The physical origin of the low solubility of nonpolar solutes in water

Elementary but general statistical‐mechanical relations are derived that relate the thermodynamic properties of the dissolution process to those of the pure solvent. A number of conclusions are drawn from qualitative arguments that these relations suggest. These include the following: (1) The low solubility of nonpolar solutes in water arises not from the fact that water molecules can form hydrogen bonds, but rather from the fact that they are small in size. (2) The large entropy decrease attending the transfer of an inert solute from a nonaqueous solvent to water is largely due to the decrease in entropy of the nonaqueous solvent as the solvent–solvent interaction is restored on removal of the solute from it. (3) It is improper to use values of thermodynamic quantities obtained from small‐molecule transfer studies for those that involve macromolecular folding and interaction.