Chapter 22
Reaction of
Benzene and
its Derivatives
22-1
Reactions of Benzene
 Substitution
at a ring carbon.
Hal oge n ati on :
H + Cl 2
Fe Cl 3
Cl + HCl
C h l orobe n ze n e
Contrast to radical
mechanism for
benzylic hyrdogens
Ni trati on:
H + HN O 3
H2 SO 4
N O2 + H2 O
Ni trobe n z e n e
22-2
Reactions of Benzene
S u lfon ati on :
H + SO 3
H2 SO 4
SO 3 H
Be n z en e s u lfon ic acid
Al k yl ati on :Friedel Crafts
H + RX
A lX3
R + HX
An al k ylbe n z en e
Acylati on :Friedel Crafts
O
A lX3
H + RCX
O
CR + HX
An acylbe n z e ne
22-3
Electrophilic Aromatic Substitution
 Electrophilic
H
aromatic substitution:
+
+ E
 We
E
+
+ H
study several common electrophiles
• how each is generated.
• the mechanism by which each replaces hydrogen.
22-4
EAS: General Mechanism
A
general mechanism
Step 1:
H +
+
E
Electrophile
+
Step 2:
H
fast
s low , rate
determin ing
+
H
E
Res on ance-s tabilized
cation intermed iate
+
E + H
E
 General
question: What are the electrophiles and
how are they generated? Look at particular
reactions.
22-5
Chlorination
Step 1: Generation of the electrophile: a chloronium ion.
Cl Cl
+
Cl
Fe Cl
Cl
+
Cl
Cl
Cl Fe Cl
+
Cl Fe Cl 4
Cl
An i on pair
C h l ori n e Fe rri c ch l ori de A m ole cu lar comple x
(a Le wis
(a Le wis
wi th a pos i ti ve ch arge con tain i n g a
ch loron i u m ion
base )
aci d)
on ch lorin e
Step 2: Attack of the chloronium ion on the ring.
+ Cl
slow , rate
determining
+
H
H
H
+
Cl
Cl
+ Cl
Resonan ce-stab ilized cation in termediate; th e positive
charge is delocalized onto three atoms of the ring22-6
Chlorination
Step 3: Proton ejection regenerates the aromatic
character of the ring.
+
H
+
Cl-FeCl3
fast
Cl + HCl + FeCl3
Cl
Cation
intermediate
Chlorobenzene
22-7
Addition vs Substitution
 Energy
diagram for the bromination of benzene.
22-8
Nitration (Nitric and Sulfuric Acids)
 Generation
of the nitronium ion, NO2+
• Step 1: Proton transfer to nitric acid.
O
HSO3 O H + H O N
O
S u lfu ric
aci d
H
HSO4 +
Ni tric
aci d
O
O N
H
O
C on jugate aci d
of n itri c acid
• Step 2: Loss of H2O gives the nitronium ion, a very
strong electrophile. Dehydrated nitric acid.
H
H
O
O N
O
H
H
O
+ O N O
Th e n itroni u m
i on
22-9
Nitration,
Attack of electrophile as before…..
Step 1: Attack of the nitronium ion) on the aromatic ring.
H
+
+ O N O
NO2
+
H
NO2
H
+
NO2
+
Re s onance -s tabil i ze d cati on i nte rme diate
Step 2: Proton transfer regenerates the aromatic ring.
H
H
O
H
+
NO2
+
NO2
+
H
O H
H
22-10
Synthesis, Nitro  Amines
 The
nitro group can be reduced to a 1° amino
group.
COOH
+ 3 H2
NO2
4-N itroben zoic acid
COOH
Ni
(3 atm)
+ 2 H2 O
NH2
4-Aminoben zoic acid
Notice the carboxylic was untouched.
22-11
Sulfonation
 Carried
out using concentrated sulfuric acid
containing dissolved sulfur trioxide.
+ SO 3
Be n z en e
H2 SO 4
SO 3 H
Be n z en e s u lfon i c aci d
22-12
Friedel-Crafts Alkylation
 Friedel-Crafts
alkylation forms a new C-C bond
between an aromatic ring and an alkyl group.
+
Benzene
Cl
AlCl3
+ HCl
2-Chloropropane
Cumene
(Isopropyl chloride) (Isopropylbenzene)
22-13
Friedel-Crafts Alkylation
Step 1: Formation of an alkyl cation as an ion pair.
R Cl
+
Cl
Al Cl
Cl
R Cl Al Cl
Cl
Cl
A molecular
comp lex
+
R+ AlCl4 A n ion pair contain ing
a carbocation
Step 2: Attack of the alkyl cation.
