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Some important organofluorine compounds. A: fluoromethane
B: isoflurane
C: a CFC
D: an HFC
E: triflic acid
F: Teflon
G: PFOS
H: fluorouracil
I: fluoxetine

Organofluorine chemistry describes the chemistry of organofluorine compounds, organic compounds that contain a carbon–fluorine bond. Organofluorine compounds find diverse applications ranging from oil and water repellents to pharmaceuticals, refrigerants, and reagents in catalysis. In addition to these applications, some organofluorine compounds are pollutants because of their contributions to ozone depletion, global warming, bioaccumulation, and toxicity. The area of organofluorine chemistry often requires special techniques associated with the handling of fluorinating agents.

The carbon–fluorine bond

Fluorine has several distinctive differences from all other substituents encountered in organic molecules. As a result, the physical and chemical properties of organofluorines can be distinctive in comparison to other organohalogens.

The carbon–fluorine bond is one of the strongest in organic chemistry (an average bond energy around 480 kJ/mol^[1]). This is significantly stronger than the bonds of carbon with other halogens (an average bond energy of e.g. C-Cl bond is around 320 kJ/mol^[1]) and is one of the reasons why fluoroorganic compounds have high thermal and chemical stability.
The carbon–fluorine bond is relatively short (around 1.4 Å^[1]).
The Van der Waals radius of the fluorine substituent is only 1.47 Å,^[1] which is shorter than in any other substituent and is close to that of hydrogen (1.2 Å). This, together with the short bond length, is the reason why there is no steric strain in polyfluorinated compounds. This is another reason for their high thermal stability. In addition, the fluorine substituents in polyfluorinated compounds efficiently shield the carbon skeleton from possible attacking reagents. This is another reason for the high chemical stability of polyfluorinated compounds.
Fluorine has the highest electronegativity of all elements: 3.98.^[1] This causes the high dipole moment of C-F bond (1.41 D^[1]).
Fluorine has the lowest polarizability of all atoms: 0.56 $\times$ 10⁻²⁴ cm³.^[1] This causes very weak dispersion forces between polyfluorinated molecules and is the reason for the often-observed boiling point reduction on fluorination as well as for the simultaneous hydrophobicity and lipophobicity of polyfluorinated compounds whereas other perhalogenated compounds are more lipophilic.

In comparison to aryl chlorides and bromides, aryl fluorides form Grignard reagents only reluctantly.^{[citation needed]} On the other hand, aryl fluorides, e.g. fluoroanilines and fluorophenols, often undergo nucleophilic substitution efficiently.^[2]

Types of organofluorine compounds

Fluorocarbons

Formally, fluorocarbons only contain carbon and fluorine. Sometimes they are called perfluorocarbons. They can be gases, liquids, waxes, or solids, depending upon their molecular weight. The simplest fluorocarbon is the gas tetrafluoromethane (CF₄). Liquids include perfluorooctane and perfluorodecalin. While fluorocarbons with single bonds are stable, unsaturated fluorocarbons are more reactive, especially those with triple bonds. Fluorocarbons are more chemically and thermally stable than hydrocarbons, reflecting the relative inertness of the C-F bond. They are also relatively lipophobic. Because of the reduced intermolecular van der Waals interactions, fluorocarbon-based compounds are sometimes used as lubricants or are highly volatile. Fluorocarbon liquids have medical applications as oxygen carriers.^{[citation needed]}

The structure of organofluorine compounds can be distinctive. As shown below, perfluorinated aliphatic compounds tend to segregate from hydrocarbons. This "like dissolves like effect" is related to the usefulness of fluorous phases and the use of PFOA in processing of fluoropolymers. In contrast to the aliphatic derivatives, perfluoroaromatic derivatives tend to form mixed phases with nonfluorinated aromatic compounds, resulting from donor-acceptor interactions between the pi-systems.

Fluoropolymers

Polymeric organofluorine compounds are numerous and commercially significant. They range from fully fluorinated species, e.g. PTFE to partially fluorinated, e.g. polyvinylidene fluoride ([CH₂CF₂]_n) and polychlorotrifluoroethylene ([CFClCF₂]_n). The fluoropolymer polytetrafluoroethylene (PTFE/Teflon) is a solid.^{[citation needed]}

Hydrofluorocarbons

Hydrofluorocarbons (HFCs), organic compounds that contain fluorine and hydrogen atoms, are the most common type of organofluorine compounds. They are commonly used in air conditioning and as refrigerants^[5] in place of the older chlorofluorocarbons such as R-12 and hydrochlorofluorocarbons such as R-21. They do not harm the ozone layer as much as the compounds they replace; however, they do contribute to global warming. Their atmospheric concentrations and contribution to anthropogenic greenhouse gas emissions are rapidly increasing, causing international concern about their radiative forcing.

Fluorocarbons with few C-F bonds behave similarly to the parent hydrocarbons, but their reactivity can be altered significantly. For example, both uracil and 5-fluorouracil are colourless, high-melting crystalline solids, but the latter is a potent anti-cancer drug. The use of the C-F bond in pharmaceuticals is predicated on this altered reactivity.^[6] Several drugs and agrochemicals contain only one fluorine center or one trifluoromethyl group.

Unlike other greenhouse gases in the Paris Agreement, hydrofluorocarbons have other international negotiations.^[7]

In September 2016, the so-called New York Declaration urged a global reduction in the use of HFCs.^[8] On 15 October 2016, due to these chemicals contribution to climate change, negotiators from 197 nations meeting at the summit of the United Nations Environment Programme in Kigali, Rwanda reached a legally-binding accord to phase out hydrofluorocarbons (HFCs) in an amendment to the Montreal Protocol.^[9]^[10]^[11]

Fluorocarbenes

As indicated throughout this article, fluorine-substituents lead to reactivity that differs strongly from classical organic chemistry. The premier example is difluorocarbene, CF₂, which is a singlet whereas carbene (CH₂) has a triplet ground state.^[12] This difference is significant because difluorocarbene is a precursor to tetrafluoroethylene.

Perfluorinated compounds

Perfluorinated compounds are fluorocarbon derivatives, as they are closely structurally related to fluorocarbons. However, they also possess new atoms such as nitrogen, iodine, or ionic groups, such as perfluorinated carboxylic acids.

Methods for preparation of C–F bonds

Organofluorine compounds are prepared by numerous routes, depending on the degree and regiochemistry of fluorination sought and the nature of the precursors. The direct fluorination of hydrocarbons with F₂, often diluted with N₂, is useful for highly fluorinated compounds:

R
₃CH + F
₂ → R
₃CF + HF

Such reactions however are often unselective and require care because hydrocarbons can uncontrollably "burn" in F
₂, analogous to the combustion of hydrocarbon in O
₂. For this reason, alternative fluorination methodologies have been developed. Generally, such methods are classified into two classes.

Electrophilic fluorination

Electrophilic fluorination rely on sources of "F⁺". Often such reagents feature N-F bonds, for example F-TEDA-BF₄. Asymmetric fluorination, whereby only one of two possible enantiomeric products are generated from a prochiral substrate, rely on electrophilic fluorination reagents.^[13] Illustrative of this approach is the preparation of a precursor to anti-inflammatory agents:^[14]

Electrosynthetic methods

A specialized but important method of electrophilic fluorination involves electrosynthesis. The method is mainly used to perfluorinate, i.e. replace all C–H bonds by C–F bonds. The hydrocarbon is dissolved or suspended in liquid HF, and the mixture is electrolyzed at 5–6 V using Ni anodes.^[15] The method was first demonstrated with the preparation of perfluoropyridine (C
₅F
₅N) from pyridine (C
₅H
₅N). Several variations of this technique have been described, including the use of molten potassium bifluoride or organic solvents.

Nucleophilic fluorination

The major alternative to electrophilic fluorination is nucleophilic fluorination using reagents that are sources of "F⁻," for Nucleophilic displacement typically of chloride and bromide. Metathesis reactions employing alkali metal fluorides are the simplest.^[16] For aliphatic compounds this is sometimes called the Finkelstein reaction, while for aromatic compounds it is known as the Halex process.

R
₃CCl + MF → R
₃CF + MCl (M = Na, K, Cs)

Alkyl monofluorides can be obtained from alcohols and Olah reagent (pyridinium fluoride) or another fluoridating agents.

The decomposition of aryldiazonium tetrafluoroborates in the Sandmeyer^[17] or Schiemann reactions exploit fluoroborates as F⁻ sources.

ArN
₂BF
₄ → ArF + N
₂ + BF
₃

Although hydrogen fluoride may appear to be an unlikely nucleophile, it is the most common source of fluoride in the synthesis of organofluorine compounds. Such reactions are often catalysed by metal fluorides such as chromium trifluoride. 1,1,1,2-Tetrafluoroethane, a replacement for CFC's, is prepared industrially using this approach:^[18]

Cl₂C=CClH + 4 HF → F₃CCFH₂ + 3 HCl

Notice that this transformation entails two reaction types, metathesis (replacement of Cl⁻ by F⁻) and hydrofluorination of an alkene.

Deoxofluorination

Deoxofluorination convert a variety of oxygen-containing groups into fluorides. The usual reagent is sulfur tetrafluoride:

RCO₂H + SF₄ → RCF₃ + SO₂ + HF

A more convenient alternative to SF₄ is the diethylaminosulfur trifluoride, which is a liquid whereas SF₄ is a corrosive gas:^[19]^[20]

C₆H₅CHO + R₂NSF₃ → C₆H₅CHF₂ + "R₂NSOF"

Apart from DAST, a wide variety of similar reagents exist, including, but not limited to, 2-pyridinesulfonyl fluoride (PyFluor) and N-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor).^[21] Many of these display improved properties such as better safety profile, higher thermodynamic stability, ease of handling, high enantioselectivity, and selectivity over elimination side-reactions.^[22]^[23]

From fluorinated building blocks

Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. (Trifluoromethyl)trimethylsilane, CF₃Si(CH₃)₃, is used as a source of the trifluoromethyl group, for example.^[24] Among the available fluorinated building blocks are CF₃X (X = Br, I), C₆F₅Br, and C₃F₇I. These species form Grignard reagents that then can be treated with a variety of electrophiles. The development of fluorous technologies (see below, under solvents) is leading to the development of reagents for the introduction of "fluorous tails".

A special but significant application of the fluorinated building block approach is the synthesis of tetrafluoroethylene, which is produced on a large-scale industrially via the intermediacy of difluorocarbene. The process begins with the thermal (600-800 °C) dehydrochlorination of chlorodifluoromethane:^[6]

CHClF₂ → CF₂ + HCl

2 CF₂ → C₂F₄

Sodium fluorodichloroacetate (CAS# 2837-90-3) is used to generate chlorofluorocarbene, for cyclopropanations.

¹⁸F-Delivery methods

The usefulness of fluorine-containing radiopharmaceuticals in ¹⁸F-positron emission tomography has motivated the development of new methods for forming C–F bonds. Because of the short half-life of ¹⁸F, these syntheses must be highly efficient, rapid, and easy.^[25] Illustrative of the methods is the preparation of fluoride-modified glucose by displacement of a triflate by a labeled fluoride nucleophile:

Biological role

Biologically synthesized organofluorines have been found in microorganisms and plants, but not animals.^[26] The most common example is fluoroacetate, which occurs as a plant defence against herbivores in at least 40 plants in Australia, Brazil and Africa.^[27] Other biologically synthesized organofluorines include ω-fluoro fatty acids, fluoroacetone, and 2-fluorocitrate which are all believed to be biosynthesized in biochemical pathways from the intermediate fluoroacetaldehyde.^[26] Adenosyl-fluoride synthase is an enzyme capable of biologically synthesizing the carbon–fluorine bond.^[28]

Applications

Organofluorine chemistry impacts many areas of everyday life and technology. The C-F bond is found in pharmaceuticals, agrichemicals, fluoropolymers, refrigerants, surfactants, anesthetics, oil-repellents, catalysis, and water-repellents, among others.

Pharmaceuticals and agrochemicals

The carbon-fluorine bond is commonly found in pharmaceuticals and agrochemicals. An estimated 1/5 of pharmaceuticals contain fluorine, including several of the top drugs.^[29]^[30] Examples include 5-fluorouracil, flunitrazepam (Rohypnol), fluoxetine (Prozac), paroxetine (Paxil), ciprofloxacin (Cipro), mefloquine, and fluconazole. Introducing the carbon–fluorine bond to organic compounds is the major challenge for medicinal chemists using organofluorine chemistry, as the carbon–fluorine bond increases the probability of having a successful drug by about a factor of ten.^[30] Over half of agricultural chemicals contain C-F bonds. A common example is trifluralin.^[31] The effectiveness of organofluorine compounds is attributed to their metabolically stability, i.e. they are not degraded rapidly so remain active. Also, fluorine acts as a bioisostere of the hydrogen atom.

