Fluorine and Fluorination Chemistry

Fluorine is a highly corrosive, reactive gas. In its elemental form, fluorine is highly toxic and must be carefully handled. Fluorine is a necessary component of many pharmaceuticals, fine chemicals, and polymers.  Fluorination reactions are designed to add fluorine to substrate molecules. There are a number of reagents available to accomplish fluorinations. A common fluorinating reagent is hydrofluoric acid, but it is also corrosive, reactive, and must be used with great care. The other issue with fluorinating with elemental fluorine or HF is specificity. They tend to be so effective at reacting with organics that it is difficult to control the position on which the fluorine atom inserts in a substrate molecule. A number of reagents have been developed that are more effective at providing controlled fluorinations. For example, DAST (diethylaminosulfur trifluoride) is commonly used to convert carbonyl and alcohols to their analogous fluoro derivatives. An even more benign reagent is SelectFluor [(1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2] octane bis(tetrafluoroborate)], which is an electrophilic fluorinating reagent that is easier to use, since it is nonvolatile and air/moisture stable.

Fluorine is widely used in industrial products; the scope of products and compounds containing fluorine is remarkable. Fluorine atoms are found in:

• Consumer Products, such as Toothpaste and Drinking Water
• Many Medicines, Antibiotics, and Anesthetics
• Air Conditioning Refrigerants
• Semiconductor Applications for Plasma Etching
• High Performance, Engineered Plastics and Polymers

In pharmaceuticals, adding fluorine atoms to substrate molecules can increase the potential for therapeutic activity. There are more than 150 Active Pharmaceutical Ingredients (APIs) that contain fluorine atoms.  Adding fluorine to a therapeutic entity can increase metabolic stability, lipophilicity, and thereby improve bioavailability.  As a result, well-controlled fluorination reactions having high specificity are frequently used in pharmaceutical research, development, and production. 

In industrial polymerization reactions, adding fluorine to a carbon-carbon backbone creates a polymer with properties such as strength, durability, inertness to chemicals, and improved surface properties.  On the molecular level, the strength of the C-F bond is the key to these performance advantages and result in the widespread use of fluoropolymers used in producing chemically resistant gaskets, such as polytetrafluoroethylene (PTFE) and fluoroelastomers.  In an example of an important fluorination polymerization, chloroform is reacted with HF to form chlorodifluoromethane, which is then heated to form tetrafluoroethylene and polymerized under high pressure using a peroxide initiator to yield PTFE. 

Fluorination reactions are performed either with nucleophilic or electrophilic reagents. Elemental fluorine gas is a common source for electrophilic fluorine, but it is highly reactive, corrosive, and toxic, requiring specialized equipment and much care in its use. Furthermore, it is so aggressive that it is difficult to control reaction specificity. For this reason, a number of compounds have been synthesized that safely provide electrophilic fluoride and provide better reaction specificity.  SelectFluor [1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)] and NFSI [N –Fluorobenzenesulfonimide] provide electrophilic fluorine and are both stable solids that enable the fluorination of aryl nucleophiles, for example. 

Nucleophilic fluorinations are readily performed with compounds such as DAST [diethylaminosulfur trifluoride] or the XtalFluors. DAST has long been used to fluorinate alcohols, ketones, and carboxylic acids, and had largely replaced the more problematic reactant, sulfur tetrafluoride gas.  Newer nucleophilic fluorinating agents, such as XtalFluor-E and XtalFluor-M, are effective for replacing hydroxyl groups and carbonyls with fluorine and eliminate some of the problems associated with DAST (such as liberating HF).  

Fluorine and fluorination reactions revolutionized the polymer industry by creating families of products with exceptional performance characteristics. The inherent advantages of fluoropolymers, including resistance to chemical attack by acids and bases, arise from the strength of the C-C bond and the even greater strength of the C-F bond. For example, in PTFE, the position of the fluorine atoms essentially form a sheath around the carbon backbone, protecting the C-C bonds from attack. Fluoropolymers are typically used in harsh chemical and high-temperature applications. Fluoroelastomers are preferred material for gaskets used in both the chemical and aerospace industries. The low coefficient of friction of fluoropolymers make them valuable as specialty lubricants and in coatings.  

