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Choreoisosteres: Pseudoatom Variation in Macrocyclic Hinges Conserves Structure and Dynamics.
Alexander J Menke1, Joseph H Reibenspies2, Casey J Patterson-Gardner1
1Department of Chemistry & Biochemistry, Texas Christian University, Fort Worth, Texas 76129, United States.
ACS Physical Chemistry Au
|March 31, 2025
Summary
Three macrocycles with isosteric substitutions exhibit identical hinge-like motion barriers. This conserved dynamic behavior allows for predictable physical properties like hydrophobicity and diffusion.
Area of Science:
- Organic Chemistry
- Chemical Dynamics
- Molecular Modeling
Background:
- Macrocyclic compounds are crucial in various chemical and biological applications.
- Understanding the dynamic behavior of macrocycles is key to predicting their properties.
- Isosteric substitutions offer a way to fine-tune molecular characteristics.
Purpose of the Study:
- To investigate the dynamic behavior of three choreoisosteric macrocycles.
- To quantify the energy barriers associated with their hinge-like motion.
- To explore the predictability of physical properties based on conserved dynamics.
Main Methods:
- Synthesis of three macrocycles with geminal dimethyl, cyclopropyl, and cyclobutyl substitutions.
- Variable-temperature 13C Nuclear Magnetic Resonance (NMR) spectroscopy to determine energy barriers.
- Analysis of physical properties including hydrophobicity and diffusion constants.
Main Results:
- All three macrocycles demonstrated a conserved, fully revolute hinge-like motion in solution.
- The energy barriers to hinging (ΔG‡) were found to be identical within experimental error (14.2-15.2 kcal/mol).
- Physical properties such as hydrophobicity and diffusion constants showed consistency with the conserved dynamic behavior.
Conclusions:
- Choreoisosteric substitutions in macrocycles can lead to conserved dynamic properties.
- The hinge-like motion and its associated energy barriers are robust across these specific isosteric changes.
- This conserved dynamic behavior facilitates the prediction of other physical properties, aiding in molecular design.
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