WELCOME

MULLESH.M
M.pharm -Part 1
Pharmaceutical Chemistry

CONTENTS
Introduction
Methods of determining reaction

mechanism
Reference

INTRODUCTION
Reaction mechanism is the step by

step sequence of elementary

reactions in a chemical change
It describes about the reactant
involved,intermediates and products

1
2

Methods 0f Determining of Mechanism

Identification of products
Determination of the
presence of intermediates

2.1 Isolation of intermediates

2.2 Detection of intermediates
2.3 Trapping of intermediates
2.4 Addition of a suspected
intermediate

Stereochemical study

6 Kinetic studies
7 Kinetic isotope effects
7.1 Deuterium isotope effects

Study of catalysis
3.1 General acid catalysis
3.2 Specific acid catalysis

Labeling study

4.1 Group labeling

4.2 Isotope labeling
.4.3 Crossover experiments
5

DETERMINATION OF
MECHANISM
IDENTIFICATION OF PRODUCTS
Mechanism must be compatible with
its products including the by-product.

Eg: 1
CH4

h
Cl Cl

H3C

Cl

This reaction fail to account for the formation of

small amount of ethane
Eg:2
NH2
H3C
O

N aO B r

H3C

NH2

H 2O
-C O 2
7

Determination of the
presence of intermediates
Isolation of intermediates
Isolate the intermediate which can give the same products
when subjected to the same reaction conditions

Eg: Neber rearrangement

R
R

OTs

B ase

CH

H
R

Azirine
R

OTs
H 2O

H2N

Determination of the presence of intermediates

Detection of an intermediate
In many cases, intermediate cannot be
isolated but can be detected by IR, NMR,
UV-Vis or other spectra.
Radical and triplet species can be
detected by ESR and by Chemically
Induced Dynamic Nuclear Polarization
(CIDNP).
10

Eg:-Free radical can be determined by

addition of double bonded compound in
the reaction mixture and its fate is traced

C
RS
H

-R S .

RS.
H

trans -stilbene
Cis - stilbene

11

Determination of the presence of intermediates

Trapping of an intermediate
In some cases, the suspected intermediate is known
to be one that reacts in a given way with a certain
compound.
Benzynes react with dienes in the Diels-Alder
reaction
O

Br
Lithium

(trap)

F
Benzyne
12

Determination of the presence of intermediates

Addition of a suspected intermediate
Perform a reaction by using a suspected intermediate
obtained by other means can be used for a negative
evidence.
Eg : Von Richter rearrangement
NO2
CO2H
von Ritcher
condition

CN

von Ritcher
condition

CO2H

13

Nitrogen
Ammonia would be compatible with
nitrile intermediate(hydrolysis product of nitrile)
14

Study of catalysis
Mechanism must be compatible with its
catalysts , initiator and inhibitors.
Utilization of catalytic amount of peroxide
and iodine usually suggests a radical
mechanism.

15

 Kinetic study of acid-base catalyzed reaction

can reveal the rate determination step (RDS.)

if it is involved with the proton transfer process
A) General acid (or base) catalysis usually
indicates that the proton transfer process
is the RDS
B) Specific acid (or base) catalysis usually
indicates that the proton transfer process
is not the RDS

16

A) General acid (or base) catalysis

In general acid catalysis all species
capable of donating protons contribute to
reaction rate acceleration.
The strongest acids are most effective
(k1 is the highest).

17

 Reactions in which proton transfer is rate-

determining exhibit general acid catalysis, f

or example diazonium coupling reactions.
When keeping the pH at a constant level
but changing the buffer concentration a ch
ange in rate signals a general acid catalysi
s. (A constant rate is evidence for a specifi
c acid catalysis.)
18

B) Specific acid (or base) catalysis

In specific acid catalysis taking place in solvent

S , the reaction rate is proportional to the

concentration of the protonated solvent
molecules .
The acid catalyst itself (AH) only contributes to
the rate acceleration by shifting the chemical
equilibrium between solvent S and AH in favor
of the SH+ species. S + AH SH+ + AEg: Acid catalysed aldol reaction
19

Labeling study
A) Isotope labeling: Difficult to obtain the
starting materials but no group alteration to
affect the mechanism.
B) Crossover experiments: The experiments
are closely related to either group or isotope
labeling.

