Radical fluorination is a type of
fluorination
In chemistry, halogenation is a chemical reaction that entails the introduction of one or more halogens into a compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, ...
reaction, complementary to nucleophilic and
electrophilic
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...
approaches.
It involves the reaction of an independently generated carbon-centered
radical
Radical may refer to:
Politics and ideology Politics
*Radical politics, the political intent of fundamental societal change
*Radicalism (historical), the Radical Movement that began in late 18th century Britain and spread to continental Europe and ...
with an atomic fluorine source and yields an
organofluorine compound
Organofluorine chemistry describes the chemistry of the organofluorines, organic compounds that contain the carbon–fluorine bond. Organofluorine compounds find diverse applications ranging from oil and water repellents to pharmaceuticals, refri ...
.
:
Historically, only three atomic fluorine sources were available for radical fluorination: Fluorine (F
2),
hypofluorites
Hypofluorous acid, chemical formula Hydrogen, HOxygen, OFluorine, F, is the only known oxoacid, oxyacid of fluorine and the only known oxoacid in which the main atom gains electrons from oxygen to create a negative oxidation state. The oxidation s ...
(O–F based reagents) and
XeF2. Their high reactivity, and the difficult handling of F
2 and the hypofluorites, limited the development of radical fluorination compared to
electrophilic
In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carri ...
and nucleophilic methods.
The uncovering of the ability of electrophilic N–F fluorinating agents to act as an atomic fluorine source
led to a renaissance in radical fluorination.
Various methodologies have since been developed for the radical formation of C–F bonds.
The radical intermediates have been generated from carboxylic acids and boronic acid derivatives, by radical addition to alkenes, or C–H and C–C bond activations. New sources of atomic fluorine are now emerging, such as metal fluoride complexes.
Sources of atomic fluorine
Fluorine gas
Fluorine gas
Fluorine is a chemical element with the symbol F and atomic number 9. It is the lightest halogen and exists at standard conditions as a highly toxic, pale yellow diatomic gas. As the most electronegative reactive element, it is extremely reactive, ...
(F
2) can act both as an electrophilic and atomic source of fluorine. The weak F–F bond strength (
) allows for
homolytic cleavage. The reaction of F
2 with organic compounds is, however, highly
exothermic
In thermodynamics, an exothermic process () is a thermodynamic process or reaction that releases energy from the system to its surroundings, usually in the form of heat, but also in a form of light (e.g. a spark, flame, or flash), electricity (e ...
and can lead to non-selective fluorinations and C–C cleavage, as well as explosions. Only a few selective radical fluorination methods have been reported. The use of fluorine for radical fluorination is mainly limited to perfluorination reactions.
O–F reagents
The O–F bond of
hypofluorite
Hypofluorous acid, chemical formula H O F, is the only known oxyacid of fluorine and the only known oxoacid in which the main atom gains electrons from oxygen to create a negative oxidation state. The oxidation state of the oxygen in hypofluorite ...
s is relatively weak. For
trifluoromethyl hypofluorite
Trifluoromethyl hypofluorite is an organofluorine compound with the formula . It exists as a colorless gas at room temperature and is highly toxic. It is a rare example of a hypofluorite (compound with an O−F bond). It is prepared by the rea ...
(CF
3OF), it has been estimated to be . The ability of trifluoromethyl hypofluorite to transfer fluorine to alkyl radicals is notably demonstrated by reacting independently generated
ethyl radical
In organic chemistry, an ethyl group (abbr. Et) is an alkyl substituent with the chemical formula, formula , derived from ethane (). ''Ethyl'' is used in the International Union of Pure and Applied Chemistry's IUPAC nomenclature of organic che ...
s from
ethene
Ethylene (IUPAC name: ethene) is a hydrocarbon which has the formula or . It is a colourless, flammable gas with a faint "sweet and musky" odour when pure. It is the simplest alkene (a hydrocarbon with carbon-carbon double bonds).
Ethylene is ...
and
tritium
Tritium ( or , ) or hydrogen-3 (symbol T or H) is a rare and radioactive isotope of hydrogen with half-life about 12 years. The nucleus of tritium (t, sometimes called a ''triton'') contains one proton and two neutrons, whereas the nucleus o ...
in the presence of CF
3OF. The high reactivity of hypofluorites has limited their application to selective radical fluorination. They can, however, be used as radical initiators for
polymerization
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer, monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are ...
