Theoretical Study of O-CH₃ Bond Dissociation Enthalpy in Anisole Systems

Understanding ubiquitous methyl transfer reactions requires a systematic study of thermodynamical parameters that could reveal valuable information about the nature of the chemical bond and the feasibility of those processes. In the present study, the O-CH₃ bond dissociation enthalpies (BDEs) of 67 compounds belonging to phenol/anisole systems were calculated employing the Gaussian-4 (G4) method. Those compounds contain different substituents including alkyl groups, electron-donating groups (EDGs), and electron-withdrawing groups (EWGs). The results show that the bigger branched alkyl groups and EDGs will destabilize the O-CH₃ bond, while EWGs have the opposite effect. A combination of different effects including steric effects, hydrogen bonds, and substituents and their position can achieve around 20 kcal/mol difference compared to the basic phenyl frame. Also, the linear correlation between σ_p ⁺ and O-CH₃ BDE can provide a reference for the O-CH₃ BDE prediction. The present study represents a step forward to establish a comprehensive O-CH₃ BDE database to understand the substituent effect and make its contribution to the rational design of inhibitors and drugs.