Electrophilic Aromatic Substitution

Electrophilic Aromatic Substitution: reaction in which a hydrogen atom of an aromatic ring is

replaced by an electrophile

General Reaction:

In this section, we are going to study several common types of electrophiles, how each is
generated and the mechanism by which each replaces Hydrogen;

General reaction mechanism:

Step1: first step is the rate determining involving interaction of the π system with the
electrophile to give a benzenium ion intermediate

Step 2: it undergoes a rapid de-protonation by the base in the second step to restore aromaticity
The benzenium ion formed exists in several resonance forms

Chlorination of benzene:
Benzene reacts with chlorine in the presence of a catalyst, replacing one of the hydrogen atoms
on the ring by a chlorine. The reactions happen at room temperature. The catalyst is either iron
chloride.
Mechanism:
Step 1: formation of a chloronium ion

Step 2: attack of the chloronium ion on the ring

Step 3: proton transfer regenerates the aromatic character of the ring

Br2 follows the same mechanism but the reactions with I2 and F2 are not synthetically useful
because I2 is too unreactive and F2 reacts too violently.

Nitration of benzene:

Nitration happens when one (or more) of the hydrogen atoms on the benzene ring is replaced by
a nitro group, NO2. Benzene is treated with a mixture of concentrated nitric acid and
concentrated sulphuric acid at a temperature not exceeding 50°C. The mixture is held at this
temperature for about half an hour. Yellow oily nitrobenzene is formed.

Mechanism:
Generation of the nitronium ion, NO2 +

Step 1: proton transfer to nitric acid

Step 2: loss of H2O gives the nitronium ion, a very strong electrophile

+
Step 1: attack of the nitronium ion (an electrophile) on the aromatic ring (a nucleophile)

Step 2: proton transfer regenerates the aromatic ring

Sulfonation of Benzene:
Introduction of sulfonic acid group to aromatic system by treatment with concentrated sulfuric
acid

Sulfur trioxide, SO3, in fuming sulfuric acid is the electrophile (This mixture is industrially
known as oleum) or Or benzene reacts slowly with sulfuric acid to give benzenesulfonic acid

(SO3 in H2SO4 is sometimes called “fuming” sulfuric acid.)

Mechanism:
Two molecules of sulfuric acid react to form electrophile and then reaction goes through the
general route

Friedel Friedel-Crafts Alkylation Crafts Alkylation

Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group

The electrophilic partner is a carbocation; it will arrange to the most stable ion: allylic>3o>2o>1o
1. The reaction requires a full equivalent of Lewis acid because the ketone product of the
reaction will complex the Lewis acid.

2. The actual electrophilic species is thought to be a bulky complex, such as R-C+=O -AlCl4-. As
a result of the size of the electrophile, para substitution is predominant when the substrate
contains an ortho/para director.

3. There are two electrophiles involved: the oxygen bound complex and the acylium ion. The
formation of acylium ion dominates when –R is aromatic since the positive charge is delocalized
to the aromatic ring.

4. The addition of the acyl group deactivates the ring toward additional substitution reactions.

Friedel-Crafts Alkylation mechanism:

Step 1: formation of an alkyl cation as an ion pair

Step 2: attack of the alkyl cation on the aromatic ring

Step 3: proton transfer regenerates the aromatic ring

There are some limitations on Friedel-Crafts alkylations:
1. carbocation rearrangements are common:

Example 1:

Example 2:
 Friedel-craft alkylation involving the rearrangement of carbocation

2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron-
withdrawing groups

When Y Equals Any of These Groups, the Benzene Ring Doe s Not Undergo Friedel -Crafts
Alkylation
3. Multiple alkylations can occur because the first alkylation is activating ( e- donating nature of
R- assists electrophilic attack on the benzene ring

Example:

The “De-activation activation” of Aromatic Systems

Friedel Friedel-Crafts Acylation Acylation
Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group:

MECHANISM FOR THE FRIEDEL-CRAFTS ACYLATION OF BENZENE

Step 1:
The acyl halide reacts with the Lewis acid to form a complex.

Step 2:
Loss of the halide to the Lewis acid forms the electrophilic acylium ion.

Step 3:
The π electrons of the aromatic C=C act as a nucleophile, attacking the electrophilic
C+. This step destroys the aromaticity giving the cyclohexadienyl cation
intermediate.

Step 4:
Removal of the proton from the sp3 C bearing the acyl- group reforms the C=C and
the aromatic system, generating HCl and regenerating the active catalyst
Acylation avoids many of the problems of alkylation.

