The carbohydrate-catalysed hydrolysis of cephalosporins

Abstract

The decomposition of cephaloridine, cephtazidime, cephaclor, cephalothin, cephaloglycin, cephalexin and cephradine catalysed by glucose, galactose, maltose, sucrose, mannitol and α-methylglucoside in aqueous solutions of pH 9–11 is reported. The rate of decomposition depends upon the structure of the cephalosporin, the more important feature being the electron withdrawing nature of the substituent attached to the exocyclic C-3 methylene carbon atom. At pH 9.5 a Hammett ρ₁ value of 2.9 is obtained from a plot of log k₂, the apparent second-order rate constant, versusσ₁ for the glucose catalysed reaction. At pH ca. 9 plots of k_∘versus catalyst concentration appear linear, but above pH ca. 10 such plots are curved. The extent of catalysis increases at higher pH values. Carbohydrates with a hemiacetal OH group are significantly better catalysts than those that do not contain this functionality, though catalysis by non-hemiacetal groups is evident. The difference in reactivity between the two types of OH at pH 9.5 lies between 10 and 15-fold. The results are interpreted in terms of a mechanism that involves nucleophilic catalysis via the hemiacetal anion of the carbohydrate. Curvature of the k_oversus[catalyst] plots is explained by the formation of non-catalytic dimer between the anionic and neutral forms of the catalyst.