Alrasheed University College

Department of Pharmacy

Reactions of
Aromatic Compounds
Lecture 2

Prepared by
Dr. Kutaiba Ibrahim Alzand
1. Electrophilic Aromatic
Substitution Reactions
 Overall reaction
 Some of the most important reactions of aromatic
compounds are those in which an electrophile replaces
one of the hydrogen atoms of the ring.

H E
E+
+ H+
Figure 15.1 Electrophilic aromatic substitution reactions.
 SO3H X

SO3 X2
H2SO4
FeX3
O

O R Cl HNO3
AlCl3 H2SO4 NO2
R
RCl
AlCl3

R
2. A General Mechanism for Electrophilic
Aromatic Substitutions

 Different chemistry with alkene

C Br C
+ Br2
C C Br

+ Br2 No Reaction
 Benzene does not undergo electrophilic
addition, but it undergoes electrophilic
aromatic substitution

H E
E A
+H A

(H substituted by E)
 Mechanism
● Step 1

+ E E
E

slow
r.d.s.

 In step 1 the electrophile takes two

electrons of the six-electron p system
to form a σ bond to one carbon atom E
of the benzene ring.
 Mechanism
● Step 2

E
B E
H
+ H B
fast

 In step 2 a proton is removed from the carbon atom

of the arenium ion that bears the electrophile,
restoring aromaticity to the ring.
PRACTICE Problem 2.1
Show how loss of a proton can be represented using each of the three
resonance structures for the arenium ion and show how each
representation leads to the formation of a benzene ring with three
alternating double bonds (i.e., six fully delocalized p electrons).
3. Halogenation of Benzene
 Benzene does not react with Br2 or Cl2 unless a Lewis
acid is present (a catalytic amount is usually
enough).
 The Lewis acids typically used are aluminum chloride
(AlCl3) and iron chloride (FeCl3) for chlorination, and
iron bromide (FeBr3) for bromination.
 The purpose of the Lewis acid is to make the halogen
a stronger electrophile.
 A mechanism for electrophilic aromatic bromination is
shown here.
 Examples
Cl
Cl2
+ HCl
FeCl3
25oC
(90%)

Br
Br2
+ HBr
FeCl3
heat
(75%)

● Reactivity: F2 > Cl2 > Br2 > I2

 Mechanism
 Step 1  Bromine combines with FeBr3
to form a complex.
FeBr3
 
Br Br Br Br FeBr3

(weak
electrophile)

Br + FeBr4

(very reactive
electrophile)
 Mechanism (Cont’d)
 Step 2
 The benzene ring donates
an electron pair to the
terminal bromine, forming
the arenium ion and
neutralizing the formal
positive charge on the
Br
other bromine.
slow r.d.s.

Br Br Br
 Mechanism (Cont’d)
 Step 3

Br
Br FeBr3 Br
H + H Br

+ FeBr3
 A proton is removed from the
(catalyst
arenium ion to form bromobenzene
regenerated)
and regenerate the catalyst.
 F2: too reactive, gives a mixture of mono-,
di- and polysubstituted products

F2 F F F
Lewis F
acid
+ +

F + others
 I2: very unreactive even in the presence of
Lewis acids; usually need to add an
2+
oxidizing agent (e.g. HNO3, Cu , H2O2)
e.g.
I
I2
(86%)
HNO3

I
I2
(65%)
CuCl2
4. Nitration of Benzene
 Benzene undergoes nitration on reaction with a mixture of
concentrated nitric acid and concentrated sulfuric acid.
 Concentrated sulfuric acid increases the rate of the reaction
by increasing the concentration of the electrophile, the
nitronium ion (NO2+), as shown in the first two steps of the
following mechanism.
NO2
conc. HNO3
+ H3O+
conc. H2SO4
50-55oC + HSO4
(85%)

 Electrophile in this case is NO2 (nitronium ion)
 Mechanism
In this step nitric
acid accepts a proton
O O from the stronger
HO S O H + HO N acid, sulfuric acid.

O O

Now that it is protonated,

nitric acid can dissociate
to form a nitronium ion.
H O
HSO4 + O N O N O + H2O
H O
(NO2)
 Mechanism (Cont’d)

The nitronium ion is

the electrophile in
nitration; it reacts
with benzene to form
a resonance-stabilized
NO2
arenium ion.
slow r.d.s.

