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Concerted nucleophilic aromatic substitutions

Nature Chemistry volume 10, pages 917–923 (2018)Cite this article

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Abstract

Nucleophilic aromatic substitution (SNAr) is one of the most widely applied reaction classes in pharmaceutical and chemical research, providing a broadly useful platform for the modification of aromatic ring scaffolds. The generally accepted mechanism for SNAr reactions involves a two-step addition–elimination sequence via a discrete, non-aromatic Meisenheimer complex. Here we use 12C/13C kinetic isotope effect (KIE) studies and computational analyses to provide evidence that prototypical SNAr reactions in fact proceed through concerted mechanisms. The KIE measurements were made possible by a new technique that leverages the high sensitivity of 19F as an NMR nucleus to quantitate the degree of isotopic fractionation. This sensitive technique permits the measurement of KIEs on 10 mg of natural abundance material in one overnight acquisition. As a result, it provides a practical tool for performing detailed mechanistic analyses of reactions that form or break C–F bonds.

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Fig. 1: Scope of study.
Fig. 2: Assessing 13C isotopic fractionation by suppressing NMR signals from fluorine atoms bound to 12C.
Fig. 3: Computational analysis of the transition from stepwise to concerted behaviour (B3LYP-D3(BJ)/jun-cc-pVTZ).
Fig. 4: Simplified Marcus analysis of stepwise versus concerted SNAr reactions.

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Data availability

User-friendly software pipelines that can be used to measure and predict KIEs are freely available at www.github.com/ekwan/PyKIE and www.github.com/ekwan/PyQuiver. Raw NMR spectra and computed quasiclassical trajectories are available from the corresponding author upon reasonable request. All other data supporting the findings of this study are available within the Article and its Supplementary Information files.

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Acknowledgements

This work was supported by the National Institutes of Health (GM-43214). The authors thank W.F. Reynolds and D.A. Singleton for helpful discussions, and S.G. Huang and W. E. Collins for assistance with NMR spectroscopy.

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Authors and Affiliations

  1. Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA

    Eugene E. Kwan, Yuwen Zeng, Harrison A. Besser & Eric N. Jacobsen

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Contributions

E.E.K., Y.Z. and H.A.B. developed the isotope effect methodology. Y.Z. synthesized the materials. E.E.K. and H.A.B. carried out the calculations. E.E.K and E.N.J. wrote the manuscript. E.N.J. guided the research.

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Correspondence to Eric N. Jacobsen.

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Supplementary information

Supplementary information

Comprehensive information on compound synthesis and characterization, NMR pulse sequences, KIE calculations and computational results

NMR archive file

Contains data related to the NMR experiments performed in this study including sample NMR spectra, processing software, raw results, and Mathematica code to calculate the KIE error bars. Readme.txt files with detailed descriptions of folder contents are included in each subfolder within the zipped file

Calculations archive file

Contains the many computational structures used in this study to generate KIE predictions and potential energy surfaces. Readme.txt files with detailed descriptions of folder contents are included in each subfolder within the zipped file

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Kwan, E.E., Zeng, Y., Besser, H.A. et al. Concerted nucleophilic aromatic substitutions. Nature Chem 10, 917–923 (2018). https://doi.org/10.1038/s41557-018-0079-7

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