Benzene Derivatives

Reactions of
Aromatic Compounds
Electrophilic
Aromatic Substitution
Electrophile substitutes for a
hydrogen on the benzene ring.
=>
Chapter 17
Mechanism
=>
Chapter 17
Bromination of
Benzene
Requires a stronger electrophile than Br .
2
Use a strong Lewis acid catalyst, FeBr3.

Br Br
FeBr3
H
H
Br
H
Br
Br
FeBr3
+
H
FeBr3
Animation
Br
Br
H
_
+ FeBr4
Animation
Animation
Br
+
Chapter 17
HBr
=>
4
Energy Diagram
for Bromination
=>
Chapter 17
Chlorination
and Iodination
Chlorination is similar to bromination.
Use AlCl3 as the Lewis acid catalyst.
Iodination requires an acidic oxidizing
agent, like nitric acid, which oxidizes
the iodine to an iodonium ion.
+
+ HNO 3 + 1/2 I2
NO2 + H2O
=>
Chapter 17
Nitration of Benzene
Use sulfuric acid with nitric acid to
form the nitronium ion electrophile.
O
H O
O H
H O
H O N
H O N
+
O
H O
H O N
+
O
O
H2O +
N+
O
Chapter 17
_
+ HSO4
NO2+ then forms a

sigma complex with
benzene, loses H+ to
form nitrobenzene. =>
7
Sulfonation
Sulfur trioxide, SO3, in fuming
sulfuric acid is the electrophile.
O
S+
O
O
S+
_
O
O
_
O
S
O
H O
S O
+
O
H
S +
O
O
HO
S
O
benzenesulfonic acid
=>
Chapter 17
Desulfonation
All steps are reversible, so sulfonic acid
group can be removed by heating in
dilute sulfuric acid.
This process is used to place deuterium
in place of hydrogen on benzene ring.
D
H
H
large excess
D2SO4/D2O
D
D
H
Chapter 17
Benzene-d6
=>
9
Nitration of Toluene
Toluene reacts 25 times faster than
benzene. The methyl group is an activator.
The product mix contains mostly ortho and
para substituted molecules.
=>
Chapter 17
10
Sigma Complex
Intermediate
is more
stable if
nitration
occurs at
the ortho
or para
position.
=>
Chapter 17
11
Energy Diagram
=>
Chapter 17
12
Activating, O-, PDirecting Substituents

Alkyl groups stabilize the sigma complex by
induction, donating electron density
through the sigma bond.
Substituents with a lone pair of electrons
stabilize the sigma complex by resonance.
OCH3
+
OCH3
NO 2
NO 2
H
H
Chapter 17
=>
13
Nitration of Anisole
Ortho attack
Meta attack
Para attack
=>
Chapter 17
14
The Amino Group

Aniline reacts with bromine water (without
a catalyst) to yield the tribromide.
Sodium bicarbonate is added to
neutralize the HBr thats also formed.
NH2
NH2
Br
Br
3 Br2
H2O, NaHCO3
Br
Chapter 17
=>
15
Summary of
Activators
Chapter 17
=>
16
Deactivating MetaDirecting Substituents

Electrophilic substitution reactions for
nitrobenzene are 100,000 times slower
than for benzene.
The product mix contains mostly the
meta isomer, only small amounts of the
ortho and para isomers.
Meta-directors deactivate all positions on
the ring, but the meta position is less
deactivated.
=>
Chapter 17
17
Ortho Substitution
on Nitrobenzene
=>
Chapter 17
18
Para Substitution
on Nitrobenzene
=>
Chapter 17
19
Meta Substitution
on Nitrobenzene
=>
Chapter 17
20
Energy Diagram
=>
Chapter 17
21
Structure of MetaDirecting Deactivators

