18. ELECTROPHILIC AROMATIC SUBSTITUTION

Electrophilic Aromatic Substitution (EAS) – Simple Pharm.D Notes

Aromatic compounds like benzene contain a ring full of delocalised π-electrons. Because of this, benzene behaves like a “source of electrons,” which makes it attractive to electrophiles (electron-seeking species). When an electrophile attacks benzene, it replaces one hydrogen. This entire process is called Electrophilic Aromatic Substitution (EAS).

Key Idea of EAS

  • A benzene ring acts as a nucleophile.
  • The electrophile attacks the ring.
  • One hydrogen is substituted by the electrophile.

General Mechanism

  1. Formation of Electrophile: The reagent reacts with an acid or catalyst to produce a strong electrophile.
  2. Electrophile Attacks Benzene: Benzene donates electrons to electrophile → forms a high-energy unstable intermediate (called arenium ion).
  3. Loss of Proton: A base removes H⁺ → aromatic stability returns → substituted benzene is formed.

Effect of Substituent Groups

Groups already attached to benzene affect:

  • How fast the reaction occurs.
  • Where the new electrophile goes on the ring.

Types of Groups

1. Activating Groups (Increase reactivity)

Examples: –OH, –NH₂, –OCH₃, –CH₃ These groups donate electrons to the benzene ring.

Direct to: Ortho & Para positions

2. Deactivating Groups (Decrease reactivity)

Examples: –NO₂, –SO₃H, –CN, –COOH These groups withdraw electrons.

Direct to: Meta position

3. Halogens

Halogens (Cl, Br) are special:

  • They are deactivating (because they withdraw electrons inductively).
  • But they still direct to ortho & para (because of resonance donation).

Important EAS Reactions

1. Nitration

Reagent: Concentrated HNO₃ + H₂SO₄ Electrophile: NO₂⁺ (nitronium ion)

Benzene → Nitrobenzene

2. Sulfonation

Reagent: Concentrated H₂SO₄ or oleum Electrophile: SO₃

Benzene → Benzene sulfonic acid (Note: This reaction is reversible.)

3. Halogenation

Reagent: Cl₂ or Br₂ with FeCl₃ / FeBr₃ Electrophile: Cl⁺ or Br⁺

Benzene → Chlorobenzene / Bromobenzene

4. Friedel–Crafts Alkylation

Reagent: Alkyl halide + AlCl₃ Electrophile: Carbocation

Benzene → Alkylbenzene

Limitations:

  • Rearrangements occur.
  • Poly-alkylation is common.
  • Fails with strong deactivators (e.g., NO₂).

5. Friedel–Crafts Acylation

Reagent: Acyl chloride + AlCl₃ Electrophile: Acylium ion (R–CO⁺)

Benzene → Aryl ketone (e.g., acetophenone)

No rearrangement occurs and no poly-substitution.

Orientation Summary

Ortho/Para Directors (Activating)

  • –OH
  • –NH₂
  • –OCH₃
  • –CH₃

Ortho/Para Directors (Deactivating)

  • Halogens (Cl, Br)

Meta Directors (Deactivating)

  • –NO₂
  • –SO₃H
  • –COOH
  • –CN

Why Do Groups Affect Orientation?

During EAS, benzene forms a temporary carbocation intermediate. Groups that can stabilise this positive charge (through resonance or electron donation) guide the electrophile to positions where stabilisation is easier (ortho/para).

Groups that withdraw electrons destabilise the intermediate at ortho/para, so substitution shifts to the meta position where the destabilisation is minimum.

Summary

  • EAS is the key reaction type for aromatic compounds.
  • Electrophile formation is the first and crucial step.
  • Substituent groups determine both speed and position of substitution.
  • Nitration, sulfonation, halogenation and Friedel–Crafts alkylation/acylation are major EAS reactions.

Detailed Notes:

For PDF style full-color notes, open the complete study material below:

PATH: PHARMD/PHARMD NOTES/ PHARMD FIRST YEAR NOTES/ ORGANIC CHEMISTRY/ PHARMACEUTICAL ORGANIC CHEMISTRY/ELECROPHILIC AROMATIC SUBSTITUTION.

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