Organofluorine chemistry describes thechemistry oforganofluorine compounds,organic compounds that contain acarbon–fluorine bond. Organofluorine compounds find diverse applications ranging fromoil andwater repellents topharmaceuticals, refrigerants, andreagents incatalysis. In addition to these applications, some organofluorine compounds arepollutants because of their contributions toozone depletion,global warming,bioaccumulation, andtoxicity. The area of organofluorine chemistry often requires special techniques associated with the handling of fluorinating agents.
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 otherorganohalogens.
In comparison to aryl chlorides and bromides, aryl fluorides formGrignard reagents only reluctantly.[citation needed] On the other hand, aryl fluorides, e.g. fluoroanilines and fluorophenols, often undergo nucleophilic substitution efficiently.[2]
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 relativelylipophobic. Because of the reduced intermolecularvan 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 ofPFOA 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.
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) andpolychlorotrifluoroethylene ([CFClCF2]n). The fluoropolymer polytetrafluoroethylene (PTFE/Teflon) is a solid.[citation needed]
Hydrofluorocarbons (HFCs), organic compounds that contain fluorine and hydrogen atoms, are the most common type of organofluorine compounds. They are commonly used inair conditioning and asrefrigerants[5] in place of the olderchlorofluorocarbons such asR-12 and hydrochlorofluorocarbons such asR-21. They do not harm the ozone layer as much as the compounds they replace; however, they do contribute toglobal warming. Their atmospheric concentrations and contribution toanthropogenic greenhouse gas emissions are rapidly increasing, causing international concern about theirradiative forcing.
Fluorocarbons with few C–Fbonds behave similarly to the parent hydrocarbons, but their reactivity can be altered significantly. For example, bothuracil and5-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 andagrochemicals contain only one fluorine center or onetrifluoromethyl group.
Unlike other greenhouse gases in theParis 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 toclimate change, negotiators from 197 nations meeting at the summit of theUnited Nations Environment Programme in Kigali, Rwanda reached a legally-binding accord to phase out hydrofluorocarbons (HFCs) in an amendment to theMontreal Protocol.[9][10][11]
As indicated throughout this article, fluorine-substituents lead to reactivity that differs strongly from classical organic chemistry. The premier example isdifluorocarbene, CF2, which is asinglet whereascarbene (CH2) has atriplet ground state.[12] This difference is significant because difluorocarbene is a precursor totetrafluoroethylene.
Perfluorinated compounds are fluorocarbon derivatives, as they are closely structurally related to fluorocarbons. However, they also possess new atoms such asnitrogen,iodine, or ionic groups, such asperfluorinated carboxylic acids.
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:
Such reactions however are often unselective and require care because hydrocarbons can uncontrollably "burn" inF
2, analogous to thecombustion of hydrocarbon inO
2. For this reason, alternative fluorination methodologies have been developed. Generally, such methods are classified into two classes.
Electrophilic fluorination rely on sources of "F+". Often such reagents feature N–F bonds, for exampleF-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]
A specialized but important method of electrophilic fluorination involveselectrosynthesis. 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 iselectrolyzed at 5–6V using Nianodes.[15] The method was first demonstrated with the preparation of perfluoropyridine (C
5F
5N) frompyridine (C
5H
5N). Several variations of this technique have been described, including the use of moltenpotassium bifluoride or organicsolvents.
The major alternative to electrophilic fluorination is nucleophilic fluorination using reagents that are sources of "F−," forNucleophilic displacement typically of chloride and bromide.Metathesis reactions employingalkali metal fluorides are the simplest.[16] For aliphatic compounds this is sometimes called theFinkelstein reaction, while for aromatic compounds it is known as theHalex process.
Alkyl monofluorides can be obtained from alcohols andOlah reagent (pyridinium fluoride) or another fluoridating agents.
The decomposition of aryldiazonium tetrafluoroborates in theSandmeyer[17] orSchiemann reactions exploitfluoroborates as F− sources.
Althoughhydrogen 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 CFCs, is prepared industrially using this approach:[18]
Notice that this transformation entails two reaction types, metathesis (replacement of Cl− by F−) and hydrofluorination of analkene.
