📋 Table of Contents
1. Free Radicals as Intermediates
Free radicals sit at the heart of some of chemistry's most important processes — from the rancidity of fats to how living organisms process atmospheric oxygen. Structurally, they are defined by one thing: the presence of one or more unpaired electrons. That lone electron gives them their characteristic paramagnetism and often a distinct colour. Unlike carbocations and carbanions (which carry a formal charge), free radicals are electrically neutral fragments formed by homolytic cleavage of a covalent bond, where each fragment retains one electron of the shared pair.
The general scheme of homolysis can be written as:
Free radicals serve as intermediates in photochemical substitution reactions, certain addition reactions, auto-oxidation of organic compounds, the Sandmeyer reaction, and — most commercially important — vinyl polymerisation.
1.1 Generation of Free Radicals
Radicals can be generated by three broad routes: photolysis, thermolysis, and redox reactions. Each has its advantages and is chosen based on the bond strength of the molecule and the reaction conditions required.
1.1.1 Generation by Photolysis
Photochemical dissociation is perhaps the cleanest method. The molecule must absorb radiation in the UV or visible range. Radiation of wavelength 600–300 nm carries energy of 200–400 kJ mol⁻¹, which is comparable to most covalent bond energies. When the absorbed energy matches the bond dissociation energy, homolysis occurs.
Acetone (propanone) in the vapour phase is one of the most studied examples. It does not undergo thermal homolysis readily, yet irradiation at 320 nm cleaves it cleanly:
The photocleavage first breaks one of the methyl-carbonyl bonds, giving a methyl radical and an acetyl radical. The acetyl radical is unstable and spontaneously loses CO to yield a second methyl radical.
Alkyl hypochlorites and nitrites also provide alkoxyl radicals cleanly on photolysis:
Chlorine itself needs 244 kJ mol⁻¹ for dissociation, achievable either by irradiation at 487.5 nm or by heating to 525 K:
Two major advantages of photolysis are worth remembering for exams. First, bonds that simply won't break at reasonable temperatures — azoalkanes, for example — can be cleaved selectively. Second, because only specific wavelengths are absorbed, a particular bond can be targeted without disturbing others in the same molecule.
1.1.2 Generation by Thermolysis
Thermal cleavage in the gaseous phase occurs readily at high temperatures. In solution, thermolysis works when the molecule contains bonds with dissociation energies below about 165 kJ mol⁻¹. Two major classes meet this criterion: peroxides (O–O bond, ~120 kJ mol⁻¹) and azo compounds (C–N bond).
Dibenzoyl peroxide is the most widely used radical initiator. The molecule consists of two dipoles joined at their negative ends; the electrostatic repulsion between the two negatively polarised oxygens assists homolysis.
The kinetics of peroxide decomposition follow first-order kinetics and are sensitive to structure. Phenylpropionyl peroxide (C₆H₅CH₂CH₂COO)₂ has a half-life of only 0.5 h at 375 K and cannot even be isolated under ordinary conditions. By contrast, (CH₃)₃CCOO)₂ has a half-life of 200 h at the same temperature.
AIBN (2,2-Azo-bis-isobutyronitrile) is the gold-standard azo radical initiator. Two factors conspire to make its decomposition easy: N₂ is an excellent leaving group, and the resulting radical is stabilised by delocalisation of the unpaired electron over the adjacent –C≡N group. Despite this, simple alkyl azo compounds (e.g., CH₃–N=N–CH₃) are stable up to 475 K, while AIBN has a half-life of only 5 minutes at 375 K.
Aryl azo compounds dissociate more readily still — triphenylmethyl azo derivatives fragment at 325 K.
Pyrolysis (cracking) of long-chain alkanes at 875 K generates radicals via C–C bond homolysis. A radical abstracts a hydrogen from a methylene group, and the resulting secondary radical undergoes β-fission to give a lower alkene plus a new radical that continues the chain.
Other Examples
1.1.3 Generation by Redox Reactions
The key advantage of redox-based generation is that radical production occurs at mild temperatures (275–325 K), avoiding the harsh conditions of thermolysis.
Fenton's reagent (FeSO₄ + H₂O₂) is the classic redox radical source. Fe²⁺ partially reduces H₂O₂ to give hydroxyl radicals:
The presence of •OH radicals is confirmed by the ability of Fenton's reagent to initiate vinyl polymerisation.
Cu⁺ ions accelerate decomposition of aroyl peroxides and are also involved in the Sandmeyer reaction, where diazonium salts (ArN₂⁺) are converted to ArCl via a radical intermediate:
Electrolytic methods also work. In Kolbe's electrolytic synthesis, carboxylate anions are oxidised at the anode to carboxylate radicals, which lose CO₂ to give alkyl radicals that dimerise:
Similarly, Grignard reagents can be electrolysed in ether to yield alkyl or aryl radicals. Cathodic reduction of ketones in aqueous acid produces radical anions (R₂C–OH)⁻• which then dimerise to pinacols.
1.2 Structure of Free Radicals
A carbon radical (R₃C•) can adopt one of two geometries: planar (sp² hybridised, unpaired electron in a p orbital) or pyramidal (sp³ hybridised, unpaired electron in an sp³ orbital). Most simple radicals fall somewhere between the two extremes.
