Transcript Electophilic Aromatic Substituion - Towson University

Substitution Reactions of Benzene and Its Derivatives:
Electrophilic Addition/Elimination Reactions.
 Benzene is aromatic: a cyclic conjugated compound with 6 
electrons
 Reactions of benzene lead to the retention of the aromatic
core
 Electrophilic aromatic substitution replaces a proton on
benzene with another electrophile
1
Aromatic Substitutions
via the Wheland Intermediates
 All electrophile additions involve a cationic intermediate that
was first proposed by G. W. Wheland of the University of
Chicago and is often called the Wheland intermediate.
2
Bromination of Aromatic Rings
 Benzene’s  electrons participate as a Lewis base in
reactions with Lewis acids
 The product is formed by loss of a proton, which is replaced
by bromine
 FeBr3 is added as a catalyst to polarize the bromine reagent
3
Addition Intermediate in Bromination
 The addition of bromine occurs in two steps
 In the first step the  electrons act as a nucleophile toward
Br2 (in a complex with FeBr3)
 This forms a cationic addition intermediate from benzene
and a bromine cation
 The intermediate is not aromatic and therefore high in
energy
4
Formation of the Product from the Intermediate
 The cationic addition
intermediate transfers
a proton to FeBr4(from Br- and FeBr3)
 This restores
aromaticity (in contrast
with addition in
alkenes)
5
Aromatic Chlorination and Iodination
 Chlorine and iodine (but not fluorine, which is too reactive)
can produce aromatic substitution with the addition of other
reagents to promote the reaction
 Chlorination requires FeCl3
 Iodine must be oxidized to form a more powerful I+ species
(with Cu+ or peroxide)
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Aromatic Nitration and Sulfonation
7
Aromatic Nitration and Sulfonation
8
Alkylation of Aromatic Rings:
The Friedel–Crafts Reaction
 Aromatic substitution of a
R+ for H
 Aluminum chloride
promotes the formation of
the carbocation
 Only alkyl halides can be
used (F, Cl, I, Br)
 Aryl halides and vinylic
halides do not react (their
carbocations are too hard
to form)
9
Alkylation of Aromatic Rings:
The Friedel–Crafts Reaction
CH3CH2Br
AlBr3
+

CH3CH2
1.
CH3CH2
Br
+
AlBr3
HBr
+
Br
AlBr3

AlBr3
2.

