Table 12.

2
Classification of Substituents in Electrophilic
Aromatic Substitution Reactions
12.12
Substituent Effects in Electrophilic
Aromatic Substitution:
Activating Substituents

Generalizations
1. All activating substituents are
ortho-para directors.

Very strongly activating

Strongly activating
Activating
Standard of comparison is H
Deactivating
Strongly deactivating
Very strongly deactivating

Electron-Releasing Groups (ERGs)

are ortho-para directing and activating
ERG

2. Halogen substituents are slightly

deactivating but ortho-para directing.
3. Strongly deactivating substituents are
meta directors.
ERGs include R, Ar, and C=C

Electron-Releasing Groups (ERGs)

Nitration of Phenol
occurs about 1000 times faster than nitration
of benzene

are ortho-para directing and activating

ERG

OH

OH
NO2

HNO3

NO2

ERGs such as OH, and OR

are
strongly activating

44%

Bromination of Anisole

OCH3

56%

Oxygen Lone Pair Stabilizes Intermediate

OCH
3

FeBr3 catalyst not necessary

OCH3

OH

OCH
3

+ OCH3
H

Br2

acetic
acid

H
Br
90%

Br

Br

Br

all atoms
have octets

Electron-Releasing Groups (ERGs)

Examples
O

ERG

ERG =

OH

OR

OCR

O
NH
2

ERGs with a lone pair on the atom directly

attached to the ring are ortho-para directing
and strongly activating

NHR

NR
2

NHCR

All of these are ortho-para directing

and strongly to very strongly activating

Lone Pair Stabilizes Intermediates for

ortho and para Substitution
+ ERG

+ ERG
H

X
H

H
H

comparable stabilization not possible for

intermediate leading to meta substitution

12.13
Substituent Effects in Electrophilic
Aromatic Substitution:
Strongly Deactivating Substituents

ERGs Stabilize Intermediates for

ortho and para Substitution
ERG

ERG

Electron-withdrawing Groups (EWGs) Destabilize

Intermediates for ortho and para Substitution

H
H

H
H

EWG
X
+

EWG
H

H
H

H
H

CF3 is a powerful EWG. It is strongly

deactivating and meta directing

Many EWGs Have a Carbonyl Group

Attached Directly to the Ring

EWG =

CH

CR

COH

COR

O
CCl
All of these are meta directing and strongly deactivating

Other EWGs Include:

EWG =

NO2
SO3H
C

All of these are meta directing and strongly deactivating

Nitration of Benzaldehyde

O2N

O
CH

Problem 12.14(a); page 499

Cl
O

HNO3
CH

O
CCl

H2SO4

O
Cl2
CCl
FeCl3

75-84%

Disulfonation of Benzene

62%

Bromination of Nitrobenzene

Br

HO3S
SO3

Br2
SO3H

H2SO4

NO2

NO2
Fe

90%

60-75%

Nitration of Chlorobenzene
Cl

Cl
12.14
Substituent Effects in Electrophilic
Aromatic Substitution:
Halogens
F, Cl, Br, and I are ortho-para directing,
but deactivating

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.

Nitration of Toluene vs. Chlorobenzene

CH3

Cl

42

42

0.029

0.029

2.5

2.5

0.009

0.009

58

0.137

12.15
Multiple Substituent Effects

The Simplest Case

Another Straightforward Case

CH3

all possible EAS sites may be equivalent

CH3

CH3
O O

Br2

CCH3

Fe

AlCl3

+ CH3COCCH3
CH3

CH3

NO2

NO2
86-90%

CH3
99%

directing effects of substituents reinforce

each other; substitution takes place ortho
to the methyl group and meta to the nitro group

Example

Generalization
strongly

regioselectivity is controlled by the

most activating substituent

Br

NHCH3

NHCH3

activating

Br

Br2
acetic
acid
Cl

Cl
87%

When activating effects are similar...