EPR spectroscopy provides the best experimental insight. The EPR spectrum of the methyl radical shows negligible 's' character in the orbital holding the odd electron, suggesting a geometry that is planar or a very shallow pyramid — so flat that the two are practically indistinguishable.
Fluorine substitution progressively distorts the geometry toward pyramidal. The 's' character increases across the series:
The •CF₃ radical is essentially pyramidal — the repulsive interaction between the singly occupied p orbital and the lone pairs on fluorine atoms is minimised by adopting pyramidal geometry. Oxygen-containing substituents behave similarly.
The most important structural rule: allylic and benzylic radicals are planar, because π-delocalisation of the odd electron requires all p orbitals of the conjugated system to be parallel. EPR, IR, and electron diffraction studies all confirm this.
At the other extreme, radicals at bridgehead carbons of bicyclic systems (like the apocamphyl radical) are forced into pyramidal geometry by the ring geometry. This is why bridgehead carbocations are nearly impossible while bridgehead radicals do form — radicals tolerate pyramidal geometry, carbocations do not.
The stereochemical consequence of radical geometry is crucial for synthesis. A planar radical (or a rapidly inverting pyramidal one) leads to racemic products, since attack from either face is equally probable. A rigid pyramidal radical would preserve configuration. In practice, most carbon radicals react with near-complete racemisation.
1.3 Stability of Free Radicals
The stability of free radicals spans a remarkable range — from •CH₃ (half-life of milliseconds) to 1,1-diphenyl-2-picrylhydrazyl radical, which can be crystallised from solvents and stored indefinitely. Understanding what governs this range is one of the most conceptually rich areas of radical chemistry.
Bond dissociation energy (BDE) is the primary quantitative measure. The smaller the BDE of the bond that generates the radical, the more stable the resulting radical. Key values from the chapter:
| Bond | D (kJ mol⁻¹) | Bond | D (kJ mol⁻¹) |
|---|---|---|---|
| CH₃–H | 426 | Cl–H | 430 |
| C₂H₅–H | 410 | Br–H | 364 |
| n-C₃H₇–H | 397 | I–H | 297 |
| (CH₃)₂CH–H | 372 | Cl–Cl | 242 |
| (CH₃)₃C–H | 360 | Br–Br | 192 |
| C₆H₅CH₂–H | 326 | F–F | 155 |
| C₆H₅–H | 426 | I–I | 150 |
| CH₃–CH₃ | 347 | HO–OH | 217 |
| H–H | 435 | CH₃–F | 451 |
Three electronic factors and one steric factor govern radical stability:
1. Inductive Effect: Alkyl groups donate electrons inductively, reducing the "electron deficiency" of the radical centre. More alkyl groups = more stable radical. This gives the familiar order:
2. Hyperconjugation: The odd electron in an alkyl radical delocalises onto the β-hydrogens through hyperconjugation. The tert-butyl radical has 9 β-hydrogens and thus 9 hyperconjugative structures, a sec-butyl radical has 5, and an n-butyl radical has only 2. More hyperconjugative structures mean greater stability.
3. Resonance: When the radical centre is conjugated with a π system (allylic, benzylic), the odd electron is delocalised over multiple atoms, dramatically increasing stability. Both allylic and benzylic radicals must be planar for maximum p-orbital overlap — a geometry requirement that also explains their resistance to dimerisation.
The triphenylmethyl radical (Gomberg's radical, 1900) is doubly stabilised: resonance delocalisation of the unpaired electron over three phenyl rings, combined with steric bulk that physically prevents two radicals from approaching close enough to form a bond.
4. Steric Effects: Formation of the tert-butyl radical by H-abstraction from isobutane is actually assisted by steric relief — the bond angle widens from ~109° (sp³) to ~120° (approaching sp²), releasing methyl-methyl repulsion.
The overall stability order of common radicals:
Beyond carbon radicals, important heteroatom radicals include nitrogen radicals such as diphenylamino radical and the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, sulphur radicals like phenylthiyl radical (from diphenyl disulphide), oxygen-centred radicals like 2,6-di-tert-butylphenoxy radical (stable in both solution and solid state), and peroxide-derived radicals.
1.4 Detection of Free Radicals
Three principal methods are used to detect radical intermediates.
Radical Inhibitors and Initiators: Adding a radical inhibitor like benzoquinone slows a radical-mediated reaction without affecting an ionic one. Conversely, adding an initiator like benzoyl peroxide speeds up radical reactions. This simple technique can tell you whether a reaction mechanism involves a radical intermediate.
Trapping Reactions: DPPH radical traps other radicals to form stable colourless products. Since DPPH is intensely coloured (purple), the bleaching of its colour provides a visual, colorimetric signal of radical presence.
ESR / EPR Spectroscopy: This is the most powerful and direct technique. Since radicals have unpaired electrons, they possess a net magnetic moment. When placed in a magnetic field, an unpaired electron can align with or against the field — two energy states. Absorption of microwave radiation causes a transition between these states, generating the ESR spectrum.