Inhaler propellant

Fluorocarbons are also used as a propellant for metered-dose inhalers used to administer some asthma medications. The current generation of propellant consists of hydrofluoroalkanes (HFA), which have replaced CFC-propellant-based inhalers. CFC inhalers were banned as of 2008^[update] as part of the Montreal Protocol^[32] because of environmental concerns with the ozone layer. HFA propellant inhalers like FloVent and ProAir ( Salbutamol ) have no generic versions available as of October 2014.

Fluorosurfactants

Fluorosurfactants, which have a polyfluorinated "tail" and a hydrophilic "head", serve as surfactants because they concentrate at the liquid-air interface due to their lipophobicity. Fluorosurfactants have low surface energies and dramatically lower surface tension. The fluorosurfactants perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) are two of the most studied because of their ubiquity, proposed toxicity, and long residence times in humans and wildlife.

Triphenylphosphine has been modified by attachment of perfluoroalkyl substituents that confer solubility in perfluorohexane as well as supercritical carbon dioxide. As a specific example, [(C₈F₁₇C₃H₆-4-C₆H₄)₃P.^[33]

Solvents

Fluorinated compounds often display distinct solubility properties. Dichlorodifluoromethane and chlorodifluoromethane were at one time widely used refrigerants. CFCs have potent ozone depletion potential due to the homolytic cleavage of the carbon-chlorine bonds; their use is largely prohibited by the Montreal Protocol. Hydrofluorocarbons (HFCs), such as tetrafluoroethane, serve as CFC replacements because they do not catalyze ozone depletion.

Oxygen exhibits a high solubility in perfluorocarbon compounds, reflecting on their lipophilicity. Perfluorodecalin has been demonstrated as a blood substitute transporting oxygen to the lungs. Fluorine-substituted ethers are volatile anesthetics, including the commercial products methoxyflurane, enflurane, isoflurane, sevoflurane and desflurane. Fluorocarbon anesthetics reduce the hazard of flammability with diethyl ether and cyclopropane. Perfluorinated alkanes are used as blood substitutes.

The solvent 1,1,1,2-tetrafluoroethane has been used for extraction of natural products such as taxol, evening primrose oil, and vanillin. 2,2,2-trifluoroethanol is an oxidation-resistant polar solvent.^[34]

Organofluorine reagents

The development of organofluorine chemistry has contributed many reagents of value beyond organofluorine chemistry. Triflic acid (CF₃SO₃H) and trifluoroacetic acid (CF₃CO₂H) are useful throughout organic synthesis. Their strong acidity is attributed to the electronegativity of the trifluoromethyl group that stabilizes the negative charge. The triflate-group (the conjugate base of the triflic acid) is a good leaving group in substitution reactions.

Fluorocarbon substituents can enhance the Lewis acidity of metal centers. A premier example is "Eufod," a coordination complex of europium(III) that features a perfluoroheptyl modified acetylacetonate ligand. This and related species are useful in organic synthesis and as "shift reagents" in NMR spectroscopy.

Fluorous phases

Highly fluorinated substituents, e.g. perfluorohexyl (C₆F₁₃) confer distinctive solubility properties to molecules, which facilitates purification of products in organic synthesis.^[35]^[36] This area, described as "fluorous chemistry," exploits the concept of like-dissolves-like in the sense that fluorine-rich compounds dissolve preferentially in fluorine-rich solvents. Because of the relative inertness of the C-F bond, such fluorous phases are compatible with harsh reagents. This theme has spawned techniques of "fluorous tagging and fluorous protection. Illustrative of fluorous technology is the use of fluoroalkyl-substituted tin hydrides for reductions, the products being easily separated from the spent tin reagent by extraction using fluorinated solvents.^[37]

Hydrophobic fluorinated ionic liquids, such as organic salts of bistriflimide or hexafluorophosphate, can form phases that are insoluble in both water and organic solvents, producing multiphasic liquids.

Fluorine-containing compounds are often featured in noncoordinating or weakly coordinating anions. Both tetrakis(pentafluorophenyl)borate, B(C₆F₅)₄⁻, and the related tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, are useful in Ziegler-Natta catalysis and related alkene polymerization methodologies. The fluorinated substituents render the anions weakly basic and enhance the solubility in weakly basic solvents, which are compatible with strong Lewis acids.

Materials science

Organofluorine compounds enjoy many niche applications in materials science. With a low coefficient of friction, fluid fluoropolymers are used as specialty lubricants. Fluorocarbon-based greases are used in demanding applications. Representative products include Fomblin and Krytox, made by Solvay Solexis and DuPont, respectively. Certain firearm lubricants such as "Tetra Gun" contain fluorocarbons. Capitalizing on their nonflammability, fluorocarbons are used in fire fighting foam. Organofluorine compounds are components of liquid crystal displays. The polymeric analogue of triflic acid, nafion is a solid acid that is used as the membrane in most low temperature fuel cells. The bifunctional monomer 4,4'-difluorobenzophenone is a precursor to PEEK-class polymers.

Biosynthesis of organofluorine compounds

In contrast to the many naturally-occurring organic compounds containing the heavier halides, chloride, bromide, and iodide, only a handful of biologically synthesized carbon-fluorine bonds are known.^[38] The most common natural organofluorine species is fluoroacetate, a toxin found in a few species of plants. Others include fluorooleic acid, fluoroacetone, nucleocidin (4'-fluoro-5'-O-sulfamoyladenosine), fluorothreonine, and 2-fluorocitrate. Several of these species are probably biosynthesized from fluoroacetaldehyde. The enzyme fluorinase catalyzed the synthesis of 5'-deoxy-5'-fluoroadenosine (see scheme to right).

History

Organofluorine chemistry began in the 1800s with the development of organic chemistry.^[18]^[39] The first organofluorine compound was discovered in 1835, when Dumas and Péligot distilled dimethyl sulfate with potassium fluoride and got fluoromethane.^[39]^[40] In 1862, Alexander Borodin pioneered a now-common method of halogen exchange: he acted on benzoyl chloride with potassium bifluoride and first synthesized benzoyl fluoride.^[39]^[41] Besides salts, organofluorine compounds were often prepared using HF as the F⁻ source because elemental fluorine, as its discoverer Henri Moissan and his followers found out, was prone to explosions when mixed with organics.^[39] Frédéric Swarts also introduced antimony fluoride in this role in 1898.^[39]^[42]

The nonflammability and nontoxicity of the chlorofluorocarbons CCl₃F and CCl₂F₂ attracted industrial attention in the 1920s. General Motors settled on these CFCs as refrigerants and had DuPont produce them via Swarts' method.^[39] In 1931, Bancroft and Wherty managed to solve fluorine's explosion problem by diluting it with inert nitrogen.^[39]

On April 6, 1938, Roy J. Plunkett a young research chemist who worked at DuPont's Jackson Laboratory in Deepwater, New Jersey, accidentally discovered polytetrafluoroethylene (PTFE).^[43]^[44]^[45] Subsequent major developments, especially in the US, benefited from expertise gained in the production of uranium hexafluoride.^[6] Starting in the late 1940s, a series of electrophilic fluorinating methodologies were introduced, beginning with CoF₃. Electrochemical fluorination ("electrofluorination") was announced, which Joseph H. Simons had developed in the 1930s to generate highly stable perfluorinated materials compatible with uranium hexafluoride.^[15] These new methodologies allowed the synthesis of C-F bonds without using elemental fluorine and without relying on metathetical methods.^{[citation needed]}

In 1957, the anticancer activity of 5-fluorouracil was described. This report provided one of the first examples of rational design of drugs.^[46] This discovery sparked a surge of interest in fluorinated pharmaceuticals and agrichemicals. The discovery of the noble gas compounds, e.g. XeF₄, provided a host of new reagents starting in the early 1960s. In the 1970s, fluorodeoxyglucose was established as a useful reagent in ¹⁸F positron emission tomography. In Nobel Prize-winning work, CFC's were shown to contribute to the depletion of atmospheric ozone. This discovery alerted the world to the negative consequences of organofluorine compounds and motivated the development of new routes to organofluorine compounds. In 2002, the first C-F bond-forming enzyme, fluorinase, was reported.^[47]

Environmental and health concerns

Only a few organofluorine compounds are acutely bioactive and highly toxic, such as fluoroacetate and perfluoroisobutene.^{[citation needed]}

Some organofluorine compounds pose significant risks and dangers to health and the environment. CFCs and HCFCs (hydrochlorofluorocarbon) deplete the ozone layer and are potent greenhouse gases. HFCs are potent greenhouse gases and are facing calls for stricter international regulation and phase out schedules as a fast-acting greenhouse emission abatement measure, as are perfluorocarbons (PFCs), and sulfur hexafluoride (SF₆).^{[citation needed]}

Because of the compound's effect on climate, the G-20 major economies agreed in 2013 to support initiatives to phase out use of HCFCs. They affirmed the roles of the Montreal Protocol and the United Nations Framework Convention on Climate Change in global HCFC accounting and reduction. The U.S. and China at the same time announced a bilateral agreement to similar effect.^[48]

Persistence and bioaccumulation

Because of the strength of the carbon–fluorine bond, many synthetic fluorocarbons and fluorocarbon-based compounds are persistent in the environment. Fluorosurfactants, such as PFOS and PFOA, are persistent global contaminants. Fluorocarbon based CFCs and tetrafluoromethane have been reported in igneous and metamorphic rock.^[26] PFOS is a persistent organic pollutant and may be harming the health of wildlife; the potential health effects of PFOA to humans are under investigation by the C8 Science Panel.

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^ Crombie A, Kim SY, Hadida S, Curran DP. "Synthesis of Tris(2-Perfluorohexylethyl)tin Hydride: A Highly Fluorinated Tin Hydride with Advantageous Features of Easy Purification". Organic Syntheses; Collected Volumes, vol. 10, p. 712.
^ O'Hagan D, Harper B (1999). "Fluorine-Containing Natural Products". Journal of Fluorine Chemistry. 100 (1–2): 127–133. Bibcode:1999JFluC.100..127O. doi:10.1016/S0022-1139(99)00201-8.
^ ^a ^b ^c ^d ^e ^f ^g Okazoe T (2009). "Overview on the history of organofluorine chemistry from the viewpoint of material industry". Proceedings of the Japan Academy. Series B, Physical and Biological Sciences. 85 (8): 276–289. Bibcode:2009PJAB...85..276O. doi:10.2183/pjab.85.276. PMC 3621566. PMID 19838009.
^ Crochard (París), Arago F, Gay-Lussac JL (1835). Annales de chimie et de physique (in French). Chez Crochard. p. 36.
^ s:fr:Page:Comptes rendus hebdomadaires des séances de l’Académie des sciences, tome 055, 1862.djvu/552
^ Belgique Académie royale des sciences, des lettres et des beaux-arts de (1898). Bulletins de l'Académie royale des sciences, des lettres et des beaux-arts de Belgique (in French). M. Hayez.{{cite book}}: CS1 maint: multiple names: authors list (link)
^ "Dr. Roy J. Plunkett: Discoverer of Fluoropolymers" (PDF). The Fluoropolymers Division Newsletter (Summer): 1–2. 1994. Archived from the original (PDF) on 2003-07-09.
^ "Roy J. Plunkett". Science History Institute. June 2016. Retrieved 21 February 2018.
^ Center for Oral History. "Roy J. Plunkett". Science History Institute. Retrieved 21 February 2018.
^ Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, et al. (March 1957). "Fluorinated pyrimidines, a new class of tumour-inhibitory compounds". Nature. 179 (4561): 663–666. Bibcode:1957Natur.179..663H. doi:10.1038/179663a0. PMID 13418758. S2CID 4296069.
^ O'Hagan D, Schaffrath C, Cobb SL, Hamilton JT, Murphy CD (March 2002). "Biochemistry: biosynthesis of an organofluorine molecule". Nature. 416 (6878): 279. Bibcode:2002Natur.416..279O. doi:10.1038/416279a. PMID 11907567. S2CID 4415511.
^ U.S. White House Press Secretary (September 6, 2013). "United States, China, and Leaders of G-20 Countries Announce Historic Progress Toward a Global Phase Down of HFCs". whitehouse.gov (Press release). Retrieved 2013-09-16 – via National Archives.

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[37] Crombie A, Kim SY, Hadida S, Curran DP. "Synthesis of Tris(2-Perfluorohexylethyl)tin Hydride: A Highly Fluorinated Tin Hydride with Advantageous Features of Easy Purification". Organic Syntheses; Collected Volumes, vol. 10, p. 712.

[38] O'Hagan D, Harper B (1999). "Fluorine-Containing Natural Products". Journal of Fluorine Chemistry. 100 (1–2): 127–133. Bibcode:1999JFluC.100..127O. doi:10.1016/S0022-1139(99)00201-8.

[tak-39] ^ ^a ^b ^c ^d ^e ^f ^g Okazoe T (2009). "Overview on the history of organofluorine chemistry from the viewpoint of material industry". Proceedings of the Japan Academy. Series B, Physical and Biological Sciences. 85 (8): 276–289. Bibcode:2009PJAB...85..276O. doi:10.2183/pjab.85.276. PMC 3621566. PMID 19838009.

