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

There is a non-linear dependence of the rate of aminolysis of benzylpenicillin and 6--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 pKa of the conjugate acid of the amine yield Brønsted 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--aminopenicillanic acid