Mechanistic Insights and Solvent Effects for the Ambident SCN ^<b>–</b> + CH ₃ Cl Reaction in Aqueous Solution: A Multilevel QM/MM Study

The ambident S_N2 reaction of SCN^- + CH₃Cl can proceed via either S-side or N-side attack, leading to distinct product formations. While previous studies have explored this reaction in the gas phase, the mechanistic details and solvent effects in aqueous solution remain unresolved. We employ a multilevel quantum mechanics/molecular mechanics approach with explicit water modeling to investigate the atomic-level ambident mechanisms, potentials of mean force, and solvent contributions for both S-side and N-side attack pathways. Our calculations reveal distinct structural and charge transfer dynamics between the S-side attack and N-side attack pathways, with the S-side transition state resembling the reactant complex more closely than the N-side transition state. Charge analysis indicates more efficient charge transfer in the S-side mechanism, correlating with its lower activation barrier. The CCSD(T) potentials of mean force yield free energy barriers of 21.4 kcal/mol for the S-side and 26.3 kcal/mol for the N-side attack, confirming the S-side preference persists in solution. Solvent effects raise the barriers by ∼31% for the S-side and ∼34% for the N-side compared to gas-phase values, with polarization and solvent energy contributions destabilizing the N-side transition state more significantly. These findings provide atomic-level insights into ambident reactivity in solution and highlight the critical role of solvent in modulating S_N2 reaction energetics and mechanisms.