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Toward a Combined Molecular Dynamics and Quantum Mechanical Approach to Understanding Solvent Effects on Chemical Processes in the Pharmaceutical Industry: The Case of a Lewis Acid-Mediated SNAr Reaction

Cite this: Org. Process Res. Dev. 2023, 27, 4, 742–754
Publication Date (Web):March 29, 2023
https://doi.org/10.1021/acs.oprd.3c00010
Copyright © 2023 American Chemical Society

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    Abstract

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    Solvation effects on chemical reactions can have a significant impact on the development of chemical processes in the pharmaceutical industry. Evaluating solvation effects at the atomic level would provide greater insight and understanding into their impact on chemical transformations. However, modeling complex reaction systems at this level of detail is challenging and a consistent approach of evaluation has not been established. Herein, we describe our initial results on the development of a practical solvation modeling protocol, which combines classical/ab initio molecular dynamics and density functional theory-based techniques with trajectory clustering, identification of solvent shells, and subsequent wave function analysis for characterizing a range of diverse interactions in the multicomponent solvation system. We describe how our solvation modeling protocol attempts to capture and describe these interactions objectively and simultaneously in the drug substance-forming step for the manufacture of 3, an SNAr reaction of aryl chloride 1 and pyrrolidine 2.

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.3c00010.

    • Brief discussion of the equilibration criteria and data for the classical MD and AIMD NPT runs; QTAIM ED values for S-1-Mg/S-2; QTAIM ED values, MDDF plots, and IGMH analysis plots for R-1-Mg/S-2, tables for comparison of key atom–atom distances from the selected classical centroid, AIMD centroid and final DFT-optimized systems of the prereaction complexes; Cartesian coordinates for the AIMD/NPT and AIMD/NVT input structures and associated CP2K input files; and Cartesian coordinates for the final DFT-optimized first solvent shell complexes (PDF)

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