+ BriC6H5

C6H5 C6H5

Diphenyl.
also be
It may
derivatives,

CH2

CH

CHa|I+

employed for

the

of Ethylene
preparation

Na +

CH2

IjCH8

CH

Allyliodide.

CH2. CH3 +

2NaI

a-Butylene.

CH2:CH.CH2iI

+ Na

IjCH2.CH:CH2
2NaI + CH2 : CH.CH2
=

CH2

CH

CH2

DiaUyl.
Acetylene

sodium,or

also be obtained

by actingon chloroform with

with finely
divided silver.
on bromof orm
conveniently

can

more

CH
CH;CL

+ 6Na

+ ClJCH

6NaCl

II

CH
The

reaction has been further extended

to the

of
preparation

termed the Cyclo-paraffins,which will not

closed-ring
hydrocarbons,
be further described,
owing to the fact that theyare of relatively
to be discussed in this
as
slightimportance
regardsthe questions
work.
Two examples
may be given.

"H2!Br
HJBr
!

Na2

2NaBr

+ CH,

Trimethyleneor
Cyelo-propane.

CH2 CH2
.

CH2;Br
i

CH2
+

Na2

2NaBr+

H2 CH2 CH2jBr
.

CH9

CH2
I

CH2

I
.

CH2

CH2

Hexamethylene or
Cyclo-hexaneor
Hexahydro-benzene.
The "Wiirtz synthesis
is

of very
consequently

wide

applicability,

but is of the greatestimportance

in the preparation
of the higher
members of the saturated hydrocarbons.
As regards
the formation
of benzene homologues,
it has been largely
replaced
by the Friedel
D

AND

ALIPHATIC

34

AROMATIC

and Crafts' method, which

be
of

that this

seen

will be described later.

synthetic
process

the
determining

HYDROCARBONS

constitutes

constitution of the

an

Further,it will
excellent means

hydrocarbons.

of the ethylene
and acetylene
series,
hydrocarbons
well as benzene homologues containingunsaturated carbon
as
be obtained by the
systems substituted in the nucleus,can readily
action of an alcoholic solution of potashon the corresponding
brom3. Unsaturated

derivative.

Ethylene.

CHJHi

Ethylbromide.
Fhenyl-ethylene.
+ KOH

C6H5CHBr.CH3

C6H5CH

Brom-ethylbenzene.
or

for

and
acetylene

CH2

+ KBr

H2O

Styrol.

its derivatives :

Acetylene.

CH2Br
|
CH2Br

CH
+ 2KOH

2KBr

2H2O

III

CH

Ethylenedibromide.
Di-phenyl-acetylene.

C6H6CHBr.CHBrC6H5

+ 2KOH

2KBr

2H2O

Stilbene bromide.
+

C6H6C;C.C6H5
Tolan.

The

reaction with

alcoholic

not onlyof
preparation,

but

such

potashis of great value for the

those menas
tioned,
types of hydrocarbons

also for unsaturated

derivatives of the

most

varied

nature.

of ethylene, the removal of the

regardsthe preparation
elements of hydrobromic
of the halogenhydrides,
acid,or generally
is often very similar to that of the elements of water.
This hydrocarbon
o
btained
the
be
o
f
alcohol
can
by
dehydration ethyl
easily
acid.
of sulphuric
by means
As

CHJH

"":

AHJ

CH0

II +H20
C

H2

will be

taken

as

HYDROCARBONS

ALIPHATIC

OF

DERIVATIVES

36

illustrations of the value of such derivatives in

chemistry.
aliphatic
synthetic
A.

Syntheses

Derivatives

Aliphatic

of

Acetic

i. On
"

or

Acid.

containinga primary group,

and then acids.
aldehydes

pass to

CH3OH

H.COH

-"

CH3.CH2OH

Formic

CH3.COH

-"

acid.

CH3.COOH

-"

Acetic acid.

Acetaldehyde.
acid acted upon

i.e.

H.COOH

-"

Formaldehyde.

ii. Acetic

Alcohols

the

alcohols

oxidation

CH2. OH

from

by phosphorustri- or penta-chloride

givesacetylchloride.
CH3.COOH
The

resultingsubstance

purpose

number

HC1

POC13+ CH3CO.C1.

is

and is used
extremelyreactive,
the acetylgroup (CH3CO)' into
introducing

of
of

PC15

bodies,e.

for the
a

large

g.

HC1+CH3CO.OC2H5

Ethylacetate.
HC1

Ethylamine.

Ethylacetamide.

CeHsNHiHj

HC1

acetate

C6H6NH. COCH3

Aniline.

iii.Calcium

CH3CO.NHC2H5

Acetanilide

distilled with

calcium

or

formate

Antifebrin.

gives acet-

aldehyde.

(CH3COO)2Ca + (H.COO)2Ca
iv. Calcium

2CH3.

acetate distilled alone,or

with

CHO

2CaCO3

the calcium

salts of

organicacids exceptformic,givesrise to the group of bodies

of the sulphonals.
substances used in the preparation
called ketones,
other

CH3
(CH3COO)2Ca

CO

CaC03

CH,L3
Dimethyl ketone
or

acetone.

ALIPHATIC

OF

SYNTHESIS

DERIVATIVES

37

CH3

(CH3COO)2Ca + (C2H5.COO)2Ca

or

Calcium

2CaCO3

+ CO

propionate.
Methyl-ethyl
ketone.

Chloral and

v.

quantityin

considerable

in

both obtained from

are

also be formed

latter may

althoughthe
obtained

chloroform

acetone,a substance

from
the

ethylalcohol,

destructive distillation

of wood.

B.

the

from

Syntheses

Halogen

derivatives

of the

Ethyl iodide treated with silver hydrate or

potashpasses over to ethylalcohol.

dilute aqueous

i.

C2H6:Ij+jA"OH C2H6OH
ii.Acted

ethylnitrileresults.
by potassiumcyanide,

upon

CaH6|Ij"+iK|CN C2H6CN

+ KI

This reaction is of considerable

the

lengthof

AgI

carbonsHydro-

the carbon chain

since by
importance,
be

can

moreover
increased,

means

of it

the resulting

capableof undergoingseveral importantchanges.

with dilute potashor acids,
the
i.e. treatment
saponification,

substance is
On

and

nitrilesabsorb water

C2H6CN

acids.

become

2H20

C2H5COOH

NH3

acid.
Propionic

with ethyliodide,
CgH5I,a substance containing
is,starting
two carbon atoms, propionic
acid,containing
three,is obtained.
the nitriles become
On reduction,
amines,thus
That

/T\T
CTT
"J[j.el/l"
"

Now

one

"

oTJ

"wHn

C" TI r^TI
VyollrVyXlolN
^

"

ATTI
Xln.
"

of primary amines,or those

generalproperties
by nitrous
CH2NH2 group, is their decomposition

of the

the
containing

"

acid with the formation

of

e. g.
alcohols,

C2H5.CH2.NH2+ HN02

C2H5.CH2OH

H2O

N2.

with ethylalcohol,
the next highermember
Consequently,
starting
of the series,
and so on, may be synthesized
alcohol,
by such
propylic

reactions.

DERIVATIVES

38

ALIPHATIC

OF

HYDROCARBONS

in alcoholic solution,
ethyliodide
upon by ammonia
givesrise to a mixture of the substituted ammonias.

iii.Acted

C2H5NH2
Ethylamine.
HI

(C2H5)2NH
Diethylamine.

C2H6;Ij+jH;N(C2H6)2HI
=

(C2H5)3N
Triethylamine.

+ C2H5I
(C2H5)3N

and

(C2H5)4N.I
ammonium-iodide.
Tetraethyl-

acts on finely
divided zinc or magnesium,
Ethyl iodide readily
derivatives. These are a particularly
forming the metallo-organic
and may be employedin a variety
reactive group of substances,
of
syntheses.The magnesium derivatives have,for the last six years,
inflammable zinc compounds.
the spontaneously
replaced
With
ethyliodide the followingreaction takes placein etherial

iv.

solution :

"

C2H6
and

compound may be employedfor many syntheses,

resulting
for example,
for those of the secondary
and tertiary
alcohols.
such as acetaldeMagnesium ethyliodide reacts with aldehydes
hyde,CH3CHO, and ketones,such as acetone, CH3.CO.CH3,
to the following
reaction :
according
the

"

*
=

vC2H5
'j**l

CH3.CH/"gI
\U"ii,
xyjJij

C
CH3

I
and

CH3.CO.CH3

MgLC2H5

CH3
resulting
compounds are decomposedby water and dilute
and tertiary
yieldingsecondaryalcohols from the aldehyde,

and the

acids
from

the ketones.

Methyl-ethyl-carbinol.

ALIPHATIC

OF

SYNTHESIS

CH3

CH

CH6

CH3

DERIVATIVES

39

Dimethyl-ethyl-carbinol.
of saturated and
employed for the synthesis
unsaturated
ethers,ketones,aldehydes,
hydrocarbons,
carboxylic
"c.
acids,
thiophenols,
phenols,
v.
Symmetricalderivatives of ethane are usuallypreparedfrom
dibromide
ethylene
CH2Br

They

also be

can

CH2Br
a

substance which

can

be

obtained by passing
easily
ethylene

CH2
CH, L2
into bromine.

This

unsaturated

hydrocarbonresults

of ethylalcohol by means
dehydration

CH2;H

The

bromide

obtained

generalreactions as

those

CH2Br

AgOH

Br

CH2Br

*CH2

Br

CH2Br

by this reaction undergoesthe

e. g.
described,
previously
CH2OH
I

COOH
Oxalic acid.

Glycol.

CH2Br

KCN

CH2CN
"
I

Sapomfication

CH2.COOH
CH0.
CH2 COOH

CH2CN

CH2Br

same

COOH
Oxidation

CH2OH

CH2Br

the

acid.
sulphuric

CH2

CH2jOH;

of

from

Succinic acid.

The

various

reactions which
synthetic

of acetoacetic ester
but
textbook,
that

it is not

or

be carried out

by means

described in any
been given to show clearly

malonic ester will be found

sufficientexamples
have
the

can

themselves but their

paraffins
oxidation productsor halogenderivatives which are
the preparation
of members
of the aliphatic
series.

more

reactive

employed in

OF

DERIVATIVES

40

OUTLINE

METHODS

OF

OF

DERIVATIVES

readiness with

HYDROCARBONS

AROMATIC

SYNTHESES

EMPLOYED

IN

AROMATIC

HYDROCARBONS.

which

THE

OF

the aromatic

take part
hydrocarbons
in the most
them
from the
varied reactions sharplydistinguishes
other group, and their reactivity
is such that they constitute the
of the aromatic derivatives.
foundation for the syntheses
practical
The rapidand brilliant development
of this group
of the chemistry
due to the fact that the parent hydrocarbons
is largely
are
easily
in the
accessible in largeamounts.
They are presentin coal-tar,
in that from wood
and
tar from
peat,and in smaller quantities
and also in some
bitumenous shales,
varieties of petroleum.
Acted
acids,the hydrocarbonsof
by nitric or sulphuric
upon
this series readily
acid derivatives,
and
pass into nitro or sulphonic
series of substances
from these,
but more
the first,
a large
especially

The

be formed.

can

Nitrobenzene,C6H5NO2, an example of the class of nitro

is formed quantitatively
derivatives,
by actingon benzene with a
A.

mixture

of nitric and

acid.
sulphuric

C6H6;H + "OH!N02
this

By
a

means

one

second with

more

C6H5NO2

H2O

introduced into the nucleus,

readily
and up to the presentit has not been
difficulty,

group

is very

than three.
nitrobenzene
to introduce more
Now
possible
be easily
of tin and
reduced to aniline,
can
C6H5NH2, by means
acid or other similar reducing
hydrochloric
agents. This substance,
which is the phenylderivative of ammonia, lends itselfparticularly
varied series of synthesis.On solution in acids
to a most
readily

found

and

with

treatment

substances

nitrous acid at

formed,e.

are

temperaturethe diazo

low

g.

^N

C6H6NH2.HC1

HN02

C6H6-N^+2H2O
Cl

Diazobenzene

chloride,
producedin

its isolation is unnecessary

all carried out in solution.

body,but
are

i. On

this

is
reaction,

since the

explosive
reactions
following
an

result.
with strong alcohol the hydrocarbons
boiling

C6H6.N2.C1 + C2H6OH
ii. Acted

C6H6 + N2

+ HC1

CH3CHO

the
or
iodide,
by cuprous bromide,chloride,
halogenderivatives are formed.
upon

C.H..N..C1

-"

C6H6C1+N2

responding
cor-

boilingwith

iii. On

DERIVATIVES

AROMATIC

OF

SYNTHESIS

the

water

diazo

41

group

is

+ HC1

replacedby

hydroxyl.

C6H5.N2.C1 + H20

C6H6OH

N2

Phenol.

solution of copper
the nitrilesare formed.
mixed with potassium
cyanide,
sulphate

by

salt is acted upon

diazo

the

iv. If

C6H6.N2.CN

C6H6CN

-*

N2

Benzonitrile.
v.

is

reduction

On

one

is
phenylhydrazine

substance

and will
derivatives,

the aromatic

reactive among

of the most

This

formed.

be described later.

C6H6 N2
.

Cl + 4H

C6H6NH

NH2

HC1

hydrochloride.
Phenylhydrazine
the
by aniline,

vi. Acted upon

C6H5

N
.

N.p

H!NHC6H6

diazoamido derivatives result.

C6H5

N.NHC6H5

+ HC1

Diazoamido-benzene.

goes
in presence of an acid undersubstance on standing
resulting
the
intramolecular change and becomes ^-amidoazo-benzene,
of the azo dyes.
simplest
representative
The

C6H5

N.NHC6H6

C6H6

-"

N"

"

j"amidoazo-benzene.

tinguishe
acids are produceddissulphonic
These
from the aliphatic.
the aromatic hydrocarbons
obtained by heatingthe former with concensubstances are readily
trated
or fuming sulphuric
by this
; it has not been found possible
than three of these sulphogroups.
to introduce more
means

B. The

ease

with which

the

C6HjH + OH;.SO2OH

C6H5SO2OH

Benzene

The

derivatives
resulting

or

their sodium

H2O

sulphonicacid.
salts possess

high

in water, and consequently

the introduction of
degreeof solubility
the sulphogroup is of the greatestvalue when such a propertyis
in many
of the organic
desirable,
dyes.
as, for instance,
The two following
reactions are characteristic of the sulphonic

acids.
i. When

fused with

in the technical

phenolsare formed,a reaction

potash,
of resorcinol and other phenols.
preparation

C6H5;S02OK +

KiOH

C6H6OH

K2SOS

used

OF

DERIVATIVES

42

ii. Distilled with

HYDROCARBONS

potassiumcyanidethe

CgHgjSO^
C. The

AROMATIC

third method

derivatives dependsupon

KjCN

C6H5CN

for the

used

nitrilesare
+

formed.

K2S03

of
preparation

the aromatic

the characteristic behaviour of the benzene

gives
homologueson oxidation. Toluene,C6H5CH3, for instance,
oxidation the
on
benzoic acid,C6H5COOH, and,generally
speaking,
side-chains are replaced
by carboxylgroups, whilst the nucleus
logues
remains untouched.
As previously
mentioned,many of the homobe synthesized
found in coal-tar,
or may
are
by the reactions
of these syntheses
described ; the most important
was
by
originated
the alkylderivatives of the aliphatic
MM.
Friedel and Crafts. When
the chlorides,
dissolved in benzene and
are
hydrocarbons,
preferably
acid is evolved and
treated with aluminium
chloride,
hydrochloric
radical is linked on to the benzene nucleus,
the aliphatic
e. g.

(i)CH.P

HjC.H,

6CH3C1 + C6H6

or

HC1

6HC1

C6H6CH3

Ce(CH3)6
Hexamethyl

CHp3
(ii)

or

3H:C6H5

3HC1

benzene,

CH(C6H5)3

Triphenylmethane.

C6H5 CHjCl+ H!C6H6

(iii)

or

HC1

C6H5 CH2
.

C6H5

Diphenyl methane.
A

similar reaction also takes

benzene with the formation of

placebetween benzoylchloride
diphenylketone.

(iv)C6H5CO!CiTfi;C6H5HC1

and

C6H5.CO.C6H5
Diphenyl ketone or
Benzophenone.

and

between

carbonylchloride

and

benzene

with

formation

of

benzoylchloride.

(v)C6HjH

CijCOCl C6H5COC1
=

+ HC1

but will only take

The reaction is of very considerable importance,
residues or
placeprovidedthe chlorine atom is attached to aliphatic
as
(iii)
such,for instance,
derivative,
cannot
for
replace
example,
C6H5C1,
Phenyl chloride,

in the side-chain of
or

above.
(iv)

methyl

benzene

chloride in reaction

(i). The

part playedby aluminium

consists in the formation

chloride probably

of double

compoundssuch

for instance,
which with methylchloride,
regenerate
C6H5A12C15,
C6H5 CH3. But besides bringingabout
A12C16and give toluene,

as

OF

DERIVATIVES

44

the alcohol behaves

and

on

AROMATIC

HYDROCARBONS

oxidation in

similar
precisely

manner

ethylalcohol,

to

C6H5CH2OH

C6H6CHO

-"

C6H5COOH

-^

Benzaldehyde.
ii. With

K!CN

This nitrilefurther behaves

and

givesthe
on

with

C6H6CH2.CH2NH2
ammonia

or

of the above

none

primary

amines

substituted
corresponding

and

secondary

result,

C6H5CH2NH2

C6H6CH2:C1+ H!NHC6H5
Now

C6H5CH2CN

like

C6H6CH2;C1 + H;NH2
or

treatment

the

KCN

and on saponificaethylnitrile,
acid,phenyl acetic,
C6H5CH2 COOH,
corresponding

reduction the amine

iii. On
amines

acid.

potassiumcyanidebenzylcyanideis formed.

C6H6CH2;C

tion

Benzole

C6H6CH2NHC6H5

reactions take

placewith

+ HC1.

chlortoluene,

C"H*"CH3
generallyspeaking,the halogen,
it is so tightlyheld that the reis attached directly
to the nucleus
actions
of
derivatives
of
the
formation
which
are
employed in the
open-chainhydrocarbonsare no longeravailable for the preparation
of the corresponding
benzene derivatives. Chlortoluene on oxidation

When

the

chlorine atom, or,

giveschlorobenzoic acid

/en
and

this substance

which
when

been
that
this

can

the chlorine atom

pass

through a

remains

number

attached

of

changes,in

to the nucleus.

all of

It is only

negativecharacteristics of the benzene ringhave

by the introduction of nitro groups,
depressed,
as, for instance,
So much
of the chlorine atom
the reactivity
so may
appears.
for instance,
be the case that in picryl
chloride,C6H2 (NO2)3C1,
the so-called

where

there is

shows

much

very

reactive

an

accumulation

about the

same

power

groups, the chlorine

of taking partin reactions as the

of three such

alluded
benzoylchloride previously

to.

CHARACTERISTICS

PHYSIOLOGICAL

OF
The

CHARACTERISTICS

PHYSIOLOGICAL

GENERAL

B.

HYDROCARBONS.

THE

are
hydrocarbons
aliphatic

on

the whole

less active

than those of the aromatic series. The

the

45

logically
physio-

lower members

of

and, if inhaled,
cause
eventually
marsh-gasseriesproducesleep,

death

by asphyxia.The
become

the carbon atoms

toxic
more

of
properties

this series increase

Hexane

numerous.

is

as

toxicant
inactively

followed by deep
a
long stage of excitement,
producing

Octane,which

anaesthesia.

is contained in the commercial

ligroine
addition,

producesa similar anaesthesia ; in

petroleum,
unsaturated
there is a tendency to vomiting (Versmann). The
and butylenehave very similar
propylene,
ethylene,
hydrocarbons,
but
those of chloroform,
action ; amylenehas properties
resembling
is not so safe. Acetylene(oneper cent, in air)
producesnarcosis
Lauder Brunton
has pointed
with failure of heart and respiration.
out that the characteristic action of these aliphatic
hydrocarbons
first
is on
to
at
excitement
the nerve
centres,tending
produce
the sensory side ; the aromatic
and then narcosis ; they act on
the other hand, act mainlyon the motor side,
on
hydrocarbons,
producing
Benzene
rise
convulsions and paralysis.1
to
gives
slight
but
the
its
of
action
is
the
on
muscles,
principal
paresis
voluntary
higher cerebral centres, producinglethargy and somnolence.
muscles.
Later,a kind of intention tremor occurs in the voluntary
and this remarkable
Diphenyl,
C6H5 C6H5,however,is practically
inert,
extends to many
diminution in physiological
of its
activity
compounds.
which is less toxic than benzene,slows the respiraNaphthalene,
tion
doses depress
; small doses raisethe blood pressure, whereas large
it. It decreases nitrogenous
metabolism,and has an antipyretic
action ; it has more
narcotic action than phenol.
The hetero-cyclic
furf urane, and thiophene
to
compoundspyrrol,
a certain extent resemble benzene in their physiological
action.
and

in crude

'

CH=CH"
v"

AA

vy

AAV

Pyrrol

;"NH

is more

toxic than

ntr/

r"TT

CH=

Pyridine CH
\CH=CH/
1

The

solid

and

liquidnonvolatile hydrocarbonsare without

through the body unaltered. Hence the
emulsion
as a food-stuff or as a drug.
petroleum

action, and

or

pass

physiological
uselessness of

PHYSIOLOGICAL

46

CHARACTERISTICS

PiperidineCH2"2~2"NH

far

reaction of
physiological

The

with the size of the

more

so

than

pyridine.

these reduced derivatives decreases

chain,thus pyrollidine
CH2

"

CH2\
NH

I
C H2" CH/
is less active than

piperidine.
The various substitution products
of the hydrocarbons
will be
dealt with in the subsequent
but some
chapters,
generalremarks on
action,
alkylgroups, as they affect physiological
may conveniently
be made

here.

i. The

action of an
physiological
increased by the entrance
generally

observed in the aromatic

chain

is increased

by

increase in molecular

series

carbon system is
aliphatic
of alkylgroups ; this is also
when
the magnitudeof the side-

the addition

of such

But with the

groups.
follows a decrease in
weight there generally

there
solubility,
"c.,and consequently
volatility,

comes

periodin

homologousserieswhen physiological
reactivity
beginsto decrease
owing to lessened absorption
by the organism. This is illustrated
in the case of the simplealcohols,
show
where the lower members
the series is ascended,whereas the higher
as
reactivity
increasing
members
are
quiteinert substances.
of the hydrogen
ii. In the cyclic
compounds the replacement
of the ringby alkylgroups causes
atoms
considerable change in
a
direction.
action,not always,however, in the same
physiological
In the case of benzene,toluene,
the effect of
xyleneand mesitylene
the number of methylgroups is to cause
of
a diminution
increasing
and to some
modification.
extent a qualitative
activity,
In aniline and thiophene,
increased
on the other hand,considerably
results from substituting
the hydrogen of the nucleus by
toxicity
is increased,
whilst
alkylgroups ; in phenolthe antiseptic
power
in
the toxic action is diminished by such substitution,
as
an

3-Cresol
3

iii.In the

creased
of the action is inpyridine
homologuesthe intensity
has the least physioby the entrance of alkylgroups. Pyridine
logical
action ; picoline
is stronger,dimethyl
(methylpyridine)
collidine (trimethyl
is about
pyridinemore
pyridine)
so, whereas
six times,
and parvuline
nearlyeighttimes as
(tetramethyl
pyridine)

as
powerful

the

does not lead to

HYDROCARBONS

THE

OF

The

parentsubstance.
a

change in the

of the

alkylgroup
as
activity
drugs,
reaction
of the
physiological
entrance

degreeof their

effect so that the

but alters their specific

derivatives resembles
resulting

47

that of the natural alkaloids.

replacementof the hydroxylhydrogen atom in the

and an
alcohols is followed by a very considerable rise in volatility
towards oxidizingagents. The hypnoticethyl
increase of stability
alcohol,
C2H5OH, for example,passes to the anaesthetic substance
inert glycerolbecomes the narcotic
ether, C2H5.O.C2H5. The
iv. The

glycerin-ether
CH,"

O"

CH,

CH

O"

CH

CH2"

O"

CH2

phenol,
C6H5OH
antiseptic

In the aromatic seriesthe

inert

phenetol,
C6H6OC2H5.
p

TT

In

pyrocatechin

/OH

"6n4\OH
the

replacementof

results in substances
a

similar

one

or

both

-1

of the

of less toxic nature.

in
replacement

the

case

becomes the

phenolichydrogen atoms
But

on

the other hand

of resorcin

C6H4(OH)21:3 giving1:3 C61

results in
In the

an

increase of

case

of 1

toxicity.
: 4-amido-phenol
/OH

follows the replacementof the phenolic

toxicity
hydrogenby either the methyl or ethylradical.
in ammonia
If the hydrogenatoms
are
v.
successively
replaced
and tertiary
primary,secondary,
by alkylgroups, the resulting
convulamines show diminishing
reaction,the special
physiological
amines pass
sant effect of ammonia
beinglost. But as the tertiary
to the ammonium
over
compounds a great increase in toxicity
in their action many
of the alkaloids.
occurs, and theyapproach
When
of the NH2
the hydrogen atoms
in aniline are
group
action of the resulting
replaced
by alkylgroups the physiological
substances corresponds
to that of the aliphatic
amines,and the convulsant action is depressed.
But, on the other hand, as previously
a

decrease in

PHYSIOLOGICAL

48

CHARACTERISTICS

remarked,the introduction of alkylsinto the nucleus of aniline

increases its convulsant action.
The

narcotic amides

C6H6CONH2,

and

of the

aromatic

such
series,

as

benzamide,

salicylamide,
i

of the amido hydrogenatoms, and

replacement
the resulting
like ammonia
substances in large
doses are convulsants,
and strychnine.
vi. The imido hydrogensin xanthine may
be substituted by
methyl,and the resulting
compounds,mono-, di-,and tri-methylwhich varies considerably
xanthine show a physiological
reactivity
from that of the parent substance.
difference is
The most striking
in the action on the cardiac muscle,which develops
to
in proportion
the number
of methyl groups.
vii. It is of course
only to be expectedthat in those cases
where the replacement
of a hydrogenatom by alkylgroups entirely
alters the chemical nature of the resulting
that a corresponding
substance,
in
For
characteristicswill appear.
change
physiological
of the carboxylic
example,the replacement
hydrogenof the organic
without acid proacids leads to the production
of bodies entirely
perties
and
the
with
thus
altered physiological
action;
(esters),
toxic oxalic acid givesrise to the narcotic diethyl
oxalate. Similarly
acid givesthe less toxic methyl ester (oil
of wintergreen).
salicylic
in the acidic or toxic substance phenolon conThe changeproduced
version
into its inert ethers has been previously
On the
mentioned.
other hand, physiological
which had been hindered by the
activity,
again be brought out by
presence of the carboxylradical,
may
of
the replacement
of the hydrogen atom, as is seen
in the case
similar is the alteration produced in the
cocaine. Somewhat
chemicallyreactive imido derivatives by substitution of the
stances.
stable subin the formation
of more
hydrogen atom, resulting
This may cause
the appearance of physiological
properties
which are absent in the parentsubstance ; thus l-phenyl-3-methyl
NH
an
pyrazolon(p.204),containing
wanting
group, is entirely
in the characteristic antipyretic
of
which
properties antipyrine,
contains an
it may
result in a decrease of
or
N.CH3 group;
stance
in case
this subof 1-hydroxy-tetra-hydro
as
toxicity,
quinoline;
(orits methyl ester)
antipyretic
properties,
possesses marked
but is a protoplasmic
cannot
be
used
a
nd
hence
as a drug.
poison,
losethis action on the

OF

HYDROCARBONS

THE

49

Filehne ascribed the toxic

Fischer and

effectsto
secondary

the

and theyfound,as expected,

presence of the reactive imido group,
this into 1-hydroxy-tetrahydro-w-ethylquino
that on converting
the stability,
theyobtained
increasing
introduced into pharmacyin
less toxic action,
and

so

derivative with

1883

under the

far

name

of Kairine.

CH2
:H

1-Hydroxy-tetrahydro-

1-Hydroxy-tetrahydron-ethylquinoline
(kairine).

quinoline.
Differences

"

The

between

ethylgroup

the

Methyl

appears to have

and

Ethyl

Groups.

certain affinity
for the central

this radical have

containing
which are entirely
pronounced
hypnoticproperties
wantingin the
shown in the
corresponding
methylderivatives. This is strikingly
whose hypnoticproperties
group of sulphones,
appear to be solely
determined
by the presence of the ethylgroup, since the methyl
derivatives are
quiteinert. 1 : 2-amidophenolhas no hypnotic
but when the hydrogen
atom of either the hydroxyl
or the
properties,
amido group is replaced
narcotic
by methyl,derivatives with slight
thus
power result,
nervous

system,as

many

substances

and

have

but
narcotic properties,
slight

the

derivative
triethyl

on

the

other hand
OCH
has

pronounced action. In this connexion it is interesting

to note

Ehrlich and Michaelis's observation that certain

amido

group

in which both

hydrogenatoms

an
dyescontaining
have been replaced
by

thus
ethyl,

-N"c:2;
'***"

PHYSIOLOGICAL

50

CHARACTERISTICS
whereas the corresponding
structure,

nerve
capableof staining
dimethylcompounds
are

\CHS
do not possess this property.It has been observed that dulcin

has

methyl
extremelysweet taste,whereas the corresponding
derivative is entirely
wanting in this property.
an

Unsatnrated

Substances.
of

stances
organicsubis the presence
in the molecule of un saturated or doubly
carbon systems. The apparently
low valencyshown
unsaturated
been
by carbon in various series of compounds has previously
of the double bond
and the difference in the significance
discussed,
in open and closed chain derivatives described (pp.26, 28).
unsaturated
derivatives containing
Generally
open-chain
speaking,
saturated bodies.
carbon atoms are more
toxic than the corresponding
toxic than
Thus allyl
times more
alcohol,
CH2 : CH.CH2OH, is fifty
Acrolein,CH : CH.COH,
alcohol,CH3. CH2. CH2OH.
fl-propyl
and croton-aldehyde,
CH3 CH : CH.COH, are more toxic than the
saturated aldehydes.
corresponding
On
the other hand, allylamine,
CH2 : CH.CH?NH2, is without
but vinylamine,
CH3 CH : CHNH2, is very
physiological
action,
toxic.
Generallyspeaking,the group (C : CH.NHg)" appears
An

importantfactor

action
physiological

in the

to be

active
especially

With

these

in this

examplesmay

respect.

comparedsafrol

be

/CH2

CH
.

CH2

C6H3^-O\nTT

3\0"CH*

the most

1
3
4

and the "much

toxic of all the etherial oils,

less

poisonous

isosafrol

CH:CH.CH3
J.JL

"V/
Q"CH2
The
be

one

doubly unsaturated
of the most

CI j CI, is stated to
di-iodo-acetylene,

toxic bodies known.

CHARACTERISTICS

PHYSIOLOGICAL

52

primaryand secondaryalcohols may be compared. Here the

have greaternarcotic and toxic characteristics
isomeric secondary
of allylamine
than the primary alcohols.
The
differing
toxicity
In the
and its isomer vinylaminehas alreadybeen mentioned.
the

aromatic

series the

isomeric

ortho,meta,

and

substitution

para

toxic
in their therapeutic
or
productsoften vary considerably
rule as to which of the three will
but there is no general
capacity,

be

and

more

which

least active.

4-nitrophenol,
C6H4
1

all more

are

1
,

4-nitrotoluene,

:4-bromtoluene,

toxic than their isomeric 1

the other hand, 1

or

is more
2-nitrobenzaldehyde
and salicylic
acid
derivative,
/OH
n
TI
is the

derivatives.

toxic than

of the three isomeric

only one

toxic

more
generally

Bokorny found that 1 : 4 compounds were

for the lower plantsand animals,thus

On

the 1 :4

acids
oxybenzoic

which

is

active.
therapeutically
Gibbs
benzenes
.06 gm.

that the toxic dose per kilo

showed

weight of

the

dioxy-

was

in the

case

of 1

C6H4"^**,
-1 gm.

with

C6

/OTT

and

in the

The

case

of

1 : 31 C6H4/Qjj,
1-0
resorcin,

three isomeric amido-toluenes

showed

gm.

very

similar

action.
amounts

into the jugularvein of a dog the

Injected
the toxic doses per kilo weight:
represented

:2-toluidine,
C6H4"3

-125 gm.,
unlike the preceding
of the
case
Occasionally,

the

are

ing
follow-

.208 gm.,
1:3=

an

logical
physio-

-10 gm.
there is
toluidines,
:

alteration in

action dependenton the relative position

of
specific
The three cresols
substituting
groups in benzene.

an

heart

exampleof

this.

and also
failure,

They stimulate the vagus centre,causing

act peripherally
the nerve
on
endings and

ISOMEBISM

53

pheral
poisons.All three cresols act equallyon the peribut ortho- and para-cresol,
the former,
nerve
especially
endings,
whereas ortho- and metamuch
are
more
powerfulvagus stimulants,
cresol act more
markedly on the vasomotor
system. Numerous
other instances will be found in the subsequent
chapters.
vasomotor

are

Stereochemical

described the connexion

in 1860

Pasteur

of molecules

and

certain moulds

that while

relationships.

their action

were

rotatorytartaric acid,they had

Emil

acid.

an

similar manner,

the

enzyme,

the

capableof breakingdown dextroaction on

the foeiw-rotatory
no
sugars which react towards
isomer being attacked by
optical

one

He

other not.

thought that

phenomenon probablylies in
'

.for doubtless the enzymes

are
possess an asymmetricstructure'.
.

on

figuration
con-

showed

ferments,and

Fischer described many

in

ferments

chemical

between

the

the

structure

of
explanation
of

the

enzyme

active and consequently

optically
This led to the view that the

of the enzyme
and of the fermentable sugar
configuration
the one may be said to fit the other as
are
so that
complementary,
it must be remembered
that we are in a state
a key fits a lock '. But
of profoundignorance
of the enzymes.
As
as to the configuration
regardsthe animal organism,Brion found that laevo- and mesotartaric acids were
oxidized to an almost equalextent and that dextro-

molecular

'

tartaric

was

racemic

acid

attacked
was

to

much

less extent

than

whereas
either,

least oxidized of all these stereochemical isomers.

These

examples are sufficient to indicate that there is an

between the stereochemical configuration
unquestionable
interdependence
of the molecule and physiological
action.
That the configuration
of the molecule has an influence upon the
of taste is illustratedin the case of fetfro-asparagine,
sense
which
is sweet, whilst the laevo-rot"tory
modification is not; dextroglutaminicacid

is

sweet,whereas the laevo acid is tasteless.

The influence of
observed in
cocaine

on

cases, thus the local anaesthetic action of dexlrothe tongue is strongerand sets in more
than that
rapidly

laevo

Mayor

states that

derivative.

most

the

isomers has been

some

of the

on

the toxicity
of
on
configuration

modification,
althoughthe effect is
laevo-nicotme

Atropine has

spinalcentres

than

observations
interesting

is twice

as

not

toxic

as

so

lasting.

the dextro

powerfulstimulatingaction
of the
hyoscyamine. But one
that made
was
originally
by Crum
more

PHYSIOLOGICAL

54

and

Brown

of

motor

iodides,
of

nerves

all

In
the

to

is

these

of

that

shown

their

bodies

of

stibonium

and
This
is

bases,

but

quinquevalent,
;

the

"

on

This

atoms.

is

that

observation

the

still

the

plane

of

change

of

appearance

divalent

but

with

derivative

fact

that

the

element,
the
the

such

appearance

of

configuration
substances

of

two

may

exist

the

to

in

action

trivalent

atoms

in

in

the

of

arrangement
Curci

KunkePs

and

also
the

of

case

as

active

in

the
shown
forms.

the

sulphur,
be

must

in

solid,

(CH3)2S,

results

sulphide

optically

to

tion
configura-

valencies

extra

changes

action.

stereochemical

.OH,

Now,

configuration

arsonium,

dimethyl-sulphide,

(CH3)3S
character.

curare

the

inert

the

trimethyl-sulphine-hydroxide,

to

shown

clearly

more

the

by

physiological

tridimensional

been

lose

curare-like

of
in

and

has

converted,

in

passage

to

it

phosphonium,

change

change

molecule

derivatives

strong

the

the

on

from

change

the

possess

on

rather

of

this

substances,
Thus

tri-

That

the

of

analogous

being

the

from

relations

ends

teristics.
charac-

20).

antimony

on

which

dependent

merely

not

and

salts

into

and

nitrogen.

arsenic,

that

indicates

clearly

of

of

individual

nitrogen

pp.

space

characteristics

iodides,

alkyl

the

on

containing

phosphorus,

physiological

action

(see

investigation

not

of

acted

(paralysis

their

losing

occurs

dependent
the

action

conversion

the

condition

by

in

changes

without

when

alkaloids,

many

curare-like

cases

is

shown

that

gained

quinquevalent

clearly

showed

muscles)

characteristic

new

who

Fraser,

alkyl

by

upon

CHARACTERISTICS

plane,
second

by

the

CHAPTEE

IN

CHANGES

ORGANIC

III

SUBSTANCES

METABOLIC

PRODUCED

BY

PROCESSES

Sulphuric and Glycuronic acid derivatives*

Compounds of
Introduction
Urea.
of Acetyl and
Amidoacetic
acid,
Sulphocyanides.
Methyl radicals. Cysteinderivatives. Processes of Oxidation and Reduction.
Syntheses

"

which have been made on the changesproduced

investigations
in organic substances by their passage through the organism have
that such changesalwaystend to the formation
led to the generalization
the pointof view of the synthetic
From
of less toxic bodies.
of drugs, it is most
important to observe that these
preparation
lead to the productionof derivatives with
modifications generally
acidic propertiesor, in other words, the introduction of
more
of an organicsubstance.
acid groups tends to lower the toxicity
of a drug throughthe system is followed,it is found
If the course
the
that no reaction takes placein the mouth, but in the stomach
of
increase in the solubility
acid presentmay
cause
an
hydrochloric
THE

"

basic

and also
substances,

cause

the anilides into aromatic

as

of basic substances

pepsinpresenthas
presentmay
the

cause

will

about

amines

and

the

acids,and

start
consequently

this

from

is that

their metallic
of the

but
salts,

much

pancreatic
juiceand

as

not only of the fats,but

saponification,
Nencki
acid.
salol,
givingphenol and salicylic

to

realize the value of this fact,and

But

his so-called

important
bring

more

of such
the

was

salol

esters

first

',
principle

upon this,will be described in detail later on.

it is in the tissues or blood that the more
profoundchanges

of oxidation

and

reduction

take

place.

various synthetic
alterations,
processes
as

absorption
region. The

bile which

the

founded

derivatives

In the intestines the alkali

littleif any action.
of organicacids,
increase in the solubility
an
or

of
decomposition
action

of such

the breakdown

mentioned,towards
previously

are
a

Besides

these

also carried

reduction

two

main

ing,
out,all tend-

in the

toxicity

PROCESSES

METABOLIC

56

The latter processes will be described

substance.
original
first,
happens that theyfollow those of oxidation
though it generally

of the

or

reduction before the final elimination of the substance in the urine.

SYNTHETIC

A.

PROCESSES.

importantthat

take

with

sulphuric
is
in importance
acids or amidoacetic acid. Next
and glycuronic
of urea
the formation
derivatives and sulphocyanides,
and, less
seldom met with, the introduction of acetylor methyl groups and
the productionof cysteinderivatives. Although this does not
Of these the most

exhaust

placeare

the various reactions which have been

it includes
described,

and in the discussion of these only a few

important,
typical
examplesof each will be given.
substance is excreted
It does not often happen that a particular
in any one
ester ; it
form, as for instance as a sulphonic
entirely
in that form,but also partially
as a glycuronic
may be found chiefly
acid derivative,
or
even
partially
unchanged,this may depend on
in the
Consequently,
dosage or other factors quite unknown.
all the

more

various reactions
of the

it must
discussed,

substance

under
synthesis

in

which

be understood

occurs
questionchiefly

that the elimination

by

of the

means

it is

but that at the same

time
described,
place,which,judgingfrom the relative amounts

others may
take
of lesser importance.
in the urine,
are
I.

Sulphonic

Esters.

The

for the production

acid required
of these substances
sulphuric
must
bodies
be formed
by the oxidation of albuminous
containingsulphur,and in this connexion it may be mentioned
that etherial hydrogensulphates
in the urine are generally
increased
in conditions interfering
with
the normal
performanceof the
hepaticfunctions. The etherial sulphatesnormallyfound in the
urine represent
onlyone-thirteenth of the total sulphates.Though
derived from tissues,
the greaterpart are due to protein
partially
in the intestine,
hence their increase in conditions
decomposition
of intestinal putrefaction
and obstruction. When
decomposition
of protein
matter within the organism is takingplaceon a large
of internal organs,
as
e. g. in foul empyemata, or
scale,
gangrene
a

similar increase in etherial

Indican

amounts

sulphatesin

the urine is noted.

which
(indoxylpotassiumsulphate),
in normal

urine,is increased under

occurs

in

small

like conditions.

OF

FORMATION

SULPHONIC

ESTERS

57

containing
hydroxyl,
(OH), in the nucleus
acid as alkali salts in
found combined with sulphuric
are
generally
acid also takingplace.
with glycuronic
the urine,synthesis
Phenol, C6H6 OH, for instance (besides
undergoingfurther
is found as phenylsulphuric
oxidation
to dioxybenzenes),
acid,
the following
reaction takingplace:
substances

Aromatic

"

C6H5OiH

OH;SO2

OH

H2O

C6H6 O.SO2
.

OH.

free acid itself is

unknown, since on liberation from its

salts by stronghydrochloric
breaks down into
acid,it immediately
sulphuricacid and phenol. Such substances,
althoughstable in
alkaline solutions,
are
or
readilydecomposedby mineral
aqueous
The

acids.

The

been diminished by this

of phenolhas consequently
toxicity
and it was
synthesis,
onlyto be expectedthat sodium or potassium
should be non- toxic substances. Further than this
phenylsulphate
the introduction of the sulphonic
acid groupinginto the ringitself,
acid
givingrise to phenolsulphonic

prr/OH
producesa

substance which

is equally
innocuous.

If the

hydroxylderivative itself is non-toxic,owing to the

groupingin the ring,then it passes unchanged
presence of some
acid
throughthe organism; an exampleof this is homogentisinic
OH

5
3\CH2.COOH

whereas the

corresponding
gentisinic
acid,
/OH

which
acid

C6H/OH

\COOH

is

eliminated as the non-toxic sulphuric

toxic,is partially
derivative. Similarly
the highlypoisonous
hydroquinone
r

"

/OH

C6H4\,OH
leaves the

Many

ester.
system in the form of its sulphonic

of the aromatic

ketones

oxidized to acids in the

body,
of
they contain a hydroxylgroup, and the possibility
combination with sulphuric
acids appears, then these
or
glycuronic

but when

are

58

METABOLIC

PROCESSES

latter syntheses
take

placeto the exclusion of the

is oxidized
phenone,C6H5 CO.CH8, for instance,
C6H,COOH, but

former.

Aceto-

to benzoic

acid,

Paeonol

C6H3^-CO.CEL

\0,CH3'5
OH

Gallacetophenone
C6H
cO.CH3

(OH
and

ResacetophenoneC6HJOH

(CO.CHg4
found

are

in the

urine

as

their

sulphuricand

glycuronicacid

derivatives.

The
causes

entrance

of

an

acid group

loss of this power

the

into the nucleus of the

phenols
acid,for
sulphuric

unitingwith

of

acid
instance,
salicylic
TT

/OH

and also the 1 :4 isomer

eliminated

as

(bothmuch

esters,but

behave

like benzoic acid.

character is lost,
however,either
r

less toxic than

by

conversion

/OH

into

phenol)are
When
an

not

the acid

ester such

as

2
^6il4\coO.CH3
or

an

amide
PIT

/OH

regaintheir characteristicsand are found as sulphuric

derivatives
(Baumann and Herter); the introduction of more
of this
the reappearance
hydroxyl groups into the ring causes
in the previously
mentioned
of gentisinic
acid or
as
case
synthesis,
acid,
protocatechuic
these bodies

fCOOH
C6HJOH

1
3

(OH

(COOH

also vanillicacid,

OCH,
C6H3
6

3lOH

a
4

METABOLIC

60

PROCESSES

with the
primary alcohol group presentis oxidized,
As regards
acid derivatives finally
result that glycuronic
appear.
the nature of the resulting
compounds,they appear to be (atall
to the
in the case
events
of aliphatic
substances),
very analogous
glucosides.
Taking chloral as an example,it is found that it is
reduced in the body and eliminated as urochloralic acid,a synthesis
which may probablybe represented
by the scheme
and then the

CCL,

1.

CHO

H2

COOH

COOH

CH.OH

CH.OH

CH.OH

CH.OH

CH.OH

CHOH

OH
.

alcohol.
Trichlorethyl

Chloral.

2.

CC13 CH2

CC13

CH.OH

-"

CH.OH

CH2

CHO

OH

/OH

CH"
\O.CH2.CC12

Glycuronicacid.
COOH
!HOH

H2O

CHOH
O
!HOH

[^-O.CH2.CC13
Urochloralic

acid.

It appears, however,that a different type of combination can

take
place; thus Y. Kotake 1 has shown that rabbits dosed with vanillin

eliminate in the urine

first reaction

acid derivative of vanillicacid,

the
glycuronic
in the oxidation of the aldehyde,
which
consisting

Chem., 45,
Zeit.f.physiol.

320.

ACID

GLYCURONIC
then condenses

with

DERIVATIVES

acid
glycuronic

without

61

the elimination of

water,

fCHO

1.

fCOOH

C6H3 O.CH8

C6H3 O.CH33

(OH

(OH

Vanillic acid.

Vanillin.

COOH

COOH

2.

1
3

(COOH

(CHOH)4

C6H3 O.CH3 =(CHOH)4

(OH

"bHO

OH

CH"

cCOOH

IO.CH3
Blum

has shown

that

thymol behaves

similar manner,

C3H7.CH3.C6H3O.C6H11O7

C3H,.CH3.C6H3OH+ CeH1007

and

in

also
Fenivessythat carbostyril

unites with

glycuronicacid

without the elimination of water,

(C6H4)C3H2N.OH+ C6H1007

(C6H2).C3H2N.O.C6HnO7.

There does not

to be any

seem

sharpline

of demarcation

drawn

these two

of these
by any of the investigators
groups
derivatives. In but relatively
few cases have they been
glycuronic

between

isolated in

that

such

state of

and

such

the
purity,
a

usuallymet with being

eliminated conjugatedwith

statement

substance

is

acid.
glycuronic
It is possible
that hydroxyderivatives of

the

serieswhich
aliphatic
combine with this acid do so in a similar manner
to trichlorethylbromal and butyl
alcohol,i.e. form true glucosides
are
; such
which are firstly
reduced to the corresponding
alcohol ; the
chloral,
less extent,the primary(except
alcohols and, to a much
secondary
and also alcohols of high
which are readily
methyland ethyl,
oxidized),
such as propylene
molecular weight;some
alcohols,
polyhydric
glycol,
1
but not glycerol; many
such
as
dichloracetone,
aliphatic
ketones,
which
reduced
their
alcohols.
Acetoacetic
to
are
firstly
secondary
ester is firstly
oxidized to carbon dioxide and acetone, and this
latter reduced to secondary
propylalcohol
; it is then eliminated as
its glycuronic
acid derivative. Finally
such
come
alcohols,
tertiary
as tertiary
butyl,tertiary
amyl,and pinacone.
On the other hand some
aromatic hydroxylderivatives may form
addition productssimilar to those producedwith vanillic acid or
1

Otto

Neubauer,Chem. Centr.,
1901,ii.314,from

46, 133-54.

Arch.

Exp. Path. Pharm.,

PROCESSES

METABOLIC

62

thymol,but

no

definite statement

Lesnik

cases.

the urine

as

that

found

both

and

a-

such derivatives

C10H7OH+C6H100,

C10H7.O.C6H906+ H20.

by Bonanni 3,found
menthol,

Pellacani 2,confirmed
of borneol and

case

placein the following

occurred in
/3-naphthol

is stated to take

elimination of water

with

made, since condensation

be

can

productin

similar

+ H20
C10H17.O.C6H906

CIOH19OH+ C6H1007

+ H20.
C]0H19O.C6H906

C10H17OH+ C6H1007

the

and
=

Schmiedebergand Meyer 4
to campherol,

found

C10H160

that

oxidized
firstly

camphor was

C10H15O.OH

-*

acid,
productwith glycuronic
+ H20.
C10H15O.OH+ C6H1007
C10H1?O.O.C6H906
to the
have
noticed reactions corresponding
Other investigators
sabinene.
and
of carvon,
latter in case
pinene,phellandrene,
that the synthetical
shown
Salkowski and Neuberg have recently
acid meltingat 150",and of composition
phenylglycuronic
and then eliminated

as

condensation
=

C6H6O.C6H906
the acid excreted in the urine of

is identical with
with
An

sheep dosed

phenol.
is that undergoneby phenetol,
interesting
synthesis

C6H6OC2H?,
which

oxidized and
is firstly

the so-called chinaethonic

as

C6H5OC2H6

eliminated with

then

acid,

1:4C6

-"

Another

method

by

of which

means

is lowered consists in the addition

brandt5

have

that

shown

and
thujonhydrate

acid
glycuronic

the

of water

thujon is

then eliminated

+ H20
O.C10H16

as

of
toxicity
;

Fromm

converted

substance

and

in the

Hilde-

body

to

derivative,
glycuronic

O.C10H17OH

and

O.CIOH17OH+ C6H1007

O.C10HI7O.C6H906.

167.

Schmiedeberg,Arch., 24,

Arch.f.Exp.

PhysioL,I, 304.
6
Zeit. f.physiol.
Chem., 33, 579.
Chem., 3, 422.
Zeit.f.physlol.

Path.

u.

Pharm., 17, 369.

Hoffmeister, Beitragz. Chem.

DERIVATIVES

Derivatives

III.

of

be obtained
may
acetic acid with dry ammonium

COOH.CH2jCl
It is soluble in

food

Amidoacetic

63

acid.

amido
glycineis the simplest
synthetically
by warming monochlor-

acid,and

and

ACID

acid, glycocoll
or

Amidoacetic

Nencki

AMIDOACETIC

OF

carbonate.

HJNH2

water,possesses

Schultzens1

to

COOH.CH2.NH2
taste,and

sweet

giverise to

by

administered

when

urea

shown

was

in

(seep. 74).

The

fact that

if introduced
appearance

with

in the

food
urine

acids

and
intravenously,

or

in

(where urea elimination is

of
the position
as
indicating
and urea.
This may
protein
must
synthesis
precedethe
contain less N

other amino

glycineand

acute

give rise to
the

fact of

yellow atrophy of

decreased

urea

their

the

liver

taken
are
correspondingly),

those bodies

as

intermediaries between

not be true,but if true,some

may
formation
of urea, as the amino acids

than C, which

or

is the

reverse

of what

in

occurs

urea.

glycineand benzoic acid takes placein the

at any rate partially.
Minced kidney substance
kidneysubstance,
and blood containing
effect this synthesis,
benzoic acid,if passed
can
kidney,is found afterwards to contain hippuric
throughthe living
The

combination

of

acid.
This

the
synthesis,
typical

is illustratedby benzoic

firstof its kind which

acid,which

forms

COOH

discovered,

acid,
hippuric
COOH

.....

CH2.NH|H
Amidoacetic

was

HOjOC.C6H5

H2O

CH2" NH.CO.C6H5

acid.

Hippuric acid.

similar reaction takes

placewith any benzene derivative which,

if oxidized in the body,gives
rise to this acid or its derivatives,
such,
for instance,
as
ethylor propylbenzene,xylene(firstly
toluene,
oxidized to

oxidized to mesitylenic
mesitylene(firstly
;?-nitrotoluene
acid),
and in the case of dogs all the nitrobenzaldehydes.
/3-bromtoluene,
chlor and brombenzoic acids,
Salicylic,^?-oxybenzoic,
nitrobenzoic,
and /3-naphthoic,
anisic,
aand cuminic acids all
toluic,
mesitylenic
1

Zeit.f.BioL, 8, 124, 1872.

METABOLIC

64

PROCESSES

form derivatives
may

be

analogousto hippuricacid. In this

mentioned that whereas phenylpropionic
acid

connexion

it

C6H5CH2.CH2.COOH
body to benzoic acid and eliminated as hippuric
acid,phenylacetic acid,C6H5CH2. COOH, forms phenylaceturic
this questionwill be
acid,C6H5CH2 CO.NH.CH2COOH
; but
further discussed under the general
headingof oxidation processes.
acid of thiophene,and
the corresponding
The a-carboxylic
aldehyde
behave in a similar manner
to
after oxidation in the organism,
is oxidized in the

benzoic acid.
is firstly
oxidized
a-methylpyridine
then eliminated

as

acid
a-carboxylic

and

derivative.
glycocoll

IV.

The mode

to the

Derivatives.

Urea

of formation of these derivatives is by

no

means

they may be formed outside the body by the action

acid on primaryor secondary
amines.
C2H6.NH.CO.NH2
C2H5.NH2 + CONH

of

clear ;

cyanic

Cyanic acid.

Ethyl urea.

it may
be that a reaction somewhat
placein the animal organism.

and

analagousto

this takes

Taurin

CH2NH2
!H2 SO.OH
.

is eliminated

as

taurocarbamic

acid

CH2.NH.CO.NH2
!
CH2
Amido-benzoic

and

SO2OH

acids similarly
form
amido-salicylic

urea

derivatives,

/COOH
and

CLHL^-OH

^NH.CO.NH2,
Schmiedebergnoticed

small

of ethylurea
quantities

C2H6.NH.CO.NH2
in the urine after

Many

carbonate.
dosingwith ethylamine

derivatives appear

in the urine

as

salts of

urea.

Sieber

FORMATION

SULPHOCYANIDES

OF

65

oxidized to
are
nitrobenzaldehydes
firstly
to nitrotheir corresponding
acids,then combine with glycocoll
and that these latter substances then formed salts
hippuric
acids,
and others found that the

with

urea.

Formation

V.

Pascheles1 showed
off

at the

formation

in

that

Sulphocyauides.

containing
easilysplitproteins
into
sulphocyanide,
potassiumcyanide
is
of
and
it
that the
the
probable
temperature
room,
from the
the animal organism of sulphocyanides

sulphurcould

KCNS,

of
some

convert

organicnitriles may be ascribed to a similar reaction. With the

of methylnitrile,
of this seriesare
CH3CN, the homologues
exception
and in their passage throughthe bodyare converted
very poisonous,
It is interesting
into the much
less toxic sulphocyanides.
to note
that

Nencki2

states

that

the stomach

under

normal

conditions

acid. Gscheidlen
sulphocyanic
in human
found it constantly
urine,and the potassiumsalt occurs
normallyin saliva,
probablyas an excretory
product.

contains

of free

minute amount

Introduction

VI.

of the

Acetyl

Radical.

interesting
examplesof the introduction of an
acetylgroup in the passage of an organicsubstance throughthe
body was observed by R. Cohn 3,who found that rabbits treated
with
converted
this into ^-acetylamido0z-nitrobenzaldehyde
One

of the most

benzoic acid.
The
to the

firstchangeconsists in the oxidation of the

acid,

PTT/COOH
C

H n

The

second,the reduction
PI

/COOH

TT

C"H"N02
and

aldehyde
group

of nitrobenzoic acid to

+6 "TT

OTT
ri
2H*0

the synthetic
formation
thirdly,

COOH

+i

of the

TJ

amidobenzoic,
yCOOH

C"H"NH2
derivative,
acetyl

.COOH

CH3
|

=C6H4/
.

\NH.CO.CH

NH; ;H;+ COOH;

1
2
8

Arch.f. exp. Paihol. u. Pharm.,34, 281.

Ber.,28, 1318.
Zeit. physiol.Chem.,18, 133-6.
9

+H20

PROCESSES

METABOLIC

66

Reactions

VII.

Jaffe and Colin

found

Acid.

Acetic

with

aldehydeof furfuran,
acid,and
corresponding

furf urol,
the

that

organismto the
but to a smaller extent
then eliminated as a glycocoll
derivative,
acid,
undergoescondensation with acetic acid to furfuracrylic
is

partlyoxidized

CH"

CH

II

II

H2!CHCOOH

II

+ CH

H20

it

CH

CH"

C.CH:0

CH

in the

C.CH

CH.COOH

v
which is then eliminated

C4H3O.CH

CH.COOH

H2O

derivative of amidoacetic

H2N.CH2

as

C4H3O.CH
of

Introduction

VIII.

COOH

the

acid,

CH.CO.NH.CH2COOH
Radical.

Methyl

is eliminated in the urine as methylpyridine

and this observation was
confirmed
pyridyl-ammoniumhydroxide,
3
of the most interesting
changesin animal
by R. Cohn
; it is one
chemistry.
that

His2 found

CH

CH

CHlH

Hoffmeister
tellurium

states that

animal

an

with

dosed

tellurium

or

compounds eliminates tellurium dimethide,Te (CH3)2

connexion it is interesting
to notice that according
to the
.

In this

observations

of

Albanese, Gottlieb,Kriiger,and

of one
or
methylatedxanthines are deprived
throughthe organism.
groups on passing
IX.

Baumann

Formation

showed

that

found
productsof proteins,
of cystein,
which
disulphide

of

Cystin

cystin,one
in urine

more

of their

the

methyl

Derivatives.

of the
in

Schmidt

cases

primarydissociation
of cystinuria,
is the

he formulated

\3H
1

Per., 20, 2311.

Zeit.

physiol.Chem., 18, 112-30.

Archw

exp. Path.

Pharm., 22.

PROCESSES

OXIDATION

68

further oxidation
complex compounds containing
oxygen
cule,
alwaystakes placeat the most highlyoxidized placein the moleprovidedthe carbon at that pointis linked to hydrogen.
Thus
ethylalcohol,
CH3 CH2OH, is oxidized to acetaldehyde,
; and
CH3.CHO, and this further to acetic acid,CH3 COOH
CHO, is converted into
"-oxypropylaldehyde,
CH3 CHOH.CH2
since the aldehyde
COOH,
acid,CH3 CHOH.CH2.
0-oxybutyric
in the molecule.
group (CHO)' is the most highlyoxidized system
be linked to
rule that a carhon atom cannot
It is a very general
than one
more
hydroxylgroup, and when attempts are made to
water is split
introduce more, i.e. on further oxidation,
off,and the
generalreactions take place,
dependingupon the number
following
of hydrogenatoms attached to the oxidized carbon :
in

Then

"

CHOH

CHO

CH

Oxidized.

=H90+

CEL

-"

CH2

CH,

CH

CH3

Butyricaldehyde.

Propyl alcohol.
or

O,

=H0+
CH
C

HS
Butyricacid.

The

and
the intermediate,
are
consequently
aldehydes

acids the finalproducts

in the oxidation

primary group
the
containing

group,

X"

With

CH2OH.

similar reaction takes

of alcohols

the

organic
the
containing

i.e.
secondaryalcohols,

and
place,

on

further oxidation

yieldketones,
CH

CH

A":
OH

CH,
CO

CH

CH,
Acetone

or

dimethylketone.

those

they

SELECTIVE

OXIDATION

69

alcohols,such as (CH3)3.C.OH,not containing

tertiary
hydrogen linked on to the alreadyoxidized carbon atom, further
oxidation is not so easy, and energetic
reagents are necessary,
With

when

breaks

the molecule

into substances of smaller carbon

down

content.
3.

CH3

CH3
Oxidation.

CH3" C.OiH

CH3.CO

-*

~H2O
[~2

Acetone.

~|

[H.COOHj
be taken as a short summary
above may
substances (thearomatic
effects of oxidation on aliphatic

of the

Although the

discussed

yet
later),

the

of the actual

nature

oxidation

will be

processes
of organic

placeon the passage

substances through the animal organism are of a different order
from those carried out in the laboratory.
selective oxidizing
Such changesare characterized by a striking
of completely
action ; thus an animal capable
breakingdown many
hours
hundred grainsof sugar to its end productsin twenty-four
is incapableof similarly
treatingsay a few grainsof sodium
which

have

been observed to take

formate,which

per cent, of the dose taken

of these
Further than this,

of 50-70

to the extent

unchangedin the urine.

two changesthe latter is much
more
readilycarried out in the
Then
dextrose and laevulose are
than
the former.
laboratory
but the sexvalent
completelydecomposed by the body cells,
alcohol mannite passes through with very littlechange. In this
of a
the replacement
case
CH2OH group by C HO or
is eliminated

"

HOH

by

C=O

bringabout completeoxidation.
acted
stereochemical isomerides are differently
Even
in alcaptonuria,
phenylalanin,
occurring
naturally
has been

sufficient to

C6H6 CH2
.

is almost

CHNH2

oxidized
quantitatively

to

upon

thus,

COOH,

acid,
homogentisinic

C6H3(OH)2.CH2.COOH,
whereas the racemised form
cent.

Then

m-

and

is

onlyoxidized

/-tartaric acids

are

to the extent of 50 per

much

more

completely

PROCESSES

METABOLIC

70

acids,and
ides.

and racemic
organism than are ^#^0-tartaric
isomerlatter acid is not decomposed into its optical

by

down

broken

this

this connexion

In

that /-tartaric is

the

action

same

racemic

it may
toxic than

more

racemic acid

than

more

the

that

be mentioned

Chabrie' found

form, and

the dextro

both

of these

; for

the following
amounts
instance,
produce
d, and 165-25 gms.
gms. I,104-24
gms.

34-26

acid.

show the characteristic selective

examplesgiven clearly
substances
action of the tissues,
oxidizingsome
completely,
rejecting
chemical or physical
others with but slight
differences.
in which
Our
the actual
ignorance of the manner
process of
realized when
it is remembered
oxidation takes placeis readily
that
of the complete oxidation
of an
no
singlecase is known
organic
solution by the oxygen
of the air. Nencki
substance in aqueous
attemptedto determine,without success, the extent of the oxidation
The

few

of sugar
at

and

albumen

on

temperature of 36" C.

The

problem

is further

in alkaline solutions

exposure
;

the amount

the

air

extremelysmall.

was

complicatedby

to

the

observation

that

in

creased,
oxidizingaction may be depressed,in others indosage with other substances ; thus
by the simultaneous
Nencki
and Sieber * found
that while the body of a healthyman
could form -82 gm. of phenol from 2 gms. of benzene,under normal
conditions this amount
dropped to -33 gm. if 2 gms. of alcohol
administered.
simultaneously
Pfliiger,
per kilo, body weight were
some

cases

Poehl,

and

the

others

shown

have

that

under

other

conditions

the

oxidizingaction of the animal organism may be increased.

It is not proposed to discuss the various
hypothesesthat have
in this connexion.
been brought forward
the
assumed
Traube
existence of oxidizingenzymes,
afterwards
shown
to be present in
the lungs, kidney, muscles, "c., by Schmiedeberg, Salkowski,
sufficie
Jaquet, "c., but their action appears to be very limited,quiteinto account
for the varietyof known
oxidation processes,
although in all probability
they play some
part in these changes.
The

suggestionthat

in

some

way

or

other the oxygen

in the

is activated

body is difficult to follow ; it is more probablethat,as Pfliiger

has suggested,
it is not the oxygen
that is activated,
but that the
is a function of proteins
of the living
activity
protoplasm.
1

Pflug.Arch., 31, 319.

ALIPHATIC

OF

OXIDATION

ALIPHATIC

OF

(a). OXIDATION
The

SUBSTANCES

71

SUBSTANCES.

oxidation of the

of the aliphatic
hydrocarbons
series on their passage through the organismhas not yet
and as may be gatheredfrom the previous
been observed,
remarks
It follows that if the petroleum
is hardlyto be expected.
emulsions
have any therapeutic
value,it cannot dependon any analogyto cod
utilized by the organism,
liver oil,
which is readily
i.e.broken down
to its end oxidation products.In fact these bodies taken by the
mouth
eliminated in an unchangedcondition in the
are
completely

Hydrocarbons.

faeces.
either completely
Primaryalcohols are oxidized,
or, in some
cases,
be
to the corresponding
the
as
unstable
acid,but, might
expected,
in
found
the
intermediate aldehydes
are
never
body; if producedat
alltheyare but transitory
to the higherstageof oxidation.
products
Formaldehyde,a saturated solution of which is termed formalin,
to the ease with
properties
probablyowes its remarkable antiseptic
which

it abstracts oxygen
the breakdown
causes

which

Combinations
such

as

milk and

and

becomes

formic

acid,a

process

of

organicmatter.
of formaldehydewith indifferent organicbodies,
and on beingintroduced
sugar are free from toxic effects,1

system it is found that one-quarterpasses

into the urine,one-tenth combines with ammonia, giving
directly
but the largest
tetramine,
part is found as formic
hexamethylene
into the animal

acid.
the

On

other

hand, chloral,CC13 CHO,

and

butyl chloral,
CC13 CH2 CHO, are not oxidized to their corresponding
acids,
but reduced to alcohols and eliminated,
as
previously
mentioned,
acid.
as compounds of glycuronic
animal
The
organism appears to exercise a greaterpower of
oxidizingethyl,propyl,or butyl groups than it possesses over
methyl; thus methyl alcohol,or its esters,and methylamine or
methyl nitrile,
give formic acid,whereas ethylalcohol or ethylamine are completely
broken down, and the highernitriles,
which
much
than
toxic
converted into sulphoare
more
are
methyl nitrile,
Albertoni has shown
alcohols,
cyanides.As regardsthe secondary
that isopropyl
alcohol,
CH3. CHOH.CH3, is partlyoxidized to
acetone,CH3. CO.CH3, and partlyunchanged.
The tertiary
such as amyl alcohol or trimethyl
alcohols,
carbinol,
.

J. Jacobsen, Chem.

Cent. Blatt.,8,

693, 1906.

METABOLIC

72

PROCESSES

difficultto oxidize than

either

primary or secondary,pass
of hydrogen by
through the body unchanged. The replacement
of the alcohols towards
chlorine causes
increase in the stability
an
alcohol,CC13 CH2OH, and
oxidizing
agents; thus trichlorethyl
alcohol,
trichlorbutyl
CC13 CH2 CH2OH, pass unchanged through
the animal organism,and are eliminated as glycuronic
derivatives.
A corresponding
is noticed in the case of the organic
acids,
protection
whereas acetic acid,CH3 COOH,
is readily
oxidized ; trichloracetic
acid or trichlorbutyric
acid are onlypartially
decomposed.
A similar protection
of the organism
action
t
he
against oxidizing
is noticed in the case
of the sulphonic
acid group ; both ethyl
sulphate,1
more

"

and

acid,
sulphoacetic

02OH

CHKcOOH
passingthroughthe body unchanged.
As regards
the polyhydric
alcohols,
glycerol,
CH0OH
CHOH

la2OH
but mannite,
oxidized,
readily

is

CH..OH

(CHOH)4
CH2OH
whereas
onlypartially,

the sugars,

CH2OH
CHOH

(c
4

and
CO

c:JHO
CHOH
CH

Dextrose.
xtrose.

Laevulose.
are

of

course

broken
completely
1

down.

Salkowski,Pflug.Arch.,5, 357.

SUBSTANCES

ALIPHATIC

OF

OXIDATION

73

productsof the primaryalcohols,

into carbonof acids,their completebreakdown
i.e. the group
than
dioxide and water is as a rule effected with greaterdifficulty
that of the alcohols or aldehydes,
yet in the animal organismthis
of formic
With the exception
process takes placewith greatease.
acid,the fattyacids are easilyoxidized,and as their molecular
CH3(CH2)16 COOH, palmitic,
magnitude increases and stearic,
Passingto

the final oxidation

CH3(CH2)U COOH,

oleic,

the unsaturated

and

C8H7
acids

CH

CH(CH2)7 COOH,
.

in the form

reached,these

are

of their

esters
glycerol

the fats.
importantgroup of food-stuffs,
such as glycolic
acid,CH2OH.COOH,
Oxy-acids,

stitute
con-

the

CH3CHOH.CH2.

COOH,1

/9-oxybutyric,

lactic acid,

/OH

CHg.CH \CO

but in phosphoruspoisoningand in several

easilyoxidized,
In
conditions this latter acid appears in the urine.
pathological
this connexion 0-oxybutyric
(and
acid,CH3. CHOH.CH2. COOH
its oxidation productacetoacetic acid,CH3 CO.CH2 COOH), may
are

be mentioned

; as

is well known

these

occur

in diabetes.

oxalic acid ; some

statements are met with as regards
Conflicting
whilst Marfori found
state that it passes unchangedinto the urine,
and that the same
that a considerable amount
was
fullyoxidized,
of which 30 per cent, of
process takes placewith sodium oxalate,
reappears in the urine.
whole of this acid injected
into a dog could
the

urine.
traces

is

taken

amount

Faust

found

that the

be recovered from

the

only
acid, CH2(COOH)2, is largelydestroyed,
passing
throughunchanged;tartronic acid,CHOH(COOH)2,
Malonic

broken down, and

completely

so

are

succinic,

CH2.COOH
CH2.COOH
and, to

very

largeextent,tartaric acid (seep. 70),

CH.OH.COOH
CH.i.OH.COOH

G.

Satta,Beitr.

Chem.

PhysiolPath.,6, 1-26, 1904.

METABOLIC

74

and

malic

PROCESSES

acid,
CH.OH.COOH

CH2.COOH
Only very

small amounts

of

acid,
glutaric
,.COOH

escape oxidation.
acids givenin moderate
Amido

broken
completely
CH2. NH2 COOH,
Glycocoll,

amounts

are

as urea.
down, the nitrogenappearing
and leucin,
CH3 (CH2)3.CHNH2 COOH, even in largeamounts,
never
CH3.CHNH2. COOH,
appear in the urine,whereas alanin,
.

acid,
aspartic

CH.NH2.COOH

to2.COOH
and

acid,
glutaminic

JHNH2.COOH
.COOH
and partially
oxidized,
partially
pass through the organism
unchanged.1
Wohlgemuth 2 has found that rabbits fed with racemised tyrosin,
leucin,asparticacid,and glutaminicacid oxidized the optical
isomeride occurring
normallyin the body, whilst the other was
excreted in the urine. Thus
is
or
partially
completely
^-tyrosin
the form in which this substance occurs
normallyin animals,and
and /- found in
when the racemised form is given,
d- is destroyed
are

the urine.
The

acid

of acetamide,
amides,with exception
CH3

CONH2,

and

oxamide,

CONH2
CONH2
which

but

broken down
as
are
as
oxidized,
partially
completely
acids. The nitriles of the acetic acid series,
their corresponding
formed
ammonium
by the dehydrationof the corresponding
are

salt,e.g.

