The Hydrophobic Effect. 3. A Key Ingredient in Predicting n-Octanol–Water Partition Coefficients

Abstract

The quantitative development of the mobile order theory in H-bonded liquids is extended to predict the n-octanol/water partition coefficient (P). The log P predictive equation strictly issued from a thermodynamic treatment reduces to a simple linear volume-log P relationship whose intercept and slope encode, respectively, the solvation and entropy effects. For noncomplexing substances, the partition coefficient values result from two volume-dependent entropic contributions reflecting (a) the difference in the exchange entropy between the solute and solvent molecules in the n-octanol and water phases, and (b) the propensity difference between the two H-bonded solvents to induce a hydrophobic effect toward the solute. Although both effects increase, although with opposite signs, compared with the growing molar volume of the partitioned compound, the hydrophobic contribution always predominates favoring the transfer of the solute into the organic phase and hence increasing its partition coefficient. When dealing with complexing chemicals, the hydrophobic effect-related term, though remaining the dominant factor in most cases, is more or less counterbalanced by the formation of H-bonds between the interacting sites of the solute and the n-octanol and water solvent molecules. The log P, corrected for the substantial content of water into n-octanol, is estimated for a number of compounds of environmental and pharmaceutical interest. The extent to which the entropic and enthalpic factors affect the overall partition coefficient value is analyzed.

Structure–Activity Relationship for Chemical Skin Permeation Enhancers: Probing the Chemical Microenvironment of the Site of Action

“…Another point of interest related to the slope value of $0.55 is that it is the value expected for the partitioning of a methylene group from a bulk aqueous phase into n-hexanol, n-octanol, or ndecanol, [28][29][30] but this value of 0.55 is somewhat low for methylene group partitioning from a bulk aqueous phase into a pure hydrocarbon environment (e.g., n-hexane) for which the methylene group increment would be expected to be $0.62. [30][31][32] This difference in the methylene group increment is reflected in the slope value of 0.89 AE 0.07 for the line shown in Figure 9 for the n-hexane-PBS system as compared with a slope of 0.98 AE 0.03 for the n-hexanol-PBS case (Figure 7) or a slope value of 0.95 AE 0.04 for the n-octanol-PBS case ( Figure 5).…”

Enhanced DNA photocleavage properties of Ru(II) terpyridine complexes upon incorporation of methylphenyl substituted terpyridine and/or the polyazine bridging ligand dpp (2,3-bis(2-pyridyl)pyrazine)

“…The values of log P in the aqueous and organic phase for the homoleptic and heteroleptic complexes are summarized in Table 4. The partition coefficients were determined using the ''shake flask" method, with n-octanol and water as solvents, which was applied to the molecules with log P values that range from À2 (most hydrophilic) to +4 (most hydrophobic) [44]. The negative values of partition coefficients of the complexes containing the tpy terminal ligand show that these complexes are hydrophilic in nature.…”

The correlation and prediction of the solubility of compounds in water using an amended solvation energy relationship

“…Mobile Order Theory [23][24][25] has recently been applied to the estimation of aqueous solubility with impressive results. 24 However, the method requires not only the entropy of fusion of solid solutes (or a mp correction term), but also a modified nonspecific solute cohesion parameter.…”