Aromatic Sub

Organic Chemistry OnLine 2000
Chapter 14
Electrophilic Aromatic Substitution-II
2000, Paul R. Young
University of Illinois at Chicago
All Rights Reserved
Electrophilic Aromatic Substitution
Acylation
Alkylation
Sulfonation
Nitration
Halogenation
C
O
R
R
SO
3
H
NO
2
X
X
+
NO
2
+
HSO
3
+ R
+
RC O
+

Br
2
/FeBr
3
Br

Fe
Br
Br
Br
Br Br

FeBr
3
functions as a Lewis Acid, binding Br
2
and
creating a source of the bromonium cation, Br
+

Br
Br
H
Br
H
H
Br

Br
loss of H
+
...the driving force for loss of H
+
is the
restoration of the aromatic system.
Br
H
Br
H
H
Br
An electrostatic potential map showing charge
distribution in the cyclohexadienyl cation intermediate.
Electron donating
substituents at these
positions will stabilize
the cationic
intermediate.

Cl
2
/FeCl
3
Cl
Cl
H

I
I
H
I
2
CuCl
2
I
...CuCl
2
/I
2
serves to generate I
+


NO
2
NO
2
+
NO
2
H
H
2
SO
4
+ HNO
3 H
2
O + NO
2
+
Nitration

SO
3
H
H
H
2
SO
4
+ SO
3 SO
3
H
+
+ HSO
4
-
SO
3
H
+
SO
3
H
Sulfonation
Friedel-Crafts Alkylation

CH
3
CH
3
H CH
3
Cl
AlCl
3

CH
3
Cl AlCl
3
CH
3
Cl + AlCl
3
Limitations of the Friedel-
Crafts Alkylation
1. Reaction limited to alkyl halides; aryl or vinyl halides do
not react.
2. Reaction does not occur on rings containing strong
electron withdrawing substituents.
3. Multiple substitutions often occur.
4. Carbocation rearrangements can occur, particularly with
1 alkyl halides.

NO
2 CN
SO
3
H
CHO COR
COOH COOR
NR
3
+

O
CH
3
H
O
CH
3
CH
3
O
Friedel-Crafts Acylation
Cl AlCl
3
CH
3
O

Cl H
3
C
O
+ AlCl
3
Friedel-Crafts Acylation
1. Multiple substitutions do not occur.
2. Carbocation rearrangements do not occur.
3. Reaction does not occur on rings containing strong
electron withdrawing substituents.
4. Acid anhydrides can also be used.

O
CH
3
...ring is deactived after mono-substitution;
multiple substitutions do not occur.

H
3
C O CH
3
O O
1. Predict the products of the following reactions.
AlCl
3
AlCl
3
Cl
Cl
O
HNO
3
/H
2
SO
4

AlCl
3
AlCl
3
Cl
Cl
O
HNO
3
/H
2
SO
4

O
CH
3

AlCl
3
AlCl
3
Cl
Cl
O
HNO
3
/H
2
SO
4

O
CH
3

NO
2

AlCl
3
AlCl
3
Cl
Cl
O
HNO
3
/H
2
SO
4

O
CH
3

NO
2

1. (con't) Predict the products of the following reactions.
AlCl
3
O
O O
FeCl
3
Cl
2
SO
3
/H
2
SO
4

AlCl
3
O
O O
FeCl
3
Cl
2
SO
3
/H
2
SO
4

Cl

AlCl
3
O
O O
FeCl
3
Cl
2
SO
3
/H
2
SO
4

Cl

SO
3
H
AlCl
3
O
O O
FeCl
3
Cl
2
SO
3
/H
2
SO
4

Cl

SO
3
H

O
CH
2
CH
3


H
2
/Pd
25 C, 1 atm
Catalytic Reduction of Aromatic
Compounds

H
2
/Pd
25 C, 1 atm

H
2
/Pd
25 C, 1 atm
H
2
, Pt/C
25 C
2000 psi


H
2
/Pd
25 C, 1 atm
H
2
, Rh/C
25 C; 1 atm
H
2
, Pt/C
25 C
2000 psi

The Reduction of Aryl Nitro Groups and Aryl
Ketones

O
H
2
/Pd
25 C, 1 atm
NO
2
H
2
/Pd
25 C, 1 atm
NH
2

...or...SnCl
2
/H
3
O
+

+
O
Zn(Hg)
H
3
O
+
Aryl ketones can also be reduced to the
hydrocarbon using the Clemmensen Reduction.

Suggest a synthesis of propylbenzene, beginning with benzene.

AlCl
3
CH
3
CH
2
CH
2
Cl

AlCl
3
CH
3
CH
2
CH
2
Cl

Cl AlCl
3
AlCl
3
CH
3
CH
2
CH
2
Cl


1,2-hydride shift
Cl AlCl
3
Cl AlCl
3
AlCl
3
CH
3
CH
2
CH
2
Cl

H
H

1,2-hydride shift
Cl AlCl
3
Cl AlCl
3
AlCl
3
CH
3
CH
2
CH
2
Cl

H
H

Suggest a synthesis of propylbenzene, beginning with benzene.