CH3.COONH4-2H2O
1
2

CH3CN,

Stolte,
Hofmeister's
Beitr"ge,5, 15, 1903.
Ber.,38, 2064,1905.

PROCESSES

METABOLIC

76

Juvalta

Accordingto

acid and
\ phthalic

/COOH

broken

are

down, in

the

case

phthalimide,2

/C

C
U

anda

also

of the former

substance

given. Pribram
per cent, of the amount
in the rabbit.
acid is excreted quantitatively
phthalic
of

over

57

to the extent
states that

Cohn
is stated by Rudolf
to be almost completely
Methyl quinoline
author showed that 1 : 2oxidized in the body,and the same
the same
to a largeextent underwent
fate,and
nitrobenzaldehyde
1 : 2oxidized to the corresponding
that only small amounts
were

nitrobenzoic acid.
Benzene

itselfis oxidized to

benzene,but
benzene

the

oxidation

is eliminated

glycuronicderivative

also 1 :4- and 1

and
phenol,

does not

go

since
further,

2-dioxy: 2-dioxy:

unchanged. Naphthaleneis eliminated as a

in a similar manner
to the jS-oxyderivatives

(/3-naphthol).
homologous benzenes undergo similar changes to those
mentioned
previously
(p.30),the side-chains being oxidized and
Thus toluene,
by COOH.
replaced
C6H5CH3 givesbenzoic acid,
The

aeid,C6H4"
gives
C.H""J;g",
toluic

xylene,
and

mesitylene,
C6H3(CH3)3 1:3:5, gives mesitylenicacid,
dized
C6H3(CH3)2COOH. Ethyl benzene,C6H6 CH2 CH3 is also oxito benzoic acid. Propyl benzene,C6H5 CH2 CH2 CH3
behaves similarly,
givingrise to the same acid,althoughisopropyl
is oxidized in the ringto a phenol-like
benzene, C6H5 CH (CH3)2,
derivative. This may be comparedwith the behaviour of cymene,
.

L3

which

Zieglershowed

Now

when

agents,such

the

gave

cumic

hydrocarbonis

dilute nitricacid

as

acid,

or

treated

chromic

with

powerfuloxidizing
acid,the propylgroup is

firstattacked,
giving
1

8
8

Juvalta,Zeit.f.physiol.Chem., 13, 26.

Koehne, Chem. Centr.,2, 296, 1894.
Chem. Centr.,2, 668, 1904.

but

when

mild

agent,such

as

caustic soda and

77

oxygen

is
(air),

is oxidized.

the methylgroup
employed,
1

SUBSTANCES

AROMATIC

OF

OXIDATION

2-Nitrotoluene,
P

/-I

TT

/N"2

is oxidized to the alcohol

and eliminated

as

acid
glycuronic

Generallyspeaking,such
and CH2 NH2, attached to
.

"

COOH

eliminated

and

/NO0

as

derivative.

radicals

as

the benzene

CH3, CH2

OH, CHO,
oxidized to

nucleus,are

acid (p.63).
hippuric

acid,
Phenylpropionic

C6H5.CH2.CH2.COOH,
acid,CH5CH : CH.COOH, are converted into benzoic
but phenylaceticacid,
acid,
C6H5 CH2 COOH, givesphenaceturic
acid,C6H5CH2. CONH.CO.NH2, and mandelic acid,2
and cinnamic

C6H5'CH\COOH,
passes

through the organismunchanged,whereas

phenylamido

acetic acid,

C6H6

CHH

giyesCeH

acid givesbenzoic acid,it cannot pass

phenylpropionic
throughthe stage of phenylacetic acid,and consequently
Knoop
considers that the oxidation of that acid can onlytake placein the
As previously
P position.
mentioned,
ethylbenzene,
C6H5 CH2 CH3,
t
hat
benzoic
a
nd
it
is
the
acid,
probable
(p.76)gives
CH2 group is
and not the methyl; this is borne out by the fact
attacked first,
that acetophenone,
C6H6COCH3, also givesbenzoic acid. Other
acids investigated
than two carbon atoms
more
by Knoop containing
in the side-chain did not givebenzoic acid. An analogous
oxidation
in the formation of /?-oxyis seen
of hydrogenin the /?position
butyricacid,
CH3. CH.OH.CH2. COOH, and the further oxidation
acetoacetic acid,CH3. CO.CH2. COOH,
and acetone,
products,
Now

since

CH3.CO.CH3,
1
*

in diabetes.

Knoop, Hofmeister's
6, 150, 1904.
BeitrSge,
Schotten,
Zeit.f.
physiol.Chem.,8, 68, 1884.

METABOLIC

78

PROCESSES

In many
oxidation in the nucleus takes
cases
the hydrogenin the 1 : 4 position
to the group

placeprovidedthat
alreadypresent is
oxidized
aniline,
C6H5NH2, is partially

itself substituted. Thus

not
to 1

4-amidophenol,
OH

K.

that

Klingenbergshowed

diphenyl,

f^

TT

Vyfi"l,

ester
givesthe sulphuric

of 1

4-oxydiphenyl,
.

Phenyl methane

to the

1:4

H6

gives1 : 4-oxyphenylmethane, and

of action isnoticed with

rise to

OH

chlor-,
brom-,and

in which
derivatives,
cystein

been attacked

has

halogenatom

the H

similar

type

which
iodo-benzene,
atom

in the 1

(seep. 66).

:4

On

gives
position

the other

hand,

C6H4NH2

Benzidine,|

C6H4NH2
oxidized

C6H4Br
1:4

I
Dibromdiphenyl,

C6H4Br

the animal

organism. Nolting,who examined

of cases, states that the hydrogenof the benzene
a largenumber
nucleus is onlyreplaced
by hydroxyl(OH) in the para positionto
be occupied
the substituting
such
group, and should this position
a type of oxidation does not take place.
From
a physiological
pointof view the oxidation of indol,
are

not

by

in the

organismis of considerable importance.When this substance

is formed
(whichhas distinct but not very marked toxic properties)
in the intestine as the result of putrefaction,
or is introduced experimentally,
it
and
t
akes
oxidation,
undergoes
absorption
rapidly
place;
in
most
probably the cellsof the liver,to indoxyl,
C(OH)

C.H/VH,
NH

REDUCTION
which

is eliminated

the

as

79

ester
potassiumsulphuric

C(O.S02OK)

CH/NcH
NH
urine

indican,owing

be identical with

the indican of

This ester is known

supposedto
case

as

this derivative

producesa

on

further oxidation

f)f~^

TT

was

which is not the

plants,
givesindigoblue,which

characteristic colour in the urine.

CO

C(OS02OK)
xv.f^TT
"^"1

^Ugll^A

to the fact that it

(\

TU2

f^

TT

CO
NO

^6114\/^'

NH

NH

"
'

C^t

\.O

TT

V~U^!f\

+ J^*loU4
y/^/6Ji4

NH

Indigo blue.

C.

The

REDUCTION.

direct reduction of the oxidized derivatives of the

aliphatic

such as alcohols,
acids,phenols,
ketones,back
series,
from which they are derived is by no
to the hydrocarbons
means
and it is not to
an
easy matter,and powerfulreagentsare required,
that such changes should occur
be expected
during the passage of
these derivatives throughthe animal organism.
of substances undergoinga process of reduction on their
The cases
to oxidation,
passage through the organismare, relatively
very rare.
is that of chloral,
One of the most interesting
CC13CHO, and butylchloral,
CC13 CH2 CHO, which are reduced to their corresponding
alcohols and eliminated as compounds of glycuronic
acid (seep. 60),
this process beingmuch
in the laboratory
difficultto accomplish
more
than the opposite
of oxidation to the corresponding
acids trichlorone
acetic and j8-trichlorpropionic.
In the aromatic seriesthe easily
reduced
quinoneundergoesthis
change in the organism,and is eliminated as hydroquinone.
Other examplesof reduction are met
with in the case
of some
nitro compounds. Thus Eric Meyer has shown
that nitrobenzene
is partially
converted into 1 : 4-amidophenol,
and

aromatic

/OH

PROCESSES

METABOLIC

80

chiefly

but

eliminated

Similarly

unchanged.

and

3-

4-nitro-

phenol,

give

their

of

some

has

nitrobenzaldehyde

been

has

Hoppe-Seyler

G.

amido

corresponding

shown

that

of

indoxyl.

manner

the

as

salt

potassium

This

change

case

of

(p. 65).

to

2-nitrophenylpropiolic acid,

^e^XC
is eliminated

alluded

previously

The

derivatives.

C.COOH,
of

probably

the

conjugated

takes

sulphuric

in

place

the

ester

following

"

! C.COOH

1.

5jT"H

Reduction

C6H4/

C6H4"

-"

"C.COOH

C"

2.

OH

C"

NH

OH

NH

Indoxyl.
C"

3.

OH

HjO.SO2OH

C"

O.SO2OH

C6H4"(\CH

NH

Indoxyl-sulphate.

organic

Many
lose

their

regain

it

colour
on

exposure

dyes,
while
to

such
in

air.

as

the

alizarin

cells

and

blue
fluids

indophenol

or

of

the

body,

blue
but

CHAPTER

THE

ALCOHOLS

AND

IV

DERIVATIVES.

THEIR

I.

AND

GENERAL
HYPNOTIC

HYPNOTICS.

OUTLINES
AND

OF

THE

GROUP

OF

PHYSIOLOGY

ANAESTHETIC

OF

DRUGS.

of anaesthetics
pharmacological
groups
and narcotics is importantin practice,
but does not depend
action or chemical constitution.
upon differences in physiological
which are
For the production
of general
volatilebodies,
anaesthesia,
whereas lessvolatile
absorbed and excreted,
most suitable,
are
rapidly
is only graduallyset
whose
liquidor solid substances,
activity
be employed for profree in the organism,
more
can
conveniently
ducing
of
latter
condition
be
The
course
can
hypnosis.
produced
method
but the
of administration
by small doses of a body like chloroform,
is inconvenient,
and the resulting
sleeprapidly
passes away.
On the other hand, largedoses of a narcotic like chloral hydrate
anaesthesia ; indeed this body was
produce completesurgical
may
THE

used

distinction between

General

MAIN

physiologicalaction of
Moore and
anaesthetics and hypnotics. Overton-Meyer theory. Traube.
Roaf on Chloroform.
Baglioni's
theory.
II. Method
of preparationand chemical and physiological
propertiesof
the Alcohols.
Esters of Halogen acids,Nitrous and Nitric,Sulphurousand
Sulphuricacids. The Ethers.
ANAESTHETICS

I.

THE

for a
intravenously

the

short time

and

in the middle

of last

century,

advantage
major operations
performedunder its influence. The disof such a procedure
is that the dosage has to be too
of the patient.
high for the completesafety
The physiological
action of the entire group of aliphatic
narcotics
is first on the highercentres of the cerebrum,then on
the lower
centres of the medulla and cord.
Eventuallythe reflexes are
G

ALCOHOLS

THE

82

and
abolished,
completely

between

this group

THEIR

AND

DERIVATIVES

this constitutes

an

importantdistinction

and the alkaloidal narcotics of which

the chief

is morphine. In largedoses this substance increases

representative
and in small doses does not depress
it.
reflex irritability,
narcotics belong to several chemical
The aliphatic
groups, the
chief beingthe alcohols,
ketones,and their derivatives.
aldehydes,
Though it appears doubtful whether methane itself is narcotic,
ethane and acetylene
direct narcotics.
Those which
are
belongto
the alcohol group
action to the hydrocarbon
their specific
owe
the latter are increased the
not to the hydroxyl.When
radicals,
narcotic action is diminished ; but the hydroxylradicals may
be
anchoringgroups. As a rule ethylcompounds are more powerfully
when
hypnoticthan methyl,especially
occurringin bodies which
offer some

The

resistance to oxidative processes.

of

carboxylappears to stop all narcotic effects,

an
though the esters containing
alkylgroup in placeof the hydrogen
of the carboxyl
radical are active. Thus urethane,
entrance

/2J"*-5^

owes

its

to
activity

weight of

the

ethylgroup.

the alcoholic group

the

The

higherthe

molecular

powerful is the hypnotic

more

action.
Thus

hedonal,

CO^?%T
is much
are

not

powerfulthan

more
as

/CH0

urethane.

rule convenient

The

and
aldehydes
as
narcotics,
they cause a

ketones
marked

preliminary
stageof excitement.
unsubstituted by halogens,
Many of the aldehydederivatives,
are
t
he
substances
often
irritant.
only feeblynarcotic, parent
being
The ketones themselves have not yielded
any bodies of great practical
importance,
althoughamong their derivatives are the valuable
sulphones.
The introduction of a halogen,especially
chlorine,
hances
greatlyenthe

narcotic

power,

but

these

of being respiratory
and
disadvantage
other halogenelements have a stillmore

There

remain

compounds have
cardiac

the great

The
depressants.

deleterious effect.

for consideration several

pointsof

theoretical

THEORIES

84

OF
Liminal

HYPNOSIS

Value.

Distribution.
o

Coefficient
Trional
Tetronal

-0018
-0013

446

4-04

"002
"002
"02
"04

Chloral hydrate
Ethyl methane
Methyl methane
Monacetin
Diacetin
Triacetin
Chloralamide

....

"006

Sulphonal
hydrate
Butylchloral
Bromal hydrate

Ml

L59
.

-66

-22
.14

"4

g^

.04
06

"05
"015

-23

"01

-3

Chlorhydrin
Dichlorhydrin
In the
in fat

"04

"

"04

"002

found

sulphonederivatives it was
also those that showed

were

the presence of

had

-106

very

"151

marked
marked
marked
more

Trional
Tetronal

1-115
4 46

more

recentlyshown that some

action when givento starved animals
powerful
the animals

to
activity

Distribution Coefficient.

slight
slight

methane
Dimethyl-sulpho
ethane
Dimethyl-sulpho
Sulphonal

that

traced this

ethylgroups.
Action.

Mansfield

soluble

activity,
greatestphysiological

and Kast

whereas in this series Baumann

that those most

has

well fed.

are

4-04

narcotics have
than is the

This,he suggests,
may

in the latter the tissue fats absorb

some

case

more

when

be due to the fact

of the narcotic and

of actingon the central nervous

system.
incapable
The Overton-Meyer
theorythen,based on the above observations,
to the cells of the central
is that indifferent substances gainaccess
in which
in the cell lipoids
nervous
system owing to their solubility
in narcotic power
and that gradations
these cellsare particularly
rich,
due to the presence of groups which increase the partition
efficient,
coare
soluble in such fatty
i.e. which render the derivatives more
the presence of the active
The theoryonly explains
substances.
render it

substance

in the

and
cell,

of
completeignorance
that there will be
nature

of ether

when

the next

this has been

effected

phase,althoughit

is

we

are

in

obvious
fairly

of the
greatdifferencesbetween inert substances,
or
chloroform,and bodies which are chemically

further would lead

hypothesis
that cells rich in lipoid
substance should show a
to the supposition
in the
absorption
preferential
; that this is not alwaysthe case is seen
such
active,

as

aniline. The

Overton

HYPNOSIS

OF

THEORIES

85

narcotics do not attack the peripheral

nervous
aliphatic
amount
of
such
bodies.
Further,
system,which contains a large
Cushny has pointedout that many benzene derivatives have a high
distribution coefficient,
though without narcotic action.

fact that the

the substance

which

of

content
osmosis.

enters the

as

to the

as

manner

and considers that it is

cell,

He

he does not hold the

as
tensions,

prevailing

of osmotic pressure.
into
Rapid penetration
to be the most essential condition for enablinga

to the nature

narcotic substance to exercise its

and
cells,

the interiorof certain

'

and
paralysing

other

have found that

we

and
velocity

osmotic

exists between

surface

effects on

near

relation

and therefore
tension,

and narcotic power run

the case, even
This he finds is really
when most varied
the
narcotics are compared. Traube considers that when

expectthat surface tension

can

not the

of
the sequence or the amount
of osmosis to the
ascribes the direction and velocity

the cells seems

we

in

determines

which
lipoid

difference of the surface

views

in his views

Overton

differs from

J. Traube

parallel'.
types of

drug has

gainedentrance to the cell it may exercise its narcotic power

in the cell lipoids.
in proportion
to its solubility
and
Moore
Roaf have recently
promulgatedthe theory that
anaesthetic substances form unstable compounds with the cell proteins,
the
of
which only last so long as sufficient partial
pressure
Beginningwith solutions
gas in the tissue fluids is maintained.
and continuing
of blood serum
their investigations
and haemoglobin,
of livingtissues (brain,
with extracts
heart,lungs,"c.),they
showed that at higherpressures chloroform and other anaesthetics
did not obey the ordinary
laws of solution,
althoughtheir curves,
of
examined in the lightof the phase rule,exclude the hypothesis
the formation of chemical compounds. Other anaesthetic substances
but no variation in
varied in the degreeto which this took place,
thus

kind

was

found

them.

among

ism
constitutes the mechanthat adsorption
It appears quitepossible
by which substances of narcotic nature are taken up in the

cells. Moore
serum

has

have
shown

for chloroform and

pressure curves
Gibbs
the characteristic form of adsorption
curves.
and

that

depressed
by the
it is

Roaf

the

vapour

further the

dissolved

moreover

surface

tension

of

the greaterwill be
substance,

that
generalprinciple

chemical

liquidis
its adsorption;
action

is

to concentration ; the latter will be greatestwhen

proportional
to
and, hence,distribution ratio are greatest.It seems
solubility
the presentwriters that these general
include the essential
principles

THEORIES

86

OF

HYPNOSIS

previoushypotheses.The
and the magnitude of
by adsorption,

basis of the

enters the cell

substance
its

effect

depends on

its

concentration.
but in the case of some
placeis pure conjecture,
with the so-called catalytic
be drawn
substances a parallel
may
that the rate of decomposition
of
reactions. Bredig has shown
solutions of hydrogenperoxide
by colloidalplatinumis roughlyproportional
What

takes

next

to the concentration of the latter substance ; the action is

',by the presence of traces of carbonhindered,that is ' poisoned
blood poisonsact similarly),
exception
the
before. Now
but on its removal the decomposition
as
proceeds
conversion of the total platinuminto a compound by the toxic
of
substance is out of the question,
owing to the extreme disparity
in a TV
the amounts
of the two substances. Thus, approximately,
normal solution of hydrogen peroxidecontaining
T^J^ colloidal

(almostwithout

monoxide

'

'

platinuman
to

stopthe

amount

"

-^

"

"

action. If this is comparedto the action of

action

is sufficient

"

10,000,000

instance,it will be
further

of carbon monoxide

may

seen

that after

be

compared to

has
adsorption

for
chloroform,
taken

that of carbon

placeits

monoxide

in

examplegivenabove.
r61e,bringingabout reactions
Strychninealso playsa corresponding
to the quantity
out of all proportion
employed.
It is generally
loidal
supposedthat the reaction broughtabout by colplatinumtakes placein the adsorbed layeron the surface of
will also be absorbed,
the platinumparticles
and either
; the poisons
coat and,hence,
means
by further chemical action or purelyphysical
isolate the active surface with an inert layer. The corresponding
picturewill be life processes takingplacethroughthe agency of
The actions may be depressed,
the
similar colloidal substances.
as
oxidation processes appear to be by the administration of ether or
with which
or the velocity
chloroform,
they are takingplacemay
be enormously
as perhaps
increased,
may be the case with strychnine.
has formulated
tions
a
Baglioni
theoryof narcosis based on observathe various groups of benzene
on
phenolderivatives. One of
these groups, containing
acetanilide,
phenylhydrazine,
benzylalcohol,
benzoic acid,and salicylic
benzaldehyde,
acid,proacetophenone,
duces
effectsonly,without convulsions. The amount
of
paralysing
varies inversely
of oxygen present
as to the amount
paralysis
produced
is a powerfulparalysing
in the side-chain. Thus
benzylalcohol
is less powerful,
and benzoic acid least. He
agent; benzaldehyde

the

ALCOHOLS

ALIPHATIC

87

thus concludes that narcotic effect also

dependson the power to

from the cinogen'compounds in the central
withdraw
oxygen
nervous
tion
system; that is,that narcosis is a reducing
process. Deprivaof oxygen, as by breathingCO2, or inert gases, such as hydrogen,
to chloroform
givesrise to a series of symptoms corresponding
of methylene
narcosis. Herter has shown, by means
blue injections,
that chloroform,ether and chloralhydrate
(aslikewise low temperatures)
of the tissues.
capacity
markedlydimmish the oxidizing
ALCOHOLS

THE

II.

OF

THE

ALIPHATIC

SERIES.

of alcohols may be regarded

as derived from water
by
of one hydrogenatom by an hydrocarbonradical ;
the replacement
The

group

contain the so-called hydroxylgroup, and their

they consequently
depend,to a very largeextent,upon the nature of the
properties
complexto which this is joined.
hydrocarbon
The primarycontain the group :CH2OH, the secondary
:CH.OH,
alcohols the hydroxylgroup is linked on to a
and in the tertiary
carbon
carrying no hydrogen atoms, e. g. (CH3)3C.OH. As
mentioned (p.68),the nature of their oxidation products,
previously
is dependent
of the aliphatic
the most important
derivatives,
among
such
upon the presence of these groupings.Thus a primaryalcohol,
to an
as
aldehyde,
givesrise firstly
CH8.CH2OH,
ethylalcohol,
to an
CH3 CHO, which passes, on further oxidation,
acetaldehyde,
On the other hand a secondary,
such as
acid,aceticacid,CH3COOH.
.

CH3

CH3

givesa ketone,CO

alcohol,CH.OH
*"0-propyl

CH3

CH3
whereas

ketones

or

alcohol on
tertiary

acetone,

similar treatment

breaks

down, giving

acids of smaller carbon content,e. g.

CH3

CH3

CH3.C.OH
CH3
Those alcohols which

-*

CH3.CO,
CO2,H2O

contain the radical of the aromatic

hydrocarbons
attached to hydroxyl,
as phenol,
such,for example,
C6H5.OH,
and physiologically
to
differencesboth chemically
show such striking
derivatives that they will be described separately.
the aliphatic

PREPARATION

88

ALCOHOLS

THE

OF

is
member
of the series,
Methyl alcohol,
CH3 OH, the simplest
of the dry distillation of wood.
o" the products
one
Ethyl alcohol,
C2H5OH, is obtained by the fermentation of sugar, and,as previously
is one of the chief starting-points
for the preparamentioned (p.36),
tion
derivatives. The various special
methods which
of the aliphatic
of this group will not
of members
be employedfor the synthesis
can
be described ; they are to be found in any textbook
on
organic
but the following
three generalmethods of preparation
chemistry,
are
important.
.

General

Methods

of

Preparation.

1. The

and especially
monohalogenderivatives of the paraffins,
in many
the iodides,
converted into alcohols,
are
cases
readily
by
simplyheatingwith water to a temperatureof 100"-120" ; thus
HI + C2H6.OH.
But
since the reaction is reC2H5I + H2O
versible,
H2O + C2H5I, it may not take
e.g. C2H5OH + HI
less
or
placeto any great extent,a state of equilibrium
beingmore
attained. In consequence, as a very generalrule,a base is
rapidly
requiredto combine with the liberated acid; thus with silver
hydratethe reaction may take placeat the ordinarytemperature,
whereas with lead oxide boiling
is generally
necessary.
the
In other cases
formation of the ester may
be desirable;
previous
this is obtained by the interactionof the halogenderivative with
and on decomposition
either silveror sodium acetate,
of the resulting
substance with potashor soda the alcohol is readily
e. g.
obtained,
=

A.

CH2Br

+2CH3.COOAg

CH2Br

CH2.(OOC.CH3)
+ 2AgBr
|

CH2.(OOC.CH3)

Ethylene dibromide.
B.

CH2.(OOC.CH3)

CH2

+ 2KOH

2CH3COOK

H2.(OOC.CH3)

OH

CH2.OH
Glycol.

2. Another

generalmethod

consists in

decomposingthe esters of
acid with water.
be readily
obtained
These esters may
sulphuric
the hydrocarbons
of the ethylene
series with concentrated
by treating
acid,e. g.
sulphuric
A.

CH2

||

OH

+S02/

CH0
Ethylene.

\OH

/O.C2H6

SO/

\\OH

acid.
Ethyl-sulphuric

OP

PROPERTIES
B.

SO/

THE

ALCOHOLS
OH

/".CSH5
+

H20

SO/

esters which

formed

are

by

acid
with sulphuric
hydrocarbons
to the carbon

givesCH"

CH

contain the acid radical attached

and

O.SO2OH

'

CH3

CH3

CH3

CH3

Y: CH2 gives\/CH3
C\

and

the alcohol
consequently
(CH3)3.C.OH.

/ XO.S02OH
CH3

CH3
3. Derivatives

of ammonia

the
containing

all

decomposedby nitrous acid

e. g.
replaced
by hydroxyl,

group

CH.OH
consequently
the alcohol

CH3

are

hydrogenatoms.
CH3

|
and

of

CH3

CH2

Thus

of the unsaturated

treatment

carriesthe least number

which

C2H5.OH.

\OH

\OH
The

89

C2H5NH2

HN02

group .NH2
solution and the

in aqueous

C2H6OH

amido

N2 + H20

Ethylamine.

CH3.CO.NH2

HNO2

CH3.CO.OH

Acetamide.
.O
.

2HN02

CO/

Carbonic

General

members

alcohols
of

(C02+ H20) + 2N2 + 2H2O

XNOH

Urea.

The

N2 + H2O

Acetic acid.

.2

CO/

are

acid.

Properties.

neutral colourless

series have
paraffin

compounds,and the lower

characteristic burning taste and

in water decreases
smell,and their solubility

increases. Thus

as

the carbon

content

methyl,ethyl,and propylalcohols are miscible

with water in all proportions.
Primary n- butylalcohol is soluble
in twelve parts of water.
Those containing
4-11 carbon atoms
are
oilsimmiscible with water, and the highermembers
solids.
are
Isomerism is first observed in the alcohols of the limit hydrocarbons
in the case of those derived from
propane, CH3. CH2. CH3,
which givesrise to a primaryCH3 CH2 CH2OH
and a secondary
.

THE

90

called wo-propyl
alcohol,
distinguished
easily
by

CH3. CHOH.CH3
their oxidation

ALCOHOLS

POLYHYDEIC

products.

on
depend essentially
and potassium
the presence of the hydroxylgroup.
Sodium
replace
rise
stances
subto
the hydrogenof this radical,
e. g. C2H5
ONa, giving
called alcoholates ; these are readily
decomposedby water,
are employedin many
synthetic
processes, form valuable condensing
pounds
agents,and may be used for the purpose of reducingnitro comof the
series to the
aromatic
correspondingazoxy

The

chemical characteristicsof the group

derivatives.
When

acted upon

e.
yieldthe esters,

by

acids

acid chlorides the alcohols readily

or

g.

C2H5OH
C2H6OH

+ HC1=

HN02

H20

C2H5C1

H20

C2H5 ONO2
.

Ethyl nitrite.

C2H5OH

H2S04

H20

C2H5O.S02OH
Ethyl sulphate.

C2H5OH

CH3COOH=

H2O

CH3COOC2H5
Ethyl acetate.

C2H6OH
C2H6OH

PC15

C6H5COC1

HC1+POC13

HCl-{-C6H5COOC2H5

C2H6C1

Ethyl benzoate.
acid or zinc chloride,
the
by sulphuric
dehydration,
converted into unsaturated hydrocarbons,
e. g.

On
are

CH2;H

alcohols

CH2
=

H.O+

CH2

CH2;OH
Polyhydric

Alcohols.

the
one
by hydroxyl,
hydrogenatom replaced
containing
pointed
hydrocarbonsmay have more, but it has been previously
out that,as a very general
rule,one carbon atom cannot carry more
than one hydroxylgroup.
Attempts to obtain CH3.CH(OH)2 by
for instance,
on
the action of silver hydrate,
CH3 CHC12 always
i.e.the
alcohol,
lead to the dehydration
productof the unknown
aldehyde,
Besides

H20
CHS.CH"JJJ
=

CH3CHO

PHYSIOLOGICAL

92

an
result,

PROPERTIES

effect unseen

OF

THE

ALCOHOLS

is injected
glycerol
intravenously.
Death may occur
after toxic doses by respiratory
failure.
and ketones,
with theirmarked physiological
Further,the aldehydes
become the inert sugars.
reactivity,
Caffeine loses its characteristic physiological
and it is
reaction,
that in this case, as with the others,
this decrease in
possible
towards oxidizing
reactivity
may be ascribed to the drop in stability
processes, which follows the entrance of the hydroxylgrouping.
may

The
the

alcohols act

when

the central

on

nervous

of their
cerebrum,the intensity

number

of carbon

atoms

present,and

series is

ascended,althoughto
exception.

some

on
system,in particular

actions

dependingupon the
as the homologous
increasing
extent methyl alcohol is an

Thus,in the case of rabbits :

Methyl alcohol,
CH3OH, 6-12 gms. without action.
Ethyl
C2H5OH, 7 gms. drunkenness,12 gms. sleep.
rc-Propyl
C3H7OH, 12 gms. producesleepin 5 minutes
"

"

"

and

fl-Butyl

C4H9OH,

death in 5 hours.

3 gms.

7 gms.
producedrunkenness,
sleepand death.
iso-Amyl(CH3)2CH.CH2OH, 2 gms. producedrowsiness.
The primaryalcohols are less narcotic than the secondary,
and
these less than the tertiary.
Thus :
ness.
alcohol,
J*0-propyl
CH3 CHOH.CH3, 2 gms. producedrowsi"

"

"

carbinol,CH3
Methyl-ethyl

CHOH.C2H6,

produce

gms.

drowsiness.

Diethyl

C2H5.CHOH.C2H5,

produce
sleep.
of the tertiary
In the case
alcohols the action dependson the
nature of the alkylradicals attached to the carbon atom
carrying
the hydroxyl group.
If that radical is methyl the reaction is
reaction is largely
weak, but if ethylthe physiological
relatively
increased (seep. 49),the increase varyingwith the number
of such
groups

present,thus

"

gms.

"

Trimethylcarbinol,
(CH^C.OH,

4 gms.

""ffl
\C.OH,
carbinol,
Dimethyl-ethyl
C2H5

Triethylcarbinol,
(C2H5)3C.OH,1

gm.

producesleep.
8 to
2|ms'
P
r,od,uce
9 hours'

sleep.

produces 10

hours'

(Comparethe substituted

urea

sleep.
derivatives,
p. 216.)

to

12

ACIDS

INORGANIC

OF

ESTERS

93

substituted
pinacones,
diprimaryalcohol glycol

similar characteristic is noticed in the

derivatives of the

inactive
physiologically

CH2OH
CH2OH
thus

"

(CH3)2.C.OH
producesleep.

10 gms.

Methyl pinacone,

(CH3)2.C.OH
3\f"lOTT
TV/I-

it.

C9H,/ I
^

"1.1

'

"

Methyl-ethyl
pmacone,

(C2H5)2.C.OHVery
|
Ethylpinacone,
(C2H5)2.C.OH

produce sleep.
*

gms.

^onvulsions.
|light
insoluble.

1-5

producedeeperand
sleep. 3

gms.

longer
produce

gms.
hours.

sleepafter 2
Owing

to the above

observations

Mering

introduced

amylene

hydrate,

CH3)
C.OH,

CH33
CH
in 1887

as

is obtained

hypnotic.It

from

the

unsaturated

described,
hydrocarbonamylene,by the generalmethod previously
ester. It has the hypnotic
i.e.throughthe agency of amylsulphuric
but is also liableto producesymptoms of
of an alcohol,
properties
intoxication with

and

nausea

It influencesthe heart and

DERIVATIVES

I.

like
respiration

OF
A.

Aliphatic

It is said to be

headache.

THE
Esters

THE

other

diuretic-

amyl compounds.

ALCOHOLS.

ESTERS.
of the

Halogen

of substances in which

Acids.

the

hydrogenatom
of the acids is replaced
by an organicradical ; they consequently
acids,
belongto two groups, (1)those obtained from the inorganic
acids
and (2)those derived from the organic
(seep. 122).
and the latter in
The former onlywill be discussed at this point,
If the halogenacids,
connexion with the organic
acids themselves.
it will be
be considered,
hydrochloric,
hydrobromicand hydriodic
the hydrogenby the radicals of the paraffins,
that on replacing
seen
The esters

are

group

this group
From
"c.
upon
thus

as

of substances

ESTERS

may be looked
the halogensubstitution productsof the limit hydrocarbons,

CH4

as

THE

thus HC1 givesCH3.C1 or C2H5C1,

results,

another

pointof

acted upon

by

CH4
But

OF

PROPERTIES

AND

PREPARATION

94

the alcohols

former view may

be

C12

givesCH3C1,
HC1

CH3C1.
in their

used
invariably
and the two
adopted,

the
preparation
reactions compared

are

+ HCl=NaCl

+ HO

General

The

chlorine
+

these derivatives

view

methods

of

preparation.

interaction of the alcohols and

or
hydrochloric
hydrois not
of
bromic acid is reversible and
unless
one
complete
is removed
formed
from the sphereof reaction.
the substances
of methyl or ethyl alcohol,zinc chloride or
in the case
Thus
the water formed.
acid may be employedto remove
But
sulphuric
with the higheralcohols unsaturated hydrocarbons
may be firstly
that
formed,and these add on the halogenacid in such a manner
isomers of the desired esters are obtained. Further,hydriodic
acid,
is
when in excess,
capableof reducingthe iodides.
especially
2. The phosphorushalogen derivatives readily
react with the
alcohols,
givingrise to substances of this class,

1.

PBr3 + 3C2H6OH

3C2H6Br + H3PO3

Phosphorus tribromide.

PI3+ 3C2H5OH

3C2H6I + H3PO3

Phosphorus tri-iodide.
chloride.
givesthe corresponding
phosphoruspentachloride
easily

General

The

esters

almost
liquids,

of the

Properties.

halogenacids

insoluble in water.

are

The

etherial,
pleasant-smelling
lower

members

are

gases

and
ordinarytemperatures,
ethylchloride,
e.g. methyl chloride,
The
chlorides boil 20"-28" lower than the
methyl bromide.
at

bromides,and

these

28"-34" lower

than

the

iodides.
corresponding
Their stability
decreases from the chlorides to the iodides,
and
their reactivity
increases in the same
direction. They
consequently
the iodides,
well adapted,
to the most varied series of
are
especially
of which
have been previously
described
reactions,
synthetic
many

(p.37).

PHYSIOLOGICAL

General

PROPERTIES

characteristics

Physiological

following

entrance

Chlorine.

of

The

95

aliphatic
compounds increases their
creases
heart, and as a very general rule in-

of chlorine into

entrance

depressanteffect

the

on

Their toxic

their narcotic action.

action appears

to

stand

their narcotic

and the latter to

properties,
of chlorine present. Thus methylchloride,
increase with the amount
CH2C12, and this less
CH3C1, is less toxic than methylenechloride,
than chloroform,CHC13 ; the fullychlorinated methane
derivative
carbon tetrachloride,
slowlyand persistently
CC14;acts much more
than chloroform,and is usuallystated to be a more
powerful heart
depressant,
althoughCushny describes it as only half as powerful as
chloroform.
Considerable interest consequently
lies in the investigation

in direct

to
relationship

the

of

substance
a

which

stimulant

be

acts

action

In moderate

followingthe

results

on

as

producedby

local

chlorine into

Thus

system and

nervous

doses it also stimulates

the

of

stimulant.

heart

the central

entrance

the

heart,an

of solutions
application

caffeine has
is

diuretic.

effect which

can

of caffeine to the

frog'sheart. Chlorcaffeine is a much feebler cardiac stimulant ; the

other actions of caffeine,
however, are still present(Pickering).
Then

narcotic

but the chlorhydrins

is physiologically
have
glycerin
inert,
action and produce paralysis
and dilation of the vessels.

Monochlorhydrin,
CH2OH.CHOH.CH2C1,
hydrin,CH2C1.CHC1.CH2C1, the most

is the least and

trichlor-

toxic.

increase in narcotic

The

properties
followingthe entrance of
led to the introduction of trichlorisopropyl
alcohol Isopral,
chlorine,
This substance may
be
CC13 CHOH.CH3, by Impens in 1903.
formed
by the action of methyl magnesium iodide (Grignard's
of the resulting
reagent,see p. 38) on chloral and the decomposition
substance by water,
.

A.

CH3

Mg.I

CC13CHO

CC13

C^OMgl
\CH3

/K

J3.

CC13

but

H20
C^-OMgl

its action

on

the

it cannot
consequently

heart
be

Mgl

is

more

given in

OH
.

CC1S.C^-OH

powerful than chloral,and

heart disease.

Similarly
alcohol,
trichlorbutyl

ESTERS

96

has been

Chloretone

hypnotic.It

HYDROCHLORIC

OF

introduced

is also known

as

an

ACID
and
anaesthetic,
antiseptic,

(aone

per cent,
It is not a very toxic substance,
solution of acetone chloroform).
the
dose being "3 to 1-5 gm.; the solutions have a local anaesthetic

action.
from

It

as

does
apparently

not

or

aneson

anesin

differ in its

action
physiological

other chlorine narcotics.

The

above

givesa generalindication of

results
physiological
the introduction of chlorine into organicsubstances ; the
following
effect of the entrance of this member
of the halogenseries,
as well
into other groups, such as the aldehydes
bromine and iodine,
and
as
will be described after the discussion of those derivatives.
acids,

Esters

of

Hydrochloric

the

Acid.

Ethyl chloride,
C2H5C1,and ethylbromide have been employed
as
generalanaesthetics ; a mixture of these and methylchloride is
Webster
known
as somnoform.
June, 1906)
Journal,
(Biochemical
these drugs,and also ethyliodide,
which,owing to its
investigated
is unsuitable for clinicalpurposes.
taste and its volatility,
unpleasant
is apparently
There
action of
difference in the physiological
no
these drugs beyond what
be attributed to their varying
may
With
time before
ceases
some
volatility.
largedoses respiration
the heart. Blood pressure after a short preliminary
rise is considerably
this
due
the
action
to
the
on
depressed, being
depressant
No action on the vagus endingswas
cardiac pump.
demonstrated,
though Cole (B.M.J.,1903, i, p. 1421) found that the vagus
liable
terminations were
paralysed.Somnoform
appears especially
failure.
to cause
respiratory
Ethyl chloride is twice as soluble in blood as in water, and experiments
action on
with dogs showed that its vapour has a paralytic
the heart muscle but that nineteen times as much
is required
to
effectas chloroform.
producethe same
Chloroform,CHC13, is obtained by the action of bleaching
powder
on

dilute alcohol

of alcohol at
washed

with

45"

or

acetone

C., and

water,

the

treated

the reaction

commences

chloroform

formed

with

concentrated

destroyother

chlorinated derivatives such

rectified. In

all

alcohol
probability

is

in the

is distilled

sulphuricacid

the presence of calcium

In the case of acetone,the

into chloroform.

intermediate

to

those of

is
hydrate,

probablyCC13 CO.CH3,

off,

ethane,and
oxidized to chloral,
firstly
as

CClgCHO, which, in
is

case

which then breaks down

converted

product

into chloroform

PROPERTIES

PHYSIOLOGICAL

97

preparation
may be obtained by the
soluble in water,
action of alkalis on chloral. It is only slightly
1 litre of saturated solution at ordinarytemperaturescontaining
is not
The pure preparation
of chloroform.
about
7 gms.
very
chloric
breaking down into the very toxic phosgene,COC12, hydrostable,
which is much
acid and chlorine ; the officialpreparation,
made
from
contains a trace of ethylalcohol,
or when
more
stable,
acetone a small quantityof that substance; both these in the
amounts
inert,and there is no reason
presentare physiologically
why chloroform preparedfrom ethylalcohol should in any way be
to that obtained from acetone.
preferred
and P. Woog have found that chloroform may be kept
Breteau
in ordinaryglass bottles in diffused daylightwithout
suffering
if any of the followingsubstances are added in
decomposition,
Oil of turpentine,
of 2-4 partsper 1,000 :
proportion
pure spermaceti,
and thymol.
menthol salicylate,
menthol geraniol,
of chloroform
The theories as to the narcotic or anaesthetic properties
have been discussed in the generalintroduction to the narcotic
as
delayedchloroform poisoning
compounds. The symptoms known
',which include a remarkable fattyinfiltrationof the liver and
in reality
those of an acid intoxication.
not infrequently
are
are
fatal,
Diminished
met with after other anaesthetics.
They are occasionally
oxidation processes characterize the action of allthe halogennarcotics;
it is supposedthat the imperfect
oxidation of the body fats gives
of these
rise to acids of the fattyseries,
and hence the production
depend on the narcosis,
symptoms. The action does not apparently
but is a special
propertyof this class of drugs.
Carbon tetrachloride,
CC14,which was originally
investigated
by
in
the
of
others
and
made
the
was
Simpson
earlydays anaesthesia,
who
found that the
subjectof more recent experimentby Marshall,
differences in action between this body and chloroform were
mainly
due to its physical
characters. It is,however, more
toxic and more
membrane
to the mucous
of the trachea and bronchi.
irritating
Recentlyit has been employed by hairdressers to clean the hair,
and a case
of accidental poisoningowing to the inhalation of the
has been reported(Lancet,
1907, i. 1725). This case was
vapour
and very nearlyhad a fatal termination.
serious,
apparently
Dichlorethane,
CH3 CHC12, the symmetricalderivative ethylene
dichloride,
CH2C1.CH2C1,and trichlorethane or methyl chloroform,
CH3 CC13,have all a very similar action to chloroform.
and acetic acid.

much

purer

"

"

ESTERS

98

HYDROBROMIC

OF

Esters

of

Hydrobromic

ACID

Acid.

alkylbromides have a similar action to the chlorides ;

thus methyl bromide, CH3Br, and ethylbromide, C2H5Br, have
and are only slightly
anaesthetic properties,
toxic,but the latter
irritation of the respiratory
substance produces
passages to a greater
chlorine derivative. The narcosis
than the corresponding
extent
producedby ethylbromide differs from that of chloroform,since it
but also ceases
sets in more
more
quickly.This is in agreerapidly,
ment
narcosis
is
which
with Schleich's theory,
to
deeper
according
the higher the boiling-point
of the anaesthetic
and lasts longer,
of ethylbromide
38",chloroform
61").
(boiling-point
The lower

Bromoform, CHBr3, has a narcotic action,and

and
1889 by Stepp in whooping-coughof children,
It is

asthma.
similar

preparedfrom

either alcohol

or

firstused in

was

also in

acetone

of

cases

in

very

to chloroform.

manner

ethylenedibromide, C2H4Br2, the toxicityincreases; the

of the
and it tends to cause
anaesthetic action is slight,
paralysis
In

extremities and
action
peculiar

breathe,and
of

It is stated

have

to

the desire
centre,diminishing
respiratory
been suggestedthat it might
consequently

the

on

it has

advantagein
The

stoppage of the heart.

to

be

asthma.
derivatives

bromine

being

less stable than

the

chlorine

and many
rapidly,
decompose more
attempts have been made to
employ such compoundsin placeof potassiumbromide in epilepsy,
the depressanteffects of this salt. Up
with the hope of avoiding
to the

however,no substitute
present,

has

been

found ; thus

hexa-

(CH2)6N4.CH3Br,
(bromalin),
methylene^tetramine-brommethylate
has not the desired effect ; the sedative action is much less than that
after-effects.
of potassiumbromide,as are also the unpleasant
has no advantage
over
bromide; it reacts
Tribromhydrin,
C3H6Br9,
It is also an
to the corresponding
trichlorhydrin.
very similarly

intestinalirritant.

useless.

is

compound

of bromine

with

oil

(seealso
which liberates the element slowlyin the organism.
lodipin),
in the
The disadvantage
of the organicbromine
preparations
of
of epilepsy
is that,althougha considerable amount
treatment
it is presentin such a form that only
bromine may be administered,
set free in the body at a time ; consequently,
small quantities
are
when it is desirable to producea rapideffect these preparations
are
Bromipin

sesame

ESTERS

100

of

Esters

II.

Nitrous

The nitrous acid esters may

acid on the alcohols,
e. g.

C2H50;H
They

ACIDS

and

be obtained

6H;NO

by

the action of nitrous

C2H5O.NO

Acid.

Nitric

characteristic smell,and

with
liquids

are

NITROGEN

THE

OF

H2O.

are

decomposed
readily

alcohol and alkaline nitrite.

corresponding
nitroethane,
e. g.
They are isomeric with the nitro paraffins,
C2H6NO2, but these on reduction yieldamines,C2H5NH2, whereas
nitrous ethylester is saponified,
the corresponding
yieldingethyl
alcohol,
C2H5OH.

by

The

alkalis into the

of nitric acid result from

esters

the interaction of alcohols

and nitric acid,e. g.

C2H50:H

OH:N02

H20

C2H5O.N02.

when
exploding
liquids,
They are pleasant-smelling
and easily
givingalcohol and
by alkalis,
saponified

Physiological
As
a

rule,the
general

entrance

rapidlyheated,
alkaline nitrate.

Properties.
of the nitro

or

nitroso group

of the
molecule increases its toxicity,
irrespective

manner

into

in which

through oxygen as in the esters,

as in nitroso and nitro paraffins.
or direct to carbon
The nitrous esters of the fattyseries do not act on the vasothe vessels,
motor
centre but directly
on
causingpowerfulexpansion.
Cash and Dunstan
specimensof
carefully-prepared
investigated
i.e.
the principal
nitrous esters. They found that,as regards
effect,
of various nitrites took the
reduction of blood pressure, the activity
administered
to animals
followingorder when equalvolumes were
by inhalation: (1) Secondary propyl,(2) tertiarybutyl,(3)
equal),
amyl,
(5)tertiary
secondarybutyl,(4) w0-butyl(nearly
(8)methyl,(9) butyl,(10)
(6) a-amyl,(7)/9-amyl(nearlyequal),
modified when
the
ethyl,(11)propyl. This order is somewhat
the duration
When
nitritesare givenby intra-vascular injections.
the order is nearlythe reverse
of subnormal pressure is considered,
and
of that givenabove ; the effect of methyl nitritebeingthe last,
propylone of the firstto disappear.
secondary

the

linkageis

effected ; whether

"

In
in

man

some

animals toxic effects in the tissueshave been

and
owing to blood changes,methaemoglobin
haemoglobinbeingformed.

death

nitric oxide

but
observed,

occurs

PROPERTIES

PHYSIOLOGICAL

Divergentviews
nitrites on

have

been held

the tissue cells; Loew

as

\ ; :.

101

to the chemical action of the

considers that

combination

molecule ; Marshall,
group of the protein
Haldane,and others consider that the nitrous acid esters act directly.
the amide

with

occurs

considers that

Binz

nitric oxide is formed

unchangedin the urine.

:
Bradburyinvestigated
CH,
Methyl nitrate
CHS
Ethylenedinitrate

small

portionis

excreted

ON02
ON00

EL.O.NO,

Nitroglycerin

CH2O.N02
CHO.

N02

H2O.N02
tetranitrate
Erythrol

CH2ON02

(CH.O.NO^

Mannitol

hexanitrate

CH2ON02
CH2ON02
fCH.
(CH.ON02)4
CH, ONO,

Erythroltetranitrateis less powerfulthan amyl nitrile or nitrobut its effects are more
prolonged
glycerin,
; mannitol hexanitrate
but its action may
is not nearly
be more
so
powerful,
prolonged.
Its main advantageis its comparatively
low cost.
mannitol pentanitrate
intermediate in action
Marshall found
between

the two.

absorbed into the blood unchanged,

is practically
Nitroglycerin
hence its powerful
action (Brunton).
and prolonged
the nitro group
is linked directly
When
Nitro
to
Paraffins.
different
an
carbon,as for instance the nitro paraffins,
entirely
reaction appears. Nitro ethane,
physiological
C2H5NO2, for instance,
has no action at all on the blood vessels,
althougha toxic substance,
death in relatively
small
and, like nitromethane,
CH3NO2, causes
doses.
Nitro

Derivatives

nitro group

of Aromatic

Series.

The

introduction of the

into the aromatic series (p.40) also raisesthe

toxicity

OF

ESTERS

102

ACIDS

SULPHUR

THE

nitrobenzene produces tremors

Thus
resultingsubstance.
and eventually
and increased reflexes,
coma.
to nitrobenzene.
similar manner
Nitrothiopheneacts in a precisely
Nitronaphtholis toxic in small doses,either given by the mouth
or
subcutaneously.On the other hand ^"-nitrotoluene,

in

the

is almost

non-toxic.

and nitrobenzene
hydroxylamine,
Nitroglycerin,
central nervous
system ; the action on the blood

chief toxic action of dinitrobenzene

of

is

of toxic
acids

which
nitrobenzaldehydes,

entrance

or

in the

decrease

the

case

converted

are

of

the
The

cells.

entire loss

or

nitrobenzoic

into acids

(p.77)

body.
of

Esters

III.

is acted
sulphite
sulphurousacid results,

Ag.S02OAg

and

Sulphurous

silver

When

of

is

the red blood

on

negativegroup causes
properties,
as, for instance,in

The

on
chiefly
secondary.

act

2C2H5l

Acids.

the ethylester
by ethyliodide,

upon

2AgI

Sulphuric

C2H5.S02OC2H6.

regardedas the derivatives of unsymmetrical

sulphurousacid ; they are decomposedby potashwith the formation
of ethylsulphonic
acid,
Such

esters

be

may

C2H5SO2OC2H5
In the aromatic

H2O

C2H6SO2OH

C2H5OH.

series the

corresponding
sulphonicacids are of very
and are
much
formed
greater importance,
by the direct action of
acid upon the benzene
derivatives,
sulphuric

C6H6;H + OHjSO2OH
This

with

very

H2O

C6H5.SO2OH.

the sulphonic
acid
introducing

largenumber

of substituted

aromatic

group

can

be used

and
derivatives,

soluble in water or whose sodium

group of substances
is soluble
in that liquid,
factor of importance in the dye
a

givesrise to
salt

of

method

industry.
The
esters

interaction of
which

alcohol

are

much

sulphuricacid
less stable than

givesthe ethylester

of

and
the

the alcohols

gives rise to
sulphonicacids. Ethyl

acid
sulphuric

THE

givesthe

Phenol

the

Unlike

103

ETHERS

ester

derivatives,the

previouslymentioned

radical is attached to oxygen,

and

in consequence

hydrocarbon
they are readily

acid and alcohol.

regenerating
decomposedby alkalis,
The introduction of these acidic groupingsinto organicsubstances
thus the toxic
results in a great drop in pharmacological
activity,
acid,
phenol givesthe inert phenolsulphonic
OH

or

the

equallyinert phenylsulphuricester (seep. 56),

OC6H,
OH

of morphia are modified and considerably

hypnoticproperties
in its sulphuric
ester.
weakened
is toxic,whereas
its sulphonicacid
Phenyl-dimethyl-pyrazol
derivative given in doses of 5-6 gms. to rabbits producesno effect.
its sulphonic
is toxic in small doses,whereas
Dinitro-naphthol
The

acid is inert.
Ehrlich's observation
to note in this connexion
interesting
basic dyes stain the cortical nerve
whereas their sulphonic
cells,

It is
that

acids do not.
B.
The

ethers

are

ETHERS.

THE

derivatives of the alcohols in which

the

hydrogen

garded
or
they may be rereplacedby alkyls,
have
derivatives of water in which both hydrogen atoms
as
been replaced
by similar or dissimilar groups ; they are consequently
classifiedas simple,such as ethyl ether,C2H6 0.C2H6 ; or mixed,
such as methyl ethylether,CH3
0.C2H5.
1. Their most
important method of preparationconsists in the
interaction of sulphuric
acid and the alcohols. Thus

of the

hydroxylgroup

is

A.

S"
The

ethyl ester of
sulphuricacid.

stagea different
ester and a mixed
sulphuric
or

OF

PROPERTIES

PHYSIOLOGICAL

104

at this

alcohol may
be allowed
ether obtained thus

CH3OH

ETHERS

THE

to react with the

SO

liquids,
only slightlysoluble in
and
the
The
lowest members
water.
liquids,
are
gases, the next
lower than
those of
much
are
highestsolids ; their boiling-points
chemical standpoint
alcohols. From
the corresponding
a
they show
attached
to
since all the hydrogen atoms
but slight
are
reactivity,
carbon.
Although not easilyattacked by oxidizingagents,they
products as their corresponding
yield,when oxidized,the same
The

ethers

neutral
volatile,

are

alcohols.

Physiological
The

Properties.
in the

replacementof hydrogen

alcohols results in the

formation

towards

processes

the oxidation

members

of the series are

of substances
of the

used

more

hydroxyl group

as

body.

much

The

stable

more

lower

the

of

volatile

anaesthetics than

hypnotics.
oxide,producinga

Dimethyl ether,(CH3)2O,acts very like nitrous

rapidand transient anaesthesia.
well
The
of diethylether,(C2H5)2O,
anaesthetic properties
are
Its action is discussed in the generalintroduction to the
known.
narcotic
The

bodies.
mixed

ethers
aliphatic

have

not

been

be of considerable interest to find out

would

and it
investigated,
whether
methyl ethyl

ether,CH3 O C2H6, which in the pure state boils at 11" C.,has

ordinarydiethylether.
any advantagesover
As the molecular magnitude of the ethers increases,
their physiological
.

reaction becomes

is

less.

Methylal,CH2(OC2H3)2,producesanaesthesia slowly; the action

and patients
prolongedand deep but somewhat
uncertain,
quickly

become

accustomed

to it.

Acetal,CH3CH(OC2H5)2,

unpleasantcardiac
The

mixed

aromatic

is also

symptoms

an

and

uncertain

and
hypnotic,

duces
pro-

considerable excitement.

ethers,such for instance as phenealiphatic

tol, C6H0 0.C2H5, are not comparable to the simple aliphatic
without anaesthetic
ethers,and the derivative mentioned is entirely
.

action.

CHAPTEE
THE

ALCOHOLS

AND

DERIVATIVES

THEIR

physiologicalcharacteristics

and

Acids.

The

derivatives

Esters,Amides,

of

Nitriles.

are
aldehydes

and
alcohols,

the

OF

PRODUCTS
I.

THE

of

Acids.

Sulphur derivatives.

OXIDATION

THE

the

(continued). The chemical

Aldehydes, Ketones, Sulphones,
Halogen substitution products,

THE

ALCOHOLS.

THE

ALDEHYDES.

the first oxidation

contain the group

(CHO)'

productsof
linked

the

to

on

primary

an

organic

radical.

They may be obtained :

which
1. By the oxidation of the primaryalcohol,
placeon warming them with potassiumbichromate
acid,
"

CH.CHOH
or

-"

C6H6CH2OH

C6H5.CHO

-"

Benzyl alcohol.
2.

Aldehydesof

both

takes
readily
and sulphuric

and
aliphatic

Benzaldehyde.
obtained

aromatic series are

the distillationof the lime salts of the

by

acids with calcium

respective

formate,

or

3.

(CH3COO)2Ca + (H.COO)2Ca

2CaCO3 + 2CH3COH

(C6H5COO)2Ca+ (H.COO)2Ca

2CaCO3 + 2C6H6COH.

Aldehydesof

the aromatic series are

obtained

by

the action of

Thus
chromyl chloride,
CrO2Cl2,upon the homologous benzenes.
toluene givesfirstly
addition product,
a brown
C6H5CH3 (CrO2Cl2)2,
which is decomposed
into benzaldehyde,
C6H6 CHO, by the action
.

of water.
The

gous
of an homoloproperties
physical
series : the lower are volatileliquids
soluble in water, but as
the molecular magnitude increases,
in that medium
their solubility
becomes less and eventually
and at the same
time theydecompose
nil,
exhibit
aldehydes

the usual

ALIPHATIC

106

AND

ALDEHYDES

AROMATIC

distillationat

In chemical respects
ordinary
they are
pressures.
neutral substances characterized by their great reactivity.
They
ducing
readily
acids,and in consequence are powerfulrepass to carboxylic
to a greaterextent than the aromatic :
agents the aliphatic
on

"

CH3.CHO
C6H6CHO
The

majorityof

the

reduction

CH3COOH

+ 0

C6H5COOH.
converted into resins

are
aldehydes
aliphatic

but those of
by the alkalis,
of acid and alcohol,
e.g.
2C6H5CHO + KOH

On

+ O

seriesgiverise to

the aromatic

C6H5COOK

mixture

C6H5CH2OH.

theyyieldprimaryalcohols :
R.CHO
R.CH2OH.
+ 2H
=

circumstances they do not unite with water,but

ordinary
of their halogensubstitution productsyieldreadily-decomposable
hydrates;e.g. chloral,
CC13.CHO, giveschloral hydrate,

Under
many

CH"^

CC13

They unite
acids,
e.g.

with

acid,formingthe
prussic

CHXHO

+ HCN

nitrilesof the

hydroxy

Nitrile of lactic acid.

Nitrile of mandelic
with

Similarly
they combine
derivatives that may

With
may

ammonia

be

line
bisulphite,
formingcrystalpurification

employedfor their

"

the

also form compoundswhich

aliphatic
aldehydes
similarly
employedfor their purification,

CH3CHO
but with the aromatic

K.CHO

NHa

amines

Aldehydes of both
hydroxylamine,
or

be

sodium

acid.

series

reaction
complicated

more

combine

H2N.NHC6H6

ECHO

CH3.

H2N.OH

with

occurs.

and
phenylhydrazine

E.CH

N.NHC6H5

RCH

N.OH

H2O.

H2O

108

THE

ALDEHYDES

of sufficientstrengthcan
be employed in this manner
antiseptic
without producingtoxic symptoms. Experimentsad hoc by one
of the presentwriters will be found in the Guy's Hospital
Reports,
vol. Iviii. Recently,formic acid and the formates have been
credited with tonic properties,
but the clinical evidence is as yet
meagre.
The
off

formylcompound of

urea,

CO(N

CH2)2,which slowlybreaks

and
formaldehyde

possesses no smell,has been introduced.

have also been formed between formaldehyde
and

the
Compounds
such as
antiseptic
group of phenols,
eugenol,thymol, and iodo
thymol; these readilybreak down into their components,and a
combined action of antiseptic
substances is obtained.
When
ammonia
acts on formaldehyde,
hexamethylenetetramine
results. This also in all probability
liberatesformaldehydein the
body,and to this may be ascribed its value as a urinaryantiseptic
;
it limits suppuration
anywhere along the urinarytract from the
and on this account is the best
kidneysto the orificeof the urethra,
we
urinaryantiseptic
possess. It goes by a number of trade names,
namely, urotropine, aminoform, formin, cystamine, cystogen,
metramine,

uretone,

urisol, and

vesaloine.

has
Paraldehyde,a polymericform of acetaldehyde,
of a very unpleasant
odour and taste. It acts

advantage
the disfirst on

the

highercerebral centres and then on other parts of the central

anaesthesia and death.
nervous
It
system,finally
producingspinal
has

action on the heart (cf.

and it may be
depressant
chloral),
is its
given for long periodswith safety.Its main disadvantage
irritant action on the gastric
It has antiseptic
mucosa.
powers,
like acetaldehyde,
and can
be combined with starch,
dextrine,
"c.,
to form antiseptic
applications.
no

Physiological Characteristics
Products

The

entrance

of the

of

Halogen

Substitution

Aldehydes.

of -chlorineinto

with
acetaldehyde
or
chloral,
trichloracetaldehyde
CC13 CHO, causes

the formation of

largeincrease
in narcotic power, but the simultaneous
action of the halogenis
of cardiac and respiratory
centres.
observed,viz.,
depression
That
the
action of chloral is due
to both
halogen and
aldehydegroups is seen by the fact that on oxidation to trichloracetic acid,CC13 COOH,
reaction disappears,
the physiological
whereas on reduction to trichlorethyl
stance
alcohol,
CC13 CH2OH, a subwith narcotic properties
is obtained,
althoughthese are much
a

OF

DERIVATIVES

HALOGEN

THE

ALDEHYDES

chloral.
original
by comparing chloral

than those of the

less powerful

109

The action of the

with paraldehyde,
be traced
chlorine may
action on cardiac and respiratory
since the latter has no depressant
and indeed is said to act as a mild cardiac tonic.
activity,
discovered in 1832 by Liebig,and is
CC13CHO, was
Chloral,
obtained by the action of chlorine upon alcohol;the reaction is
and will be found discussed in works on
organic
complicated,
which polymerizes
liquid,
chemistry. It is an oily,pungent-smelling
it combines with water,
on
keeping. Unlike acetaldehyde
derivative,
forminga crystalline

CCl3CH""g
substance which,contraryto the generalrule,
a
hydrate,
contains two
hydroxylgroups linked into one carbon atom. It
dilute solutions of alkali,
yieldschloroform with even
readily
this that led
it was
CHCl3 + H.COOK,and
CCl3.CHO + KOH
chloral

Liebreich in 1869

supposedthat

this

it might be
hypnoticaction,%since
would take placein the body;
decomposition

to

try

its

however,shown later that chloral is reduced to trichlorethyl

stance
alcohol,
CC13COH, and is eliminated as a derivative of this sub-

it was,

and

the
acid (seep. 60); consequently
glycuronic

old idea

reaction had to be abandoned.

of its physiological

powerfulaction than
but the effectspass off more
chloral,
rapidly.Butyl chloral hydrate
certain.
is said not to depressthe heart,but this is by no means
effect on the fifth nerve.
for its specific
There is no explanation
and pyramidon.
Trigemin is a compound of butylchloral hydrate
and
brom
iodo substitution productsof
The
corresponding
show very considerably
diminished hypnoticaction.
acetaldehyde
irritation of the
Bromal, CBr3 CH(OH)2, in animals causes
respiratory
passages, and in largerdoses dyspnoeaand cyanosis;
stilllarger
doses produceanaesthesia but not hypnosis.
of bromine by iodine
lodal,CI3.CH(OH)2. The replacement
and
nerve-endings
appears to increase the action upon peripheral
muscles,but the substance has only slighthypnoticproperties.
The mono-iodo derivative CH2I.CH(OH)2 has not such a powerful
action as chloral,
but has a strongdepressant
action on the heart.
of the aldehydegroupingin chloral it is
Owing to the reactivity
to modify the substance in various directions;
possible
up to the
presentit has been found that all those derivatives which easily
off chloral in the organismshow the ordinary
chloral reaction,
split
Butyl chloral,
CC13 CH2
.

CHO, has

more

HALOGEN

110

whereas
or

the

givenany

OF

stable either do

more

very

THE

ALDEHYDES

possess hypnoticproperties
with other hypnotics
have

not

Combinations

toxic substances.

are

not

DERIVATIVES

thus
results,
striking-

chloral

alcoholate,

CC1*-CH\OC2H6)
by the addition of chloral and alcohol has no advantages
the hydrateitself.
over
Dormiol, introduced by Fuchs,and formed by the union of chloral
and amyl alcohol,
formed

.OH

yCHg
CCL

CHO

OH-C"-CH3
\r

CCL

if

CH"nu

p/
"

25

being easilybroken down,

very stable,
It has a
solution in water, into its constituents.

is not

and

taste,and its action is

Chloral urethane

not

probablyeven
by
smell
penetrating

reliable.

(ural,soninal),

CC13-^\NH.COOC2H6,
preparedin
might be added

the

hope that

hypnoticeffects of ethylurethane
to that of chloral.
An
on
apparentlyidentical
off before the
The hypnoticeffect wears
body is known as nralinm.
of the hindquarters
the
toxic,and in animals paralysis
accompanies
salivation,
itching,
sleepinduced by the drug. Diarrhoea,diuresis,
of
and disturbances
are
respiration
producedby largedoses.
chloral was
combined with acetone, which has a slight
Similarly,
but the resulting
chloral acetone,
narcotic action,
substance,
was

the

CC13 CHOH.CH2
.

CO.CH3

and in the organism is dehydrated

possesses but littlenarcotic action,
On the other
with formation of CC13.CH : CH.CO.CH3.
aromatic
derivative chloral acetophenone,
corresponding
CC13.CH.OH.CH2. CO.C6H5 (thecombination with acetophenone,
has not the slightest
but
hypnoticaction,
a
powerfulhypnotic),

hand

the

like the

compound
previous

it is eliminated

as

CC13.CH: CH.CO.C6H5.
Then, in another

compoundof
amide.

direction,
Mering and
formamide and chloral,
chloral

This is formed
CCL.CHO

by

the direct union

+ H.CONHo

Zuntz

introduced

formamide,
of the

two,

or

the

chloral

DERIVATIVES

ALDEHYDE
a

reaction which

does

derivative has

acetaldehyde.This

but
chloral,

action than

harmful

take

not

111

place with the unsubstituted

a
slightlybitter taste,less
the other hand

on

Since urochloralicacid is found in

hypnoticpower.
in
action probably
dependson its slow decomposition

much

less

the

urine,its

the

organism

into chloral itself.

Chloral

ammonia,
CC1'CH

"vNTH2,

was

intended to combine

with

the stimulant action of ammonia

the

hypnoticaction
on

of chloral

the heart and

hydrate
respiration.

productsof chloral with various aldoximes and

ketoximes have givenproducts
of no pharmacological
value. These
formed according
to the general
reaction
derivatives,
The

condensation

N.OH

CC13

CHO

C.C13

soluble in water.
slightly
from the condensation
The productsresulting
various sugars have been investigated
by Hauriot

are

but

of chloral with
and

Eichet,and

others.

Milk-sugarchloralide has

no

tiform fitswith bronchorrhoea

narcotic

but produces
action,
epilep-

and

asphyxia.
and glucose
combined as chloralose,
are
water)
but is less easily
rapidhypnotic,
C8HnCl3O6. It is a somewhat
tolerated than chloral hydrate.It may producerestlessness,
diplopia,
and
main
I
ts
is
toxic
action
the retremors,
on
haemoglobinuria.
spiratory
from
Chloral (free

Eichet says it acts on the grey matter of the cortex

the cord being unaffected. The uncertain results are said
cerebri,
centre.

to be due

to the formation of

which is toxic without

and
excitement,

has

second

compound, parachloralose,

beinghypnotic.

Arabino-chloralose is
of

easilysoluble
minimum

in

water, producesno

stage

lethal dose

equalto twice that

chloralose. It is,however,a much
less powerfulhypnotic.
A second compound,pararabinois onlyslightly
soluble.
chloralose,
The
pentose compounds are probablyless active and less toxic
in the body.
owing to their greaterstability
When
chloral reacts with antipyrine
several substances result
hypnal,C13H15N2O3C13,
meltingat 67"-68",and chloralantipyrin
formed at a highertemperatureand possessing
C13H13C13N2O2,
no
reaction. Hypnal
has a similar toxic and hypnotic
physiological
action to chloral hydrate. The toxic dose is the same, so that the
a

of

"

THE

112

KETONES

of the chloral.
heightensthe toxicity
presence of antipyrin
used as an analgesic
a hypnotic.
as well as

products of choral with

have little or no
by Tappeiner,
hypnotics,investigated
The

various

condensation

It is

aromatic

logical
physio-

reaction.
II.
ketones

The

are

THE

KETONES.
of substances

group
contain the

closelyrelated

to the

both
carboxylgroup linked,in the case of
aldehydes,
the former compounds,to alkylgroup, but in the case of aldehydes
to an alkyl
group and hydrogen.

CH3

CH3
Dimethylketone,

CO

CO

Acetaldehyde.

will be noticed in their more

relationships
and generalreactions. They
preparation

The
of

in
classes,

two

similar

CO.CH3
CH3.CO.C2H5.
They are formed by

acetone,CH3

to

the

Mixed,

such

manner

; and

the oxidation of

CH3.CHOH.CH3

importantmethods

may
ethers :
as

be divided into

Simple,such as
methyl ethylketone,

alcohols,
secondary

-"

CH3.CO.CH3

-"

C6H5.CO.CH3

alcohol.
Iso-propyl

C6H5 CHOH.CH3
.

Phenylmethyl carbinol.
or

by

Acetophenone.

the distillationof the lime-salt of the

(CH3COO)2Ca
(C6H5COO)2Ca
ketones

whereas the mixed

acid,
corresponding

CaC03 + CH3COCH3
CaCO3 + C6H5.CO.C6H5

are

obtained from the lime-salt of two

acids,

(C2H3COO)2Ca

2CH3. CO.C2H5 + CaCO3

(C6H6COO)2Ca+ (CH3COO),Ca

2C6H6COCH3

(CH3COO)2Ca
The

series

ketones
are

are

volatile

readilyoxidized

2CaCO3.

neutral

bodies,and the lower members of the

etherial-smelling
liquids.They are much less

than

substances do not

the

and
aldehydes,
polymerize.

unlike

that

group

of

PROPERTIES

PHYSIOLOGICAL
Their reactionswith

acid resemble very

and prussic
phenylhydrazine,
hydroxylamine,

of the

those
closely

(CH3)2CO+ H2N.NHC6H5
C6H6CO.CH3 + H2N.OH
CH3.CO.CH3

113

+ HCN

previous
group,

(CH3)2C: N.NHC6H5 + H2O

C6H5 C(N.OH).CH3

react with sodium bisulphite,

a methyl group
containing
be employedfor puriderivatives which may
fication
formingcrystalline
owing to the ease with which they are obtained,and
then decomposedby acids or alkalis with the recovery of the

Those

ketone.

CH3.CO.CH3

NaHS03

and

Physiological

Characteristics.

action closely
resemble the
generalphysiological
alcohols,
they give rise to narcosis and loweringof the blood
intoxicationand sleep,
pressure. Acetone, CH3 CO.CH3, produces
but is less powerfulthan ether or chloroform and less toxic than
traceableto the ethylgroups,
properties,
ethylalcohol. The hypnotic
in diethyl
which
seen
ketone,C2H6.CO C2H6 (Propion),
are
clearly
and anaesthetic,
in
but its solubility
introduced as a hypnotic
was
is not great,and this,
combined with an unpleasant
water
taste,
The

ketones in

renders it of littleuse.

noticed in dipropyl
are
ketone,
hypnoticproperties
in water
but as the molecular magnitudeincreases the solubility
not likelyto be of any
and the higherketones are
decreases,
value.
pharmacological
action which accompanies
the
The diminution in physiological
introduction of hydroxylgroups is observed in the case
of the
inert ketoses (ketone
justas it is in that of the aldehydes.
sugars)
The stability
of the ketonic acids depends
the relativepositions
on
of the ketonic and carboxyl
groupings.Thus acetoacetic ester,
CH3CO.CH2.COOH, is very unstable,readilybreakingdown
Similar

into acetone.

