Entropic trends in aqueous solutions of the common functional groups

While much is known about the properties of small organic molecules in aqueous solution, one quantity that has eluded a detailed understanding is their entropy. Different functional groups interact in diverse ways with water molecules and thereby influence a molecule's solubility, conformation and association behaviour. Experiment can access the total entropy of solvation but struggles to give a more detailed break-down of the entropic components. Established theoretical and computational methods based on perturbation give insight into changes in solute–solvent and solvent–solvent entropy components, but these multibody terms that represent changes are not intuitive to interpret and can be expensive or difficult to evaluate. Partition-function methods, on the other hand, have the capability of determining the entropy of every degree of freedom of every molecule in the system. They do this by determining effective potentials for each degree of freedom, and evaluating the associated entropy component from the partition function of the effective potential. The obstacle to such an approach has been finding a reliable way to define and derive these effective potentials. This we have overcome in a two-fold manner: firstly, the shape of the effective potential for each molecule, which relates to vibrational and librational motion of the confined molecule, is derived from the magnitudes of the forces and torques measured in a molecular dynamics simulation of the solution; secondly, the number of minima for each effective potential, which relates to the number of positions and orientations in solution, is derived from the translational and rotational discretisations by the surrounding solvent molecules. This method has been shown to successfully reproduce the entropy of liquid water and to examine the entropy loss of water around noble-gas solutes. In this work, we extend the approach to reveal the nature of water's entropy around small organic molecules with a range of functional groups. The vibrational and librational entropies of solutes and water decrease for solutes with more polar atoms, as would be expected. The number of solute orientations depends on solute size, whereas the number of water orientations depends on the number of polar atoms in the solute. Solutes are classified according to how their donors and acceptors affect water's orientational entropy. Agreement of the calculated standard Gibbs free energy of solvation with experiment is very good with a mean-unsigned error of 2.5 kJ mol⁻¹, but the entropies and enthalpies, not being negative enough, could be improved with better force fields.