Solvent assisted olefin epoxidation: fluorine emerges a winner

A nice application of both computational techniques and kinetics (entropy of activation etc.) in elucidating the role of hydrogen bonded networks of H2O2 and hexafluoroisopropanol (HFIP) in the epoxidation of olefins. Some of the ordered clusters look almost like the active site of an enzyme; no wonder the barriers for oxygen transfer decrease. Also, fluorinated solvents are highly hydrophobic, so I would not be surprised if that property alone contributes to a very specific degree of ordering. All those h-bonds made me giddy.



HFIP and related solvents have interesting effects on both organic reactions and conformations of biomolecules. For example, addition of TFE to peptide and protein solutions can increase helicity. A simple and nice model was proposed by Balaram, which explained this effect by virtue of the fact that since F is a poor h-bond acceptor, the NH of the amide backbone no longer had to sacrifice its usual NH---C=O h-bond for one with the solvent (like water) and thus could engage better in helix formation.

In this account, some of the C-H---F distances are right outside the sum of vdW radii of the atoms. Weak C-H h-bonds are interesting entities, and unlike 'normal' h-bonds, their scope and definition is much looser, and is emphatically not restrained to having them within the sum of vdW radii; the h-bond potential minimum is of lesser energy and shallower. In such cases, comparative studies of geometry and energy have to be performed to assess whether these are 'true' h-bonds. The boundary is thin and nebulous though, but there is an excellent book on this state of affairs as well as the whole gamut of h-bonding interactions- The Weak Hydrogen Bond in Structural Chemistry and Biology. I find this slippery boundary of h-bond definition in many cases, a delicious example of the inexact yet rationalizable nature of chemistry.

One of those factoids which looks deceptively obvious and hence can be misconstrued, is that organic fluorine is a good h-bond acceptor. Not so! And Jack Dunitz has written a neat article ("Organic Fluorine Hardly Ever Accepts Hydrogen Bonds") in which he did a comparative study of the CSD (Camb. Struct. Database) and concluded that out of some 6000 structures with fluorine, only 30 or so had features which maybe could indicate h-bonding with fluorine. In the case of further data, it's best to assume that a fluorine in a molecule will not h-bond. As usual, the case could be quite different in a crystal.

Another thing to note again is the authors' use of MP2, which handles dispersion much better than DFT.

Reference: Albrecht Berkessel and Jens A. Adrio, J. Am. Chem. Soc., ASAP Article 10.1021/ja0620181