Quantum mechanical study of beta-lactam reactivity: The effect of solvation on barriers of reaction and stability of transition states and reaction intermediates

beta-Lactams are widely used in medicine as potent antibacterials and in ch emistry as synthetic intermediates. The investigation of the intrinsic reac tivity of beta-lactams is important for the understanding of the mechanisms of action and inactivation of beta-lactamases and penicillin-binding prote ins. Ab initio quantum mechanical calculations using a polarizable continuu m model to estimate solvation effects have been utilized to analyze the hyd rolysis and methanolysis of selected beta-lactams and simple amides. The ro les of four-membered ring strain, reduced amide resonance, substituent and ring fusion effects on hydrolysis, and methanol-mediated hydrolysis of thes e compounds have been studied by reconstructing the corresponding reaction pathways in gas and solution. Strong correlations have been found between t he calculated kinetic, structural, and electronic properties of these compo unds and the experimental data. The findings in this paper shed light on th e contributions of the various structural elements to the reactivity of bet a-lactams. Insights into this reactivity could prove very useful in the des ign of novel potent antimicrobials.