A Benchmark Study of Quantum Mechanics and Quantum Mechanics-Molecular Mechanics Methods for Carbocation Chemistry

Shani Zev, Prashant Kumar Gupta, Efrat Pahima, Dan Thomas Major

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Carbocations play key roles in classical organic reactions and have also been implicated in several enzyme families. A hallmark of carbocation chemistry is multitudes of competing reaction pathways, and to be able to distinguish between pathways with quantum chemical calculations, it is necessary to approach chemical accuracy for relative energies between carbocations. Here, we present an extensive study of the performance of selected density functional theory (DFT) methods in describing the thermochemistry and kinetics of carbocations and their corresponding neutral alkenes both in the gas-phase and within a hybrid quantum mechanics-molecular mechanics (QM/MM) framework. The density functionals are benchmarked against accurate ab initio methods such as CBS-QB3 and DLPNO-CCSD(T). Based on the findings in the gas-phase calculations of carbocations and alkenes, the best functionals are chosen and tested further for non-covalent interactions in model systems using QM and QM/MM methods. We compute the interaction energies between a model carbocation/alkane and model ?, dipole, and hydrophobic systems using DFT and QM(DFT)/MM and compare with DLPNO-CCSD(T). These latter model systems are representative of side chains of amino acids such as phenylalanine/tyrosine, tryptophan, asparagine/glutamine, serine/threonine, methionine, and other hydrophobic groups. The Lennard-Jones parameters of the QM atoms in QM(DFT)/MM calculations are modified to obtain an optimal fit with the QM energies. Finally, a selected carbocation reaction is studied in the gas phase and in implicit chloroform solvent using QM and in explicit chloroform solvent using QM/MM and umbrella sampling simulations. This study highlights the highest accuracy possible with selected density functionals and QM/MM methods but also some limitations in using QM/MM methods for carbocation systems.

Original languageEnglish
Pages (from-to)167-178
Number of pages12
JournalJournal of Chemical Theory and Computation
Issue number1
StatePublished - 11 Jan 2022

Bibliographical note

Publisher Copyright:
© 2021 American Chemical Society.


This work was supported by the Israel Ministry of Science, Technology and Space (Grant # 3-16310) and the Israeli Science Foundation (Grant # 1683/18). S.Z. received support from the Israel Ministry of Science, Technology and Space via a Navon fellowship (# 1241).

FundersFunder number
Ministry of Science, Technology and Space3-16310
Israel Science Foundation1683/18, 1241


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