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Exploring the Effects of Water on the Mechanism of the Catalyst-Free Reaction between Isatin and 3-Methyl-2-pyrazolin-5-one from the Mixed Implicit/Explicit Multiple Types of Water Clusters.

Density functional theory calculations with implicit/explicit water cluster models were conducted to pursue deeper understandings about the mechanism and the water effects in the reaction of isatin with 3-methyl-2-pyrazolin-5-one. The proposed preferential mechanistic scenario here undergoes three major steps: first, 3-methyl-2-pyrazolin-5-one converts to its enol form and then, the aldol addition reaction takes place between isatin and enol to generate the intermediate INT2, followed finally by the tautomerization of INT2 to become the product 3-pyrazolone. The computed results indicate that the direct aldol reaction without the water auxiliary is feasible in the second step and the remaining tautomerization steps (steps 1, 3, and 4) assisted by tri-, tri-, and six-water cluster models, respectively, are the most favorable cases. It is further noted that more hydrogen bonding interactions in the tri-water auxiliary reaction are essential for the reduction of the free energy barrier ΔG⧧ in the proton transfer largely than those assisted by the other types of water cluster models. The origin of the more stable transition state in the rate-determining step of the tri-water cluster model is ascribed to smaller cyclic strain and more global electron density transfer associated to its structure than the other types of water cluster models.