Page 686 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

668 CH 3 O O
H +
+
CH CO CCH (CH ) C O CCH CH CCH + + O CCH
CHAPTER 7 2 2 3 3 2 3 3 3 3
Addition, Condensation
and Substitution Other examples of synthetically useful acylating reagents are given in Section 3.4 of
Reactions of Carbonyl
Compounds Part B.

7.5. Intramolecular Catalysis of Carbonyl Substitution Reactions

The reactions of carbonyl compounds have provided an important testing ground
for developing an understanding of intramolecular catalysis, which is a neighboring-
group interaction that accelerates a reaction. Studies in intramolecular catalysis have
been designed to determine how much more efficiently a given functional group
can act as a catalyst when it is part of the reacting molecule and located in a
position that enables an encounter between the catalytic group and the reaction
center. These studies are relevant to understanding biological mechanisms, because
enzymes achieve exceedingly efficient catalysis by bringing together at the “active
site” combinations of basic, acidic, and nucleophilic groups in a geometry that is
particularly favorable for reaction. The present section illustrates some of the facts
that have emerged from these studies and the mechanistic conclusions that have been
drawn.
It was pointed out in the mechanistic discussion concerning acetal hydrolysis
that general acid catalysis occurs only for acetals having special structural features
(see p. 641) Usually, specific acid catalysis operates. The question of whether
general acid catalysis can be observed in intramolecular reactions has been of
interest because intramolecular general acid catalysis is thought to play a part in
the mechanism of action of the enzyme lysozyme, which hydrolyzes the acetal
linkage present in certain polysaccharides. One group of molecules that has been
examined as a model system are acetals derived from o-hydroxybenzoic acid
(salicylic acid). 66

R CO 2 H
O C O
CO H H
2
The pH-rate profile for hydrolysis of the benzaldehyde acetal (see Figure 7.10) indicates
that of the species that are available, the monoanion of the acetal is the most reactive.
The reaction is fastest in the pH range where the concentration of the monoanion is at
a maximum. The neutral molecule decreases in concentration with increasing pH and
the converse is true for the dianion.

R CO 2 H R CO 2 – R CO 2 –
K a1 K a2
O C O O C O O C O
CO 2 H H CO 2 H H CO 2 – H

66
E. Anderson and T. H. Fife, J. Am. Chem. Soc., 95, 6437 (1973).