Chapter 21: Ester Enolates
21.1: Ester  Hydrogens and Their pKa’s. The -protons
of esters are less acidic that ketones and aldehydes.
Typical pKa’s of carbonyl compounds (-protons):
aldehydes 17
O
O
ketones
19
C
C
H C
CH
H C
H
H C
esters
24
O
amides
30
H C C N
C
H C
N(CH )
nitriles
25
Acidity of 1,3-dicarbonyl compounds
3
3
3
O
C
3
OCH3
3
3
3 2
O
O
H3C
C
H3C
OCH3
H3CO
O
C
C
C
O
O
OCH3
CH3
ketone
pKa= 19
ester
pKa= 24
O
C
H3C
C
C
C
O
O
OCH3
H3C
C
C
C
CH3
H H
H H
H H
1,3-diester
pKa= 13
1,3-keto ester
pKa= 11
1,3-diketone
pKa= 9
191
21.2: The Claisen Condensation Reaction. Base-promoted
condensation of two esters to give a -keto-ester product
O
2
H3C C OEt
Ethyl acetate
NaOEt
EtOH
then H3O+
O
O
H3C CH CH2 C OEt
Ethyl 3-oxobutanoate
(Ethyl acetoacetate)
Mechanism (Fig. 21.1, page 884-5) is a nucleophilic acyl
substitution of an ester by an ester enolate and is related to the
mechanism of the aldol condensation.
192
21.3: Intramolecular Claisen Condensation: The Dieckmann
Cyclization. Dieckmann Cyclization works best with 1,6-diesters,
to give a 5-membered cyclic -keto ester product, and 1,7-diesters
to give 6-membered cyclic -keto ester product.
O
OEt
O
OEt
O
O
EtONa, EtOH
CO2Et
EtONa, EtOH
OEt
O
CO2Et
OEt
O
Mechanism: same as the Claisen Condensation
193
21.4: Mixed Claisen Condensations. Similar restrictions as the
mixed aldol condensation.
O
Four possible products
O
H3CH2CH2C
C
C
EtONa,
EtOH
O
OEt
+
H3C
C
C
C5
C
O
C
OEt
H3C H
O
then H3O+
C3
C
H3CH2C
C
C
O
O
C
OEt
C
H3CH2CH2CH2C
H3C H
OEt
H
H3CH2CH2C
O
C
O
C
H3CH2C
OEt
H H
H H
C
H3CH2CH2CH2C
O
C
H3CH2CH2C
C
OEt
H
Esters with no -protons can only act as the electrophile
O
C
OEt
+
H3C
C
C
O
EtONa,
EtOH
O
C
C
OEt
C
OEt
H3C H
then H3O+
H H
O
Discrete (in situ) generation of an ester enolate with LDA
O
O
H3CH2CH2C
C
C
LDA, THF, -78°C
OEt
H3C
O Li+
H3CH2CH2C
H H
C
C
C
C
H H
OEt
then H2O+
H
O
OEt
H3CH2C
C
O
C
H3CH2CH2C
C
OEt
H
O
O
H3C
C
C
H H
LDA, THF, -78°C
OEt
O
H3C
C
H
C
Li+
H3CH2CH2C
C
C
H H
OEt
then
H3O+
O
OEt
H3CH2CH2CH2C
C
O
C
C
H3C H
OEt
194
21.5: Acylation of Ketones with Esters. An alternative to the
Claisen condensations and Dieckmann cyclization.
b)
O
a) LDA, THF, -78° C
O
H3CO
O
C
O
O
OCH3
OCH3
H3CO- Na+,
H3COH
Equivalent to a mixed
Claisen condensation
O
O
b)
a) LDA, THF, -78° C
Equivalent to a
Dieckmann cyclization
H3CO
O
O
C
OCH3
OR
+
O
O
H3C
O
C
OCH3
OCH3
H3CO- Na+,
H3COH
O
H3CO
O
OCH3
195
21.6: Ketone Synthesis via -Keto Esters. The -keto ester
products of a Claisen condensation or Dieckmann cyclization
can be hydrolyzed to the -keto acid and decarboxylated to the
ketone.
O
H3CH2CO
C
O
C
C
NaOH, H2O
OCH2CH3
H R
or H3O+
H
O
O
C
C
C
H
- CO2
O
H
OH
H R
O
C
C
H
OH
H3CH2CO
O
C
C
C
H R
O
NaOH, H2O
R'
or H3O+
O
C
H
R
C
C
H R
H
- CO2
O
R'
H
C
C
OH
H R
enol
O
O
tautomerization
C
carboxylic
acid
O
C
R
enol
O
tautomerization
R'
H
C
C
R'
H R
ketone
196
21.7: Acetoacetic Ester Synthesis. The anion of ethyl
acetoacetate can be alkylated using an alkyl halide (SN2). The
product, a -keto ester, is then hydrolyzed to the -keto acid and
decarboxylated to the ketone.
