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WK15 Chapter 22 Benzos
WK15 Chapter 22 Benzos
WK15 Chapter 22 Benzos
Reactions of
Benzene &
Its Derivatives
Chapter 22 1
Reactions of Benzene
The most characteristic reaction of
aromatic compounds is substitution at
a ring carbon:
Halogenation:
Fe Cl 3
H + Cl 2 Cl + HCl
Chlorobenzene
Nitration:
H2 SO 4
H + HN O 3 N O2 + H2 O
Nitrobenzene
2
Organic Lecture Series
Reactions of Benzene
Sulfonation:
H2 SO4
H + SO3 SO3 H
Benzenesulfonic acid
Alkylation:
A lX 3
H + RX R + HX
An alkylbenzene
Acylation:
O O
A lX 3
H + RC X CR + HX
An acylbenzene
3
R
R Cl
AlCl3
Arenes Alkylbenzenes
4
Organic Lecture Series
• In this section:
– several common types of electrophiles
– how each is generated
– the mechanism by which each replaces
hydrogen
5
+
+
Chlorination
+
H - f ast
+ Cl-FeCl3 Cl + HCl + FeCl3
Cl
Cation Chlorobenzene
intermediate
Bromination
F eBr3
H + Br 2 Br + HBr
Bromobenzene
10
Organic Lecture Series
11
Nitration
• Generation of the nitronium ion, NO2+
– Step 1: proton transfer to nitric acid
O H O
HSO3 O H + H O N HSO4 + O N
O H O
Sulfuric N itric Conju gate acid
acid pKa= -3 acid pKa= -1.4 of nitric acid
H NO2 NO2
H H
O + + + O H
H H
13
COOH COOH
Ni
+ 3 H2 + 2 H2 O
(3 atm)
NO2 NH2
4-N itroben zoic acid 4-Aminoben zoic acid
14
Organic Lecture Series
Sulfonation
H2 SO4
+ SO3 SO3 H
Friedel-Crafts Alkylation
AlCl3
+ Cl + HCl
H
+ Cl AlCl3 R + AlCl3 + HCl
R
17
AlCl3
+ Cl + HCl
18
Organic Lecture Series
Friedel-Crafts Alkylation
2. F-C alkylation fails on benzene rings bearing
one or more of these strongly electron-
withdrawing groups
Y
AlCl3
+ RX N o reacti on
O O O O O
CH CR COH COR CNH2
+
SO3 H C N NO2 NR3
CF3 CCl3
19
20
Organic Lecture Series
The “De-activation” of
Aromatic Systems
O
Cl O
AlCl3 + HCl
••
R -C C l + A l-C l
••
Cl
An acyl Aluminum
chloride chloride
O Cl O
+ - (2)
•• + -
R -C Cl Al Cl R -C A lC l 4
••
Cl
A molecular complex A n ion pair
with a positive charge containing an
charge on chlorine acylium ion
23
complete valence
shells
+ +
R-C O: R-C O:
:
2-Methylpropanoyl
chloride
O
N 2 H 4 , KOH
diethylene
2-Methyl-1- glycol Isobutylbenzene
phenyl-1-propanone
25
Only a trace
26
Organic Lecture Series
ortho +
Su bstitu ent ortho meta para p ara meta
OCH3 44 - 55 99 trace
CH3 58 4 38 96 4
Cl 70 - 30 100 trace
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
• 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
Organic Lecture Series
Di- and Polysubstitution
• 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
30
Di- and Polysubstitution Organic Lecture Series
:
:
activating N H2 N HR N R2 OH OR
Ortho-para Directing
