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Daley
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Organic
Chemistry
Chapter 18
Aromatic Substitution Reactions
18.1 Mechanism of Aromatic Electrophilic Substitution
18.2 The Nitration of Benzene
917
18.3 Halogenation and Sulfonation of Benzene
18.4 Friedel-Crafts Alkylation and Acylation
18.5 Effects of Monosubstituted Arenes on Substitution
18.6 Rate Effects with Monosubstituted Arenes
18.7 Classification of Substituents
935
18.8 Friedel-Crafts Acylation
943
Synthesis of o-Benzoylbenzoic Acid
947
18.9 Multiple Substituent Effects
948
18.10 Substitution on Polycyclic Arenes
951
18.11 Diazotization
954
Synthesis of Methyl Orange
957
Sidebar - Sulfa Drugs
958
18.12 Other Diazonium Salt Reactions
961
18.13 Nucleophilic Aromatic Substitution
963
18.14 Benzyne
965
Synthesis of Trypticene
968
18.15 Synthesis Examples
969
Key Ideas from Chapter 18
975
914
920
924
928
932
Organic Chemistry - Ch 18
912
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5 July 2005
Organic Chemistry - Ch 18
913
Chapter 18
Aromatic Substitution
Reactions
Chapter Outline
18.1
18.2
18.3
18.4
Friedel-Crafts Alkylation
Formation of alkyl benzenes
18.5
18.6
18.7
Classification of Substituents
A listing of common substituents showing their directive and rate
controlling effects
18.8
Friedel-Crafts Acylation
Formation of acyl benzenes
18.9
18.10
18.11
Diazotization
Diazotization and the use of the diazonium ion as an electrophile
18.12
18.13
18.14
Benzyne
The formation and reaction of the reactive benzyne intermediate
18.15
Synthesis Examples
Organic synthesis using aromatic electrophilic substitution reactions
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Organic Chemistry - Ch 18
914
Objectives
Understand the mechanism for aromatic electrophilic substitution
reactions
Recognize appropriate electrophiles that will substitute on an
aromatic ring
Be able to predict the position of a new substitution on an aromatic
ring with one or more existing substituents
Know how the structure of one substituent affects the rate of
reaction for adding a second substituent on the ring
Know the diazotization reaction and how the diazonium salts react
Understand the nucleophilic substitution reaction and its
mechanism
Be able to use the reactions in this chapter in synthesis
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Organic Chemistry - Ch 18
915
Nu:
Nu
The
A complex is a
resonance-stabilized
carbocation
intermediate.
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Organic Chemistry - Ch 18
916
Base:
Electrophilic aromatic
substitution is a
reaction in which an
electrophile displaces
another atom.
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Organic Chemistry - Ch 18
917
G2
G1
+ H
+ E
Go
Reaction Progress
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5 July 2005
Organic Chemistry - Ch 18
The nitration of
benzene is the reaction
of a benzenoid
compound with the
NO electrophile.
2
918
HNO3
H2SO4
50 - 55oC
Dehydration of
alcohols is discussed in
Section 13.9, page 000.
Nitrobenzene
(85%)
HO
NO2
OSO3H
HO
NO2
NO2
NO2
complex
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Organic Chemistry - Ch 18
919
NO2
NO2
Solution
In this reaction, a deuterium replaces one of the hydrogens on the ring. The
D2SO4 is the source of D electrophile. The formation of the complex
involves reaction of the ring with the electrophile.
D
D
OSO3D
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Organic Chemistry - Ch 18
920
D
H
OSO3D
Exercise 18.2
Write a mechanism for the formation of a nitronium ion from nitric
acid alone.
2FeCl3
2FeBr3
Cl
Br
Cl
Br
FeCl3
FeBr3
Cl
Cl
Br
Br
FeCl3
FeBr3
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5 July 2005
Organic Chemistry - Ch 18
921
Br
Br
FeBr3
Br
Br
Br
FeBr3
Figure 18.2 shows the reaction progress diagram for the bromination
of benzene. Note that G2 < G1 , so formation of the complex is
the rate-determining step.
H
H
Br
Br
Br
Br
Br
G2
G1
Br
+ HBr
Go
+ Br2
Reaction Progress
Figure 18.2. The reaction progress diagram for the bromination of benzene.
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5 July 2005
Organic Chemistry - Ch 18
922
I
I2
HNO3
Iodobenzene
(86%)
Exercise 18.3
An important technique for the introduction of fluorine onto an
aromatic ring is via a two-step thallation procedure. Benzene reacts
with thallium trifluoracetate (Tl(OOCCF3)3) to form an
organothallium intermediate. This intermediate reacts with KF and
BF3 to form the fluorobenzene.
