Molecular orbital parameters as predictors of skin sensitization potential of halo- and pseudohalobenzenes acting as SNAr electrophiles.

The electrophilic reactivity of a training set of 20 halo- and pseudohalobenzenes, 10 of which are reported skin sensitizers and 10 of which are reported nonsensitizers, has been modeled by MO-calculated indices using the AM1 and PM3 Hamiltonians. The electronic structures of parent molecules and the corresponding Meisenheimer intermediates (sigma-complexes) were evaluated. The NH2 group and the H atom were both studied as model nucleophile-derived substituents in the sigma-complexes. The LUMO energy differences between the parent compounds and their Meisenheimer complexes together with the maximum acceptor superdelocalizabilities determined over the aromatic reaction sites were found to discriminate correctly the sensitizing/reactive from nonsensitizing/unreactive compounds of the training set of 20 compounds. The predictive applicability of these MO indices was confirmed with a test set of seven further compounds for which sensitization data are reported in the literature. A statistically based discriminant analysis provides a model which predicts whether or not an SNAr electrophile will be a sensitizer and estimates the degree of confidence in the prediction.