Radical (chemistry)

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

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

The hydroxyl radical, Lewis structure shown, contains one unpaired electron.

Lewis dot structure of a Hydroxide ion compared to a hydroxyl radical

In chemistry, a radical, also known as a free radical, is an atom, molecule, or ion that has at least one unpaired valence electron. With some exceptions, these unpaired electrons make radicals highly chemically reactive. Many radicals spontaneously dimerize. Most organic radicals have short lifetimes.

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

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

Radicals are important in combustion, atmospheric chemistry, polymerization, plasma chemistry, biochemistry, and many other chemical processes. A majority of natural products are generated by radical-generating enzymes. In living organisms, the radicals superoxide and nitric oxide and 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 dubbed redox signaling. A radical may be trapped within a solvent cage or 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 through homolysis of 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

Homolysis makes 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. The homolytic bond dissociation energies, usually abbreviated as "ΔH °" are a measure of bond strength. Splitting H₂ into 2 H^•, for example, requires a ΔH ° of +435 kJ/mol, while splitting Cl₂ into 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.

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 of lithium naphthalene results from the lithium naphthanide radical.

Classically, radicals form by one-electron reductions. Typically one-electron reduced organic compounds are unstable. Stability is conferred to the radical anion when the charge can be delocalized. Examples include alkali metal naphthenides, anthracenides, and ketyls.

Radical formation from other radicals

Abstraction

Radical abstraction between a benzoyloxy radical and hydrogen bromide

Hydrogen abstraction generates radicals. To achieve this reaction, the C-H bond of the H-atom donor must be weak, which is rarely the case in organic compounds. Allylic and especiall doubly allylic C-H bonds are prone to abstraction by O₂. This reaction is the basis of drying oils, such as linoleic acid derivatives.

Addition

Radical addition of a bromine radical to a substituted alkene

In free-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 underpins radical polymerization, technology that produces many plastics.

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

A large variety of inorganic radicals, as well as a smaller number of organic radicals, are stable and in fact isolable. Nitric oxide (NO) is well known example of an isolable inorganic radical, and Fremy's salt (Potassium nitrosodisulfonate, (KSO₃)₂NO) is a related example. Many thiazyl radicals are known, despite limited π resonance stabilization (see below).

The term "stable radical" bears a pernicious ambiguity. Radicals' behavior varies with distinct thermodynamic and kinetic stabilities, and no general rule connects the two. For example, resonance delocalization thermodynamically stabilizes benzyl radicals, but those radicals undergo rapid, diffusion-limited dimerization. Under normal conditions, their kinetic lifetime measures in nanoseconds. Conversely, H^• is highly reactive (thermodynamically unstable), but also the most abundant chemical in the universe (kinetically stable) because it exists primarily in low-density environments.

Following Griller and Ingold's extremely influential 1976 review, modern chemists call a carbon-centered radical R^• stabilized if the corresponding R–H bond is weaker than in an alkane; the radical is persistent if the radical lifetime lasts longer than the encounter limit. Persistence is almost exclusively a steric effect. However, orbitals of high angular momentum (d or f), delocalization, and the α effect can all make organic radicals stabilized.

2,2,6,6-Tetramethylpiperidinyloxyl is a robust organic radical.

The radical of commerce 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) illustrates these phenomena: the methyl substituents shield the N-hydroxypiperidinyl core radical for persistence; and the vicinal nitrogen and oxygen lone pairs weaken any bonds that might form to oxygen, keeping the radical stabilized. Consequently TEMPO behaves, aside from its paramagnetism, like a normal organic compound.

Singly-occupied molecular orbitals

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

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

In molecular orbital theory, a radical electronic structure is characterized by a highest-energy filled molecular orbital that contains only an unpaired electron. That orbital is called the "singly-occupied molecular orbital" or SOMO, and is traditionally filled spin-up without loss of generality. Radical compounds are thermodynamically unstable because fixed nuclear positions cannot simultaneously minimize the filled spin-up orbital energies (which include the SOMO) and the filled spin-down orbital energies (which do not). Thus a SOMO whose energy depends little on nuclear position can produce a relatively stabilized radical. Two common types of such SOMOs are a d orbital, which requires only Jahn-Teller distortion; and a SOMO delocalized over a large portion of the molecule or crystal, which requires little motion at each nucleus.

