Chapter 15

Reactions of Aromatic Compounds

Electrophilic Aromatic Substitution
Arene (Ar-H) is the generic term for an aromatic hydrocarbon
-The aryl group (Ar) is derived by removal of a hydrogen atom from an arene
Aromatic compounds undergo electrophilic aromatic substitution (EAS)
-The electrophile has a full or partial positive charge
X
X2, FeX3 + HX Halogenation
(Section 15.3)
(X = Cl, Br)

NO2 Nitration
HONO2
+ H2O (Section 15.4)
H2SO4

SO3H Sulfonation
SO3
(Section 15.5)
H2SO4

R
RCl, AlCl3 Friedel-Crafts Alkylation
+ HCl
(Sections 15.6 and 15.8)
(R can rearrange)
O
O
C Friedel-Crafts Acylation
RC Cl , AlCl3 R + HCl
(Sections 15.7 and 15.9)

Chapter 15 2
A General Mechanism for Electrophilic Aromatic
Substitution: Arenium Ion Intermediates
Benzene reacts with an electrophile using two of its p electrons
-This first step is like an addition to an ordinary double bond
Unlike an addition reaction, the benzene ring reacts further so that
it may regenerate the very stable aromatic system
In step 1 of the mechanism, the electrophile reacts with two
electrons from the aromatic ring to form an arenium ion
-The arenium ion is stabilized by resonance which delocalizes the charge

+ E E E

Step 1 E A H H H
+ +

Arenium Ion
(a delocalized cyclohexadienyl cation)

In step 2, a proton is removed and the aromatic system is regenerated

+ E E

Step 2 H + H A
:A

Chapter 15 3
 The energy diagram of this reaction shows that the first step is
highly endothermic and has a large ∆G‡ (1)
-The first step requires the loss of aromaticity of the very stable benzene ring,
which is highly unfavorable
-The first step is rate-determining
The second step is highly exothermic and has a small ∆G‡ (2)
-The ring regains its aromatic stabilization, which is a highly favorable process

 
 
 
E 1 H E H
 2 Step 1 +:A
 A  +E A   Slow, rate determining

E H H E

Free Energy

∆G‡ (1) ∆G‡ (2)

Step 2
E A 
+ H A Fast

H A
H E
E

E
:A

Reaction Coordinate

Chapter 15 4
Halogenation of Benzene
Halogenation of benzene requires the presence of a Lewis acid

Cl
FeCl3
+ Cl2 o
+ HCl
25 C

Chlorobenzene (90%)
Br
FeBr3
+ Br2 + HBr
heat

Bromobenzene (75%)
Fluorination occurs so rapidly it is hard to stop at
monofluorination of the ring
-A special apparatus is used to perform this reaction
Iodine is so unreactive that an alternative method must be used
I
HNO3
+ l2

(86%)

Chapter 15 5
 In the step 1 of the mechanism, bromine reacts with ferric bromide
to generate an electrophilic bromine species
In step 2, the highly electrophilic bromine reacts with p electrons
of the benzene ring, forming an arenium ion
In step 3, a proton is removed from the arenium ion and
aromaticity is regenerated
-The FeBr3 catalyst is regenerated

+
Step 1 Br Br + FeBr3 Br Br FeBr3 Br+ + Br FeBr3
Bromine combines with FeBr3 to form a complex that dissociates
to form a positive bromine ion and FeBr4-.
H
Br
H
Br
+ H
Br
Step 2 +
slow
+ Br
+ +

Arenium Ion
The positive bromine ion attacks benzene to form an arenium ion.
Step 3 H Br FeBr 3
Br Br
+ H Br + FeBr3
+
A proton is removed from the arenium ion to become bromobenzene.

Chapter 15 6
Nitration of Benzene
Nitration of benzene occurs with a mixture of concentrated nitric
and sulfuric acids
-The electrophile for the reaction is the nitronium ion (NO2+)
O H O
+ +
Step 1 OSO 3H H + H O N
-
H O
+
N
-
+ HSO4-
(H2SO4) O O

In this step nitric acid accepts a proton from the stronger acid, sulfuric acid.

