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 alpha,beta-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 (CH3SH) 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 Delta E-double dagger 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 alpha-substitution. By contrast, the reduction in k(GSH) through beta-substitution is well captured by Delta E-double dagger. Empirical correction for the alpha-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 alpha,beta-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 (EC50). The developed approach may add in the predictive hazard evaluation of alpha,beta-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.