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[41] s:fr:Page:Comptes rendus hebdomadaires des séances de l’Académie des sciences, tome 055, 1862.djvu/552

[42] Belgique Académie royale des sciences, des lettres et des beaux-arts de (1898). Bulletins de l'Académie royale des sciences, des lettres et des beaux-arts de Belgique (in French). M. Hayez.{{cite book}}: CS1 maint: multiple names: authors list (link)

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[44] "Roy J. Plunkett". Science History Institute. June 2016. Retrieved 21 February 2018.

[45] Center for Oral History. "Roy J. Plunkett". Science History Institute. Retrieved 21 February 2018.

[46] Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, et al. (March 1957). "Fluorinated pyrimidines, a new class of tumour-inhibitory compounds". Nature. 179 (4561): 663–666. Bibcode:1957Natur.179..663H. doi:10.1038/179663a0. PMID 13418758. S2CID 4296069.

[47] O'Hagan D, Schaffrath C, Cobb SL, Hamilton JT, Murphy CD (March 2002). "Biochemistry: biosynthesis of an organofluorine molecule". Nature. 416 (6878): 279. Bibcode:2002Natur.416..279O. doi:10.1038/416279a. PMID 11907567. S2CID 4415511.

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@@ Line 1: / Line 1: @@
 {{Short description|Study of chemical compounds containing fluorine-carbon bonds}}
+{{cs1 config|name-list-style=vanc|display-authors=6}}
 [[Image:Fluorocarbon-montage.svg|thumb|85px|Some important organofluorine compounds.
@@ Line 16: / Line 17: @@
 {{main|Carbon-fluorine bond}}
 Fluorine has several distinctive differences from all other substituents encountered in organic molecules. As a result, the physical and chemical properties of organofluorines can be distinctive in comparison to other [[organohalogens]].
-# The [[carbon–fluorine bond]] is one of the strongest in organic chemistry (an average bond energy around 480 kJ/mol<ref name="Kirsch">Kirsch, Peer ''Modern fluoroorganic chemistry: synthesis, reactivity, applications''. Wiley-VCH, 2004.</ref>). This is significantly stronger than the bonds of carbon with other halogens (an average bond energy of e.g. C-Cl bond is around 320 kJ/mol<ref name="Kirsch" />) and is one of the reasons why fluoroorganic compounds have high thermal and chemical stability.
+# The [[carbon–fluorine bond]] is one of the strongest in organic chemistry (an average bond energy around 480 kJ/mol<ref name="Kirsch">{{cite book | vauthors = Kirsch P | title = Modern fluoroorganic chemistry: synthesis, reactivity, applications | publisher = Wiley-VCH | date = 2004 }}</ref>). This is significantly stronger than the bonds of carbon with other halogens (an average bond energy of e.g. C-Cl bond is around 320 kJ/mol<ref name="Kirsch" />) and is one of the reasons why fluoroorganic compounds have high thermal and chemical stability.
 # The [[carbon–fluorine bond]] is relatively short (around 1.4 Å<ref name="Kirsch" />).
-# The [[Van der Waals radius]] of the fluorine substituent is only 1.47 Å,<ref name="Kirsch" /> which is shorter than in any other substituent and is close to that of hydrogen (1.2 Å). This, together with the short bond length, is the reason why there is no steric strain in polyfluorinated compounds. This is another reason for their high thermal stability. In addition, the fluorine substituents in polyfluorinated compounds efficiently shield the carbon skeleton from possible attacking reagents. This is another reason for the high chemical stability of polyfluorinated compounds.
+# The [[Van der Waals radius]] of the fluorine substituent is only 1.47 Å,<ref name="Kirsch" /> which is shorter than in any other substituent and is close to that of hydrogen (1.2 Å). This, together with the short bond length, is the reason why there is no [[Van der Wahls strain|steric strain]] in polyfluorinated compounds. This is another reason for their high thermal stability. In addition, the fluorine substituents in polyfluorinated compounds efficiently shield the carbon skeleton from possible attacking reagents. This is another reason for the high chemical stability of polyfluorinated compounds.
 # Fluorine has the highest [[electronegativity]] of all elements: 3.98.<ref name="Kirsch" /> This causes the high [[Bond dipole moment|dipole moment]] of C-F bond (1.41 D<ref name="Kirsch" />).
 # Fluorine has the lowest polarizability of all atoms: 0.56 <math>\times</math> 10<sup>−24</sup> cm<sup>3</sup>.<ref name="Kirsch" /> This causes very weak [[dispersion forces]] between polyfluorinated molecules and is the reason for the often-observed boiling point reduction on fluorination as well as for the simultaneous [[hydrophobicity]] and [[lipophobicity]] of polyfluorinated compounds whereas other perhalogenated compounds are more [[lipophilic]].
-In comparison to aryl chlorides and bromides, aryl fluorides form [[Grignard reagent]]s only reluctantly.  On the other hand, aryl fluorides, e.g. fluoro[[aniline]]s and fluoro[[phenol]]s, often undergo nucleophilic substitution efficiently.
+In comparison to aryl chlorides and bromides, aryl fluorides form [[Grignard reagent]]s only reluctantly.{{citation needed|date=March 2024}}  On the other hand, aryl fluorides, e.g. fluoro[[aniline]]s and fluoro[[phenol]]s, often undergo nucleophilic substitution efficiently.<ref>{{cite book | vauthors = Warren S, Wyatt P |title=Organic Synthesis: the disconnection approach|edition=2nd |publisher=Wiley|year=2008|pages=12–13}}</ref>
 ==Types of organofluorine compounds==
 ===Fluorocarbons===
+{{main|Perfluorocarbon}}
-Formally, [[fluorocarbon]]s only contain carbon and fluorine. Sometimes they are called perfluorocarbons. They can be gases, liquids, waxes, or solids, depending upon their molecular weight. The simplest fluorocarbon is the gas tetrafluoromethane (CF<sub>4</sub>). Liquids include perfluorooctane and perfluorodecalin. While fluorocarbons with single bonds are stable, unsaturated fluorocarbons are more reactive, especially those with triple bonds. [[Fluorocarbon]]s are more chemically and thermally stable than hydrocarbons, reflecting the relative inertness of the C-F bond. They are also relatively [[lipophobic]]. Because of the reduced intermolecular [[van der Waals force|van der Waals interactions]], fluorocarbon-based compounds are sometimes used as lubricants or are highly volatile. Fluorocarbon liquids have medical applications as oxygen carriers.
+Formally, [[fluorocarbon]]s only contain carbon and fluorine. Sometimes they are called perfluorocarbons. They can be gases, liquids, waxes, or solids, depending upon their molecular weight. The simplest fluorocarbon is the gas tetrafluoromethane (CF<sub>4</sub>). Liquids include perfluorooctane and perfluorodecalin. While fluorocarbons with single bonds are stable, unsaturated fluorocarbons are more reactive, especially those with triple bonds. [[Fluorocarbon]]s are more chemically and thermally stable than hydrocarbons, reflecting the relative inertness of the C-F bond. They are also relatively [[lipophobic]]. Because of the reduced intermolecular [[van der Waals force|van der Waals interactions]], fluorocarbon-based compounds are sometimes used as lubricants or are highly volatile. Fluorocarbon liquids have medical applications as oxygen carriers.{{citation needed|date=May 2023}}
 The structure of organofluorine compounds can be distinctive.  As shown below, perfluorinated aliphatic compounds tend to segregate from hydrocarbons.  This "like dissolves like effect" is related to the usefulness of fluorous phases and the use of [[PFOA]] in processing of fluoropolymers.  In contrast to the aliphatic derivatives, perfluoroaromatic derivatives tend to form mixed phases with nonfluorinated aromatic compounds, resulting from donor-acceptor interactions between the pi-systems.
-[[Image:Aliphatic Fluorocarbon.jpg|right|thumb|225px|Segregation of alkyl and perfluoroalkyl substituents.<ref>{{cite journal | doi = 10.1524/zkri.1996.211.12.945 |author1=J. Lapasset |author2=J. Moret |author3=M. Melas |author4=A. Collet |author5=M. Viguier |author6=H. Blancou | title = Crystal structure of 12,12,13,13,14,14,15,15,16,16,17,17,17-tridecafluoroheptadecan-1-ol, C<sub>17</sub>H<sub>23</sub>F<sub>13</sub>O | journal = [[Z. Kristallogr.]] | year = 1996 | volume = 211 | pages = 945–946 | issue = 12|bibcode = 1996ZK....211..945L }}[[Cambridge Structural Database|CSD]] entry TULQOG.</ref>]]
+[[Image:Aliphatic Fluorocarbon.jpg|right|thumb|225px|Segregation of alkyl and perfluoroalkyl substituents.<ref>{{cite journal | doi = 10.1524/zkri.1996.211.12.945 | vauthors = Lapasset J, Moret J, Melas M, Collet A, Viguier M, Blancou H | title = Crystal structure of 12,12,13,13,14,14,15,15,16,16,17,17,17-tridecafluoroheptadecan-1-ol, C<sub>17</sub>H<sub>23</sub>F<sub>13</sub>O | journal = [[Z. Kristallogr.]] | year = 1996 | volume = 211 | pages = 945–946 | issue = 12|bibcode = 1996ZK....211..945L }}[[Cambridge Structural Database|CSD]] entry TULQOG.</ref>]]
-[[Image:Aromatic Fluorocarbon.jpg|right|thumb|150px|Packing in a crystal pentafluorotolan (C<sub>6</sub>F<sub>5</sub>CCC<sub>6</sub>H<sub>5</sub>), illustrating the donor-acceptor interactions between the fluorinated and nonfluorinated rings.<ref>{{cite journal |author1=C.E. Smith |author2=P.S. Smith |author3=R.Ll. Thomas |author4=E.G. Robins |author5=J.C. Collings |author6=Chaoyang Dai |author7=A.J. Scott |author8=S. Borwick |author9=A.S. Batsanov |author10=S.W. Watt |author11=S.J. Clark |author12=C. Viney |author13=J.A.K. Howard |author14=W. Clegg |author15=T.B. Marder | title = Arene-perfluoroarene interactions in crystal engineering: structural preferences in polyfluorinated tolans | journal = [[J. Mater. Chem.]] | year = 2004 | volume = 14 | pages = 413 | doi = 10.1039/b314094f | issue = 3}} [[Cambridge Structural Database|CSD]] entry ASIJIV.</ref>]]
+[[Image:Aromatic Fluorocarbon.jpg|right|thumb|150px|Packing in a crystal pentafluorotolan (C<sub>6</sub>F<sub>5</sub>CCC<sub>6</sub>H<sub>5</sub>), illustrating the donor-acceptor interactions between the fluorinated and nonfluorinated rings.<ref>{{cite journal | vauthors = Smith CE, Smith PS, Thomas RL, Robins EG, Collings JC, Dai C, Scott AJ, Borwick S, Batsanov AS, Watt SW, Clark SJ, Viney C, Howard JA, Clegg W, Marder TB | title = Arene-perfluoroarene interactions in crystal engineering: structural preferences in polyfluorinated tolans | journal = [[J. Mater. Chem.]] | year = 2004 | volume = 14 | pages = 413–420 | doi = 10.1039/b314094f | issue = 3}} [[Cambridge Structural Database|CSD]] entry ASIJIV.</ref>]]
 ===Fluoropolymers===
+{{main|Fluoropolymer}}
-Polymeric organofluorine compounds are numerous and commercially significant. They range from fully fluorinated species, e.g. [[PTFE]] to partially fluorinated, e.g. [[polyvinylidene fluoride]] ([CH<sub>2</sub>CF<sub>2</sub>]<sub>n</sub>) and [[polychlorotrifluoroethylene]] ([CFClCF<sub>2</sub>]<sub>n</sub>).  The fluoropolymer polytetrafluoroethylene (PTFE/Teflon) is a solid.
+Polymeric organofluorine compounds are numerous and commercially significant. They range from fully fluorinated species, e.g. [[PTFE]] to partially fluorinated, e.g. [[polyvinylidene fluoride]] ([CH<sub>2</sub>CF<sub>2</sub>]<sub>n</sub>) and [[polychlorotrifluoroethylene]] ([CFClCF<sub>2</sub>]<sub>n</sub>).  The fluoropolymer polytetrafluoroethylene (PTFE/Teflon) is a solid.{{citation needed|date=May 2023}}
 ===Hydrofluorocarbons===
-{{main|Hydrofluorocarbon|l1=Hydrofluorocarbons}}
+{{main|Hydrofluorocarbon}}
 Hydrofluorocarbons (HFCs), organic compounds that contain fluorine and hydrogen atoms, are the most common type of organofluorine compounds. They are commonly used in [[air conditioning]] and as [[refrigerants]]<ref name="milman-2016">