O
Tl(OCCF3)2
Tl(OCCF3)3
F
KF, BF3
H2SO4
Benzenesulfonic acid
(95%)
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5 July 2005
Organic Chemistry - Ch 18
Azeotropic distillation
is discussed in Section
8.2, page 000. Benzene
and water form an
azeotrope boiling at
69.4oC having a
composition of 91%
benzene and 9% water.
Chemists form fuming
sulfuric acid by adding
sulfur trioxide to
concentrated sulfuric
acid.
923
H2SO4
SO3 + H2O
O
S
O
O
S
OH
SO3H
Exercise 18.4
Write a mechanism to explain the presence of SO3 in sulfuric acid.
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5 July 2005
Organic Chemistry - Ch 18
924
The Friedel-Crafts
reaction uses a
carbocation or acylium
ion as the electrophile
with benzenoid
aromatic compounds.
CH3CH2Cl
AlCl3
Ethylbenzene
(84%)
Carbocation
rearrangements are
introduced in Section
12.4, page 000.
CH3CH2
Cl
AlCl3
CH3CH2
Cl
AlCl3
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Organic Chemistry - Ch 18
925
CH3CH2
Cl
CH2CH3
AlCl3
AlCl4
CH2CH3
Rearrangement of the alkyl group can occur during a FriedelCrafts alkylation, so the product of the alkylation is almost never
exclusively a primary alkyl benzene, unless the primary carbocation
cannot rearrange. For example, the reaction of 1-chloropropane with
benzene in the presence of aluminum chloride produces
isopropylbenzene and propyl benzene in a 2:1 ratio.
CH(CH3)2
67%
CH3CH2CH2Cl
Isopropylbenzene
AlCl3
CH2CH2CH3
33%
Propylbenzene
CH3CH2CH2
Cl
AlCl3
CH3CHCH2
Cl
AlCl3
CH3CHCH3
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Cl
AlCl3
5 July 2005
Organic Chemistry - Ch 18
926
CH2Cl
AlCl3
Solution
In the presence of a Lewis acid catalyst like AlCl3, benzyl chloride forms the
benzyl cation. The benzyl cation is the electrophile that reacts with the
benzene to form diphenylmethane.
CH2Cl
CH2
AlCl3
Diphenylmethane
Exercise 18.5
Propose a step-by-step mechanism for the synthesis of
cyclopentylbenzene from benzene, chlorocyclopentane, and aluminum
chloride.
Lewis acids other than AlCl3 catalyze Friedel-Crafts reactions.
These catalysts include most any Lewis acid that can form a
carbocation from an alkyl halide. Some examples are FeCl3, ZnCl2,
and BF3.
Chapters 12 through 14 cover a number of reactions involving
carbocations. Electrophilic attack on benzene by a carbocation is
simply another of those reactions. Any reagent that forms a
carbocation, not just the ones specifically mentioned in this chapter,
can catalyze a Friedel-Crafts alkylation. For example, a mixture of
propene and liquid hydrogen fluoride, being used as both solvent and
proton donor, reacts with benzene to produce isopropylbenzene.
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Organic Chemistry - Ch 18
927
CH3CH
CH(CH3)2
CH2
HF
Isopropylbenzene
(75%)
Exercise 18.6
Write a step-by-step mechanism for the reaction of cyclopentene with
benzene in liquid HF.
Alcohols in acidic media undergo reactions that are comparable
to the reactions of alkyl halides with Lewis acids. Just like the alkyl
halides, alcohol substrates also readily rearrange as they lose the
OH group to form the carbocation. For example, isobutyl alcohol with
boron trifluoride (BF3) as a catalyst, reacts with benzene to produce
tert-butylbenzene. The reaction produces tert-butylbenzene instead of
isobutylbenzene because a hydride shift in the isobutyl alcohol occurs
at the same time that it loses the OH group, thus producing the
more stable carbocation intermediate.
C(CH3)3
(CH3)2CHCH2OH
BF3
tert-Butylbenzene
(64%)
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Organic Chemistry - Ch 18
928
remaining 97% forms in the ortho and para positions (63% ortho and
34% para.
