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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
Published on: September 28, 2022
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Shape-Shifting Tetralactam Macrocycles: Protonation-Activated Convergent Hydrogen Bonding
Dexin Liu1, Andrew Victoria1, Alexander Mariscal1
1Department of Chemistry, University of South Florida, Tampa, FL, USA.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|December 15, 2025
Summary
Researchers developed shape-shifting macrocycles that switch from low to high binding affinity upon protonation. This breakthrough in synthetic receptor design enables tunable molecular recognition for advanced sensing and separation applications.
Area of Science:
- Supramolecular Chemistry
- Organic Chemistry
- Materials Science
Background:
- Designing synthetic receptors with both high binding affinity and dynamic, stimuli-responsive control is crucial for applications in sensing, separation, and molecular machinery.
- Current limitations exist in achieving tunable affinity and selectivity in synthetic receptor systems.
Purpose of the Study:
- To develop a novel class of shape-shifting tetralactam macrocycles with embedded 2,4-pyridinedicarboxamide units as responsive elements.
- To demonstrate reversible conformational changes and significant binding enhancement upon protonation.
- To establish a robust strategy for adaptive hydrogen-bonding receptors with tunable recognition properties.
Main Methods:
- Synthesis of tetralactam macrocycles with 2,4-pyridinedicarboxamide units.
- Characterization of conformational changes using X-ray crystallography and solution-phase Nuclear Magnetic Resonance (NMR) spectroscopy.
- Binding studies to determine association constants for polyhalide anions, including BrIBr⁻.
- Computational analysis to elucidate the factors contributing to binding enhancement.
Main Results:
- The synthesized macrocycles exhibit distinct conformations in neutral and protonated states.
- Protonation triggers a reversible conformational reorganization, forming a high-affinity binding pocket.
- A >10⁵-fold binding enhancement was observed upon protonation, with association constants reaching 135,000 M⁻¹ for BrIBr⁻.
- Computational analysis confirmed synergistic contributions from hydrogen bonding, electrostatic attraction, and van der Waals interactions.
Conclusions:
- A novel strategy for designing adaptive hydrogen-bonding receptors has been established.
- These receptors can dynamically switch between low- and high-affinity states without compromising structural integrity.
- The findings pave the way for developing smart molecular systems with precisely tunable recognition capabilities for advanced applications.
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