Accurate Calculation of Solvation Free Energies in Supercritical Fluids by Fully Atomistic Simulations: Probing the Theory of Solutions in Energy Representation.

Abstract

Accurate calculation of solvation free energies (SFEs) is a fundamental problem of theoretical chemistry. In this work we perform a careful validation of the theory of solutions in energy representation (ER method) developed by Matubayasi et al. [J. Chem. Phys. 2000, 113, 6070-6081] for SFE calculations in supercritical solvents. This method can be seen as a bridge between the molecular simulations and the classical (not quantum) density functional theory (DFT) formulated in energy representation. We performed extensive calculations of SFEs of organic molecules of different chemical natures in pure supercritical CO2 (sc-CO2) and in sc-CO2 with addition of 6 mol % of ethanol, acetone, and n-hexane as cosolvents. We show that the ER method reproduces SFE data calculated by a method free of theoretical approximations (the Bennett's acceptance ratio) with the mean absolute error of only 0.05 kcal/mol. However, the ER method requires by an order less computational resources. Also, we show that the quality of ER calculations should be carefully monitored since the lack of sampling can result into a considerable bias in predictions. The present calculations reproduce the trends in the cosolvent-induced solubility enhancement factors observed in experimental data. Thus, we think that molecular simulations coupled with the ER method can be used for quick calculations of the effect of variation of temperature, pressure, and cosolvent concentration on SFE and hence solubility of bioactive compounds in supercritical fluids. This should dramatically reduce the burden of experimental work on optimizing solvency of supercritical solvents.