Organic Lecture Series
Reactions of
Benzene &
Its Derivatives
Chapter 22
1
Organic Lecture Series
Reactions of Benzene
The most characteristic reaction of
aromatic compounds is substitution at
a ring carbon:
Halogenation:
H + Cl 2
Fe Cl 3
Cl + HCl
Chlorobenzene
Nitration:
H + HN O 3
H2 SO 4
N O2 + H2 O
Nitrobenzene
2
Organic Lecture Series
Reactions of Benzene
Sulfonation:
H + SO3
H2 SO4
SO3 H
Benzenesulfonic acid
Alkylation:
H
+
RX
A lX 3
R
+
HX
An alkylbenzene
Acylation:
O
H
+
O
A lX 3
RC X
CR + HX
An acylbenzene
3
Organic Lecture Series
Carbon-Carbon Bond Formations:
R
R
Cl
AlCl3
Arenes
Alkylbenzenes
4
Organic Lecture Series
Electrophilic Aromatic Substitution
• Electrophilic aromatic substitution: a
reaction in which a hydrogen atom of an
aromatic ring is replaced by an
electrophile
H
E
+
+ E
+ H+
• In this section:
– several common types of electrophiles
– how each is generated
– the mechanism by which each replaces
hydrogen
5
Organic Lecture Series
EAS: General Mechanism
• A general mechanism
+
H + E
Step 1:
Electrophile
+
Step 2:
H
fast
s low , rate
determin ing
+
H
E
Res on ance-s tabilized
cation intermed iate
+
E + H
E
• Key question: What is the electrophile and
how is it generated?
6
Organic Lecture Series
+
+
7
Organic Lecture Series
Chlorination
Step 1: formation of a chloronium ion
Cl
Cl
+
Cl
Fe Cl
Cl
+
Cl
Chlorin e Ferric chloride
(a Lew is
(a Lew is
bas e)
acid )
Cl
+
-
Cl
Cl Fe Cl
Cl
A molecular comp lex
w ith a positive ch arge
on ch lorine
FeCl4 -
An ion p air
contain ing a
ch loronium ion
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 ring 8
Organic Lecture Series
Chlorination
Step 3: proton transfer regenerates
the aromatic character of the ring
+
H
+
Cl-FeCl3
Cl
Cation
intermediate
f ast
Cl
+ HCl
+ FeCl3
Chlorobenzene
9
Organic Lecture Series
Bromination
H + Br 2
F eBr3
Br + HBr
Bromobenzene
This is the general method for
Substitution of halogen onto a benzene ring
(CANNOT be halogenated by Free Radical Mechanism)
10
Organic Lecture Series
Bromination-Why not addn of Br2?
Regains Aromatic Energy
11
Organic Lecture Series
Nitration
• Generation of the nitronium ion, NO2+
– Step 1: proton transfer to nitric acid
O
HSO3 O H + H O N
O
O
O N
H
O
H
HSO4
+
Conju gate acid
of nitric acid
Sulfuric
N itric
acid pKa= -3 acid pKa= -1.4
– Step 2: loss of H2O gives the nitronium ion, a
very strong electrophile
H
H
O
O N
O
H
H
O
+ O N O
The nitronium
ion
12
Organic Lecture Series
Nitration
Step 1: attack of the nitronium ion (an electrophile) on
the aromatic ring (a nucleophile)
H
+
+
O N O
NO2
+
H
NO2
H
+
NO2
+
Resonance-stabilized cation intermediate
Step 2: proton transfer regenerates the aromatic ring
H
H
O
+
NO2
NO2
+
+
H
H
O H
H
13
Organic Lecture Series
Nitration
• A particular value of nitration is that the
nitro group can be reduced to a 1° amino
group
COOH
COOH
+ 3 H2
NO2
4-N itroben zoic acid
Ni
(3 atm)
+ 2 H2 O
NH2
4-Aminoben zoic acid
14
Organic Lecture Series
Sulfonation
• Carried out using concentrated sulfuric
acid containing dissolved sulfur trioxide
+
SO3
H2 SO4
Benzene
SO3 H
B enzenesulfonic acid
(SO3 in H2SO4 is sometimes called “fuming” sulfuric acid.)
