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 substitutions


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.

Data availability

User-friendly software pipelines that can be used to measure and predict KIEs are freely available at and 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.


  1. 1.

    Williams, A. Concerted Organic and Bio-Organic Mechanisms (CRC, Boca Raton, FL, 1999).

  2. 2.

    Terrier, F. Modern Nucleophilic Aromatic Substitution (Wiley-VCH, Weinheim, 2013).

  3. 3.

    Terrier, F. Rate and equilibrium studies in Jackson–Meisenheimer complexes. Chem. Rev. 82, 77–152 (1982).

    CAS  Google Scholar 

  4. 4.

    Brown, D. G. & Boström, J. Analysis of past and present synthetic methodologies on medicinal chemistry: where have all the new reactions gone? J. Med. Chem. 59, 4443–4458 (2016).

    CAS  PubMed  Google Scholar 

  5. 5.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Neumann, C. N. & Ritter, T. Facile C–F bond formation through a concerted nucleophilic aromatic substitution mediated by the PhenoFluor reagent. Acc. Chem. Res. 50, 2822–2833 (2017).

    CAS  PubMed  Google Scholar 

  7. 7.

    Lucchini, V., Modena, G. & Pasquato, L. An authentic case of in-plane nucleophilic vinylic substitution: the anionotropic rearrangement of di-tert-butyl thiirenium ions into thietium ions. J. Am. Chem. Soc. 115, 4527–4531 (1993).

    CAS  Google Scholar 

  8. 8.

    Glukhovtsev, M. N., Pross, A. & Radom, L. Is SN2 substitution with inversion of configuration at vinylic carbon feasible? J. Am. Chem. Soc. 116, 5961–5962 (1994).

    CAS  Google Scholar 

  9. 9.

    Lucchini, V., Modena, G. & Pasquato, L. SN2 and AdN-E mechanisms in bimolecular nucleophilic substitutions at vinyl carbon: the relevance of the LUMO symmetry of the electrophile. J. Am. Chem. Soc. 117, 2297–2300 (1995).

    CAS  Google Scholar 

  10. 10.

    Okayama, T., Takino, T., Sato, K. & Ochiai, M. In-plane vinylic SN2 substitution and intramolecular β-elimination of β-alkylvinyl(chloro)-λ3-iodanes. J. Am. Chem. Soc. 120, 2275–2282 (1998).

    Google Scholar 

  11. 11.

    Bach, R. D., Baboul, A. G. & Schlegel, H. B. Inversion vs. retention of configuration for nucleophilic substitution at vinylic carbon. J. Am. Chem. Soc. 123, 5787–5793 (2001).

    CAS  PubMed  Google Scholar 

  12. 12.

    Williams, A. Concerted mechanisms of acyl group transfer reactions in solution. Acc. Chem. Res. 22, 387–392 (1989).

    CAS  Google Scholar 

  13. 13.

    Curran, T. P., Farrar, C. R., Niazy, O. & Williams, A. Structure activity studies on the equilibrium reaction between phenolate ions and 2-aryoxazolin-5-one—data consistent with a concerted acyl group transfer mechanism. J. Am. Chem. Soc. 102, 6828–6837 (1980).

    CAS  Google Scholar 

  14. 14.

    Chrystiuk, E. & Williams, A. A single transition state in the transfer of methoxycarbonyl group between isoquinoline and substituted pyridines. J. Am. Chem. Soc. 109, 3040–3046 (1987).

    CAS  Google Scholar 

  15. 15.

    Ba-Saif, S. A., Luthra, A. K. & Williams, A. Concertedness in acyl group transfer: a single transition state in acetyl transfer between phenolate ion nucleophiles. J. Am. Chem. Soc. 109, 6362–6368 (1987).

    CAS  Google Scholar 

  16. 16.

    Ba-Saif, S. A., Luthra, A. K. & Williams, A. Concerted acetyl group transfer between substituted phenolate ion nucleophiles: variation of transition state structure as a function of substituent. J. Am. Chem. Soc. 111, 2647–2652 (1989).