Commonly Used Fluorpolymers Include:

• PTFE (Polytetrafluoroethylene) as Wire Insulation
• PFA (perfluoroalkoxy alkane) in Piping and Fitting in the Chemical Industry
• FEP (fluorinated ethylene propylene) as Plastic Labwear and Release Film in Composite Manufacture
• ETFE (ethylene tetrafluoroethylene) for High Temperature Applications in Aerospace and Aviation
• PVDF (polyvinylidene fluoride) as Piping Materials in the Chemical and Pharmaceutical Industries
• ECTFE (ethylene chlorotrifluoroethylene) for Electrostatic Powder Coatings of Metals

Understanding the kinetics and thermodynamics of fluorinations is important in order to achieve reaction objectives and to ensure reaction/chemical process safety. Depending on substrate, fluorinating agent and reaction conditions, fluorinations can be quite energetic and require careful monitoring and control; this is especially true during reaction scale-up. Chemical synthesis reactors and reaction calorimeters deliver precise reactor control, measure reaction energetics, and model the effect of variables on reaction performance. FTIR and Raman Spectroscopy track and monitor key reaction species to provide kinetics data, support for proposed mechanisms, and a better understanding how variables effect overall reaction progress and performance.  When it is necessary to obtain a reaction sample for offline analysis, EasySampler performs automated, safe, and unattended sampling. Researchers often use chemical synthesis reactors in conjunction with spectroscopy and/or EasySampler in situ sampling to obtain the information required for a thorough understanding of fluorination reactions and processes.

View a Live eDemo from your work or home office on your schedule.

The authors describe a reaction in which fluorine from a perfluorinated ligand transfers to an electrophile, which leads to the synthesis of a new fluorinated compound and a dimerized version of the monodefluorinated organorhodium complex.   This transfer arises from C-F bond activation, which formerly was considered to be difficult to accomplish due to the strength of the bond.  Severing the C-F bond in the ligand of the rhodium complex [(η⁵ ,κ₂C− C₅Me₄CH₂C₆F₅CH₂NC₃H₂NMe)−RhCl] frees nucleophilic fluoride and converts the acyl moiety of the toluyl chloride electrophile to an acyl fluoride, and leads to the formation of the metallocyclic compound. 

The researchers investigated fluoride transfer to other substrates including anhydrides.  In one experiment, the transfer of fluoride to acetic anhydride was tracked by ReactIR. They report that the intensity of the anhydride C-O band (1268cm-1) and the rhodium complex [(η⁵,κ₂C−C₅Me₄CH₂C₆F₅CH₂NC₃H₂NMe)−RhCl] C-F band (1386 cm-1) diminishes, while concurrently a new band arising from the acyl fluoride C-F bond (1346 cm-1) increases proportionally in intensity.  This supports the observation of the transfer of the fluoride from one substrate to the other.  

Patrick J. Morgan, Magnus W. D. Hanson-Heine, Hayden P. Thomas, Graham C. Saunders, Andrew C. Marr, Peter Licence, “C−F Bond Activation of a Perfluorinated Ligand Leading to Nucleophilic Fluorination of an Organic Electrophile”, Organometallics, 2020,  https://dx.doi.org/10.1021/acs.organomet.0c00176 

The authors describe a method to prepare AgOCF₃ at room temperature and demonstrate its capabilities in trifluoromethoxylations and as a source for carbonyl fluoride (O=CF₂).  This enabled the synthesis of N-alkyl/aryl and N-CF₃ carbamoyl fluorides from secondary amines and isothiocyanides.

To better understand the mechanism by which the salt releases O=CF₂, a number of experiments were initiated.   ReactIR measurements showed that the salt does not release O=CF₂ upon heating, and that the salt solution was stable for several hours at 50^oC.   When isothiocyanate was introduced, ReactIR measurements showed a decrease in the 974 cm-1 band associated with AgOCF₃ and the rapid increase of a band at 1245 cm-1 from formation of O=CF₂.  The researchers performed reactions of various isothiocyanates with AgOCF₃ to determine whether a N-CF₃ carbamoyl moiety could be identified.  They observed two new IR bands arising: at 1641 cm-1 from the desulfurization product R-N-C=CF₂ and at 1848 cm-1 from theN-CF₃ carbamoyl.  

Summarizing: ReactIR measurements indicate that AgOCF₃ does not liberate O=CF₂ until it is activated by a nucleophilic co-reagent, supporting the researchers observations about the stability of the salt.  This enabled the synthesis of a number of carbamoyl fluorides from secondary amines and isothiocyanides. 

Abdurrahman Turksoy, Thomas Scattolin, Samir Bouayad‐Gervais, “Facile Access to AgOCF3 and Its New Applications as a Reservoir for OCF2 for the Direct Synthesis of N−CF3, Aryl or Alkyl Carbamoyl Fluorides” Chem. Euro. J., 2020, https://doi.org/10.1002/chem.202000116

Masafumi Sugiyama, Midori Akiyama, Kohei Nishiyama, Takashi Okazoe, Kyoko Nozak, “Synthesis of Fluorinated Dialkyl Carbonates from Carbon Dioxide as a Carbonyl Source“, ChemSusChem, 2020, https://doi.org/10.1002/cssc.202000090  

Abdurrahman Turksoy, Thomas Scattolin, Samir Bouayad‐Gervais, “Facile Access to AgOCF3 and Its New Applications as a Reservoir for OCF2 for the Direct Synthesis of N−CF3, Aryl or Alkyl Carbamoyl Fluorides” Chem. Euro. J., 2020, https://doi.org/10.1002/chem.202000116