At high resolution, the single ESR line splits due to coupling of the odd electron with adjacent protons. If n protons couple equally, the spectrum shows n + 1 lines. The methyl radical •CH₃ (3 equivalent protons) shows 4 lines. The cycloheptatrienyl radical •C₇H₇ (7 equivalent protons) shows 8 equally spaced lines, directly confirming that the odd electron is delocalised equally over all 7 positions.
ESR spectroscopy can detect radicals at concentrations as low as 10⁻⁸ M. Phenyl radical in solutions of benzoyl peroxide can be detected at a concentration of about 2.5 × 10⁻⁶ g L⁻¹.
1.5 Mechanism of Free Radical Reactions
Once started, radical reactions typically tear through a substrate at great speed because they propagate via chain reactions. A single initiation event can trigger thousands of bond-forming and bond-breaking steps before termination occurs. The three phases — initiation, propagation, termination — are distinctly defined and each plays a different kinetic role.
Initiation: An energy-consuming, slow step that generates the first radicals. Compounds with weak bonds (peroxides, azo compounds, halogens) serve as initiators, generating radicals on thermolysis or photolysis.
Propagation: Each propagation step generates a new radical from a non-radical species and a molecule with an even number of electrons. The number of productive propagation cycles per initiation event is the kinetic chain length. For photochemical chlorination of methane:
The chlorine radical here is a chain carrier — it is consumed in step 1 and regenerated in step 2.
Termination: Two radical species combine to give a neutral, even-electron molecule. Termination is exothermic. The kinetic chain length is inversely related to the frequency of termination events. For chlorination of methane, termination involves:
1.5.1 The SRN1 Mechanism
The SRN1 mechanism — Substitution, Radical, Nucleophilic, Unimolecular — was discovered by Bunnett and Kim in 1970 and is designated T + DN + AN by IUPAC. It describes aromatic nucleophilic substitution proceeding through radical anion intermediates rather than the classical addition-elimination (SNAr) pathway.
The mechanism begins with a single electron transfer (SET) from an external donor to the aryl halide substrate, producing a radical anion. This radical anion then expels the halide leaving group, generating an aryl radical. The nucleophile attacks the aryl radical, forming a new radical anion which transfers its extra electron to another molecule of substrate, propagating the chain:
| Step | Reaction |
|---|---|
| Initiation | e⁻ + ArX → [ArX]⁻• |
| Propagation 1 | [ArX]⁻• → Ar• + X⁻ |
| Propagation 2 | Ar• + Y⁻ → [ArY]⁻• |
| Propagation 3 | [ArY]⁻• + ArX → ArY + [ArX]⁻• |
| Overall | ArX + Y⁻ → ArY + X⁻ |
1.5.2 The Cage Effect and Non-Chain SRN1 Reactions
In solution, newly formed radical pairs are initially surrounded by a "cage" of solvent molecules that restricts their immediate separation. Before they can diffuse apart, some radical pairs couple inside the cage — this is the cage effect or radical cage effect.
The classic demonstration involves triphenylmethyl radical. Instead of giving hexaphenylethane (Ph₃C–CPh₃) as expected from simple dimerisation, the actual product is the Gomberg dimer — a compound where one phenyl group has added across the double bond of another triphenylmethyl unit. The cage effect drives this unusual product distribution.
Non-chain SRN1 reactions occur inside these solvent cages, where the restriction of movement prevents chain propagation. Stepwise substitution within the cage gives the product directly without chain amplification.
1.6 Free Radical Reactions
1.6.1 Halogenation (Substitution Reactions)
Halogenation of alkanes is the most important free radical substitution reaction. All four halogens have been studied, and the differences in their reactivities and selectivities are highly instructive.
Chlorination requires 244 kJ mol⁻¹ for initiation. Both propagation steps are exothermic, so the chain length is long and the reaction can become explosive. Hydrogen atoms are substituted in the order tertiary > secondary > primary, consistent with radical stability. In chlorination of propane, n-propyl and isopropyl chlorides form in a 1:1 ratio despite there being 6 primary and only 2 secondary hydrogens — showing that secondary H abstraction is 3× faster per hydrogen atom.
Bromination is fundamentally different. The H-abstraction step is endothermic for bromine (ΔH = +63 kJ mol⁻¹ for methane), unlike the exothermic H-abstraction by chlorine. This means bromine is far less reactive — but far more selective. Gaseous bromination of isobutane gives 99% tertiary bromide, even though probability factors favour the primary product 9:1.
N-Bromosuccinimide (NBS) is the reagent of choice for allylic and benzylic bromination. NBS maintains a very low concentration of molecular bromine in solution by reacting with any HBr that forms:
The low bromine concentration ensures allylic/benzylic radical formation is preferred over addition to double bonds, because the resonance-stabilised allylic radical is the thermodynamic sink of the reaction.
Iodination of alkanes is practically impossible. The H-abstraction step has ΔH = +130 kJ mol⁻¹ — strongly endothermic. HI is in fact a reducing agent for alkyl iodides.
