Theoretical study of hydrolysis and aminolysis of cephalosporin and thioxocephalosporin

To elucidate the mechanism of alkaline hydrolysis and aminolysis of cephalosporin (Cep) and its thioxo analogue, thioxocephalosporin (Thi), density functional theory and continuum dielectric method were used to map out the solution-phase free-energy profiles. The hydrolysis reactivity of Cep was similar to that of Thi, but Cep was much slower in aminolysis than Thi due to different expulsion between the incoming hydroxide anion and amine. Furthermore, the rate-limiting step for Cep, in both hydrolysis and aminolysis, was the approaching of the negatively charged ion toward the anionic reactant to form a tetrahedral intermediate, and the breakdown of four-membered β-lactam for Thi. The predicted rate-limiting step and relative energy barrier for the hydrolysis and aminolysis of Cep and Thi were in agreement with the experimental results. By establishing model systems, the different reactivity between Cep and Thi was rationalized through amide resonance.