16.9
Preparation of Epoxides:
A Review and a Preview
Preparation of Epoxides
Epoxides are prepared by two major methods.
Both begin with alkenes.
reaction of alkenes with peroxy acids
(Section 6.18)
conversion of alkenes to vicinal
halohydrins, followed by treatment
with base (Section 16.10)
16.10
Conversion of Vicinal Halohydrins
to Epoxides
Example
H
H
OH
H
Br
NaOH
O
H2O
H
(81%)
Example
H
H
OH
NaOH
O
H2O
H
H
Br
•• –
•• O ••
via:
H
H
•• Br ••
••
(81%)
Epoxidation via Vicinal Halohydrins
Br
Br2
H2O
OH
anti
addition
Epoxidation via Vicinal Halohydrins
Br
Br2
NaOH
H2O
O
OH
anti
addition
inversion
corresponds to overall syn addition of
oxygen to the double bond
Epoxidation via Vicinal Halohydrins
H3C
H
Br
H
Br2
H2O
CH3
H3C
H
H
CH3
NaOH
O
OH
anti
addition
inversion
corresponds to overall syn addition of
oxygen to the double bond
Epoxidation via Vicinal Halohydrins
H3C
H
Br
H
Br2
H2O
CH3
H3C
H
H
CH3
NaOH
H3C
H
O
OH
anti
addition
H
CH3
inversion
corresponds to overall syn addition of
oxygen to the double bond
16.11
Reactions of Epoxides:
A Review and a Preview
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
Example
CH2MgCl
CH2
+ H2C
O
1. diethyl ether
2. H3O+
CH2CH2CH2OH
(71%)
In general...
Reactions of epoxides involve attack by a
nucleophile and proceed with ring-opening.
For ethylene oxide:
Nu—H
CH2
+ H2C
O
Nu—CH2CH2O—H
In general...
For epoxides where the two carbons of the
ring are differently substituted:
Nucleophiles attack here
when the reaction is
catalyzed by acids:
Anionic nucleophiles
attack here:
R
CH2
C
H
O
16.12
Nucleophilic Ring-Opening
Reactions of Epoxides
Example
CH2
H2C
O
NaOCH2CH3
CH3CH2OH
CH3CH2O
CH2CH2OH
(50%)
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
••
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
••
CH3CH2
••
O
••
CH2CH2
• –
••
O
•••
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
••
CH3CH2
••
O
••
CH2CH2
• –
••
O
•••
– •
•• O
•
H
CH2CH3
CH3CH2
Mechanism
•• –
O ••
••
CH2
H2C
O ••
– •
•• O
•
••
CH3CH2
CH3CH2
••
O
••
••
O
••
CH2CH2
• –
••
O
•••
CH2CH2
•
O
•••
CH2CH3
H
H
– •
•• O
•
•
•
CH2CH3
Example
CH2
H2C
O
KSCH2CH2CH2CH3
ethanol-water, 0°C
CH3CH2CH2CH2S
CH2CH2OH
(99%)
Stereochemistry
H
H
NaOCH2CH3
O
CH3CH2OH
OCH2CH3
H
H
OH
(67%)
Inversion of configuration at carbon being
attacked by nucleophile
Suggests SN2-like transition state
Stereochemistry
H3C
H
R
H3C H
CH3
R
O
R
NH3
H2O
H2 N
H
H
S
OH
CH3
(70%)
Inversion of configuration at carbon being
attacked by nucleophile
Suggests SN2-like transition state
Stereochemistry
H3C
H
R
CH3
R
R
NH3
H2O
O
H3C H
H2 N
H
H
S
OH
CH3
d+
H3N
(70%)
H3C
H
O
H3C
H
d-
Anionic nucleophile attacks less-crowded carbon
H3C
CH3
C
C
H
O
NaOCH3
CH3OH
CH3O
CH3
CH3CH
CCH3
OH
CH3
(53%)
consistent with SN2-like transition state
Anionic nucleophile attacks less-crowded carbon
MgBr
+
CHCH3
H2C
O
1. diethyl ether
2. H3O+
CH2CHCH3
OH
(60%)
Lithium aluminum hydride reduces epoxides
CH(CH2)7CH3
H2C
O
Hydride attacks
less-crowded
carbon
H3C
1. LiAlH4, diethyl ether
2. H2O
CH(CH2)7CH3
OH
(90%)
16.13
Acid-Catalyzed Ring-Opening
Reactions of Epoxides
Example
CH2
H2C
O
CH3CH2OH
CH3CH2OCH2CH2OH
H2SO4, 25°C
(87-92%)
CH3CH2OCH2CH2OCH2CH3 formed only on
heating and/or longer reaction times
Example
CH2
H2C
O
HBr
10°C
BrCH2CH2OH
(87-92%)
BrCH2CH2Br formed only on heating and/or
longer reaction times
Mechanism
H2C
+
O ••
••
••
•• Br
••
CH2
H
H2C
•• –
• Br •
• •
••
CH2
+
O ••
H
Mechanism
H2C
CH2
H2C
+
O ••
••
••
•• Br
••
•• –
•• Br •
•
••
H
CH2
+
O ••
H
••
• Br •
•
•
CH2CH2
•
O
•••
H
Figure 16.6
Acid-Catalyzed Hydrolysis of Ethylene Oxide
Step 1
H2C
H
+
O ••
••
•• O
+
H
CH2
H
H2C
H
•• O ••
H
CH2
+
O ••
H
Figure 16.6
Acid-Catalyzed Hydrolysis of Ethylene Oxide
H
Step 2
O ••
H
••
H2C
H
+
O ••
H
+ •
H O•
CH2CH2
CH2
•
O
•
H
Figure 16.6
Acid-Catalyzed Hydrolysis of Ethylene Oxide
H
+
H O ••
Step 3
H
H
H
H
O ••
••
•O•
• •
H
CH2CH2
+ •
H O•
CH2CH2
•
O
•
•
O
••
•
H
H
Acid-Catalyzed Ring Opening of Epoxides
Characteristics:
nucleophile attacks more substituted carbon
of protonated epoxide
inversion of configuration at site of nucleophilic
attack
Nucleophile attacks more-substituted carbon
H3C
CH3
C
C
H
O
CH3OH
H2SO4
CH3
OCH3
CH3CH
OH
CCH3
CH3
(76%)
consistent with carbocation character at
transition state
Stereochemistry
H
H
OH
O
HBr
H
H
Br
(73%)
Inversion of configuration at carbon being
attacked by nucleophile
Stereochemistry
H3C
H
R
H3C H
CH3
R
O
CH3OH
H2SO4
R
CH3O
H
H
S
OH
CH3
(57%)
Inversion of configuration at carbon being
attacked by nucleophile
Stereochemistry
H3C
H
R
CH3
R
R
CH3OH
O
CH3O
H2SO4
H3C H
H
H
S
CH3
d+
CH3O
H
H3C
H
d+
H3C
H
d+
O H
OH
anti-Hydroxylation of Alkenes
H
H
O
CH3COOH
O
H
H2O
HClO4
H
H
OH
H
(80%)
OH