CH3
CH3
CH3
CH3
NO2
HNO3
H2SO4
+
NO2
NO2
o-Nitrotoluene
63%
An ortho, para
directing group guides
an incoming
electrophile to either
the ortho or para
position on the ring.
m-Nitrotoluene
3%
p-Nitrotoluene
34%
CF3
HNO3
CF3
CF3
NO2
+
H2SO4
+
NO2
NO2
(Trifluoromethyl)
benzene
o-Nitro(trifluoromethyl)benzene
6%
m-Nitro(trifluoro- p-Nitro(trifluoromethyl)benzene
methyl)benzene
91%
3%
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Organic Chemistry - Ch 18
929
CH3
NO2
CH3
NO2
NO2
H
Para Substitution
CH3
NO2
CH3
CH3
NO2
NO2
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Organic Chemistry - Ch 18
CH3
930
CH3
NO2
H
Ortho
complex
Para
NO2
complex
CH3
CH3
NO2
NO2
NO2
The meta-substituted complex is much less stable than the orthoand para-substituted complexes.
A methyl group is an electron-donating group, and although it
activates all three positions relative to benzene, it activates the ortho
and para positions more than the meta positions. This increased
reactivity at the ortho and para sites directs the incoming
electrophiles primarily to those positions. All alkyl groups are electron
donating; thus, they are all ortho, para directing groups.
In contrast to the methyl group, the trifluoromethyl group is
strongly electron withdrawing. Because of the high electronegativity of
the fluorines, the CF bond is quite polar with the positive end of the
dipole at the carbon.
F
F
C
F
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Organic Chemistry - Ch 18
931
complex. Both the ortho and the para complexes have one
resonance contributor with a positive charge on the carbon bearing the
CF3 group; whereas, none of the resonance contributors in the meta
complex has a positive charge on the carbon bearing the CF3 group.
Ortho Substitution
CF3
CF3
NO2
NO2
CF3
NO2
H
Para Substitution
CF3
CF3
CF3
NO2
NO2
NO2
Meta Substitution
CF3
CF3
CF3
NO2
NO2
NO2
The positive charge on the carbon of the ring and the partial
positive charge on the trifluoromethyl group strongly destabilize the
ortho and para complexes.
+
CF3
NO2
CF3
H
H
NO2
Para complex
Ortho complex
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Organic Chemistry - Ch 18
932
44
Meta
2.4
Para
59
for
the
4.6 x 106
69. x 106
4.5 x 106
nitration
of
benzene,
toluene,
and
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Organic Chemistry - Ch 18
933
the meta complex contributors are more stable than the others.
Nevertheless the meta complex benefits from the electron-donating
ability of the methyl group. Thus, the complex from toluene is more
stable than the complex formed from benzene, and it reacts faster than
benzene in electrophilic aromatic substitution reactions. The presence
of the methyl group increases the rate of reaction of toluene at all
three sites, especially the ortho and para positions. Because of this
increased rate of reaction in comparison to benzene, the methyl group
is called an activating ortho, para director.
The greater the stability of the product of a reaction in a
family of related reactions, in this case the intermediate complex,
the less energy of activation required to form it. Figure 18.3 shows the
relationship of the energies of activation for the formation of benzenes
one complex and toluenes three. All three complexes from the
reaction of toluene are more stable than the complex from benzene;
therefore, they need less energy to form.
Figure 18.3 also shows the energy relationship among the
various complexes of toluene. Recall from Section 18.5 that 63% of
the product forms in the ortho position and 34% in the para position.
Thus, the ortho position has nearly twice as much substitution as does
the para position. Because there are two ortho sites and only one para
site, you would expect exactly a 2:1 ratio of product if both had
identical reactivity. However, the methyl group sterically hinders the
ortho position slightly, which causes the reaction to require more
energy to place the electrophile in an ortho position.
H
NO2
G1
Meta
Ortho
Para
CH3
NO2
NO2
Reaction Progress
Figure 18.3. The relative activation energies for the formation of the complexes of
benzene and ortho, meta, and para substitutions in toluene.
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Organic Chemistry - Ch 18
A deactivating meta
directing group reacts
slower than benzene
and directs an
incoming electrophile
to the meta position.
934
NO2
Ortho
Para
Meta
G1
NO2
CF3
+
NO2
Reaction Progress
Figure 18.4. The relative activation energies for the formation of the complexes of
benzene and ortho, meta, and para substitutions in (trifluoromethyl)benzene.
Exercise 18.8
The rate of nitration of 1,3-dimethylbenzene (m-xylene) is 100 times
as fast as 1,4-dimethylbenzene (p-xylene). Predict the product(s) of
nitration for both xylenes. If there are more than one isomer, which
would you expect to be the major product? Explain the difference in
the relative rates.
