Molecules, flexible sterically crowded

Table II shows some literature examples of the breakdown in additivity which can occur in flexible molecules (Compounds 1-4) or in sterically crowded molecules such as the diphenylmethanes (Compounds 5 and 6). In the first four cases, a dipole is probably interacting with polarizable 7r-electrons of the aromatic ring. In Compound 5, the overall shape probably prevents water molecules from forming a solvate iceberg between the two rings—a situation which can be considered an intramolecular hydrophobic bond. In Compound 6 a combination of intramolecular hydrophobic effects and possibly interaction of the side chain dipole with one or both aromatic rings leads to a wide discrepancy between experimentally determined and calculated log F values.

It has been shown by Tute and collaborators (228) that the theoretical evaluation of logP on the basis of additivity principles can lead to misleading results for certain molecules (e.g., heterocyclics, sterically crowded or conformationally flexible molecules). This difficulty has been recently rationalized for rigid structures (229) Experimentally measured logP values are therefore more reliable than those estimated from component it values ... 

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