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 oxygen andtriplet 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, andelectrolysis are 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,plasma chemistry,biochemistry, and many other chemical processes. A majority of natural products are generated by radical-generating enzymes. In living organisms, the radicalssuperoxide andnitric 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 dubbedredox signaling. A radical may be trapped within asolvent cage or be otherwise bound.
Radicals are either (1) formed from spin-paired molecules or (2) from other radicals. Radicals are formed from spin-paired molecules throughhomolysis of weak bonds or electron transfer, also known as reduction. Radicals are formed from other radicals through substitution,addition, and elimination reactions.
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.[3] The homolyticbond dissociation energies, usually abbreviated as "ΔH °" are a measure of bond strength. Splitting H2 into 2 H•, for example, requires a ΔH ° of +435kJ/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.[citation needed]
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.[4]
Homolysis of dibenzoyl peroxide producing two benzoyloxy radicals
The deep colour oflithium naphthalene results 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 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 ofdrying oils, such aslinoleic acid derivatives.
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.[5][6]
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.[7]
A radical elimination reaction of a benzoyloxy radical
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, andFremy's salt (Potassium nitrosodisulfonate, (KSO3)2NO) is a related example. Manythiazyl radicals are known, despite limited πresonance stabilization (see below).[8][9]
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 stabilizesbenzyl radicals, but those radicals undergo rapid,diffusion-limited dimerization. Under normal conditions, their kinetic lifetimemeasures in nanoseconds.[10] Conversely, H• is highly reactive (thermodynamically unstable), but also themost abundant chemical in the universe (kinetically stable)because it exists primarily in low-density environments.[citation needed]
Following Griller and Ingold's extremely influential 1976 review,[10] modern chemists call a carbon-centered radical R•stabilized if the corresponding R–H bond isweaker than in analkane; the radical ispersistent if the radical lifetime lasts longer than the encounter limit.[11] Persistence is almost exclusively a steric effect.[10] However, orbitals of highangular momentum (d orf), delocalization, and theα effect can all make organic radicals stabilized.
Molecular orbital diagram of a radical with an electron-donating groupMolecular orbital diagram of a radical with an electron-withdrawing group
Inmolecular orbital theory, a radical electronic structure is characterized by ahighest-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-upwithout loss of generality.[3]: 977 Radical compounds are thermodynamically unstable becausefixed nuclear positions cannot simultaneously minimize the filledspin-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 ad orbital,[12] which requires onlyJahn-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]
The relative stabilities of tertiary, secondary, primary and methyl radicals can be explained by hyperconjugation
Many of the abovefunctional groups areelectron-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".[16]
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, athree-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 resultinghybrid 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 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.[citation needed]
Most main-group radicals are in notional equilibrium withclosed-shell dimers. For example,nitrogen dioxide equilibrates withdinitrogen tetroxide, andtributyltin radicals equilibrate withhexabutyldistannane [de]. Consequently radicals may be stabilized when thedimeric 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.[17] Likewise, thequinonic loss of aromaticity inGomberg's dimer predisposes the compound towards homolysis.
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 toHund's rule of maximum multiplicity. The relative stability of the oxygen diradical is primarily due to thespin-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.[19] Diradicals can also occur inmetal-oxo complexes, lending themselves for studies ofspin forbidden reactions intransition metal chemistry.[20]Carbenes in their triplet state can be viewed as diradicals centred on the same atom, while these are usually highly reactivepersistent carbenes are known, with N-heterocyclic carbenes being the most common example.
Tripletcarbenes andnitrenes are diradicals. Their chemical properties are distinct from the properties of their singlet analogues.
A familiar radical reaction iscombustion. Theoxygen molecule is a stablediradical, best represented by•O–O•. Becausespins of the electrons are parallel, this molecule is stable. While theground state of oxygen is this unreactive spin-unpaired (triplet) diradical, an extremely reactive spin-paired (singlet) state is available. For combustion to occur, theenergy 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. Theflammability of a given material strongly depends on the concentration of radicals that must be obtained before initiation and propagation reactions dominate leading tocombustion 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).
Manypolymerization 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 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 addition steps:
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, O2 reacts with many organic compounds to generate radicals together with thehydroperoxide radical.Drying oils and alkyd paints harden due to radical crosslinking initiated by oxygen from the atmosphere.
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 ofnitrogen dioxide to an oxygen atom andnitric oxide (seeeq. 1.1 below), which plays a key role insmog formation—and the photodissociation of ozone to give the excited oxygen atom O(1D) (seeeq. 1.2 below). The net and return reactions are also shown (eq. 1.3 andeq. 1.4, respectively).
eq. 1.1
eq. 1.2
eq. 1.3
eq. 1.4
In the upper atmosphere, the photodissociation of normally unreactivechlorofluorocarbons (CFCs) by solarultraviolet radiation is an important source of radicals (see eq. 1 below). These reactions give thechlorine radical, Cl•, which catalyzes the conversion ofozone to O2, thus facilitatingozone depletion (eq. 2.2–eq. 2.4 below).
eq. 2.1
eq. 2.2
eq. 2.3
eq. 2.4
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 asrefrigerants has been restricted.
