Coordination Cages Based on Bis(pyrazolylpyridine) Ligands: Structures, Dynamic Behavior, Guest Binding, and Catalysis.

We describe here a family of coordination cages with interesting structural, guest-binding, and catalytic properties. Flexible bridging ligands containing two bidentate pyrazolylpyridine termini assemble with transition-metal dications to afford coordination cages containing a metal ion at each vertex, a bridging ligand spanning each edge, and a 2:3 metal:ligand ratio. This stoichiometry is expressed in structures ranging from M4 L6 tetrahedra to M16 L24 tetracapped truncated tetrahedra, which are stabilized by the formation of π-stacked arrays between electron-rich and electron-poor ligand segments that form around the cage periphery. In some cases concentration- and/or temperature-dependent equilibria between multiple cage structures occur, arising from a balance between entropy, which favors the formation of a larger number of smaller assemblies, and enthalpy, which maximizes both interligand aromatic stacking and solvophobic effects in the larger assembles. The cages are hollow and can accommodate guests-often anions or solvent molecules-in the central cavity. For one cage family, M8 L12 species with an approximately cubic structure and a ca. 400 Å3 cavity, the guest binding properties have been studied extensively. This cage can accommodate a wide range of neutral organic guests, with binding in water being driven principally by the hydrophobic effect, which leads to binding constants of up to 108 M-1 . The accumulation of a large amount of empirical data on guest binding in the M8 L12 cage in water provided the basis for a predictive tool for in silico screening of potential guests using the molecular docking program GOLD; this methodology has allowed the identification of numerous new guests with accurately predicted binding constants and provides a transformative new approach to exploring the host/guest chemistry of cages. Binding of benzisoxazole inside the M8 L12 cage results in substantial rate enhancements-by a factor of up to 2 × 105 -of the Kemp elimination, in which benzisoxazole reacts to give 2-cyanophenolate. Catalysis arises because the 16+ cage cation accumulates anions around the surface by ion pairing, leading to a high effective concentration of hydroxide ions surrounding the guest even when the bulk pH is modest. Thus, the catalysis relies on the operation of two orthogonal interactions that bring the reaction partners together: hydrophobic guest binding in the cavity, which is lined with CH groups from the ligands, and ion pairing around the highly cationic cage surface. A consequence of this is that under some conditions the product of the cage-catalyzed Kemp elimination (the 2-cyanophenolate anion) itself accumulates around the cage surface and deprotonates another benzisoxazole guest, perpetuating the reaction in an autocatalytic manner. Thus, different anions accumulating around the cage can act as partners for reaction with a cavity-bound guest, opening up the possibility that the M8 L12 cage can act as a general catalyst for reactions of electrophilic guests with surface-bound anions.