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Organic Chemistry 2 Unit 4: Electrophilic Aromatic Substitution

Benzene rings react with strong electrophiles by substitution, not addition, and the groups already on the ring control both how fast the ring reacts and where the new group goes, which is the key to planning aromatic syntheses.

Covers: EAS mechanism and the arenium ion, Halogenation, nitration and sulfonation, Friedel-Crafts alkylation and acylation, Activating, deactivating and directing effects, Rings with two or more substituents, Multistep aromatic synthesis, Nucleophilic aromatic substitution and benzyne

Study guide

Electrophilic aromatic substitution (EAS) has two steps. First, the π electrons of the ring attack a strong electrophile, forming a resonance-stabilized carbocation called the arenium ion or sigma complex; this step breaks aromaticity and is rate-determining. Second, a base removes the proton from the sp³ carbon, restoring aromaticity. Each EAS reaction differs only in how the electrophile is made. Bromination and chlorination use Br₂ or Cl₂ with a Lewis acid (FeBr₃, FeCl₃ or AlCl₃) to make an X⁺ equivalent. Nitration uses HNO₃ and H₂SO₄ to make the nitronium ion, NO₂⁺. Sulfonation uses fuming sulfuric acid (SO₃ in H₂SO₄) and is reversible: heating with dilute aqueous acid removes the SO₃H group.

Friedel-Crafts alkylation uses an alkyl halide with AlCl₃ to make a carbocation (or a carbocation-like complex) that alkylates the ring. It has three classic limitations. The carbocation can rearrange, so 1-chloropropane gives mainly isopropylbenzene. The product is more reactive than the starting material, so polyalkylation occurs. And the reaction fails on strongly deactivated rings (such as nitrobenzene) and on rings bearing NH₂, NHR or NR₂, whose nitrogen complexes the Lewis acid. Friedel-Crafts acylation, with an acid chloride and AlCl₃, forms a resonance-stabilized acylium ion, R–C≡O⁺, that does not rearrange. The acyl product is deactivated, so only one acylation occurs. Reducing the ketone with Zn(Hg)/HCl (Clemmensen) or H₂NNH₂/KOH (Wolff-Kishner) gives a straight-chain alkylbenzene.

Substituents already on the ring change both rate and orientation. Activating groups donate electron density and make the ring react faster than benzene; all of them direct ortho/para. Strong activators are –NH₂, –NR₂, –OH and –O⁻; moderate ones are –OR and –NHCOR; weak ones are alkyl groups and phenyl. Deactivating groups withdraw electron density and slow the reaction. Most direct meta: –NO₂, –NR₃⁺, –CF₃, –CN, –SO₃H, –CHO, –COR, –COOH and –COOR. Halogens are the exception: they are weakly deactivating because of induction but direct ortho/para because a lone pair can stabilize the arenium ion by resonance. The explanation is always the arenium ion: ortho or para attack places positive charge on the carbon bearing the substituent, which a donor stabilizes and an acceptor destabilizes.

When a ring already has two substituents, the strongest activator controls where the next group goes. If the groups reinforce each other, the product is clear. If they conflict, follow the more strongly activating group, and avoid the position between two groups that are meta to each other because it is sterically crowded. Synthesis planning depends on the order of steps. To make a meta-disubstituted product, install the meta director first; to make ortho/para products, install the ortho/para director first and separate the isomers (para is usually major). Useful interconversions change a group's directing effect: reducing NO₂ to NH₂ with Sn/HCl or H₂/Pd turns a meta director into an ortho/para director, and oxidizing an alkyl group with KMnO₄ turns an ortho/para director into the meta-directing COOH.

Aryl halides also undergo nucleophilic aromatic substitution under special conditions. In the addition–elimination (SNAr) mechanism, a nucleophile adds to the carbon bearing the leaving group to form a resonance-stabilized carbanion called a Meisenheimer complex, then the leaving group departs. SNAr requires strong electron-withdrawing groups such as NO₂ ortho or para to the leaving group, which delocalize the negative charge; a meta NO₂ does not help. Because the addition step is rate-determining, fluoride is the best leaving group in SNAr, the reverse of SN2. Without activating groups, very strong bases such as NaNH₂ in NH₃ can eliminate HX to form a highly reactive benzyne intermediate, which adds the nucleophile at either end of the strained triple bond, often giving a mixture of products.

