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The chemical reactivity of penicillins and other b-lactam antibiotics

By Philip Proctor, Nigel P. Gensmantel and Michael I. Page

Abstract

The rates of the acid catalysed hydrolysis of penicillins and cephalosporins are linear in Ho and, unlike other amides, show no rate maximum with increasing acidity. Electron-withdrawing substituents at C-6 in penicillins decrease the rate of hydrolysis with a I of ca.4 and they decrease the rate when attached to the amine leaving group. The acylamido-group at C-6 in penicillins, but not at C-7 in cephalosporins, exhibits neighbouring group participation with a rate enhancement of ca. 103. The absence of penicillenic acid formation from benzylpenicillin in acidic solution is not due to the ionisation of the carboxy-group. These observations are rationalised by a scheme, involving N-protonation and formation of an acylium ion intermediate. The alkaline hydrolysis of penicillins proceeds 102 faster than a -lactam after correction for substituent effects. There is no evidence for substantial inhibition of amide resonance in the bicyclic -lactam antibiotics, little evidence to indicate extra strain in these systems and no evidence that expulsion of the leaving group at C-3 in cephalosporins occurs in the transition stat

Topics: Q1, QD
Publisher: Royal Society of Chemistry
OAI identifier: oai:eprints.hud.ac.uk:6214
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