What do many of the high-technology products that we almost take for granted like chemically stable polymers, pharmaceuticals and agrochemicals with enhanced activity, next-generation photo resists and long-life elastomers have in common? In many cases, you’ll find fluorine in them. Why did this once-exotic, highly reactive element become so important?
There are many reasons why organic compounds are fluorinated, most of which may be understood in terms of fluorine’s unique atomic properties. Fluorine is the most electronegative of all elements and it has one of the highest ionization potentials. The low polarizability and relatively small size of the fluorine atom also affect electronic and bonding properties.
Many physical and spectroscopic properties are affected by these factors, including boiling point, dielectric constant, surface tension, density, viscosity, critical temperature and UV absorption. Fluorination can dramatically alter the solvent properties of an organic molecule. Lipophilicity, which is an important property in biological systems, may be dramatically affected by fluorination, particularly when the fluorine is placed near a heteroatom in the molecule.
Another significant aspect of fluorine’s influence, particularly for biological systems, is its relatively small size. Fluorine is considered to be roughly equal in size to a hydroxyl group, thus the replacement of an OH group with a fluorine atom in a molecule can lead to major changes in the compound’s reactivity without significantly changing the fundamental size or shape of the molecule.
The acidity of acids, alcohols, amides and most C-H acids increases with the addition of fluorine or fluorinated groups to a molecule, and can be quite large. For the same reasons, the basicity of almost all amines, ethers and carbonyl compounds is reduced by the addition of fluorine or fluorinated groups to the molecule. Fluorination often leads to greater thermal and oxidative stability for the resultant compound, as well as greater resistance to many common nucleophilic reactions.
All of these properties have been used to design molecules for advanced applications, particularly in the last few decades.
In the pharmaceutical and agrochemical fields, the rapid increase in biologically active fluorinated compounds has come about because of a greater understanding of the impact of fluorine on the physical and chemical properties of organic molecules. This trend has been aided by the development of new synthetic methodologies and fluorinated reagents for incorporating fluorine or fluorinated substituents into the desired framework. Fluorinated compounds have shown efficacy as antibacterials, antifungicides, antibiotics, protease inhibitors and anticancer agents, among many other applications. Fluorinated compounds are widely used as fungicides, herbicides, and insecticides, and often show significantly more potency than their non-fluorinated analogues. The increased potency allows lower application rates.
One of the most striking pharmaceutical applications of fluorine substitution has been found in fluorinated inhalation anesthetics. Fluorination of ethers and other small molecules with anesthetic properties was initially pursued in an effort to reduce flammability and minimize side effects shown by old agents such as diethyl ether. Halothane was one the first of these fluorinated compounds and rapidly gained widespread use throughout the medical world. More recent fluorinated anesthetics such as isoflurane, sevoflurane and desflurane exhibit improved properties such as fast uptake and elimination, reduced metabolism to toxic species and stability to various conditions found in the anesthetic environment.
Historically, refrigerants, foam blowing agents, solvents and polymers have been the high volume fluorinated products. Originally, chlorofluorocarbon (CFC) and hydrochlorofluorocarbon (HCFC) refrigerants, foam blowing agents and solvents were popular because they were nonflammable, non-toxic, thermally stable and gave good efficiency. With the discovery that these compounds depleted the earth’s ozone layer because of their chlorine content and stability, hydrofluorocarbon (HFC) replacements were developed. Environmentally friendly with essentially the same performance benefits as the CFCs and HCFCs, they continue to be high volume products containing fluorine.
Fluorinated polymers are widely used in industry for a large number of applications, and typically are prepared by free-radical polymerization. Highly fluorinated polymers possess high thermal and chemical stability, solvent resistance, low flammability, low moisture absorption, low surface tension/energy, low dielectric constant and excellent weatherability, among many unique properties. Use of less fluorinated monomers leads to modifications of these physical properties in the resultant polymers. Replacement of fluorine with chlorine leads to materials with better mechanical and melt-processing properties, but lowers thermal and chemical resistance. Further modification of physical properties is accomplished by a variety of techniques.
