Model solvent systems for QSAR. Part 3. An LSER analysis of the ‘critical quartet.’ New light on hydrogen bond strength and directionality

Hydrogen bonding part 46: a review of the correlation and prediction of transport properties by an lfer method: physicochemical properties, brain penetration and skin permeability

“…There remain three descriptors that have to be obtained, viz and n 2 H, &a 2 H &b 2 H. Firstly, we should point out that for a number of solutes, speciücally some anilines, pyridines and sulfoxides (but not sulfones), the hydrogen-bond basicity appears to alter with the water-solvent system, as ürst observed by Leahy et al 45 We have dealt with this problem by assigning two values to these &b 2 particular compounds, the original value for use &b 2 H in systems where the solvent is very immiscible with water (eg alkanes, chloroform, benzene, etc) and an additional descriptor for use in solvents that are &b 2 0 somewhat miscible with water (eg octanol, ether, ethyl acetate). We note that this alternative descriptor is only needed for the speciüc solutes in the more miscible solvents, and that for partition between water and very immiscible solvents, the descrip&b 2 H tor is still used for the speciüc solutes.…”

Lipophilicity and Its Relationship with Passive Drug Permeation

“…However, the log P oct scale of lipophilicity alone is not effective in modelling the crossing of any kind of cell membranes due to large differences in their biophysical properties (33,34). Thus, four types of isotropic solvent systems (amphiprotic, inert, hydrogen-bond donor and hydrogen-bond acceptor), called the 'critical quartet' (e.g., n-octanol/water, alkanes/ water, chloroform/water, and dibutyl ether/water), are necessary in order to cover adequately the range of biophysical properties of membranes (35,36). The 'critical quartet' expresses in partly overlapping and partly complementary ways the recognition forces that account for membrane partitioning and biological selectivity (37,38).…”

Measurement of the relative hydrophobicity of organic compounds without organic solvent. Effects of salt composition and pH on organic acids and nonionic compounds

“…Partitioning of a series of organic compounds in di-n-butyl ether±water system 7 showed the trend opposite to the one observed in DCE 1 ±water relative to octanol± water system due to H-bond acceptor capacity of di-n-butyl ether. An effort to examine the intermolecular forces governing partition behavior of organic compounds in different solvent biphasic systems using the so-called``critical quarter'' methodology 8,9 is obviously an important endeavor. However, the fact that this endeavor was undertaken to improve the characterization of lipophilicity by octanol±water partitioning just stresses the fact that octanol (or any other organic solvent, except possibly alkanes that are technically inapplicable) is not an inert organic solvent, and it actively interacts with compounds being partitioned in a compoundspeci®c manner.…”