H O O
+ +
Step 2 H O N
-
H2O + N
+
O
O

Nitronium ion

Now that it is protonated, nitric acid can dissociate to form a nitronium ion

O
slow
H H + H
+
Step 3 N NO 2 NO 2 NO 2
+ +
O

Arenium Ion
The nitronium ion is the actual electrophile in nitration; it reacts with
benzene to form a resonance-stabilized arenium ion.
+ H NO2 +
O H H O H
Step 4 NO 2 + +
H H
The arenium ion then loses a proton to a Lewis base and becomes nitrobenzene.

Chapter 15 7
Sulfonation of Benzene
Sulfonation occurs most rapidly using fuming sulfuric acid
(concentrated sulfuric acid that contains SO3)
-The reaction also occurs in conc. sulfuric acid, which generates small quantities
of SO3, as shown in step 1 below
-
Step 1 2 H2SO4 SO3 + H3O+ + HSO4
This equilibrium produces SO3 in
concentrated H2SO4
O
O slow +
Step 2 -
other resonance structures
+ S S O
O O H
O
SO3 is the actual electrophile that reacts with benzene to form an arenium ion.

O O
+ fast
Step 3 HSO4- + S O
-
S O
-
+ H2SO4
H
O O
A proton is removed from the arenium ion to form a benzenesulfonate ion.

O O
fast
+ -
Step 4 S O
-
+ H O H S O H + H2O

O H O
The benzenesulfonate ion accepts a proton to become benzenesulfonic acid.

Chapter 15 8
Sulfonation is an equilibrium reaction; all steps involved are
equilibria
-The sulfonation product is favored by use of concentrated or fuming sulfuric acid
-Desulfonation can be accomplished using dilute sulfuric acid (i.e. with a high
concentration of water), or by passing steam through the reaction and collecting
the volatile desulfonated compound as it distils with the steam

SO 3H
+ H2SO4 + H2O

Chapter 15 9
Friedel-Crafts Alkylation
An aromatic ring can be alkylated by an alkyl halide in the
presence of a Lewis acid
-The Lewis acid serves to generate a carbocation electrophile
R
AlCl3
+ R X + HX

Cl
Step 1 H3C
CH Cl + Al
H3C Cl Cl
Cl Cl
This is a Lewis acid-base H3C H3C
+ – + –
reaction (see Section 3.2B). CH Cl Al Cl CH + Cl Al Cl
H3C H3C Cl
Cl

The complex dissociates to form a carbocation and AlCl4-

CH3 + CH3
Step 2 +
+ HC CH other resonance structures

CH3 H CH3
The carbocation, acting as an electrophile, reacts with
benzene to produce an arenium ion.

Cl CH3
+ CH3
–
Step 3 CH + Cl Al Cl CH + HCl + AlCl3
H Cl CH3
CH3
A proton is removed from the arenium ion to form isopropylbenzene.
This step also regenerates the AlCl3, and liberates HCl.

Chapter 15 10
Primary alkyl halides probably do not form discreet carbocations
but the primary carbon in the complex develops considerable
positive charge
 
RCH 2 ---- AlCl 3

Any compound that can form a carbocation can be used to

alkylate an aromatic ring
CH(CH3)2
0
0C
+ CH3CH CH2
HF
propene
isopropylbenzene (cumene)
(84%)

00C
+
HF
cyclohexene
cyclohexcylbenzene
(62%)

600C
+ HO + H2O
BF3

cyclohexanol cyclohexcylbenzene
(56%)

Chapter 15 11
Friedel-Crafts Acylation
An acyl group has a carbonyl attached to some R group
O
O

CH 3 C C

Actyl Benzoyl
group group
(ethanoyl group)

Friedel-Crafts acylation requires reaction of an acid chloride or

acid anhydride with a Lewis acid such as aluminium
O
chloride
C CH3
O AlCl3
+ + HCl
H3C C Cl excess
benzene Acetophenone
Acetyl 800C
chloride (methyl phenyl ketone 97%)
O O
AlCl3
+
H3C C C CH3 O
excess
O
benzene +
H3C C
H3C COH
800C
O

Acetic anhydride Acetophenone

(a carboxylic acid anhydride) (82-85%)