NO2 NO2 NO2

 Mechanism (Cont’d)

NO2
H2O NO2
H + H3O+

The arenium ion then loses a proton to a Lewis

base and becomes nitrobenzene.
PRACTICE Problem 2.2
Given that the pKa of H2SO4 is—9 and that of HNO3 is—1.4, explain
why nitration occurs more rapidly in a mixture of concentrated
nitric and sulfuric acids than in concentrated nitric acid alone.

Answer
The rate is dependent on the concentration of NO2+ ion formed
from protonated nitric acid.
Because H2SO4 (HOSO3H) is a stronger acid, a mixture of it and
HNO3 will contain a higher concentration of protonated nitric acid
than will nitric acid alone. That is, the reaction,

produces more protonated nitric acid than the reaction,

5. Sulfonation of Benzene
 Benzene reacts with fuming sulfuric acid at room temperature
to produce benzenesulfonic acid. Fuming sulfuric acid is sulfuric
acid that contains added sulfur trioxide (SO3).
 Sulfonation also takes place in concentrated sulfuric acid alone,
but more slowly. Under either condition, the electrophile
appears to be sulfur trioxide.

 In concentrated sulfuric acid, sulfur trioxide is produced in an

equilibrium in which H2SO4 acts as both an acid and a base.
5. Sulfonation of Benzene
 Mechanism
● Step 1
O H
O O
+ H O S O H
S S
O O O O O
+

SO3 is protonated to O
form SO3H+ O S O H
O
● Step 2
H
O
S O O H
O O
S other
O + resonance
slow H structures

SO3H+ reacts as an electrophile with the

benzene ring to form an arenium ion
● Step 3

O O H
S O
fast
O S O H
H HSO4
O + H2SO4

Loss of a proton from the arenium ion restores

aromaticity to the ring and regenerates the
acid catalyst
 All of the steps in sulfonation are equilibria, which means
that the overall reaction is reversible.
 The position of equilibrium can be influenced by the
conditions we employ.
 If we want to sulfonate the ring (install a sulfonic acid
group), we use concentrated sulfuric acid or—better yet—
fuming sulfuric acid. Under these conditions the position of
equilibrium lies appreciably to the right, and we obtain
benzenesulfonic acid in good yield.
 If we want to desulfonate the ring (remove a sulfonic acid
group), we employ dilute sulfuric acid and usually pass steam
through the mixture. Under these conditions—with a high
concentration of water—the equilibrium lies appreciably to
the left and desulfonation occurs.
 We shall see later that sulfonation and desulfonation
reactions are often used in synthetic work.

 We sometimes install a sulfonate group as a protecting

group, to temporarily block its position from electrophilic
aromatic substitution, or as a directing group, to
influence the position of another substitution relative to
it. When it is no longer needed we remove the sulfonate
group.
 Sulfonation & Desulfonation

SO3, conc. H2SO4

25oC - 80oC
SO3H

dil. H2SO4

H2O, 100oC
6. Friedel–Crafts Alkylation
 The following is a general equation for a Friedel–
Crafts alkylation reaction:

 The mechanism for the reaction starts with the

formation of a carbocation.
 The carbocation then acts as an electrophile and
attacks the benzene ring to form an arenium ion.
 The arenium ion then loses a proton.
6. Friedel–Crafts Alkylation
R
R X
+ HX
Lewis acid
(e.g. AlCl3)
R = alkyl group
(not aryl or vinyl)


 Electrophile in this case is R
● R = 2o or 3o
 
  o
● or R ClAlCl3 (R = 1 )
 Mechanism
 Step 1
 This mechanism is illustrated below using 2-chloropropane
and benzene.
The complex dissociates to
form a carbocation and AlCl4-.