CH3

CH3
HNO3

Steric effects control regioselectivity when

electronic effects are similar
CH3

CH3

NO2

HNO3

H2SO4
CH3
C(CH3)3

C(CH3)3
88%

substitution occurs ortho to the smaller group

H2SO4

CH3
NO2
98%

position between two substituents is last

position to be substituted

Factors to Consider

12.16
Regioselective Synthesis of Disubstituted
Aromatic Compounds

order of introduction of substituents to ensure

correct orientation

Synthesis of m-Bromoacetophenone

Synthesis of m-Bromoacetophenone

Br

Br
Which substituent
should be
introduced first?

para

If bromine is introduced first,

p-bromoacetophenone is major
product.

CCH3

CCH3

meta

Synthesis of m-Bromoacetophenone
Factors to Consider
Br
O
CCH3
O O
CH3COCCH3
AlCl3

Br2
O
CCH3

AlCl3

order of introduction of substituents to ensure

correct orientation
Friedel-Crafts reactions (alkylation, acylation)
cannot be carried out on strongly deactivated
aromatics

Synthesis of m-Nitroacetophenone

Synthesis of m-Nitroacetophenone

NO2

NO2

Which substituent
should be
introduced first?

If NO2 is introduced first,

the next step (Friedel-Crafts
acylation) fails.

CCH3

CCH3

Synthesis of m-Nitroacetophenone
Factors to Consider
O2N

O
CCH3

O O
CH3COCCH3
AlCl3

HNO3
O
CCH3

H2SO4

order of introduction of substituents to ensure

correct orientation
Friedel-Crafts reactions (alkylation, acylation)
cannot be carried out on strongly deactivated
aromatics
sometimes electrophilic aromatic substitution
must be combined with a functional group
transformation

Synthesis of p-Nitrobenzoic Acid from Toluene

Synthesis of p-Nitrobenzoic Acid from Toluene

CO2H

CH3
CH3

CO2H

Which first?
(oxidation of methyl
group or nitration of
ring)

NO2

nitration gives
m-nitrobenzoic
acid

CH3
CH3

oxidation gives
p-nitrobenzoic
acid
NO2

Synthesis of p-Nitrobenzoic Acid from Toluene

CO2H
CH3

12.17
Substitution in Naphthalene

CH3
HNO3

NO2
Na2Cr2O7, H2O
H2SO4, heat

H2SO4
NO2

Naphthalene
H

EAS in Naphthalene

CCH3

CH3CCl

AlCl3

H
H
two sites possible for electrophilic
aromatic substitution

90%
is faster at C-1 than at C-2

all other sites at which substitution can occur

are equivalent to 1 and 2

EAS in Naphthalene

EAS in Naphthalene

H
+

+
+

when attack is at C-1

carbocation is stabilized by allylic resonance
benzenoid character of other ring is maintained

E
H

E
+

when attack is at C-2

in order for carbocation to be stabilized by allylic
resonance, the benzenoid character of the other
ring is sacrificed

Generalization

There is none.
12.18
Substitution in
Heterocyclic Aromatic Compounds

There are so many different kinds of heterocyclic

aromatic compounds that no generalization
is possible.
Some heterocyclic aromatic compounds
are very reactive toward electrophilic
aromatic substitution, others are very unreactive..

Pyridine

Pyridine

SO3, H2SO4
N
Pyridine is very unreactive; it resembles
nitrobenzene in its reactivity.
Presence of electronegative atom (N) in ring
causes electrons to be held more strongly than
in benzene.

SO3H

HgSO4, 230C
N

N
71%

Pyridine can be sulfonated at high temperature.

EAS takes place at C-3.

Example: Furan

Pyrrole, Furan, and Thiophene

O O

H
Have 1 less ring atom than benzene or
pyridine to hold same number of electrons
(6).
electrons are held less strongly.
These compounds are relatively reactive
toward EAS.

+ CH3COCCH3
O

BF3

CCH3

75-92%
undergoes EAS readily
C-2 is most reactive position