Levulinic

acid,CH3COCH2CH2 COOH,
and at the same
time much more
stable,
.

more

on

the other

toxic.

hand,is

SULPHONALS

THE

114

and aromatic,are
Ketones,both simpleand mixed, aliphatic

served
ob-

Benzophenone,
C6H5 COC6H5
hypnotic
properties.
less than the aliphatic
derivatives.
has a slightaction but much
ketones the action depends
In the mixed aromatic and aliphatic
largelyon the nature of the latter radical. Thus acetophenone,
C6H5CO.CH3 (Hypnone),has a marked hypnoticaction.
of
The attemptswhich have been made to increase the solubility
tuted
by the introduction of the amido group or its substiacetophenone
derivatives have not led to substances of practical
importance.
has
more
a
powerfulaction
Phenyl ethylketone,C6H5COC2H6,
than acetophenone.
to possess

THE

OF

DERIVATIVES

KETONES.

SULPHONALS.
When

is withdrawn

water

from

mixture

of alcohol and

hyde,
alde-

the acetals result,

CH3CHO
but

The
are

2C2H5OH

CH3CH(OC2H5)2 + H2O,

reaction does not take placewith the ketones.

corresponding
however, are known, and
corresponding
sulphurderivatives,
obtained by the action of a dehydrating
chloric
agent,such as hydroa

acid

on

mixture of ketone and

CH3

thioalcohol,

CH3

...,

TT^Q/^

TT

I..--'
....Jl:bU2"l5
co+

H2o

C*

TI

c"
I XS.C2H5

I'...... HiSC2H6
Acetone.

| yD.U2H5

Ethyl mercaptan.

Acetone-ethyl
mercaptol.

The

with an unpleasant
substances are liquids
smell,and are
resulting
oxidized by potassium
readily
permanganateto a group of substances
called sulphones,
CH3
CH3
|yS02C2H5
SC2H5
+04
C"
IXS02C2H5
S.C2H5
CH3
CH3
=

Acetone-diethyl
sulphone.

Many

of these derivatives,
investigated
by Baumann

have valuable

hypnoticproperties.

and

Kast,

PHYSIOLOGICAL

116

OF

PROPERTIES

longedaction than

powerful and
sulphonal.

is much
(Tetronal)

less soluble than the other

C2H5\p /SO2C2H5 (Trional)has

CH3/

\SO2C2H5

SULPHONES

and

/^2TT5compounds
o^o-tl/r
6

..

more

..

has

the
,i

"

,,

of all the

hypnoticaction

pro-

powerful
sulphones.
most
,

of the action of these sulphonesis consequently

intensity
of ethyl groups
they contain : this,
dependent on the number
the distinction does
is only true for dogs. Clinically,
apparently,
not hold good.
Sulphonal and trional are only slightlysoluble in water, and
their action tends to
hence are but slowlyabsorbed ; consequently,
if continued
be unduly prolonged; also the use of these substances,
for a long time, may
bring about destructive action on the red
and consequenthaematoporphyrinuria.
blood corpuscles
of these derivatives,
To increase the solubility
attempts have
active amido
substitution
to producepharmacologically
been made
but so far without success.
products,
the interesting
As regardsthe metabolic changesof the sulphones,
The

observation
outside the
less extent
least stable

been

has

made

that

those

which

are

and are
reactive,
body are physiologically
broken
down
by the organism,whereas
are

and
inert,

pass

to

stable

most
a

those

greateror
that

through unchanged. Thus,

are

of the

mentioned substances,ethylene-diethyl
sulphone,
methypreviously
decomposedby alcoholic potash),
methysulphone(easily
lene-diethyl
sulphone,ethylidene-dimethyl
sulphone are found
lene-dimethyl
unaltered in the urine; whereas
sulphonal,reversed sulphonal,
unacted
and tetronal (substances
trional,
upon by acids and alkalis,
to a varying extent
and reducingagents)are
and most
oxidizing
decomposed.
It is,however, true that sulphonals,
which are but slightly
stable,
and hence readily
decomposed in the body, may have no hypnotic
action.
Thus the diethyl
sulphonepreparedfrom acetoacetic ester,
f

CH3 C(S02C2H6)2 CH2

.

COOC2H5,

hypnoticaction,although no trace of it can be

is true of its ethylderivative,
urine,and the same

has

no

'

found

CH8. C(S02C2H6)2 CH(C2H6).COOC2H5)

.

in

spiteof

the number

of

ethylgroups.

in the

ACIDS

THE

THE

III.

117

ACIDS.

by the presence of the soand their basicity

determined by the
.COOH
called
acids of the paraffin
series are
of these present. The
number
of their highermembers
termed fatty,
owing to the occurrence
in the natural fats; these substances,
on
boilingwith alkalis,
alkali salts soaps;
and the corresponding
give rise to glycerin
ester into an
acid and
and hence the process of converting
an
alcohol has been termed saponification.
organicacids
carboxyl
group

The

characterized

are

"

Methods

The

of

Preparation.

are
:
importantgeneralmethods of preparation
oxidation of the primaryalcohols and aldehydes,

most

1. The

"

CH3.CH2OH
CHo.CHO

-+

CH3.COOH

-"

CH3COOH

and in the aromatic

series,

C6H5CH2OH
C6H5COH
2. The

addition

with

treatment

reaction may

CH3CN

C6H5CN

+
+

often carried
nitriles,

acid and
sulphuric

cent,

per
be effected by

CH3.CH2CN

-*"

to the

of water

50

C6H5COOH
C6H5COOH.

-*

of

means

2H20 + HC1
2H20 + HC1
H2O + KOH

water.

out

Or

by
the

alkalis,
CH3COOH + NH4C1
C6H5COOH + NH4C1
+ NH3
CH3CH2COOK

acids are readily

obtained from
monocarboxylic
the benzene homologuesby oxidation (seep. 42) (other
methods
will be mentioned later),
3. The

aromatic

C6H5CH3

+ 3O

C6H5COOH

H2O

Toluene.

O.C6H4(CH3)2

C6H4(COOH)2

_"

Phthalic

o-Xylene.
The

lower members

of the

fattyseries are

this

propertyrapidlydecreases with

The

lower may
are

acid.

soluble in water, but

molecular weight.
increasing

be distilledwithout

decomposed. As

the

bers
change,but the highermemmolecular magnitude increases the

diminishes.
acidity
The aromatic acids

are

found

in
(partly

the free

in
state)

many

THE

118

ACIDS

organism; they result from

and are crystalline
solids
of albuminous
the decomposition
substances,
and are
which generally
sublime undecomposed,
only soluble with
in water.
difficulty
and

balsams

and
resins,

in the animal

Physiological

Properties.

of
carboxylgroup into the members
of the acids,
in the formation
the limit hydrocarbons,
resulting
toxic action. The
givesrise to a class of substances with but slight
it is in most
of its
first member, formic acid,is exceptional,
as
chemical characteristics. Thus, unlike acetic acid,it is a powerful
be
action may
its antiseptic
reducingagent, to which, probably,
it forms
and, unlike the other members of the series,
partlyascribed,
and its nitrile,
acid chloride,
acid,(HCN), has acidic prono
prussic
perties
acid
than
it
much
acetic.
a
more
is,further,
powerful
;
acid
formic
has the most powerfulantiseptic
Of the fattyseries,
acid least;on the other hand, the
acetic less,
properties,
propionic
action of the benzene substituted acids increases with
corresponding
increase of molecular weight. Thus phenylacetic
acid,
The

of the acidic

entrance

C6H5CH2COOH,
C6H5.CH2.CH2.COOH,
phenylpropionic,
acid,C6H5CH2 CH2 CH2 COOH.
phenylbutyric

is less powerfulthan
this less than

Formic
the

is much

acid

more

toxic

than

the
has

series,except butyricacid, which

other

also

and

members

of

slightnarcotic

properties.
The

introduction of the

in the formation

hydroxylgroup

into

acid,resulting
butyric

of

acid,CH3.CHOH.CH2.COOH,
/8-oxybutyric
isomerides,
givesrise to a substance which exists in three optical
the
with
ascribed to
presence of an asymmetriccarbon atom marked
star ; the inactive acid has no
a
action,but the other
physiological
modifications

produceacid intoxication similar

to that

seen

in diabetic

coma.

In

very similar

manner

modifications
optical
acid is the most
acid is not
With

of
intraperitoneal
injections

of tartaric acid show

the dextro acid about

toxic,

that the

the various

laevo-rotatory

whereas
one-half,

than one-quarteras toxic as the laevo form.

the dibasic acids the simplest,
oxalic,
more

COOH

COOH,

racemic

PROPERTIES

PHYSIOLOGICAL

119

rapidlydecreases

but the toxicity

toxic,
very
are
separated,
groups
is

as

the

carboxyl

CH2.COOH

;XXij malonicacid,

succmic

acid,

COOH

CH2

CH2COOH
acid.
glutaric

H2
COOH

CH0.
L2
In the unsaturated

acids,
H.C.COOH

COOH.C.H
and

fumaric,

maleic,
H.C.COOH

H.C.COOH
the

difference due
that

showed

to

former

the

Fodera
is very marked.
non-toxic,whereas the latter was

structural form
was

poisonousfor higheranimals.
The acids of the fattyseries,
probablyowing to the presence of
do not show
the carboxylgroup, do not show narcotic properties,
or
them to any marked
extent.
Butyricacid has a slightaction which
be traced to the ethyl group, C2H6 CH.COOH
; it is more
may
.

in

marked

acid,
dimethyl-acetic

and stillmore

in

acid,
dimethylethylacetic
CEU

CH3 C.COOH,

C2H6)

producesleepand 4-5 sleepand death (rabbits).

into aromatic
stances
subThe
introduction of the carboxyl group
is of great pharmacological
importance,since a drop in
in doses of
not
be taken
toxicityresults. Thus benzene may
than 2 to 8 gms. per day,whereas
benzoic acid,C6H5COOH,
more
of which

is very

3-5 gms.

much

less

be taken in doses of 12 to 16 gms.

may
acid has no physiological
Naphthalenein largedoses is toxic ; its carboxylic
reaction.

but
administered,

toxic,and
Not
1

than

more

3- and

to

2 gms.

of

phenol can

acid,
4-hydroxybenzoic

be

RADICALS

120
have

no

OF

acid,the
action,and salicylic

in doses twice to three times

symptoms appearing. The

benzoic acid,

as

ACIDS

THE
1

:2

derivative,
may

be

given

great as those of phenolwithout toxic

toxic aniline becomes

the inert ^-amido

C6H4\COOH,
by the introduction of the carboxylgroup into the nucleus. The
of hydrogenin the methyl group in phenacetin,
replacement

with the formation

of
p

TT

/OC2H5

COOH
C6M4\NH.CO.CH2.

bringsabout

the loss of its toxic and

therapeutic
properties.

Allusion may be made here to the introduction

of the acid radical
The radical
active basic bodies.
of either series into physiologically
lactic

of acetic

acid,or acetyl,
(CH3CO)',of

benzoic

acid, or

"c., can

readilyreplacethe hydrogen of

throughthe

acid,or lactyl,

acid,or
benzoyl,(C6H5.CO)',salicylic

interaction of the acid itself

the amido

or

imido

salicyl,

group

the

acid
corresponding
chloride with the base in question(see
pp. 36, 43).
substances are of great importance
in the synthetic
The resulting
of drugs; from a chemical
standpointsuch derivatives
preparation
and less readily
oxidized than the bases from which
more
stable,
are
substitution products
soluble
are
more
theyare obtained. The lactyl
and the salicyl
least ; and the latter are broken
than the acetyl,
with such difficulty
down
by the organismthat,as a generalrule,
action.
The
pharmacological
they do not possess physiological

reaction of this group

they are
The

of substances

or

is that of the

base

from

which

obtained.

action of the

benzoylresidue when introduced into the

alkaloids is remarkable ; thus ecgonine-methyl-ester
(see
p. 259) has
but its benzoyl
i.e. cocaine,
no anaesthetic action,
derivative,
possesses
most powerfulproperties.

ALIPHATIC

OF

DERIVATIVES

HALOGEN

ACIDS

121

to the
of aconitine stands in intimate relationship
toxicity
benzoyland acetylgroups presentin that alkaloid ; when these are
substance has no action. Even
eliminated the resulting
splitting
and the loss of
off the acetylresidue causes
a
drop in toxicity,
the respiratory
the stimulating
on
action,shown
by aconitine,

The

centres.

DERIVATIVES
A.

OF

ORGANIC

THE

Substitution

Halogen

ACIDS.

Products.

halogenderivatives of the fattyacids may be obtained,like

the
parent acids,by the oxidation of chlorinated alcohols or
aldehydes,
CC13.CHO
CC13.COOH
The

-*

Chloral.
or

by

Trichloracetic

the direct substitution of the

residue

acid.

hydrogen of

the

hydrocarbon

by halogens.

These derivatives have

acids from

which

they are

than the
pronouncedacidic properties
otherwise theyshow very similar
derived,

more

characteristics.

Physiological
The

replacementof hydrogenby

Action.

the

halogens,as

previously

noticed in other cases, causes

increase in narcotic action;thus
an
is quiteinert,
sodium
acetate
but sodium
monochlor
acetate,

the further
CH2Cl.COONa, has pronounced narcotic properties;
this characteristic,
replacementof hydrogen,instead of increasing
about
diminution.
Dichloracetic acid has less action
a
brings
than

the

mono

whereas
derivative,

trichloraceticacid,
CC13
.

has very slight,

if any, corresponding
reaction.
physiological
the difference in the action may
case
be ascribed to the

COOH,
In this

varying
Monochloracetic is easily
decomposed
at body temperature; trichlor is most
on
even
and
heating,
stable,
dichloraceticof intermediate stability.
It is possible
that the narcotic
action of the first two acids is due to the liberation of hydrochloric
acid in the cerebral cortex,since in animals rendered drowsy
by these
the
acids
of sodium
symptoms are diminished by the injection
carbonate into the vessels. Also,trichloracetic acid does not give
rise to hydrochloric
acid on decomposition,
but to chloroform,
and,

of the substances.
stability

as

has
stated,
already

no

narcotic action.

ESTERS

122

OF

ORGANIC

ACIDS

In the other substituted acids the introduction of chlorine

lessens the

narcotic

sodium

action,thus

butyrateis

times
somemore

Crotonic acid is twice

trichlorbutyrate.

powerfulthan sodium
powerfulan hypnoticas the monochlor
The
replacementof hydrogen in

as

derivative.
acetic acid

by bromine and
monoiodo
results in substances with narcotic action,
bromine
having less action than the corresponding

iodine also
acetic acid
derivative.
Monobromacid

and

to

very

much

less extent

monochlor-acetic

in frogs.
producemuscular rigidity

The

B.

Esters.

those of the
organicacids resemble very closely
mineral
acids previously
described (p.93),and are
obtained by
analogousmethods; the most importantbeing the interaction of
acid and alcohol,
an
e. g.

The

esters of the

CH3COOiH

OH:C2H6

H2O

CH3COOC2H5
Ethyl

As

this reaction

water

with

the reformation

the presence of
is removed

The

is reversible

as

(ethylacetate

of alcohol

or

acetate.

is

decomposedby

it is carried out in
acid),

or sulphuric
acids,or
hydrochloric

the volatile ester

it is formed.

esters of the

fattyacids are neutral,volatile,

ling
pleasant-smelin
water.
i
nsoluble
liquids,
generally
They are preparedin
of fruit essences
for the artificialproduction
largequantities
; the
acetic ester of amyl-alcohol,
CHgCOO.CgHjj,in dilute solution is
used as pear oil; the octyl
ester has the odour of oranges ; the isoamyl
acid smells like pineapple.
ester of propionic
heated with water, or more
with
When
rapidlyand completely
solutions of the alkalis,
they are decomposed into alcohol and
acid,

CH3.COOC2H5

+ KOH

CH3COOK

C2H5OH.

Physiological Characteristics.
The loss of the acidic properties
of the acids

by the replacement
of the hydroxylhydrogen by alkylgroups producesin the esters
those of the alcohols.
properties
closely
resembling
pharmacological
irritationof the throat and
Ethylformate,H.COOC2H5, produces

124

OF

PROPERTIES

PHYSIOLOGICAL

salts of the

acids
original

or

CH3CONH2
CH3CONH2

or

into ammonia

H2O

+ KOH

AMIDES

THE
and

the acids themselves,

CH3COONH4
CH3COOK + NH3.

Physiological Properties.

produceconvulsions similar to those

has less action,and butylset up by picrotoxin
; propionamide
amide stillless ; the action of the last-named only occurs
through
the
On
other
and the liberation of ammonia.
hand,
decomposition
butylamidehas a most powerfulnarcotic action,and this property
of formin the case
decreases in the seriestillit disappears
entirely
and

Formamide

amide.

Lactamide

acetamide

and

have
/2-oxybutylamide

the

same

action

as

propionamide.
properties
; this
of benzamide,
C6H5CONH2, althoughlargedoses
substances :
also in the following

The aromatic
case

and

amides have narcotic

is seen
are

in the

necessary,

"

benzamide,
jt?-methyl
the amide

of anisic acid,

Phenylacetamide,
C6H5CH2CONH2, is a weaker hypnoticthan
but
benzamide. Amidoacetamide,NH2
CH2CONH2, has no action,
its benzoylderivative,
the amide of hippuric
acid,
.

C6H6CO.NH.CH2CONH2,
narcotic properties.
slight
The amide of cinnamic
acid,C6H5CH : CH.CONH2, has strong
hypnoticproperties.
When
the hydrogenatoms of the amido group in benzamide
are
the
narcotic
action
is depressed,
replaced
by methylor ethylgroups,
and the resulting
substance producessymptoms similar to those of
This may
and strychnine.
be observed in the following
ammonia

has

series :

"

C6H6CONH2

C6H5CONH.CH3
Methyl

benzamide.

C6H6CONH.C2H6

C6H5CON(CH3)2

Ethyl benzamide.

Dimethyl benzamide.

NITRILES

THE

125

Urea is the diamide of carbonic acid,

"/NH,

nn/OH

CU\OH

-"

to note, in connexion
(seep. 216),and it is interesting
of benzamide,that benzoylurea,
narcotic properties

with the

CO/NHCOC6H5

CO\NH2
does not show

any similar

reaction.
physiological

The

D.

nitrilesresult from the

The

Nitrites.

of
dehydration

the acid

amides,e.

g.

;; CH3CN,
=

and

on

the

of
absorption

pass back into the amides,and then

their ammonium
salts,

water

into the acids themselves

or

CH3CN

H20

CH3CONH2

CH3COONH4.
CH3CONH2 + H2O
substances on the
They are obtained by the action of dehydrating
acid amides,or by the action of an alcoholic solution of potassium
series,
cyanideon an alkylderivative of the aliphatic
=

C2H5I+

KCN

C2H5CN

+ KI.

consists in the distillationof

preparation
with potassium
cyanide,
potassiumalkylsulphates
Another

method

of

C6H5SO2OK

+ KCN

K2SO3

the

C2H6CN

C6H6CN,

an
usuallyinsoluble in water, possessing
liquids
without decomposition.
etherial smell and distilling
agreeable

The

nitriles are

Physiological
The

nitrile of formic

Properties.

acid,or prussic
acid,HCN, differs from
its homologues
by its greattoxicity.
Methyl nitrile,
CH3CN, is,for
much
less poisonous
instance,
; but,on the other hand, the isomeric
it is said
so
methylcarbylamine,
toxic,more
CH3NC, is extremely
than prussic
that prussic
acid,and it seems, therefore,
quitelikely
acid itself has the constitution HNC,
in which
nitrogenis

quinquevalent.

PHYSIOLOGICAL

126

Bunge

PROPERTIES

found

that

the

OF

nitrile of oxalic

THE

NITRILES

acid,i.e.

cyanogen,

CN
CN
has one-fourth the

of prussic
acid.
toxicity
The toxicity
of the nitriles of the fattyseries increases with the
increase of molecular weight; thus Verbruggefound for rabbits :
"

Acetonitrile

Propionitrile

-13 gm.
-065

per kilo
"

Butyronitrile -010

The
the
=

-045

being"20

"

"

"

"

"

gm.,

benzonitrile
series,

Barthe

and

Ferre

into acetonitrilelowers
the

is less

for

it is -60
0-tolylnitrile

The

introduction of the

thonitrile 1-0 gm.

acetonitrile raises the

"

"

carboxylgroup
a
cid
2-0 gms.,
cyanetic

1-5 gm.
In the aromatic

"

"

introduction of the

thus
toxicity,

dose

"

"

-009
Isobutyronitrile

Isovaleronitrile

body weight

ethylester,however
the
poisonous,

toxic

and

naph-

gm.,

for

phenyl residue into

-05
which, in this case,
toxicity,
the three substances,
investigated
=

gm.

CH2.COOC2H5

fH\COOCH3

CN

I/CN
\COOCH3
CH2COOC2H5

first one
(CH2COOCH3)' group in cyanby inserting
The firsthad
and then a second similar group.
acetic methylester,
and was
most similar to
the most energetic
reaction,
physiological

formed

cyanogen;

then

came

the

second,and

the third showed

no

toxic

action.
SULPHUR

DERIVATIVES.

in
in the alcohols is replaced
resulting
by sulphur,
oxygen
the formation of the mercaptans,such as methylmercaptan,
CH3SH,

When

is observed,
althoughthese derivatives have
toxicity
action than sulphuretted
less physiological
hydrogen,SH2. They
and
the central nervous
act mainly on
system,causingparalysis
failure. The merand finally
death from respiratory
captans
convulsions,
characterized by their strong odour,which increases
are
with the molecular weight.
an

increase in

SULPHUR

The

mercaptans

hydrogen

is still further

ethers.

central

alkyl group

an

Methyl sulphide,

origin; ethyl sulphide

the

not

by

atom

powerful

odour

of

physiologicalreactivityof
the

depressed by

the

etted
sulphur-

replacement

of both

by alkyl groups.

atoms

latter derivatives

the

has

and

consequently, the

hydrogen
Of

of the

produces paralysis of

physiologicallyinactive

127

hydrogen

sulphides,the analogues

in

CH3.S.CH3,
is

of the

replacement

further

results

DERIVATIVES

the

unsaturated

alkyl sulphide,

C3H5\ci

C3H5/S"
has

been

injectionsin
In

by

cholera, and

for

used

rise in toxic

the

of oxygen

by sulphur

is followed

does

not

act

the

upon

heart, whereas

possessing hypnotic properties,is

powerful

poison.
in which

acids

Patty

sulphur replacesone

two

or

of oxygen

atoms

non-toxic.

are

Carbon
central

bisulphide

amaurosis,

is

toxic

and

powerful poison, acting mainly

Workers

system.

nervous

develop
to

replacement

example,

trithioaldehyde,also
heart

subcutaneous

properties.

for

Paraldehyde,

oil for

in

of tuberculosis.

cases

aldehydes

the

solution

in

phenomena

in

caoutchouc

factories

headache,

"

occasionallyparaplegia.

Its

on

the

ally
occasion-

giddiness, deafness,
direct

action

appears

be narcotic.
The

xanthates, e.

g.

cs/"$H"
\SNa

(substances

which

have
disulphide),
narcosis
salts

can

"

the

easily decomposed

similar

into

physiological action

produced

in

man

by these

alcohol
to

bodies.

and

CS2;
Their

carbon

general
alkaline

antiseptics.

are

[Note.
with

be

are

Other

sulphur compounds

corresponding

oxygen

will

be

discussed

derivatives.]

in connexion

CHAPTER
HYDKOXYL

AROMATIC

DERIVATIVES.

"

Main

Group of

Aromatic

septics.
Anti-

physiological
propertiesof Phenols, Cresols,Di- and
of the antiseptic
Recent
of Phenol
Tri-oxybenzenes.
investigations
power
and its derivatives Creosote,
and
their
derivatives.
Guaiacol,
"

Chemical

VI

I.

and

MONO-,

DI-,

AND

TRI-OXYBENZENES.

substitution of

hydrogen in the aromatic nucleus by hydroxyl

to
of substances which correspond
a group
givesrise to the phenols,
the tertiary
alcohols of the fattyseries,
since they do not yieldacid
oxidation. Like the alcohols they are distinguished
on
or ketones
as
di-,"c., accordingto the number of hydrogen atoms
mono-,
replaced
by the hydroxylgroup.
THE

Methods

of

Preparation.

indicated (p.41) by the

They may be obtained,as previously
with
the sulphates,
decompositionof the diazo salts,especially
1.

boilingwater,

C6H5
2.

They

sodium

or

N
.

N.HS04

also result from

H2O

the fusion of the

N2

H2SO4

acids
sulphonic

with

potassiumhydrate,
C6H5.SO2ONa

+ NaOH

General

The

C6H5OH

Na2SO3 + C6H6OH

Properties.

have strongly
marked
phenols,in contrast to the alcohols,
acidic properties,
which
enhanced
are
by the entrance of more
Thus
phenol readilygives
negativegroups into the nucleus.
sodium phenate,
C6H6ONa, when treated with caustic soda,but is

THE

OF

PROPERTIES

PHENOLS

sodium carbonate with

of decomposing"
incapable
that salt. On the other hand nitro-phenol,

and

129

the formation

of

acid,
picric

C6H2\OH
are

powerfulto
sufficiently
with the formation
The

renders

nate
the carbo-

liberate carbon dioxide from

of the

phenates.
corresponding
in the benzene nucleus
presence of the hydroxylgroup
of other hydrogenatoms
more
by
easy the replacement

chlorine,
bromine,or nitro groups.

replaced
by alcohol
hydroxylgroup is readily
sodium phenate,
treated with methylor ethyl
or acid radicals. Thus
iodide,
givesrise to anisol,
C6H5OC2H5;
C6H5OCH3, or phenetol,
these derivatives are very stable and are not decomposed
by potash.
The acid esters result from (1)the interaction of phenolor the
phenateswith the acid chlorides.
NaCl-f C6H5O.(CH3CO),
C6H5ONa + CH3COCl
the phenolsand acids with phosphorus
or (2)digesting
oxychloride
or pentachloride.
phenolsall the hydroxylhydrogenatoms
(3)In the polyhydric
be replaced
with acetic anhydride
by acetyl
groups, by heating
may
The

hydrogenof

the

and sodium

acetate.

from these reactions are readily

posed
decomresulting
thus phenylacetate,
into their componentsby alkalis,
C6H5O.OCCH3 + KOH
C6H5OH + CH3COOK.
Nencki,in 1886, was the firstto realize the importanceof this
since by their formation
group of substances for pharmacology,
both the phenols
and acids with which theyare combined lose their
caustic properties,
and the resulting
derivatives are slowlybroken
down
the intestinalcanal,
where the physiological
onlyon reaching
action of their componentscomes
into play.
This method
termed
of treating
substances is generally
phenolic
Nencki's
Salol Principle, since salol,
C6H6O.(OC.C6H4OH), was

The acid esters

the firstof these derivatives introduced.

The

acidic nature

of the

phenolscan

also be eliminated

by

the

etherial carbonates,
formation of carbonates,
corresponding
or amides.
Carbonates are formed by the
agency of phosgene,
(i)C6H5ONa + Cl.COCl
C6H5O.COCl + NaCl
and
C6H5O.COC1 + H2O
(ii)
C6H5O.COOH + HCL
=

1C

is

ammonia

When

DERIVATIVES

HYDROXYL

AEOMATIC

130

the

brought into play at

second

phase of

the

the amides result,

reaction,

C6H5O.COC1

NH3

C6H5O.CONH2

by
directly

be obtained
derivatives may
chloride on the phenolsor their

such

or
urea

C6H5OH

C1.CONH2

The substances of this group

the

action

of

C6H6O.CONH2.

solids and
generally

are

HC1,

salts,

HC1

are

soluble in

water.

Chlorformic ester

C6H6ONa
bodies of this

givesrise to

Cl.COOC2H5

the
=

Nad

C6H5O.COOC2H5

insoluble in
liquids,
type are usually
of

esters
sulphuric
(p.102).
The

water.

been
phenolhave previously

Homologous
The

esters,
corresponding

mentioned

Phenols.

three cresols 0, m, p

L3
are

found in coal-tar and

beechwood-tar,
thymol,
OH

C6H3 CH3
C3H7
in oil of

6
.

thyme. Carvacrol,

(OH

CeH8JCH,

(C3H7
.

in the oil of certain varieties of

cannot

satureja.These substituted phenols

acids
be oxidized to their corresponding

acid,unless the hydrogenof the hydroxylgroup

or

acid radicals.

Folyhydric
Several

are

of

of chromic
by means
is replaced
by alkyl

found

Phenols.

of the dihydric
phenols,
representatives

in

plantsor

may

be obtained

as

plantsubstances.
Pyrocatechol,
p

u"

/OH

IT
*

-i

.
'

'

products
decomposition

AROMATIC

132

Phenol

HYDROXYL

DERIVATIVES

itself or the oil of cloves is

used for the same

frequently
the benzene ring,
which is not

The antipyretic
action of
purpose.
lost in the phenolseries,
cannot
be utilized for obvious
action

The

on

but
hydroxyls,

the

spinalcord

in other

phenol and

the

the animal

becomes

decreases

with

reasons.

the

number

is increased.
respectsthe toxicity

of
Thus

dioxybenzenes
producespasms in frogs,whereas
trioxybenzene
(1:2:3)onlyproducesshivering
; on the other hand,
Binet holds that the toxic
the

phenolsare

by

the

traceable to

introduction

of

action of these is seen

in

and

comatose

more

atoxic than with resordin.

and convulsions)
of
symptoms (collapse
the benzene nucleus,
but are modified

OH

acylgroups.

or

The

antagonistic

OCH3

MkTi

OCH3
/

Li

guaiacol|

and veratrol

\n

V
decrease in toxicity.
The carboxyl
progressive
group
also modifies the toxicity
acid,
; gallic

which

show

COOH

and is a much
less powerfulblood poison
shivering,
than
pyrogallol.The lower phenolsare protoplasmic
poisons,
but this propertyis lost in the highermembers
causingcoagulation,
of the series,
e.g. phloroglucin,

producesno

OH

of the phenolsare depressed

properties
by the replacement
in the nucleus by alkylgroups, whereas
of hydrogen atoms
characteristics are increased.
This alteration,
ever,
howantiseptic

The

the

is

toxic

more

marked

with

3-cresol than with the others

; recent

of 1 : 2-cresol lies very

have shown that the toxicity
investigations
1 : 4-cresol is greater. As regards
that of phenol,whereas
near
the 1 : 3 derivative is more
properties
antiseptic
powerfulthan the
1

4, and ortho cresol is the weakest of the three.

ANTISEPTICS

CRESOL
and Lubbert

Koch

have

133

attention to the

drawn

great value of

thymol,
OH

I /"^TT

| /^1

TT

/?

VV^g-tl-

CTT
6J131 U"13

antiseptic.
The homologousphenols,
however,are much less soluble in water
and various methods have been tried by which
than phenolitself,
The majorityof these have been based on
to modifythis factor.
as

an

the

of different

use

derivatives in various

caustic soda,soaps,

or

of these
for instance,
the solution,
solvents,
such as
fats,or in solutions of different salts,

calcium

hydrate.

is a solid compoundof pure w-cresol

instance,
potassiumcresotinate,
for

Metakalin,

and

fCH3
ICOOK,
in

sodium

soap, and itcontains the least toxic but most

of the
antiseptic
Lysol

powerfully

three cresols.

is oil of tar mixed

with

linseed

or

fattyoil,and

pletely
com-

with potashin the presence of alcohol. It is not

saponified
and may
toxic as carbolic,
so
so
or
irritating
vary in antiseptic
of the different cresols.
strength
owing to varyingproportions
is an emulsion of cresols in resin soap, and is destroyed
Creolin
caustic alkalis,
and sodium chloride. It contains
by mineral acids,
varyingamounts of the different cresols.
has a bactericidal
of creolin,
Cyllin, an improved preparation
when tested with
power sixteen times that of pure phenol(Rideal)
used.
B. Typhosus medicinal' cyllin
Klein finds it thirty
was
times as strongwhen tested with B. pestis.
Jonesen1 experimented
with dogs in nitrogenous
serving
obequilibrium,
the effects of cresols on their outputof nitrogen,
ammonia,
and indigo. The cresol was
the
eliminated by
none
entirely
urine,
found in the faeces. During the periods
in which cresol was
was
ever
of the H2SO4
giventhe ammonia decreased,
owing to the conjugation
with cresol. The effect on indigovaried with the different isomers,
f

"

the

and the least with

greatestaugmentationoccurred with ortho-,

the para derivative beingintermediate.

flzefo-cresol,

also to

smaller extent

Biochem.

The

cresols are

the
with glycuronic
acid,
conjugated

vol.i,fasc. 5
Zeitschr.,

and

6, pp. 399-407, 1907.

amount

AROMATIC

134

HYDROXYL

beinggreaterthe
meta-cresol it
and

also varied

with
directly

the

able
recover-

toxicity.With

46-5 per cent.,with 0r^o-cresol 30-35

it fell to 27 per cent, of the amount
_para-cresol

with

These

toxic the cresol. The total amount

more

the urine

from

DERIVATIVES

per cent.,

was

phenomena,

as

also the

of

ingested.
merely

be

course
toxicity,
may
o
f
rapidity absorption.
have
various
recentlyinvestigated

the results of variations in the

Bechhold

Ehrlich1

and

and
phenolderivatives,

have shown

into the nucleus

bromine

1. that the entrance

"

of chlorine

of

septic
phenolcauses an increase in antiIn the following
of phenol
comparisonsan amount
power.
pared
equalto 1,000 gm. molecules was taken,and againstit were comof various substances,
the quantities
also in gm. molecules,
necessary to preventthe growth of certain bacteria in a givenfluid.
or

Phenol

1000

Trichlor

bacillus
Diphtheria

"40

"

Tribrom

"22

"

Tetrachlor

16
"

Pentachlor

"

Pentabrom

"

"

7
"

"

"

"

"

the last case, for instance,

one
gm. molecule of
the growth of
phenolhas the same action in preventing
In

bacillus as 500 gm.

2. The

entrance

molecules of
of

increase

noticed in the

was

phenol.
into the nucleus

alkylgroups

mentioned,increases
previously
case

"

9"

of

; thus

"

"

"

ft

Tetrabrom

^~

P'

1000

bacillus
Diphtheria

"'"

"

Dibrom-jo-xylenol
=

Tribrom-^-xylenol
=

ol=

"

"

"

"

)"

"

3)

JJ

"

"

-9

Dibrompseudocumin

similar

16

phenol

phenol,as

value,and
antiseptic
the halogenderivatives

Tetrabr"m-0-cresol
CeBr4"(oH3
jy

of

its

Phenol
Tetrachlor

pentabrom
diphtheria

"22

3-9

"L3

6-5
"

Zeit.fur.Phys. Chem.,47, 173,1906.

Hoppe-Seyler's

ANTISEPTIC

That

VALUES

135

is twentytimes
is,tribrom-w-xylenol

as

active

as

tribrom-

phenol. Tetrabrom-0-cresol is about sixteen times as active as

This brominated
cresol is but very slightly
toxic ;
tetrachlor-phenol.
bacillus in less than two
a
one
per cent, solution kills diphtheria
one
minutes, whereas a corresponding
per cent, phenol solution
than ten.
more
Further,the same
strengthsolution kills
requires
bacillus coli in less than five minutes,whereas phenolrequires
sixty.
of two phenol nuclei,as, for example,
combination
3. The

jo-dihydroxy-diphenyl,
C6H4.OH

C6H4.OH,
or

the derivatives of

diphenylmethane, such

followingtable,as well
powerfulthan phenol.

as

their chlorinated

Phenol

jo-dioxy-diphenyl,
OH.C6H4.C6H4.OH
Tetrachlor

1000

as

those

givenin

are
derivatives,

the

more

bacillus
Diphtheria

47

=16

phenol

,,

"

Tetrachlor-0-diphenyl,

OH.C6H2C12 C6H2C12 OH

-7

Tetrabrom-0-diphenyl,

OH.C6H2Br2.C6H2Br2OH=

-4

methane,
Tetrabrom-^-dioxy-diphenyl

CH2(C6H2Br2OH)2
methane,
exabrom-j^-dioxy-diphenyl
CH2(C6HBr3OH)2

1-8

"14

1 carbinol,
exabrom-jt?-dioxy-dipheny

CH.OH.(C6HBr3OH)2
4. The

combination

decreases the

of two

-6

phenolgroups by means

of CO

SO2

or

antiseptic
power.
Phenol

1000

Diphtheriabacillus

=1-8

Tetrabrom-dioxy-diphenyl-methane

"

Tetrabrom-dioxy-benzophenone,
OH.C6H2Br2.CO.C6H2Br2OH ="177
Tetrabrom-dioxy-diphenyl-sulphone,
"34
OH.C6H2Br2.S02.C6H2Br2OH
=

"

AROMATIC

136
5. The

HYDROXYL
of the

entrance

antiseptic
power

of the

DERIVATIVES

acid

the
grouping (COOH) depresses
phenols.
Phenol
1000
bacillus
Diphtheria
=

Tetrachlor

phenol,

C6H.C14.OH

16

"

"

"

"

acid,
Tetrachlor-^-oxybenzoic
\TT

683

C6H2C13 OH
acid,
Trichlor-phenoxy-acetic

Tricolor

phenol,

"740

Tribrom

"40

phenol

22

acid,
Tribrom-phenoxy-acetic
49"

As

of the halogen derivatives of

regardsthe relative toxicity

it is found
phenol,

convulsant
the

that the entrance

the

further

whereas
phenolitself,
powerful; the latter

All the solutions were

was

bromine

atom

introduction

causes

reduces

the

also lowers

rise in this

phenol are about equalto

tetra and penta halogenderivatives are more
stances.
in fact may be regardedas very toxic sub-

and tribrom
characteristic,

c.c.

and
characteristic of phenolitself,
so
action,

but
toxicity,

viz. 100

of

or

trichlor

of alkali,
amount
up with the same
solution contained 6-5 c.c. of normal caustic soda. It

observed that the

in such solutions.

made

of phenoland
toxicity

"?-cresolwas

depressed

VALUES

BACTERICIDAL
The

substances
following

also

were

137

:
investigated
"

(a)Tetrabrom-hydroquinone-phthalein.
B.

with
1 in 80,000 (compared
DipUJieriae.Antiseptic

l"/osolution,more than 2 less than 6

with l"/oo
10 minutes (compared
HgCl2
-5"^solution,

less than 1
B.
B.

200,000

Bactericidal

HgCl2).
minutes

1 in

minute).

action.
Typkosus.1 in 400, no antiseptic
Pyocyaneus.No bactericidalaction. 3 "/oin 60 minutes
with 5"/00
HgCl2 in less than 15 minutes).
Animal

Guinea-pigs,
weight

pared
(com-

Experiments.

250-370

gms.

"/osolution :

cutaneouslyand 5-7 c.c. by oesophagealtube

caused death (peritonitis).
intraperitoneally
"

c.c.

sub-

action; 3

no

c.c.

(b) Tetrabrom-hydroquinoiie-phthaleiii-oxinie.
B.

in
1 in 80,000; bactericidal 1 "/oo
Liphtheriae.Antiseptic
than

B.
M.

more

15 minutes.

or bactericidal action in 1 in 200.

Typhosus.No antiseptic
Gonorrhoeas.
and bactericidal in 1 in 1,600.
Antiseptic

Animal

^Experiments.

weight. l"/o solutions: subcuother effect. 1 c.c. intraperipainful

toneally,
taneously3 c.c. were
; no
action.
doses
16
no
c.c.
by oesophageal
Repeated
tube
in
other
produced traces of albumin
urine,but no
Guinea-pigs 250-510

gms.

action.

(c)Hexabrom-dioxyphenyl-carbinol.
E.

Diphtkeriae. Antisepticand

bactericidal in

in

320,000

solution.
IB. Pseudodiphtheriae.
1 in
Antiseptic

128,000.

1 in 5,000.
Streptococcus
Pyog. Antiseptic

B. Coli.
B.

1 in 80.
Antiseptic
1 in
Pyocyaneus.Antiseptic

B. Coli.

Bactericidal 3

400.

"/ solution in

over

60 minutes.

/ O

Bactericidal 1 "/o
solution from 30 to
Staphylococci.
"in
B. Pyocyaneus.5 "/osolution
NaOH
from 15
Meat
1 in

could not

100,nor

be sterilizedwith

milk with 1 in

1 in

1,000.

60 minutes.
to

200, nor

30

minutes.

serum

with

AROMATIC

138

HYDROXYL
Animal

White

weight

mouse,

toneallykilled in
1-5

DERIVATIVES

Experiments.

15 gms.

-8

intraperi-

c.c.

of
Rabbit,2,100 gms.,
c.c.
fatal.
Guinea-pigsweighing

minutes.

30

"/osolution

45

was
"/osolution intravenously

of hind limbs
showed
300 gms.
only transient paralysis
solution was
Others
1 c.c. of a 3 "/o
intracardially.
injected
500

took 25

to 620 gms.

the bromine

derivative

was

of

c.c.

10 c.c.
"/osolution per
taste is unpleasant
and burning.

given this

solution
"/0

os

os.

per

producedno

infected with

mice

and
Rabbits,guinea-pigs,
were

excreted in the faeces in 7

of 1

Man.

when

ing
weigh-

Most

of

days.

illeffects. The

various

organisms
(intravenously,
"c.)but

solution in various ways

without any effect.

(d) Hexabroin-dioxyphenyl-methoxy-methaiie.
1 in

Animal

White

mice, about

weight.

15 gms.

"/oin

less than

Bactericidal 1

-8 c.c.
"/osolution,

bromide

5 to
"/o,

only was

doses had

no

fatal

effect on

tetrabrom-ortho-diphenol.

200,000

to

1 in 640,000;

tericidal
bac-

2 minutes.

Animal
The

and

in

1
Diphtheriae.Antiseptic

B. Coli.

tericidal
bac-

Experiments.

(e)Tetrachlor-ortho-diphenol
1

400.

Local necrosis. Sublethal

subcutaneously.
animals infected with trypanosomiasis.

B.

640,000

320,000.

1 in
Pyocyaneus.Antiseptic

B.

to 1 in

in 200,000

1
Antiseptic
Diphtheriae.

3.

30 minutes.

Experiments.

used.

-3 gms.

in 10

c.c.

fatal for

was

-1 c.c. of 1 % solution intraperitoneguinea-pigs

subcutaneously.
No
fatal for white mice.
was
allyand -25 c.c. subcutaneously
with subeffect was
producedon infected animals by injections

lethal doses.

(f) Tetrabrom-ortho-cresol.
B.

1
Diphtheriae.Antiseptic
1 in 320,000.

B. Coli.

Bactericidal

in

200,000-160,000;

solution in
l"/o

bactericidal

lessthan 5 minutes.

This

like
derivative,

constituents

DERIVATIVES

HYDROXYL

AROMATIC

140

in the

previousone, is decomposedinto its

intestine by the pancreatic
juiceand

the

small

bacteria.

Epicarin, introduced in 1899,

acid,
/3-oxynaphthol-0-oxy-;?2-tolu

[-CH2-C6H3"g"OH]

HO.C10H6
is obtained

by the

dissolved in acetic

action of

acid on /3-naphthol
chlormethylsalicylic

acid,

/COOK

C6H3^OH

C6H

\CH2C1+ C10H7OH

"COOH
/ OH

\CH2" C10H6 OH
.

+ HC1.

It has

It
and forms salts soluble in water.
powerfulacid properties,
is a powerful
and non-irritating
and is mainly excreted
antiseptic,
for the skin.
unchanged. It has been used as an antiparasitic
acid,
/3-naphthylamine
sulphonic
-OH

JS02OH,
readilycombines with nitrites,
forming the innocuous diazo
compound. It has thus been employed in cases of poisoningby
and also to preventthe urine becomingalkaline in diseases
nitrites,
very

of the bladder.
The action of the

halogenderivatives of naphtholhas

not been

investigated.
POLYHYDRIC
I.

A.

PHENOLS.

Dioxybenzenes.

and the antiseptic

action
According to Frankel, the toxicity
with
increases
the number
of hydrogen atoms in the benzene
nucleus replaced
by hydroxylgroups. On the other hand,Schmiedei.e. resorcin,
berg states that one of the dioxybenzenes,
1 3,
C6H4"(oH
:

is less toxic,
and

has less antiseptic

power

than

phenol. The trioxy

derivative,
more
pyrogallol,
C6H3(OH)3, however, is certainly
than
resorcin.
the
Of
three isomeric dioxybenzenes,
poisonous
the 1 : 2 derivative,
is the most toxic,
then the 1 : 4
pyrocatechin,
is the least
hydroquinone,whilst resorcin,the 1:3 derivative,
and consequently
the onlyisomer employedin medicine.
poisonous,
It isformed by fusing
acids with caustic soda,
any of the disulphonic

which
1

stable of

141

change takes placewith the

is the most
and that 1 : 3-dioxybenzene
1 : 2-sulphonates,
for such
the three isomers at the temperaturesrequisite
that

means

and

GUAIACOL

AND

CREOSOTE

intramolecular

an

reactions.
derivative
monoacetyl

The

C6H4"(o.COCH3

1:3
goes

the

by

name

Dioxybenzenes.

of

Derivatives

Etherial

B.

Creosote

of Euresol.

beechwood-tar consists

from

of
chiefly

mixture

of

cresols,
phenol,
guaiacol,

and its homologues,

creosol,

C,H,"CH,)"g"H"
the action of creosote is very
to the presence of phenols,
but is
similar to that of phenolitself. It has antiseptic
properties,

Owing

the free

hydroxylgrouping,and

based

the

on

the presence of
duced,
derivatives have been intro-

The latter dependson

toxic and has caustic action.

many

in order
principle,

salol

to

overcome

this

characteristic.
objectionable
The
down

this purpose
into their components in the intestine.
esters which

Creosote

an

been

"

is obtained

by the

alkaline solution of creosote.

carbonic acid

by

this

means

all break

preparedfor

for instance,
like
carbonate,

of several substances
on

have

"

action of
formation

The

producesa

creosote itself

very

mixture

chloride
carbonyl
of the ester of

great drop in toxicity

mixture.
original
Other esters of creosote have been preparedand introduced into
but these have been all replaced
by what is supposedto
medicine,
be the most powerfulphysiological
agent presentin the mixture,
viz. guaiacol,
its derivatives. It is probable,
or
though,that the
methyl ester of homobrenzcatechin,

and the loss of the caustic action of the

/CH3
C6H3\-OCH3
\OH
which is presentin creosote,may

constituent,
since,
important
should
stated,its toxicity
judgingfrom what has been previously
which
but its antiseptic
be less,
than that of guaiacol,
value greater,
has no methylgroup substituted in the nucleus.
This homologueis
be

an

HYDROXYL

AROMATIC

142

difficultto isolate from

into

DERIVATIVES

mixture,and

the

has

duced
yet been intro-

not

pharmacology.
anisol to the

1 : 2-nitro
resulting

reduction of

and
by nitration,

anisol

from

is obtained

Gnaiacol

derivative j this is then

amido

diazotized and boiled with water.

C6H4.OCH3

C6

-*

OH

PH/N:N.OH
"-6n4
It is

toxic

PTT
^

n.o

irritatesthe

and
substance,

\OCH3

cutaneous
Its sub-

gastricmucosa.

is

dangerous,owing to the collapseand cardiac

it may
depression
produce.In toxic doses it producesexcitation,
of the central nervous
followed by paralysis
system,the former
symptoms beingless marked in the higheranimals. It is less toxic
and more
than phenol.
powerfully
antiseptic
use

Acid

Inorganic
A.

Guaiacol carbonate

1.

Esters
or

of

Guaiacol.

Duotal,

OCH3
v^vyga.I4
\O.C6H4 OCH3

results from
salt of

carbonylchloride

the interaction of

and

the sodium

guaiacol.
T

+COC12
In

this reaction

guaiacolmay

such,
hydroxyl derivatives,

2NaCl

CO(OC6H4.OCH3)2

be

replacedby

for

instance, as

largenumber

of

menthol, eugenol,

"c.
carvacrol,
and
carbonate)
(creosote

Creosotal

therefore tasteless. The

miscible with

alcohol

and

soluble
powder slightly
2. Mixed

obtained

by

former

carbonates

is

oils,and

Duotal

both

are

odourless

yellowalmost
the

latter

and
insoluble,

white

liquid
crystalline

glycerin.
radicals
aromatic and aliphatic

in oil and
of

the action of chloroformic esters

other allied substances,

such

as

on

may

be

sodium

and
creosol,
eugenol,

guaiacolor
carvacrol,

carbonate,
Ethyl-guaiacol
or

generally
X.ONa

+ Cl.COOR

GUAIACOL

OF

ESTERS

143

in distinction to the carbonate,

are
derivatives,
resulting
suitable
for
but
have
little
and on this ground are
injection,
liquids,
practical
importance.
allied substances can
be
esters of guaiacoland
3. Carbamic
chloride and the phenolor its
obtained by the interaction of urea

The

sodium

salt.
NaC1

CO"\O.cXOCH3
.CONH2
the following
Instead of guaiacol,
hydroxylderivatives have been
"c.
eugenol,
thymol,geraniol,
employed: Menthol,carvacrol,
B. Phosphateof guaiacol
or
Phosphatol, PO(OC6H4 OCH3)3,
intended to combine the action of phosphoruswith that of
was
=

"

the cresol in

cases

of tuberculosis.

is obtained by
(Guaiacophosphal)
Phosphiteof guaiacol
trichlorideon the sodium salt,
action of phosphorus

C.

3NaCl

the

P(O.C6H4.OCH3)3.

crystalline
powder,and, in distinction to the phosphateand
is soluble in fattyoils. Under the name
is
carbonate,
Phosphotal
sold a mixture
of the phosphorousethers of the creosote phenols
90 per cent, creosote and 9 per cent.
(neutral
phosphites)
containing
It is a

P0Oo
/

It is not caustic and

is much

less toxic than

creosote.

and aliphatic
esters of phenols
radicals have
sulphuric
been obtained by the action of ethylchlorsulphuric
acid upon alkaline
solutions of guaiacol.
D.

Mixed

The various

mentioned may be used

phenolicsubstances previously
in placeof guaiacol,
and the ethylgroup can be replaced
by methyl,
"c.
butyl,

Organic
Various

acid
aliphatic

Acid

Esters

of

Guaiacol.

esters of

and similar phenols,

guaiacol
or
of the mixture creosote,
have been prepared.They are formed by
heatinga mixture of the acid,phenol,and a dehydrating
agent,
such as phosphorus
to a temperatureof 135".
Thus in
trichloride,
the

case

of oleic acid,

CH3 (CH2)7 CH
.

HaO

CH(CH2)6 CH2CO|OH;

0^X0(0!

(Guaiacol
oleate),

this ester is liquid

and insolublein water.

DERIVATIVES

HYDROXYL

AROMATIC

144

The valerianic ester

1

Geosote,

or

9. C

TT

^""^

soluble in dilute
liquidinsoluble in water,only slightly
of alcohol,
and soluble in largequantities
acids and alkalies,
ether,
aromatic
character and a penetrating
"c. It has an oily
chloroform,
is a similar preparation,
said to be less pure.
odour.
Eosote
of this group is unnecessary, and it is hardly
Further description
value greaterthan the
likelythat derivatives of pharmacological

is also

carbonate

can

be found in this class.

and
aromatic acid esters have been prepared
similar manner,
Thus the benzoic acid ester of guaiacol
or
Benzosol,
investigated.
In

but this substance is decomposedwith rather

introduced,
and its product,
benzoic acid,is
than the carbonate,
more
difficulty
as
an
of littlepharmacological
value,except possibly
expectorant
has been

urinarydisinfectant.
acid ester
The salicylic

and

TT

or

Guaiacolsalol,

/OCH3

L6H4\o.OC.C6H4OH,
which
melting-point,
and the antiseptic
in the small intestine into guaiacol
breaks down
does not take placeat all
acid,but again this decomposition
salicylic
of these aromatic
and in order to decrease the stability
readily,
in
esters an amido
group has been introduced into the 1 : 4 position
the benzoylradical" /?-acetamido-benzoyl-guaiacol,

like the

is a
derivative,
previous

TT

Ta
This substance

chloride

on

may
sodium

solidwith low

/OCHg

*\Q.C"H4 NH(COCH3).
.

be obtained

by

the action of 1

4-nitrobenzoyl

guaiacol.

C.H/S"1+ C,H /"1H*

=

NaCl

C6H4"PCH"

substance is then reduced,and the acetylgroup

resulting
introduced in the ordinary
way.
than
derivative
is decomposedwith greaterease
this
Although
that its value can be greater
the benzoic acid ester,it is improbable
mentioned.
than others previously
The

DERIVATIVES

GUAIACOL

Attempts
A.
of

Einhorn

and

Solubility

increase

to

145

Hiitz have introduced the

of

Guaiacol.

acid
hydrochloric

salt

or Guaiasanol,
diethyl-glycocoll-guaiacol,

CH3

.COCH2N(C2H5)2 HC1.
.

This

may

be

obtained

derivative
chloracetyl

of

by the action
guaiacol,

CH3

"

of

on
diethylamine

the

/OCH,

TT

-OCH3

".COCH2N(C2H5)2.
This substance is soluble in
and
carbonates,

is broken

as
an
water,precipitated

oilybase by

in the intestine in the usual way.

Its antiseptic
action is equalto that of boracic acid,it is slightly

anaesthetic and very

rabbits producedno
B.

The

down

toxic.
slightly

Three grams

in
subcutaneously

symptoms.

method
simplest

of

is to form the
increasing
solubility
acids,whose sodium or potassiumsalts are soluble in
sulphonic
water.
This has been carried out with guaiacol,
althoughthe
is
rule that such
to the general
resulting
compound no exception
derivatives have less physiological
action than the parentsubstance.
1 : 2-guaiacolsulphonate
of potash,
or Thiocol,

X)CH3

C6H /OH
\S02OK
*

introduced

was

by C.

Schwarz

in

the

1898, and may be obtained by

temperaturebelow 80" C. The

of guaiacol
at a
sulphonation
introduction of the sulphonic
group

results in

completeloss of
the characteristictaste and smell of guaiacol,
and a loweringof
As might be expected
from the presence of the
antiseptic
power.
acid grouping,
it passes unchangedthroughthe body.
The 1 : 4-sulphonic
acid of guaiacol
resultswhen the sulphonation
a

is carried out at

thisderivativeand itssalts

have

their objectionable
action

on

no

but
highertemperatures,
value owing to
pharmacological

the stomach.

The process of sulphonation

be carried out with a large
can
clearly
number of phenolsubstances,
but
or with such mixtures as
creosote,
in all cases the resulting
substances will have less antiseptic
power.
L

AROMATIC

146

and

Snlphosote
with

HYDROXYL
Sirolin

are

DERIVATIVES
of
preparations

thiocol

combined

flavouring1
agents.

C.

It has

been

found

that

the

glycerinester

of

or
guaiacol,

Guaiamar,

/OCH8
by the action of monochlorthe phenoland glycerin
or
hydrin on sodium guaiacol,
by treating
with a dehydratingsubstance.
It is decomposed in the body like
the other esters,
but its bitter aromatic
to be against
taste appears
its use as a guaiacolsubstitute.
is soluble in water

D.

The

; it may

introduction

guaiacol,
givingrise to

be obtained

of the

carboxylgroup

into the nucleus

of

the acid

/OCH3

C6H /OH

'

\COOH
results in

substance

with

and
no
antiseptic
great
power
its
itself
the
to
advantageover
phenol
owing
slightsolubility.
E. By the action of monochloracetic
acid on 1 : 2-dioxybenzene
in

presence

of

less

alkali,there results brenzcatechin-monoacetic

an

acid,

C6H/"Na+
This
water

substance
and

Cl.CH2COOH

goes

almost

by

the

tasteless.

CJT

/O.CH.COOH
L2X

of Guaiacetin;

name

It is similar

to

it is soluble

guaiacolin

in

the toxic

symptoms it produces.
GENERAL

REMARKS

ON

CREOSOTE

DERIVATIVES.

only active constituent of creosote which has been at all

Other bodies have,
widelyemployed is guaiacol,
C6H4 OCH3 OH.
the monomethyl ether of
such as creosol,
however, been isolated,
The

homopyrocatechin.
/CH,

C6H3fOCH3
\OH

which

has been

mentioned.
previously
Veratrol,the dimethyl ether C6H4(OCH3)2, though less toxic
than guaiacol. The correis more
to the gastric
mucosa
sponding
irritating
monoethylether

AROMATIC

148

DERIVATIVES

HYDROXYL

Another

of

derivative

is

pyrogallol

Galla-acetophenone,
or

methyl-keto-trioxybenzene,

it

CO.C6H2(OH)3;

CH3

is

obtained

by

heating

acetic

acid,

pyrogallic

acid,

dehydrating

and

such

agent

chloride.

zinc

It

antiseptic

powerful

has

is

and

properties,

less

as

toxic

pyrogallol.

than

It

does

not

stain

linen,

but

is

not

such
an

active

local

application

for

psoriasis.

VII

CHAPTER

"

Tannic

(CONTINUED).

DERIVATIVES

HYDROXYL

AROMATIC
Acids.

acid derivatives. Nencki's

Salicylic

Classification of

The

Salol

Hydroxy

Principle.

Gallic Acids.

and

HYDROXYBENZOIC

ACIDS.

reaction
remarked that the pharmacological
previously
is very considerably
diminished by the introduction of
of benzene
benzoic acid,C6H5COOH,
the carboxylgroup, and the resulting
much
result.
be given in largedoses without
physiological
may
of the aliphatic
On the other hand, the phenylsubstitution products
acids,such as phenyl acetic,C6H5 CH2COOH, phenylpropionic,
C6H5CH2 CH2 COOH, and phenylbutyricacid,
IT has been

C6H5CH2 CH2 CH2 COOH,

.

show

The

form

strongerthan phenoland

antiseptic
power

increase of molecular
unsaturated
of its sodium

Landerer

in

1892.

and
benzaldehyde

magnitude.
cinnamic acid,C7H5CH

salt,the so-called Hetol,

It

acetic acid

in

the

introduced

by

CH.COOH,
was

by the condensation
synthesis),
(Perkin's
be

may

with
increasing

C6H5CHJO+ H2]CH.COOH

obtained

H2O

C6H5CH

of

CH.COOH.

in experimental
animals
leucocytosis
thus thought that valuable
and also in man.
It was
(rabbits),
results might be obtained in tuberculous disease by increasing
factory,
satisThe clinical results have not been altogether
phagocytosis.
and the treatment
has never
been at all generally
adopted,
It

causes

considerable

at any rate in this

country;

of 903

cases

collected from the literature

41 per cent, died or were

unaffected.
Based on the salol principle
number
a large
have

been

introduced

ester,Hetocresol,

into

pharmacology.

of esters of this acid

Thus

the 1

C6H6CH :CH.CO.OC6H4. CH3,is an

3-cresol

insoluble

powder

HYDROXY-ACIDS

AROMATIC

THE

150

intended

for

use

as

local

to
application

tuberculous

"c.
sinuses,
The

ester,Styracol, C6H5CH
guaiacol

CH.CO.OC6H4.OCH3,

in the body.
and is said to liberate85 per cent, of guaiacol
is tasteless,
It is intended as a substitute for that drug,and to combine
the
of
supposedadvantages

Physiological

Effects

Radical

acid.

cinnamic

produced
into

the

by

Entrance

Nucleus

of

of

the

Carboxyl

Phenol.

the
carboxyl
group is introduced into the phenolnucleus,
reaction of the resulting
substance depends on the
physiological
relative positions
of the two substituents ; in all three isomers,
is noticed.
however,a very greatdropin toxicity
When
the two groups are next to each other,i.e.1 : 2-oxybenzoic
or salicylic
acid,

When

j"COOH

L-OH
substance has antiseptic
allied to
resulting
closely
properties
phenol,and at the same time other characteristics appear which are
if at all,
in the hydroxylsubstance itself. Thus
barelynoticeable,
acid has an antipyretic
salicylic
a
action,and more
particularly
action in rheumatism.
On the other hand, both 1 : 3-oxyspecific
benzoic acid,
the

COOH

and the 1

derivative,
COOH

have
have

lost all the physiological

characteristicsof phenol,
and
entirely
neither the antiseptic
the therapeutic
nor
action of salicylic

acid,the ortho derivative.

PHYSIOLOGICAL
When

the

PROPERTIES
of the

hydrogenatom

hydroxylgroup

151

is

replaced
by

methyl,

action of the 1 : 2 derivative is very much weaker

physiological
than salicylic
it has onlyslight
and antipyretic
acid itself,
antiseptic
and,in the case of animals,is onlytoxic in largedoses. The
action,
anisic acid,has no pharmacological
1 : 4 derivative,
corresponding
reaction at all,
and passes unchangedthroughthe organism.
the introduction of a methyl group into the nucleus of
Whereas
whilst raisingthe antiseptic
phenol tends to lower the toxicity,
of salicylic
acid is as follows:
power, the result in the case
acid (/3-cresotinic
OM0-homosalicylic
acid)
the

"

1
LoC

WV^V^JiJt

\GH3

*W

and in relatively
small doses
the most reactive,
physiologically
of the muscles of the heart,/?ara-homoproducesa paralysis
is

salicylic
(a-cresotinic
acid)
X)H

C6H3^-COOH 2
\CH3

whereas wfo-homosalicylic
itself,
salicylic

has less reaction than

OH

C6H3;"COOH

\CH3

1
2
3

reaction.
producesno pharmacological
The oxynaphthoic
acids have a similar action to salicylic
but
acid,
and in doses of 1"5 gm.
though more powerfulthey are also caustic,
producefatal results in rabbits.

A.

SALICYLIC

AND

ACID

ITS

DERIVATIVES.

acid occurs
in the free state in buds of Spiraea
Salicylic
ulmaria,
and as methyl ester in oil of Gaultheria procumbens(oil
of wintergreen).
It may
be preparedby the action of carbon dioxide on sodium
phenateat a temperatureof 180"-220",

2C6H6ONa

C02

C6H4

ACID

SALICYLIC

152

sodium phenate
be modified by saturating
reaction may
with carbon dioxide under pressure, when sodium phenylcarbonate
This

results,

C.H.ON.
This

substance, heated

intramolecular

to

change to
ro/

CU\

CO,

120"-130"

sodium

ONa

CO"(""aH

under

pressure,

undergoes

salicylate,
r

"

/OH

^^xcOONa.

OaH.

acid has a sweet,acid taste,and in this form onlyhas

Salicylic
action.
Its sodium salt is a crystalline
powder with an
antiseptic
and hence
sweet taste ; it is decomposed
by mineral acids,
unpleasant,
also in the

stomach,with

the liberation of the free acid.

its sodium
salt have
acid and
objectionable
salicylic
tinnitus
aurium, headache,delirium,
secondaryactions deafness,
Both

"

haematuria,albuminuria,$c.
In order to

these

overcome

a large
properties
objectionable
variety
have been preparedand many
duced
intro-

acid derivatives
salicylic
the first to lead the way into
into pharmacy. Nencki
was
and to combine
in
field of pharmacodynamics,
this new
together,
reactive components. He
the form
of esters,two physiologically
of the toxicity
of these components,the slow
found that,in spite
of the
esters in the organism led to derivatives
breakdown
of relatively
slighttoxicity.Such esters,generallypossessing
and
caustic
taste
no
action,
hardly any
pass unchanged
and
in
the
duodenum
the
are
stomach,
decomposed
by the
through
The acid formed by this saponificaaction of alkali and enzymes.
and the physiological
action of the
tion is neutralized by the alkali,
commences
liberated,
by
phenol,which is slowlyand continuously
this
of
from
that
From
the
view
soregion.
point
reabsorption
in
the
has
been
to
salol
alluded
called
principle
already
previous
substances and their derivatives.
pages on phenolic
If it is desired to obtain only the pharmacological
reaction of
be combined
with an
it must
rivativ
the acid,then clearly
hydroxyldewhich itself possesses little or no physiological
activity
;
allied
alcohol or an
substance.
that is,preferably
an
aliphatic
acid,owing to the presence of the hydroxylas well as
Salicylic
the carboxyl
groups, can playthe part of both phenoland acid,and
the derivatives employedin medicine may be classifiedas follows :
of

'

'

"

I. Those

153

of hydrogen atom
by replacement
formula
of general

formed

substances

group,

DERIVATIVES

OF

CLASSIFICATION

of

carboxyl

/OH

TT

to the nature of the radical

according
nature,i.e. physiologically
R, viz. : (a)Those in which R is of an aliphatic
in
the
is
which
radical
of
and (b)those
a phenolic,
inactive,
nature.
and, hence,antiseptic
derivatives formed
II. Those
by replacinghydrogen of the
hydroxylgroup, of generalformula

These

further subdivided

are

X cannot

j,

be the radical of

alcohols for
aliphatic

given(p.151),but must be of
down in the organismwith the
III. Derivatives

in

/DA.

TT

which

type which

liberation of
both

previously
will be easily
broken
free salicylic
acid.
reasons

hydrogen atoms

have

been

replaced,
/OX

Subdivided
Class II

in this manner,
it will be noticed that Class I (a)and
contain closely
allied substances,
i.e. derivatives whose

action
physiological

is very similar to

Class

acid
salicylic

itself.

(a).

Methylsalicylate,

(oilof wintergreen),
can
milk

in

10-20
sweet

to the stomach.

minim

be

as
giveninternally

doses.

taste of sodium

an

emulsion

or

in

It is very active,has not the unpleasant

but
is
salicylate, often very irritating

it is useful
Appliedexternally,

in acute

muscular

rheumatism.

Ethyl salicylate,
H

investigated
owing to the fact that ethylderivatives are often
than the corresponding
methyl. Accordingto Houghton, it is onlyhalf as toxic as the previously
mentioned substance.
was

less harmful

SALICYLIC

154

The

DERIVATIVES

ACID

ester
monoglycerin

of

Glycosal,
acid,
salicylic

/OH
is obtained

by the action of condensingagents,such as 60 per

acid and glycerin.
of salicylic
acid on
cent, sulphuric
a mixture
but is found to be
The triglycerin
ester has also been investigated,
reabsorbed to nothinglike the same
extent as the mono
derivative,
of which about 96 per cent, undergoes
that process.
in
It is a crystalline
soluble in water, more
so
powder,slightly
alcohol and glycerin.It possesses no odour,and is intended for
and is
it is not irritating,
internal and external use.
Externally
fairlyrapidlyabsorbed,appearingin the urine about six hours
the skin.
after a solution in alcohol has been painted
on
The methoxymethylester of salicylic
acid,Mesotan,
OH

introduced

was

by

ether
chlormethyl

Floret in 1902, and is obtained

sodium

on

by

the action of

salicylate,

.CH2 O.CH3
.

NaCl

C6H4

and very readily

breaks down
It is unstable,
in presence
into formaldehyde,
a reaction probably
expressedby the

of water

following

reaction :

"

6H4\COO.
CH2

It is used
and

as

O.CH3

H20

in acute rheumatism
to painful
local application
joints

similar conditions. It has been observed to

and should therefore be

not

employed in weak

easilyabsorbed,e. g.

vaseline

and
dilutions,

olive oil. The

or

unstable.
Salacetol,
Acetol-salicylic
ester,
/OH

C6H4\COO.CH2

producedermatitis,

CO.CH3,

in media

is
preparation

DERIVATIVES

ACID

SALICYLIC

156

and many
other similar hydroxyl
the following
placeof phenol,
acid throughthe agency
substances may be combined with salicylic
of phosphorus
:
oxy-chloride
In

"

1.

2. 1

and

a-

/3-naphthol
.

2-, 1

Thymol

3-, 1

4-cresol

"

^6^4\COOC

C6H4"gJoc
,

molecule of resorcin giving

4. One

C"H"COO.C10H13
C6H4"^"QQ
Q jj

QH

or

the

corresponding
methoxy

derivatives

5. Guaiacol

7.

9. GaUicacid
.

/OH

C6

phenolscalled creosote.

l:4-nitrophenol

8. Gaultheriaoil

In

mixture of

"

6. The

^n4\COO.C6H4OCH

"

acid,the
placeof salicylic

"

C6

inert anisic acid,

be used to carry physiologically

active phenolsin the form of
Thus
the anisic acid derivatives,
esters.
their respective
among
may

of
others,

the

have
following

2. Guaiacol

3- Creoso1

.....

been

:
prepared
"

C,
c

and

acid has been replaced

acids.
salicylic
by the homosalicylic
The above examplesshow the largenumber of permutationsand
combinations which can
be made between acids and hydroxyl-confor example,
tainingsubstances ; theyare all decomposedlike salol,
and

substances with novel

action
pharmacological

cannot

be looked

SALOL
for in this group.

One

GROUP
have

may

an

157

advantageover

another

as

with which it breaks up in the

or the ease
solubility
reaction to appear.
and so allows its physiological
duodenum
It
will be evident that there are possibilities
enough to enable fresh
derivatives of this type to be continually
placedon the market,
of these possessing
advantagesover the
althoughthe probability
is but slight.
older preparations
An exampleis givenby Frankel of the manner
in which a drug
althoughits constitution would indicate at once
may be introduced,
that it is valueless. Thus 1 : 2-methoxyor ethoxybenzoic
acid on
nitration givesa 5-nitro derivative,

regardstaste

or

/COOH
C6H O.CH3
/

\N02

This

reduced

was

derivative

by

and

1
2
5

into the

converted

acetyl
corresponding

of acetic anhydride,

means

/COOH

C6H/OCH3
\NH(COCH3).
Now

such

of the

owing to the presence

action of

neither have

substance would

carboxylgroup,

acid,since it does not

salicylic

group.
In this group

of

the

aeid
salicylic

phenacetinreaction,

nor

the

contain the

derivatives

physiological
free hydroxyl

salicyl-acetyl-/?-ami

phenolether,or Salophen,

C6H4"(cOO.C6H4
NH(COCH3),
.

may

be

mentioned; it

be obtained

by

the reduction of the

acid,followed by the
salicylic
substance into its acetylderivative. It

ester
p-nitrophenol
of the amido

can

of

conversion
is almost

insoluble in water, and has no

taste or
smell,and is of small
but on decomposition
rise to 1 : 4in the organismit gives
toxicity,

acetylamido
phenol,

substance

but very slight

and more
possessing
antiseptic
action,
in its physiological
nearlyrelated,
action,to the aniline antipyretics
than to phenol. It is unaffected by pepsin,
but decomposed
in the
a

small

intestine. Its

employedfor the

action
antipyretic

action
salicyl

is

but
feeble,

in acute rheumatism.

it may

be

158

ACID

SALICYLIC

DERIVATIVES

Class

acid,or
Acetyl-salicylic

II.

