An activated sulfonylating agent that undergoes general base-catalyzed hydrolysis by amines in preference to aminolysis

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

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

(Chemical Equation Presented) Activated sulfonyl derivatives, similar to acyl ones, usually undergo aminolysis with amines in water as nucleophilic attack by the amine is preferred to hydrolysis. However, despite being active sulfonyl derivatives, four-membered heterocyclic sulfonamides, β-sultams, do not undergo aminolysis in aqueous solution but preferentially react to give hydrolysis products only. The rate of the reaction of β-sultams in buffered solutions of simple primary amines shows a first-order dependence on amine concentrations attributed to general base-catalyzed hydrolysis by the amine. Even N-benzyl-4,4-dimethyl-3-oxo-β-sultam, which is both a β-sultam and a β-lactam, undergoes hydrolysis at the sulfonyl center rather than aminolysis at either the sulfonyl or acyl center. The solvent kinetic isotope effects (SKIE, kH2O/kD2O) for the amine-catalyzed hydrolyses are 1.4 and 1.9 for the hydrolysis of N-benzoyl-β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, respectively, compatible with a general base-catalyzed mechanism. The amine-catalyzed hydrolysis gives a Bronsted β value of +0.9 for both N-benzoyl β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, indicating that the general base amine is almost fully protonated in the transition state. A general base-catalyzed mechanism for hydrolysis rather than nucleophilic attack was also deduced for the reaction of N-benzyl-4,4-dimethyl-3-oxo-β-sultam with carboxylate anions based on a SKIE of 1.7-1.9 and rate constants which fit the Bronsted plot for amines. In contrast to acyl transfer reactions, those for sulfonyl transfer appear to show an inverse reactivity-selectivity relationship - the most active compounds being the most selective. The lack of reactivity of β-sultams toward amine nucleophiles appears to be related to the mechanism of ring opening of β-sultams with a decreased reactivity toward amines relative to hydroxide ion, probably related to the expulsion of the relatively poor leaving group amide anion.

Original languageEnglish
Pages (from-to)4504-4512
Number of pages9
JournalJournal of Organic Chemistry
Volume73
Issue number12
Early online date15 May 2008
DOIs
Publication statusPublished - 20 Jun 2008

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Amines
Hydrolysis
Anions
naphthosultone
Derivatives
Lactams
Nucleophiles
Sulfonamides
Amides
Isotopes
Rate constants
Kinetics
Water

Cite this

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title = "An activated sulfonylating agent that undergoes general base-catalyzed hydrolysis by amines in preference to aminolysis",
abstract = "(Chemical Equation Presented) Activated sulfonyl derivatives, similar to acyl ones, usually undergo aminolysis with amines in water as nucleophilic attack by the amine is preferred to hydrolysis. However, despite being active sulfonyl derivatives, four-membered heterocyclic sulfonamides, β-sultams, do not undergo aminolysis in aqueous solution but preferentially react to give hydrolysis products only. The rate of the reaction of β-sultams in buffered solutions of simple primary amines shows a first-order dependence on amine concentrations attributed to general base-catalyzed hydrolysis by the amine. Even N-benzyl-4,4-dimethyl-3-oxo-β-sultam, which is both a β-sultam and a β-lactam, undergoes hydrolysis at the sulfonyl center rather than aminolysis at either the sulfonyl or acyl center. The solvent kinetic isotope effects (SKIE, kH2O/kD2O) for the amine-catalyzed hydrolyses are 1.4 and 1.9 for the hydrolysis of N-benzoyl-β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, respectively, compatible with a general base-catalyzed mechanism. The amine-catalyzed hydrolysis gives a Bronsted β value of +0.9 for both N-benzoyl β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, indicating that the general base amine is almost fully protonated in the transition state. A general base-catalyzed mechanism for hydrolysis rather than nucleophilic attack was also deduced for the reaction of N-benzyl-4,4-dimethyl-3-oxo-β-sultam with carboxylate anions based on a SKIE of 1.7-1.9 and rate constants which fit the Bronsted plot for amines. In contrast to acyl transfer reactions, those for sulfonyl transfer appear to show an inverse reactivity-selectivity relationship - the most active compounds being the most selective. The lack of reactivity of β-sultams toward amine nucleophiles appears to be related to the mechanism of ring opening of β-sultams with a decreased reactivity toward amines relative to hydroxide ion, probably related to the expulsion of the relatively poor leaving group amide anion.",
author = "Tsang, {Wing Y.} and Naveed Ahmed and Karl Hemming and Page, {Michael I.}",
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An activated sulfonylating agent that undergoes general base-catalyzed hydrolysis by amines in preference to aminolysis. / Tsang, Wing Y.; Ahmed, Naveed; Hemming, Karl; Page, Michael I.

