Regiochemistry of nucleophilic attack by the guanine 2-amino group at the ring positions of nitrenium ions derived from carcinogenic polycyclic arylamines and nitroarenes: Molecular orbital calculations and simple models

Semiempirical AM1 molecular orbital calculations are used to compute the en ergetics of addition of the guanine 2-amino group to alternative ring posit ions of aryl nitrenium ions with the general structure ArNH+, where Ar is t he phenyl and various positional isomers of the naphthyl, pyrenyl, and benz o[a]pyrenyl groups. The syn or anti orientation of the NH+ group, and facto rs akin to classical localization energies, are identified as key component s of the differential energetics of addition to alternative ring sites. The regiochemistry predicted by the AM1 method can be qualitatively reproduced using simple HMO calculations that require trivial computational effort an d, almost as well, using PMO theory that does not require the use of a comp uter at all. In the latter approach, the most reactive ring positions are p redicted to be those where the nonbonding orbital coefficients, ao,, in the analogous odd alternant hydrocarbons are largest. These results are discus sed in relation to the available experimental data for the formation of deo xyguanosin-2-yl adducts when DNA is exposed to presumed nitrenium ion precu rsors.