5 July 2005
Organic Chemistry - Ch 18
935
OCH3
OCH3
OCH3
OCH3
The first three resonance structures are identical to the ones drawn
for para-substituted toluene in Section 18.5. The fourth resonance
structure, however, is particularly stable because the nonbonding pair
of electrons on the oxygen atom helps stabilize the positive charge. In
fact, this is the major resonance contributor because all the atoms
have filled orbitals in their valence shells.
All meta directors inductively destabilize the complex
because they have a partial positive or a full positive charge on the
atom attached to the ring thereby discouraging substitution at sites
ortho or para to the substituent. By default, the reactive site is the
meta position because it is not directly destabilized by the substituent.
For example, the least stable resonance contributor for nitrobenzene
has a positive charge on the carbon bearing the nitrogen. The nitro
group nitrogen also has a formal positive charge.
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Organic Chemistry - Ch 18
936
Substituent
Product
Orientation
NH2
Ortho, Para
NHR
Ortho, Para
NR2
Ortho, Para
OH
Ortho, Para
Strongly activating
Ortho, Para
NHCR
OR
Ortho, Para
Ortho, Para
OCR
Activating
Reference
Ortho, Para
Ar
Ortho, Para
CH=CR2
Ortho, Para
Deactivating
Ortho, Para
(X=F,Cl,Br,I)
CH2
X
Strongly deactivating
Ortho, Para
Meta
CR
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Organic Chemistry - Ch 18
937
Effect on Rate
Substituent
Product
Orientation
Meta
COH
Meta
COR
Meta
CH
Meta
CCl
C N
Meta
SO3H
Meta
CF3
Meta
NH3
Meta
NO2
Meta
NR 3
Meta
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5 July 2005
Organic Chemistry - Ch 18
938
OH
OH
OH
NO2
NO2
NO2
OH
NO2
H
Major contributor
Para Substitution
OH
NO2
OH
NO2
OH
NO2
OH
H
NO2
Major contributor
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Organic Chemistry - Ch 18
939
OH
OH
OH
NO2
NO2
NO2
Br
HNO3
H2SO4
Br
Br
+
NO2
NO2
NO2
39%
1%
60%
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5 July 2005
Organic Chemistry - Ch 18
940
Br
Br
NO2
NO2
Both resonance
contributors have
full octets on all
atoms.
Br
Br
NO2
NO2
H
Exercise 18.9
Aniline (C6H5NH2) is more reactive towards electrophilic substitution
than is acetanilide (C6H5NHCOCH3). Explain this difference in
reactivity.
When using highly activating substituent groups, limiting the
number of incoming substituents to only one is difficult. For example,
phenol reacts rapidly with bromine in water to form a quantitative
yield of 2,4,6-tribromophenol.
OH
OH
Br
Br
Br2
H2O
Br
2,4,6-Tribromophenol
(100%)
Solved Exercise 18.3
Complete the following reactions showing the major monosubstitution
product(s) from each reaction.
a)
Br
Br2
Fe
Solution
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Organic Chemistry - Ch 18
941
Bromine is a weakly deactivating ortho, para directing group. Thus, you will
get a mixture of ortho and para substitution products. Because bromine is
large, there will be a larger fraction of para than ortho product.
Br
Br
Br2
Br
+
Fe
Br
Br
b)
OCH3
CH3CH2CH2Cl
AlCl3
Solution
The methoxy group is an activating ortho, para directing group. Thus, you
will get a mixture of ortho and para substitution. Because the oxygen is
small, the ortho product will likely predominate. In this case, the electrophile
will rearrange to form a secondary carbocation. Thus, the product is an
isopropyl-substituted anisole.
OCH3
CH3CH2CH2Cl
OCH3
OCH3
+
AlCl3
CHCH3 CH3CH
CH3
CH3
c)
O
COCH3
HNO3
H2SO4
Solution
The ester functional group is a deactivating meta directing group. Thus, the
product will have a nitro group substituted meta to the ester group.
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Organic Chemistry - Ch 18
942
COCH3
COCH3
HNO3
H2SO4
NO2
CH3
CH3Cl
CH3Cl
AlCl3
AlCl3
CH3
CH3
+
CH3
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5 July 2005
Organic Chemistry - Ch 18
943
CCH3
CH3CCl
AlCl3
AlCl3
CH3CH2CCl
AlCl3
CH3CH2CCl
Acid-base complex
AlCl3
CH3CH2C
CH3CH2CCl
CH3CH2C
Acyl cation
An acyl cation reacts with benzene in much the same way as any other
electrophile.
