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17.8
Acetal Formation
Some reactions of aldehydes and ketones progress
beyond the nucleophilic addition stage
Acetal formation
Imine formation
Enamine formation
Compounds related to imines
The Wittig reaction
Recall Hydration of Aldehydes and Ketones
R
C
O ••
••
R'
HOH
R
••
HO
••
C
R'
••
O
••
H
Alcohols Under Analogous Reaction
with Aldehydes and Ketones
R
C
O ••
••
R'
R"OH
R
••
R"O
••
C
R'
••
O
••
H
Product is called
a hemiacetal.
Hemiacetal reacts further in acid to yield an acetal
R
••
R"O
••
C
••
O
••
H
Product is called
an acetal.
R'
ROH, H+
R
••
R"O
••
C
R'
••
O
••
H
Product is called
a hemiacetal.
Example
O
CH + 2CH3CH2OH
HCl
CH(OCH2CH3)2
+ H2O
Benzaldehyde diethyl acetal (66%)
Diols Form Cyclic Acetals
O
CH3(CH2)5CH
+
HOCH2CH2OH
benzene
p-toluenesulfonic acid
H2C
CH2
O
O
+ H2O
C
(81%)
H
(CH2)5CH3
In general:
Position of equilibrium is usually unfavorable
for acetal formation from ketones.
Important exception:
Cyclic acetals can be prepared from ketones.
Example
O
C6H5CH2CCH3 +
HOCH2CH2OH
benzene
p-toluenesulfonic acid
H2C
CH2
O
O
(78%)
C6H5CH2
C
CH3
+ H2O
Mechanism of Acetal Formation
First stage is analogous to hydration and
leads to hemiacetal
acid-catalyzed nucleophilic addition
of alcohol to C=O
Mechanism
H
R
•• O ••
H
C
••
O••
H
O ••
+
R
Mechanism
H
R
•• O ••
H
C
•• +
•• O ••
O
H
R
Mechanism
R
•• O ••
H
C
•• +
O
H
Mechanism
R
••
H
O
+
C
••
O ••
H
Mechanism
R
••
H
O
+
••
O
R
••
H
C
••
O ••
H
Mechanism
R
••
O
••
C
••
O ••
H
H
+
O
R
••
H
Mechanism of Acetal Formation
Second stage is hemiacetal-to-acetal conversion
involves carbocation chemistry
Hemiacetal-to-acetal Stage
H
R
••
O
••
C
••
O ••
H
H
O ••
+
R
Hemiacetal-to-acetal Stage
R
••
O
••
C
••
H
H
•• O ••
O+
H
R
Hemiacetal-to-acetal Stage
R
••
O
••
C
••
H
O+
H
Hemiacetal-to-acetal Stage
R
••
O
••
C+
••
H
•• O
H
Hemiacetal-to-acetal Stage
R
R
••
O
••
C+
+
O
••
C
Carbocation is stabilized by delocalization
of unshared electron pair of oxygen
Hemiacetal-to-acetal Stage
R
••
O
••
C+
••
R
•• O
H
Hemiacetal-to-acetal Stage
R
••
O
••
C
••
R
O+
H
Hemiacetal-to-acetal Stage
R
••
O
••
C
••
R
O+
H
••
R
•• O
H
Hemiacetal-to-acetal Stage
R
••
O
••
C
••
R
O
••
H
••
R
O
+
H
Hydrolysis of Acetals
OR"
R
C
O
C
R' + H2O
OR"
mechanism:
R
reverse of acetal formation;
hemiacetal is intermediate
application:
aldehydes and ketones can be
"protected" as acetals.
+
R'
2R"OH
17.9
Acetals as Protecting Groups
Example
The conversion shown cannot be carried out
directly...
O
CH3CCH2CH2C
CH
1. NaNH2
2. CH3I
O
CH3CCH2CH2C
CCH3
because the carbonyl group and the
carbanion are incompatible functional
groups.
O
CH3CCH2CH2C
C:
–
Strategy
1) protect C=O
2) alkylate
3) restore C=O
Example: Protect
O
CH3CCH2CH2C
CH +
HOCH2CH2OH
benzene
p-toluenesulfonic acid
H2C
CH2
O
O
C
CH3
CH2CH2C
CH
Example: Alkylate
H2C
CH2
O
O
C
CH3
1. NaNH2
2. CH3I
CH2CH2C
CCH3
H2C
CH2
O
O
C
CH3
CH2CH2C
CH
Example: Deprotect
H2C
CH2
O
O
H2O
C
CH3
CH2CH2C
CCH3
HCl
O
HOCH2CH2OH
+
CH3CCH2CH2C
(96%)
CCH3