Fluorination is the opposite extreme — it is uncontrollably exothermic (both propagation steps are highly exothermic, −138 and −296 kJ mol⁻¹). Fluorination must be carried out in the gas phase, diluted with nitrogen, and it can even occur in the dark at 195 K without initiators.
Polar Effects in Halogenation: Radical stability alone does not always determine which hydrogen is abstracted. In the photochlorination of 1-chlorobutane, the α-carbon (adjacent to Cl) is actually the least reactive despite being secondary, because the electronegative Cl substituent destabilises the developing radical at the adjacent position. The relative reactivities in 1-chlorobutane are:
1.6.2 Addition Reactions
Free radical addition reactions include addition of halogens and hydrogen halides to alkenes, telomerisation, and polymerisation.
Addition of chlorine and bromine to ethene in the vapour phase or non-polar solvents under light proceeds through a radical mechanism. Addition of iodine is endothermic and does not proceed. An important consequence of bromine addition to alkenes is their cis-trans isomerisation — bromine radicals add reversibly, and rotation around C–C in the intermediate allows equilibration to the more stable trans isomer.
Anti-Markovnikov Addition of HBr (Peroxide / Kharasch Effect): In the presence of peroxides or light, HBr adds to propene to give 1-bromopropane (anti-Markovnikov), rather than the ionic 2-bromopropane:
| Conditions | Mechanism | Intermediate | Product |
|---|---|---|---|
| No peroxide (dark) | Ionic | 2° carbocation | 2-bromopropane (Markovnikov) |
| Peroxide (light) | Radical | 2° free radical | 1-bromopropane (anti-Markovnikov) |
The key: in radical addition, bromine atom (not H⁺) adds first to the terminal carbon, generating the more stable secondary radical at the internal carbon. That secondary radical then abstracts H from HBr to give the product and a new Br• (chain propagation).
This peroxide-catalysed anti-Markovnikov addition is exclusively observed for HBr — not HCl (second propagation step endothermic) or HI (first step endothermic).
Radical addition of HBr is stereospecifically trans at low temperature. Addition of DBr to cis-2-butene gives the trans addition product, confirming the radical mechanism's stereoselectivity.
1.6.3 Auto-Oxidation
Auto-oxidation is a radical chain reaction initiated by oxygen (a diradical itself) or UV radiation. It produces peroxides and hydroperoxides from organic substrates under mild conditions.
The general mechanism:
In many cases the hydroperoxide product itself decomposes to generate new radicals, making the reaction autocatalytic. This is why diethyl ether stored for a long time forms explosive hydroperoxides.
H-abstraction by oxygen follows the same selectivity as other radicals: tertiary > secondary > primary, with allylic and benzylic positions particularly reactive. Linseed oil "dries" (hardens) partly through oxidative cross-linking of its unsaturated fatty acid chains.
Benzaldehyde auto-oxidises to benzoic acid via a perbenzoate radical intermediate, catalysed by Fe³⁺/Fe²⁺ redox cycling. Antioxidants like phenols or aromatic amines inhibit aldehyde auto-oxidation by donating H• to the peroxy radical, breaking the chain.
Lead tetra-acetate cleaves 1,2-glycols (vicinal diols) via a radical mechanism — a diradical obtained from the glycol fragments into two ketone molecules. Notably, cis diols are cleaved faster than trans diols, consistent with the cyclic intermediate proposed.
1.6.4 Rearrangements
Unlike carbocations (which rearrange readily), free radical rearrangements are uncommon. The energy barrier to 1,2-alkyl migration in radicals is much higher. However, 1,2-aryl migration does occur, because the migrating phenyl can form a bridged (cyclic) intermediate stabilised by delocalisation.
1.7 Radical Ions
A radical ion combines the features of a radical (unpaired electron) and an ion (net charge). When a neutral radical gains an electron it becomes a radical anion; when it loses an electron it becomes a radical cation.
Radical Anions (Semiquinones): Controlled reduction of quinones in basic solution produces semiquinones, which are moderately stable radical anions. On acidification, semiquinones disproportionate to quinone + hydroquinone, which can form π-molecular complexes (e.g., quinhydrone). Semiquinones are characterised by ESR spectroscopy.
Wurster Radical Cations occupy the most stable end of the radical cation spectrum. In these species, both the positive charge and the unpaired electron are extensively delocalised over the aromatic π system. The N,N,N',N'-tetramethyl-p-phenylenediamine radical cation is the archetypal example.
At the other extreme, CH₄⁺• (methane radical cation) is extremely unstable, formed only in the gas phase by electron bombardment in mass spectrometry.
2. Carbenes as Intermediates
Carbenes are among the most reactive species in organic chemistry — neutral, divalent carbon intermediates with only six electrons in their valence shell. The simplest is methylene (:CH₂), where carbon forms two C–H bonds and retains two non-bonding electrons. With only a sextet, carbenes are intensely electron-deficient and expected to be nucleophilic, yet they exhibit predominantly electrophilic behaviour in reactions.
The isoelectronic comparison is instructive: dimethylcarbene (CH₃)₂C: is isoelectronic with trimethylborane (CH₃)₃B — both have an electron-sextet at the central atom, both act as electrophiles.