+
+
R+
H
R
+
H
R
H
+
R
A re s onance-s tabil iz e d cati on
Step 3: Proton transfer regenerates the aromatic ring.
H
R
+ Cl AlCl3
R + AlCl3 + HCl
22-14
Friedel-Crafts Alkylation
 There
are four major limitations on Friedel-Crafts
alkylations:
1. Carbocation rearrangements are common
Cl
+
Be n z en e
Isobu tyl
ch loride
CH3
CH3 CHCH2 -Cl
+ AlCl3
Isobutyl ch loride
A lCl 3
+ HCl
tert- Bu tyl ben z e n e
CH3
+
CH3 C-CH2 -Cl-AlCl3
H
a molecu lar
complex
CH3
+
CH3 C
AlCl4
-
CH3
an ion pair
22-15
Friedel-Crafts Alkylation
2. F-C alkylation fails on benzene rings bearing one or
more of these strongly electron-withdrawing groups.
Y
+ RX
AlCl3
N o reacti on
Wh en Y Equ als A n y of Th es e G rou p s, th e Ben ze n e
Ri ng D oe s N o t U n d ergo Fri ed el -Crafts A lk ylation
O
CH
O
CR
SO3 H
C N
CF3
CCl3
O
COH
NO2
O
COR
NR3
O
CNH2
+
22-16
Friedel-Crafts Alkylation
3. F-C multiple alkylation can occur more rapidly than
monoalkylation. The first alkyl group activates the ring
to the second substitution.
4. The steps in the Friedel Crafts Alkylation are reversible
and rearrangments may occur.
22-17
Friedel-Crafts Acylation
 Friedel-Crafts
acylation forms a new C-C bond
between a benzene ring and an acyl group.
O
O
+ CH3 CCl
Benzen e
AlCl3
Acetyl
ch loride
Cl
+ HCl
Acetop henone
O
O
AlCl3
4-Phenylbutan oyl
chlorid e
+ HCl
-Tetralon e
22-18
Friedel-Crafts Acylation
 The
electrophile is an acylium ion.
••
O
••
R-C Cl
••
An acyl
ch loride
Cl
(1)
+ Al-Cl
Cl
Al u min u m
ch loride
O + Cl
(2)
••
R-C Cl Al Cl
••
Cl
A m ole cul ar com pl e x
wi th a pos itive ch arge
ch arge on ch lorin e
O
R-C+ AlCl4A n i on pair
con tain i n g an
acyl iu m ion
22-19
Friedel-Crafts Acylation
• An acylium ion is represented as a resonance hybrid
of two major contributing structures.
O:
:
+
R-C
com ple te val e n ce
s h el l s
+
R-C O:
Th e m ore i mportan t
con tribu ti n g s tru ctu re
 Friedel-Crafts
acylations are free of major
limitation of Friedel-Crafts alkylations; acylium
ions do not rearrange, do not polyacylate (why?),
do not rearrange.
22-20
Synthesis, Friedel-Crafts Acylation
 preparation
of unrearranged alkylbenzenes.
O
+ Cl
A lCl 3
2-Meth ylpropan oyl
ch loride
O
N 2 H 4 , KOH
die th yl e n e
gl ycol
2-Meth yl-1Isobu tyl be n z e n e
ph e nyl -1-propanon e
What else could be
used here?
22-21
Other Aromatic Alkylations
 Carbocations
are generated by
• treatment of an alkene with a proton acid, most
commonly H2SO4, H3PO4, or HF/BF3.
+
Benzene
CH3 CH=CH2
H3 PO4
Propene
Cumene
• treating an alkene with a Lewis acid.
+
AlCl 3
Be nz ene Cyclohe xe ne
Phe nyl cycl ohe xane
22-22
Other Aromatic Alkylations
• and by treating an alcohol with H2SO4 or H3PO4.
+
HO
H3 PO 4
Be n z en e 2-Me th yl-2-propan ol
(tert- Bu tyl al coh ol)
+ H2 O
2-Me th yl-2ph e n yl propan e
(tert- Bu tyl be nz e n e )
22-23
Di- and Polysubstitution
 Orientation
on nitration of monosubstituted
benzenes.