Cl AlCl3 Cl AlCl3

This is a Lewis acid–base

reaction

+ AlCl4
 Mechanism (Cont’d)
 Step 2

The carbocation, acting

as an electrophile, reacts
with benzene to produce
an arenium ion.
 Mechanism (Cont’d)

Cl AlCl3
H

A proton is removed from the arenium + HCl

ion to form isopropylbenzene. This step
also regenerates the AlCl3 and liberates + AlCl3
HCl. (catalyst
regenerated)
 When R—X is a primary halide, a simple carbocation probably
does not form. Instead, the aluminum chloride forms a
complex with the alkyl halide, and this complex acts as the
electrophile.
 The complex is one in which the carbon–halogen bond is
nearly broken—and one in which the carbon atom has a
considerable positive charge:

 Even though this complex is not a simple carbocation, it acts

as if it were and it transfers a positive alkyl group to the
aromatic ring.
 These complexes react so much like carbocations that they
also undergo typical carbocation rearrangements.
 Friedel–Crafts alkylations are not restricted to the use of alkyl halides
and aluminum chloride. Other pairs of reagents that form carbocations
(or species like carbocations) may be used in Friedel–Crafts alkylations
as well.
 Note: Not necessary to start with alkyl halide,
other possible functional groups can be used to
generate a reactive carbocation
e.g.
+ H+

via
H+
 OH

BF3
+
60oC

via H
O BF3
PRACTICE Problem 2.3
Outline all steps in a reasonable mechanism for the formation of
isopropylbenzene from propene and benzene in liquid HF. Your mechanism
must account for the product being isopropylbenzene, not propylbenzene.
7. Friedel–Crafts Acylation
O
 The R C group is called an acyl group, and a reaction
whereby an acyl group is introduced into a compound is
called an acylation reaction.
 Two common acyl groups are the acetyl group and the
benzoyl group. (The benzoyl group should not be
confused with the benzyl group, -CH2C6H5).
 The Friedel–Crafts acylation reaction is often carried out by
treating the aromatic compound with an acyl halide (often an
acyl chloride). Unless the aromatic compound is one that is
highly reactive, the reaction requires the addition of at least one
equivalent of a Lewis acid (such as AlCl3) as well. The product
of the reaction is an aryl ketone:
 Acyl chlorides, also called acid chlorides, are easily
prepared by treating carboxylic acids with thionyl chloride
(SOCl2) or phosphorus pentachloride (PCl5):
 Friedel–Crafts acylations can also be carried out using
carboxylic acid anhydrides. For example,

 In most Friedel–Crafts acylations the electrophile appears

to be an acylium ion formed from an acyl halide in the
following way:
7. Friedel–Crafts Acylation
O
 Acyl group: R C
O

O AlCl3 R
+
R Cl 80oC


 Electrophile in this case is R–C≡O (acylium ion)
 Mechanism
In most Friedel–Crafts acylations the electrophile appears to be an
acylium ion formed from an acyl halide in the following way:

O O
+ AlCl3 R C Cl AlCl3
R Cl

AlCl4 + R C O R C O
 Mechanism (Cont’d)

The acylium ion, acting

as an electrophile, reacts
with benzene to form the
arenium ion.

R C O

O O O

R R R
 Mechanism (Cont’d)
O O
R
Cl AlCl3 R
H

A proton is removed from the arenium + HCl

ion, forming the aryl ketone.
+ AlCl3
(catalyst
regenerated)
 Acid chlorides (or acyl chlorides)
O
C
R Cl

● Can be prepared by

SOCl2
O O
C or C
R OH R Cl

PCl5
Solved Problem 2.1
Show how an acylium ion could be formed from acetic anhydride
in the presence of AlCl3.

Strategy and Answer:

We recognize that AlCl3 is a Lewis acid and that an acid anhydride,
because it has multiple unshared electron pairs, is a Lewis base. A
reasonable mechanism starts with a Lewis acid–base reaction and
proceeds to form an acylium ion in the following way.
8. Limitations of Friedel–Crafts
Reactions
 When the carbocation formed from an
alkyl halide, alkene, or alcohol can
rearrange to one or more carbocations
that are more stable, it usually does so,
and the major products obtained from
the reaction are usually those from the
more stable carbocations.
 For example
(not formed)
AlCl3
+ Cl

AlCl3

(How is this
formed?)
 Reason 1o cation (not stable)

