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E/Z Energetics for Molecular Modeling and Design.
John P Terhorst1, William L Jorgensen
1Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107.
Journal of Chemical Theory and Computation
|September 28, 2010
Summary
Quantum mechanical calculations provide thermochemical data for organic molecules with E/Z equilibria. These findings aid molecular design and protein-ligand docking by predicting conformational preferences.
Area of Science:
- Computational chemistry
- Organic chemistry
- Molecular modeling
Background:
- E/Z isomerism is crucial in organic chemistry, impacting molecular properties and biological activity.
- Accurate prediction of conformational preferences is vital for molecular design and drug discovery.
- Quantum mechanical (QM) calculations offer a powerful tool for determining molecular energetics.
Purpose of the Study:
- To compute thermochemical data for 18 organic molecules with E/Z conformational equilibria using QM methods.
- To analyze the factors influencing E/Z preferences, including steric and electronic effects.
- To evaluate the impact of hydration on E/Z equilibria using continuum solvent models.
Main Methods:
- G3B3 quantum mechanical calculations were employed to determine molecular properties.
- Relative energies, enthalpies, free energies, and dipole moments were calculated for E/Z isomer pairs.
- The GB/SA continuum solvent model was used to estimate free energies of hydration.
Main Results:
- Thermochemical data, including free-energy differences at 298 K, were reported for 18 E/Z isomer pairs.
- E/Z free-energy differences varied significantly, from +8.2 kcal/mol (1,3-dimethyl carbamate) to -6.4 kcal/mol (acetone oxime).
- Steric and electronic effects were identified as key factors rationalizing the observed variations in E/Z preferences.
Conclusions:
- The calculated thermochemical data are essential for molecular design and evaluating protein-ligand docking structures.
- Differential hydration effects are unlikely to alter the preferred direction of E/Z equilibria.
- Further investigations using explicit solvent models are recommended for a comprehensive understanding of hydration effects.
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