Aspirin,

"(CH3CO)
introduced

acid.
by Dreser in 1899 as a substitute for salicylic
It is obtained by the action of acetic anhydrideor acetyl
chloride
acid at high temperatures. It is largely
used instead
on
salicylic
of sodium
in acute rheumatism.
It is thought to be
salicylate
better toleratedby the stomach,and onlyrarely
givesrise to unpleasant
have occasionally
been observed.
symptoms. Erythema and pruritus
acid,
Salicyl-acetic
was

).CHCOOH

is obtained

by actingupon

the sodium

salt of the

anilide,

".NHC6H5,
with the sodium

/ONa

salt of chloracetic acid

Cl.CH2COONa
_

On

heatingwith

"

/O-CHaCpONa

NftC1

alkalis this is decomposed

:
"

^T
O.TT
+NaOH

.CHCOONa

p
+CH
,

Class

"

III.

Methyl
methylester,
Acetylsalicylic

rhodin,

0(COCH3)
is

and
not affected by dilute acids,
colourless crystalline
substance,

It is stated to be
undecomposedin the stomach.
consequently
with enfeebled digestion
than sodium
better adaptedfor patients
salicylate.
is the methylester of benzoylsalicylic
Benzosalin
acid,

(COC6H5)
and does not
decomposedtillit reaches the small intestine,
off phenol,
it appears to possess no particular
but,beyondthis,
split
compounds.
advantagesover other salicyl

it is not

ACID

TANNIC

DERIVATIVES.

widely distributed

acids,or tannins,occur

tannic

The

ITS

AND

ACID

TANNIC

B.

159

in the

pounds
vegetablekingdom. They are soluble in water, and form comand are consequently
and with animal hides,
with gelatin
of leather. They also precipitate
employed in the manufacture
of gallic
acid,
proteinsolutions. Some appear to be glucosides
dilute
w
ith
acids,givegrape
(OH)3 C6H2 COOH, and, on boiling
in placeof sugar.
acid ; others contain phloroglucin
sugar and gallic
Pure tannic acid,however, appears to be a digallic
acid,since on
warming with dilute acids or alkalis it givesrise to that acid alone.
Like salicylic
acid,it has antiseptic
properties
; its main property
astrinand is known
as
is due to its local action on protoplasm,
acid and pyrogallol
as gallic
;
gency '. It appears in the urine partly
in
tannic
is
acid
in some
some
passedunchanged,
cases, apparently,
But tannic acid has two characteristics
ester.
others as a sulphuric
infectant
which
stand in the way of its employment as an intestinal disit possesses an objectionable
taste,and,secondly,
Firstly,
it loses its antiseptic
bining
propertyin the stomach,owing to its commembrane.
bodies in its contents or mucous
with protein
it is necessary to obtain derivatives which
can
Consequently,
pass
be
that
like
in
decomposed, salol,
unchangedthrough
organ, but will
For this purpose various acetylderivatives have
the duodenum.
tannic
and it has been found that the triacetyl
been investigated,
acid and those substances containing
more
acetylgroups are not
have not
decomposedby the intestinal juice,and consequently
action.
the required
.

'

When

tannic

acid is treated with

acetic anhydride,
however,a mixture of
acid

which
results,

H.

Meyer and

mixture
mono-

F. Miiller

of acetic acid and

and

tannic
di-acetyl
introduced into pharmacy

of Taxmigen, C14H8(COCH3)2O9.
This body is insoluble in water, and consequently
tasteless. It is
in 1894

under

the

name

precipitated
by acids. At body temperature
it forms a stickymass
in presence of water, but it can
be
obtained in tablets which obviate this disadvantage.Both this
and the next mentioned
acid.
body appear in the urine as gallic

dissolved

by

alkalis and

In another direction tannic

acid derivatives have

been

obtained

by combination with albuminous substances. Gottlieb and others

but the resulting
precipitated
compound
egg albumen with the acid,
is decomposedin the stomach.
it
for 6-10
is
heated
If,however,
hours at 110" C.,it loses this property,
and is not broken down into

DERIVATIVES

ACID

TANNIC

160

This

its constituents until it reaches the duodenum.

it contains

of Taxmalbin;
goes by the name
is named
A similar preparation
this

be obtained

type can

Hoiithin.

preparation

50 per cent, of tannin.

of
Other preparations

solutions
gelatine
by precipitating

with

with casein (Tannocase).These bodies

or
(Tannocol),
what their purpose was, it seems
fulfiltheir purpose, but considering
in
recommended
not a littlecurious that they should be seriously
diseased conditions of the lower bowel to be givenper rectum.
with
The combination of an antiseptic
substance,formaldehyde,
tannic acid is methyleneditannic acid,or Tannoforin,
tannic

acid

'\CUH909
obtained

by

acid on a solution of
hydrochloric
acid,or by heating the components

the action of
tannic

and

pressure.
soluble in
It is onlyslightly

Tannic
and

the

substance
resulting

under

and devoid
water, soluble in alcohol,

It appears to be mainly useful

acid has also been combined with

of odour.

aldehyde
form-

is termed

external

application.
tetramine,
hexamethylene

as

an

Tannopin

or

Tannon,

(CH2)6N4(C14HM09)3)
and consequently
formaldehyde,
action as the direct
will not have so powerfulan antiseptic
down
compound of tannin and formalin. It is only broken
for use
is intended
in alkaline solutions,
and
as
a
urinary

body will

but this

not

liberate

so

much

disinfectant.
is

Tannal

tannate

has the formula

NOTE.

With

"

quiteas

in the very

aluminium, it

is insoluble in

water, and

+ IOH2O.
A12(OH)4(CMH9O9)2

regardto

it may
derivatives,

be found

of

the clinicalvalue of these two

be remarked

that sodium

efficaciousand suitable

largemajorityof

as

classes of

will probably
salicylate
any
When

of the
this

newer

ducts
prois not

body
nausea
or
vomitingoccurs,
by
the glucoside
salicin,
(seep. 322),may be tried or acetylsalicylic
the
acid. General toxic symptoms are met by either diminishing
dose or by givingsome
which is less rapidlyand completely
preparation
of the active
absorbed or contains a smaller proportion
well tolerated

the

cases.

stomach,that is if

principle.
As
some

to the tannic acid substitutes those combined

form

or

other appear

to be the most

with

proteinin
justifiable.
scientifically

CHAPTEE
ANTISEPTIC

and the Alkali iodides. Derivatives

lodofonn

lodoform

I.

and

IODOFORM, CHI3, was

the first solid

introduced

IODINE.

of Allied

Substances

AND

in

"

CONTAINING

ANTISEPTICS

IODINE

place of
containingSulphur Ichthyol.

Classification of substances

lodoform.

SULPHUR."

CONTAINING

SUBSTANCES

OTHER

AND

VIII

Physiological

Action.

introduced
antiseptic

into

be obtained by the action of iodine,in the

It may
of the alkalis,
of aliphatic
on
a largenumber
derivatives,

pharmacy.
presence

It is generally
"c.
ethylalcohol,acetone,acetaldehyde,
solution of either soda or
preparedby adding iodine to a warm
potashin dilute alcohol or acetone ; the iodoform formed separates

such

out

as

and

is filteredoff. The

iodates ;

on

the addition of

solution contains alkaline iodides and

a

further

the passage of a slow stream

of
in the liberation of free
(resulting

and

iodoform

of alcohol (oracetone)
quantity
chlorine throughthe solution
further quantityof
a
iodine),

out.
separates

It may

also be obtained

of a solution of alcohol
by the electrolysis
whilst a slow stream of
(oracetone)
containing
potassiumiodide,
carbon dioxide is beingpassedthroughit.
It is unnecessary to describe the characteristicproperties
of this
well-known
substance. As such, it is not an antiseptic,
and its
action dependson the liberation of free iodine by the action of the
secretions of the wound
Owing
upon which or in which it is used.
to its physical
characteristics(itmelts at 120" and volatilizesreadily
at medium
it cannot be sterilizedby heat.
temperatures)
lodoform
its objectionable
possesses two great disadvantagesfirstly,
the fact that it may be absorbed from
smell,and,secondly,
wounds and consequently
give rise to toxic symptoms. Various
these objections
to its use, and
attemptshave been made to overcome
three classes of compounds have been producedas substitutes :
"

"

A. Unstable

compounds

substances

or

mixtures

or
tendingto destroy

of iodoform

with

lessen its smell.

various

CONTAINING

ANTISEPTICS

162

IODINE

Insoluble and unstable iodine derivatives.

B.

but
different type to iodoform
itself,
totally
have a similar
which,like it,liberate iodine and consequently
action.
physiological

C. Derivatives of

A.

Class

To this group belongsiodoformin,

productof hexamethylenetetramine

alwaysa slightsmell

has
the

ease

with

which

and

iodoform,but

of the latter

it is broken

addition

(CH2)6N4.CHI3,an

down

into

this

pound
com-

substance,owing

to

its constituents

by

It contains 75 per cent, iodoform.

lodoformal, althoughnot a derivative of iodoform,may

moisture.

be

tioned
men-

of hexamethylene,
and is
place. It is the hydriodide
said to possess higherantiseptic
Its action
power than iodoform.
probablydepends on its dissociation into hexamethyleneand
hydriodicacid, this latter substance being readilydecomposed,
givingfree iodine.
of iodoform
Various tannic acid and albuminous
preparations
in this

been

have
an

put on

the

odourless

almost

sterilizedat 100" and

as
are

market, such for instance

is stated not

as does iodoform
readily
and
merelymixtures,

substances
many
will not further be described.

compoundsof

substances have been introduced.

lodolene

is

an

albumen, which

itself. But

Class

Various unstable

be
may
to give rise to iodine-eczema

with

compound

iodoformogen,

as

of this

type

B.

iodine and

albumen

which goes
It is a
iodo derivative of albumen.
That

or

glutinous

of
name
by
yellowpowder
the

insoluble in the

solvents.
ordinary
of iodine and a glutinous
substance;
lodyloform is a preparation
it is a yellowish-brown
odourless powderinsoluble in water and containing
is
that
it
of
s
tates
iodine.
10 per cent,
Sperling
equivalent
in disinfecting
to iodoform
power, but is less efficacious in the
treatment

of wounds.

compoundsof

iodine with tein

prothe former is insoluble in water,the latter soluble.

lodeigon

and

peptoiodeigon

are

Class

It is necessary

that

an

C.

iodoform substitute should be

but have
solid,
possessing
antiseptic
properties,

no

an

insoluble

smell and

only

slight
toxicity.Since the characteristicaction of iodoform is due

ANTISEPTICS

164

CONTAINING

Belongingto a different class from

or lodol,
tetra-iodo-pyrrol
I.C"

IODINE
the

previouscompounds is

C.I

It is obtained

by the action of iodine on alkaline solutions of pyrrol,

or by firstly
obtaining
tetrachlorpyrrol
by the action of chlorine on
and then decomposing
this derivative with potassium
pyrrol,
iodide,
1.

C4H4

2.

C4C14

NH
NH

+ 8C1
+ 4KI

4HC1

4KC1

C4C14 NH

C4I4 NH.

lodol.

The

action
physiological

powder,is very

of

similar to

which is a tasteless and odourless

iodol,
but it adheres better
that of iodoform,

to the

and the surface of wounds.

epidermis
one-half
a substitute for potassium
as
iodide,
in the urine,showingthat it is broken up in

II.

Iodine-containing
element

Antiseptics
in

the

It has also been used

as

of the iodine reappears

the

not

body.

liberating

that

organism.

The
the

derivatives owe
their increased antiseptic
following
power to
of hydrogenby iodine,
but,unlike the previously
replacement

mentioned

iodine is not liberated.

substances,
has marked
Quinoline,
as well as
1-oxyquinoline,

and
antipyretic
characteristic is increased by

and the latter

antiseptic
properties,
the
the replacement
of hydrogenby iodine. Based on this,
two compoundshave been introduced into pharmacy:

ing
follow-

"

SO2OH

acid or Loretin,
Quinoline-l-oxy-2-iodo-4-sulphonic

I'
OH

This is obtained from

1-oxyquinoline
by the action of cold fuming
acid ; the sodium
salt of the resulting
acid is
sulphuric
sulphonic
then treated with iodine. It is a yellow,
insoluble powder,
tasteless,

DERIVATIVES

SOZOIODOL
and

mixed

when

sodium

with

bicarbonate

It is used in tuberculosis and

Griserin,

165

goes

by

the

of

name

other infectious diseases.

Cl

or vioform,
l-oxy-2-iodo-4-chlor-quinoline

introduced in 1900

was

by

E. Tavel and Tomarkim.

substance acted
and the resulting
is chlorinated,
1-oxyquinoline
iodide solution. It is a greyish-yellow
upon by iodine in potassium
tasteless powder,insoluble in water, and without smell ; it may be
sterilizedby heatingto 100",at highertemperaturesdecomposition
sets in. It is stated to have a more
powerfulaction than iodoform.
acid were
gated
investiThe iodine derivatives of 1 : 4-phenol
sulphonic
by Ostermayerin 1880, and introduced under the name
When
of Sozoiodol
phenolis acted upon by warm
preparations.
acid the chief productis /(-phenol
acid,
sulphuric
sulphuric
I

)2OH.
When

potassiumsalt of this acid is treated with

of potashis
di-iodide of ^o-phenol
sulphonate

solution of the

chloride of

the
iodine,

formed,

acid upon
The free acid may be obtained by the action of sulphuric
of Sozoiodolic
the barium salt; it goes by the name
acid,
H

and

is soluble in water

The

sodium

with the
or

salt is

of
exception

and alcohol.
more

soluble in water

the mercury

compound

than

the

potassium;

all the salts

are

more

less soluble in that medium.

preparations
pass unchangedthroughthe organism,
action.
and it is difficult
to imaginethat theypossess any pronounced
phonic
Phenol
has antiseptic
but the introduction of the sulproperties,
The

sozoiodol

is the invariable rule,in a decrease

results,
as
and although the introduction
characteristics;
physiological
group

iodine atoms

in
of

into the molecule of this substance tends to raise the

166

ANTISEPTICS

antiseptic
power,

CONTAINING

it cannot

do

so

to any

IODINE
in

greatextent

substance

acid.
as
possessingsuch powerfulacid properties
phenolsulphuric
Frankel
of

that it is onlythe zinc and

remarks

mercury salts which are

their reactivity
not to the

in all

value,and

these owe
probability
but to the metallic ion.
radical,
(sozoiodol),

acid

lodo-anisol,

X)CH3

TT

introduced in 1904, and is obtained from the 1

was

4-iodanisol,

cwj00*
the action of

by

On

which givesrise to
chlorine,

with

treatment

caustic alkali this iodochloride

gives iodoso-

anisol,

this is boiled with

when

and
takes

water

the

followingdecomposition

place:
"

/OCH3

TT

2p

/OCH3 s

/OCH3

TT

soluble in cold water, and

substance,
explosive
onlyslightly
is used mixed with an equalquantity
of calcium phosphate,
or made
and to
into a paste with glycerin.It behaves like a superoxide,
this may possibly
be ascribed its action ; if this is the case it may
be compared to benzoylperoxide(C6H5CO)2 02, which has also
be applied
been recommended
as a useful antiseptic
locally
; it may
and does not giverise to symptoms of irritation owing
as a powder,
It is an

to its mild

anaesthetic effect.
is

Losophane

tri-iododerivative of 1

It contains 80

per cent, iodine. It is a

in alcohol,
and has been used in
oil,
"fec.,

is,however, too irritantto

Nosophen

is tetra-iodo

and

soluble
only slightly

that

of

of
iodine,

which

be of much

3-cresol,

crystalline
powder soluble
skin diseases. It
parasitic

value.

It
phenolphthalein.
in alcohol.
it contains

It has
60

it is said to
dustingpowder. Internally,

per

is insoluble in water
a

slightodour

cent.

pass

It is used

like
as

throughthe system

unchanged.
salt.

The

is its sodium

Antiosin

is soluble in

former

the
antiseptic;

ALKALI

FOR

SUBSTITUTES

IODIDES

167

salt and Eudoxiii

its bismuth

water,and is

non-toxic

and intended for

insoluble,

latter is

external
in

use

tract.
gastro-intestinal
is shown
of iodine in various preparations
The proportion
table,modified from one given in Martindale and
following
cott'sextra Pharmacopoeia(10thedition)
:

factive
putre-

conditions of the

in the

West-

"

Iodine not liberated.

easilyliberated.

Iodine

per cent.

per cent.

80-0
Losophen
Di-iodo salicylic

96-6
90-0
50-0
28-5

lodoform
lodol
Aristol

Europhen

per cent.

Sozoiodol

50-0

acid
66-67
acid 50-0
lodo salicylic

INTRODUCED

SUBSTANCES

ORGANIC

Pass unchanged through

animal organism.

PLACE

OF

IODIDES.

ALKALI

THE

IN

and occasionally
character,
objectionable,
very inconvenient,
isticsof potassium
of many noniodide have led to the investigation
toxic iodine-containing
organicsubstances. It is clear that to bring
about the same
reaction as the alkaline iodides,
these
physiological
sequently
organicderivatives must be decomposedin the body,and that conthe onlydifference between them will be that,instead of
the rapidabsorption
of the former,a slower process will take place,
the ease
with which the organic
or
dependenton their stability,

The

derivative is broken down

in the

lines similar to those

On

iodine has

been

combined

system.

indicated with
previously
with proteinmatter, and

bodies,

other
one

of such

bodies
"

It passes uncontains 21-5 per cent, of that element.

changed
throughthe stomach,and is decomposedin the intestinal

lodalbin,

canal ; the

of iodine commences
reabsorption
formed by the
lodipin is a preparation

saturated oils; of the

of the

account
taste.

Two

ease

oil of
latter,

with

which

varieties of this

sesame

from

10 per cent, iodine and

containing

region.

addition of iodine to
is said to be the

digestedand
on
are
preparation
it is

that

best,on

its freedom

the

un-

from

market, one

suitable for internal administration,

and

the other 24 per cent, specially

useful for injections.
It appears to be a most
reliable substitute for potassium
iodide,
and is most
is

useful for subcutaneous

onlyslowlyexcreted by

in which
injections,

the urine.

case

iodine

ANTISEPTICS

168

CONTAINING

SULPHUR

be accustomed to the use of

Accordingto Lesser,patients
may
of this derivative.
iodides by means
of subcutaneous
injections
when
jected,
insubcutaneously
Experimentshave shown that iodipin,
and only
remains for a long time at the seat of injection,
slowlybecomes absorbed by the tissues in the form of potassium
the body is shown by the fact that
iodide. Its diffusion throughout
scales of a syphilide
iodine was
detected in the epithelial
during
the administration of the drug.
is di-iodo-hydroxy-propane,
lothion
CH2I.CHI.CH2OH, and
it is intended
or
hypodermically,
though it cannot be used internally
as

substitute for

beingby

the method
potassiumiodide,

tration
of adminis-

inunction.

CONTAINING

SUBSTANCES

SULPHUR.

though an inert body,is,like iodoform,capableof

Sulphuritself,
effects when ib is broughtin contact with fresh
producingantiseptic
tissues. It has been employed instead of iodoform in surgery for
cavities and for other purposes ; the tissuesround
packingsuppurating
blackened and sloughaway, and a strongsmell of sulphuretted
are
hydrogen is observed,which would indicate a reducingprocess.
Lane, who was the firstto employit in this way in 1893, thinks the
of sulphurous
sequently
action is due to the formation
acid,which is subacid. A powerful reaction appears
oxidized to sulphuric
to take place,
and, as a rule,it is unsafe and unnecessary to leave
than 24 hours.1
the sulphurin contact with the tissues for more
Organicsulphurderivatives in which sulphuris in the divalent
and hence unoxidized condition have mild antiseptic
combined
action,
with the propertyof promotingthe formation of granulation
and consequently
attemptshave been made to arrive
tissue,
many
action to iodoform,
at substances which might have a corresponding
but

far without

so

Thus
on

any

marked

success.

thio-resorcin,
C6H4O2S2,obtained by the

solution of resorcin in

the cutaneous

cannot
potash,

irritation which

be

action of

sulphur
employedowing to

it produces.

OH

Sulphaminol,

has not provedof value.

from oxy-diphenyl-amine,
prepared
A combined
sulphurand iodine derivative is the ethyliodide
1

Med.

Chi. Trans., vol. 78.

169

ICHTHYOL
addition
goes

by

compound
the

of

allylurea

(seethiosinamine,
p. 218) which

of Tiodine,

name

CS\NH2C2H6I.
substance soluble in water in all proportions,
crystalline
and readily
or
absorbed by the organismwhen taken by the mouth
doses it is said to be absolutely
In therapeutic
hypodermically.
This is a

non-toxic.
ICHTHYOL.
haps
commonly employedorganicsulphurcompound is perchemical constitution has not
whose
that known
as
ichthyol,
It is a bituminous
product containing
yet been determined.
about 15 per cent, of sulphur. Ordinarymedicinal ichthyolis
of
of ammonia, but corresponding
preparations
sulphoichthyolate
pleasant
lithium,sodium and zinc are manufactured.
Owing to the unmodifications of the
smell and taste of ichthyol,
numerous
is prepared
substances have been prepared.Desichthyol
original
and is tasteless.
steam
on
ichthyol,
by the action of superheated
The

most

combination

with

albumin,Ichthalbin,

has neither taste

nor

is

and
insoluble,

quently
conse-

odour.

preparedby the action of formaldehyde,and

is only very slightly
soluble in alkaline fluids,
though tasteless,
its action is slow.
so that internally
Various salts of the sulphonic
acid have been introduced,
such
is

Ichthoform

as

and Ichthargan, the silver

Perrichthyol, the iron derivative,

compoundsof phenolswith anytin, the ammonia

salt of a hydrocarbon
and conobtained with ichthyol
taining
sulphonate,
33 per cent, of ichthyol
acid.
sulphonic
Various bodies have also been preparedwhich closely
resemble
and is
ichthyol.Thiol is a mixture of sulphonized
hydrocarbons,
obtained by heatinggas oil with sulphur. Tumenol
and petroBlubber and lanolin have also
snlphol are similar preparations.
been combined with sulphur
when treated with sulphur,
; and lysol,

salt. Anytols

becomes

are

soluble in water,and
of the properties
of ichthyol.All these bodies of

converted

showing some
unknown

into

constitution

which

are

dark

brown

mass,

of the natural duct,

proconstitution ; but,besides

imitations
empirical

is also of unknown

chemical

these,a largenumber
as

without

of pure chemical substances have been suggested

to
the
value
have
as
same
likely
ichthyol
therapeutic

its aesthetic

disulphodisadvantages.
Alkyl sulphides,

of

cyanide
biazol

potassium,

tried

and

has

Frankel

the

The

1.

various

found

the

of

efficacy

sulphur

the

in

separated

sulphydril

The

compound

3.

The

compound

Frankel

basis

all

have

compounds

unoxidized

in

not

the

"

firmly

form,

an

and

considers

of

form

an

easily

group.

must

that

he

are

in

present

which
on

These

depends.

molecule,

must

suggests

points

essential

ichthyol
be

must

combined

2.

sulphur

other

thio-

oxide,

thio-dinaphthyol-

wanting.

formulated

therapeutic

SULPHUR

alkyl-thio-urea,
and

derivatives,

been

as

CONTAINING

SUBSTANCES

170

be

unsaturated.

be

cyclic

these

in

character.

best

conditions

satisfied

are

by

taking

thiophene,

CH"

CH

II

II

CH

CH

Y
certain

ichthyol

derivatives

in

their

of

which

pharmacological

are

stated

to

properties.

correspond

very

closely

to

172

DERIVATIVES

OF

AMMONIA

They are characterized by their property of unitingwith alkyl

halogenderivatives,
whereby the trivalent nitrogenpasses over to
the pentavalent
condition
substances
(seep. 2). The resulting
be regardedas ammonium
haloids in which the hydrogen
may
atoms
are
replacedby the alkylgroup,
+ HI

NH3

NH4I; (CH3)3N+ CH3I

Ammonium
iodide.

General
1.

Methods

Primary

employed

amines

may

Tetra-methyl

Methyl

+4H

in the

+4H

action of ammonia

derivatives

of

the

by

reduction of the

the

of sodium.

means

CH3.CH2.NH2

C6H5CH2.NH2.
Benzylamine.

in alcoholic solution

aliphatic

series

givesrise

and tertiary
amines,and
primary,secondary,
ammonium

Amines.

Ethylamine.

Benzonitrile.

2. The

of the

preparation

obtained

be

nitrile.

C6H6CN

iodide.

ammonium

in alcoholic solution,
nitriles,
by

CH3CN

(CH8)4N.I

the halogen

on

to

also of the

mixture

of

quaternary

the isolation of any singleproductis an

The
will be found
described in the textbooks.

salts,and

which
operation
method is chiefly
those
of tertiary
used for the preparation
amines
of primaryor secondary
isolated but for the production
most easily
the formation of other productsis to be avoided; in the former
is best
of its derivatives,
phthalimide,
case, instead of ammonia, one
employed.
which easily
Phthalimide readily
givesa potassiumderivative,
interacts with ethyliodide,
for example,givingthe corresponding
ethylphthalimide,
"

"

This

substance is then
acid

primary

For

method

or

decomposedby means
acid and
alkali,
givingphthalic

of
the

chloric
strong hydrocorresponding

amine,

the
can

amines
of secondary
preparation
be used.

the

followingindirect

THE

OF

PREPARATION

AMINES

173

for instance,
aniline,
C6H6NH2 is treated with ethyliodide,
is the product
the tertiary
diethylaniline
amine, C6H6N(C2H5)2,

When

most

isolated.
easily

treatment

with nitrous

This substance

nitroso-derivative on

givesa

acid,
_

aniline.
jMiitroso-dietliyl

This,on

and Diethylheating with potash,forms nitroso-phenol

amine,

In the

case

of the halogen

reaction with

no

derivatives

ammonia, similar

to

of the

that

aromatic

series,

takes
just described,

place. It is onlywhen such a substituent as the nitro group has

a
hydrogen atom in the nucleus in the o and p position
replaced
that the characteristic propertyof the benzene
to the halogen,
of interacting.
When
complexis weakened,and ammonia is capable
three such groups

are

for instance in

as
present,

chloride,
picryl

-N02
N02
N02
Cl
and
of the chlorine atom is greatly
increased,
reactivity
amine.
givesrise to the corresponding
very readily

the

ammonia

(N02)3
NH2
In the aromatic
are

the true analogues

of the aliphatic
amines
series,

those derivatives containing

the amido

group in the side-chain,

for instance.
This substance,
ever,
how-

benzylamine,
C6H5 CH2NH2,
the corresponding
on
may be obtained by the action of ammonia
halogenderivative,
C6H6CH2C1, that is by a reaction analogousto
that which takes placewith the aliphatic
halogensubstitution
products.
3. Amido
compounds result from the reduction of the nitro
derivatives of either aliphatic
this method
or aromatic series. But
is entirely
of preparation
confined to the latter hydrocarbons,
owing
to the ease with which the nitro substitution products
of this series
.

are
a

obtained.
commercial

is reduced
for instance,
Nitro-benzene,
scale

of iron and

by means

C6H6NO2 +

6H

to aniline

acid
hydrochloric

C6H5NH2

"

2H2O.

on

DERIVATIVES

174

OF

AMMONIA

Secondaryamines of the aromatic series may be obtained

aniline heated
the acetylderivatives of the primary. Thus
acetic acid givesacetanilide,

C6H5NHiH| + CH3COiOHi
and

when

with

C6H5NH(COCH3),

by sodium in
sodium
corresponding

toluene,the

as

is acted upon

this substance

solvent,such

H2O

from

indifferent

an

derivative

is

obtained,

C6H6NH(COCH3)

+ Na

CeH6N"^CH

H +

reacts with an
readily
aliphatic
halogenderivative giving
which on treatment with potash
the corresponding
alkyl-acetanilide,
is broken down into the secondary
amine and acetic acid,

This

t;w^^
ii.

+KOH
C6H6N"(^H

C6H5NHC2H5

CH3COOK

Ethylaniline.
series on treatment with
aliphatic
less carbon atom.
one
containing

4. Acid amides of the

potashgive amines
phaseof the reaction consists in
or

CH3CONH2
These

Br2+

derivatives are

CH3CONHBr

KOH

the formation of
=

+ 3KOH

KBr

+ KBr

into

K2CO3

The first

bromamides,

CH3CONHBr

then further broken down

bromine

H2O

amines,

CH3NH2
Methylamine.

to the
applicable
five carbon atoms.
containing

This method
those
In

is

the aromatic

series this reaction is used

of
production

anthranilic

in the

of the

success

of the

amides

acid,and has been

one

of

...

of the chief factors

phthalicacid.

""

rw/CONHBr

C"H4\COOK
Anthranilic

acid.

to

for the commercial

indigosynthesis.

Mon-amide

in.

fattyseriesup

OF

PROPERTIES

General

The

lower

of the

AMINES

Ammonia

of the

Properties
members

THE

aliphatic

175

Derivatives.
amines

are

gases

with

soluble in water; the higher

readily
and it is onlyin the case
of those
also soluble,
members
are
liquids
in this liquid
with high molecular magnitude that the solubility
bases than ammonia, the basicity
becomes slight.They are stronger
to the number
in proportion
of alkylgroups replacing
increasing
ammonia.
hydrogenatoms of the original

odour,and

ammoniacal

On

the other

hand, in

are

the

case

of aromatic

amines,this property
base; diphenylamine,

aniline is a weak
powerfullydepressed,
this
(C6H5)2NH, stillweaker; and in triphenylamine,
(C6H5)3N,
characteristichas entirely
The entrance of halogen
disappeared.
into the nucleus of aniline further depresses
atoms
or nitro groups
its already
basic properties.
slight
The aromatic amines
colourless liquids
are
or
solids,
having a
and characteristicsmell ; unlike the aliphatic
peculiar
theyhave no
and are onlyslightly
alkaline reaction,
soluble in water.
of primaryand secondary
The reactivity
amines of both series,
is dependenton the ease with which
as comparedwith the tertiary,
the hydrogenatoms of the original
ammonia
are
replaced.In the
aromatic series,
unlike the aliphatic,
the hydrogen atoms
in the
amines may be replaced
primaryand secondary
by potassium.
is

Primary

and

characteristic manner

of both

Amines

Secondary

with nitrous acid.

series behave

Primary amines

in

of the

fattyseriesyieldalcohols,

C2H6NH2+ HN02
In

the aromatic

C2H5OH

H2O

the important
di-azo
series,

N2.

reaction takes

place

(seep. 41).
The

i.

Secondary

Amines

of both series givenitrosamines,

(C2H5)2NH+ HN02

H20

(C2H6)2NO
Diethyl-nitrosamine.

ii.

C6H5NH.CH3

HN02=

H20

C6H6

Nitrosamine of methyl aniline.

The

nitrosamines of the aromatic series undergo an interesting

intramolecular change,on treating
their alcoholic solution with
when jo-nitroso
derivatives are
hydrochloric
acid,
_"

obtained.

NO.C6H4.NHCH3.
aniline.
#-nitroso-inethyl

176

DERIVATIVES

The

Tertiary

Amines

AMMONIA

OF
the

of

Aliphatic

Series

either do not

Teact at all with nitrous

or are
acid,
decomposed; whereas
completely
in the aromatic series,
in the 1 : 4 position
in
the hydrogen atom
the ringis attacked,
with the formation of jt?-nitroso
derivatives.

(CH3)2N.C6H5+HN02

(CH3)2N.C6H4.NO + H20.

aniline.
jp-nitroso-dimethyl

The

of littleif any physiological

importance,
the following
statements and reactions will only

amines
aliphatic

and in consequence
applyto the amines

Both

aniline and

are

of the aromatic series.

^-amidophenol,

sensitive to

be
oxidizingagents,but their stability
can
increased by their conversion into a group of derivatives
very largely
called the Anilides.
These may be obtained by the action of
the acid,or acid chloride or anhydride,
the amine (see
on
p. 120).

are

very

C6H5NH.COCH3

Acetanilide.

C6H5NH|Hj

C^COps

C6H6NHjHi +

or

CH3CO:Clf C6H5NH.COCH3
=

C6H5NH.COC6H5

HC1

HC1

Benzanilide.

It is
radicals

possible
by
in placeof

this
the

means

to introduce

hydrogen of

either

of different
variety
primary or secondary
a

amines.
The

acid anilides

distilledwithout

very
change,and
are

stable

derivatives,
theycan

often be

nitrated or sulphonated.
directly
and
They are characterized by their great power of crystallization,
of the aromatic
of detecting
serve
as
a means
consequently
many
The

also

introduction of the acidic grouping,

as

presses
demight be expected,
the basic characteristics,
methyl acetamide,
CH3NH.COCH3,
is only slightly
is decomof
acetanilide
the
posed
basic,
hydrochloride
by water. Modified characteristicssimilar to this are observed
the entrance of acidic groupingsinto basic substances.
Thus
on
the
powerful base methylamine,CH3NH2, becomes glycocol,
of hydrogenby the acidic
COOH.CH2 NH2, on the replacement
in this substance both the basic properties
COOH
of the
group;
are
NH2 group and the characteristicsof the COOH
very consider.

THE

AMINES

177

powerfulacidic properties,
of the hydroxyl
hydrogenatom ;
replacement

Phenol, C6H5OH,

ably modified.

salts by the

and forms

OF

PROPERTIES

PHYSIOLOGICAL

has

jo-amidophenol,
~)H

by the

lost this salt-forming

NH2 group, has entirely
of aniline being still
the alreadyslightbasic properties
depressed.

entrance of the

power,
further
The

anilidesare
alkalis or

with

broken

down

heatingwith

into their componentson

mineral

placein the

Physiological Properties.

effect following
the
physiological

residue is

and
dependent,firstly

nucleus into which

the

decomposition
taking

organism.
General

The

acids,and the physiological

to this

reaction of these derivatives is due

treatment

it

enters,and

a
nitrogencomplex;thirdly

is
reactivity

noticed when

entrance

on
chiefly,
secondlyon

of the ammonia

the nature
the

curious variation of

of the

of
reactivity
physiological

trivalent derivatives pass

over

into

those of the ammonium

type.
and its salts,
remarkable in differing
from
are
itself,
which are in combination depressant,
whereas
the caustic alkalis,
Ammonia

ammonia

is a stimulant.

producestetanic convulsions,
in origin
spinal
partly
; the convulsions are not so
character as those producedby strychnine.
The
spinalreflexes is,however, increased. It also
and respiration
due
: the latter action is probably

ammonia
injected,
Intravenously

cerebral and
partly
markedlyreflexin
of the
irritability
the heart
quickens
to

stimulation

of the

centre

in the

medulla.

The

rise of blood

follows the preliminary

is
fall,
pressure, which almost immediately
but appears to be partly,
not due to central action,
at least,
a consequence
of the increased cardiac action. The
the action of ammonia

of the motor

nerve

main

differencebetween

is due to the rapidparalysis

strychnine
endingsby the former,which preventsthe
and

of tetanus.
supervention
When
the hydrogenatoms are replaced
by radicalsof the aliphatic
and
the resulting
hydrocarbonsthese characteristics disappear,
and tertiary
amines irritatethe mucous
secondary,
brane,
memprimary,
but otherwise have slight,
if any, physiological
reaction.
Further,the replacementof two
hydrogen atoms by amido
or pentadiamine,
NH^CH^NHg,
groups, e. g. in tetramethylene
N

OF

DERIVATIVES

178

methylenediamine,
NH2

CH2

(CH^

AMMONIA

NH2, givesrise to similarly

inactive substances.

hydroxylin
replaces

the amido

When

group
formation
in
the
resulting

of bodies

the

acids,
aliphatic

of the nature

of

acetamide,

inactive bodies
pharmacologically
result. If the amido
hydrogen in the aliphatic
replaces
group
the result is similar.
nucleus of these acids,
NH2. CH2. COOH,
amido
acids,
/3-amidopropionic
acetic,NH2 CH2 CH2 COOH,
.

"c.,are

that

it is againfound

CH3CONH2,

but
inert,

unlike

acetamide

these

are

broken

down

in the

described (p.74).
organism,as previously
COO
Betaine,
trimethylglycocol,

is

under
its hydrochloride,

and
inactive,
physiologically

Acidol, has

introduced

been

as

solid substitute for

the

of

hydrochloric

soluble in water, and contains 23-78

acid ; it is very readily
off in the stomach.
acid,which is slowlysplit

per cent.

in the benzene
a hydrogenatom
group replaces
and a comof aniline result,
of the nature
pletely

the amido

When

name

nucleus,substances

pharmacological
properties
appear ;
of a large
the basis for the synthesis
this observation has formed
which will be described later.
group of so-called 'antipyretics',
new

and

valuable set of

group into the aromatic nucleus

givesrise to powerfullytoxic substances unlike the corresponding
The

entrance

of

second

amido

diamines.
aliphatic

primary aromatic amine to a secondaryis

alteration in physiological
followed by a corresponding
properties.
and have
and amyl aniline are less toxic than aniline,
Methyl,ethyl,
muscular
lost the power which that substance possesses of producing
about the paralysis
of
spasms, but,on the other hand, they bring
similar
the peripheral
endingsof the motor nerves, in a somewhat
action
to the alkylalkaloids,
manner
althoughwithout the curare
of the quinquevalent
nitrogenderivatives. (Compare action of
antifebrin and exalgin.)
The

passage

The

presence

most
toxicity,

is a
to

of

result in an
increase of
group may
due to increase of reactivity.
Thus,guanidin
probably
of

an

imido

three imido groups, is,

according
theobromine with one, and this more

poison.Xanthine,with
powerful
Eilehne,more

toxic than

180

DERIVATIVES

OF

AMMONIA

with the
in the organism,
great resistance to decomposition

result

almost completely,
inactive
or
they are usuallycompletely,
the
that whereas
it must
be remembered
But
physiologically.
of perhapslactic and citric acids,
with exception
radicals,
aliphatic
have no pharmacological
of the aromatic acids have
action,some
as
a considerable effect,
(p.151).
such,for instance,
salicylic
if such an acid is one of the decomposition
products
Consequently,
with
of the acyl-nitrogen
its action will appear together
derivative,
that

that of the basic residue.

B.

Hydrogen

of

Group

Hydroxyl

Acid

by

Radicals.

of hydrogenof the amido group by acid

replacement
different action is
radicals bringsabout a decrease in toxicity,
a
placed.
disnoticed when the hydrogen of an hydroxylgroup is similarly
the

Whereas

In

this

case

increase

an

is
properties

in toxic

noticed.

Ecgoninemethyl ester,C10H16NO2 OH, has no local anaesthetic

of the hydroxylhydrogenby benzoyl,
action ; by the replacement
cocaine results,
C10H16NO2 0.COC6H5, a powerfullocalanaesthetic.
toxic than lupinine.
is much more
Benzoyllupinine
.

C10H18N.O.CO.C6H6

C10H18N.OH

Benzoyl-lupinine.

Lupinine.

Mono-acetylmorphine,diacetylmorphine (Heroine),
benzoyl
and
have
similar
a
dibenzoylmorphine
morphine,
physiological
but are far more
action to codeine (methylmorphine),
toxic. The
the respiratory
effect on the spinal
on
cord,and especially
depressant
centre,is much
greaterthan that of morphine. Compared with
one-tenth of the dose will producea similar narcotic effect.
codeine,
Veratrine may be split
up by the action of an alkali into cevine
and tiglinic
acid,

C32H4,N09+ H20
has

the

toxicity,
owing to

same

C,H,Oi+ CfrH41^0,
Cevine.

Tiglinicacid.

Veratrine.

Cevine

action
physiological

the absence

as

but its
veratrine,

of the substituted acid group,

is ten

times less.

producedby the introduction of the acid

toxicity
action of that group in
group does not dependon the physiological
certain anchoring groups in
but upon its power of covering
itself,
the molecule,
so that the latter,
can
resistant,
beingmore generally
the central or peripheral
action (i.
e. on
nervous
producea specific
The increase in

'

AROMATIC

OF

DERIVATIVES

AMINES

system).The acid radical may also form an anchoring'

group
for the production
of a special
physiological
response.

and

of Calm
discovery

itself

DERIVATIVES.

ANILINE
The

181

Hepp

that aniline

is
(oracetanilide)

and also possesses antineuralgic

a
properties,
powerfulantipyretic,
has led to the prowith the low priceof this substance,
together
duction
of its derivatives.
of a largenumber
its salts have

and

action,like
powerfulantipyretic
it produces
spasmodicmuscular contractions of central

Aniline

and
phenol,
The main toxic symptoms are weakness,
does ammonia.
as
origin,
and finally
with or without vomiting
collapse,
cyanosis,
dizziness,
due to direct irritationof the gastric
mucosa.

Aniline

also breaks

up

the

red

blood

the
cells,liberating

haemoglobin.
Toxic

symptoms of

similar nature

but less pronouncedcharacter

workers in the
observed among
at one
Aniline was
oil is used.1

in which aniline
dyeingindustry,
time employed as a remedy for
the vapour being
and other forms of tuberculous disease,
phthisis
inhaled in combination with certain aromatic antiseptics.
Like
most
schemes for internal antisepsis,
however,this failed when
test; the tubercle bacilli in the blood-stream
put to a practical
whereas the patients
exhibited symptoms of
remained unaffected,
poisoningdue to the presence of the drug.
that when the reactive amido
It was
onlyto be expected
group is
stable by replacing
rendered more
hydrogenwith the acetylgroup,
should be a far less toxic
acetanilide (antifebrin)
the resulting
are

substance.

C6H6NH(COCH3),

shows the

generalreaction
aniline. It reduces fever,has similar antineuralgic
as
properties,
and a similar though less marked
action on the red blood corpuscles
;
is
but the effect,
it
the
of
the
anilide
on
decomposition
dependentas
in the organism,
is not producedso rapidly
as by the free base. No
effect on
metabolism
with therapeutic
doses.
occurs
nitrogenous
In pyrexia
diminution may occur.
a
slight
Acetanilide is oxidized in the body to jt?-aminophenol
and is
excreted in the urine partlyas oxycarbanile,
Antifebrin,

Dearden, British

Medical

Association

same

Meeting,1902.

DERIVATIVES

182

OF

AROMATIC

AMINES

and /"-aminophenol.
The
latter is further
/?-acetyl-aminophenol,
changed by combination with sulphuricand glycuronicacids.
These
changes in structure diminish the toxicityof aniline or
their antipyretic
but do not destroy
action.
acetanilide,
entirely
The most varied acid radicals have been introduced in placeof
but without the production
of subthe acetyt
stances
group in acetanilide,
reaction ; since this factor is
with any novel physiological
of the decomposition
of these derivatives
a function
unquestionably
this was
into aniline,
hardlyto be expected. It is only when the
characteristics of its own
that
enteringgroup has physiological
with those of aniline.
these may
simultaneously
appear
:
Among substances of this type are the following
formed
1. Formanilide,C6H5NH(OCH),
by rapidlyheating
with
oxalic acid and aniline,
formic acid. It
or
treatinganiline
has powerfulantipyretic
and analgesic
and acts as a
properties,
"

local

but
anaesthetic,

is much

toxic

more

than

this
acetanilide,

being undoubtedlydue to the fact that it is much more

easily
dilute
acids.
decomposedby
2. Benzanilide,
C6H5NH(COC6H5), is only broken down by the
and consequently
largerdoses are required
organismwith difficulty,
than in the

case

of acetanilide.

Salicylanilide,
anisanilide,
C6H5NH(COC6H4
OH), and
C6H5NH(COC6H4 OCH3), like most derivatives of this type,are.
that their
onlybroken down by the organismwith such difficulty
reaction is but slight.
physiological
of acetanilide by the formation
Attempts to increase the solubility
3.

of such

substances

acetanilidoacetic acid and

as

acetic acid,by the action of chloracetic acid

on

formanilido-

acetanilide or form-

anilide,
"

when

C1.CH2

COOH

HC1

C6H4]

since these
(COCH3)'or (CHO)',gave negativeresults,

substances,
havinglost their basic characteristicsand become acidsr

obey the generalrule that such derivatives therebylose their physiological

F
ormanilidoacetic
acid,however, owing to its
properties.
is
toxic
about
formanilide.
For similar reasons,
as
as
instability,
Cosparin,
p

"

/NHCOCH3

^"n*\
the

SO2ONa

of acetanilide,
obtained by
jp-sulphonate

the action of acetic acid

PROPERTIES

PHYSIOLOGICAL

183

acid,
sulphanilic

on

should have

since
importance,
physiological

no

its action

can

only

acid.
sulphanilic
of acetanilide and phenacetin,
In order to increase the solubility
derivatives were
obtained containing
the sulphonic
group in placeof
the hydrogenof the methane radical ; these were
prepared
firstly
by
of
dehydratingthe aniline salt of monochloracetic acid by means
phosphorus
pentoxide,

dependon

into the inert

its decomposition

CH2C1.COO(C6H5NH3)-H20
and

heatingthis
sulphite

then

sodium

CH2C1.CO.NHC6H6,

latter substance

in aqueous

solution with

"

C6H5NH.(COCH2C1)+ Na2S03
=

NaCl

C6H5NH.(CO.CH2.SO2ONa)

The

substances are much more

soluble than acetanilide or
resulting
which is stated to be the
and, if their action is similar,
phenacetin,
be broken down in the organism,the acidic groupcase, theymust
ing
not beingsufficiently
stable for them to obey the general
rule.
Another
method of modifyingthe action of aniline,
that is of
it into a urethane
stable,consists in converting
making it more
derivative by the action of chlorformic ester
"

C6H6NHiH+ CljCOOC2H6

HC1 +

C6H5NH.COOC2H6
Phenyl urethane.

The

termed Enphorin, is much

less toxic
resulting
substance,
than aniline. Physiologically
its action resembles that of acetanilide
rather than that of urethane.
It depresses
the temperature,
and has considerable analgesic
Large doses weaken the
properties.
It has also a bactericidal action,
and has
pulseand respiration.
been employed to check
suppuration.It is not of value as a
hypnoticlike other urethane derivatives (hedonal,
"c.). It does
not lead to the formation
doses it acts
of methaemoglobin.In large
like a urethane derivative,
the central nervous
paralysing
system ;
the effect is very similar to the paretic
action of alcohol. In
moderate

doses it is said to decrease metabolic processes, but its

action is similar to that of the other bodies of this group,
antipyretic

beingdue to the dilatation of the cutaneous vessels. It increases

the conjugated
in the urine,and is partlyexcreted as
sulphates
that this derivative
indication consequently
an
oxyphenylurethane,
is less toxic than euphorin
itself(seep. 196).

Whereas

the

is

OF

DERIVATIVES

184

has powerfully
toxic
Exalgin (methylacetanilide)
Methyleupliorin,
corresponding

perties,
pro-

indifferent substance.

almost

an

/-AMIDO-PHENOL

secondaryamine, methylthe
aniline,
C6H5NHCH3, a substance is obtained which paralyses
motor
nerve
endings. Exalgin, which is the acetylderivative of
this,
When

has

aniline

somewhat

is converted

similar

into the

action

but
acetanilide,

to

powerfully
and profuse

convulsions
secondaryreaction,
producingepileptic
salivation. Death results from respiratory
failure. The convulsions
be stoppedby the induction of anaesthesia,
and are probably
can
doses propartlycerebral and partlyspinal.Smaller (non-toxic)
duce
in mammals
a
nd
of
arterialpressure.
a fall
lethargy
the replacement
of aniline by any of the toluidines has
Finally,
no
advantages,since they act on the red blood corpuscles,
forming
to aniline itself.
methaemoglobinin a similar manner
On injection
into the jugularvein of a dog the lethal dose of
these bases per kilo, weight has been found
to be : or^o-toluidine

toxic

"208 gm., 1
But when

3-toluidine -125 gm., 1

converted

into their

4-toluidine -1 gm.

acetylderivatives

difference is noticed ; both 1 : 3 and 1:4

characteristicis onlynoticed with the 1 : 2

only the

barini states

3 derivative that

has

are

non

considerable

and
-toxic,

substance.

it is

Then

and
antipyretic
properties,

that it is less toxic and

has

this

Bar-

stronger action than

antifebrin.
Aniline

and

either the

than

the
depress

^-toluidine

the former substances

/-derivative
; further,
temperatureto a greaterextent than the latter.
o-

DERIVATIVES
On

capacitymore
depressthe respiratory

or

OF

/-AMIDO-PHENOL,

C6H4"

1:4.*

their passage

acetanilide,
or
through the organism,aniline,
active derivatives of
speaking,any of the physiologically
generally
1

1 :2-amido

is inactive,
the
but when
phenol,unlike the 1 : 4 derivative,
hydroxyl hydrogen atom is replaced by alkyl radicals,bodies possessing
narcotic
propertiesresult ; the 1 : 2 and 1 : 3 present no pharmacological
toxic than the para derivative.
advantage,and are both more

PROPERTIES

PHYSIOLOGICAL

185

converted in ^-amido-phenol,
which
partially
acid.
is eliminated as a sulphonate
a compound of glycuronic
or as
that such changesalways tend to
Since observations have shown
it was
vestigat
but natural to inthe production
of less toxic derivatives,
value of this substituted aniline. The
the therapeutic
these substances,are

chemical

nature

of this

substance,and

characteristics of each substituent

by

the

modifications

their simultaneous

of the
presence

pharmacological
viz. energetic
those to be expected,
action,
antipyretic
are
properties
and haemolytic
action than is shown by aniline.
but much less toxicity
The whole group of physiologically
active derivatives of aniline or
in the organismwith the producbroken down
are
tion
jo-amido-phenol
reaction in the
of this latter substance,and the indophenol
urine may be taken as a test for their reactivity.
action
Trenpeland Hinsberghave stated that the antipyretic
of aniline and ^-amido-phenolderivatives appears to be, within
of
to the amount
certain limits,
or
nearlyproportional
proportional
aniline or /"-amido-phenol
formed in the organism'.
or
phenetidin
On the other hand, if these substances are not formed
e. if no
(i.
is
then the preparation
indophenolreaction with the urine occurs),
not physiologically
active.
in the

molecule,have alreadybeen described

the

'

Thus,
C
Methacetin,

C
Phenacetin,
/OC1

and

are

decomposedin
readily

the

and
giving/"-amido-phenol,
organism,

show

characteristics similar
physiological
phenacetin,

in which
acetamido

TT

C6H4\\rTj n
acetamidophenol-propyl-ether,

to those

derivatives of

CH3, C2H6,C3H7,or wo-propylgroups.

phenol,
=

But

ethyl-

which

is not

has no antipyretic
or other action.
decomposed,
It will be readily
that the generalphysiological
reaction of
seen
the whole of the /?-amido-phenol
derivatives will be that of the free
base itself,
and that
or of itsethoxyor methoxy substitution product,

OF

DERIVATIVES

186

J9-AMIDO-PHENOL

added to this reaction will be that of the radical attached

amido
for

group

example,this

In the

of acid derivatives of the

; in the case

case

of

would

to thei

series,
aliphatic

be nil.

two
//-amido-phenol,

tions
different classes of modifica-

hydrogen of the hydroxyl

of the
the hydrogen atoms
be replaced
or
can
by radicals,
group
amido group can be similarly
displaced.
The replacement
of H in the NH2 group by acetyl,
givingacetamido-phenol,
can

be

either the

carried out;

of a substance with powerful

antipyretic,
production
but of much
and possibly
antineuralgic,
slightnarcotic properties,
than the original
lower toxicity
substance. The further replacement
of the hydrogenof the hydroxylgroup by methyl,

results in the

/OCH3

C6U4\NHCOCH3
causes
(methacetin),
a

an

decrease in the action

and
properties
replaced
by ethyl,

increase in both the former

on

the blood ;
TT

/OC2H(

tion
the narcotic action is increased,
and a further diminu(phenacetin),
in the formation of methaemoglobin
is noticed. The maximum
and antineuralgic
action is found in the case of methyl,
antipyretic
minishes
action dibut lesser toxicity
in case
of ethyl. The antipyretic
with the increasing
molecular magnitude of the group
H of the hydroxyl. In one
then, the possible
direction,
replacing
variations as regardsalkylgroups replacing
that hydrogenatom is
limited to either methyl or ethyl.
In phenacetin
the hydrogenatom R,

ft

"

,COCH3,
be

replaced
by acid groups, which will be
radicals of the aliphatic
hydrocarbons.The

may

discussed later,
or
of

by

methyl
increase in the narcotic and also in the antineuralgic
causes
an
but the substance has onlya slight
properties,
antipyretic
power.
in
similar
in
increase
decrease
a
Replacedby ethyl,
toxicity,
and decrease in antipyretic
noticed.
are
narcotic,
properties
entrance

OF

DERIVATIVES

188

^-AMIDO-PHENOL

of p-mtro phenolin a
preparation
is
means
easy ; the method of preparation
is diazotized and treated with a phenoland
As

state of

the

OC2H5

/OC2H5
2
-

purityis by

jo-Phenetidin
carbonate,

modified.
sodium

/OC2H5

and

the

no

N.C6H4

into the

converted
resultingcompound is readily

OH

di-ethoxy

derivative

which, on reduction,
givestwo

Half

of the

yieldis

N.C6H4 OC2H5,
.

molecules of

phenetidin
"

of
phenacetiri
by means
of
acetic acid,and the other half again used for the preparation
of phenetidin.
a fresh quantity
the toxic effect of this substance is not great.
Physiologically
grams
DujardinBeaumetz gave 2-5 grams to a rabbit weighing2"26 kilowithout
and 2 grams
have been givenfor
any toxic effect,
Large doses produce
every kilogrambody-weightin other animals.
the characteristic aniline action on the red corpuscles,
the blood
becomes thick and purple,
shows the spectrum of methand finally
haemoglobin. The darkeningof the urine also takes place,and
action
substance appears. The
a reducing
occasionally
antipyretic
is thus explained
by Schmiedeberg.In the first place,metabolism
experimentshave shown that the nitrogenexcretion is increased
with small doses,and onlydecreased with largeones ; thus a direct
of the fall
metabolism cannot be the cause
decrease in nitrogenous

then

converted

into

'

'

in

temperature.Now,
raised by puncture of
of

if animals

in which

the corpus striatum

of its congeners,

phenacetinor one
morphine (-01"02 grams,

the

temperaturehas been

are

givenmoderate

or

even

small

doses

doses

of

J" | grain),a fall of temperatureis

observed after one or two hours,which,however, is onlytemporary.
in
If this experiment,
and the animal placed
however,is performed,
incubator at 31-32" C.,no fall of temperaturetakes place
an
; thus,
and
the fall of temperaturemust
be induced by increased heat-loss,
not by diminished heat production.Large doses of these drugs,
the
however, paralyse
The
due

to

centre for heat

heat-loss is shown

dilatation of the

production.
to be
by plethysmographic
experiments
cutaneous
with a corresponding
vessels,

contraction of the internal arterioles.

PHYSIOLOGICAL
The

PROPERTIES

action of
characteristic analgesic

to its effect

on

Phenacetin

189

is mainly due
phenacetin

the sensory tracts in the cord.

soluble in
is,however, only slightly

water, and

sequently
con-

onlyslowlyabsorbed. Many attemptshave been made

without
the stability
of
to increase the solubility
so
diminishing
its decomposition
the substance as to cause
or
rapiddecomposition
of
acid,whereby the toxic
hydrochloric
by a 2 per cent, solution
For
would be formed in the stomach.
of phenetidin
hydrochloride
is

this purpose various acid radicals have been introduced into the
which are classified
basic NH2 group, and the following
examples,
to
according
some

cases

the

has

show that (1)onlyin

typeof chemical modification,
scribed
the desired result followed;(2)the substances de-

illustrate the modifications in the

be obtained

can
no

by

substance has

such variations of

been

reaction which
physiological
the molecular structure ; (3)

with
obtained,by such modifications,

any

of course
nor
was
properties,
pharmacological
likely,
if the action of these derivatives actually
it most proas
depends,
bably
into one and the same
does,on their decomposition
substance,
or its ethylether.
jo-amido-phenol
this

novel

Class

1.

I.

Formyl-phenetidin,

formed

by actingwith formic acid and sodium formate on phenetidin,

has an action entirely
different from that of the other derivatives of
this substance.
The
effect almost entirely
antipyretic
disappears,
and is replaced
a
ction
the
cells of
on
by a powerfullydepressant
the spinal
cord. It is,in fact,
a physiological
to strychantagonist
nine,
but unfortunately
it has no therapeutic
value in checking
convulsions caused by disease.
2. Propyl-phenetidm,
r IT /OC2H5

^M4\NH.(COCH2.CH3)

termed Triphenin by Mering,has similar properties

to phenacetin,
but its slight
results in slow absorption,
and consequent
solubility
mild physiological
reactivity.
3.

Lactyl-phenetidin,
5

is obtained by
(Lactophenin),
heatingthe

lactic acid salt of the

190

OF

DERIVATIVES

jo-AMIDO-PHENOL

130"-180",or by heatinglactic anhydrideor lactic ester

with
be obtained by
the base to this temperature; or it may
by OH,
replacingthe halogen in a-brompropionyl-phenetidin
base to

Its action appears

agency of aqueous sodium acetate.
but it is more
soluble ; the
to be identical with that of phenacetin,

throughthe

action is
antipyretic
In rabbits its
slighter.It is mainlyvaluable as an antineuralgic.
the animal
resembles that produced
effect closely
by chloral hydrate,
to painful
remainingunconscious and motionless,and irresponsive
and circulation are not affected
reflexes,
though the respiration
It is more
liable than phenacetin
to lead to the
(Schmiedeberg).
in the stomach.
of phenetidin
formation of the toxic hydrochloride
4. jo-Ethoxyphenyl-succinimide
(Pyrantin)

narcotic action is well

is obtained

by

marked, though

the action of succinic

sodium

and

but is said to have

analgesic,

5.

no

anhydride on

It is

salt is soluble in water.

The

the

an

the

base.

uncertain

toxic action

on

antipyretic
haemoglobin.

Diacet-phenetidin
)C2H
CfiH4
4

theoreticalgrounds,to prove a more

on
powerful
thoughtlikely,
in
this
but
actual
not
than phenacetin,
was
practice
antipyretic
was

established.
6.

It is very unstable.

Salicyl-phenetidin
TT

/OCH

is
majorityof such derivatives,
It was
nally
origionly broken down in the organismwith difficulty.
of
in order to avoid the formation
introduced to replace
salol,
but
juice,
phenolin the organism. It is unaffected by the gastric
but
decomposed by the pancreatic.It is slightlyantipyretic,
portionof the molecule. It
appears mainlyactive as to the salicyl
increase in the
is mostly excreted unchanged in the urine. No
Quinic acid producesa similarly
conjugatedsulphatesoccurs.
inert compound with phenetidin.
like
(Salophenor Saliphenin),

the

PROPERTIES

PHYSIOLOGICAL

191

7. Amygdophenin,

C6H4\NH2CO.CH(OH).C6H5,
is obtained

with
by heating/^zra-phenetidin

130"-170" C.
the
of

The

mandelic

acid

diminishes

action by diminishing
the
antipyretic
absorption.

Class

A.

Attempts

to increase the

ordinarymethods
introduction of

mandelic

acid

at

the

toxicityand
and rapidity
solubility

II.

of phenacetinby
solubility
that is by
organicchemistry,

employed in
(COOH) or (SO2OH)

group

into the

the
the

nucleus,

to lead to the desired result,

since Nencki had shown
unlikely
such changestend to destroyphysiological
activity.Thus,
the soluble phenacetin
acid,
sulphonic

were

that

both

C6H3f-NH.COCH3

\S02OH
and

phenacetin
acid,
carboxylic

0"H5
C6H3f-NH.COCH3

\COOH

but
preparedin Schering's
are
laboratory,
Fhesin,

the sodium

salt of the former

very

reactive.
slightly

acid,

XOC2H5

C6H/NHCOCH3
\S02ONa
is

light-brown
powder,soluble in water,with a slightly
astringent
salt taste. It is employedin doses of 15-30 grains,
and apparently
and antipyretic
action.
possesses analgesic
a

On

the other

hand, the introduction of a second amido group

into the nucleus,
another possibility
for the preparation
affording
of soluble derivatives,
is not feasible,
since it results in a large
increase in

toxicity.
B. The replacement
of hydrogen in the amido
group by acid
radicals has led to the preparation
of several substances of greater
than
solubility phenacetin.But it was hardlyto be expectedthat,
if the stability
of the body were
such as to allow of its decomposition,
in the organism,
there should be any
giving
^-amido-phenol

192

DERIVATIVES

OF

considerable decrease in

^-AMIDO-PHENOL
the other

hand,the stability
might be expectedto

on
toxicity
; if,

great,then the presence

of acid groups
giverise to substances with littleif any physiological
activity.
was

1. The

citricacid derivatives of
i.

are
phenetidin

"

CH2COOH
C.OH.COOH

Apolysin,

CH2
ii.

CH2

CO-NH.C6H4.

OC2H5

CO.NH.C6H4 OC2H5
.

C.OH.COOH

CH2

CO.NH.C6H4 OC2H5.
.

is soluble in about

partsof cold water,

and

freely
migraine,
but is said by some
observers to have neither the analgesic
the
nor
of phenacetin.It is,like lactophenin,
easily
antipyretic
properties
acid in the stomach, givingrise to
decomposedby the hydrochloric
salt ; this producesboth local and general
the toxic phenetidin
no
decomposition
occurs,
symptoms. If injectedsubcutaneously
and
the substance
into
the
its
urine;
only
passes unchanged
action then is due to the acid radicals.
physiological
Apolysiu

in hot water,

and
alcohol,

80

glycerin.It has been

CH2

used

in

CO.NH.C6H4OC2H5

/^tr"?he?\
C.OH.CO.NH.C6H4OC2H5

(Citrophenm),
,

CH2.CO.NH.C6H4.OC2H5
Its action
taste.
pleasant
resembles that of phenacetin.The formula
given above was that
however, states that it is merely the
given by Boos ; Hildebrand,
is similar to that of
citrate of phenetidin
; its action physiologically
and not to that of a true substitution product.
a salt of phenetidin,
of iron,which
Chemicallyit givesa red coloration with perchloride
apolysindoes not. It is a blood poisonlike the other phenetidin

is soluble in 40

partsof water, and

has

salts.
2. Schmidt

acid,
preparedethoxy-succinanilic

.CO.CH2.CH2.CO.OH,

PROPERTIES

PHYSIOLOGICAL
and

193

acid,
ethoxytartranilic
r

"

/OC2H5

C6H4\NH.CO.CHOH.CH.OH.COOH,
owing to the introduction of the acid group, these
action.
antipyretic
3. In a similar manner
ethoxyphenyl-glycin,

but
no

has been found to possess

bodies have

".CH2.COOH,
value.
pharmacological

no

4. Fheiiosal,

"C0H,

D.CH2.O.C6H4.COOH,
obtained

acid with phenetidin

to 120 ",is
by heatingsalicylacetic
in water,alcohol,
a white crystalline
powder,soluble with difficulty
and ether. It has a bitter acrid taste,and has been employedfor
its antipyretic
and analgesic
which, however, are but
qualities,
slight.
Class

III.

of pheMajert,in order to increase the solubility

nacetin,
amido-phenacetin
prepared
(glycocoll,-phenetidin,Ph.en
Schmidt

and

OC0He

by the action of ammonia

is soluble in
hydrochloride

bromacetylphenetidin. The
16 partsof water, forming a solution
and
of bitter,
saline taste. It has the usual phenacetin-like
action,
few authors state that it is an antiperiodic.
This is not, however,
a
accepted.It appears to have some antiseptic
generally
perties,
proit
has
been
substitute
for
as
a
as
employed externally
on

iodoform.
is more
owing to its solubility,
hydrochloride,
rapidly
than
a
nd
acts
absorbed, consequently more quickly
phenacetin. It
is said to be more
and to be an efficientsubstitute
powerfully
analgesic,
in acute rheumatism.
for salicylates
It may
as
an
antipyretic
and cyanosis.Mosse considers it of value in septic
cause
collapse
infections only. It is rapidly
excreted by the kidneys,
that its
so
Phenocoll

action is but

transitory.

acid
Salocoll, its salicylic
which

is insoluble in water.

compound,is the onlysalt of phenocoll

Its action resembles that of the

substances.
o

parent

DERIVATIVES

194

OF

jo-AMIDO-PHENOL

Class

Various

condensation

IV.

with aldehydes
and
productsof phenetidin

ketones have been

1.

and investigated.
prepared
Salicyl-phenetidin
"C2H5
OH
: CH.C6H4
.

is preparedby the action of salicylaldehyde

direct or in
(Malakin),
alcoholic solution on phenetidin.
It is almost insoluble in water,
and onlyslightly
its action is
soluble in alcohol. As an antipyretic,
said to be slow,but itis a useful analgesic.
The dose is 8-25 grains.
Its insolubility
interfereswith its physiological
action.
2.

Methyl-benzylidene-phenetidin,

obtained

on
phenetidin.The citric
acetophenone
acid salt of this derivative goes by the name
of Malarin.
The
insoluble in water,but freely
soluble
substance is practically
original
in hot alcohol. It has a bitter taste,and is employed as an antipyretic
and analgesic
in doses of 7 grainsseveral times daily. It

by

the action of

but is of littlevalue as a
directions,
hypnoticas it is markedlytoxic,and its action is too precipitate.

has considerable action in these

3.

Vanillin-phenetidin,
^6"4\N

CH.C6H3

is antipyretic
preparedby the action of phenetidinon vanillin,
and antiseptic,
and also contracts the blood vessels. It is,however,
to be of practical
value as a substitute for phenacetin.
too expensive
Various js?-amido-phenol
derivatives of substituted vanillins have
been investigated.
carbonate,prepared
Vanillinethyl
by the action

of chlorformic ester
of

on

an

alcoholic solution of vanillin in presence

potassiumhydrate,

yCOH
C6H3"-OCH3

4
\O.COOC2H5

or

vanillin,
phenacetyl3

\O.CH2.COOC6H6,
may

vanillin in
replace

these reactions.

OF

DERIVATIVES

196

^-AMIDO-PHENOL

phenol. It is said to
but the antipyretic
and
and neuralgia,
be of value in rheumatism
within the organism
narcotic actions are very slight,
decomposition
takingplaceslowly.
acetamide
5. j9-Acetamidophenoxyl
which
nacetin,

is then converted into acetamido

.CH.CONH

is obtained

by

the action of monochlor-aeetamide

acet-^?-amido
alcoholic potash.
on

of
phenolin presence of the calculated amount
derivative is obtained in a similar manner
The corresponding
lactyl
action.
It has marked
from lactyl-/?-amido-phenol.
antipyretic

VI.

Class

through the organism,phenyl urethane,

is partially
converted into p-oxyC6H5NH.COOC2H5 (Euphorin),
those previously
as
principles
phenyl urethane,and, on the same
On

its passage

mentioned,this substance

and

many

of its derivatives have

been

introduced into
1.

pharmacology.
^-oxyphenylurethane,
OH

but may
It is practically
non-toxic,
urethane
2. Acetyl-/"-oxyphenyl

CH/

rigors.
produceslight
(Neurodin),

/OH
/C
/COCH

XN^C
by the entrance of
and analgesic
actions.
the acetylgroup, as are also the antipyretic
It is very insoluble in cold water, and its antipyretic
action,though
is somewhat
uncertain.
rapid,

The

3.

toxic effects

are

still further

reduced

urethane,
p-ethoxyphenyl

.COOC2H6"
has a much
certain action
more
althoughnot free from toxic effects,
in loweringthe temperature than
those derivatives previously

mentioned.

PHYSIOLOGICAL

The

4.

PROPERTIES

of

derivative

acetyl

this

197

substance,

/oc2H6

C6H/
is named

Thermodin.

toxic

and
in

acid

acid

and

is said

but

have

to

medicinal

in

been

observed.

therefore

be

is

It

It is

action
claimed

also

the

on

is

it

except
with

mild

heart

that

gradual,

combined

It

way.

be

to

insoluble

very

administered

similar

some

depressant

no

doses.

derivatives

Various

Merck

prepared by
into

chloride

in

diuretic,

respiration

or

destroys

group

+a.

rnn

obtained

the

plas-

been

acid

or

reaction

derivatives

which
:

takes

"

NHCOR

rn/"-C6H4

"

\0.cX

have

by passing carbonyl

following equation

the

C]2

series

urethane

alkali; the

of

represented by

H
C"H"\NH.COB

be

may

/?-oxyphenyl

of

urethane

oxyphenyl

presence

/OH

the

one

solution

be

may

of

^-phenetidin

place

not

is said

malariae.

modium

of

antipyretic

in

or

syrup,

effect

Its

should

and

media,

acetic

have

symptoms

/COCH3

NH.COR

9TTP1
2H

"

OC3H7

OC2H5

If

sodium
be

the

is carried

reaction

in the

following

alcoholic

in

C6H5.

solution

formed.

are

manner

OIH

C2H5
,

carbonates

alcoholate, mixed

expressed

out

CH3

The

in

of

presence

reaction

may

"

+;CliCOJCl:

C6H4"(
XNH.COR
9TTP1
-

in

On

varying

the

above

the

_i_
1 +

OC2H5,

P
C

OC3H7;

alcohol,the

derivatives.

groups

CH3)

C2H6J

methyl

or

C6HS.

propyl replace ethyl

CHAPTEE
THE

MAIN

X
ANTIPYRETICS

SYNTHETIC

(CONTINUED).
action of Phenylhydrazineand
Hydrazine and its derivatives. Physiological
its derivatives. The
Pyrazolon group
Antipyrine,Pyramidon. General
derivatives.
characteristics of the Ammonia
Summary of Physiological
GROUP

OF

"

"

"

OF

DERIVATIVES

II.

PHENYLHYDRAZINE.

NH2, is a strong base and an

toxic substance ; its most important
derivative is phenylextremely
hydrazine,
NH2, a body which is largelyemployed in
C6H6NH
chemistry,
synthetic
ammonia, hydrazine,
NH2

LIKE

"

"

and

Preparation

Properties.

Phenyl-hydrazine
may be obtained by the reduction of the diazoof
benzene salts,
C6H5N : N.C1, throughthe agency of acid sulphites
the alkalies on the yellowpotassiumsalt of diazobenzene sulphonic
is
acid,whereby colourless potassiumbenzenehydrazine
sulphonate
formed directly,
C6H6N

N.S02OK

KHS03+H20
C6H6NH.NH.SO2OK

resulting
sulphonateis heated
is formed
hydrochloride
phenylhydrazine
When

the

with

KHSO4.

acid,
hydrochloric

"

C6H6NH.NH.SO2OK

+ HC1

H2O
C6H5NH.NH2

simplermethod

somewhat

consists in the

for

HC1
.

KHSO4.

the

reduction of

of hydrazine
preparation
phenyldiazobenzene chloride by

chloride,

stannous

C6H5N

:N.Cl

2SnCl2+

4HCl

C6H6NH.NH.HCl

2SnCl4.

and stannic
phenylhydrazine
hydrochloride
and the solution
chloride separatesout, is decomposedby potash,
lation
extracted with ether ; the free base may then be purified
by distilThe

double

in

salt of

vacua.

is
Phenylhydrazine

stronglybasic substance,more

readily

PROPERTIES

PHYSIOLOGICAL

199

and is a most
solution,
Fehling's
and (ii)
importantreagent for the identificationof (i)aldehydes
the following
reactions :
with which it undergoes
general
ketones,

oxidized than

aniline ; it reduces

"

i.

