DEPROTONATION AND HYDRIDE SHIFTS IN NITRENIUM AND IMINIUM FORMS OF AMINOIMIDAZOLE-AZAARENE MUTAGENS

The mutagenicity of many 2-aminoimidazole-azaarenes (AIA) is thought t o be mediated by the nitrenium form of the exocyclic amine. This hypot hesis is supported by the numerous correlations found between calculat ed and experimentally-measured chemical properties for the nitreniums and the mutagenic potencies of the nitreniums and their parent amines. One factor favoring high mutagenic potency is the presence of a methy l substituent in the 1- or 3-imidazole position. In this paper, we inv estigate both the deprotonation of the imidazole ring nitrogens in non -N-methylated AIA mutagens and the plausibility of a chemical pathway involving a 1-4 hydride shift to form an iminium ion, thereby stabiliz ing the cationic N-methyl substituted AIA mutagens. It has been widely noted that factors that stabilize the nitrenium moiety lead to signif icantly higher mutagenic potency; hence, the transformation of the nit renium to a more stable species might be expected to increase the pote ncy, provided that it does not eliminate the electrophilic reactivity of the compound. Using ab initio quantum chemistry and polarizable con tinuum solvation models, we find that the imidazole ring nitrogens of the nitrenium ions are extremely acidic. This suggests that upon forma tion of the exocyclic nitrenium these sites will deprotonate to form a neutral imine. We have also studied the 1-4 hydride shift from an imi dazole ring methyl to the exocyclic nitrenium to form an iminium. We p redict that for AIA mutagens with just two fused rings the resulting i minium species are more stable in the gas phase than the corresponding nitreniums, For mutagens with larger conjugated systems, the nitreniu m is stabilized by resonance and is more stable than the corresponding iminium. In the aqueous phase, however, the Iminium form is predicted to be more stable than the nitreniums for all poly-cyclic compounds s tudied. Although equilibrium calculations favor the iminium form, thes e have been experimentally shown to be short-lived and their actual co ncentration will depend on the complex kinetics of AIA mutagen metabol ism. The quantum chemical results also show a strong correlation betwe en the relative iminium-nitrenium energy difference and the charge on the exocyclic nitrogen. (C) 1997 Elsevier Science Ireland Ltd.