Su bstitu ent ortho
Favor
ortho/para
substitution
Favor meta
substitution
meta
-
para
ortho +
p ara
meta
55
38
99
96
trace
4
30
100
trace
OCH3
CH3
44
58
Cl
70
4
-
Br
37
1
62
99
1
COOH
18
80
2
20
80
CN
NO2
19
6.4
80
93.2
1
0.3
20
6.7
80
93.2
22-24
Directivity of substituents
22-25
Di- and Polysubstitution
 Two
ways to characterize the substituent
• Orientation:
• Some substituents direct preferentially to ortho & para
positions; others to meta positions.
• Substituents are classified as either ortho-para directing or
meta directing toward further substitution.
• Rate
• Some substituents cause the rate of a second substitution to be
greater than that for benzene itself; others cause the rate to be
lower.
• Substituents are classified as activating or deactivating toward
further substitution.
22-26
Di- and Polysubstitution
• -OCH3 is ortho-para directing.
OCH3
OCH3
OCH3
NO2
+ HNO3
+
CH 3 COOH
An isole
o-N itroanis ole
(44%)
+ H2 O
NO2
p-N itroanis ole
(55%)
• -COOH is meta directing.
COOH
+ HNO3
Ben zoic
acid
H2 SO4
COOH
NO2
COOH
+
100°C
COOH
+
NO2
o-N itroben zoic
acid
(18%)
m-N itroben zoic
acid
(80%)
NO2
p-N itrobenzoic
acid
(2%) 22-27
:
O
O
:
:
N HCAr
OCR
I:
:
Br :
:
Cl :
:
:
F:
O
O
O
O
CH
O
CR
COH
COR
N O2
OCAr
Recall the polysubstitution in
FC alkylation.
R
CNH 2
O
:
:
:
N HCR
:
Meta Directing
:
O
:
:
OR
:
S tron gly
de activati n g
OH
:
Mode rate ly
de activati n g
N R2
:
W eak l y
de activati n g
N HR
:
W eak l y
acti vatin g
N H2
:
Mode rate ly
acti vatin g
:
S tron gly
acti vatin g
:
Ortho-para D irecting
Di- and Polysubstitution
SO 3 H
N H3
+
C N
CF3
CCl3
22-28
Di- and Polysubstitution
 Generalizations:
• Directivity: Alkyl, phenyl, and all substituents in which
the atom bonded to the ring has an unshared pair of
electrons are ortho-para directing. All other
substituents are meta directing.
• Activation: All ortho-para directing groups except the
halogens are activating toward further substitution.
The halogens are weakly deactivating.
22-29
Di- and Polysubstitution
• The order of steps is important.
CH 3
COOH
HNO3
K2 Cr2 O7
H2 SO4
H 2 SO4
CH 3
NO2
NO2
p-N itroben zoic
acid
COOH
COOH
K2 Cr2 O7
HNO3
H2 SO4
H2 SO4
NO2
m-N itroben zoic
acid
22-30
Theory of Directing Effects
 The
rate of EAS is limited by the slowest step in
the reaction.
 For almost every EAS, the rate-determining step
is attack of E+ on the aromatic ring to give a
resonance-stabilized cation intermediate.
 The more stable this cation intermediate, the
faster the rate-determining step and the faster
the overall reaction.
22-31
Theory of Directing Effects
 The
orientation is controlled by the stability of
the carbocation being formed by attack of the
electrophile.
 Products
are formed under kinetic control.
22-32
Theory of Directing Effects, ortho-para director.
• -OCH3: assume ortho-para attack. Here only para
attack is shown.
o,p director
OCH3
OCH3
slow
+ N O2 +
:
:
:OCH3
:
:
+
:OCH3
OCH3
: OCH3
+
N O2
(d)
fast
- H+
+
H
N O2
+
H
N O2
(e)
N O2
H
(f)
H
N O2
(g)
Very stable resonance structure. Why?
22-33
Theory of Directing Effects , ortho-para director.
• -OCH3; look at meta attack.
OCH3
o,p director
+ N O2
+
OCH3
+
H
N O2
(a)
s low
OCH3
OCH3
+
fas t
H - H+
H
N O2
(b)
+ N O2
OCH3
N O2
(c)
No corresponding resonance structure putting
positive charge on oxygen.
22-34
Theory of Directing Effects, meta director.
• -CO2H : assume ortho-para attack.
COOH
Meta director
+ NO2 + slow
COOH
COOH
COOH
COOH
fast
-H+
H NO2
(d)
H NO2
H NO2
(e)
The mos t disfavored
contribu ting structu re
NO2
(f)
Disfavored because CO2H is
electron withdrawing
22-35
Theory of Directing Effects, meta director.
• -CO2H; assume meta attack.