-{{cite news | last = Milman | first = Oliver | title = 100 countries push to phase out potentially disastrous greenhouse gas | date = 22 September 2016 | work = The Guardian | location = London, UK | url = https://www.theguardian.com/environment/2016/sep/22/100-countries-phase-out-hydrofluorocarbons-greenhouse-gas | access-date = 2016-09-22}}</ref> in place of the older [[chlorofluorocarbon]]s such as [[Dichlorodifluoromethane|R-12]] and hydrochlorofluorocarbons such as [[Dichlorofluoromethane|R-21]]. They do not harm the ozone layer as much as the compounds they replace; however, they do contribute to [[global warming]]. Their atmospheric concentrations and contribution to [[anthropogenic greenhouse gas]] emissions are rapidly increasing, causing international concern about their [[radiative forcing]].
+{{cite news | vauthors = Milman O | title = 100 countries push to phase out potentially disastrous greenhouse gas | date = 22 September 2016 | work = The Guardian | location = London, UK | url = https://www.theguardian.com/environment/2016/sep/22/100-countries-phase-out-hydrofluorocarbons-greenhouse-gas | access-date = 2016-09-22}}</ref> in place of the older [[chlorofluorocarbon]]s such as [[Dichlorodifluoromethane|R-12]] and hydrochlorofluorocarbons such as [[Dichlorofluoromethane|R-21]]. They do not harm the ozone layer as much as the compounds they replace; however, they do contribute to [[global warming]]. Their atmospheric concentrations and contribution to [[anthropogenic greenhouse gas]] emissions are rapidly increasing, causing international concern about their [[radiative forcing]].
-Fluorocarbons with few C-F [[Chemical bond|bonds]] behave similarly to the parent hydrocarbons, but their reactivity can be altered significantly. For example, both [[uracil]] and [[5-fluorouracil]] are colourless, high-melting crystalline solids, but the latter is a potent anti-cancer drug.  The use of the C-F bond in pharmaceuticals is predicated on this altered reactivity.<ref name=Ullmann>G. Siegemund, W. Schwertfeger, A. Feiring, B. Smart, F. Behr, H. Vogel, B. McKusick "Fluorine Compounds, Organic" in "Ullmann's Encyclopedia of Industrial Chemistry" 2005, Wiley-VCH, Weinheim. {{doi|10.1002/14356007.a11_349}}</ref> Several drugs and [[agrochemical]]s contain only one fluorine center or one [[trifluoromethyl]] group.
+Fluorocarbons with few C-F [[Chemical bond|bonds]] behave similarly to the parent hydrocarbons, but their reactivity can be altered significantly. For example, both [[uracil]] and [[5-fluorouracil]] are colourless, high-melting crystalline solids, but the latter is a potent anti-cancer drug.  The use of the C-F bond in pharmaceuticals is predicated on this altered reactivity.<ref name=Ullmann>{{cite book | vauthors = Siegemund G, Schwertfeger W, Feiring A, Smart B, Behr F, Vogel H, McKusick B | chapter = Fluorine Compounds, Organic | title = Ullmann's Encyclopedia of Industrial Chemistry | date = 2005 | publisher = Wiley-VCH | location = Weinheim | doi = 10.1002/14356007.a11_349 | isbn = 978-3-527-30385-4 }}</ref> Several drugs and [[agrochemical]]s contain only one fluorine center or one [[trifluoromethyl]] group.
-Unlike other greenhouse gases in the [[Paris Agreement]], hydrofluorocarbons have other international negotiations.<ref>{{cite news |last=Davenport |first=Carol |date=July 23, 2016 |title=A Sequel to the Paris Climate Accord Takes Shape in Vienna |url=https://www.nytimes.com/2016/07/24/world/europe/vienna-sequel-paris-climate-accord.html |newspaper=NYT |access-date=17 August 2016}}</ref>
+Unlike other greenhouse gases in the [[Paris Agreement]], hydrofluorocarbons have other international negotiations.<ref>{{cite news | vauthors = Davenport C |date=July 23, 2016 |title=A Sequel to the Paris Climate Accord Takes Shape in Vienna |url=https://www.nytimes.com/2016/07/24/world/europe/vienna-sequel-paris-climate-accord.html |newspaper=NYT |access-date=17 August 2016}}</ref>
-In September 2016, the so-called New York Declaration urged a global reduction in the use of HFCs.<ref name="ny-declaration-on-hfcs-2016">{{cite web | title = The New York Declaration of the Coalition to Secure an Ambitious HFC Amendment | date = 22 September 2016 | publisher = US Department of State | location = Washington, DC | access-date = 2016-09-22 | url = https://2009-2017.state.gov/e/oes/rls/pr/2016/262236.htm}}</ref> On 15 October 2016, due to these chemicals contribution to [[global warming|climate change]], negotiators from 197 nations meeting at the summit of the [[United Nations Environment Programme]] in Kigali, Rwanda reached a legally-binding accord to phase out hydrofluorocarbons (HFCs) in an amendment to the [[Montreal Protocol]].<ref>Chris Johnston, Oliver Milman, John Vidal and agencies, [https://www.theguardian.com/environment/2016/oct/15/climate-change-environmentalists-hail-deal-to-limit-use-of-hydrofluorocarbons "Climate change: global deal reached to limit use of hydrofluorocarbons"], ''[[The Guardian]]'', Saturday 15 October 2016 (page visited on 15 October 2016).</ref><ref>{{cite web | url =https://www.bbc.co.uk/news/science-environment-37665529|title=Climate change: 'Monumental' deal to cut HFCs, fastest growing greenhouse gases|publisher=BBC News| date=15 October 2016| access-date =15 October 2016}}</ref><ref>{{cite web | url =https://www.nytimes.com/2016/10/15/world/africa/kigali-deal-hfc-air-conditioners.html?emc=edit_na_20161015&nlid=63247675&ref=cta&_r=0|title= Nations, Fighting Powerful Refrigerant That Warms Planet, Reach Landmark Deal|work=New York Times| date=15 October 2016| access-date=15 October 2016}}</ref>
+In September 2016, the so-called New York Declaration urged a global reduction in the use of HFCs.<ref name="ny-declaration-on-hfcs-2016">{{cite web | title = The New York Declaration of the Coalition to Secure an Ambitious HFC Amendment | date = 22 September 2016 | publisher = US Department of State | location = Washington, DC | access-date = 2016-09-22 | url = https://2009-2017.state.gov/e/oes/rls/pr/2016/262236.htm}}</ref> On 15 October 2016, due to these chemicals contribution to [[global warming|climate change]], negotiators from 197 nations meeting at the summit of the [[United Nations Environment Programme]] in Kigali, Rwanda reached a legally-binding accord to phase out hydrofluorocarbons (HFCs) in an amendment to the [[Montreal Protocol]].<ref>{{cite web | vauthors = Johnston C, Milman O, Vidal J | url = https://www.theguardian.com/environment/2016/oct/15/climate-change-environmentalists-hail-deal-to-limit-use-of-hydrofluorocarbons | title = Climate change: global deal reached to limit use of hydrofluorocarbons | work = [[The Guardian]] | date = 15 October 2016 }}</ref><ref>{{cite web | vauthors = McGrath M | url =https://www.bbc.co.uk/news/science-environment-37665529|title=Climate change: 'Monumental' deal to cut HFCs, fastest growing greenhouse gases|publisher=BBC News| date=15 October 2016| access-date =15 October 2016}}</ref><ref>{{cite web | url =https://www.nytimes.com/2016/10/15/world/africa/kigali-deal-hfc-air-conditioners.html?emc=edit_na_20161015&nlid=63247675&ref=cta&_r=0|title= Nations, Fighting Powerful Refrigerant That Warms Planet, Reach Landmark Deal|work=New York Times| date=15 October 2016| access-date=15 October 2016}}</ref>
 ===Fluorocarbenes===
-As indicated throughout this article, fluorine-substituents lead to reactivity that differs strongly from classical organic chemistry. The premier example is [[difluorocarbene]], CF<sub>2</sub>, which is a [[Singlet state|singlet]] whereas [[carbene]] (CH<sub>2</sub>) has a [[triplet state|triplet]] ground state.<ref>{{Cite journal |author1=Dana Lyn S. Brahms |author2=William P. Dailey | title = Fluorinated Carbenes | journal =  Chemical Reviews | doi = 10.1021/cr941141k | year = 1996 | volume = 96 | pages = 1585–1632 | pmid = 11848805 | issue = 5}}</ref>  This difference is significant because difluorocarbene is a precursor to [[tetrafluoroethylene]].
+As indicated throughout this article, fluorine-substituents lead to reactivity that differs strongly from classical organic chemistry. The premier example is [[difluorocarbene]], CF<sub>2</sub>, which is a [[Singlet state|singlet]] whereas [[carbene]] (CH<sub>2</sub>) has a [[triplet state|triplet]] ground state.<ref>{{cite journal | vauthors = Brahms DL, Dailey WP | title = Fluorinated Carbenes | journal = Chemical Reviews | volume = 96 | issue = 5 | pages = 1585–1632 | date = August 1996 | pmid = 11848805 | doi = 10.1021/cr941141k }}</ref>  This difference is significant because difluorocarbene is a precursor to [[tetrafluoroethylene]].
 ===Perfluorinated compounds===
@@ Line 55: / Line 58: @@
 ==Methods for preparation of C–F bonds==
-[[Organofluorine compounds]] are prepared by numerous routes, depending on the degree and regiochemistry of fluorination sought and the nature of the precursors.  The direct fluorination of hydrocarbons with F<sub>2</sub>, often diluted with N<sub>2</sub>, is useful for highly fluorinated compounds:
+Organofluorine compounds are prepared by numerous routes, depending on the degree and regiochemistry of fluorination sought and the nature of the precursors.  The direct fluorination of hydrocarbons with F<sub>2</sub>, often diluted with N<sub>2</sub>, is useful for highly fluorinated compounds:
 :{{chem|R|3|CH}} + {{chem|F|2}} → {{chem|R|3|CF}} + {{chem|HF}}
@@ Line 63: / Line 66: @@
 ===Electrophilic fluorination===
 {{see also|electrophilic fluorination}}
-Electrophilic fluorination rely on sources of "F<sup>+</sup>".  Often such reagents feature N-F bonds, for example [[F-TEDA-BF4|F-TEDA-BF<sub>4</sub>]].  Asymmetric fluorination, whereby only one of two possible enantiomeric products are generated from a prochiral substrate, rely on electrophilic fluorination reagents.<ref>{{cite journal | last1 = Brunet | first1 = Vincent A. | last2 = O'Hagan | first2 = David | year = 2008 | title = Catalytic Asymmetric Fluorination Comes of Age | journal = Angewandte Chemie International Edition | volume = 47 | pages = 1179–1182 | doi = 10.1002/anie.200704700 | pmid = 18161722 | issue = 7}}</ref>  Illustrative of this approach is the preparation of a precursor to anti-inflammatory agents:<ref>{{cite journal |author1=Stéphane Caron |author2=Robert W. Dugger |author3=Sally Gut Ruggeri |author4=John A. Ragan |author5=David H. Brown Ripin | title = Large-Scale Oxidations in the Pharmaceutical Industry | journal = [[Chemical Reviews]] | year = 2006 | volume = 106 | pages = 2943–2989 | doi = 10.1021/cr040679f | pmid = 16836305 | issue = 7}}</ref>
+Electrophilic fluorination rely on sources of "F<sup>+</sup>".  Often such reagents feature N-F bonds, for example [[F-TEDA-BF4|F-TEDA-BF<sub>4</sub>]].  Asymmetric fluorination, whereby only one of two possible enantiomeric products are generated from a prochiral substrate, rely on electrophilic fluorination reagents.<ref>{{cite journal | vauthors = Brunet VA, O'Hagan D | title = Catalytic asymmetric fluorination comes of age | journal = Angewandte Chemie | volume = 47 | issue = 7 | pages = 1179–1182 | year = 2008 | pmid = 18161722 | doi = 10.1002/anie.200704700 }}</ref>  Illustrative of this approach is the preparation of a precursor to anti-inflammatory agents:<ref>{{cite journal | vauthors = Caron S, Dugger RW, Ruggeri SG, Ragan JA, Ripin DH | title = Large-scale oxidations in the pharmaceutical industry | journal = Chemical Reviews | volume = 106 | issue = 7 | pages = 2943–2989 | date = July 2006 | pmid = 16836305 | doi = 10.1021/cr040679f }}</ref>
 :[[Image:SelectfluorRxn.png|480px|center]]
@@ Line 69: / Line 72: @@
 ====Electrosynthetic methods====
