Chapter 22

Reaction of
Benzene and
its Derivatives
22-1

Reactions of Benzene

Substitution at a ring carbon.

Halogenation:
H + Cl2

FeCl3

Cl + HCl
Chlorobenzene

Contrast to radical
mechanism for
benzylic hyrdogens

Nitration:
H + HNO3

H2 SO4

NO2 + H2 O
Nitrobenzene

22-2

Reactions of Benzene
Sulfonation:
H + SO3

H2 SO4

SO3 H

Benzenesulfonic acid
Alkylation: Friedel Crafts
H + RX

AlX3

R + HX
An alkylbenzene

Acylation: Friedel Crafts

O
AlX3
H + RCX

O
CR + HX
An acylbenzene
22-3

Electrophilic Aromatic Substitution

Electrophilic aromatic substitution:

H

+ E

+ H

We study several common electrophiles

how each is generated.
the mechanism by which each replaces hydrogen.

22-4

EAS: General Mechanism

A general mechanism
Step 1:

H + E

Electrophile
+
Step 2:

H
E

fast

slow, rate
determining

E
Resonance-stabilized
cation intermediate
E + H+

General question: What are the electrophiles and

how are they generated? Look at particular
reactions.
22-5

Chlorination
Step 1: Generation of the electrophile: a chloronium ion.
Cl
Cl Cl + Fe Cl
Cl
Chlorine Ferric chloride
(a Lewis
(a Lewis
base)
acid)

Cl

Cl

Cl Fe Cl
Cl
A molecular complex
with a positive charge
on chlorine

Cl FeCl4
An ion pair
containing a
chloronium ion

Step 2: Attack of the chloronium ion on the ring.

+ Cl

slow, rate
determining
+

+
Cl

Cl

+ Cl
Resonance-stabilized cation intermediate; the positive
charge is delocalized onto three atoms of the ring22-6

Chlorination
Step 3: Proton ejection regenerates the aromatic
character of the ring.
+

H
Cl

Cation
intermediate

+ Cl-FeCl3

fast

Cl + HCl + FeCl3
Chlorobenzene

22-7

Addition vs Substitution

Energy diagram for the bromination of benzene.

22-8

Nitration (Nitric and Sulfuric Acids)

Generation of the nitronium ion, NO2+

Step 1: Proton transfer to nitric acid.
O
HSO3 O H + H O N
O
Sulfuric
acid

O
O N
H
O
H

HSO4 +

Nitric
acid

Conjugate acid
of nitric acid

Step 2: Loss of H2O gives the nitronium ion, a very

strong electrophile.
Dehydrated
nitric acid.
O
H
H

O N
H
O

+ O N O

The nitronium
ion

22-9

Nitration,
Attack of electrophile as before..
Step 1: Attack of the nitronium ion) on the aromatic ring.
H
+
+ O N O

NO2
+

NO2

H
+

NO2

+
Resonance-stabilized cation intermediate

Step 2: Proton transfer regenerates the aromatic ring.

H
H

H NO2
O

NO2
+

H
H

O H

22-10

Synthesis, Nitro Amines

The nitro group can be reduced to a 1 amino

group.
COOH
+ 3H2
NO2
4-Nitrobenzoic acid

COOH
Ni
(3 atm)

+ 2H2O

NH2
4-Aminobenzoic acid

Notice the carboxylic was untouched.

22-11

Sulfonation

Carried out using concentrated sulfuric acid

containing dissolved sulfur trioxide.
+ SO3
Benzene

H2 SO4

SO3 H
Benzenesulfonic acid

22-12

Friedel-Crafts Alkylation

Friedel-Crafts alkylation forms a new C-C bond

between an aromatic ring and an alkyl group.
+
Benzene

Cl

AlCl3

+ HCl

2-Chloropropane
Cumene
(Isopropyl chloride) (Isopropylbenzene)

22-13

Friedel-Crafts Alkylation
Step 1: Formation of an alkyl cation as an ion pair.
R Cl

Cl
Al Cl
Cl

Cl
R Cl Al Cl
Cl
A molecular
complex
+

R+ AlCl4 An ion pair containing

a carbocation

Step 2: Attack of the alkyl cation.

+
+ R+

H
R

+R

A resonance-stabilized cation

Step 3: Proton transfer regenerates the aromatic ring.

H
R

+ Cl AlCl3

R + AlCl3 + HCl
22-14

Friedel-Crafts Alkylation

There are four major limitations on Friedel-Crafts

alkylations:
1. Carbocation rearrangements are common
Cl

Benzene

CH3
CH3 CHCH2 -Cl

Isobutyl
chloride

+ AlCl3

Isobutyl chloride

AlCl3

+ HCl

tert-Butylbenzene

CH3
+
CH3 C-CH2 -Cl-AlCl3
H
a molecular
complex

CH3
CH3 C+ AlCl4 CH3
an ion pair

22-15

Friedel-Crafts Alkylation
2. F-C alkylation fails on benzene rings bearing one or
more of these strongly electron-withdrawing groups.
Y
+ RX

AlCl3

No reaction

When Y Equals Any of These Groups, the Benzene

Ring Does No t Undergo Friedel-Crafts Alkylation
O
CH

O
CR

SO3 H

C N

CF3

CCl3

O
COH
NO2

O
COR
NR3

O
CNH2

22-16

Friedel-Crafts Alkylation
3. F-C multiple alkylation can occur more rapidly than
monoalkylation. The first alkyl group activates the ring
to the second substitution.

4. The steps in the Friedel Crafts Alkylation are reversible

and rearrangments may occur.

22-17

Friedel-Crafts Acylation

Friedel-Crafts acylation forms a new C-C bond

between a benzene ring and an acyl group.
O
+ CH3CCl
Benzene

O
AlCl3

Acetyl
chloride
Cl

+ HCl
Acetophenone
O

O
AlCl3

4-Phenylbutanoyl
chloride

+ HCl
-Tetralone

22-18

Friedel-Crafts Acylation

The electrophile is an acylium ion.

R-C Cl

An acyl
chloride

Cl
+ Al-Cl
Cl
Aluminum
chloride

(1)

O + Cl
(2)

R-C Cl Al Cl

Cl
A molecular complex
with a positive charge
charge on chlorine

O
R-C+ AlCl4An ion pair
containing an
acylium ion

22-19

Friedel-Crafts Acylation
An acylium ion is represented as a resonance hybrid
of two major contributing structures.

O:

+
R-C

complete valence
shells
+
R-C O:
The more important
contributing structure

Friedel-Crafts acylations are free of major

limitation of Friedel-Crafts alkylations; acylium
ions do not rearrange, do not polyacylate (why?),
do not rearrange.
22-20

Synthesis, Friedel-Crafts Acylation

preparation of unrearranged alkylbenzenes.

O
+ Cl

AlCl3

2-Methylpropanoyl
chloride

O
N2H4, KOH
diethylene
glycol
Isobutylbenzene

2-Methyl-1phenyl-1-propanone

What else could be

used here?
22-21

Other Aromatic Alkylations

Carbocations are generated by

treatment of an alkene with a proton acid, most
commonly H2SO4, H3PO4, or HF/BF3.
+
Benzene

CH3CH=CH2

H3PO4

Propene

Cumene

AlCl3

Benzene Cyclohexene
Phenylcyclohexane
an alkene with a Lewis
acid.
treating

22-22

Other Aromatic Alkylations

and by treating an alcohol with H2SO4 or H3PO4.
+
Benzene

HO

H3 PO4

2-Methyl-2-propanol
(tert-Butyl alcohol)

+ H2 O

2-Methyl-2phenylpropane
(tert-Butylbenzene)

22-23

Di- and Polysubstitution

Orientation on nitration of monosubstituted

benzenes.
Substituent ortho

Favor
ortho/para
substitution

Favor meta
substitution

meta
-

para

ortho +
para

meta

55
38

99
96

trace
4

30

100

trace

OCH3
CH3

44
58

Cl

70

4
-

Br

37

62

99

COOH

18

80

20

80

CN

19

80

20

80

NO2

6.4

93.2

0.3

6.7

93.2
22-24

Directivity of substituents

22-25

Di- and Polysubstitution

Two ways to characterize the substituent

Orientation:
Somesubstituentsdirectpreferentiallytoortho&para
positions;otherstometapositions.
Substituentsareclassifiedaseitherorthoparadirectingor
orthoparadirecting
metadirectingtowardfurthersubstitution.
metadirecting
Rate
Somesubstituentscausetherateofasecondsubstitutionto
begreaterthanthatforbenzeneitself;otherscausetherateto
belower.
Substituentsareclassifiedasactivatingor
activating deactivating
deactivating
towardfurthersubstitution.
22-26

Di- and Polysubstitution

-OCH3 is ortho-para directing.
OCH3
+ HNO3

OCH3
NO2
CH3COOH
o-Nitroanisole
(44%)

Anisole

COOH is meta directing.

COOH
-COOH
+ HNO3
Benzoic
acid

H2 SO4

NO2

100C

OCH3
+

+ H2 O

NO2
p-Nitroanisole
(55%)

COOH
+

+
NO2

o-Nitrobenzoic
acid
(18%)

COOH

m-Nitrobenzoic
acid
(80%)

NO2
p-Nitrobenzoic
acid
(2%) 22-27

Cl :

Br :

Meta Directing

OCAr

Recall the polysubstitution in

FC alkylation.

R
F:

OCR

NHCAr

NHCR

I:

CH
O

CR

COH

COR

CNH2
NO2

OR

Strongly
deactivating

OH

Moderately
deactivating

NR2

Weakly
deactivating

NHR
:

Weakly
activating

NH2

Moderately
activating

Strongly
activating

Ortho-para Directing

Di- and Polysubstitution

SO3 H
NH3

C N
CF3

CCl3

22-28

Di- and Polysubstitution

Generalizations:
Directivity: Alkyl, phenyl, and all substituents in which
the atom bonded to the ring has an unshared pair of
electrons are ortho-para directing. All other
substituents are meta directing.

Activation: All ortho-para directing groups except the

halogens are activating toward further substitution.
The halogens are weakly deactivating.

22-29

Di- and Polysubstitution

The order of steps is important.
CH3

COOH

HNO3

K2 Cr2O7

H2SO4

H2SO4

CH3

K2 Cr2 O7
H2 SO4

NO2

NO2
p-Nitrobenzoic
acid

COOH

COOH
HNO3
H2SO4

NO2
m-Nitrobenzoic
acid

22-30

Theory of Directing Effects

The rate of EAS is limited by the slowest step in

the reaction.
For almost every EAS, the rate-determining step
is attack of E+ on the aromatic ring to give a
resonance-stabilized cation intermediate.
The more stable this cation intermediate, the
faster the rate-determining step and the faster the
overall reaction.

22-31

Theory of Directing Effects

The orientation is controlled by the stability of

the carbocation being formed by attack of the
electrophile.

Products are formed under kinetic control.

22-32

Theory of Directing Effects, ortho-para director.

-OCH3: assume ortho-para attack. Here only para
attack is shown.
o,p director

OCH3

+ NO2 +

OCH3

slow

: OCH3

: OCH3

: OCH3

OCH3

+
NO2
(d)

fast

-H+

+
H

NO2

+
H
(e)

NO2

H
(f)

NO2

NO2

(g)

Very stable resonance structure. Why?

22-33

Theory of Directing Effects , ortho-para director.

-OCH3; look at meta attack.
OCH3
+ NO2

OCH3
+
H

slow

OCH3
+

OCH3
fast
H -H+

NO2
(a)

o,p director

(b)

NO2

+ NO2

OCH3

NO2

(c)

No corresponding resonance structure putting

positive charge on oxygen.
22-34

Theory of Directing Effects, meta director.

-CO2H : assume ortho-para attack.
COOH
+ NO2

Meta director

slow

COOH

COOH

COOH

COOH
fast
+
-H

H NO2
(d)

H NO2

H NO2

(e)
(f)
The most disfavored
contributing structure

Disfavored because CO2H is

electron withdrawing

NO2

22-35

Theory of Directing Effects, meta director.

-CO2H; assume meta attack.
COOH
+ NO2

slow

COOH

(a)

Meta director

COOH

NO2

NO2

NO2

(b)

COOH

COOH
fast
+
-H

NO2

(c)

22-36

Activating-Deactivating Resonance Effects

Any resonance effect,

effect such as that of -NH2, -OH,
and -OR, that delocalizes the positive charge on
the cation by has an activating effect toward
further EAS.

Any resonance effect,

effect such as that of -NO2, -CN,
-C=O, and -SO3H, that decreases electron density
on the ring deactivates the ring toward further
EAS.
22-37

Activating-Deactivating Inductive Effects

Any inductive effect,

effect such as that of -CH3 or other
alkyl group, that releases electron density toward
the ring activates the ring toward further EAS.

Any inductive effect,

effect such as that of halogen,
-NR3+, -CCl3, or -CF3, that decreases electron
density on the ring deactivates the ring toward
further EAS.

22-38

Activating-Deactivating: Halogens
For the halogens, the inductive and resonance effects
oppose each other. Inductive is somewhat stronger.
Result: halogens are deactivating but ortho-para
directing.
:Cl

H
E

+
:Cl

+E

: :

: :

: Cl

H
E

22-39

Nucleophilic Aromatic Substitution

Aryl halides do not undergo nucleophilic

substitution by either SN1 or SN2 pathways.

They do undergo nucleophilic substitutions, but

by two mechanisms.
Benzyne using strong base.
Addition/elimination typically with nitro activating
groups.

22-40

Benzyne Intermediates

When heated under pressure with aqueous

NaOH, chlorobenzene is converted to sodium
phenoxide.
Neutralization with HCl gives phenol.
-

Cl

O Na
+ 2NaOH

Chlorobenzene

H2O
o

pressure, 300 C

+ NaCl + H2O
Sodium
phenoxide

22-41

Benzyne Intermediates (strong base)

The same reaction with 2-chlorotoluene gives a
mixture of ortho- and meta-cresol.
CH3

Cl

CH3

1. NaOH, heat, pressure

2. HCl, H2O

CH3

OH
+

OH
2-Methylphenol 3-Methylphenol
(o-Cresol)
(m-Cresol)

The same type of reaction can be brought about using

sodium
CH3
CH3 amide in liquid ammonia.
CH
3

+ NaNH2
Cl

NH3 (l)
o

(-33 C)

+ NaCl

+
NH2

NH2
4-Methylaniline 3-Methylaniline
(p-Toluidine)
(m-Toluidine)

22-42

Benzyne Intermediates
-elimination of HX gives a benzyne intermediate, that
then adds the nucleophile to give products.

22-43

Benzyne Intermediates
But wait, do we believe this crazy idea? We need some evidence.

22-44

Benzyne Intermediates
The deuterated fluoride below exchanges the D with
solvent ammonia although the deuterated bromide does
not. This indicates a relatively rapid exchange process for
the fluoro compound.

next

22-45

Benzyne Intermediates
explanation

22-46

Orientation

The methyl group is essentially just a marker to

allow the observation of the mixture of products.
Consider the methoxy group, -OCH3, stabilizing
of positive charge via resonance but also
inductively withdrawing.
The methoxy group is not in resonance with the
negative charge of the anion, Inductive Effect
dominates. Next slide.

22-47

Benzyne Intermediates
D

Get
same
product

Explation
next

22-48

Benzyne Intermediates
explanation

22-49

Addition-Elimination (nitro groups)

When an aryl halide contains electron-withdrawing
NO2 groups ortho and/or para to X, nucleophilic
aromatic substitution takes place readily.
-

Cl
NO2

Na2 CO3, H2 O

O Na
NO2

100 C
NO2

1-Chloro-2,4dinitrobenzene

NO2

Sodium 2,4-dinitrophenoxide

Neutralization with HCl gives the phenol.

22-50

Meisenheimer Complex
Reaction involves formation of reactive intermediate
called a Meisenheimer complex.
O
+N
O

slow, rate
determining
Cl + Nu
(1)
NO2
O
+N
O

Cl
Nu
NO2

fast
(2)

O
+N
O

Nu + :Cl

NO2

A Meisenheimer complex

Similar to nucleophilic subsititution on carboxylic acid

derivatives.

22-51