Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Concerted nucleophilic aromatic substitution with 19F and 18F

A Corrigendum to this article was published on 03 August 2016


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

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.

Accession codes

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.


  1. Fernández, I., Frenking, G. & Uggerud, E. Rate-determining factors in nucleophilic aromatic substitution reactions. J. Org. Chem. 75, 2971–2980 (2010)

    Article  Google Scholar 

  2. Terrier, F. Modern Nucleophilic Aromatic Substitution 1–94 (Wiley, 2013)

  3. Chéron, N., El Kaïm, L., Grimaud, L. & Fleurat-Lessard, P. Evidences for the key role of hydrogen bonds in nucleophilic aromatic substitution reactions. Chemistry 17, 14929–14934 (2011)

    Article  Google Scholar 

  4. Picazo, E., Houk, K. N. & Garg, N. K. Computational predictions of substituted benzyne and indolyne regioselectivities. Tetrahedr. Lett. 56, 3511–3514 (2015)

    Article  CAS  Google Scholar 

  5. Crampton, M. R. in Organic Reaction Mechanisms—2010: An Annual Survey Covering the Literature Dated January to December 2010 (ed. Knipe, A. C. ) 175–190 (Wiley, 2012)

  6. Lloyd-Jones, G. C., Moseley, J. D. & Renny, J. S. Mechanism and application of the Newman-Kwart O→S rearrangement of O-aryl thiocarbamates. Synthesis 2008, 661–689 (2008)

    Article  Google Scholar 

  7. Tang, P., Wang, W. & Ritter, T. Deoxyfluorination of phenols. J. Am. Chem. Soc. 133, 11482–11484 (2011)

    Article  CAS  Google Scholar 

  8. Fujimoto, T., Becker, F. & Ritter, T. PhenoFluor: practical synthesis, new formulation, and deoxyfluorination of heteroaromatics. Org. Process Res. Dev. 18, 1041–1044 (2014)

    Article  CAS  Google Scholar 

  9. Glukhovtsev, M. N., Bach, R. D. & Laiter, S. Single-step and multistep mechanisms of aromatic nucleophilic substitution of halobenzenes and halonitrobenzenes with halide anions: ab initio computational study. J. Org. Chem. 62, 4036–4046 (1997)

    Article  CAS  Google Scholar 

  10. Fry, S. E. & Pienta, N. J. Effects of molten salts on reactions. Nucleophilic aromatic substitution by halide ions in molten dodecyltributylphosphonium salts. J. Am. Chem. Soc. 107, 6399–6400 (1985)

    Article  CAS  Google Scholar 

  11. Hunter, A. et al. Stepwise versus concerted mechanisms at trigonal carbon: transfer of the 1,3,5-triazinyl group between aryl oxide ions in aqueous solution. J. Am. Chem. Soc. 117, 5484–5491 (1995)

    Article  CAS  Google Scholar 

  12. Renfrew, A. H. M., Taylor, J. A., Whitmore, J. M. J. & Williams, A. A single transition state in nucleophilic aromatic substitution: reaction of phenolate ions with 2-(4-nitrophenoxy)-4,6-dimethoxy-1,3,5-triazine in aqueous solution. J. Chem. Soc. Perkin Trans. 2 1993, 1703–1704 (1993)

    Article  Google Scholar 

  13. Dub, P. A. et al. C–F bond breaking through aromatic nucleophilic substitution with a hydroxo ligand mediated via water bifunctional activation. Bull. Chem. Soc. Jpn 86, 557–568 (2013)

    Article  CAS  Google Scholar 

  14. Goryunov, L. I. et al. Di- and trifluorobenzenes in reactions with Me2EM (E = P, N; M = SiMe3, SnMe3, Li) reagents: evidence for a concerted mechanism of aromatic nucleophilic substitution. Eur. J. Org. Chem. 2010, 1111–1123 (2010)

