Trifluoromethyl: An Amphiphilic Noncovalent Bonding Partner.

The traditional "Fδ- " picture of fluorine suggests that it can only interact with electrophilic centers such as backbone-carbonyl carbon atoms or hydrogen-bond donors in proteins. We show that this view, which neglects polarization, is incomplete and the trifluoromethyl groups can act both as electrophiles and nucleophiles to form noncovalent interactions. The underlying polarization mechanism is based on the anomeric effect and is only fully operative if the geometry is allowed to relax. MP2/aug-cc-pVDZ calculations on model systems demonstrate the effect of the unusual group polarizability of trifluoromethyl. A survey of the Protein Databank reveals more than 600 weak interactions involving a trifluorotoluene moiety. The unique combination of the anomeric effect and the group-polarization process associated with it in CF3 allows its most negative molecular electrostatic potential (MEP) on the surface in contact with a nucleophile to become zero, so that the area of positive MEP on the backside of the carbon atom becomes dominant. However, the reverse polarization is also facile, so that CF3 can also act as an H-bond acceptor for cations such as the guanidinium group of arginine.