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Concerted nucleophilic aromatic substitutions

Nature Chemistryvolume 10pages917923 (2018) | Download Citation

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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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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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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Eric N. Jacobsen.

Supplementary information

  1. Supplementary information

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

  2. 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

  3. 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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https://doi.org/10.1038/s41557-018-0079-7

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