Theoretical study of amine-assisted aminolysis of penicillins - The kinetic role of the carboxylate group

The beta -lactam ring opening of 3 alpha -carboxypenam through a methylamin e aminolysis reaction catalyzed by another methylamine molecule is studied at the B3LYP/6-31+G(*) level of theory. Two different neutral mechanisms ha ve been found: a concerted one and a stepwise route through two neutral tet rahedral intermediates. In the gas-phase the most favorable mechanism is st epwise, in which the carboxylate group of 3 alpha -carboxypenam participate s directly in the reaction coordinate as a proton shuttle. In aqueous solut ion the concerted mechanism is the most favored route in which the electros tatic effect of the carboxylate group plays an important role by enhancemen t of the solute-solvent interaction. The structure and molecular properties of the concerted transition state correlate well with the experimentally r eported Bronsted beta value and with the greater catalytic advantage of ami nes 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 beta -lactam antibiotics, but also to understand their hydrol ysis in aqueous or enzymatic environments.