Reactivities of Acrylic and Methacrylic Acids in a Nucleophilic Addition Model of Their Biological Activity

The reactivities of derivatives of acrylic acid in nucleonhilic Michael addition are evaluated from a study of the mechanism of addition of a nucleophile, F^-, to the activated double bond of acrylic acid (AA) and methacrylic acid (MAA). This reaction has been proposed to be the underlying mechanism for the toxicity of such compounds. The differences in the molecular properties of AA and MAA that account for the differences in their reactivity toward the nucleophile, as well as the differences in the structure and energy of the resulting carbanions, are calculated with ab initio methods of quantum chemistry using the split valence 6-31++G and 6-31G basis sets. The effects of correlation energy and of basis set superposition errors (BSSE) are evaluated for the main points on the potential energy curve, the transition state (TS) and the stable carbanion (SC). A difference of 3 kcal/mol in the stabilization energy of SC for AA compared to MAA is found with both basis sets used as well as after correction of BSSE. Electron correlation does not change this conclusion. Comparisons of calculated electron density distributions and molecular electrostatic potential maps for the two molecules, combined with the analysis of the energy terms calculated for the various stages of the interaction, reveal that the attacked carbon in the double bond of the two molecules carries a larger electron density in MAA than in AA. This charge density is directly responsible for the more negative electrostatic potential generated by MAA along the path of approach of the nucleophile and for the larger energy required to distort the MAA molecule upon close-contact interaction with the nucleophile. Thus, both the incipient, electrostatically controlled stage of the reaction with the nucleophile and the final stage of production of the carbanion are energetically preferred for AA compared to MAA. The good agreement between the results of these calculations and the experimental findings showing the lower toxicity of MAA derivatives as compared to AA derivatives underlines the discriminating powers of the molecular properties and adds support to the hypothesis that Michael addition in biological systems is a likely molecular mechanism for the toxicity of such compounds. Useful tools for predicting the biological activity of untested compounds in this series are thus obtainable on the basis of clear mechanistic hypotheses and discriminant molecular properties.