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Chapter 16
Ethers, Epoxides, and
Sulfides

Nomenclature of Ethers
Substitutive IUPAC Nomenclature: name as
alkoxy derivatives of alkanes
Functional Class Nomenclature: name the
groups attached to oxygen in alphabetical order
as separate words; ether is last word.
CH3OCH2 CH3
CH3CH2OCH2 CH3
methoxyethane
ethoxyethane
ethyl methyl ether
diethyl
y ether
CH3CH2OCH2CH2CH2Cl
1-chloro-3-ethoxypropane
3-chloropropyl ethyl ether

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Nomenclature of Sulfides
Substitutive IUPAC Nomenclature: name as
alkylthio derivatives of alkanes.
Functional Class Nomenclature: Analogous
g
to
ethers, but replace ether as last word in the name
by sulfide
CH3SCH2 CH3
CH3CH2SCH2 CH3
methylthioethane
ethylthioethane
ethyl methyl sulfide
diethyl sulfide
SCH3
(methylthio)cyclopentane
cyclopentyl methyl sulfide

Names of Cyclic Ethers and Sulfides

O
O
O
O
Oxane
Oxirane Oxetane Oxolane
(Ethylene
(TetraHydroFuran)(tetrahydropyran)
oxide)
S
Thiirane

S
Thiolane

S
Thietane

S
Thiane

O
1,4-Dioxane
O

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Polyethers

The Diethers 1,2-dimethoxyethane CH3O

CH2CH2OCH3 and 1,4-dioxane are used as
solvents
Diglyme (used in hydroboration) is a triether; it is
diethylene glycol dimethyl ether: CH3O
CH2CH2OCH2CH2OCH3
The sulfur analogs (RS) of alkoxy groups are
alkylthio groups

Structure and Bonding in Ethers and

Epoxides

bent geometry at oxygen analogous to water and

alcohols
bond angles at oxygen are sensitive to steric
effects
O
O
O
CH3
CH3
H
CH3
H
H
112
108.5
105
105
O
(CH3)3C

C(CH3)3
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An oxygen atom affects geometry in

much the same way as a CH2 group

Most stable
conformation of diethyl
ether resembles that of
pentane (staggered).

Most stable conformation

of tetrahydropyran
resembles that of
cyclohexane (chair).

Physical Properties of Ethers

boiling point
36C
35C

OH

Ethers resemble alkanes

more than alcohols in
respect of boiling point
Intermolecular hydrogen
bonding possible in
alcohols; not possible
in alkanes or ethers.

117C

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Physical Properties of Ethers

solubility in water
(g/100 mL)

Ethers are more like

alcohols in respect of
their solubility in water
very small
Hydrogen bonding to
water possible for ethers
7.5
and alcohols; not possible
for
f alkanes.
lk

OH

Crown Ethers
Structure

cyclic polyethers derived from repeating units of

OCH2CH2

Properties

form stable complexes with metal ions

Applications

synthetic reactions involving anions

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18-Crown-6

O
O

O
K+
O

O
O

negative charge concentrated

in cavity inside the molecule
forms stable Lewis acid/Lewis
base complex with K+
K+F is not soluble in benzene
but 18-crown-6 complex of K+
dissolves in benzene
F carried into benzene
to preserve electroneutrality
A water soluble compound KF
is carried over (dissolved) into
the organic phase

Ion-Complexing and Solubility

O

O
O

O
O

O
O

K+F
benzene

O
K+
O

O
O
+ F

18-crown-6 complex of K+ dissolves in benzene;

F carried into benzene to preserve
electroneutrality

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Application to organic synthesis

Complexation of K+ by 18-crown-6 solubilizes
potassium salts in benzene.
Anion of salt is in a relatively unsolvated state in
b
benzene
((sometimes
ti
referred
f
d tto as a naked
k d
anion).
Unsolvated anion is very reactive.
Only catalytic quantities of 18-crown-6 are
needed.
KF
18-crown-6
CH3(CH2)6CH2F
CH3(CH2)6CH2Br
benzene
(92%)
90C