    CAS  Google Scholar 

  17. 17.

    Han, C. & Braumann, J. I. Gas phase nucleophilic displacement reactions of negative ions with carbonyl compounds. J. Am. Chem. Soc. 101, 3715–3724 (1979).

    Google Scholar 

  18. 18.

    Kim, J. K. & Caserio, M. C. Acyl-transfer reactions in the gas phase: the question of tetrahedral intermediates. J. Am. Chem. Soc. 103, 2124–2127 (1981).

    CAS  Google Scholar 

  19. 19.

    Guthrie, J. P. Concerted mechanism for alcoholysis of esters: an examination of the requirements. J. Am. Chem. Soc. 113, 3941–3949 (1991).

    CAS  Google Scholar 

  20. 20.

    Guthrie, J. P. & Pike, D. C. Hydration of acylimidazoles: tetrahedral intermediates in acylimidazole hydrolysis and nucleophilic attack by imidazoles on esters: the question of concerted mechanisms for acyl transfer. Can. J. Chem. 65, 1951–1969 (1987).

    CAS  Google Scholar 

  21. 21.

    Hengge, A. C. & Hess, R. A. concerted or stepwise mechanisms for acyl transfer reactions of p-nitrophenyl acetate? transition state structures from isotope effects. J. Am. Chem. Soc. 116, 11256–11263 (1994).

    CAS  Google Scholar 

  22. 22.

    Blake, J. F. & Jorgensen, W. L. Ab initio study of the displacement reactions of chloride ion with formyl and acetyl chloride. J. Am. Chem. Soc. 109, 3856–3861 (1987).

    CAS  Google Scholar 

  23. 23.

    Fox, J. M., Dmitrenko, O., Liao, L. & Bach, R. D. Computational studies of nucleophilic substitution at carbonyl carbon: the SN2 mechanism versus the tetrahedral intermediate in organic synthesis. J. Org. Chem. 69, 7317–7328 (2004).

    CAS  PubMed  Google Scholar 

  24. 24.

    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, 1703–1704 (1993).

    Google Scholar 

  25. 25.

    Xu, S. et al. The DMAP-catalyzed acetylation of alcohols–a mechanistic study. Chem. Eur. J. 11, 4751–4757 2005).

    CAS  PubMed  Google Scholar 

  26. 26.

    Skoog, M. T. & Jencks, W. P. Reactions of pyridines and primary amines with N-phosphorylated pyridines. J. Am. Chem. Soc. 106, 7597–7606 (1984).

    CAS  Google Scholar 

  27. 27.

    Bourne, N., Chrystiuk, E., Davis, A. M. & Williams, A. A single transition state in the reaction of aryl diphenylphosphinate esters with phenolate ions in aqueous solution. J. Am. Chem. Soc. 110, 1890–1895 (1988).

    CAS  Google Scholar 

  28. 28.

    Bourne, N. & Williams, A. Evidence for a single transition state in the transfer of the phosphoryl group to nitrogen nucleophiles from pyridino-N-phosphonates. J. Am. Chem. Soc. 106, 7591–7596 (1984).

    CAS  Google Scholar 

  29. 29.

    Buchwald, S. L., Friedman, J. M. & Knowles, J. R. Stereochemistry of nucleophilic displacement on two phosphoric monoesters and a phosphoguanidine: the role of metaphosphate. J. Am. Chem. Soc. 106, 4911–4916 (1984).

    CAS  Google Scholar 

  30. 30.

    Andersen, K. K., Caret, R. I. & Karup–Nielsen, I. Nucleophilic substitution at tricoordinate sulfur(iv): stereochemistry of dialkylarylsulfonium salt formation from alkyl aryl sulfoxides. J. Am. Chem. Soc. 96, 8026–8032 (1974).

    CAS  Google Scholar 

  31. 31.

