Force Field Benchmark of Organic Liquids. 2. Gibbs Energy of Solvation

Abstract

Quantitative prediction of physical properties of liquids is a longstanding goal of molecular simulation. Here, we evaluate the predictive power of the Generalized Amber Force Field (Wang et al. J. Comput. Chem. 2004, 25, 1157-1174) for the Gibbs energy of solvation of organic molecules in organic solvents using the thermodynamics integration (TI) method. The results are compared to experimental data, to a model based on quantitative structure property relations (QSPR), and to the conductor-like screening models for realistic solvation (COSMO-RS) model. Although the TI calculations yield slightly better correlation to experimental results than the other models, in all fairness we should conclude that the difference between the models is minor since both QSPR and COSMO-RS yield a slightly lower RMSD from that of the experiment (<3.5 kJ/mol). By analyzing which molecules (either as solvents or solutes) are outliers in the TI calculations, we can pinpoint where additional parametrization efforts are needed. For the force field based TI calculations, deviations from the experiment occur in particular when compounds containing nitro or ester groups are solvated into other liquids, suggesting that the interaction between these groups and solvents may be too strong. In the COSMO-RS calculations, outliers mainly occur when compounds containing (in particular aromatic) rings are solvated despite using a ring correction term in the calculations.

Evaluation of solvation free energies for small molecules with the AMOEBA polarizable force field

“…Our findings that chloroform solvation free energies have the largest errors to experiment, despite reasonable correlation for GAFF, are consistent with the recent results of Zhang et al36 …”

“…This study showed good agreement (<1.0 kcal mol −1 ) of solvation free energies with experiment, albeit in four related polar solvents and three related nonpolar solvents 35. In a larger study, Zhang et al compared the performance of GAFF with three different prediction methodologies for solvation free energies (thermodynamic integration, a quantitative structure‐property relationship [QSPR] and the conductor‐like screening model for realistic solvation [COSMO‐RS]), employing a wide range of organic solvents 36. These studies involved the evaluation of Gibbs solvation free energies for 228 organic molecules in organic solvents compared against experimental data.…”

Using MD Simulations To Calculate How Solvents Modulate Solubility

“…The recent reported work of Zhang et al 31 also examined solvation free energies in non-aqueous solvents, comparing alchemical techniques with an empirical technique based on quantitative structure property relations, and quantum mechanical calculations with COSMO-RS. It found that the alchemical approach was not a clear winner, with the other two models in fact performing slightly better.…”

“…It seems likely that this may be precisely because of the relative abundance of solubility data compared to solvation free energy data. Specifically, the QSPR and COSMO-RS methods employed by Zhang et al 31 have both been specifically fit at least in part to reproduce solvation free energies, and given the relatively small amount of solvation free energy data available, their training may have involved some of the same compounds on which they were tested. In contrast, the vast amount of solubility data available – and the lack of training of the methods tested on solubility data – means that the present test gives less of an advantage to empirical or semi-empirical methods.…”

“…Following in the footsteps of earlier work, 29 one notable recent study 31 reported calculations of the solvation free energy for different solutes in a variety of organic solvents. Experimental solvation free energy data was obtained from the databases of Katritzky et al , 32,33 which appears to draw both on direct measurements of solvation and on vapor pressure measurements 2 …”