Octanol/water partition coefficients fragment approach

Principles of Use. Leo s approach (Hansch and Leo [14]) to the estimation of octanol/water partition coefficients uses empirically derived atomic or group fragment constants (f) and structural factors (F). All calculations are carried out in terms of log Kow ... 

One of the earliest applications of expert systems in the field of QSAR was the development of calculation schemes for octanol/water partition coefficients. Although the early work with n constants had shown that they were more or less additive, a number of anomalies had been identified. In addition, in order to calculate log P values from n constants it is necessary to have a measured log P for the parent and this, of course, is often unavailable. One approach to the question of how to calculate log P from chemical structure is to analyse a large number of measured log P values so as to determine the average contribution of particular chemical fragments (Nys and Rekker 1973). The fragment contributions constitute the rules of the expert system, extra rules being supplied in the form of correction factors. Operation of this expert system consists of the following few simple steps. 

Laboratory measurements of and S, can be costly and difficult. Various methods, including group contribution technique and quantitative structure (or property) property relationships (QSPRs or QPPRs), are available to estimate and S., from which o values can be derived. A direct approach of predicting o has also been established based on the dependence of cosolvency on solute hydrophobicity. Among a number of polarity indices, octanol/water partition coefficient, was initially chosen by Yalkowsky and Roseman for correlation with o, due mainly to the abundance of available experimental data and the wide acceptance of the Hansch-Leo fragment method for its estimation. is a macroscopic property which does not necessarily correlate with microscale polarity indices such as dipole moment, and only in a rank order correlates with other macroscopic polarity indicators such as surface tension, relative permittivity, and solubility parameter. 

Solution of equations 5-1 and 5-2 requires site-specific values as well as chemical-specific values. Critical chemical-specific properties in the above equations are the Henry s law constant (H), the organic carbon/water partition coefficient (Koc), and the effective diffusion coefficient through soil (Deff). Henry s law constants are estimated using solubility and vapor pressure values obtained from data compilations. The Koc is estimated from the octanol-water coefficient (Kow) and is commonly estimated from the Hansch and Leo (1979) fragment constant approach (TPHCWG 1997b) ... 

Lipophilicity in particular, as reflected in partition coefficients between aqueous and non-aqueous media most commonly water (or aqueous buffer) and Z-octanol,has received much attention [105,141,152,153,176,199,232,233]. Logic )W for the octanol-water system has been shown to be approximately additive and constitutive, and hence, schemes for its a priori calculation from molecular structure have been devised using either substituent tt values or substructural fragment constants [289, 299]. The approximate nature of any partition coefficient has been frequently emphasized and, indeed, some of the structural features that cause unreliability have been identified and accommodated. Other complications such as steric effects, conformational effects, and substitution at the active positions of hetero-aromatic rings have been observed but cannot as yet be accounted for completely and systematically. Theoretical statistical and topological methods to approach some of these problems have been reported [116-119,175,289,300]. The observations of linear relationships among partition coefficients between water and various organic solvents have been extended and qualified to include other dose-response relationships [120-122,160,161,299-302]. 

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