Lipophilicity is usually expressed by the partition coefficient (logP), a molecular parameter which describes the partitioning equilibrium of a solute molecule between water and an immiscible lipid-like organic solvent. By convention, the ratio of concentrations in the two phases is given with the organic phase as numerator, so that a positive value for logP reflects a preference for the lipid phase, and a negative value reflects a relative affinity for water. Also by convention, where ionizable molecules are concerned, log/' refers to the neutral species whereas what is actually measured may be the distribution coefficient, log£>. The distribution coefficient refers to the ratio of total concentrations of ionized and unionized species across both phases.

Many workers have emphasized that the value of logP depends largely on interactions made by the solute with the water phase, either being repelled by water (hydrophobic effect) or solvated by water through hydrogen bonds or other polar forces (hy-drophilic effect). Such emphasis has encouraged use of the term hydrophobicity, and in medicinal chemistry and particularly for QSAR the substituent constants, jt, and fragment constants, /, are almost universally described as hydrophobic substituent parameters or hydrophobic fragmental constants.

Use of the term hydrophobicity has also been dependent on a perception of the thermodynamics of partitioning of strictly nonpolar solutes such as the aliphatic and aromatic hydrocarbons between water and a lipid phase, and on a particular use of the term "hydrophobic bonding" to describe the tendency of nonpolar groups to associate in aqueous solution, thereby reducing the extent of contact with neighboring water molecules. As discussed by Némethy [1], the formation of such "hydrophobic bonds" has long been considered to be driven by an entropy effect: the water molecules become more ordered around exposed nonpolar residues, and when the hydrophobic "bond" is formed, the order decreases, resulting in a favorable entropy and hence free energy of formation. For over 30 years, it has been commonly supposed that the "hydrophobic" interaction between nonpolar side chains of a protein, associated with formation and breakdown of layers of abnormal water, makes a prominent contribution to the stability of the native, folded form. The existence, nature, and effect of "hydrophobic hydration" is today a subject of intense controversy (see sction 2.4.2).

Use of the term hydrophobicity by the Hansch group [2], who in 1964 pioneered the use of octanol/water as the standard solvent pair for measurement, could also be justified on the grounds that this particular solvent pair is such that polar effects are similar in each phase. Both water and octanol have hydroxyl groups that can participate in polar interactions with the solute molecule, and moreover there is a considerable amount of water within the octanol phase. So, an octanol/water logP value will emphasize differences in hydrocarbon interactions with water and with lipid, but tend to hide differences in the interaction of polar and hydrogen-bonding groups.

Recent studies have clearly and repeatedly shown that logP in general incorporates two major contributions, namely a "bulk" term reflecting both hydrophobic (entropic) and dispersion (enthalpic) effects, and electrostatic terms reflecting hydrogen bonds and other dipole-dipole effects. Moreover, the emphasis on interaction of the solute with the water phase has been challenged; more emphasis has now been placed on enthalpic interactions within the lipid phase; free energy simulations have been carried out and thermodynamic measurements have been made to better understand fundamental interactions of the solute with each phase. As a result, traditional explanations of partitioning in terms of "hydrophobic bonding" have had to be reconsidered.

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