In: Journal of Organic Chemistry, Vol. 73, No. 12, 20.06.2008, p. 4504-4512.

Research output: Contribution to journalArticle

TY - JOUR

T1 - An activated sulfonylating agent that undergoes general base-catalyzed hydrolysis by amines in preference to aminolysis

AU - Tsang, Wing Y.

AU - Ahmed, Naveed

AU - Hemming, Karl

AU - Page, Michael I.

PY - 2008/6/20

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N2 - (Chemical Equation Presented) Activated sulfonyl derivatives, similar to acyl ones, usually undergo aminolysis with amines in water as nucleophilic attack by the amine is preferred to hydrolysis. However, despite being active sulfonyl derivatives, four-membered heterocyclic sulfonamides, β-sultams, do not undergo aminolysis in aqueous solution but preferentially react to give hydrolysis products only. The rate of the reaction of β-sultams in buffered solutions of simple primary amines shows a first-order dependence on amine concentrations attributed to general base-catalyzed hydrolysis by the amine. Even N-benzyl-4,4-dimethyl-3-oxo-β-sultam, which is both a β-sultam and a β-lactam, undergoes hydrolysis at the sulfonyl center rather than aminolysis at either the sulfonyl or acyl center. The solvent kinetic isotope effects (SKIE, kH2O/kD2O) for the amine-catalyzed hydrolyses are 1.4 and 1.9 for the hydrolysis of N-benzoyl-β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, respectively, compatible with a general base-catalyzed mechanism. The amine-catalyzed hydrolysis gives a Bronsted β value of +0.9 for both N-benzoyl β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, indicating that the general base amine is almost fully protonated in the transition state. A general base-catalyzed mechanism for hydrolysis rather than nucleophilic attack was also deduced for the reaction of N-benzyl-4,4-dimethyl-3-oxo-β-sultam with carboxylate anions based on a SKIE of 1.7-1.9 and rate constants which fit the Bronsted plot for amines. In contrast to acyl transfer reactions, those for sulfonyl transfer appear to show an inverse reactivity-selectivity relationship - the most active compounds being the most selective. The lack of reactivity of β-sultams toward amine nucleophiles appears to be related to the mechanism of ring opening of β-sultams with a decreased reactivity toward amines relative to hydroxide ion, probably related to the expulsion of the relatively poor leaving group amide anion.

AB - (Chemical Equation Presented) Activated sulfonyl derivatives, similar to acyl ones, usually undergo aminolysis with amines in water as nucleophilic attack by the amine is preferred to hydrolysis. However, despite being active sulfonyl derivatives, four-membered heterocyclic sulfonamides, β-sultams, do not undergo aminolysis in aqueous solution but preferentially react to give hydrolysis products only. The rate of the reaction of β-sultams in buffered solutions of simple primary amines shows a first-order dependence on amine concentrations attributed to general base-catalyzed hydrolysis by the amine. Even N-benzyl-4,4-dimethyl-3-oxo-β-sultam, which is both a β-sultam and a β-lactam, undergoes hydrolysis at the sulfonyl center rather than aminolysis at either the sulfonyl or acyl center. The solvent kinetic isotope effects (SKIE, kH2O/kD2O) for the amine-catalyzed hydrolyses are 1.4 and 1.9 for the hydrolysis of N-benzoyl-β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, respectively, compatible with a general base-catalyzed mechanism. The amine-catalyzed hydrolysis gives a Bronsted β value of +0.9 for both N-benzoyl β-sultam and N-benzyl-4,4-dimethyl-3-oxo-β-sultam, indicating that the general base amine is almost fully protonated in the transition state. A general base-catalyzed mechanism for hydrolysis rather than nucleophilic attack was also deduced for the reaction of N-benzyl-4,4-dimethyl-3-oxo-β-sultam with carboxylate anions based on a SKIE of 1.7-1.9 and rate constants which fit the Bronsted plot for amines. In contrast to acyl transfer reactions, those for sulfonyl transfer appear to show an inverse reactivity-selectivity relationship - the most active compounds being the most selective. The lack of reactivity of β-sultams toward amine nucleophiles appears to be related to the mechanism of ring opening of β-sultams with a decreased reactivity toward amines relative to hydroxide ion, probably related to the expulsion of the relatively poor leaving group amide anion.

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