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Concerted nucleophilic aromatic substitution with 19F− and 18F−

Nature volume 534, pages 369–373 (2016)Cite this article

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A Corrigendum to this article was published on 03 August 2016

Abstract

Nucleophilic aromatic substitution (SNAr) is widely used by organic chemists to functionalize aromatic molecules, and it is the most commonly used method to generate arenes that contain 18F for use in positron-emission tomography (PET) imaging1. A wide range of nucleophiles exhibit SNAr reactivity, and the operational simplicity of the reaction means that the transformation can be conducted reliably and on large scales2. During SNAr, attack of a nucleophile at a carbon atom bearing a ‘leaving group’ leads to a negatively charged intermediate called a Meisenheimer complex. Only arenes with electron-withdrawing substituents can sufficiently stabilize the resulting build-up of negative charge during Meisenheimer complex formation, limiting the scope of SNAr reactions: the most common SNAr substrates contain strong π-acceptors in the ortho and/or para position(s)3. Here we present an unusual concerted nucleophilic aromatic substitution reaction (CSNAr) that is not limited to electron-poor arenes, because it does not proceed via a Meisenheimer intermediate. We show a phenol deoxyfluorination reaction for which CSNAr is favoured over a stepwise displacement. Mechanistic insights enabled us to develop a functional-group-tolerant 18F-deoxyfluorination reaction of phenols, which can be used to synthesize 18F-PET probes. Selective 18F introduction, without the need for the common, but cumbersome, azeotropic drying of 18F, can now be accomplished from phenols as starting materials, and provides access to 18F-labelled compounds not accessible through conventional chemistry.

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Figure 1: Comparison of orbital interactions and energy profiles in SNAr and CSNAr.
Figure 2: Proposed mechanism of PhenoFluor-mediated deoxyfluorination.
Figure 3: 18F isotopolugue 2.
Figure 4: Deoxyfluorination of phenols and heterophenols with 18F.

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Data deposits

Atomic coordinates and structure factors for the reported crystal structures have been deposited in the Cambridge Crystallographic Data Centre under accession number CCDC-1419728.

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Acknowledgements

We thank the Patty and Michael Phelps Foundation and the National Institutes of Health (NIH) National Institute of General Medical Sciences (GM088237) for funding. Radioisotope production and use were enabled by a shared instrument grant from the NIH (1S10RR017208). We thank S. Arlow and C. Kleinlein for preliminary mechanistic work and H. Lee for assistance with X-ray crystallography. We thank N. A. Stephenson for a synthetic precursor for S6 as well as the 19F-standard for this substrate.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, 02138, Massachusetts, USA

    Constanze N. Neumann & Tobias Ritter

  2. Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA

    Jacob M. Hooker & Tobias Ritter

  3. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, 02129, Massachusetts, USA

    Jacob M. Hooker

  4. Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, Mülheim an der Ruhr, D-45470, Germany

    Tobias Ritter

Authors
  1. Constanze N. Neumann
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  2. Jacob M. Hooker
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Contributions

C.N.N. designed and performed the experiments, with input from T.R. and J.M.H. C.N.C. analysed the data. T.R. directed the project. C.N.N. and T.R. prepared the manuscript with input from J.M.H.

Corresponding author

Correspondence to Tobias Ritter.

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The authors declare no competing financial interests.

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This file contains Supplementary Text and Data, Supplementary Figures 1-47, Supplementary Tables 1-5 and Supplementary References – see contents pages for full details. (PDF 10669 kb)

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Neumann, C., Hooker, J. & Ritter, T. Concerted nucleophilic aromatic substitution with 19F− and 18F−. Nature 534, 369–373 (2016). https://doi.org/10.1038/nature17667

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