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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.^[3]: 977 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.^{[citation needed]} Two common types of such SOMOs are a d orbital,^[12] which requires only Jahn-Teller distortion;^{[citation needed]} and a SOMO delocalized over a large portion of the molecule or crystal,^{[13]: 649–650} which requires little motion at each nucleus.^{[citation needed]}

SOMOs can in principle be of any type, but amongst the main group atoms, almost all known stable radicals have a π-type SOMO.^[11] 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.^[14]

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.^[3]: 978 Indeed, radicals are particularly stable if they can delocalize into both an electron-withdrawing and an electron-donating group, the “capto-dative effect“.^[15]

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.^[3]: 979

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.^[3]: 978

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.^{[citation needed]}

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 [de]. 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.^[16] Likewise, the quinonic loss of aromaticity in Gomberg’s dimer predisposes the compound towards homolysis.^{[citation needed]}

In other cases, radical dimers may form a “π dimer“, analogous to a donor-acceptor complex but without charge transfer.^[17]

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.^{[citation needed]}

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 exist, or be obtained – as in laboratory conditions, 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).^{[citation needed]}

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^•).^{[citation needed]}

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:

Newer radical polymerization methods are known as living radical polymerization. Variants include reversible addition-fragmentation chain transfer (RAFT) and atom transfer radical polymerization (ATRP).^{[citation needed]}

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.^{[citation needed]}

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).

