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164 Chapter 7
7.3 Claisen enzymes
In the presence of alkoxide ions, carboxylic esters react via an ester enolate
intermediate to form b-keto-esters. This reaction, illustrated in Figure 7.9 for
ethyl butyrate, is known as the Claisen ester condensation. The Claisen ester
condensation requires more vigorous reaction conditions than the aldol
condensation, since the C2H proton adjacent to an ester is signiWcantly less
acidic than the C2H proton adjacent to a ketone.
Claisen reactions also occur in biological systems, using thioesters rather
than oxygen esters. Since the sulphur atom of a thioester is larger than oxygen
and utilises 3p valence electrons rather than 2p electrons, there is consequently
much less overlap between the sulphur lone pair of electrons and the carbonyl
group than in the oxygen equivalent. Thus the carbonyl group of a thioester
behaves more like a ketone in terms of reactivity than an ester. Shown in Figure
7.10 are pK a values for formation of enolate or enolate equivalents for a
selection of ketone and ester systems. The Wrst set of data highlight the dramatic
increase in acidity of an iminium salt compared to a ketone, which rationalises
the use of enamine intermediates in the class I aldolases. From the second set of
data we can see that the pK a of a b-keto-thioester is similar to that of a
b-diketone, and signiWcantly less than for a b-keto-ester.
The thioester used for biological Claisen ester reactions is the coenzyme
A (CoA) ester that we encountered in Chapter 5 as an acyl transfer
coenzyme. Acetyl Co A is the substrate for several types of carbon–carbon
forming reactions, shown in Figure 7.11.
O
O − OEt
OEt
NaOEt
CO 2 Et
EtO −
H
O
OEt
O
Figure 7.9 Example of a Claisen reaction.
pKa
O
O −
pKa
O O
H
+ H
R
+ 19-20
8.4
R
O
O − O O
H
+ H
RO
+ 24-25
10.5
RO
MeO
+
NEt 2 NEt 2
O O
H
+ H
R
+ 10-12 AcNH
8.5
R
S
Figure 7.10 pK a values for enolate formation.