Comprehensive Study Notes on Electrophilic Aromatic Substitution

Structural Drawing Problems:
- Problem 1: Draw the structure for the following:
- a. 2-phenylhexane
- b. Benzyl alcohol
- c. 3-benzylpentane
- d. Bromomethylbenzene
Toxicity of Benzene:
- Benzene: Widely used in chemical synthesis and as a solvent.
- Toxic substance causing:
- Central nervous system effects.
- Bone marrow ailments.
- Linked to leukemia and aplastic anemia.
- Studies indicate a higher-than-average incidence of leukemia in industrial workers exposed to as little as 1 ppm of benzene.
- Replacement Solvent: Toluene, though a central nervous system depressant, does not cause leukemia or aplastic anemia. Notably, "glue sniffing" leads to narcotic effects due to toluene's presence in glue.

Electrophilic Aromatic Substitution Reactions Overview:
- Aromatic compounds like benzene react via electrophilic aromatic substitution (EAS).
- An electrophile substitutes for a hydrogen on an aromatic ring carbon.
Common Types of Electrophilic Aromatic Substitution Reactions:
1. Halogenation:
- Electrophile: Halogens (Br, Cl, I).
- Reaction involves substituting hydrogen with a halogen.
1. Nitration:
- Electrophile: Nitro group (NO₂).
- Hydrogen is substituted by the nitro group.
1. Sulfonation:
- Electrophile: Sulfonic acid group (SO₃H).
- Substituting hydrogen with sulfonic acid group.
1. Friedel–Crafts Acylation:
- Electrophile: Acyl group (RCO).
- Hydrogen is replaced by an acyl group.
1. Friedel–Crafts Alkylation:
- Electrophile: Alkyl group (R).
- An alkyl group substitutes for hydrogen.
Mechanism Steps of Electrophilic Aromatic Substitution:
- Step 1: Electrophile (Y⁺) adds to the nucleophilic benzene ring, forming a carbocation intermediate.
- Step 2: A base in the reaction mixture removes a proton from the carbocation, and the electrons from the bond between the proton and the carbon move back into the ring, restoring aromaticity.
- Electron Flow in Mechanism Visualization:
- $( ext{H + Y}^{+} ightarrow ext{Carbocation} ightarrow ext{Base removes proton})$

Halogenation (Bromination and Chlorination):
- Catalysts: Required Lewis acid catalysts (e.g., ferric bromide [FeBr₃] for bromination & ferric chloride [FeCl₃] for chlorination).
- Lewis Acid Definition: A compound that accepts a share in an electron pair.
Bromination Reaction:
- $ext{Br}2 + ext{FeBr}3 ightarrow ext{Br}^+ + ext{FeBr}_4^-$
Chlorination Reaction:
- $ext{Cl}2 + ext{FeCl}3 ightarrow ext{Cl}^+ + ext{FeCl}_4^-$
Reason for Catalyst Requirement:
- Benzene's stability due to aromaticity reduces its reactivity compared to alkenes.
- More stable, better electrophiles are required, specifically, a Lewis acid makes Br₂ and Cl₂ better electrophiles by weakening their bonds.
Mechanism for Bromination and Chlorination:
1. Electrophile generation from the respective halogen and catalyst.
2. Electrophile adds to benzene, forming a carbocation intermediate.
3. Base removes proton restoring aromaticity.
Energy Consideration in Steps:
- First step endergonic and slow (loss of aromaticity).
- Second step is fast and exergonic (regaining aromaticity).
Visual Representation:
- Figure 18.1: Reaction coordinate diagram illustrating energy profile of electrophilic aromatic substitution.

Mechanism for Bromination Detailed:
- Reaction:
- $ext{Br} + ext{FeBr}3 ightarrow ext{Br}^+ + ext{FeBr}4$
- Problem 2: Hydration inactivates FeBr₃ due to moisture interaction.
Iodination of Benzene:
- Using I₂ with an oxidizing agent such as hydrogen peroxide (H₂O₂).
- Process yields iodonium ion (I⁺):
- $ext{H}2 ext{O}2 + ext{I}2 ightarrow 2 ext{I}^+ + 2 ext{H}2 ext{O}$
Mechanism for Iodination:
- The iodonium ion (I⁺) adds to benzene, followed by a base removing a proton to restore aromaticity.
Recognition of Catalyst Behavior:
- Ferric bromide and ferric chloride deactivate upon moisture exposure; hence, generated in situ.

Nitration Overview:
- Reagents: Nitric acid requiring sulfuric acid for catalysis.
- Reaction Mechanism:
- $ext{HNO}3 + ext{H}2 ext{SO}4 ightarrow ext{NO}2^+ + ext{H}_2 ext{O}$
Nitronium Ion Formation:
- Protonation of nitric acid followed by loss of water generates a nitronium ion,
- This is the required electrophile for nitration.
Thyroxine Example in Application:
- Thyroxine: Hormone increasing metabolic rates for fats, carbs, and proteins.
- Sourced from tyrosine and iodine via iodoperoxidase mechanisms, emphasizing iodine’s dietary importance.
Health Implications:
- Iodine deficiency causes intellectual disability; correction through thyroxine supplements like Synthroid.

Detailed Mechanism for Nitration:
- Steps involve:
- Electrophile addition to benzene.
- Base removal of proton from carbocation intermediate.

Sulfonation Overview:
- Utilizes concentrated sulfuric acid or fuming sulfuric acid for generating the electrophile.
Electrophile Formation:
- Mechanism generates the +SO₃H electrophile:
- $ext{HSO}3 + ext{H}2 ext{SO}4 ightarrow ext{HSO}3^+ + ext{H}_2 ext{O}$
Mechanism Steps:
1. Electrophile attaches to benzene.
2. Base in the mixture removes the proton from the carbon that formed the bond with the electrophile.

Friedel–Crafts Reactions Overview:
- Friedel–Crafts Acylation: Adds acyl group via an acyl chloride or an acid anhydride.
- $ext{acyl chloride} + ext{AlCl}_3 ightarrow ext{acylium ion}$
Mechanism Summary:
- Electrophile (acylium ion) adds to benzene ring.
- Proton removal by a base in the mixture.
Desulfonation Overview:
- Sulfonation is reversible; heating benzenesulfonic acid in dilute acid.

Friedel–Crafts Alkylation Overview:
- Substitutes an alkyl group on benzene using alkyl halides and a Lewis acid catalyst (e.g., AlCl₃).
- $R ext{Cl} + ext{AlCl}3 ightarrow R^{+} + ext{AlCl}4^{-}$
Example Mechanics:
- The electrophile adds to the benzene.
- The base removes the resulting proton from the carbon that formed the bond with the electrophile.
Reactions with Acid Anhydrides:
- Acyl halides can generate unstable complexes that require careful handling during Friedel–Crafts reactions, leading to subsequent reactions for the acylation process.