Reactions of Ethers
Ethers are relatively unreactive.
unreactive.
Ethers & Epoxides
Ethers are often used as solvents in organic
reactions.
Ethers oxidize in air to form explosive
hydroperoxides and peroxides.
“Crown”
Crown” ethers are useful as enhancers in
nucleophilic substitution and other reactions
Crown Ethers
structure
cyclic polyethers derived from repeating
— OCH2CH2— units
Crown Ethers
properties
form stable complexes with metal ions
applications
synthetic reactions involving anions
naming
x = total # of atoms in ring: [x] Crown- # of oxygen atoms
18-Crown-6
O
O
O
O
O
O
negative charge concentrated in cavity inside
the molecule
Question
• What is the name of the crown ether show at the right?
•
A)
12-crown-4
•
B)
10-crown-5
•
C)
15-crown-5
•
D)
18-crown-6
18-Crown-6
Ion-Complexing and Solubility
O
O
O
K + F–
K+
O
not soluble in toluene
O
O
forms stable Lewis acid/Lewis base complex
with K+
Ion-Complexing and Solubility
Ion-Complexing and Solubility
O
O
O
O
O
O
O
K + F–
F–
O
O
K+
O
O
toluene
O
O
O
Application to organic synthesis
O
O
O
O
O
K+
O
O
O
18-crown-6 complex of K+ dissolves
in benzene
Ion-Complexing and Solubility
O
toluene
O
add 18-crown-6
O
O
toluene
O
F – carried into toluene
to preserve electroneutrality
O
O
O
+ F–
Complexation of K+ by 18-crown-6
"solubilizes" potassium salts in toluene
Anion of salt is in a relatively unsolvated state
in toluene (sometimes referred to as a "naked
anion")
Unsolvated anions are very reactive
Only catalytic quantities of 18-crown-6 are
needed
Example
Question
KF
CH3(CH2)6CH2 Br
18-crown-6
toluene
• Which reaction is the best candidate for catalysis by 18crown-6? (Which reaction proceeds faster in the presence of
the crown ether than in its absence?)
CH3(CH2)6CH2 F
(92%)
•
•
•
•
A)
B)
C)
D)
Bromobutane + KCN (in toluene)
Phenol + Br2 (in water)
Butanol + H2CrO4 (in water)
CH3CH2CH2CHO + H2 (in ethanol)
Ion Size & Crown Ether Complexes
Question
• Which crown ether would provide the fastest rate for the
following reaction?
K+
CH2 O3SCF3
18-Crown-6
CH2 I
toluene
Na+
15-Crown-5
LiI
Li+
•
•
•
•
A)
B)
C)
D)
12-crown-4
10-crown-5
15-crown-5
18-crown-6
12-Crown-4
Example
CH3CH2 CH2CH2ONa + CH3CH2I
The Williamson Ether Synthesis
Just another SN2 reaction →
primary alkyl halide (substrate) + alkoxide (nucleophile)
nucleophile)
CH3CH2 CH2CH2OCH2CH3 + NaI
(71%)
1o Halides & Alkoxides
Another Example
Alkoxide ion can be derived
Alkyl halide must
from primary, secondary, or
be primary
tertiary alcohol
CH2Cl
+
CH3CHCH3
CH3CHCH3
CH2OH
HCl or SOCl2
Na (s)
CH3CHCH3
CH2Cl +
ONa
ONa
CH2OCHCH3
OH
CH2OCHCH3
(84%)
CH3
CH3
Question
• Which of the following best represents the rate-determining
transition state for the reaction shown below?
(84%)
What if the alkyl halide is not primary?
SN 2 vs E2
CH2ONa + CH3CHCH3
Br
• A)
B)
CH2OH
• C)
+
H2 C
D)
Elimination produces
the major product.
Question
• The most effective pair of reagents for the preparation of tertbutyl ethyl ether is
•
A)
potassium tert-butoxide and ethyl bromide.
