Types of Organic Reactions: Substitution, Elimination, Addition and Aromatic Substitution

11.1Aliphatic nucleophilic substitution

A nucleophile (Nu⁻, an electron-pair donor) replaces a leaving group X on an sp³ carbon: Nu⁻ + R–X → R–Nu + X⁻. Two limiting mechanisms are recognised by their rate laws and their stereochemistry.

SN2: bimolecular, one step

• Nu attacks the carbon from the side opposite to X (backside attack); bond making and bond breaking happen together through a trigonal bipyramidal transition state.
• Stereochemistry: complete inversion (Walden inversion). Hughes’ experiment: optically active 2-iodooctane with radioactive I⁻ racemises at twice the rate of iodide exchange, because each exchange inverts one molecule, which cancels one unchanged molecule.
• Substrate: CH₃ > 1° > 2° ≫ 3° (tertiary practically does not react). Branching at the β-carbon also hinders: neopentyl bromide is about 10⁵ times slower than ethyl bromide.
• Fast substrates: allyl and benzyl halides (the π system overlaps the transition state), α-halo ketones and α-halo nitriles (very fast), ClCH₂OCH₃. Among cycloalkyl halides, cyclopentyl is fastest; cyclopropyl and cyclobutyl are very slow (angle strain in the 120° transition state); cyclohexyl is slowed by axial hydrogens.
• No SN2 at vinyl, aryl or bridgehead carbons: no backside approach, and C–X has partial double-bond character in vinyl and aryl halides.

SN1: unimolecular, two steps

• The slow step is ionisation, so the rate does not depend on the nucleophile and follows carbocation stability: 3° > 2° ≫ 1°; benzylic and allylic cations are stabilised by resonance (Ph₃C⁺ > Ph₂CH⁺ > PhCH₂⁺). Electron-donating para groups (–OMe, –SMe, –NHCOCH₃, alkyl) speed up the ionisation of benzylic substrates; –NO₂ slows it.
• Stereochemistry: the planar carbocation is attacked from both faces: racemisation, usually with some excess of inversion, because the departing X⁻ still shields one face (ion pair).
• The carbocation can rearrange (1,2-H or 1,2-alkyl shift, unit 12) and can lose H⁺ (E1 competes).
• Bridgehead cations that cannot become planar ionise very slowly. A crowded tertiary substrate ionises faster than expected because going to the planar cation relieves strain (steric acceleration, B-strain).

Factors that decide the rate

• Nucleophilicity parallels basicity for the same attacking atom (RO⁻ > HO⁻ > RCOO⁻ > ROH). Down a group, in protic solvents, nucleophilicity rises: I⁻ > Br⁻ > Cl⁻ > F⁻ and RS⁻ > RO⁻, because small ions are strongly hydrogen-bonded. In polar aprotic solvents the order follows basicity: F⁻ > Cl⁻ > Br⁻ > I⁻.
• Hughes–Ingold solvent rules: a more polar solvent speeds up a reaction in which charge is created in the transition state (SN1 of neutral RX; R₃N + RX, the Menshutkin reaction), and slightly slows one in which charge is dispersed (Nu⁻ + RX by SN2). Charge destroyed (HO⁻ + R–NMe₃⁺) is slowed strongly.
• Ambident nucleophiles (enolates, CN⁻, NO₂⁻) can react at two atoms. Enolates usually alkylate on carbon; an intramolecular reaction takes the atom that closes the less strained ring (a six-membered O-ring beats a four-membered C-ring).

Useful substitutions

• Alcohols + HX: ROH₂⁺ is formed first; reactivity HI > HBr > HCl (acid strength and nucleophilicity of X⁻). 3° alcohols react by SN1, 1° by SN2; HCl needs ZnCl₂ (Lucas reagent: 3° turbid at once, 2° in minutes, 1° not at room temperature).
• SOCl₂ alone gives retention (SNi, internal return from the chlorosulfite); with pyridine, free Cl⁻ attacks and the product is inverted.
• Ether cleavage by HI: the protonated ether is attacked by I⁻ at the less hindered sp³ carbon (SN2) or ionises at a tertiary carbon (SN1). Anisole gives phenol + CH₃I; the aryl–O bond is never cleaved.
• Acidity decides which site reacts: with one equivalent of NaH, a phenol (pKₐ ≈ 10) is deprotonated before an alcohol (≈ 16); an active CH₂ between two C=O groups (pKₐ ≈ 11–13) before an ordinary ketone α-H.
• Acetoacetic and malonic ester syntheses: alkylate the stabilised carbanion, then hydrolyse and heat; a β-keto acid or malonic acid loses CO₂.