Chapter 15 12
Acid chlorides are made from carboxylic acids
O
O
800C
CH3 COH + SOCl2 CH3 C Cl + SO2 + HCl
Acetic Thionyl
Acetyl
acid chloride
chloride
(80-90%)

O O

COH + PCl5 CCl + POCl3 + HCl

Benzoic Phosphorus Benzoyl
acid pentachloride chloride
(90%)

Chapter 15 13
The electrophile in Friedel-Crafts acylation is an acylium ion
-The acylium ion is stabilized by resonance

O O
+
-
Step 1 R C Cl + AlCl3 R C Cl AlCl3

O
+ - + + -
+
Step 2 R C Cl AlCl3 R C O R C O + AlCl4

An acylium ion
(a resonance hybrid )
R
R +
C
Step 3 + C H O other resonance structures
O+
Arenium ion
The acylium ion, acting as an electrophile,
reacts with benzena to form the arenium ion.
R
R
C Cl C
Step 4 H O +
-
O +
Cl Al Cl HCl + AlCl3
Cl

A proton is removed from the arenium ion, forming the aryl ketone
R R

C C
Step 5 O + AlCl3 O AlCl3
+ -

The ketone, acting as a Lewis base, reacts with

Aluminium chloride ( a Lewis acis) to form a complex.

Chapter 15 14
Limitations of Friedel-Crafts Reactions
In Friedel-Crafts alkylation, the alkyl carbocation intermediate may
rearrange to a more stable carbocation prior to alkylation
-The reaction of n-butyl bromide leads to a mixture of products derived from
primary and secondary carbocations
A lC l3   +
CH 3CH 2CH 2CH 2 Br CH 3CH 2 CH 2 CHCH 3 BrAlCl 3 CH 3CH 2 CH 2CHCH 3
-
H (-BrAlCl3 )
(-AlCl3 )
(-HBr) (-H+)
CH 3CH 2CH 2CH 2 CH 3CH 2CH 2CH 2

Butylbenzene sec-Butylbenzene
(32-36 % of mixture) (64-68 % of mixture)

Powerful electron-withdrawing groups make an aromatic ring

much less reactive toward Friedel-Crafts alkylation or acylation
-Amino groups also make the ring less reactive to Friedel-Crafts reaction because
they become electron-withdrawing groups upon Lewis acid-base reaction with the
Lewis acid catalyst
O OH O R
NO 2 C CF 3 HO 3S NH2
N(CH3)3 C

CH3

These usually give poor yields in

Friedel-Crafts reactions.

Chapter 15 15
Aryl and vinyl halides cannot be used in Friedel-Crafts reactions
because they do not form carbocations readily
Cl

+ AlCl 3

no Friedel-Crafts reaction

Cl
C C AlCl 3
+
no Friedel-Crafts reaction

Polyalkylation occurs frequently with Friedel-Crafts alkylation

because the first alkyl group introduced activates the ring toward
further substitution
-Polyacylation does not occur because the acyl group deactivates the aromatic
ring to further substitution
CH(CH3)2 CH(CH3)2

H3C
BF3
+ CHOH
60 oC
+
H3C
CH(CH3)2
Isopropyl
p-Diisopropylbenzene
benzene
(24 %) (14%)

Chapter 15 16
Synthetic Applications of Friedel-Crafts
Acylations: The Clemmensen Reduction
Primary alkyl halides often yield rearranged products in FriedelCrafts
Crafts alkylation which is a major limitation of this reaction
Unbranched alkylbenzenes can be obtained in good yield by
acylation followed by Clemmensen reduction
-Clemmensen reduction reduces phenyl ketones to the methylene (CH2) group
O
O
C
AlCl3
CH3CH2 CCl CH 2CH 3
HCl
Propanoyl Ethyl phenyl ketone
chloride (90 %)
O

CCH 2CH 3 CH 2CH 2CH 3

Zn(Hg)

HCl
(reflux)

Ethyl phenyl Propylbenzene

ketone (80 %)

O
Zn(Hg)
ArCR Ar CH2R
HCl, reflux
Chapter 15 17
This method can be used to add a ring to an aromatic ring starting
with a cyclic anhydride
-Note that the Clemmensen reagents do not reduce the carboxylic acid

