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> "Benzene resists addition because adding to it would break aromaticity. But benzene readily substitutes — replacing one H with an electrophile while preserving aromaticity. EAS is the chemistry of compromising electrons reluctantly: lose...

In This Chapter

Chapter 21 — Electrophilic Aromatic Substitution: The Reactions of Benzene

"Benzene resists addition because adding to it would break aromaticity. But benzene readily substitutes — replacing one H with an electrophile while preserving aromaticity. EAS is the chemistry of compromising electrons reluctantly: lose aromaticity briefly to do the chemistry, then restore aromaticity by losing a proton." — paraphrase from a physical organic text

"Almost every aromatic compound in industry — dyes, drugs, polymers, pesticides — was made via electrophilic aromatic substitution at some step. Master EAS, and you have access to the aromatic chemistry that powers a major fraction of the chemical industry."

This chapter introduces the canonical reaction of aromatics: electrophilic aromatic substitution (EAS). The key insight: aromatics substitute rather than add, because addition would destroy aromaticity (~36 kcal/mol of stabilization for benzene). The mechanism is a two-step electrophile-attack-then-deprotonate cycle.

The five major EAS reactions: 1. Halogenation (Cl₂, Br₂ with Lewis acid catalyst). 2. Nitration (HNO₃ + H₂SO₄). 3. Sulfonation (SO₃ in H₂SO₄). 4. Friedel-Crafts alkylation (R-X + AlCl₃). 5. Friedel-Crafts acylation (R-COCl + AlCl₃).

Each generates a specific electrophile; the rest of the mechanism is the same. EAS is one of the most-used reaction types in industrial and pharmaceutical chemistry.

By the end of this chapter you should be able to: - Draw the full mechanism of EAS (electrophile attack → arenium ion → deprotonation). - Identify the electrophile generated in each named EAS reaction. - Predict products of halogenation, nitration, sulfonation, FC alkylation, FC acylation. - Recognize the limitations of FC alkylation (rearrangement, polyalkylation). - Use FC acylation + reduction (Clemmensen/Wolff-Kishner) to install linear alkyl chains. - Connect EAS to industrial applications (dyes, drugs, polymers).

21.1 The general EAS mechanism

The EAS mechanism is two steps. Memorize this; every EAS reaction follows it.

Step 1: Electrophile attacks the ring

A strong electrophile (E⁺) attacks the aromatic π system. One of the ring's π electrons forms a new bond to E. The ring carbon attacking E becomes sp³ (with 4 substituents: one H, one E, one ring C on each side). The remaining 5 ring carbons hold a positive charge that is delocalized across them (3-atom allylic cation-like).

This intermediate is called the arenium ion (or sigma complex or Wheland intermediate). It is positively charged and non-aromatic (one ring atom is sp³).

The arenium ion is reactive but stabilized by resonance — the positive charge is shared across 3 ring atoms. Three resonance structures: - Positive at C2 (ortho to attack). - Positive at C4 (para to attack). - Positive at C6 (ortho to attack on the other side).

Step 2: Deprotonation restores aromaticity

A weak base (the solvent, the conjugate base of the catalyst, etc.) removes the H from the sp³ ring carbon. The C-H σ bond's electrons return to the ring, restoring aromaticity.

The product: aromatic ring with one H replaced by the electrophile.

Mechanism Map 21.1: Generic EAS. 1. E⁺ + Ar-H (where Ar-H is benzene) → arenium ion (positively charged σ-complex; one C is sp³ with H and E both attached; positive charge delocalized over 3 other C's). 2. Arenium ion + base → Ar-E (with electrophile installed) + base·H⁺. Net: Ar-H + E⁺ + base → Ar-E + base·H⁺.

Why the rate-limiting step is electrophile attack

Step 1 (electrophile attack) is slow because it disrupts aromaticity (~36 kcal/mol penalty). The TS is high in energy.

Step 2 (deprotonation) is fast because it restores aromaticity (~36 kcal/mol gain).

The rate-limiting step is step 1 — the formation of the arenium ion. Different electrophiles have different rates because they have different abilities to compensate for breaking aromaticity.

Reaction coordinate diagram

         Energy
           |
           |        Arenium ion
           |       /         \
           |  TS₁ /           \ TS₂
           |     /             \
           |    /               \
   Ar-H + E⁺ ◯                   ◯ Ar-E + H⁺
           |
           ─────────────────────→ Reaction coordinate

The arenium ion is at the top; its barrier (TS₁) determines the rate.

21.2 Halogenation: Cl₂ and Br₂ with Lewis acid

Direct chlorination or bromination of benzene requires a Lewis acid catalyst (FeCl₃ for Cl₂; FeBr₃ for Br₂).

