Chapter 12 - Reactions of Benzene - EAS
12.1
Introduction to benzene vs. alkenes
12.2
Mechanistic principles of Electrophilic Aromatic Subsitution
12.3
Nitration of benzene, reduction to aminobenzenes
12.4
Sulfonation of benzene
12.5
Halogenation of benzene
12.6
Friedel-Crafts alkylation of benzene
12.7
Friedel-Crafts alkylation of benzene
12.8
Alkylbenzenes via acylation then reduction
12.9
Rate and regioselectivity in EAS
12.10
Nitration of toluene - rate and regioselectivity
12.11
Nitration of CF3-benzene - rate and regioselectivity
12.12
Substituent effects in EAS: Activating Substituents
12.13
Substituent effects in EAS: Strongly Deactivating Substituents
12.14
Substituent effects in EAS: Halogens
12.15
Multiple substituent effects in EAS
12.16
Regioselective synthesis of disubstituted aromatic compounds
12.17
Substitution in Naphthalene
12.18
Substitution in heterocyclic aromatic compounds
Chapter 12 - Reactions of Benzene - EAS
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Introduction – Benzene vs. Alkenes
Br Br
Br
no heat
dark
Br
Br
Br
no heat
dark
no colour change
(no reaction)
Completely delocalized (6) pi system lends stability (aromatic)
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12.2 Mechanistic Principles of EAS
Alkenes react by addition
E
Y
E
E
Y
Y
Benzene reacts by substitution
E
Y
H
Y
E
-H
Y
E
Resonance-stabilized cation
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General Mechanism of EAS on Benzene
Energy diagram for EAS in benzene
Figure 12.1
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Electrophilic Aromatic Substitutions on Benzene
H
HNO3, H2SO4
NO2
H
SO3, H2SO4
SO3H
H
Br2, Fe
12.3 Nitration
12.4 Sulfonation
12.5 Halogenation
Br
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12.6 Friedel-Crafts Alkylation of Benzene
H
CH3CH2Cl
CH2CH3
AlCl3
CH3
H
C CH3
(CH3)3CCl
CH3
AlCl3
H3 C
H
Cl
CH3
CH3
C CH3
CH3
AlCl3
Problems:
Alkyl groups may rearrange during reaction
Products are more reactive than benzene
Uses:
Alkyl benzenes readily oxidized to benzoic acids using KMnO4
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12.7 Friedel-Crafts Acylation of Benzene
H
O
O
RCCl
C
R
AlCl3
O
H
H3 C
O
O
O
CCH3
CH3
AlCl3
O
RCCl
AlCl3
O
RC
R C O
Products react more slowly than benzene - cleaner reaction
No carbocation rearrangements
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12.8 Alkylbenzenes via Acylation/Reduction
O
Zn, HCl
C
(Clemmensen)
H H
C
R
R
or
NH2NH2, KOH
heat
(Wolff-Kischner)
O
Cl
AlCl3
Zn, HCl
O
Make the acyl benzene first (clean, high yielding reaction)
Reduce the ketone group down to the methylene (C=O to CH2)
Avoids rearrangement problems, better yields
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Aminobenzenes via Nitration/Reduction (not in text)
H
O
N
Sn, HCl
N
O
H
H
H
HNO3, H2SO4
NO2
Sn, HCl
N
H
Make the nitro benzene first, clean high yielding reaction
Reduce the nitro group down to the amine
Difficult to introduce the amino group by other methods
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12.9 Activation and Deactivation by Substituents (Rates)
X
X
HNO3, H2SO4
NO2
CF3
H
0.000025
1.0
CH3
25
Relative rates in nitration reaction
now bringing in a second substituent
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12.9 Nitration of Toluene vs Nitration of (Trifluoromethyl)benzene
CH3
CH3
HNO3, H2SO4
CH3
CH3
NO2
+
+
NO2
NO2
63%
3%
34%
CH3 is said to be an ortho/para director (o/p director) - Regioselectivity
CF3
CF3
HNO3, H2SO4
CF3
CF3
NO2
+
+
NO2
NO2
6%
91%
3%
CF3 is said to be a meta director (m director) - Regioselectivity
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12.10 Rate and Regioselectivity in Nitration of Toluene
CH3
CH3
HNO3, H2SO4
CH3
CH3
NO2
+
+
NO2
NO2
63%
3%
34%
Fig. 12.5 – Energy diagrams for toluene nitration (vs. benzene)
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12.11 Rate and Regioselectivity in Nitration of CF3C6H5
CF3
CF3
CF3
HNO3, H2SO4
CF3
NO2
+
+
NO2
NO2
6%
91%
Fig. 12.6 – Energy diagrams for CF3C6H5 nitration (vs. benzene)
3%
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12.12 Substituent Effects – Activating Substituents
General :
all activating groups are o/p directors
halogens are slightly deactivating but are o/p directors
strongly deactivating groups are m directors
Activating Substituents
O
R
alkyl
OCH3
Example:
RO
HO
hydroxyl
HNO3, H2SO4
RCO
alkoxy
acyloxy
OCH3
OCH3
NO2
+
NO2
Alkyl groups stabilize carbocation by hyperconjugation
Lone pairs on O (and others like N) stabilize by resonance
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12.13 Subst. Effects – Strongly Deactivating Substituents
O
O
O
HC
R C
HO C
aldehyde
ketone
carboxylic acid
Cl
O
O
C
RO C
ester
acyl chloride
O
HO S
N C
O2N
O
nitrile
sulfonic acid
NO2
nitro
NO2
Br2, Fe
Example:
Br
Second substituent goes meta by default – best carbocation
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12.14 Substituent Effects – Halogens
X
X
X = F, Cl, Br
X = F, Cl, Br
X
Reactivity (i.e. rate) is a balance between inductive effect (EW) and resonance effect
(ED) – larger Cl, Br, I do not push lone pair into pi system as well as F, O, N, which are all
first row (2p)
Example:
Cl
Cl
HNO3, H2SO4
Cl
Cl
NO2
+
+
NO2
NO2
30%
1%
69%
Regioselectivity - second substituent goes o/p – better carbocations
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12.15 Multiple Substituent Effects
CH3
O
H3C
O
NHCH3
CH3 O
O
CH3
NHCH3
Br
Br2, acetic acid
CH3
AlCl3
Cl
CH3
CH3
Cl
87%
99%
Br
Br2, Fe
NO2
CH3
CH3
CH3
NO2
CH3
NO2
HNO3, H2SO4
C(CH3)3
86%
C(CH3)3
88%
Interplay between power of directing group and size of substituents
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12.16 Regioselective Synthesis of Disubstituted Derivs.
O
O
CH3
O
CH3
CH3
Br
Br
NO2
CO2H
CH2CH3
Br
NO2
Have to be careful about when to introduce each substituent
Remember – isomers (e.g. o/p mixtures) may be separated
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12.17-12.18 Substitution in Other Aromatic Systems
12.17 Naphthalene
O
CH3
O
O
CH3CCl
CH3
but not
AlCl3
90%
12.18 Heterocycles
SO3H
SO3, H2SO4
N
HgSO4, 230 oC
O
H3C
O
N
O
O
BF3
CH3
CH3
O
O
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