Advanced Molecular Electron Density Theory Study of the Substituent Effects in Nucleophilic Substitution Reactions

The energetic and structural effects of the CH₃, CHCH₂, Ph, CHO, and OCH₃ groups present on the tetrahedral carbon involved in nucleophilic substitution (SN) reactions of primary substituted carbons have been studied within the molecular electron density theory (MEDT). Electron localization function analysis at the ground state indicates no remarkable electronic changes in the tetrahedral carbon due to substitution. The low electrophilic character of the substrates suggests that they lack the propensity to react with nucleophiles. The activation energies of the three selected series of SN reactions, which include the participation of a strong nucleophile and a very good leaving group (LG), range from 0.3 to 23.5 kcal·mol^-1, decreasing in each series in the order CH₃ > H > CHCH₂ ≈ CHO > Ph > OCH₃, with the last group being highly activating. A relative interacting atomic energy analysis of the transition state structures involved in the series of symmetric SN reactions involving chloride anion Cl^- allows for an understanding of the electronic effects of these groups on the kinetics of these reactions. The present MEDT study emphasizes that both the electronic effects of the groups present on the primary substituted tetrahedral carbon and the nature of the LG can shift the molecular mechanism of the SN reactions from an S_N2 to an S_N1 one.