•
B)
potassium tert-butoxide and ethanol.
•
C)
sodium ethoxide and tert-butyl bromide.
•
D)
tert-butyl alcohol and ethyl bromide
Preparation of Epoxides
CHCH3
Preparation of Epoxides
Epoxidation of Alkenes
O
Epoxides are prepared by two major methods.
Both begin with alkenes.
C
C
+
RCOO
RCOOH
peroxy acid
Reaction of alkenes with peroxy acids
Conversion of alkenes to vicinal
halohydrins, followed by treatment
with base.
O
C
+
C
RCOH
O
Stereochemistry of Epoxidation
Example
O
O
+ CH3 COO
COOH
C
C
+
syn addition
O
O
RCOO
RCOOH
+ CH3 COH
(52%)
O
C
+
C
RCOH
O
Example
H
H
OH
Conversion of Vicinal Halohydrins
to Epoxides
NaOH
O
H2 O
H
H
Br
•• –
•• O ••
via:
H
H
• Br •
• •
••
(81%)
Epoxidation via Vicinal Halohydrins
Epoxidation via Vicinal Halohydrins
Br
Br2
H3C
NaOH
H2O
O
OH
anti
addition
H
Br
H
CH3
Br2
H3C
H
H2O
H
CH3
Corresponds to overall syn addition of
oxygen to the double bond.
inversion
Corresponds to overall syn addition of
oxygen to the double bond.
Reactions of Epoxides
All reactions involve nucleophilic attack
at carbon and lead to opening of the ring.
Reactions of Epoxides
An example is the reaction of ethylene oxide
with a Grignard reagent as a method for the
synthesis of alcohols.
Reaction of Grignard Reagents
with Epoxides
R
MgX
MgX
CH2
H2 C
O
CH2
Example
CH2MgCl
MgCl
R
CH2
+ H2 C
O
CH2
OMgX
MgX
H3 O+
RCH2CH2OH
H
CH3
O
OH
anti
addition
inversion
H3C
H
NaOH
1. diethyl ether
2. H3O+
CH2CH2 CH2OH
(71%)
In General...
In General...
Reactions of epoxides involve attack by a
nucleophile and proceed with ring-opening.
For ethylene oxide:
+ H2 C
Nu—
Nu—H
CH2
For epoxides where the two carbons of the
ring are differently substituted:
Anionic nucleophiles
attack here.
(less hindered)
Nucleophiles attack here
when the reaction is
catalyzed by acids.
O
R
CH2
C
H
O
Nu—
Nu—CH2CH2 O—H
Example
H2 C
CH2
O
Nucleophilic Ring-Opening
NaOCH2 CH3
Reactions of Epoxides
CH3CH2 OH
CH3CH2 O
CH2CH2 OH
(50%)
CH3CH2
Mechanism
•• –
O ••
••
H2 C
H2 C
CH2
O ••
CH3CH2
O
••
CH2CH2
•• –
O ••
••
CH2CH3
KSCH2CH2CH2 CH3
ethanol-water, 0°C
H
CH3CH2 CH2CH2S
CH3CH2
••
O
••
CH2CH2
••
O
••
H
CH2
O
– ••
•O
•
••
••
Example
– ••
•O
•
••
CH2CH3
CH2CH2 OH
(99%)
Stereochemistry
H
H
NaOCH2 CH3
O
CH3CH2 OH
Anionic Nucleophile Attacks Less-crowded Carbon
OCH2CH3
H
H3 C
CH3
C
C
H
OH
(67%)
H
CH3
O
CH3CH
CCH3
OH
Stereochemistry
What is the product isolated when the epoxide below reacts
with NaOCH3 in CH3OH?
H3 C
H
R
A)
CH3
Consistent with SN 2-like transition state
Question
•
CH3OH
CH3O
(53%)
Inversion of configuration at carbon being
attacked by nucleophile.
Suggests SN 2-like transition state.