    Bourne, N., Hopkins, A. & Williams, A. Single transition state for sulfuryl group transfer between pyridine nucleophiles. J. Am. Chem. Soc. 107, 4327–4331 (1985).

    CAS  Google Scholar 

  32. 32.

    D’Rozario, P., Smyth, R. L. & Williams, A. Evidence for a single transition state in the intramolecular transfer of a sulfonyl group between oxyanion donor and acceptors. J. Am. Chem. Soc. 106, 5027–5028 (1984).

    Google Scholar 

  33. 33.

    Deacon, T., Farrar, C. R., Sikkel, B. J. & Williams, A. Reactions of nucleophiles with strained cyclic sulfonate esters: Bronsted relationships for rate and equilibrium constants for variation of phenolate anion nucleophile and leaving group. J. Am. Chem. Soc. 100, 2525–2534 (1978).

    CAS  Google Scholar 

  34. 34.

    Koh, H.-J. & Um, I.-H. Kinetic study on quinuclidinolysis of O-phenyl O-Y-substituted-phenyl thionocarbonates: effects of changing nonleaving group from thionobenzoyl to phenyloxythionocarbonyl on reactivity and transition-state structure. Bull. Korean Chem. Soc. 38, 1091–1096 (2017).

    CAS  Google Scholar 

  35. 35.

    Renfrew, A. H. M., Rettura, D., Taylor, J. A., Whitmore, J. M. J. & Williams, A. 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).

    Google Scholar 

  36. 36.

    Cullum, N. R. et al. Effective charge on the nucleophile and leaving group during the stepwise transfer of the triazinyl group between pyridines in aqueous solution. J. Am. Chem. Soc. 117, 9200–9205 (1995).

    CAS  Google Scholar 

  37. 37.

    Renfrew, A. H. M., Taylor, J. A., Whitmore, J. M. J. & Williams, A. Timing of bonding changes in fundamental reactions in solution: pyridinolysis of a triazinylpyridinium salt. J. Chem. Soc. Perkin Trans. 2 0, 2383–2384 (1994).

    CAS  Google Scholar 

  38. 38.

    Kikushima, K., Grellier, M., Ohashi, M. & Ogoshi, S. Transition-metal-free hydrodefluorination of polyfluoroarenes by a concerted nucleophilic aromatic substitution with a hydrosilicate. Angew. Chem. Int. Ed. 56, 16191–16196 (2017).

    CAS  Google Scholar 

  39. 39.

    Ong, D. Y., Tejo, C., Xu, K., Hirao, H. & Chiba, S. Hydrodehalogenation of haloarenes by a sodium hydride–iodide composite. Angew. Chem. Int. Ed. 56, 1840–1844 (2017).

    CAS  Google Scholar 

  40. 40.

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

    CAS  Google Scholar 

  41. 41.

    Zheng, Y.-J. & Bruice, T. C. On the dehalogenation mechanism of 4-chlorobenzoyl CoA by4-chlorobenzoyl CoA dehalogenase: insights from study on the nonenzymatic reaction. J. Am. Chem. Soc. 119, 3868–3877 (1997).

    CAS  Google Scholar 

  42. 42.

    Baker, J. & Muir, M. The Meisenheimer model for predicting the principal site of for nucleophilic substitution in aromatic perfluorocarbons—generalization to include ring-nitrogen atoms and non-fluorine ring substituents. Can. J. Chem. 88, 588–597 (2010).

    CAS  Google Scholar 

  43. 43.

    Goryunov, L. et al. Di- and tri-fluorobenzenes in reactions with Me2 EM (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).

    Google Scholar 

  44. 44.

    Cairns, A. G., Senn, H. M., Murphy, M. P. & Hartley, R. C. Expanding the palette of phenanthridinium cations. Chem. Eur. J. 20, 3742–3751 (2014).

    CAS  PubMed  Google Scholar 

  45. 45.

    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).