COOH
Meta director
+ NO2
+
slow
COOH
(a)
COOH
H
H
NO2
NO2
(b)
COOH
COOH
H
NO2
fast
+
-H
NO2
(c)
22-36
Activating-Deactivating Resonance Effects
 Any
resonance effect, such as that of -NH2, -OH,
and -OR, that delocalizes the positive charge on
the cation by has an activating effect toward
further EAS.
 Any
resonance effect, such as that of -NO2, -CN, C=O, and -SO3H, that decreases electron density
on the ring deactivates the ring toward further
EAS.
22-37
Activating-Deactivating Inductive Effects
 Any
inductive effect, such as that of -CH3 or
other alkyl group, that releases electron density
toward the ring activates the ring toward further
EAS.
 Any
inductive effect, such as that of halogen,
-NR3+, -CCl3, or -CF3, that decreases electron
density on the ring deactivates the ring toward
further EAS.
22-38
Activating-Deactivating: Halogens
• For the halogens, the inductive and resonance effects
oppose each other. Inductive is somewhat stronger.
• Result: halogens are deactivating but ortho-para
directing.
:Cl
+
H
E
+
:Cl
:
+ E
: :
: :
:Cl
+
H
E
22-39
Nucleophilic Aromatic Substitution
 Aryl
halides do not undergo nucleophilic
substitution by either SN1 or SN2 pathways.
 They do undergo nucleophilic substitutions, but
by two mechanisms.
• Benzyne using strong base.
• Addition/elimination typically with nitro activating
groups.
22-40
Benzyne Intermediates
 When
heated under pressure with aqueous
NaOH, chlorobenzene is converted to sodium
phenoxide.
• Neutralization with HCl gives phenol.
-
Cl
+
O Na
+ 2NaOH
H2 O
o
pressure, 300 C
Chlorobenzene
+ NaCl + H2 O
Sodium
phenoxide
22-41
Benzyne Intermediates (strong base)
• The same reaction with 2-chlorotoluene gives a
mixture of ortho- and meta-cresol.
CH3
Cl
CH3
OH
1. NaOH, heat, pres sure
2. HCl, H2 O
CH3
+
OH
2-Methylphenol 3-Methylphenol
(o-Cresol)
(m-Cresol)
• The same type of reaction can be brought about using
sodium amide in liquid ammonia.
CH3
CH3
+ NaNH2
Cl
NH3 (l)
o
(-33 C)
CH3
+ NaCl
+
NH2
NH2
4-Methylaniline 3-Methylanilin e
(p-Toluid ine)
(m-Toluidin e)
22-42
Benzyne Intermediates
• -elimination of HX gives a benzyne intermediate, that
then adds the nucleophile to give products.
CH3
CH3
NaNH2
H
Cl
-elimin ation
A b enzyne
intermediate
22-43
Benzyne Intermediates
But wait, do we believe this crazy idea? We need some evidence….
A
B
22-44
Benzyne Intermediates
The deuterated fluoride below exchanges the D with
solvent ammonia although the deuterated bromide does
not. This indicates a relatively rapid exchange process for
the fluoro compound.
C
next
22-45
Benzyne Intermediates
explanation
22-46
Orientation
 The
methyl group is essentially just a marker to
allow the observation of the mixture of products.
 Consider the methoxy group, -OCH3, stabilizing
of positive charge via resonance but also
inductively withdrawing.
 The methoxy group is not in resonance with the
negative charge of the anion, Inductive Effect
dominates. Next slide.
22-47
Benzyne Intermediates
D
Get
same
product
Explation
next
22-48
Benzyne Intermediates
explanation
22-49
Addition-Elimination (nitro groups)
• When an aryl halide contains electron-withdrawing
NO2 groups ortho and/or para to X, nucleophilic
aromatic substitution takes place readily.
-
Cl
NO2
Na2 CO3 , H2 O
+
O Na
NO2
o
100 C
NO2
1-Ch loro-2,4dinitrobenzen e
NO2
Sodiu m 2,4-din itroph enoxide
• Neutralization with HCl gives the phenol.
22-50
Meisenheimer Complex
• Reaction involves formation of reactive intermediate
called a Meisenheimer complex.
O
+N
O
Cl +
slow , rate
d eterminin g
Nu
(1 )
NO2
O
+N
O
Cl
Nu
NO2
O
fast
(2 )
+N
O
Nu + :Cl
NO2
A Meisenh eimer complex
Similar to nucleophilic subsititution on carboxylic acid
derivatives.
22-51