H
Cl + AlCl + AlCl4
3

1,2-hydride
shift

H 3o cation
(more
stable)
 When benzene is alkylated with butyl bromide, for example, some of
the developing butyl cations rearrange by a hydride shift. Some of the
developing 1o carbocations (see following reactions) become more
stable 2o carbocations. Then benzene reacts with both kinds of
carbocations to form both butylbenzene and secbutylbenzene:
 Friedel–Crafts reactions usually give poor yields
when powerful electron-withdrawing groups are
present on the aromatic ring or when the ring
bears an –NH2, –NHR, or –NR2 group. This applies
to both alkylations and acylations.
O OH O R
NO2 N(CH3)3 CF3 SO3H NH2
>

>

>

>

>

>
These usually give poor yields
in Friedel-Crafts reactions
 The amino groups, –NH2, –NHR, and –NR2, are
changed into powerful electron-withdrawing
groups by the Lewis acids used to catalyze Friedel-
Crafts reactions
H
H H
N H N AlCl3

>
+ AlCl3

Does not undergo a

Friedel-Crafts reaction
 Aryl and vinylic halides cannot be used as
the halide component because they do not
form carbocations readily
Cl
sp2
, AlCl 3
No Friedel-Crafts
reaction
sp2

Cl , AlCl 3 No Friedel-Crafts
reaction
 Polyalkylations often occur

OH BF3
+ +
60oC

(24%) (14%)
Solved Problem 2.2
When benzene reacts with 1-chloro-2,2-dimethylpropane (neopentyl chloride) in
the presence of aluminum chloride, the major product is 2-methyl-2-
phenylbutane, not 2,2-dimethyl-1-phenylpropane (neopentylbenzene). Explain
this result.

Strategy and Answer:

The carbocation formed by direct reaction of AlCl3 with 1-chloro-2,2-
dimethylpropane would be a primary carbocation; however, it rearranges to the
more stable tertiary carbocation before it can react with the benzene ring.
Practice Problem 2.4
Provide a mechanism that accounts for the following result.

Answer
9. Synthetic Applications of Friedel-Crafts
Acylations: The Clemmensen Reduction
& Wolff–Kishner Reductions

 Rearrangements of the carbon chain do not occur

in Friedel–Crafts acylations
 The acylium ion, because it is stabilized by
resonance, is more stable than most other
carbocations. Thus, there is no driving force for a
rearrangement.
 The carbonyl group of an aryl ketone
can be reduced to a CH2 group

R [H] R
9A. The Clemmensen Reduction
 One general method for reducing a ketone to a methylene
group—called the Clemmensen reduction—consists of
refluxing the ketone with hydrochloric acid containing
amalgamated zinc.
O

R Zn/Hg R
HCl
reflux
 Clemmensen reduction of ketones
● A very useful reaction for making
alkyl benzenes that cannot be made
via Friedel-Crafts alkylations
e.g.
?
 Clemmensen reduction of ketones
● Cannot use Friedel-Crafts alkylation

Cl

gives
AlCl3

but
NOT
 Rearrangements of carbon chains do
not occur in Friedel-Crafts acylations
O

O AlCl3 R
+
R Cl 80oC

(no rearrangement
of the R group)
 O
O Zn/Hg
conc. HCl
Cl
reflux

AlCl3
9B. The Wolff–Kishner Reduction
 Another method for reducing a ketone to a methylene group is
the Wolff–Kishner reduction, which involves heating the ketone
with hydrazine and base.
 The Wolff–Kishner reduction complements the Clemmensen
reduction in that it is conducted under basic conditions, whereas
the Clemmensen reduction involves acidic conditions.
 The Wolff–Kishner reduction proceeds via a hydrazone
intermediate that is not isolated during the reaction.
 Ethyl phenyl ketone can be reduced to propylbenzene by the
Wolff–Kishner reduction as follows, for example.
9B. The Wolff–Kishner Reduction

NH2
O N

NH2NH2, KOH

heat

Hydrazone intermediate

H2O + N2 +

(82%)
Practice Problem 2.5
Starting with benzene and the appropriate acyl chloride or
acid anhydride, outline a synthesis of each of the following:
Answer:
10. Substituents Can Affect Both the
Reactivity of the Ring and the
Orientation of the Incoming Group

 Two questions have to be addressed:

● Reactivity
● Regiochemistry
 Reactivity
Y Y

E
faster or slower than
E
E

Y = EDG (electron-donating group) or

EWG (electron-withdrawing group)
● Regiochemistry
Y Y Y Y
E
E

E
E
(ortho) (meta) (para)
(o) (m) ( p)

Statistical mixture of o-, m-, p-

products, or any preference?
10.A How Do Substituents Affect
Reactivity?
G G
E



 other
+ E A H resonance
structure

Electrophilic
reagent Arenium
A substituted ion
benzene
Z donates Y withdraws
electrons electrons
Z Y

>

>
The ring is more The ring is electron
electron rich and poor and reacts
reacts faster with more slowly with
an electrophile an electrophile
● Reactivity
 Since electrophilic aromatic substitution is
electrophilic in nature, and the rate
determining step (r.d.s.) is the attack of an

electrophile (E ) with the benzene -electrons,
an increase in e⊖ density in the benzene ring
will increase the reactivity of the aromatic ring
towards attack of an electrophile, and result in
a faster reaction.
● Reactivity
⊖
 On the other hand, a decrease in e
density in the benzene ring will decrease
the reactivity of the aromatic ring towards
the attack of an electrophile, and result in
a slower reaction.
● Reactivity
Substituent

–EDG

Increasing activity
–H

–EWG
● Reactivity
 EDG (electron-donating group) on
benzene ring
 Increases electron density in the benzene ring
 More reactive towards electrophilic aromatic
substitution
● Reactivity
 EWG (electron-withdrawing group) on
benzene ring
 Decreases electron density in the
benzene ring
 Less reactive towards electrophilic
aromatic substitution
● Reactivity towards electrophilic
aromatic substitution

EDG EWG

> >
 Regiochemistry: directing effect
● General aspects
 Either o-, p- directing or m-
directing
 Rate-determining step is -
electrons on the benzene ring

attacking an electrophile (E )
 Y

o r t ho
attack

Y Y Y
E E E

o -I o -II o -III
 Y

met a
attack

Y Y Y

E E E
m -I m -II m -III
 Y

p ar a
attack

Y Y Y

p -I p -II p -III
E E E
 If you look at these Y
resonance structures
E
closely, you will notice that
for ortho- or para- o-I
substitution, each has one
resonance form with the
positive charge attached to Y
the carbon that directly
attached to the substituent
Y (o-I and p-II)
p-II
E
 When Y = EWG, these resonance
forms (o-I and p-II) are highly unstable
and unfavorable, thus not favoring the
formation of o- and p- regioisomers,
and m- product will form preferentially
 On the other hand, if Y = EDG, these
resonance forms (o-I and p-II) are
extra-stable (due to resonance effect
or positive inductive effect of Y), thus
favoring the formation of o- and p-
regioisomers
 Classification of different substituents
Y
Y (EDG)
–NH2, –NR2 Strongly o-, p-
–OH, –O

activating directing
–NHCOR Moderately o-, p-
–OR activating directing
–R (alkyl) Weakly o-, p-
–Ph activating directing
–H NA NA
 Classification of different substituents
Y
Y (EWG)

–Halide Weakly o-, p-

(F, Cl, Br, I) deactivating directing
–COOR, –COR,
Moderately m-
–CHO, –COOH,
deactivating directing
–SO3H, –CN
–CF3, –CCl3, Strongly m-
–NO2, –⊕NR3 deactivating directing
11. How Substituents Affect
Electrophilic Aromatic
Substitution: A Closer Look
11A. Reactivity: The Effect of Electron-Releasing
& Electron-Withdrawing Groups

 If G is an electron-releasing group (relative to

hydrogen), the reaction occurs faster than the
corresponding reaction of benzene
G G G


When G is
electron
+ E  donating,
  the
 reaction is
H E H E faster
G releases Transition state Arenium ion
electrons. is stabilized is stabilized
 If G is an electron-withdrawing group, the
reaction is slower than that of benzene

G G G



>
>

>
+ E 
 

H E H E

G withdraws Transition state Arenium ion

electrons is destabilized is destabilized

When G is electron withdrawing,

the reaction is slower
11B. Inductive & Resonance Effects:
Theory of Orientation
 Two types of EDG
by resonance effect
(i) OR NR2
(donates electron
towards the benzene
or ring through
resonance)

