Synthetic Organofluorine Chemistry

Living Edition
| Editors: Jinbo Hu, Teruo Umemoto

Balz-Schiemann Reaction

  • Chuanfa Ni
  • Bo Xing
  • Jinbo HuEmail author
Living reference work entry


Aryl fluorides are important structural motifs in pharmaceuticals [ 1, 2, 3], and nearly 20% of 200 best-selling drugs in 2018 contain at least one (hetero)aryl fluoride motif [ 4]. The past decade has witnessed significant progress in the development of aromatic C-F bond formation, especially via transition metal-mediated or catalyzed processes [ 5]. However, among all the available methods, Balz-Schiemann reaction (Scheme 1) is one of the most widely used methods for large-scale industrial production of aryl fluorides due to ready availability of the starting materials [ 6].
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  1. 1.
    Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Fluorine in Medicinal Cchemistry. Chem. Soc. Rev. 2008, 37, 320–330.CrossRefGoogle Scholar
  2. 2.
    Kirk, K. L. Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments. Org. Process Res. Dev. 2008, 12, 305–321.CrossRefGoogle Scholar
  3. 3.
    Mgller, K. Faeh, C. Diederich, F. O. Fluorine in Pharmaceuticals: Looking Beyond Intuition. Science 2007, 317, 1881–1886.CrossRefGoogle Scholar
  4. 4.
  5. 5.
    Campbell, M. G.; Ritter, T. Modern Carbon−Fluorine Bond Forming Reactions for Aryl Fluoride Synthesis. Chem. Rev. 2015, 115, 612–633.CrossRefGoogle Scholar
  6. 6.
    Kürti, L.; Czakó, B. Balz-Schiemann Reaction (Schiemann Reaction) In Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms. Amsterdam: Elsevier, 2005, pp 34–35.Google Scholar
  7. 7.
    Balz, G.; Schiemann, G. Über aromatische Fluorverbindungen, I. Ein neues Verfahren zu ihrer Darstellung. Ber. Dtsch. Chem. Ges. B. 1927, 60, 1186–1190.CrossRefGoogle Scholar
  8. 8.
    Finger, G. C.; Oesterling, R. E. Aromatic Fluorine Compounds. VI. Displacement of Aryl Fluorine in Diazonium Salts. J. Am. Chem. Soc. 1956, 78, 2593–2596.CrossRefGoogle Scholar
  9. 9.
    Swain, C. G.; Rogers, R. J. Mechanism of Formation of Aryl Fluorides from Arenediazonium Fluoborates. J. Am. Chem. Soc. 1975, 97, 799–800.CrossRefGoogle Scholar
  10. 10.
    Milner, D. J. Fluoroaromatics from Arylamines: A Convenient One-Pot Conversion Using Nitrosonium Tetrafluoroborate. Synth. Commun. 1992, 22, 73–82.CrossRefGoogle Scholar
  11. 11.
    Garel, L.; Saint-Jalmes, L. One-Pot Fluoro-De-diazoniation of Anilines in Organic Medium. Tetrahedron Lett. 2006, 47, 5705–5708.CrossRefGoogle Scholar
  12. 12.
    Yu, Z.; Lv, Y.; Yu, C.; Su, W. Continuous Flow Reactor for Balz-Schiemann Reaction: a New Procedure for the Preparation of Aromatic Fluorides. Tetrahedron Lett. 2013, 54, 1261–1263.CrossRefGoogle Scholar
  13. 13.
    Park, N. H.; Senter, T. J.; Buchwald, S. L. Rapid Synthesis of Aryl Fluorides in Continuous Flow through the Balz-Schiemann Reaction. Angew. Chem. Int. Ed. 2016, 55, 11907–11911.CrossRefGoogle Scholar
  14. 14.
    Ferm R. L.; Werf, C. V. Synthesis of Aromatic Fluorides through Diazotization in Anhydrous Hydrogen Fluoride. J. Am. Chem. Soc. 1950, 72, 4809–4810.CrossRefGoogle Scholar
  15. 15.
    Welch, J.; Olah, G. A. Onium Ions. XII. Heterolytic Dediazoniation of Benzenediazonium Ions by Halide Ions in Pyridinium Polyhydrogen Fluoride Solution Giving Isomeric Halobenzenes Reflecting Ambident Reactivity of Benzenediazonium Ions and Intermediate Phenyl Cation as Well as Subsequent Aryne Formation. J. Am. Chem. Soc. 1975, 97, 208–210.CrossRefGoogle Scholar
  16. 16.
    Rutherford, K. G.; Redmond, W.; Rigamonti, J. The Use of Hexafluorophosphoric Acid in the Schiemann Reaction. J. Org. Chem. 1961, 26, 5149–5152.CrossRefGoogle Scholar
  17. 17.
    Sellers, C., Suschitzky, H. The Use of Arenediazonium Hexafluoro-Antimonates and -Arsenates in the Preparation of Aryl Fluorides. J. Chem. Soc., C 1968, 2317–2319.Google Scholar
