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

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 SN2 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 SN2 reactions at carbon centres, the rate constant for SN2 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 pKA 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.