Mechanism

  1. Generate the electrophile: $Cl_2 + FeCl_3 \to Cl^+ + FeCl_4^-$. The Lewis acid pulls an electron pair from one Cl atom, generating a more-electrophilic chlorine.

  2. EAS step 1: $C_6H_6 + Cl^+ \to C_6H_6Cl^+$ (arenium ion).

  3. EAS step 2: $C_6H_6Cl^+ + FeCl_4^- \to C_6H_5Cl + HCl + FeCl_3$ (deprotonation; FeCl₃ catalyst regenerated).

Why Lewis acid is needed

Cl₂ alone is not electrophilic enough to attack the aromatic ring. The Lewis acid (FeCl₃) activates Cl₂ by polarizing the Cl-Cl bond.

For Br₂, FeBr₃ is the Lewis acid. For I₂, the Lewis acid + a strong oxidant (like H₂O₂ or HNO₃) is typically used.

For F₂, no catalyst is typically needed (F₂ is highly reactive on its own), but F₂ tends to over-fluorinate or attack unselectively. Selective fluorination is hard.

Selectivity

Halogenation gives the mono-halogenated product if conditions are controlled. Excess halogen can give multiple substitutions (especially if the ring is activated by the first halogen — but actually halogens are slightly deactivating, so multiple halogenation is moderate; see Ch 22).

21.3 Nitration: HNO₃ + H₂SO₄

Nitration adds an NO₂ group to the aromatic ring.

Mechanism

  1. Generate the electrophile: $HNO_3 + H_2SO_4 \to H_2NO_3^+ + HSO_4^- \to NO_2^+ + H_3O^+ + HSO_4^-$.

The nitronium ion (NO₂⁺) is the electrophile. It's a small, very electrophilic cation.

  1. EAS step 1: $C_6H_6 + NO_2^+ \to C_6H_6(NO_2)^+$ (arenium ion).

  2. EAS step 2: $C_6H_6(NO_2)^+ + HSO_4^- \to C_6H_5NO_2 + H_2SO_4$.

Industrial use

Nitration of benzene gives nitrobenzene. Used as: - Precursor to aniline (via reduction; Ch 22). - Precursor to many dyes and pharmaceuticals. - Solvent for some industrial processes.

Aniline → many dyes (azo dyes, etc.; via diazonium chemistry, Ch 30).

Multiple nitration

Nitrobenzene is deactivated for further EAS (Ch 22). So mononitration is the typical outcome under controlled conditions. Forcing conditions (high T, more HNO₃) can give 1,3-dinitrobenzene; even stronger conditions give 1,3,5-trinitrobenzene (TNT precursor; Ch 22 case study).

21.4 Sulfonation: SO₃ in H₂SO₄

Sulfonation adds an SO₃H group to the aromatic ring.

Mechanism

  1. Generate the electrophile: SO₃ itself is the electrophile (or H₂SO₄ generates SO₃ via dehydration). Concentrated sulfuric acid can also be the source.

  2. EAS step 1: $C_6H_6 + SO_3 \to C_6H_5(SO_3)^+H^-$ (arenium ion equivalent; concerted attack by SO₃ with the π electrons attacking S).

  3. EAS step 2: deprotonation gives Ar-SO₃H.

Reversibility

Sulfonation is reversible. Unlike halogenation or nitration (essentially irreversible), sulfonation can be reversed by treatment with hot dilute H₂SO₄ + heat (de-sulfonation).

Use in synthesis

Sulfonation is used: - Industrially: produces sulfonic acids (used in detergents, dyes). - As a directing group: a sulfonate group can be installed, used to direct further EAS, and then removed (using the reversibility). - In dye chemistry: sulfonate groups improve water solubility.

Detergents

Linear alkylbenzene sulfonate (LAS) is a major component of laundry detergents. Made by: 1. Friedel-Crafts alkylation of benzene with linear C₁₀-C₁₃ alkenes. 2. Sulfonation of the alkylbenzene.

Total LAS production: ~3 million tons/year.

21.5 Friedel-Crafts alkylation: R-X + AlCl₃

Friedel-Crafts alkylation installs an alkyl group on the aromatic ring.

Mechanism

  1. Generate the electrophile: $R-X + AlCl_3 \to R^+ + AlCl_4^-$ (or for tertiary halides, the cation forms readily; for primary halides, the carbocation rearranges or the AlCl₃-RX complex is the effective electrophile).