The atom attached to the aromatic ring
will have a partial positive charge.
Electron density is withdrawn
inductively along the sigma bond, so the
ring is less electron-rich than benzene.
=>
Chapter 17
22
Summary of
Deactivators
=>
Chapter 17
23
More Deactivators
=>
Chapter 17
24
Halobenzenes
Halogens are deactivating toward
electrophilic substitution, but are ortho,
para-directing!
Since halogens are very electronegative,
they withdraw electron density from the
ring inductively along the sigma bond.
But halogens have lone pairs of
electrons that can stabilize the sigma
complex by resonance.
=>
Chapter 17
25
Sigma Complex
for Bromobenzene
Para attack
Ortho attack
Br
Br
(+)
Br
Br
(+)
H
E
(+)
(+)
(+)
E+
(+)
H E
Ortho and para attacks produce a bromonium ion

and other resonance structures.
Meta attack
Br
Br
(+)
(+)
No bromonium ion
possible with meta attack.
=>
Chapter 17
26
Energy Diagram
=>
Chapter 17
27
Summary of
Directing Effects
=>
Chapter 17
28
Multiple Substituents
The most strongly activating substituent
will determine the position of the next
substitution. May have mixtures.
OCH3
OCH3
SO3H
SO3
O2N
H2SO4
OCH3
+
O2N
O2N
SO3H
=>
Chapter 17
29
Friedel-Crafts Alkylation
Synthesis of alkyl benzenes from
alkyl halides and a Lewis acid,
usually AlCl3.
Reactions of alkyl halide with Lewis
acid produces a carbocation which is
the electrophile.
Other sources of carbocations:
alkenes + HF or alcohols + BF3.
=>
Chapter 17
30
Examples of
Carbocation Formation
Cl
CH3
CH CH3
_
CH3 +
C Cl AlCl3
H3C H
+ AlCl3
H2C
OH
H3C
CH CH3
CH CH3
BF3
F
+
H3C CH CH3
HF
+ BF3
H O
H3C
CH CH3
Chapter 17
_
+
H3C CH CH3 + HOBF3
=>
31
Formation of
Alkyl Benzene
CH3
+C
CH3
F
H
+
CH(CH3)2
CH(CH3)2
B OH
CH3
CH
+
CH3
HF
F
F
B OH
=>
Chapter 17
32
Limitations of
Friedel-Crafts
Reaction fails if benzene has a substituent
that is more deactivating than halogen.
Carbocations rearrange. Reaction of
benzene with n-propyl chloride and AlCl3
produces isopropylbenzene.
The alkylbenzene product is more reactive
than benzene, so polyalkylation occurs.
=>
Chapter 17
33
Friedel-Crafts
Acylation
Acyl chloride is used in place of alkyl
chloride.
The acylium ion intermediate is
resonance stabilized and does not
rearrange like a carbocation.
The product is a phenyl ketone that is
less reactive than benzene.
=>
Chapter 17
34
Mechanism of Acylation
O
R C Cl
+ _
R C Cl AlCl3
AlCl3
+ _
R C Cl AlCl3
_
AlCl4
C+
R
+
R C O
Cl
_
AlCl3
+
R C O
O
C
HCl
R +
AlCl3
=>
Chapter 17
35
Clemmensen
Reduction
Acylbenzenes can be converted to
alkylbenzenes by treatment with
aqueous HCl and amalgamated zinc.
O
O
+ CH3CH2C
Cl
1) AlCl3
C CH2CH3
2) H2O
Zn(Hg)
CH2CH2CH3
aq. HCl
=>
Chapter 17
36
Gatterman-Koch
Formylation
Formyl chloride is unstable. Use a high
pressure mixture of CO, HCl, and catalyst.
Product is benzaldehyde.
O
H C Cl
CO + HCl
AlCl3/CuCl
C+
C H
_
+
H C O AlCl4
HCl
=>
Chapter 17
37
Nucleophilic
Aromatic Substitution
A nucleophile replaces a leaving
group on the aromatic ring.
Electron-withdrawing substituents
activate the ring for nucleophilic
substitution.
=>
Chapter 17
38
Examples of
Nucleophilic
Substitution
=>
Chapter 17
39
Addition-Elimination
Mechanism
=>
Chapter 17
40
Benzyne Mechanism
Reactant is halobenzene with no
electron-withdrawing groups on the ring.
Use a very strong base like NaNH2.
=>
Chapter 17
41
Benzyne Intermediate
NH2
NH2
NH2
NH2
H
or
H
H
CH3
CH3
H
CH3
H
CH3
para-toluidine
meta-toluidine
Chapter 17
=>
42
Chlorination of
Benzene
Addition to the benzene ring may occur
with high heat and pressure (or light).
The first Cl2 addition is difficult, but the
next 2 moles add rapidly.
The product, benzene hexachloride, is
an insecticide.
=>
Chapter 17
43
Catalytic
Hydrogenation
Elevated heat and pressure is required.

