SN2 Substitution Reactions at the Amide Nitrogen in the Anomeric Mutagens, N-Acyloxy-N-alkoxyamides

Katie L. Cavanagh; Stephen A. Glover; Helen L. Price; Rhiannon R. Schumacher

doi:10.1071/CH09166

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S_N2 Substitution Reactions at the Amide Nitrogen in the Anomeric Mutagens, N-Acyloxy-N-alkoxyamides

Katie L. Cavanagh ^A , Stephen A. Glover ^A ^B , Helen L. Price ^A and Rhiannon R. Schumacher ^A

+ Author Affiliations

- Author Affiliations

^A Department of Chemistry, School of Science and Technology, University of New England, Armidale, NSW 2351, Australia.

^B Corresponding author. Email: sglover@une.edu.au

Australian Journal of Chemistry 62(7) 700-710 https://doi.org/10.1071/CH09166
Submitted: 19 March 2009 Accepted: 14 May 2009 Published: 13 July 2009

Abstract

N-Acyloxy-N-alkoxyamides 1a are unusual anomeric amides that are pyramidal at the nitrogen because of bis oxyl substitution. Through this configuration, they lose most of their amide character and resemble α-haloketones in reactivity. They are susceptible to S_N2 reactions at nitrogen, a process that is responsible for their mutagenic behaviour. Kinetic studies have been carried out with the nucleophile N-methylaniline that show that, like S_N2 reactions at carbon centres, the rate constant for S_N2 displacement of carboxylate is lowered by branching β to the nitrogen centre, or bulky groups on the alkoxyl side chain. Branching or bulky groups on the carboxylate leaving group, however, do not impact on the rate of substitution, which is mostly controlled by the pK_A of the departing carboxylate group. These results are in line with computed properties for the model reaction of ammonia with N-acetoxy-N-methoxyacetamide but are in contrast to the role of steric effects on their mutagenicity.

Acknowledgement

The authors are grateful to Dr David Tucker for assistance with recording of ¹⁵N NMR spectra.

References

^¶ Heteroatom rearrangements on nitrogen; first presented to the 2nd Heron Island Conference on Reactive Intermediates and Unusual Molecules, Heron Island, Australia, 1994.

^‡ Electron density-electrostatic potential energy surface.

SN2 Substitution Reactions at the Amide Nitrogen in the Anomeric Mutagens, N-Acyloxy-N-alkoxyamides

Abstract

Acknowledgement

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S_N2 Substitution Reactions at the Amide Nitrogen in the Anomeric Mutagens, N-Acyloxy-N-alkoxyamides