•
NaOCH
NaOCH3
H3 C H
B)
R
O
CH3
NH3
H2 O
H2 N
H
S
R
H
OH
CH3
(70%)
•
C)
D)
Inversion of configuration at carbon being
attacked by nucleophile.
Suggests SN 2-like transition state.
Stereochemistry
H3 C
H
R
Question
• What is the product of the reaction shown?
CH3
R
NH3
H2 O
O
H3 C H
H2 N
H
S
R
H
OH
CH3
δ+
H3 N
(70%)
H3 C
H
O
H3 C
H
δ-
• A)
B)
• C)
D)
Anionic Nucleophile Attacks Less-crowded Carbon
MgBr
MgBr
+
H2 C
Lithium Aluminum Hydride Reduces Epoxides
H2 C
CHCH3
O
O
1. diethyl ether
2. H3O+
CH(CH2)7CH3
Hydride attacks
less-crowded
carbon
CH2CHCH3
H3 C
OH
1. LiAlH4, diethyl ether
2. H2O
CH(CH2)7CH3
OH
(60%)
(90%)
Example
Acid-Catalyzed Ring-Opening
Reactions of Epoxides
CH2
H2 C
O
CH3CH2 OH
H2 SO4, 25°C
CH3CH2 OCH2 CH2O H
(87-92%)
CH3CH2OCH2CH2OCH2 CH3 formed only on heating
and/or longer reaction times.
Mechanism
Example
H2 C
CH2
H2 C
O
HBr
10°C
BrCH
BrCH2 CH2 O H
(87-92%)
BrCH2CH2 Br formed only on heating and/or
longer reaction times.
••
• Br
•
••
CH2
+
•
O•
•• –
• Br •
• •
••
H2 C
••
H
CH2
+
O ••
H
••
• Br •
•
•
CH2CH2
••
O
••
H
Acid-Catalyzed Hydrolysis of Ethylene Oxide
Acid-Catalyzed Hydrolysis of Ethylene Oxide
Step 1
H
Step 2
O ••
H
H2 C
H
CH2
H2 C
+
O ••
H
••
•• O
+
+
H
•• O ••
H
+
O ••
Acid-Catalyzed Hydrolysis of Ethylene Oxide
H
H
+ •
H O•
CH2CH2
••
••
Inversion of configuration at site of nucleophilic
attack.
••
O
••
H
H
Stereochemistry
Nucleophile Attacks More-substituted Carbon
H
H
H3 C
CH3
C
C
H
O
CH3OH
H2 SO4
CH3
H
Nucleophile attacks more substituted carbon
of protonated epoxide.
H
•O•
• •
O
••
Characteristics:
H
CH2CH2
••
O
Acid-Catalyzed Ring Opening of Epoxides
H
+
H O ••
H
CH2
+
•
O•
H
CH2CH2
O ••
••
H2 C
H
+ •
H O•
H
H
Step 3
••
CH2
OCH3
CH3CH
OH
CCH3
CH3
(76%)
Consistent with carbocation character at
transition state
O
H
HBr
OH
H
Br
(73%)
Inversion of configuration at carbon being
attacked by nucleophile
Stereochemistry
H3 C
H
R
H3 C H
R
O
Stereochemistry
CH3
CH3OH
H2 SO4
CH3O
H3 C
R
H
H
S
OH
CH3
H
CH3
R
CH3OH
O
R
H2 SO4
H3 C H
H3 C
H
δ+
δ+
CH3O
H
H3 C
δ+
O H
H
anti-Hydroxylation of Alkenes
Question
•
H
S
CH3
(57%)
Inversion of configuration at carbon being
attacked by nucleophile
CH3O
R
H
What is the product isolated when the epoxide at the right
reacts with CH3OH and H2SO4?
H
O
H
CH3COO
COOH
O
H
•
A)
H
B)
H2 O
H
•
C)
OH
D)
H
(80%)
OH
HClO4
OH