Deoxofluorination convert a variety of oxygen-containing groups into fluorides. The usual reagent issulfur tetrafluoride:
A more convenient alternative to SF4 is thediethylaminosulfur trifluoride, which is a liquid whereas SF4 is a corrosive gas:[19][20]
Apart from DAST, a wide variety of similar reagents exist, including, but not limited to, 2-pyridinesulfonyl fluoride (PyFluor) andN-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]
Many organofluorine compounds are generated from reagents that deliver perfluoroalkyl and perfluoroaryl groups. (Trifluoromethyl)trimethylsilane, CF3Si(CH3)3, is used as a source of thetrifluoromethyl group, for example.[24] Among the available fluorinated building blocks are CF3X (X = Br, I), C6F5Br, and C3F7I. These species formGrignard reagents that then can be treated with a variety ofelectrophiles. 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 oftetrafluoroethylene, which is produced on a large-scale industrially via the intermediacy of difluorocarbene. The process begins with the thermal (600–800 °C) dehydrochlorination ofchlorodifluoromethane:[6]
Sodium fluorodichloroacetate (CAS# 2837-90-3) is used to generate chlorofluorocarbene, for cyclopropanations.
The usefulness of fluorine-containingradiopharmaceuticals in18F-positron emission tomography has motivated the development of new methods for forming C–F bonds. Because of the short half-life of18F, these syntheses must be highly efficient, rapid, and easy.[25] Illustrative of the methods is the preparation offluoride-modified glucose by displacement of atriflate by a labeled fluoride nucleophile:
Biologically synthesized organofluorines have been found in microorganisms and plants, but not animals.[26] The most common example isfluoroacetate, which occurs as aplant defence against herbivores in at least 40 plants in Australia, Brazil and Africa.[27] Other biologically synthesized organofluorines include ω-fluorofatty acids,fluoroacetone, and2-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]
Organofluorine chemistry impacts many areas of everyday life and technology. The C–F bond is found inpharmaceuticals,agrochemicals,fluoropolymers,refrigerants,surfactants,anesthetics,oil-repellents,catalysts, andwater-repellents, among others.
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 include5-fluorouracil,flunitrazepam (Rohypnol),fluoxetine (Prozac),paroxetine (Paxil),ciprofloxacin (Cipro),mefloquine, andfluconazole. 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 istrifluralin.[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 abioisostere of thehydrogen atom.
Fluorocarbons are also used as a propellant formetered-dose inhalers used to administer some asthma medications. The current generation of propellant consists of hydrofluoroalkanes (HFA), which have replacedCFC-propellant-based inhalers.CFC inhalers were banned as of 2008[update] as part of theMontreal Protocol[32] because of environmental concerns with the ozone layer. HFA propellant inhalers likeFloVent and ProAir (Salbutamol) have no generic versions available as of October 2014.
Fluorosurfactants, which have a polyfluorinated "tail" and ahydrophilic "head", serve assurfactants because they concentrate at the liquid-air interface due to theirlipophobicity. Fluorosurfactants have low surface energies and dramatically lower surface tension. The fluorosurfactantsperfluorooctanesulfonic acid (PFOS) andperfluorooctanoic 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 inperfluorohexane as well assupercritical carbon dioxide. As a specific example, [(C8F17C3H6-4-C6H4)3P.[33]
Fluorinated compounds often display distinct solubility properties.Dichlorodifluoromethane andchlorodifluoromethane were at one time widely used refrigerants. CFCs have potentozone depletion potential due to thehomolytic cleavage of the carbon-chlorine bonds; their use is largely prohibited by theMontreal Protocol.Hydrofluorocarbons (HFCs), such astetrafluoroethane, 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 ablood substitute transporting oxygen to the lungs. Fluorine-substitutedethers arevolatile anesthetics, including the commercial productsmethoxyflurane,enflurane,isoflurane,sevoflurane anddesflurane. Fluorocarbon anesthetics reduce the hazard of flammability withdiethyl ether andcyclopropane. Perfluorinated alkanes are used asblood substitutes.
The solvent1,1,1,2-tetrafluoroethane has been used forextraction ofnatural products such astaxol,evening primrose oil, andvanillin.2,2,2-trifluoroethanol is an oxidation-resistant polar solvent.[34]
The development of organofluorine chemistry has contributed many reagents of value beyond organofluorine chemistry.Triflic acid (CF3SO3H) andtrifluoroacetic acid (CF3CO2H) are useful throughoutorganic synthesis. Their strong acidity is attributed to theelectronegativity of thetrifluoromethyl group that stabilizes the negative charge. The triflate-group (the conjugate base of the triflic acid) is a goodleaving group in substitution reactions.
