Radical (chemistry)

"Free radical" redirects here. For the aging theory, seeFree-radical theory of aging.For other uses, seeFree radical (disambiguation).

This article is about free radicals. For radicals within larger molecules, seeMoiety (chemistry).

Thehydroxyl radical,Lewis structureshown, contains one unpaired electron.

Hydroxideion compared to ahydroxyl radical

Inchemistry,aradical,also known as afree radical,is anatom,molecule,orionthat has at least oneunpaired valence electron. With some exceptions, these unpaired electrons make radicals highlychemically reactive.Many radicals spontaneouslydimerize.Most organic radicals have short lifetimes.

A notable example of a radical is thehydroxyl radical(HO·), a molecule that has one unpaired electron on the oxygen atom. Two other examples aretriplet oxygenandtriplet carbene(꞉CH
₂) which have two unpaired electrons.

Radicals may be generated in a number of ways, but typical methods involveredox reactions,ionizing radiation,heat, electrical discharges, andelectrolysisare known to produce radicals. Radicals are intermediates in many chemical reactions, more so than is apparent from the balanced equations.

Radicals are important incombustion,atmospheric chemistry,polymerization,plasmachemistry,biochemistry,and many other chemical processes. A majority of natural products are generated by radical-generating enzymes. In living organisms, the radicalssuperoxideandnitric oxideand their reaction products regulate many processes, such as control of vascular tone and thus blood pressure. They also play a key role in the intermediary metabolism of various biological compounds. Such radicals can even be messengers in a process dubbedredox signaling.A radical may be trapped within asolvent cageor be otherwise bound.

Formation

Radicals are either (1) formed from spin-paired molecules or (2) from other radicals. Radicals are formed from spin-paired molecules throughhomolysisof weak bonds or electron transfer, also known as reduction. Radicals are formed from other radicals through substitution,addition,and elimination reactions.

Radical formation from spin-paired molecules

Homolysis

Homolysis of a bromine molecule producing two bromine radicals

Homolysismakes two new radicals from a spin-paired molecule by breaking a covalent bond, leaving each of the fragments with one of the electrons in the bond.Because breaking a chemical bond requires energy,homolysisoccurs under the addition of heat or light. Thebond dissociation energyassociated with homolysis depends on the stability of a given compound, and some weak bonds are able to homolyze at relatively lower temperatures.

Some homolysis reactions are particularly important because they serve as an initiator for other radical reactions. One such example is the homolysis of halogens, which occurs under light and serves as the driving force for radical halogenation reactions.

Another notable reaction is the homolysis of dibenzoyl peroxide, which results in the formation of two benzoyloxy radicals and acts as an initiator for many radical reactions.

Homolysis of dibenzoyl peroxide producing two benzoyloxy radicals

Reduction

The deep colour oflithium naphthaleneresults from the lithium naphthanide radical.

Classically radicals form by one-electronreductions.Typically one-electron reduced organic compounds are unstable. Stability is conferred to the radical anion when the charge can bedelocalized.Examples include alkali metalnaphthenides,anthracenides,andketyls.

Radical formation from other radicals

Abstraction

Radical abstraction between a benzoyloxy radical and hydrogen bromide

Hydrogen abstractiongenerates radicals. To achieve this reaction, the C-H bond of the H-atom donor must weak, which is rarely the case in organic compounds.Allylicand especiall doubly allylic C-H bonds are prone to abstraction by O₂.This reaction is the basis ofdrying oils,such aslinoleic acidderivatives.

Addition

Radical addition of a bromine radical to a substituted alkene

Infree-radical additions,a radical adds to a spin-paired substrate. When applied to organic compounds, the reaction usually entails addition to an alkene. This addition generates a new radical, which can add to yet another alkene, etc. This behavior underpinsradical polymerization,technology that produces manyplastics.

Elimination

Radical elimination can be viewed as the reverse of radical addition. In radical elimination, an unstable radical compound breaks down into a spin-paired molecule and a new radical compound. Shown below is an example of a radical elimination reaction, where a benzoyloxy radical breaks down into a phenyl radical and a carbon dioxide molecule.

