Solvent design for a Menschutkin reaction by using CAMD and DFT calculations
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abstract
The design of solvents that optimise reaction performance is challenging due to the complexity of solvent effects on reactions. We propose an ab initio computer-aided methodology for identifying optimal solvents based on a combination of quantum mechanical calculations and empirical models. In the first step of the approach, a number of quantum mechanical calculations are performed to predict the relative rate constant for the reaction of interest in several solvents. A continuum solvation model is used to model solvent effects on the relative thermodynamic stability of reactants and the transition state. This is then used to develop a surrogate model based on a linear free energy relation, the solvatochromic equation, and on group contribution techniques. This simplified model allows the fast identification of alternative solvents via an optimisation-based computer-aided molecular design approach due to its low computational cost. We apply the proposed approach in the case of the Menschutkin reaction between pyridine and phenacyl bromide to identify solvents that maximise the rate constant. The results are compared to experimental reaction rate data and show that the method is capable of designing promising solvents. 2010 Elsevier B.V. All rights reserved.
