The aminolysis of penicillin derivatives. Rate constants for the formation and breakdown of the tetrahedral addition intermediate

Abstract

There is a non-linear dependence of the rate of aminolysis of benzylpenicillin and 6-β-aminopenicillanic acid upon hydroxide ion concentration which is interpreted in terms of formation of a tetrahedral addition intermediate. At high concentrations of hydroxide ion the rate-limiting step is formation of the tetrahedral intermediate but at low concentrations it is the diffusion-controlled encounter of the intermediate and hydroxide ion. Rate constants for the formation of the intermediate and its breakdown to reactants are reported for a variety of amines. The dependence of these rate constants upon the pK_a of the conjugate acid of the amine yield Brønsted β values of ca. 0.3 and –0.6 for the formation and breakdown of the intermediate, respectively. There is thus quite a large dependence of the rate of expulsion of the amine from the intermediate upon the basicity of the amine despite the rate constants for this step being ca. 10⁹–10¹⁰ s^–1. Possible stereoelectronic control in the breakdown of the tetrahedral intermediate is discussed. There is no evidence for intramolecular general base catalysis in the formation of the tetrahedral intermediate from 6-β-aminopenicillanic acid.