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
• 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 of how variables affect 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.