A radical elimination reaction of a benzoyloxy radical

Stability

Stability of organic radicals

The radical derived fromα-tocopherol

The generation and reactivity of organic radicals are dependent on both their thermodynamic stability and the kinetic stability, also known as the persistency. This distinction is necessary because these two types of stability do not always correlate with each other. For example, benzylic radicals, which its weak benzylic C−H bond strength, are thermodynamically stabilized due to resonance delocalization. However, these radicals kinetically transient because they can undergoes rapid, diffusion-limited dimerization, resulting in a lifetime that is less than a few nanosecond. To avoid confusion, particularly for carbon-centered radicals, Griller and Ingold introduced the following definitions:"Stabilized should be used to describe a carbon-centered radical, R·,when the R−H bond strength is weaker than the appropriate C−H bond of alkane. "" Persistent should be used to describe a radical that has a lifetime that is significantly greater than methyl [radical] under the same condition. "While relationships between thermodynamic stability and kinetic persistency is highly case dependent, organic radicals can be generally stabilized by any or all of these factors: presence of electronegativity, delocalization, and steric hindrance.The compound2,2,6,6-tetramethylpiperidinyloxylillustrates the combination of all three factors. It is a commercially available solid that, aside from being magnetic, behaves like a normal organic compound.

Electronegativity

Organic radicals are inherently electron deficient thus the greater the electronegativity of the atom on which the unpaired electron resides the less stable the radical.Between carbon, nitrogen, and oxygen, for example, carbon is the most stable and oxygen the least stable.

Electronegativity also factors into the stability of carbon atoms of different hybridizations. Greater s-character correlates to higher electronegativity of the carbon atom (due to the close proximity of s orbitals to the nucleus), and the greater the electronegativity the less stable a radical.sp-hybridized carbons (50% s-character) form the least stable radicals compared to sp³-hybridized carbons (25% s-character) which form the most stable radicals.

Delocalization

The delocalization of electrons across the structure of a radical, also known as its ability to form one or more resonance structures, allows for the electron-deficiency to be spread over several atoms, minimizing instability. Delocalization usually occurs in the presence of electron-donating groups, such as hydroxyl groups (−OH), ethers (−OR), adjacent alkenes, and amines (−NH₂or −NR), or electron-withdrawing groups, such as C=O or C≡N.

Molecular orbital diagram of a radical with an electron-donating group

Delocalization effects can also be understood usingmolecular orbital theoryas a lens, more specifically, by examining the intramolecular interaction of the unpaired electron with a donating group's pair of electrons or the empty π* orbital of an electron-withdrawing group in the form of a molecular orbital diagram. The HOMO of a radical is singly-occupied hence the orbital is aptly referred to as the SOMO, or the Singly-Occupied Molecular Orbital. For an electron-donating group, the SOMO interacts with the lower energy lone pair to form a new lower-energy filled bonding-orbital and a singly-filled new SOMO, higher in energy than the original. While the energy of the unpaired electron has increased, the decrease in energy of the lone pair forming the new bonding orbital outweighs the increase in energy of the new SOMO, resulting in a net decrease of the energy of the molecule. Therefore, electron-donating groups help stabilize radicals.

Molecular orbital diagram of a radical with an electron-withdrawing group

With a group that is instead electron-withdrawing, the SOMO then interacts with the empty π* orbital. There are no electrons occupying the higher energy orbital formed, while a new SOMO forms that is lower in energy. This results in a lower energy and higher stability of the radical species. Both donating groups and withdrawing groups stabilize radicals.

Another well-known albeit weaker form of delocalization ishyperconjugation.In radical chemistry, radicals are stabilized by hyperconjugation with adjacent alkyl groups. The donation of sigma (σ) C−H bonds into the partially empty radical orbitals helps to differentiate the stabilities of radicals on tertiary, secondary, and primary carbons. Tertiary carbon radicals have three σ C-H bonds that donate, secondary radicals only two, and primary radicals only one. Therefore, tertiary radicals are the most stable and primary radicals the least stable.

