Predicting Michael-acceptor reactivity and toxicity through quantum chemical transition-state calculations.

The electrophilic reactivity of Michael acceptors is an important determinant of their toxicity. For a set of 35 α,β-unsaturated aldehydes, ketones and esters with experimental rate constants of their reaction with glutathione (GSH), k(GSH), quantum chemical transition-state calculations of the corresponding Michael addition of the model nucleophile methane thiol (CH(3)SH) have been performed at the B3LYP/6-31G** level, focusing on the 1,2-olefin addition pathway without and with initial protonation. Inclusion of Boltzmann-weighting of conformational flexibility yields intrinsic reaction barriers ΔE(‡) that for the case of initial protonation correctly reflect the structural variation of k(GSH) across all three compound classes, except that they fail to account for a systematic (essentially incremental) decrease in reactivity upon α-substitution. By contrast, the reduction in k(GSH) through β-substitution is well captured by ΔE(‡). Empirical correction for the α-substitution effect yields a high squared correlation coefficient (r(2) = 0.96) for the quantum chemical prediction of log k(GSH), thus enabling an in silico screening of the toxicity-relevant electrophilicity of α,β-unsaturated carbonyls. The latter is demonstrated through application of the calculation scheme for a larger set of 46 Michael-acceptor aldehydes, ketones and esters with experimental values for their toxicity toward the ciliates Tetrahymena pyriformis in terms of 50% growth inhibition values after 48 h exposure (EC(50)). The developed approach may add in the predictive hazard evaluation of α,β-unsaturated carbonyls such as for the European REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) Directive, enabling in particular an early identification of toxicity-relevant Michael-acceptor reactivity.