Intramolecular general acid catalysis in the aminolysis of β-lactam antibiotics

Abstract

The rate of aminolysis of benzylpenicillin and cephaloridine by hydroxylamine, unlike other amines, shows only a first order dependence on amine concentration. The rate enhancement compared with that predicted from a Bronsted plot for other primary amines with benzylpenicillin is greater than 10⁶. This is much more than an α-effect and is compatible with rate-limiting formation of the tetrahedral intermediate due to a rapid intramolecular general acid catalysed breakdown of the intermediate. For cephaloridine, the rate enhancement is greater than 10⁴ which demonstrates that β-lactam C–N bond fission and expulsion of the leaving group at C3′ are not concerted.