Possible catalysts: Pt, Pd, Ni, Ru, Rh.
Reduction cannot be stopped at an
intermediate stage.
CH3
CH3
3 H2, 1000 psi
Ru, 100C
CH3
Chapter 17
CH3 =>
44
Birch Reduction:
Regiospecific
A carbon with an e--withdrawing group
O
O
is reduced.
C
OH
Na,
NH3
_
O
CH3CH2OH
A carbon with an e--releasing group

is not reduced.
OCH3
Li, NH3
(CH3)3COH, THF
Chapter 17
OCH3
=>
45
Birch Mechanism
=>
Chapter 17
46
Side-Chain Oxidation
Alkylbenzenes are oxidized to benzoic
acid by hot KMnO4 or Na2Cr2O7/H2SO4.
CH(CH3)2
CH CH2
KMnO4, OH
H2O, heat
_
COO
_
COO
=>
Chapter 17
47
Side-Chain
Halogenation
Benzylic position is the most reactive.
Chlorination is not as selective as

bromination, results in mixtures.
Br2 reacts only at the benzylic position.
Br
CH2CH2CH3
Br2, h
CHCH2CH3
=>
Chapter 17
48
SN1 Reactions
Benzylic carbocations are resonancestabilized, easily formed.
Benzyl halides undergo SN1 reactions.
CH2Br
CH3CH2OH, heat
CH2OCH2CH3
=>
Chapter 17
49
SN2 Reactions
Benzylic halides are 100 times more
reactive than primary halides via S N2.
Transition state is stabilized by ring.
=>
Chapter 17
50
Reactions of Phenols
Some reactions like aliphatic alcohols:
phenol + carboxylic acid ester
phenol + aq. NaOH phenoxide ion
Oxidation to quinones: 1,4-diketones.

O
OH
Na2Cr2O7, H2SO4
CH3
CH3
=>
O
Chapter 17
51
Quinones
Hydroquinone is used as a developer
for film. It reacts with light-sensitized
AgBr grains, converting it to black Ag.
Coenzyme Q is an oxidizing agent
found in the mitochondria of cells.
=>
Chapter 17
52
Electrophilic
Substitution of
Phenols
Phenols and phenoxides are highly reactive.
Only a weak catalyst (HF) required for

Friedel-Crafts reaction.
Tribromination occurs without catalyst.
Even reacts with CO2.
O
O
-
CO2, OH
O
C
OH
O
O
C
OH
=>
salicylic acid
Chapter 17
53
End of Chapter 17
Chapter 17
54

Benzene Derivatives

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Benzene Derivatives

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Reactions of

Use a strong Lewis acid catalyst, FeBr3.

NO2+ then forms a

Activating, O-, PDirecting Substituents

The Amino Group

Deactivating MetaDirecting Substituents

Structure of MetaDirecting Deactivators

Ortho and para attacks produce a bromonium ion

Elevated heat and pressure is required.

A carbon with an e--releasing group

Chlorination is not as selective as

Oxidation to quinones: 1,4-diketones.

Only a weak catalyst (HF) required for

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