O O O
C CCH2 CH2COH
H2C AlCl3 Zn(Hg), HCl

+ H2C O
(88%) reflux
C ( 83-90%)

O
Benzene Succinic 3-Benzoylpropanoic acid
(excess) anhydride

O
CH2 CH2CH2 COH CH2
SOCl2 AlCl3, CS2
CH2
80 oC ( 74 -91%)
(> 95%) CH2
HC
O
CH2

4 - Phenylbutanoic 4 - Phenylbutanoyl Tetralone

acid Chloride

Chapter 15 18
Effects of Substituents on Reactivity and
Orientation
The nature of groups already on an aromatic ring affect both the
reactivity and orientation of future substitution
-Activating groups cause the aromatic ring to be more reactive than benzene
-Deactivating groups cause the aromatic ring to be less reactive than benzene
-Ortho-para directors direct future substitution to the ortho and para positions
-Meta directors direct future substitution to the meta position
Activating Groups: Ortho-Para Directors
All activating groups are also ortho-para directors
-The halides are also ortho-para directors but are mildly deactivating
The methyl group of toluene is an ortho-para director
-Toluene reacts more readily than benzene, e.g. at a lower temperatures than benzene
CH3

An activating
group

More reactive than benzene

toward electrophilic substitution

Chapter 15 19
The methyl group of toluene is an ortho-para director
Ortho Para Meta
CH 3 CH 3
CH 3 CH 3
H
NO 2
HNO3
+ +
H2SO4
H
NO2
H
NO 2

o-Nitrotoluene p-Nitrotoluene m-Nitrotoluene

(59%) (37%) (4%)

Amino and hydroxyl groups are also activating and ortho-para

directors
-These groups are so activating that catalysts are often not necessary
NH
H2 NH
H2
OH
H OH
H
Br Br Br Br
Br2 Br2
H2O H2O

Br Br
2,4,6-Tribromoaniline 2,4,6-Tribromophenol
(~100%) (~100%)

Alkyl groups and heteroatoms with one or more unshared electron

pairs directly bonded to the aromatic ring will be ortho-para
directors (see chart on slide 22)

Chapter 15 20
Deactivating Groups: Meta Directors
Strong electron-withdrawing groups such as nitro, carboxyl, and
sulfonate are deactivators and meta directors
NO
H 2 NO
H 2 NO
H 2 NO
H 2
NO
H 2
HNO3

H2SO4 + +
H
NO2
NO
H 2
(6%) (1%) (93%)

Halo Substitutents: Deactivating Ortho-Para Directors

Chloro and bromo groups are weakly deactivating but are also
ortho, para directors
-In electrophilic substitution of chlorobenzene, the ortho and para products are
major:
Ortho Para Total Ortho Meta
Product Product and para Product
Reaction (%) (%) (%) (%)

Chlorination 39 55 94 6
Bromination 11 87 98 2
Nitration 30 70 100
Sulfonation 100 100

Chapter 15 21
Classification of Substitutents

Ortho- Para Directors Meta Directors

Strongly
.. activating Moderately Deactivating
.. ..
NH2, NHR, NR2 C N
.. ..
OH, O SO3H
.. ..
Moderately
.. Activating
.. CO2H, CO2R
NHCOCH3, NHCOR CHO, COR
.. ..
OCH
.. OR
.. Strongly Deactivating
3
Weakly Activating NO2
CH3 C2H5 R NR3+
C6H5 CF3 CCl3
Weakly
.. Deactivating
..
F
.. Cl
.. Br I

Chapter 15 22
Theory of Substituent Effects on Electrophilic
Substitution
Reactivity: The Effect of Electron-Releasing and
Electron-Withdrawing Groups
Electron-releasing groups activate the ring toward further reaction
-Electron-releasing groups stabilize the transition state of the first step of
substitution and lead to lower DG‡? and faster rates of reaction
Electron-withdrawing groups deactivate the ring toward further
reaction
-Electron-withdrawing groups destabilize the transition state and lead to higher
Q Q  Q
+ E  Reaction
+   is faster