    CAS  Google Scholar 

  46. 46.

    Giroldo, T., Xavier, L. A. & Riveros, J. M. An unusually fast nucleophilic aromatic displacement reaction: the gas-phase reaction of fluoride ions with nitrobenzene. Angew. Chem. Int. Ed. 43, 3588–3590 (2004).

    CAS  Google Scholar 

  47. 47.

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

    PubMed  Google Scholar 

  48. 48.

    Liljenberg, M. et al. Predicting regioselectivity in nucleophilic aromatic substitution. J. Org. Chem. 77, 3262–3269 (2012).

    CAS  PubMed  Google Scholar 

  49. 49.

    Liljenberg, M., Brinck, T., Rein, T. & Svensson, M. Utilizing the σ-complex stability for quantifying reactivity in nucleophilic substitutions of aromatic fluorides. Beil. J. Org. Chem. 9, 791–799 (2013).

    CAS  Google Scholar 

  50. 50.

    Clayden, J., Greeves, N., Warren, S. in Organic Chemistry, 2nd edn, 518 (Oxford Univ. Press, Oxford, 2012).

  51. 51.

    Persson, J., Axelsson, S. & Matsson, O. Solvent dependent leaving group fluorine kinetic isotope effect in a nucleophilic aromatic substitution reaction. J. Am. Chem. Soc. 118, 20–23 (1996).

    CAS  Google Scholar 

  52. 52.

    Singleton, D. A. & Thomas, A. A. High-precision simultaneous determination of multiple small kinetic isotope effects at natural abundance. J. Am. Chem. Soc. 117, 9357–9358 (1995).

    CAS  Google Scholar 

  53. 53.

    Claridge, T. D. High-Resolution NMR Techniques in Organic Chemistry (Elsevier, New York, NY, 2016).

  54. 54.

    Chan, J., Tang, A. & Bennett, A. J. A stepwise solvent-promoted SNi reaction of α-d-glucopyranosyl fluoride: mechanistic implications for retaining glycosyltransferases. J. Am. Chem. Soc. 134, 1212–1220 (2012).

    CAS  PubMed  Google Scholar 

  55. 55.

    Westaway, K. C. Determining transition state structure using kinetic isotope effects. J. Label. Compd Radiopharm. 50, 989–1005 (2007).

    CAS  Google Scholar 

  56. 56.

    Matsson, O., Dybala-Defratyka, A., Rostkowski, M., Paneth, P. & Westaway, K. C. A theoretical investigation of α-carbon kinetic isotope effects and their relationship to the transition-state structure of SN2 reactions. J. Org. Chem. 10, 4022–4027 (2005).

    Google Scholar 

  57. 57.

    Kwan, E. E., Park, Y., Besser, H. A., Anderson, T. L. & Jacobsen, E. N. Sensitive and accurate 13C kinetic isotope effect measurements enabled by polarization transfer. J. Am. Chem. Soc. 139, 43–46 (2017).

    CAS  PubMed  Google Scholar 

  58. 58.

    Papajak, E., Zheng, J., Xu, X., Leverentz, H. R. & Truhlar, D. G. Perspectives on basis sets beautiful: seasonal plantings of diffuse basis functions. J. Chem. Theory Comput. 7, 3027–3034 (2011).

    CAS  PubMed  Google Scholar 

  59. 59.

    Riplinger, C. & Neese, F. An efficient and near linear scaling pair natural orbital based local coupled cluster method. J. Chem. Phys. 138, 034106 (2013).

    PubMed  Google Scholar 

  60. 60.

    Karplus, M., Porter, R. & Sharma, R. Exchange reactions with activation energy. I. Simple barrier potential for (H, H2). J. Chem. Phys. 43, 3259–3287 (1965).

    CAS  Google Scholar 

  61. 61.

    Melander, L. C. & Saunders, W. H. Reaction Rates of Isotopic Molecules (Wiley, New York, NY, 1980).