.
XeF2
Xenon difluoride
Xenon difluoride is a powerful fluorinating agent with the chemical formula , and one of the most stable xenon compounds. Like most covalent inorganic fluorides it is moisture-sensitive. It decomposes on contact with water vapor, but is otherwis ...
(XeF
2) has mainly been used for radical fluorination in radical decarboxylative fluorination reactions. In this
Hunsdiecker-type reaction, xenon difluoride is used to generate the radical intermediate, as well as the fluorine transfer source.
:
XeF
2 can also be used to generate aryl radicals from
arylsilanes, and act as an atomic fluorine source to furnish aryl fluorides.
:
N–F reagents
Selectfluor
Selectfluor, a trademark of Air Products and Chemicals, is a reagent in chemistry that is used as a fluorine donor. This compound is a derivative of the nucleophillic base DABCO. It is a colourless salt that tolerates air and even water. It has ...
and ''N''-fluorobenzenesulfonimide (NFSI) are traditionally used as
electrophilic sources of fluorine, but their ability to transfer fluorine to alkyl radicals has recently been demonstrated.
They are now commonly used as fluorine transfer agents to alkyl radicals.
Others
Examples of radical fluorination using
bromine trifluoride
Bromine trifluoride is an interhalogen compound with the formula BrF3. At room temperature, it is a straw-coloured liquid with a pungent odor which decomposes violently on contact with water and organic compounds. It is a powerful fluorinating age ...
(BrF
3) and fluorinated solvents have been reported. Recent examples in radical fluorination suggest that in-situ generated metal fluoride complexes can also act as fluorine transfer agents to alkyl radicals.
Radical fluorination methodologies
Decarboxylative fluorination
The
thermolysis
Thermal decomposition, or thermolysis, is a chemical decomposition caused by heat. The decomposition temperature of a substance is the temperature at which the substance chemically decomposes. The reaction is usually endothermic as heat is req ...
of
''t''-butyl perester
In organic chemistry, organic peroxides are organic compounds containing the peroxide functional group (). If the R′ is hydrogen, the compounds are called hydroperoxides, which are discussed in that article. The O−O bond of peroxides easily b ...
s has been used to generate alkyl radicals in presence of NFSI and Selectfluor.
The radicals' intermediates were efficiently fluorinated, demonstrating the ability of the two electrophilic fluorinating agents to transfer fluorine to alkyl radicals.
:
Carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxylic ...
s can be used as radical precursors in radical fluorination methods. Metal catalysts such as
silver
Silver is a chemical element with the Symbol (chemistry), symbol Ag (from the Latin ', derived from the Proto-Indo-European wikt:Reconstruction:Proto-Indo-European/h₂erǵ-, ''h₂erǵ'': "shiny" or "white") and atomic number 47. A soft, whi ...
and
manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
have been used to induce the fluorodecarboxylation. The fluorodecarboxylation of carboxylic acids can also be triggered using
photoredox catalysis Photoredox catalysis is a branch of photochemistry that uses single-electron transfer. Photoredox catalysts are generally drawn from three classes of materials: transition-metal complexes, organic dyes, and semiconductors. While organic photoredox ...
. More specifically, phenoxyacetic acid derivatives have been shown to undergo fluorodecarboxylation when directly exposed to
ultraviolet
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nanometer, nm (with a corresponding frequency around 30 Hertz, PHz) to 400 nm (750 Hertz, THz), shorter than that of visible light, but longer than ...
irradiation or via the use of a
photosensitizer
Photosensitizers produce a physicochemical change in a neighboring molecule by either donating an electron to the substrate or by abstracting a hydrogen atom from the substrate. At the end of this process, the photosensitizer eventually returns to ...
.
:
Radical fluorination of alkenes
Alkyl radicals generated from
radical addition
In organic chemistry, free-radical addition is an addition reaction which involves free radicals. The addition may occur between a radical and a non-radical, or between two radicals.
The basic steps with examples of the free-radical addition (al ...
s to
alkene
In organic chemistry, an alkene is a hydrocarbon containing a carbon–carbon double bond.
Alkene is often used as synonym of olefin, that is, any hydrocarbon containing one or more double bonds.H. Stephen Stoker (2015): General, Organic, an ...
s have also been fluorinated.