The relative stabilities of tertiary, secondary, primary and methyl radicals can be explained by hyperconjugation

Steric hindrance

Radical form ofN-hydroxypiperidine

Most simply, the greater the steric hindrance the more difficult it is for reactions to take place, and the radical form is favored by default. For example, compare the hydrogen-abstracted form ofN-hydroxypiperidineto the moleculeTEMPO.TEMPO, or (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl, is too sterically hindered by the additional methyl groups to react making it stable enough to be sold commercially in its radical form.N-Hydroxypiperidine, however, does not have the four methyl groups to impede the way of a reacting molecule so the structure is unstable.

Facile H-atom donors

The stability of many (or most) organic radicals is not indicated by their isolability but is manifested in their ability to function as donors of H^•.This property reflects a weakened bond to hydrogen, usually O−H but sometimes N−H or C−H. This behavior is important because these H^•donors serve as antioxidants in biology and in commerce. Illustrative isα-tocopherol(vitamin E). The tocopherol radical itself is insufficiently stable for isolation, but the parent molecule is a highly effective hydrogen-atom donor. The C−H bond is weakened intriphenylmethyl(trityl) derivatives.

2,2,6,6-Tetramethylpiperidinyloxylis an example of a robust organic radical.

Inorganic radicals

A large variety of inorganic radicals are stable and in fact isolable. Examples include most first-row transition metal complexes.

With regard to main group radicals, the most abundant radical in the universe is also the most abundant chemical in the universe, H^•.Most main group radicals are not howeverisolable,despite their intrinsic stability. Hydrogen radicals for example combine eagerly to form H₂.Nitric oxide(NO) is well known example of an isolable inorganic radical.Fremy's salt(Potassium nitrosodisulfonate, (KSO₃)₂NO) is a related example. Manythiazylradicals are known, despite limited extent of πresonance stabilization.

Many radicals can be envisioned as the products ofbreaking of covalent bondsbyhomolysis.The homolyticbond dissociation energies,usually abbreviated as "ΔH ° "are a measure of bond strength. Splitting H₂into 2 H^•,for example, requires a ΔH ° of +435kJ/mol,while splitting Cl₂into two Cl^•requires a ΔH ° of +243 kJ/mol. For weak bonds, homolysis can be induced thermally. Strong bonds require high energy photons or even flames to induce homolysis.

Diradicals

Diradicalsare molecules containing two radical centers.Dioxygen(O₂) is an important example of a stable diradical.Singlet oxygen,the lowest-energy non-radical state of dioxygen, is less stable than the diradical due toHund's rule of maximum multiplicity.The relative stability of the oxygen diradical is primarily due to thespin-forbiddennature of the triplet-singlet transition required for it to grab electrons, i.e., "oxidize".The diradical state of oxygen also results in its paramagnetic character, which is demonstrated by its attraction to an external magnet.Diradicals can also occur inmetal-oxo complexes,lending themselves for studies ofspin forbidden reactionsintransition metalchemistry.Carbenesin their triplet state can be viewed as diradicals centred on the same atom, while these are usually highly reactivepersistent carbenesare known, with N-heterocyclic carbenes being the most common example.

Tripletcarbenesandnitrenesare diradicals. Their chemical properties are distinct from the properties of their singlet analogues.

Occurrence of radicals

Combustion

Spectrum of the blue flame from abutanetorch showing excited molecular radical band emission andSwan bands

Main article:Combustion § Reaction mechanism

A familiar radical reaction iscombustion.Theoxygenmolecule is a stablediradical,best represented by^•O–O^•.Becausespinsof the electrons are parallel, this molecule is stable. While theground stateof oxygen is this unreactive spin-unpaired (triplet) diradical, an extremely reactive spin-paired (singlet) state is available. For combustion to occur, theenergy barrierbetween these must be overcome. This barrier can be overcome by heat, requiring high temperatures. The triplet-singlet transition is also "forbidden".This presents an additional barrier to the reaction. It also means molecular oxygen is relatively unreactive at room temperature except in the presence of a catalytic heavy atom such as iron or copper.

