Accessing the Free Energy Profile of a Ring Closure in a Proline-Catalyzed Reaction Using a Reactive Force Field

The free energy profile of a ring closure involving a carboxylate and an iminium functional group in a proline-derived compound is determined by applying the adaptive biasing force scheme along molecular dynamics simulations. As the reaction considered implies the formation of a covalent bond, the system is modeled with a reactive force field (FF), namely ReaxFF. The impact of the surrounding water molecules on the reaction mechanism is investigated in detail using three FF models for the water molecules. In particular, a hybrid reactive/non-reactive FF is used to assess explicit solvent effects while avoiding solute–solvent reactions. Combined with existing experimental observations, our results provide an explanation for the role of water molecules in the proline-catalyzed aldol reaction, which is one of the hallmark reactions in organocatalysis.