Substitution or elimination?

• 1° RX + good nucleophile: SN2. 1° RX + bulky base (t-BuO⁻): E2.
• 2° RX + strong base (RO⁻, HO⁻): mainly E2; + weak base, good nucleophile (I⁻, RS⁻, CN⁻, N₃⁻) in aprotic solvent: SN2.
• 3° RX + strong base: E2; in neutral protic solvent (solvolysis): SN1 + E1. Heat favours elimination.

11.2Elimination reactions: E1, E2 and E1cB

A β-elimination removes H from the β-carbon and X from the α-carbon to form a C=C. The three mechanisms differ in timing: in E1 the C–X bond breaks first, in E2 both bonds break together, in E1cB the C–H bond breaks first.

E1

• Rate = k[RX]: first order; the base is not in the rate law. Doubling [RX] doubles the rate; doubling the base does nothing.
• Goes through the same carbocation as SN1, so 3° > 2° and polar protic solvents help. Weak base, heat.
• Gives the more substituted (Saytzeff/Zaitsev) alkene, and the more stable E isomer; carbocation rearrangements are common.
• Acid dehydration of alcohols is E1 for 3° and 2° alcohols: rate 3° > 2° > 1°; a cation that is also allylic or benzylic forms fastest. 1-Methylcyclohexanol gives mainly 1-methylcyclohexene (endocyclic, trisubstituted), not methylenecyclohexane.

E2

• Strong base, one step. The H and X must be anti-periplanar (dihedral angle 180°). This makes E2 stereospecific: each diastereomer gives its own alkene geometry. Place H and X anti in a Newman projection and read off which groups end up cis.
• Cyclohexanes: H and X must both be axial (trans-diaxial). If X can be axial only in a crowded conformer, E2 is slow; if the only axial β-H lies on the less substituted side, the less substituted alkene forms. Menthyl chloride (Cl axial only with all groups axial) gives only 2-menthene; neomenthyl chloride gives mainly the Zaitsev 3-menthene, faster. The β-isomer of hexachlorocyclohexane (all Cl equatorial) is extremely slow.
• Syn elimination happens where anti is impossible: in rigid norbornyl and bicyclo[2.2.2] systems, the exo H syn-periplanar (0°) to X is removed.
• Kinetic isotope effect: if both H and D are available on suitable positions, H is removed preferentially.

E1cB

• The base removes an acidic β-H first (β-C=O, NO₂, CN, SO₂R), giving a stabilised carbanion; a poor leaving group (OR, OH, F, NR₃⁺) then departs. Examples: dehydration of aldols, loss of NMe₃ from Mannich bases (β-amino ketones), ring opening of lactones next to an acidic CH₂.
• The alkene formed is conjugated with the activating group, usually as the more stable E isomer.

Saytzeff or Hofmann

• Saytzeff (Zaitsev) rule: the more substituted, more stable alkene is the main product (E1; E2 with small bases and good leaving groups: Br, I, OTs).
• Hofmann rule: the less substituted alkene is the main product when (i) the base is bulky (t-BuO⁻, Et₃CO⁻): bulkier base, more Hofmann; (ii) the leaving group is poor and the transition state is carbanion-like (F, NR₃⁺, SR₂⁺): 2-fluorohexane gives mainly hex-1-ene, 2-iodohexane mainly hex-2-ene; (iii) the more substituted β-carbon has no H anti to X.
• Hofmann exhaustive methylation: an amine is methylated to R–NMe₃⁺ I⁻, converted to the hydroxide and heated; E2 removes H from the least substituted β-carbon and expels NMe₃. Repeated on cyclic amines, it opens the ring and finally removes N as trimethylamine. It cannot cleave an aryl–N bond, and a benzylic NMe₃⁺ with no β-H does not eliminate. It was used to find the skeletons of alkaloids (coniine is 2-propylpiperidine).

Other eliminations

• Ei (syn) pyrolysis: esters (acetates) at about 400 °C, xanthates (Chugaev), amine oxides (Cope) eliminate through a cyclic transition state with syn H and leaving group; no base.
• α-Elimination: a very strong base removes H from the carbon that carries X, giving a carbene (CHCl₃ + base → :CCl₂). A label that stays on the α-carbon or is lost from it tells α from β-elimination.
• Addition or elimination? Addition joins two molecules (ΔS < 0, ΔH < 0); elimination does the reverse. By ΔG = ΔH − TΔS, addition is favoured at low temperature, elimination at high temperature.