E H E H

Q releases Transition state Arenium ion is

electrons is stabilized stabilized
Q Q  Q

+ E+    Reaction is
slower
E H E H
Q withdraws Transition state is Arenium ion is
electrons destabilized destabilized

Chapter 15 23
 The following free-energy profiles compare the stability of the first
transition state in electrophilic substitution when various types of
substitutents are already on the ring
-These substitutents are electron-withdrawing, neutral (e.g., H), and electrondonating
Q


 Q
E H 

Q
  
E H
E H  

 
  
  Q
E H 
Free Energy

E H
 

E H
Q G(1) G(2) G(3)
+E+ Q

+E+

(1)
(2) (3)

Reaction Coordinate

Chapter 15 24
Inductive and Resonance Effects: Theory of Orientation
The inductive effect of some substituent Q arises from the
interaction of the polarized bond to Q with the developing positive
charge in the ring as an electrophile reacts with it
-If Q is an electron-withdrawing group then attack on the ring is slowed because
this leads to additional positive charge on the ring

 +
Q <
(e.g., Q = F, Cl, or Br)

The following are some other groups that have an electronwithdrawing effect
because the atom directly attached to the ring has a partial or full positive
charge Z O
O -

^
NR3  
> (R =alkyl or H) > C > Z > N+ > S+ OH

 O-
Z O
O O

> C G > C+ G G = H, R, OH, or OR

Electron-withdrawing groups with a full or partial

charge on the batom attached to the ring

Chapter 15 25
The resonance effect of Q refers to its ability to increase or
decrease the resonance stabilization of the arenium ion
-When Q has a lone pair on the atom directly attached to the ring it can stabilize
the arenium by contributing a fourth resonance form

Q+
Q
H

E +
H E
H

H
H

Electron-donating resonance ability is summarized below

.. .. .. .. ..
Most electron donating NH2 NR2 > .OH
. OR
.. > .X. :
Least elektron donating

Chapter 15 26
 Meta-directing Groups
All meta-directing groups have either a partial or full positive
charge on the atom directly attached to the aromatic ring
The trifluoromethyl group destabilizes the arenium ion
intermediate in ortho and para substitution pathways
-The arenium ion resulting from meta substitution is not so destabilized and
therefore meta substitution is favored
Ortho Attack
CF3 CF3 CF3 CF3
+ E
E E E +

H H H
+ +
Highly unstable
contributor
Meta Attack CF 3
CF3 CF3 CF3
CF 3
CF3

+ + H2SO4
E E
+
E
+ HNO 3
E H H + H

Para Attack NO 2
Trifluoromethylbenzene (-100%)
CF3 CF3
CF3 CF3

+ +
+
E H E
H E H E
Highly unstable
contributor
Chapter 15 27
 Ortho-Para Directing Groups
Many ortho-para directors are groups that have a lone pair of
electrons on the atom directly attached to the ring

At least one
unbonding as in
electron pair

N O Cl
Q H H H
Aniline Phenol Chorobenzene

Chapter 15 28
 Activating groups having unshared electrons on the atom bonded
to the ring exert primarily a resonance effect
-The aromatic ring is activated because of the resonance effect of these groups
-They are ortho-para directors because they contribute a fourth important
resonance form which stabilizes the arenium ion in the cases of ortho and para
substitution only
-The fourth resonance form that involves the heteroatom is particularly important
because the octet rule is satisfied for all atoms in the arenium ion
Relatively stable
contributor
+ +
H H H
H +
+
E E E E
E +
NH2 NH2 NH2
NH2 NH2

Meta Attack + H
H H
+
E E
E E
+
+
NH2 NH2 NH2
NH2

Para Attack Relatively stable

contributor
E H E H E H
+
E E H
+ +

NH 2
NH 2 NH 2 NH 2

Chapter 15 29
 Halo groups are ortho-para directors but are also deactivating
-The electron-withdrawing inductive effect of the halide is the primary influence
that deactivates haloaromatic compounds toward electrophilic aromatic
substitution
-The electron-donating resonance effect of the halogen’?s unshared electron pairs
is the primary ortho-para directing influence