:
:
O O O O
Moderately
:
:
:
Weakly
activating R
Weakly
:
:
:
deactivating F: Cl : Br : I:
:
O O O O
Meta Directing
CH CR CO H CO R
Moderately
deactivating O
CNH 2 SO 3 H C N
Strongly +
deactivating N O2 N H3 C F3 C C l3
32
Di- and Polysubstitution Organic Lecture Series
COOH COOH
K2 Cr2 O7 HNO3
H2 SO4 H2 SO4
NO2
m-N itroben zoic
acid
33
OCH3
slow
+ N O2 +
36
Organic Lecture Series
Nitration of anisole
-OCH3: examine the ortho-para attack:
OCH3 OCH3
slow
+ N O2 +
+ N O2
:
:
:
:
:OCH3 :OCH3 OCH3 : OCH3
fast
+ - H+
+ +
H N O2 H N O2 H N O2 H N O2
(d) (e) (f) (g)
fast
H H H -H+
NO2
NO2 NO2 NO2
(a) (b) (c)
38
Organic Lecture Series
Nitration of benzoic acid
COOH
+ NO2
+ slow
fast
+
-H
H NO2 H NO2 H NO2 NO2
(d) (e) (f)
The mos t disfavored
contribu ting structu re
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
H + H
: :
: :
+
:Cl + E :Cl + :Cl
E
:
E
43
:
:
activating N H2 N HR N R2 OH OR
Ortho-para Directing
:
:
O O O O
Moderately
:
:
:
Weakly
activating R
Weakly
:
:
:
deactivating F: Cl : Br : I:
:
O O O O
Meta Directing
CH CR CO H CO R
Moderately
deactivating O
CNH 2 SO 3 H C N
Strongly +
deactivating N O2 N H3 C F3 C C l3
44
Organic Lecture Series
Medicinal Chemistry
Benzodiazepins
1) Sedative-hypnotic
2) Anticonvulsant
3) Muscle relaxant
Valium
® 4) Anxiolytic
45
NH2
N O
Cl Cl
Friedel-Crafts
Acylation
H3C
O
NH2 N
O
X
Cl
Cl Cl
46
Organic Lecture Series
Medicinal Chemistry
NO2 NH2
Cl2 HNO3 H2
FeCl3 H2SO4 Pt or Pd
Cl Cl Cl
Separate o from p
47
Cl N
Cl
Cl
48
Organic Lecture Series
Medicinal Chemistry
O
H3C
H3C O
N CH3 N
O
Cl O
Cl
AlCl3
Cl
49
Cl
O
Cl 1) NaOH O
Cl
2) O
Cl
Cl
NH3
H3C
H3C O
O
N
N
NH2
O N
Cl loss H2O Cl
formation
of imine
50
Medicinal Chemistry
Organic Lecture Series
Chlorpromazine
treatment of schizophrenia and (Thorazine)
acute psychotic states and
delirium.
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
Medicinal Chemistry
Organic Lecture Series
52
Medicinal Chemistry
Organic Lecture Series
O O O
O O 1) LiAlH 4 O
NH 3 NH 2
CONH 2
COCl 2) H 3O +
F F
F
53
Medicinal Chemistry
Organic Lecture Series
Michael Reaction in Context
O 2 eq CO 2CH3
O CO2CH 3 O O
NH 2 N
CO2 CH 3
F F
54
Medicinal Chemistry
Organic Lecture Series
O
CO 2CH3 NaOCH3 O O
O O N
N CO 2CH3
CO2 CH 3 CH 3OH
F
F
55
Medicinal Chemistry
Organic Lecture Series
O 1) NaOH O
O 2) H3O+ O
O O
N 3) Δ N
CO 2CH3
F F
56
Medicinal Chemistry
Organic Lecture Series
OH
O
O
O N Cl
O 1) Cl MgBr
N
F
2) H 3O +
F
Haloperidol
57
NH3
O O
O O
NH2 1) LiAlH4
CONH2
2) H3O+
F
F
2 eq CO2CH3
O
CO2CH3 NaOCH3 O O
O O N
N CO2CH3
CO2CH3 CH3OH
F
F
1) NaOH
2) H3O+
3)
O
OH
O O
O 1) Cl MgBr N
N Cl
2) H3O+
Haloperidol
F 58
F