1. Only substitutes once, because the acyl group is deactivating.

2. No rearrangement takes place because of resonance stabilized acyl cation.

3. An acyl cation does not rearrange

4. The acylation product can be reduced to get alkyl product

 Organic Lecture Series

Di- and Polysubstitution

Orientation on nitration of monosubstituted
benzenes:

ortho +
Su bstitu ent ortho meta para p ara meta
OCH3 44 - 55 99 trace
CH3 58 4 38 96 4
Cl 70 - 30 100 trace
Br 37 1 62 99 1
COOH 18 80 2 20 80
CN 19 80 1 20 80
NO2 6.4 93.2 0.3 6.7 93.2
27

Organic Lecture Series

Di- and Polysubstitution

• Orientation:
–certain substituents direct
preferentially to ortho & para
positions; others to meta positions
–substituents are classified as either
ortho-para directing or meta
directing toward further
substitution
28
 Organic Lecture Series
Di- and Polysubstitution

• Rate
–certain substituents cause the rate
of a second substitution to be
greater than that for benzene itself;
others cause the rate to be lower
–substituents are classified as
activating or deactivating toward
further substitution

29

Organic Lecture Series

30
 Di- and Polysubstitution Organic Lecture Series

– -OCH3 is ortho-para directing:

OCH3 OCH3 OCH3
NO2
+ HNO3 + + H2 O
CH3 COOH
NO2
An isole o-N itroanis ole p-N itroanis ole
(44%) (55%)
– -CO2H is meta directing
COOH COOH COOH COOH
H2 SO4 NO2
+ HNO3 + +
100°C
NO2
Ben zoic NO2
acid
o-N itro- m-N itro- p-N itro-
ben zoic ben zoic benzoic
acid acid acid
(18%) (80%) (2%) 31

Organic Lecture Series

Di- and Polysubstitution
Strongly
:

:
:

activating N H2 N HR N R2 OH OR
Ortho-para Directing

:
:

O O O O
Moderately
:

:
:

activating N HCR N HCAr O CR O CAr

:

Weakly
activating R

Weakly
:

:
:

deactivating F: Cl : Br : I:
:

O O O O
Meta Directing

CH CR CO H CO R
Moderately
deactivating O
CNH 2 SO 3 H C N
Strongly +
deactivating N O2 N H3 C F3 C C l3

32
 Di- and Polysubstitution Organic Lecture Series

the order of steps is important:

CH3 COOH
HNO3 K2 Cr2 O7
H2 SO4 H2 SO4
CH3 NO2 NO2
p-N itroben zoic
acid

COOH COOH
K2 Cr2 O7 HNO3
H2 SO4 H2 SO4
NO2
m-N itroben zoic
acid
33

Organic Lecture Series

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
34
 Organic Lecture Series
Theory of Directing Effects
• For ortho-para directors, ortho-para
attack forms a more stable cation
than meta attack
– ortho-para products are formed faster
than meta products
• For meta directors, meta attack forms
a more stable cation than ortho-para
attack
– meta products are formed faster than
ortho-para products
35

Organic Lecture Series

Theory of Directing Effects
Nitration of anisole
-OCH3; examine the meta attack:

OCH3
slow
+ N O2 +

OCH3 OCH3 OCH3 OCH3

+ + fast
H H H - H+
N O2
N O2 N O2 + N O2
(a) (b) (c)

36
 Organic Lecture Series

Nitration of anisole
-OCH3: examine the ortho-para attack:
OCH3 OCH3

slow
+ N O2 +

+ N O2
:

:
:

:
:OCH3 :OCH3 OCH3 : OCH3
fast
+ - H+
+ +
H N O2 H N O2 H N O2 H N O2
(d) (e) (f) (g)

This resonance structure accounts for the selectivity

37

Organic Lecture Series

Theory of Directing Effects

Nitration of benzoic acid

-NO2; examine the meta attack:

COOH
+
+ NO2 slow

COOH COOH COOH COOH

fast
H H H -H+
NO2
NO2 NO2 NO2
(a) (b) (c)

38
 Organic Lecture Series
Nitration of benzoic acid

-NO2: assume ortho-para attack:

COOH

+ NO2
+ slow

COOH COOH COOH COOH

fast
+
-H
H NO2 H NO2 H NO2 NO2
(d) (e) (f)
The mos t disfavored
contribu ting structu re

This resonance structure accounts for the selectivity 39

Organic Lecture Series

Activating-Deactivating

• Any resonance effect,

effect such as that of -
NH2, -OH, and -OR, that delocalizes the
positive charge on the cation intermediate
lowers the activation energy for its
formation, and has an activating effect
toward further EAS
• Any resonance effect,
effect such as that of -
NO2, -CN, -CO, and -SO3H, that
decreases electron density on the ring
deactivates the ring toward further EAS
40
 Organic Lecture Series
Activating-Deactivating

• 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
41

Organic Lecture Series

Di- and Polysubstitution
• Generalizations:
– alkyl, phenyl, and all other 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
– all ortho-para directing groups except
the halogens are activating toward
further substitution;
– the halogens are weakly deactivating
42
 Organic Lecture Series

Activating-Deactivating
¾for the halogens,
halogens the inductive and
resonance effects run counter to each
other, but the former is somewhat
stronger
¾the net effect is that halogens are
deactivating but ortho-para directing
H + H
: :
: :

+
:Cl + E :Cl + :Cl
E

:
E

43

Organic Lecture Series

Di- and Polysubstitution
Strongly
:

:
:

activating N H2 N HR N R2 OH OR
Ortho-para Directing

:
:

O O O O
Moderately
:

:
:

activating N HCR N HCAr O CR O CAr

:

Weakly
activating R

Weakly
:

:
:

deactivating F: Cl : Br : I:
:

O O O O
Meta Directing

CH CR CO H CO R
Moderately
deactivating O
CNH 2 SO 3 H C N
Strongly +
deactivating N O2 N H3 C F3 C C l3

44