Topic Two

Aromatic reactions

Electrophilic Aromatic Substitution

Side-chain Reactions
Directing Effects
Synthesis
Nucleophilic Aromatic Substitution
Unusual Reactions

With FeCl3 catalyst, Br2 reacts with benzene to form

bromobenzene + HBr (substitution!). Double bonds remain.
Electrophilic Aromatic Substitution

E
E
H E
H :base
+ H-base
EAS Reactions of Benzene
NO2

CHO Cl

O
CR Br

R I

SO3H
Halogenation

• Analogous reactions with I2 and F2 are not synthetically useful

because I2 is too unreactive and F2 reacts too violently.
Bromination mechanism
Energy Diagram for Bromination
Nitration

NO2
HNO3, H2SO 4
+ H2O

Formation of electrophile
+ -
HNO3 + H2SO 4 NO2 + H2O + HSO4
Nitration Mechanism
Sulfonation is Reversible

fuming sulfuric acid

H SO3H
SO 3, H2SO 4

O
S
O O H OSO 3H

SO3H
OSO 3H
H
Desulfonation
Friedel-Crafts Alkylation
Examples of Carbocation Formation

Cl CH3 + _
CH3 CH CH3 + AlCl3 C Cl AlCl3
H3C H

_
HF F
+
H2C CH CH3 H3C CH CH3

+ BF3
H O
OH _
BF3 +
H3C CH CH3 H3C CH CH3 H3C CH CH3 + HOBF3
Friedel-Crafts Alkylation Mechanism
CH3 CH3
CH3 C Cl AlCl3 CH3 C AlCl4
CH3 CH3
t-butyl carbocation

CH3 (CH3)3C (CH3)3C (CH3)3C

CH3 C
H
CH3
resonance stabilized intermediate
Cl AlCl3
(CH3)3C
+ HCl
(+ AlCl3)
Carbocation Generated From Alkene
Unexpected Product?
CH2CH2CH2CH3
CH3CH2CH2CH2Cl, AlCl3 minor product

CH3
CHCH2CH3
major product

Carbocations
rearrange…
Reaction of benzene with n-propyl
chloride
Limitations of Friedel-Crafts

• Carbocations rearrange. Reaction of benzene with n-

propyl chloride and AlCl3 produces isopropylbenzene.

• Reaction fails if benzene has a substituent that is more

deactivating than halogen.

• The alkylbenzene product is more reactive than benzene,

so polyalkylation occurs.
Friedel-Crafts Acylation
Friedel-Crafts Acylation mechanism

O
O
+ -
C   C
Cl AlCl3 R C O AlCl4
R R
acylium ion

O
O
C
C R
H Cl AlCl3
R

O O O
C C C
R R R
H H H

O
C
R + HCl
Acylations

CH3 CH3 O
O
CH3CH2CH2CH2CCl CCH2CH2CH2CH3

TiCl4 in CH2Cl2 + HCl

CH3 CH3

Starting materials that contain both a benzene ring and an

electrophile are capable of intramolecular Friedel-Crafts reactions.
Side Chain Reactions

1) Reduction of Aromatic Ketones

(can also reduce alkenes and alkynes)

H2, Pd/C
in ethanol

Alternatively, use Zn(Hg), dil. HCl to avoid reduction of alkenes and

alkynes). Clemmensen reduction
Straight-chain Alkylation can be
accomplished in 2 steps: Acylation, then Reduction

CH2CH2CH3 CH(CH3)2
CH3CH2CH2Cl
AlCl3 minor + major

H2, Pd/C
O O
CH3CH2CCl CCH2CH3
AlCl3
2) Oxidation of Alkyl Substituents
O
CH3 COH
KMnO4, H2O

CO2H
KMnO4
H2O

CH3 CO2H
KMnO4, H2O

CH(CH3)2 CO2H
3) Benzylic Bromination with NBS
benzylic hydrogen
H Br

NBS, CCl4, h

O • Benzylic carbocations are

resonance-stabilized, easily formed.
• Benzyl halides undergo SN1
NBS NBr

O reactions

C H 3 CH 2 O H, heat
CH 2Br C H 2 O CH 2C H 3
Mechanism of Side-Chain Halogenation
4) Alkali Fusion of Sulfonic Acids

SO3H OH
o
1) NaOH, 300 C
+
2) H3O
phenol
5) Reduction of Nitro Groups

NO2 1) SnCl2, HCl NH2

2) NaOH
or H2 on Pt
Directing Effects

EDG EWG

electron donating groups electron withdrawing groups

activate ring deactivate ring

atom attached is atom attached is

usually sp3 usually sp2 or sp
ortho /para-Directing
Activating groups

OCH3 OCH3 OCH3 OCH3

+
 OCH3
- -
 

-

Nitration of Anisole
Activating ortho/para directors
OCH3 OCH3 OCH3
NO2
HNO3, H2SO 4
+

ortho para
NO2
Energy diagram
Nitration of Toluene
meta-Directing
Deactivating Groups
O O O O
CH CH CH CH

 -
O
CH
+ ortho and para positions
 
+
are deactivated toward
EAS
+
Electron-withdrawing nitro group directs
meta
meta Directors
Comparison

CH3 Brominated product

ortho meta para rel. rate
63 3 34 25
rate rel. to
Br2, FeBr3 benzene
CF3
ortho meta para
6 91 3 0.000025
Halogens
Deactivators and o,p-Directors