(ii) CH3 by positive inductive

>

effect (donates electron

towards the benzene
ring through the  bond)
 Two types of EDG
● The resonance effect is usually
stronger than the positive
inductive effect if the atoms
directly attached to the benzene
ring are in the same row as
carbon in the periodic table
 Similar to an EDG, an EWG can withdraw electrons
from the benzene ring by the resonance effect or
by the negative inductive effect

O
C Deactivate the ring by the
CH3
e.g. resonance effect
F
>

C> F Deactivate the ring by the

F negative inductive effect
11C. Meta-Directing Groups
EWG EWG

E
(EWG ≠ halogen)
E
(major)

 EWG = –COOR, –COR, –CHO, –CF3,

–NO2, etc.
 For example CF3

NO2
(ortho)

CF3 CF3 CF3

NO2 NO2 NO2

CF3
-H
(highly unstable due to
NO2 the negative inductive
(ortho)

(not favorable)
effect of –CF3)
 CF3 (highly unstable due to negative
inductive effect of –CF3)

CF3 CF3 CF3

NO2 -H
(para)

NO2 NO2 NO2 CF3

(para)
(not favorable) NO2
CF3
(positive charge never
attaches to the carbon
NO2 directly attached to the
(meta) EWG: –CF3)  relatively
more favorable
CF3 CF3 CF3

NO2 NO2 NO2

CF3

-H
(relatively more (meta)
favorable than o-, p- products) NO2
11D. Ortho/Para-Directing Groups
EDG EDG EDG
E
E
+

E
ortho para
(major)

 EDG = –NR2, –OR, –OH, etc.

 For example OCH3

NO2
(ortho)

OCH3 OCH3 OCH3 OCH3

NO2 NO2 NO2 NO2

OCH3
NO2 (extra resonance
-H
structure due to
(ortho)
(favorable)
positive mesomeric
effect of –OCH3)
 OCH3 OCH3 OCH3

(para)

NO2 - H+

NO2 NO2 NO2

OCH3 OCH3

OCH3

NO2
(para)
NO2 (favorable)

(extra resonance structure due to resonance

effect of –OCH3)
OCH3 (3 resonance structures
only, no extra stabilization
NO2
by resonance effect of
(meta) –OCH3)  less favorable
OCH3 OCH3 OCH3

NO2 NO2 NO2

OCH3
-H (meta)
(less favorable)

NO2
 For halogens, two opposing effects

Cl Cl

>

Negative inductive effect: Resonance effect:

withdraws electron donates electron
density from the density to the
benzene ring benzene ring
 Overall
● Halogens are weak deactivating
groups
 Negative inductive effect >
resonance effect in this case
 Regiochemistry Cl

NO2
(ortho)

Cl Cl Cl Cl
NO2 NO2 NO2 NO2

Cl
NO2 (extra resonance
-H
structure due to
(ortho) resonance effect of
(favorable)
–Cl)
 Cl Cl Cl

(para)

NO2 -H
NO2 NO2 NO2
Cl Cl

Cl

NO2
(para)
NO2 (favorable)

(extra resonance structure due to resonance

effect of –Cl)
 (3 resonance structures
Cl
only, no extra stabilization
NO2 by the resonance effect of
(meta) –Cl)  less favorable
Cl Cl Cl

NO2 NO2 NO2

Cl
-H (meta)
(less favorable)

NO2
11E. Ortho/Para Direction and
Reactivity of Alkylbenzenes

R R R


>

>
>

+ E 
 

H E H E

Transition state Arenium ion

is stabilized is stabilized
 CH3
 Ortho attack

Relatively
E
stable
contributor
CH3 CH3 CH3

>
E E E
 Meta attack CH3

CH3 CH3 CH3

E E E
 CH3
 Para attack

Relatively
stable
E
contributor
CH3 CH3 CH3
>

E E E
11F. Summary of Substituent Effects
on Orientation and Reactivity
Y Y (EDG)
–NH2, –NR2 Strongly o-, p-
–OH, –O

activating directing

–NHCOR Moderately o-, p-

–OR activating directing

–R (alkyl) Weakly o-, p-

–Ph activating directing
–H NA NA
Y Y (EWG)

