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 (HF<sub>2</sub><sup>–</sup>) 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 HF<sub>2</sub><sup>–</sup>. Computational investigation indicates that HF<sub>2</sub><sup>–</sup> and Cl<sup>–</sup> should have similar binding affinities to the parent triazolophane <i>in the gas phase</i>. Evaluation of the binding geometries revealed a preference for binding of the linear HF<sub>2</sub><sup>–</sup> 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 <sup>1</sup>H NMR spectroscopy studies are consistent with the calculated structural aspects, binding affinities <i>in solution</i> 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, HF<sub>2</sub><sup>–</sup> < Cl<sup>–</sup>. 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 (<i>K</i> ∼ 10<sup>6</sup> M<sup>–1</sup>) increased and was also found to remain equal to chloride <i>in the gas and solution phases</i>. The new oblate cavity appeared to hold the HF<sub>2</sub><sup>–</sup> 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.