Chapter 12: Reactions of Arenes: Electrophilic Aromatic

Substitution
12.1: Representative Electrophilic Aromatic Substitution
Reactions of Benzene

E= -Cl, -Br, -I (halogenation)

-NO2 (nitration)
-SO3H (sulfonation) (Table 12.1)
-R (alkylation)
(acylation)
275

12.2: Mechanistic Principles of Electrophilic Aromatic

Substitution
Recall the electophilic addition of HBr (or Br2) to alkenes (Ch. 6)
H H Br
+ H Br + Br

nucleophile electrophile

Most aromatic rings (benzene) are not sufficiently nucleophilic

to react with electrophiles. Catalysts are often needed to
increase the reactivity of the electrophiles.

Mechanism: a π-bond of benzene acts as a nucleophile and

“attacks” the electrophile leading to a resonance stabilized
cyclohexadienyl carbocation. Loss of a proton gives the
substitution product and restores aromaticity.

276

1
 H
H H
+ E-X
H H
H

H H H H
E E E
H E H H H
H H
HX + H +
X H H
H H H H H
X X
H H H H

Electrophilic substitution: Resonance stabilized Electrophilic addition:

product regains cyclohexadienyl cation products lose
aromatic stabilization intermediate aromatic stabilization

Aromaticity is worth ~ 130-150 KJ/mol

277

12.3: Nitration of Benzene O

HNO3, H2SO4 N
O

H2O

O O O
HO N + H2SO4 H2O N N + H2O
O O O

Nitric acid Sulfuric acid Nitronium

pKa~ -1.3 pKa~ -2.0 Ion

278

2
12.4: Sulfonation of Benzene
O O
SO3, H2SO4 S
OH
sulfur analogue of
a carboxylic acids
H2O
Benzene
sulfonic acid

O O
O S + H2SO4 HO S + HSO4-
O O

279

12.5: Halogenation of Benzene

Cl2, FeCl3 Cl

Br
Br2, FeBr3

I2, CuCl2 I

For X= Cl or Br
!+ !-
X X FeX3 X X FeX

I2 + Cu2+ 2 I+ + 2 Cu+

280

3
12.6: Friedel-Crafts Alkylation of Benzene
Cl AlCl3
+ + HCl

alkyl halide
(electroiphile)

Cl AlCl3 + AlCl4
strong
Lewis acid carbocation

281

Since the Friedel-Crafts alkylation goes through a carbocation

intermediate, skeletal rearrangements of the alkyl halide are
common
AlCl3 +
+ Cl

(not observed)

AlCl3
+ Cl +

(65 %) (35 %)

282

4
 alkyl halide:
halide = F, Cl, Br, I
must be an alkyl halide; vinyl and aryl halides do not react
the aromatic substrate:
can not have strong electron withdrawing substituents,
nor an amino group
Y Y ≠ NO2, C≡N, -SO3H
O (R= ketone, aldehyde, carboxylic acids,
R ester)
-NH2, NHR, NR2, -N+R3,

F-C alkylation is often difficult to stop after one alkylation reaction

AlCl3 (H3C)3C-Cl
+ (H3C)3C-Cl
AlCl3
initial product is
more reactive major product
than benzene 283

12.7: Friedel-Crafts Acylation of Benzene O

O C
R
O
AlCl3
+
Cl
C
R
R
acyl group

O O O
C + AlCl3 C AlCl4
R Cl C
R R

The acylated product is less reactive than benzene toward

electrophilic aromatic substitution. F-C acylation can be
stopped after one acyl group is added 284

5
12.8: Synthesis of Alkylbenzenes by Acylation-Reduction
Ketones and aldehydes can be reduced to the alkanes with:
Zn(Hg), HCl (Clemmensen Reduction)
H2NNH2 , KOH (Wolff-Kishner Reduction)
O
Zn(Hg), HCl
-or-