Combustion consists of various radical chain reactions that the singlet radical can initiate. Theflammabilityof a given material strongly depends on the concentration of radicals that must be obtained before initiation and propagation reactions dominate leading tocombustionof the material. Once the combustible material has been consumed, termination reactions again dominate and the flame dies out. As indicated, promotion of propagation or termination reactions alters flammability. For example, because lead itself deactivates radicals in the gasoline-air mixture,tetraethyl leadwas once commonly added to gasoline. This prevents the combustion from initiating in an uncontrolled manner or in unburnt residues (engine knocking) or premature ignition (preignition).

When a hydrocarbon is burned, a large number of different oxygen radicals are involved. Initially,hydroperoxyl radical(HOO^•) are formed. These then react further to giveorganic hydroperoxidesthat break up intohydroxyl radicals(HO^•).

Polymerization

Manypolymerizationreactions are initiated by radicals. Polymerization involves an initial radical adding to non-radical (usually an alkene) to give new radicals. This process is the basis of theradical chain reaction.The art of polymerization entails the method by which the initiating radical is introduced. For example,methyl methacrylate(MMA) can be polymerized to producePoly(methyl methacrylate)(PMMA – Plexiglas or Perspex) via a repeating series ofradical additionsteps:

Radical intermediates in the formation of polymethacrylate (plexiglas or perspex)

Newer radical polymerization methods are known asliving radical polymerization.Variants include reversible addition-fragmentation chain transfer (RAFT) and atom transfer radical polymerization (ATRP).

Being a prevalent radical, O₂reacts with many organic compounds to generate radicals together with thehydroperoxideradical.Drying oilsand alkyd paints harden due to radical crosslinking initiated by oxygen from the atmosphere.

Atmospheric radicals

See also:Oxygen cycleandOzone-oxygen cycle

The most common radical in the lower atmosphere is molecular dioxygen.Photodissociationof source molecules produces other radicals. In the lower atmosphere, important radical are produced by the photodissociation ofnitrogen dioxideto an oxygen atom andnitric oxide(seeeq. 1.1below), which plays a key role insmogformation—and the photodissociation of ozone to give the excited oxygen atom O(1D) (seeeq. 1.2below). The net and return reactions are also shown (eq. 1.3andeq. 1.4,respectively).

${\ce {NO2 ->[h \nu] NO + O}}$(eq. 1.1)

${\ce {O + O2 -> O3}}$(eq. 1.2)

${\ce {NO2 + O2 ->[h \nu] NO + O3}}$(eq. 1.3)

${\ce {NO + O3 -> NO2 + O2}}$(eq. 1.4)

In the upper atmosphere, the photodissociation of normally unreactivechlorofluorocarbons(CFCs) by solarultraviolet radiationis an important source of radicals (see eq. 1 below). These reactions give thechlorineradical, Cl^•,which catalyzes the conversion ofozoneto O₂,thus facilitatingozone depletion(eq. 2.2–eq. 2.4below).

${\ce {CFCS->[h\nu ]Cl^{\bullet }}}$(eq. 2.1)

${\ce {Cl^{\bullet }{}+O3->ClO^{\bullet }{}+O2}}$(eq. 2.2)

${\ce {O3 ->[h \nu] O + O2}}$(eq. 2.3)

${\ce {O{}+ClO^{\bullet }->Cl^{\bullet }{}+O2}}$(eq. 2.4)

${\ce {2O3 ->[h \nu] 3O2}}$(eq. 2.5)

Such reactions cause the depletion of theozone layer,especially since the chlorine radical is free to engage in another reaction chain; consequently, the use of chlorofluorocarbons asrefrigerantshas been restricted.

In biology

See also:Dioxygen in biological reactions

Structure of thedeoxyadenosyl radical,a common biosynthetic intermediate

An approximate structure oflignin,which constitutes about 30% of plant matter. It is formed by radical reactions.

