Do docking sites persist upon fluorination? The didamantyl ether-aromatics challenge for rotational spectroscopy and theory

Fluorinated derivatives of biological molecules have proved to be highly efficient at modifying the biological activity of a given protein through changes in the stability and the kind of docking interactions. These interactions can be hindered or facilitated based on the hydrophilic/hydrophobic character of a particular protein region. Diadamantyl ether (C$_{20}$H$_{30}$O) possesses both kinds of docking sites, serving as a good template to model these important contacts with aromatic fluorinated counterparts. We report here an experimental study on the structures of several complexes between diadamantyl ether and benzene as well as a series of fluorinated benzenes to analyze the effect of H → F substitution on the interaction and structure of the resulting molecular clusters using rotational spectroscopy. All experimentally observed complexes are largely dominated by London dispersion interactions with the hydrogen‐terminated surface areas of diadamantyl ether. Already single substitution of one hydrogen atom with fluorine changes the preferred docking site of the complexes. However, the overall contributions of the different intermolecular interactions are similar for the different complexes, contrary to previous studies focusing on the difference in interactions using fluorinated and non‐fluorinated molecules