–Halide Weakly o-, p-

(F, Cl, Br, I) deactivating directing

–COOR, –COR,
Moderately m-
–CHO, –COOH,
deactivating directing
–SO3H, –CN

–CF3, –CCl3, Strongly m-

–NO2, –⊕NR3 deactivating directing
12. Reactions of the Side Chain
of Alkylbenzenes

CH3

Methylbenzene Ethylbenzene Isopropylbenzene Phenylethene

(toluene) (cumene) (styrene or
vinylbenzene)
12A. Benzylic Radicals and Cations
R H CH2 CH2

- RH

Methylbenzene The benzyl

(toluene) radical

C C C C

Benzylic radicals are stabilized by resonance

 C LG C

- LG

A benzyl
cation

C C C C

Benzylic cations are stabilized by resonance

12B. Benzylic Halogenation of the
Side Chain
CH3 CH2Cl
Cl2
heat or
light
Cl2
heat or light

CCl3 CHCl2
Cl2
heat or
light
 Mechanism
● Chain initiation
peroxides
X X 2X
heat or
light

● Chain propagation
H H
C6H5 C H + X C6H5 C + H X
H H
 ● Chain propagation
H H
C6H5 C + X X C6H5 C X +X
H H

● Chain termination
H H
C6H5 C + X C6H5 C X
H H
 e.g.
CH3 NBS, ROOR or light
Br

O
Benzyl bromide
(–bromotoluene)
NBS is N Br (64%)

Br NaOEt OEt
EtOH

Benzyl ethyl ether

13. Alkenylbenzenes
13A. Stability of Conjugated Alkenyl-
benzenes
 Alkenylbenzenes that have their side-chain
double bond conjugated with the benzene
ring are more stable than those that do not
non-conjugated
C system
C C
C C
is more
C
stable than
conjugated
system
 Example
H+
OH heat

(not observed)

- Ha

Ha Hb

- Hb
13B. Additions to the Double Bond of
Alkenylbenzenes

HBr
RO OR Br
heat

Br

HBr
(no
peroxides)
  Mechanism (top reaction)
RO OR 2 RO

RO + H Br Br + RO H
Br

Br
+ Br
(more stable (less stable)
benzylic radical)

+ H Br
Br Br
 Mechanism (bottom reaction)
H

  (more stable (less stable)

H Br
benzylic cation)

Br
Br
13C. Oxidation of the Side Chain

O
CH3
1. KMnO4, HO-,  OH

2. H3O+

(100%)
 O

1. KMnO4, HO-,  OH

2. H3O+
O

1. KMnO4, HO-,  OH

2. H3O+
O

1. KMnO4, HO-,  OH

2. H3O+
O O

1. KMnO4, HO-,  OH

2. H3O+
 Using hot alkaline KMnO4, alkyl,
alkenyl, alkynyl and acyl groups all
oxidized to –COOH group
 For alkyl benzene, 3o alkyl groups resist
oxidation

1. KMnO4, HO-, 
No Reaction
2. H3O+

● Need benzylic hydrogen for alkyl

group oxidation
13D. Oxidation of the Benzene Ring

1. O3, CH3CO2H O
R R
2. H2O2 OH
14. Synthetic Applications

CH3

How?

NO2
 CH3 group: ortho-, para-directing
 NO2 group: meta-directing
CH3 CH3

CH3Cl conc. HNO 3

AlCl3 conc. H 2SO4
heat
NO2

CH3
NO2
+
 If the order is reversed  the wrong
regioisomer is produced
CH3
conc. HNO3 CH3Cl
conc. H2SO4 AlCl3
heat
NO2 NO2

CH3
NOT

NO2
 COOH

NO2
 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-directing
 Route 1
CH3

conc. HNO3 CH3Cl

conc. H2SO4 AlCl3
heat NO2 NO2

COOH

1. KMnO4, HO-, 
2. H3O+
NO2
 Route 2
CH3 COO
H
CH3Cl 1. KMnO4, HO-, 
AlCl3 2. H3O+

COOH

conc. HNO3
conc. H2SO4
NO2 heat
 Which synthetic route is better?
● Recall “Limitations of Friedel-Crafts
Reactions, Section 15.8”
 Friedel–Crafts reactions usually give
poor yields when powerful electron-
withdrawing groups are present on
the aromatic ring or when the ring
bears an –NH2, –NHR, or –NR2
group. This applies to both
alkylations and acylations
 Route 2 is a better route
 Br

 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 reduction
 O

Cl
AlCl3 Br2
FeBr3
O

Br Br

Zn/Hg
HCl, heat

O
14A. Use of Protecting and Blocking
Groups
 Protected amino groups
● Example

NH2 NH2
?

