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Dynamics and Entropy of Cyclohexane Rings Control pH-Responsive Reactivity
Sunyoung Kang1, Chanwoo Noh1, Hyosik Kang2
1Department of Chemistry, Seoul National University, Seoul 08826, Republic of Korea.
JACS Au
|November 29, 2021
Summary
Activation entropy, not typically a primary factor, dictates unimolecular reaction rates. Ring dynamics and substituent geometry in six-membered rings significantly influence this entropy, affecting degradation.
Area of Science:
- Chemical Kinetics
- Organic Chemistry
- Molecular Dynamics
Background:
- Activation entropy (ΔS‡) is generally secondary to activation enthalpy in determining unimolecular reaction rates.
- The conformational dynamics of cyclic compounds can significantly impact their reactivity.
- Understanding factors influencing degradation pathways is crucial for molecular design.
Purpose of the Study:
- To investigate the role of activation entropy (ΔS‡) in the intramolecular degradation of six-membered ring compounds.
- To elucidate how ring-flipping motion and substituent geometry influence ΔS‡ and reactivity.
- To explain the distinct pH-dependent degradation kinetics observed between cis and trans isomers of 1,2-cyclohexanecarboxylic acid amide (1,2-CHCAA).
Main Methods:
- Kinetic analysis of pH-dependent degradation.
- Molecular Dynamics (MD) simulations to study conformational dynamics.
- Variable Temperature Nuclear Magnetic Resonance (VT-NMR) spectroscopy to analyze ring conformations.
Main Results:
- Activation entropy (ΔS‡) was found to be the dominant factor in the intramolecular degradation of six-membered rings.
- A significant difference in ΔS‡ (16.02 cal·mol⁻¹·K⁻¹) was observed between cis and trans-1,2-CHCAA isomers, explaining their differing degradation rates.
- Trans-1,2-CHCAA exhibits dynamic conformational interconversion (chair-twisted boat), while the cis isomer prefers a chair conformation, influenced by steric repulsion.
- Inhibiting ring inversion motion, e.g., via methylation, enhances the degradation of the trans isomer.
Conclusions:
- Molecular reactivity in unimolecular reactions can be strongly modulated by spatial arrangement and dynamic conformational properties.
- Activation entropy, influenced by conformational flexibility, plays a critical role in the degradation of cyclic compounds.
- This study provides insights for designing molecules with tailored reactivity based on dynamic conformational changes.
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