Theoretical study of aza-polycyclic aromatic hydrocarbons (aza-PAHs), modelling carbocations from oxidized metabolites and their covalent adducts with representative nucleophiles.

Protonation of the epoxides, diol epoxides, and dihydrodiols of benzo[h]quinoline (BhQ), benzo[f]quinoline (BfQ), phenanthrene (Phe), benzo[c]phenanthridine (BcPhen), and chrysene (Chry) were studied by DFT at the B3LYP/6-31G* level, and selected cases were calculated with the 6-31+G* diffuse-function augmented basis set for comparison purposes. Bay-region carbocations were formed from O-protonated epoxides via a barrierless processes. Relative carbocation stabilities were determined in the gas phase and with water as solvent (PCM method). The presence of a heteroatom changes the regioselectivity of epoxide ring opening, in some cases favoring non-bay-region carbocations. The epoxide ring opening mode is also greatly influenced by N-protonation. The dications resulting from initial N-protonation followed by epoxide protonation were also studied by DFT. Charge delocalization modes in the resulting mono- and dications were derived by GIAO-NMR (based on Delta delta13C values) and via the NPA-derived changes in charges. Relative aromaticity in different rings in the arenium ions was gauged by NICS. In representative cases, the covalent adducts (syn and anti) formed by reaction of the benzylic carbocations derived from diol epoxides and dihydrodiols with methoxide and methanethiolate anions were studied. Relative energies (in the gas phase and with water as solvent) and geometries of the adducts formed by quenching of the carbocations derived from BhQ and Phe-epoxides with guanine via the exocyclic amino group and via the N-7 were also investigated computationally. Although aqueous phase calculations change the energy for the addition reactions because of greater stabilization of the reactants, relative reactivity trends remain the same. The data are discussed, taking into account the available experimental results concerning the biological activity of these compounds.