Hydride
In chemistry, a hydride is formally the anion of hydrogen( H−). The term is applied loosely. At one extreme, all compounds containing covalently bound H atoms are called hydrides: water (H2O) is a hydride of oxygen, ammonia is a hydride of ...
s and nitrogen-, carbon-, and phosphorus-centered radicals have been employed, yielding a wide range of fluorinated difunctionalized compounds.
Fluorination of boronic acid derivatives
Alkyl fluorides have been synthesized via radicals generated from
boronic acid
A boronic acid is an organic compound related to boric acid () in which one of the three hydroxyl groups () is replaced by an alkyl or aryl group (represented by R in the general formula ). As a compound containing a carbon–boron bond, membe ...
derivatives using
silver
Silver is a chemical element with the Symbol (chemistry), symbol Ag (from the Latin ', derived from the Proto-Indo-European wikt:Reconstruction:Proto-Indo-European/h₂erǵ-, ''h₂erǵ'': "shiny" or "white") and atomic number 47. A soft, whi ...
.
:
C(sp3)–H fluorination
One major advantage of radical fluorination is that it allows the direct fluorination of remote C–H bonds. Metal catalysts such as
manganese
Manganese is a chemical element with the symbol Mn and atomic number 25. It is a hard, brittle, silvery metal, often found in minerals in combination with iron. Manganese is a transition metal with a multifaceted array of industrial alloy use ...
,
copper
Copper is a chemical element with the symbol Cu (from la, cuprum) and atomic number 29. It is a soft, malleable, and ductile metal with very high thermal and electrical conductivity. A freshly exposed surface of pure copper has a pinkis ...
, and
tungsten
Tungsten, or wolfram, is a chemical element with the symbol W and atomic number 74. Tungsten is a rare metal found naturally on Earth almost exclusively as compounds with other elements. It was identified as a new element in 1781 and first isolat ...
have been used to promote the reaction. Metal-free C(sp
3)–H fluorinations rely on the use of radical initiators (
triethylborane
Triethylborane (TEB), also called triethylboron, is an organoborane (a compound with a B–C bond). It is a colorless pyrophoric liquid. Its chemical formula is or , abbreviated . It is soluble in organic solvents tetrahydrofuran and hexane.
Pr ...
, persulfates or ''N''-oxyl radicals
) or organic photocatalysts.
Some methods have also been developed to selectively fluorinate
benzyl
In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group.
Nomenclature
In IUPAC nomenclature, the prefix benzyl refers to a substi ...
ic C–H bonds.
C–C bond activation
Cyclobutanol
Cyclobutanol is an organic compound with the chemical formula C4H8O. It contains a cyclobutyl group with a hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom cov ...
s and
cyclopropanol
Cyclopropanol is an organic compound with the chemical formula C3H6O. It contains a cyclopropyl group with a hydroxyl group attached to it. The compound is highly unstable due to the three-membered ring, and is susceptible to reactions that open t ...
s have been used as radical precursors for the synthesis of β- or γ-fluoroketones. The strained rings undergo C–C bond cleavage in presence of a silver
or an
iron
Iron () is a chemical element with symbol Fe (from la, ferrum) and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, right in f ...
catalyst
or when exposed to
ultraviolet light
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiation i ...
in presence of a
photosensitizer
Photosensitizers produce a physicochemical change in a neighboring molecule by either donating an electron to the substrate or by abstracting a hydrogen atom from the substrate. At the end of this process, the photosensitizer eventually returns to ...
.
:
Potential applications
One potential application of radical fluorination is for efficiently accessing novel moieties to serve as building blocks in
medicinal chemistry
Medicinal or pharmaceutical chemistry is a scientific discipline at the intersection of chemistry and pharmacy involved with designing and developing pharmaceutical drugs. Medicinal chemistry involves the identification, synthesis and developm ...
.
Derivatives of
propellane
In organic chemistry, propellane is any member of a class of polycyclic hydrocarbons, whose carbon skeleton consists of three rings of carbon atoms sharing a common carbon–carbon covalent bond. The concept was introduced in 1966 by D. Ginsbu ...
with reactive functional groups, such as the
hydrochloride
In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative na ...
salt of 3-fluorobicyclo
.1.1entan-1-amine, are accessible by this approach.
References
{{reflist
Free radical reactions
Organofluorides