The only existing O-H...F-C bond...not

This is a beautiful piece of data re-interpretation. A few years ago, there was a report published about a compound which supposedly demonstrated the only instance of a solution O-H...F-C hydrogen bond. This seemed to provide some support for hydrogen bonding involving fluorine.

Now a Spanish group has published a nice paper in CC that provides a refutation and re-interpretation of the data that along with some calculations, indicates that the observed data is not due to a C-F...H-O hydrogen bond, but simply due to steric hindrance that makes the three fluorines of a CF3 group non-equivalent. In the former interpretation, it was assumed that the non-equivalence of two Fs of this group with the third F indicated that the third F was involved in hydrogen bonding. The new interpretation says that it is steric hindrance that prevents rapid rotation of the CF3 group, and makes the three Fs non-equivalent. Calculations support the interpretation.

Thus, now we will have to look for other instances in which there is bonafide C-F...H-O bonding. Quite a neat piece of careful data analysis supported by crystallography and quantum chemical caclulations.

Another fact mentioned in the paper reminds me of one of the more memorable papers that I have read; Stanford's Eric Kool's demonstration that difluorotoluene- an isostere of thymine in which Ns are replaced by Cs and Os are replaced by Fs- behaves like thymine when DNA polymerase inserts it opposite adenine.

Reference:
Is there any bona fide example of O–HF–C bond in solution? The cases of HOC(CF3)2(4-X-2,6-C6H2(CF3)2) (X = Si(i-Pr)3, CF3)
Chem. Commun., 2007, 4384 - 4386, DOI: 10.1039/b710304b

Fluorine in pharmaceuticals

Among the lessons which I learnt in graduate school was another important one: organic fluorine rarely forms hydrogen bonds. The layman's explanation for this phenomenon is that F holds tightly on to its electrons and does not share them.

However, there are enough number of examples among protein-ligand interactions, although much fewer than the other ones, to warrant attention to the role of F in drugs. The review in the latest issue of Science does exactly that. (DOI: 10.1126/science.1131943)

Some of the salient points I got from this and other reviews:

1. F as bioisostere: As is known, because of its similar size, F can be a good bioisostere for O, and C-F bonds can stand in for C-O bonds. The review mentions C-CF3 as substitute for C-O, and vinyl C=C-F as substitute for peptide bonds. The introduction of F can considerably alter conformational preferences. The review mentions the interesting case of O-CH3 vs O-CF3 bonded to an aromatic ring. In the former, the group is in the plane of the ring because of pi-orbital conjugation with the ring, whereas in the latter, O-antibonding C-F orbital conjugation destroys this preference and swings the group orthogonal to the ring.

2. F as acidity promoter: It is well-known that F increases the acidity of amines. In some cases, one can decrease the pKa to below 7, so that the amines will not be protonated at physiological pH. This can have the consequence both of improving permeability by increasing the neutral form of the amine, and radically changing the binding mode. A remarkable example is of a series of thrombin inhibitors, where the pKa could be decreased from 10 to <2 by introducing well-positioned Fs. I have already talked about the exceptional case of 3-F piperidines.

3. F as lipophilicity enhancer: Another important property of increasing the logD value. The review also mentions cases where the logD actually falls. F's lipophilicity has been famously incorporated into Teflon®, and hexafluoroisopropanol and hexafluoroacetone are often used to enhance alpha-helical content of peptides on the basis of this property. Balaram and Rajan have argued that these solvents actually "dry" the peptides ("Teflon coated peptides")

4. F as H-bonder: A unique property of this chap. I always remember a review by Dunitz in which he statistically examined a large number of CSD entries and found an exceedingly small number of cases where organic F could be a bonafide H-bond acceptor. However, there are also cases, where F in ligands shows close proximity to C-H, N-H, and most interestingly, C=O bonds where F interacts with the carbonyl carbon. This is in contrast to the recently investigated "halogen bonds" where Br and Cl seem to interact with carbonyl oxygen in proteins.

Clearly, F's behaviour in enhancing protein-drug interactions is valuable. And it remains as interesting and enigmatic as ever. An always colorful beast.