Ortho Attack +
Cl Cl Cl Cl Cl
E E E E
+ +
E
H H H H
+ +
Cl Relatively stable
Meta Attack contributor
Cl Cl
Inactive effect of chlorine Cl
atom deactives ring Cl
+ +
H
H H
E
+ E + E
E
Meta Attack
Cl Cl
Cl Cl

+ + H
H
H
+ E E
E E +

Chapter 15 30
Ortho-Para Direction and Reactivity of Alkylbenzenes
Alkyl groups activate aromatic rings by inductively stabilizing the
transition state leading to the arenium ion
Alkyl groups are ortho-para directors because they inductively
stabilize one of the resonance forms of the arenium ion in ortho
and para substitution
Ortho Attack
H H
H
H
H C H H C H
H C H
H C H E
E +
+
E H
H
R R R +
+ Relatively stable
+ contributor
+ E + +
Meta Attack
H H
H H
+
E H H C H H C H
E H H C H H C H
Arenium ion + +
H
Trasnsition state is stabilized H
H

is stabilized E
+
E E
E

Para Attack H
H H
H
H C H H C H
H C H H C H
+

+ +
+
E E H E H
E H
Relatively stable
contributor
Chapter 15 31
Reactions of the Side Chain of Alkylbenzenes
Benzylic Radicals and Cations
When toluene undergoes hydrogen abstraction from its methyl
group it produces a benzyl radical
-A benzylic radical is a radical in which the carbon bearing the unpaired electron is
directly bonded to an aromatic ring

H CH2 CH A
C H
R 2 benzylic
 RH hydrogen
Benzylic
carbon
Methylbenzene The benzyl A benzylic
(toluene) radical radical

Departure of a leaving group by an SN1 process from a benzylic

position leads to formation of a benzylic cation
+
C LG

LG 

A benzylic
cation

Chapter 15 32
Benylic radicals and cations are stabilized by resonance
delocalization of the radical and positive charge, respectively

+ +
C C C C C

+ +

Benzylic radicals are Benzylic cations are

stabilized by resonance stabilized by resonance

Chapter 15 33
Halogenation of the Side Chain: Benzylic Radicals
Benzylic halogenation takes place under conditions which favor
radical reactions
Reaction of N-bromosuccinamide with toluene in the presence of
light leads to allylic bromination
-Recall N-bromosuccinamide produces a low concentration of bromine which
favors radical reaction
O O

CH3 + N Br
light CH2 Br + N H
CCl4

O O
Benzyl bromide
NBS (-bromotoluene)
(64%)

Reaction of toluene with excess chlorine can produce multiple

benzylic chlorinations
CH3 CH2Cl HC Cl2 C Cl3

Cl2 Cl2 Cl2

heat heat heat
or light or light or light
Benzyl Dichloromethyl- Trichloromethyl-
chloride benzene benzene

Chapter 15 34
 Chain Initiation
peroxides,
heat
Step 1: X X or light
2 X.

Chain Propagation

H H
. C.
Step 2: H5C6 C H +X C6H6
+ H X
H
H
Benzyl
radical

H H
Step 3: C6H5 C. +X X C6H5 C X+X .
H
H

Benzyl Benzyl
radical halide

When ethylbenzene or propylbenzene react under radical

conditions, halogenation occurs primarily at the benzylic position

Chapter 15 35
Alkenylbenzenes
Stability of Conjugated Alkenylbenzenes
Conjugated alkenyl benzenes are more stable than nonconjugated
alkenylbenzenes
-Dehydration of the alcohol below yields only the more stable conjugated alkenyl benzene
H
C

H H C C
HA, beat
C C C (-H2O)
OH

Additions to the Double Bond of Alkenylbenzenes

Additions proceed through the most stable benzylic radical or
benzylic cation intermediates
CH CHCH3 HBr CH2CHCH3
peroxides
Br
1-Phenilpropene 2-Bromo-1-phenylpropane

HBr
CH=CHCH3 CHCH2CH3
(no peroxides)
Br
1-Phenylpropene 1-Bromo-1-phenylpropane

Chapter 15 36
Oxidation of the Side Chain
Alkyl and unsaturated side chains of aromatic rings can be
oxidized to the carboxylic acid using hot KMnO4
-
(1) KMnO4;OH , heat
CH3 (2) H3O
+ COH