Preparation of Ethers
Acid catalyzed condensation of alcohols (15.7)
Addition of alcohols to alkenes
Williamson ether synthesis

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Acid-Catalyzed Condensation of Alcohols*

2 CH3CH2CH2CH2OH

H2SO4, 130C
CH3CH2CH2CH2OCH2CH2CH2CH3
(60%)
*Discussed earlier in Section 15.7
Method works best for the synthesis of symmetrical
ethers

Addition of Alcohols to Alkenes

(CH3)2C=CH2 + CH3OH

H+

(CH3)3COCH3
tert-Butyl
tert
Butyl methyl ether

tert-Butyl methyl ether (MTBE) was produced on

a scale exceeding 15 billion pounds per year in
the U.S. during the 1990s.
It is an effective octane booster in gasoline, but
contaminates gro
ground
nd water
ater if it leaks from
storage tanks; use discontinued.
Further use of MTBE is unlikely.

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The Williamson Ether Synthesis

Think SN2!

primary alkyl halide + alkoxide nucleophile

Alkyl halide must be primary or methyl
Alkoxide ion can be derived from methyl, primary,
secondary, or tertiary alcohol.
CH3CH2CH2CH2ONa + CH3CH2I
CH3CH2CH2CH2OCH2CH3 + NaI
(71%)

Another Example
Tertiary and secondary (crowded) alkyl halides
readily undergo E2 elimination reactions in the
presence of strong bases such as alkoxides
CH2Cl

CH3CHCH3
ONa

CH2OCHCH3
(84%)

CH3

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Origin of Reactants
CH3CHCH3

CH2OH

OH
HCl
CH2Cl

Na
+

CH3CHCH3
ONa

CH2OCHCH3

(84%)

CH3

Summary of reactions of ethers

No reactions of ethers encountered to this point.
Ethers are relatively unreactive.
Their low level of reactivity is one reason why
ethers are often used as solvents in chemical
reactions.
Ethers oxidize in air to form explosive
hydroperoxides and peroxides.

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Acid-Catalyzed Cleavage of Ethers

CH3CHCH2CH3 HBr

CH3CHCH2CH3 + CH3Br

heat

OCH3

Br

(81%)

The two alkyl groups of ether each yield an alkyl

halide in the acid catalyzed reaction
Cyclic ethers give ring opening reactions
HI
150C

ICH2CH2CH2CH2I
(65%)

Mechanism
CH3CHCH2CH3
O
CH3

CH3CHCH2CH3
Br

Br

CH3CHCH2CH3

Br

HBr

O
CH3

+
H

CH3CHCH2CH3
O
H

Br CH
3

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Mechanism

ICH2CH2CH2CH2I

HI

HI

I

O+
H

Preparation of Epoxides
Epoxides are prepared by two major methods.
Both begin with alkenes.
Reaction of alkenes with peroxy acids (Section
6.19)
Conversion of alkenes to vicinal halohydrins,
followed by treatment with base (Section 16.10)

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Conversion of Vicinal Halohydrins to

Epoxides
H

H
OH

NaOH

H2O

Br
via:

(81%) H

H
H
Br

Epoxidation via Vicinal Halohydrins

Br
Br2

NaOH

H2O

anti
addition

OH

inversion

Corresponds to overall syn addition of oxygen to

the double bond.

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Reactions of Epoxides

All reactions involve nucleophilic attack at

carbon and lead to opening of the ring.
An example is the reaction of ethylene oxide
with a Grignard reagent (discussed in Section
15.4 as a method for the synthesis of alcohols).

Reaction of Grignard Reagents with

Epoxides
R

MgX
CH2

H2C
O

R
CH2

CH2

OMgX
H3O+

RCH2CH2OH
Reactions of epoxides involve attack by a
nucleophile and proceed with ring-opening.