[h \\nu] NO + O”}}’>

NO2 + O2 ->[h \\nu] NO + O3</chem>”},”3″:{“wt”:”{{EquationRef|eq. 1.3}}”}},”i”:0}}]}’> NO + O3 -> NO2 + O2</chem>”},”3″:{“wt”:”{{EquationRef|eq. 1.4}}”}},”i”:0}}]}’> eq. 2.2–eq. 2.4 below). Cl^\\bullet {}+ O3 -> ClO^\\bullet {}+ O2</chem>”},”3″:{“wt”:”{{EquationRef|eq. 2.2}}”}},”i”:0}}]}’> O3 ->[h \\nu] O + O2</chem>”},”3″:{“wt”:”{{EquationRef|eq. 2.3}}”}},”i”:0}}]}’> O {}+ ClO^\\bullet -> Cl^\\bullet {}+ O2</chem>”},”3″:{“wt”:”{{EquationRef|eq. 2.4}}”}},”i”:0}}]}’> 2O3 ->[h \\nu] 3O2</chem>”},”3″:{“wt”:”{{EquationRef|eq. 2.5}}”}},”i”:0}}]}’> See also: Dioxygen in biological 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,[21] 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.[22] Radicals may also be involved in Parkinson’s disease, senile and drug-induced deafness, schizophrenia, and Alzheimer’s.[23] 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.[citation needed] 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.[24] 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.[25] 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.[26] Some of the symptoms of aging such as atherosclerosis are also attributed to radical induced oxidation of cholesterol to 7-ketocholesterol.[27] In addition, radicals contribute to alcohol-induced liver damage.[28] Radicals produced by cigarette smoke are implicated in inactivation of alpha 1-antitrypsin in the lung. This process promotes the development of emphysema.[citation needed] 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.[29] 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.[30] Reactive oxygen species are also used in controlled reactions involving singlet dioxygen known as type II photooxygenation reactions after Dexter energy transfer (triplet-triplet annihilation) from natural triplet dioxygen 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.[31] 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: Radical reaction mechanisms use single-headed arrows to depict the movement of single electrons: 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.[citation needed] 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.[citation needed] 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 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.[citation needed] 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.[citation needed] 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.[32][33] 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)”.[34] 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.[35] 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 References ↑ IUPAC Gold Book radical (free radical) PDF Archived 2017-03-02 at the Wayback Machine ↑ Hayyan, M.; Hashim, M.A.; Anjkut, I.M. (2016). “Superoxide Ion: Generation and Chemical Implications”. Chem. Rev. 116 (5): 3029–85. doi:10.1021/acs.chemrev.5b00407. PMID 26875845. 1 2 3 4 5 6 Clayden, Jonathan; Greeves, Nick; Warren, Stuart G. (2012). Organic chemistry (2nd ed.). Oxford: Oxford University Press. ISBN 978-0-19-927029-3. OCLC 761379371. ↑ “Diacyl Peroxides”. polymerdatabase.com. Retrieved 2020-12-08. ↑ Gridnev, Alexei A.; Ittel, Steven D. (2001). “Catalytic Chain Transfer in Free-Radical Polymerizations”. Chemical Reviews. 101 (12): 3611–3660. doi:10.1021/cr9901236. PMID 11740917. ↑ Monroe, Bruce M.; Weed, Gregory C. (1993). “Photoinitiators for free-radical-initiated photoimaging systems”. Chemical Reviews. 93: 435–448. doi:10.1021/cr00017a019. ↑ Su, Wei-Fang (2013), Su, Wei-Fang (ed.), “Radical Chain Polymerization”, Principles of Polymer Design and Synthesis, Lecture Notes in Chemistry, vol. 82, Berlin, Heidelberg: Springer, pp. 137–183, doi:10.1007/978-3-642-38730-2_7, ISBN 978-3-642-38730-2{{citation}}: CS1 maint: work parameter with ISBN (link) ↑ Oakley, Richard T. (1988). “Cyclic and Heterocyclic Thiazenes” (PDF). Progress in Inorganic Chemistry. Cyclic and Heterocyclic Thiazenes (section). Vol. 36. pp. 299–391. doi:10.1002/9780470166376.ch4. ISBN 978-0-470-16637-6. Archived from the original (PDF) on 2015-09-23. Retrieved 2011-03-31. ↑ Rawson, J; Banister, A; Lavender, I (1995). The Chemistry of Dithiadiazolylium and Dithiadiazolyl Rings**Dedicated to Dr. Z. V. Hauptman, in appreciation of his important contribution to sulfur-nitrogen and carbon-sulfur-nitrogen chemistry. Advances in Heterocyclic Chemistry. Vol. 62. pp. 137–247. doi:10.1016/S0065-2725(08)60422-5. ISBN 978-0-12-020762-6. 1 2 3 Griller, David; Ingold, Keith U. (1976). “Persistent carbon-centered radicals”. Accounts of Chemical Research. 9: 13–19. doi:10.1021/ar50097a003. 1 2 Hicks 2010, p. 231. ↑ Power, Philip P. (2003) [19 July 2002]. “Persistent and stable radicals of the heavier main group elements and related species”. Chemical Reviews. 