 {{main|Electrofluorination}}
-A specialized but important method of electrophilic fluorination involves [[electrosynthesis]].  The method is mainly used to perfluorinate, i.e. replace all C–H bonds by C–F bonds.  The hydrocarbon is dissolved or suspended in liquid HF, and the mixture is [[electrolysis|electrolyzed]] at 5–6 [[volt|V]] using Ni [[anodes]].<ref name=Simons>{{cite journal | last1 = Simons | first1 = J. H. | year = 1949 | title = The Electrochemical Process for the Production of Fluorocarbons | journal = Journal of the Electrochemical Society | volume = 95 | issue = 2| pages = 47–66 | doi = 10.1149/1.2776733 }}</ref>  The method was first demonstrated with the preparation of perfluoropyridine ({{chem|C|5|F|5|N}}) from [[pyridine]] ({{chem|C|5|H|5|N}}). Several variations of this technique have been described, including the use of molten [[potassium bifluoride]] or organic [[solvents]].
+A specialized but important method of electrophilic fluorination involves [[electrosynthesis]].  The method is mainly used to perfluorinate, i.e. replace all C–H bonds by C–F bonds.  The hydrocarbon is dissolved or suspended in liquid HF, and the mixture is [[electrolysis|electrolyzed]] at 5–6 [[volt|V]] using Ni [[anodes]].<ref name=Simons>{{cite journal | vauthors = Simons JH | year = 1949 | title = The Electrochemical Process for the Production of Fluorocarbons | journal = Journal of the Electrochemical Society | volume = 95 | issue = 2| pages = 47–66 | doi = 10.1149/1.2776733 }}</ref>  The method was first demonstrated with the preparation of perfluoropyridine ({{chem|C|5|F|5|N}}) from [[pyridine]] ({{chem|C|5|H|5|N}}). Several variations of this technique have been described, including the use of molten [[potassium bifluoride]] or organic [[solvents]].
 ===Nucleophilic fluorination===
-The major alternative to electrophilic fluorination is, naturally, nucleophilic fluorination using reagents that are sources of "F<sup>−</sup>," for [[Nucleophilic displacement]] typically of chloride and bromide.  [[Salt metathesis reaction|Metathesis]] reactions employing [[alkali metal]] fluorides are the simplest.<ref>{{OrgSynth  | author = Vogel, A. I.; Leicester, J.; Macey, W. A. T. | title = n-Hexyl Fluoride | collvol = 4 | collvolpages = 525 | prep = cv4p0525}}</ref> For aliphatic compounds this is sometimes called the [[Finkelstein reaction]], while for aromatic compounds it is known as the [[Halex process]].
+The major alternative to electrophilic fluorination is nucleophilic fluorination using reagents that are sources of "F<sup>−</sup>," for [[Nucleophilic displacement]] typically of chloride and bromide.  [[Salt metathesis reaction|Metathesis]] reactions employing [[alkali metal]] fluorides are the simplest.<ref>{{OrgSynth  | vauthors = Vogel AI, Leicester J, Macey WA | title = n-Hexyl Fluoride | collvol = 4 | collvolpages = 525 | prep = cv4p0525}}</ref> For aliphatic compounds this is sometimes called the [[Finkelstein reaction]], while for aromatic compounds it is known as the [[Halex process]].
 :{{chem|R|3|CCl}} + {{chem|MF}} → {{chem|R|3|CF}} + {{chem|MCl}} (M = Na, K, Cs)
@@ Line 78: / Line 81: @@
 Alkyl monofluorides can be obtained from alcohols and [[Olah reagent]] (pyridinium fluoride) or another fluoridating agents.
-The decomposition of aryldiazonium tetrafluoroborates  in the [[Sandmeyer reaction|Sandmeyer]]<ref>{{OrgSynth | author = Flood, D. T. | title = Fluorobenzene | collvol = 2 | collvolpages = 295 | prep = cv2p0295}}</ref> or [[Schiemann reaction]]s exploit [[fluoroborate]]s as F<sup>−</sup> sources.
+The decomposition of aryldiazonium tetrafluoroborates  in the [[Sandmeyer reaction|Sandmeyer]]<ref>{{OrgSynth | vauthors = Flood DT | title = Fluorobenzene | collvol = 2 | collvolpages = 295 | prep = cv2p0295}}</ref> or [[Schiemann reaction]]s exploit [[fluoroborate]]s as F<sup>−</sup> sources.
 :{{chem|ArN|2|BF|4}} → {{chem|ArF}} + {{chem|N|2}} + {{chem|BF|3}}
-Although [[hydrogen fluoride]] may appear to be an unlikely nucleophile, it is the most common source of fluoride in the synthesis of organofluorine compounds. Such reactions are often catalysed by metal fluorides such as chromium trifluoride. [[1,1,1,2-Tetrafluoroethane]], a replacement for CFC's, is prepared industrially using this approach:<ref name=Dobi>{{Cite journal | author = William R. Dolbier Jr. | title = Fluorine Chemistry at the Millennium | journal =  Journal of Fluorine Chemistry | doi = 10.1016/j.jfluchem.2004.09.033 | year = 2005 | volume = 126 | pages = 157–163 | issue = 2}}</ref>
+Although [[hydrogen fluoride]] may appear to be an unlikely nucleophile, it is the most common source of fluoride in the synthesis of organofluorine compounds. Such reactions are often catalysed by metal fluorides such as chromium trifluoride. [[1,1,1,2-Tetrafluoroethane]], a replacement for CFC's, is prepared industrially using this approach:<ref name=Dobi>{{Cite journal | vauthors = Dolbier Jr WR | title = Fluorine Chemistry at the Millennium | journal =  Journal of Fluorine Chemistry | doi = 10.1016/j.jfluchem.2004.09.033 | year = 2005 | volume = 126 | pages = 157–163 | issue = 2| bibcode = 2005JFluC.126..157D }}</ref>
 :[[Trichloroethylene|Cl<sub>2</sub>C=CClH]] + 4 HF → F<sub>3</sub>CCFH<sub>2</sub> + 3 HCl
 Notice that this transformation entails two reaction types, metathesis (replacement of Cl<sup>−</sup> by F<sup>−</sup>) and hydrofluorination of an [[alkene]].
 ===Deoxofluorination===
-Deoxofluorination agents effect the replacement [[hydroxyl]] and [[carbonyl]] groups with one and two fluorides, respectively. One such reagent, useful for fluoride for oxide exchange in carbonyl compounds, is [[sulfur tetrafluoride]]:
+[[Fluorination by sulfur tetrafluoride|Deoxofluorination]] convert a variety of oxygen-containing groups into fluorides. The usual reagent is [[sulfur tetrafluoride]]:
 :RCO<sub>2</sub>H + SF<sub>4</sub> → RCF<sub>3</sub> + [[Sulfur dioxide|SO<sub>2</sub>]] + HF
+A more convenient alternative to SF<sub>4</sub> is the [[diethylaminosulfur trifluoride]], which is a liquid whereas SF<sub>4</sub> is a corrosive gas:<ref name=March>{{March6th|page=1299}}</ref><ref>{{cite book|doi=10.1002/0471264180.or034.02 |chapter=Fluorination by Sulfur Tetrafluoride |title=Organic Reactions |date=1985 | vauthors = Wang CJ |pages=319–400 |isbn=978-0-471-26418-7 }}</ref>
-Alternates to SF<sub>4</sub> include the [[diethylaminosulfur trifluoride]] (DAST, NEt<sub>2</sub>SF<sub>3</sub>) and [[bis(2-methoxyethyl)aminosulfur trifluoride]] (deoxo-fluor). These organic reagents are easier to handle and more selective:<ref>{{cite journal |author1=Gauri S. Lal |author2=Guido P. Pez |author3=Reno J. Pesaresi |author4=Frank M. Prozonic | doi = 10.1039/a808517j | title =  Bis(2-methoxyethyl)aminosulfur trifluoride: a new broad-spectrum deoxofluorinating agent with enhanced thermal stability | year =  1999 | journal =  Chemical Communications | pages =  215–216 | issue =  2}}</ref>
+:{{chem2|C6H5CHO  +  R2NSF3  ->  C6H5CHF2  +  "R2NSOF"}}
+Apart from DAST, a wide variety of similar reagents exist, including, but not limited to, 2-pyridinesulfonyl fluoride (PyFluor) and ''N''-tosyl-4-chlorobenzenesulfonimidoyl fluoride (SulfoxFluor).<ref>{{cite journal | vauthors = Aggarwal T, Verma AK |title=Achievements in fluorination using variable reagents through a deoxyfluorination reaction |journal=Organic Chemistry Frontiers |date=2021 |volume=8 |issue=22 |pages=6452–6468 |doi=10.1039/D1QO00952D}}</ref> Many of these display improved properties such as better safety profile, higher thermodynamic stability, ease of handling, high enantioselectivity, and selectivity over elimination side-reactions.<ref>{{cite journal | vauthors = Nielsen MK, Ugaz CR, Li W, Doyle AG | title = PyFluor: A Low-Cost, Stable, and Selective Deoxyfluorination Reagent | journal = Journal of the American Chemical Society | volume = 137 | issue = 30 | pages = 9571–9574 | date = August 2015 | pmid = 26177230 | doi = 10.1021/jacs.5b06307 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Guo J, Kuang C, Rong J, Li L, Ni C, Hu J | title = Rapid Deoxyfluorination of Alcohols with N-Tosyl-4-chlorobenzenesulfonimidoyl Fluoride (SulfoxFluor) at Room Temperature | journal = Chemistry | volume = 25 | issue = 30 | pages = 7259–7264 | date = May 2019 | pmid = 30869818 | doi = 10.1002/chem.201901176 }}</ref>
-:[[Image:Deoxo-Fluor application.png|380px|center|bis(2-methoxyethyl)aminosulfur trifluoride reaction]]
 ===From fluorinated building blocks===
-Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. (Trifluoromethyl)trimethylsilane, CF<sub>3</sub>Si(CH<sub>3</sub>)<sub>3</sub>, is used as a source of the [[trifluoromethyl]] group, for example.<ref>{{OrgSynth | title = 1-trifluoromethyl)-1-cyclohexanol| author = Pichika Ramaiah, Ramesh Krishnamurti, and G. K. Surya Prakash | collvolume = 9 | pages = 232 | year = 1998 | prep = cv9P0711}}</ref>  Among the available fluorinated building blocks are CF<sub>3</sub>X (X = Br, I), C<sub>6</sub>F<sub>5</sub>Br, and C<sub>3</sub>F<sub>7</sub>I.  These species form [[Grignard reagents]] that then can be treated with a variety of [[electrophile]]s. The development of fluorous technologies (see below, under solvents) is leading to the development of reagents for the introduction of "fluorous tails".
+Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. (Trifluoromethyl)trimethylsilane, CF<sub>3</sub>Si(CH<sub>3</sub>)<sub>3</sub>, is used as a source of the [[trifluoromethyl]] group, for example.<ref>{{OrgSynth | title = 1-trifluoromethyl)-1-cyclohexanol| vauthors = Ramaiah P, Krishnamurti R, Surya Prakash GK | collvolume = 9 | pages = 232 | year = 1998 | prep = cv9P0711}}</ref>  Among the available fluorinated building blocks are CF<sub>3</sub>X (X = Br, I), C<sub>6</sub>F<sub>5</sub>Br, and C<sub>3</sub>F<sub>7</sub>I.  These species form [[Grignard reagents]] that then can be treated with a variety of [[electrophile]]s. The development of fluorous technologies (see below, under solvents) is leading to the development of reagents for the introduction of "fluorous tails".
 A special but significant application of the fluorinated building block approach is the synthesis of [[tetrafluoroethylene]], which is produced on a large-scale industrially via the intermediacy of difluorocarbene.  The process begins with the thermal (600-800&nbsp;°C) dehydrochlorination of [[chlorodifluoromethane]]:<ref name=Ullmann/>
@@ Line 102: / Line 106: @@
 ===<sup>18</sup>F-Delivery methods===
-The usefulness of fluorine-containing [[radiopharmaceutical]]s in <sup>18</sup>F-[[positron emission tomography]] has motivated the development of new methods for forming C–F bonds. Because of the short half-life of <sup>18</sup>F, these syntheses must be highly efficient, rapid, and easy.<ref>{{cite journal | author = Le Bars, D. | title = Fluorine-18 and Medical Imaging: Radiopharmaceuticals for Positron Emission Tomography | journal = [[Journal of Fluorine Chemistry]] | year = 2006 | volume = 127 | pages = 1488–1493 | doi = 10.1016/j.jfluchem.2006.09.015 | issue = 11}}.</ref> Illustrative of the methods is the preparation of [[fluoroglucose|fluoride-modified glucose]] by displacement of a [[triflate]] by a labeled fluoride nucleophile:
+The usefulness of fluorine-containing [[radiopharmaceutical]]s in <sup>18</sup>F-[[positron emission tomography]] has motivated the development of new methods for forming C–F bonds. Because of the short half-life of <sup>18</sup>F, these syntheses must be highly efficient, rapid, and easy.<ref>{{cite journal | vauthors = Le Bars D | title = Fluorine-18 and Medical Imaging: Radiopharmaceuticals for Positron Emission Tomography | journal = [[Journal of Fluorine Chemistry]] | year = 2006 | volume = 127 | pages = 1488–1493 | doi = 10.1016/j.jfluchem.2006.09.015 | issue = 11| bibcode = 2006JFluC.127.1488L }}</ref> Illustrative of the methods is the preparation of [[fluoroglucose|fluoride-modified glucose]] by displacement of a [[triflate]] by a labeled fluoride nucleophile:
