Hydrophobic substituent constant

R. Franke, S. Dove and R. Kuehne, Hydrophobicity and hydrophobic interactions, 1. On the physical nature of aromatic hydrophobic substituent constants. Eur. J. Med. Chem., 14 (1979) 363-374. 

Lipophilic substituent constants are also known as hydrophobic substituent constants. They represent the contribution that a group makes to the partition coefficient and were defined by Hansch and co-workers by the equation ... 

The distribution coefficient refers to the hydrophobicity of the entire molecule. Within a family of organic compounds it is sometimes useful to deal with hydrophobic substituent constants that relate the hydrophobicity of a derivative, log Px, to that of the parent molecule, log P. Therefore, a substituent parameter, n, has been defined [21] as... 

Similarly, the partitioning of nitroimidazoles into octanol-water, log Poet and into four liposome preparations with different lipid composition, log KM, was determined and regression equations were derived to explain the observed variation in the pharmacokinetic parameters of these drugs [85]. The log fCM ranged from 1.5 to 0.5 and was at least two- to threefold greater than log Poct (Table 4.24). In addition, the hydrophobic substituent constants of functional groups in various partitioning systems... 

Tab. 4.25 Hydrophobic substituent constants of functional groups of nitroimi-dazoles in liposome (I—IV) systems and in the n-octanol-saline (Poct) (see Tab. 4.24). (Adapted from Tab. 4 of ref. 85)...

At first sight these may appear to be reasonably diverse in terms of their chemistry even though there are three halogens in the set. The it values are nicely spread out from hydrophilic (-1.23) to hydrophobic (1.44) but, unfortunately, so are the o values. In general there is no correlation between the hydrophobic substituent constant it and the electronic substituent constant o, but for this set the squared correlation coefficient between these two physicochemical properties is 0.95. In much the same way as the methyl-futile set is uninformative, so would this set be in terms of distinguishing electronic effects from hydrophobic effects in any QSAR model derived from it. 

Hansch-Fujita hydrophobic substituent constants - lipophilicity descriptors... 

These hydrophobic substituent constants are commonly used in - Hansch analysis to encode the lipophilic behavior of the substituents the hpophiUcity of the whole molecule is obtained by adding to the lipophilicity of the unsubstituted parent compound (logPn) the lipophilic contributions of the substituents ... 

This parameter is often used as a substituent steric constant in - Hansch analysis. In order to put the molar refractivities of the substituents on approximately the same scale as the - hydrophobic substituent constants Jt, the substituent MR values are often scaled down by the factor 0.1. 

The most popular substituent constants are electronic substituent constants, - Hansch-Fujita hydrophobic substituent constants and -> steric substituent constants such as - Taft steric constant, - Charton steric constant, -> substituent front strain, and - steric density parameter. 

MR molar refractivity it hydrophobic substituent constant and Op overall electronic constants for meta- and para-position K and p Swain-Lupton resonance and field constants L Sterimol length parameter B1 and B5 Sterimol B parameters SD Dash-Behera steric density parameter. 

Greco, G., Novellino, E., Pellecchia, M., Silipo, C. and Vittoria, A. (1993). Use of the Hydrophobic Substituent Constant in a Comparative Molecular Field Analysis (CoMFA) on a Set of Anilides Inhibiting the Hill Reaction. SAR QSAR Environ.Res., 1,301-334. 

The analysis of the parameters representing the effect of the medium in terms of extrathermodynamical relations has shown (see above, section A.2) that the hydrophobic substituent constant it depends on the molecules from which it is derived. For example, hydrophobic constants derived from the octanol/water partition coefficients of aromatic molecules differ from those obtained from aliphatic molecules (112). Collander s equation (111) provides the empirical basis for the evaluation of logP values for the same molecule in different solvents. However, solvents with markedly different solvation properties (e.g., hydrogen bonding ability) do not conform to Collander s equation (see below, section C.3). 

In 1962, the first formal QSAR paper was published by Hansch—considered by many as the father of QSAR—in which was emphasized the role of the octanol to water partition coefficient (logP) [46], Shortly thereafter, in 1964, publication of a method to compute a hydrophobic substituent constant k from log/ values [47] led many investigators with access to toxicity data to... 

The MR parameter has the dimensions of volume and can correlate with the hydrophobic substituent constant n it can be used as a crude measure of bulk. However, the parameter has a component proportional to polarisability. These potential complications can be avoided by careful experimental design so that the chosen substituents have tc values which are not linear with their MR parameters. The coefficient of MR in the free energy equation can be used to indicate a steric interaction (-ve) coefficient or an interaction involving dispersion forces (+ve coefficient). 

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