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

Wing Y. Tsang, Naveed Ahmed, Michael I. Page

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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/kD2O RNH2, 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.

Original languageEnglish
Pages (from-to)485-493
Number of pages9
JournalOrganic and Biomolecular Chemistry
Volume5
Issue number3
Early online date21 Dec 2006
DOIs
Publication statusPublished - 7 Feb 2007

Fingerprint

Lactams
amines
Amines
amides
Amides
nucleophiles
Nucleophiles
fission
Anions
Rate constants
penicillin
anions
Propylamines
Cephaloridine
expulsion
Imides
imides
isotope effect
Isotopes
Penicillins

Cite this

Tsang, Wing Y. ; Ahmed, Naveed ; Page, Michael I. / The aminolysis of N-aroyl β-lactams occurs by a concerted mechanism. In: Organic and Biomolecular Chemistry. 2007 ; Vol. 5, No. 3. pp. 485-493.
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abstract = "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 Br{\o}nsted 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 Br{\o}nsted 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/kD2O RNH2, of 1.01 for the aminolysis of N-benzoyl β-lactam with 2-methoxyethylamine. The Br{\o}nsted βlg value decreases from -1.03 to -0.71 as the amine nucleophile is changed from 2-cyanoethylamine to propylamine. The Br{\o}nsted 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 Br{\o}nsted 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.",
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The aminolysis of N-aroyl β-lactams occurs by a concerted mechanism. / Tsang, Wing Y.; Ahmed, Naveed; Page, Michael I.

In: Organic and Biomolecular Chemistry, Vol. 5, No. 3, 07.02.2007, p. 485-493.

Research output: Contribution to journalArticle

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N2 - 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/kD2O RNH2, 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.

AB - 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/kD2O RNH2, 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.

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