CH3

CH3
2;N.NHPh

H2O

+ CH

H2O

N.NHPh1

Acetaldehyde.

C6H5CHp

H2jN.NHPh

C6H6CH

N.NHPh

Benzaldehyde.
ii.

CH3

CH3
CjO

H2;N.NHPh

H20

+ C

N.NHPh

CH3

CH3

CH3

CH3
=

H9O

+ C

N.NHPh

by Emil
developmentof the chemistryof the carbohydrates
based upon reactions similar to these,
since that
Fischer was largely
alcohols.
composedof ketonic or aldehydic
group is entirely
There are few classesof organic
substances which lend themselves
of ring systems containing
to the synthesis
more
nitrogen
readily
and its derivatives. From
than do phenylhydrazine
the pharmacologi
which
derivatives,
pointof view,the pyrazolon
among
is antipyrine,
and will be described
are
by far the most important,
The

later.

Physiological

Properties.

and ketones,
with aldehydes
of phenylhydrazine
reactivity
with its powerful
reducingaction,
together
giveit very pronounced
toxic properties.
and to a lesser
Like hydroxylamine,
NH2OH, hydrazineitself,
it brings
extent aniline,
about destruction of the red blood corpuscles
and decomposition
besides beinga powerful
of the haemoglobin,
protoplasmic
blood
in
the
poison.The brown pigmentformed
appears to
be partly
and partly
derived from phenyla substance
hydrazine
methaemoglobin
itself (Hoppe-Seyler).
Death takes placefrom general
of cerebral origin,
paralysis
by convulsions. The adminiaccompanied
The

The

radical

Phenyl,C6H6,may

be written

Ph,Methyl Me,

and

Ethyl Et.

OF

DERIVATIVES

200

PHENYLHYDRAZINE

is followed
stration of phenylhydrazine
in the urine. The
the

or
toxicity,

various

rather

reaction

to

in

attemptswhich
bring about a

the

appearance of allantoin
have been made to reduce

by the

more

organism,follow

phenylhydrazine
protracted
those
very closely

employedin the case of aniline.

of the base
the stability
reaction,
corresponding
By a completely
be increased by the replacement
of the amido hydrogenatom by
can
the acetyl
substance,
acetylphenyl-hydragroup, but the resulting
is still capableof
zine, C6H5NH" NH(COCH3)
(Hydracetin),
althoughto a less extent than the
reducingFehling'ssolution,
fall
marked
and collapse,
substance. Intense depression
original
and diminution of the amount
of
of temperature,
haemoglobinuria,
small doses. Medicinally,
follow even
urine excreted,
on
only
is
the
had
it
been
that
maximum
"2 gram
dose,so
(3 grains)
have
been
much
to employ it,it would
cheaper than
possible
antipyrine.
The intense staining
of the tissues after death is evidence of the
extent to which
haemoglobinis broken up by this substance. It
has
been employed,like pyrogallic
acid, in the treatment of
but practically
is too toxic even
for external application.1
psoriasis,
Diacetyl
phenylhydrazine,
C6H5NH" N (COCH3)2,is less toxic,
but has a cumulative action as a haemic
poison. Thus, though a
it
is
to employ it therapeutically.
powerfulantipyretic, not possible
that a-j5-diacetyl
In this connexion it may be mentioned
hydrazine,
phenyl-

XCOCH3

C6H6 N/.

_NH(COCH3),

the interaction of sodium

and
phenylhydrazine,
ether,
does not appear to have been tried,
althoughfrom
acetylchloride,
its action
of reducingFehling's
the fact that it is capable
solution,
from that of the above-mentioned
to differ much
bodies.
is not likely
In a very similar manner
the amido
hydrogen atom has been
but the resulting
replaced
by the radical benzoyl,
benzoylphenylhydrazine,
the
in
doses
blood
C6H5NH" NH(COC6H5), acts on

obtained

by

that have

no

action

the central

on

This is also true of

nervous

system.

ethylene-phenylhydrazine,
/NH2

/NH2

C6H6.N^C2H4-N.C6H6
1

Berl. Klin. Woch., 1899.

PROPERTIES

PHYSIOLOGICAL
and

201

derivative
its succinyl

/NH(CO.C2H4COOH)

C6H6.N^-C2H4-

/NH(COC2H4
-N.C,H5

COOH)

placement
toxicityof phenylhydrazineis lowered by the rebut
acid
the presence of
of hydrogen by alkylor
groups,
of acetyl-methyl- or ethyl-phenylhydrazine,
in the case

relative

The

both, as

ing
generalaction on the blood,althoughthe loweris sufficiently
of toxicity
marked, and it might be worth while
the physiological
to investigate
of dimethylacetyl
reactivity
phenylhydrazine,
does not decrease the

is

which

In the

the acidic

of

loweringthe toxicity
attempts have been made to
the phenylhydrazineradical into substances containing
Thus
laevulinic acid,
(COOH) group.

hope

introduce

stable substance.

more

CH3.CO.CH2.CH2.COOH,
reacts

in the

base,in the form of its acetate in aqueous solution,

generalmanner
described,yieldingthe hydrazone
previously

with the

CH3.C.CH2.CH2.COOH
N.NH.C6H5
This
is

body

has been termed

Laevulinic

Antithermin.

acid itself

toxic,and its compound,

for

generaluse

Based

on

the

; it is
same

too poisonous
though actively
antipyretic,
also liable to cause
gastricirritation.
idea,the substance Orthin

,NH.NH2

C6H/OH

\COOH
has

been

lowers

and

the

introduced.

The

presence

but the substance

toxicity,

of the

acid

is unreliable

grouping again
as

an

antipyretic

produces undesirable by-effects.

Attempts to modify the action of phenylhydrazine

duction
by the introof the salicyl
residue into a-phenylmethylhydrazine

DERIVATIVES

PYRAZOLON

202

(whichis

less toxic than

somewhat

the unsubstituted

result in the formation

of salicyl
aldehyde,

means

C6H5 N^^-N

known

as

Agathin,

CH.C6H4

of the

base),by
hydrazone

OH
.

odourless body insoluble

tasteless,

in water.

action only in doses of

antineuralgic
bears out the generalobservation
4-6 gms. (3i~3i ss),
a fact which
that salicyl
derivatives of this type are onlydecomposedwith such
difficulty
by the organismthat they are unsuitable as antipyretics
and antineuralgics.
It may produceviolent headache.1
It will be seen from the above that it has not been found possible
has on the
to eliminate the powerfulaction which phenylhydrazine
and it does not seem
red blood corpuscles,
likelythat any of the
methods described can be so modified as to yieldsubstances of the
value.
pharmacological
slightest
But

this substance shows

its

TYPE

OF

DERIVATIVES

PYRAZOLON

III.

THE

ANTIPYRINE.

OF

the first derivative of this group,

Phenyl-3-methyl
pyrazolon,
obtained by Knorr, in 1883,throughthe interaction of phenylwas
hydrazine
is a
and acetoacetic ester. The formation of pyrazolon
acid esters react in a similar manner.
general
one, and other /3-ketonic
will be easier to follow if the
of antipyrine
As the formation
2
for acetoacetic ester is employed,
enolic formula
CH.COOC2H5,
CH3.C(OH)
of the reaction will be adopted although its
this explanation
accuracy is perhapsquestionable.
The first phase of the reaction consists in the formation of a
hydrazone
i.
CH3
CH3
1.

"

C.JOH+HJNH"

c"

NHC6H5

Journ., vol. xxiii,

p. 86.

Pharm.

Acetoacetic

the

NHC6H5

COOC2H5

COOC2H5

were

NH"

ester reacts

certain conditions

under

as

if its constitution

expressedby the formula CH3 CO.CH2 COOC2H6 ;

Such a substance
formula CH3 C(OH) : CH.COOC2H5.

meric

under

others, by

is termed

'

Tauto-

'

and the first is called the

Keto

'

and

the second the

'

Enol

'

form.

204

PHYSIOLOGICAL

PROPERTIES

Many modifications
and will be
discovery,
chemistry.

of this
found

Physiological Properties
It is

to note
interesting

are

absent
entirely

OF

have been made

synthesis
in the largertextbooks on

of Antipyrine

that
in

ANTIPYRINE

and

since its

organic

its derivatives.

the characteristic antipyrine

properties

l-phenyl-3-methyl
pyrazolon,

CH"

CO-N.C6H6,
and

it is onlywhen

that these appear

the imido

hydrogenatom

is replaced
by

methyl,

CH3
N.CH3
II
CH

io_:
'6AJ-5

With
centres

action on
(Phenazone)the paralysing

Antipyrine
in the mid

brain is not well marked.

It is not

the motor

but
narcotic,

and
haemoglobin,
collapse,
convulsions. The latter are well marked in frogswith doses of
in
from 50-60 mgm.
It has the greatadvantageof easy solubility
action is not due to any influence on the
Its antipyretic
water.
of the blood. Sweating,
as
heat-loss,
capacity
accelerating
oxygen
also has but a small share,for the fall of temperatureproduced
by
belladonna.
when
has
been
occurs
sweating
prevented
antipyrine
by
It does not act,however,when the higherpartsof the brain are cut
cerebri. In
off by section through the cord or through the crus
fever experimentally
producedby damage to the corpus striatum
a fall of temperature.
produces
antipyrine
this effect is due to the dilatation of the cutaneous
Most probably

in

it

largedoses

vessels and
In

stimulated

in the

consequentincrease

animals

some

as

producesdestruction

by
a

of heat-loss.

(including
man)

this process

that

compensatorymeasure.

respiratory
activity.

of

heat

is

the thermotaxic

centre

is
production

forthwith

In man,

there
also,

so

creased
in-

is a decrease

DERIVATIVES

ANTIPYRINE

205

uninfluenced in
Nitrogenousmetabolism,which is practically
is decreased in pyrexial
conditions when this drug is administere
health,
but is dependentmerelyon
This is not a direct action,
effect of the drug, which
cannot
the antipyretic
influence the
increased nitrogen
waste due to toxic processes.
As an analgesic,
it is largely
used,and the number of cases in
have occurred does not appear to be great.
which bad by-effects
first introduced,
Se"e gave 15 grainsevery hour up to 50
When
but it is not now
100 grains,
or
given in these largedoses. In
in which unpleasant
cases
symptoms (collapse,
oedema,rashes,
"c.)
these have not alwaysbeen the result of largedoses.
have appeared,
Guttmann
took 15 grainsof antireportsa case in which a man
pyrinein five days,which produceda condition closely
resembling

cholera,
except that diarrhoea

not

was

present,and

there

was

dusky rash on the abdomen.

is found in the urine to some
extent unchanged,but
Antipyrine
acid derivative;
most
as
a
chiefly
glycuronic
probablyoxidation,
with the formation of oxyantipyrine,
this synthesis.
precedes
When j"-tolyl
hydrazine

is

employed in

the

instead
pyrazolonsynthesis,

of the

phenyl

derivative,
Tolylpyrine

CH3
-N.CH3
CH

CO"
is obtained.

It is

more

N,r.C6H4.CH3

than antipyrine,
and
irritating
action is
analgesic

the circulation unfavourably,

while its

affects
not

so

pronounced.
The

acid salts of
salicylic

introduced under the

names

obtained
the
them

both

and tolylpyrine
have
antipyrine

of Salipyrine and

by meltingtogetherthe
derivativescontain
resulting
a

constituents
a

free

Tolysal.
on

These

been
are

the water

carboxylgroup,

bath ;
and from

series of salts may

be obtained. They are readily
posed
decominto their constituents by hydrochloric
acid, and their
1

Pharm.

Journ.,vol. xxiii. p.

605.

DERIVATIVES

ANTIPYRINE

206

that of

reaction corresponds
to
physiological

mixture

of anti-

acid.
pyrineand salicylic
derivatives

Several

of

type have

this

been

introduced

into

for example:
pharmacology,
"

Tussol

is the mandelic

pyrine. It

has

been

acid

givenas

(C6H6CH.OH.COOH) salt of antia

remedy for whooping cough in

cgms. per diem for children under one

to age for older children. There
proportionately

doses of 15-30

year, and more

is no evidence

which is well tolerated by children.

antipyrine,
and antiHypnal, or Hypnol, is a compound of chloralhydrate
and to have less action on
pyrine. It is said to be more soporific
but its generaltoxicity
the circulation than
is higher.
chloral,
is still more
toxic,and has no advantages
Bichloral-antipyrine
chloral or hypnal.1
over
is a soluble white
and antipyrine)
Anilopyrine (Acetanilide
has no particular
advantageover a mixture
powder,but apparently
of the two bodies which has long been a favourite prescription
for
and headaches of various sorts.
neuralgia
Bodies
of this type, owing to the ease
with which they are
less
fruitcan
decomposed,
onlyact as mixtures,and it is consequently
reactions
to search for substances with new
physiological
that it is superior
to

amongst derivatives

of such

nature.

is the only antipyrine

4-dimethylamido
-antipyrine,
derivative which has provedof value. It is obtained by the
reactions :
following
nitrous acid acts on
solution of antipyrine
1. When
a
hydrois obtained
chloride,
nitroso-antipyrine

Fyramidon,

or

"

"

CH3
C

CH3

A-KN.CH3
C

N.CEU
+

HN09

CO"
2. This

on

NO"

C(
JO-N.C.H,

N.C.H.
reduction

givesamido antipyrine,
GEL

.CH3
NH2"

CO-N.C6H6
1

Pharm.

Journ.,vol. xxi,p. 161.

PROPERTIES

PHYSIOLOGICAL
which

is isolated by

of its

means

methylation
givesPyramidon

207

and
benzylidene
derivative,

on

"

CH3
C

N.CH,

(CH3)2N.C
CO"

N.
V

Pyramidonis a
and is a
solution,

solid which

dissolves in water, givingan

alkaline

powerfulbase than antipyrine.The dose is

about one-third that usually
givenin the case of the latter drug.
It has no irritant effect on the stomach,
and may also be prescribed
and heart disease,
in nephritis
its effect on
the circulation is
as
but slight.It is not a blood poison. It has been used on the
continent both as an
and an analgesic,
but in this
antipyretic
country its use is mainly as a drug of the latter class. It is
excreted in the urine partlyunchanged,partly
as
acid,
glycuronic
and partly
as uramino-antipyrine
more

"

CHQ

N.CH3
NH,

CO.NH"

-N.C6H5
After the exhibition of
in the urine

pyramidona derivative occasionally

appears
becomes oxidized and produces
the
standing,

which,on
red colouring
matter,rubazonic acid.
It has

been

suggestedthat pyramidonshould not be givento

of antipyrine
diabetics,
it
run
derivatives,
as, contraryto the general
increases nitrogenous
metabolism.
GENERAL

CHARACTERISTICS
The

three

SUMMARY

OF

OF

THE

THE
AMMONIA

PHYSIOLOGICAL
DERIVATIVES.

and antipyrine
antifebrin,
substances,
phenacetin,
taken
be
of the entire series of
as
(phenazone)
representative
may
which have justbeen described. They are
synthetic
antipyretics
not onlychemically
but therapeutically
representative
bodies,
they
valuable than all the other members
are
of the
probablymore
classes to which they belongput together.From the pharmacological
of
view
be
considered
true antipyretics
point
they may
as
;

PROPERTIES

PHYSIOLOGICAL

208

they so influence the thermotaxic centre that it

vaso-dilatation to take placeduring
a
causes
generalcutaneous
thus producing
increased heat-loss and a fallin temperature.
pyrexia,
That they are not mere
generalvaso-dilators is shown by the fact
is very
that the deep vessels are not affected. This,a central action,
from the effect producedby the external
different physiologically
but the thermotaxic
of cold,when
heat-loss is increased,
application
is to say,

that

is uninfluenced.

centre

maintains

certain

constant
fairly
pyrexiathis ratio

and heat-loss ; in
does not
production

lead to

ratio between

centre

heat-production

and increased heataltered,

the
sufficientincrease in heat-loss;

influence
so
antipyretics

true

health,the thermotaxic

In

or

is

sensitize the thermotaxic

centre

This may or may

not be
a valuable measure
therapeutically
; at presentthe tendencyis to
to reduce the temperature in this way,
consider it disadvantageous

that the ratio tends to return to normal.

drugsare mainlyused for other purposes.

antipyretic
for
action is a function of the benzene
The antipyretic
nucleus,
it is shared by such varied derivatives as
phenol,pyrocatechin,
and the
acid,aniline and its derivatives,
phenylhydrazine,
salicyl
ajomatic semi-carbazides R.NH.NH.CO.NH2.
Phenyl-azo-imide,
and

the

in mammals.
and analgesic
Moreover,
antipyretic
and quinoline,
have the same
such as pyridine
ringformations,

also acts
other

as

an

action.
physiological
the other

On

The

ethylester

hand,all ringcompoundsare
of

not active antipyretics.

acid,
a-naphthylazoacetoacetic
P

TT "M
010H7JN

"

"NT PTT *

and phenanthren,
are
a-acetone-naphthalide
examplesof inactive
substances with ringstructures.
The side-chains in the above-mentioned compoundsvary so much
pyretic
that it is clear that no importance
be attached to them as antican
to enable the molecule to
agents. Their function is possibly
anchor
purpose

itself to the cells in the central

the basic chains

are

more

nervous

system,and

suitablethan the acid.

for this

Aniline

is

than phenol,
but less powerfulthan
powerfulantipyretic
its physiological
partly
phenylhydrazine
activity
; the latter owes
a

more

to its chemical

The

second

instability.
action
therapeutic

of these

bodies,which, as

has

OF

DERIVATIVES

AMMONIA

209

is
been noted is at presentthe most generally
employed,
previously
and slightly
the analgesic
hypnoticpowers which they possess.
but is apparently
the
This is not solely
due to the benzene ring,
One factor is the
either jointly
result of two factors,
or separately.
CH3 CO.NH.R.
Ethylpresence of the ketonic group, such as
other
ketones
The
and
second
are
hypnotics.
ketone,acetophenone,
accounts for the
factor is the ethoxy group, which apparently
whilst in
derivatives,
hypnoticeffectin some of the jo-amino-phenol
other bodies both these factors are united.
and some
lactophenin
be considered in detail,
The two main groups may
now
as
they
of
to
their
chemical
different
interest
points
corresponding
present
.

structure.

The

group of which

and pyramidonare typesowes

antipyrine

which
to the ring formation,
properties
antipyretic
element.
The monomethyl pyrazolon
nitrogen

its

contains

CH3
C

NH
H

CO"
is not

in antipyrine
itself the
antipyretic;

the
replacing
acts

as

The

N.-C6H5
second

hydrogen of the imido radical

methyl group

therefore
apparently

anchoringgroup.
intensifiesthe
phenylradical apparently
an

effect can

be obtained without

it; in

action

; some

pyretic
anti-

view,however,of the

known

effect of benzene,
the pyrazolon
antipyretic
ringmight be
this
regarded as intensifying by the substitution of one of the
The introduction of the basic group (in pyrahydrogenatoms.
derivatives are toxic,
midon)increases the reaction. w0-Pyrazolon
but not antipyretic.
The aniline and /?0ra-amino-phenol
derivatives can be considered
the action dependson the liberationof the latterin the
as
together,
organism. Acetyl-^-amino-acetophenone,
p

/COCH3

^^XNHCOCH,,
has

no

because the para

antipyretic
action,

the formation of

C6H4OH.NH2.

designedto producea

slow and

group,

COCH^ prevents
be regarded
as

These bodies may

gradual aniline or jt?-amino-phenol

PHYSIOLOGICAL

210

reaction ;

PROPERTIES

it were, methods ofdosage. This beingso, it is

obvious that those compoundsfrom which the parent substance is

theyare,

slowlyevolved

as

will be little toxic and

also less efficientas

pyretics,
anti-

will alwaysbe dangerous

powerfulantipyretics

whereas the
in

practice.
be specified
of these substances may
toxic properties
as
action on the central nervous
(1)a general
system,and (2)a special
of the red cells and formation
action on the blood (disintegration
The generaltoxic action is practically
of methaemoglobin).
the
for aniline and phenol,
and differs in degreeonlyowing to the
same
fact that primary amines are
active physiologically
than
more
alcohols. There is,however,no generalagreement in the relative
of the two series of compounds,though as a generalrule
toxicity
The

contain but

those which

one

side-chain

the most

are

toxic.

The

lengthof the side-chains also has a certain influence,

The following
table is given by Frankel :
"

The

action

basic group

as

blood

hence

this respect;ammonia
zine producethe same
atoms

is dependenton
poisons

is more
phenylhydrazine

the presence of the

active than aniline in

and hydraand, still more, hydroxylamine

effect. The

of the base does not

substitution of the two

necessarily
modifythis action.

Exalgin,

.W"CO"IL.

hydrogen

PHYSIOLOGICAL

212

hydroxyl

with
residue

in

similar

to

this

by

group

place

an

If
is

phenacetin
that
is

produced
so

acid

aliphatic

action.

toxic

easily

o"

substitution

the

action;

physiological

out

PROPERTIES

occurs;

that

it

of

unstable

too

group

has

acid

an

no

of

atom

alkyl

an

alcohol

detached

hydrogen

hydrogen

by

replaced

by

produces

second

the

the

the

the

pound,
com-

basic

narcosis
in

group

physiological

importance.
Compounds
for

practical

derived

purposes.

from

ortho-

or

wtfta-phenetidin

are

too

toxic

XI

CHAPTEE
GROUP

I. THE

from

derived

Hypnotics

Hedonal.

UREA

URETHANES,

or

UREIDES.

AND

Thio-urea.

Urea.

Urethane.

"

Thiosinamine.

hypnotics.

Veronal

GROUP

PURINE

II. THE

of Xanthine

of substances

Modification

tonics.

Diuretics

PILOCARFINE."

AND

type.

Cardiac

and

Diaphoretics.

Pilo-

carpine.

URETHANES,

OF

GROUP

THE

I.

AND

UREA,

THE

UREIDES.

of

to those
r*c\/

dibasic

C*C\s

Carbamic

acid.

\OC2H{
Urethane.

in the free

acid is unknown

Carbamic

respectsanalogous

/~N"TT

x"WH"
C*C\s

J\OH

acid.

Carbonic

in all

are

acid,thus-"

yOTT

"\OH

A.

amides, which

acid forms

CARBONIC

Urea.

state,but its ammonium

salt,
C(

.ONH4,
present in

is

commercial

toxic, probably owing

symptoms

to

similar to those

labile

its very
caused

by

This

substance

character,and

ammonia.

But

more

A.

The

urethanes

substituted

are

ammonias,

its

esters,the

stable and

the

they

nature

Urethanes.

The

obtained
on

is

produces

consequentlyless toxic
hypnotic propertiesdepending upon the
possess, moreover,
of the organic radical replacingthe hydroxyl hydrogen.
urethanes, are

much

carbonate.

ammonium

by

the

action

ammonia

of

esters of chlor-carbonic

or

acid1

the

Phenyl urethane,
or

This

method
with

(p. 130).

of

the

introducing

the

Euphorin.

(COOC2H6)

resulting depression

of

radical into basic

toxicity,is

one

or

often

other

stances,
sub-

employed

URETHANES

THE

214

by the action of heat

alcohol,
corresponding
and

on

of

mixture

nitrate and

urea

the

Methy-propyl-

Methyl-propyl-carbinol.

ure

thane.

Hedonal.

Physiological Properties.
Binet has found that the

of these derivatives
physiological
reactivity
to the magnitude of the alcohol radical.
increases according
without
The introduction of the acetylgroup lowers the toxicity
the physiological
action.
In the case of warmotherwise altering
blooded
of these substances is as
animals, the relative toxicity

follows

"

when

H.COCH3
O.R
pn

spiteof
the

on

when

/NH2

"

the presence

of

no

action

CH3

C2H5

amido

an

CH3
C2H5

has

group,

no

1
1-5
2

...

4
.

effect
depressant

the

stimulant
contrary,it has some
doses which exceed those given therapeutically.

centre
respiratory

but onlyin
action,
It has

R
"

LU\O.X

in

; on

blood

on

pressure

or

the

pulse rate, and is

derivatives. Its hypnotic
on

like all the urea

markedly diuretic,
but not sufficiently
action is rapid,
powerfulfor use in cases where
in largedoses it does not
there is any pain or distress. Even
converted into urea.
Small
appear in the urine,but is apparently
doses are said to decrease nitrogenous
metabolism,whereas large
doses have

contraryeffect.
Di-urethane,
NH(COOC2H5)2, is a
a

to the presence of

acts

The
a

second

powerfulnarcotic,
owing

more

alkylradical.

to urethane,
similarly
being narcotic

dose

is double

that

of

chloral.

diuretic.
powerfully
has been employed as

and

It

to generalanaesthesia with chloroform

preliminary
;
is slow, and it must
be given at least an hour

its

tion
absorp-

before the

There

anaesthetic.
its

however, other

are,

this

employment in
practical
Urea

B.

firstsynthesized
by Wohler

which

solution

of its aqueous

serious

to
objections

Derivatives.

nn/NH2
in 1828

intra-molecular

undergoesan

more

215

manner.

its

and

Urea,
was

UREA

OF

DERIVATIVES

from ammonium

the
on
transposition

w0-cyanate,

evaporation

"

CO:N.NH4
It is found in various animal

-"

in the urine of mammals,

fluids,
chiefly

insoluble nitrate.
and may be separated
as the somewhat
It may also be prepared
by the following
synthetic
processes

"

Urethane.

2.

Diethyl-carbonate.
3.

CO^ocH

Chlorformic

3NH3

ester.

in longneedles,
or rhombic
crystallizes
prisms,which have
a
coolingtaste. It is soluble in 1 part cold water, 5 of alcohol,
but almost insoluble in ether. It is decomposedby nitrous acid,as
the amido group.
all substances containing
are

Urea

The

Alkyl

employedin
1.

Ureas

the

of

urea

be

preparedby

reactions similar to those

itself,

ureas.
Mono-alkyl

Urethane.
2.

case

may

Ethyl-amine.

Ethyl urea.

ureas.
Di-alkyl
A. Unsymmetrical.

Diethyl-amine.

urea.
a-Diethyl

PHYSIOLOGICAL

216
B.

PROPERTIES

Symmetrical.

ro/^^Q^s

S.

Chlorformic

4.

TT OTT

^u"^NHC2H5+L2H6oid
Diethylurea.

ester.

urea.
Tetra-alkyl

3.

urea.
Tetra-ethyl

alkylureas

The

the

with
substances,
crystalline

are

of
exception

and show the same

characteristic
derivatives,
reactions and properties
as
urea
itself,
and, like it,form salts with

substitution

the

tetra

one

of acid.
equivalent

Physiological Properties.
for animals or higherplants.
toxic properties
slight
It has no action at all on the lower plants. Its chief effect in the
and it also has a very slight
animal body is to producediuresis,
Toxic doses (injections
of Tj^ the total bodynarcotic action.
weight in rabbits)
producespasms and opisthotonos.Ammonia
Urea

has but

set free in the blood.

is not

it is found
hydrogenof the amido group is replaced,
that the simplealkylureas
have no narcotic action;with those
containingtertiaryalkyl groups the generalcharacteristic is
observed (seep. 92),viz. that a tertiary
methyl
system containing
When

the

groups, such

as

"

/CH3
C^-CH,

\CH3

is less reactive than

"

those

containingethyl,such

as

/C2H5
/C2H6
or
butyl tertiary
heptyl, C"-C2H6
C^-CH3 tertiary
"

\C2H6

\CH3
(a)

CO^5

3-4
3

(b) COrVr^

gms.

gms.
Vv* Inactive
25

without action.
but no
producedrowsiness,
sleep.
set
b
ases
ethylamine
are
apparently

free in the

body.

OP

217

DERIVATIVES

UREA

producesleepNH2
is

This
drate

r/"3

as

hypnotic;

but

tive,which

longerto

easilysoluble,takes
decompose.
is not

into

passes

(e)

\C

C0"

amylene hysleepoccurs

later,"winl?tothefactthattllisderi

\CH

(d) CCK
^

active than

more

It

^changed.

H
5

rvQjj2
\
_

and

has

the

is very

urine

stable,

action.
physiological

no

produces sleep after 2 hours,

Precede(ity a Period of intoxication.
1

Urea

The
under

gm.

containing

Derivative

urea
a-monobronW*0-valeryl

the

name

of Bromnral

Bromine.

has been

introduced

by

Saam

"

\NH.CO.CHBr.CH.(CH3)2.
It is not

in hot water,
but dissolves readily
easilysoluble in .cold,
thinks that the narcotic
ether,alcohol,and weak alkalies;Saam
action of this drug depends upon three factors.
The main
hypnotic
is the

M0-propylradical

in the

valerianic

acid, but

its action

is

of the urea
intensified,
firstlyby the presence
grouping, and
The correspondingchlorine comsecondlyby the bromine atom.
pound
is but slightlyhypnotic,the iodine compound is inactive.
The
lethal dose for rabbits begins at 1
gm. per kilo, body-weight;
in dogs, "5
mainly on the
gm.
per kilo, produced toxic effects,
while larger doses produced death
from
respiration,
respiratory
t
he
heart remaining unaffected.
The hypnotic action is
failure,
mild, and is interfered with by the presence of pain,cough, or active
delirium.

DERIVATIVES

SULPHUR

218

Sulphur
Thio-urea

OF

UREA

of Urea.

Derivatives

sulphocarbamine,

or

NH

is obtained

pa

AT

XTTT

N.NH4

P^5/

/NT
IT
X

^NH*

of its reactions indicate

Many
formula

to 170"-180"
thio-cyanate

by heatingammonium

C.

constitution

expressed
by

the

"

HN."
and bringsabout
slowingof the pulseand respiration,
of central origin,
and death in
cardiac failure,
generalparalysis
It

causes

convulsions.

Allyl-thio-urea

C
Phenyl-thio-urea

Ethyl.thio.ureaCS^fa
Acetyl-thio-ureaC
toxic,as
actively

are

are

groups
AH

are

also

compounds in

substituted with different

i

r\o/^

j-t.'

both

ammo

radicals,
e.g.

HC-Jtlo

Allyl-phenyl-thio-urea^vN"HC

which

Methyl-ethyl-thio-urea
and
symmetricalcompounds, however, like urea itself,
have only very slight
physiological
dimethyl or diphenylurea
The

action.
Of
one

these
of

pharmacological
importance. In

death occurring
with
narcosis,

oedema

of the

is the

only
produces
and
lungs
hydrothorax.
system,largerdoses

or
Thiosinamine,
bodies,allyl-thio-urea,

toxic doses

it

Very small doses excite the central nervous

depressit. Thiosinamine appears to have a characteristic action
it causes
tissue. When
scar
on
injected
subcutaneously
organized
and softeningof cicatricialbands and adhesions. This
absorption
action,however,does

not

appear

to be constant.

220

UREIDES

and

the

correspondingdipropyl-malonyl-urea
"

They
stand

that

state

of

the

NH"

CO

XN H"

CO

series

investigatedfthe

three

mentioned

and
prominently in point of hypnotic action
that diethyl-acetyl-urea
is about
experiments have shown
equal in
to sulphonal,that
hypnotic power
dipropyl-malonyl-urea is about
out

four

times

powerful,

as

after-effect.
these

two, and

and

taste

these

hence

This
be

dose

for

substance,which

would

to

appear

midway

action

all the

advantages
be

the

hitherto

with

most

longed
pro-

between

regard

valuable

of

is stated

to

therapeuticpurposes/
the

by

goes

prompt hypnotic, and

it may

less than

costs

it has

as

remarkably

stands

intensityof

Inasmuch

it
solubility,

of veronal

in

surpasses

derivatives

new

infrequentlyhas

not

Diethyl-malonyl-urea

employed hypnotics.
to

but

that

of Veronal,

name

be

mentioned

of

Trional, or

the

that

effective

other

any

hypnotic

excepting chloral hydrate.

Veronal

be

may

acid with

obtained

in presence

urea

of

the

condensation

of sodium

ethylate,

by

diethylmalonic

HINEL
s

HiNH

CO;OC2H6

Veronal

is also

kidneys.
heart.
to

It

It has

dimmish

diuretic,but

does

not

no

action

before

;
a

on

nitrogenous

(135 grains) having

results

influence

"/ gm.

per

been

the

it has
the

blood

occurs.

or

pressure

in

on

single dose
can

be

the

depress the
It is said

toxicityis low,

The

kilogram body-weight

direct toxic action

action

mucosa.
gastro-intestinal

metabolism.
taken

irritant

no

without

given

to

9 gms.
serious

animals

PURINE

THE

II.

compounds of
purine
The

DERIVATIVES

ITS

AND

PURINE

this group

221

GROUP.
all derived from

are

the substance

"

N=CH
CH

C"

NH

of animal
complexis found in a largenumber of the products
and plantlife,
namely,uric acid,xanthine,guanine,theobromine
"c.
caffeine,
(foundin cocoa beans),
This

is based

Their nomenclature

the scheme

on

1 N

"

1
2C

5C"

Li
3 N"

Nv

/C8

6" N/
9

thus

NH"

CO

60

C"

N"

CO

CO

C"

N"

CH3.N"

C"

N'

CH3

XJH,
NHV

"CO
[__C"

NH'

Uric acid
2:6:

Caffeine

or

8-triketo-purine.
NH"

or

1:3: 7-trimethyl-2
: 6-diketo-purine,

CO

CO

i-LN"

CH3

Theobromine
8

or

: 6-diketo-purine.
7-dimethyl-2

The

of this group was

carried out by
systematicinvestigation
Emil Fischer and his students,
and the following
of uric
synthesis

acid will

givesome

1. Malonic
to
oxychloride

idea of the

generalmethod adopted.

acid condenses with

urea

or
givemalonyl-urea,

NHjH
CO

NH;H

OHiCO
+.

CH2
OHiCO

in presence of
barbituric acid,

NH"

CO

CO

CH2+2H20

NH"

CO

phosphorus

OF

SYNTHESIS

222
2.

converted into

Malonyl-ureais

wo-nitroso derivative

an

by

"

3. Reduced

with

amido

NH"

CO

CO

NH"

CO

N.OH

this substance

acid
hydriodic

givesthe

sponding
corre-

derivative
NH"

CO

CO

CH,NH2

NH"

CO

4. This amido-barbituric acid

acid on
givespseudo-uric

treatment

potassiumcyanate
"

NH"

CO

CO

CH.NH2

NH"

CO

givesuric acid
NH"

CO

CO

C"

+ CO:NH

CO

NH

JOH

C"

Purine itselfmay

purine, obtained

potassiumurate

CO

CO

CH"

NH"

CO

!
HjNH

be isolated

by

the

NH"

CO

CO

C"

NHV

II

NH"

by the

"co+H2o

reduction of 2

action of

"

||

/H

II II
N-C"

+POCL
N"f
"C.OH

Cl"

NH

C"

||

N"

||
C

"

N=CH
on

reduction

-"

CH

"

NHv

"C.H

II II
N_c

8-trichlor-

phosphorusoxychlorideon
N=C.C1

C"

NH2

NIT

C"

N=C.OH
OH.C

NHCO"

"

II

NH"

NH"

acid treated with dilute mineral acids loses water

5. Pseudo-uric
and

ACID

of nitrous acid

means

with

URIC

1.

in
dimethyl-urea

CH3"

manner

CO

very

CH3-N"

CH2

OHiCO

CH3 NjH
CH3-N-CO
CO

3.

HN02

CO

N"

CO
+ 4H

-"

CH3"

N-CO

This derivative

CH3"

N"

CO

CO

CH"

N"

CO

CO

CO

N.OH

H2O

CO

CH3"

COC:N.OH

CH3

CO

CH3.N"

CH3.N"
CH3"

"

CO

CH3.N"

CH2

N"

CH3"

2.

synthesized

COCH2

2H20+

be

similar to the above:

OHjCO

N;H

223

in tea, may

Kossel found

Theophylline, which
from

THEOPHYLLINE

OF

SYNTHESIS

N"

CO

CO

CHNH2

N"

CO

acted upon with

CO:NH

CH3

"

NH"

CO"

NH2

acid.
l:3-dimethyl-pseudo-uric

4.

CH8"

N"

CO

CO

C"

"N"

CO

CH8.N"
NH

CO

"

C.|OH

CO

H20+

CH

HNH

.
"

N"C"
JL 1

C"

NH

V-/

XN XI

1 : 3-Dimethyluric acid,or
1 : 3-Dimethyl-2
: 6 : 9-triketo-

purine.
this uric acid derivative is treated with chloride of

5. When

and the

CH3"

substance
resulting

N"

CO

CO

C"

NHv

N"

C"

NH

CH3"

P5"ls

N"

CO

CO

C"

||

"CO

CH8

'

N"

NH

N-(

CH"
CH3
CH"

CO

reduced
^\J

I
CH3

phorus,
phos-

is formed.
reduced,theophylline

N"C

.NH

V^.l"XJ.v

II

"H

N^

or
Theophylline,
1 : 3-dimethyl-2
: 6-diketo-purine.

"CC1

PILOCARPINE

224

Pilocarpine has been introduced into this group,

althoughit does
not contain the purinecomplex. Like theobromine,
theophylline,
and caffeine,
it contains a glyoxalin
ring. Jaborandi leaves contain
and the
three alkaloids,
and jaborine,
pilocarpidine
pilocarpine,
most
constitutional formula
recent researches pointthe following
for the firstsubstance

"

CH"

C2H6"

the

CH

CH-CH2

of the

glyoxalinring being shown by the many

bears to the methylglyoxalin
derivatives.
relationships
pilocarpine
presence

Physiological

Reactions

of

Derivatives.

Purine

Purine itself
N=CH
C"

HC

NH

H
acts
to

on

the cerebrum

like the ammonium

produceconvulsions.

These

It also

and has
salts,

of
producesrigidity

actions it transmits to its

tendency

the muscles.

caffeine and
derivatives,

theo-

bromine.
A.

Oxy-derivatives.

6-Oxy-purine
NH"

CO

CH

C"

NHV

JUL_N"CH
has a power
Sarcine),
but no rigidity;
in dogs,it is said
allantoine,

of

(Hy poxanthine,

HN"

CH"

oi
"CO

to

NH
CO

NH,

tetanic spasms,
producing
be largely
oxidized into

DERIVATIVES

OXY-PURINE

225

substance,however, is stated by Baldi to increase the

of the spinal
cord,and to producemuscular rigidity
excitability
This

in

Hall

frogs. Walker

doses,and found

small

alterations in the bone

rabbits dailyfor two months with

injected
changesin the liver cells and
degenerative
marrow.

is excreted mainlyas uric acid. It is said

In man, hypoxanthine
six hours, producingincreased reflex irritability
to act in about

and

and

general tonic contractions.

fatal dose for dogs.
tetanus,but only muscular rigidity.

spontaneous spasms,

50-100

constitute

mgms.

8-Oxypurineproducesno

then

Its action is but feeble.

B.

To

pass

and

Alkyl

Oxyalkyl

Derivatives.

corresponding
7-methylmethyl derivatives,
the
muscles
than
purine,but is
powerfullyon
has no action
poison. 1 gram subcutaneously

to the

on

purineacts

more

nevertheless

weak

dogs.
is a tetanizing
: 7-Dimethyl-6-oxypurine
agent,and also produces
in
but
less
t
han
acts
caffeine.
rigidity frogs,
powerfully
7 : 9-Dimethyl-8-oxypurine
and
producesboth muscular rigidity
tonic convulsions similarly
the
to the previouscompound, and
the two monoxypurines,
differences between
from which they are
are
derived,
probablydue merelyto differences in rate of absorption.
on

C.

is
8-Dioxypurine

but is said to have

Xanthine,

Dioxy

Derivatives.

too insoluble to have

action

some

on

the central

any
nervous

marked

action,
system.

6-dioxy-purine,
HN"

CO

OC

C"

NHV

J"^ri
U\r"Ti
W

has

no

has the

marked
same

diuretic

action

D.

The

two

on

action,but

muscle and

Dioxy-alkyl

producehaematuria. It
spinalcord as 8-oxypurine.
may

Derivatives.

act similarly
to caffeine and
monomethyl-xanthines
both on the muscles and on the nervous
theobromine,
system,but
are
more
powerfultonic convulsants.

DERIVATIVES

XANTHINE

226

has more
action
paralysing
(7-methyl-xanthine)
and is generally
the cord than 3-methyl-xanthine,
on
more
powerful,
much.
The
so
though it does not raise the reflex excitability
is a diuretic for dogs.
3-methyl-xanthine
Theobr
: 6-dioxypurine,
online, 3 7-dimethyl-2
Heteroxanthine

HN"

CO

CH3

OC

C"

N\

C"

H3C.N"
is

very

action.
such

severe

it has

no

action

on

action

that of

resembles

the

on

on

as

caffeine. Like

muscular

and
activity

but it has
caffeine,

In toxic doses it produces

more

convulsions

coagulatingaction

Its

powerful diuretic.

of muscle
irritability

"CH,

II

no

constrictor
vaso-

but
rigidity,

xanthine,it has

but
protoplasm,

not

direct

unlike xanthine

the heart.

known
: 6-dioxypurin),
Theophyllin
(1: 3-dimethyl-2
trade name
Theocine,

CH3N"
3

CO

CO

C"

also

by

its

-NH

||
CH3.N"
is

it has no action
powerfuldiuretic;
system,but acts more
markedlyon

more

nervous

mine.

C-

Its diuretic effect is said

on

the heart

muscle

last

than

or

central
theobro-

long as that of
In two cases
it producedgastric
theobromine.
haemorrhageand
also observed experimentally
in animals.
death ; this was
Paraxanthine
: 6-dioxypurine),
(1: 7-dimethyl-2

CH3"
has

yet more

muscular

not

to

so

powerful diuretic action,and also producesmore

and
rigidity

than
paralysis

dimethyldioxypurines.

either of the

other two

223

XANTHINE

1:3:

DERIVATIVES

9-Trimethyl-xanthine,
CH3

N"

CO

CO

C-N,

CH3.N"

less active than

is much

"CH,

II
C"

caffeine;

CH3
it producesthe

but more
and less convulsions.
rigidity,
paralysis
is very similar
l:3:7:"-Tetramethyl-xanthine

same

muscular

in its action to

caffeine.
Two

methyl compounds

of the insoluble 6

are
8-dioxypurine
or
known, namely
l:7:9-trimethyl-6:
8-dioxypurine,
which has a much slighter
and 7 : 8-dimethylaction than caffeine,
which acts very slightly
also,in a similar manner
6:8-dioxypurihe,
to theophylline.
:

i$0-caffeme

E.

Trioxy

Derivatives.

The next

or uric
acid, which is
oxypurineis 2 :.6: 8-trioxypurine,
uric acid is active,
and produces
inactive. But 1 : 3 :7 :9-tetra-methyl
and tetanic convulsions.
muscular rigidity,
paralysis,

MODIFICATIONS

OF

SUBSTANCES

OF

XANTHINE

TYPE.

value is
but its practical
powerfuldiuretic,
much diminished by the fact that it is onlyabsorbed with difficulty.
The formation of double salts which
are
easilysoluble is achieved
of the combination of this purinebase with an alkali,
by means
is

Theobromine

thus

"

compound of sodium theobromine with sodium

The salicylate
takes
50 per cent, theobromine.
salicylate
containing
is

Dinretin

no

effect.
part in the physiological

sodium.

This

may

advantage,as lithium
produceundesirable by-effects.

but otherwise
rapid,

might even

Aguriii is sodium
Theobromine

in water.

compound,lithium being substituted for

the absorption
make
somewhat
more
possibly

similar

is a

Uropherin

has

no

theobromine

salicylate is

combined
an

acid

with

is not inert and

sodium

salt,and

acetate.

is also soluble

DERIVATIVES

XANTHINE
sodium

Tlieocine

very
The

is said to be somewhat

acetate

safer than

It
producedserious by-effects.
occasionally

has

which
theocine,

229

powerfuldiuretic.
attempts to producecaffeine

derivatives of

is

value
practical

have not been successful.

Sympherol

is

acid compoundof caffeine,

sulphuric
N"

CH3,

CO

Jo

CH3
.SO2OH.

N"

CH3.
Its salts are
the

on

C"

with the

but
soluble,
easily

central

of the
disappearance

system the diuretic action vanishes also ;

nervous

very bitter taste and

Chloral and caffeine have been combined

they have

moreover,

action

are

not

stable.

lizing
hope of neutrathe stimulating
but the drug so produced
action of the latter,
has no diuretic action and merelybehaves like chloral hydrate.
Ethoxycaffeine,

CO

CH3*-N"

C"

CO

Nx

"C.OC,H5,

I II
C"

CH3.N"
is

in the

but also narcotic.

diuretic,
is inactive.
Methoxycaffeine
said to
Theacyl-amino-caffeinesare
action

any

on

GENERAL

The

REVIEW

introduction of

effect of the
whereas

the central

powerfuldiureticswithout

system.

nervous

PURINE

OF

methyl groups

purinesand

be

increases both the diuretic

also their action

it decreases the action

on

DERIVATIVES.

on

the central

voluntarymuscle,
system and

nervous

generaltoxic effect. The introduction of oxygen alters the

but in no regular
relative intensity
of the various actions,
manner.
The
influence of a CO
to vary
seems
accordingas it is
group
rule it produces
placedbetween NCH3 or NH groups. As a general
but on the other hand guanineis less toxic
a reduction in toxicity,
than xanthine,
CO group less
one
thoughcontaining
the

"

REVIEW

230

PURINE

OF
HN"

DERIVATIVES

CO
NHv

C"

H2N.C

^CH

|| ||
N"

(Guanine)

hydroxylgroup into the caffeine molecule

inactive body,probablyowing to the
reduces it to a physiologically
fact that it is thus converted into a substance which is easily
decomposed in the organism. The formation of an ether with
methyl or ethylproducesa compound which at firstgivesrise to no
symptoms except those of a generalintoxication. Subsequently,
resemblingthat producedby caffeine occurs.
however, a rigidity
The introduction of

than that of caffeine,

the blood pressure is less marked
doses in man
but does not differ from it in quality.Medium
are

The

action

on

but
narcotic,
distinctly

diuresis onlyoccurs

with

fatal doses.

which is practically
non-toxic,
Caffeine-methyl-hydroxide,
CH3.N-" CO

CH3

i
CH3

.uu
/\
CH3OH

has

diuretic action,
nor

no

has

caffeidine,
CO

CH3NH"

i-i
||

"CH

CH3NH- [_C_N
a
though this in largedoses
decomposition
productof caffeine,
and paralysis
of central origin.
producesmuscular rigidity
but
The diuretic action is,however,not attributable to the larger
the purine bodies are
to the smaller of the two ringsof which
is
formed, and the same
central nervous
system.
The

thus

of the action

true

pyrimidine
compoundsare

derived from

"

N=CH
HCH

UH

on

the muscles

and

nucleus formulated

PILOCARPINE
1

231

: 5-diamino-2 : 6-dioxypyrimidine,
3-dimethyl-4

CO

CH3.N"

C"

NH2

C"

NH2

OC

CH3.N"
is inactive until the second
two

the
ringis formed by linking
(imidazol)
nitrogen
systemsby the (CH) group, thus
"

results.
theophylline

when

The introduction of
action of

like that of hydroxyl,

diminishes the
chlorine,

but the cyanogen

caffeine,

it.
group intensifies

PILOCARPINE.
The

imidazol

or

ring,
glyoxalin
CH-NHv

"CH,

II
CH

for which
purinebodies and to pilocarpine;
the latter body is described here.
reason
This alkaloid,
CnH16N2O2,giveson oxidation homopilopicacid,
in allprobability
a substance represented
by the structural formula
is

common

to

the

"

C2H6.CH"
CO

CH.CH2COOH
CH0

Y
It is

thoughtto

act

haptophore
group.
destroyedby means

as

of this derivative is

If the lactone structure

of alkalis,
the

resulting

substance,

C2H6

CH

COOH

is

CH2 CH2COOH
CH2OH

inert (Marshall).
This
physiologically

seems

true
generally

of

PILOCARPINE

232

has

similar

with

bodies

constitution

constitution.

expressed by

alkaloid

The
the

formula

in

all

in

producing

probability

"

CH3
CH"

CH"

CO

CH0

C2H5"

CH0C

Ns

Y
effects of

characteristic

in

it acts

the

lastly it

oculomotor

thus

will

similarlyto

in

and

of
with

be

of

these

group

Jaborine

of

the

to

heart

stimulation, through

post-ganglionic

muscle

in the
fibres

nerve

It

myosis.

times

is

same

of

the

thus

the

very

which

less,is

pilocarpine.

with
in

It possesses

pilocarpineand

efficient

from

than

still weaker
a

to

it

connect

shown

that

doses

in the

acts

and

at

least

same

twenty

(Marshall).

differs

apparently

endeavoured

tions
determina-

pyridine nucleus.

large doses

Older

investigations have

recent

weaker

nicotine.

alkaloid

the

is isomeric

in

is

of

contain

not

Pilocarpidine,

CH3

fibres

vagus

to

atropine.

bodies, but

two

It is six

weaker

endings

nerve

unstriped

it resembles

sense

constitution

Isopilocarpine

times

all

determined.

the

electrical

as

the

muscarine,

pilocarpinedoes

way.

been

that, physiologically,pilocarpine acts

seen

less accurate
the

the

iris,producing

physiologicalantagonist
It

the

the

to

On

way

on

not

stimulating

stimulates

It

acts

nerve

in

same

'.

endings

nerve

and

way,

the

exactly

pilocarpinehas

all kinds.

of

secreting glands

glyoxolin portion

mainly

acts

Filocarpine

'

the

part played by

The

pilocarpine in possessing
pilocarpine.

condensation
an

one

product

of two

atropine-likeaction.

molecules

XII

CHAPTER
THE
of

Chemical

ALKALOIDS.

classification.

group

General

principles of

Coniine, Nicotine, and

"

physiological introduction.

and

Alkaloidal

action.

The

Method

Pyridine

allied substances.

THE

ALKALOIDS.

vegetable alkaloids are a group of substances,nearly all

abundant
in the dicotyledons.
tertiaryamines, which are specially
that one
It is seldom
alkaloid only is present,as a rule there are
and they generallyoccur
combined
with the so-called plant
many,
acids
citric,
are
malic,and tannic,althougha considerable number
found
associated
with
peculiaracids; the quinine alkaloids,for
with quinicacid,the opium group with meconic acid,and the
instance,
aconitine with aconitic acid.
The discovery
of pyridinein 1846 by
and of quinolinein the previous
Anderson
year by Runge, together
THE

"

with

the elucidation

first great
found

of the constitution

of these

substances,was

the

Gerhardt

had

of the alkaloids.
step in the investigation

strychnine,cinconine,and quinine heated with

whereas nicotine,
brucine,and others
potash gave quinoline,
coniine,
heated with zinc dust gave either pyridineor its homologues. The
then, appear to be derived from pyridineand quinolinein
alkaloids,
the

in 1842

same

way

that

that the aromatic

substances

are

derived from

benzene.

caffeine,and theobromine, which

exceptionof pilocarpine,
have been described under the purinederivatives,
this class of organic
derivatives may
be defined as productsof plant life derived from
those two substances or from
related to them.
nuclei closely
Before
propertiesof the group, a
discussingthe physiological
short account
of the chemistry of these ring complexes will be
given.
With

the

I.

Pyridine,C6H6N,
from

bone

AND

PYRIDINE

oil,and

are

and

many

also found

of its

PIPERIDINE.

homologues

can

be

obtained

in coal tar.

towards
Pyridine itself shows great stability
oxidizing agents,
but its homologues behave
in a similar manner
to those of benzene,
being converted on oxidation into acids which still contain the

pyridinenucleus.

234

SYNTHESIS

As

in the

OF

of the aromatic

case

to be due to the presence

assumed

PYRIDINE
this behaviour
derivatives,

of

six-membered

is

ing
ring contain-

nitrogenatom"

one

CH
'H

or,

as

it will be written in the

following
pages

CHk

X!H

The formation of

ing
from pentamethylenediamine
by heatpyridine
and the oxidation of the resulting
the hydrochloride,
piperidine
is in agreement with this conception
:
"

xCH2.CH2.NH;H
1.

CH2"

+HC1

XCH2.CH3.JNH2

2.

formation of pyridine
tives
derivasynthetic
is due
to Hantzch, and
consists in the condensation of
/3-ketocompounds (such as acetoacetic ester)with aldehydesand
One

used in the

method

ammonia.
tion
exampleof this condensation is seen in the followingformaof dihydro-collidine-dicarboxylic
ester by the interaction of
ammonia, and acetoacetic ester
acetaldehyde,
An

"

CH3
CH

A-

H20
HiC.COOCoH
H:u.uuuu2"i5

;."j;"i
C2H6OOC.CiH

II

C-H3

/\

II

C^OOC.G/ ^C.COOC.H

_^

:O.CH"

/^TT

NOH
i

p"l

Jo

C*TI

cu3.c\yo.ciis

OH;/

NH

rr

,2

-+

2H00

""NH"
On

oxidation,the dihydro derivative yieldsthe corresponding

pyridinesubstitution product,which

on

givesthe
saponification

OF

SYNTHESIS

236

CCXNIINE

Reducing agents convert pyridineor

or piperidine,
hydro-pyrjdine

its derivatives into hexa-

CH
CH

/\CH2
or

HH

has
Piperidine
acid in pepper

NH

odour of pepper

an

and

occurs

as

salt of

piperic

(piperine).

Coniine,a-propyl-piperidine,

H,.CH9.CH,
H

found

in hemlock

Startingfrom
manner

1.

and

seeds,was

this
pyridine,

the

firstalkaloid to be
carried out

was

synthesized.
the following

"

Pyridineacted

upon

by methyliodide givesan iodomethylate,

this substance is heated

when

to 300" C. it

change, characteristic of
givesa-methyl-pyridine,

2.

in

condenses
a-Methyl-pyridine

this

at

molecular
undergoesan intraand
type of derivative,

high temperaturewith

par-

forminga-allyl-pyridme
aldehyde,
"

0;CH.CH

CH:CH.CH3.

but
reduction givesa-propyl-piperidine,
on
a-Allyl-pyridine
coniine is
whereas
the resulting
substance is optically
inactive,
with
substance is crystallized
When
the synthetic
dextro-rotatory.
3.

acid,^atfr0-coniine-tartrate separatesout first;and

decomposed with potash,eoniine,identical with the

dextro-t"rtaric
if this is

natural

product,is

formed.

PYRROL

II.

is

bone

feeblybasic body

is
; its structure

represented
by

II

II

CH

CH

acid
hydriodic

reduction with

the formula

by

the

"

:
"'.;;

in coal tar and

CH

CH"

On

found

carbon chain united

oil,containinga four-membered

imide group

237

PYRROLIDINE.

AND

PYRROL

C4H6N,
Pyrrol,

DERIVATIVES

ITS

AND

and

it givestetraphosphorus,

or pyrrolidine,
hydropyrrol

CH0"

CH2,
or

CH,

CH2

YH

This substance is
obtained
chloride

from

(ina

and
strongerbase than pyrrol,

much

may

be

penta-methylene-diamine
by heating its hydrosimilar manner

to

piperidine)
"

CH2"

/CH2CH2.NHiH

CH2/
2\CH2.;NH2"
"

+ HC1

NH4C1

CH2

\V/

CH

I
CH2

NH

From

number
a large
ft-methyl-pyrrolidine

of different alkaloids

of the

atropine-cocaine
group are derived. They are substitution
of a combined piperidine
nucleus
and pyrrolidine
products
CH
CH2
CH2
"

Pyrrolidine
CH2
N.CH3 Piperidine
-CH

CH2

-CH2

Ecgonine,for instance,which is formed by the action

mineral acids or barytawater, on cocaine,
has the
constitutional formula

CH2"

"

CH

CH.COOH

N.CH0

CH.OH

JH

CII2

of

centrated
con-

ing
follow-

238

SYNTHESIS

III.
The
method

QUINOLINE

OF

QUINOLINE.

in bone oil,
bases occur
with pyridine
and their
quinoline
all pointto the constituof synthesis
and decomposition
tional

formula

"

CH

CH

or

That

is,a

of benzene

combination

in its
well shown, for instance,

glyoxal,
(B) or

the

and
benzaldehyde

pyridinenuclei. This is
from (A) 0-toluidine and
synthesis

of a-methyl-quinoline
from
production

acetone

0-amido-

"

H:TT
:rl0
f

and

/"VOTI

/^TT
\^JnL

\J:U"1

A.

One

generalmethod

for the formation

quinolineand its
substituted in the benzene nucleus,
is due to Skraup,
derivatives,
and consists in heatinganiline,
acid with
and sulphuric
glycerin,
some
oxidizing
agent,such as arsenic acid or nitrobenzene. In all
acrolein is formed
probability
by the dehydrationof glycerin;
this combines
with aniline,
is
which
forming acrolein-aniline,
then oxidized to quinoline
:
of

"

1.

CH2OH
CHOH

CH2
-

2H2O

CH

CH0OH
2.

C6H6N[H2"+
6jHC.CH: CH2

CHO
=

H20

C6H6N

CH.CH

CH2

QUINOLINE

OF

PROPERTIES

239

hydrogenatoms in
replaceable
are
by a, /3,y, those
designated
quinoline
The three

the

nucleus
pyridine

of the benzene

of

nucleus

with 1, 2, 3, 4.
4

Another

consists in

method

the latter B

former

numberingthe

Py 1,2, 3

and

1-4.
4

The

bases are liquids

a
odour,
quinoline
possessing
penetrating
bases. They are but slightly
are
and, like the pyridines,
tertiary
attacked by nitric or chromic acids,
but are oxidized by potassium

permanganate
nucleus

On

to

acids,the
a-#-pyridine-dicarboxylic

benzene

:
being destroyed
"

reduction with zinc and

takes up four

hydrochloric
acid,the pyridinenucleus
hydrogenatoms, givingtetra-hydro-quinoline,
CH,

or

NH

[H

considerable

since
reduction,

fattyamine

change in
the

chemical

characteristics follows

substance behaves
resulting

attached to

an

aromatic nucleus.

like

this

secondary

ISO-QUINOLINE

240

IV.

ISO-QUINOLINE.
is similar to

2*0-Quinoline,
C9H7N,
with

it in the

isomeric;it

occurs

coal tar.

oxidation it

for this

On
reason

and others

with
quinoline,

crude

material

which

it is

obtained from

yields
acid,and
/3-y-pyridine-dicarboxylic
the following
formula has been assigned

to it:"

CH

COOH
OOH

Oxidation

On

it givesa powerfulbase,tetra-hydro-w0-quinoline.
reduction,

IV

(A).

DERIVATIVES.

QUINAZOLINE

in which a (CH) group

Quinazoline may be regarded
as quinoline,
to the
is replaced
by a second nitrogenatom in the 1 : 3 position

alreadypresent.

one

N
CH

Quinazoline.

Quinoline.

and, on
dihydro derivative of this substance is of interest,
will be alluded to in this
to quinoline,
account of its relationship
nucleus does
place,although,as far as is known, the quinazoline
The

appear in any of the alkaloids.

is acted upon
When
o-nitro-benzylchloride
reaction takes place
:

not

by

ing
aniline the follow-

"

,N02
+

H0C1

C6H5NH2

HC1

C6H4"(

XCH0. NHC6H5

substance
givesa formylderivative
resulting
readily
acted upon by formic acid.

The

NO,

when

CHO

H2.N.C6H,

DERIVATIVES

QUINAZOLINE
reduction

On

zoline

241

formyl compound gives phenyl-dihydro-quina-

the

"

NO ^-^0

"X1
'

CHO
"

,H4"

^~*

I
'

1JLV/

-*

C.H/

CHiO!

'\CH2-N.C6H5

CH2-N.C6H6
N=CH

derivative o"

pyretic
was
dihydro-quinazoline
expectedto possess antibut was
found to have only slighttoxic action
properties,
and to give rise to a subjective
duced
feelingof hunger. It was introinto pharmacy, either as a free base or as the hydrochloride,
under the name
of Orexine, but owing to the objectionable
taste of
these substances they have been replacedby the tannate, a chalky,
soluble in dilute hydrowhite,odourless and tasteless powder,readily
chloric
acid and hence also in the gastricjuice,
but, like the base
This

insoluble
itself,

in water.

It is said to aid
acid in the

and
digestion

stomach

to increase the

it

has,however, in

to the gastricmucosa,
irritating
producevomiting.

too

and

!H2
no

action,whereas

the

methyl derivative

/Wen,

is

very toxic substance.

some

cases

hydrochloric
proved

unless well diluted may

Diphenyl-dihydro-quinazoline

has

secretion of

MORPHOLINE

242
V.

AND

MORPHOLINE

PHENANTHRENE

AND

PHENANTHRENE.

A. Knorr

formula

the
as
designated
morpholine
is represented
as follows :

base whose constitutional

"

This

compound is extremelyinteresting,
owing to its relationship
to the opium alkaloids. The
to the old method
of
objections
from diethanol-amine and sulphuric
acid are the difficulties
preparation
in obtaining
the amine and also its high price.
experienced

In

1901, however,Marckwald

obtained by
easily

the

and

Chain

found

that

it could be

reactions :
following

"

o-Toluene sulphamide.

CH2 OC10H7+
.

2KOH

Brom-ethyl-j3-naphthyl
ether.

C6H4\S02N(CH2
+ 2KBr
CH2 OC10H7)2

2. This derivative is

into

2H2O

quantitatively
decomposedby mineral
and morpholine.
acid,/3-naphthol,
toluene,
sulphuric
.

acids

N(CH2 CH2 OC10H7)2+ 3H2O

.

B.

with anthracene,
in
Phenanthrene,C14H10,
occurs, together
and its constitutional formula is represented
follows :
coal-tar,
as
"

the
Owing to its intimate connexion with the opium alkaloids,
studyof its derivatives has received considerable attention during
the last few years.
Pschorr

and

his

students

have

devised

new

methods

for its

and Schmidt
have investigated
the sulphonic
Werner
synthesis;
acids and their decomposition
the nitro and amido compounds,
products,
and also the derivatives of phenanthraquinone.

CLASSIFICATION

244

chemical
character
and

The

ALKALOIDS

into five or
six groups,
standpoint
accordingto the
of the nitrogen-bearing
ringfrom which theyare derived,

the various members

rough

OF

resemblance

groups, the

are
described,

I. The

II. The

of the different groups exhibit a certain

each other in their physiological
action.

to

parent substances

of which

have been

previously

"

Pyridine

nicotine.
coniine,
containing
containingcocaine, atropine,
group,

group,

Fyrrolidine

hyoscyamine.
III. The

Quinoline

containingquinine,cinchonine,

group,

brucine.
strychnine,
IV.

The

/w-Quinolinegroup,

narcotine,
containing
hydrastine,

berberine.
cotarnine,
V.

The

(?)-Phenanthrene
group,

Morpholine

containingthe

thebaine.
opium alkaloids,
morphine,codeine,
In the first group
the peripheral
nervous

which

contained substances

are

system,though central

act

effects are

mainly on
also to be

obtained.
In the second

group

observed,
mainly
doses have

an

certain

actions are
specialized
endings,but here also large
the
nervous
system,especially

somewhat

on

sensory nerve
effect on the central

highercerebral centres.
The third group

contains

toxic
powerfully
action on
preferential

substances

protoplasm;they have a certain

cellsin the spinal
cord,which is more
the group than others;they have

marked

in

living

the

nerve

members

some

if any
little,

very

for

of

peripheral

action.
In the fourth group are a number
of bodies which do not entirely
differin their action from those of the third and fifth groups ; they
have
are

central action

also muscle

mainly on
poisons.

the

medulla,but

to

extent

some

In the fifth group central action againpredominates,

and in man
this action is especially
noticeable,
owing to the high degree of

developmentwhich

the

cerebral centres attain.

The

members

of

this group have also an action on the cord resemblingthat of some

members
of the fourth group.
of artificialalkaloids,
The production
of a largenumber
differing
in various directions from
constitution of which
on

the

is

various factors in the

positionof

the

those

natural

has
determined,

alkaloids the

thrown

action
physiological

substitutinggroups

chemical

considerable

of these bodies.

may

be

light
Thus

altered;their

THE

NUCLEUS

AND

THE

SUBSTITUTING

GROUPS

constitutionvaried in many ways, or theymay be removed

As a rule,
action of an alkaloid
the main physiological

245

altogether.
can
onlybe

destroyedby profoundalterations in the atom-groups

of the molecule. The
which constitute the central ringor nucleus
functions of the substituents appear to be mostly'haptophore';
that is,theyenable the central groups to combine with the protoplasm
of certain cells and thus to producetheir proper effect.If they
to entirely
removed
are
or so modified as
destroytheir haptophoric
action of the drug will be correspondingly
power, the pharmacological
altered. But on replacing
the haptophoric
or restoring
group,
characteristicswill return,as the central nucleus has
the original
altered

or

'

'

remained

all the while intact.

Thus

the

phenol-hydroxyl
group

in

morphineseems necessary for the manifestation of the narcotic action,

forif the hydrogenis replaced
by acid or alkylradicals this effect
can
no
longerbe obtained (p.293); on the other hand, the wellknown physiological
differencesbetween morphineand apomorphine
due to correspondingly
radical changesin the central part of
are
the molecule (p.301).
If the side-chain is extended to a great extent,the physiological
action of the ringmay be lost,
and the effect of the alkylportion
of
the molecule become preponderatingly
obvious. An exampleof this
compounds.
may be found (p.251) in the pyridine
An example,
too, of the effect of alkylsubstituents is well seen
in the a-keto-piperidine
series (or^0-oximes).
a-Oxy-a-pipecoline

CH3-C

is

more

active than

piperidon
"

CH2

CH/NCH,

is five
/?-methyl-hexanone-w0-oxime
compound (experiments
on
mice).

times

as

active

as

the

GROUPS

SUBSTITUTING

OF

EFFECT

246

Trimethyl-heptanone-w0-oxime
CH3
CHS

0"

CHn

"

C-Ho\

"

"o

"VTTJ/

ntr

nxr

CH

CHo"

NH'

"

CH
is much

more

fullyon

the motor

The

vyJtl

0.tL"
"

NHX

CH"

CH2"

more

power

namely,
methyl-propyl-heptanone-^0-oxime,

C/Hgv

"

acts

endings.

nerve

isomers of

two

hexanone-M0-oxime,and

toxic than

CH2

"CO

and

{-'H

"

"

^"H2\

"CO

CH2"

C3H7

NHX

CH"

CH3

to one
another,and differ from the parent base
similarly
in producingless convulsive effect and more
narcosis ; they are also
action on the motor nerve
more
endings.
powerfulin the paralytic
Trimethyl-z"0-propyl-piperidon

act very

CH

CH3"

CH/\CH2

CH""

CHV

or

CH3"

CH/\CH"
CHA/CO

/TO
TH

is ten

times

CH3

NH

the alkylgroups suppress

poisonousas piperidon;
action on the
the convulsive action and accentuate the paralyzing
motor
nerve
endings,which is not very marked even with fatal

doses of the
Certain

as

parent substance.

pointsas

importance.

If the

to the

ring are also of

action
physiological

structure of the central

ring itself is broken,the

is lost.

which

Examples of this may be seen in 5-amido-valerianic acid,

by the loss of water givespiperidon
CH

CH2
=

H2O

CH

NHiH

NH

and

CLOSED

AND

OPEN

RINGS

acid and a-pyrrolidon,

"S-y-Amido-butyric
GEL

CH,.

,CH2
=

cni

H20

two

marked

bodies

jCH2

cu^yco

colon

NHJH
The

247

NH

in which

the
the

action,whereas

without

are
ring is not closed,
derivatives
closed-ring

by loss of the elements of water

perhapspicrotoxin).
Similarly,
pentamethylene-diamine
them

act

like

formed

any

from

strychnine
(or

rH/CH2.CH2.NH2

CU2\CH2.CH2.NH2
toxic,whereas

the closed-chain

formed
derivative,
piperidine,
from it by loss of ammonia
(seep. 234),has a definitetoxic action.
which has onlyone-tenth the toxic power of nicotine,
Metanicotine,
may also be cited as an example(p.256).
of groups in the ring influences the activity
The number
of the
compound,but does not produceany alteration in kind. Piperidine,
with five. The
a six-membered
ring,is more toxic than pyrollidine
of the N atom in the double benzene-pyridine
ringdoes not
position
thus quinoline
and ^0-quinoline
are
appear to be of importance,
is not

identical.
physiologically
On

the other

of
hand, the replacement

CH

in benzene

group

difference in the action of the

marked
a
by nitrogencauses
compound and its derivatives. Thus bases derived from
resulting
characterized by
the benzene ring alone,aniline for example,
are
their power of reducingthe body temperature and breakingup
whereas pyridinehas neither antiseptic
the red blood cells,
nor
The
condensation of a benzene
and pyridine
antipyretic
power.
results in powerfully
toxic and antiseptic
bodies,
ring (quinoline)
and naphbut the double benzene nuclei,
diphenyl,
phenanthrene,
thalene,
have no antipyretic
derivatives. The condensation of two
series (dipyridine,
parapicoline,
ringsof the pyridine
"c.)givesrise
in their action the natural alkaloids,
to bodies resembling
to which
related.
theyare chemically

Some

idea of the variations in action which

changes in

ring-structure
may

artificialring compounds the

"

be

conditioned

are

gained from

such
isoximes,
cyclic

study of
as

by
the

piperidon,

CYCLIC-KETONES

AND

ISO-OXIMES

248

and imines,
The first
piperidine.
cyclohexanone,
all contain the group (CO.NH) in the ring;they are the least
and have least paralysing
action on the
toxic of the three series,
motor
nerve
system. They are
endingsand the central nervous
i.e. convulsions
characterized by producingpicrotoxin-like
convulsions,
dependent on excitation of bulbar and possiblycortical
The lower
centres,unaccompaniedby increased reflex irritability.
in the highermembers
of the series are the least active,
members

ketones,such

the

as

effectsare
picrotoxin

most

marked.

CH,
CH,

CH

CH,

CO
NH

Pyrrolidon.

CH2"

CH,

CH2

CH5

CH0

CO

NH
Hexanonisoxim

The

e.