20

Isotope labeling
D can be detected by NMR, IR and MS
13C can be detected by 13C-NMR and MS
14C can be traced by its radio activity
15N can be detected by 15N-NMR
18O can be detected by MS

e.g.

*
RCOO - +

BrCN

O-

O
R

*
RCN

O-

Br

R
Br

N C O
isolated
intermediate

C + C
N

21

Isotope labeling
The hydrolysis of ester proceed through alkyl
or acyl cleavage

R'

H218O

O
R

OH

+ R'OH

18

18

R'

H2O

OH

+ R'18OH

In these cases, the products can be easily

identified by MS.
22

Crossover Experiments
Use for distinguishing between intra- and intermolecular reaction

B
+

+
A'

B'

B'

A'

No crossover product

+
A'

B'

B'

A'

Crossover products
indicate intermolecular
reaction.
The method requires
identification of products
in the mixture.
.

+
A' + B'

crossover
products

23

Crossover Experiments

Is benzidine rearrangement an inter- or intramolecular process?

H H
N N
H2N

OR

H H
N N

OR

NH2

RO
H 2N

OR'

H H
N N

OR'

R'O
H 2N

R=OCH3
R`=OC2H5

OR
NH 2
OR'
NH 2

No crossover product indicates an intramolecular rearrangement

24

Stereochemical evidences

SN2 reaction
OTs
KOAc

and
OTs

The reaction is stereospecific

OAc with 100% inversion indicating
that the reaction is concerted
and the nucleophile attacks
from the back side of the
leaving group.
The proposed transition state
OAc
is a trigonal bipyramid.

KOAc

Ph

AcO

OTs
H

CH3

25

Mechanistic information obtained

from kinetic studies
Order of reaction can give information

about which molecules take part in rate

determining step and the previous steps.
Changes in rate constants upon structural
and condition changes can give much
information about mechanisms. (Linear
free energy relationships)

26

Kinetic isotopic
effect
Exchange of an atom in the starting product of a
reaction for one of its heavier isotope leads to
reduction in reaction rate
When a hydrogen in a reactant molecule is
replaced by deuterium, there is a change in the
rate
Such changes are known as deuterium isotope
effect
It is expressed by KH/kD
27

Types of kinetic isotope effects

Primary kinetic isotope effects
Secondary kinetic isotope effects
i. Normal
ii.Inverse
Kinetic solvent isotope effects

28

Primary kinetic isotopic

effects
When reaction rate is decreased by the

exchange of D for a H from the X-H(X=C, N, O,

S, etc..) that is cleaved during rate-determining
step
Elevation of activation energy of RDS
KH/kD is up to 7
Extent of bond cleavage or formation can be
inferred
29

Secondary kinetic isotope effects

The chemical bond varied by the isotopic exchange is not

cleaved during the reaction

KH/kD is 0.7 to 1.5

Normal secondary kinetic isotope effect (KH/kD >

1) reaction rate is reduced by exchanging an

atom for one its heavier isotopes
Inverse secondary kinetic isotope effect(KH/kD
<1) reaction rate is increases by exchanging an
atom for one its heavier isotopes
30

Kinetic solvent isotope

effects
Reaction rate is influenced by an isotopic

exchange of the solvent, rather than that of a

reactant that has been exchanged for one of its
isotopes
Eg: H2O is exchanged for D2O

31

Reference
Jerry march; advanced organic chemistry

4th edition page no:297-327

www.chemgapedia.com
www.wikipedia.com

Discussion

34