15
Organic Lecture Series
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
(Isoprop yl chlorid e) (Isopropylbenzen e)
The electrophilic partner is a carbocation;
it will arrange to the most stable ion: allylic>3o>2o>1o
16
Friedel-Crafts Alkylation
Organic Lecture Series
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 on the aromatic ring
+
R+
+
H
H
+
R
H
R
+
R
A resonance-stabilized cation
Step 3: proton transfer regenerates the aromatic ring
H
R
R + AlCl3 + HCl
+ Cl AlCl3
17
Friedel-Crafts Alkylation
Organic Lecture Series
There are two major limitations on Friedel-Crafts
alkylations:
1. carbocation rearrangements are common:
Cl
+
Benzene
CH3
CH3 CHCH2 -Cl
Isobutyl
chloride
+ AlCl3
I sobutyl chloride
AlCl3
+ HCl
tert-Butylbenzene
CH3
+
CH3 C-CH2 -Cl-AlCl3
H
a molecular
complex
CH3
CH3 C+ AlCl4 CH3
an ion pair
18
Organic Lecture Series
Friedel-Crafts Alkylation
2. F-C alkylation fails on benzene rings bearing
one or more of these strongly electronwithdrawing 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
+
19
Organic Lecture Series
20
Organic Lecture Series
The “De-activation” of
Aromatic Systems
Note: deactivation refers to the rate of EAS
21
Friedel-Crafts Acylation
Organic Lecture Series
• 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
α-Tetralon e
22
Organic Lecture Series
Friedel-Crafts Acylation
• The electrophile is an acylium ion
O
Cl
••
••
+
R -C C l
••
An acyl
chloride
(1)
A l-C l
Cl
Aluminum
chloride
O
R -C
+
••
Cl
••
Cl
-
O
(2)
Al Cl
Cl
A molecular complex
with a positive charge
charge on chlorine
R -C
+
A lC l 4
-
A n ion pair
containing an
acylium ion
23
Friedel-Crafts Acylation
Organic Lecture Series
– an acylium ion is a resonance hybrid of two
major contributing structures
O:
:
+
R-C
complete valence
shells
+
R-C O:
The more important
contributing structure
• F-C acylations are free of a major
limitation of F-C alkylations; acylium
ions do not rearrange.
24
Friedel-Crafts Acylation
Organic Lecture Series
A special value of F-C acylations is preparation
of unrearranged alkylbenzenes:
O
+ Cl
A lCl 3
2-Methylpropanoyl
chloride
O
2-Methyl-1phenyl-1-propanone
N 2 H 4 , KOH
diethylene
glycol
Isobutylbenzene
25
Organic Lecture Series
Di- and Polysubstitution
Only a trace
26
Organic Lecture Series
Di- and Polysubstitution
Orientation on nitration of monosubstituted
benzenes:
Su bstitu ent ortho
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
19
80
1
20
80
NO2
6.4
93.2
0.3
6.7
93.2
27
Organic Lecture Series
Di- and Polysubstitution
• Orientation:
–certain 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
28
Di- and Polysubstitution
Organic Lecture Series
• Rate
–certain 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
29
Organic Lecture Series
30
Di- and Polysubstitution
Organic Lecture Series
– -OCH3 is ortho-para directing:
OCH3
OCH3
NO2
OCH3
+ HNO3
+
CH3 COOH
An isole
+ H2 O
NO2
p-N itroanis ole
(55%)
o-N itroanis ole
(44%)
– -CO2H is meta directing
COOH
+ HNO3
H2 SO4
COOH
NO2
+
NO2
o-N itroben zoic
acid
(18%)
:
OH
OR
Moderately
activating
O
N HCR
O
N HCAr
O
O CR
:
:
:
:
O
O CAr
R
+
I:
:
N H3
:
Br :
:
Cl :
:
:
N O2
:
:
Moderately
deactivating
O
O