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Organic Chemistry - Ch 18
944
CCH2CH3
CH3CH2C
O
CCH2CH3
AlCl4
RC
OCR
O
AlCl3
RC
O
+
Cl3Al
OCR
Exercise 18.10
In some low polarity solvents, the acid/base complex does not readily
form the acylium ion. Thus, the acid/base complex is the reacting
species. Write a mechanism for this reaction. (Hint: Refer to Chapter 8
for a starter.)
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Organic Chemistry - Ch 18
945
CR
RCCl
CH2R
reduce
AlCl3
The Clemmensen
reduction is a method
used to convert the
carbonyl group to a
CH2 group.
CCH2CH3
Zn(Hg)
HCl
CH3CH2CCl
AlCl3
CH2CH2CH3
Propylbenzene
(71% overall)
The Wolff-Kishner
reduction is another
method used to convert
the carbonyl group to a
CH2 group.
O
CC(CH3)3
NH2NH2, KOH
CH2C(CH3)3
Diethylene glycol
reflux
(2,2-Dimethyl-1-propyl)benzene
(76% overall)
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5 July 2005
Organic Chemistry - Ch 18
946
Exercise 18.11
Propose a synthesis for each of the following substituted aromatics.
a) tert-Butylbenzene b) 2-Methyl-1-phenylpropane
c) Butylbenzene
d) Toluene
e) Neopentylbenzene [PhCH2C(CH3)3]
Sample solution
c)
O
CCH2CH2CH3
CH3CH2CH2CCl
AlCl3
NH2NH2, KOH
Diethylene glycol
reflux
CH2CH2CH2CH3
O
AlCl3
O
Phthalic anhydride
OH
O
o-Benzoylbenzoic acid
(55%)
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Organic Chemistry - Ch 18
947
CH3
Br
Br2
Fe
CH3
CH3
All sites are
equivalent
CH3
Br
Br2
Fe
C(CH3)3
C(CH3)3
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Organic Chemistry - Ch 18
948
CH3
Br
Br2
Fe
NO2
NO2
Ortho to the CH3
and meta to the NO2
NH2
Br
Br2
Fe
Cl
Deactivated by Cl
Cl
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5 July 2005
Organic Chemistry - Ch 18
949
O
NHCCH3
Cl
Solution
Because of the nonbonding electrons on the nitrogen attached to the ring, the
amide group is a strongly activating ortho, para director. The chlorine is a
weakly deactivating ortho, para director. Thus, the sites ortho to the amide
group are more reactive than the sites ortho to the chlorine.
O
O
NHCCH3
NHCCH3
Br2
Fe
Br
Cl
Cl
b)
O
O2N
COCH3
Both the ester and the nitro groups are deactivating meta directors. Because
they are meta to each other, they both direct towards the same site on the
ring.
O
O
O2N
O2N
COCH3
COCH3
Br2
Fe
Br
Exercise 18.12
Predict the major mononitration product(s) for each of the following
aromatic compounds.
a) m-Dichlorobenzene
d) 4-Ethylbenzoic acid
b) p-Methylphenol
e) 1,3-Dimethylbenzene
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c) m-Nitroanisole
f) 2,6-Dichloroanisole
5 July 2005
Organic Chemistry - Ch 18
950
Sample solution
b) The OH group is a much stronger activating group than
the CH3 group, so the OH group directs the position of the nitro
group.
OH
OH
NO2
HNO3
H2SO4
CH3
CH3
8
9
7
6
2
3
10
5
Naphthalene
NO2
HNO3
CH3COOH
(CH3CO)2O
warm
1-Nitronaphthalene
91%
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2-Nitronaphthalene
9%
5 July 2005
Organic Chemistry - Ch 18
951
NO2
NO2
NO2
NO2
NO2
The first two contributors possess two factors that give them more
stability than the other three resonance contributors and the
resonance contributors in the C2 complex. Both resonance
contributors have one ring in which the aromaticity is undisturbed,
and each of the two aromatic contributors in the other ring also has an
allylic resonance. Thus, these two contributors have a special stability
due to the delocalization of the positive charge between C2 and C4.
On the other hand, only one of the resonance contributors for
the reaction at C2 has aromatic character in either ring. The
remaining resonance contributors are not aromatic. Formation of the
C2 complex is a higher energy pathway than electrophilic attack at
C1.
Reaction at C2
NO2
NO2
NO2
H
NO2
NO2
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5 July 2005
Organic Chemistry - Ch 18
Thermodynamic versus
kinetic control of a
reaction is discussed in
Section 16.4, page 000.