O
CH
3
CH
2
C
O
Cl
AlCl
3


AlCl
3
H
2
/Pd
25 C, 1 atm
CH
3
CH
2
C
O
Cl
O
Reactions of Arylamines

H
2
/Pd
25 C, 1 atm
NO
2
NH
2

...or...SnCl
2
/H
3
O
+
Reactions of Arylamines

H
2
/Pd
25 C, 1 atm
NO
2
NH
2

...or...SnCl
2
/H
3
O
+

NH
2 N
N
HNO
2
H
2
SO
4
A diazonium salt.

H
3
PO
2
, H
2
O
HCl, CuCl
HBr, CuBr
KI

N
2
+

H
3
PO
2
, H
2
O
HCl, CuCl
HBr, CuBr
KI

N
2
+


H
3
PO
2
, H
2
O
HCl, CuCl
HBr, CuBr
KI

N
2
+

Cl
Sandmeyer Reaction

H
3
PO
2
, H
2
O
HCl, CuCl
HBr, CuBr
KI

N
2
+

Cl

Br

H
3
PO
2
, H
2
O
HCl, CuCl
HBr, CuBr
KI

N
2
+

Cl

Br

I

KCN, CuCN
H
+
/H
2
O
OH
N
CH
3
CH
3

N
2
+

KCN, CuCN
H
+
/H
2
O
OH
N
CH
3
CH
3

N
2
+

CN

KCN, CuCN
H
+
/H
2
O
OH
N
CH
3
CH
3

N
2
+

CN

OH

KCN, CuCN
H
+
/H
2
O
OH
N
CH
3
CH
3

N
2
+

CN

OH

N
N
OH

OH
The oxygen atom in phenol is electron-releasing by resonance,
activating the ring to electrophilic aromatic substitution
ortho- and para- to the oxygen.

OH

OH

OH

OH

OH

OH
OH
OH
OH

OH

Because of the increased electron density, an electrophile will
attack the phenol ring preferentially at these positions.

OH


N
N
A diazonium salt acting as
an electrophile.

N
N
OH
OH

N
N
H
+
OH
N
N
H
H

N
N
OH
OH

N
N
H
+
OH
N
N
H
H
A diazonium
coupling product.

KCN, CuCN
H
+
/H
2
O
OH
N
CH
3
CH
3

N
2
+

CN

OH

N
N
OH


KCN, CuCN
H
+
/H
2
O
OH
N
CH
3
CH
3

N
2
+

CN

OH

N
N
OH

N
N
N
CH
3
CH
3

NH
2
NH
2
Br
Br
Br
Br
2

OH

OH
Br
Br
Br
Br
2
Arylamines and Phenols are so highly activated towards
electrophilic aromatic substitution that they react with
bromine in the absence of a catalyst to give tribromo adducts.
Reactivity of Substituted Benzenes
1. Substituents effect the reactivity of aromatic rings.
2. Substituents also effect the orientation or
regiochemistry of the reaction.

NO
2
CN
SO
3
H
CHO
COR
COOH
COOR
NR
3
+
NH
2
OCH
3
OH
N
H
C
O
CH
3
CH
3
F
Br
Cl
I
H
strongly
activating
strongly
deactivating
Electrostatic potential maps clearly show the effect of
substituents on electron density in a substituted benzene ring.
Aniline, strongly
activating
Benzene Benzonitrile,
strongly deactivating
Aniline, strongly
activating
Aniline, strongly
activating
Aniline, strongly
activating

OCH
3
E

OCH
3
OCH
3
OCH
3 OCH
3
Br
H
Br
H
H
Br
Electron donating
the cationic
intermediate.
Recall that positive charge in the cyclohexadienyl cation
intermediate is delocalized to the ortho- and para- positions.

OCH
3
E
Because of this, attack to form the cationic intermediate will
occur predominately ortho- and para- to an electron donating
substituent.
Electron donating
the cationic
intermediate.

ortho &
para
directing

NO
2
CN
SO
3
H
CHO
COR
COOH
COOR
NR
3
+
NH
2
OCH
3
OH
N
H
C
O
CH
3
CH
3
F
Br
Cl
I
H
strongly
activating
strongly
deactivating

Cl
Cl Cl
Cl
Cl
E
...halogens are deactivating inductively,
but activate the ring through resonance.

CH
3
HNO
3
/H
2
SO
4
CH
3
NO
2
CH
3
NO
2
CH
3
NO
2
63% 3%
34%
...the alkyl group is activating and increases electron density
in the ortho and para positions; thus, nitration generates
predominately ortho and para products.