Br Br Br
CH2CH3
CH3CH2Cl
+
AlCl3
rel. rate = 0.5
CH2CH3

Inductively withdrawing, hence deactivating

Resonance donation causes o,p directing
More Limitations with Friedel Crafts Reactions
Ring must be at least as
activated (reactive) as
Cl Cl

CH3CH2Cl, TiCl 4 + ortho

O
NO2 CH2CH3
ClCCH3, AlCl3
No Reaction
Substituent Summary
Reactions of Rings with
Two or More Substituents

Activating Group Controls Reaction

OCH3 OCH3
Cl
Cl2, FeCl3

NO2 NO2
The (More) Activated Ring Reacts

O SO 3 O
H2SO 4
CO CO SO3H
*
deactivated activated
(+ some ortho)
Mixtures with Conflicting Directing Effects
Provide the Reagents

NH2

C(CH3)3
Br
Must Acylate First
NH2

O
ClCCH2CH2CH2CH3
AlCl3 H2, Pt/C
NO2

HNO3
H2SO 4

O meta director O
Sulfonic Acid Blocks para Position
C(CH3)3
Br

+
H3O
(CH3)3CBr H
AlCl3

C(CH3)3 C(CH3)3 C(CH3)3

Br
SO 3, H2SO 4 Br2, FeBr3
blocks para

SO3H SO3H
Give the Reagents

CO2H

CH3
Cl
O
Provide the Reagents

CH2CH3

Br OH
O CH2CH3
1) ClCCH3, AlCl3
2) SO 3, H2SO 4
3) Br2, FeBr3 Br OH
1) 4) H2 Pd/C
o
5) NaOH, 300 C 5,6)
+
6) H3O
O O O

2) 3) 4)

SO3H Br SO3H Br SO3H

Provide the Reagents

HO2C
Cl

1) AlCl3 HO2C

2) Cl

O AlCl3 6) workup w/
+
3) KMnO4, H2O HO2C H3O

1) 4) H2, Pd/C
5) NBS, h
6) NaOCH3 in CH3OH, heat
(E2 elim of HBr) HO2C Br
5)

HO2C 4)
2) 3)

O O
Nucleophilic Aromatic Substitution

❑A nucleophile replaces a leaving group on the aromatic ring.

❑This is an addition–elimination reaction.
❑Electron-withdrawing substituents activate the ring for
nucleophilic substitution.
Examples of Nucleophilic Substitution

=>
Mechanism of Nucleophilic Aromatic
Substitution

Step 1: Attack by hydroxide gives a resonance-stabilized complex.

Step 2: Loss of chloride gives the product. Step 3: Excess base deprotonates the product.
Activated Positions

❑Nitro groups ortho and para to the halogen stabilize the

intermediate (and the transition state leading to it).
❑Electron-withdrawing groups are essential for the reaction to
occur.
Benzyne Reaction
Elimination-Addition

❑Reactant is halobenzene with no electron-withdrawing groups on

the ring.
❑Use a very strong base like NaNH2.
Benzyne Mechanism

❑Sodium amide abstract a proton.

❑The benzyne intermediate forms when the bromide is
expelled and the electrons on the sp2 orbital adjacent
to it overlap with the empty sp2 orbital of the carbon
that lost the bromide.
❑Benzynes are very reactive species due to the high
strain of the triple bond.
Nucleophilic Substitution on the
Benzyne Intermediate
Other reactions

Chlorination of Benzene

❑Addition to the benzene ring may occur

with excess of chlorine under heat and
pressure.
❑The first Cl2 addition is difficult, but the
next two moles add rapidly.

An insecticide
Catalytic Hydrogenation

CH 3 CH 3

3 H 2, 1000 psi
Ru, 100°C
CH 3 CH 3

❑Elevated heat and pressure is required.

❑Possible catalysts: Pt, Pd, Ni, Ru, Rh.
❑Reduction cannot be stopped at an intermediate
stage.
Birch Reduction
H H H
H H H H
Na or Li
NH3 (l), ROH
H H H H
H H H

❑This reaction reduces the aromatic ring to a non conjugated 1,4-

cyclohexadiene.
❑The reducing agent is sodium or lithium in a mixture of liquid
ammonia and alcohol.
Mechanism of the Birch Reduction
Limitations of the Birch Reduction
Oxidation of Phenols
OH O
Cl Cl
Na2Cr2O7
H2SO4

O
2-chloro-1,4-benzoquinone

❑Phenol will react with oxidizing agents to produce

quinones.
❑Quinones are conjugated 1,4-diketones and can easily
be reduced to hydroquinones and vice versa.
❑This can also happen (slowly) in the presence of air.
Diazotization of Arylamines

The reaction of aniline with nitrous acid (NaNO2 + H+ → HONO) leads

to an aryl diazonium cation, a valuable precursor to other functional
groups.

Aryl diazonium salts react with nucleophiles in a substitution reaction.

N
N Nu
+ Nu: + N N
67
Diazotization mechanism

68
Synthetic Transformations of Aryl Diazonium Salts.

N
X
N

Cu2O, HCl, HBr,

NaI HBF4 Cu(CN) H3PO2
H2O CuCl CuBr

OH I F Cl Br CN H

*Sandmeyer reaction: promoted by Cu(I) salts

69
Advantages of the aryl diazonium salt intermediate:
1) Introduces aryl substituents that are not otherwise easily
accessible, such as -OH, -F, -I, and -CN.
2) Allows preparation of substituted arenes with substitution
patterns that can not be prepared by other means.

Suggest the synthesis of the following aromatic compounds from benzene

CH3
CH3
I CH2CH3

Br
Br Br

70