Partitioning Solvophobic and Dispersion Forces in Alkyl and Perfluoroalkyl Cohesion

Fluorine substituents have become a widespread and important drug component, their introduction facilitated by the development of safe and selective fluorinating agents. Organofluorine affects nearly all physical and adsorption, distribution, metabolism, and excretion properties of a lead compound. Its inductive effects are relatively well understood, enhancing bioavailability, for example, by reducing the basicity of neighboring amines. In contrast, exploration of the specific influence of carbon-fluorine single bonds on docking interactions, whether through direct contact with the protein or through stereoelectronic effects on molecular conformation of the drug, has only recently begun. Here, we review experimental progress in this vein and add complementary analysis based on comprehensive searches in the Cambridge Structural Database and the Protein Data Bank.

Interactions of "organic fluorine" have gained great interest not only in the context of crystal engineering, but also in the systematic design of functional materials. The first part of this tutorial review presents an overview on interactions known by organic fluorine. This involves π-π(F), C-F···H, F···F, C-F···π(F), C-F···π, C-F···M(+), C-F···C=O and anion-π(F) interactions, as well as other halogen bonds. The effect of the exchange of H vs. F is discussed by means of several examples and a short introduction to the young field of "fluorous" chemistry is given. The second part is dedicated to numerous applications of fluorine and fluorous interactions. It is shown how application of fluorination is used to enable a number of reactions, to improve materials properties and even open up new fields of research.