2.1 Generation of Carbenes
Carbenes are generated in situ — they are far too reactive to be isolated and stored.
From Diazomethane or Ketene (Photolysis/Thermolysis):
Diazomethane and ketene are isoelectronic, as are N₂ and CO — a useful conceptual parallel.
From Haloalkanes (α-Elimination): Treatment of chloroform with potassium tert-butoxide generates dichlorocarbene via α-elimination (simultaneous loss of H and Cl from the same carbon):
Similarly, CH₂Cl₂ + n-BuLi → :CHCl (chlorocarbene). This is α-elimination (1,1-elimination), in contrast to the usual β-elimination (1,2-elimination).
From Methylene Iodide (Simmons-Smith Reaction):
The intermediate ICH₂ZnI is a carbenoid — not a true carbene but a carbene-like species that reacts similarly. The Simmons-Smith reaction is the standard method for stereospecific cyclopropanation of alkenes.
From Sodium Trichloroacetate:
From p-Tosylhydrazones: Thermal or photochemical decomposition of the alkali metal salts of p-toluenesulfonylhydrazones of aldehydes/ketones generates carbenes via diazo intermediates.
From Epoxides: Photolysis of epoxides (themselves made from olefins by peracid epoxidation) generates carbenes.
From Diazirines: Diaziridines are oxidised to diazirines, which on photolysis give carbenes + N₂.
From Tetrazoles: Thermolysis opens the tetrazole ring with sequential loss of two N₂ molecules, eventually yielding a carbene.
From Ylides: Thermal or photolytic decomposition of sulfonium ylides gives carbenes + dimethylsulfide.
From Trichloromethyltrihalosilanes: Pyrolysis at 250°C gives :CCl₂ + SiX₃Cl.
2.2 Structure and Stability of Carbenes
The electronic spectra of carbenes reveal two distinct electronic states — singlet and triplet — which differ in both geometry and reactivity.
In a carbene, two of carbon's four low-energy orbitals are used for bonding. The remaining two orbitals accommodate the two non-bonding electrons. If both electrons occupy the same orbital with paired (antiparallel) spins, the carbene is in the singlet state. If they occupy different orbitals with parallel spins, it is in the triplet state (a diradical).
| Property | Singlet Carbene | Triplet Carbene |
|---|---|---|
| Electron spins | Antiparallel (paired) | Parallel (unpaired) |
| Hybridisation | sp² (bent) | sp (linear/near-linear) |
| RCR bond angle | 103–110° | 136–180° |
| Behaviour | Like R₃C⁺ (electrophile) | Like diradical (radical-like) |
| Formed in | Liquid phase photolysis | Gas phase photolysis (+ inert gas) |
| Stability | Less stable (electron repulsion) | More stable (ground state) |
| Addition stereochemistry | Stereospecific (concerted syn) | Non-stereospecific (stepwise) |
Changeover from singlet to triplet state is called inter-system crossing. In liquid-phase photolysis of diazomethane, singlet methylene is generated initially; in gas-phase photolysis with an inert gas present, collisions cause inter-system crossing to the triplet.
Substituents bearing lone pairs (halogens, oxygen, nitrogen) stabilise carbenes by donating electrons into the vacant p orbital, creating partial double-bond character (e.g., :CCl₂ is stabilised by Cl lone pair donation).
2.3 Reactions of Carbenes
Carbenes typically undergo three types of reactions: cycloaddition, insertion, and rearrangement.
2.3.1 Cycloaddition Reactions
Addition of a carbene across a C=C double bond is the most synthetically important carbene reaction and gives a cyclopropane ring. Singlet carbene adds in a concerted, stereospecific manner (retention of alkene geometry). Triplet carbene adds stepwise via a diradical intermediate, losing stereochemical information.
Dichlorocarbene adds to trans-2-butene to give exclusively trans-dimethyldibromocyclopropane, confirming singlet (concerted) addition:
The syn addition of a carbene to a cyclic alkene gives a bicyclic product with cis bridgehead stereochemistry. Addition of chlorocarbene to cyclohexene gives 7-chloronorcarnane (cis-bicyclo[4.1.0]heptane).
In heterocyclic chemistry, carbene cycloaddition followed by ring-opening can expand rings. The reaction of pyrrole with chloroform/KOH (via :CCl₂) expands the 5-membered ring to give 3-chloropyridine — a 5→6 ring expansion.
2.3.2 Insertion Reactions
Singlet methylene inserts into C–H bonds of alkanes, alcohols, acids, and even benzene. The mechanism involves attack on the back lobe of the C–H bond, leading to inversion of configuration at the insertion site.
Insertion into propane gives both butane (63%) and 2-methylpropane (37%), showing that singlet methylene inserts without strong selectivity for H-type (though tertiary is slightly preferred).
Insertion into O–H bonds of alcohols and acids provides the most convenient synthesis of methyl ethers and esters:
Methylene also inserts into benzene to give cycloheptatriene — a ring expansion of the 6-membered ring to 7.
Dichlorocarbene and Simmons-Smith carbene do not show insertion reactions — they react exclusively via cycloaddition.