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For Ethylene Oxide

CH2

NuH + H2C

NuCH2CH2OH

O
CH2

CH2MgCl + H2C
O
1. diethyl ether
2. H3O+

CH2CH2CH2OH
(71%)

In General...
For epoxides where the two carbons of the ring are
differently substituted:
Nucleophiles attack here
when the reaction is
catalyzed by acids:
R

CH2

C
H

Anionic nucleophiles
attack here:

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Ring Opening Reactions of Epoxides

CH2

H2C
O

CH3CH2O CH2CH2OH
(50%)

NaOCH2CH3
CH3CH2OH

CH3CH2

CH2

H2C

CH3CH2

CH3CH2

CH2CH2

CH2CH2

CH2CH3

CH2CH3

Example
CH2 KSCH2CH2CH2CH3

H2C
O

ethanol-water, 0C
CH3CH2CH2CH2S CH2CH2OH
(99%)

The reaction is stereospecific

The nucleophile attacks from the backside
resulting in inversion of configuration at the
reaction site

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Stereochemistry

H
H

NaOCH2CH3

CH3CH2OH

OCH2CH3
H
H (67%)

OH
Inversion of configuration at carbon being
attacked by nucleophile.
Suggests SN2-like transition state.
CH3
H3C
R

H3C H

NH3
H2O

H2N

OH

CH3

(70%)

Stereochemistry
H3C
H
R

CH3

H3C H
+
H3N

NH3
H2O

H2N

OH

(70%)
CH3

H3C
H
O
H3C

Consistent with SN2-like transition state

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Anionic (Basic) Nucleophile Attacks Lesscrowded Carbon

H3C

CH3
C

C
H

NaOCH3

CH3OH

CH3O

CH3

CH3CH

CCH3

(53%)

OH

CH3
MgBr + H2C

CHCH3

1. diethyl ether
2. H3O+

O
CH2CHCH3
(60%)

OH

Lithium Aluminum Hydride Reduces

Epoxides
CH(CH2)7CH3

H2C
O

1. LiAlH4, diethyl ether

2. H2O

Hydride attacks lesscrowded carbon.

H3C

CH(CH2)7CH3
OH

(90%)

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Acid Catalyzed Ring Opening Reactions

H2C

CH2 CH CH OH
3
2
CH3CH2OCH2CH2OH
O
(87-92%)
(87
92%)
H SO , 25
25C
C
2

CH3CH2OCH2CH2OCH2CH3 formed only on

heating and/or longer reaction times.
CH2

H2C
O

HBr

BrCH2CH2OH

10C

(87-92%)

BrCH2CH2Br formed only on heating and/or longer

reaction times.

Mechanism

CH2

H2C

H2C

Br

Br

CH2
+
O
H

Br

CH2CH2

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Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 1

CH2

H2C

Step 2

CH2
+
O
H

H2C
H
H

H2C

+
O
CH2CH2

CH2

+
O
H

Acid-Catalyzed Hydrolysis of Ethylene Oxide

Step 3

H
+
H O

H
O

CH2CH2

+
H O
CH2CH2

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Acid-Catalyzed Hydrolysis of Ethylene Oxide

Characteristics:
Nucleophile attacks more substituted carbon of
protonated epoxide.
Inversion of configuration at site of nucleophilic
attack.
H3C

CH3
C

C
H

CH3OH

CH3

H2SO4

OCH3
CH3CH

CCH3

OH CH3
(76%)
Consistent with carbocation character at
transition state
O

Stereochemistry
H

OH
O

HBr

(73%)
H

H
Br
Inversion of configuration at carbon being
attacked by nucleophile
H3C
H
R

H3C H

CH3

CH3OH
H2SO4

CH3O

H
H

CH3

OH

(57%)

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Stereochemistry
H3C
H

CH3

CH3OH

CH3O

H2SO4

H3C H

OH

CH3

+
CH3O
H

H3C
H
+
H3C

+
O H

anti-Hydroxylation of Alkenes
H

CH3COOH

H
H
H2O

H
OH

HClO4

H
(80%)

OH

+ enantiomer

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Epoxides in Biological Processes

Naturally occurring epoxides are common

Are involved in numerous biological processes

+ O2 + H+

+ NADH
C

enzyme

+ H2O + NAD+

Biosynthesis of epoxides is an enzyme-catalyzed

oxygen transfer from O2 to alkene
Enzymes are referred to as monooxygenases

Biological Epoxidation of Squalene

This reaction is an important step in the

biosynthesis of cholesterol.