Fluorocarbon substituents can enhance theLewis acidity of metal centers. A premier example is "Eufod," a coordination complex of europium(III) that features a perfluoroheptyl modifiedacetylacetonateligand. This and related species are useful in organic synthesis and as "shift reagents" inNMR spectroscopy.
Highly fluorinated substituents, e.g. perfluorohexyl (C6F13) confer distinctive solubility properties to molecules, which facilitates purification of products inorganic 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 andfluorous 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 fluorinatedionic liquids, such as organic salts ofbistriflimide orhexafluorophosphate, can form phases that are insoluble in both water and organic solvents, producingmultiphasic liquids.
Fluorine-containing compounds are often featured innoncoordinating or weakly coordinating anions. Both tetrakis(pentafluorophenyl)borate, B(C6F5)4−, and the relatedtetrakis[3,5-bis(trifluoromethyl)phenyl]borate, are useful inZiegler–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.
Organofluorine compounds enjoy many niche applications inmaterials science. With a lowcoefficient of friction, fluid fluoropolymers are used as specialty lubricants. Fluorocarbon-based greases are used in demanding applications. Representative products include Fomblin andKrytox, made by Solvay Solexis andDuPont, 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 ofliquid crystal displays. The polymeric analogue of triflic acid,nafion is a solid acid that is used as the membrane in most low temperaturefuel cells. The bifunctional monomer4,4'-difluorobenzophenone is a precursor toPEEK-class polymers.
In contrast to the many naturally-occurring organic compounds containing the heavierhalides, chloride, bromide, and iodide, only a handful of biologically synthesized carbon-fluorine bonds are known.[38] The most common natural organofluorine species isfluoroacetate, a toxin found in a few species of plants. Others includefluorooleic acid,fluoroacetone, nucleocidin (4'-fluoro-5'-O-sulfamoyladenosine),fluorothreonine, and2-fluorocitrate. Several of these species are probably biosynthesized fromfluoroacetaldehyde. Theenzymefluorinase catalyzed the synthesis of5'-deoxy-5'-fluoroadenosine (see scheme to right).
Organofluorine chemistry began in the 1800s with the development of organic chemistry.[18][39] The first organofluorine compound was discovered in 1835, whenDumas andPéligot distilleddimethyl sulfate withpotassium fluoride and gotfluoromethane.[39][40] In 1862,Alexander Borodin pioneered a now-common method of halogen exchange: he acted onbenzoyl chloride withpotassium bifluoride and first synthesizedbenzoyl fluoride.[39][41] Besides salts, organofluorine compounds were often prepared usingHF as the F− source because elemental fluorine, as its discovererHenri Moissan and his followers found out, was prone to explosions when mixed with organics.[39]Frédéric Swarts also introducedantimony fluoride in this role in 1898.[39][42]
The nonflammability and nontoxicity of thechlorofluorocarbons CCl3F and CCl2F2 attracted industrial attention in the 1920s.General Motors settled on these CFCs as refrigerants and hadDuPont 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 atDuPont's Jackson Laboratory inDeepwater, New Jersey, accidentally discoveredpolytetrafluoroethylene (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 withCoF3. Electrochemical fluorination ("electrofluorination") was announced, whichJoseph H. Simons had developed in the 1930s to generate highly stable perfluorinated materials compatible withuranium 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 thenoble 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 in18Fpositron emission tomography. In Nobel Prize-winning work, CFCs 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]
Only a few organofluorine compounds are acutely bioactive and highly toxic, such as fluoroacetate andperfluoroisobutene.[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 potentgreenhouse 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 areperfluorocarbons (PFCs), andsulfur hexafluoride (SF6).[citation needed]
Because of the compound's effect on climate, theG-20 major economies agreed in 2013 to support initiatives to phase out use of HCFCs. They affirmed the roles of theMontreal Protocol and theUnited 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]
Because of the strength of the carbon–fluorine bond, many synthetic fluorocarbons and fluorocarbon-based compounds are persistent in the environment. Fluorosurfactants, such asPFOS andPFOA, are persistent global contaminants. Fluorocarbon based CFCs andtetrafluoromethane have been reported inigneous andmetamorphic rock.[26] PFOS is apersistent 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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