  2. EAS step 1: $C_6H_6 + R^+ \to C_6H_6R^+$ (arenium ion).

  3. EAS step 2: $C_6H_6R^+ + AlCl_4^- \to C_6H_5R + HCl + AlCl_3$.

Limitations of Friedel-Crafts alkylation

The "Friedel-Crafts alkylation" of benzene has several limitations:

1. Carbocation rearrangement

If the alkyl halide gives a primary carbocation, it rearranges to a more-stable secondary or tertiary cation before attacking the ring. Result: the alkyl group on the product is rearranged.

Example: 1-chloropropane + benzene + AlCl₃ → mostly isopropylbenzene (cumene), not n-propylbenzene. The 1° cation rearranged to 2°.

To get straight-chain alkyl groups, use Friedel-Crafts acylation + reduction (next section).

2. Polyalkylation

Once the ring has one alkyl group, it is activated (Ch 22) for further EAS. So mono-alkylation often goes to di-, tri-, or polyalkylation.

To control: use excess benzene to give mono-substituted product (statistical preference).

3. Doesn't work on deactivated rings

Aromatic rings with strong electron-withdrawing groups (NO₂, CN, COOH, COR) are deactivated for EAS. Friedel-Crafts alkylation in particular doesn't work on rings with NO₂.

So if you have nitrobenzene and want to add an alkyl group, you can't FC alkylate it. Reduce the NO₂ to NH₂ first (Ch 22), then FC alkylate; then re-oxidize NH₂ to NO₂ if needed.

4. Doesn't work with vinyl or aryl halides

Friedel-Crafts requires a carbocation. Vinyl and aryl halides don't ionize to give cations under normal conditions. So FC alkylation of benzene with vinyl chloride or chlorobenzene fails.

For making aryl-aryl bonds, use Pd cross-coupling (Ch 37).

21.6 Friedel-Crafts acylation: R-COCl + AlCl₃

Friedel-Crafts acylation installs an acyl group (RC(=O)-) on the aromatic ring.

Mechanism

  1. Generate the electrophile: $R-COCl + AlCl_3 \to R-C \equiv O^+ + AlCl_4^-$. The acylium ion (R-C≡O⁺) is the electrophile.

The acylium is resonance-stabilized: $R-C^+=O \leftrightarrow R-C \equiv O^+$. The triple-bond resonance contribution makes it stable enough to handle.

  1. EAS step 1: $C_6H_6 + R-C \equiv O^+ \to C_6H_6(COR)^+$ (arenium ion).

  2. EAS step 2: deprotonation gives the aryl ketone.

Why FC acylation is preferred over FC alkylation

No rearrangement

Acylium ion is resonance-stabilized; it doesn't rearrange like alkyl carbocations do. So you get clean acylation at the desired position.

No polyacylation

The acyl group (-C(=O)R) is deactivating (electron-withdrawing). Once on the ring, it slows down further EAS dramatically. Mono-acylation dominates.

This is the opposite of FC alkylation (where alkyl groups activate for further substitution).

Two-step strategy: acylation + reduction

To install a linear alkyl group on benzene: 1. Friedel-Crafts acylate with an acyl chloride: Ar-H + RCOCl + AlCl₃ → Ar-COR. 2. Reduce the ketone to a CH₂: Ar-COR → Ar-CH₂-R.

Reduction options: - Clemmensen reduction: Zn(Hg) + HCl. Uses zinc amalgam in HCl. Reduces C=O to CH₂. - Wolff-Kishner reduction: hydrazine + KOH (in glycol; reflux). The C=O is converted to a hydrazone, then a base-induced loss of N₂ gives the CH₂.

Both reductions go from C=O directly to CH₂ (no intermediate alcohol). The result: an aryl group with a linear alkyl substituent.

Industrial example

Cumene (isopropylbenzene) is industrially made by FC alkylation of benzene with propylene (a vinyl-like substrate that gives 2° cation directly):

$$C_6H_6 + CH_3CH=CH_2 + H_3PO_4 \to C_6H_5CH(CH_3)_2$$

Cumene is then oxidized to cumene hydroperoxide, which is hydrolyzed to phenol + acetone (the Hock process; Ch 18 case study). This is the major industrial route to phenol.

21.7 Other EAS reactions

Beyond the five "named" reactions, other EAS reactions include:

Mercuration

$ArH + Hg(OAc)_2 \to ArHgOAc + HOAc$. Mercuration of aromatics (similar to alkene oxymercuration; Ch 16). Used historically; less common now due to mercury toxicity.

Formylation (Gattermann-Koch)

$ArH + CO + HCl + AlCl_3 \to ArCHO$. Gives aryl aldehyde. The electrophile is essentially HCO⁺ (formyl cation). Modern alternatives are more common.

