Archive for the ‘solubility’ Category

Intermolecular CH—pi interaction

September 14, 2007

 Dissecting out interactions between hydrophobic organic residues, particular those made in the context of a ligand binding to a protein (eg. enzyme or receptor) is difficult since it is hard to seperate the energy contributed by dissolution of the molecule from the energy of interaction with the protein.

 A recent Angewandte article (Angewandte Int. Ed., 2007, 6833) by Craig Wilcox from the University of Pittsburgh describes an interesting “molecular tool” for measuring weak “hydrophobic” interactions between organic residues which also takes into account the desolvation of the substituent.

The system is referred to as a “molecular torsion balance” and in some ways it resembles an old fashion two-pan balance. The actual molecule is a little more complicated looking, but it is rather straight forward to synthesize.


The balance measures the interaction of the test group (R) with the stationary phenyl group, while the corresponding rotomer places it “into solvent”. The group sheds these solvent molecules when the balance rotates to place it over the stationary phenyl group. The torsional equilibrium is directly proportional to the free energy difference (ΔG) between each rotamer. The equilibrium is easily measured using NMR.

In the study at hand the test substituents were all alkyl groups and therefore the type of interaction evaluated was that between the C-H portion of the alkyl groups and the p cloud of the phenyl ring. The results are shown in the table. There don’t appear to be any surprises in that the larger groups favor interaction with the aryl group and water enhances this effect due to desolvation.  Assuming that the CH-p interaction is the same in chloroform and water, the difference between ΔG (water) and ΔG (chloroform) provides a measure of the desolvation effect.


August 24th

August 24, 2007

I’ll confess that most of the theoretical methods are beyond me, but I found the premise of a recently published paper in Angewandte Int. Ed. intriguing.

Based on experiment and theory David Beratan (Duke University) shows that with certain chiral molecules the solvent directly contributes to the observed Optical Rotation (OR) of the solute.  They propose that the solvent sorrounding the chiral molecule creates a chiral shell, or in their words a “chiral imprint” and as such is capabable to exhibit an OR by itself  if the solvent molecules interact with the polarized light.

If true I think this finding has broader implications since it might be useful in the development of more accurate solvation models. For instance the results are not predicted by continuum solvent models.

Another interesting question is to what extent might the solvent shell contribute to the outcome of stereoselective reactions?


Word of the week…Racemate

March 29, 2007

The definition of racemate, an equimolar mixture of enantiomers, is old hat to most of us having learned it in our introductory organic chemistry courses. And so it was for me until recently.

Being a synthetic chemist, I don’t have much time or energy to gain a deep understanding of physicochemical properties. Therefore, I was not surprised to find that I was ignorant of the fact that in the solid state racemates come in two flavors and that the IUPAC has developed specefic nomenclature to define each. There is a “racemic compound” where the two enantiomers are co-crystallized homogenously into a single crystal. However, racemates can also exist as “racemic conglomerates” which describes the situation where the two enantiomers crystallize separately but still might be occluded in a single particle.

Tangentially related to this topic is Wallach’s rule which states that racemic crystals (ie. racemic compounds) are more dense than the crystals of the pure enantiomers. Which makes me think…since increased crystalline density is generally associated with increased stability and increased crystalline stability can be correlated with reduced aqueous solubility, one would expect that racemates would be less soluble than their pure enantiomers. I did a search of the literature see if this was the case and come up with the examples below..there appears to be a  slight trend.