Thermodynamics of apolar solvation in mixed aqueous solvents.

摘要

Solubility of apolar molecules in aqueous media influences a number of natural and industrial processes. Examples range from the bioavailability of small-molecule pharmaceuticals to the fate of synthetic chemicals in the environment. Apolar solvation also plays a role in biological processes such as protein folding. Most theoretical investigations in the literature have focused on pure water as the solvent despite the fact that many natural and industrial systems include relatively high concentrations of cosolvents. Examples of common cosolvents include salts, alcohols, polyols, and carbohydrates. Despite the importance of mixed aqueous solvents, little work has been done to understand apolar solvation in these mixtures. Using molecular dynamics and statistical and classical thermodynamics, this thesis provides a systematic and extensive theoretical study of apolar solvation thermodynamics over a wide range of temperatures, pressures, and cosolvent compositions (up to 30 w/w% and 60 w/w% for the chosen cosolvents). The transfer free energy, enthalpy, and entropy of methane and hard sphere solutes are calculated in binary water-cosolvent (water-methanol, -ethanol, -sorbitol) mixtures, and a common molecular basis is shown to describe and predict the results across a broad range of solvent conditions.;From a classical thermodynamics perspective, characteristic properties of water (i.e., temperature of maximum density and temperature of minimum solubility) are predicted by MD simulation to be suppressed to lower temperatures upon addition of either methanol or sorbitol as the cosolvent. This behavior holds across a wide range of temperature, pressure, and cosolvent concentration. By contrast, apolar solute solubility is increased by addition of methanol, but decreased by addition of sorbitol. These findings are in conflict with traditional classification schemes such as structure-making/-breaking and hydrophobic enhancement/suppression, and highlight the limitations of such heuristics for rationalizing cosolvent effects on solubility. Exact statistical mechanical theories of mixtures such as Kirkwood-Buff theory are also confirmed to be have limited predictive capability due to practical implementation issues that have been suggested previously in the literature.;From a molecular perspective, it is shown that the distribution of void space is the dominant controlling factor that determines the sign and magnitude of the free energy of apolar solute dissolution in these water-cosolvent mixtures. This finding complements the literature for pure water and shows apolar solvation for small solutes is dominated by the work of cavity formation. Additionally, this thesis shows for the first time that the transfer free energy of apolar solutes from water to mixed aqueous solvents can be described by a common dependence on solvent packing fraction. This dependence is independent of temperature, pressure, and the cosolvent identity. The results also provide a clear molecular scale explanation for anomalous behaviors observed in simulation and experiment for apolar solvation in methanol-water mixtures; specifically, a minimum in apolar solute solubility is observed as a function of methanol concentration. Such solubility minima are shown to be due solely to the non-monotonic dependence of packing fraction on solvent composition (under isobaric conditions). This unusual behavior is due to competing effects between changes in the average molecular density and changes in the bulk density as solvent composition is changed at fixed temperature and pressure. This highlights that it is unnecessary to invoke arguments regarding alterations in hydrogen-bond network structures or the stability of hydrogen-bonded systems in order to explain any of these anomalous or characteristic solvation properties of water or mixed aqueous solvents. Rather, the attractive interactions between solvent molecules primarily determine the bulk density at a given temperature and pressure, and (small) apolar solute solubility is then determined by the efficiency with which solvent molecules pack (i.e., purely steric considerations) at that bulk density.;Motivated by these findings, a thermodynamic cycle approach is proposed that separates the overall transfer process (at constant temperature and pressure) into two steps. The first step captures primarily the effects of changing solvent-solute interactions via changes in the solvent chemical composition. It occurs at fixed mass density to experimentally approximate fixed packing fraction. The second step is an expansion or compression of the binary cosolvent-water mixture to achieve the same pressure as the initial state point for the cycle. In such a manner, the effects of density changes with pressure (i.e., the equation of state, EoS) are quantified. Transfer free energies and enthalpies for methane across a range of solvents are captured qualitatively and semi-quantitatively using only the EoS step. The EoS step alone is able to quantitatively describe entropies of transfer; further emphasizing the dominant role of cavity formation and void distributions in apolar solvation across a range of solvents. Extension of this thermodynamic cycle approach to analyze protein unfolding is briefly presented, and illustrates a number of additional challenges for accurately capturing solvation thermodynamics of proteins in mixed aqueous solvents.