Computational Insights into Mechanism and Kinetics of Organic Reactions: Multiscale Modeling of SN2 and Claisen Rearrangements

Abstract This study explores the application of quantum mechanical (QM) and multiscale computational methods in elucidating the reaction mechanisms and kinetics of SN2 reactions and the Claisen rearrangement. The aim is to assess the accuracy and efficacy of these methods in predicting experimental outcomes for these organic reactions. By employing various variants of QM/MM, QM1/QM2, and QM1/QM2/MM methodologies, we investigated the mechanisms and kinetics parameters involving methyl iodide with NH2OH and NH2O− for SN2 reactions, as well as the Claisen rearrangement of 8-(vinyloxy)dec-9-enoate. Our results emphasize the importance of explicitly considering solvent effects in the calculations for accurate reproduction of transition state geometry and energetics, particularly evident in SN2 reactions. Multiscale methods, notably QM/MM and QM1/QM2, demonstrated promising performance in predicting activation energies, with some variants showing close agreement with experimental values. Additionally, the study highlights the significant influence of the MM active region size on the accuracy of calculated activation energies. For the Claisen rearrangement, both QM-only and multiscale methods successfully reproduced the proposed reaction mechanism, although discrepancies were observed in the calculated activation free energies. This study underscores the critical role of method selection and setup parameters in computational chemistry studies, with implications for future research aimed at refining computational models to improve predictive capabilities in organic reaction studies. Additionally, a Python code for setting up multiscale calculations with ORCA is introduced, available on GitHub at https://github.com/iranimehdi/pdbtoORCA.