Structure and efficiency in intramolecular and enzymic catalysis: intramolecular general base catalysis. Hydrolysis of monoaryl malonates

Abstract

The hydrolysis of monoaryl malonate anions is subjectto intramolecular general base catalysis by the ionised carboxy-group. The mechanism does not change when the angle, and thus the distance also, between the catalytic and substrate groups is varied in a series of dialkylmalonic acid derivatives. This makes it possible to examine the dependence of reactivity on geometry, which includes such factors as orbital alignment, in a system uncomplicated by strain or steric effects. The sensitivity is small: over a range of structural variation sufficient to produce enormous effects on reactivity in intramolecular nucleophilic catalysis, the efficiency of intramolecular general base catalysis changes by a factor of less than ten. Catalytic efficiency is also low in absolute terms, reaching a limiting effective concentration of ca. 100M, to be compared with 10⁸ M for intramolecular nucleophilic catalysis uncomplicated by strain. The difference is ascribed to differences in transition state properties, particularly internal entropies, for the two mechanisms. The explanation has important implications for the origins of high efficiency in enzymic catalysis.