Structure of thedeoxyadenosyl radical, a common biosynthetic intermediate[21]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 asgranulocytes andmacrophages. Radicals are involved incell signalling processes,[22] known asredox signaling. For example, radical attack oflinoleic acid produces a series of13-hydroxyoctadecadienoic acids and9-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.[23]
Radicals may also be involved inParkinson's disease, senile and drug-induceddeafness,schizophrenia, andAlzheimer's.[24] 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 pigmentarymelanin abnormalities, deafness, arthritis, and diabetes mellitus. Thefree-radical theory of aging proposes that radicals underlie theaging 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 theenzymessuperoxide dismutase,catalase,glutathione peroxidase andglutathione reductase. In addition,antioxidants play a key role in these defense mechanisms. These are often the three vitamins,vitamin A,vitamin C andvitamin E andpolyphenol antioxidants. Furthermore, there is good evidence indicating thatbilirubin anduric acid can 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.[25]
Reactive oxygen species or 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 ofoxygen and have important roles in cell signaling.Two important oxygen-centered radicals aresuperoxide andhydroxyl 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,diabetes and major disorders.[26] Many forms ofcancer are thought to be the result of reactions between radicals andDNA, potentially resulting inmutations that can adversely affect thecell cycle and potentially lead to malignancy.[27] Some of the symptoms ofaging such asatherosclerosis are also attributed to radical induced oxidation of cholesterol to 7-ketocholesterol.[28] In addition radicals contribute toalcohol-inducedliver damage, perhaps more than alcohol itself. Radicals produced bycigarettesmoke are implicated in inactivation ofalpha 1-antitrypsin in thelung. This process promotes the development ofemphysema.
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, liketitanium oxide andoctyl methoxycinnamate.[29]
Reactive oxygen species are also used in controlled reactions involving singlet dioxygen known as type IIphotooxygenation reactions afterDexter 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 newpoylmethine dyes.[31]
In chemical equations, radicals are frequently denoted by a dot placed immediately to the right of the atomic symbol or molecular formula as follows:
Radicalreaction mechanisms use single-headed arrows to depict the movement of single electrons:
Example of an arrow-pushing mechanism for an internal radical reaction.
Thehomolytic 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.
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:
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 group or 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 group orsubstituent, 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 theory was developed.Louis-Bernard Guyton de Morveau introduced the phrase "radical" in 1785 and the phrase was employed byAntoine Lavoisier in 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 termradical inradical theory was also used for bound parts of the molecule, especially when they remain unchanged in reactions. These are now calledfunctional 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 inmass spectrometry when broken apart by irradiation with energetic electrons.
In most fields of chemistry, the historical definition of radicals contends that the molecules have nonzero electron spin. However, in fields includingspectroscopy andastrochemistry, 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]
^Gridnev, Alexei A.; Ittel, Steven D. (2001). "Catalytic Chain Transfer in Free-Radical Polymerizations".Chemical Reviews.101 (12):3611–3660.doi:10.1021/cr9901236.PMID11740917.
^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,ISBN978-3-642-38730-2
^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.ISBN978-0-12-020762-6.
^abcGriller, David; Ingold, Keith U. (1976). "Persistent carbon-centered radicals".Accounts of Chemical Research.9:13–19.doi:10.1021/ar50097a003.
^Power, Philip P. (2003) [19 July 2002]. "Persistent and stable radicals of the heavier main group elements and related species".Chemical Reviews.103. American Chemical Society: 789.doi:10.1021/cr020406p.
^Carey, Francis A.; Sundberg, Richard J. (1984).Advanced Organic Chemistry. Vol. A: Structures and Mechanisms (2 ed.). New York: Plenum.ISBN0-306-41087-7.LCCN84-8229.
^Hicks 2011, p. 231. sfn error: no target: CITEREFHicks2011 (help)
^Carey & Sundberg 1984, pp. 649–650. AsSmith (2023),March's Organic Chemistry (8th ed.) pp. 254, 256 notes, a contrary view is suggested in
Gronert, S. (2006) inJ. Org. Chem., vol. 71, pp. 7045–;
——— (2007) inOrg. 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 fromESR studies. However, there is also experimental and theoretical evidence against it," with extensive citations on both sides.
^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.doi:10.1021/ja9809915.
^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.PMID10381209.
^An overview of the role of radicals in biology and of the use of electron spin resonance in their detection may be found inRhodes C.J. (2000).Toxicology of the Human Environment – the critical role of free radicals. London: Taylor and Francis.ISBN978-0-7484-0916-7.
^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.doi:10.1007/s10811-010-9564-0.S2CID27537163.
^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.doi:10.1039/b206338g.PMID12661594.S2CID27248506.
^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.doi:10.1021/ja01333a041.
