Theoretical Study of Amine-Assisted Aminolysis of Penicillins − The Kinetic Role of the Carboxylate Group

Abstract

The β-lactam ring opening of 3α-carboxypenam through a methylamine aminolysis reaction catalyzed by another methylamine molecule is studied at the B3LYP/6−31+G* level of theory. Two different neutral mechanisms have been found: a concerted one and a stepwise route through two neutral tetrahedral intermediates. In the gas-phase the most favorable mechanism is stepwise, in which the carboxylate group of 3α-carboxypenam participates directly in the reaction coordinate as a proton shuttle. In aqueous solution the concerted mechanism is the most favored route in which the electrostatic effect of the carboxylate group plays an important role by enhancement of the solute-solvent interaction. The structure and molecular properties of the concerted transition state correlate well with the experimentally reported Bronsted β value and with the greater catalytic advantage of amines compared with water in the aminolysis of penicillins. These effects of the carboxylate group may be of some relevance, not only to understand the aminolysis of β-lactam antibiotics, but also to understand their hydrolysis in aqueous or enzymatic environments.