Key ideas

• EAS proceeds through a resonance-stabilized arenium ion, and forming it is the slow step.
• Each EAS reaction is defined by how its electrophile (Br⁺, NO₂⁺, SO₃, R⁺, RCO⁺) is generated.
• Friedel-Crafts alkylation suffers from rearrangement and polyalkylation; acylation avoids both.
• Activators are ortho/para directors; most deactivators are meta directors; halogens deactivate but direct ortho/para.
• The most strongly activating group controls substitution on a polysubstituted ring.
• Order of steps matters in synthesis, and functional-group interconversions can switch directing effects.
• SNAr needs ortho/para electron-withdrawing groups; benzyne forms from unactivated aryl halides and strong base.

Formulas and rules

Common mistakes

• Running Friedel-Crafts on nitrobenzene or aniline, where it fails.
• Forgetting carbocation rearrangement in Friedel-Crafts alkylation with primary halides.
• Calling halogens meta directors because they deactivate the ring.
• Installing groups in the wrong order, such as nitrating after bromination when a meta product is wanted.
• Applying SN2 leaving-group trends to SNAr, where fluoride reacts fastest.

Before the test, make sure you can

• Draw the full EAS mechanism, including the arenium ion and its resonance forms.
• Give reagents that generate each EAS electrophile.
• Explain the limitations of Friedel-Crafts alkylation and how acylation plus reduction avoids them.
• Classify substituents as activating or deactivating and predict ortho/para or meta orientation.
• Predict the major product of EAS on disubstituted rings.
• Plan multistep syntheses of disubstituted benzenes in the correct order.
• Predict SNAr and benzyne products and explain the requirements for each.
• Calculate the percent yield of an aromatic substitution.

Words to know

Electrophilic aromatic substitution

Replacement of a ring H by an electrophile through an arenium ion, keeping the aromatic ring.

Arenium ion (sigma complex)

The resonance-stabilized cyclohexadienyl cation formed when an electrophile adds to an aromatic ring.

Nitronium ion

NO₂⁺, the electrophile in nitration, formed from HNO₃ and H₂SO₄.

Lewis acid catalyst

A compound such as FeBr₃ or AlCl₃ that accepts an electron pair and activates halogens or alkyl and acyl halides.

Friedel-Crafts alkylation

Attachment of an alkyl group to an aromatic ring using an alkyl halide and AlCl₃.

Friedel-Crafts acylation

Attachment of an acyl group using an acid chloride and AlCl₃, giving an aryl ketone without rearrangement.

Acylium ion

R–C≡O⁺, the resonance-stabilized electrophile in Friedel-Crafts acylation.

Polyalkylation

Multiple alkylations in Friedel-Crafts alkylation because the product ring is more reactive than the starting ring.

Activating group

A substituent that donates electron density and makes the ring react faster than benzene in EAS.

Deactivating group

A substituent that withdraws electron density and makes the ring react slower than benzene in EAS.

Ortho/para director

A group that directs incoming electrophiles to the positions adjacent to or opposite itself.

Meta director

A group, usually deactivating with a positive or partially positive atom attached to the ring, that directs electrophiles to the 1,3 position.

Clemmensen reduction

Reduction of a ketone C=O to CH₂ using zinc amalgam and HCl.

Wolff-Kishner reduction

Reduction of a ketone C=O to CH₂ using hydrazine and KOH with heat.

Blocking group

A removable group, such as SO₃H, placed on a ring to block a position during synthesis.

Meisenheimer complex

The resonance-stabilized anionic intermediate in nucleophilic aromatic substitution.

Benzyne

A highly reactive aromatic intermediate with a strained triple bond in the ring, formed by elimination from an aryl halide.

Sample practice questions

30 more questions like these, from level 1 to 5, are in the practice set.