Chapter 22-Benzos PDF

Organic Lecture Series
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
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
Carbon-Carbon Bond Formations:
R
R Cl
AlCl3
Arenes Alkylbenzenes
4
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
EAS: General Mechanism

• A general mechanism
s low , rate +
+
determin ing H
Step 1: H + E
E
Electro- Res on ance-s tabilized
phile cation intermed iate
+
H fast +
Step 2: E + H
E
• Key question: What is the electrophile and

how is it generated?
6
+
+

Chlorination
Step 1: formation of a chloronium ion
Cl +
Cl
- +
Cl Cl + Fe Cl Cl Cl Fe Cl Cl FeCl4 -
Cl Cl
Chlorin e Ferric chloride A molecular comp lex An ion p air
(a Lew is (a Lew is w ith a positive ch arge contain ing a
bas e) acid ) on ch lorine ch loronium ion
Step 2: attack of the chloronium ion on the ring

slow , rate
determining
+ Cl
+
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
Chlorination
Step 3: proton transfer regenerates

the aromatic character of the ring
+
H - f ast
+ Cl-FeCl3 Cl + HCl + FeCl3
Cl
Cation Chlorobenzene
intermediate
Bromination
F eBr3
H + Br 2 Br + HBr
Bromobenzene
This is the general method for

Substitution of halogen onto a benzene ring
(CANNOT be halogenated by Free Radical Mechanism)
10
Bromination-Why not addn of Br2?
Regains Aromatic Energy
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
– Step 2: loss of H2O gives the nitronium ion, a

very strong electrophile
O H
H
O N O + O N O
H H
O The nitronium
ion 12
Nitration
Step 1: attack of the nitronium ion (an electrophile) on
the aromatic ring (a nucleophile)
H NO2 H NO2 H NO2
+ + +
+ O N O
+
Resonance-stabilized cation intermediate
Step 2: proton transfer regenerates the aromatic ring
H NO2 NO2
H H
O + + + O H
H H
13

Nitration
• A particular value of nitration is that the

nitro group can be reduced to a 1° amino
group
COOH COOH
Ni
+ 3 H2 + 2 H2 O
(3 atm)
NO2 NH2
4-N itroben zoic acid 4-Aminoben zoic acid
14
Sulfonation
• Carried out using concentrated sulfuric

acid containing dissolved sulfur trioxide
H2 SO4
+ SO3 SO3 H
Benzene B enzenesulfonic acid
(SO3 in H2SO4 is sometimes called “fuming” sulfuric acid.)

15
Friedel-Crafts Alkylation
• Friedel-Crafts alkylation forms a new C-C

bond between an aromatic ring and an
alkyl group
AlCl3
+ Cl + HCl
Benzene 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
Step 1: formation of an alkyl cation as an ion pair
Cl Cl +
-
R Cl + Al Cl R Cl Al Cl R+ AlCl4 -
Cl Cl
A molecular A n ion pair contain ing
comp lex a carbocation
Step 2: attack of the alkyl cation on the aromatic ring

+
H H H
+ R+ +
R R R
+
A resonance-stabilized cation
Step 3: proton transfer regenerates the aromatic ring
H
+ Cl AlCl3 R + AlCl3 + HCl
R
17

There are two major limitations on Friedel-Crafts
alkylations:
1. carbocation rearrangements are common:
AlCl3
+ Cl + HCl
Benzene Isobutyl tert-Butylbenzene

chloride
CH3 CH3 + CH3

-
CH3 CHCH2 -Cl + AlCl3 CH3 C-CH2 -Cl-AlCl3 CH3 C+ AlCl4 -
H CH3
I sobutyl chloride a molecular an ion pair
complex
18
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
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 O O O O
CH CR COH COR CNH2
+
SO3 H C N NO2 NR3
CF3 CCl3
19
20
The “De-activation” of
Aromatic Systems
Note: deactivation refers to the rate of EAS

21

Friedel-Crafts Acylation
• Friedel-Crafts acylation forms a new C-C

bond between a benzene ring and an acyl
group:
O
O AlCl3
+ CH3 CCl + HCl
Benzen e Acetyl Acetop henone

ch loride
O
Cl O
AlCl3 + HCl
4-Phenylbutan oyl α-Tetralon e

chlorid e
22
• The electrophile is an acylium ion
O Cl (1)
••
••
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

– an acylium ion is a resonance hybrid of two
major contributing structures
complete valence
shells
+ +
R-C O: 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
A special value of F-C acylations is preparation

of unrearranged alkylbenzenes:
O
A lCl 3
+ Cl
2-Methylpropanoyl
chloride
O
N 2 H 4 , KOH
diethylene
2-Methyl-1- glycol Isobutylbenzene
phenyl-1-propanone
25
Di- and Polysubstitution
Only a trace
26

Orientation on nitration of monosubstituted
benzenes:
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
• 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
– -OCH3 is ortho-para directing:

OCH3 OCH3 OCH3
NO2
+ HNO3 + + H2 O
CH3 COOH
NO2
An isole o-N itroanis ole p-N itroanis ole
(44%) (55%)
– -CO2H is meta directing
COOH COOH COOH COOH
H2 SO4 NO2
+ HNO3 + +
100°C
NO2
Ben zoic NO2
acid
o-N itro- m-N itro- p-N itro-
ben zoic ben zoic benzoic
acid acid acid
(18%) (80%) (2%) 31

Strongly
:
:
:
activating N H2 N HR N R2 OH OR
Ortho-para Directing
:
:
O O O O
Moderately
:
:
:
activating N HCR N HCAr O CR O CAr