Among the many applications found commercially, fluoropolymers are used as coatings, vessel liners, films, wiring insulation, gaskets, seals, lab equipment and hoses. Fluoropolymers find wide use in the ultra-high purity processing done by the semiconductor industry. They are also used as containers, non-stick additives in inks, finishes and lubricants. Fluoroelastomers are prepared from the some of the same monomers as the fluoropolymers, but are not crystalline and derive their structural strength from cross-linking. They are usually employed in sealing applications, particularly in hostile environments such as aircraft, chemical and petroleum plants, and long-life automotive systems.
The chlorofluoropolymers are used in chemical processing equipment such as gaskets and valve seats. Due to the low gas permeability of films made from this material, it is used in packaging air- and moisture-sensitive materials like drugs. The lower molecular weight polymers are widely used for lubrication in aggressive environments where the use of hydrocarbon lubricants is dangerous. They are available as oils, greases and waxes. The chemical and cryogenic gas industries use a great deal of these lubricants in a variety of processing equipment. Modern aircraft can use the oils as nonflammable hydraulic fluids.
Other applications for fluoropolymers include membrane systems, typically ion-exchange membranes, for enhanced chemical and thermal stability in harsh environments. Many of the fuel cell technologies being developed today for automobiles use fluoropolymer membranes.
A relatively new area of interest for fluorinated polymers has grown out of the drive to develop materials for 157 nm optical lithography, particularly photoresists. These photoresists will be required to get smaller features on future generation semiconductor chips. To date, photoresist polymers incorporating fluorine and/or fluorinated substituents have been found to exhibit the best combination of optical transparency at 157 nm, etch resistance and solubility properties. An enormous amount of resources by many companies and research groups has gone into developing fluoropolymers with the desired properties and many different synthetic strategies have evolved that use a variety of fluorinated monomers.
Fluorinated surfactants are widely used as emulsifying and dispersing agents, while related compounds are used as repellant finishes or soil-release finishes for textiles. These compounds depend on the ability of fluorine to alter surface-energy properties to be effective.
Many of the basic fluoro-organic “building blocks” for these products are made using either hydrogen fluoride or elemental fluorine. Hydrogen fluoride (HF) is less reactive but cheaper. While HF and fluorine are very useful as sources of fluorine, they are quite hazardous and require special handling procedures and strict use of personal protective equipment (PPE). Any exposure to HF or fluorine must be taken very seriously because of the danger of hypocalcemia, which is the depletion of calcium in the body caused by its precipitation with fluoride ions. Fluoride ions readily penetrate the skin. Untreated exposure can lead to death. HF solutions as dilute as 2% can cause skin or eye burns and untreated burns about the size of one’s palm may also result in death. HF and fluorine burns are among the few that require chemical treatment, which must be done to neutralize the fluoride ions. The specialized treatment may include iced neutralizing chemical soaks, injections and nebulizers if exposure is by inhalation.
Additionally, some of the fluorinated products are toxic also. In particular, mono fluoroacetates and a variety of fluoro and fluorochloro olefins are quite toxic.
Fluorine and HF are also difficult to handle. Commercially, fluorine is often handled diluted to 20% with nitrogen gas but even at this concentration, the most reactive element can react explosively with organic materials including polytetrafluoroethylene (PTFE). Fluorine in dilute and pure form is usually handled in metals such as Monel 400 and nickel. The formation and maintenance of a passivating fluoride layer that inhibits further corrosion is important.
Hydrogen fluoride is relatively easier to handle but is still one of the most corrosive compounds that a typical chemical plant will have to deal with. At room temperature, certain grades of carbon steels and stainless steels can handle anhydrous HF. However, routine inspections must be carried out on carbon steel vessels to look for corrosion and, in particular, hydrogen blistering. These blisters are formed when iron fluoride is formed at the wall of the vessel and the liberated hydrogen atom migrates into the steel and joins with another hydrogen atom. The resulting hydrogen molecule is too large to migrate further and the hydrogen gas accumulates. Amazingly high pressure builds and the blister that forms is enough to split the wall of the vessel.
At high temperatures, more exotic alloys are required. Depending on conditions, Monel 400 is probably best all round but Hastelloy C276, Inconel 600 or Alloy 20 may be needed.
Materials for aqueous HF service depend on concentration and temperature. The alloys mentioned above have some utility as well as fluorinated plastics and polypropylene.
Glass and silica-based ceramics or silica containing alloys are never suitable for fluorine or HF service.