Chemistry of benzene:

Electrophilic Aromatic Substitution

SEAr

Doç. Dr. Esra ÖNEN BAYRAM

 Reactivity of aromatic compounds
• The most common reaction: electrophilic
substitution.
• The reaction of an electrophile with the ring and
substitution of an H.
 Reactivity of aromatic compounds
• The most common reaction: electrophilic
substitution.

• The reaction of an electrophile with the ring and

substitution of an H.

• Reaction rather specific to aromatic compounds:

a way to test aromaticity.

• Possibility to intoduce many groups.

Reactivity of aromatic compounds
 SEAr: Bromination
• Double bond in aromatics: less reactive
Addition of FeBr3 as a catalyst to enhance the
polarization of Br2
 SEAr: Bromination
First step: Addition
• Attack of the double bond on polarized Br2
Formation of a non-aromatic carbocation

• More stable than typical alkyl cation because of

resonance forms, but lost aromaticity thus less
stable than the reactant.
 SEAr: Bromination
Second step: Elimination
• Loss of a hydrogen: transfer of a proton to
FeBr4-
 SEAr: Bromination
Second step: Elimination
• Why elimination instead of the nucleophilic
attack of Br-?

Aromaticity restored!!
SEAr = AE+ E
 SEAr: Chlorination and Iodation
• Possibility to introduce I and Cl.

• But F too reactive, difficulties to limit its

introduction to only one atom.

• Chlorination:
– Activation of Cl2 : use of FeCl3 (similar to Br)

– Reaction often used for synthesizing pharmaceuticals

(ex: diazepam or valium)
 SEAr: Chlorination and Iodation
• Iodation: Iodine not reactive enough
 converted into I+ , a more powerful
electrophile, by H2O2 or CuCl2.
 SEAr: Nitration
• Electrophile: the nitronium ion NO2+:
– Not stable: has to be prepared in situ
– Generation from nitric acid: HNO3
SEAr: Nitration
 SEAr: Nitration
• Nitration does not occur in nature.

• BUT used very often since lead to arylamines

ArNH2 when reduced by reagents such as
SnCl2.
 SEAr: Sulfonation
• Substitution of H with SO3.

• Electrophile: HNO3+ or neutral SO3 prepared from

fuming sulfuric acid (a mixture of H2SO4 and SO3).
 SEAr: Sulfonation
• Substitution of H with SO3.

• Electrophile: HNO3+ or neutral SO3 prepared from

fuming sulfuric acid (a mixture of H2SO4 and SO3).

• Obtained by the same 2-step reaction.

• Can occur forward and backward:

– Strong acid: sulfonation
– Aqueous acid and high temperature: desulfonation
SEAr: Sulfonation
 SEAr: Sulfonation
• Does not occur in nature.

• Useful for generating sulfanilamides (antibiotics).

• Useful intermediates for generation phenol products:

– heating with NaOH at 300⁰C followed by neutralization
(alkali fusion)
– Ex: preparation of p-cresol
 SEAr: Alkylation
The Friedel-Crafts reaction
• Electrophile: R-Cl in the presence of AlCl3
Generation of R+

• Mechanism similar to the other SEAr

 SEAr: Alkylation
The Friedel-Crafts reaction
 SEAr: Alkylation
The Friedel-Crafts reaction
• Electrophile: R-Cl in the presence of AlCl3
Generation of R+

• Mechanism similar to the other SEAr

• Limitations:
– OK with alkyl halides only (no reaction with aryl or
vinylic halides since corresponding carbocations too
difficult to form)
 SEAr: Alkylation
The Friedel-Crafts reaction
• Electrophile: R-Cl in the presence of AlCl3
Generation of R+

• Mechanism similar to the other SEAr

• Limitations:
– OK with alkyl halides only (no reaction with aryl or vinylic
halides since corresponding carbocations too difficult to
form)
– NO reaction of substitution of the ring with some groups
 SEAr: Alkylation
The Friedel-Crafts reaction
• Electrophile: R-Cl in the presence of AlCl3
 Generation of R+

• Mechanism similar to the other SEAr

• Limitations:
– OK with alkyl halides only (no reaction with aryl or vinylic halides since
corresponding carbocations too difficult to form)

– NO reaction of substitution of the ring with some groups

– Possibility to have polyalkylation since alkyl groups are activating

groups
 SEAr: Alkylation
The Friedel-Crafts reaction
• Electrophile: R-Cl in the presence of AlCl3
 Generation of R+

• Mechanism similar to the other SEAr

• Limitations:
– OK with alkyl halides only (no reaction with aryl or vinylic halides since
corresponding carbocations too difficult to form)

– NO reaction of substitution of the ring with some groups

– Possibility to have polyalkylation since alkyl groups are activating

groups

– Carbocation rearrangements particularly with primary halides.