SOMOs can in principle be of any type, but amongst the main group atoms, almost all known stable radicals have a π-type SOMO. Consequently SOMOs delocalize like other π bonds: to nearby lone pairs on hydroxyl groups (−OH), ethers (−OR), or amines (−NH₂ or −NR); to conjugated π bonds in alkenes, carbonyls, or nitriles; or in hyperconjugation to nearby hydrogen- or fluorine-rich moieties.

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

Many of the above functional groups are electron-donating, but electron donation is not necessary to achieve SOMO delocalization, and electron withdrawal functions just as well. Indeed, radicals are particularly stable if they can delocalize into both an electron-withdrawing and an electron-donating group, the "capto-dative effect".

In the electron-donating case, the SOMO interacts with the lower energy lone pair to form a new, lower-energy, filled, delocalized bond orbital and a new, higher-energy antibonding SOMO (in net, a three-electron bond). Because the new bonding orbital contains more electrons than the SOMO, the resulting electronic state reduces molecular energy.

In the electron-withdrawing case, the SOMO interacts with an empty σ* or π* antibonding orbital. That antibonding orbital has less energy than the isolated SOMO, as does the resulting hybrid orbital.

Common equilibria

The radical derived from α-tocopherol

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 is α-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 in triphenylmethyl (trityl) derivatives.

Most main-group radicals are in notional equilibrium with closed-shell dimers. For example, nitrogen dioxide equilibrates with dinitrogen tetroxide, and tributyltin radicals equilibrate with hexabutyldistannane. Consequently radicals may be stabilized when the dimeric bond is weak. For example, compounds with a radical localized to atoms with adjacent lone pairs experience a powerful α effect when dimerized, such that the dimer may practically never form. Likewise, the quinonic loss of aromaticity in Gomberg's dimer predisposes the compound towards homolysis.

In other cases, radical dimers may form a "π dimer", analogous to a donor-acceptor complex but without charge transfer.

Diradicals

Diradicals are 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 to Hund's rule of maximum multiplicity. The relative stability of the oxygen diradical is primarily due to the spin-forbidden nature 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 in metal-oxo complexes, lending themselves for studies of spin forbidden reactions in transition metal chemistry. Carbenes in their triplet state can be viewed as diradicals centred on the same atom, while these are usually highly reactive persistent carbenes are known, with N-heterocyclic carbenes being the most common example.

Triplet carbenes and nitrenes are diradicals. Their chemical properties are distinct from the properties of their singlet analogues.

Occurrence of radicals

Combustion

Spectrum of the blue flame from a butane torch showing excited molecular radical band emission and Swan bands

Main article: Combustion § Reaction mechanism

A familiar radical reaction is combustion. The oxygen molecule is a stable diradical, best represented by ^•O–O^•. Because spins of the electrons are parallel, this molecule is stable. While the ground state of oxygen is this unreactive spin-unpaired (triplet) diradical, an extremely reactive spin-paired (singlet) state is available. For combustion to occur, the energy barrier between 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. The flammability of a given material strongly depends on the concentration of radicals that must be obtained before initiation and propagation reactions dominate leading to combustion of 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 lead was 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 give organic hydroperoxides that break up into hydroxyl radicals (HO^•).

Polymerization

Many polymerization reactions 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 the radical 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 produce Poly(methyl methacrylate) (PMMA – Plexiglas or Perspex) via a repeating series of radical addition steps:

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

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

Being a prevalent radical, O₂ reacts with many organic compounds to generate radicals together with the hydroperoxide radical. Drying oils and alkyd paints harden due to radical crosslinking initiated by oxygen from the atmosphere.

Atmospheric radicals

See also: Oxygen cycle and Ozone-oxygen cycle

The most common radical in the lower atmosphere is molecular dioxygen. Photodissociation of source molecules produces other radicals. In the lower atmosphere, important radical are produced by the photodissociation of nitrogen dioxide to an oxygen atom and nitric oxide (see eq. 1.1 below), which plays a key role in smog formation—and the photodissociation of ozone to give the excited oxygen atom O(1D) (see eq. 1.2 below). The net and return reactions are also shown (eq. 1.3 and eq. 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 unreactive chlorofluorocarbons (CFCs) by solar ultraviolet radiation is an important source of radicals (see eq. 1 below). These reactions give the chlorine radical, Cl^•, which catalyzes the conversion of ozone to O₂, thus facilitating ozone depletion (eq. 2.2–eq. 2.4 below).