CH2

ketones,

CH/\CH2

cnlJCH

CH2^CH
; the imines

the motor
the

of
paralysis

toxic,producemore

more

endings. In

nerve

variation

and have
all,

all three series the

in the selective action of these

variation in the
implies
in the

toxic of

but
origin,
most

no

vulsions
con-

action

on

largerringsare

active.

more

The

are

the most

central

they act, a matter which

(p. 19). From this pointof view the

body

considered

on

which

regardedas a number
locks,but
protoplasmic

of

keys,each

it must

compounds

sarily
neces-

of the different structures

protoplasm

of which

also be admitted

has

alreadybeen

alkaloids may be
will fit into certain
that the locks

are

often very bad ones, as in many

instances differently
shapedkeys
will turn them.
in
Thus,
chloroform,
general,
quinine,
morphine,

THE

GROUP

PYRIDINE

249

lower the body temperature,whilst strychnine,

aconitine,
and cocaine raise it a very miscellaneous
caffeine,
nicotine,
picrotoxin,

and

"

list from

the

structural

point of

view

"

and

later

on

exampleswill be seen under such well-defined actions as

local anaesthesia and mydriasis
(p.260).
that is,
Loew
those
classed
alkaloids
as
The
are
special
poisons,
by
which do not in sufficiently
destroy
protoplasm.
strongdilution invariably
e. g. that of
They act onlyon certain kinds of protoplasm,
the central nervous
system,but do not damage other kinds (see
p. 17).
of the pharmacological
The toxic action is merelyan exaggeration
used as drugs,
the dosagebeing so
action of the alkaloids when
that stimulation and not destruction is producedin the
regulated
cell bodies. It may, of course, happen that with smaller doses the
toxic action of the drug entirely
disappears,
owing to the dilution
abundant

being

too

great to

affect those

structures

on

the disturbance

of

when given
quinine,
depends. For instance,
does not
in largeenough doses to destroythe malarial parasite,
effect on the cerebrum.
necessarily
produceits specific
We
shall now
proceedto consider the various alkaloids of which
the chemical structure is known, adopting
the classification
previously
mentioned.
the opium alkaloids which
For practical
convenience,
to two groups have been considered together.
belongchemically
Hordenine is separately
described (see
p. 303).
In order not to interrupt
the
unduly
arrangementof the alkaloids
has been added in which the various
a chemical
on
basis,a chapter
substitution products
introduced into practice
are
synthetic
recently
similar to the alkaloids
described. These,thoughpharmacologically
and
often very different chemically,
are
theyare intended to replace,
in a
hence it was
thoughtadvisable to deal with them separately
to the systematic
account of the alkaloidal
chaptersupplementary
which

the fatal issue

I.
The

THE

PYRIDINE

GROUP.

alkaloids to be considered in this group are coniine

principal
and its stereoisomer,
methylconiine,
conhydrineand its isomer
from hemlock),
nicotine and nicoteine
pseudo-conhydrine
(derived
and piperine
(fromtobacco),
(fromblack pepper).
and chemically
in
these bodies vary considerably
Physiologically
and it will be well to begin with the simplest,
complexity,
namely
that substance forming
the chemical basis of that group, pyridine.

GROUP

PYRIDINE

250

as it does
This,containing

one

in the
of tertiary
nitrogen

atom

ring,

is very inactive j
CH

CH/NCH
CH

results in the formation of

which
hydration,

the much

more

active

an

imide group,

produces

body,piperidine,
ca
C]

Pyridine, which is a

with
liquid

and distinctive odour,

powerful
if inhaled,
stimulates the fifth,nerve
and producesdyspnoea,
then
and eventually
slow,shallow breathing,
sleep.In very largedoses
it paralyses
the sensorium,producingcompleteanaesthesia and
abolition of reflexes,
inhibit respiration;
smaller doses may
on
stimulation of the vagus centre in dogs breathing
in
stops expiration.
Small doses act on the heart,
the force and slowing
increasing
the rhythm of the beat ; largedoses paralyse
the muscle,causing
Doses
a fall of blood pressure, and finally
stopthe heart altogether.
of 1 gram
(15minims)per diem produceno symptoms.
and also pyrollidine,
which is formulated
Piperidine,
a

"

CH,"

H,

and

CH0

or

H.

cyclohexamethylene-imine
CH

CH0"

CH,
H
have

much

the

same

action,producingin cold-blooded animals

252

CONIINE

Couiine

is propyl-piperidine
"

)" CH2.CH2.CH,
"
2.

IH

though similar in its action to piperipowerfulstill,

dine. It acts probably
mainly on motor nerve endings,
producing
It also raises the blood pressure, by local action
muscular paralysis.
and slows the pulseby action on
the peripheral
the
on
vessels,
centre
or
terminations;there is also slightquickeningof
vagus
followed by retardation,an
effect probablypartly
respiration,
central and partlyperipheral.
has a similar
e"0-Propyl-piperidine
but it has only one-third of the toxicity
action to coniine,
of that
It is

more

substance.
iso-Coniine

acts
apparently

^-Methyl-coniine

like coniine.

"

CH,.CH0.CH,

The imide

hydrogenof

coniine in this compound is

now

by
replaced

methyl group; no great physiological

change,however,occurs.
is much
less toxic. The muscular spasms occurring
Dimethyl-coniine
after coniine poisoning
absent
authors
be
said
to
are
by some
after methyl-coniine,
which also acts more
the spinal
on
specifically

cord.

Its fatal dose is one-third less than that of coniine.

Conhydrine

NH
and

than
act less powerfully
its isomer,pseudo-conhydrine,

doses being -03,*2,and over

proportional
(Findlay).
body-weightin guinea-pigs

the

-3 grams

per

coniine,

kilogram

having two atoms of

of interest,
as
are
they are thoughtto
hydrogenless than coniine,
illustrate the action of the double bond (see
p. 50).
A

series of bodies known

as

Coniceines,

THE

CONICEINES

253

y-Coniceine

CH2

CH/NcCH
CH2 CH2

"

is said to be seventeen

the
ceine,

is

stereo-isomer of "$-and

be

may

be formulated

CH3

toxic than

more

constitution of which

may

times

coniine

is also
uncertain,

e-coniceine.

and

a-coni-

toxic

more

; it

which
5-Coniceine,

"

CH

CH/TSCH.
CHA

is less

UCH.CH2

to the
active,
owing possibly

CH2. CH3

presence

of

tertiary
nitrogen

atom.

which
/3-Coniceine,

has

probablythe

structural formula

"

CH

is less toxic than a-coniceine. The latter is more

toxic than coniine.

have been previously

mentioned
and ethyl-piperidine
Pipecoline
homologuesof the composition
(seep. 251). The piperidine
C7H15N,
and
that
termed
is di-methylpiperidine
are
ethyl-piperidine,
whereas the methyl-ethyl
derivatives are called copellilupetidines,
dines. These substances are formed by the reduction of the corresponding
with sodium and alcohol.
homologouspyridines
of these compounds increases approximately
in
The
toxicity
their molecular
as
geometrical
progression,
weight increases in
This holds good,however, only up to
arithmetical progression.
the iso-butyl
and hexyl derivatives,
marked
which both show
a
decrease in toxicity.
1:2:4:8:5:4.
The proportions
are
acts like curare
Lupetidine
(a-a'-dimethyl-piperidine)
; it has no
cardiac action,but paralyses
It has a toxic
special
respiration.

PIPERIDINE

254

action

HOMOLOGUES

cells,
producingvacuolation;the central
and there is some
local anaesthetic
affected,
system is slightly
the red blood

on

nervous

action.

producessalivation and
/?-Ethyl-piperidine
(/3-lupetidine)
convulsions.

It is not

cells so much

as

toxic

tetanic

which it
j3-propyl-piperidine,
otherwise resembles ; the latter,
again,is not so toxic as coniine.
in addithe most powerfulpoisonof this series,
tion
Propyl-lupetidine,
has a marked
effect
to its action on the motor
nerve
endings,
the central nervous
on
system,but does not damage the red blood
so

as

the other members

of the series.

the heart and has a true

paralyses
w0-Butyl-lupetidine
action; it also paralysesthe motor nerve
endings. In
this effect is but slightly
observed.
lupetidine
Copellidine

narcotic

hexyl-

an,

is twice

toxic

as

as

and
lupetidine,

acts

the
on
principally

motor

endings.
Piperylalkin,

nerve

"

CH2.CH2.OH

Pipecolylalkin,

CH2.CH2OH
H
and

methyl-pipecolylalkin,

-CH2 CH2OH
.

r.CH3
have

been

The
investigated.
physiologically

of
paralysis
From

first two

produce

last appears to be innocuous.

consideration of these compounds it will be seen that not
central

the
origin,

onlythe size but also the

of
position

the side-chain in relation to

NICOTINE
the N

in the

255

action"
influence physiological

ringmay

asymmetrical
symmetrical.As

to the
quitesimilarly

compoundsdo not behave

a
rule,too, though not always,the alkaloids in which
active than
stituents are attached to nitrogenare more
which

the groups

are

the subthose in

linked to carbon.

Stilbazoline

IH
has

littlepower
The

of

but
excitingconvulsions,

fatal dose is about

three times

is
as

powerfullyparalysing.
of
that
as
large

coniine.

Piperine, which has

structural formula

represented
by

CO"

N"

CO.CH

CH,

CH.CH

but has less action in contracting

the
to piperidine,
similarly
arterioles. This appears to be due to the attachment of
peripheral
the acid radical to the nitrogen
instead of one
of the carbon atoms
in the ring.
molecular structure,
has a somewhat more
Nicotine
complicated
and in all probability
is a-pyridyl-/3-tetrahydro-#-methyl-pyr
it may be represented
formula :
by the following
acts

"

CH3
N

CH2
On

oxidation it givesrise to

acid,
/3-pyridine-carboxylic
COOH

NICOTINE

256
and

DERIVATIVES

is

of pyridine;starting
a
from
/3-derivative
consequently
Pictet
and
have
base
a
/?-amido-pyridine,
Crepieux
synthesized
of the natural alkaloid.
showingall the properties
The action of nicotine closely
but it is
resembles that of coniine,
ately
more
powerful. If givenin doses not largeenough to be immedinicotine
fatal,
stimulation
origin,

causes

of the

clonic and

tonic convulsions

of central

respiratory
centre,a rise followed by a fall
and finally
of the whole
extreme depression

of arterial blood pressure,

central nervous
system,which

in death.

ends

Nerve

cells in the

hence after preliminary

stimulation
gangliaare paralysed,
peripheral
there is diminution in the secretory
of glands. Small doses
activity
slow the heart,largerdoses render its action rapidand irregular.
This is partly
vagal and partlydue to direct action on the musculature.
The action on the blood vessels is peripheral,
and differs
that of adrenalin in that

from

followed

by

periodof

it lasts for

shorter

time,and

is

vaso-dilatation.

Nicoteiue

CH,

has

similar but

more

powerfulaction

than

nicotine,
apparently

traceable to the presence of the double bond, whereas oxynicotine,

obtained by the action of hydrogen peroxideon
nicotine,is
Its constitution is that of

weaker.
the

and
aldehyde,

an

ringis probablybroken
pyrrolidine

in its formation

"

CH3
NH

CH/
CH

Metanicotine,
nine times

as

which

acts like

CHO
CH,

is much
nicotine,

to producethe
largeis required

onlyfatal in double the time.

is represented
by the formula
is

"

The

toxic

constitution

weaker.

A dose

symptoms, and
of metanicotine

NICOTINE

DERIVATIVES

257

NH.CH3

and

it

these

the

ring

is

is

ring

pyrrolidine

formation

original

the

compounds

two

though

methyl-/3-pyridyl-"$-butyl-amine.

consequently

is

essential

not

physiological

action

This

destroyed.

for

Thus

remains,

shows

production

the

of

in

that

the

the

pyrrolidine

action.

physiological

The

curious

point

pressure

by

hydrated

atoms,

but

also

in

or

that

of

the

raise
The

to

due

some

action

only

to

substituent

and

group

the

the
to

the

presence

give

it

from
most

arterial

which

rest,

are

the

constricting

of

from

The
the

nicotine

presence

action

requires

lowers

by

which

the

degree.

all

pressure

similar,

very

itself

whereas

arterial

are

in

pyridine

synergetic

compound
some

that

marked
not

markedly

heart,

the

weakening

be

may

is

bodies

these

differ

they

difference

arteries.

respect

latent

of

bodies,

smaller

ring,

but

onwards,

pyridine

all

of

effects

has

in

this

the

pyrrolidine

pyridine,

which

of

extra

actuality.

hydrogen

is

XIII

CHAPTER
THE

ALKALOIDS

(CONTINUED). Pyrrolidinegroup
"

Hyoscyamine. Quinolinegroup
Strychnineand Brucine.
II.

THE

"

The constitution of Cocaine

CH2"

Cocaine,Atropine,

Quinine,Cinchonine, and their substitutes.

PYRROLIDINE

CH2"

"

is

GROUP.

expressed
by

the formula

CH

CH.COOCH3

N.CH3

CH.O(C6H6CO)

CH

CH2

"

and is thus

the two hydrogenatoms

benzoyl-ecgonine-methyl-ester,
in the carboxyland
hydroxylgroups having been replacedby
methyl and benzoylrespectively.
The chief physiological
of cocaine are :
properties
1. It stimulates the vaso-motor
centre and partially
paralyses
It also acts slightly
the vagus.
to
stimulant
the accelerator
a
as
"

nerves

to the heart.

2. Its action

For these

reasons

the blood pressure is raised.

cerebral and

centres is at
spino-medullary
firstexcitant and then profoundly
depressant.It thus causes death
of the respiratory
centre.
by convulsions or paralysis
and vacuolation of
3. It causes
peculiarfoam-like degeneration
the liver cells,
which Ehrlich says is quitecharacteristicin mice.
4. It raises the body temperature.
6. It dilatesthe pupil.
on

the

'

'

6. It increases power of muscular

local anaesthesia.
7. It produces

Cocaine

thus

work.

differs remarkablyfrom

in
predecessor,
ecgonine,

its

action.
physiological

This substance

CH2"

CHQ"

its immediate

CH

CH.COOH

N.CHQ

CH.OH

CH-

CH2

chemical

PHYSIOLOGICAL

260

both

o" which

molecule.

chemical

remaininggroups will
of Temperature. This

4. Elevation

and the

correlated to the

are

The

ACTION

onlysubstance

which

the

be considered.

now

is

of

structure

quitea

exhibits it in

marked

property,

powerfulmanner

more

is /3-tetrahydro-naphthylamine
"

CH,
H.NH2

It appears

onlysimilar but due

body,namely,increased heat production

process in the
central stimulation. It does not

to the

by

effect is not
that its physiological

same

occur

in animals

under

the

influence of chloral.

.5.
on

This action is due to

MydriaticAction.

the motor

be abolished

to the dilator fibres of the

nerves

by muscarine.

Its exact

effect
stimulating

and
iris,

ture
relation to the chemical struc-

be derived from

known, but
the ecgoninering,which, though

causes
mydriatic,

some

of the molecule of cocaine

thus cannot

is not

dilatation of the

pupilin

cats.

it appears

to

generally
The benzoyl
It is probably
not

is essential for the appearance of this action.

which isassociated with the
on the structural arrangement,
dependent
group

is also mydriatic.
as j3-tetrahydro-naphthylamine
temperature,
muscular
action which has been attributed,
6. The
effect on
has not been shown to depend
with accuracy, to cocaine,
apparently

rise of

chemical groups
special
be attributed partly
to
perhaps,
on

on

in

any

the.central

nervous

the true stimulant

system,which

nitrogenouselimination.

injhebodyis said to

contained in the molecule.

follow

is

It may,

action of cocaine

accompaniedby

d.ecrease.

A diminution in the oxidizing r"mflflgff*i

on

the administrM"

att|hfldm^y.

attribute of cocaine
importantphysiological
from
a
practical
point of view is its power of producinglocal
and anaesthesia.
Not only pain but all sensations are
analgesia
to
affected ; for instance,
cocaine is applied
taste is abolished when
of the mouth,and heat and cold cannot be felt.
the mucous
membrane
The local anaesthetic action of cocaine dependspartlyon the
and partly
the presence and
structure of the ecgoninenucleus,
on
relative positions
of the two substituting
groups.
nucleus is possibly
The ecgonine
the least importantfactor in the
other
it has been found that many
of anaesthesia,
as
production
7.

By

far the most

COCAINE

OF

similar

providedtheypossess
substances,
theories have

this effect. Various

261

been

can
substituents,
produce
forward
to
the
put
explain

quently
ecgoninering,several of which have subsefeature of ecgonineis
been disproved.The most
striking
its arrangement in a double ring,and this suggesteditself as
action of cocaine. However,
causal factor in the physiological
a

part playedby

the

substance,w-methyl-benzoyl-oxy-tetramethyl-piperidin-c
but a single
is a local anaesthetic,
though containing
methyl-ester,
a

ring"
CH2"

"

CH

CH3" C(CH3)" CH2

CH.COOCH3

N.CH3

CH.O(C6H5CO)

CH

CH2

--

N.CH3
CH3" C(CH3)" CH2
"c.
w-Methyl-benzoyl,

Cocaine.

fact,it has been found that a largenumber of substances,

such as phenol,
/?0ra-chlorphenol,
picricacid,salicyl-methyl-ester
The
"c., have anaesthetic or analgesic
properties.
phenacetin,
simplestbody producingthese effects is the methyl ester of
The (N.CH3)group may be replaced
benzoic acid,C5H4COOCH3.
by (NH), the resulting
productbeingnor-^-ecgonine
CH2" CH" CH.COOH
In

"

NH

CH2"

CH.OH

CH"

CH2

in
as
This, when benzoyl and methyl groups are introduced,
but
a powerful
anaesthetic,
ordinarycocaine,producesnor-cocaine,
too toxic for

practical
purposes

"

the

toxicity
probablybeingdue

the presence of the imide group (NH)".

That
the ecgoninering has its influence

the anaesthetic

by the fact that certain

not affecting
the substituting
alterations,
groups, may be accompanied
version
by alterationsin the anaesthetic potencyof cocaine. Thus its coninto a quaternarybase by the addition of methyl-iodide
the distinctivecocaine action,
and substitutes a curare-like
destroys
in its place.
one
07^/"0-Chlor-cocame and
#^fa-nitro-cocaine have
only slight
has no anaesthetic action,
anaesthetic properties
; weta-oxy-cocaine
and in largedoses producesdegeneration
of
but is slightly
toxic,
the liver cells. The fl^a-amido compound producesneither anaesof
properties

cocaine

seems

to be shown

on

to

COCAINE

262
thesia

nor

DERIVATIVES

destruction of liver cells. The

latter

propertycan,

however, be restored by introducing

benzoylor
amido

group,

By

means.

and

acetylinto the
body is producedby this

anaesthetic
powerfully

the action of chlorformic ester

on

the amido

derivative,

a
actingon
strong anaesthetic,
produced,
and givingrise to toxic symptoms
liver characteristically,

cocaine-urethane

is

the

"

CH

CH.COOCH3

N.CH3

CH.O(C6H6CO)

CH

CH2

CH2"

(COOC2H5)NH"

CH

"

Cocaine

urethane.

vating
as acti(CH3.COO) group is essentialto the action of cocaine,
It may be replaced
the inhibitory
carboxyl
by other
group.
acyls.
Thus coca-ethyline,
containingthe (C2H5COO) group, coca"c.,have been prepared,
propyline(C3H7COO), coca-^o-butyrine,
cocaine in practice.
but have no advantagesover
and
benzoyl-nor-ecgonine,
ecgonineitself,
Benzoyl-ecgonine,
The

have

anaesthetic action.

no

By

the abstraction of water

an

anhydrideof ecgoninecan

be

formed,
CH9"

CH

CH.COOH

CH2"
has
which, like ecgonine,

N.CH3

CH

CH

CH

no

anaesthetic action.

Its ester is also

inactive
"

CH

CH0"

I
N.CH3
r*TT

^Jlo

In the firstcase

of the

the

f^TT
"

v^Xl-

CH.COOCH3
I
CH
-CH

inactivity
may

be

explained
by

the presence

In the second case this explanation

cannot
carboxylgroup.
hold good,and recourse
be had to the essential change in the
must
to the presence of the double bond.
ecgoninering,and possibly
The (CH3.COO) group has also been thoughtto exercise a specific
effect on the physiological
action. This view may
strengthening

263

DERIVATIVE

TROPINONE

benzoyl-ecgonine-nitri
supported
by the fact that laevo-rofatory
in
its action
weak
is comparatively
though anaesthetic,
be

"

CH2"

CH

CH.CN

N.CHQ

CH.O(C6H5CO)

I
As

ja

CH-

CH0"

the facts that the

this are
against

benzoylester

of

pseudo-

tropine,

CH2"

CH

-CEL
H.CH

N.CH3
CH*" -G CH

(CH3COO) group, isa powerfulanaesthetic (though

is a weak one),
while the methylated
benzoyl
tropine-benzoyl-ester
has
ester of a-cocaine (an isomeric body obtained from tropinone)
which contains

no

no

anaesthetic action.

CH2"

CH-

C"(CN

CH,," CH

-CO

CH0

CH2
HCN

N.CHfl

N.CH3
CH2"

CH

CH2"

CH2

CH

CH2

Tropinone-cyanhydrine.

Tropinone.

TI

CH2"

CH-

COOH

I
CH2

ca

N.CH,

CH2"

CH

N.CH,

CH2
a-Cocaine.

a-Ecgonine.
It would

be

to attribute the weakening of the

therefore,
safer,

action of the nitrileof laevo-rotaiory

physiological
benzoyl-ecgonine
to some
actual antagonistic
effect of the (CN)X group, similar to
that of the original
carboxyl.
The importance
of the benzoyl
group is shown by the fact that
in

its absence

substances

no

anaesthetic effect occurs,

containingit, such

derivatives of

as

and

moreover

many

the
benzoyl-tropine,

and
morphine,hydro-cotarnine,
quinine,

benzoyl

cinchonine

ANAESTHIOPHORE

264

local anaesthetics.

are

In the

ecgoninederivatives it cannot act

replacementof the carboxylby a COOR

simultaneous

without

group, and
substance

the presence
as

benzoic

GROUP

of these two

alone in such

groups

C6H5COOCH3,
methyl-ester,

simple

is sufficientto

producelocal anaesthesia.
In accordance with the nomenclature

of the

theoryof dye-stuffs,
it is called by Erhlich the
anaesthiophoregroup, while the
(N.CH3)group he calls auxotox
(seep. 22). The former cannot be
series;and if replacedby
replacedby any acid of the aliphatic
'

'

'

'

or

acid,the anaesthetic effects are

aromatic

another

either abolished

diminished.

much

Phenylacetyl
(C6H5CH2CO) ecgoninehas

slightanaesthetic

action.

Again, atropinehas slightanaesthetic

acid
with tropic
compound of tropeine

This
properties.

is

"

Homatropine,in

which

acid
tropic

is replaced
by mandelic

acid,

C6H6.CH"g"OH
j
has

anaesthetic action.

more

where
benzoic acid,C6H6COOH,
the
Benzoyltropine,
replaces
acid,is a powerfullocal anaesthetic.
tropic
Cocaine existsnaturally
as a Zaevo-rotaiory
body. A dextro-rotatory
be prepared which
cocaine can
only differs from the ordinary
cocaine in producinga more
and one
rapidand intense anaesthesia,
which
The

passes off in

shorter time.

generalconclusions

the relation between

action of cocaine

are

to be drawn

the chemical

from

the

observations

constitution and

on

physiological

"

the vaso(1) The action on the central nervous

system (including
due to the j^rrolidine
motor
are
effect)
ring^from which cocaine is
derived.
originally
action on the liver is a special
attribute of
(2) The peculiar
ecgonine,and is partlydependent on the presence of tertiary
nitrogen.
(3)The elevation of temperatureand the peculiareffect on

muscular

(4) The

be traced to any
mydriaticeffect also is not

energy

cannot

chemical structure.

chemical factors.
special
yet accounted for in the

ATROPINE
anaesthetic effect is

(5)The

265
the presence
to the ecgonine

largely
dependenton

but is also due

alkyland benzoylradicals,,
altered without destroying
or
ring,as this cannot be materially
this action. Of all these factors the presence of the
diminishing
other
as
numerous
benzoylgroup appears to be the most important,
this radical exhibit a similar pharmacological
compoundscontaining

of the

effect.
ATROPINE.

by
Both

and cocaine is accombetween atropine

panied
similarity
which
is no less remarkable.
similarity
physiological

chemical

The

are

with bases which

esters combined

merelyin respectof one carboxyl

group
CH2
CH2" CH
CH2"

differfrom

another

one

"

CH2"

N.CHQ

CH."
CH.OH

CH

CH2

CH

CH.COOH

N.CH,

CH.OH

CH-

CH,

"

Ecgonine.

Tropine.

and tropic
acid,the latter body
Atropineis the ester of tropine
nucleus and an asymmetriccarbon atoma benzyl
containing
"

C6H5-CH\COOH
Tropic acid.
Thus

atropine is
"

CH2"

CH
N

CH2
.CH3

H2" CH
CH2
action of atropine
is complicated;
its effects
The physiological
the organism depend largely
on
on
dosage,and divergentviews
of action. Atropineacts
stillheld on the details of its mode
are
the central nervous
on
firstly
system, producing(inlargetoxic
In small medifollowed by profounddepression.
cinal
delirium,
doses)
doses its action on the cerebrum is generally
not noticeable.
-

Toxic

doses also raise the

extent.

of the

nerves

to

sometimes
temperature,

to

very

siderable
con-

Its

the terminations
action paralyses
peripheral
muscle (including
glandsand unstriped
secretory

iridis in mammals); it has some

action on sensory
sphincter
muscle it has
nerve
endings,but on the nerves
supplyingstriped
action. It also paralyses
the vagus terminations to
no
practically

the

266
the

ATROPINE
heart.

The

AND

COCAINE

comparisonbetween

thus be set forth in tabular form

atropineand

"

Cocaine.

Atropine.
Cerebral

and

medullary
centres

Cardiac

( (largedoses)

cocaine may

deliriant
sedative

deliriant

j(smallerdoses)no sedative effect

( (final
profounddepression
action)

profounddepression

J
depressant

depressant

Temperature

raised

raised

Bloodvessels

contracted
(central) contracted (central)
of
of blood pressure)
blood
(rise
pressure) (rise

Eye
Sensory nerves

powerfulmydriatic
slight local anaes-

vagus

terminations

lesspowerfulmydriatic

powerful local

thetic
anaes-

thetic
Nerves

to

paralysed

un-

no

action

stripedmuscle
Nerves

to

action,except in
doses,when they are
by largedoses,

no

stripedmuscle
(

Muscle

j by

unstripedmuscle

large
paralysed

no

very

action,except when

locally
applied
possibly increases
of action
stripedmuscle

paralysed

power

stimulated
small, "
"
striped muscle, unaffected

in

o'

to

secreting

"

paralysed

when
j "lands,

{
Liver

no

these actions

specialaction

secre-

tion is paralysed

specificdegeneration
(mice)

the first fact which is brought

analysed,
and cocaine is sometoxic action of atropine
out is that the general
what
followed by depression
of the cerebral
similar. The excitation,
and medullarycentres,
the rise of blood pressure and temperature,
and the inhibitory
action on the vagus terminations seem
common
and local anaescharacteristicsof the two drugs. The mydriatic
thetic
actions differ mainlyin degree.
The action of atropine
muscle is to a certain extent
on
unstriped
muscle.
analogousto the action of cocaine on striped
Very small
doses of atropine
muscle fibres and increase
stimulate involuntary
their conductingpower:
has probablya
cocaine taken internally
effect on voluntarymuscle, and here the dose which
stimulating
reaches the muscle must be very small.
actually
The main differencesare, then,the characteristicaction of atropine
muscle and secreting
to unstriped
the nerves
on
glands(though
cocaine is said to act on these glandswhen locally
and the
applied),
When

are

GENERALIZATION

LADENBURG'S

268

in
mydriasis

in

this,as in toxic doses it causes

when
tropineis combined with
effect is obtained.

certain aromatic

containingalcoholic hydroxyl. Thus

in

But

the

it is

only

acids that the full

acids all resemble

aromatic

These

cats.

one

another

combinations

with

//""ITT/~\TT

acid
tropic

(forming

at

mandelic acid

(forminghomatr

and atrolactinicacid

C6H

opine)

opine),

C6H5C"-CH3

\COOH

whilst those
all mydriatic,

either (1)no aromatic acid,

containing
ah aromatic acid withlike lactyl-,
out
or succinyl-tropeine,
or (2)
acetyl-,
like cinnamic acid,
matic
hydroxyl,
C6H5CH : CH.COOH, or (3)an aroacid with hydroxylof the phenoltype,like salicyl-tropeine,
are

CH2"

CH2"
without

are

The

CH

--

CH2

N.CH3

CH.O(CO.C6H4 OH)

CH

CH2

action.
mydriatic

influence of

an

aromatic

acid

alcoholic hydroxyl
containing

in

forth mydriatic
in the base is not confined to
calling
properties
but also occurs
the derivatives of tropine,
in such allied substances
1
and
as
ra-methyl-triacetone-alkamme
#-methyl-vinyl-diacetone
the
of
but only
which
mandelic
acid
esters
alkamine,
are
mydriatic,
in

one

stereo-isomericform.

thus illustrated,
which is known
as
principle
Ladenburg's
Those tropeines
:
generalization'',
onlyare
may thus be expressed
of mydriatic
action which are combined with an acid sidepossessed
chain possessing
a benzene
ring and an aliphatic
hydroxyl/
and
and
Jowett
and Pyman2 have
Marshall,Jowett
Hann,
shown
that this generalization
is not absolute.
Thus
terebyl
formulae R
tropeine
(infollowing
tropine
radical),
The

'

'

"

(CH3)2:C"CH.CO.R
C

The

(seepp.

has
hydrochloride
306,316).

CH0

been introduced
2

Tram.

into medicine

as

euphthalmine

Chem. Soc.,1900, 1906 and

1907.

ACTION

MYDRIATIC
contains neither

which

aliphatic
hydroxyl,is

ring nor

benzene

though its
mydriatic,
distinctly
atropine.

269

action is much

weaker than that o"

Phthalide-carboxyl-tropeine,

aCKCO.R
c"
which is similar to

homatropine,

apTT/OH
C\CO.R

has also marked

of

On

action.
mydriatic

the other

hand, the lactone

0-carboxyphenyl-glyceryl-tropeine,
/\
f \"( pTT/OH
H",
E

IJ"
which

contains

benzene

COO
and

group

alcoholic

is only
hydroxyl,

but
are moderately
feeblymydriatic
active,
; intravenous injections
not direct instillations
into the conjunctiva.
The relativeposition
of the benzoyland nitrogengroups appears
is a combination or
like ecgonine,
to be of importance.Tropine,
condensation of two rings,
and piperidine.
It is to
a pyrrolidine

the latterthat the side-chains are

CH2" CH2

"

attached

CH2

CH2

N.CH2

N.
N.CH3

CH2

CH2

CH2

CH2

"

CH,"

CH2

"

CH

CH,

N.CH3

CH.OR

CH

C.

n-Methylpyrollidine. n-Methylpiperidine.
to the nitrogen,
The radical R is in the para or y position
relatively
and this is also the case with the alkamines havingmydriatic
action,

thus

"

(CH3)2: C

CH2

N.CH3

(CH3)2:CThe
presence

effect which
mydriatic

-CH2

is thus

of certain side-chains is a

CH.OR

broughtinto

action

propertyinherent

in the

by

the

parent

MYDBIATIC

270

substance.
this

Stereo-isomers

ACTION
found

are

to

behave

in
differently

has alreadybeen noted,in two

as
respect. Tropineexists,
forms.
forms
with
The
mandelic
second,pseudo-tropine,

such

acid

isomer

homatropinewhich has no mydriaticaction.

Moreover,the addition of methyl bromide to the nitrogengroup
action * :
enfeebles the physiological
an

of

"

CH

CH

XT/-"*
IN "

fITT
l_/
Jig

P
^"

",jj

rrrr
v" XI

PITT
vy J10

It must

CH

v""

be remarked

H2

the effectof atropine

that,physiologically,

from that of cocaine. The effect

eye differs somewhat
of cocaine is to stimulate the dilator fibres supplied
by the sympathetic,
the

on

and

to paralyse
the sphincter
fibres from
only partially
There is no action on the ciliary
muscle
the oculo-motor nerve.
the lightreflex. Atropine,
the other hand, certainly
on
or
on
fibres and the circular muscle fibresof
the sphincter
nerve
paralyses

the iristhemselves

of
lightby paralysis

and

muscle.
a

it also abolishes the reaction for accommodation

Whether

action of

terminations

nerve

it also stimulates the

and
disputed
point,

It
interpreted.

the

seems

the

in

with

consonance

suppose that it has

the terminations of the dilator nerve.

on

to
atropine

ciliary
fibres is

nerve
sympathetic

evidence
experimental

more

in the

has been

variously
the general
logical
physioinfluence
no
exciting

is clearly
action of atropine
mydriatic
onlypartof its general
action on the nerves
muscle
to unstriped
muscle,and on the unstriped
fibres themselves;and though direct evidence as to the chemical
the intesfactors producing
the well-known
action of atropine
tine,
on
there is no reason
to suppose
bladder,
"c.,is not forthcoming,
that these factors are other than those which produceits effectson

The

is known
the eye. Its action on secreto-motor
to be distinct
nerves
from the central action which
raises the blood pressure.
As, like
the other peripheral
effects of atropine,
the secreto-inhibitory
action
is
a

it may
antagonized
by pilocarpine,

perhapsbe

assumed

to rest

on

similar constitutional basis.

inactive ; hyoscyamine, its isomer,exists in

Atropineis optically
that the tropine
It is possible
two forms,dextro- and laevo-Yotatory.
and atropine
is optically
nucleus in the isomers hyoscyamine
inactive,
1

This

time.

substance, like homatropine,acts

This is due to

more

more

rapidabsorptionand

rapidlyand
excretion.

for

shorter

that the isomerism

and

GROUP

QUINOLINE

THE

of these substances

271

dependsonly on

the

acid radical present

of the tropic
or inactivity
; it has been
activity
that in the living
plantonlydextro- and fotfvo-hyoscyamine
suggested
to givethe inactive atropine.
occur, but that on dryingthese combine

Considerable differences
isomers.
optical
spinalcord :

these

observed

are

in the

action
physiological

respectof the excitant action

In

of

the

on

"

is strongest
; then ^-hyoscyamine.
; then atropine
d-Hyoscyamine
On

the other

hand, in respectof

the action

the

on

iris,
secreting

and the vagus, the order is :

glands,
(1)^-Hyoscyamine
; (3)^-hyoscyamine.
; (2)atropine
The conclusion is that the action of atropine
dependson
"

the two, /- and

each
^-hyoscyamine,

of which

its

taining
con-

exerts

its

action.
specific
physiological

Paralysis
(ii)

of sensory

nerve

endings. This is not

so

marked

which only
Benzoyl tropine,
differsfrom cocaine in the absence of the COOCH3 group, is a local
anaesthetic,
thoughnot so powerfulas cocaine. Its isomer,benzoyl
is a more
pseudo-tropine
powerfullocal anaesthetic
(tropo-cocaine),
than cocaine. Aliphaticesters of tropinehave no
anaesthetic
Thus in atropine,
have been
as in the substances which
properties.
enumerated when dealing
the benzoylgroup seems
with cocaine,
to
be of greatimportance
of the
out the anaesthetic power
in calling
a

as
propertyof atropine

III.
The

alkaloids

of
principles
quinoline

has

of cocaine.

THE

QUINOLINE

belongingto

cinchona

action which

and

nux

somewhat

this group

vomica.

GROUP.
form
The

the

chief active

parent substance,

resembles that of

it is
as
quinine,
and antipyretic.
It cannot,however,be used theraan
antiseptic
and even
it provokesvomiting,
as
in small doses is liable
peutically,
to producecollapse,
and oedema of the
respiratory
disturbances,
lungs.
Qninoline has a marked
action;it also affects the
antiseptic
an

DERIVATIVES

QUINOLINE

272

metabolic cellprocesses
the

so

of

amount

energy
lowered.
is
production

that the intake of oxygen is decreased,

and
producedis diminished; thus the heat

with
however,it is a feeble antipyretic,
Compared with quinine,
littleaction on the malarial parasite
; in pneumonia it completely

failed to reduce the

temperature(Brieger).

muscles and loss of

of voluntary
"6-1-0 gram produces
paralysis
and is eventually
fatal. Quinoline is not exreflexes in rabbits,
creted

such,but appears in the urine

precipitable
by bromine,stated by Donart
as

action of

in the

form

of

body
to be carboxypyridine.
molecule is
the quinoline
a

hydrogenwhen added to
noted with pyridine.
the same
as was
kills rabbits in two hours in doses of
Tetrahydro-^-oxy-quinoline
has hardlyany effect.
"6 gram ; a similar dose of jo-oxy-quinoline
and pyridine
remarkable
^0-Quinoline,quinoline,
present some
analogies.The first two are not only similar in physiological
action,but identically
actingcompounds may be derived from
of
an
either,
importantpractical
pointowing to the expensiveness
effect
the first-named body. Hydrationhas a similar intensifying
The

all three.

on

Decahydro-quinoline,
CH0

CH

CH2

CH0

CH

CH2

H2
in small doses. Generally,
even
line
quinopowerfulblood poison,
and
pyridineact more
powerfullyon the central nervous
and piperisystem,and on the heart,whereas decahydro-quinoline
dine have a more
rapidlydestructive effect on the red blood cells.
an
placedbody,more
closely
Hexahydro-quinoline,
intermediately
base.
action on the
It has marked
resembles the non-hydrated

is

heart and

nervous

system,and

less

on

the blood.

derivatives of quinoline
and
rule,the quinquevalent
nitrogen
with
do not show a curare-like action,
thus contrasting
w0-quinoline
and the bodies obtained from
the corresponding
aniline derivatives,
As

and
methyl iodides of both quinoline
chloride and diquino^0-quinoline,
oxyethyl-quinoline-ammonium
line-dimethyl-sulphate,

the natural alkaloids.

The

QUINOLINE

DERIVATIVES

273

Quinotoxine

CH3 S04H

CH3 SO4H

are exceptions,
two quinquevalent
nitrogen
atoms)
(abodycontaining

and all act like curare.

Quinaldine

(a-methyl-quinoline),

lepidine
(y-methyl-quinoline),

a-y-dimethyl-quinoline,

l-tolu-quinoline,

and

have

3-tolu-quinoline

been

investigated
by Stockman,who finds that the physiological
the nervous
with
as regards
activity
system varies inversely
of substituted methyl groups, but that the relative
the number
of the methyland nitrogen
not of any importance.
are
positions
T

KAIROLINE

274

in
methoxylin the para position
action of quinoline.
the antipyretic
nucleus weakens
or j"-quinanisol,
jo-Methoxy-quinoiine,
The

on

introduction of

reduction becomes

the benzene

Thalline,

CH

H
action in malaria, is a powerful antipyretic
specific
and is also very actively
destructive to the red blood cells.
do tetraIt produces,
necrosis of the renal papillae,
as
moreover,
and its
awa-thalline,
or ^o-thalline,
acetyl-thalline,
hydro-quinoline,
and thio-urea compounds.
urea
The introduction of an acid or alkylradical into the NH
group of
action.
does not affect the physiological
tetrahydro-quinoline

which

The

has

no

of OH

groups
quinoline
compounds has the
presence

in the benzene nucleus of the reduced

pyretic
the antigeneraleffect of accelerating
action and also of renderingit more
possibly
transitory,
and elimination. Two
substances
rapidabsorption
owing to more
illustratethese points
:
"

Eairolin

A,

and Kairoliu

or

B,

w-ethyl-tetrahydro-quinoline,

or

ft-methyl-tetrahydro-quinoline

CONSTITUTION

276

QUININE

OF

AND

CINCHONINE

the cellsof the nervous

poisons
system,and the effects of quinine
the special
must
on
senses
probablybe attributed to a direct
is certainly
action on the sensory epithelium.General metabolism
depressed,as might be expectedfrom a protoplasmic
poison.
and probablyincreased
There is also diminished heat production
heat loss.
cally
and Cinchonine, C19H22N2O,differ chemiQuinine, C20H24N2O2,
in that

in quinine
hydrogenatom in cinchonine is replaced
active.
by oxymethyl; physiologically,
quinineis much the more
Both consist of two parts,a quinoline
ring,the existence of which
has long been established,
and a residual part,the constitution of

which

is stilla matter

of discussion.

formulae
Skraup givesthe following
CH

"

CH

1\CH.CH
CH/1\CH

CH/T\CH.CH CH2
:

CH

',or
Loipon-anteil
portion

CHJcH
HO.cl
CHcH
HO.c

HO.ct"H*ICH

resid"l

o
I

Cinchonine.

OCH3
Quinine.
is

Cinchonine

than

isomer,and

more

toxic than

its
cinchonidine,

of Hesse
oxycinchonines

the two

and

Langlois.

ence,
methyl group, however, which constitutes the chemical differto producethe typical
does not in itselfseem
quinineeffect ;
intensification
it may be replaced
or amyl,with an
propyl,
by ethyl,
The

rather than

diminution

Cupreine,
has
remijia,

an

of

action.
physiological

alkaloid found

in

an

of plant,
the
species
quinineand cinchonine,

allied

considerable resemblance to

C19H20N2.(OH)2,
Cupreine,
Cinchonine,C19H21N2 OH,
Quinine,C19H20N2 OH.OCH3,
.

Cupreineis
quininebeing methyl-cupreine.1
even

than

cinchonine,and
1

only

Schmiedeberg.

less active
half

as

logically
physio-

toxic

as

CINCHOTOXINE

277

the
but its alkylsubstitution productsare active,
as
are
quinine,
homologousquininebodies. It thus appears that the alkylgroups
and the fact that the
to the hydroxyl,
merelyact as a protective
active than methyl may be explained
more
are
by the
higheralkyls
with which the latter is oxidized.
relative difficulty
It is thought that in the organism part of the cinchonine is
in the para position
the introduction of OH
oxidized to cupreine,
beinga usual form of oxidation in the body,and that thus the typical
of the dose of cinchonine
quinineaction is produced.The largeness
effect is thought to be due to the
necessary to producea marked
The artificialremoval of CH3
formed.
small amount
of cupreine
but in an isomeric body,
from quininedoes not result in cupreine,
to producequinine
apoquinine,
though converselyit is possible
in which the latter substance
from cupreine.The small amount
valuable procedure.
in nature preventsthis beinga practically
occurs
It is not, however,now
thought that the specific
quinineaction
is due to the quinoline
of the
but to the residual portion
portion,
certain
the so-called Loipon-Anteil
molecule,
; and in this portion
factors. It is possible,
for
groups are considered to be the principal
'

'

to
instance,

the C.OH

convert

results in the formation

ring complex.
without
entirely

known

resembles

is

much

digitoxin
"

CH

CH

H2C/1\CH.CH:CH2 HoCX
dig

\CH.CH:CH2

UrL

HOC

'

0:C

CH2. C9H6N
Cinchonine.

But

and
cinchotoxine,

as

action of quinine
physiological
; it is very

and somewhat
toxic,

more

an

productis

The
the

of

group in cinchonine into CO, this

NH
group and the rupture of the

it cannot
lost

be decided whether

-CH2.C9H6N
Cinchotoxine.

the characteristic effects of

owing to the breakingof the ringor the appearance

of the ketone group in placeof the alcoholic hydroxyl.
The vinylgroup is not apparently
of importance
in determining
but it is remarkable that quinineis the only
the general
toxicity,
drug containinga side-chain with a double bond.
antipyretic
quinineare

ANTIPYRETIC

278

S. Frankel

ACTION

OF

QUININE

has

a body (acetylamino-safrol)
synthesized
resembling
an
containing
allylgroup, but though it appeared
to reduce the temperature
in experimental
animals,it had no action
in malaria.
that of quinine
resembling
It must be remembered
that the so-called antipyretic
action of
quinineis to a largeextent due to its toxic action on lower organisms,
such as the plasmodium malariae. It is this action really
which placesit at the head of the list of antipyretics.
It has,
to possess a slight
however, been shown experimentally
power of
action. This is
reducingtemperature,
apartfrom any paraciticidal
heat production
most probably
due to a general
a result of diminishing
inhibition of protein
metabolism ; in other words, by a toxic action
on
living
protoplasm.
It is,however,probable
that the double bond is associated here
elsewhere with considerable physiological
as
activity.The body
known
in which vinylis replaced
as
quitenine,
by carboxyl,

but
phenacetin,

C18H21N202"CH

Oxidation

:CH2

C18H21N2O2"COOH

Quinine.
has very littleaction
is due to the presence
cannot be decided.1

Quitenine.
as

of

poison,but whether this

protoplasmic
the absence of vinyl,or both,
carboxyl,

It is clear,
of the
however,that the residual portion
is the

one

on

which its physiological

action

molecule
quinine

depends,and

that

the

quinoline
portionmerely acts as a link which enables it to
exert its specific
action;in the quinoline
portionthe presence of
is also essential.
oxymethylin the para position
Quinidine is a d#ztfr0-rotatory
with a similar action physioquinine,
logically.
It is also,
however,narcotic.

The

numerous

isomers

of

cinchonine

produceconvulsions.
in which hydrogenis introduced into the quinoline
Hydroquinine,
and inhibiting
ring,is a very poisonous
body,producingparalysis
in quite small doses.
Half a gram
has
respiration
subcutaneously

been fatal to

an

animal.

substance which differs from quininein conDesoxy-quinine,

a
taining
no
hydroxylin the residual portion,
givesall the reactions
1

Hunt, however, has shown

quinine derivatives in which the vinyl

has been altered to .CH2.CH3, .CHOH.CH3, .CHC1.CH3, have the
group
toxic action as the parent substance on infusoria (Archiv.
same
Internat.
de Pharmacodyn. Bd. 12. 1904).
that

SUBSTITUTES

QUININE
of

quinine.A

substance
corresponding

279
be

can

formed

from

cin-

chonine.
bodies

These

are

ten times

toxic than their precursors.

more

CH

CH

CH2
CH2/1\^CH.CH

CH2
CH/^CH.CH

CH(CHJCH,

NK

CH2

CH2 C9H5N.OCH3
.

INTENDED

SUBSTITUTES

'

the

from

C9H6

Desoxy-cinchonine.

DesOXy-quinine.

Apart

CH2

CH!

REPLACE

TO

of the toxic

occurrence

QUININE.

symptoms

cinchonism ',which the administration of

known

as

this
produce,

quinine
may
its intensely
bitter taste
practice,

drawbacks in
drug has two special
of salts of
insoluble character. Hence a number
and its relatively
hand
on the one
quinineand other compoundshave been introduced,
with a view of abolishing
the taste,and on the other of increasing
of the drug. As a matter of fact these two aims are
the solubility
with one
The only quinine
another.
not compatible
compounds
which
these

are

the insoluble

tasteless are

compounds the

ones.

In the soluble salts of

characteristic bitter taste is restored.

For

therefore,
convenience,
quininesubstitutes will be divided into two
and the
the insoluble ones intended for oral administration,
classes,
suitable for

soluble ones

I.

hypodermicor
Insoluble

in

intravenous

injection.

Water.

ordinarysalts,the tannate,an amorphous powder

with a tannic acid solution,
is
obtained by actingon the sulphate
tasteless. It is,however, uncertain in its action,and
practically
Among

the

in the small intestine. Esters formed

is firstbroken down

hydroxylgroup
and
tasteless,
ester of

portionhave also been produced.

is practically
acid ester of quinine,
propionic

in the

is the

Euquinine

from the

residual

is said not to irritate the stomach.

is known
diquinine

carbonic acid

This

body is soluble in
dilute acids,
so that it dissolvesin the stomach;it is not reprecipitated
as

Aristoquin.

in the intestine*

C,H.COO.OC1,H11N,0
Euqumme.

Aristoquin,

QUININE

280

SUBSTITUTES

of
rapidlyexcreted as the hydrochloride
is stated to be lower.
for man
quinine,and its toxicity
acid ester
Saloquinine is the salicylic

Aristoquinis

not

so

"

20H23N20
and
to show
pleasant
untherapeutically,
more
by-effects
frequently.The dosagemust, of course, be
of saloquinine
has
double that of ordinaryquinine. A salicylate
also been produced,which is insoluble,
and is intended
to combine
and quininewithout their bitter taste.
the advantagesof salicylates
These
two
quently
compounds are soluble in dilute acids,and are consein
stomach.
the
decomposed
An t"0-valeryl
ester of quininehas also been synthesized,
but is
It is similar to the salicyl
not on the market.
compound.
is
of quinine
Quinaphthol
/3-naphthol-a-monosulphate
It

is said to be

less active

"

(C10H6 OH.S03H)
.

and is

C20HMN202

yellowpowder,containingabout

quinine,
very
soluble in hot water and alcohol. It is decomposed in the
slightly
and is primarily
intended as an intestinal antiseptic.
intestine,
a

Quinaphenin

42 per cent,

is quinine-phenetidin-carboxylic
acid
"

it has no
white,very insoluble powder. Therapeutically
mixture of the two
over
a
advantage,beyond that of tastelessness,
It

is

bodies.

II.

Besides

the

Soluble

in

Water.

ciently
of which are suffiordinarysalts of quinine,some
soluble for hypodermic injection,
bodies have been
two
introduced for this purpose,
namely, Quiuopyrine and Quinine
first of these is a compound of
The
Hydrochloro-Carbamide.
and is a white powder easily
and antipyrine,
quininehydrochloride,
soluble in water.
It is unsuitable for internal administration,
owing
to its toxicity.The
second
is a compound of urea
with quinine
and hydrochloric
acid,soluble in one partof water. Its disadvantage
is that it contains very littlequinine.

STRYCHNINE

281

BRUCINE.

AND

STRYCHNINE

knowledgeof the chemical structure of these two bodies is

of the carbon
is known
as to the nature
very imperfect.But little
or as to the partsplayedby the
ringsof which theyare constructed,
and nitrogen. It appears probablethat one
nitrogenis
oxygen
indol ring,and that its basic
or
situated in a reduced quinoline
The
character is modified by the presence of a carboxylgroup.
Our

formula for

thus
will be represented
strychnine

"

(C20H220)CO

The
the

action
physiological

of strychnine

cord,whereby the
spinal
stimuli into

sensory

evidence
the

and

Schafer

pointsto

terminations
has

mainlyon

the cells of

resistance to the translation of

reflected muscular

some

is

action

structure between

of the

sensory

described intermediate

is removed.

the anterior motor

nerve

fibres in the

cells in the

slight
The
cells
cord.

horns
posterior

pyramidaltract with the lower motor neurons, and

connected with the sensory nerve
which are intimately
endingsin
the posterior
horns. Its action on the medulla may be said roughly
to correspond
to that on
the cord,while,with regard to the
senses
acute,
cerebrum, the special
appear to be rendered more
thoughthere is no evidence to show how this takes place.Lightand
the most easily
to be
have been shown
tactile impressions,
tested,
improvedby small doses. The remainingactions of strychnine,
of much
not
theoretical
are
though importanttherapeutically,
as
interest,
theydepend either upon the central action (e.
g. vagus
and vaso-constrictor effects),
the convulsions (increased
tion
formaor on

which

link the

Of more
dioxide,and increased heat production).
from the presentpointof view,isthe action of strychnine
on
interest,
lower forms of life.The higher
animals,owing to the preponderating
effect of strychnine
the nervous
of its action
on
system,show none
as a protoplasmic
poison.But on protozoaits action is very similar
of carbon

that

to

of

to
quinine,

which

it is

and
chemicallyrelated,

it is

that its effects on higherinvertebrates (e.g.

are
possible
Ascaris)
mainlydue to its toxic action on protoplasm.1
1

Shrieder

explainsthe resistance of some

closingtheir mouths when placed in
thus act onlythrough the skin.

to their
can

ascarides to
a

strychnineas due
drug,which

solution of the

DERIVATIVES

STRYCHNINE

282

Piperidon,

NH

which is a-keto-piperidine,
is stated

by some authorities to have the

action on the spinal
cord as strychnine.
Its activity
same
depends,
stated (see
as previously
p. 246),on the closure of the ring; at any
is of course
rate,fl-amino-valerianicacid,in which earboxyl
present,
has

no

action.

whether the action of strychnine

on
question
dependsupon the presence of the piperidon
group
The

the

cord
spinal

NH

is

complicated
by the presence of the second oxygen atom in the
it may be said that the characteristic
molecule.
strychnine
Briefly,
action dependson the presence of loth oxygen
atoms ; removal of
either lessens the activity,
removal of both destroys
it.
Thus

is more

Desoxystryclinine

bitter than

but
strychnine

Dihydrostrychnoline

has

no

action

on

AJ

less toxic.
"j

the cord.

Strychnidine

(C20H22OCH2
is bitter,
and

stands
physiologically

between

and desoxy
strychnine

strychnine.
Strychnoline

is inactive.

reduction
Electrolytic
(Tafel),

of

strychninegives rise to

two

bodies

XIV

CHAPTEE
ALKALOIDS

THE

"so-quinoline
(CONTINUED).
group
Morpholine (?)-Phenanthrenegroup

Cotarnine, Berberine.
Codeine, and Opium Alkaloids.

IV.
IN this group
effectsof which
of them

are

are

"

"

Hydrastine,
Morphine,

Hordenine.

GROUP.

^o-QUINOLINE
contained

number

of

the therapeutic
alkaloids,

in degreeif not in kind.

differ considerably,

Some

derived from

Opium,
viz, Papaverine,
Narcotine,
Narceine

others from

Cannadensis,
Hydrastis
viz. Hydrastine,
Berberine.

latter

used in order to arrest

plant has been extensively
and it has
haemorrhage,
owing to its action as a vaso-constrictor,
also been employed in placeof ergot to stimulate uterine contractions.
It has thus very little in common
with opium from the
pointof view,and it is a curious fact that its alkaloidal
therapeutic
of those
should be so closely
related chemically
to some
principles
found in the last-named
plant.
The

Hydrastine

C21H21NOg,has

the formula

"

CH2

and

differs from

narcotine

Its

action
physiological
regardsits direct action

and

the uterus.

in

one
possessing

is stilla matter
on

the muscular

of

some

methoxyl group less.

as
doubt,especially

walls of the smaller bloodvessels

In toxic doses it has

an

action

resembling

HYDRASTINE
that of

but
strychnine,

itis also a direct muscle

irritant. In
the
paralyses
a

short

moderate

285

poisonand

doses,it stimulates

in the medulla

and

intestinal
gastro-

and

then

cord,and, after possibly

both voluntary
and involuntary
depresses
stageof excitation,

muscle.
In

centres

HYDRASTININE

AND

Many

medicine

authors

its main

assert that

it has

direct ecbolic action.

lies in its action

value

on

the

medullary

and respiratory
centres
centres,wherebythe vagus, vaso-constrictor,
and the blood pressure rises. Its action on involuntary
are
stimulated,
cardiac

muscle,however,causes
maintained

weakness,and the

rise is not

for

long.
its strychnine-like
action is interesting,
the latter
Theoretically,
alkaloid belonging
to a group which is chemically
related
so closely

(quinoline).
is decomposed,
water is taken
hydrastine
and opianic
acid,are produced.
bodies,
hydrastinine
When

C21H21N06+ H20

CIOHM06

acid has
Opianic

and

two

CnH:3NOs

Opianic acid.

Hydrastine.

up,

Hydrastinine.

the constitutional formula

CHO

acid and cotarnine.

narcotine yields
opianic
Similarly,
+ C12H16N04
C22H27N07+ H20
C10H1006
=

Cotarnine.

Narcotine.

and cotarnine
Hydrastinine
CH2

have very similar constitutionsCH,

CR

H.CH3
:HO

Hydrastinine.
The
known
The

of
position

with

Cotarnine.

and
dioxymethylene-

are
methoxy-groups

not

certainty.

aldehyde
group CHO,

in the formula

for

best
hydrastinine,

most
explainsits physiological
alkaloidal vaso-concharacters,
strictors havingthis group (cf.
yohimbine,
which,however,has but
effecton the arterioles).
a slight

HYDRASTININE

286

The

It has

parent substance.
weaken

differs markedlyfrom

action of hydrastinine
the

heart ;

on

convulsant

no

the other

hand,

cerebral cortical cells. Its action

yet decided

on

and
action,"
it is

that

of its

it does not

of
depressant

the uterine muscle

the

is not

it has any direct effect on

of raising
the blood pressure is more
the arterial walls. Its power
It is also a mydriatic.
sustained owing to cardiac stimulation.
is it

nor
certain,

whether

failure. The action of hydrastine

owing to respiratory
the blood pressure may be regarded
as
on
partof its strychnine-like
the other hand, has a more
on
Hydrastinine,
properties.
specialized
the
of the cardiac muscle.
The
contractility
power, and heightens
same
effect,
namely,a rise in blood pressure, is thus producedby
in the two bodies,
different means
somewhat
and is moreover
a
in hydrastinine.
marked
much
more
Accordingto the aldehyde
formula,it contains the group
NH.CH3. It is thus a secondary
amine, and contains a hydrogen atom
replaceable
by methyl.
ammonium
A pentavalent
body of this kind, trimethyl-hydrastyl
has been prepared. It has but little vaso-constrictor
chloride,
with an initialrise of blood
action ; it produces
a general
paralysis,
pressure followed by a fall. Death occurs, as with curare, from
of the respiratory
muscles (peripheral).
paralysis
An oxidation product,
acid,
hydrastininic
Death

occurs

"

CO.NH.CH3

inactive.
is physiologically

Opianic

CHO

acid

kJo
OCH

has

It
narcotic properties.
slight

is almost

inactive in the

case

of

animals,but in the case of cold-blooded animals it

and very slight
of central origin,
muscular
narcosis,
produces
paralysis
warm-blooded

contractions.

Its combination

with

the

molecule seems
hydrastinine
to producea diminution of physiological
well as certain
as
activity,
marked
alterations in the latter which have already
been noted.

Narcotine,
alkaloids of the

Cot

ar

nine,

and

morphinegroup

Hydrocotarnine
;

they may

resemble

other

be considered here in

their relation to
been
recently
'

COTAKNINE

287

Two
hydrastinine.

o" the salts of cotarnine have

introduced into

use

result is

that

'Styptol'. These trade names

phthalate,
but it is probable
that
for which they are intended,
different
producedby these drugs in a somewhat

Cotarnine

manner.

as

the

Stypticin ', and

indicate the

known
medicine,the hydrochloride,

which
hydrochloride,

retains

the
slightly

cotic
nar-

has no vaso-constrictor action,nor

of narcotine,
properties
of the blood. Its effect as a
does it increase the coagulability
is thought to be due to its slowingthe respiratory
ments,
movestyptic
retarded and the
whereby the blood stream is somewhat
The phthalic
acid compound has
formation
of a clot favoured.
if largedoses are given,by
also a distinct sedative effect,
followed,
It has no action on the heart,
and death.
convulsions,paralysis,
failure. It is said to induce
from
but death occurs
respiratory
direct action in
It appears to have some
for it is not a vaso-constrictor. This
bleeding,
checkingcapillary

uterine contractions.

action

is,at

any

acid,
rate,in part due to the phthalic

PTT/COOH
U^*\COOB
as

neutral

phthalateof

ammonium

,"

acts

but
similarly

not

so

powerfully.
Narcotine

and

with
hydrastine,

their various derivatives and

and the
compounds,act on the whole in very similar manner,
with one another. The
secondary
productscorrespond
fairly
closely
main points
of difference are that all narcotine derivatives tend to
the narcotine action of the original
while the
substance,
reproduce
act most
productsformed from hydrastine
markedly on the
arteriolesand the blood pressure.
is a marked
Methyl-narcotimide
uncertain in its action
sometimes

on

man,

local anaesthetic

sometimes

the amide

is

resemblingmorphineand

codeine.

is a vaso-dilator,
and
Methyl-hydrastamide

tried as

has been

fully
unsuccess-

an

emmenagogue.
Berberine, C20H17NO4,the

remainingalkaloid

of

has
hydrastis,
in which it is presentin the drug.
very littleaction in the amount
20 grams
have failed to produceany symptoms in
(300 grains)
It is said to be completely
man.
decomposedin the body,thus
from hydrastine,
which is excreted unchanged in the
differing
urine. Its constitution is expressed,
in all probability,
by the

formula

"

288

MORPHOLINE

GROUP

(P)-PHENANTHRENE

OCH3
Large doses lower the blood pressure, raise the body temperature,
and finally
of central
increase peristalsis,
producegeneralparalysis
it probably
acts
canadensis,
origin.As a constituent of hydrastis
onlyas a bitter '.
which contains four atoms more
of hydrogen,
Hydro-berberine,
the blood pressure by its action on the
is a vaso-constrictor,
raising
It also producesconvulsions of spinal
centre in the medulla.
originbefore the final paralysis.The generalchange in physiological
action producedby the addition of hydrogen is thus well
illustrated. Berberilic acid,
f

CH^0"C"H2CO-NH-CH2
'

"

CH2

COOH
like the

C6H2"(")"CH2

COOH

is physiooxidation productof hydrastine,

logically
corresponding

inactive.

V.

MOEPHOLINE(?)-PHENANTHRENE
Alkaloids

Opium

is said to contain

five non-basic

no

some
substances,

Besides these there

are

numerous

of

GROUP.

Opium.

lessthan

besides
twenty-onealkaloids,

of which

are

active.
physiologically

alkaloidal bodies which

have

been

and of these a few are of

producedfrom the opium bases,
artificially
importance.
pharmacological
the
Chemically, opium alkaloids fall into two main groups, the
Physiologically
w0-quinoline
group.
group and the phenanthrene
also,two main groups may be described,namely,those with the
attributes of morphineand those resemblingthebaine.
physiological
Unfortunatelythese two groups do not correspondin the very

ALKALOIDS

OPIUM

289

for instance,
belongchemically
morphineand thebaine,
to the phenanthrene
group.
and properties
of these bodies
Before considering
the composition
in detail,
observations may be made.
the
a few general
Chemically,
of the structure of morphinecannot be regarded
as settled,
question
with all the
neither of the suggested
formulae is in consonance
as
much
attention must be givento the details
facts. Physiologically,
the action of these bases in the organism.
of any experiments
on
least; both

The discordant results which have

been
occasionally

obtained make

dependsboth on the size of the dose of any given

and the species
of animal employedin the experiment.For
alkaloid,
and
C. Bernard described morphineas soporific
instance,
originally
thebaine as tetanizing,
and the other alkaloids have been classed as
belongingto one or other of these groups. As a matter of fact,
however,careful experimentwith graduateddoses has shown that
but that they are
all the opium alkaloids possess both actions,
Thus
developedin very different proportions.
though Bernard's
it clear that much

is very convenient and marks

classification

bodies,it must be remembered

and

that in

no

that

substance is either

the main

action of these

substances occur,
intermediary
the soporific
the tetanizing
or

absent.
entirely
With
regardto the various artificialproductswhich have been
it will be found that in generalthey
constructed from morphine,
in a qualitative
only differ from that substance physiologically
of the molecule
so longas onlythe circumferential portions
manner,

action

altered.

are

structure is broken

If,however, the intimate

down,

in their pharmacological
productswill result differing
entirely
properties
(cf.
apomorphine).
The principal
alkaloids belongingto the phenanthrenegroup
are:

"

Morphine,
Codeine,
Thebaine.
Those of the

w-quinolinegroup are :
Papaverine,
"

Narcotine,
Narceine,
Laudanosine,
Laudanine,
Cotarnine,

Hydro-cotarnine.

MORPHINE

290

have already
hydro-cotarnine
been partially
considered in connexion with the zso-quinoline
group.
in
this
with
dealt
in
section
be
far
so
will,
however,
briefly
They
connects them with the opium alkaloids.
as their pharmacology
cotarnine
these,narcotine,

Of

and

Morphine,

C17H19NO3.

morphine is based on its apparent origin

and morpholine,
from two bodies,
phenanthrene
justas cocaine and
in a double-ring
atropine
tropine.
originate
is represented
Phenanthrene
by the formula
Knorr's

formula

for

10

The

For
as

not

numbers

of nomenclature

of its derivatives.

and after oxidation is eliminated

dogs this substance is inert,
acid. This reaction,
compound of glycuronic
however,appears
to be

as
universal,

however, one
and

indicate the method

or

more

in

animals

some

it has

hydroxylgroups

substances
9-phenanthrol,

are

narcotic effect.

introduced,
e. g.

If,
2, 3,

obtained

producingsevere tetanic
convulsions in warm-blooded
animals.
Phenanthrene- 9-carboxylic
and phenanthreneacid,4-methoxy-phenanthrene-9-carboxylic
acid,
acid have a similar action.
The introduction of more
3-sulphonic
oxymethyl or acetylgroups, however, has the effect of lessening
both the toxicity
and the tetanizing
action. It does not appear
are

that any

phenanthrenederivatives as yet known have any narcotic

effect,
though one compound of phenanthrene-quinone,
CO

CO

namely 2-brom-phenanthrene-l-sulphonic
acid,is said to have a
action on the respiratory
centre.
morphine-like
Morphine is supposedto be a derivative of tetrahydro-dioxyto which the morpholine
phenanthrene,
complex is united. Knorr
the
alkaloid
to
the structural formula
assigned
"

NAPHTHALAN-MORPHOLINE

292
and

codeine in its chemical

bases.
morpholine

and

It is

than any of the synthetic

relationships
combination of tetrahydro-naphthalene,

morpholine,
O

N
H

and has the formula

S. Frankel throws

"

doubts

on

the resemblance

action of this substance and

Leubuscher

that of

between

morphine on

the

logical
physio-

man,

but

states that it is very close.

assumptionthat the phenanthrenenucleus was

the more
importantportionof the morphinemolecule,synthesized
of which he gave
to the hydrochloride
an
amido-oxy-phenanthrene,
Vahlen, on

the

name

the

Morpbigeuiu

"

Many derivatives of this body were obtained

but chemically
morphinephysiologically,
they were
however,called
1

AnnaUn, 307, 172, 1899.

which

acted

not pure.

like

One,

HYDROXYL

PHENOLIC

THE

293

Epiosin

N.CH,

analgesicand slightnarcotic action,and to

thus resembling
codeine. It did not, however,
produceconvulsions,
whereas it did raise the blood pressure, thus differing
slow the pulse,
also greatquantitative
from morphine. There were
differences,
about
dionine.
to
"12 gm. corresponding
however,
Pschorr,
-3gm.
and states that the original
is at fault,
holds that all this work
substance was
not morphigeninbut a nitrogen-free
phenanthrene
said

was

have

to

derivative.
It is to the presence of the phenolic
phine
hydroxylgroup that morits acid properties.
The
owes
hydrogen may be replaced

by

an

alkylgroup, or an acid radical. If

action
change in the physiological

characteristic narcotic
lost.
marked

more

The
than

effect is either

narcotic
on

developmentof

the
the

this is

done,a

takes

place,and

diminished

much

effect of

The

this

which

seen

shows

be

the

to the introduction of any

from the facts that

tirely
en-

plex
com-

toxic

diminution

of

accompanies
phenolichydroxyl by
anchoring group for

substitution of the hydrogen of the

any
another group, is due to a destruction of the
is so may

or

morphine on man
lower animals,owing to the more
highestnervous
centres,and its

also,for similar reasons, far greater.

and the increase in tetanizing
action,
power

not

the

is much

effect is

narcosis and

able
remark-

'

'

new

(1)any

factor.

That

substitution

this

product

those compounded with

effect,
physiological
acids are, however, rather more
easilydissociated in
in which two morphine molecules
organism; (2)a dimorphine,
united by an ethylene
e. g.
residue,
Ethylene-dimorphine,
same

organic
in-

the
are

CHN0

is without
Of the

narcotic effect.

both natural and artificial,

substances,
more
less resemblingmorphine in action,it will only be
necessary
mention
or

have

numerous

few which either illustratea

been

used in medicine.
actually

or

to

pharmaco-dynamic
principle,

CODEINE

294

DIONINE

AND

C17H18NO2 OCH3.

Codeine,

morphinein which the hydrogen of

has been replaced
the
by methyl,and the
constitutional formula for this alkaloid is consequently
dependent
that of morphine. It was
obtained in 1881 by Grimaux
on
by the
and an alkali on morphine,
action of methyl-iodide
This is the

methylether
phenol-hydroxyl
group

of

/O"

CH3O\

CH2

'

^N"
Alcohol

CH2

hydroxyl.

CH3
in man
and its sedative action on the
Owing to its small toxicity
it is largely
employedin therapeutics.
mentally,
Experirespiratory
mucosa,
it stands midway between
morphine and thebaine. It is
much
toxic for animals than morphine. Metabolic
more
processes
is
and
not
less
marked.
to be
so
influenced, constipation
seem
is incapable
of forming an ether corresponding
to the
Codeine
morphinetherof morphine,in which linkagetakes placethrough
the distinctive methyl group would in that
as
hydroxyl,
phenolic
case

be lost.

Acetyl

codeine

O"

(CH3CO)CK

"

"
"

CH2

XN-CH2
CH,

but is practically
it does not
as
useless,
prepared,
and causes
extreme reflex irritability
respiration
(Dreser).

has

been

Dionine

C,H5 Ox
.

affect

/O"

CH2
|
\N" CH2

"C14H10"

HO/

CH3
is the

of ethyl morphine,and
differs somewhat
hydrochloride
which
markedlyfrom the numerous
morphine substitution products
have been constructed and tested physiologically.
In the firstplace
it is very easilysoluble in water, and is therefore suitable for
and in the second placeit is father
more
hypodermicinjection,
powerfulin its action than the corresponding
methyl derivative
rule,ethylic
(codeine).In this it illustrates a general practical

HEROINE

295

effective physiologically
than those
more
compounds beingusually
of methyl. Higher homologuesand substitutions with aromatic
radicals act less powerfully
than codeine and dionine.
and has been employedin
Dionine has also analgesic
properties,
and occasionally
ophthalmicpractice.It is not a local anaesthetic,
sets up

irritation of the

some

with
conjunctiva

considerable chemosis

(Hinshelwood).
Heroine.

