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Oil and water do not mix. The disaffinity of oil for water, with its unusual temperature dependence, is called the hydrophobic effect. It is important to understand the factors underlying the hydrophobic effect because they appear to play key roles in membrane and micelle formation, protein folding, ligand-protein and protein−protein binding, chromatographic retention, possibly nucleic acid interactions, and the partitioning of drugs, metabolites, and toxins throughout the environment and living systems. Here, we survey experimental and theoretical studies of nonpolar solute partitioning into water. We note that the hydrophobic effect is not just due to “water ordering” and not merely due to small size effects of water. The properties vary substantially with temperature and solute shape. Also, we discuss the limitations of using oil/water partitioning as the basis for some thermodynamic models in chemistry and biology.

We model the aqueous solvation of a nonpolar solute as a function of its radius. We use a simplified statistical mechanical model of water, the Mercedes Benz (MB) model, in NPT Monte Carlo simulations. This model has previously been shown to predict qualitatively the volume anomalies of pure water and the free energy, enthalpy, entropy, heat capacity, and volume change for inserting a nonpolar solute into water. We find a very different mechanism for the aqueous solvation of large nonpolar solutes (much larger than a water) than for smaller solutes. Small solute transfer involves a large hydrophobic heat capacity; its disaffinity for cold water (room temperature or below) is due to the ordering of the neighboring waters (entropic), while its disaffinity for hot water is due to the breaking of hydrogen bonds among the neighboring waters (enthalpic). In contrast, transferring large nonpolar solutes into water involves no such large changes in heat capacity or entropy. In this regard, large nonpolar solutes are not “hydrophobic”; their solvation follows classical regular solution theory. Putting a large nonpolar surface into water breaks hydrogen bonds at all temperatures. Therefore, the traditional “iceberg” model that first-shell water structure melts out with temperature should not apply to large solutes. These results also explain why the free energy of creating an oil/water interface (75 cal Å^-2 mol^-1) is greater than threefold for small molecule transfers (25 cal Å^-2 mol^-1). A key conclusion is that hydrophobicity depends not only on the surface area of a solute but also on its shape and curvature.