Shape‐Shifting Tetralactam Macrocycles: Protonation‐Activated Convergent Hydrogen Bonding

ABSTRACT Integrating high binding affinity with dynamic, stimuli‐responsive control represents a pivotal objective in synthetic receptor design, with far‐reaching implications for sensing, separation, and molecular machinery. We report a class of shape‐shifting tetralactam macrocycles featuring embedded 2,4‐pyridinedicarboxamide units as switching elements. In their neutral state, these macrocycles adopt divergent hydrogen‐bonding conformations that exhibit low substrate affinity. Upon protonation, a reversible conformational reorganization occurs, reorienting four amide N–H groups toward the cavity to form a convergent, high‐affinity hydrogen‐bonding pocket. Conformational switching was confirmed by X‐ray crystallography and solution‐phase NMR. Upon protonation, these macrocycles exhibit >10⁵‐fold binding enhancement, achieving association constants up to 135,000 M −1 for the polyhalide anion BrIBr − . Computational analysis reveals that this dramatic increase arises from synergistic hydrogen bonding, electrostatic attraction, and van der Waals interactions. These findings establish a robust strategy for designing adaptive hydrogen‐bonding receptors that combine dynamic switching with high substrate affinity and selectivity. The ability to toggle between low‐ and high‐affinity states without sacrificing structural integrity sets the stage for expanding the scope of smart molecular systems with tunable recognition properties.