Text Related to Segment 20.05 ©2002 Claude E. Wintner
We
now
may
return
profitably
to
the
previously
introduced
addition/substitution dichotomy of carbonyl chemistry. In basic medium the aldol
condensation is the result of addition of an enolate anion to the carbonyl group of an
aldehyde or ketone. Since it is a general property of esters that they undergo
instead substitution at the carbonyl functionality, we also may expect to see such a
substitution reaction involving an enolate anion.
Indeed, under appropriate
conditions this is readily observed, and termed the Claisen condensation or, simply,
the ester condensation. When two molecules of ethyl acetate are treated with a full
mole of sodium ethylate in ethanol, followed by an acidic workup, ethyl acetoacetate
(so-called "acetoacetic ester") is produced.
Although the pKA of ethyl acetate
is 22, and that of ethanol is only 18, sodium ethylate nevertheless is a strong enough
base to produce a concentration of the ethyl acetate enolate anion requisite for
addition to other molecules of ethyl acetate at their carbonyl groups at a reasonable
rate. In turn, this reaction is followed by displacement of ethylate anion from the
addition complex, the result being a β-keto ester. Herein lies the crux for the
success of the Claisen condensation, allowing it to be driven forward to completion
under circumstances that otherwise would be thermodynamically unfavorable: the
pK A of ethyl acetoacetate at the carbon atom doubly activated by the two carbonyl
groups is only 10. In other words, ethyl acetoacetate is more acidic than is ethanol,
by 8 orders of magnitude. Hence, given the full mole of sodium ethylate employed
in the reaction, the ethyl acetoacetate effectively is removed from the reaction as
soon as it is produced, being transformed instead to its corresponding stable
delocalized conjugate anion, the five-orbital-six-electron system shown in the figure:
1 full mole
O
O
H 3C
OEt
H
O
EtO Na
CH2
EtOH
OEt
two molecules pK = 22
A
of ethyl acetate
O
H 3C
pKA = 18
C
H2
pKA = 10
Claisen (Ester)
Condensation
O
EtO Na
O
workup in acid
C
OEt
H2
ethyl acetoacetate,
often called
"acetoacetic ester"
O
C
H
O
OEt
OEt
H 3C
C
H
O
OEt
H 3C
O
C
H
formation of
delocalized
anion
condensation + elimination = substitution
O
C
H
O
mechanism:
EtO
O
driving force for the
reaction is the formation
of the delocalized anion:
a five-orbital-six-electron
system
functionality: -keto ester
H 3C
O
H 3C
H 3C
O
OEt
OEt
EtO
H 2C
ethyl acetate
H 3C
H 3C
elimination
(overall,
substitution)
enolate
formation
enolate
EtO
EtO
O
H
H
O
H
H
EtO
H 3C
O
condensation
EtO
O
H 3C
second molecule
of ethyl acetate
the Claisen or ester condensation, illustrated for ethyl acetate
O
O
The above analysis explains why a full mole of base is necessary to run the Claisen
condensation, as well as why this condensation reaction cannot be carried out in acid,
where the final driving force cannot exist.
As the β-hydroxy carbonyl or α,β -unsaturated carbonyl functionalities are
distinguishing indications of the aldol condensation, so is the β-keto ester functionality
the hallmark of the Claisen condensation. And, just as for the aldol condensation, so
also for the Claisen: intramolecular reaction will lead to cyclic molecules, here cyclic βketo esters. The cyclic Claisen condensation, generally referred to as the Dieckmann
condensation, is exemplified by the cyclization of diethyl heptanedioate to form 2carboethoxy cyclohexanone. Again, the difference between the cyclic and acyclic
cases simply amounts to a tether — here of three methylene groups — joining the
two ethyl acetate moieties of the acyclic case:
H2
C
H 2C
1) 1 full mole
CH2
O
H 2C
O
H 2C
OEt
OEt
new C—C bond
EtO Na
in EtOH
2) workup in acid
O
EtO
Dieckmann product
(functionality:
-keto ester)
(2-carboethoxy
cyclohexanone)
diethyl heptanedioate
O
mechanism:
EtO
H 2C
H2
C
H
EtO
H 2C
EtO
H2
C
O
C
H2
O
H
H 2C
O
H 2C
EtO
C
H2
O
product
(via delocalized
anion and
subsequent acid
workup)
the Dieckmann condensation, illustrated for diethyl heptanedioate
©2002 Claude E. Wintner