CH3CH2
Br

AlBr3
CH2CH3
H
+ AlBr4
10
Multiple alkylations can occur because the
first alkylation is activating
11
Carbocation Rearrangements During Alkylation
12
Carbocation Rearrangements During Alkylation
13
Acylation of Aromatic Rings
 Reaction of an acid chloride (RCOCl) and an
aromatic ring in the presence of AlCl3 introduces
acyl group, COR
14
Mechanism of Friedel-Crafts Acylation
15
Reduction of Aryl Alkyl Ketones Allows Synthesis
of Non-rearranged Alkyl Benzenes.
 Aromatic ring activates neighboring carbonyl group toward
reduction.
 Ketone is converted into an alkylbenzene by catalytic
hydrogenation over Pd catalyst, or Wolff-Kishner or Clemensen
reductions.
16
Reduction of Aryl Alkyl Ketones Allows Synthesis
of Non-rearranged Alkyl Benzenes.
CH3
C
CH3
CH3
O
H3C
C
+
H3C
Cl
C
CH3
C
CH3
AlCl3
C
CH3
CH3
O
Zn/Hg + HCl
CH3
C
CH3
CH3
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Summary of reduction nucleophiles in 1,2-additions
to aromatic C=O groups.
Nucleophile
Reaction Conditions
Reaction mode
(Purpose)
N2H4
1. N 2H4 / H3O+
2. OH - / DMSO
Intermolecular 1,2-addition
(Wolff-Kishner reduction of
aldehyde s, ketones;
synthe sis of hyd razones, alkane s
and alkyl benzene s)
H2
H2 / (Me/C)
Me = Pd, Pt, Ni
Intermolecular 1,2-addition
(reduction of aldehyde s,
ketones and esters;
synthe sis of alcohols
and alkane s)
H2
Zn/Hg amalgam
in HCl
Clemensen Reduction
(reduction of aryl ketones to
alkyl aromatic compound s)
and d eriva t ives
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Substituent Effects in Aromatic Rings
 Substituents can cause a compound to be (much) more or (much)
less reactive than benzene and affect the orientation of the
reaction.
 There substituents are: ortho- and para-directing activators,
ortho- and para-directing deactivators, and meta-directing
deactivators.
19
Summary Table:
Effect of Substituents in Aromatic Substitution
20
The Explanation of Substituent Effects
 Activating groups
donate electrons to
the ring, stabilizing
the Wheland
intermediate
(carbocation).
 Deactivating
groups withdraw
electrons from the
ring, destabilizing
the Wheland
intermediate.
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Origins of Substituent Effects: Inductive Effects
 The overall effect of a substituent is defined by the interplay of inductive effects
and resonance effects.
 Inductive effect - withdrawal or donation of electrons through s bonds.
 Controlled by electronegativity and the polarity of bonds in functional groups,
i.e. halogens, C=O, CN, and NO2 withdraw electrons through s bond connected
to ring.
 Alkyl group inductive effect is to donate electrons.
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Origins of Substituent Effects: Resonance Effects
 Resonance effect - withdrawal or donation of electrons through a 
bond due to the overlap of a p orbital on the substituent with a p
orbital on the aromatic ring.
 C=O, CN, and NO2 substituents withdraw electrons from the aromatic
ring by resonance, i.e. the  electrons flow from the rings to the
substituents.
23
Origins of Substituent Effects: Resonance Effects
 Resonance effect - withdrawal or donation of electrons through a 
bond due to the overlap of a p orbital on the substituent with a p
orbital on the aromatic ring.
 Halogen, OH, alkoxyl (OR), and amino substituents donate electrons,
i.e. the  electrons flow from the substituents to the ring.
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N
NH2
C
Br
N
Br
C
Br
OH
H
H
Br
Br
Br
O
O
25
Ortho- and Para-Directing
Activators: Alkyl Groups
26
Ortho- and Para-Directing Activators:
OH and NH2
27
Ortho- and Para-Directing
Deactivators: Halogens
28
Meta-Directing Deactivators
 Inductive and resonance effects reinforce each other.
 Ortho and para intermediates destabilized by deactivation of
the carbocation intermediate
29
Disubstituted Benzenes:
Additivity of Effects
 If the directing effects of the two groups are the same, the
result is additive.
30
Disubstituted Benzenes:
Opposition of Effects
 If the directing effects of the two groups are different, the more powerful
activating group decides the principal outcome. Usually the mixture of
products results.
31
Linked Benzenes:
Opposition of Effects
O
CH3Br / AlBr3
N
H
O
N
H
32
Diazonium Salts: The Sandmeyer Reaction
 Primary arylamines react with HNO2, yielding stable
arenediazonium salts.
 The N2 group can be replaced by a nucleophile.
33
Reactions of Arenediazonium Salts Allow
Formation of “Impossibly” Substituted Aromatic
Rings.
 Typical synthetid sequence consists of:
 (1) nitration, (2) reduction, (3) diazotization, and (4) nucleophilic
substitution
34
Preparation of Aryl Halides
 Reaction of an arenediazonium salt with CuCl or CuBr gives
aryl halides (Sandmeyer Reaction).
 Aryl iodides form from reaction with NaI without a copper(I)
salt.
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Br
?
X = Br, I, F
X
O
N
O
O
N
O
Br2 / AlBr3
BF4NO2
Br
NH2
Fe / HCl
+N Cl2
KNO2 / HCl
Br
HBr/ CuCN
Br
Br
I
NaI
HBF4
Br
F
36
Br
Br
Preparation of Aryl Nitriles and
Carboxylic Acids
 An arenediazonium salt and CuCN yield the nitrile, ArCN, which can be
hydrolyzed to ArCOOH.
O
KMnO4
OH
O
OH
CH3Br / AlBr3
37
O
OH
?
O
N
BF4NO2
O
O
O
CH3Br / AlBr3
H2N
Fe / HCl
N
O
KNO2 / HCl
KCN / CuCN
OH
H3O+
38
Reduction to a CH aromatic bond
 By treatment of a diazonium salt with hypophosphorous acid, H3PO2
39
Reduction via diazonium salts
X
Br
Br
H3PO2
0ЎC or RT
Br
N2 Cl
Br
NH2
NO2
Br
KNO2
Br2
0ЎC/H2O
HCl, 0ЎC
Br
Br
Br
NH2
Br
Br
Br
Fe
HCl
Br
40
Preparation of complex phenols
v.s.
CO2H
CO2CH3
OH
OH
from
phenol
CO2CH3
CO2CH3
CO2CH3
OH
Fe
HCl
NO2 BF4
meta
NO2
meta
NH2
KNO2
NaOH
CO2
OH
CO2CH3
HCl, 0ЎC
CO2CH3
CO2H
H3O+
OH
N2 Cl
41