Difficulty: Intermediate | Prerequisites: Electrophilic additions, carbonyl basics, resonance structures
This set covers three reaction families that appear throughout Orgo II synthesis problems. Electrophilic aromatic substitution (EAS) puts new groups on benzene rings. Radical reactions use single-electron mechanisms for selective halogenation and anti-Markovnikov addition. Oxidations and reductions let you move up and down the oxidation ladder (alcohol to aldehyde to acid, or the reverse), cleave double bonds, and selectively reduce triple bonds. These are the toolkit reactions you will combine in multi-step synthesis.
Electrophilic aromatic substitution (EAS) puts new groups on benzene rings using Lewis acid catalysts, with directing effects controlling where the new group lands. Radical reactions use single-electron chain mechanisms for selective benzylic halogenation and anti-Markovnikov HBr addition. Oxidation and reduction reactions let you move functional groups up and down the oxidation ladder, cleave alkenes into carbonyls, and selectively reduce alkynes to cis or trans alkenes.
Electrophilic aromatic substitution (EAS)
The general mechanism by which benzene rings react with electrophiles. The electrophile attacks the pi system, forming an arenium ion (sigma complex), then a proton is lost to restore aromaticity. In simple terms, a group replaces a hydrogen on the ring without breaking the aromatic system.
Friedel-Crafts alkylation
Benzene + RCl/AlCl3 gives an alkylbenzene. AlCl3 is a Lewis acid catalyst that generates the carbocation electrophile. Caveat: carbocation rearrangements can occur, and the product is more reactive than benzene, so polyalkylation is possible.
Friedel-Crafts acylation
Benzene + RCOCl/AlCl3 gives an aryl ketone. No rearrangement (the acylium ion is resonance-stabilised). The product is deactivated, so no polyacylation.
Nitronium ion (NO2+)
The electrophile in aromatic nitration, generated from HNO3 + H2SO4.
Activating group / ortho-para director
An electron-donating group on the ring (e.g. -OH, -NH2, -OR, -alkyl) that increases reactivity and directs incoming electrophiles to the ortho and para positions.
Deactivating group / meta director
An electron-withdrawing group (e.g. -NO2, -CN, -COOH, -COR) that decreases reactivity and directs incoming electrophiles to the meta position.
Halogens as directors
Halogens are deactivating (they withdraw electrons inductively) but ortho/para-directing (they donate electrons through resonance). This is the exception that students must memorise.
Benzylic radical
A radical on a carbon adjacent to a benzene ring. Stabilised by resonance delocalisation into the ring, making benzylic positions highly selective for radical halogenation.
PCC (pyridinium chlorochromate)
A mild oxidising agent that converts 1° alcohols to aldehydes without over-oxidation to carboxylic acids. Works in anhydrous CH2Cl2.
Clemmensen reduction
Carbonyl + Zn(Hg)/HCl reduces a C=O all the way to CH2. Used after Friedel-Crafts acylation to get the equivalent of an alkylation without rearrangement.
Ozonolysis
Alkene + O3, then a reductive workup (Zn or DMS), cleaves the double bond into two carbonyl fragments (aldehydes and/or ketones). Useful for determining alkene structure by identifying the fragments.
The four classic EAS reactions
Friedel-Crafts alkylation: Benzene + RCl/AlCl3 gives alkylbenzene. Rearrangements possible (1° carbocations rearrange to 2° or 3°). Product is activated, so polyalkylation can occur.
Friedel-Crafts acylation: Benzene + RCOCl/AlCl3 gives aryl ketone. No rearrangement (acylium ion is stable). Product is deactivated, so reaction stops at monosubstitution.
Nitration: Benzene + HNO3/H2SO4 gives nitrobenzene via NO2+ electrophile.
Bromination: Benzene + Br2/FeBr3 gives bromobenzene.
Directing effects
Activators (electron donors) direct ortho/para: -OH, -OR, -NH2, -NHR, -NR2, -alkyl, -NHCOR. These groups increase electron density in the ring, making it more reactive and stabilising the arenium ion at the ortho and para positions.
Deactivators (electron withdrawers) direct meta: -NO2, -CN, -SO3H, -COR, -COOR, -COOH, -CHO. These groups pull electron density from the ring, destabilising the arenium ion at ortho/para, leaving meta as the least disfavoured position.
Halogens are the exception: deactivating (inductive withdrawal) but ortho/para-directing (resonance donation). Think of them as weak donors by resonance that are overall deactivating.
Synthesis tip: Friedel-Crafts acylation then Clemmensen reduction
To add a straight-chain alkyl group to benzene without rearrangement, first acylate (no rearrangement), then reduce the ketone to the CH2 with Zn(Hg)/HCl (Clemmensen) or NH2NH2/KOH (Wolff-Kishner).
Benzylic and allylic halogenation
Toluene + Br2/hv gives benzyl bromide. The benzylic radical is stabilised by resonance into the ring, making this position highly selective.
Alkane + Br2/hv gives alkyl bromide with selectivity: 3° > 2° >> 1°. Bromine radicals are selective (they react with the most stable radical intermediate). Chlorine is less selective.
Radical addition of HBr
Alkene + HBr + peroxide gives anti-Markovnikov alkyl bromide. The peroxide generates radicals, flipping the mechanism from ionic to radical. Br adds to the less substituted carbon first (forming the more stable radical), then H adds.
This only works with HBr, not HCl or HI. The energetics of the chain steps are only favourable for bromine.
Oxidation of alcohols
1° alcohol + PCC gives aldehyde (stops here because PCC works in anhydrous conditions).
