Page 676 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

658 The preceding discussion has touched on the most fundamental aspects of ester
hydrolysis mechanisms. Much effort has been devoted to establishing some of the finer
CHAPTER 7
details, particularly concerning proton transfers during the formation and breakdown
Addition, Condensation of the tetrahedral intermediates. These studies have been undertaken in part because of
and Substitution
Reactions of Carbonyl the importance of hydrolytic reactions in biological systems, which are catalyzed by
Compounds enzymes. The detailed mechanistic studies of ester hydrolysis laid the groundwork for
understanding the catalytic mechanisms of the hydrolytic enzymes. Discussions of the
biological mechanisms and their relationship to the fundamental mechanistic studies
are available in several books that discuss enzyme catalysis in terms of molecular
mechanisms. 39
Esters react with alcohols in either acidic or basic solution to exchange alkoxy
groups (ester interchange) by a mechanism that parallels hydrolysis. The alcohol or
alkoxide acts as the nucleophile.

–
O O O
R"O –
RCOR' + R"OH RC OR' RCOR" + R'OH
OR"
O OH O
H +
RCOR' + R"OH RC OR' RCOR" + R'OH
OR"

As in the case of hydrolysis, there has been a good deal of study of substituent effects,
solvent effects, isotopic exchange, kinetics, and the catalysis of these processes. 40 In
contrast to hydrolysis, the alcoholysis reaction is reversible in both acidic and basic
solutions. The key intermediate is the tetrahedral adduct. Its fate is determined mainly
by the relative basicity of the two alkoxy groups. A tetrahedral intermediate generated
by addition of methoxide ion to a p-nitrophenyl ester, for example, breaks down
exclusively by elimination of the much less basic p-nitrophenoxide ion.

O – O
RC OCH 3 RCOCH 3 + – O Ph-4-NO 2
O Ph-4-NO 2

In general, the equilibrium in a base-catalyzed alcohol exchange reaction lies in the
direction of incorporation of the less acidic alcohol in the ester. This is a reflection
both of the kinetic factor, the more acidic alcohol being a better leaving group, and the
greater stabilization provided to the carbonyl group by the more electron-rich alkoxy
substituent.

39 T. C. Bruice and S. J. Benkovic, Bioorganic Mechanisms, Vol. 1, W. A. Benjamin, New York, 1966,
pp. 1–258; W. P. Jencks, Catalysis in Chemistry and Enzymology, McGraw-Hill, New York, 1969;
M. L. Bender, Mechanisms of Homogeneous Catalysis from Protons to Proteins, Wiley-Interscience,
New York, 1971; C. Walsh, Enzymatic Reaction Mechanisms, W. H. Freeman, San Francisco, 1979;
A. Fersht, Enzyme Structure and Mechanism, 2nd Edition, W. H. Freeman, New York, 1985.
40
C. G. Mitton, R. L. Schowen, M. Gresser, and J. Shapely, J. Am. Chem. Soc., 91, 2036 (1969);
C. G. Mitton, M. Gresser, and R. L. Schowen, J. Am. Chem. Soc., 91, 2045 (1969).