Local Electrophilicity Predicts the Toxicity-Relevant Reactivity of Michael Acceptors

Electrophilic substances can form covalent bonds to proteins and DNA, resulting in reactive toxicity and according diseases such as dermal or respiratory sensitization and mutagenicity. Employing site-specific quantum chemical parameters for quantifying the energy change associated with the gain or loss of electronic charge, two new local electrophilicity parameters are derived. Application to a set of 31 α,β-unsaturated carbonyl compounds and their experimental rates of reaction toward glutathione as a model nucleophile yields r 2 values up to 0.95, outperforming both the global electrophilicity and its earlier introduced local variant based on the condensed-to-atom Fukui function. A second data set demonstrates the suitability of the new reactivity parameters to also model Mayr’s electrophilicity parameter, again superior to existing approaches. The results indicate the suitability of the new parameters to screen, without experimental investigation, organic compounds for their electrophilic reactivity in general, and for their potential to exert reactive toxicity in particular.