Vilsmeier-Haack

$ArH + DMF + POCl_3 \to ArCHO$. Mild formylation method; widely used in pharma.

Reimer-Tiemann

$ArOH + CHCl_3 + NaOH \to o-\text{hydroxybenzaldehyde}$. Specific for phenols; gives ortho hydroxy-aldehyde via dichlorocarbene intermediate.

Kolbe-Schmitt

$ArO^- + CO_2 \to o-\text{ArOH-COOH}$ (e.g., phenoxide + CO₂ → salicylic acid, the precursor to aspirin; Ch 26).

21.8 EAS in pharmaceutical synthesis

EAS is one of the most-used reactions in pharmaceutical synthesis. Examples:

Aspirin (acetylsalicylic acid)

Synthesis (Ch 26 case study): 1. Phenol + CO₂ + NaOH → sodium salicylate (Kolbe-Schmitt; an EAS-like process). 2. Acidify → salicylic acid. 3. Acylate with acetic anhydride → aspirin.

Acetaminophen

Synthesis: 1. Phenol + nitric acid → 4-nitrophenol (EAS nitration). 2. Reduction → 4-aminophenol. 3. Acetylation with acetic anhydride → acetaminophen.

Sulfa drugs

Various sulfa antibacterials (sulfamethoxazole, etc.) use EAS sulfonation in their synthesis. Sulfonation + chlorosulfonation + amine addition gives the sulfonamide functional group.

Many other drugs

Almost any drug containing an aromatic ring with substituents was made using EAS at some step. This includes: - Atorvastatin (Lipitor). - Sertraline (Zoloft). - Naproxen. - Many antibiotics, antifungals, antivirals.

EAS is the workhorse for building substituted aromatics.

21.9 Industrial EAS

Beyond pharma, EAS is used industrially for:

  • Dyes: aromatic substitution + diazonium coupling = azo dyes (Ch 30).
  • Polymers: styrene (from FC alkylation), polyester precursors (terephthalic acid from p-xylene oxidation), polyurethane precursors.
  • Detergents: linear alkylbenzene sulfonate.
  • Pesticides: many contain aromatic rings.
  • Explosives: TNT (trinitrotoluene; from toluene + 3 nitrations; Ch 22 case study).

Total industrial EAS chemistry: many millions of tons per year.

21.10 Spectroscopy of substituted aromatics

After EAS, the product (substituted benzene) shows:

IR

  • Aromatic C=C at 1500-1600 cm⁻¹.
  • C-H stretch at ~3000 cm⁻¹.
  • Substitution pattern: out-of-plane bending peaks at 700-900 cm⁻¹ are diagnostic.
  • Mono-substituted: 690-710, 730-770.
  • 1,2-disubstituted (ortho): 730-770.
  • 1,3-disubstituted (meta): 880, 760, 690.
  • 1,4-disubstituted (para): 800-840.

¹H NMR

  • Aromatic H at δ 7-8 ppm (ring current).
  • Substitution patterns produce characteristic coupling: e.g., para-disubstituted gives an apparent doublet of doublets or AA'BB' system.

¹³C NMR

  • Aromatic C at δ 120-150 ppm.

Mass spec

  • Aromatic fragmentation: loss of substituent + formation of tropylium cation (m/z 91 from toluene-like compounds).

21.11 Summary

  1. Aromatics substitute rather than add (preserves aromaticity).
  2. EAS mechanism (2 steps): electrophile attack → arenium ion (sp³ C, positive charge delocalized over 3 atoms) → deprotonation → restored aromatic ring.
  3. Halogenation (Cl₂ + FeCl₃ or Br₂ + FeBr₃): generates Cl⁺ or Br⁺ as electrophile.
  4. Nitration (HNO₃ + H₂SO₄): nitronium ion (NO₂⁺) is the electrophile.
  5. Sulfonation (SO₃ in H₂SO₄): SO₃ is the electrophile; reversible.
  6. Friedel-Crafts alkylation (R-X + AlCl₃): R⁺ as electrophile. Limitations: rearrangement (1° cations), polyalkylation, doesn't work on deactivated rings.
  7. Friedel-Crafts acylation (RCOCl + AlCl₃): acylium R-C≡O⁺ as electrophile. No rearrangement, no polyacylation.
  8. Acylation + reduction (Clemmensen or Wolff-Kishner) gives a linear alkyl group on the ring — preferred over direct alkylation.
  9. Industrial EAS: dyes, drugs, polymers, detergents, pesticides, explosives.

Chapter 22 covers substituent effects — how existing groups on the ring direct further EAS to ortho/para or meta positions.