Shape-Shifting Tetralactam Macrocycles: Protonation-Activated Convergent Hydrogen Bonding.

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.