 :[[Image:FDGprep.png|380px]]
 ==Biological role==
-Biologically synthesized organofluorines have been found in microorganisms and plants, but not animals.<ref name="Murphy2003">Murphy CD, Schaffrath C, O'Hagan D.: [https://www.ncbi.nlm.nih.gov/pubmed/12738270 "Fluorinated natural products: the biosynthesis of fluoroacetate and 4-fluorothreonine in ''Streptomyces cattleya''"] Chemosphere. 2003 Jul;52(2):455-61.</ref> The most common example is fluoroacetate, which occurs as a [[plant defence against herbivores]] in at least 40 plants in Australia, Brazil and Africa.<ref name="Proudfoot">{{cite journal |pages=213–9 |doi=10.2165/00139709-200625040-00002 |title=Sodium Fluoroacetate Poisoning |year=2006 |last1=Proudfoot |first1=Alex T |last2=Bradberry |first2=Sally M |last3=Vale |first3=J Allister |journal=Toxicological Reviews |volume=25 |issue=4 |pmid=17288493|s2cid=29189551 }}</ref> Other biologically synthesized organofluorines include ω-fluoro [[fatty acid]]s, [[fluoroacetone]], and [[fluorocitric acid|2-fluorocitrate]] which are all believed to be biosynthesized in biochemical pathways from the intermediate fluoroacetaldehyde.<ref name="Murphy2003" /> [[Adenosyl-fluoride synthase]] is an enzyme capable of biologically synthesizing the carbon–fluorine bond.<ref>{{cite journal |doi=10.1038/416279a |title=Biochemistry: Biosynthesis of an organofluorine molecule |year=2002 |last1=O'Hagan |first1=David |last2=Schaffrath |first2=Christoph |last3=Cobb |first3=Steven L. |last4=Hamilton |first4=John T. G. |last5=Murphy |first5=Cormac D. |journal=Nature |volume=416 |issue=6878 |pages=279 |pmid=11907567|bibcode=2002Natur.416..279O |s2cid=4415511 |doi-access=free }}</ref> Man made carbon–fluorine bonds are commonly found in pharmaceuticals and [[agrichemicals]] because it adds stability to the carbon framework; also, the relatively [[covalent radius of fluorine|small size]] of fluorine is convenient as fluorine acts as an approximate [[bioisostere]] of the hydrogen. Introducing the carbon–fluorine bond to organic compounds is the major challenge for medicinal chemists using organofluorine chemistry, as the carbon–fluorine bond increases the probability of having a successful drug by about a factor of ten.<ref name=Thayer>{{cite journal
+Biologically synthesized organofluorines have been found in microorganisms and plants, but not animals.<ref name="Murphy2003">Murphy CD, Schaffrath C, O'Hagan D.: [https://www.ncbi.nlm.nih.gov/pubmed/12738270 "Fluorinated natural products: the biosynthesis of fluoroacetate and 4-fluorothreonine in ''Streptomyces cattleya''"] Chemosphere. 2003 Jul;52(2):455-61.</ref> The most common example is [[fluoroacetate]], which occurs as a [[plant defence against herbivores]] in at least 40 plants in Australia, Brazil and Africa.<ref name="Proudfoot">{{cite journal | vauthors = Proudfoot AT, Bradberry SM, Vale JA | title = Sodium fluoroacetate poisoning | journal = Toxicological Reviews | volume = 25 | issue = 4 | pages = 213–219 | year = 2006 | pmid = 17288493 | doi = 10.2165/00139709-200625040-00002 | s2cid = 29189551 }}</ref> Other biologically synthesized organofluorines include ω-fluoro [[fatty acid]]s, [[fluoroacetone]], and [[fluorocitric acid|2-fluorocitrate]] which are all believed to be biosynthesized in biochemical pathways from the intermediate fluoroacetaldehyde.<ref name="Murphy2003" /> [[Adenosyl-fluoride synthase]] is an enzyme capable of biologically synthesizing the carbon–fluorine bond.<ref>{{cite journal | vauthors = O'Hagan D, Schaffrath C, Cobb SL, Hamilton JT, Murphy CD | title = Biochemistry: biosynthesis of an organofluorine molecule | journal = Nature | volume = 416 | issue = 6878 | pages = 279 | date = March 2002 | pmid = 11907567 | doi = 10.1038/416279a | s2cid = 4415511 | doi-access = free | bibcode = 2002Natur.416..279O }}</ref>
-| first=Ann M. |last=Thayer
-| date        =5 June 2006
-| title       =Fabulous Fluorine
-| journal     =Chemical & Engineering News
-| volume      =84
-| issue       =23
-| pages       =15–24
-| url         =http://pubs.acs.org/cen/coverstory/84/8423cover1.html
-| access-date  =17 January 2009
-|doi=10.1021/cen-v084n023.p015
-}}</ref> An estimated 20% of pharmaceuticals, and 30&ndash;40% of agrichemicals are organofluorines, including several of the top drugs.<ref name=Thayer/> Examples include [[5-fluorouracil]], [[fluoxetine]] (Prozac), [[paroxetine]] (Paxil), [[ciprofloxacin]] (Cipro), [[mefloquine]], and [[fluconazole]].
 ==Applications==
@@ Line 123: / Line 116: @@
 ===Pharmaceuticals and agrochemicals===
-The carbon-fluorine bond is commonly found in pharmaceuticals and agrochemicals because it is generally metabolically stable and fluorine acts as a [[bioisostere]] of the [[hydrogen]] atom. An estimated 1/5 of pharmaceuticals contain fluorine, including several of the top drugs.<ref>Ann M. Thayer "Fabulous Fluorine" Chemical and Engineering News, June 5, 2006, Volume 84, pp. 15-24.  http://pubs.acs.org/cen/coverstory/84/8423cover1.html</ref> Examples include [[5-fluorouracil]], [[flunitrazepam]] (Rohypnol), [[fluoxetine]] (Prozac), [[paroxetine]] (Paxil), [[ciprofloxacin]] (Cipro), [[mefloquine]], and [[fluconazole]]. Fluorine-substituted [[ethers]] are [[volatile anesthetic]]s, including the commercial products [[methoxyflurane]], [[enflurane]], [[isoflurane]], [[sevoflurane]] and [[desflurane]]. Fluorocarbon anesthetics reduce the hazard of flammability with [[diethyl ether]] and [[cyclopropane]]. Perfluorinated alkanes are used as [[blood substitute]]s.
+The carbon-fluorine bond is commonly found in pharmaceuticals and agrochemicals. An estimated 1/5 of pharmaceuticals contain fluorine, including several of the top drugs.<ref>{{cite journal | vauthors = Inoue M, Sumii Y, Shibata N | title = Contribution of Organofluorine Compounds to Pharmaceuticals | journal = ACS Omega | volume = 5 | issue = 19 | pages = 10633–10640 | date = May 2020 | pmid = 32455181 | pmc = 7240833 | doi = 10.1021/acsomega.0c00830 }}</ref><ref name=Thayer>{{cite journal | vauthors= Thayer AM | title = Fabulous Fluorine | journal = Chemical and Engineering News | date = June 5, 2006 | volume = 84 | issue = 23 | pages = 15–24 | doi = 10.1021/cen-v084n023.p015 | url =  http://pubs.acs.org/cen/coverstory/84/8423cover1.html }}</ref> Examples include [[5-fluorouracil]], [[flunitrazepam]] (Rohypnol), [[fluoxetine]] (Prozac), [[paroxetine]] (Paxil), [[ciprofloxacin]] (Cipro), [[mefloquine]], and [[fluconazole]]. Introducing the carbon–fluorine bond to organic compounds is the major challenge for medicinal chemists using organofluorine chemistry, as the carbon–fluorine bond increases the probability of having a successful drug by about a factor of ten.<ref name=Thayer/>  Over half of agricultural chemicals contain C-F bonds.  A common example is [[trifluralin]].<ref>{{cite journal |doi=10.1016/j.isci.2020.101467 |title=Current Contributions of Organofluorine Compounds to the Agrochemical Industry |date=2020 |last1=Ogawa |first1=Yuta |last2=Tokunaga |first2=Etsuko |last3=Kobayashi |first3=Osamu |last4=Hirai |first4=Kenji |last5=Shibata |first5=Norio |journal=iScience |volume=23 |issue=9 |pmid=32891056 |pmc=7479632 |bibcode=2020iSci...23j1467O }}</ref>  The effectiveness of organofluorine compounds is attributed to their metabolically stability, i.e. they are not degraded rapidly so remain active.  Also, fluorine acts as a [[bioisostere]] of the [[hydrogen]] atom.
 ===Inhaler propellant===
@@ Line 129: / Line 122: @@
 === Fluorosurfactants ===
-Fluorosurfactants, which have a polyfluorinated "tail" and a [[hydrophilic]] "head", serve as [[surfactants]] because they concentrate at the liquid-air interface due to their [[lipophobicity]]. Fluorosurfactants have low surface energies and dramatically lower surface tension. The fluorosurfactants [[perfluorooctanesulfonic acid]] (PFOS) and [[perfluorooctanoic acid]] (PFOA) are two of the most studied because of their ubiquity, toxicity, and long residence times in humans and wildlife.
+Fluorosurfactants, which have a polyfluorinated "tail" and a [[hydrophilic]] "head", serve as [[surfactants]] because they concentrate at the liquid-air interface due to their [[lipophobicity]]. Fluorosurfactants have low surface energies and dramatically lower surface tension. The fluorosurfactants [[perfluorooctanesulfonic acid]] (PFOS) and [[perfluorooctanoic acid]] (PFOA) are two of the most studied because of their ubiquity, proposed toxicity, and long residence times in humans and wildlife.
+[[Triphenylphosphine]] has been modified by attachment of perfluoroalkyl substituents that confer solubility in [[perfluorohexane]] as well as [[supercritical carbon dioxide]].  As a specific example, [(C<sub>8</sub>F<sub>17</sub>C<sub>3</sub>H<sub>6</sub>-4-C<sub>6</sub>H<sub>4</sub>)<sub>3</sub>P.<ref>{{cite book | vauthors = Peters JC, Thomas JC | chapter = Ligands, Reagents, and Methods in Organometallic Synthesis | title = Comprehensive Organometallic Chemistry III | date = 2007 | volume = 1 | pages = 59–92 | doi = 10.1016/B0-08-045047-4/00002-9 | isbn = 978-0-08-045047-6 }}</ref>
 === Solvents ===
-Fluorinated compounds often display distinct solubility properties. [[Dichlorodifluoromethane]] and [[chlorodifluoromethane]] were at one time widely used refrigerants. CFCs have potent [[ozone depletion]] potential due to the [[homolysis (chemistry)|homolytic cleavage]] of the carbon-chlorine bonds; their use is largely prohibited by the [[Montreal Protocol]]. [[Hydrofluorocarbons]] (HFCs), such as [[tetrafluoroethane]], serve as CFC replacements because they do not catalyze ozone depletion. [[Oxygen]] exhibits a high solubility in perfluorocarbon compounds, reflecting on their lipophilicity. [[Perfluorodecalin]] has been demonstrated as a [[blood substitute]] transporting oxygen to the lungs.
+Fluorinated compounds often display distinct solubility properties. [[Dichlorodifluoromethane]] and [[chlorodifluoromethane]] were at one time widely used refrigerants. CFCs have potent [[ozone depletion]] potential due to the [[homolysis (chemistry)|homolytic cleavage]] of the carbon-chlorine bonds; their use is largely prohibited by the [[Montreal Protocol]]. [[Hydrofluorocarbons]] (HFCs), such as [[tetrafluoroethane]], serve as CFC replacements because they do not catalyze ozone depletion.
+[[Oxygen]] exhibits a high solubility in perfluorocarbon compounds, reflecting on their lipophilicity. [[Perfluorodecalin]] has been demonstrated as a [[blood substitute]] transporting oxygen to the lungs. Fluorine-substituted [[ethers]] are [[volatile anesthetic]]s, including the commercial products [[methoxyflurane]], [[enflurane]], [[isoflurane]], [[sevoflurane]] and [[desflurane]]. Fluorocarbon anesthetics reduce the hazard of flammability with [[diethyl ether]] and [[cyclopropane]]. Perfluorinated alkanes are used as [[blood substitute]]s.
-The solvent [[1,1,1,2-tetrafluoroethane]] has been used for [[Liquid-liquid extraction|extraction]] of [[natural products]] such as [[taxol]], [[evening primrose oil]], and [[vanillin]].  [[2,2,2-trifluoroethanol]] is an oxidation-resistant polar solvent.<ref>{{OrgSynth | title = Mild and Selective Oxidation of Sulfur Compounds in Trifluorethanol: Diphenyl Disulfide and Methyle Phenyl Sulfoxide| author = Kabayadi S. Ravikumar, Venkitasamy Kesavan, Benoit Crousse, Danièle Bonnet-Delpon, and Jean-Pierre Bégué | volume = 80 | pages = 184 | year = 2003 | prep = v80p0184}}</ref>