Radicals play important roles in biology. Many of these are necessary for life, such as the intracellular killing of bacteria by phagocytic cells such asgranulocytesandmacrophages.Radicals are involved incell signallingprocesses,known asredox signaling.For example, radical attack oflinoleic acidproduces a series of13-hydroxyoctadecadienoic acidsand9-hydroxyoctadecadienoic acids,which may act to regulate localized tissue inflammatory and/or healing responses, pain perception, and the proliferation of malignant cells. Radical attacks on arachidonic acid and docosahexaenoic acid produce a similar but broader array of signaling products.

Radicals may also be involved inParkinson's disease,senile and drug-induceddeafness,schizophrenia,andAlzheimer's.The classic free-radical syndrome, the iron-storage diseasehemochromatosis,is typically associated with a constellation of free-radical-related symptoms including movement disorder, psychosis, skin pigmentarymelaninabnormalities, deafness, arthritis, and diabetes mellitus. Thefree-radical theoryof aging proposes that radicals underlie theaging processitself. Similarly, the process of mitohormesissuggests that repeated exposure to radicals may extend life span.

Because radicals are necessary for life, the body has a number of mechanisms to minimize radical-induced damage and to repair damage that occurs, such as theenzymessuperoxide dismutase,catalase,glutathione peroxidaseandglutathione reductase.In addition,antioxidantsplay a key role in these defense mechanisms. These are often the three vitamins,vitamin A,vitamin Candvitamin Eandpolyphenol antioxidants.Furthermore, there is good evidence indicating thatbilirubinanduric acidcan act as antioxidants to help neutralize certain radicals. Bilirubin comes from the breakdown ofred blood cells' contents, while uric acid is a breakdown product ofpurines.Too much bilirubin, though, can lead tojaundice,which could eventually damage the central nervous system, while too much uric acid causesgout.

Reactive oxygen species

Reactive oxygen speciesor ROS are species such assuperoxide,hydrogen peroxide,andhydroxyl radical,commonly associated with cell damage. ROS form as a natural by-product of the normal metabolism ofoxygenand have important roles in cell signaling. Two important oxygen-centered radicals aresuperoxideandhydroxyl radical.They derive from molecular oxygen under reducing conditions. However, because of their reactivity, these same radicals can participate in unwanted side reactions resulting in cell damage. Excessive amounts of these radicals can lead to cell injury anddeath,which may contribute to many diseases such ascancer,stroke,myocardial infarction,diabetesand major disorders.Many forms ofcancerare thought to be the result of reactions between radicals andDNA,potentially resulting inmutationsthat can adversely affect thecell cycleand potentially lead to malignancy.Some of the symptoms ofagingsuch asatherosclerosisare also attributed to radical induced oxidation of cholesterol to 7-ketocholesterol.In addition radicals contribute toalcohol-inducedliverdamage, perhaps more than alcohol itself. Radicals produced bycigarettesmokeare implicated in inactivation ofAlpha 1-antitrypsinin thelung.This process promotes the development ofemphysema.

Oxybenzonehas been found to form radicals in sunlight, and therefore may be associated with cell damage as well. This only occurred when it was combined with other ingredients commonly found in sunscreens, liketitanium oxideandoctyl methoxycinnamate.

ROS attack thepolyunsaturated fatty acid,linoleic acid,to form a series of13-hydroxyoctadecadienoic acidand9-hydroxyoctadecadienoic acidproducts that serve as signaling molecules that may trigger responses that counter the tissue injury which caused their formation. ROS attacks other polyunsaturated fatty acids, e.g.arachidonic acidanddocosahexaenoic acid,to produce a similar series of signaling products.

Reactive oxygen species are also used in controlled reactions involving singlet dioxygen${}^{1}\mathrm {O} _{2}$known as type IIphotooxygenationreactions afterDexterenergy transfer (triplet-triplet annihilation) from natural triplet dioxygen${}^{3}\mathrm {O} _{2}$and triplet excited state of a photosensitizer. Typical chemical transformations with this singlet dioxygen species involve, among others, conversion of cellulosic biowaste into newpoylmethinedyes.