O
CH
CR
CO H
O
SO 3 H
CNH 2
F:
:
Weakly
deactivating
Strongly
deactivating
:
:
N R2
:
:
N HR
:
:
N H2
:
Strongly
activating
Weakly
activating
31
Organic Lecture Series
:
Ortho-para Directing
NO2
p-N itrobenzoic
acid
(2%)
m-N itroben zoic
acid
(80%)
Di- and Polysubstitution
Meta Directing
COOH
+
100°C
Ben zoic
acid
COOH
O
CO R
C N
C F3
C C l3
32
Di- and Polysubstitution
Organic Lecture Series
the order of steps is important:
CH3
COOH
HNO3
K2 Cr2 O7
H2 SO4
H2 SO4
CH3
NO2
NO2
p-N itroben zoic
acid
COOH
COOH
K2 Cr2 O7
HNO3
H2 SO4
H2 SO4
NO2
m-N itroben zoic
acid
33
Organic Lecture Series
Theory of Directing Effects
• The rate of EAS is limited by the slowest
step in the reaction
• For almost every EAS, the ratedetermining step is attack of E+ on the
aromatic ring to give a resonancestabilized cation intermediate
• The more stable this cation
intermediate, the faster the ratedetermining step and the faster the
overall reaction
34
Organic Lecture Series
Theory of Directing Effects
• For ortho-para directors, ortho-para
attack forms a more stable cation
than meta attack
– ortho-para products are formed faster
than meta products
• For meta directors, meta attack forms
a more stable cation than ortho-para
attack
– meta products are formed faster than
ortho-para products
35
Theory of Directing Effects
Organic Lecture Series
Nitration of anisole
-OCH3; examine the meta attack:
OCH3
+ N O2 +
OCH3
+
H
slow
OCH3
+
H
N O2
(a)
N O2
(b)
OCH3
fast
H - H+
+ N O2
(c)
OCH3
N O2
36
Organic Lecture Series
Nitration of anisole
-OCH3: examine the ortho-para attack:
OCH3
OCH3
slow
+ N O2 +
:
:
:OCH3
:
:
+
:OCH3
OCH3
: OCH3
+
fast
- H+
+
+
N O2
H
N O2
H
(d)
N O2
H
N O2
(e)
N O2
H
(f)
(g)
This resonance structure accounts for the selectivity
37
Organic Lecture Series
Theory of Directing Effects
Nitration of benzoic acid
-NO2; examine the meta attack:
COOH
+
+ NO2 slow
COOH
(a)
COOH
H
H
H
NO2
NO2
NO2
(b)
COOH
COOH
fast
-H+
NO2
(c)
38
Nitration of benzoic acid
Organic Lecture Series
-NO2: assume ortho-para attack:
COOH
+ NO2
+
slow
COOH
COOH
COOH
COOH
fast
+
-H
H NO2
(d)
H NO2
(e)
The mos t disfavored
contribu ting structu re
H NO2
NO2
(f)
This resonance structure accounts for the selectivity
Activating-Deactivating
39
Organic Lecture Series
• Any resonance effect,
effect such as that of NH2, -OH, and -OR, that delocalizes the
positive charge on the cation intermediate
lowers the activation energy for its
formation, and has an activating effect
toward further EAS
• Any resonance effect,
effect such as that of NO2, -CN, -CO, and -SO3H, that
decreases electron density on the ring
deactivates the ring toward further EAS
40
Activating-Deactivating
Organic Lecture Series
• Any inductive effect,
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,
effect such as that of
halogen, -NR3+, -CCl3, or -CF3, that
decreases electron density on the
ring deactivates the ring toward
further EAS
41
Di- and Polysubstitution
Organic Lecture Series
• Generalizations:
– alkyl, phenyl, and all other substituents
in which the atom bonded to the ring has
an unshared pair of electrons are orthopara directing; all other substituents are
meta directing