+The solvent [[1,1,1,2-tetrafluoroethane]] has been used for [[Liquid-liquid extraction|extraction]] of [[natural products]] such as [[taxol]], [[evening primrose oil]], and [[vanillin]].  [[2,2,2-trifluoroethanol]] is an oxidation-resistant polar solvent.<ref>{{OrgSynth | title = Mild and Selective Oxidation of Sulfur Compounds in Trifluorethanol: Diphenyl Disulfide and Methyle Phenyl Sulfoxide| vauthors = Ravikumar KS, Kesavan V, Crousse B, Bonnet-Delpon D, Bégué JP | volume = 80 | pages = 184 | year = 2003 | prep = v80p0184}}</ref>
 ===Organofluorine reagents===
 The development of organofluorine chemistry has contributed many reagents of value beyond organofluorine chemistry. [[Triflic acid]] (CF<sub>3</sub>SO<sub>3</sub>H) and [[trifluoroacetic acid]] (CF<sub>3</sub>CO<sub>2</sub>H) are useful throughout [[organic synthesis]].  Their strong acidity is attributed to the [[electronegativity]] of the [[trifluoromethyl]] group that stabilizes the negative charge. The triflate-group (the conjugate base of the triflic acid) is a good [[leaving group]] in substitution reactions.
+Fluorocarbon substituents can enhance the [[Lewis acid]]ity of metal centers.  A premier example is "[[Eufod]]," a coordination complex of europium(III) that features a perfluoroheptyl modified [[acetylacetonate]] [[ligand]].  This and related species are useful in organic synthesis and as "shift reagents" in [[NMR spectroscopy]].
 ===Fluorous phases===
-Of topical interest in the area of "Green Chemistry,"<ref>E.G. Hopea, A.P. Abbotta, D.L. Daviesa, G.A. Solana and A.M. Stuarta "Green Organometallic Chemistry" in Comprehensive Organometallic Chemistry III, 2007, Volume 12, Pages 837-864. {{doi|10.1016/B0-08-045047-4/00182-5}}</ref> highly fluorinated substituents, e.g. perfluorohexyl (C<sub>6</sub>F<sub>13</sub>) confer distinctive solubility properties to molecules, which facilitates purification of products in [[organic synthesis]].<ref>J. A. Gladysz, [[Dennis Patrick Curran|D. P. Curran]], I. T. Horváth (Eds.) "Handbook of Fluorous Chemistry", Wiley–VCH, Weinheim, 2004.  {{ISBN|978-3-527-30617-6}}.</ref>  This area, described as "[[fluorous]] chemistry," exploits the concept of like-dissolves-like in the sense that fluorine-rich compounds dissolve preferentially in fluorine-rich solvents.  Because of the relative inertness of the C-F bond, such fluorous phases are compatible with even harsh reagents.  This theme has spawned techniques of "fluorous tagging'' and ''fluorous protection''.  Illustrative of fluorous technology is the use of fluoroalkyl-substituted tin hydrides for reductions, the products being easily separated from the spent tin reagent by extraction using fluorinated solvents.<ref>{{OrgSynth | author = Aimee Crombie, Sun-Young Kim, Sabine Hadida, and [[Dennis Patrick Curran|Dennis P. Curran]] | title =Synthesis of Tris(2-Perfluorohexylethyl)tin Hydride: A Highly Fluorinated Tin Hydride with Advantageous Features of Easy Purification | collvol = 10 | collvolpages = 712 | prep = CV79P0001}}</ref>
+Highly fluorinated substituents, e.g. perfluorohexyl (C<sub>6</sub>F<sub>13</sub>) confer distinctive solubility properties to molecules, which facilitates purification of products in [[organic synthesis]].<ref>{{cite book | veditors = Gladysz JA, [[Dennis Patrick Curran|Curran DP]], Horváth IT |title=Handbook of Fluorous Chemistry |date=2004 |publisher=Wiley-VCH |location=Weinheim |isbn=978-3-527-30617-6}}</ref><ref>{{cite book | vauthors = Hope EG, Abbott AP, Davies DL, Solan GA, Stuart AM | chapter = Green Organometallic Chemistry | title = Comprehensive Organometallic Chemistry III | date = 2007 | volume = 12 | pages = 837–864 | doi = 10.1016/B0-08-045047-4/00182-5 | isbn = 978-0-08-045047-6 }}</ref> This area, described as "[[fluorous]] chemistry," exploits the concept of like-dissolves-like in the sense that fluorine-rich compounds dissolve preferentially in fluorine-rich solvents.  Because of the relative inertness of the C-F bond, such fluorous phases are compatible with harsh reagents.  This theme has spawned techniques of "fluorous tagging'' and ''fluorous protection''.  Illustrative of fluorous technology is the use of fluoroalkyl-substituted tin hydrides for reductions, the products being easily separated from the spent tin reagent by extraction using fluorinated solvents.<ref>{{OrgSynth | vauthors = Crombie A, Kim SY, Hadida S, [[Dennis Patrick Curran|Curran DP]] | title =Synthesis of Tris(2-Perfluorohexylethyl)tin Hydride: A Highly Fluorinated Tin Hydride with Advantageous Features of Easy Purification | collvol = 10 | collvolpages = 712 | prep = CV79P0001}}</ref>
 Hydrophobic fluorinated [[ionic liquid]]s, such as organic salts of [[bistriflimide]] or [[hexafluorophosphate]], can form phases that are insoluble in both water and organic solvents, producing [[multiphasic liquid]]s.
-===Organofluorine ligands in transition metal chemistry===
-Organofluorine ligands have long been featured in [[organometallic chemistry|organometallic]] and [[coordination chemistry]].  One advantage to F-containing ligands is the convenience of [[fluorine-19 NMR|<sup>19</sup>F NMR spectroscopy]] for monitoring reactions.  The organofluorine compounds can serve as a "sigma-donor ligand," as illustrated by the titanium(III) derivative [(C<sub>5</sub>Me<sub>5</sub>)<sub>2</sub>Ti(FC<sub>6</sub>H<sub>5</sub>)]BPh<sub>4</sub>.  Most often, however, fluorocarbon substituents are used to enhance the [[Lewis acid]]ity of metal centers.  A premier example is "[[Eufod]]," a coordination complex of europium(III) that features a perfluoroheptyl modified [[acetylacetonate]] [[ligand]].  This and related species are useful in organic synthesis and as "shift reagents" in [[NMR spectroscopy]].
-[[Image:Cp*Ti(FPh)+.png|thumb|180px|left|Structure of [(C<sub>5</sub>Me<sub>5</sub>)<sub>2</sub>Ti(FC<sub>6</sub>H<sub>5</sub>)]<sup>+</sup>, a coordination complex of an organofluorine ligand.]]
-In an area where coordination chemistry and [[materials science]] overlap, the fluorination of organic ligands is used to tune the properties of component molecules.  For example, the degree and regiochemistry of fluorination of metalated 2-phenylpyridine ligands in platinum(II) complexes significantly modifies the emission properties of the complexes.<ref>M.E. Thompson, P.E. Djurovich, S. Barlow and S. Marder "Organometallic Complexes for Optoelectronic Applications" Comprehensive Organometallic Chemistry III, 2007, Volume 12, Pages 101-194. {{doi|10.1016/B0-08-045047-4/00169-2}}</ref>
-The coordination chemistry of organofluorine ligands also embraces fluorous technologies.  For example, [[triphenylphosphine]] has been modified by attachment of perfluoroalkyl substituents that confer solubility in [[perfluorohexane]] as well as [[supercritical carbon dioxide]].  As a specific example, [(C<sub>8</sub>F<sub>17</sub>C<sub>3</sub>H<sub>6</sub>-4-C<sub>6</sub>H<sub>4</sub>)<sub>3</sub>P.<ref>J.C. Peters, J.C. Thomas "Ligands, Reagents, and Methods in Organometallic Synthesis" in Comprehensive Organometallic Chemistry III, 2007, Volume 1, Pages 59-92. {{doi|10.1016/B0-08-045047-4/00002-9}}</ref>
-====C-F bond activation====
-An active area of organometallic chemistry encompasses the scission of C-F bonds by transition metal-based reagents.  Both stoichiometric and catalytic reactions have been developed and are of interest from the perspectives of organic synthesis and remediation of xenochemicals.<ref>R.N. Perutz and T. Braun "Transition Metal-mediated C–F Bond Activation" Comprehensive Organometallic Chemistry III, 2007, Volume 1, Pages 725-758.  {{doi|10.1016/B0-08-045047-4/00028-5}}.</ref>  C-F bond activation has been classified as follows "(i) oxidative addition of fluorocarbon, (ii) M–C bond formation with HF elimination, (iii) M–C bond formation with fluorosilane elimination, (iv) [[hydrodefluorination]] of fluorocarbon with M–F bond formation, (v) nucleophilic attack on fluorocarbon, and (vi) defluorination of fluorocarbon".  An illustrative metal-mediated C-F activation reaction is the defluorination of fluorohexane by a zirconium di[[hydride]], an analogue of [[Schwartz's reagent]]:
-:(C<sub>5</sub>Me<sub>5</sub>)<sub>2</sub>ZrH<sub>2</sub>  +  1-FC<sub>6</sub>H<sub>13</sub>  →  (C<sub>5</sub>Me<sub>5</sub>)<sub>2</sub>ZrH(F)  +  [[hexane|C<sub>6</sub>H<sub>14</sub>]]
-====Fluorocarbon anions in Ziegler-Natta catalysis====
 Fluorine-containing compounds are often featured in [[non-coordinating anions|noncoordinating or weakly coordinating]] anions.  Both tetrakis(pentafluorophenyl)borate, B(C<sub>6</sub>F<sub>5</sub>)<sub>4</sub><sup>−</sup>, and the related [[tetrakis(3,5-bis(trifluoromethyl)phenyl)borate|tetrakis[3,5-bis(trifluoromethyl)phenyl]borate]], are useful in [[Ziegler-Natta catalysis]] and related alkene polymerization methodologies.  The fluorinated substituents render the anions weakly basic and enhance the solubility in weakly basic solvents, which are compatible with strong Lewis acids.
@@ Line 164: / Line 150: @@
 ==Biosynthesis of organofluorine compounds==
 :[[Image:Fluorinase.png|right|430px]]
-In contrast to the many naturally-occurring organic compounds containing the heavier [[halide]]s, chloride, bromide, and iodide, only a handful of biologically synthesized carbon-fluorine bonds are known.<ref>{{cite journal | year = 1999 | title = Fluorine-Containing Natural Products | journal = Journal of Fluorine Chemistry | first2 = David | volume = 100  | issue = 1–2 | last2 = B. Harper | pages = 127–133 | doi = 10.1016/S0022-1139(99)00201-8 | author = O'Hagan, D.}}</ref> The most common natural organofluorine species is [[fluoroacetic acid|fluoroacetate]], a toxin found in a few species of plants. Others include fluorooleic acid, [[fluoroacetone]], nucleocidin (4'-fluoro-5'-O-sulfamoyladenosine), [[fluorothreonine]], and [[fluorocitric acid|2-fluorocitrate]].  Several of these species are probably biosynthesized from [[fluoroacetaldehyde]]. The [[enzyme]] [[fluorinase]] catalyzed the synthesis of [[5'-deoxy-5'-fluoroadenosine]] (see scheme to right).
+In contrast to the many naturally-occurring organic compounds containing the heavier [[halide]]s, chloride, bromide, and iodide, only a handful of biologically synthesized carbon-fluorine bonds are known.<ref>{{cite journal | year = 1999 | title = Fluorine-Containing Natural Products | journal = Journal of Fluorine Chemistry | volume = 100  | issue = 1–2 | pages = 127–133 | doi = 10.1016/S0022-1139(99)00201-8 | vauthors = O'Hagan D, Harper B | bibcode = 1999JFluC.100..127O }}</ref> The most common natural organofluorine species is [[fluoroacetic acid|fluoroacetate]], a toxin found in a few species of plants. Others include fluorooleic acid, [[fluoroacetone]], nucleocidin (4'-fluoro-5'-O-sulfamoyladenosine), [[fluorothreonine]], and [[fluorocitric acid|2-fluorocitrate]].  Several of these species are probably biosynthesized from [[fluoroacetaldehyde]]. The [[enzyme]] [[fluorinase]] catalyzed the synthesis of [[5'-deoxy-5'-fluoroadenosine]] (see scheme to right).
 ==History==
