Medium Effects on the 1,3-Dipolar Cycloaddition of Pyridazinium Dicyanomethanide with Ethyl Vinyl Ketone in Pure and Mixed Solvents from QM/MM Simulations

Abstract

The 1,3-dipolar cycloaddition reaction between pyridazinium dicyanomethanide <b>1</b> and ethyl vinyl ketone (EVK) has been reported to be a concerted mechanism based on gas-phase ab initio calculations. Our current investigation of this 1,3-dipolar cycloaddition reaction in water, methanol, acetonitrile, H₂O–CH₃CN, and CH₃OH–CH₃CN mixtures using novel two-dimensional potentials of mean force (2-D PMF) calculations coupled to QM/MM simulations predicts an alternative free energy surface that supports a stepwise mechanism. The results for the kinetic effect are uniformly in close accord with experimental data and reflect a trigger point for the exponential rate rise in water–acetonitrile mixture. When methanol replaced water, the rate enhancements are more gradual, and there is no trigger point. Calculations in pure solvents and their mixtures at 25 °C and with pure water and acetonitrile at 37 °C indicate that the secondary bridging H-bonding from the first water molecules is necessary for the exponential rate enhancements, which is strong supported by the experimental results. This work provides new insight into solvent effects on 1,3-dipolar cycloaddition reaction