An amine/amide mixed covalent organic tetrahedral cage 1 (H-12) was synthesized and characterized. The H-12 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-C-3 symmetric "compressed tetrahedron" structure, or one in which there are two sets of three stacked pyridine units related by a pseudo-S-4 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 center dot 4H(2)O or F-center dot 4H(2)O, as observed crystallographically. In solution, however, F-19 NMR spectroscopy indicates that H-12 encapsulates fluoride ion through direct amide hydrogen bonding. By collectively combining one-dimensional H-1, C-13, and F-19 with two-dimensional H-1-H-1 COSY, H-1-C-13 HSQC, and H-1-F-19 HETCOR NMR techniques, the solution binding mode of fluoride can be ascertained as consisting of four sets of independent structural subunits with C-3 symmetry. A complex deuterium exchange process for the fluoride complex can also be unraveled by multiple NMR techniques.