Correlation of log P with molecular connectivity in hydroxyureas: influence of conformational system on log P

The correlation of log P (in octanol--water) with the nonempirical, topologically dependent, calculated molecular connectivity index (1chiv) delineates substituted hydroxyureas into two families of linearly related groups of compounds. The first group, composed of the 3-substituted ethyl, n-propyl, and n-butyl analogs, is more hydrophilic than the 1-substituted methyl and ethyl and the 3-substituted isopropyl and tert-butyl analogs. The unsubstituted model compound hydroxyurea appears between the two groups in equal volumes of octanol. In octanol--water ratios of 5:1, log P approaches the range of the more hydrophilic group in high concentrations and becomes more lipophilic (similar to the other group) in lower concentrations. The differences in the relative hydrophilicities--lipophilicities of the two groups are rationalized in terms of the equilibri of internally hydrogen-bonded, conformers to those that allow optimal interactions with solvent, water, or other hydroxyurea molecules. The concentration dependency observed with hydroxyurea appears to be due to the ease of interconversion of intermolecularly bonded conformers to those interacting with water, whereas the involvement of internally bonded conformers, which are apparently present to a greater degree in lower concentrations, increases the relative lipophilicity.