952
Less interference
H
SO3H
SO3H
H
Naphthalene-1-sulfonic acid
Naphthalene-2-sulfonic acid
75oC,
Exercise 18.13
Following an analysis similar to that above, find the most reactive site
for electrophilic substitution on anthracene.
Anthracene
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5 July 2005
Organic Chemistry - Ch 18
953
18.11 Diazotization
An aryl diazonium salt
has the formula
ArN2. An aryl
diazonium salt is made
from an aryl amine.
NaNO2, HCl
Cl
H2O, 0-5oC
The electrophile used to react with the amine to form the aryl
diazonium salt is the mild NO electrophile. The following
mechanism shows how the aryl diazonium salt forms from HCl and
NaNO2. The NO ion is resonance-stabilized, so it forms relatively
easily.
HO
NaNO2 + HCl
HO
O +
O + NaCl
HO
HO
H
Diazotization is the
name of the process
that forms a diazonium
salt.
+ H2O
N
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Organic Chemistry - Ch 18
954
NH2
OH2
H
OH
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5 July 2005
Organic Chemistry - Ch 18
955
H2O
N
OH
OH
OH
4-Phenylazophenol
An azo compound
OH
+
O2N
COOH
N
OH
COOH
O2N
Alizarin yellow
(82%)
N(CH3)2
+
HO3S
N
N(CH3)2
HO3S
Methyl orange
(70%)
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5 July 2005
Organic Chemistry - Ch 18
956
HO
N
N
HO
+
O2N
O2N
Para red
(76%)
NH2
1) Na2CO3
Sulfanilic acid
HO3S
N(CH3)2
Methyl orange
(70%)
Dissolve 0.6 g of anhydrous sodium carbonate in 50 mL of water. Add 1.75 g (10 mmol)
of sulfanilic acid to the solution and heat until it dissolves. Cool the solution to room
temperature and add 0.8 g of sodium nitrite. Cool in an ice bath until the temperature
is below 10oC then add 2.5 mL of concentrated hydrochloric acid. A precipitate of
diazonium salt will form. Keep this reaction mixture cold. In a separate flask, dissolve
1.3 mL (10 mmol) of N,N-dimethyl aniline in 1.0 mL of glacial acetic acid. Add this
solution to the reaction mixture. Keep cold for about 15 minutes. During this time a
red precipitate will form. Add 15 mL of 10% sodium hydroxide. Check to see if the
solution is basic. If not, add more 10% sodium hydroxide until the solution is basic.
Heat this solution to boiling and boil until most of the solid is dissolved. Carefully add
5 g of sodium chloride to the boiling solution. Allow the mixture to cool, then cool it
further in ice. Filter the solution. Wash the flask with two ice-cold portions of
saturated sodium chloride solution and pour these through the methyl orange in the
filter. Dissolve the solid in 150 mL of boiling water. All of the solid will not dissolve,
but the sodium chloride contaminant will dissolve. Boil the solution for 5-10 minutes.
Cool the solution to room temperature then place in an ice bath. When cold, filter the
solid and allow it to dry. Yield of methyl orange is 2.15 g (70%), m.p. decomposes.
Discussion Questions
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5 July 2005
Organic Chemistry - Ch 18
957
1. The pH of the reaction mixture is important to the course of the coupling reaction
with N,N-dimethylaniline. The rate of the coupling reaction increases with
increasing pH. Explain this behavior.
2. Methyl orange, and all other azo compounds, is brightly colored. What molecular
features of azo compounds explain the colors of these molecules?
Exercise 18.14
Propose a synthesis for each of the following compounds.
a)
b)
N
CH3
N
N
SO2NH2
(CH3)2N
CH3
OCH3
c)
d)
N
NH2
N(CH3)2
NO2
Cl
Sample Solution
c)
NH2
NaNO2, H2SO4
H2O, 0 - 5oC
NO2
NH2
NH2
NO2
[SIDEBAR]
Sulfa Drugs
The introduction of sulfa drugs in the 1930s hailed the
beginning of modern drug therapy. Before their introduction, even a
minor bacterial infection could become potentially life-threatening.
Because at first no one understood how sulfa drugs worked, even
physicians considered them as almost magical.