${\ce {CFCS->[h\nu ]Cl^{\bullet }}}$ 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 the ozone layer, especially since the chlorine radical is free to engage in another reaction chain; consequently, the use of chlorofluorocarbons as refrigerants has been restricted.

In biology

See also: Dioxygen in biological reactions

Structure of the deoxyadenosyl radical, a common biosynthetic intermediate

An approximate structure of lignin, 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 as granulocytes and macrophages. Radicals are involved in cell signalling processes, known as redox signaling. For example, radical attack of linoleic acid produces a series of 13-hydroxyoctadecadienoic acids and 9-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 in Parkinson's disease, senile and drug-induced deafness, schizophrenia, and Alzheimer's. The classic free-radical syndrome, the iron-storage disease hemochromatosis, is typically associated with a constellation of free-radical-related symptoms including movement disorder, psychosis, skin pigmentary melanin abnormalities, deafness, arthritis, and diabetes mellitus. The free-radical theory of aging proposes that radicals underlie the aging process itself. Similarly, the process of mitohormesis suggests 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 the enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. In addition, antioxidants play a key role in these defense mechanisms. These are often the three vitamins, vitamin A, vitamin C and vitamin E and polyphenol antioxidants. Furthermore, there is good evidence indicating that bilirubin and uric acid can act as antioxidants to help neutralize certain radicals. Bilirubin comes from the breakdown of red blood cells' contents, while uric acid is a breakdown product of purines. Too much bilirubin, though, can lead to jaundice, which could eventually damage the central nervous system, while too much uric acid causes gout.

Reactive oxygen species

Reactive oxygen species or ROS are species such as superoxide, hydrogen peroxide, and hydroxyl radical, commonly associated with cell damage. ROS form as a natural by-product of the normal metabolism of oxygen and have important roles in cell signaling. Two important oxygen-centered radicals are superoxide and hydroxyl 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 and death, which may contribute to many diseases such as cancer, stroke, myocardial infarction, diabetes and major disorders. Many forms of cancer are thought to be the result of reactions between radicals and DNA, potentially resulting in mutations that can adversely affect the cell cycle and potentially lead to malignancy. Some of the symptoms of aging such as atherosclerosis are also attributed to radical induced oxidation of cholesterol to 7-ketocholesterol. In addition radicals contribute to alcohol-induced liver damage, perhaps more than alcohol itself. Radicals produced by cigarette smoke are implicated in inactivation of alpha 1-antitrypsin in the lung. This process promotes the development of emphysema.

Oxybenzone has 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, like titanium oxide and octyl methoxycinnamate.

ROS attack the polyunsaturated fatty acid, linoleic acid, to form a series of 13-hydroxyoctadecadienoic acid and 9-hydroxyoctadecadienoic acid products 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 acid and docosahexaenoic 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 II photooxygenation reactions after Dexter energy 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 new poylmethine dyes.

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:

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

Radical reaction mechanisms use single-headed arrows to depict the movement of single electrons:

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

The homolytic cleavage 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 in radical addition and radical substitution as reactive intermediates. Chain reactions involving radicals can usually be divided into three distinct processes. These are initiation, propagation, and termination.

• Initiation reactions 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.
• Propagation reactions are those reactions involving radicals in which the total number of radicals remains the same.
• Termination reactions 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

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 a methyl group or a carboxyl, whether it was part of a larger molecule or a molecule on its own. A radical is often known as an R 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 a functional group or substituent, 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 obsolete radical theory was developed. Louis-Bernard Guyton de Morveau introduced the phrase "radical" in 1785 and the phrase was employed by Antoine Lavoisier in 1789 in his Traité Élémentaire de Chimie. A radical was then identified as the root base of certain acids (the Latin word "radix" meaning "root"). Historically, the term radical in radical theory was also used for bound parts of the molecule, especially when they remain unchanged in reactions. These are now called functional groups. For example, methyl alcohol was 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 in mass spectrometry when broken apart by irradiation with energetic electrons.

In a modern context the first organic (carbon–containing) radical identified was the triphenylmethyl radical, (C₆H₅)₃C^•. This species was discovered by Moses Gomberg in 1900. In 1933 Morris S. Kharasch and Frank Mayo proposed that free radicals were responsible for anti-Markovnikov addition of hydrogen bromide to allyl bromide.

In most fields of chemistry, the historical definition of radicals contends that the molecules have nonzero electron spin. However, in fields including spectroscopy and astrochemistry, 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, CH₂ and 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.

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