Arenes Reactions ch12 2022 Updated
Arenes Reactions ch12 2022 Updated
Arenes Reactions ch12 2022 Updated
Chapter 12
In this chapter we will consider:
Explain the mechanistic basis for the action of activating ortho, para-
directing groups and deactivating meta-directing groups.
Nitration
Sulfonation
Halogenation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation (carbonyl groups)
Nitration of Benzene
H H2SO4 NO2
+ HONO2
+ H2O
Nitric acid: HNO3
Nitrobenzene
(95%)
Sulfonation of Benzene
O
H heat SO2OH
+ HOS-OH
+ H2O
O
Sulfuric acid
Benzenesulfonic acid
(100%)
Halogenation of Benzene
H FeBr3 Br
+ Br2
+ HBr
Bromobenzene
(65-75%)
Friedel-Crafts Alkylation of Benzene
H AlCl3 C(CH3)3
+ (CH3)3CCl
+ HCl
tert-Butylbenzene
(60%)
Friedel-Crafts Acylation of Benzene
O
O
H AlCl3 CCH2CH3
+ CH3CH2CCl
+ HCl
1-Phenyl-1-propanone
(88%)
12.2
Mechanistic Principles
of
Electrophilic Aromatic Substitution
Step 1: attack of electrophile
from π-electron system of aromatic ring
E+
H H H H E
H H H +
H
H H H H
Arenium ion
highly endothermic (heat needed)
carbocation is allylic, but not aromatic
Step 2: loss of a proton from the carbocation
intermediate
H H H H E
H E H +
H
H H H+ H H
highly exothermic
this step restores aromaticity of ring
Based on this general mechanism:
Nitration of Benzene
Nitration of Benzene
H H2SO4 NO2
+ HONO2
+ H2O
+
Electrophile is
•• O
••
N O ••
••
nitronium ion
Step 1: attack of nitronium cation
on π-electron system of aromatic ring
NO2+
H H H H NO2
H H H +
H
H H H H
Step 2: loss of a proton from the carbocation
intermediate
H H H H NO2
H NO2 H +
H
H H H+ H H
Where does nitronium ion come from?
•• •• – •• •• –
•• O + O •• ••O + O ••
•• ••
N H2SO4 N
+O
•• O ••
•• H H H
+ ••
O
•• O
••
N O ••
••
+
H •• H
12.4
Sulfonation of Benzene
Sulfonation of Benzene
H heat SO2OH
+ HOSO2OH
+ H2O
•• •• –
•• O + O ••
••
Several electrophiles present: S
a major one is sulfur trioxide
•• O
••
Step 1: attack of sulfur trioxide
on π-electron system of aromatic ring
SO3
H H H H SO3–
H H H +
H
H H H H
Step 2: loss of a proton from the carbocation
intermediate
H H H H SO3–
H SO3– H +
H
H H H+ H H
Step 3: protonation of benzenesulfonate ion
H H H2SO4 H H
H SO3– H SO3H
H H H H
12.5
Halogenation of Benzene
Halogenation of Benzene
H FeBr3 Br
+ Br2
+ HBr
+
•• •• •• •• –
•• Br Br •• + FeBr3 •• Br Br FeBr3
•• •• •• ••
Empty p orbital
Complex
Lewis base: Lewis acid:
Electron donnor Electron acceptor
+ –
Br Br FeBr3
H H H H Br
H H H +
H
H H H H
+ FeBr4–
Step 2: loss of a proton from the carbocation
intermediate
H H H H Br
H Br H +
H
H H H+ H H
12.6
H AlCl3 C(CH3)3
+ (CH3)3CCl
+ HCl
H3C
Electrophile is +
C CH3
tert-butyl cation
H3C
Role of AlCl3
+ •• –
(CH3)3C + •• Cl AlCl3
••
Step 1: attack of tert-butyl cation
on π-electron system of aromatic ring
+
C(CH3)3
H H H H C(CH3)3
H H H +
H
H H H H
Step 2: loss of a proton from the carbocation
intermediate
H H H H C(CH3)3
H C(CH3)3 H +
H
H H H+ H H
Rearrangements in Friedel-Crafts Alkylation
H C(CH3)3
AlCl3
+ (CH3)2CHCH2Cl
H H
+ –
•• +
H3C C CH2 Cl AlCl3 H3C C CH2
••
CH3 CH3
• –
+ ••C AlC
••
H l l3
•
H3C C+ CH2
Carbocation
Rearrangement
CH3
Reactions Related to Friedel-Crafts Alkylation
H
H2SO4
+
Cyclohexylbenzene
(65-68%)
Cyclohexene is protonated by sulfuric acid,
giving cyclohexyl cation which will be attacked
by the benzene ring
Reactions Related to Friedel-Crafts Alkylation
H
H2SO4
+
Cyclohexylbenzene
O
O
H AlCl3 CCH2CH3
+ CH3CH2CCl
+ HCl
+ •• +
CH3CH2C O •• CH3CH2C O ••
Step 1: attack of the acyl cation on π-electron system
of aromatic ring
O
O
CCH2CH3
H H + H H CCH2CH3
H H H +
H
H H H H
AlCl3
+ HCl
Acid Anhydrides
Acetophenone
(76-83%)
+ CH3COH
12.8
Acylation-Reduction
Acylation-Reduction
O O
H CR
RCCl
AlCl3 Zn(Hg), HCl
CH2R
Clemmensen reduction
Acylation-Reduction
O O
H CR
RCCl
AlCl3 H2NNH2, KOH,
glycol, heat
CH2R
Wolff-Kishner reduction
Example: Preparation of isobutylbenzene
CH2CH(CH3)2 ?
