Partition coefficient, relationship with solubility

Kaiser, K.L.E., Dixon, D.G., Hodson, PV. (1984) QSAR studies on chlorophenols, chlorobenzenes and para-substituted phenols. In QSAR in Environmental Toxicology. Kaiser, K. L. E., Ed., pp. 189-206, D. Reidel Publishing Co., Dordrecht, The Netherlands. Kamlet, M.J., Doherty, R.M., Carr, P.W., Mackay, D., Abraham, M.H., Taft, R.W. (1988) Linear solvation energy relationship. 44. Parameter estimation rules that allow accurate prediction of octanol/water partition coefficients and other solubility and toxicity properties of polychlorinated biphenyls and polycyclic aromatic hydrocarbons. Environ. Sci. Technol. 22, 503-509. Kanazawa, J. (1981) Measurement of the bioconcentration factors of pesticides by fresh-water fish and their correlation with physicochemical properties of acute toxicities. Pest. Sci. 12, 417-424. 

Figure 8.17. Relationship between octanol-water partition coefficients (Kow) and solubility of several organic chemicals. Note the extensive range in solubilities of the organic chemicals (adapted from Chiou et ah, 1977, with permission).

Fig. 1. The relationship between octanol-water partition coefficient and water solubility for various classes of liquid and solid organic compounds in comparison with the ideal line. Data for liquid compounds are from Hansch et al. 44) and those for solid compounds from Chiou et al. 18) and Tulp and Hutzinger lOOy.

In 1868 two Scottish scientists, Crum Brown and Fraser [4] recognized that a relation exists between the physiological action of a substance and its chemical composition and constitution. That recognition was in effect the birth of the science that has come to be known as quantitative structure-activity relationship (QSAR) studies a QSAR is a mathematical equation that relates a biological or other property to structural and/or physicochemical properties of a series of (usually) related compounds. Shortly afterwards, Richardson [5] showed that the narcotic effect of primary aliphatic alcohols varied with their molecular weight, and in 1893 Richet [6] observed that the toxicities of a variety of simple polar chemicals such as alcohols, ethers, and ketones were inversely correlated with their aqueous solubilities. Probably the best known of the very early work in the field was that of Overton [7] and Meyer [8], who found that the narcotic effect of simple chemicals increased with their oil-water partition coefficient and postulated that this reflected the partitioning of a chemical between the aqueous exobiophase and a lipophilic receptor. This, as it turned out, was most prescient, for about 70% of published QSARs contain a term relating to partition coefficient [9]. 

Despite the work of Overton and Meyer, it was to be many years before structure-activity relationships were explored further. In 1939 Ferguson [10] postulated that the toxic dose of a chemical is a constant fraction of its aqueous solubility hence toxicity should increase as aqueous solubility decreases. Because aqueous solubility and oil-water partition coefficient are inversely related, it follows that toxicity should increase with partition coefficient. Although this has been found to be true up to a point, it does not continue ad infinitum. Toxicity (and indeed, any biological response) generally increases initially with partition coefficient, but then tends to fall again. This can be explained simply as a reluctance of very hydrophobic chemicals to leave a lipid phase and enter the next aqueous biophase [11]. An example of this is shown by a QSAR that models toxicity of barbiturates to the mouse [12] ... 

Also in Table 3.4 are some solubility relationships (including partition coefficients) and one transport property. In these cases, the molecule in question is interacting with other kinds, and the product vo-2ot is found to be of less importance. Instead, cr2ot, cr2, and a2 often appear in the equations, along with terms involving molecular size. 

Such relationships have been applied to solubility, vapor pressure, Kow, KAW, KOA, Henry s law constant, reactivities, bioconcentration data and several other environmentally relevant partition coefficients. Of particular value are relationships involving various manifestations of toxicity, but these are beyond the scope of this handbook. These relationships are valuable because they permit values to be checked for reasonableness and (with some caution) interpolation is possible to estimate undetermined values. They may be used (with extreme caution ) for extrapolation. 

Bruggeman, W. A., van der Steen, J., Hutzinger, O. (1982) Reversed-phase thin-layer chromatography of polynuclear aromatic hydrocarbons and chlorinated biphenyls. Relationship with hydrophobicity as measured by aqueous solubility and octanol-water partition coefficient. J. Chromatogr. 238, 335-346. 