CH
3
H
E
CH
3
E
H
CH
3
E
H
CH
3
+
E
a tertiary
carbocation
...alkyl groups activate ortho and para because the sigma-
complex intermediates yield more stable tertiary carbocations.

CN
HNO
3
/H
2
SO
4
CN
NO
2
CN
NO
2
CN
NO
2
17% 81%
2%
...the cyano group is deactivating; nitration generates
predominately meta product.

NO
2
N
O O
N
O O
N
O O
E
N
O O

Recall that electron donating
substituents ortho- and para-
to the sigma intermediate will
stabilize the cationic
intermediate.
Deactivating meta-directing groups...
NO
2
When electron withdrawing substituents
are present ortho- or para- to the sigma
intermediate substitution is forced meta-
because there is reduced electron density in
the other positions.
Deactivating meta-directing groups...
NO
2

N
O O
E
N
O O
N
O O
N
O O
NO
2
...electrophilic attack occurs at the meta

positions because the ortho and para
positions are electron deficient.

ortho- &
para-
directing

NO
2
CN
SO
3
H
CHO
COR
COOH
COOR
NR
3
+
NH
2
OCH
3
OH
N
H
C
O
CH
3
CH
3
F
Br
Cl
I
H
strongly
activating
strongly
deactivating
meta-
directing

CH
3
NO
2
HNO
3
/H
2
SO
4
Orientation Effects in Disubstituted Benzenes

CH
3
NO
2
HNO
3
/H
2
SO
4
CH
3
NO
2
NO
2
CH
3
NO
2
NO
2
O
2
N
methyl directs ortho
nitro directs meta
Trinitrotoluene

CH
3
NO
2
HNO
3
/H
2
SO
4
CH
3
NO
2
NO
2
CH
3
NO
2
NO
2
O
2
N
methyl directs ortho
nitro directs meta
TriNitroToluene

CH
3
O
CH
3
Br
2
/FeBr
3

CH
3
O
CH
3
Br
2
/FeBr
3
CH
3
O
CH
3
Br
...when substituents direct to different positions, the
most powerful group will dominate.

CH
3
Cl
Cl
2
/FeCl
3

CH
3
Cl
Cl
2
/FeCl
3
CH
3
Cl
Cl
CH
3
Cl
Cl
CH
3
Cl
Cl
+
...product not observed;
too hindered
Nucleophilic Aromatic Substitution

F
NO
2
NO
2
HO
-
OH
NO
2
NO
2

F
NO
2
O
2
N
HO
-
...S
N
2 attack is not possible;
S
N
1 would generate the unstable aryl cation.

F
NO
2
NO
2
NO
2
NO
2

F
NO
2
NO
2
HO
-
NO
2
NO
2
OH
F
NO
2
NO
2
OH
NO
2
NO
2
OH
F
...addition
...elimination
The Addition-Elimination Mechanism

N
NO
2
OH
F
O
O
N
NO
2
OH
F
O
O
...the carbanion at the ortho- position is stabilizedby
resonance with the oxygens of the nitro group

N
NO
2
OH
F
O
O
N
NO
2
OH
F
O
O
+ F
NO
2
OH
N
O
O
elimination

CH
3
SO
3
H
NO
2
Br
2
/FeBr
3
I
2
/CuCl
2
Cl
2
/FeCl
3

CH
3
SO
3
H
NO
2
Br
2
/FeBr
3
I
2
/CuCl
2
Cl
2
/FeCl
3
CH
3
Cl
+ ortho isomer

CH
3
SO
3
H
NO
2
Br
2
/FeBr
3
I
2
/CuCl
2
Cl
2
/FeCl
3
CH
3
Cl
SO
3
H Br
+ ortho isomer

CH
3
SO
3
H
NO
2
Br
2
/FeBr
3
I
2
/CuCl
2
Cl
2
/FeCl
3
CH
3
Cl
SO
3
H Br
NO
2
I
+ ortho isomer

CH
3
CH(CH
3
)
2
Cl
SO
3
/H
2
SO
4
excess HNO
3
/H
2
SO
4
Cl
O
C
AlCl
3

CH
3
CH(CH
3
)
2
Cl
SO
3
/H
2
SO
4
excess HNO
3
/H
2
SO
4
Cl
O
C
AlCl
3
Cl
HO
3
S
+ ortho isomer

CH
3
CH(CH
3
)
2
Cl
SO
3
/H
2
SO
4
excess HNO
3
/H
2
SO
4
Cl
O
C
AlCl
3
CH
3
NO
2
O
2
N NO
2
Cl
HO
3
S
+ ortho isomer

CH
3
CH(CH
3
)
2
Cl
SO
3
/H
2
SO
4
excess HNO
3
/H
2
SO
4
Cl
O
C
AlCl
3
CH
3
NO
2
O
2
N NO
2
CH(CH
3
)
2
O
Cl
HO
3
S
+ ortho isomer

Aromatic Sub

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Organic Chemistry OnLine 2000

...electrophilic attack occurs at the meta

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