Understanding Rate Accelerations for Diels-Alder Reactions in Solution Using Enhanced QM/MM Methodology
Orlando Acevedo1, William L Jorgensen1
1Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, and Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107.
Journal of Chemical Theory and Computation
|December 4, 2015
Summary
This study explores Diels-Alder reactions in various solvents using quantum mechanics/molecular mechanics (QM/MM) calculations. QM/MM accurately predicts reaction rates, highlighting solvent effects like hydrogen bonding and hydrophobic interactions.
Area of Science:
- Computational Chemistry
- Physical Organic Chemistry
- Chemical Kinetics
Background:
- Diels-Alder reactions are crucial in organic synthesis.
- Previous studies used limited solvent conditions and methods.
- Understanding solvent effects on reaction rates is vital.
Purpose of the Study:
- Investigate Diels-Alder reactions of cyclopentadiene with various dienophiles.
- Evaluate the performance of QM/MM calculations in multiple solvents.
- Elucidate the dominant factors influencing reaction rate variations.
Main Methods:
- Employed QM/MM calculations with PDDG/PM3.
- Computed two-dimensional potentials of mean force (PMFs) in water, methanol, acetonitrile, and hexane.
- Compared QM/MM results with experimental data and ab initio calculations.
Main Results:
- QM/MM accurately reproduced experimental free energies of activation across solvents.
- Calculated increases in activation energy upon transfer from water to organic solvents.
- Ab initio methods with continuum solvent models showed accuracy in water but failed to capture solvent-dependent rate changes.
Conclusions:
- QM/MM methodology is effective for studying solvent effects on Diels-Alder reactions.
- Hydrogen bonding and hydrophobic effects significantly influence reaction rates.
- The study provides improved geometries and accurate activation free energies.
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