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Molecules. 2018 Oct 31;23(11). pii: E2830. doi: 10.3390/molecules23112830.

Polarizable ab initio QM/MM Study of the Reaction Mechanism of N-tert-Butyloxycarbonylation of Aniline in [EMIm][BF₄].

Author information

1
Department of Chemistry, University of North Texas, Denton, TX 76201, USA. erikvazquezmontelongo@my.unt.edu.
2
Department of Chemistry, University of North Texas, Denton, TX 76201, USA. enriquevazquezcervantes@my.unt.edu.
3
Department of Chemistry, University of North Texas, Denton, TX 76201, USA. andres@unt.edu.
4
The Center for Advanced Scientific Computing and Modeling (CASCaM), University of North Texas, Denton, TX 76201, USA. andres@unt.edu.

Abstract

N-t e r t-butoxycarbonylation of amines in solution (water, organic solvents, or ionic liquids) is a common reaction for the preparation of drug molecules. To understand the reaction mechanism and the role of the solvent, quantum mechanical/molecular mechanical simulations using a polarizable multipolar force field with long⁻range electrostatic corrections were used to optimize the minimum energy paths (MEPs) associated with various possible reaction mechanisms employing the nudged elastic band (NEB) and the quadratic string method (QSM). The calculated reaction energies and energy barriers were compared with the corresponding gas-phase and dichloromethane results. Complementary Electron Localization Function (ELF)/NCI analyses provide insights on the critical structures along the MEP. The calculated results suggest the most likely path involves a sequential mechanism with the rate⁻limiting step corresponding to the nucleophilic attack of the aniline, followed by proton transfer and the release of CO 2 without the direct involvement of imidazolium cations as catalysts.

KEYWORDS:

QM/MM; minimum energy path; non–covalent interactions; topological analysis

PMID:
30384470
PMCID:
PMC6278528
DOI:
10.3390/molecules23112830
[Indexed for MEDLINE]
Free PMC Article

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