History and nomenclature

Moses Gomberg(1866–1947), the founder of radical chemistry

Until late in the 20th century the word "radical" was used in chemistry to indicate any connected group of atoms, such as amethyl groupor acarboxyl,whether it was part of a larger molecule or a molecule on its own. A radical is often known as anR group.The qualifier "free" was then needed to specify the unbound case. Following recent nomenclature revisions, a part of a larger molecule is now called afunctional grouporsubstituent,and "radical" now implies "free". However, the old nomenclature may still appear in some books.

The term radical was already in use when the now obsoleteradical theorywas developed.Louis-Bernard Guyton de Morveauintroduced the phrase "radical" in 1785 and the phrase was employed byAntoine Lavoisierin 1789 in hisTraité Élémentaire de Chimie.A radical was then identified as the root base of certain acids (the Latin word "radix" meaning "root" ). Historically, the termradicalinradical theorywas also used for bound parts of the molecule, especially when they remain unchanged in reactions. These are now calledfunctional groups.For example,methyl alcoholwas described as consisting of a methyl "radical" and a hydroxyl "radical". Neither are radicals in the modern chemical sense, as they are permanently bound to each other, and have no unpaired, reactive electrons; however, they can be observed as radicals inmass spectrometrywhen broken apart by irradiation with energetic electrons.

In a modern context the firstorganic(carbon–containing) radical identified was thetriphenylmethyl radical,(C₆H₅)₃C^•.This species was discovered byMoses Gombergin 1900. In 1933Morris S. KharaschandFrank Mayoproposed that free radicals were responsible foranti-Markovnikov additionofhydrogen bromidetoallyl bromide.

In most fields of chemistry, the historical definition of radicals contends that the molecules have nonzero electron spin. However, in fields includingspectroscopyandastrochemistry,the definition is slightly different.Gerhard Herzberg,who won the Nobel prize for his research into the electron structure and geometry of radicals, suggested a looser definition of free radicals: "any transient (chemically unstable) species (atom, molecule, or ion)".The main point of his suggestion is that there are many chemically unstable molecules that have zero spin, such as C₂,C₃,CH₂and so on. This definition is more convenient for discussions of transient chemical processes and astrochemistry; therefore researchers in these fields prefer to use this loose definition.

Depiction in chemical reactions

In chemical equations, radicals are frequently denoted by a dot placed immediately to the right of the atomic symbol or molecular formula as follows:

$\mathrm {Cl} _{2}\;\xrightarrow {UV} \;2{\mathrm {Cl} ^{\bullet }}$

Radicalreaction mechanismsuse single-headed arrows to depict the movement of single electrons:

Example of an arrow-pushing mechanism for an internal radical reaction.

Thehomolyticcleavage of the breaking bond is drawn with a "fish-hook" arrow to distinguish from the usual movement of two electrons depicted by a standard curly arrow. The second electron of the breaking bond also moves to pair up with the attacking radical electron.

Radicals also take part inradical additionandradical substitutionasreactive intermediates.Chain reactionsinvolving radicals can usually be divided into three distinct processes. These areinitiation,propagation,andtermination.

• Initiationreactions are those that result in a net increase in the number of radicals. They may involve the formation of radicals from stable species as in Reaction 1 above or they may involve reactions of radicals with stable species to form more radicals.
• Propagationreactions are those reactions involving radicals in which the total number of radicals remains the same.
• Terminationreactions are those reactions resulting in a net decrease in the number of radicals. Typically two radicals combine to form a more stable species, for example:

  2 Cl^•→ Cl₂

See also

• Electron pair
• Globally Harmonized System of Classification and Labelling of Chemicals
• Hofmann–Löffler reaction

Free radical research

• ARC Centre of Excellence for Free Radical Chemistry and Biotechnology