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5 July 2005
Organic Chemistry - Ch 18
958
H2N
SO2NH2
p-[(2,4-Diaminophenyl)azo]benzenesulfonamide
In
1932,
Gerhard
Domagk
tested
p-[(2,4diaminophenyl)azo]benzenesulfonamide, later marketed under the
trade name Prontosil, on a ten-month-old boy sick with a dangerous
staphylococcal infection. The boy rapidly recovered. Domagk was
awarded the 1939 Nobel Prize in medicine or physiology for this work,
although he was forced to decline the Prize by the Nazi German
Government.
So, Prontosil worked. It had saved a childs life. But how?
Research had already shown that it was inactive in vitro. Why then
was it active in vivo? Identifying the mechanism by which Prontosil
combats bacterial infections was a major step in the development of
pharmacology.
The goal of the I. G. Farben research group was to find a dye
toxic to bacteria. Prontosil had healed a child with a bacterial
infection, yet, obviously it was not toxic to the bacteria. In vitro
studies had proven that fact. In conclusion, the researchers decided
that Prontosils toxicity observed in vivo must be from something
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5 July 2005
Organic Chemistry - Ch 18
959
H2N
in vivo
H2N
SO2NH2
SO2NH2
Sulfanilamide
H2N
SO2NH2
Sulfanilamide
COOH
p-Aminobenzoic acid
H2N
S
SO2NH
N
SO2NH
Sulfadiazine
Sulfathiazole
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5 July 2005
Organic Chemistry - Ch 18
960
The Sandmeyer
reaction converts a
diazonium salt to an
aryl chloride, bromide,
or nitrile.
X
CuX
Br
CuBr
NO2
NO2
1-Bromo-3-nitrobenzene
(87%)
NH2
NaNO2, H2SO4
Cl
CN
CuCN
H2O, 0 - 5oC
Cl
2-Chlorobenzonitrile
(75%)
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5 July 2005
Organic Chemistry - Ch 18
961
NH2
Cl
NaNO2, H2SO4
H2O, 0 - 5oC
NH2O2S
CuCl
NH2O2S
4-Chlorobenzenesulfonamide
(71%)
Chemists use
Schiemann reactions to
produce aryl fluorides
that are otherwise
difficult to produce.
1) HBF4
2) heat
Fluorobenzene
(83%)
NH2
NaNO2, H2SO4
H2O, 0 - 5oC
KI
CH3
3-Iodotoluene
(82%)
warm
CH3
OH
CH3
3-Methylphenol
(74%)
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5 July 2005
Organic Chemistry - Ch 18
962
Br
NH2
Br
Br
NaNO2, H2SO4
H2O, 0 - 5oC
H3PO2
Br
Br
2,4,6-Tribromobenzene
(68%)
D3PO2
Deuterobenzene
(81%)
Exercise 18.15
Propose a synthesis of 3-chloroethylbenzene from benzene.
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5 July 2005
Organic Chemistry - Ch 18
963
Cl
OH
NO2
NaOH
80oC
NO2
NO2
NO2
2,4-Dinitrophenol
(95%)
Cl
Cl
Cl
OH
OH
Cl
OH
NO2
OH
NO2
NO2
OH
Cl
OH
NO2
NO2
NO2
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5 July 2005
Organic Chemistry - Ch 18
964
Fluorine is also the smallest of the halides, thus giving less steric
hindrance to the reaction of the nucleophile than the other halides.
Table 18.3 shows the relative rates of reaction for the halogens.
Aryl Halide
ArF
ArCl
ArBr
ArI
Rate
310
1.0
0.8
0.4
Rate
1.4 x 108
1
2.9 x 105
Too fast
to measure
Table 18.4. Relative rate of reaction for various chloronitrobenzenes with sodium
methoxide in methanol at 50oC.
Exercise 18.16
Reaction of 1,2-dichloro-3,5-dinitrobenzene with sodium methoxide in
methanol produces a single product, C7H5ClN2O5. What is the
structure of the product?
18.14 Benzyne
Although
aryl
halides
without
electron-withdrawing
substituents also undergo nucleophilic substitution reactions, they
require extreme conditions or very strong bases. For example the
commercial Dow process used for making phenol involves heating
chlorobenzene with sodium hydroxide at 350oC.
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5 July 2005
Organic Chemistry - Ch 18
965
Cl
OH
H
NaOH
350oC
Phenol
(98%)
NH2
NaNH2
NH3, -33oC
Aniline
(100%)
CH3
NaNH2
NH3, 33oC
Br
CH3
NH2
NH2
4-Methylaniline
(p-Toluidine)
50%
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3-Methylaniline
(m-Toluidine)
50%
5 July 2005
Organic Chemistry - Ch 18
966
a Benzyne
Poor overlap
After benzyne forms, the amide ion can attack it on either end
of its weak, reactive triple bond. This part of the reaction produces a
benzene anion. The benzene anion then removes a proton from an
ammonia molecule giving the final products, 3-methylaniline and 4methylaniline.