2.3.3 Rearrangement Reactions
Wolff Rearrangement: α-Diazoketones, on treatment with Ag₂O or UV light, give carbene intermediates that rearrange by 1,2-shift to ketenes. Ketenes are then trapped by nucleophilic solvents.
The Wolff rearrangement is the key step in Arndt-Eistert synthesis, which converts a carboxylic acid into its next higher homologue (one extra carbon).
Ring Contraction: When a cyclic diazoketone decomposes, the Wolff rearrangement contracts the ring by one carbon.
Reimer-Tiemann Reaction: Phenol + CHCl₃ + KOH → o-hydroxybenzaldehyde. Dichlorocarbene generated from chloroform attacks the electron-rich phenoxide ring, ultimately giving the aldehyde after hydrolysis.
Carbylamine Reaction: Primary amine + CHCl₃ + KOH → isocyanide (carbylamine, bad smell). Dichlorocarbene reacts with the primary amine, and elimination of HCl gives the isocyanide. This is a test for primary amines.
Wittig Reaction: Dichlorocarbene reacts with triphenylphosphine to give a phosphorus ylide (:CCl₂–PPh₃⁺), which then reacts with a ketone to give a 1,1-dichloroalkene.
Ethylorthoformate Synthesis: :CCl₂ + EtOH → EtO–CHCl₂ → (EtO)₃CH + 2Cl⁻. Used industrially.
3. Nitrenes as Intermediates
Nitrenes are the nitrogen analogues of carbenes — neutral, monovalent nitrogen species with only six valence electrons. The nitrene NH is also known as imidogen, azene, or imene. Like carbenes, they are highly reactive with lifetimes of a few microseconds. Unlike carbenes, nitrenes are slightly more stable due to the lower N–H dissociation energy of the amine radical compared to C–H.
The generation, structure, and reactions of nitrenes closely parallel those of carbenes, making comparative questions common in exams.
3.1 Generation of Nitrenes
From Azides (Thermolysis or Photolysis): The most common method. Azides lose N₂ to give nitrenes, analogous to diazo compounds losing N₂ to give carbenes:
Hydrazoic acid (HN₃) on UV irradiation gives HN:. Sulfonyl azides, azidoformates, aryl azides, and alkyl azides all work similarly. Cyanogen azide (NCN₃) gives cyanonitrene (NC–N:) on photolysis at 210–300 nm.
Thermolysis of phenyl azide in aniline gives 2-phenylamino-3H-azepine via ring expansion — a nitrene undergoes ring expansion of the benzene ring to a 7-membered azepine.
From Oxidation-Reduction Reactions: Some substrates generate nitrenes through redox: - Cyanamide + PhI(OAc)₂ → NC–N: (cyanonitrene) - R₂N–NH₂ + Pb(OAc)₄ → R₂N–N: + Pb(OAc)₂ - Nitrosobenzene + P(OEt)₃ → Ph–N: + O=P(OEt)₃
These redox methods have no analogue in carbene chemistry — an important distinction.
From Isocyanates: Photolysis expels CO, analogous to carbene generation from ketenes:
From Oxaziridines: Photolysis of the strained 3-membered O–N–C ring gives carbene + nitrene fragments.
From Sulfinylamines: Gas-phase pyrolysis of Ph–N=S=O gives Ph–N: + SO.
From N-Benzenesulphonoxy Carbamates: Base-induced elimination of benzenesulphonate generates carboalkoxynitrene :N–CO–OEt.
3.2 Structure and Stability of Nitrenes
Like carbenes, nitrenes exist as singlet and triplet forms:
| Property | Singlet Nitrene | Triplet Nitrene |
|---|---|---|
| Non-bonding electrons | Two paired lone pairs + empty p | One lone pair + two unpaired electrons (parallel) |
| Behaviour | Electrophilic, inserts into C–H | Diradical, abstracts H |
| Addition | Stereospecific to alkenes | Non-stereospecific |
| Initial state | Formed first from precursor | Formed after intersystem crossing |
| Ground state | — | Yes (lower energy) |
Nitrenes can be trapped by CO (giving isocyanate) and by alkenes (giving aziridines). The trapped products confirm their formation and allow characterisation.
3.3 Reactions of Nitrenes
3.3.1 Coupling / Dimerisation
At high nitrene concentrations (flash photolysis, inert solvents), two nitrene molecules couple:
Azobenzenes are frequently obtained as by-products in reactions involving aryl nitrenes.
3.3.2 Hydrogen Abstraction
Triplet nitrenes abstract H from C–H bonds. The mechanism involves formation of an amino radical and a carbon radical with parallel spins; since they cannot immediately couple (spin reversal required), the amino radical abstracts a second H from solvent to give a primary amine:
3.3.3 Insertion Reactions
Singlet nitrenes insert into C–H bonds to give amines or amides. The selectivity order is: tertiary C–H > secondary C–H > primary C–H, identical to singlet carbene insertion. Alkyl nitrenes give alkylamines; acyl nitrenes give amides.
