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Issue 3, 2007
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The aminolysis of N-aroyl β-lactams occurs by a concerted mechanism

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N-Aroyl β-lactams are imides with exo- and endocyclic acyl centres which react with amines in aqueous solution to give the ring opened β-lactam aminolysis product. Unlike the strongly base catalysed aminolysis of β-lactam antiobiotics, such as penicillins and cephaloridines, the rate law for the aminolysis of N-aroyl β-lactams is dominated by a term with a first-order dependence on amine concentration in its free base form, indicative of an uncatalysed aminolysis reaction. The second-order rate constants for this uncatalysed aminolysis of N-p-methoxybenzoyl β-lactam with a series of substituted amines generates a Brønsted βnuc value of +0.90. This is indicative of a large development of positive effective charge on the amine nucleophile in the transition state. Similarly, the rate constants for the reaction of 2-cyanoethylamine with substituted N-aroyl β-lactams gives a Brønsted βlg value of −1.03 for different amide leaving groups and is indicative of considerable change in effective charge on the leaving group in the transition state. These observations are compatible with either a late transition state for the formation of the tetrahedral intermediate of a stepwise mechanism or a concerted mechanism with simultaneous bond formation and fission in which the amide leaving group is expelled as an anion. Amide anion expulsion is also indicated by an insignificant solvent kinetic isotope effect, kH2ORNH2/kD2ORNH2, of 1.01 for the aminolysis of N-benzoyl β-lactam with 2-methoxyethylamine. The Brønsted βlg value decreases from −1.03 to −0.71 as the amine nucleophile is changed from 2-cyanoethylamine to propylamine. The Brønsted βnuc value is more invariant although it changes from +0.90 to +0.85 on changing the amide leaving group from p-methoxy to p-chloro substituted. The sensitivity of the Brønsted βnuc and βlg values to the nucleofugality of the amide leaving group and the nucleophilicity of the amine nucleophiles, respectively, indicate coupled bond formation and bond fission processes.

Graphical abstract: The aminolysis of N-aroyl β-lactams occurs by a concerted mechanism

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Publication details

The article was received on 09 Nov 2006, accepted on 30 Nov 2006 and first published on 21 Dec 2006

Article type: Paper
DOI: 10.1039/B616420J
Org. Biomol. Chem., 2007,5, 485-493

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    The aminolysis of N-aroyl β-lactams occurs by a concerted mechanism

    W. Y. Tsang, N. Ahmed and M. I. Page, Org. Biomol. Chem., 2007, 5, 485
    DOI: 10.1039/B616420J

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