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Preparation of Sulfides: RSR'

Prepared by nucleophilic substitution (SN2).

CH3CHCH

CH2

R'

NaSCH3

R'

CH3CHCH

CH2

methanol
Cl

SCH3

Oxidation of RSR: Sulfoxides and Sulfones

O

R'

+
S R'

2+
S R'
O

sulfide

sulfoxide

sulfone

Either the sulfoxide or the sulfone can be isolated

depending on the oxidizing agent and reaction
conditions.

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Sulfoxides and Sulfones

NaIO4

water

SCH3

+
SCH3

(91%)
Sodium metaperiodate oxidizes sulfides to sulfoxides
and no further.

O
H2O2
2+

SCH CH2
SCH CH2

(2 equiv)
O (74-78%)

1 equiv of H2O2 or a peroxy acid gives a sulfoxide,
2 equiv give a sulfone.

Sulfides Can Act as Nucleophiles

R"

+
S

R'

R'
Product is a sulfonium salt.

CH3(CH2)10CH2SCH3

CH3I

R"

+
CH3(CH2)10CH2SCH3 I
CH3

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Biological Alkylation of Sulfides

SAM (S-adenosylmethionine) is a biological
methyl transfer agent.
It is formed in a nucleophilic substitution reaction;
S of methionine reacts with a primary carbon of
ATP and displaces triphosphate

Biological Alkylation of Sulfides

Nucleophiles, esp. N atoms of amines, attack the
methyl C atom of SAM.
In one reaction, norepinephrine is converted to
epinephrine

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Infrared Spectroscopy
CO stretching of ethers: 1070 and 1150 cm-1
(strong)
Epoxides exhibit bands for CO stretching at:
810-950 cm-1 (asymmetric stretch) and 1250 cm-1
(symmetric stretch).
There is also a third band in the range 750-840
cm-1.
CH2(CH2)8CH3
H
C
H

C
O

= 837, 917, and 1265 cm-1

Infrared Spectroscopy

Sulfoxides exhibit strong SO absorption in the

range 1030-1070 cm-1.
Sulfones
Su
o es have
a e ttwo
oS
SO
O absorptions:
abso pt o s
-1
1120-1160 cm (symmetric stretch) and 12901350 cm-1 (asymmetric stretch).

O

++
O
H3C S CH3
+
H3C S CH3
O

= 1050 cm-1

= 1139 and 1298 cm-1

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1H

NMR

HCO proton is deshielded by O; range is ca.

3.3-4.0 ppm.

0.8 ppm

1.4 ppm

0.8 ppm

CH3 CH2 CH2 OCH2 CH2 CH3

3.2 ppm

1H

NMR

HCS proton is less deshielded than HCO.

CH3 CH2 CH2 SCH2 CH2 CH3

2.5 ppm
Oxidation of sulfides to sulfoxide deshields an
adjacent CH proton by 0.3-0.5 ppm.
An additional 0.3-0.5 ppm downfield shift occurs
on oxidation of the sulfoxide to the sulfone.

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13C

Carbons of COC
appear in the range
57-87 ppm.
26
O

68

NMR

But the ring

g carbons
of epoxides are
somewhat more
shielded.
CH2(CH2)2CH3

H
47 C
H

C 52
O

UV-VIS
Simple ethers have their absorption maximum at
about 185 nm and are transparent to ultraviolet
radiation above about 220 nm
nm.

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Mass Spectrometry
Molecular ion fragments to give oxygen-stabilized
carbocation.
+
CH3CH2O

CHCH2CH3

m/z 102

CH3

+
CH3CH2O

CH

m/z 73

CH3

+
CH3CH2O

CHCH2CH3

m/z 87

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