11.3Addition to C=C and C≡C

The π electrons of an alkene attack an electrophile E⁺. The first step (usually rate-determining) gives a carbocation or a bridged (onium) ion; a nucleophile completes the addition.

Reactivity and regiochemistry

• Electron-rich alkenes react faster: CH₂=CHOCH₃ > CH₂=CHCH₃ > CH₂=CH₂ > CH₂=CHBr > CH₂=CH–NMe₃⁺ > CH₂=CHNO₂. More alkyl groups, faster (Me₂C=CH₂ ≫ CH₂=CH₂). −I and −M groups slow the reaction.
• Markovnikov’s rule: E⁺ (H⁺) adds to the carbon that gives the more stable carbocation. In HOCl and HOBr the electrophile is Cl⁺ or Br⁺ (O is more electronegative), so OH ends on the more substituted carbon.
• Words: regioselective (one constitutional orientation preferred), stereoselective (one stereoisomer preferred), stereospecific (stereoisomeric reactants give stereoisomeric products). A reaction that makes no stereocentre cannot be stereospecific.

The common additions

• Halogenation: the bromonium ion is opened from the back, so addition is anti. cis-But-2-ene gives (±)-2,3-dibromobutane; trans-but-2-ene gives meso. In water or methanol the solvent, present in large excess, captures the bromonium ion at the carbon that better holds positive charge (halohydrin, halo-ether). Next to a ring O (dihydropyran), that carbon is the one attached to O.
• Hydration routes compared: acid hydration can rearrange (1,2-H or 1,2-CH₃ shift to a more stable cation); oxymercuration–demercuration gives the Markovnikov alcohol without rearrangement; hydroboration–oxidation gives the anti-Markovnikov alcohol, syn. With 3,3-dimethylbut-1-ene they give 2,3-dimethylbutan-2-ol, 3,3-dimethylbutan-2-ol and 3,3-dimethylbutan-1-ol respectively.
• An internal OH or CO₂H can open the onium ion instead of the solvent: iodolactonisation, iodoetherification and intramolecular oxymercuration close five- or six-membered rings.
• Peroxide (Kharasch) effect only with HBr: a radical chain needs both propagation steps exothermic. With HCl the H-abstraction step is endothermic (strong H–Cl bond); with HI the I• addition step is endothermic (weak C–I bond). Br• adds to the terminal carbon to give the more stable radical.
• Epoxidation with peracids is electrophilic: electron-rich C=C first; the alkene geometry is kept (cis alkene gives cis epoxide); the less hindered face is attacked (an axial angular methyl blocks its own face). An electron-poor C=C (enone, enoate) is epoxidised by a nucleophile instead: H₂O₂/NaOH (conjugate addition, then ring closure). Sharpless epoxidation works on allylic alcohols with Ti(OiPr)₄, t-BuOOH and a chiral tartrate; the tartrate chooses the face. Epoxides open by SN2, trans-diaxially in rigid rings (Fürst–Plattner).
• Radical halogenation (Cl₂ or Br₂, light): H is abstracted where the radical is most stable: allylic, benzylic > 3° > 2° > 1° > vinylic. Bromine is far more selective than chlorine.

Dienes, alkynes and conjugate additions

• Conjugated dienes give an allylic cation and so 1,2- and 1,4-adducts. The 1,2-product forms faster (kinetic control, low temperature); the 1,4-product is usually more stable (thermodynamic control, higher temperature). The more substituted alkene decides which product is more stable, so check each case.
• Diels–Alder: diene + dienophile, concerted, syn on both partners; with cyclic dienes the endo adduct is kinetically preferred.
• Alkynes: H₂/Lindlar (Pd/BaSO₄ or CaCO₃, quinoline) gives the cis alkene; Na/liquid NH₃ gives the trans alkene; Hg²⁺/H₂SO₄ hydration gives a ketone (via the enol); hydroboration of a terminal alkyne gives an aldehyde.
• Michael (conjugate) addition: a stabilised carbanion (malonate, β-keto ester enolate, amine) adds to the β-carbon of an α,β-unsaturated carbonyl, nitrile or nitro compound. The acceptor needs the C=C conjugated with an electron-withdrawing group; an enol ester or enol ether is electron-rich and is not an acceptor. Michael + intramolecular Claisen gives dimedone; Michael + aldol gives the Robinson annulation.
• Ionic polymerisation: styrenes with donor para groups polymerise by the cationic route; with acceptor groups (NO₂, CN, CF₃) by the anionic route.