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Fluorination

The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures and local laws regarding handling chemicals

General Overview

Fluorine is a very widely utilized element in the construction of pharmaceutical molecules. It can be used as a reactive handle – aryl fluorides in SNAr reactions, leaving halides in metal–catalysed processes, but is more typically left in the API molecule to impart specific biological properties to the molecule. Reagents for the synthesis of carbon-fluorine bonds can be sub-divided into electrophilic (F+ reagents) / acidic reagents or nucleophilic F– sources. More typically in API synthesis, the fluorine is introduced during the synthesis through the use of commercially available fluorinated starting materials.

  • Chiral carbon-fluorine bonds can be constructed using chiral ligands/ complexes.
  • The introduction of 18F is important for PET agents.
  • Some F– reagents are also used as basic catalysts or for the deprotection of silyl ethers.

All Fluorine reagents are obtained principally from fluorspar (CaF2) which is regarded at medium risk of depletion. Fluorine is widely used and is used in many chemicals, but is used exclusively in a dispersive fashion, e.g. cannot be recovered or recycled. Limiting or replacing fluorine, if practical, is recommended. Poly-fluorinated materials tend to be very persistent and bioaccumulate in the environment. Several fluorine-based reagents are used for deprotection and dehydration as well as for the construction of C-F bonds.

Green Criteria for Fluorination 

  1. Reagents should be selected to minimize safety issues. Large molar excesses of reagents should be avoided if possible.
  2. For electrophilic fluorination, the least reactive F+ reagent should be used.
  3. Reagents with lower mass intensity should be used if possible.
  4. Chemical materials of construction compatibility needs careful analysis.
  5. The process has no major safety issues and the generation of hazardous waste is minimised and controlled.
  6. Solvents should be chosen to minimize any potential safety and environmental impact.

General Literature Reviews on Fluorination

Adams, J. P.; Alder, C. M.; Andrews, I.; Bullion, A. M.;Campbell-Crawford, M.; Darcy, M. G.; Hayler, J. D.; Henderson, R. K.; Oare, C. A.; Pendrak, I.; et al. Development of GSK’s Reagent Guides – Embedding Sustainability into Reagent Selection. Green Chem. 2013, 15, 1542-1549.

Champagne, P. A.; Desroches, J.; Hamel, J-D.; Vandamme, M.; Paquin, J-F. Monofluorination of Organic Compounds: 10 Years of Innovation. Chem. Rev. 2015, 115, 9073-9174.

Wu, J. Review of Recent Advances in Nucleophilic C–F Bond-Forming. Tetrahedron Lett. 2014, 55, 4289–4294.

Walker, M. C.; Chang, M. C. Y. Natural and Engineered Biosynthesis of Fluorinated Natural Products. Chem. Soc. Rev. 2014, 43, 6527-6536.

Harsanyi, A.; Sandford, G. Organofluorine Chemistry: Applications, Sources and Sustainability. Green Chem. 2015, 17, 2081-2086.

Ahrens, T.; Kohlmann, J.; Ahrens, M.; Braun, T. Functionalization of Fluorinated Molecules by Transition-Metal-Mediated C−F Bond Activation To Access Fluorinated Building Blocks. Chem. Rev. 2015, 115, 931–972.

Campbell, M. G.; Ritter, T. Modern Carbon−Fluorine Bond Forming Reactions for Aryl Fluoride Synthesis. Chem. Rev. 2015, 115, 612-633.

Wang, J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in Pharmaceutical Industry: Fluorine-Containing Drugs Introduced to the Market in the Last Decade (2001−2011). Chem. Rev. 2014, 114, 2432−2506.

Ni, C.; Hu, M.; Hu, J. Good Partnership between Sulfur and Fluorine: Sulfur-Based Fluorination and Fluoroalkylation Reagents for Organic Synthesis. Chem. Rev. 2015, 115, 765–825.

Campbell, M. G.; Ritter, T. Late-Stage Fluorination: From Fundamentals to Application. Org. Process Res. Dev. 2014, 18, 474−480.

Kirk, K. L. Fluorination in Medicinal Chemistry: Methods, Strategies, and Recent Developments. Org. Process Res. Dev.2008,12, 305–321.

Filler, R.; Saha, R. Fluorine in Medicinal Chemistry: A Century of Progress and a 60-Year Retrospective of Selected Highlights. Future Med. Chem. 2009, 1, 777-791.

Ojima, I. Exploration of Fluorine Chemistry at the Multidisciplinary Interface of Chemistry and Biology. J. Org. Chem.2013,78, 6358−6383.

Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications. Wiley: Weinheim, Germany, 2004.

Ishida, S.; Sheppard, T.; Nishikata, T. Site Selectivities in Fluorination. Tetrahedron Lett. 2018,59, 789-798.

Bume, D. D.; Harry, S. A.; Lectka, T.; Pitts, C. R. Catalyzed and Promoted Aliphatic Fluorination. J. Org. Chem. 2018, 83, 8803-8814.

Special Consideration on Safety Issues using Fluorinating Reagents

F2 and many F+ -equivalent reagents are highly reactive and can react violently with oxidizable chemicals/solvents and need to be handled with caution. Some can be explosive alone or in combination with other materials. Materials like DAST can be unstable at higher temperatures.

F+ reagents and those containing/generating  HF can be acutely toxic if inhaled and can cause very severe burns. Nuclophilic F– reagents can generate HF if acidified.

Apart from toxicity and handling issues, HF is high corrosive to glass and some other materials. The fluoride anion can also be corrosive, especially in combination with other reagents, so materialscompatibility testing needs to be carried out before any scale-up procedures.