A particularly elegant example is the stereospecific insertion of cyanonitrene (NC–N:) into cis and trans 1,2-dimethylcyclohexane. The singlet nitrene inserts with retention of configuration at the tertiary C–H, giving the cis or trans insertion product respectively with high selectivity.
In aromatic systems, intramolecular insertion gives products in good yield — useful for building ring systems. For example, 2-azidodiphenyl → 9H-carbazole via intramolecular C–H insertion.
3.3.4 1,3-Dipolar Cycloadditions
Nitrenes add to alkenes to give aziridines. Since nitrenes (and azides as nitrene precursors) are three-atom 4π dipolar species, they participate in 1,3-dipolar cycloadditions to give 5-membered ring products:
This is how photolysis of ethyl azidoformate in benzonitrile gives a 1,3,4-oxadiazole.
3.3.5 Rearrangement Reactions
Nitrene rearrangements are rapid — often occurring at the same time the nitrene forms. The dominant pathway is a 1,2-shift of an alkyl, aryl, or H group from the adjacent carbon to the electron-deficient nitrogen, giving an imine:
Acyl nitrenes (R–CO–N:) rearrange to isocyanates (R–N=C=O) by 1,2-shift of R from C to N. This is the mechanistic basis of three of the most important amine syntheses:
| Rearrangement | Starting Material | Key Intermediate | Product |
|---|---|---|---|
| Hofmann Rearrangement | RCONH₂ + Br₂/NaOH | Acyl nitrene R–CO–N: → isocyanate | RNH₂ (one C fewer) + CO₂ |
| Curtius Rearrangement | RCO–N₃ (acid azide, heat) | Acyl nitrene → isocyanate | RNCO → RNH₂ or RNHCOOR' |
| Schmidt Rearrangement | RCOOH + HN₃ / H⁺ | Azido intermediate → nitrene → isocyanate | RNH₂ + CO₂ |
The Curtius rearrangement applied to cyclopentane carboxylic acid using diphenylphosphoryl azide (DPPA) and t-BuOH gives the Boc-protected amine — a widely used amino acid synthesis strategy.
4. Arynes (Benzynes) as Intermediates
Arynes are the last group of reactive intermediates in this course, and they are among the most surprising — aromatic compounds that function as electrophiles toward nucleophiles. The simplest and most studied is benzyne (1,2-dehydrobenzene), formed by removal of two adjacent substituents from a benzene ring.
In aromatic nucleophilic substitution, two mechanisms operate. When electron-withdrawing groups (NO₂) activate the ring at ortho/para positions, addition-elimination (SNAr) predominates with clean, regiospecific substitution. When no activating groups are present — or when an electron-donating group is present — drastic conditions are required and the elimination-addition (benzyne) mechanism operates, often giving two products from a single substrate.
4.1 Generation of Benzynes
Benzynes have a lifetime of 10⁻⁵–10⁻⁴ seconds and cannot be isolated. Multiple routes generate them:
From o-Aminobenzoic Acid (Anthranilic Acid):
From Aryl Halides + Strong Base: KNH₂ or C₆H₅Li removes the ortho-H, and the resulting carbanion expels X⁻ to give benzyne. In protic solvents, the elimination is concerted; in aprotic solvents, it is stepwise. Ortho-dihalides treated with reactive metals also give benzynes.
From 1,2-Bromofluorobenzene via Grignard or Organolithium Reagents:
Rate follows: Na > Mg > Li >> Cu*.
From Iodophenyl Mercuric Iodide: Flash photolysis gives benzyne + HgI₂.
From Ortho-Diaminobenzene: Diazotisation with NaNO₂, then Pb(OAc)₄ at room temperature releases 2N₂ and gives benzyne.
From Benzenetrifluoromethane Sulphonate + LDA: Treatment at −70°C for 1–5 h generates benzyne.
From Benzenethiadiazole-1,1-Dioxide: Thermal decomposition releases SO₂ and N₂ to give benzyne.
From Phthaloyl Peroxide: Photolysis at 77 K gives benzyne via a lactone intermediate then loss of CO₂.
From Benzocyclobutadione: Photolysis at 77 K loses 2 CO to give benzyne.
From 3-Diazobenzofuranone: Photolysis at 77 K gives benzyne + 2CO₂ + N₂.
In the absence of a reagent to trap it, benzyne dimerises to diphenylene or trimerises (triphenylene) — both observations serve as chemical proof of benzyne formation.
4.2 Structure and Stability of Benzynes
Benzyne differs from benzene in having two fewer hydrogens and one extra bond between two ortho carbons — formally a C≡C triple bond. But this "triple bond" is very different from an alkyne triple bond.
In alkynes, the two sp carbons form a σ-bond using sp hybrid orbitals, and the two remaining p orbitals form two orthogonal π-bonds. This requires linearity (180° bond angle). In benzyne, the hexagonal geometry demands ~120° bond angles. The third bond cannot use sp orbitals; instead, it forms by lateral overlap of two sp² orbitals, giving a weak, strained π-bond in the plane of the ring.
This in-plane π-bond has little interaction with the aromatic π cloud (which is above and below the ring) and is severely strained — hence benzyne's extreme reactivity.
