Chemistry and Structure of a Host–Guest Relationship: The Power of NMR and X‑ray Diffraction in Tandem

An amine/amide mixed covalent organic tetrahedral cage <b>1</b> (<i><b>H</b></i>_<b>12</b>) was synthesized and characterized. The <i><b>H</b></i>_<b>12</b> cage contains 12 amide NH groups plus four tertiary amine N groups, the latter of which are positioned in a pseudo-tetrahedral array. Crystallographic findings indicate that the tetrahedral host can adopt either a pseudo-<i>C</i>₃ symmetric “compressed tetrahedron” structure, or one in which there are two sets of three stacked pyridine units related by a pseudo-S₄ axis. The latter conformation is ideal for encapsulating small pentameric clusters, either a water molecule or a fluoride ion surrounded by a tetrahedral array of water molecules, i.e., H₂O·4H₂O or F^–·4H₂O, as observed crystallographically. In solution, however, ¹⁹F NMR spectroscopy indicates that <i><b>H</b></i>_<b>12</b> encapsulates fluoride ion through direct amide hydrogen bonding. By collectively combining one-dimensional ¹H, ¹³C, and ¹⁹F with two-dimensional ¹H–¹H COSY, ¹H–¹³C HSQC, and ¹H–¹⁹F HETCOR NMR techniques, the solution binding mode of fluoride can be ascertained as consisting of four sets of independent structural subunits with <i>C</i>₃ symmetry. A complex deuterium exchange process for the fluoride complex can also be unraveled by multiple NMR techniques