An Overlooked yet Ubiquitous Fluoride Congenitor: Binding Bifluoride in Triazolophanes Using Computer-Aided Design

Despite its ubiquity during the binding and sensing of fluoride, the role of bifluoride (HF₂^–) and its binding properties are almost always overlooked. Here, we give one of the first examinations of bifluoride recognition in which we use computer-aided design to modify the cavity shape of triazolophanes to better match with HF₂^–. Computational investigation indicates that HF₂^– and Cl^– should have similar binding affinities to the parent triazolophane in the gas phase. Evaluation of the binding geometries revealed a preference for binding of the linear HF₂^– along the north–south axis with a smaller Boltzmann weighted population aligned east–west and all states being accessed rapidly through in-plane precessional rotations of the anion. While the ¹H NMR spectroscopy studies are consistent with the calculated structural aspects, binding affinities in solution were determined to be significantly smaller for the bifluoride than the chloride. Computed geometries suggested that a 20° tilting of the bifluoride (stemming from the cavity size) could account for the 25-fold difference between the two binding affinities, HF₂^– < Cl^–. Structural variations to the triazolophane’s geometry and electronic modifications to the network of hydrogen bond donors were subsequently screened in a stepwise manner using density functional theory calculations to yield a final design that eliminates the tilting. Correspondingly, the bifluoride’s binding affinity (K ∼ 10⁶ M^–1) increased and was also found to remain equal to chloride in the gas and solution phases. The new oblate cavity appeared to hold the HF₂^– in a single east–west arrangement. Our findings demonstrate the promising ability of computer-aided design to fine-tune the structural and electronic match in anion receptors as a means to control the arrangement and binding strength of a desired guest.