-Organofluorine chemistry began in the 1800s with the development of organic chemistry.<ref name=Dobi/><ref name="tak">{{Cite journal |last=Okazoe |first=Takashi |date=2009 |title=Overview on the history of organofluorine chemistry from the viewpoint of material industry |journal=Proceedings of the Japan Academy, Series B |language=en |volume=85 |issue=8 |pages=276–289 |doi=10.2183/pjab.85.276 |pmid=19838009 |issn=0386-2208|doi-access=free |pmc=3621566 |bibcode=2009PJAB...85..276O}}</ref> The first organofluorine compounds were prepared using [[antimony trifluoride]] as the F<sup>−</sup> source. The nonflammability and nontoxicity of the [[chlorofluorocarbon]]s CCl<sub>3</sub>F and CCl<sub>2</sub>F<sub>2</sub> attracted industrial attention in the 1920s. On April 6, 1938, [[Roy J. Plunkett]] a young research chemist who worked at [[DuPont (1802–2017)|DuPont]]'s Jackson Laboratory in [[Deepwater, New Jersey]], accidentally discovered [[polytetrafluoroethylene]] (PTFE).<ref>{{cite journal|title=Dr. Roy J. Plunkett: Discoverer of Fluoropolymers|journal=The Fluoropolymers Division Newsletter|year=1994|issue=Summer|pages=1–2|url=http://www.fluoropolymers.org/news/PlunkArt94.pdf|archive-url=https://web.archive.org/web/20030709071637/http://www.fluoropolymers.org/news/PlunkArt94.pdf|url-status=dead|archive-date=2003-07-09}}</ref><ref>{{cite web| title= Roy J. Plunkett |url=https://www.sciencehistory.org/historical-profile/roy-j-plunkett|website= [[Science History Institute]]|access-date=21 February 2018|date=June 2016}}</ref><ref>{{cite web|author=Center for Oral History| title= Roy J. Plunkett |url=https://oh.sciencehistory.org/oral-histories/plunkett-roy-j|website= [[Science History Institute]]|access-date=21 February 2018}}</ref> Subsequent major developments, especially in the US, benefited from expertise gained in the production of uranium hexafluoride.<ref name=Ullmann/>
+Organofluorine chemistry began in the 1800s with the development of organic chemistry.<ref name=Dobi/><ref name="tak">{{cite journal |last=Okazoe |first=Takashi |vauthors= |date=2009 |title=Overview on the history of organofluorine chemistry from the viewpoint of material industry |journal=Proceedings of the Japan Academy. Series B, Physical and Biological Sciences |volume=85 |issue=8 |pages=276–289 |bibcode=2009PJAB...85..276O |doi=10.2183/pjab.85.276 |pmc=3621566 |pmid=19838009 |doi-access=free}}</ref> The first organofluorine compound was discovered in 1835, when [[Jean-Baptiste Dumas|Dumas]] and [[Eugène-Melchior Péligot|Péligot]] distilled [[dimethyl sulfate]] with [[potassium fluoride]] and got [[fluoromethane]].<ref name="tak" /><ref>{{Cite book |last=Crochard (París) |url=https://books.google.com/books?id=yCpCAAAAcAAJ&pg=PA36 |title=Annales de chimie et de physique |last2=Arago |first2=François |last3=Gay-Lussac |first3=Joseph Louis |date=1835 |publisher=Chez Crochard |pages=36 |language=fr}}</ref> In 1862, [[Alexander Borodin]] pioneered a now-common method of halogen exchange: he acted on [[benzoyl chloride]] with [[potassium bifluoride]] and first synthesized [[benzoyl fluoride]].<ref name="tak" /><ref>[[s:fr:Page:Comptes rendus hebdomadaires des séances de l’Académie des sciences, tome 055, 1862.djvu/552]]</ref> Besides salts, organofluorine compounds were often prepared using [[Hydrogen fluoride|HF]] as the F<sup>−</sup> source because elemental fluorine, as its discoverer [[Henri Moissan]] and his followers found out, was prone to explosions when mixed with organics.<ref name="tak" /> [[Frédéric Swarts]] also introduced [[antimony fluoride]] in this role in 1898.<ref name="tak" /><ref>{{Cite book |last=Belgique |first=Académie royale des sciences, des lettres et des beaux-arts de |url=https://books.google.com/books?id=Lf8TAAAAYAAJ&pg=PA375 |title=Bulletins de l'Académie royale des sciences, des lettres et des beaux-arts de Belgique |date=1898 |publisher=M. Hayez |language=fr}}</ref>
-Starting in the late 1940s, a series of electrophilic fluorinating methodologies were introduced, beginning with [[cobalt trifluoride|CoF<sub>3</sub>]]. Electrochemical fluorination ("[[electrofluorination]]") was announced, which [[Joseph H. Simons]] had developed in the 1930s to generate highly stable perfluorinated materials compatible with [[uranium hexafluoride]].<ref name=Simons/> These new methodologies allowed the synthesis of C-F bonds without using elemental fluorine and without relying on metathetical methods.
+The nonflammability and nontoxicity of the [[chlorofluorocarbon]]s CCl<sub>3</sub>F and CCl<sub>2</sub>F<sub>2</sub> attracted industrial attention in the 1920s. [[General Motors]] settled on these CFCs as refrigerants and had [[DuPont]] produce them via Swarts' method.<ref name="tak" /> In 1931, Bancroft and Wherty managed to solve fluorine's explosion problem by diluting it with inert nitrogen.<ref name="tak" />
-In 1957, the anticancer activity of 5-fluorouracil was described.  This report provided one of the first examples of rational design of drugs.<ref>{{cite journal |author1=C. Heidelberger |author2=N. K. Chaudhuri |author3=P. Danneberg |author4=D. Mooren |author5=L. Griesbach |author6=R. Duschinsky |author7=R. J. Schnitzer |author8=E. Pleven |author9=J. Schreiner | doi = 10.1038/179663a0 | title = Fluorinated Pyrimidines, A New Class of Tumour-Inhibitory Compounds | year = 1957 | journal = Nature | volume = 179 | pages = 663–6 | pmid = 13418758 | issue = 4561|bibcode = 1957Natur.179..663H |s2cid=4296069}}</ref>  This discovery sparked a surge of interest in fluorinated pharmaceuticals and agrichemicals.  The discovery of the [[noble gas compound]]s, e.g. XeF<sub>4</sub>, provided a host of new reagents starting in the early 1960s.  In the 1970s, [[fluorodeoxyglucose]] was established as a useful reagent in <sup>18</sup>F [[positron emission tomography]]. In Nobel Prize-winning work, CFC's were shown to contribute to the depletion of atmospheric ozone.  This discovery alerted the world to the negative consequences of organofluorine compounds and motivated the development of new routes to organofluorine compounds.  In 2002, the first C-F bond-forming enzyme, [[fluorinase]], was reported.<ref>{{cite journal | year = 2002 | title = Biochemistry: biosynthesis of an organofluorine molecule | journal = Nature  | volume = 416 | pages = 279  | pmid = 11907567 | doi = 10.1038/416279a | issue = 6878 | author1 = O'Hagan, D | author2 = Schaffrath, C | author3 = Cobb, S. L | author4 = Hamilton, J. T | author5 = Murphy, C. D |bibcode = 2002Natur.416..279O | s2cid = 4415511 | doi-access = free}}</ref>
+On April 6, 1938, [[Roy J. Plunkett]] a young research chemist who worked at [[DuPont (1802–2017)|DuPont]]'s Jackson Laboratory in [[Deepwater, New Jersey]], accidentally discovered [[polytetrafluoroethylene]] (PTFE).<ref>{{cite journal|title=Dr. Roy J. Plunkett: Discoverer of Fluoropolymers|journal=The Fluoropolymers Division Newsletter|year=1994|issue=Summer|pages=1–2|url=http://www.fluoropolymers.org/news/PlunkArt94.pdf|archive-url=https://web.archive.org/web/20030709071637/http://www.fluoropolymers.org/news/PlunkArt94.pdf|url-status=dead|archive-date=2003-07-09}}</ref><ref>{{cite web| title= Roy J. Plunkett |url=https://www.sciencehistory.org/historical-profile/roy-j-plunkett|website= [[Science History Institute]]|access-date=21 February 2018|date=June 2016}}</ref><ref>{{cite web|author=Center for Oral History| title= Roy J. Plunkett |url=https://oh.sciencehistory.org/oral-histories/plunkett-roy-j|website= [[Science History Institute]]|access-date=21 February 2018}}</ref> Subsequent major developments, especially in the US, benefited from expertise gained in the production of uranium hexafluoride.<ref name="Ullmann" />
+Starting in the late 1940s, a series of electrophilic fluorinating methodologies were introduced, beginning with [[cobalt trifluoride|CoF<sub>3</sub>]]. Electrochemical fluorination ("[[electrofluorination]]") was announced, which [[Joseph H. Simons]] had developed in the 1930s to generate highly stable perfluorinated materials compatible with [[uranium hexafluoride]].<ref name="Simons" /> These new methodologies allowed the synthesis of C-F bonds without using elemental fluorine and without relying on metathetical methods.{{citation needed|date=May 2023}}
+In 1957, the anticancer activity of 5-fluorouracil was described.  This report provided one of the first examples of rational design of drugs.<ref>{{cite journal | vauthors = Heidelberger C, Chaudhuri NK, Danneberg P, Mooren D, Griesbach L, Duschinsky R, Schnitzer RJ, Pleven E, Scheiner J | title = Fluorinated pyrimidines, a new class of tumour-inhibitory compounds | journal = Nature | volume = 179 | issue = 4561 | pages = 663–666 | date = March 1957 | pmid = 13418758 | doi = 10.1038/179663a0 | s2cid = 4296069 | bibcode = 1957Natur.179..663H }}</ref>  This discovery sparked a surge of interest in fluorinated pharmaceuticals and agrichemicals.  The discovery of the [[noble gas compound]]s, e.g. XeF<sub>4</sub>, provided a host of new reagents starting in the early 1960s.  In the 1970s, [[fluorodeoxyglucose]] was established as a useful reagent in <sup>18</sup>F [[positron emission tomography]]. In Nobel Prize-winning work, CFC's were shown to contribute to the depletion of atmospheric ozone.  This discovery alerted the world to the negative consequences of organofluorine compounds and motivated the development of new routes to organofluorine compounds.  In 2002, the first C-F bond-forming enzyme, [[fluorinase]], was reported.<ref>{{cite journal | vauthors = O'Hagan D, Schaffrath C, Cobb SL, Hamilton JT, Murphy CD | title = Biochemistry: biosynthesis of an organofluorine molecule | journal = Nature | volume = 416 | issue = 6878 | pages = 279 | date = March 2002 | pmid = 11907567 | doi = 10.1038/416279a | s2cid = 4415511 | doi-access = free | bibcode = 2002Natur.416..279O }}</ref>
 == Environmental and health concerns ==
-Only a few organofluorine compounds are acutely bioactive and highly toxic, such as fluoroacetate and perfluoroisobutene.
+Only a few organofluorine compounds are acutely bioactive and highly toxic, such as fluoroacetate and [[perfluoroisobutene]].{{citation needed|date=May 2023}}
-Some organofluorine compounds pose significant risks and dangers to health and the environment. CFCs and HCFCs ([[HCFC|hydrochlorofluorocarbon]]) [[ozone depletion|deplete the ozone layer]] and are potent [[greenhouse gases]]. HFCs are potent greenhouse gases and are facing calls for stricter international regulation and phase out schedules as a fast-acting greenhouse emission abatement measure, as are [[perfluorocarbons]] (PFCs), and sulphur hexafluoride (SF<sub>6</sub>).
+Some organofluorine compounds pose significant risks and dangers to health and the environment. CFCs and HCFCs ([[HCFC|hydrochlorofluorocarbon]]) [[ozone depletion|deplete the ozone layer]] and are potent [[greenhouse gases]]. HFCs are potent greenhouse gases and are facing calls for stricter international regulation and phase out schedules as a fast-acting greenhouse emission abatement measure, as are [[perfluorocarbons]] (PFCs), and [[sulfur hexafluoride]] (SF<sub>6</sub>).{{citation needed|date=May 2023}}
 Because of the compound's effect on climate, the [[G-20 major economies]] agreed in 2013 to support initiatives to phase out use of HCFCs. They affirmed the roles of the [[Montreal Protocol]] and the [[United Nations Framework Convention on Climate Change]] in global HCFC accounting and reduction. The U.S. and China at the same time announced a bilateral agreement to similar effect.<ref name="whitehouse-2013-09-06">{{cite press release |title=United States, China, and Leaders of G-20 Countries Announce Historic Progress Toward a Global Phase Down of HFCs |author=U.S. White House Press Secretary |url=https://obamawhitehouse.archives.gov/the-press-office/2013/09/06/united-states-china-and-leaders-g-20-countries-announce-historic-progres |date=September 6, 2013 |via=[[NARA|National Archives]] |work=[[whitehouse.gov]] |access-date=2013-09-16}}</ref>
@@ Line 185: / Line 175: @@
 * [[Hydrofluoroolefin]]
-==References==
+== References ==
 {{reflist|30em}}
+{{ChemicalBondsToCarbon}}
 [[Category:Organofluorides]]