Quantitative structure-water solubility relationships

The correlation between aqueous solubility and molar volume discussed by McAuliffe [5] for hydrocarbons, and the importance of the cavity term in the solvatochromic approach, indicates a significant solubility dependence on the molecular size and shape of solutes. Molecular size and shape parameters frequently used in quantitative structure-water solubility relationships (QSWSRs) are molecular volume and molecular connectivity indices. Moriguchi et al. [33] evaluated the following relationship to estimate Cw of apolar compounds and a variety of derivatives with hydrophilic groups ... 

A diverse collection of quantitative property-water solubility relationships (QPWSR) is available in the literature. These QPWSR differ in their solubility representation (Cw, Sw, Xw), spectrum of independent variables, and applicability with respect to structure and physical state (liquid or solid). The following types of QPWSR are considered ... 

Two approaches to quantify/fQ, i.e., to establish a quantitative relationship between the structural features of a compoimd and its properties, are described in this section quantitative structure-property relationships (QSPR) and linear free energy relationships (LFER) cf. Section 3.4.2.2). The LFER approach is important for historical reasons because it contributed the first attempt to predict the property of a compound from an analysis of its structure. LFERs can be established only for congeneric series of compounds, i.e., sets of compounds that share the same skeleton and only have variations in the substituents attached to this skeleton. As examples of a QSPR approach, currently available methods for the prediction of the octanol/water partition coefficient, log P, and of aqueous solubility, log S, of organic compoimds are described in Section 10.1.4 and Section 10.15, respectively. 

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]. 

Raevsky, O. A., Schaper, K.-J. Physicochemical descriptors governing the solubility and partitioning of chemicals in water-solvent-gas systems. In Abstracts of 12th International Workshop on Quantitative Structure-Activity Relationships in Environmental Toxicology, Lyon, France, 2006, p. 23. 

There is a continuing effort to extend the long-established concept of quantitative-structure-activity-relationships (QSARs) to quantitative-structure-property relationships (QSPRs) to compute all relevant environmental physical-chemical properties (such as aqueous solubility, vapor pressure, octanol-water partition coefficient, Henry s law constant, bioconcentration factor (BCF), sorption coefficient and environmental reaction rate constants from molecular structure). 

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]. 

Octanol/water partition coefficients, Pow, which measure the relative solubilities of solutes in octanol and in water, are widely used as descriptors in quantitative structure-activity relationships (QSAR), for example in pharmacological and toxicological applications.49 Since experimental values of these are not always available, a number of procedures for predicting them have been proposed (see references in Brinck et al.).50... 

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. 

The relationship between odour quality and chemical structure is of considerable practical and theoretical interest. A numt r of methods have been used to determine quantitatively the relationships between the structure of a molecule and its odour quality (7). Though quantitative results were not obtained, a number of interesting theories were present in that the intermolecular interaction in olfaction involved electrostatic attraction, hydrophobic bonding, van der Waals forces, hydrogen bonding, and dipole-dipole interactions. Hydrophobic interactions also appeared to be a major force for substrate binding in olfaction. It had previously been shown that lipophilicity and water solubility were factors diat significandy influenced the odour thresholds of the pyrazines (8),... 

There are several properties of a chemical that are related to exposure potential or overall reactivity for which structure-based predictive models are available. The relevant properties discussed here are bioaccumulation, oral, dermal, and inhalation bioavailability and reactivity. These prediction methods are based on a combination of in vitro assays and quantitative structure-activity relationships (QSARs) [3]. QSARs are simple, usually linear, mathematical models that use chemical structure descriptors to predict first-order physicochemical properties, such as water solubility. Other, similar models can then be constructed that use the first-order physicochemical properties to predict more complex properties, including those of interest here. Chemical descriptors are properties that can be calculated directly from a chemical structure graph and can include abstract quantities, such as connectivity indices, or more intuitive properties, such as dipole moment or total surface area. QSAR models are parameterized using training data from sets of chemicals for which both structure and chemical properties are known, and are validated against other (independent) sets of chemicals. 

A9.5.2.4.1 For organic substances experimentally derived high-quality Kow values, or values which are evaluated in reviews and assigned as the recommended values , are preferred over other determinations of Kow. When no experimental data of high quality are available, validated Quantitative Structure Activity Relationships (QSARs) for log Kow may be used in the classification process. Such validated QSARs may be used without modification to the agreed criteria if they are restricted to chemicals for which their applicability is well characterized. For substances like strong acids and bases, substances which react with the eluent, or surface-active substances, a QSAR estimated value of Kow or an estimate based on individual -octanol and water solubilities should be provided instead of an analytical determination of Kow (EEC A.8., 1992 OECD 117, 1989). Measurements should be taken on ionizable substances in their non-ionized form (free acid or free base) only by using an appropriate buffer with pH below pK for free acid or above the pK for free base. 

Many hydrophobic molecules such as vitamin A, vitamin D and steroid hormones play vital roles in a variety of cellular processes. Because of the low solubility of these molecules in water, it has been difficult to measure the binding properties of the site-directed mutants of the proteins that interact with these hydrophobic ligands such as cellular retinoic acid binding proteins (CRABPs) (Zhang et al. 1992 Chen et al. 1995). This has greatly hampered the studies of the quantitative structure-function relationships of these important proteins. 

A convenient point of departure is that of the increasingly popular quantitative structure activity relationships (QSAR) mentioned above [696,699,11], which derive adsorbate-adsorbent interaction indices from, for example, water solubility data, molecular connectivities [697], n-octanol-water partition coefficients, reversed-phase liquid chromatography capacity factors [723], or linear solvation energy relationships (LSER). 

The relationship between a chemical s structure and its biological action has been studied extensively for over a century (16). In cases where there is not a complete understanding of the mechanism/mode of action or where the influence of functional groups is not known or obvious, there is a vast body of knowledge on how different structural features within a class of chemicals may correlate with various levels of hazard. Structure-activity relations (SAR) or their mathematical treatment. Quantitative SAR (QSAR) have been developed for myriad endpoints including cancer, developmental and reproductive effects, aquatic toxicity, boiling points, water solubility and many others hazard endpoints. An instructor therefore has many opportunities to incorporate the concept of SAR at several points in the curriculum. 

Three major approaches to the prediction of aqueous solubility of organic chemicals using Quantitative Structure Activity Relationship (QSAR) techniques arc reviewed. The rationale behind six QSAR models derived from these three approaches, and the quality of their fit to the experimental data are summarized. Their utility and predictive ability are examined and compared on a common basis. Three of the models employed octanol-water partition coefficient as the primary descriptor, while two others used the solvatochromic parameters. The sixth model utilized a combination of connectivity indexes and a modified polarizability parameter. Considering the case of usage, predictive ability, and the range of applicability, the model derived from the connectivity- polarizability approach appears to have greater utility value. 

The water solubilities are an indirect, and inversely proportional, measurement of hpophflicity. As alkyl chain length increases, the water solubility decreases (increase in lipohilicity) and the toxicity increases. With AE, the lipohilicity can be altered by both alkyl chain length and EO number. Quantitative structure activity relationship (QSAR) models have... 

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. 

A novel approach to this problem suggested itself from our work on hydrolysis of S-bound sulfoxide. The unique properties of DMSO in its pharmacological actions, such as membrane transport and membrane penetration, are well known (41) and the water-solubilising properties in its metal complexes was readily apparent from the good aqueous solubility of the M-DMSO species. Further, the lability seemed qualitatively of the order of halide (a point confirmed quantitatively during the course of these experiments (23)) and these observations prompted us to probe the following structure-activity relationship ... 

---