Benzyne can also be represented as a dipolar (zwitterionic) resonance structure. X-ray data consistent with this view show the C₁–C₂ bond length (1.22 Å) is shorter than C₂–C₃ (1.44 Å) and C₁–C₆ (1.42 Å), consistent with extra bonding character at C₁–C₂.
4.3 Reactions of Arynes
4.3.1 Orientation in Aryne Reactions
Two factors control where the incoming nucleophile ends up after the aryne is attacked:
Factor 1 — Acidity of H removed: When a substituent Z is at the ortho or para position of the leaving group X, only one benzyne can form. But with Z at the meta position, two different benzynes can form. The one derived by removing the more acidic H is preferred. Electron-withdrawing Z makes the ortho-H more acidic (favoured); electron-donating Z makes the para-H less acidic.
Factor 2 — Stability of carbanion on nucleophilic attack: The nucleophile can attack either carbon of the benzyne triple bond. It prefers the position that gives the more stable carbanion. For -I groups (electron withdrawing), the more stable carbanion has the negative charge closer to the substituent.
4.3.2 Amination Reactions (The Benzyne Proof)
The definitive proof of benzyne formation came from the reaction of ¹⁴C-labelled 1-chlorobenzene with KNH₂/liquid NH₃. The product aniline was equally labelled at C-1 and C-2 (47:53 ratio), confirming a symmetric intermediate (benzyne) attacked with equal probability at both carbons.
The reaction of p-chlorotoluene with KNH₂/NH₃ gives a mixture of m- and p-toluidines (not just p-toluidine), explicable only through a 3,4-benzyne intermediate formed by base-mediated elimination.
Both o-bromoanisole and m-bromoanisole with sodamide give the same product: m-aminoanisole (m-anisidine). This is consistent with formation of the same 2,3-benzyne from both starting materials — the more acidic ortho-H adjacent to OCH₃ is removed in both cases, and the carbanion ortho to OCH₃ (stabilised by -I) gives the observed m-anisidine.
The leaving group order in aromatic SNAr (addition-elimination): F > NO₂ > OTs > SOPh > Cl, Br, I > N₃ > NR₃⁺ > OAr, OR, SR, NH₂.
4.3.3 Substitution Reactions (Mechanism)
The elimination-addition mechanism for benzyne-mediated substitution has two distinct stages:
Elimination stage (rate-determining): A strong base abstracts the ortho proton (slow, RDS), and the carbanion expels the halide to give benzyne.
Addition stage: The nucleophile adds to one carbon of the benzyne (step i), giving an aryl carbanion, which is then protonated by solvent (step ii).
An isotope effect confirms the mechanism: o-deuterobromobenzene reacts more slowly than bromobenzene with amide ion (since C–D bond is stronger than C–H, loss of proton in RDS is slower — a primary kinetic isotope effect).
2,6-Disubstituted aryl halides do not react with amide ion in liquid NH₃ because there are no ortho hydrogens to remove — direct chemical evidence that the mechanism requires ortho-H.
4.3.4 Cycloaddition Reactions
Benzyne is an excellent dienophile (electron-deficient π bond) and undergoes [4+2] Diels-Alder cycloadditions with dienes:
Benzyne also undergoes [2+2] cycloaddition with alkenes to give benzocyclobutene derivatives, and [3+2] cycloadditions with dipolar systems.
Benzyne undergoes dimerisation (→ diphenylene) and trimerisation (→ triphenylene) in the absence of external reagents — these are additional proofs of benzyne formation.
Benzyne participates in ring closure reactions. N-methyl-2-(m-chlorophenyl)ethanamine + C₆H₅Li → N-methylindoline, via intramolecular nucleophilic addition to the benzyne C≡C bond.
5. MCQs with Answers
The following 50 questions cover all four intermediates at the level of IIT-JAM, CSIR-NET, GATE, TGT and PGT. Attempt each before checking the answer.
5.1 Free Radicals (Questions 1–18)
5.2 Carbenes (Questions 19–30)
5.3 Nitrenes (Questions 31–40)
5.4 Arynes/Benzynes (Questions 41–50)
• O–O bond (peroxides): ~120 kJ mol⁻¹ | Cl–Cl: 242 kJ mol⁻¹ | Br–Br: 192 kJ mol⁻¹
• (CH₃)₃C–H: 360 kJ mol⁻¹ | C₆H₅CH₂–H: 326 kJ mol⁻¹ | CH₃–H: 426 kJ mol⁻¹
• Fluorination ΔH (CH₃): both propagation steps exothermic (–138 and –296 kJ mol⁻¹)
• Iodination H-abstraction: +130 kJ mol⁻¹ (very endothermic → slow)
• ESR detects radicals at 10⁻⁸ M | n equivalent H → n+1 ESR lines
• Singlet carbene RCR angle: 103–110° (sp²) | Triplet: 136–180° (sp)
• Benzyne lifetime: 10⁻⁵–10⁻⁴ s | Nitrene lifetime: few microseconds
• Hofmann: 4 moles NaOH consumed | All three rearrangements (Hofmann, Curtius, Schmidt) go through acyl nitrene → isocyanate