(CH3)2CHCH2Cl
AlCl3
To prevent carbocation rearrangement,
acylation followed by reduction are C(CH3)3
best sequences to prepare alkylbenzenes
Use Acylation-Reduction Instead
+ (CH3)2CHCCl
HCl
O
CCH(CH3)2
Rate and Regioselectivity in
Electrophilic Aromatic Substitution
- Rate of EAS
- Regioselectivity of EAS
G
E+
Effect on Rate
A methyl group is an
activating substituent.
Trifluoromethyl Group
(Trifluoromethyl)benzene
CF3
undergoes nitration 40,000
times more slowly than benzene .
A trifluoromethyl group is a
deactivating substituent.
Interpretation
Increasing reactivity
Effect on Regioselectivity
NO2
HNO3
+ +
acetic
NO2
anhydride
NO2
34% 3% 63%
o- and p-nitrotoluene together comprise 97%
of the product
a methyl group is an ortho-para director
Nitration of (Trifluoromethyl)benzene
NO2
HNO3
+ +
H2SO4
NO2
NO2
6% 91% 3%
m-nitro(trifluoromethyl)benzene comprises
91% of the product
a trifluoromethyl group is a meta director
Summary of EAS features
H H H
this resonance
form is a
tertiary
carbocation
para Nitration of Toluene
H H H H H + H
NO2 NO2 NO2
H H H
all the resonance forms have their positive
charge on a secondary carbon
Nitration of Toluene: Interpretation
CH3
1
1 1 42 42
1 1 2.5 2.5
1 58
All of the available ring positions in toluene are more
reactive than a single position of benzene.
A methyl group activates all of the ring positions but
the effect is greatest at the ortho and para positons.
Steric hindrance by the methyl group makes each
ortho position slightly less reactive than para.
Nitration of Toluene vs. tert-Butylbenzene
CH3
42 42 4.5 4.5
2.5 2.5 3 3
58 75
CF3
(ii)
by positive inductive effect
(donates electron towards
the benzene ring through
sigma bond)
Resonance and Inductive Effects
Positive mesomeric
effect is usually
(ii) stronger than
positive inductive
effect
Nitration of Phenol
NO2
44% 56%
Bromination of Anisole
OCH3 OCH3
Br2
acetic
acid
Br
90%
Oxygen Lone Pair Stabilizes Intermediate
•• •• ••
•• OCH •• OCH + OCH3
3 3
H H H + H H H
+
H H H H H H
H Br H Br H Br
Carbocation is stabilized
through resonance effect
from oxygen lone pair
EDGs Stabilize Intermediates for
ortho and para Substitution
•• EDG •• EDG
X
H + H + H
H
H H H H
H H X
Electron-Donating Groups (EDGs)
•• EDG
•• NH •• NHR •• NR •• NHCR
2 2
Cl Cl Cl Cl
NO2
HNO3
+ +
H2SO4 NO2
NO2
30% 1% 69%
•• Cl •• Cl
X
H + H + H
H
H H H H
H H X
—COH —COR
O
—CCl
—EWG = —NO2
—SO3H
—C N
O
+
N
O-
O
S-OH
O
C N
Nitration of Benzaldehyde
O2N
O O
HNO3
CH CH
H2SO4
Halogenation
Cl
O O
Cl2
CCl CCl
FeCl3
Disulfonation of Benzene
HO3S
SO3
SO3H
H2SO4
Bromination of Nitrobenzene
Br
Br2
NO2 NO2
Fe
60-75%
Synthesis of p-Nitrobenzoic Acid from Toluene
CO2H
CH3
CH3
HNO3 NO2
Na2Cr2O7, H2O
H2SO4 H2SO4, heat
NO2
Multiple Substituent Effects
The Simplest Case
CH3 CH3
99%
Another Straightforward Case
CH3 CH3
Br2 Br
Fe
NO2 NO2
86-90%
directing effects of substituents reinforce
each other; substitution takes place ortho
to the methyl group and meta to the nitro group
Generalization
strongly NHCH3
activating
Br2
acetic
acid
deactivating
Cl
The Simplest Case
acetic
acid
deactivating
Cl Cl
When activating effects are similar...
