Semiempirical calculations of substituent effects on the reactions of cephem-like beta-lactam molecules

Abstract

Semiempirical PM3 MO calculations are applied to estimate both 1-atom (X=S, O, C) and 3-substituent CY=R, CH(2)R, SR, CH(2)SR) effects on the reactions of some 1-atom-replaced and 3-substituted cephem-like beta-lactam compounds of thiacephems, oxacephems, and carbacephems. Stabilization energy (SE) of the reaction intermediate for the reaction with a hydroxyl ion can be used to evaluate the facility of a reaction and selected as a chemical reactivity index. With the 1-atom effect only, the SE values obtained imply that thiacephems are generally more reactive than the other two cephem-like molecules and the reactivity order is thiacephems>oxacephems>carbacephems. When it comes to the 3-substituent (Y=R, CH(2)R, SR, CH(2)SR) effect, chemical reactivity can be best realized by using a 3-substituted thiacephem molecule capable of giving a resonance-stabilized and electron-rich leaving group after the reaction with a nucleophile. SE values, however, decrease in most cases when an additional intervening ethylene group is present (Y=CH(2)R, CH(2)SR). The overall 3-substituent reactivity tendency is SR>CH(2)SR>R>CH(2)R.