Patrick J. Morgan, Magnus W. D. Hanson-Heine, Hayden P. Thomas, Graham C. Saunders, Andrew C. Marr, Peter Licence, “C−F Bond Activation of a Perfluorinated Ligand Leading to Nucleophilic Fluorination of an Organic Electrophile”, Organometallics, 2020,  https://dx.doi.org/10.1021/acs.organomet.0c00176

Lara Amini-Rentsch, Ennio Vanoli, Sylvia Richard-Bildstein, Roger Marti, Gianvito Vilé, “A Novel and Efficient Continuous-Flow Route To Prepare Trifluoromethylated N-Fused Heterocycles for Drug Discovery and Pharmaceutical Manufacturing”, Ind. Eng. Chem. Res. 2019, 58, 24, 10164-10171

Daniel W. Widlicka, Alexander Gontcharov, Ruchi Mehta, Dylan J. Pedro, and Robert North  “Enantiospecific Synthesis of (3R,4R)‑1-Benzyl-4-fluoropyrrolidin-3- amine Utilizing a Burgess-Type Transformation”, Org. Process Res. Dev. 2019, 23, 1970−1978

Alyssa M. Hua, Samantha L. Bidwell, Sarah I. Baker, Hrant P. Hratchian, Ryan D. Baxter, “Experimental and Theoretical Evidence for Nitrogen−Fluorine Halogen Bonding in Silver-Initiated Radical Fluorinations”, ACS Catal. 2019, 9, 3322−3326

Biagia Musio, Elena Gala, Steven V. Ley, “Real-Time Spectroscopic Analysis Enabling Quantitative and Safe Consumption of Fluoroform during Nucleophilic Trifluoromethylation in Flow”, ACS Sustainable Chem. Eng. 2018, 6(1), 1489-1495

Qiang Yang, Pablo J. Cabrera, Xiaoyong Li, Min Sheng, Nick X. Wang, “Safety Evaluation of the Copper-Mediated Cross-Coupling of 2-Bromopyridines with Ethyl Bromodifluoroacetate”,Org. Process Res. Dev. 2018, 22(10) 1441-1447       rc-1

Thomas Scattolin, Maoping Pu, and Franziska Schoenebeck, “Investigation of (Me4N)SCF3 as a Stable, Solid and Safe Reservoir for S=CF2 as a Surrogate for Thiophosgene”, Chem. Eur. J.,2017, https://doi.org/10.1002/chem.201705240

Jordan D. Galloway, Duy N. Mai, Ryan D. Baxter, “Silver-Catalyzed Minisci Reactions Using Selectfluor as a Mild Oxidant”, Org. Lett. 2017, 19, 5772−5775

Zsombor Gonda, Ferenc Béke, Orsolya Tischler, Milán Petró, Zoltán Novák, Balázs L. Tóth, “Erythrosine B Catalyzed Visible‐Light Photoredox Arylation–Cyclization of N‐Alkyl‐N‐aryl‐2‐(trifluoromethyl)acrylamides to 3‐(Trifluoromethyl)indolin‐2‐one Derivatives”, Eur. J. Org. Chem. 2017, 2112–2117

Thomas Scattolin, Kristina Deckers, Franziska Schoenebeck, “Direct Synthesis of Acyl Fluorides from Carboxylic Acids with the Bench-Stable Solid Reagent (Me4N)SCF3”, Org. Lett. 2017, 19, 5740−5743

Alyssa M. Hua, Duy N. Mai, Ramon Martinez, Ryan D. Baxter, “Radical C−H Fluorination Using Unprotected Amino Acids as Radical Precursors” Org. Lett. 2017, 19(11) 2949-2952

Nunzio Denora, Angela Lopedota , Modesto de Candia, Saverio Cellamare, Leonardo Degennaro, Renzo Luisi, Antonietta Mele, Domenico Tricarico, Annalisa Cutrignelli, Valentino Laquintana, Cosimo D. Altomare, Massimo Franco, Vincenzo Dimiccoli, Anna Tolomeo, Antonio Scilimati,  “Pharmaceutical development of novel lactate-based 6-fluoro-L-DOPA formulations”, European Journal of Pharmaceutical Sciences 2017, 99, 361–368

Tao Xu, Yichen Wu, Zheliang Yuan, Hairong Guan,Guosheng Liu, “Mechanistic Investigation on the Silver-Catalyzed Oxidative Intramolecular Aminofluorination of Alkynes”, Organometallics, 2016, 35(10), 1347-1349

Antal Harsanyi and Graham Sandford, “Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters”, Green Chem., 2015, 17, 3000–3009

Peng Zhang, Dr. Christian Wolf,  “Catalytic Enantioselective Difluoroalkylation of Aldehydes”, Angew. Chem., 2013, https://doi.org/10.1002/anie.201303551