A Comparison of the Reactivity and Mutagenicity of <i>N</i>-(Benzoyloxy)-<i>N</i>-(benzyloxy)benzamides

Abstract

A new series of N -(acyloxy)- N -alkoxybenzamides, N -(benzoyloxy)- N -(benzyloxy)benzamides 7 have been synthesized and have been found to be direct acting mutagens in Salmonella TA100. They undergo A Al 1 solvolysis to give N -benzoyl- N -(benzyloxy)nitrenium ions 3 under conditions of acid catalysis as well as unusual B Al 2 reactions at nitrogen with hydroxide. The latter process affords as intermediates the anomeric hydroxamic esters 4 which rearrange intramolecularly to esters in a HERON reaction. Rates of acid-catalyzed solvolysis and reaction with hydroxide ions correlate with Hammett σ values with low sensitivity (ρ = +0.32 and +0.55, respectively) in accordance with the A Al 1 and B Al 2 mechanisms. Mutagenicity for the series also appears to correlate with Hammett σ values but with low, negative sensitivity (ρ = −0.57), and their biological activity may be attributable to their stability under conditions of the Ames assay and hydrophobic binding to DNA, rather than their chemical reactivity.