Benzoic acid
(~ 100% )
O
CH2CH2CH2R C OH
-
(1) KMnO4 ' OH
heat
+
(2) H3O
Benzoic acid
An alkylbenzene

C6H5CH CHCH3

or
C6H5C CCH3 -
(1) KMnO4' OH , heat O
+
C6H5COH
(2) H3O
or
O
C6H5CCH2CH3

Chapter 15 37
Synthetic Applications
When designing a synthesis of substituted benzenes, the order in
which the substituents are introduced is crucial
Example: Synthesize ortho-, meta-, and para-nitrobenzoic acid
from toluene
CH3 CO2H

(1) KMnO4' OH-, heat

(2) H3O+
CH3
NO2 NO2
HNO3 p-Nitrotoluene p-Nitrobenzoic
H2SO4 (separate ortho from para) acid

CH3 CO2H
NO2 NO2
(1) KMnO4' OH-, heat
(2) H3O+

O-Nitrotoluene o-Nitrobenzoic acid

CH3 CH2H CO2H

(1) KMnO4' OH-, heat HNO3

(2) H3O+ H2SO4
heat NO2
Benzoic acid m-Nitrobenzoic
acid

Chapter 15 38
Use of Protecting and Blocking Groups
Strong activating groups such as amino and hydroxyl cause the
aromatic ring to be so reactive that unwanted reactions can take
place
-These groups activate aromatic rings to oxidation by nitric acid when nitration is
attempted; the ring is destroyed
-An amino group can be protected (and turned into a moderately activating group)
by acetylation

Chapter 15 39
Example: The synthesis of p- and o-nitroaniline from aniline
-A sulfonic acid group is used as a blocking group to force ortho substitution
O O O

NH2 NHCCH3 NHCCH3 NHCCH3

NO2
CH3COCl HNO3
+
base H2SO4

NO2
Aniline Acetanilide o-Nitro-ace
p-Nitro-acet tanilide
anilide (trace)
(90%)

(1) H,O, H2SO4, heat

(2) OH-

This step removes NH2

O
the CH3C group + CH3CO-
and replaces it with
an H.
NO2

p-Nitroaniline

NHCOCH3 NHCOCH3 NHCOCH3 NH2

NO2 NO2
concd HNO3 (1) H2O
H2SO4 H2SO4
heat
-
(2) OH
SO3H SO3H o-Nitroaniline
Acetanilide (56%)
Chapter 15 40
Orientation in Disubstituted Benzenes
When two substituents are present on the ring initially, the more
powerful activating group generally determines the orientation of
subsequent substitution
-Ortho-para directors determine orientation over meta directors
-Substitution does not occur between meta substituents due to steric hindrance

NHCOCH3 NHCOCH3
NHCOCH3
Cl
Cl2
CH3CO2H +
CH3 Cl
CH3
CH3
(major product) (minor product)

Cl Cl Cl
Cl
O2N NO2
HNO3
H2SO4 + +
Br Br Br
Br
NO2
(62%) (37%) (1%)

Chapter 15 41
Allylic and Benzylic Halides in Nucleophilic
Substitution Reactions
Allylic and benzylic halides are classified in similar fashion to
other halides

H R R R' R R
CH2X
C X C X – –
Ar CH 2X Ar C X Ar C X
C C C C
C C R
R'

1o Allylic 1o Benzylic 2o Benzylic 3o Benzylic

2o Allylic 3o Allylic

Chapter 15 42
Both primary and secondary allylic and benzylic halides can
undergo SN1 or SN2 reaction
-These primary halides are able to undergo SN1 reaction because of the added
stability of the allylic and benzylic carbocation
Tertiary allylic and benzylic halides can only undergo SN1 reaction
These halides give mainly SN2 These halides give mainly SN1
reactions reactions

CH3 X R CH2 X R CH X

R'
R
R' C X

These halides may give either SN1 or R

SN2 reactions.
R
Ar CH2 X Ar CH X –
Ar C X
R R

H R
CH2 X C X R R'
C C C C C X
C C

Chapter 15 43