James C. Fishbein

Secondary α-deuterium kinetic isotope effects in the decomposition of simple α-acetoxydialkylnitrosamines: Nitrosiminium ion intermediates

Abstract Secondary α-deuterium kinetic isotope effects for the pH independent decay of two (N-nitrosoalkylamino)methylacetates (4) and two (N-nitrosoalkylamino)propyl acetates (5) have been determined at 52 °C in aqueous solution, ionic strength 1 M. In all cases the isotope effects are kobsdH/kobsdD ∼ 1.1 – 1.2 (per hydrogen). It is concluded that the direction and magnitude of the isotope effects are inconsistent with mechanisms involving rate limiting reaction at the carbonyl group; and, are consistent with the formation of N-nitrosiminium ions in, or prior to, the rate limiting step.

Nature of nitrenium:carboxylate ion pair intermediates in the hydrolysis of O-aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines

O-Aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines [aroyl = benzoyl (1a), 3-nitrobenzoyl (1b), and pentafluorobenzoyl (1c)] are solvolysed in aqueous solutions by rate-limiting ionization to nitrenium : carboxylate ion pair intermediates. These in part collapse at the ortho position to give unstable 1,5-dimethyl-5-aroyloxy-6-acetyliminocyclohexa-l,3-dimes 2 that react further as described in the previous paper. The ion pairs from 1 also proceed directly to products of substitution para to the acetylamino group—4-aroyloxy-2,6-dimethylacetanilide 5, a product of internal return, and 4-hydroxy-2,6-dimethylacetanilide 6, a product of water addition. These same products also arise via ionization of 2. The ratio 5:6 obtained directly from 1 is significantly lower than that from 2, demonstrating that 1 and 2 do not ionize to exactly the same ion pairs. Experiments with 1a in the presence of bromide show that the yield of the cyclohexadiene is unaffected, while the yields of 5 and 6 are decreased, albeit to different amounts. Two new products, 4-bromo-2,6-dimethylacetanilide and 2,6-dimethylacetanilide, are observed in their places. Experiments with 1c in acid solutions demonstrate that the yield of cyclohexadiene can be decreased by H+, by protonation of the carboxylate ion in the ion pair. Using the H+ reaction as a clock, the lifetime of this ion pair, the initial ion pair in the ionization of 1, is calculated as ca. 10 ps. Thus this ion pair is too short-lived to react with external nucleophiles, and probably also with solvent. The trapping data for the p-ester 5 are shown to be inconsistent with a mechanism where a single ion pair serves as precursor, and this product is proposed to arise in part from a short-lived ion pair, and in part from a longer-lived one. The latter ion pair is probably also the species that gives rise to the p-phenol 6 by reaction with water. Using the bromide reaction as the clock, this ion pair is shown to have a lifetime of 0.25–0.50 ns. A number of mechanistic models incorporating these features are consistent with the experimental results, and two of these are discussed. Whatever the mechanism a minimum of three shortlived ion pair intermediates is required.

Cyclohexadienes from the rearrangement of O-aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines. Reaction in aqueous solution to meta- and para-substituted 2,6-dimethylacetanilides

O-Aroyl-N-acetyl-N-(2,6-dimethylphenyl)hydroxylamines (aroyl = benzoyl, 3-nitrobenzoyl, and pentafluorobenzoyl) rearrange in acetonitrile to 1,5-dimethyl-5-aroyloxy-6-N-acetyliminocyclohexa-1,3-dienes that can be isolated as pure compounds. These cyclohexadienes react in aqueous solutions, producing m-aroyloxy- and m-hydroxy-2,6-dimethylacetanilides in an H+-catalysed reaction and the corresponding para products in a non-catalysed reaction. Analysis of the effect of the aroyloxy group suggests that the latter reaction involves heterolysis to a reactive, non-selective, ion pair that collapses to the para product, or reacts at this position with water. The meta products arise from the N-protonated cyclohexadiene reacting with solvent in a conjugate addition to give the meta-substituted phenol, or in an intramolecular reaction with the carbonyl group to give the rearranged ester. This latter reaction is proposed to proceed via an intermediate 1,3-dioxolan-2-ylium ion. The nucleophiles azide, phenylsulfinate and the methyl thioglycolate anion react in a bimolecular fashion to give meta-substituted 2,6-dimethylacetanilides. With phenylsulfinate this requires H+, while methyl thioglycolate anion reacts with the neutral cyclohexadiene. Azide exhibits reaction by both processes. These reactions are proposed to involve conjugate additions, either to the N-protonated cyclohexadiene, or, with better nucleophiles, directly on the neutral compound. These cyclohexadienes model intermediates that may form during the metabolism of certain carcinogenic amines. These results establish the presence of three electrophilic species capable of reacting with cellular nucleophiles—the highly reactive and non-selective cation formed in the heterolysis, the less reactive and more selective N-protonated species, and the neutral cyclohexadiene itself. The last electrophile is relatively unreactive, but can be a target of very good nucleophiles such as thiol anions.