Br
Problem
 Not a selective synthesis, o- and p-
products + dibrominated and
tribrominated products will form
NH2 NH2 NH2
Br2
+
Br Br

Br
NH2
+ + others
Br Br
Solution
 Introduce a deactivating group on
–NH2
O H
NH2 N O
CH3 Cl
pyridine CH3

(an amide)
 The amide group is less activating than
–NH2 group
● No problem for over bromination

 The steric bulkiness of this group also

decreases the formation of the o-
brominated product
 NH2 NH2

Br

O
1. H2SO4,
(hydrolysis
Cl H2O, 
of amide)
pyridine 2. HO-

NHCOCH3 NHCOCH3

Br2, FeBr3
Br
 NH2 NH2

Br

Problem
 Difficult to get o-product without
getting p-product
 Over nitration
Solution
 Use of a –SO3H blocking group at the
p-position which can be removed later
NH2 NH2

NO2
O
1. dil. H2SO4
Cl 100oC
pyridine 2. HO-

NHCOCH3 NHCOCH3 NHCOCH3

SO3 HNO3
conc. H2SO4 SO3H H2SO4 SO3H NO2
60oC
14B. Orientation in Disubstituted
Benzenes
 Directing effect of EDG usually
outweighs that of EWG

 With two EDGs, the directing effect is

usually controlled by the stronger EDG
Examples [only major product(s) shown]
CH3 CH3
NO2
NO2
(i)

CF3 CF3

OMe OMe OMe

COCH3 Br COCH3 COCH3
(ii) +
Br

Br
 Substitution does not occur to an
appreciable extent between meta-
substituents if another position is open
Cl Cl Cl Cl
X O2N NO2
HNO3
+ +
H2SO4
Br Br Br Br
NO2
62% 37% 1%
 NHCOCH3 NHCOCH3

NO2
(iii)
COOMe COOMe
NO2

NHCOCH3
O 2N

COOMe
 OCH3
CH3
Cl
(iv)

OCH3 OCH3
CH3 Cl CH3
+

Cl
 Cl

Br
(v)
NO2

Cl Cl
Br
+
NO2 NO2
Br
15. Allylic and Benzylic Halides in
Nucleophilic Substitution
Reactions
R R'
H R
CH2X C C
X X
C C C C C C

1o Allylic 2o Allylic 3o Allylic

H H R
Ar C X Ar C X Ar C X
H R R'
1o Benzylic 2o Benzylic 3o Benzylic
 A Summary of Alkyl, Allylic, & Benzylic
Halides in SN Reactions
● These halides give mainly SN2
reactions:
H3C X R CH2 X R CH X
R'

● These halides may give either SN1

or SN2 reactions:
R
H
CH2 X C
X
Ar CH2 X Ar CH X C C C C
R
 A Summary of Alkyl, Allylic, & Benzylic
Halides in SN Reactions
● These halides afford mainly SN1
reactions:
R'
R
R R C
X
R' C X Ar C X C C
R" R'
16. Reduction of Aromatic
Compounds

H2/Ni H2/Ni
+
slow fast
benzene cyclohexadienes cyclohexene

H2/Ni
fast

cyclohexane
16A. The Birch Reduction

Na
NH3, EtOH

benzene 1,4-cyclohexadiene
 Mechanism
Na
etc.
 
benzene benzene radical anion

EtOH

Na
H H etc.

H H
cyclohexadienyl radical
H
 EtOH
H H etc. H H


H H H
cyclohexadienyl anion 1,4-cyclohexadiene
 Synthesis of 2-cyclohexenones
OCH3 OCH3
Li
liq. NH3
EtOH (84%)

H3O+
H2O

O
2-cyclohexenone