H2NNH2, KOH

Aryl Ketone

Cl + + +
AlCl3

O
O
Zn(Hg), HCl
Cl -or-

AlCl3 H2NNH2, KOH

Rearrangements and multiple alkylations

are not observed for the F-C acylation
285

12.9: Rate and Regioselectivity in Electrophilic Aromatic

Substitution - The nature of a substituent already present on
the benzene ring affects the rate and regioselectivity (relative
position) of electrophilic aromatic substitution.
A substituent (-X) is said to be activating if the rate of electrophilic
aromatic substitution of the substituted benzene (C6H5X) is
faster than benzene.
A substituent (-X) is said to be deactivating if the rate of
electrophilic aromatic substitution of the substituted benzene
(C6H5X) is slower than benzene.
Relative rate of nitration:
CF3 CH3

(trifluoromethyl)benzene benzene toluene

2.5 x 10-5 1 20-25

deactivating activating 286

6
 CH3 CH3 CH3 CH3
NO2
H2SO4, HNO3
+ +

NO2
toluene NO2
o-nitrotoluene m-nitrotoluene p-nitrotoluene
(63%) (3%) (34%)

CF3 CF3 CF3 CF3

NO2
H2SO4, HNO3
+ +

NO2
(trifluoromethyl)benzene NO2
o-nitro-(trifluoromethyl) m-nitro-(trifluoromethyl) p-nitro-(trifluoromethyl)
benzene benzene benzene
(6%) (91%) (3%)

A substituent (-X) is said to be an ortho-para director if it directs

an incoming electrophile to positions ortho and/or para to itself.
A substituent (-X) is said to be an meta director if it directs
an incoming electrophile to position meta to itself.

287

Substituents are characterized as either electron-donating or

electron-withdrawing and alter the electron density of the
aromatic ring through:
1. Inductive effects: ability of a substituent to donate or withdraw
electron density through σ-bonds due to electronegativity
differences and bond polarities of a functional group
!- O!
- -
!+ N O!
+
C C! !- CH3
!+ X R N
O

X= F, Cl,
Br, I
Electron-withdrawing groups Electron-donating group

2. Resonance effects: ability of a substituent to donate or

withdraw electrons through non-bonding pairs of electrons or
overlap π-bonds (conjugation).
O O
N
C C N X OCH3
R O

Electron-withdrawing groups Electron-donating groups

288

7
The rate (activating or deactivating) and regiochemistry
(ortho-para vs meta directing) can be understood by examining
the influence of the substituent on the stability of the cyclohexa-
dienyl cation intermediate.
12.10: Rate and Regioselectivity in the Nitration of Toluene:
Regioselectivity: The carbocation intermediate from o- or
p-addition can be stabilized by the substituent through inductive
effects and hyperconjugation.

ortho
63%

CH3

meta
3%

para
34%
289

Activating groups increase the rate of electrophilic aromatic

substitution at all positions of the ring.
Partial rate factors - relative rate of electrophilic aromatic
substitution compared to benzene
H3C
CH3 H3C C CH3

42 42 4.5 4.5
2.5 2.5 3 3
58 75

Electron rich aromatic rings are more nucleophlic.

All activating group donate electrons through inductive effects
and/or resonance. Electron-donating groups stabilize the
carbocation intermediate of electrophilic aromatic substitution.

290

8
12.11: Rate and Regioselectivity in the Nitration of
(Trifluoromethyl)benzene - Regioselectivity: The carbocation
intermediate from o- or p-addition is destabilized by the
electron-withdrawing substituent. This directs addition to the
m-position.

ortho
6%

CF3

meta
91%

para
3%

291

Dactivating groups decrease the rate of electrophilic aromatic

substitution at all positions of the ring.
Partial rate factors - relative rate of electrophilic aromatic
substitution compared to benzene
CF3

4.5 x 10-6 4.5 x 10-6

6.7 x 10-5 6.7 x 10-5

4.5 x 10-6

Electron deficient aromatic rings are less nucleophlic.

All deactivating group withdraw electrons through inductive
effects and/or resonance. Electron-withdrawing groups
destabilize the carbocation intermediate of electrophilic aromatic
substitution.

