Controllable Modulation of Interactive Site Spacing in Porous Coordination Cages: A Key to Substantial Synergistic Catalysis Enhancement

The controllable spatial arrangement of active sites in confined environments is key to designing efficient supramolecular catalysts, yet achieving such control, particularly with atomic‐level precision, remains a synthetic challenge. We introduce a ligand‐engineering strategy that enables Ångstrom‐level precision in regulating the distance between cooperative active sites in isostructural porous coordination cages, enhancing catalytic performance. Three trigonal‐prismatic cages were constructed using calixarene‐based tetra‐cobalt clusters and V‐shaped dicarboxylate ligands functionalized with –NH 2 groups. Single‐crystal X‐ray diffraction shows these cages share identical topological features, with the distance between Brønsted acidic μ 4 –H 2 O sites and basic –NH 2 sites adjustable from 12.4 Å ( PCC‐16 ) to 5.6 Å ( PCC‐17 ). In the Knoevenagel condensation, PCC‐17 shows superior activity, achieving up to 96% yield, outperforming PCC‐16 and nonfunctionalized PCC‐15 . This highlights the impact of reducing intersite distance on substrate activation and intermediate coupling. Fluorescence titration, control experiments, and theoretical calculations confirm a synergistic “acid–base” dual‐activation mechanism. Computational studies support that shortened distances enhance intermediate stabilization. The system also has a broad substrate scope and excellent stability. This work demonstrates the potential of ligand‐directed and controllable spatial organization for advancing cage‐based catalytic materials, highlighting the dramatic impact of intersite distance on cooperative catalysis.