Conformation-Driven Duality in the MBH Proton-Transfer Mechanism: A Dynamic View of Solvent and Entropic Effects.

Understanding how the solvent structure and molecular conformation dictate reaction mechanisms is essential for advancing organocatalysis. In this work, the solvent effect on the proton-transfer step (rate-determining) of the Morita-Baylis-Hillman (MBH) reaction in a protic medium was investigated through a combination of ab initio molecular dynamics, well-tempered metadynamics, and on-flow NMR kinetic experiments. The simulations reveal two competing proton-transfer pathways involving solvent-assisted and acid-base mechanisms. These pathways have comparable free energy barriers and are driven mostly by the entropy and conformational preference of the zwitterionic intermediate. Conformational free energy surfaces, combined with NMR analysis, show that bulky substituents in the electrophilic partner may cause a steric effect that hinders proton-transfer accessibility and suppresses MBH adduct formation. These findings establish a direct relationship between conformation and proton-transfer reactivity, highlighting the importance of dynamically addressing the explicit solvation in the MBH reaction.