  62. 62.

    Marcus, R. A. & Sutin, N. Electron transfers in chemistry and biology. Biochim. Biophys. Acta 811, 265–322 (1985).

    CAS  Google Scholar 

  63. 63.

    Shaik, S. S. & Hiberty, P. C. A Chemist’s Guide to Valence Bond Theory (Wiley, New York, NY, 2007).

  64. 64.

    Silverstein, T. P. Marcus theory: thermodynamics can control the kinetics of electron transfer reactions. J. Chem. Educ. 89, 1159–1167 (2012).

    CAS  Google Scholar 

  65. 65.

    Bunnett, J. F. & Zahler, R. E. Aromatic nucleophilic substitution reactions. Chem. Rev. 49, 273–412 (1951).

    CAS  Google Scholar 

  66. 66.

    Marenich, A. V., Jerome, S. V., Cramer, C. J. & Truhlar, D. G. Charge model 5: an extension of Hirshfeld population analysis for the accurate description of molecular interactions in gaseous and condensed phases. J. Chem. Theory Comput. 8, 527–541 (2012).

    CAS  PubMed  Google Scholar 

  67. 67.

    Chen, Z., Wannere, C. S., Corminboeuf, C., Puchta, R. & Schleyer, P. V. R. Nucleus-independent chemical shifts (NICS) as an aromaticity criterion. Chem. Rev. 105, 3842–3888 (2005).

    CAS  PubMed  Google Scholar 

  68. 68.

    Glendening, E. D. et al. NBO 6.0 (Theoretical Chemistry Institute, 2013);

  69. 69.

    Jackson, C. J. & Gazzolo, F. H. Am. Chem. J. 23, 376 (1900).

    CAS  Google Scholar 

  70. 70.

    Meisenheimer, J. Ueber reactionen aromatischer nitrokörper. Justus Liebigs Ann. Chem. 323, 205–246 (1902).

    CAS  Google Scholar 

  71. 71.

    Helmus, J. J. nmrglue

  72. 72.

    Frisch, M. J. et al. Gaussian 09 and 16 (Gaussian Inc.).

  73. 73.

    Kwan, E. E. & Anderson, T. L. PyQuiver

  74. 74.

    Zheng, J. et al. GAUSSRATE 2016 (University of Minnesota).

  75. 75.

    Zheng, J. et al. POLYRATE 2016 (University of Minnesota).

  76. 76.

    Neese, F. The ORCA program system. Wiley Inter. Rev. Comp. Mol. Sci. 2, 73–78 (2012).

    CAS  Google Scholar 

  77. 77.

    Takano, Y. & Houk, K. N. Benchmarking the conductor-like polarizable continuum model (CPCM) for aqueous solvation free energies of neutral and ionic organic molecules. J. Chem. Theory Comput. 1, 70–77 (2005).

    PubMed  Google Scholar 

  78. 78.

    Kongsted, J. & Mennucci, B. How to model solvent effects on molecular properties using quantum chemistry? Insights from polarizable discrete or continuum solvation models. J. Phys. Chem. A. 111, 9890–9900 (2007).

    CAS  PubMed  Google Scholar 

  79. 79.

    Cappelli, C., Monti, S., Scalmani, G. & Barone, V. On the calculation of vibrational frequencies for molecules in solution beyond the harmonic approximation. J. Chem. Theory Comput. 6, 1660–1669 (2010).

    CAS  PubMed  Google Scholar 

  80. 80.

    Zimmerman, P. Reliable transition state searches integrated with the growing string method. J. Chem. Theory Comput. 9, 3043–3050 (2013).

    CAS  PubMed  Google Scholar 

Download references


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.

Author information




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.

Corresponding author

Correspondence to Eric N. Jacobsen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kwan, E.E., Zeng, Y., Besser, H.A. et al. Concerted nucleophilic aromatic substitutions. Nature Chem 10, 917–923 (2018).

Download citation

Further reading


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