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Theorigin of diastereoselectivity and role of water in the uncatalyzed aldol reaction of N-methyl-2,4-thiazolidinedione with N-methyl-isatin have been investigatedbyMonte Carlo statistical mechanics simulations withthe QM/MM model using the PDDG/PM3 asthe QM method under the "on water"and "in water"environments.For the titlereactionat vacuum-water interface,the QM/MM-based2D free energy maps showed that both Path I and Path II followeda stepwise mechanism and the C-C bond formation was thediastereoselectivity determiningstep.The calculated ΔG≠values of31.40 and 33.93 kcal/mol for rate-limiting stepsof path I and path II on water,respectively,indicated that the path I was the favorable and yieldedthe high diastereoselectivity in favor of the anti product(dr,98.5:1.5),which was ofexcellent agreement with experimental diastereoselectivity(dr,98:2).The enhancingof hydrogen bonding interaction isthe main reason which leadsto rate acceleration for the aldol reactionthrough stabilizingthe transition state.