Measurements of aqueous solubility and partition coefficient between cellulose acetate and water were compared for thirty disperse dyes and an approximate inverse relationship was postulated [60]. This can only be valid to a limited extent, however, because the partition ratio also depends on the saturation solubility of the dye in cellulose acetate. This property varies from dye to dye and is not directly related to aqueous solubility. The solubilities of four dyes in a range of solvents were compared with their saturation values on cellulose acetate. Solubilities in benzene showed no significant correlation. With the other solvents the degree of correlation increased in the order ethanol < ethyl acetate < 20% aqueous diethylene glycol diacetate (CH3COOCH2CH2OCH2CH2OCOCH3). The last-named compound was suggested as a model with polar groups similar to those in cellulose acetate [86]. 

Pollutants with high VP tend to concentrate more in the vapor phase as compared to soil or water. Therefore, VP is a key physicochemical property essential for the assessment of chemical distribution in the environment. This property is also used in the design of various chemical engineering processes [49]. Additionally, VP can be used for the estimation of other important physicochemical properties. For example, one can calculate Henry s law constant, soil sorption coefficient, and partition coefficient from VP and aqueous solubility. We were therefore interested to model this important physicochemical property using quantitative structure-property relationships (QSPRs) based on calculated molecular descriptors [27]. 

Relationships such as Eqs. (45) and (46) have been utilized extensively in correlating solubility properties (such as gas/liquid and liquid/liquid partition coefficients), retention volumes in gas/solid chromatography, capacity factors in high-pressure liquid chromatography, etc.199 200 For instance, gas/liquid partition coefficients for each of 35 different liquid stationary phases were represented with R > 0.985.205 Other applications have been in biochemical and pharmacological areas,199 200 e.g., enzyme inhibition and pollutant effects. 

K generally varies only by factors of three to five for a given solute (12). K typically correlates well with physico-chemical properties of the sorbate, such as aqueous solubility (S) or the octanol-water partition coefficient (K ), again suggesting that hydrophobic interaction predominates. The correlation of Koc with K has led to the definition of linear free-energy relationships (LFER) of the form... 

A number of empirical relationships have been published which could be used to predict partition coefficients from solubility data [19-29, 65, 72, 78-97]. Comparisons among these relationships may be confusing since different sets of compounds and different solubility terms are used. A theoretical analysis of partition coefficient with reference to aqueous solubility is important because it illustrates the thermodynamic principles underlying the partitioning process. The objective of that relationship is its utility for both predicting and validating reported values for partition coefficients. 

The general relationship between the type of solute and its retention can be seen by comparing the retention factors, k, of a set of standard compounds with their octanol-water partition coefficients, i.e. the logP value (listed in Table 4.1), as a measure of their relative solubility in water. The logarithm of the retention factor, log k, of these compounds measured in 50% aqueous acetonitrile on an octadecyl-bonded silica gel column shows a close linear relationship (Figure 4.1). 

A quantitative analysis of the structure-retention relationship can be derived by using the relative solubility of solutes in water. One parameter is the partition coefficient, log P, of the analyte measured as the octanol-water partition distribution. In early work, reversed-phase liquid chromatography was used to measure log P values for drug design. Log P values were later used to predict the retention times in reversed-phase liquid chromatography.The calculation of the molecular properties can be performed with the aid of computational chemical calculations. In this chapter, examples of these quantitative structure-retention relationships are described. 

Gas-liquid relationships, in the geochemical sense, should be considered liquid-solid-gas interactions in the subsurface. The subsurface gas phase is composed of a mixture of gases with various properties, usually found in the free pore spaces of the solid phase. Processes involved in the gas-liquid and gas-solid interface interactions are controlled by factors such as vapor pressure-volatilization, adsorption, solubility, pressure, and temperature. The solubility of a pure gas in a closed system containing water reaches an equilibrium concentration at a constant pressure and temperature. A gas-liquid equilibrium may be described by a partition coefficient, relative volatilization and Henry s law. 

The concept of equilibrium distribution is another area where names can cause much confusion. The equilibrium distribution of a compound between the gas and liquid phase has been expressed in various forms, i. e. Bunsen coefficientfi, solubility ratio s, Henry s Law constant expressed dimensionless Hc, or with dimensions H. These are summarized in along with equations showing the relationships between them. Another more general term to describe the equilibrium concentrations between two phases is the partition coefficient, denoted by K. It is often used to describe the partitioning of a compound between two liquid phases. 

The octanol/water coefficient (log P) is the standard molecular descriptor used to provide the chemical property of the hydrophobicity of a molecule. Compounds with high partition coefficients usually have very low aqueous solubility. This will decrease the chance of attack by hydroxyl radicals and lead to a lower rate constant. Nevertheless, the linear relationships with log P do not reproduce similar trends of several chemical classes such as alkane and phenol. They could be either positive or negative linear relationships. Alkene (R2 < 0.67), benzene (R2 < 0.78), carboxylic acid (R2 < 0.74), and halide (R2 < 0.55) classes do not provide significant correlations. 

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