:
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
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
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
34
• 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

Nitration of anisole
-OCH3; examine the meta attack:
OCH3
slow
+ N O2 +
OCH3 OCH3 OCH3 OCH3

+ + fast
H H H - H+
N O2
N O2 N O2 + N O2
(a) (b) (c)
36
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)
This resonance structure accounts for the selectivity

37

Nitration of benzoic acid
-NO2; examine the meta attack:

COOH
+
+ NO2 slow
COOH COOH COOH COOH
fast
H H H -H+
NO2
NO2 NO2 NO2
(a) (b) (c)
38
Nitration of benzoic acid
-NO2: assume ortho-para attack:
COOH
+ NO2
+ slow
COOH COOH COOH COOH
fast
+
-H
H NO2 H NO2 H NO2 NO2
(d) (e) (f)
The mos t disfavored
contribu ting structu re
This resonance structure accounts for the selectivity 39

Activating-Deactivating
• 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,
NO2, -CN, -CO, and -SO3H, that
decreases electron density on the ring
deactivates the ring toward further EAS
40
• Any inductive effect,

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

• Generalizations:
– alkyl, phenyl, and all other 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
– all ortho-para directing groups except
the halogens are activating toward
further substitution;
– the halogens are weakly deactivating
42
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

Strongly
:
:
:
activating N H2 N HR N R2 OH OR
Ortho-para Directing
:
:
O O O O
Moderately
:
:
:
activating N HCR N HCAr O CR O CAr

:
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
Medicinal Chemistry
Benzodiazepins
1) Sedative-hypnotic
2) Anticonvulsant
3) Muscle relaxant
Valium
® 4) Anxiolytic
45

Retrosynthetic Analysis Medicinal Chemistry
H 3C H 3C
O O
N N
NH2
N O
Cl Cl
Friedel-Crafts
Acylation
H3C
O
NH2 N
O
X
Cl
Cl Cl
46
Medicinal Chemistry
Short Problem Using EAS: the synthesis of p-Aminochlorobenzene
NO2 NH2
Cl2 HNO3 H2
FeCl3 H2SO4 Pt or Pd
Cl Cl Cl
Separate o from p
47

Medicinal Chemistry
The Synthesis of the amide section:

O
H3C
NH2 NH H3C
O O N CH3
NaH
O
CH3Br
Cl N
Cl
Cl
48
Medicinal Chemistry
Friedel Crafts Acylation:
O
H3C
H3C O
N CH3 N
O
Cl O
Cl
AlCl3
Cl
Amide is activating & o p directing
49

Medicinal Chemistry
H3C
O H3C
N O
N
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
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
52
Medicinal Chemistry
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
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
Dieckmann Condensation in Context
O
CO 2CH3 NaOCH3 O O
O O N
N CO 2CH3
CO2 CH 3 CH 3OH
F
F
55
Medicinal Chemistry
O 1) NaOH O
O 2) H3O+ O
O O
N 3) Δ N
CO 2CH3
F F
56
Medicinal Chemistry
OH
O
O
O N Cl
O 1) Cl MgBr
N
F
2) H 3O +
F
Haloperidol
57

O O
O O
AlCl3 1) HO OH / H+
O COOH COCl
2) SOCl2
F
F F
O
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

Chapter 22-Benzos PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Chapter 22-Benzos PDF

Uploaded by

Copyright:

Available Formats

Organic Lecture Series

Organic Lecture Series

Organic Lecture Series

Carbon-Carbon Bond Formations:

Electrophilic Aromatic Substitution

Organic Lecture Series

EAS: General Mechanism

• Key question: What is the electrophile and

Organic Lecture Series

Step 2: attack of the chloronium ion on the ring

Step 3: proton transfer regenerates

Organic Lecture Series

This is the general method for

Bromination-Why not addn of Br2?

Regains Aromatic Energy

Organic Lecture Series

– Step 2: loss of H2O gives the nitronium ion, a

Step 2: proton transfer regenerates the aromatic ring

Organic Lecture Series

• A particular value of nitration is that the

• Carried out using concentrated sulfuric

Benzene B enzenesulfonic acid

(SO3 in H2SO4 is sometimes called “fuming” sulfuric acid.)

Organic Lecture Series

• Friedel-Crafts alkylation forms a new C-C

Benzene 2-Chloropropane Cumene

The electrophilic partner is a carbocation;

Step 2: attack of the alkyl cation on the aromatic ring

Organic Lecture Series

Benzene Isobutyl tert-Butylbenzene

CH3 CH3 + CH3

Wh en Y Equ als A n y of Th es e G rou p s, th e Ben ze n e

Organic Lecture Series

Note: deactivation refers to the rate of EAS

Organic Lecture Series

• Friedel-Crafts acylation forms a new C-C

Benzen e Acetyl Acetop henone

4-Phenylbutan oyl α-Tetralon e

Organic Lecture Series

The more important

• F-C acylations are free of a major

A special value of F-C acylations is preparation

Organic Lecture Series

Di- and Polysubstitution

Di- and Polysubstitution

Organic Lecture Series

Di- and Polysubstitution

Organic Lecture Series

– -OCH3 is ortho-para directing:

Organic Lecture Series

activating N HCR N HCAr O CR O CAr

the order of steps is important:

Organic Lecture Series

Theory of Directing Effects

Organic Lecture Series

OCH3 OCH3 OCH3 OCH3

This resonance structure accounts for the selectivity

Organic Lecture Series

Theory of Directing Effects

-NO2; examine the meta attack:

COOH COOH COOH COOH

-NO2: assume ortho-para attack:

COOH COOH COOH COOH