1° alcohol + KMnO4 or CrO3 (Jones reagent, aqueous conditions) gives carboxylic acid (over-oxidation past the aldehyde).
2° alcohol + CrO3 or KMnO4 gives ketone. Ketones cannot be oxidised further under these conditions.
Reduction of carbonyls
Ketone/aldehyde + NaBH4 or LiAlH4 gives alcohol.
Ester + LiAlH4 gives two 1° alcohols (one from each side of the ester).
Amide + LiAlH4 gives amine.
Carbonyl + Zn(Hg)/HCl (Clemmensen reduction) gives CH2 (removes the oxygen entirely). Acidic conditions.
Carbonyl + NH2NH2/KOH (Wolff-Kishner reduction) gives CH2. Basic conditions. Choose Clemmensen or Wolff-Kishner based on whether the substrate is acid- or base-sensitive.
Alkene and alkyne cleavage
Ozonolysis (O3, then Zn or DMS) cleaves alkenes into aldehydes and/or ketones.
KMnO4 (hot, concentrated) cleaves alkenes to carboxylic acids (or ketones from tetrasubstituted ends).
Alkylbenzene side chain + KMnO4/NaOH, heat gives benzoic acid regardless of side-chain length.
Selective alkyne reductions
Alkyne + Lindlar's catalyst/H2 gives cis-alkene (syn addition of H2, catalyst is poisoned to stop at the alkene).
Internal alkyne + Na/NH3 (liquid) gives trans-alkene (dissolving metal reduction, anti addition via radical anion intermediates).
Students confuse Friedel-Crafts alkylation and acylation. Alkylation uses RCl and can rearrange; acylation uses RCOCl and cannot. If a problem asks for a straight-chain alkyl group on benzene, acylation followed by Clemmensen reduction is the correct route.
Halogens being ortho/para directors despite being deactivating is a frequent exam stumble. The key is to recognise that resonance donation (which controls directing) and inductive withdrawal (which controls reactivity) are separate effects.
PCC vs. KMnO4/CrO3 for oxidising 1° alcohols: PCC stops at the aldehyde, Jones/KMnO4 goes to the carboxylic acid. Choosing the wrong oxidant gives the wrong product.
Radical addition of HBr only works with peroxide present. Without peroxide, HBr follows the normal ionic Markovnikov pathway.
⚠️ Directing effects are tested constantly. Given a disubstituted benzene target, you must determine the correct order of EAS reactions based on which group directs where.
⚠️ Friedel-Crafts reactions do not work on strongly deactivated rings (nitrobenzene, for instance). This is a common trick question.
⚠️ PCC vs. Jones oxidation is a one-reagent-difference question that changes the product entirely.
⚠️ Lindlar (cis) vs. Na/NH3 (trans) for alkyne reduction: the stereochemistry of the alkene product depends entirely on which reagent is used.
True or False: Friedel-Crafts alkylation can produce rearranged products. (True)
Fill in the blank: Halogens on a benzene ring are ______ directors but overall ______ groups. (Ortho/para; deactivating)
True or False: PCC oxidises a primary alcohol to a carboxylic acid. (False: PCC stops at the aldehyde.)
Fill in the blank: Alkyne + Lindlar's catalyst/H2 gives a ______-alkene. (Cis)
True or False: Radical addition of HBr gives Markovnikov products. (False: it gives anti-Markovnikov products.)
Q: You want to synthesise propylbenzene (a straight three-carbon chain on benzene) without any rearranged products. What is the two-step route?
A: Friedel-Crafts acylation with CH3CH2COCl/AlCl3 to give the aryl ketone, then Clemmensen reduction (Zn(Hg)/HCl) to reduce the carbonyl to CH2. Acylation avoids the rearrangement that would occur with Friedel-Crafts alkylation.
Q: Predict the major product when toluene is treated with Br2/FeBr3.
A: Ortho-bromotoluene and para-bromotoluene (a mixture of the two). The methyl group is an activating, ortho/para-directing group. Para is usually the major product due to less steric hindrance.
Q: A primary alcohol is treated with PCC. A different sample of the same alcohol is treated with KMnO4. What are the two products?
A: PCC gives the aldehyde. KMnO4 gives the carboxylic acid.
Q: How do you selectively reduce an internal alkyne to a trans-alkene?
A: Dissolving metal reduction: Na in liquid NH3. This produces the trans-alkene via anti addition through radical anion intermediates.
EAS connects to carbonyl chemistry through Friedel-Crafts acylation (the product is an aryl ketone that can be further reduced or functionalised). Radical reactions connect to substitution and elimination by offering an alternative pathway with different selectivity. The oxidation/reduction ladder ties everything together in synthesis: you often need to oxidise or reduce a functional group to set up the next reaction in a multi-step sequence. The Sandmeyer reaction (aniline to aryl halide via diazonium salt) bridges EAS with nucleophilic aromatic substitution.
Electrophilic aromatic substitution, EAS, Friedel-Crafts alkylation, Friedel-Crafts acylation, nitration, nitronium ion, bromination, Lewis acid catalyst, AlCl3, FeBr3, directing effects, ortho-para director, meta director, activating group, deactivating group, halogen directing, benzylic radical, radical halogenation, NBS, free radical, anti-Markovnikov radical HBr, peroxide effect, PCC, pyridinium chlorochromate, Jones oxidation, CrO3, KMnO4, Clemmensen reduction, Wolff-Kishner, ozonolysis, Lindlar catalyst, dissolving metal reduction, Na/NH3, Sandmeyer reaction, diazonium salt, benzoic acid, side-chain oxidation, Orgo 2, organic chemistry II, CHEM 210