CH3
CH3
CH3
H
NH2
NH2
NH2
NH2
H
3-Methylaniline
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5 July 2005
Organic Chemistry - Ch 18
967
CH3
CH3
CH3
NH2
NH2
NH2
NH2
4-Methylaniline
Mg, THF
MgBr
o-Bromofluorobenzene
(78%)
Synthesis of Trypticene
NH2
(CH3)2CHCH2CH2NO2
COOH
Anthranilic acid
Trypticene
(70%)
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5 July 2005
Organic Chemistry - Ch 18
968
Exercise 18.17
What structure would you expect from the formation of a Grignard
reagent from 1-bromo-2-fluoro-4,5-dimethylbenzene in the presence of
furan?
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5 July 2005
Organic Chemistry - Ch 18
969
O
CCH3
?
Br
p-Bromoacetophenone
CCH3
CH3CCl
AlCl3
Br
Br
4-Bromoacetophenone
CCH3
CH3CCl
AlCl3
Br
Br
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5 July 2005
Organic Chemistry - Ch 18
970
18.2 (page 000), however, that the sulfonic acid group brominates meta
to itself, which would be in the wrong position. An amine group, on the
other hand, is an ortho, para director, so it would place the bromine in
the correct position. In fact, an amine group is such a strong activating
group that it usually causes trisubstitution on a benzene ring.
NH2
NH2
Br
Br
Br2
H2O, NaHCO3
Br
2,4,6-Tribromobenzene
NH2
Zn (or Sn)
HCl
NH2
Zn
HCl
HNO3
H2SO4
Br2
H2O, NaHCO3
NH2
Br
Br
H3PO2
Br
NaNO2, H2SO4
Br
H2O, 0 - 10oC
Br
Br
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5 July 2005
Organic Chemistry - Ch 18
971
The third target molecule for you to synthesize is 4-nitro-3propylphenol from benzene.
OH
?
O2N
4-Nitro-3-propylphenol
4-Nitro-3-propylphenol
has
three
possible
immediate
precursors: 4-nitrophenol, 2-propylnitrobenzene, and 3-propylphenol.
However, 4-nitrophenol will not work because it would give 4-nitro-2propylphenol in a Friedel-Crafts reaction. A Friedel-Crafts reaction is
the reaction you use to add the propyl group. 2-Propylnitrobenzene
will not work either because the propyl and nitro group would direct
the phenol to C5 instead of para to the nitro group. Nitration of 3propylphenol, on the other hand, places the nitro group in the correct
positionthe para position. This is the precursor that you must use,
even though the reaction also gives some nitration ortho to the OH
group and para to the propyl group.
OH
O2N
OH
O2N
OH
O2N
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5 July 2005
Organic Chemistry - Ch 18
972
OH
NaNO2, H2SO4
warm
H2O, 0 - 10oC
3-Propylphenol
HNO3
AlCl3
H2SO4
NO2
O
1-(3-Nitrophenyl)-1-propanone
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5 July 2005
Organic Chemistry - Ch 18
973
NO2
NH2
Zn(Hg)
HCl
3-Propylaniline
HNO3
AlCl3
H2SO4
NO2
Zn(Hg)
HCl
OH
warm
OH
HNO3
H2O, 0 - 10oC
CH3COOH
O2N
NH2
NaNO2, H2SO4
Exercise 18.18
When planning a synthesis, knowing what not to do is as important as
knowing what to do. The following syntheses have a flaw. What
product would you expect to obtain from each of the following
schemes? Additionally, propose an alternative synthesis that would
prepare the products shown. You may use any stable monosubstituted
benzene molecule as a starting material.
a)
Cl
Br
CH3CH2CH2Cl
Cl2
AlCl3
Fe
Br
CH3CH2CH2
b)
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5 July 2005
Organic Chemistry - Ch 18
974
OCH3
OCH3
HNO3
Br2
H2SO4
Fe
NO2
Br
c)
COOH
COOH
O
CH3CH2CCl
HNO3
AlCl3
H2SO4
O2N
CCH2CH3
O
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5 July 2005
Organic Chemistry - Ch 18
975
Electron-withdrawing
substituents
direct
electrophiles to the meta position on the ring.
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incoming
5 July 2005
Organic Chemistry - Ch 18
976
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5 July 2005
Organic Chemistry - Ch 18
977
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