Theoretical Study of the Substituent Effect on the Diradical Character of <i>α</i>-Substituted <i>α</i>,3-Didehydrotoluenes

Enediyne anticancer antibiotics exert their bioactivity by generating reactive diradical species that cleave DNA. Singlet diradicals can exhibit zwitterionic character, therefore, the enediyne-derived singlet diradicals are sometimes inactivated via ionic reaction with water. The research group to which one of the authors belonged previously proposed the possibility that the zwitterionic character of the α,3-didehydrotoluene diradical could be suppressed by introducing an electron-withdrawing group to its benzylic position. In this paper, the correlation between the electron-withdrawing properties of the benzylic substituents and the diradical character of the α,3-didehydrotoluene was investigated based on density functional theory (DFT) calculation, and the calculation results supporting the above hypothesis were obtained. Furthermore, it was suggested that the charge in the zwitterionic intermediate can be predicted by DFT calculation.