103 (3). American Chemical Society: 789–810. doi:10.1021/cr020406p. PMID 12630853. ↑ Carey, Francis A.; Sundberg, Richard J. (1984). Advanced Organic Chemistry. Vol. A: Structures and Mechanisms (2 ed.). New York: Plenum. ISBN 0-306-41087-7. LCCN 84-8229. ↑ Carey & Sundberg 1984, pp. 649–650. As Smith (2023), March’s Organic Chemistry (8th ed.) pp. 254, 256 notes, a contrary view is suggested in Gronert, S. (2006) in J. Org. Chem., vol. 71, pp. 7045–; ——— (2007) in Org. Lett., vol. 9, pp. 2211–; and Galli, C.; Guarnieri, A.; Koch, H.; Mencarelli, P.; and Rappoport, Z. (1997) J. Org. Chem., vol. 62, pp. 4072–. ↑ Carey & Sundberg 1984, p. 651. Smith 2023, p. 256 writes: “There is some evidence in favor of the captodative effect, some of it from ESR studies. However, there is also experimental and theoretical evidence against it,” with extensive citations on both sides. ↑ Hicks, Robin G., ed. (2010). Stable Radicals. Wiley. pp. 317–318. ISBN 978-0-470-77083-2. ↑ Hicks, Robin G. (30 Mar 2007) [23 Nov 2006]. “What’s new in stable radical chemistry?”. Organic & Biomolecular Chemistry. 5 (9). The Royal Society of Chemistry: 1324–1328, 1331–1335. doi:10.1039/b617142g. PMID 17464399. ↑ However, paramagnetism does not necessarily imply radical character.[citation needed] ↑ Linde, C.; Åkermark, B.; Norrby, P.-O.; Svensson, M. (1999). “Timing is Critical: Effect of Spin Changes on the Diastereoselectivity in Mn(Salen)-Catalyzed Epoxidation”. Journal of the American Chemical Society. 121 (21): 5083–84. Bibcode:1999JAChS.121.5083L. doi:10.1021/ja9809915. ↑ Broderick, J.B.; Duffus, B.R.; Duschene, K.S.; Shepard, E.M. (2014). “Radical S-Adenosylmethionine Enzymes”. Chemical Reviews. 114 (8): 4229–317. doi:10.1021/cr4004709. PMC 4002137. PMID 24476342. ↑ Pacher P, Beckman JS, Liaudet L (2007). “Nitric oxide and peroxynitrite in health and disease”. Physiol. Rev. 87 (1): 315–424. doi:10.1152/physrev.00029.2006. PMC 2248324. PMID 17237348. ↑ Njie-Mbye, Ya Fatou; Kulkarni-Chitnis, Madhura; Opere, Catherine A.; Barrett, Aaron; Ohia, Sunny E. (2013). “Lipid peroxidation: pathophysiological and pharmacological implications in the eye”. Frontiers in Physiology. 4: 366. doi:10.3389/fphys.2013.00366. PMC 3863722. PMID 24379787. ↑ Floyd, R.A. (1999). “Neuroinflammatory processes are important in neurodegenerative diseases: An hypothesis to explain the increased formation of reactive oxygen and nitrogen species as major factors involved in neurodegenerative disease development”. Free Radical Biology and Medicine. 26 (9–10): 1346–55. doi:10.1016/s0891-5849(98)00293-7. PMID 10381209. ↑ An overview of the role of radicals in biology and of the use of electron spin resonance in their detection may be found in Rhodes C.J. (2000). Toxicology of the Human Environment – the critical role of free radicals. London: Taylor and Francis. ISBN 978-0-7484-0916-7. ↑ Rajamani Karthikeyan; Manivasagam T; Anantharaman P; Balasubramanian T; Somasundaram ST (2011). “Chemopreventive effect of Padina boergesenii extracts on ferric nitrilotriacetate (Fe-NTA)-induced oxidative damage in Wistar rats”. J. Appl. Phycol. 23 (2): 257–63. Bibcode:2011JAPco..23..257K. doi:10.1007/s10811-010-9564-0. S2CID 27537163. ↑ Mukherjee, P.K.; Marcheselli, V.L.; Serhan, C.N.; Bazan, N.G. (2004). “Neuroprotecin D1: A docosahexanoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress”. Proceedings of the National Academy of Sciences of the USA. 101 (22): 8491–96. Bibcode:2004PNAS..101.8491M. doi:10.1073/pnas.0402531101. PMC 420421. PMID 15152078. ↑ Lyons, MA; Brown, AJ (1999). “7-Ketocholesterol”. Int. J. Biochem. Cell Biol. 31 (3–4): 369–75. doi:10.1016/s1357-2725(98)00123-x. PMID 10224662. ↑ Wu, Defeng; Cederbaum, Arthur I. (2003). “Alcohol, Oxidative Stress, and Free Radical Damage”. Alcohol Research & Health: the Journal of the National Institute on Alcohol Abuse and Alcoholism. 27 (4): 277–84. PMID 15540798. ↑ Serpone, N; Salinaro, A; Emeline, AV; Horikoshi, S; Hidaka, H; Zhao, JC (2002). “An in vitro systematic spectroscopic examination of the photostabilities of a random set of commercial sunscreen lotions and their chemical UVB/UVA active agents”. Photochemical & Photobiological Sciences. 1 (12): 970–81. Bibcode:2002PhPhS…1..970S. doi:10.1039/b206338g. PMID 12661594. S2CID 27248506. ↑ Njie-Mbye, Ya Fatou; Kulkarni-Chitnis, Madhura; Opere, Catherine A.; Barrett, Aaron; Ohia, Sunny E. (2013). “Lipid peroxidation: pathophysiological and pharmacological implications in the eye”. Frontiers in Physiology. 4: 366. doi:10.3389/fphys.2013.00366. PMC 3863722. PMID 24379787. ↑ Desvals, Arthur; Fortino, Mariagrazia; Lefebvre, Corentin; Rogier, Johann; Michelin, Clément; Alioui, Samy; Rousset, Elodie; Pedone, Alfonso; Lemercier, Gilles; Hoffmann, Norbert (2022-05-16). “Synthesis and characterization of polymethine dyes carrying thiobarbituric and carboxylic acid moieties” (PDF). New Journal of Chemistry. 46 (19): 8971–8980. doi:10.1039/D2NJ00684G. ISSN 1369-9261. S2CID 248165785. ↑ Kharasch, M. S. (1933). “The Peroxide Effect in the Addition of Reagents to Unsaturated Compounds. I. The Addition of Hydrogen Bromide to Allyl Bromide”. Journal of the American Chemical Society. 55 (6): 2468–2496. Bibcode:1933JAChS..55.2468K. doi:10.1021/ja01333a041. ↑ Yan, M; Lo, JC; Edwards, JT; Baran, PS (2016). “Radicals: Reactive Intermediates with Translational Potential”. J Am Chem Soc. 138 (39): 12692–12714. Bibcode:2016JAChS.13812692Y. doi:10.1021/jacs.6b08856. PMC 5054485. PMID 27631602. ↑ G. Herzberg (1971), “The spectra and structures of simple free radicals”, ISBN 0-486-65821-X. ↑ 28th International Symposium on Free Radicals Archived 2007-07-16 at the Wayback Machine.