This is

diacetyl
compound, both the alcoholic and phenolic
hydroxylgroups being substituted. It is thus a diacetic ester of
morphine
CH3CO.(X
/O" CH2
/C14H10\ I
a

"

XN"

CH,CO.(X

CH9

CH3
Its action
to

be

more

on

the

and is said
selective,
of morphine. It is,at any rate,

is in
respiration

sedative than

that

some

way

is
powerfulthan codeine. The frequencyof the respiration
and cough is checked.
It has no marked
anaesthetic
diminished,
but is generally
to its use
action,
Harnack, who objected
soporific.
remarked that acetyl
therapeutically,
owing to itstoxic properties,
substitution products
of hetero-cyclic
manifested
compoundsusually
high toxicity.This, however,is not exactlytrue, and the fact
toxic
to be that the acetylgroup renders a substance more
seems
when it replaces
hydroxylhydrogen,and less toxic when it replaces
amide hydrogen(S.Frankel).Examples may be found in atropine,
toxic than tropine,
and homatropine,
which are more
scopolamine,
toxic than ecgonine. The best
and cocaine,
which again is more
where the substitution
example,however,may be found in aconitine,
of acetyl
for the hydroxyl
group converts an almost inert body
into a powerfulpoison,
while the introduction of two more
acetyl
decrease the toxicity
(Cash
groups has no effect exceptto slightly
action
and Dunstan). Heroine is largely
used owing to its specific
the respiratory
fatal dose for rabbits is
The minimal
centre.
on
said to be a littlelargerthan that of codeine (-1gram per kilo,
is only
body-weight),but the minimal effective dose in practice
is usually
one-tenth that of codeine. The hydrochloride
prescribed
The mono-acetyl
owing to its solubility.
compound is not employed,
it is more
like morphinein its action,
having less tendencyto promore

MORPHINE

296
duce

DERIVATIVES

CODEINE

AND

tetanic

convulsions,
greaterhypnoticpower,
action
heroine. It has,however,no special

than

and

less toxicity

the

on

respiratory

organs.

Benzoyl morphine

"

C6H5CO.O
CH2

"

CH3
action of this

The

similar to that of

compound is very

codeine,

and thus illustrates the rule that the substitution products

of

phine
mor-

action to the fact that the anchoring

physiological
and that the group
covered,
group for the narcotic effect is partly
introduced for this purpose is of comparatively
small importance.
however,benzoylmorphine,which has been introduced
Practically,
of Peronine, has the disadvantage
into pharmacy under the name
and also of
of being less soluble than either heroine or dionine,
a
burning taste.
possessing
owe

their

Less

Important

Morpho-chinoline

Artificial

Derivatives.

ether

/O"

OC9H6NV

CH,

N-CH
CH
is

of

It has the main

value.
practical
of the respiracharacteristics of codeine,
causingspasm, especially
tory
and
rise
of
It
acts
blood
a
muscles,
through the
pressure.

interesting,
though

no

centres in the medulla.

Chlorine and bromine

and

hydrogen atoms,

narcotic

The

have
with

been
the

substituted for various

generalresult

of

hydroxyl
the
destroying

effect.
chloride

of

codeine

CHO

/O"

CH

|
N-CH

is

powerfulmuscle poison,in addition

codeine-like action. This is supposedto
a

to

a
possessing
general

be due

to

the

halogen,

which

is known

it is curious that

as

muscle

wo-MORPHINE

AND

METHO-CODEINE

297

poison(asfor example in CHC13),but

morphinetrichloride,

X)-CHC1(?)

Cl

CK

I
"C14H10"
XN"

CH2

CH3
is

which contains three chlorine atoms

Metho-codeine

muscle poison.
onlya slight

"

CH2

/O

CH0(X

HCK

CH2

H3

with a consequent
structure in this compound is broken,
ringThere
action.
narcotic and
no
are
change in the physiological
and slight
but onlymuscle poisoning
depression
actions,
tetanizing
that the urine
of the cord.
blood change also,
There is some
so
resembles apomorphine,
becomes deepgreen. It thus clearly
except
to be
considered
that it producesno vomiting; it was
formerly
with that body.
identical in composition
the respiratory
the pupils,
It has no
action on
but depresses
centres
like morphine; unlike that drug it increases the blood
of the heart. Its stereo-isomer has a similar
pressure, and frequency
The

action.

obtained,togetherwith small
of an isomeric derivative /3-/s0-morphine,
quantities
by the action
of water
on
brom-morphine. The followingformula has been
:
suggested
CH2" CH2
^-Morphine

is

substance

"

"

N.CH3
The

2"0-codeinehas
corresponding

but neither
prepared,
of these derivatives has any narcotic action,even
when givenin
If the constitutional formula given above is correct,
gram doses.
the failure in physiological
action may be attributed to the change
of the morpholine
in position
as
ring,which is there represented
attached to one benzene nucleus only.
Compounds of morphine and codeine,in which the nitrogenis
also been

298

THEBAINE

have
quinquevalent,
and
brommethylates

been

investigated.
They

have the formulae

ca

the

are

so-called

"

CH.(X

"CH,

CH

'"\i

HO

CH,

CH,

theyare
Physiologically,

Bi

characterized

by a greatdiminution of
due to their rapidand completeelimination in the urine.
toxicity,
In cats the tetanizing
action is especially
diminished.
Thebaine,
This

C19H21NO3.

structural formula
a possible
substance,

below,is

for which

is written

different from morphine,

it
as
only physiologically
narcosis and is an active tetanizing
no
producespractically
agent,
but differs also chemically
in being derived from a dihydrophenanand in havingboth its
threne,instead of a tetrahydrophenanthrene,
hydroxylhydrogensreplaced
by methyl groups.
not

CH2" CH2" N.CH3

O.CH,

O.CH

The fact that it does not

owing

to the

absence

of

differences in the number

producea morphineeffect is probably

an
anchoring'OH group, as well as to
combined with the
of hydrogen atoms
'

phenanthrenering.
By the action of dilute HC1, a substance known as
be produced,
which has a generalparalysing
action.
be represented
follows :
as
may possibly

thebenine

Its structure

"

CH2
OCH

"

CH2\

NH.CH,

\0

CH
*

The

positionof

these

hydrogen atoms

can

is not certain.

NARCOTINE

300

AND

COTARNINE

has

the OH
narcotic action,
which
as
no
practically
group is absent,
The
as
serves
an
anchoringgroup to the cells of the cerebrum.
has not been
anchoringgroup for the spinalcord (tetanizing)

identified.

has

also

C20H25NO4,which

Laudanine,

constitution similar to that of

three

and

methoxygroups,

methoxy

in two

of
in place
hydroxyl,

one

laudanosine,
owing

stereo-isomers,

but
laudanosine,

contained in that alkaloid.

groups
converted
into racemic
laudanosine.

poisonthan

occurs

The
It

to the

contains

the four

racemic

form

be

less

should

it has

fact that

only
methoxy
can

be

powerful
one

less

group.

Narcotine,
in its chemical

C22H23NO7, closelyresembles hydrastine(p.284)

structure,it is methoxy-hydrastine
"

O.CH,

Its action

resembles

that

of

morphine,but

is much

feebler;it

and a
producesa short period of slightexaltation of sensibility,
and then loss of sensation,
and paralysis.
littleshivering,
intoxication,
loss of sensibility
Some
in the eyes and of the nerves
to electrical
action predominates.It is said
stimulation occurs.
The soporific
the stageof narcosis (Mohr),
that in cats tetanic convulsions precede
while in man
doses are onlyused as an antipyretic.
It
therapeutic
is also stated to be aphrodisiac.
is a decomposition
and its conCotarnine
stitution
productof narcotine,
is most probably
represented
by the formula
"

H.CH,
O.CH,

opianicacid,C10H10O5
productis the non-nitrogenous
action on motor nerves, but
(p.286). It has a slightparalysing
other

The

not

more

which

than

other

contains two

members

less atoms

of the

group.

Hydro-cotarnine,

of hydrogen than

acts
cotarnine,

but
to codeine,
similarly
than morphine.

Narceine,

by

the

action

written

potashon

substituted

below, since

301

is,however,more

toxic

is very

probably
represented

it may

be obtained

by

the

of narcotine,
is said to be
iodomethylate
or more
(Mohr). It is a tertiary
base,
gram

the

inactive in doses of 1
and

It

is less toxic.

the constitution of which

formula

of

APOCODEINE

AND

APOMORPHINE

ketone.
phenyl-benzyl
O.CH

has
Its

compound of narceine combined

been introduced into pharmacy under the
action resembles that of morphine,but
sodium

with sodium

salicylate

name

of Antispasxuiu.

is

times
fortyto fifty

weaker.
is said to produce convulsions and
Narceine-phenyl-hydrazone
in doses of "! gram
paralysis
respiratory
per kilo, body-weight.
been introduced,
has recently
under
Narceine-ethyl-hydrochloride
cinal
the name
of Narcyl, as a remedy for irritable cough. The medi-

dose is -06 gram.

Apomorphine

and

Apocodeine.

Dehydrating agents act on morphine in two ways, either by

and tetramorphine,
producingcondensation products trimorphine
molecule of water, givingrise to
one
"c.,or by simplyabstracting
apomorphine, C17H19NO3" H2O
C17H17NO2.This substance can
to contain (1)two
be shown
free hydroxylgroups, and (2)tertiary
to Pschorr,
it is a derivative
nitrogenin ringformation ; according
of phenanthrene-quinoline
"

"

CH2 N.CH3

APOCODEINE

AND

APOMORPHINE

302

of the hydroxylin the ringis,however,conjectural.

position
is
marked
by slightnarcotic action,
Physiologically,
apomorphine
but by a considerable degreeof excitory
power, followed by paralysis
The emetic action of morphine is
cord and medulla.
of the spinal
immenselyincreased. It will be noted that the constitution given
above for apomorphinedoes not resemble that of morphine at all
but not the
The phenanthrene
ringis indeed represented,
closely.
alternative structure
an
morpholine.Hence Pschorr has suggested
the so-called pyridineformula
for morphine,
The

'

'

"

arrangement, however, does not explaincertain chemical

off of morphol and morphenol from
reactions,
e.g. the splitting
This

morphine.
It will be

seen

that,whatever

the real structure

of

morphinemay

be, apomorphineis not derived from it solely

by the abstraction of
also involves
water, but that its production
the

ring systems to

which

the

profoundalterations
differences must
physiological

in

be

attributed.
The

of apomorphine(Euporphin)is a
methylbromide

emetic,and has

less action

of water from codeine

elements

on

the heart.

The

less powerful

removal

of the

givesrise to a substance (apocodeine)

reactions,
having similar physiological
though not so powerful.
Its constitution is not definitely
known, as it has been found
to prove the presence of one
free OH
impossible
group, which by
analogyit should contain.
Apocodeiue has been shown by Dixon to exert a nicotine-like
action on nerve
cells,and this fact suggeststhat the purgative
with their paralysing
action
action of opium alkaloidsvaries directly
the sympathetic
on
ganglia. Larger doses paralysemotor nerve
endings firstthose of skeletal muscles and then those of the arterial
and the acceleratorfibresto
walls;later those of intestineand bladder,
"

HOKDENINE

heart

the

Owinguse

Addendum

malt.

from

is

It

formula

following

forms

The

dog

being
is

vagus

larger

is

-3

gm.

doses

per

gram

given
body
1

death

to

Eend.,

dissolving

Leger

readily

for

suggested

pulse

closely
1906,

the

it

the

or

follows

rabbit

per

respiratory

resembles

that

ib.,

rise

on

the

os.

of

142,

vigorously

blood

pressure

fatal

action

of
dose
of

is
this

itself.

"

1906,

the

administration

The

phenol

110.

of

for

doses

and

When

failure.

108.

142,

dose

small

slowly

more

Camus.3

lethal
After

and

water,

by

minimum

centre.

rate

in

investigated

beats

vagus

dog

heart

the

the

soluble

intravenously.

kilo

the

been

toxic,

very

from

occurs

therefore

Comp.

not

paralyse

kilo,

has

readily

are

has

action

and

of

which

salts

per

stimulated,

acceleration

and
1

of

sulphate

Leger

E.

C6

:4

pharmacological

whose

number

substance,

by

"

It

ether

purgative.

obtained

body

crystalline

or

ganglionic

Alkaloids.

alkaloidal

an

colourless

chloroform,

alcohol,

in

is

the

on

hypodermic

as

to

C10H15ON,

Hordenine,1

action

its

to

its

suggested

has

he

cells,

nerve

affected.

are

303

""., 1906,

143,

234.

CHAPTER
SYNTHETIC

PRODUCTS

WITH

XV

PHYSIOLOGICAL

ACTION

SIMILAR

TO

HYDRASTIS."
Derivatives of Piperidine,
Pyrrolidine,
Oxy-amido-benzoicacid,j9ara-Amido-phenol,
Guanidine, Tertiary
Amyl-alcohol. Halogen and other derivatives. Substitutes for Atropine,
Hydrastis.

COCAINE, ATROPINE,

Amido-

and

number

of

duced,
synthetic
productshave recentlybeen introthe physiological
action of which
resembles
that of various
natural
alkaloids. Structurally
resemble the
they often closely
and in some
bodies they are intended to replace,
cases
they have
certain pharmacological
of
advantagesas regardstoxicity,
rapidity
action,"c. For convenience they will here be grouped according
to the alkaloid they are intended to replace,
i.e. according
to their
The
various salts of quinineand other
physiological
properties.
bodies introduced as improvementson quininehave alreadybeen
not true substitutes but merelymodifications
as these are
described,
of the original
alkaloid.
LAftGE

I.
A.
A

group

SUBSTITUTES

Derivatives

of

FOR

Piperidine

of bodies has been introduced

COCAINE.
and
as

Pyrrolidine.

cocaine

the
substitutes,

between physiostudyof which admirablyillustratesthe relationship

logical
action and chemical structure,
those
from
derived
namely,
and their corresponding
alcohols.
triacetone-amine,
diacetone-amine,
The
first two of these are
formed by the action of ammonia
on
acetone

"

CH3

CH3

Ao
iH,

CH,
diacetone-amine.

(*)

TBIACETONE-AMINE

OF

SYNTHESIS

CO

CH3
T

CO

305

2NH3

\riTJ
CH

(CH3)C\JC(CH3)2
NH
triacetone-amine.

with acetone,
on heating
givestriacetone-amine
Diacetone-amine,
CO

CO

CH/\CH2

CH/\CH3

NH

NH2
Aldehydereacts

"

in

similar manner,

and

by this means

seriesof

Thus
bases similar to triacetone-amine may
be synthesized.
givesthe so-calledvinyl-diacetoner-amine
aldehyde

acet-

"

CO

CO

CH,/\CH3
+

CHj/NcH,,
+H2"

COH.CHq=

3(CH3)2CVCH(CH3)

(CH^Ov

KH

NH2
By

the action of

on
methylamineand ethylamine
acetone,alkyl

derivativesof diacetone-amine

formed.

are

Triacetone-amine

CH3
CH3"
"

CH2
I

CH3"

NH

CO

CH

CH3
has

curare-likeaction ;
powerful

its reduced derivativealkamine

CH3
/~1TT

vyXljj

CH3"

/-I
Vy

"

fVTT
"

^stt.^

NH

CH.OH

CH2

CH,

306 COMPARISON
and
the

"TRIACETONE-AMINE

ECGONINE

OF

the

compounds derived therefrom

introduction of a carboxyl
group

manifest

similar

action;

CH,

CH3"

CH2

CH3"

CH

abolishes this action

more

substance which

but producesa
altogether

toxic.
powerfully
comparisonof the

is

methyl derivative of triacetone-alkamine

and ecgoninereveals a rewith that of tropine
markable
for Merling to predict
so that it was
possible
similarity,
the physiological
action of the derivatives of methyl-triacetonealkamine by a knowledge of those of the corresponding
ecgonine
compounds.
A

structure

of the

L3

Triacetone-methyl-alkamine.

CH2"

CH2"

CH

CH.COOH

N.CH3

CH.OH

CH

CH2

Ecgonine.

CH2"

CH2"

CH

CH2

N.CH3

CH.OH

CH

CH2

Tropine.

carboxyl
group is introduced into the firstof these derivatives,
the main
a body is produced
ecgoninestillmore closely,
resembling
stands in a different relation to
differences beingthat the carboxyl
and the second ringis not closed :
the nitrogen,
If

"

308

DERIVATIVES

in normal

saline at

OF

TRIACETONE-AMINE

body temperature,(2)mixing some

adrenalin

solution with the local anaesthetic.

The

benzoylgroup

in eucaine cannot

be

out
replaced
by acetylwithloss of anaesthetic action (asis the case with cocaine),
but other
aromatic radicals may replace
the benzoyland leave the local anaesthetic
action intact. The amygdalicacid derivative,
however,is an
exception.
The derivatives of triacetone-alkamine behave similarly
to those
of the carboxyl
derivative,
though neither of the parent substances
has any
local anaesthetic power.
The alkyl group in eucaine
which replaces
the carboxylic
hydrogen is not of physiological
thus forming a contrast to cocaine.
importance,
is a local anaesthetic
Benzoyl-triaeetone-alkamine-carboxyl
"

CH3
C

CH3"

CH2

NH *

CH3"

cooH

CH2

"H,
and triaceton^-alkamine

Triacetone-amine,

CH3
CH3"

CH3"

CH3

CH2

NH

CO

CH2

CH3"

CH3"

CH2

NH

CH.OH

CH2

CH3
CH3
whereas
triacetone-alkaminelocal
irritation,
produceonly slight
carboxyl
CH3
CH3"

CH2

NH

0/OH

I\COOH
CH3"

"

CH3

C Ho

DERIVATIVES

PYRROLIDINE
is a
be

309

group
powerfullocal irritant. The carboxyl
which
be
for this effect,
may
responsible
esters are, however,two
bodies from which
they are

esterification. These
toxic than

the

seems

much

or

therefore to
modified

three times

derived;

by

more

thus

the

producedby the substitution of cinnamylfor benzoyl

of cinnamyl-#-methyl-triaceto
in a-eucaine
the methyl-ester
toxic than the corresponding
is three times more
alkamine-carboxyl
derivative

"

"

The latter and

cinnamyl-w-methyl-triacetone-alkamine.

the

sponding
corre-

compound are among the leasttoxic bodies of the

series; the phenyland amygdyl derivatives are the most toxic. The
and methyl),
though much more toxic than
alkylderivatives (ethyl
methane

the mother

less

are
substances,

so

than

the aromatic

substitution

products.
homologue of benzoyl-triacetone-alkamine,
benzoylhas a powerfullocal anaesthetic
/S-hydroxy-tetramethyl-pyrrolidine
and is less toxic than jS-eucaine
action,
lower

"

CH3

CH8"

CH2

NH
C

CH3"

CH.O.COCflH6

CH3
The mandelic acid ester

H.O.CO.(CHOH)C6Hf

action on the pupilthan euphthalmine,

which it
slighter
resembles. In fact,a completeseries of derivatives can be
closely
obtained from the pyrrolidine
base corresponding
physiologically
to those from
thus illustrating
the close relationship
pyridine,

has

between

The

these two bodies.

generalaction

of the bodies of the eucaine group, when

given

OXY-AMIDO-BENZOIC

310

ACIDS

largerdoses than those necessary to producethe therapeutic

is paralysis
of the central nervous
effect,
or
system after a more
less marked
periodof excitation. Those which contain carboxyl
with or without the ester group)produceincrease in reflexes,
(either
and finally
excitement,
generaltonic and clonic convulsions,
lysis.
parais
unaffected.
The peripheral
nervous
system
In the bodies without a carboxylgroup
the excitement is of
and is more
shorter duration,
the generalparalysis
appears earlier,
complete. The motor nerve endingsare acted on as in the case of
the vagus.
doses paralyse
Generallyspeaking,
curare, and larger
the
toxic symptoms of a-eucaine and
the two classes are typified
by
/3-eucaine
respectively.

in

B.

Derivatives

Another

of

Ainido

and

Oxyamido

Benzoic

Acid.

seriesof local anaesthetics has been

of which
introduced,
and Heintz found that the benzoyl
orthoform is typical.Einhorn
acid possessedanaesthetic properties,
esters of oxy-amido-benzoic
and on the analogyof cocaine thoughtthat,if the benzoylgroup
ever,
were
removed,the anaesthetic action would disappear.This,howthe benzoyl
found not to be the case, and by replacing
was
instances
more
powerfulsubstances were in some
intensely
group
produced.
or painful
on
Many of these compounds,however,are irritating
but
and
effect.
anaesthetic
a slight
injection, some have
acid
The methylester of 0-amino-#"-oxybenzoic

H2
but the methyl
producesan anaesthesia which is hardlyperceptible,
acid
ester of jo-amido-w-oxybenzoic

is well

being

known
very

as

the local anaesthetic Orthoform.

slightlysoluble is also

but

This

feeblytoxic.

body
It

is,

appliedto the nerve

endings,
directly
skin or mucous
to the unbroken
and is useless when applied
brane.
memis not available in practice,
Its soluble hydrochloride
owing
Orthoform
has also been
to the pain producedby its injection.
dermatitis of an
observed to give rise to severe
erythematous,

however, only active when

ORTHOFORM-NEU
or even
pustular,
more
so
(rather

gangrenous
than

Orthoform-nen

type.

311
It is also somewhat

morphinehydrochloride).
the methyl
(the new
orthoform),

expensive
ester

of

acid,
j0-hydroxy-7"-amido-benzoic

is much

and
cheaper,

but except
equallyactive physiologically,
have the same
orthoform.
as
disadvantages

for this it appears to

is soluble,
but irritant. It may
Its hydrochloride

acid,a
79-oxy-benzoic

substance which

be obtained from

results from

the action of

potassium
phenateat a temperatureof 200-220 "C.
this acid is acted upon
When
by dilute nitric acid,#z-nitro-oxybenzoic acid results,
which is then converted into its methyl ester
carbon-dioxide

and reduced

on

"

COOH

COOH

COOCH8

COOCH3

OH
OH
semble
large number of bodies have been preparedwhich reof
It
has
but onlya few are
been
use.
orthoform,
any practical
found generally
that those containing
a
hydroxylgroup in the
benzene nucleus,
those
either free or substituted,
all irritant;
are
which do not exhibit this structure are unirritating.
In
order to obtain a soluble compound, Einhorn
prepared
of
amido
of this
and
derivatives
the
acids
glycocoll
carboxy-amido
series. These compoundsprovedto have anaesthetic properties,
but
differed from the mother-substance in being stronglybasic and
easilysoluble in water. Their anaesthetic powers do not in any
to the substances from which theyare
quantitatively
way correspond

very

derived.

isthe

Nirvanine

methylester of diethyl-glycocoll-7"-amido-0

benzoic acid

"

OH

NH.COCH2N(C2H5)2

AND

ANAESTHESIN

312

It is less toxic than

NOVOCAIN

orthoform,and

It is very soluble in water.

injections
producepainand

It has

has also

no

action

action.
antiseptic

an

on

the unbroken

local oedema, and it is far too

ophthalmicwork.
The
acid
ethylester of 7?-amino-benzoic

skin ;

irritating

for

and is known

as

It is obtained

is

local

anaesthetic,

Anaesthesin,

by

the series of reactions formulated

as

follows

"

C6H6CH3
NO2

Toluene.

NO2

2?-nitrotoluene.

COOC2H5

acid.
^-nitro-benzoic

,COOC2H5

reduced

ethylester of
acid*
#-nitro-benzoic
Its action is similar to that of orthoform.
is the

Novocain

of the diethyl-amino-ethynol
ester
hydrochloride

acid
of jt?-amido-benzoic
"

COO.C2H4N(C2H6)2 HC1
.

It is said to be non-irritant
in

one

part of water,

and

even

in

strongsolutions.

the solution may

It is soluble

be boiled without

is slight.
decomposition.Its toxicity
The

substances above

novocain,are

of
enumerated,with the possible
exception

obviouslyunsuitable

for

anaesthesia.
producingsurgical
They have,however,been employedwith varyingsuccess
to allay
gastric
pain,due either to an organiclesion or to functional
derangement.
Anaesthesin has also been employedto allayvomiting,
when due
to causes
within the stomach,but seeing
that in most of these cases
the vomitingserves
irritant and nocuous
to remove
substance,
an
the fieldof utility
be someto
for the drug in this direction appears
what
limited.
As illustrating
the purelylocal action of anaes-

thesin

on

the

gastricmucosa,

effectsof tartar

but
emetic,

it is found
not those of

that it will counteract

the

apomorphine(Reiss).

313

HOLOCAINE

Derivatives

C.

of

jo-Amido

Phenol.

aniline derivatives,
thoughmainlyused

The

as

analgesics,
general

and in some
local anaesthetic action,
slight
value.
marked to givethem a practical
sufficiently
Phenetidin,
OC2H5

have

with

combined

when
known

as

second

ring,givesrise

this

propertyis

to the

compound

Holocaine.

Holocaiue, the condensation

and phenproductof ^-phenetidine

acetin,

CH3.CjOjNH.C6H4.OC2H6

OC2H6"^
)"-NC.NH,C6H4OC2H5
;

CH3
as

of jo-diethoxy-etheny
is the hydrochloride
employedin practice,

diphenylamine
"

CH8C"^
\

producesa rapidanaesthesia.
It keeps well, but has the disadvantage
of being only slightly
soluble. In toxic doses it produces
generalconvulsions. Its practical
has been limited to ophthalmicoperations
application
; two or
three dropsof a 1 per cent, solution produceanaesthesia within
It is more

one

toxic than

minute, and

but
cocaine,

two

or

it

three instillations at intervals of five

minutes will render the eye anaestheticfor about forty

minutes.
Numerous
similar compoundshave been tried experimentally,
but

found

to have

advantageover holocaine. They are, all

of them, also antiseptics.
It appears that in this series the ortho
and para compoundshave equalphysiological
properties.
are

no

STOVAINE

314

AND

Gnanidine

D.

guanidinecompounds,of

ALYPIN

Derivatives.

which

largenumber have been

less toxic than cocaine ; theyact more
are
tested,
promptlyand for
their solutions are stable. They are, however,
a longertime,and
and the solution of the most powerfulof the series is
irritating;
decomposedby light. This body,known as Acoine, is the hydrochloride of di^-anisykmonophenetyl-guanidine,
The

OCH3.HC1

OCH3

Derivatives

E.

Amyl

of Tertiary

Alcohol.

by stovaine and alypinmay

represented
derivatives of dimethyl-ethyl-carbinol

A
as

group

be

regarded

"

CH3
C2H5"

C"

OH

CH3
Stovaine

Alypin:

"

"

CH2.N(CH3)2

CH3
C2H6"

C"

O.COC6H5

C2H5"

CH2.N(CH3)2 HC1

is about
is

dimethyl-amino-benzoyldimethyl-ethyl-carbinol.
Stovaine

as

O.COC6H5

CH2 N(CH3)2

or,

C"

or,

HC1
.

tetra-methyl-diamiuo-benzoylethyl-dimethyl-carbinol.

differsfrom cocaine in many important

points
; whilst it
powerfulin anaesthetic action it is onlyhalf as toxic ; it

not
vaso-dilator,

It has

and has
vaso-constrictor,

toxic effect on

the

acid reaction to litmus paper, and is decomposed

in the presence of alkalis. It appears to be unsuitable for instillation
but may
tration
into the conjunctiva,
be usefully
employedfor infil-

heart.

an

anaesthesia.

As

much

as

20

been
grainshave frequently

EUPHTHALMINE

316

(Heliotropin),
C6H3.(CHO).(OCH2O).1:3:4, are

less

pronounced

local anaesthetics.

II.
Not

onlycan

SUBSTITUTES

FOE

ATROPINE.

bodies

resemblance to cocaine
havinga physiological
be derived from triacetone alkamine (see
but by altering
the
p. 306),
side-chain a mydriatic
substance similar in constitution and action
to atropine
it will be remembered,
be obtained. Atropine,
is
may
the ester of tropic
acid and tropine;
homatropinethe ester with
mandelic

mandelic

acid.

The

alkamine

is mydriatic

acid

ester

of

methyl-triacetone

"

CH"

It will be noted that the

is in
hydroxyl

the para

as regards
position

as in tropine.
nitrogen,
Vinyl-diacetone-alkamine,

the

may

be treated in

isomeric

similar manner

with like results. Two

exist,owing
"-methyl-vinyl-diacetone-alkamines

presence of
an

an

asterisk on

asymmetriccarbon

atom

in the

ring,marked

stereoto

the

with

the above formula.

derivative is not

mydriatic;justas the
is
isomeric with homatropine,
mandelic acid ester of i|r-tropine,
of the ^-esteris known
inactive ; the hydrochloride
as
Euphthalanaesthetic
has no
It is easilysoluble in water, and
xnine.
properties.
The

a-mandelic

acid

317

ADRENALIN

Euphthalmineresembles atropinein checkingthe

secretion of

the effects of pilocarpine

counteracting
in frogsparesis,
and eserine. In toxic doses it causes
convulsions,
and death from cardiac failure. It differs from atropine
dyspnoea,
in its retarding
action on the pulserate,due to its action on the
the

gastric
mucosa,

vagus

and in

the cardiac muscle.

centre and

and is similar in itsaction

methyl-nitrate,
atropine
of a somewhat
to the methylbromide ; it produces
a mydriasis
during
ennature,and is thus not a suitable substitute for homatropine.
for a preparation
of the methylbromide;
Mydriasine is the trade name
of this bodyhave already
been described (p.
the properties
270).
mandelic acid ester of pyrrolidine
The corresponding
merely
of the sphincter
iridis to light;that of
destroysthe reactivity
is

Emnydrine

/S-hydroxy^tetramethyl-pyrrolidine
CH3
CH3"

CH2

NH

CH3"

CHOH

CHfl
is similar to

but is weaker
euphthalmine
physiologically,

in

mydri-

atic and toxic action,

III.
The

the

SUBSTITUTES

HYDRASTIS.

FOB

introduced into medicine is

importantbody recently
from the supra-renal
and known
extract prepared
nalin,
as Adreglands,
tution
"c. The chemical constihemisine,
epinephrin,
supra- renalin,
of this body is not absolutely
but the balance of
decided,
most

evidence is in favour of the formula

CH.OH.CH2

Its action
causes

NHCH3

is chiefly
on
physiologically
unstriped
muscle,which

to contract

by

direct stimulation.

that after the dilator pupillae

muscle

has

Thus

been

Elliott has

it

shown

separated
entirely

ADRENALIN

318
its

from

the

nervous

of
application

iris whose

and thus

for

connexions
adrenalin

months

some

it will contract

than
rapidlyand completely

more

on
an

supplyis intact. It does not act, however,on

is not normallyinnervated by the sympathetic,

nervous

plainmuscle

DERIVATIVES

which

is without action

on

the muscles

of the

and
bronchioles,
venously
intradose of ""$mgm.

pulmonaryand cerebral blood-vessels. A

in rabbits doubles the generalarterial blood
injected
givesa distinct
pressure, and less than one-millionth of a gram
action on unstriped
action. In addition to its specific
muscle supplied
has
The
adrenalin
the
toxic
actions.
certain
sympathetic,
by
NH.CH8 groupingis resistant in the body,and suggestsa protoplasmic
As
of
it
and
a matter
fact, produces glycosuria
poison.
changesin the liver and kidneys. It appears also to
inflammatory
have a specially
toxic action on the cardiac muscle of dogs (Elliott).
from
Death
occur
large doses,with symptoms of collapse,
may
and paralysis
of the central nervous
system without any
coma,
the

increase in blood pressure.

Catechol,

the

from
parent-substance

doses

TT

/OH

,
.

in
derived,
chemically
kilogram body-weightproducesan

which

of about

adrenalin is

2 mgms.
per
rise of arterial pressure, and
appreciable

this is also the

case

with

simplerchemical derivatives;for instance,pyrocate"c.

chloracetyl-pyrocatechin,
Replacementof the
aldehyde,
renders these bodies inactive.
hydroxyl-hydrogen
phenolic
is a ketone obtained by the oxidation of the optically
Adrenalone
An
derivative of adrenalin.
active tribenzene-sulphone
optically
with
the
is
identical
which otherwise
inactive product,
apparently
derivative of the ketone,has been synthesized
by the
corresponding
action of methylamine,CH3NH2, on
many
chuic

of its

/OH

.....

C6H /OH
\CO.CH2C1

.....

(a derivative

which

has

much

the

same

as
activity
physiological

catechol).

Cp.CH, NHCH3

CO.CH2C1
+

CH3NH2

OH

319

ADRENALONE
The

ketone
synthetic

reduction

on

alcohol,
givesthe corresponding

/CHOH.CH2NHCH3

C6H3"-OH
\OH
reaction as adrenalin,
although
producesas greata physiological
in its
it is not identical with the natural product,differing
chiefly
optical
inactivity.The ketone itself has a vaso-constrictor action,
of the simplerpyrocatechin
but is hardlymore
powerfulthan some
which

derivatives mentioned

above.

of bodies have
adrenalone a large number
synthetic
preparedwhich may be grouped into the followingclasses l :
From

been

"

I.
II.

C6H3(OH)2 CO.CH2NH2.
Derivatives of the type C6H8(OH)2.CO.CH2NHR.
.

(a) Where

is in

aliphatic
group,
heptyl.

amyl,and
(b)Where
(c)Where

R
R

III. Derivatives

of

e.

an

g.

methyl,ethyl,

benzyl.
is purelyaromatic,e. g. phenyl,tolyl,
naphthyl.
the type C6H3(OH)2.CO.CH2.NR2,
e.g.
is

mixed

e.

group,

g.

dimethyl,diamyl.
IV.

Derivatives

of the ammonium

type

C6H3(OH)2 CO.CH2

NR3OH,

"c.
trimethyl,
dimethyl-phenyl,
Classes I and II (a)all produce a marked
rise
Physiologically,
in arterial pressure in doses of about 1 mgm.
per kilogram bodyto adrenalin.
stances
Subweight,their reduction bases actingsimilarly
but less powerfully,
and approxiin Class II (b)act similarly
mate
followed
to those in Class II (c)which
a fall of pressure
cause
cases
cause
a
by a slightrise. Their reduction productsin some
not
marked
of
rise
active as
so
pressure, but on the whole they are
e.

those
Class
is

g. salts of

of
II

the

first two

(a),but

groups.

the reduction

apparentlyless active,but

Class

have been

therefore need
from

dealt with

not

be

in their

further

which

have

placeamong

noticed

be
practical
standpoint,

is less active

vaso-constrictor

the

and
alkaloids,

here; they cannot,

considered

as

H. D.

Dalkin, Journ. PhysioL,xxxii,May,

over,
more-

substitutes for

hydrastis.
1

than

productsare very powerful. Class IV

have been tested.
only a few members

Nicotine,coniine,and other bodies

action

III

1905.

CHAPTER
THE

GLUCOSIDES,

XVI

Sinigrin,Sinalbin, Jalapin,Amygdalin, Coniferin,

Phlorizin,Strophanthin,Saponarin,"c. Purgativesderived from Anthra"

quinone.
THE
THE

Glncosides

GLUCOSIDES.
a

are

class of

which

substances
vegetable

on

hydrolysis
give rise to various aromatic derivatives and sugars
but often rhamnose
chiefly
glucose,
or
pentose,and occasionally
"

to

mixture

The

name

chemical

of several sugars.
indicates botanical rather than

The
relationships.

or
pharmacological

chemical

common

the
characteristic,

carbohydratenucleus,is probablyof great importancein plant

physiology,
beingthe nutritive portionof the molecule ; the residual
and is probablynot a mere
portionis also of importance,
excretion,
at
time
From
as
was
the pharmacological
one
thought.
pointof
mine
nucleus appears to increase but not to deterview, the carbohydrate
of these bodies. The one
the activity
to the rule
exception
that the glucoside
is more
active than its non-carbohydrate
moiety
to
obtained from
a
is,according
Frankel,eonsolidine,
glucoside
This
and its
of central origin,
burrage.
body producesparalysis
is three times more
toxic. A number
decomposition
consolein,
product,
of glucosides
be prepared
can
though few of these are
artificially,
of pharmacological
importance.Van Rijnl classifiesthe naturally
occurring
glucosides
accordingto the plantsfrom which they are
derived. He remarks that,in the presentstate of our knowledge
of the structure of these bodies,
a
completechemical classification
is not possible;
but even
the structure of all glucosides
were
known, a botanical classificationwould still stand,as, in
accurately
contain similar chemical components.
general,
plantsof alliedspecies
For

the

be found

more

are

structure

in

As

convenient.

glucosides,
only a
used

chemical

presentpurpose, however, a
few

out

of

medicine,and

determined.

These
1

Die

with

the

may

be

have

of natural
had

the

products

their chemical

as
was
classified,

Glykoside,1900.

with

so
alkaloids,

largenumber

still fewer

classification will

suggested

FROM

OBTAINED

GLUCOSIDES

PEPPER

321

by Umney, accordingto the chemical character of the non-glucose

portionof the molecule. He divided them into four groups, as
and anthracene derivatives,
and, as far
benzene,styrolene,
ethylene,
this classificationwill be followed. Some
as
glucosides,
possible,
been
added
his
h
ave
to
not in Umney's original
list,
groups, of
from a pharmacological
which the last is the most interesting
point
of view.
It will be

of the

group

if anything,is known
in this
little,
of constitution and physiological
interdependence
that

seen

very

action.
Class

I.

derivatives include a number of

ethylene
characterized by
mustard and tropaeolum
seeds,

their

taste,and all alliedto, or derived from, mustard

oil.

bodies derived from

The

Sinigrin,
of

of
C10H16NS2KO94- H2O, isthe glucoside

is also found

and

black pepper,
It is the potassiumsalt

in horse-radish root.

myronic acid,and

formula

sharpburning

probablyhas

the

followingconstitutional

"

O.S02OK
S.C6HU05
II

N.C3H6
On

it givesrise to allyl-mustard
decomposition
oil,C3H6N
and potassium
glucose,
bisulphate.
Sinalbin,
from

S,

the corresponding
derived
C30H42N2S2O15,
glucoside

white pepper

is
O"

SO2OC16H24O6
S.C6HU06

N.CH2.C6H4.OH
When

decomposed,it givessinalbin-mustard oil,C7H7O.N:C:S,

and the sulphuric
acid ester of sinapin.
glucose,
Sinapinis a compound of choline and sinapinic
acid
"

OH

CH30/\OCH3
O]
/fJH
!H:CH"

"

^1

CO.C2H4(3

SALICIN

322

AND

HELICIN

which has not yet been isolated,

is the origin
of
Glycotropaeolin,
oil and benzoyl-cyanide,
in the seeds of Tropaeolum
benzoyl-mustard
and the investigation
majus. Experimentson its aqueous solution,
of its derivatives,
suggestthe constitutional formula
"

O~SO2OK
C.S.(
.C6Hn06-f-aAq

N.CH2C6H5
of Scammony
active principle
Jalapin(Scammonin),C34H56O16,the
is a glucoside,
(Convolvulus
scammonia),
splitting
up when
with dilute acids into glucose
and jalapinolic
acid,to which
the constitution
assigns

heated
Kramer

"

"CHCH.OH .(C10H20)COOH
This acid has the

the substance obtained

as
composition
from ipomoein(theglucoside
from Ipomoeapanduratus)
by heating
into sugar, "-methylit with dilute acids,when decomposition
takes place.
crotonic acid (?),
and ipomeolic
acid,C16H32O3,
same

Class

The

benzene

group
which is
glucoside

II.

contains bodies allied to Salicin,

decomposedby

dilute acids into

C13H18O7,
glucoseand

saligenin
"

CHoOH

Ganltherin,

the glucoside
from
C14H18O8,

acid methyl ester

givessalicylic

and

Gaultkeria

procumbent,

when decomposedby
glucose,

dilute acids.

Helicin,

is the corresponding
aldehydeto
C13H16O7,

salicin
"

"C6HU06
It exists also in

an

which givesno
amorphous form (wo-helicin),

aldehydereactions.
Michael

obtained this

synthetically
by the
glucoside

action of

an

AESCULIN

324
the

B.

Tuberculosis,
mainly as

stimulant

to the

of
activity

the

cells of the host.

Amygdalin,

contained in almonds

mespilus,
"c.),is

pyrus,

and

(primus,
many other plants
derivative of the nitrileof mandelic acid,

and

the sugar is
does not contain

which
probablymaltose,or a similar di-glucose,
free aldehydegroup, since amygdalin has no
a
action of Fehling's
solution.
Its physiological
action depends on its decomposition
in the small
with liberation of
intestine,

C20H27NOn+ 2H20

HCN.

2C6H1206+ C6H5CHO

HCN

Prussic acid.

Benzaldehyde.
Class

With

III.

few

this group does not contain bodies of any

exceptions
interest.
great physiological
is phenyl-ethylene,
Styrolene
C6H5CH : CH2.
obtained from the horse-chestnut
a glucoside
Aesculin, C16H16O9,
and other plants,
and
when treated with dilute acids,glucose,
gives,
is isomeric with daphnetin(fromDaphne
a body which
aesculetin,
pressed
Mezereum);the constitution of these substances is probablyexby the formulae
"

OH

HOj/No

CO

"

CO

CH:CH

-~

Aesculetin.

CH:CH

Daphnetin.

dioxy-coumarin.A tincture of the horse-chestnut has

The dried bark of Daphne
been prescribed
as
an
emmenagogue.
but
Mezereum
and externally
is a gastric
a
stimulant,
rubefacient,
this action is probably
and not to the glucoside.
due to the volatile oil,
Both

The
which

are

solution of aesculin has

aqueous
can

be

seen

marked

in the urine fifteen minutes

injection.It has been used

in

lupusas

has
C16H22O8,

an

CH-O.CHO5

after

fluorescence,

hypodermic

to the Finsen
auxiliary

the structural formula

/CH

blue

is due to the fluorescence.

its value
lighttreatment,apparently

Coniferin,

CH.CH2OH

1
3

"

PHLORIZIN

325

(i)gluco-vanillin,

Derivatives of it are

/CHO

\OCH3

3
C6H3^O.C6Hn06

obtained

by the

careful oxidation of

and (ii)
coniferin,
glucovanillie

acid,

L3

obtained

by

oxidation of coniferin by

10-15

have

grams

Hesperidin
dilute

is

former

The

convulsant

action

no

on

potassiumpermanganate.
for
but
some
poison
animals,

man.

in resinous varietiesof

occurs

of

means

on
cifrus,
heatingwith

acid givesrhamnose,glucose,
and hesperetin
:
sulphuric
"

+ 3H20
C50H60027

C6H1406+

Rhamnoee.

C6H12O6+

Glucose.

Hesperetin.

C16HUO6

has probably
constitution :
the following
Hesperetin

"

,CH

CH.COO.C6H3(OH)2

\OCH3
In

the alkaloid the

joinedto

rhamnose

Fhlorizin

is the

hydrogen atoms
and glucose.

of the

of this
onlyglucoside

group

hydroxylgroups

are

which is interesting

physiological
standpoint.Its action is well known, and is
the body formed when glucose
shared in a less degreeby phloretin,
has been split
off.
has a constitution expressed
Phloretin
by the formula
from

"

OH

CO"
C

This is based

on

acid
phloretinic

its decomposition
by

and
potashinto phloroglucin

"

"

4, r

IT

^"14CH(CH3).COOH

In its chemical reactions phloretin

is similar to Cotoin, a
obtained from coto bark (species
which has
undetermined),

glucoside
a special
action on the intestinalvessels. These are dilated,
and thus absorption
is favoured.
It has no astringent
but is
or
antiseptic
action,

STROPHANTHIN

326

used in anti-diarrhoeic mixtures

largely
The sugar-free
nucleus is stated to have

in the form of

the constitution

tincture.

(Schmiede-

berg)"

/(OH),

C6H2fCO.C6H5
\OCH3
is

methylenedicotoin,
CH2(C14HnO4)2
; it has
bitter taste of cotoin,is more
powerful in action,and
bactericidal (Pharm.J.,i. 1900,p. 531).
Fortoin

Several

been

of these

; two

Strophanthin
from

have

substances

Strophantkus
Kombe, and

are

described

under

the

not

the

is also

name

of

glucosidesobtained
crystalline
an
amorphous preparation

the other

hispidus.Arnaud, and later Kohn and Kulisch,

Strophanthus
from S. Kom.be.
isolated a substance of the composition,
C31H48O12,
and its aqueous solution is optically
has a bitter taste,
This glucoside
it yieldsstrophanthidin,
and a sugar or
inactive. On hydrolysis
of sugars whose
mixture
compositionhas not been determined.
Strophanthidin,
C19H28O4,or C28H40O6,althougha very hygroscopic

from

substance

is not

soluble in water.

which is termed ^-strophanthin,

isolated
was
preparation,
from Strophanthus
grainsby Thorns. The formula C30H46O129 H2O
its value in conditions of
to it ; Schedel showed
has been assigned
The amorphous strophanthin
obtained from the
cardiac weakness.
is givenin much
smaller doses than
seeds of Strophanthns
hispidus,
but whether it is more
the previous
derivative,
powerfulin its action,
has not yet been decided.
toxic properties,
or has more
also be included Iridin, C24H25O13,
In these groups must
a glucoside
obtained
from the Iris florentina
with a complexstructure,
and
Merck's

Iris versicolor.
It

breaks

down

into glucoseand
saponification
latter body yieldsiretol (oxymethyl-

on
primarily

C18H16O8.
irigenine,

This

phloroglucin),
OH

OH

formic

acid,and iridinicacid,
OH
CH

on

heatingwith

concentrated solution of

potash.

SAPONABIN

327

Iridin is a

cholagogue
purgative.
and other
found in Saponariaofficinalis,
a
Saponarin,
glucoside
plantsmay probablybe classed here. With iodine this derivative
givesrise to the blue colour characteristicof starch,and hence was
of that substance.
formerlyregardedas an amorphousvariety
this substance,
found on
investigated
Barger,who has recently
and
that it yielded
a
glucose,
body named saponaretin,
hydrolysis
matter
obtained by
another identical with vitexin,a colouring
of the glucoside
of Titex littoralif,
Perkin from the decomposition
and supposed
to have a constitution represented
by the formula
"

H"

C6H4.OH

1:4

Saponaretin
may be identical with homovitexin (Perkin).
Scoparinmay be methoxy-vitexin.
the decomposition
Bhamnetin,
productof the glucosidesof
various species
of Ehamnus, including
R. Purshiana,is stated to
have the following
constitution :
"

CH,O

which, on
colouring
matter,like Quercitrin C21H22O12,
and the carbohydrate
rhamnose.
hydrolysis,
givesrise to quercetin
It also is a

Quercetin
OH

is found combined

free in many
varietiesof plants,
such
flowers of the horse-chestnut,
and the berries of

leaves and

phoea rhamnoides.
in

onion

rinds.

(from Ehus

and

Perkin and Hummel

Rhamnetin

is

found

an

as

the

Hippo-

identicalpigment

Fisetin
mono-diethyl-quercetin,
is mono-oxy-quercetin,
and a pigment in the
Cotinus)

ANTHRAQUINONE

328
leaves and

stems

of

some

of
species

tamaris

is

methyl ether

of

quercetin
"

Chrysin,

of oxygen
less,can be
benzoic acid,and acetic acid,justas
phloroglucin,
which

has

three atoms

decomposedinto
quercetin
yields

acid.
acid,and glycolic
phloroglucin,
protocatechuic

Class

contains

This group

number

IV.

of

purgativebodies

derived from

anthraquinone
"

CO

Chrysophauic

acid, dioxy-methyl-anthraquinone,

OH'

["CeHaOCeH3"H

it
purgativeprinciple
presentin rhubarb. As a glucoside,
which has not yet been isolated in the same
as chrysophan,
occurs
plant.Increase in the hydroxylgroups producesincreased purgative
as in Emodin,
action,
trioxy-methyl-anthraquinone
is

"

ca
"

OH/

(The orientation of

: NOH

these derivatives is not

identical emodin

An

xcox

occurs

in

certain.)

rhubarb,and combined

with rham-

in frangula
bark (Buckthorn)
glucoside
; the form obtained
The
oxidation productof emodin,
aloes differs slightly.1
from
is intermediate physiologically
between emodin and
aloechrysin,
nose

as

acid.
chrysophanic
1

There

are

fifteen

isomers.
possible
theoretically

329

DERIVATIVES
Whereas

the oxygen

appears

to

increase the

of
intensity

the

the methyl group

is also of importance,
position
the synthetic
side,
appears to be of littleimportance.Vieth,from
table.
arrangedthe following
of the substituting
The numbers in the formula show the position
and
action,

groups

its

:"

CO

Most

active,
Anthrapurpurin,
l:2:7-trioxy-anthraquinone.
strong,Flavopurpurin,1:2:6
"
1:2:3
strong,Anthragallol,

\ as
J as
| as strong,Purpur-oxy-anthin,
l:3-dioxy-anthraquinone.
Alizarin (Bordeaux),
1:2:3: 4-tetraoxy-anthraquinone
Y1^as strong,
""$as strong,Purpurin,
l:2:4-trioxy-anthraquinone.
"

"

number

"

of

acid (hexa-oxy-anthraproductssuch as rufigallic

nitroacetyl-rufigallic-tetramethyl
ether,
ordinary
quinone),
alizarin,
and cyaninare inactive. Some of the active bodies contain
purpurin,
and some
do not.
a methylgroup
The purgative
have been variously
attributed to the
properties
anthracene group, to the ketonic groups in anthraquinone,
and to
the latter in the presence of hydroxyland aliphatic
side-chains.
of the natural glucosides
The greateractivity
when
as purgatives,
tic decomposition
is due to the
comparedwith their hydroly
products,
fact that the latter are too rapidly
and
absorbed from the intestine,
A

thus lose their laxative effect.

A
"

number

of

from
starting

and

bodies have
synthetic

aloin,which

contains several

combined

been

has the formula

hydroxylgroups;

in order to

from
prepared

producebodies

anthracene

+ 1"H2O,
C17H18O7

these have

which,while

been

variously
the
possessing

action,have not the bitter taste of the parentsubstance.

purgative
The compounds should also be more
stable and thus more
active
for reasons
noted.
already
The
methylene radical may replacetwo hydrogen atoms of
and triacetylhydroxyl groups, and tribromaloin,C17H15Br3O7,
have been preparedand found
aloin,C17H16(C2H3O)3O7,
The

last named

Fnrgatin

or

to be active.

is also tasteless.

Fnrgatol is a diacetate of

(1:2:7anthrapurpurin

SAPONINS

330

the

irritates

kidneys,

red

stained

and

Marshall

laxative.

mild

a
trioxy-anthraquinone),

in

pain

causes

the

that

it

urine

is

states

the

back;

(Dixon).

Exodine

is

gallic acid

is

mild.

hexamethyl

The
but

apparently diacetyl-rufigallic-tetramethyl-ether
(rufi-

l:2:3:5:6:7-hexaoxy-anthraquinone); its

these

rufigallicacid

of

has

purgative

is

perties,
pro-

acid,the pentapossessedby acetyl-rufigallic

diacetyl-tetramethylether of this anthraquinone
not

are

the

methyl ether, or

ether

action

derivative.

[Purgen,

not

absorbed

to

not

belonging

to this

phenol-phthalein,and

is

extent.]

considerable

any

is

group,

Saponins.
series of

A
are

of

known,
view,

These

as

of

are

are

them

are

empiricalformulae

for

which,

the

solution

frothy

part, have

most

the

exceptions,to

some

alone

the

from

property of producing

corresponding,with

the

pharmacological point
drugs frequentlyused in practice.

many

saponins, bodies

the

which

great importance

among

characteristic
and

glucosidicbodies,of

with

the

water,
formula

general

CnH2n_8O10.
Various
of carbon
and

but

atoms,

constructed, according

definite

specialpharmacological

bodies

propertieshas

been

not

confusion

calls the

exists

class

entire

products Saponins.
the

term

applied to

somewhat

the

E.
'

the

to

Van

Rijn
to

Dixon

more

calls the

that

notes

active

members

made

the

groups

out.

The

usually inert.
Schmiedeberg

hydrolytic decomposition

entire

individual

some

'

the

number

these

employed.

terms

Sapotoxins, and

Sapotoxin
W.

first group.

as

the

to

correspondence between

produced by hydrolysis (sapogenins)are

Some

be

been

have

groups

class

Saponins, applying

members
term

of the

of

Robert's

Sapotoxins
(

group,

but

should
is used

loosely'.

Senegin, quillaia,sapotoxin, saponin, digitonin, quillaiac acid,

polygallic acid, sarsa-saponin,and
more

important

members

of the

smilax-saponin

group.

are

among

the

DEPENDENCE

332

owing
the

OF

TASTE

to the fact that the

and

this is also true

in

bodies not

in the

but
solution,

CONSTITUTION

solution is

by

in

of

case

the

to
applieddirectly

becomes

structure

stimulated
directly

are

organs

body in

chemical
terminations,

nerve

ON

ance;
greatimport-

smell,where

contact

the end

of emanations

form,

gaseous

of

as

shown

"

by

of
the

careful researches of Aitken.

Thus the process

stimulated is more

by which the end organs of taste and smell are

nearlyanalogousto the process by which a
thread (oran animal cell)
than that by which
takes up a dye-stuff
the retina records the impressions
of various kinds of light.
Our presentknowledgeof the subject
of intra-molecular vibrations
is so slight
that nothingmore
than the mere
can
suggestion
be thrown

out that

likewise due

to

the stimulus

not indirectly,
to the
directly,

odorous
which
taste

substance.
have

are

Several

been shown

at any

of taste and

case

smell is

transmitted
movement,
vibratory
sensitiveend organs by the sapidor
facts in the generalrelationships

of

type

some

in the

chemical

to exist between

with such

rate consonant

structure

and

view.

In MendeleefFs

classificationof the elements it will be

periodic
noticed that those possessing
taste are mostlyfound in the
a sweet
third (boron,
aluminium, scandium, yttrium,lanthanum) and
that
fourth (lead,
It is interesting
to note
cerium)groups.
in the second group, but which shows
which occurs
beryllium,
such marked
taste.
the

On

second

sulphurin

resemblance
the other

to the

hand, the

third,should

bitter elements

also possess a sweet

found mainly in
are

(magnesium,zinc,cadmium, mercury); while

sixth group often givesrise to bitter compounds,

group

the

and chlorine in the seventh

The

group to sweet ones.

characteristic taste of acids and bases

dependsupon

their

giving rise to the acid and the

the stronger the acid
hydroxylto the alkaline taste ; consequently
the more
pronounced
(thatis,the greaterthe degreeof dissociation)
holds good with the
is the acidic taste.
A similar relationship
lose their taste on conversion
alkalis. Organic acids consequently

the hydrogen
dissociation,

ion

into esters.

taste
between
remainingfacts concerningthe relationships
for anything
and smell and chemical constitution are too disjointed
like systematic
arrangement. They will therefore be groupedunder
dependence,
main headings,
a few
which,while not showing any mutual interevidence to be presented
will enable the experimental
in a more
manner.
orderly

The

DERIVATIVES

HYDROXYL

333

organiccompounds,substances with very low or with

tasteless.
very high molecular weightare usually
out that among
1. Sternberg1has pointed
organicsubstances
is necessary in order to produce
a certain
harmony or equilibrium
Among

'

sweet

The

former

the
disturbed,

taste ; if this is much

alkyland hydroxyl
groups must
onlyexceed the latter by one.

be

taste is lost.

sweet

equalin number, or

the

Thus
OH

in
X

CH2OH
|
CHOH
-in,
glycerin
'

OH.CHf

NC

inosite,
OH.CHk
"HX

JCH.OH

--

CH,

"

"H

,!H
CH'
and

I
methylglucoside,

rhamnose, (CHOH).

(CHOH),
JHO

[2OH
all sweet; so are the
saccharides are tasteless.
are

But

but
di-saccharides,

the

tri- and

poly-

methylrhamnoside

CH3
(CHOH)3
I

CH"OCH3
and
is bitter,

the

ethylderivative stillmore
CH3

so

"

(CHOH)3

in
1

Geschmack

und

Geruch,Dr.

Wilhelm

Sternberg,and

many

papers.

INFLUENCE

334

OF

THE

PHENYL

RADICAL

series the polyhydric

alcohols,
aliphatic
oxy-aldehydes,
and oxy-ketones
characterized by their sweet
taste. In the
are
series from ethylalcohol to mannite, C6H8(OH)6 the taste increases
of hydroxylgroups.
in proportion
to the number
Grape sugar,
an
CHO, containing
CH2OH(CHOH)4
aldehydegroup, is sweeter
than mannite.
of the sugars
Slightalterations in the composition
alter their taste,and the condensation productsof the
completely
sugars with ketones are all bitter. The replacementof hydroxyl
hydrogenby acid radicals converts the sugars into bitter substances,
and further replacement
producestasteless derivatives. Although
acid,COOH
grape
sugar is sweet, glycuronic
(CHOH)4 CHO,
2. In the

has the characteristicacid taste.

nitro group
direction or another.
3. The

and

does

not

to influence taste in

appear

one

benzene,
Amyl nitrite and similar compounds,nitrosweet.
are
l:2-nitro-phenol
Trinitro-phenol
(picric
acid)
is
bitter.
are
dinitro-monochlor-phenol
Nitro-dichlor-phenol

tasteless.
4. Another

fact,connected

most

probablywith

molecular

brium,
equili-

is the passage of a sweet substance into a bitter by the

of positive
replacement
alkylgroups by negativephenyl radicals,

thus:

"

Bitter.

Sweet.

(1)

C6H5.CHOH.CH2OH
Phenyl-glycol.

CH3.CHOH.CH2OH
1 : 2-Dioxy-propane.

C6H6 CHOH.CHOH.CH2OH
cerol.
a-phenyl-gly

(2)CH3.CHOH.CHOH.CH2OH
1:2: 3-Trioxy-butaue.

CH2OH.(CHOH)3

(3)CH2OH.(CHOH)3.CH.CH.OCH3

Methyl-glucoside.

The

-CH2OH or chlorine or bromine

does not diminish
phenyl-glucoside

introduction of

aromatic nucleus

taste,thus

of

for their bitter taste.

similar way

coside
enzyl-glu

radicals in the natural

of aromatic

the

presence
in
accounts

CH.CH.O.CH2C6H6
0

Possiblyit is
which
glucosides

into the
the

bitter

"

phenyl-glucoside,
C6HU06 O.C6H5)
salicin,C6HU06.O.C6H4.CH2OH
mono-chlor

salicin,

TT

r\

r\

TT

/CHoOri

2,

GROUPS

335

but benzoyl-salicin
(populin),
bitter,

are

C6Hn06
is

AMIDO

OF

INFLUENCE

sweet,and

to

C6H4 CH20(COC4H6))

the introduction of

second

benzoylgroup

givesrise

tastelessbody.

Tetra-acetyl-chlor-salicin
C6H7(COCH3)405
.

is also

and
tasteless,

so

0.C6H3"^OH

the
is helicin,

aldehydeof salicin,

C6HU06-O.C6H4.CHO.
either of aliphatic
or aromatic series,
are
usually
Hydrocarbons,
tasteless. The introduction of oxygen
or
however, or of
nitrogen,
5.

the appearance
of a
definite conditions may
cause
this quality.Sternberghence calls them
possessing

both, under
substance

'

Sapiphoregroups.
radicals must be combined in order to proPositive and negative
duce
the effect,
with
and positive
positive
negative
hydroxyls
alkyls,
amido
Thus
when
with negativecarboxyls.
NH2 and
groups
in close proximityin a molecule (i.
COOH
the
occur
e.
groups
the effect is more
a
position)
pronouncedthan when they are
separated
by carbon atoms (/3and y positions)
; a-amido-carboxylic
acids of the aliphatic
for instance,
are
sweet,but /3-amidoseries,
valerianic acid is only slightly
so, and has a bitter after-taste,
whereas y-amido-butyric
acid has lost the sweet taste. a-Amido'

acid,
"-oxy-propionic

CH3.CH.OH.CH,Hj
and

acid,
a-amido-/3-oxy-valerianic

CH3 CH2
.

are

CHOH.CH"^^H

quitesweet,whereas a-oxy-jS-amido-propionic,

CH3.CHNH2.CH"g"?oHj
is not.

dine

In

this connexion

it is

to note
interesting

acid
carboxylic

CH2" CH2
CH0
NH

has also a sweet taste.

CH. .COOH

that

a-pyrroli-

INFLUENCE

336

AMIDO

OF

GROUPS

always hold good, the

negativephenyl nucleus playingan importantpart,as mentioned
in the case
of phenylglycerin. Thus phenyl-amidopreviously
the

In

series this does not

aromatic

acetic acid,

is

but a-amido-)3-phenyl-propionic
acid is sweet
tasteless,

When

the substituents

berg compares

the

and

(NH2

COOH)

ortho derivatives to the

"

"

ring,Sternsubstances.
a-aliphatic
are

in the

Thus
1

is sweet,whereas
NH
,

is tasteless.

Further,l:2-amido

whereas the 1:3 and

The

ortho

1:4

amido

acid
salicylic
acids

derivative
sulphonated

has the characteristicacid taste

sweet,
slightly

tasteless.

are

of benzoic

the

is

acid,

sulphamide,

S0NH2
is

but the corresponding

inner anhydride,
tasteless,
0-anhydrosulph-

amine-benzoic

has
name

an

acid,

sweet taste,
and
intensely
of Saccharin.

then
means

been

It is obtained from

100" C., which

nating
sulphonic
acid,
at

has

givesthe

the resulting
substance
converting
of phosphorus
and
pentachloride,

introduced under

the

toluene

best

by firstly
sulphoyieldof l:2-toluene-

into the

sulphochloride
by

this into the

amide,

S0NH

is then
through the agency of ammonia.
o-Tolyl-sulphamide
oxidized by potassiumpermanganate, and if the solution is kept
alkaline the potassiumsalt of "?-sulphamine-benzoic
acid,

SACCHARIN

337

0NH2
formed,but when the free acid is liberated by
and saccharin results
occurs
acid,dehydration
is

of

means

mineral

"

/SO2V

.S02NH;H

C6H/

H20

\CO;OH
to 1891 the commercial

"NH
C6H4"
\CO/

saccharin

contained 40 per cent.

usually
is based
of the tasteless 1 :4 derivative. One method of separation
of these substances in xylene,
saccharin
the differingon
solubility
but the other insoluble.
soluble,
beingSaccharin passes unchanged through the organism; the sodium
of Crystallose, the ammonium
salt goes by the name
is termed

Up

Sncramine.

Saccharin stillretains its sweet

nucleus is replaced
by

but
a

NH2

taste when

hydrogen atom

of

"

corresponding
replacement
by

nitro group

gives rise

to

substance with bitter taste.

The

of
replacement

results in
6.

the imide

hydrogenby the ethylgroup

tastelesssubstance.

acid
Salicylic

is

sweet,and its amide,

i

n
""H

TI

is

but although0z*oxybenzoic
acid is also sweet, its
tasteless;
amide,

is bitter ; its dehydration

however,the nitrile
product,

is sweet.
one,

Among

the

nitro derivatives of

viz.
H

C6H

-,

\COOH

only
^-oxybenzoic

DIBASIC

338
is

sweet,the others

tasteless ; all the

are

but the
tasteless,

also

are

ACIDS

acids
dinitro-w-oxybenzoic

trinitro acid is bitter.

acids are tasteless.

dioxybenzoic
7. The presence of two carboxyl
groups in the molecule and the
effectof NH2 groups on taste is illustratedby the following
facts :
The

"

Malonic

acid,CH2(COOH)2, and

succinic acid

CH2.COOH
CH2.COOH
have the

acid
ordinary

is sour, and

so

acid
methyl-amido-malonic

taste ;

acid
is aspartic

"

I
CHNH2.COOH

CH0. COOH
m

acid,

Diamido-succinic

CH.NH2.COOH
CH.NH2.COOH
a

substance which is onlyvery

solublein water,istasteless.
slightly

acid
Dextro-glutaminic

PTT/CH2.COOH

n2\CH.NH2.COOH

is sweet,and

so

acid,i.e. dextro-asparagin,
aspartic
CH.NH2.COOH

is the amide of

CH2.CONH2
ester
Imido^succinic-ethyl

CH.COOH

I "H
CH.COOC2H6
is

whereas
bitter,

its amide

CH.CONH2

I "H
CH.COOC2H5
is sweet.
of
effects of stereochemical influences upon the sense
taste have been previously
mentioned (seep. 53). This influence
8. The

is but

or
slight,

at all events has

so

far

only been

noticed in

few

CQ
1

AND

CONSTITUTION

CYCLIC

340

/NH.C6H4

J\NH2

OC2H5

4-phenetolcarbamide

TASTE

ro/NH.C6H4

carbamide.
Di-_p-phenetol

(Duloin).

Tasteless.

the toxic substance

organism,giving rise

in the

down

Sucrol, breaks

or

OC2H5

J\NH.C6H4.OC2H5

Sweet.

Dulcin,

to

phenetidin,

its physiological
action
consequently

is similar to that of the

phena-

cetin derivatives.
11. The
taste.

conversion

Thus

of chain

into

cyclicderivatives

also affects

acid,NH2
y-amido-butyric

CH2

CH2. CH2

pyrrolidonI

frH-

CH2

is

COOH,

is

tasteless,

is

tasteless,

bitter,

-CO

CH2

CH2

CH2

COOH
.

5-amido-valerianic acid I

NH2
C
.

oxy-piperidon|
NH

Sarcosin

H2

is bitter.

CO

is slightly
sweet,

C JOOH

whereas

its

anhydride
CH3
CH2"

N"

CO
is bitter.

CO

"

N"

CH2

CH3

N(CH3)3.CH(C2H6).COOH
acid |
Trimethyl-amido-butyric

is sweet,

OH

the

anhydridebitter.
Sternbergascribes the

constitution.

bitter taste of the alkaloids to their

cyclic

AND

ODOUR

CONSTITUTION

CHEMICAL

II.

341

ODOUR.

knowledge of the correlation of odour and structure has

for the purpose of producingsynthetic
been mainly acquired
perfumes,
carried on in Germany and France.
In
an
largely
industry
the short sketch which follows the authors are mainly indebted to
Our

2,the former from

Georg Cohn1 and Zwaardemaker
side.
chemical,and the latter from the physiological

the works
the

The

of

most

condition for the

necessary

of
production

since it is found that bodies of low

substance is volatility,
"

associated with high molecular weight

generally
"

odorous

an

have

volatility
effect

no

But the molecular magnitude must

fall
olfactory
organs.
within certain limits ; frequently
those with low molecular weight
such as the volatile aldehydesof the aliphatic
series have
at all;
odours,whereas the highermembers have none
unpleasant
between these limits lie citral and citronellal (p.344),which are
of higher molecular
typicalscents,and the aromatic aldehydes,
odours.
weight,which also have pleasant
Some
importancemust also be ascribed to the concentration of
the odorous substance and most probablyto the nature of the
solvent. Such substances as vanillin,
cumarin,and ionone,
piperonal,
on

the

"

"

have

very

different odour when

they possess when

in perfumeryowe

much
their

in

diluted.

strongsolution
The

odour
pleasant

small variation in the concentration of

to that wiiich

natural

essentialoils used

to several

and
constituents,

bring about great

may
alterations in the odour of the oil itself. It is generally
stated that
cannot
artificial
benzaldehyde

one

be used for the

more

varieties
expensive

it from minute traces

of freeing
impossibility
acid and /2-naphthylamine
have no odour
of impurities.
Phenylacetic
but smell disagreeably
in the crystalline
when in solution.
condition,
This property has been
compared to the variation in colour
is dissolved in water,and
sometimes observed when
a solid dye-stuff
has been noted between the way in which odours
a further similarity
adhere to certain bodies like paper, woven
and the
materials,
,"c.,
process of dyeing.
of primary
1. The chemical constitution of a substance is clearly
in determining
its odour,but at presentlittleis known
importance
of the general
correlationbetween these two.
Followingthe analogy
certain Osmophore groups have been described,
with the dyes,
such
of scent,owing to the

'

1904.
Die Riechstoffe,

'

des Geruchs,1895.
Physiologic

GROUPS

OSMOPHOKE

342

hydroxyl(OH), aldehyde(CHO), ketone (.CO.),ether (.O.),

nitrile (CN), nitro (NO2), azoimide
(N3),which may condition
and such groups may
odour in various bodies previously
odourless,
odour.
or
unpleasant
obviously
give rise to substances of pleasant
is impossible
in the
the basis o" the osmophores
But a classification
on
is a classification
presentstate of our knowledge.Equallyimpossible

as

odour,as there are no words in any

the onlyterms
in use
languageby which odours may be described,
to some
other odour,such as
beingthose which pointa similarity
', vinous ',"c.
camphoraceous
2. Two or more
osmophoregroups may be presentin the same
another without materially
altering
body,or one may often replace
the odour; thus benzaldehyde,
benzonitrile,
nitrobenzene,
phenylazoimide,have all a very similar smell. The introduction of several
to an increase in the molecular
substituent groups, however,leading
based

the character of the

on

'

weight,may

for the observed diminution in the

account

of
intensity

the odour of the

derivative.
resulting
have a similar smell ; this is
3. Homologous derivatives usually
noticed in the case of the methyland ethylesters of salicylic
acid,
the corresponding
or
or the methyl and ethylethers of /3-naphthol,
di-derivatives of hydroquinone.
in the esters and ethers may
But the ethylgroup
lead to a
in the odour,whereas
diminution
the methyl derivatives
striking
ester of anthranilic acid,
scented (compare
are
p. 49). Thus the ethyl

1;2C"H4"(co6c2H5,
only a slightsmell ;
methyl ester has the odour
has

the

M0-butylester

none,

but the

of orange blossoms.
In the aromatic series the entrance
of a methyl group

into the

ringdoes
and

not

alterationin the odour

much

cause

nitro-toluene

are

very

Radicals

nitro-benzene

methylvanillin,
methylfrom which theyare derived.

very likethe substances

rich in carbon have a considerable influence

illustratedin the table

The

; thus

and
similar,

cumarin,smell

e.

has

on

on

odour,as

the next

page.
radical
it prohave
to
a
as
function,
amyl
special
duces
appears
uniform odour in the bodies into which it is introduced,

amyl-and diamyl-aniline.
amyl-methyl-ketone,
g. amyl-alcohol,
introduced into the
4. The halogensonly influence odour when

and
side-chains,

not

when

substituted

in the nucleus

of aromatic

and the chlorinated

brom-jtf-naphthol
-methyl-ether
have a similar smell to the parentsubstances.
benzaldebydes

derivatives; thus

INFLUENCE
5. Phenols

those with
groups,

olefine

6.

in several volatile oils.

of alcoholic and

radicals
Nitrogen-containing

odours,and

The

propenyl

carboxyl
group

substances.
phenolic
playan importantpart in

for this purpose

odour,and
than
importance

characteristic

343

the allylor
substituents,
especially

found

the odour
destroys

RADICALS

have

phenol ethers

and

are

NITROGEN

OF

the nitro group

mining
deter-

is of

more

the nitrile.

""0-propyl-phthalide,

CH.CH(CH8)2
CO
Phthalide

has

no

smell.

wo-propylidene-phthalide,

CH

C:C(OH3)2

C6H4""0
CO

CH.C4H9
butyl-phthalide,
C6H4"(
CO
all smell of

celery.

4-tolyl-acetylene,CH3
C6H4
.

C |CH,

1 : 4-ethyl-phenyl-acetylene,

C/2-H-5
Cg.H4
"

Fhenyl-acetylene
an

has

smell.
unpleasant
C6H5.C;CH

OH,

both smell of anise.