CH3 CH3
HNO3 NO2
H2SO4
C(CH3)3 C(CH3)3
CH3
HNO3
H2SO4
CH3
Steric effects control regioselectivity when
electronic effects are similar
HNO3 NO2
H2SO4
CH3 CH3 CH3
0%
NO2
Steric hindrance of
98%
2 CH3 groups prevent
the formation of that
isomer
Identify the product(s) from bromination reaction
of the following compounds
Use
Predict the product from the following reaction
Meta director
o,p
Ortho-para director
Classification of Substituents
+1
-1
+1-3=-2
-1 -1
Replace methyl by
methoxy
Applications
Replace methyl by
methoxy +3
-1 +3-3=0
-1 -1
Replace methyl by
methoxy
Applications
-3
-2
-3
-2
Both groups are meta directors
Electrostatic Potential Map of Benzene Derivatives
Br
O
CCH3
Br
Which substituent
should be
introduced first?
CCH3
Synthesis of m-Bromoacetophenone
Br para
CCH3 meta
Synthesis of m-Bromoacetophenone
O
O
CH3CCl
CCH3
AlCl3
Br2
AlCl3
Br
O
CCH3
Factors to Consider
The presence of +
will make it very
strongly
deactivation group
O2N
O
CCH3
NO2
Which substituent
should be
introduced first?
CCH3
Synthesis of m-Nitroacetophenone
NO2
Which substituent
should be
introduced first?
CCH3
Synthesis of m-Nitroacetophenone
NO2
CCH3
Synthesis of m-Nitroacetophenone
O2N
O
CCH3
O O
HNO3
CH3COCCH3 H2SO4
O
AlCl3 CCH3
Factors to Consider
CH3 CO2H
NO2
Two reactions are required:
1- oxidation of methyl group to carboxylic acid
2- nitration reaction
CH3
oxidation gives
p-nitrobenzoic
acid
NO2
Synthesis of p-Nitrobenzoic Acid from Toluene
CO2H
CH3
CH3
HNO3 NO2
Na2Cr2O7, H2O
H2SO4 H2SO4, heat
NO2
Synthesis Applications
Design the synthesis of m-Nitrobenzoic acid
Route
1
Synthesis of m-Nitrobenzoic acid
Route
2
Which synthetic route is better
Problem
❖ Difficult to get o-product without getting p-
product
❖ Over nitration (introduction of additional nitro
group)
Protected amino group
Solution
❖ Use of amide group to deactivate amino group
❖ Use of a –SO3H blocking group at the p-position
which can be removed later in acidic medium
Protected amino group
Propose a plausible synthesis for each of the following transformations
1- Br2
2- HNO3/H2SO4 1- HNO3/H2SO4
2- Br2
1- KMnO4 1- H2SO4/SO3
2- HNO3/H2SO4 2- HNO3/H2SO4
3- KMnO4
4- H+/H2O
Each of the following syntheses will not produce the desired
product. In each case, identify the flaw in the synthesis
Strategy:
1- Analyze what groups are required : nitro, carboxylic acid and propyl
2- Identify the reactions required to introduce these groups
3- Identify the reaction orders on the basis of groups position
Design a synthesis of each compound starting from benzene
Strategy:
1- Analyze what groups are required : nitro, carboxylic acid and propyl
2- Identify the reactions required to introduce these groups
3- Identify the reaction orders on the basis of groups position
Alkylation + oxidation
Acylation + reduction
Nitration
Design a synthesis of each compound starting from benzene