 SEAr: Alkylation
The Friedel-Crafts reaction
• Carbocation rearrangement with
butylchloride:
 SEAr: Alkylation
The Friedel-Crafts reaction
• Carbocation rearrangement with 1-chloro-2,2-
dimethylpropane:
 SEAr: Acylation
The Friedel-Crafts reaction
• Electrophile: acyl chloride activated similarly with AlCl3

• Mechanism: similar SEAr

• Does not occur more than once since carbonyl group is a

deactivating group.
 Reactions with
substituted aromatic rings
• Substituents affect the reactivity of the ring:
activators and deactivators

• Substituents affect the orientation of the

reaction:
o-, m- or p- orientation.

• Controlled by an interplay of inductive and

resonance effects.
 Reactions with
substituted aromatic rings
• The inductive effect:
– Withdrawing or donating electrons due to
electronegativity.
– Cl, OH, carbonyl, cyano, nitrile, nitro groups (-I)

– Alkyl groups (+I)

 Reactions with
substituted aromatic rings
• The resonance effect:
– Electron-withdrawal:
 Reactions with
substituted aromatic rings
• The resonance effect:
– Electron-withdrawal: draw the resonance forms of
benzaldehyde.
 Reactions with
substituted aromatic rings
• The resonance effect:
– Electron-donating:
 Reactions with
substituted aromatic rings
• The resonance effect:
– Electron-donating in phenol: draw the resonance
forms of phenol
Reactions with substituted aromatic rings
Reactivity
• Electron donating groups: stabilization of the carbocation
intermediate.
activators.

• Electron-withdrawing groups: destabilization of the carbocation

intermediate.
 deactivators.

• Inductive vs resonance effect:

– Do not necessarily act in the same direction

– When effects in opposite directions, the strongest predominates.

Ex: -OH, -OR, -NH2 activating since strong ED resonance effect and
weak EW inductive effect.
-X deactivating since weak ED resonance effect and strong EW
inductive effect.
Reactions with substituted aromatic rings
Orientation
• o-, p- activators: alkyl groups

With o- and p- substitution a

resonance form with a tertiary
carbocation.
Reactions with substituted aromatic rings
Orientation
• o-, p- activators: OH and NH2 groups

With o- and p- substitution a resonance

form where the positive charged is
stabilized by donation of an electron pair.
Reactions with substituted aromatic rings
Orientation
• o-, p- deactivators: halogen groups

With o- and p- substitution a resonance

form where the positive charged is
stabilized by donation of an electron pair.
Reactions with substituted aromatic rings
Orientation
• m- deactivators

With o- and p- substitution a resonance

form where the positive charged is
destabilized by the EWG.
 Reactions with
substituted aromatic rings
 Reactions with
substituted aromatic rings
• Trisubstituted benzenes:
– If directing groups with the same effect: additivity
 Reactions with
substituted aromatic rings
• Trisubstituted benzenes:
– If directing groups with opposite effects: the more
powerful activating group orients the reaction.
(BUT mixtures are obtained)
 Reactions with
substituted aromatic rings
• Trisubstituted benzenes:
– m- disubsituted compounds not reactive: the
reaction site is too hindered
Other reactions with benzene

- Nucleophilic aromatic substitution: SNAr

- Oxydation reactions
- Reduction reactions
 Nucleophilic Aromatic Substitution
SNAr
• SN: presence of leaving group and a nucleophile.

• Leaving group: halide (reactions with aryl halides)

• Goes through a carbanion:

necessity to have EWG on o- and p- positions:
stabilization of the intermediate.
Nucleophilic Aromatic Substitution
SNAr
 Benzyne
• Can be prepared when chlorobenzene is
transformed into phenol in aqueous NaOH at
340°C.
 Benzyne
• Highly distorted alkyne.

• Triple bond with sp2 hybridized C:

– One  bond from p-p overlap
– Second  bond from sp2-sp2 overlap
 Oxidation of aromatic compounds
• Benzene inert to strong oxidizing agents such
as KMnO4 or Na2Cr2O7

• Possibility to convert alkyl side chains into

COOH:
 Oxidation of aromatic compounds
• Benzene inert to strong oxidizing agents such
as KMnO4 or Na2Cr2O7

• Possibility to convert alkyl side chains into

COOH:
 Oxidation of aromatic compounds
• Benzene inert to strong oxidizing agents such as
KMnO4 or Na2Cr2O7

• Possibility to convert alkyl side chains into COOH.

• Necessity to have a CH next to the aromatic ring.

Oxidation of aromatic compounds
• Bromination of side chains: reaction of an
alkylbenzene with N-bromosuccinimide (NBS)
 Oxidation of aromatic compounds
• Bromination of side chains: a radical reaction.
1) Generation of a benzylic radical

2) Attack of a Br2 that results from the reaction HBr

and NBS.

3) Formation of a Br· that cycles back to generate a

new benzylic radical.
 Oxidation of aromatic compounds
• Bromination of side chains: a radical reaction.
Reduction of aromatic compounds
• Aromatic rings inert to H2 addition in classical
conditions that reduce alkenes.

• Possibility to selectively reduce a double bond in

the presence of an aromatic ring.

• Reducing aromatic double bonds require

powerful reducing conditions: high pressure and
rhodium catalyst.
Reduction of aromatic compounds
• Aromatic rings activates neighbouring
carbonyl group towards reduction.
• Ketone converted into alkylbenzene by
catalytic hydrogenation over Pd catalyst.