Relationships between partitioning solvent systems

Leo, A. and Hansch, C. (1971a). Linear Free-Energy Relationships Between Partitioning Solvent Systems. J.Org.Chem., 36,1539-1544. 

Essentially, extraction of an analyte from one phase into a second phase is dependent upon two main factors solubility and equilibrium. The principle by which solvent extraction is successful is that like dissolves like . To identify which solvent performs best in which system, a number of chemical properties must be considered to determine the efficiency and success of an extraction [77]. Separation of a solute from solid, liquid or gaseous sample by using a suitable solvent is reliant upon the relationship described by Nemst s distribution or partition law. The traditional distribution or partition coefficient is defined as Kn = Cs/C, where Cs is the concentration of the solute in the solid and Ci is the species concentration in the liquid. A small Kd value stands for a more powerful solvent which is more likely to accumulate the target analyte. The shape of the partition isotherm can be used to deduce the behaviour of the solute in the extracting solvent. In theory, partitioning of the analyte between polymer and solvent prevents complete extraction. However, as the quantity of extracting solvent is much larger than that of the polymeric material, and the partition coefficients usually favour the solvent, in practice at equilibrium very low levels in the polymer will result. 

Partition coefficients from different solvent systems can also be compared and converted to the octanol/water scale, as was suggested by Collander (116). He stressed the importance of the following linear relationship log 2 = a logPj + b. This type of relationship works well when the two solvents are both alkanols. However, when two solvent systems have varying hydrogen bond donor and acceptor capabilities, the relationship tends to fray. A classical example involves the relationship between log P values in chloroform and octanol (117,118). 

Numerous efforts 38,40,42 46 51) were undertaken to find out in what manner the aqueous solubility and the partition coefficients of different solutes in water-organic solvent biphasic systems are related to the size of the solute molecules. Since the solute packing into the solvent clearly depends on the solute surface, a relationship between surface area and solution thermodynamics seems to be reasonable. 

The relationship between a and b. described by Eq. (12) seems to clarify why both coefficients are considered 10-53-62> to be slightly different measures of the relative hydrophobic character of the organic solvent in a given partitioning system. 

The above considerations show that it is the values of the ratio Aj/E, and not just the A values that should be compared to examine the estimates of the relative hydro-phobicity of polar groups of solutes obtained when using different partitioning systems 63). An analysis of the ratio Aj/Ej values for aliphatic alcohols, amines, and fatty acids, calculated from the known partition coefficients for these solutes in various solvent systems, indicated 63 that there is a relationship between the ratio value and the solubility of water in a given organic solvent. This relationship is described as ... 

Several hundreds of linear relationships between various kinds of (mostly nonspecific) biological data and n-octanol/water partition coefficients have been published e.g. [18, 182]). However, the choice of n-octanol/water as the standard system for drug partitioning must be reconsidered in the light of some recent results. Principal component analysis of partition coefficients from different solvent systems [188 —190] shows that lipophilicity depends on solute bulk, polar, and hydrogen-bonding effects [189] isotropic surface areas, i.e. areas where no water molecules bind and hydrated surface areas, were correlated with the first and the second principal components of such an analysis [190]. 

The presumed relationships between partitioning in different solvent/water systems (organic phases A and B) according to the Collander equation (1951)... 

Meanwhile attention was drawn to the overriding importance of a physical property when, at the turn of the present century, Overton and Meyer independently put forward a Lipoid Theory of Cellular Depression (Meyer, 1899 Overton, 1901). This stated that chemically inert substances, of widely different molecular structures, exert depressant properties on those cells (particularly those of the central nervous system) that are rich in lipids and that the higher the partition coefficient (between any lipid solvent and water) the greater the depressant action. This statement requires only insertion of the words, up to the point where hydrophilic properties are almost extinguished after partition coefficient to outline the present day viewpoint. It is now appreciated that the relationship between lipophilicity and depression of nerve functioning is a parabolic one, because substances that are entirely lipophilic become trapped in other lipids and do not enter the cell (Hansch et al., 1968). Table 2.1 offers... 

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]. 

Factors leading to insolubility in water were discussed in Section 10.2.1.1. Provided they are not highly polymerized, such hydrophobic substances are generally soluble in non-aqueous solvents. In a two-phase system formed by an aqueous phase and a second phase immiscible with it a solute will partition between them until its activity is the same in both. The Nernst partition isotherm quantifies this relationship in the form... 

Typical applications of reversed-phase chromatography are shown in Table 2. Beyond analytical apphca-tions, RP-TLC on bonded phases is also a tool for physicochemical measurements, particularly for molecular hpophilicity determination of biologically active compounds. Hydrophobicity can be measured by partition between an immiscible polar and nonpolar solvent pair, particularly in the reference system n-oc-tanol-water. The partition coefficient, P, is frequently used to interpret quantitative structure-activity relationships (QSAR studies). 

The additive property of the partition coefficient has been investigated in the study of solute partitioning in solvent-water systems. Fujita et al. 31) examined the relationship for the distribution of solutes between octanol and water, and in a fashion analogous to the Hammett a constant, defined a substituent constant II as... 

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