  18. 18.
    Deaminative Fluorination of Anilines with Silicon Tetrafluoride: Utility of Silicon Tetrafluoride as a Fluorine Source Tamura, M.; Shibakami, M.; Sekiya, A. Eur. J. Org. Chem. 1998, 1998, 725−727Google Scholar
  19. 19.
    Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. A.; Olah, G. A. Synthetic Methods and Reactions. 63: Pyridinium Poly(hydrogen fluoride) (30% Pyridine-70% Hydrogen Fluoride): A Convenient Reagent for Organic Fluorination Reactions. J. Org. Chem. 1979, 44, 3872–3881.CrossRefGoogle Scholar
  20. 20.
    Fukuhara, T.; Yoneda, N.; Sawada, T.; Suzuki, A. An Improved Procedure for Diazotization Fluoro-Dediazoniation of Anilines Using Organic Base-HF Agents. Synth. Commun. 1987, 17, 685–692.CrossRefGoogle Scholar
  21. 21.
    Yoneda, N.; Fukuhara, T. Facile Preparation of Aromatic Fluorides by Deaminative Fluorination of Aminoarenes Using Hydrogen Fluoride Combined with Bases. Tetrahedron, 1996, 52, 23–36.CrossRefGoogle Scholar
  22. 22.
    Shinhama, K.; Aki, S.; Furuta, T.; Minamikawa, J. Facile Conversion of Arenediazonium Salts to the Corresponding Fluoroarenes Using Boron Trifluoride Diethyl Ether Complex. Synth. Commun. 1993, 23, 1577–1582.CrossRefGoogle Scholar
  23. 23.
    Heredia-Moya, J.; Kirk, K. L. Photochemical Schiemann Reaction in Ionic Liquids. J. Fluorine Chem. 2007, 128, 674–678.CrossRefGoogle Scholar
  24. 24.
    Laali, K. K.; Gettwert, V. J. Fluorodediazoniation in Ionic Liquid Solvents: New Life for the Balz-Schiemann Reaction. J. Fluorine Chem. 2001, 107, 31–34.CrossRefGoogle Scholar
  25. 25.
    Döbele, M.; Vanderheiden, S.; Jung, N.; Bräse, S. Synthesis of Aryl Fluorides on a Solid Support and in Solution by Utilizing a Fluorinated Solvent. Angew. Chem. Int. Ed. 2010, 49, 5986–5988.CrossRefGoogle Scholar
  26. 26.
    Xing, B.; Ni, C.; Hu, J. Hypervalent Iodine(III)-Catalyzed Balz–Schiemann Fluorination under Mild Conditions. Angew. Chem. Int. Ed. 2018, 57, 9896–9900.CrossRefGoogle Scholar
  27. 27.
    El Dine, T. M.; Sadek, O.; Gras, E.; Perrin, D. M. Expanding the Balz-Schiemann Reaction: Organotrifluoroborates Serve as Competent Sources of Fluoride Ion for Fluoro-Dediazoniation. Chem. Eur. J. 2018, 24, 14933–14937.CrossRefGoogle Scholar
  28. 28.
    Satyamurthy, N.; Barrio, J. R.; Schmidt, D. G.; Kammerer, C.; Bida, G. T.; Phelps, M. E. Acid-Catalyzed Thermal Decomposition of l-Aryl-3,3-dialkyltriazenes in the Presence of Nucleophiles. J. Org. Chem. 1990, 55, 4560–4564.CrossRefGoogle Scholar
  29. 29.
    Wallach, O.; Heusler, Fr. Ueber organische Fluorverbindungen. Justus Liebigs Ann. Chem. 1888, 243, 219–244.CrossRefGoogle Scholar
  30. 30.
    Pages, T.; Langlois, B. R. Fluorination of Aromatic Compounds from 1-Aryl-3,3-dimethyltriazenes and Fluoride Anions in Acidic Medium 1: A Model for 18F Labeling. J. Fluorine Chem. 2001, 107, 321–327.CrossRefGoogle Scholar
  31. 31.
    Kovac, M.; Anderluh, M.; Vercouillie, J.; Guilloteau, D.; Emond, P.; Mavel, S. Aromatic Fluoro-De-triazenation with Boron Trifluoride Diethyl Etherate under Non-protic Acid Conditions. J. Fluorine Chem. 2013, 147, 5–9.CrossRefGoogle Scholar
  32. 32.
    Zhu, Z.; Colbry, N. L.; Lovdahl, M.; Mennen, K. E.; Acciacca, A.; Beylin, V. G.; Clark, J. D.; Belmont, D. T. Practical Alternative Synthesis of 1-(8-Fluoro-naphthalen-1-yl)piperazine. Org. Process Res. Dev. 2007, 11, 907–909.CrossRefGoogle Scholar
  33. 33.
    Chu, C.-K.; Kim, J.-H.; Kim, D. W.; Chung, K.-H.; Katzenellenbogen, J. A.; Chi, D. Y. Aromatic Fluorination by Decomposition of Triazenes in Ionic Liquids. Bull. Korean Chem. Soc. 2005, 26, 599–602.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic ChemistryUniversity of Chinese Academy of Sciences, Chinese Academy of SciencesShanghaiChina