O
H3C
C
EtO
C
CO2Et + RH2C-X
H H
ethyl acetoacetate
EtOH
alkyl
halide
O
Na+
C
CO2Et
HCl, 
H3C
C
RH2C H
EtO Na+,
EtOH
O
O
C
CO2H
H3C
C
RH2C H
H3C
C
C
CH2R
H H
ketone
R'H2C-X
O
O
C
C
H3C
C
OEt
R'H2C CH2R
HCl, 
O
O
C
C
H3C
C
OH
R'H2C CH2R
O
H3C
C
C
CH2R
H CH2R'
An acetoacetic ester can undergo one or two alkylations to give
an -substituted or -disubstituted acetoacetic ester
The enolates of acetoacetic esters are synthetic equivalents to
197
ketone enolates
-Keto esters other than ethyl acetoacetate may be used. The
products of a Claisen condensation or Dieckmann cyclization
are acetoacetic esters (-keto esters)
O
O
EtONa, EtOH
OEt
O
CO2Et
O
O
EtONa,
EtOH
H3O+
CO2Et

Br
then H3O+
acetoacetic
ester
OEt
Dieckmann cyclization
NaOEt
O
2 H3CH2C C OEt
EtOH
then H3O+
O
H3CH2C C
O
HC C OEt
acetoacetic
ester
CH3
EtONa,
EtOH
O
Br H3CH2C C
O
C C OEt
CH3
H3O+

O H
H3CH2C C C CH2CH=CH2
CH3
Claisen condensation
198
21.8: The Malonic Acid Synthesis.
overall reaction
CO2Et
EtO
+
RH2C-X
EtO2C
EtOH
CO2Et
diethyl
malonate
Et= ethyl
Na+
alkyl
halide
C
CO2Et
HCl, 
CO2H
RH2C-CH2-CO2H
carboxylic
acid
R'H2C-X
HCl, 
EtO2C
C
RH2C H
RH2C H
EtO Na+,
EtOH
HO2C
C
CO2Et
RH2C CH2R'
HO2C
C
CO2H
RH2C CH2R'
CH2R
CH CO2H
R'H2C
carboxylic
acid
199
O
H
C
C
CH3
+ H3CO
O
H
H H
H3C
C
O
C
C
OCH3
+ H3CO
H3C
H H
O
C
C
C
C
OCH3
+ H3COH
pKa= 16
H
O
C
CH3
O
acetoacetic ester
pKa= 11
H
+ H3COH
pKa= 16
H
acetoacetic ester
pKa= 19
O
C
C
O
+ EtO
OEt
H
H H
C
C
+
OEt
EtOH
pKa= 16
H
ethyl acetate
pKa= 25
O
O
EtO
C
C
C
+ EtO
OEt
H H
diethyl malonate
pKa= 13
EtO
O
O
C
C
C
+
OEt
EtOH
pKa= 16
H
200
Summary:
Malonic ester synthesis: equivalent to the alkylation of a
carboxylic (acetic) acid enolate
Acetoacetic ester synthesis: equivalent to the alkylation of an
ketone (acetone) enolate
21.9: Michael Addition of Stablized Anions. Enolates of
malonic and acetoacetic esters undergo Michael (1,4-) addition
to ,-unsaturated ketones.
O
H3 C
C
O
C
CH2
H
electrophile
+
EtO
C
EtONa,
EtOH
O
C
C
CH3
H H
O
H H O
C
C
C
H3C
C
C
CH3
H H H CO2Et
nucleophile
This Michael addition product can be decarboxylated
O
H H O
H3O+,
C
C
C
H3C
C
C
CH3 - EtOH,
-CO2
H H H CO2Et
O
H H O
C
C
C
H3C
C
C
CH3
H H H H
201
21.10: Reactions of LDA-Generated Ester Enolates.
Ester enolates can be generated with LDA in THF rapidly and
quantitatively. The resulting enolates can undergo carbonyl
addition reactions with other esters, aldehydes, ketones or
alkylation reactions with alkyl halides or tosylates.
O
C
O
OEt LDA, THF
C
RH2C-X
CH2R
OEt
CO2Et
-78° C
O
O
O
RH2C-X
LDA, THF
O
O
O
CH2R
-78° C
202