– all ortho-para directing groups except
the halogens are activating toward
further substitution;
– the halogens are weakly deactivating
42
Organic Lecture Series
Activating-Deactivating
¾for the halogens,
halogens the inductive and
resonance effects run counter to each
other, but the former is somewhat
stronger
¾the net effect is that halogens are
deactivating but ortho-para directing
:Cl
+ E
H
+
+
H
:
: :
: :
:Cl
+
E
:Cl
E
43
OR
Moderately
activating
O
N HCR
O
N HCAr
O
O CR
:
:
:
O
O CAr
R
+
I:
:
N H3
:
Br :
:
Cl :
:
:
N O2
:
Moderately
deactivating
O
O
O
CH
CR
CO H
O
SO 3 H
CNH 2
F:
:
Weakly
deactivating
Strongly
deactivating
:
Weakly
activating
:
Meta Directing
:
OH
:
:
N R2
:
:
N HR
:
:
N H2
:
Strongly
activating
:
Ortho-para Directing
Di- and Polysubstitution
Organic Lecture Series
O
CO R
C N
C F3
C C l3
44
Organic Lecture Series
Medicinal
Chemistry
Benzodiazepins
1) Sedative-hypnotic
2) Anticonvulsant
3) Muscle relaxant
Valium
4) Anxiolytic
®
45
Organic Lecture Series
Medicinal
Chemistry
Retrosynthetic Analysis
H 3C
H 3C
O
N
O
N
NH2
Cl
N
O
Cl
Friedel-Crafts
Acylation
H3C
O
N
NH2
O
X
Cl
Cl
Cl
46
Organic Lecture Series
Medicinal
Chemistry
Short Problem Using EAS: the synthesis of p-Aminochlorobenzene
NH2
NO2
Cl2
HNO3
H2
FeCl3
H2SO4
Pt or Pd
Cl
Cl
Cl
Separate o from p
47
Organic Lecture Series
Medicinal
Chemistry
The Synthesis of the amide section:
O
H3C
NH2
NH
O
O
H3C
N
CH3
NaH
O
CH3Br
Cl
Cl
N
Cl
48
Organic Lecture Series
Medicinal
Chemistry
Friedel Crafts Acylation:
O
H3C
H3C
N
O
N
CH3
O
Cl
O
Cl
AlCl3
Cl
Amide is activating & o p directing
49
Organic Lecture Series
Medicinal
Chemistry
H3C
H3C
O
N
Cl
O
Cl
O
N
1) NaOH
2)
O
Cl
O
Cl
Cl
NH3
H3C
H3C
O
O
N
N
NH2
Cl
O
loss H2O
Cl
N
formation
of imine
50
Organic Lecture Series
Medicinal
Chemistry
treatment of schizophrenia and
acute psychotic states and
delirium.
Chlorpromazine
(Thorazine)
The introduction (1950) of chlorpromazine into
clinical use has been described as the single
greatest advance in psychiatric care,
dramatically improving the prognosis of patients
in psychiatric hospitals worldwide the availability
of antipsychotic drugs curtailed indiscriminate
use of electroconvulsive therapy and
psychosurgery, and was one of the driving
forces behind the deinstitutionalization
movement.
51
Organic Lecture Series
Medicinal
Chemistry
52
Organic Lecture Series
Medicinal
Chemistry
O
O
O
NH 3
O
CONH 2
COCl
O
1) LiAlH 4
O
NH 2
2) H 3O +
F
F
F
53
Michael Reaction in Context
O
F
O
NH 2
2 eq
CO2CH 3
O
Organic Lecture Series
Medicinal
Chemistry
O
CO 2CH3
N
CO2 CH 3
F
54
Organic Lecture Series
Medicinal
Chemistry
Dieckmann Condensation in Context
O
O
CO 2CH3
O
N
O
NaOCH3
CO2 CH 3
O
N
CH 3OH
CO 2CH3
F
F
55
Organic Lecture Series
Medicinal
Chemistry
O
O
O
N
O
1) NaOH
2) H3O+
3) Δ
O
CO 2CH3
F
O
N
F
56
Organic Lecture Series
Medicinal
Chemistry
OH
O
O
O
1) Cl
O
N
MgBr
Cl
N
F
2) H 3O +
F
Haloperidol
57
Organic Lecture Series
O
O
AlCl3
COOH
O
1) HO
O
OH / H+
O
COCl
2) SOCl2
F
F
O
F
NH3
O
O
O
NH2
CONH2
2) H3O+
F
F
2 eq
O
1) LiAlH4
CO2CH3
O
O
O
CO2CH3
N
CO2CH3
O
NaOCH3
O
N
CO2CH3
CH3OH
F
F
1) NaOH
2) H3O+
3)
O
OH
O
1) Cl
N
F
Haloperidol
MgBr
O
O
N
Cl
2) H3O+
F
58