The Role of Water in the Catalyst‐Free Aldol Reaction of Water‐Insoluble N‐Methyl‐2,4‐thiazolidinedione with N‐Methylisatin from QM/MM Monte Carlo Simulations

The role of water in the uncatalyzed aldol reaction of N‐methyl‐2,4‐thiazolidinedione with N‐methylisatin is investigated through Monte Carlo statistical mechanics simulations that utilize free energy perturbation theory and the mixed quantum mechanics and molecular mechanics (QM/MM) model with PDDG/PM3 for the QM method in “on‐water” and DMSO environments. There are several conceivable orientations between thiazolidinedione and isatin in the process of C−C bond formation. However, the formation of the C−C bond takes place between the re face of isatin and the si face of (E)‐enol of the thiazolidinedione to form the preferred anti‐type product, which results from enhanced hydrogen‐bonding interactions between water molecules and the oxygen atoms undergoing bond breakage and bond formation during the reaction. Novel insights into the effect of water on the aldol reaction are presented herein. How does your aldol go? Mixed quantum mechanics and molecular mechanics (QM/MM) Monte Carlo simulations with free energy perturbation theory are performed to investigate the effects of solvents on the uncatalyzed aldol reaction of N‐methyl‐2,4‐thiazolidinedione with N‐methylisatin “on‐water” and in DMSO (see figure). Rate acceleration on‐water is attributed to enhanced hydrogen‐bond interactions between water molecules and the reaction system as the reaction proceeds.