This post got prompted one by Dan at Practical Fragments and I'm going to ask you to first take a look at that and at the comments. Now I'd like you to look at some measured octanol/water logP values that I pulled from the Sangster Research Laboratories logPow database. The question I'd like to put to you is whether you think that these measured logP values truly reflect the energetic costs of moving the different isomeric methylimidazoles from water to a truly non-polar environment like a hydrophobic binding pocket in a protein.
Let's take a look these figures. The least lipophilic compound of the set is N-methylimidazole in which the hydrogen bond donor of imidazole has been capped, although the partition coefficients for the three compounds are all very similar. It seems that the octanol/water partitioning system just doesn't seem to 'see' the hydrogen bond donors of the 2-methyl and 4/5-methyl isomers.
Octanol has a hydroxyl group and, in the context of a shake-flask logP determination, gets pretty wet (~2M), making it a unconvincing model for the hydrophobic core of a lipid bilayer or a hydrophobic binding pocket. In contrast, alkanes lack hydrogen bonding capability which also means that they also dissolve less water. The catch is that alkane/water partition coefficients are more difficult to measure than their octanol/water equivalents since polar solutes are poorly soluble in alkane solvents.
The difference between octanol/water and alkane/water logP values for a compound (often termed ?logP) is one measure of the polarity of the compound. The octanol/water logP of phenol is 1.5 and it would be reasonable to describe it as lipophilic. However in the alkane/water system the situation is reversed and the logP of -0.6 would lead to phenol being described as hydrophilic.
I'll leave things here for now because this post is really just a teaser and I will be returning to the theme in more depth in the future. If you're interested in finding out more take a look at my harangue from the March 2011 PhysChem Forum at Syngenta and the article that goes with it. I'd also recommend reading this review by Wolfenden if you're interested in the relevance of alkane/water logP values to protein structure and function.
Toulmin, Kenny & Wood, Toward prediction of alkane/water partition coefficients. J. Med. Chem. 2008, 51, 3720-3730. DOI
Wolfenden, Experimental Measures of Amino Acid Hydrophobicity and the Topology of Transmembrane and Globular Proteins. J. Gen. Physiol. 2007, 129, 357-362. DOI