Theoretical Study of the Alkaline Hydrolysis of an Oxo-β-Lactam Structure

• Published in: The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory Vol. 103; no. 44; pp. 8879 - 8884
• Main Authors: Coll, Miguel, Frau, Juan, Vilanova, Bartolomé, Donoso, Josefa, Muñoz, Francisco, Blanco, Francisco García
• Format: Journal Article
• Language: English
• Published: American Chemical Society 04.11.1999
• ISSN: 1089-5639; 1520-5215
• DOI: 10.1021/jp991958n

Various potential mechanisms for the alkaline hydrolysis of an oxo-β-lactam in the gas phase (Scheme ) were examined in the light of ab initio data obtained at the RHF/6-31+G*//RHF/6-31+G* and MP2/6-31+G*//MP2/6-31+G* levels. The influence of the solvent was also examined from IPCM (isodensity polarizable continuum model) computations at the RHF/6-31+G* level. In penicillins and cephalosporins, alkaline hydrolysis begins with a nucleophilic attack on the carbonyl group of the β-lactam ring, which is followed by cleavage of the C7−N4 bond. In the oxo-β-lactam studied, the process additionally involves cleavage of the C7−O6 bond in the ring. In fact, this cleavage is subject to a very small activation energy, as little as 0.21 kcal/mol versus the 14.15 kcal/mol for the typical cleavage energy (based on MP2/6-31+G*//MP2/6-31+G* calculations) for the C7−N4 bond. In addition, the hydrolysis end products are more stable than those resulting from the typical cleavage. Consequently, the alkaline hydrolysis involving cleavage of the C7−O6 bonds is kinetically and thermodynamically more favorable than the classical hydrolysis mechanism for penicillins and cephalosporins. This suggests that oxo-β-lactams might act as β-lactamase inhibitors.