    Article  Google Scholar 

  15. Nawaz, F. et al. Temporary intramolecular generation of pyridine carbenes in metal-free three-component C–H bond functionalisation/aryl-transfer reactions. Chemistry 19, 17578–17583 (2013)

    Article  CAS  Google Scholar 

  16. Renfrew, A. H. M., Taylor, J. A., Whitmore, J. M. J. & Williams, A. Timing of bonding changes in fundamental reactions in solutions: pyridinolysis of a triazinylpyridinium salt. J. Chem. Soc. Perkin Trans. 2 1994, 2383–2384 (1994)

    Article  Google Scholar 

  17. Williams, A. The diagnosis of concerted organic mechanisms. Chem. Soc. Rev. 23, 93–100 (1994)

    Article  CAS  Google Scholar 

  18. Sawyer, C. B. & Kirsch, J. F. Kinetic isotope effects for reactions of methyl formate-methoxyl-18O. J. Am. Chem. Soc. 95, 7375–7381 (1973)

    Article  CAS  Google Scholar 

  19. Lasne, M.-C. et al. in Contrast Agents II Vol. 222 (ed. Krause, W. ) Ch. 7, 201–258 (Springer, 2002)

  20. Matsson, O. & MacMillar, S. Isotope effects for fluorine-18 and carbon-11 in the study of reaction mechanisms. J. Labelled Comp. Radiopharm. 50, 982–988 (2007)

    Article  CAS  Google Scholar 

  21. Yamabe, S., Minato, T. & Kawabata, Y. The importance of the σ*–π* orbital mixing for the nucleophilic displacement on the unsaturated carbon. Can. J. Chem. 62, 235–240 (1984)

    Article  CAS  Google Scholar 

  22. Mu, L. et al. 18F-radiolabeling of aromatic compounds using triarylsulfonium salts. Eur. J. Org. Chem. 2012, 889–892 (2012)

    Article  CAS  Google Scholar 

  23. Sun, H. & DiMagno, S. G. Room-temperature nucleophilic aromatic fluorination: experimental and theoretical studies. Angew. Chem. Int. Ed. 45, 2720–2725 (2006)

    Article  CAS  Google Scholar 

  24. Neumann, C. N. & Ritter, T. Late-stage fluorination: fancy novelty or useful tool? Angew. Chem. Int. Ed. 54, 3216–3221 (2015)

    Article  CAS  Google Scholar 

  25. Tredwell, M. et al. A general copper-mediated nucleophilic 18F fluorination of arenes. Angew. Chem. Int. Ed. 53, 7751–7755 (2014)

    Article  CAS  Google Scholar 

  26. Gao, Z. et al. Metal-free oxidative fluorination of phenols with [18F]fluoride. Angew. Chem. Int. Ed. 51, 6733–6737 (2012)

    Article  CAS  Google Scholar 

  27. Ichiishi, N. et al. Copper-catalyzed [18F]fluorination of (mesityl)(aryl)iodonium salts. Org. Lett. 16, 3224–3227 (2014)

    Article  CAS  Google Scholar 

  28. Lee, E., Hooker, J. M. & Ritter, T. Nickel-mediated oxidative fluorination for PET with aqueous [18F]fluoride. J. Am. Chem. Soc. 134, 17456–17458 (2012)

    Article  CAS  Google Scholar 

  29. Lee, E. et al. A fluoride-derived electrophilic late-stage fluorination reagent for PET imaging. Science 334, 639–642 (2011)

    Article  CAS  ADS  Google Scholar 

  30. Bronner, S. M., Goetz, A. E. & Garg, N. K. Overturning indolyne regioselectivities and synthesis of indolactam V. J. Am. Chem. Soc. 133, 3832–3835 (2011)

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

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)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Neumann, C., Hooker, J. & Ritter, T. Concerted nucleophilic aromatic substitution with 19F and 18F. Nature 534, 369–373 (2016).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing