Reactions of Arenes

Chapter 12
In this chapter we will consider:

• General parameters that allow for reactions of benzene

• How substituents on a benzene ring can impact

reactivity and the ability to undergo additional
substitutions

• Reactions that can convert a given substituent into new

functional groups
 Intended Learning Objectives ILOs:
Explain the mechanism of the electrophilic aromatic substitution
reactions of benzene: halogenation, nitration, sulfonation, Friedel-Crafts
alkylation, and Friedel-Crafts acylation.

Explain the mechanistic basis for the action of activating ortho, para-
directing groups and deactivating meta-directing groups.

Explain why the halogens are deactivating ortho, para-directing groups.

Describe the synthesis of substituted aromatic compounds.

Explain the orientation of electrophile on benzene ring in the presence

of multiple substituents.
 12.1
Electrophilic Aromatic Substitution
Reactions of Benzene
 H E
δ δ
+E +H
+ –Y Y

Electrophilic aromatic substitutions include:

Nitration
Sulfonation
Halogenation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation (carbonyl groups)
 Nitration of Benzene

H H2SO4 NO2
+ HONO2
+ H2O
Nitric acid: HNO3

Nitrobenzene
(95%)
 Sulfonation of Benzene

O
H heat SO2OH
+ HOS-OH
+ H2O
O
Sulfuric acid
Benzenesulfonic acid
(100%)
 Halogenation of Benzene

H FeBr3 Br
+ Br2
+ HBr

Bromobenzene
(65-75%)
Friedel-Crafts Alkylation of Benzene

H AlCl3 C(CH3)3
+ (CH3)3CCl
+ HCl

tert-Butylbenzene
(60%)
Friedel-Crafts Acylation of Benzene

O
O
H AlCl3 CCH2CH3
+ CH3CH2CCl
+ HCl

1-Phenyl-1-propanone
(88%)
 12.2

Mechanistic Principles
of
Electrophilic Aromatic Substitution
Step 1: attack of electrophile
from π-electron system of aromatic ring

E+
H H H H E
H H H +
H
H H H H
Arenium ion
highly endothermic (heat needed)
carbocation is allylic, but not aromatic
Step 2: loss of a proton from the carbocation
intermediate

H H H H E
H E H +
H
H H H+ H H

highly exothermic
this step restores aromaticity of ring
 Based on this general mechanism:

what remains is to identify the electrophile in

nitration, sulfonation, halogenation, Friedel-
Crafts alkylation, and Friedel-Crafts acylation
to establish the mechanism of specific
electrophilic aromatic substitutions
 12.3

Nitration of Benzene
Nitration of Benzene

H H2SO4 NO2
+ HONO2
+ H2O

+
Electrophile is
•• O
••
N O ••
••
nitronium ion
Step 1: attack of nitronium cation
on π-electron system of aromatic ring

NO2+
H H H H NO2
H H H +
H
H H H H
Step 2: loss of a proton from the carbocation
intermediate

H H H H NO2
H NO2 H +
H
H H H+ H H
 Where does nitronium ion come from?

•• •• – •• •• –
•• O + O •• ••O + O ••
•• ••
N H2SO4 N
+O
•• O ••
•• H H H

+ ••
O
•• O
••
N O ••
••
+
H •• H
 12.4

Sulfonation of Benzene
 Sulfonation of Benzene

H heat SO2OH
+ HOSO2OH
+ H2O

•• •• –
•• O + O ••
••
Several electrophiles present: S
a major one is sulfur trioxide
•• O
••
Step 1: attack of sulfur trioxide
on π-electron system of aromatic ring

SO3
H H H H SO3–
H H H +
H
H H H H
Step 2: loss of a proton from the carbocation
intermediate

H H H H SO3–
H SO3– H +
H
H H H+ H H
Step 3: protonation of benzenesulfonate ion

H H H2SO4 H H
H SO3– H SO3H
H H H H
 12.5
Halogenation of Benzene
 Halogenation of Benzene

H FeBr3 Br
+ Br2
+ HBr

Electrophile is a complex between FeBr3 and Br2.

 The Br2-FeBr3 Complex

+
•• •• •• •• –
•• Br Br •• + FeBr3 •• Br Br FeBr3
•• •• •• ••
Empty p orbital
Complex
Lewis base: Lewis acid:
Electron donnor Electron acceptor

The Br2-FeBr3 complex is more electrophilic

than Br2 alone.
 Step 1: attack of Br2-FeBr3 complex
on π-electron system of aromatic ring

+ –
Br Br FeBr3
H H H H Br
H H H +
H
H H H H

+ FeBr4–
Step 2: loss of a proton from the carbocation
intermediate

H H H H Br
H Br H +
H
H H H+ H H
 12.6

Friedel-Crafts Alkylation of Benzene

Friedel-Crafts Alkylation of Benzene

H AlCl3 C(CH3)3
+ (CH3)3CCl
+ HCl

H3C
Electrophile is +
C CH3
tert-butyl cation
H3C
 Role of AlCl3

acts as a Lewis acid to promote ionization

of the alkyl halide
+
•• •• –
(CH3)3C Cl •• + AlCl3 (CH3)3C Cl AlCl3
•• ••
Empty p orbital

+ •• –
(CH3)3C + •• Cl AlCl3
••
Step 1: attack of tert-butyl cation
on π-electron system of aromatic ring

+
C(CH3)3
H H H H C(CH3)3
H H H +
H
H H H H
Step 2: loss of a proton from the carbocation
intermediate

H H H H C(CH3)3
H C(CH3)3 H +
H
H H H+ H H
Rearrangements in Friedel-Crafts Alkylation

Carbocations are intermediates.

Therefore, rearrangements can occur

H C(CH3)3
AlCl3
+ (CH3)2CHCH2Cl

Isobutyl chloride tert-Butylbenzene

(66%)
 Rearrangements in Friedel-Crafts Alkylation

H H
+ –
•• +
H3C C CH2 Cl AlCl3 H3C C CH2
••
CH3 CH3
• –
+ ••C AlC
••
H l l3
•
H3C C+ CH2
Carbocation
Rearrangement
CH3
Reactions Related to Friedel-Crafts Alkylation

H
H2SO4
+

Cyclohexylbenzene
(65-68%)
Cyclohexene is protonated by sulfuric acid,
giving cyclohexyl cation which will be attacked
by the benzene ring
Reactions Related to Friedel-Crafts Alkylation

H
H2SO4
+

Cyclohexylbenzene

Cyclohexenol is protonated by sulfuric acid,

giving cyclohexyl cation which will be attacked
by the benzene ring
 12.7

Friedel-Crafts Acylation of Benzene

 Friedel-Crafts Acylation of Benzene

O
O
H AlCl3 CCH2CH3
+ CH3CH2CCl
+ HCl

Electrophile is an acyl cation

+ •• +
CH3CH2C O •• CH3CH2C O ••
Step 1: attack of the acyl cation on π-electron system
of aromatic ring
O
O
CCH2CH3
H H + H H CCH2CH3
H H H +
H
H H H H

Step 2: loss of a proton from the carbocation

intermediate
O
H H
H CCH2CH3
H H H+
Intramolecular Friedel-Crafts Acylation of Benzene

AlCl3

+ HCl
 Acid Anhydrides

can be used instead of acyl chlorides

O
O O
H AlCl3 CCH3
+ CH3COCCH3

Acetophenone
(76-83%)

+ CH3COH
 12.8

Acylation-Reduction
 Acylation-Reduction

permits primary alkyl groups to be attached

to an aromatic ring

O O
H CR
RCCl
AlCl3 Zn(Hg), HCl

CH2R
Clemmensen reduction
 Acylation-Reduction

permits primary alkyl groups to be attached

to an aromatic ring

O O
H CR
RCCl
AlCl3 H2NNH2, KOH,
glycol, heat

CH2R
Wolff-Kishner reduction
 Example: Preparation of isobutylbenzene

CH2CH(CH3)2 ?

(CH3)2CHCH2Cl
AlCl3
To prevent carbocation rearrangement,
acylation followed by reduction are C(CH3)3
best sequences to prepare alkylbenzenes
 Use Acylation-Reduction Instead

+ (CH3)2CHCCl

AlCl3 Zn(Hg) CH2CH(CH3)2

HCl
O

CCH(CH3)2
 Rate and Regioselectivity in
Electrophilic Aromatic Substitution

A substituent already present on the ring affect

- Rate of EAS

- Regioselectivity of EAS
G
E+
 Effect on Rate

Activating substituents increase the rate

of EAS compared to that of benzene.

Deactivating substituents decrease

the rate of EAS compared to benzene.
 Methyl Group

CH3 Toluene undergoes nitration

20-25 times faster than
benzene.

A methyl group is an
activating substituent.
 Trifluoromethyl Group

(Trifluoromethyl)benzene
CF3
undergoes nitration 40,000
times more slowly than benzene .

A trifluoromethyl group is a
deactivating substituent.
 Interpretation

Ring is electron rich Ring is electron poor &

& reacts faster with E+ reacts more slowly with E+
 Inductive Effect

Flow of electron through sigma

bond

CH3 donates electrons CF3 withdraws electrons

To ring From the ring
F electronegative atom
 Reactivity

Electron Donating Electron Withdrawing

Group: EDG Group: EWG

increase in e⊖ density in decrease in e⊖ density in

the benzene ring will the benzene ring will
increase the reactivity of decrease the reactivity of
the aromatic ring towards the aromatic ring towards
attack of an electrophile, the attack of an electrophile,
and result in a faster and result in a slower
reaction reaction
 Reactivity

Increasing reactivity
 Effect on Regioselectivity

Substituent on ring orients the position of

electrophile:

Ortho-para directors direct an incoming

electrophile to positions ortho and/or
para to themselves.

Meta directors direct an incoming

electrophile to positions meta to
themselves.
 Nitration of Toluene

CH3 CH3 CH3 CH3

NO2
HNO3
+ +
acetic
NO2
anhydride
NO2
34% 3% 63%
o- and p-nitrotoluene together comprise 97%
of the product
a methyl group is an ortho-para director
 Nitration of (Trifluoromethyl)benzene

CF3 CF3 CF3 CF3

NO2
HNO3
+ +
H2SO4
NO2
NO2
6% 91% 3%
m-nitro(trifluoromethyl)benzene comprises
91% of the product
a trifluoromethyl group is a meta director
 Summary of EAS features

Activating Substituent De-activating Substituent

Electron donating group Electron withdrawing

group
React faster
React slower
Ortho-Para directors
Meta directors
Rate and Regioselectivity
in the
Nitration of Toluene
 Carbocation Stability Controls Regioselectivity

CH3 CH3 CH3

NO2
H H H H H
H +
+ +
H H H H H H
NO2
H H NO2 H
gives ortho gives para gives meta
 Carbocation Stability Controls Regioselectivity

CH3 CH3 CH3

NO2
H H H H H
H +
+ +
H H H H H H
NO2
H H NO2 H
gives ortho gives para gives meta

more stable less stable

 ortho Nitration of Toluene

CH3 CH3 CH3

NO2 NO2 NO2
H H H +
H H H
+ +
H H H H H H

H H H
this resonance
form is a
tertiary
carbocation
 para Nitration of Toluene

CH3 CH3 CH3

H H H + H H H
+ +
H H H H H H
H NO2 H NO2 H NO2
this resonance
form is a tertiary
carbocation
 para Nitration of Toluene

CH3 CH3 CH3

H H H + H H H
+ +
H H H H H H
H NO2 H NO2 H NO2

the rate-determining intermediate in the para

nitration of toluene has tertiary carbocation
character
 meta Nitration of Toluene

CH3 CH3 CH3

H H H H H H
+ +

H H H H H + H
NO2 NO2 NO2
H H H
all the resonance forms have their positive
charge on a secondary carbon
 Nitration of Toluene: Interpretation

• The rate-determining intermediates for ortho and para

nitration each have a resonance form that is a tertiary
carbocation. All of the resonance forms for the rate-
determining intermediate in meta nitration are
secondary carbocations.

• Tertiary carbocations, being more stable, are formed

faster than secondary ones. Therefore, the
intermediates for attack at the ortho and para
positions are formed faster than the intermediate for
attack at the meta position. This explains why the
major products are o- and p-nitrotoluene.
 Nitration of Toluene: Partial Rate Factors

• The experimentally determined reaction rate can be

combined with the ortho/meta/para distribution to give
partial rate factors for substitution at the various ring
positions.
• Expressed as a numerical value, a partial rate factor
tells you by how much the rate of substitution at a
particular position is faster (or slower) than at a single
position of benzene.
 Nitration of Toluene: Partial Rate Factors

CH3
1
1 1 42 42
1 1 2.5 2.5
1 58
All of the available ring positions in toluene are more
reactive than a single position of benzene.
A methyl group activates all of the ring positions but
the effect is greatest at the ortho and para positons.
Steric hindrance by the methyl group makes each
ortho position slightly less reactive than para.
 Nitration of Toluene vs. tert-Butylbenzene

CH3

CH3 H3C C CH3

42 42 4.5 4.5
2.5 2.5 3 3
58 75

tert-Butyl is activating and ortho-para directing

tert-Butyl crowds the ortho positions and decreases
the rate of attack at those positions (steric hindrance).
 Rate and Regioselectivity
in the
Nitration of (Trifluoromethyl)benzene
 A Key Point
Inductive
Effect
H3C C+ F3C C+

A methyl group is electron-donating and

stabilizes a carbocation.
Because F is so electronegative, a CF3 group
destabilizes a carbocation.
Inductive Effect Rule:
Electron donating groups stabilize adjacent positive charge
Electron withdrawing groups stabilize adjacent negative charge
 Carbocation Stability Controls Regioselectivity

CF3 CF3 CF3

NO2
H H H H H
H +
+ +
H H H H H H
NO2
H H NO2 H
gives ortho gives para gives meta
 Carbocation Stability Controls Regioselectivity

CF3 CF3 CF3

NO2
H H H H H
H +
+ +
H H H H H H
NO2
H H NO2 H
gives ortho gives para gives meta

less stable more stable

 Nitration of (Trifluoromethyl)benzene

CF3 CF3 CF3

NO2
H H + H H H
+ +
H
H H H H H H
H NO2 NO2
H H
ortho & para resonance forms Least unstable
are destabilized resonance form
Presence of positive charge on
the carbon that bears the CF3
group makes them unstable
Nitration of (Trifluoromethyl)benzene: Interpretation

The rate-determining intermediates for ortho and para

nitration each have a resonance form in which the
positive charge is on a carbon that bears a CF3
group. Such a resonance structure is strongly
destabilized. The intermediate in meta nitration
avoids such a structure. It is the least unstable of
three unstable intermediates and is the one from
which most of the product is formed.
 Nitration of (Trifluoromethyl)benzene:
Partial Rate Factors

CF3

4.5 x 10-6 4.5 x 10-6

67 x 10-6 67 x 10-6
4.5 x 10-6
All of the available ring positions in
(trifluoromethyl)benzene are much less reactive than
a single position of benzene.
A CF3 group deactivates all of the ring positions but
the degree of deactivation is greatest at the ortho and
para positions.
Substituent Effects in Electrophilic
Aromatic Substitution:
Activating Substituents
 Table 12.2

Classification of Substituents in Electrophilic

Aromatic Substitution Reactions

Very strongly activating

Strongly activating
Activating
Standard of comparison is H
(benzene)
Deactivating
Strongly deactivating
Very strongly deactivating
 Generalizations

1. All activating substituents are

ortho-para directors.

2. Halogen substituents are weakly

deactivating but ortho-para directing.

3. Strongly deactivating substituents are

meta directors.
 Resonance and Inductive Effects

Two types of Electron Donating Group

(i)
by positive mesomeric
effect (donates
electron towards the
benzene ring through
resonance effect)

(ii)
by positive inductive effect
(donates electron towards
the benzene ring through
sigma bond)
 Resonance and Inductive Effects

Two types of Electron Donating Group

(i)

Positive mesomeric
effect is usually
(ii) stronger than
positive inductive
effect
 Nitration of Phenol

occurs about 1000 times faster than nitration

of benzene
OH OH OH
NO2
HNO3
+

NO2
44% 56%
 Bromination of Anisole

FeBr3 catalyst not necessary

OCH3 OCH3

Br2

acetic
acid
Br
90%
 Oxygen Lone Pair Stabilizes Intermediate

•• •• ••
•• OCH •• OCH + OCH3
3 3

H H H + H H H
+
H H H H H H
H Br H Br H Br
Carbocation is stabilized
through resonance effect
from oxygen lone pair
 EDGs Stabilize Intermediates for
ortho and para Substitution

•• EDG •• EDG
X
H + H + H
H
H H H H

H H X
 Electron-Donating Groups (EDGs)

•• EDG

EDGs with a lone pair on the atom directly

attached to the ring are ortho-para directing
and strongly activating
 Examples
O
••
•• OH •• ••
•• EDG = •• OR •• OCR

•• NH •• NHR •• NR •• NHCR
2 2

All of these are ortho-para directing

and strongly to very strongly activating
Substituent Effects in Electrophilic
Aromatic Substitution:
Halogens

F, Cl, Br, and I

are ortho-para directing,
but deactivating
 Nitration of Chlorobenzene

Cl Cl Cl Cl

NO2
HNO3
+ +
H2SO4 NO2
NO2
30% 1% 69%

The rate of nitration of chlorobenzene is about

30 times slower than that of benzene.
 For halogens, two opposing effects

negative inductive effect positive mesomeric effect

withdrawing electron donating electron
density from the density to the
benzene ring benzene ring
For halogens, two opposing effects

Halogens are weak

deactivating groups
Negative inductive
effect > positive
mesomeric effect in
this case)
 halogens, ortho-para director

•• Cl •• Cl
X
H + H + H
H
H H H H

H H X

ortho-para resonance forms are stabilized through resonance

from halogen lone pair
Substituent Effects in Electrophilic
Aromatic Substitution:
Strongly Deactivating Substituents
 Resonance and Inductive Effects

Similar to EDG, EWG can withdraw electrons from the

benzene ring by resonance effect (negative mesomeric
effect) or by negative inductive effect

Deactivate the ring by

resonance effect

Deactivate the ring by

negative inductive effect
 Many EWGs Have a Carbonyl Group
Attached Directly to the Ring
O O

—EWG = —CH —CR

O O

—COH —COR
O

—CCl

All of these are meta directing and deactivating

 Other EWGs Include:

—EWG = —NO2

—SO3H

—C N

All of these are meta directing and strongly deactivating

 Other EWGs Include:

O
+
N
O-
O

S-OH
O

C N
Nitration of Benzaldehyde

O2N
O O
HNO3
CH CH
H2SO4
 Halogenation

Cl
O O
Cl2
CCl CCl
FeCl3
Disulfonation of Benzene

HO3S

SO3
SO3H
H2SO4
Bromination of Nitrobenzene

Br

Br2
NO2 NO2
Fe
60-75%
Synthesis of p-Nitrobenzoic Acid from Toluene

CO2H

CH3

CH3
HNO3 NO2
Na2Cr2O7, H2O
H2SO4 H2SO4, heat

NO2
Multiple Substituent Effects
 The Simplest Case

all possible EAS sites may be equivalent

CH3 CH3 O
O O CCH3
AlCl3
+ CH3COCCH3

CH3 CH3

99%
 Another Straightforward Case

CH3 CH3

Br2 Br

Fe

NO2 NO2
86-90%
directing effects of substituents reinforce
each other; substitution takes place ortho
to the methyl group and meta to the nitro group
 Generalization

Regioselectivity is controlled by the

most activating substituent
 The Simplest Case

all possible EAS sites may not be equivalent

strongly NHCH3
activating
Br2
acetic
acid
deactivating
Cl
 The Simplest Case

all possible EAS sites may not be equivalent

strongly NHCH3 NHCH3

activating
Br2 Br

acetic
acid
deactivating
Cl Cl
 When activating effects are similar...

CH3 CH3
HNO3 NO2

H2SO4

C(CH3)3 C(CH3)3

All sites are activated and substitution occurs

ortho to the smaller group
 Steric effects control regioselectivity when
electronic effects are similar

CH3
HNO3

H2SO4
CH3
 Steric effects control regioselectivity when
electronic effects are similar

CH3 CH3 CH3

HNO3 NO2

H2SO4
CH3 CH3 CH3
0%
NO2
Steric hindrance of
98%
2 CH3 groups prevent
the formation of that
isomer
 Identify the product(s) from bromination reaction
of the following compounds

Which substituents will direct the electrophile: -OH or –NHCOCH3

Both groups are activating group
OH: Very Strongly Activating (Lone pair fully engaged with Ar)
NHCOCH3: Strongly Activating (Lone pair partially engaged with Ar

OH will direct the electrophile position

Identify the product(s) from bromination reaction
of the following compounds
 Summary

When benzene consists of only 2 substituents, the

strongest activating group will direct the electrophile

What about benzene ring with more than 2 substituents?

Predict the product from the following reaction

Use
Predict the product from the following reaction

Meta director

o,p

Ortho-para director
 Classification of Substituents

+3 Very strongly activating: OH, OR, NH2, NHR, NR2

+2 Strongly activating : -OCOR, -NCOR
+1 Activating: -Alkyl
Standard of comparison is H (benzene)
-1 Deactivating: -CF3, -X O
-2 Strongly deactivating: -CN, -SO3H, —CR
-3 Very strongly deactivating: -NO2
(because of positive charge on N)

Nb can be used to identify the most activating carbon

 Applications

Predict the product from the following reaction

 Applications

+1

-1
+1-3=-2

-1 -1

The highest value represents the most

-3 activating position
Applications
 Applications

Replace methyl by
methoxy
 Applications
Replace methyl by
methoxy +3

-1 +3-3=0

-1 -1

-3 The highest value represents the most

activating position
 Applications

Replace methyl by
methoxy
 Applications

Both groups are meta directors

 Applications

-3

-2

-3

-2
Both groups are meta directors
 Electrostatic Potential Map of Benzene Derivatives

Benzen Tolue Anilin Nitrobenzen

e n e e
Synthesis of Substituted Aromatic Compounds
 Factors to Consider

1-Order of introduction of substituents to

ensure correct orientation
 Synthesis of m-Bromoacetophenone

Br
O

CCH3

Which substituent should

be introduced first?
Synthesis of m-Bromoacetophenone

Br
Which substituent
should be
introduced first?

CCH3
Synthesis of m-Bromoacetophenone

Br para

If bromine is introduced first,

p-bromoacetophenone is major
product.
O

CCH3 meta
Synthesis of m-Bromoacetophenone

O
O
CH3CCl
CCH3
AlCl3
Br2
AlCl3
Br
O

CCH3
 Factors to Consider

1-Order of introduction of substituents to ensure

correct orientation

2- Friedel-Crafts reactions (alkylation, acylation)

failed to carry out in the presence of nitro group
on aromatic
 Factors to Consider

Very strongly deactivated groups form a

stronger complex with AlCl3

The presence of +
will make it very
strongly
deactivation group

No Friedel-Crafts reactions in the

presence of NO2 group
 Synthesis of m-Nitroacetophenone

O2N
O

CCH3

Two reactions are required:

1- Acylation
2- Nitration

What will be the order of the reactions?

Synthesis of m-Nitroacetophenone

NO2
Which substituent
should be
introduced first?

CCH3
Synthesis of m-Nitroacetophenone

NO2
Which substituent
should be
introduced first?

CCH3
Synthesis of m-Nitroacetophenone

NO2

If NO2 is introduced first,

the next step (Friedel-Crafts
acylation) fails.
O

CCH3
 Synthesis of m-Nitroacetophenone

O2N
O

CCH3

O O
HNO3
CH3COCCH3 H2SO4
O

AlCl3 CCH3
 Factors to Consider

1-Order of introduction of substituents to ensure

correct orientation

2-Friedel-Crafts reactions (alkylation, acylation)

failed to carry out in the presence of nitro group
on aromatics

2-Sometimes electrophilic aromatic substitution

must be combined with a functional group
transformation
 Synthesis of p-Nitrobenzoic Acid from Toluene

CH3 CO2H

NO2
Two reactions are required:
1- oxidation of methyl group to carboxylic acid
2- nitration reaction

What will be the order of the reaction?

Synthesis of p-Nitrobenzoic Acid from Toluene
CO2H
nitration gives
m-nitrobenzoic
CH3
acid

CH3

oxidation gives
p-nitrobenzoic
acid
NO2
Synthesis of p-Nitrobenzoic Acid from Toluene

CO2H

CH3

CH3
HNO3 NO2
Na2Cr2O7, H2O
H2SO4 H2SO4, heat

NO2
Synthesis Applications
 Design the synthesis of m-Nitrobenzoic acid

❖ We do not know how to substitute a hydrogen on a

benzene ring with a –COOH group.
❖ However, side chain oxidation of alkylbenzene could
provide the –COOH group
❖ Both the –COOH group and the NO2 group are meta-
directors
 synthesis of m-Nitrobenzoic acid

Route
1
 Synthesis of m-Nitrobenzoic acid

Route
2
 Which synthetic route is better

Limitations of Friedel-Crafts Reactions

⧫ Friedel–Crafts reactions failed in the

presence of nitro group

⧫ Route 1 is a better route

 Design the synthesis of m-bromo-
ethylbenzene

❖ Both Br and Et groups are ortho-, para-directing

❖ How to make them meta to each other?
❖ Recall: an acyl group is meta-directing and can be
reduced to an alkyl group by Clemmensen ketone
reduction
Synthesis of m-bromo-ethylbenzene
Use of Protecting and Blocking
Groups in Synthesis
 Protected amino group

Not selective due to

highly activated amino
group
 Protected amino group
Solution: Introduction of a deactivated group on –NH2

❖ The amide group is less activating than –NH2 group

● No problem for over bromination
❖ The steric bulkiness of this group also prevents the
formation of o-product
❖ Amide group readily eliminated by acid or basic
hydrolysis
Protected amino group
 Protected amino group

Problem
❖ Difficult to get o-product without getting p-
product
❖ Over nitration (introduction of additional nitro
group)
 Protected amino group

Solution
❖ Use of amide group to deactivate amino group
❖ Use of a –SO3H blocking group at the p-position
which can be removed later in acidic medium
Protected amino group
Propose a plausible synthesis for each of the following transformations

1- Br2
2- HNO3/H2SO4 1- HNO3/H2SO4
2- Br2

1- KMnO4 1- H2SO4/SO3
2- HNO3/H2SO4 2- HNO3/H2SO4
3- KMnO4
4- H+/H2O
 Each of the following syntheses will not produce the desired
product. In each case, identify the flaw in the synthesis

Friedel-Craft reaction fails in

the presence of nitro group Br is ortho/para director, acylation will not take
Place in meta position

The position in para must be isopropyl Br will be located exclusively in para

group due to carbocation rearrangement Position due to steric hindrance from
to form the most stable carbocation ter-butyl group
 Design synthesis of compound starting from
benzene
Strategy:
1- Analyze what groups are required

2- Identify the reactions required to introduce these groups

3- Identify the reaction orders on the basis of groups position

 Design a synthesis of each compound starting from benzene

Strategy:
1- Analyze what groups are required : nitro, carboxylic acid and propyl
2- Identify the reactions required to introduce these groups
3- Identify the reaction orders on the basis of groups position
 Design a synthesis of each compound starting from benzene

Strategy:
1- Analyze what groups are required : nitro, carboxylic acid and propyl
2- Identify the reactions required to introduce these groups
3- Identify the reaction orders on the basis of groups position
Alkylation + oxidation

Acylation + reduction

Nitration
Design a synthesis of each compound starting from benzene