1

4-w0-propyl-phenyl-acetylene,
(CH3)2CH.C6H4.C;CH,

*-trimethyl-phenyl-acetylene,

(CH3)3C6H2.C;CH,
have

etherial smell.
pleasant

odours. The
extremelydisagreeable
Methylhigherhomologues of trinitro-benzene smell of musk.
of the
benzoate has the characteristic slightsmell of so many
""0-Nitriles generally
have

aromatic
blossom.

whereas the 1 : 4-amido derivative smells of orange

esters,
In

the

series of nitro derivatives

nitro group may be replaced

by the azoimide
odour of the original
substance.

smellingof musk a
the
without altering

PERFUMES

344

7. It is among
the higheralcohols and ketones,and especially
the
that the majorityof substances used in perfumeryis to
aldehydes,
be found.

each
from

The

class.

The

isolation and

essential

the

contains

followinglist
oils and

few

typicalexamplesof

identification of

such

substances

artificial production,
or

their

the

has been
synthesisof closelyallied derivatives,
developedwith
during the last twenty-five
great success
years, and has resulted
in an
industryof considerable importance:
"

Alcohols

1. Linalool

odour

resembles that of

mayflower

/OH

(CH3)2 C
.

CH.CH2

CH2

C^-CH

CH2

\CH3
2. Citronellol
"

(CH3)2 C

3. Geraniol

CH.CH2

ring structures
(lilac
odour).

Among

These alcohols
have

"

been

and

so

found

CH2

far

CH2OH
roses

"

C(CH3) : CH.CH2OH

borneol,menthol, terpineol
with

onlythose

in

"

found

are

roses

"

CH(CH3). CH2

"

atoms

CH2

....

(CH3)2 C
4.

CH.CH2

"

volatile oils

than

more

be

may

"

eightcarbon

converted

into

(seep. 122) and variations in odour obtained. Thus the

odour
of oil
linalool and geraniolesters of acetic acid have an
of bergamot. The esters of borneol all possess an odour similar to
diminishes with an increase in
the acetate,the intensity
of which
the molecular weight of the acid. The acetate of ^-borneol is present
esters

in oil of

hemlock, valerian,
kesso,"c.

Aldehydes
1. Citral

or

2. Cinnamic

geranial
(CH3)2C: CH.CH2
aldehyde
.

odour

CH2

C(CH3) : CH.CHO
cinnamon
"

C6H6CH:

"

"

"

"

CH.CHO
vanilla

3. Vanillin

"

/CHO

C6H
4.

resembles that of lemons

/OCH3 8

Piperonal

"

!HO

"

"

heliotrope

PERFUMES
Ketones

1.

Methyl-ethyl-acetone
.

odour resembles that of peppermint

cyclo-hexanone,
e.g. pulegone
(odourof caraway)
Camphor,fenchone,carvone

2. Various
3.

345

derivatives of

4. lonone

odour resembles that of fresh violets

of
5. Various substitution products
Phenols

and

1. Carvacrol

"

Phenol-ethers

acetophenone,
C6H5.CO.CH3.

odour resembles that of

/OH

thyme

C6H/CH3 3
\C3H76
2.

Thymol

/OH

s
r" TJ
CTJ
6"13^-U3"17

\"H3
ether
3. 0-naphthol-methyl

thyme

"

"

oilof neroli

"

C10H7.O.CH3
4.

oil of sassafras

Safrol

L3\

'

\CH2.CH;CH2 4

5.

oil of cloves

Eugenol

/OHH
C.HQ^-0 OCH,

l"
2
4

8. Isomeric

relationships
naturally
play an importantpart in
teristics
characodour,as theydo with regardto other physical
conditioning
and
of organiccompounds, Thus ^o-vanillin is scentless,
in the artificial
musks

and in many

"

e.

g. in

trinitro-i/r-butyl-ethyl-benzo

similar derivatives

havingthe

same

odour,the

three

INFLUENCE

346

nitro groups

placed,otherwise
symmetrically

be

must

RELATIONSHIPS

ISOMERIC

OF

this

teristic
charac-

is lost.
The

1:2

nucleus
1

and

1:4

(but seldom

substituted

are

in

the

smell; the

1:

isomer

1:3

CO.C6H4

is without

the

benzene

artificial scents.

the

of

many

:4-methoxy-acetophenone,
CH3

in
1:3) positions

scent.

Thus

OCH3, has a pleasant

l:2-amido-acetophenone,
.

2-amido-benzaldehyde,
JHO

have strong odours,whereas

2-nitro-phenol

and

1:3

and

derivatives have

1:4

mentioned

this

In

none.

the

corresponding

connexion

it may

be

that

and
anis-aldealthough salicyl
(orthoderivative)
in nature, neither the
hydes (para) both occur
corresponding
its
derivatives
found.
nor
are
0z-oxy-benzaldehyde
alter
9. Reduction
a
scent,but does not render it disagreeable,
may
in the followingcases.
Cinnamic
seen
as
aldehyde,

C6H5CH:CH.CHO,
smells of cinnamon.

The

reduced

derivative,
C6H5 CH2
.

has

most

characteristic odour

of lilac and
o

has the odour

of

"

CH2

CHO,

Coumarin

jasmine.

co

woodruff,also noticeable in melilotin

/O

"

CO

CflH4
Unsatnrated

generallyhave powerful odours.

pleasant
Triply-linkedcarbon systems are frequentlyassociated with unand
thus
odours,
phenyl-propiol-aldehyde,
C6H6C C.CHO,
1 : 2-nitro-phenyl-acetylene,
able.
NO2 C6H4 C | CH, are most disagree10.

substances

"

This

which

may

be contrasted

with

the

effect of the

double

bond,

usuallygives rise to bodies with pleasantsmells; compare

in storax
is found
which
oil,and various
styrene,C6H6CH:CH2,
other instance* which
have been previously
given.

348

CRITICISM

OF

LOEWS

THEORY

the colour passes from red to violet-red,

and in
by methyl radicals,
hexa-methylrosaniline becomes violet-blue. The replacement
of hydrogenatoms by ethylor phenylgroups intensifiesthis effect.
Hexa-ethylrosaniline is violet with a blue nuance, and the triphenylsubstitution productis blue.
Allusion has already
been inade (p.22) to the auxochrome groups
described by Witt.
These are of two kinds,basic and acid,so that
from each chromogen two series of analogousdyes
may often be
thus
obtained,

"

Acid

Dyes.

Auxochrome

Basic

(OH).

Auxochrome

Oxy-azo-benzene.
Bioxy-azo-benzene.

Diamido-azo-benzene.

Rosolic acid.

Rosaniline.

Thionol.

Thionol ine.

introduction of
to
will,

group

(NH2).

Amido-azo-benzene.

Aposafranone,
The

Dyes.

some

Aposafranine.
than

more

one

acid

or

basic auxochrome

of the
extent,tend to deepen the intensity

colour.
the

Largelyon
stuffs Ehrlich

which

groundsof

has criticizedthe

allusion has been

evidence
follows

he

his observations

has

collected

on

in

'

substitution
earlier

an

this

the action of

theoryof

chapter(p.17).

pointmay

be

dye-

Loew,

summarized

to

The
as

dyesthe amido group, or groups, undergo

and
interaction with substances containing
a
aldehyderadicals,
changeof colour is produced. Thus red fuchsin becomes violet when
treated with an aldehyde.Now, in the case
of the substituting
Loew
poisons,
supposedthat an interaction took placebetween
these and amido or aldehydegroups presentin the livingprotoplasm.
:

"

But

In

made

'

on

some

basic

Ehrlich has

never

been

able to observe

that

colour

changesof the type mentioned occur in the body, either with this
basic dye which reacts with aldehyde
groups, or with certain other
which
azonium base obtained from safranine)
Kehrmann's
dyes(e.g.
acteristic
amido groups, causingcharinteract with substances containing
changesof colour.
which very readily
such as anilin and benzaldehyde,
Other bodies,
have also been employed,but no
condense to benzylidene-anilin,
substance,or
derivative of either anilin and an aldehydecontaining
1

Studies in Immunity,

xxxiv.
1906,jchap.

HYPOTHESES

EHRLICH'S
of

benzaldehydeand

from

amido

an

group,

349

has

ever

been

extracted

the tissues.

employedthe aromatic dyes to elucidate the

and drugs in the animal body,or, in other
distribution of poisons
words, to throw lighton the selective action of cells. Thus he
with ;?0ra-phenylene-diainme,
which
shows that the brown staining
of
the
round the central tendon
is most marked
diaphragm,and the
and tongue,is due to the more
muscles of the eye, larynx,,
copious
dance
blood supplyof these muscles,that is,to the presence of an abunin these situations the motor
of oxygen.
nerve
Similarly,
with
blue.
stained
methylene
endingswere more intensely
From observations of this character Ehrlich deduces the hypothesis
stances
that the various cellsof the body take up different chemical subin a greateror less degreeaccordingto their 'chemical
Ehrlich

also

has

environment
"c.

'

absence

"

Thus

or

nerve

action,
presence of oxygen, alkaline or acid reenvironending,if in a neutral or acid ment,

but when the surrounding

will take up the dye alizarin,
reaction
is alkaline it is stained by quitda different substance,
namely,

methyleneblue.
It is possible
to modify the
addition of other substances

distribution of

; thus

the

dye-stuff
by the
of the nerve
endings
staining
a

of methyleneblue,which
intra vitam,may
be
occurs
by means
preventedby the addition of the soluble acid dye called orange
for the methylene
that is,has a strongeraffinity
green. The latter,
is comblue than the nerve
pounded
endingspossess. On this principle

the well-known
The

introduction of

Triacid

endings(e.
g.
blue

taste

buds)in

stain.

body may

second

in the tissues; thus Bismarck

'

brown
the

also render

does not

frog,but

the

dye active
stain peripheral
nerve
addition of methylene
a

endingsto take a double colour. In permanent

the
the
blue
stain
and
brown
quicklyfades,
preparations
only
remains. Ehrlich believes that this principle
underlies many of the
'abnormal
in inherited or acquired
actions of drugs,especially
'.
hyper-sensitiveness
Besides these somewhat
theoretical results,
observations on the
action of the organicdye-stuffs
have also,of recent
physiological
value; and it is quite
years, begun to lead to results of practical
that importantdevelopments
in therapeutics
result
possible
may
from a further studyof these derivatives. Many possess a remarkable
bactericidal action,
but it has not as yet provedpossible
to
employ them againstordinarybacterial infections. The parasitic
causes

the

nerve

350

PICRIC

ACID

trypanosomes have,however,been shown

both in

animals
experimental

and

in

to be

markedlyinfluenced

by treatment with certain

such as malachite green G (seep. 354),and trypan red
dye-stuffs,
(seep. 352). These bodies are thought to act by favouringthe
developmentof immunizingsubstances within the organism.
Malachite
has also been
employed by F. Loeffler for
green
colonies of B. coli and B. typhiabdominalis ; the growth
separating
of the former organism was
prevented
by an admixture of this dye
with the culture medium, the colonies of the latter remaining
man

unaffected.

Class

NITKO
Picric

Acid,

DERIVATIVES

I.
OF

C6H2(NO2)3OH,and

PHENOLS.

THE

Dinitro-cresol"

CH3

OH

introduction of the nitro group

into

creases
phenolicsubstances intoxic action.
Both
are
powerfulblood
and respiratory
renal irritants,
the
depressants,
poisons,
especially
The group
of
latter,possibly
owing to its greater solubility.
naphtholnitro-derivativesincludes Martius yellow,
The

and
the antiseptic

OH

which
of

is similar in its action to dinitro-cresol. The introduction

in the formation of dinitroresulting
grouping,
sulphonic

acid,
l-naphthol-7-sulphonic
OH

SO2OH

naphtholyellowS, has

the usual effect of

the toxicity.
destroying

AZO-DYES
Anrantia

or

Kaiser

351

is the ammonium

Yellow

sodium

or

salt of

hexa-nitro-diphenylamine,

NH/C6H2(N03)3

H\C6H2(N03)3

is stated to have

and

toxic

properties.
Class

Azo

The

azo-dyesare

II.

DYES.

class of substances

contain

as

chromo-

previouslymentioned, azo-benzene
itself,
C6H5.N:N.C6H6, although possessinga red colour,is not
of auxochrome
a dye-stuff
; by the entrance
groups, such as hydroxyl
and amido, the colouring
power
appears, and the shade is modified.
The simplest
like most simpledyes,are yellow,
and their
azo-dyes,
the nature
of the auxochrome
tint is dependentfirstly
on
group, and
secondlyon that of the carbon complex. They may be made to pass
and in some
Blue azo-dyes
to brown.
cases
through red to violet,
far only been obtained from those substances containing
have
so
the

phore

.N:N.

which

group

As

in the molecule.
several azo-groups
Those containing
the benzene
brown ; those containingthe naphnucleus are yellow,orange
or
thalene,

violetby the entrance of several of the latter nuclei,

black dyes are produced.
is extremelyeasy.
generalrule their technical preparation
red ;

blue

or

As

Aniline,for instance,is diazotized

the solution

is added

to

an

in the usual

and

way,

alkaline solution of the

when

phenol or

its

or
sulphonate,
oxy-azo-benzene
Tropaeolin ,Y. is formed
1. C6H5NH2
C6H6N:NC1.
NaCl + C6H5N : N.C6H4OH.
2. C6H6N : N.C1 + C6H5ONa
"

-"

or
a/3-naphphenolmay be replacedby resorcin,
various sulphonates,
acid. Sulphanilic
acid
or
salicylic

In this reaction

thol,their
and

benzidine

C6H4NH2

be used in
may
of dye-stuffs
can
The
so

easy.

and consequently
a
placeof aniline,
largenumber
be obtained.

combination

Some,

such

of diazo
as

bodies with

amines,as
1 : 3-phenylene-diamine,

rule,is

not

AZO-DYES

352

is
in neutral aqueous solution;thus chrysoidin
directly
solutions of diazo-benzene chloride
obtained by mixing equivalent
and l:3-phenylene-diamine,

combine

C6H5.N

N.C1 +

C.H4

in other cases,

But

as

solution
diphenylamine,

with

HC1.

C6H5N :N.C3H+
in

methylated

with a strongsolution of the diazo derivative

and treatment
spirits
is requisite.
The
acid group, are, as might
a sulphonic
containing
azo-dyes,
used for
but
toxic substances,1and
be expected,
are
slightly
Bordeaux
wines (Rouge soluble,
B, Ponceau R, Orange 1,
colouring
Jaune

Those
solide).

without

such groups

have

also,as

rule,but

slight
poisonous
properties.
C6H5

Chrysoidin

and

albuminuria
producesslight
In

N.C6H3

dilute solution it

has toxic

marked

reduction of

cholera
agglutinates

very
It has antiseptic
but
properties,
Bismarck

HC1

no

and

body-weight.
other

vibrios.

action.
specific

C.

brown

properties.
OH

/"

CH.N:N"

Sudani

~\

65

o
but
albuminuria,
slight
produces

the m-mtro

compoundis non-toxic.

N02

"OH
_N

.-N"

/"

"\

o
Trypan

Bed

is

benzidine

dye

obtained from benzidine-mono-

acid by diazotization and combination

with
sulphonic
salt of the disulphonic
acid of /3-naphthylamine.
It has
constitutional formula

p.

For

sodium

the following

"

of dye-stuffs,
toxicity
see

892, 1907.

the

G. M. Meyer, American

Chem.Soc.. vol. 29,

AZO-DYES

NH2

SO2ONa
O2ONa

NH2

SO2ONa

353

C6H3" C6H4"

N"

SO2ONa

N-

SO2ONa

8O2ONa
Ehrlich and

with this substance

Shiga experimented

on

mice

1 per cent, solutions were

injected
trypanosomiasis.
This had a very marked
in doses of -5 to 1-0 c.c.
subcutaneously
which the
though temporary destructive action on the parasites,
effect on the body of the host,
observers attributed to a special
substances. Animals
leadingto the productionof parasiticidal
to a greatextent against
after cure were protected
a second infection.
by Nicolle and Mesnil),
thoughdiffering
Trypan Blue (prepared

infected with

in chemical
on

has an action similar to that of trypan red

constitution,
the trypanosomes
; Ehrlich states that strainsrendered resistant to

the

one

are

also immune

to the

other,thoughtheymay

be

destroyed

by fuchsin or by the use of atoxyl(the sodium salt of para

amido-phenyl-arsenic
acid).Thus in Ehrlich's words l this specific
resistanceconstitutesa cribrum therapeuticum
or therapeutic
sieve,
by
which any new
of
this
He
classified.
remedy
type may be
possesses
strain of trypanosomeswhich are resistantto all these pharmacoa
infected with this strain is
dynamic agents; and thus,if a mouse
cured by any new
drug,the latter cannot belongto one of these

Ponceau

C6H5.N:N

4 G.B.

is non-toxic.

BO2ONa
Di-phenylamine
orange
C6H

1:4

but
producesalbuminuria,
on

N:N.C6H4.NH.C6H5
otherwise has onlyslight
toxic

the other hand its isomer Metanil

action ;

yellow

/SCXONa
1:3
C6H4"
XN:N.C6H4.NH.C6H5
is toxic for

dogsin

doses of 20 gms. after 4

due to the presence of free

1

Harben

days. This
diphenylamine.

Lecture,1907,Lancet,ii,1907,p.
A

351.

is probably

DI-

354

AND

TRI-PHENYL-METHANE

Class

Di-

DYES

III.

TKI-PHENYL-METHANE

AND

DYES.

diphenyl-methane
dyes is Fyoktanin, in its pure
Auramin
O (mixedwith dextrin it goes by the name
of imido-tetramethylI,II,III). It is the hydrochloride

the

Among

state termed
of Auramin

methane
diamido-diphenyl

"

(CH8)2N.CeH4C.C6H4N(CH3)2HC1
.

NH
Brilliant

Green,

also known

as

malachite green

G, and diamond

of tetraethyl-di-jtjara-am
ethylgreen, is the sulphate
triphenyl-carbidride,

green

G,

or

'6AJ^

It has

alreadybeen mentioned,owing to the fact that it has been

employedby Wendelstadt to destroythe trypanosomesof tse-tse
flydisease.
Methyl

is

Violet

mixture

of the

of the
hydrochlorides

hexa-

methyl-pararosaniline,

penta-methyl-benzyl-pararosaniline
antiseptic
; it is a stronger
than the yellowpyoktaninand relatively
less toxic. It has been
used locally
for inoperable
cancer.
A largenumber
similar
of
derivatives have been studied and
found to have antiseptic
which
differ but slightly
from
properties,
those of the parentdyes.
has a constitution expressed
Rosaniline
Fnchsin
or
by the
formula
following
and

"

NH2.C2H4X

NH2\rH)
CH/^s/

does not
or jt^zra-Magenta (pararosaniline)
7?-Fuchsin
methyl group.
The antiseptic
been
powers of these bodies have never
be in direct relation with their stainingproperties,
but
the presence of the aromatic nuclei.
on
dependentirely
Eosin, the alkali salt of

Noguchi to have

the power

has been
tetrabromfluorescein,
of

certain toxins
neutralizing

contain

shown

to

appear

to

shown

by

occurring

APPENDIX
PAGE
various

20.

The

followingtable,showing

ammonium

bases, has

been

the

modified

of

curare-like

action

from

given by

one

and Loos.
In place of the minimum
dose of each
H. Hildebrandt
substance capable of producing complete paralysisper kilo, body-

weight, curarine has

assignedto the others.
The

minimum

been

taken

unity

as

dose of curarine is "008

m.

values
proportional

and

gm.

Curarine
.

...

1
.

1.

100

'"
V
Methyl-strychnine
sulphate
acid
Methyl ester of strychnine-iodoacetic
Ethyl-strychnine
sulphate
"""
2. Benzyl-atropine
bromide
3. Benzyl-brucine
bromide
Methyl-brucineiodide
4. Methyl cinchonine sulphate
Methyl ester of cinchonine-iodoacetic acid
Amyl-cinchonine iodide
5. Tetra-methyl-ammonium iodide
6.
iodide
Benzyl-nicotine
Methyl-nicotinesulphate
/..-.*.
iodide
*'
Ethyl-nicotine
;
7.
"""".
Benzyl-tropineiodide
acid
Methyl ester of tropine-iodoacetic
.

"

"

.*

"

""

312

..

"

187

75

187

"

"

312
312

.....

"

"

'

625
625
3750

375

12500

'

"

18750

PAGE
do not
showed

54. There

produce

are

certain number

curare-like

effect.

Thus

of ammonium

Fraser

7500
12500

and

bases which
Crum

Brown

attached
to
methyl and halogen groups were
of
nicotine
there
was
curare
no
pyrrolidinering
action ; this appeared,however, when
the nitrogen in the pyridine
Loos
made
showed
was
ring
quinquevalent.
years ago that
many
the intensity
of the curare-like action depended largelyon the nature
of the added
Thus
ethyl strychninesulphate,ethyl
alkyl groups.
less
nicotine sulphate,and amyl cinchonine sulphateare respectively
The chlormethylate
active than the correspondingmethyl-sulphates.
of papaverine(Pohl)and the correspondingderivatives of cotarnine and
The
variety of
hydrastinine(Fiihner)have no action whatever.
difference to the productionof the curare
effect,
no
halogen makes
the
if
takes
differences
but considerable
noted
are
place of
oxygen
the halogen element (Hildebrandt).

the

that when

the

nitrogenin the

PAGE

64.

Hildebrandt

(salicylic
acid)leaves

the

states

that

whereas

body conjugated with

o-oxybenzoic acid
glycine,the para

APPENDIX

357

compound is eliminated as a glycuronicacid

chem. 1904, Bd. xliii).
physiol.
PAGE

207.

Kobert

has

derivative

investigatedvarious

results
antipyrinetype with the following

3-Antipyrineaccordingto

substances of the

"

Michaelis is constituted
CO"

(Zeitschr.

as

follows

"

N.CH,

CH

CH3.C
It is

active

more

poison than the ordinary5-antipyrine

; this is

traceable
apparently
directly

bonyl
On

N.C6H6

to the different way

in which

the

car-

is linked in the two

group

the other hand

substances.
formulated
iso-antipyrine,

C6H5.C

by

Michaelis

N.CH3

.CHa
is less toxic than

but
3-antipyrine,

whereas

pyramidon has
3-pyramidon

more

so

than

ordinaryantipyrine
;
antipyrine,

powerful action than

more

CO"

N.CH3

(CH3)2N.C
CH3.C
has

N.C6H5

less toxic than the parent

is much
slighteraction,
and, further,
of the N(CH3)2
that
is
to say, the entrance
substance,3-antipyrine
;
whereas
increases the action,
a decrease
group into ordinaryantipyrine
follows its introduction into 3-antipyrine
into
or
tso-antipyrine.
a

PAGE

in the

272.

body

PAGE

to

288.

Ftihner

has

is oxidized
shown
that quinoline
recently
thus exactly
resembling aniline.
jpara-oxy-quinoline,

Hydroberberineis

stereo-isomer of canadine,an
quantitiesin Hydrastis canadensis ;
is structurally
very similar to the
substitution
of
methyl
product
hydroberberine (F. Meyer), and is
inactive. The
physiologically
correspondingethyl derivative slows
the respiration
the blood
and pulse rate,but has no influence on

alkaloid

occurringin very small

corydaline,from Corydaliscava,

pressure

(Meyer and Heinz).

the

APPENDIX

358

differences
is

taste

on

whilst

bitter,

Warburg)

tasteless,

almost

whereas

is

when

which

stereo-chemical
of

variety

sweet

prepared

which

Fischer

(E.
in

occurring

artificially

the

of

Zaew-rotatory

variety

dextro-rotatory

tryptophane,

influence

the
the

leucin,

(1)

are:

the

(2)

of

examples

Further

338.

PAGE

the

and
is

body

substance

is

aromatic

ring

sweet

(Ellinger).
346.

PAGE

Perkin

necessarily

not

He

shown

has

produce
the

instances

that
alteration

any

aliphatic

of

closure

terpineol

an

the

in

of

odour

does

substance.

"

CH
-

CH/

H3C"
and

cyclic

corresponding

the

body

xjCH

CH2\

/C

"CH.C""CH.C-CH3

CH3.O
\CH"

with

regard
There

malachite

has

action

decreased
and

green

investigated
on

in

activity
in

derivatives

oxy

The
effect
azo-green

introduction
in

of

are

almost

Berl.

the

is

action

di-

tri-oxy

and

or

thus

has

chrome-

trypanocide

much

violet,

inactive.

Klin.

Wochenschr.

Nos.

on

the

other
than

violet.

methyl

radicals

of

derivatives
;

powerful

more

green

carboxyl

the

diminishing

rosanilines

substituted

or^o-oxy-hexamethyl-rosaniline

malachite

of

various

trypanosomes.

trimethoxy-pararosaniline

hand,
the

their

to

is

Ehrlich

352.

PAGE

\O

CH

9-12,

1907.

more

chrome-blue

marked
and

INDEX
Acrolein, 50.

139.

Abrastol,

action
Acetal, physiological

Acetaldehyde,

of,104.

derivatives,319.

"

dation
oxamide, partial oxibody of,74.
Acetamido-phenol -benzoate,195.
Acetanilide,181.
tional
of constituAcetic acid,determination
formula, 10 ; preparation of,
117 ; reactions with, in body, 66.
Acetoacetic
acid,113.
Acetone, 112, 113.
diethyl-sulphone, 114.
Acetoneamine
derivatives,comparison
with ecgonine, 306.
Acetophenone, 114.
Acetyl chloride,reactions of,36.
Acetyl-codeine,294.
properties, 27 ;
Acetylene, chemical
metallic
derivatives
logical
of, 28 ; physioaction of,45 ; preparation of,
33, 34.
50.
di-iodo-,
147.
Acetyl-pyrogallol,
ing
radical,120 ; introduction of, durof substances
through
passage
Acetamide

and

in

"

324.
Aescnlin,
202.
Agathin,
Ag-urin, 228.

Aitken, on smell,332.
Alcaptonuria, 75.
87.
Alcohols,aliphatic,classification,
81 ; taste of,
Alcohols
and derivatives,
334.

characteristics,90 ;
Alcohols, chemical
of
action
physiological
comparison
of
primary, 92 ; comparison of
son
primary and secondary,52 ; compariof physiological
action of primary,
secondary, and tertiary,92; effect
on
physiologicalaction of replacement
of hydrogen of OH
group, 47 ;
of preparation,88 ;
general methods
general physiologicalproperties,91 ;
general properties,89 ; polyhydric,
90 ; secondary and
tertiarypreparation
of, 89 ; used in perfumery,
344.

"

body,

65.

Acetyl -salicyclic
acid, 158.
Acid-amides, physiologicalproperties
of, 124, 178 ; preparation and properties,
123.
Acid

radicals,introduction
basic substances,120.
dissociation
Acid, salicylic,
Acidol,

of,

into

of,16.

178.

Acids, amido-, taste of,335.

aromatic, physiologicalaction,119,
120 ; syntheseswith glycine in body,

"

63.

halogen

"

substitution

products

of

121, 122.
aliphatic,
"

"

hydroxy aromatic, 149.

physiological effect following
of

in

COOH

placement
re-

group,

4o"
"

physiologicalpropertiesof the, 118;

preparation and properties of, 117,
118.

Acoine,
Aconitic

318.

Adrenalone,

124.

Acetamide,

317.

Adrenalin,

preparation of,36.

Aldehydes,
phite on,
"

action

of sodium

bi-sul-

106.

aromatic, physiologicalaction,107

phatic,
products of ali108 ; physiologicalaction of,
107 ; polymerization of, 107 ; preparation
of, 105 ; propertiesof,104,
105 ; used in perfumery, 344.
87.
Aliphatic alcohols,classification,
aromatic
derivatives,
Aliphatic and
subdivisions,13.
Aliphatic and aromatic series,relative
pharmacological action,20.
Aliphatic derivatives,general methods
of synthesis,35 ; synthesis from
hols,
alcoacetic acid, 36 ; synthesis from
36 ; synthesis from
halogen
derivatives,37.
Aliphatic dibasic acids,taste of, 338.
Aliphatic hydrocarbons, 24 ; physiological
45.
characteristics,
Alkali
iodides,
organic substitutes,

halogen

substitution

167.
314.

acid,51.
Aconitinc, 121.

Alkaloids,233

; action

of

substituting

245 ;
alkyl substituents,
groups,
action of, 245 ; bitter taste of, 340 ;

360

INDEX

classification of,244 ; curare

action of
quinquevalent nitrogen derivatives,
istics,
character54 ; general physiological
243 ; Loew's
specialpoisons,
249 ; opium, 288 ; opium, containing
tso-quinoline ring, 299 ; pyridine

of, 249.
group
Alkyl and oxy-alkylderivatives

of uric

acid,225.
ureas, preparation of,215.
50.
Allyl-alcohol,
sulphide, 127.
thiourea,218.
trimethyl ammonium
hydrate,51.

"

"

"

"

Allylamine,50.
Aloin, 329.
Alypin, 314.
do-ace

Ami

"

in

body,

body

with

"

of,

63.

of

derivatives

benzoic

jp-brom -benzene,

63 ;

acid,

"

action

of

nitrous

acid

on,

89.
"

"

"

"

Amylene
hydrate,
312.
Anaesthesin,
Anaesthetic

108.

Aminoform,

derivatives
of

mary
of, 171 ; sumphysiological action
of,

207.

physiologicalpropertiesof, 177.

Ammonium
20.

93.

of

action

benzoic

acid

derivatives,310.
of glycocoll derivatives
of
power
benzoic acids,311.
Anaesthetics
tion
and
hypnotics, distincbetween, 81; main
of,
group
"

96.

Anesin,
Aneson,

96, 315.

Anil

ides,physiologicalaction of,179 ;
preparation of, 176 ; stabilityof,

176.
Aniline

and
of

parison
phenol derivatives,comphysiologicalaction of,

210.
"

and

thiophene,increased toxicityon
of alkyls,46.
methyl and
ethyl, physiological
propertiesof,178.
181.
Aniline, derivatives,
physiologicalaction of,181.
tives,
primary and secondary derivaintroduction

"

47.

206.

Anilopyrine,

Anisanilide,182.
Anisol, 129.
163.

Annidalin,

Anthracene, 30.
329
Anthraquinone derivatives,

bases, curareform

action,

gatives,
; pur-

328.
181.

Antifebrin,

Antiosin,

167.
group

of

synthetic,

171.

Antipyrine,

171 ; effect produced

classification,
of acidic groups,
by entrance
176,
177 ; general methods
of preparation,
172 ; physiological
propertiesof,177 ;
preparation
of, 37, 38; primary,
171 ; primary, secondary,
and tertiary
reactions
of, 175 ; propertiesof,175 ;
tertiary,171.

U,

"

of,

aromatic,preparation of,173, 174.

Ammonia,

"

Amyl-acetate, 122.
with
local
alcohol, derivatives
anaesthetic
action,314.
nitrite,100.
radical,influence on odour, 342.

Antipyretics,main

aliphatic,physiologicalaction
47.

"

191.

Amyg-dophenin,

63 ;

chlorbenzoic

acid,63 ; cuminic
acids,63 ; mesitylenic acid,63 ; naphthoic acids, 63 ;
nitrobenzoic
acid, 63 ; p-nitro-tolu63 ; phenyl acetic
acid, 64 ;
ene,
salicylic
acid,63 ; xylene, 63.
syntheses with, in body, 56.
Amido-acids, aliphatic,taste of, 335 ;
aromatic, taste of,336 ; oxidation of,
in body, 74 ; 7 taste of,340.
Amido-benzoic
of urea
acid,formation
derivative
in body, 64.
a-Amido-cinnamic
acid, oxidation of,
in body, 75.
Amido-dibasic
acids,taste of,338.
of, 184 ;
p-Amido-phenol, derivatives
types of derivatives,186.
Amido-salicylicacid,formation of urea
derivative
in body, 64.
Amido-valerianic
acid,taste of,335.

Amines,

324.

Amyffdalin,

81.

derivatives

acid,

formation
(glycine),
in

compounds, quaternary,
physiologicalaction of,179.

tamide, 124.

Amido-acetic
formed

Ammonium

"

"

48, 2O4.

chloral,111.
physiologicalaction

of, 204, 205,

209.

preparationof,202.
acid salts of,205.
salicylic
Antiseptics,aromatic, 128.
containing iodine,161 : comparison
of,167.

"

"

"

Antispasmin,

301.

Antithermin,
Anytin, 169.

201.

Anytols, 169.
Apocodeiue,
301, 302.
Apolysin, 192.
Apomorphine,

301.

Arabino-chloralose,111.

INDEX

361

Benzaldehyde, preparationof,105.
Benzamide, 124.
Benzanilide, 182.
Aristoquin, 279, 280.
a
ction
Aromatic
tional
of constituof,
Benzene, determination
acids,physiological
formula,,11, 12.
119, 120.
128.
antiseptics,
Benzene-derivatives,comparison of
phuric
action of nitric and sultoxicity of isomers, 52; different
derivatives,
acid on, 40 ; outline of syntypes of,43.
thetic
Benzene
methods
for preparation of,
homologues,oxidation of,30 ;
reduction
40 ; oxidation
of in organism, 75.
tion,
of, 31 ; physiologicalac46 ; preparation of, 33 ; synesters of halogen acids,99.
thesis
halogen derivatives, preparation
of,42.
from
40
Benzene
diazo-compounds,
hydrocarbons, 28; nature of
; stability
double
bonds
of,99.
in, 28, 29.
Benzene
istics
hydrocarbons, preparation from
nucleus, negative character40.
diazo-derivatives,
of,29.
hydroxy acids,149.
Benzene, physiologicalaction of, 45 ;
128.
sources
hydroxyl derivatives,
of, 30 ; stabilityof ring
ketones,preparationof,42.
complex, 30.
nitro derivatives, 101.
Benzene
sulphonic acids,preparation
substances
oxidized
in body :
line,
aniof,41.
78 ; benzene, 76; benzidine,78;
Benzenes, di-oxy,taste of,339.
76; di-phenyl, 78; ethyl- Benzidine, not oxidized in body, 78 ;
cymene,
value in dye industry, 351.
benzene, 76; indol,78; naphthalene,
76 ;
Benzoic acid, 149 ; derivatives,with
nitro-toluene, 77 ; phenyllocal anaesthetic
methane, 78 ; phenyl-propionicacid,
action,310.
77 ; propyl-benzene, 76 ; toluene,
Benzo-naphthol,139.
Arbuttn,
Aristol,

S23.

163.

"

"

"

"

"

"

"

"

"

"

"

76.
"

substances,physiologicalaction
introduction

119.
Arsonium

of COOH

lowing
fol-

group,

bases,physiologicalaction,

54.
Asaprol,

139.

and
Asparagine, dextro,

difference
toevo,

in taste,53.
Aspirin, 158.

Asymmetric

carbon

264

Atropine,

atom, theory of,5.

Benzosal, 144.
158.
Benzosalin,
323.
Benzoyl-arbutin,
180.
Benzoyl-lupinene,
Benzoyl-morphine,296.

Benzoyl radical,120.
taste of,335.
Benzoyl-salicin,
Benzylamine, 173.
parison,
Benzyl chloride andchlortoluene, com-

central actions

comparison with
of,265

of,267 ;
stitution
cocaine,266 ; con-

; effect

on

eye

pared
com-

with
cocaine, 270 ; mydriatic
ings
endaction,270 ; paralysisof nerve
to involuntary muscle, 267 ;
nerve
paralysisof sensory
endings
caused
by, 271 ; physiologicalaction
dependent on two opticalisomers,
271 ; physiologicalaction of, 265 ;
316.
substitutes,
Auramin
O, 354.
351.

Aurantia,
Auxochrome

126.
Benzonitrile,
Benzophenone, 114.

43.

Betaine, 178.
Betol, 139.

Bile, action of,55.

B ism ark brown, 352.
Bisulphide of carbon, 127.
of toxicity of
Bokorny, comparison
benzene
isomers, 52.
Borneol, glycuronic acid derivatives
of,62.
Bredig on colloidal solutions,86.
Brilliant

of

green,

Witt, 348.
groups
1.
Avogadro's hypothesis,

Brom-acetic

Azo-dyes, 351.
physiologicalaction of,352.

Bromalin,

"

Bactericidal

action

of

dyes,349.

Baglioni,theory of narcosis,86.
Bauman
and Kast on sulphonals,114,
115.

Bechhold
of

and

Ehrlich,antisepticvalue

phenols, 134.

287.

Berberlne,

Bromal,

354.

acid, 122.

109.
98.

Brom-benzene, 99.
Bromine, derivatives of urea, 217.
Bromine, organic preparations of, for
epilepsy,98.
98.
Bromipin,
98.
Broxnoform,
217.
Bromural,
281.
Brucine,

362

INDEX

Brunton

and

Cash,

ammonium

pounds,
com-

20.

Butyl-amide, 124.
Butyl-chloral,109.
reduction

"

body, 79.

of, in

163.
tso-Butyl-o-cresol,
Butyric acid,119.

phenols, antisepticaction
of,134.
Chlorine,physiologicalcharacteristics
followingentrance of,95.
Chloroform,
96, 97.
Chloroform

acetone,

Caffeine, 227.

Chlor-toluene
of introduction

group, 92.
Cahn
and
Hepp,

of

(OH)

and

benzylchloride,

comparison, 43.

Choline,51.
aniline

derivatives,

Chromium

181.

oxychloride,preparation of
aldehyde, 105.

aromatic

Camphor, glycuronic acid

derivatives

of,62.
Carbamic

315.

Chloroform, 'delayed poisoning,'97;

fall of temperature after narcotic
doses,16.

126.
Butyronitrile,

Caffeine,effect

Chlorinated

328.

Chrysin,

Chrysoidin, 352.
esters of

guaiacol,143.
Chrysophanic
acid, 328.
Cinchona
Carbon-bisulphide,127.
alkaloids,271.
Carbon, tendency to self-combination, Cinchonine, oxidation of
7.
Carbon
Carbonic

97.
tetrachloride,
derivatives
acid,ammonia

Cinchonine

of,

213.

Carbostyril,synthesiswith glycuronic
acid,61.
Carvacrol,130.
Cash
and
Dunstan, on nitrous esters.
100.

Citric

sure,
pres-

Cellotropin,

323.

derivatives

of

oxidation

in

phenetidin,

views,

Environment,'

262

acids,physiological properties
of,121.
Chloral, 108, 109.
Chloral-acetophenone,110.
110.
Chloral-alcoholate,
110.

110.

of urochloralic acid
Chloral,formation
in body, 60 ; reduction
of,in body, 79.
Chloral-hydrate,106.
production of surgicalanaesthesia,

"

81.

Codeine,
"

Chloralose, 111.

Chlorbenzene, 99.
physiologicalaction of,
Chlor-caffeine,
95.

96, 315.
carbon, physiological
of, 95.

Chloretone,
Chlorides

of

(CH3COO)

group,

'

294.

acetyl derivative of, 294 ; chloride

of,296.
86.
Colloidal solutions,
Compound radicals,theory of,1.
252.

Conhydrine,

Coniceines,252.
Coniferin,

-urethane,110.

of
of

'

Ehrlich's

Chloral-ammonia, 111.
Chloral-antipyrine,111.

action

258.

(C6H,COO) group,
263 :
anaesthiophore group, 264 ;
classification of physiological
action,
258 ; comparison with atropine, 266 ;
ence
derivatives,261 ; dextro,laevo,differof
in action of, 53 ; elevation
temperature effect,260 ; mydriatic
action
of, 260 ; production of local
anaesthesia,260 ; relations between
tion,
constituphysiological action and
264 ; substitutes for,304.
Cocaine-urethane,262.

Chloracetic

-formamide,

120, 180,

o-Cocaine,263.
Cocaine, action

349.

Chloral-amide,

192.

Coca-ethyline,262.
Coca-propyline,262.

taste, 340.
Chemical

action

acid

Cocaine,

Cells,selective action of, 19 ; staining

reactions,19.
Cevine, decomposition product of
veratrine,180.
Chain
into cyclicderivatives,
effect on

Chloral

276.

quinine,

192.
Citrophen,

of arterial

318.

Chloral

and

Cinchotoxine, 277.
Cinnamic
acid,51, 149;
body, 77.
Citral,344.

344.
Citronellol,

Catalyticpoisons,17.
Catechol,causing rise

in organism.

277.

Coniine,

324.
252.

252.
tso-Coniine,
Coniine
252.
derivatives,
Coniine, synthesis of,236.
Constitutional
quired,
formulae, factors re9 ; acetic acid,10 ; benzene,
11.

254.
Copellidine,

364

INDEX

Eosin, 354.

Ferrichthyol,

Eosote, 144.
Epicarin, 140.
Epiosin, 293.

Fischer

and

169.
Filehne

on

Kairine,49.

327.

Fisetin,

Formaldehyde, 71.
101.
Erythrol tetranitrate,
compounds of,107, 108.
of prepara71.
Esters, general methods
Formalin,
tion,
90,94, 122 ; general properties, Formamide, 124.
94 ; physiologicalproperties, 122,
107.
Formamint,
123.
Formanilide, 182.
of halogen acids, 93.
Formic
118.
acid,antisepticproperties,
of hydriodic acid,99.
Forxnin, 108.
of hydrobromic acid,98.
Formyl-phenetidin, 189.
of hydrochloric acid, 96.
Formyl-urea, 108.
of inorganicacids,93-103.
Fortoin, 326.
of nitrous and nitric acids,100.
Fraser
and
Crum
Brown, ammonium
of salicylic
acid,odour of,342.
compounds, 20.
of sulphurous and
and Losev, Theory of dyeing,
sulphuric acids, Freundlich
"

"

"

"

"

"

"

"

"

102.

22.

used

"

in

Ethers,

perfumery,

formation

Friedel

344.

from

alcohols

sulting
re-

in
lessened
toxicity,47
action of,103 ; preparaphysiological
tion
and propertiesof,103, 104.

229.
Ethoxy-caffeine,
190.
p-Ethoxy-phenyl-succinimide,

and

Fuchsin,

synthesis,42.

Craft's

354.

Fumaric

acid, 119.
Furfurane, physiologicalaction
Furfurol,synthesiswith acetic
body, 66.

Ethyl acetate,122, 123.

Ethyl alcohol,preparationof,88.
Ethylainine,decomposition by nitrous
acid,89.

Gallacetophenone,58, 148.
Gallic acid,132, 159.

Ethyl-benzamide,124.

Geosote,

Ethyl bromide, 98.

Ethyl chloride,96.
123.
Ethyl ester of tyrosin,
Ethyl-formate, 122.
Ethyl-guaiacolcarbonate,142.
Ethyl iodide,99.
Ethyl mercaptan, 114.
Ethyl and methyl groups, physiological
49.
differences,
153.
Ethyl -salicylate,
Ethylene, physiologicalaction of,45.
Ethylene dibromide, 98.

Geraniol,344.
Glucosides,320.
320;
classification,

115.
Ethylene-diethyl-sulphone,

Ethylene-dimorphine, 293.
Ethylene hydrocarbons, preparation
of,33, 34.
115.
Ethylidene-dimethyl-sulphone,

Eucaine, A and
167.
Eudoxin,
Eugallol, 147.

Eugenol,
"

use

in

(a and "), 307.

131.

perfumery,345.

317.
Enmydrine,
Euphorin,
183, 196, 213.
316.
Euphtfcalmine,
302.
Euporphin,
195.
Eupyrin,
279.
Euquinine,
Euresol, 141.
163.
Enropnen,
Exalgin,
184, 210.
Ezodine, 330.

of, 45.
acid in

322.

Gaultherin,

acid,57.

Gentisinic

144.

of, 333,

taste

"

334.

Glutaminic

acid,dextro

ence
laevo,differ-

and

in taste, 53.
Glutaric
acid,119.

Glycine,derivatives

of,formed

in

body,

63.
and
of amido
Glycocoll, derivatives
311.
benzoic
acids,
oxy-amido
in body, 63.
derivatives
of, formed
Glycocoll-phenetidin,193.
Glycol,preparation of,88.

"

154.

Qlycosal,

Glycuronic acid derivatives,59.

Glycuronic acid,derivatives of,formed
in body :
borneol,62 ; camphor, 62 ;
thol,
choral,60 ; dichloracetone, 61 ; men62 ; naphthol, 62 ; pinacone,
61 ; pinene, 62 ; phellandrene, 62 ;
phenetol, 62 ; primary alcohols,61 ;
sabinene, 62 ; thujon, 62 ; vanillin,
"

61.
substances
of in

causing

form derivatives
with, 61
with, in body, 56.
Griserin,
Guaiacol,

syntheses

165.

146.

Guaiacetin,

"

appearance
which

urine, 59; substances

142.

attempts

to increase

solubilityof,

INDEX
carbamic

145;

esters

of,142,143
organic esters of, 143
of,145.
esters

ganic
of, 143; inor; oleate,143 ;
; sulphonates

144.

Guaiacolsalol,

143.

Gnaiacophosphal,
146.
Guaiamar,

Guanidine,

Hypnosis, theory of Overton

and
Meyer, 83, 84 ; views on, 85, 86.
Hypnotic action of ureides,219, 220.
Hypnotics and anaesthetics,
distinction
between, 81; main
of,
group
81.

82,

214.

Imido

and

Hexane,
Hinsberg

25, 45.
Trenpel

on

185.

Hippuric acid,formation
Holocaine,

tors,
fac-

acids,taste of,338.
of NH

group

of

replacing

by alkyls,48.

Indol, oxidation in body, 78.

Indophenol reaction,with aniline derivatives

acid, derivatives
and

several

Indican,urine, 79.

150.

185.
Inertia

iodoform, 162.

tannic

on

effect
Imido-derivatives,

Hexamethylene-tetramine,108.
"

efficacydependent
170.

Heroine, 180, 295.

325.
Hesperidin,
Heteroxanthine, 226.

"

169.
169.

Ichthyol, 169.
"

25.

Hetocresol,
Hetol, 149.

169.

Ichthalbin,
Ichtharsan,
Ichthoform,

322.

Helicin,

114.

Hypnone,

178.

Halogen acids,aromatic esters of,99.

Halogen derivatives of aromatic series,
of,178.
stability
Halogens, influence on odour,342.

Heptane,

111,206.

Hypnal,

145.

Ouaiasanol,

Hedonal,

365

of carbon

systems, 8.

Intestines,action
lodal,109.

of,160.

of alkali in, 55.

167.
vatives, Zodalbin,
aniline derilodeig-on, 162.
of in

body,63.

313.

Homatropine, 264, 268.

Homogentisinic acid,57.
smell
Homologous derivatives,

Iodide

of

163.
tso-butyl-o-cresol,

Iodides,organic substitutes,
167.
Iodine antiseptics,
comparison of,167.

Iodine, containing antiseptics,161

entrance

of,342.

160.
HontMn,
303.
Hordenine,
200.
Hydracetin,
284.
Hydrastine,

into

and
aliphatic

aromatic

substances,163.
Zodipin,

167.

Xodo-auisol, 166.

lodo-compounds,aromatic, 99.
99, 161, 162.

Iodoform,

Hydrastinine,285, 286.

Iodoform, classes

Hydrastininic acid,286.
Hydriodic acid,esters of,99.
Hydrobromic acid,esters of,98.
24.
Hydrocarbons, aliphatic,
Hydrocarbons,aliphaticaromatic

of

161,
substitutes,

162.

taste

162.
lodoformal,
162.
lodoformin,
162.
lodoformog-en,
164.

lodol,
of, 335 ; aliphatic not oxidized in
Zodolene, 162.
the body, 71 ; benzene, 28
; benzene,
162.
lodyloform,
sources
of preparaof,30 ; methods
tion,
345.
lonone,
32 ; paraffins,
24 ; paraffins,
paration
prelothion, 168.
of,32 ; physiological
teristics,
charac-

Iridin, 326.

45.

Hydrochloric acid,esters of,98.

Hydrocotarnine,

286.
Hydroquinine, 278.

Hydroquinone, 57, 131, 140.

taste of,339.
Hydroxy acids,aromatic, 149.
Hydroxy-benzoic acids, 119, 120.
168.

Isomeric

influence
relationships,

derivatives.

interdependence of physiological
action,51.
Iso-oximes,cyclicketones,
246,248.
"

232.
Iso-pilocarpine,
Isopral, 95.

constitution
iso-quinoline,
Hydroxyl derivatives,
aromatic, 128.
Hydroxy lamine, action on aldehyde,
106.

Ryoscyamine,

270.

on

of smell, 345.
Isomerism, 4, 5.
sense

"

Hydroxy-propane, iodine

Irigenin,326.

Jaborine, 232.
Jalapin, 322.

of,240.

366

INDEX

Kairine, 49, 275.

Merling, physiologicalaction
tone-amine
306.
derivatives,

A, B, 274.

Kairolin

Kaiser

yellow, 351.
Ketones, aromatic, oxidation of, in
fication
body, 57 ; preparation of,42 ; classiand preparation,112 ; cylic,
246, 248 ; preparation of, 86, 37 ;
properties of, 112; reaction with
phenyl-hydrazine, "c.,112; used in
perfumery, 345.
Ketonic
acids,stabilityof,113.
Robert's paradox, 19.

in

acid,appearance

49.
differences,

'

Methyl- chloroform, 97.

Methyl-coniine,252.
Methylecgonine, 120.
probable value of,
Methyl-ethyl-ether,
mydri-

104.

184.

Methylenphorin,

Methyl

299.

group,

147.

introduction

of substances

passage
66.

compounds,

124.

Methylbromide,98.

Lepidine, 273.
Leuco

116.
sulphonals,

133.

Methyl-benzamide,

195.

'

of

yellow, 353.
Methacetin, 185.
Methane, preparation of,32.
Metho-codeine, 297.
Methylacetate,123.
Methyl alcohol,preparation of,88.
Methyl and ethyl groups, physiological

urine, 73.

Lactyl-phenetidin,189.
Lactyl radical,120.
Lactyl-tropeine,267.
Ladenbui-g'sgeneralizationon
atic action,268.
Laudanine, 300.
Lenigallol,

processes, 55.

changes

Metanil

Lactylamido-phenol-ethyl-carbonate,

Landanosine,

Metabolic
Metakalin,

189.

Lactophenin,

154.

of, during
through body,

Methyl-keto trioxybenzene,148.
Methyl nitrile,
125, 126.

347.

acid, 113.
values,83, 84.
Linalool,344.
of
Lipoid substances, solubility
Levulinic

Methyl

Liminal

153.
Methyl salicylate,
Methyl sulphide,127.
Methyl violet,354.
Methylal, physiological

cotics
nar-

in, 83.
'

Loew's

substitution

by Ehrlich, 348

'

theory,criticism
theory of poisons,

17.
164.

Loretin,

Lupetidines,253, 254.
Lupinene, 180.
Lysol,

; action

on

ria,
bacte-

350.
194.
194.

Maleic

acid,119.
acid,119.
Mannitol
hexanitrate,101.
Marsh
gas, physiologicalaction of,45.
Martius's
yellow, 350.
Mercaptans, 126.
Mercapturic acids, formation
of, in
body, 67.
Mercury, bromide, chloride,cyanide,
Malonic

15.

Mercury salts,double
15, 16.

determination

and

of anaesthetic

Magnesium, organic derivatives,38

synthesis with, 38.

Malakin,
Malarin,

of,

Methylene blue, 355.

Methylene diethyl-sulphone,115.

Moore

354

action

104.

Eoaf, hypothesis on action

substances, 85 ; on
chloroform, 85.
Morphenol, 291.

133.

green,

158.

of,9.

Lysol, sulphur preparation,169.

Malachite

rhodin,

108.
Metramine,
139.
Mikrocidine,
Molecular
magnitude,

166.

Losophane,

ace-

256.
Metanicotine,

Lactamide,124.
Lactic

Mesotan,
Metabolic

of

292.
Morphigenin,
290.
Morphine,
"

tion
benzoyl derivative, 296 ; constituof, 293;
of, 291; derivatives
vative,
di-acetylderivative,295 ; ethyl deri294 ; * pyridine,'formula
for,
302.

tso-Morphine,297.
Morphol, 291.
Morpholine and phenanthrene, 242.
alkaloids,
Morpholine-phenanthrene
288.

Morpho-quinoline ether,296.
Morphothebaine, 299.
345.
Musk, artificial,
Mydriasine,

compounds

of,

317.

ization,
Mydriatic action, Ladenburg's general268.

367

INDEX

action
Nitro-thiophene,physiological

291.
Naphthalan-morpholine,

Naphthalene,

30.

logical
of, in body, 76 ; physioaction of,45.
Naphthol, a- and 0-, glycuronicacid
derivatives
of,62.
Naphthol-sulphonic acid,139.
Naphthols, 139.
Naphthylamine-sulphonicacid,140.
oxidation

"

301.

Narceine,
Narcotic

action,enhanced by entrance
into molecule, 82.
alcohols, aldehydes, ketones,

of,102.
Nitro-toluene,oxidation in body, 77.
Nitrogen, influence on odour, 343.
and nitric acid,esters of,100 ;
Nitrous
physiologicalaction of,100.
oxidation
in
Ndlting, on
processes
body, 78.
166.

Nosophen,
Novocain,
Nux

312.
vomica, 271.

of chlorine
of

"

82.

effects,
depressedby carboxyl

group,
Narcotic

82.

Odour,

Oil

Narcotics, aliphatic, groups

action
physiological

of,81.

JTarcotine, 286, 300.

JTarcyl, 301.

Nencki, salol principle,55, 129; sulphocyanic acid in stomach, 65.

Neurine, 51.
Nenrodin,
Nicoteine,

Nicotine,

196.
256.
255.

Nicotine, difference between

laevo,53.
Nirvanine,

dextro and

311.

Nitriles,
aromatic, 126.
aromatic, preparationof,41, 42.
formation
of
sulphocyanides in
body, 65.
of fattyseries,
toxicityof,126.
odour
of, 343 ; physiologicalproperties,
125, 126 ; preparation of,
37, 125; reactions of, 37, 125.
odour of,343.
t'so-Nitriles,
tissue
action
on
Nitrites, chemical
101.
cells,
oxidation in body,
Nitrobenzaldehyde,

physical factors,

of Wintergreen,

153.

Olefines, chemical

propertiesof,26.
Opianic acid, physiologicalproperties
of,286.
Opium alkaloids,288; classification,
289 ; containing tso-quinolinering,
299.

Opticalisomers,5.
Opticallyactive tartaric acids,6.
Orcin, 131.
Orcinol,taste of,339.
241.

Orexine,

Organic dyes, 347.

Orthin, 201.
310.
Orthoform,
311.
Orthoform-neu,

'Osmophore*
presence
342.

"

"

on

341.

of sulphones, 115,
properties

of, 82;

341.

dependence

"

116.

"

action of,45.
physiological

"

Narcotic

"

Octane, 25.

of

groups,
several

in

341, 342;
molecule,

Overton, Meyer and, theory of hypnosis,

83, 84.
acid,oxidation
toxicityof,118.

Oxalic

Oxalic

and

succinic

in

body of, 73

acids, synthesis
ethylene,39.
Oxidation, differences between
methyl
and
63.
ethyl groups, 71 ; general process
of, 67, 68, 69.
changes of, in
rn-Nitrobenzaldehyde,
in organism, theories of,70.
body, 65.
of aromatic
derivatives in body, 75.
Nitrobenzene,reduction of,in body, 79.
of aromatic
Nitro-compounds, aromatic, reduction
substances, Nolting's
rule,78.
of,173.
of stereochemical
Nitro-derivatives, aromatic
series,
isomerides,69.
102.
physiologicalaction,101,
processes in the body taking place
with :
odour of,342.
Alanin, 74 ; alcohols, 71 ;
stances,
Nitro-glycerine,
101, 102.
aliphaticacids, 73; aliphatic sub71 ; amido-acids, 74 ; dextrose,
Nitro-group,influence on taste,334.
69 ; esters,71 ; formaldehyde,
Nitro-naphthol, physiological action
of,102.
71; formate of soda,69; glutaricacid,
101.
74 ; glycerol,72 ; glycolicacid,73 ;
Nitre-paraffins,
Nitro-phenol,129.
hydrocarbons, 71; malic acid, 74;
malonic
Nitro-phenols,reduction
of,by organacid, 73 ; mannite, 69, 72 ;
ism,
80.
methyl alcohol,71 ; methylainine,
71 ; nitriles, 71 ; oxalic acid, 73 ;
Nitro-phenyl-propiolic
acid,reduction
73 ; oxy-butyric acid,73 ;
of,by organism, 80.
oxy -acids,
from

"

"

"

"

"

"

"

368

INDEX

phenylalanine, 69

secondary

hols,
alco-

71 ; succinic
acid, 73 ; sugars,
69, 72 ; tartaric acid,69, 70, 73 ; tartronic
acid, 73; tertiary alcohols,

Phenol, changes of,in body,

with

local

57 ; derivatives

anaesthetic

action, 313.
esters,129.

Phenol

71.
166.
Phenolphthalein, tetra-iodo,
Phenols
and phenol ethers, characterOxidation,selective,
istic
69, 70.
odour
Oxidizing poisons, 17.
of,343.
Oxy -benzenes,comparison of toxicity, Phenols, antisepticvalues,and general
52 ; preparation and
of
properties,
conclusions, 139 ; elimination
128.
acidic
nature
logous,
homo130;
of, 129,
130 ; introduction
of COOH
Oxybenzoic acids,150.
Oxybutyric acid,118.
into, 150; local anaesthetic
group
action of, 315; physiologicalaction
Oxycarbanil, 181.
195.
Oxyphenacetin-salicylate,
of,131, 132; polyhydric, 130; preparation
of, 128; preparation from
diazo-compounds, 41 ; propertiesof,
129.
Paeonol, 58.
Pancreatic
juice,action of,55.
Phenol-sulphonic acid,57.
299.

Papaverine,

hydrocarbons, 24

Paraffin

preparation

of,32.
Paraffins, chemical
isomerism

in

properties, 26;

the,

nitro-com-

25 ;

in
of, 101 ; occurrence
nature, 25; physical propertiesof,

pounds

Phenylacetamide, 124.
Phenyl acetate,129.
Phenyl-acetic acid, antiseptic properties
of,118.
glyciiiein body,
synthesis with
64 ; with a-methyl-pyridine,64.
Phenylacetylene and its derivatives,

"

24.

odour

Paraldehyde^lOS.

of, 343.

Phenylalanin,

Pararosaniline, 347.

oxidation

of, in body,

75.

Paraxanthine, 226.
configuration and
Pasteur, chemical
ferments, 53.
Penicillium
acid,7 ;

193.

Phenosal,

Parabino-chloralose, 111.

on
glaucum, action
mandelic
on
acid, 7.

Pentamethylene-diamine,
Pentane, 25.
Pepper, glucosidesof,321.

Phenyl- azoimide, 208.

Phenyl-ethyl-ketone,114.
Phenyl-ethylene, glucosides

lactic

derived

from, 324.

(styrol),
preparationof,34.
Phenylhydrazine, action on aldehydes,
tives
106 ; action on ketones, 113 ; derivaof,200. 201, 202 ; physiological
action
of, 199 ; preparation of, 41,

"

247.

Peptoiodeiffon, 162.
296.
Peronine,
Petroleum
emulsion, 45.

198; reactions

of, 199.

Phenyl-methane, 183.
169.
Petrosnlphol,
derivatives,196.
Pharmacology, relation to therapeutics, Phenyl-propionicacid,oxidation of,in
14.
body, 64.
186, 187, 188.
Phenyl radical,effect on taste,334.
Phenacetin,
bility
Phesiii, 191.
Phenacetin, attempts to increase soluPhiladelphiayellow, 355.
of, 191 ; theory of physiological
"

action, 211.
Phenanthrene

morpholine, 242.
derivatives, 189, 190;
and

Phenetidin,
derivatives

with

action, 313,

314 ;

ortho

formation

from,

in

body,

193.
Phenocoll,
aniline
and
Phenol
of

meta

and

of,

guaiacol,

143.

Phospliine,

of

Phosphonium

chinaethonic

355.

bases,

physiological

action, 54.

62.

Phosphotal,
parison
derivatives, com-

physiological action

phenol-ethersused
345.

132 ; taste of, 339.

Phosphate and phosphite of

aliphatic ethers,

of,

210.
Phenol

Phloroglucin,physiologicalaction

Phosphatol,

"

104 ;

and

325.
325.

143.

212.
derivatives,
Phenetol, 129.
comparison with
acid

anaesthetic

local

Fhloretin,
Pnlorizin,

in perfumery,

143.

of, in body,
acid, oxidation
76 ; preparation of, 117.
Phthalide
and
its derivatives,odour
of, 343.
Phtlialimide,in preparation of am-

Phthalic

INDEX
ines, 172; oxidation

in

the

body,

76.
Picric

acid,129,350.
Picrylchloride,173.
232.
Pilocarpidine,
Pilocarpine, 231, 232.
constitution
of,224.
Pinacol,131.
Pinacones,physiologicalaction of,93.
254.
Pipecolylalkin,
action of,46,
Piperidine,physiological
"

369
comparison with
quinoline, "c.,
272 ;
derivatives, differences in
physiologicalaction,257 ; group of
249 ; homologues, physioalkaloids,
logical
action,46,251, 253 ; physiological
action of,45, 25O ; synthesis
of,234.
Pyrocatechol,130, 140.
Pyrogallicacid, 131, 140, 147 ; taste
of, 339.
constitution of,
Pyrrol and pyrrolidine,
237.

25O.

Piperidon,245.
246.
derivatives,

"

"

"

258.
Pyrrolidinealkaloids,

255.

Piperine,

Piperonal,use in perfumery,
Piperylalkin,254.

Pyrrolidon,248.

344.

17 ; Loew's theory,
Poisons, 'catalytic,'

17, 348; 'oxidizing,'17; special,

18; 'substituting/17, 348.
Polygallicacid,330.
Polyhydric phenols,130.
Polymerizationof aldehydes, 107.
Ponceau, 4 G. B., 353.
Popnlin,

323.

Quinine and

of tyrosin and
Protein, occurrence
phenylalanin in, 75.
Proteins,difficultyin determination
of composition, 7.
Protocatechuic acid,58.
Protoplasm, Loew's theory,17.
Prussic acid,125.

270.
Pseudo-tropine,

benzoyl ester,263.

148.
Psoriasis,

Purgatin, 329.
Pnrgatol, 329.
Purg-en, 330.

organic compounds,

methods
used, 8.
Purine
derivatives,
general review
229.
group,

8 ;

Pyrantin,

Quinine, insoluble derivatives of,279 ;

'
tives
Loipon-Anteil,'
277; soluble deriva279.
of,280 ; substitutes,
Quinoline, action of oxidizing agents
of reducing agents
on, 239 : action
271 ; antiseptics,
on, 239 ; alkaloids,
165
164,
quinine,
; comparison with
272 ; homologues,273 ; 1-hydroxy48 ; tso-quinoline,
tetra-hydro-,
pyridine, comparison of, 272 ; methyl-,
of in body, 76 ; 1-oxyoxidation
165 ; l-oxy-2-iodo-42-iodo-4-chlor,
sulphonic acid, 164 ; physiological
action, 272 ; reduced
derivatives,
272 ; synthesisof,238 ; tetrahydrow-ethyl-,274 ; tetrahydro-"-methyl,
tion,
284; classificatso-Quinoline-alkaloids,
289 ; nucleus,opium alkaloids,

299.

"

Pyramidon,

cinchonine, 276.

274.

of,

221.

nomenclature, 221.
Purine, physiologicalaction
synthesis of, 222.
Pyoktanin, 354.

280.

280.

280.
Quinine-hydrochloro-carbamide,

of, 92.

"

327.

Quillaia,330.
Quillaiacacid,330.
Quinaldine, 273.
p-Quinanisol,274.
Quinaphthol,

Propion, 113.

of

Quercetin,

compounds,
of, 179.

240.
Quinazolinederivatives,
Quinidine,278.
Quinine,action of vinylradical,
277,278.

Propionamide, 124.
126.
Propionitrile,
Propyl-phenetidin,189.
action
Propyl, n- and iso-,
physiological

Purification

Quaternary ammonium
physiologicalaction

Quinaphenin,

Populin, taste of,335.

Primary amines, 171.

"

physiologicalaction of,45.
tetra-iodo-,164.

of,224

280.
Quinopyrine,
Quitenine,278.
Racemic

206.
190.

acid, 6; Pasteur's investigations

on, 6.

202.
Pyrazolon derivatives,
Pyridine, action of oxidizing agents
on, 235; action of reducing agents on,
236 ; and
piperidine,233 ; changes
of,during passage through body,66 ;

Bb

of smell,
Reduction, influence on sense
346 ; processes taking place in body,

Resacetophenone, 58.
Resorcinol,131, 140.
Resorcin,thio-,168.

370

INDEX
327.

Rhamnetin,

Khamnose,
Bhodin,
Roaf

and

Sirolin, 146.

methyl-, taste of,333.

158.
methyl-,
Moore, anaesthetic

Snake

substances,

85.

of

eosin

on

110.
Somnal,
96.
Somnoform,
Sozoiodol, preparations,164, 165.
Sozoiodolic
acid, 165.
influences
Stereochemical
on
sense

"

336.

derivatives,336, 337.
Safrol,345.
toxic propertiesof,50
"

"

iso-,50.

154.
Salacetol,
155.
Salen,
Salicin,

action

venoms,

355.

Solubilityand volatilityin relation

physiologicalaction,14, 15, 46.

Rosaniline,354.
347.
its derivatives,
Saccharin,

Smilax-saponin,330.

to

of

taste,338.
"

relationshipsand

tion,
physiologicalac-

53.

322.

Stereo -isomerism, 5.

Salicyl-acetyl-p -amidophenol

ether,

157.
182.
Salicylanilide,
190, 194.
Salicyl-phenetidin,

Sternberg on

taste,333.

Stilbazoline, 255.
Stibonium
bases,physiologicalaction,
54.

of
Salicylradical, 120.
Stockman,
physiological action
273.
quinoline derivatives,
Salicylicacid,120, 150, 152.
rivative,
acetol ester
of, 154 ; acetyl deStomach, action of hydrochloric acid
classification
of
tives,
derivain, 55 ; presence of sulphocyanicacid
158;
tives
153 ; derivatives,
151; derivain, 65.
salol principle,156;
based
on
Stovaine, 314.
tion
derivatives, taste of, 337 ; dissociaof, 16; glycerin ester, 154;

326.
Strophanthin,
Structural
formulae, 3 ; determination
methoxy-methyl ester of,154; preof,3.
paration
of, 151 ; reduction
of, to
Strychnidine, 282.
281, 283.
pimelic acid,31 ; salts of antipyrine, Strychnine,
Stypticin, 287.
Styptol, 287.

205.
190.

Saliphenin,
Ealipyrine,

205.

Styracol, 150.

Salocoll, 193.
Salol, 155.

Styrolene,324.

156, 157.
principle, 55, 152

Salol group,
"

synthesizedon,

of type

substances

"

derivatives

156.

of,156.

157, 190.
Salophen,
280.
Saloquinine,
1

'

Sapiphore groups
Saponaretin,327.
Saponarin,

327.

55.
Saponification,

Substituted
ureas, preparationof,215.
Substitutingpoisons,17.
Succinie
acid,119.
Succinic
and
oxalic
acids, synthesis
from
ethylene, 39.
337.
Sucramine,
Sncrol, 340.

of

Sternberg,335.

Sudan

1,352.
168.

Sulphaminol,

Sulphocyanides, formation

of in body,

65.

115, 116.
Sulphonals,preparation of, 114.
Sulphones and sulphonals,distribution
co-efficient of,84.
Saturated
and unsaturated
derivatives,
26.
Sulphonic acid group, influence
on
Scaxu.zn.onin, 322.
physiologicalaction, 103 ; protection
cotics,
against oxidation in organism, 72.
Schmiedeberg, classification of narin
the
Sulphonic esters, formation
"c.,20 ; relation of therapeutics
to pharmacology, 14.
body with : Gallacetophenone, 58 ;
gentisinicacid, 57 ; homogentisinic
Scoparin, 327.
Secondary amines, 171.
acid,57 ; hydroquinone, 57 ; paeonol,
330.
58 ; phenol, 57 ; vanillic acid, 58 ;
Senegin,
iso-vanillic acid,58; veratric acid,59.
of taste and smell, 331.
Senses
146.
Sesame
oil,iodine preparationof,167.
Sulphosote,
321.
Sinalbin,
Sulphur, antiseptics containing, 186 ;
126
derivatives of urea,
derivatives,
Sinapin, 321.
Saponins,

330.

Sulphonal,

Sapotoxines,330.
Sarsa-saponin,330.

"

"

Sinig-iin, 321.

218.

INDEX

372
Urea,

"

derivatives

Vanillin,phenetidin,194.
in perfumery, 344.
use

containing bromine,

217 ; derivatives, taste of,339.

of derivatives
formation
in

"

Vaselines, 26.

body

Velocity of reactions,8.
Taurine, 64 ; amido-benzoic
Veratric
64
acid, 59.
amido-salicylicacid,
acid,
;
64.
Veratrine,decomposition
products of,
ethylamine-carbonate,
rivatives 180.
preparation of, 215 ; quinine deVeratrol,146.
of,280.
Veronal, 220.
ureides,and urethanes, 213.
108.
Ureas
action
Vesaloine,
substituted,physiological
Vinylamine, toxic propertiesof, 50.
of, 216; sulphur derivatives,218;
Vinyl-diacetone-amine, 305.
synthesisof,1.
165.
Vioform,
Ureides, classification of,219.
214.
Volatilityand solubilityin relation to
Urethane,
Urethane, phenyl, 183 ; derivatives of,
physiologicalaction,14, 15, 46.
with

"

64 ;

"

"

196.

Urethanes, preparation of,213.

225

; dioxy
synthesis,221, 222.
Urine
indican, 79,

Witt, theory of dyes, 22.

Wurtz, synthesisof hydrocarbons, 32.

derivatives,225 ;

Xanthates,127.
Xan

TJrisol, 108.
228.
Uropherin,
108.

"

Valency, theory of, 1, 2j

of,2.

Xanthines,
organism

acid,58.

iso-Vanillic

tri-

groups,

178.

tives,
tri-methyl derivaphysiologicalaction of, 48.
and
tetra-methyl derivatives,

mono-,

di-,and

228.

Valeronitrile, 126.
Vanillic

derivatives,225, 226.

effect of NH

variation
"

225.

thine,

Xanthine
"

Urotropixi,

oil, 153.

Wintersrreen

urea, and ureides,213.

108.
Uretone,
tives,
Uric acid,alkyl and
oxy-alkyl deriva"

acid, 50.

pending
Vanillin,piperonal,"c., odour of,deon
YohimMne,
concentration,341.

OXFORD
PRINTER

:
TO

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THE

HART

UNIVERSITY

methylated,
on, 66.

285.

action

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