292

9
12.12: Substituent Effects in Electrophilic Aromatic
Substitution: Activating Substituents
All activating substituents increase the rate of electrophilic
aromatic substitution and are ortho-para directors.
Nitration of phenol: the -OH is a very strong activating group

ortho
50%

OH

meta
0%

para
50%

293

Substituents that have an O or N atom directly attached to the

aromatic ring are strong activators. Phenol, anisole, and anilines
are very strong activators and do not require strong Lewis Acid
catalysts to undergo electrophilic aromatic substutution.
O O
-alkyl, -vinyl, -aryl H -OH, -OCH3, -NH2
O C R N C R

activators strong activators very strong activators

12.13: Substituent Effects in Electrophilic Aromatic

Substitution: Strongly Deactivating Substituents
Strong deactivators are meta directors

O O O O O O
C H C R C OH C OR C N S O N CF3
O O

strong deactivators very strong deactivators

294

10
12.14: Substituent Effects in Electrophilic Aromatic
Substitution: Halogens - Halogens are deactivating because
they are strong electron withdrawing groups (inductive effect);
however, they have non-bonding pairs of electrons and can also
donate electrons (resonance effect), and are ortho-para directors.

ortho
30%

Cl

meta
1%

para
69%

295

Table 12.2, p. 491

O O
-NO2 -SO3H -CO2H CH -Br -F alkyl O C R -OR -NH2

O -CO2R -I -Cl -H O
-NR3 C N H -OH
C R N C R

strong deactivators deactivators strong activators

(meta directors) (ortho/para directors) (ortho/para directors)

12.15: Multiple Substituent Effects - The individual directing

effect of each substituent must be considered in order to
determine the overall directing effect of a disubstituted
benzene toward further electrophilic substitution.

296

11
1. When the individual directing effects of the two groups
reinforce, further electrophilic substitution is directed to the
common position.
-CH3 directs here -CH3 directs here
CH3 CH3
-NO2 directs here -NO2 directs here Br2, FeBr3 Br

NO2 NO2

2. When the individual directing effects of two groups oppose, the

stronger activating group has the dominant influence; however,
mixtures of products are often produced.
-OH directs here OH OH
-OH directs here
Br2, FeBr3 Br

-CH3 directs here -CH3 directs here

CH3 CH3

297

3. Further substitution between two existing substituents

rarely occurs. Start with an ortho-disubstituted benzene to
synthesize 1,2,3-trisubstituted benzenes
-CH3 directs here -CH3 directs here CH3 CH3 CH3
CH3
-Cl directs here -Cl directs here Br2, FeBr3 Br Br
+ +

Cl Cl Cl Cl
Br
not observed
-CH3 directs here -Cl directs here

-Br directs here

-CH3 directs here CH3 -Cl directs here

Br Br

Cl
-Br directs here -Br directs here -Br directs here

-CH3 directs here -Cl directs here

CHO CHO CHO

Cl2, FeCl3
Br Br Br
+
-Br directs here -Br directs here Cl Cl
-CHO directs here -CHO directs here
298

12
12.16: Regioselective Synthesis of Disubstituted Aromatic
Compounds
Consider the directing effects of the substituents to determine
the order of their introduction to ensure the 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

CO2H

Br NO2

299

m-director
NO2 deactivating

o,p-director
Cl o,p-director
deactivating
activating

300

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 Summary of electrophilic aromatic substitution of benzene
Zanger, M.; Gennaro, A. R.; McKee, J. R. J. Chem. Ed. 1993, 70 (12) , 985-987

SO3, X2, HNO3, RCH2X, RCOCl,

H2SO4 H2SO4 AlCl3 AlCl3
catalyst
SO3H X O R
NO2 CH2R
[H]

(m-) (o-, p-) (m-) (o-, p-) (m-)

NBS,
h! [O] [O]

Br R
CO2H

(o-, p-) (m-)

12.17: Substitution in Naphthalene (please read)

12.18: Substitution in Heterocyclic Aromatic Compounds
(please read) 301

14