Electrophilic substitution reaction of chem

1. Chapter 17 1
Electrophilic
Aromatic Substitution
Electrophile substitutes for a hydrogen on
the benzene ring.
=>

2. Chapter 17 2
Mechanism
=>

3. Chapter 17 3
Energy Diagram
for Bromination
=>

4. Chapter 17 4
Bromination of Benzene
• Requires a stronger electrophile than Br2.
• Use a strong Lewis acid catalyst, FeBr3.
Br Br FeBr3 Br Br FeBr3
Br Br FeBr3
H
H
H
H
H
H
H
H
H
H
H
H
Br
+ + FeBr4
_
Br
HBr
+

5. Chapter 17 5
Chlorination
and Iodination
• Chlorination is similar to bromination.
Use AlCl3 as the Lewis acid catalyst.
• Iodination requires an acidic oxidizing
agent, like nitric acid, which oxidizes the
iodine to an iodonium ion.
H
+
HNO3 I2
1/2 I
+
NO2 H2O
+ +
+ +
=>

6. Chapter 17 6
Nitration of Benzene
Use sulfuric acid with nitric acid to form
the nitronium ion electrophile.
H O N
O
O
H O S O H
O
O
+ HSO4
_
H O N
O
H
O
+
H O N
O
H
O
+
H2O + N
O
O
+
NO2
+ then forms a
sigma complex with
benzene, loses H+ to
form nitrobenzene. =>

7. Chapter 17 7
Sulfonation
Sulfur trioxide, SO3, in fuming sulfuric acid
is the electrophile.
S
O
O O
S
O
O O
S
O
O O
S
O
O O
+ + +
_
_ _
S
O
O
O
H
S
O
O
O
H
+
_
S
HO
O
O
benzenesulfonic acid
=>

8. Chapter 17 8
Desulfonation
• All steps are reversible, so sulfonic acid
group can be removed by heating in
dilute sulfuric acid.
• This process is used to place deuterium
in place of hydrogen on benzene ring.
Benzene-d6
=>
D
D
D
D
D
D
D2SO4/D2O
large excess
H
H
H
H
H
H

9. Chapter 17 9
Nitration of Toluene
• Toluene reacts 25 times faster than benzene.
The methyl group is an activator.
• The product mix contains mostly ortho and
para substituted molecules.
=>

10. Chapter 17 10
Sigma Complex
Intermediate
is more
stable if
nitration
occurs at
the ortho
or para
position.
=>

11. Chapter 17 11
Energy Diagram
=>

12. Chapter 17 12
Activating, O-, P-
Directing Substituents
• Alkyl groups stabilize the sigma complex
by induction, donating electron density
through the sigma bond.
• Substituents with a lone pair of electrons
stabilize the sigma complex by resonance.
OCH3
H
NO2
+
OCH3
H
NO2
+
=>

13. NITRATION OF ANISOLE

14. H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
H NO2
H
O CH3
+
O CH3
+ N
O
O
+
Nitration of Anisole
NO2
O CH3
NO2
O CH3
BENZENIUM ION INTERMEDIATES
actual
products
activated
ring
ortho meta para
ortho para
+

15. H NO2
H
O CH3
+
H NO2
H
O CH3
+
H NO2
H
O CH3
+
H NO2
H
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
H
H
NO2
O CH3
+
ortho
meta
para :
:
EXTRA!
EXTRA!

16. Energy Profiles
meta
ortho
para
NITRATION OF ANISOLE
benzenium
intermediate
RECALL:
HAMMOND
POSTULATE
Ea
benzenium
intermediates
have more
resonance
ortho-para
director

17. H
H
NO2
O CH3
+
:B elimination
_
H
NO2
O CH3
H
H
NO2
O CH3
+
:B
addition
_
H
H
NO2
B
O CH3
doesn’t happen
resonance would be lost
restores aromatic ring
resonance
ADDITION REACTION
ELIMINATION REACTION
BENZENIUM IONS GIVE ELIMINATION INSTEAD OF ADDITION
( 36 Kcal / mole )
X

18. Chapter 17 18
The Amino Group
Aniline reacts with bromine water (without a
catalyst) to yield the tribromide. Sodium
bicarbonate is added to neutralize the
HBr that’s also formed.
NH2
Br2
3
H2O, NaHCO3
NH2
Br
Br
Br
=>

19. Chapter 17 19
Summary of
Activators
=>

20. Chapter 17 20
Deactivating Meta-
Directing Substituents
• Electrophilic substitution reactions for
nitrobenzene are 100,000 times slower
than for benzene.
• The product mix contains mostly the
meta isomer, only small amounts of the
ortho and para isomers.
• Meta-directors deactivate all positions
on the ring, but the meta position is less
deactivated.
=>

21. Chapter 17 21
Ortho Substitution
on Nitrobenzene
=>

22. Chapter 17 22
Para Substitution
on Nitrobenzene
=>

23. Chapter 17 23
Meta Substitution
on Nitrobenzene
=>

24. Chapter 17 24
Energy Diagram
=>

25. Chapter 17 25
Structure of Meta-
Directing Deactivators
• The atom attached to the aromatic ring
will have a partial positive charge.
• Electron density is withdrawn inductively
along the sigma bond, so the ring is less
electron-rich than benzene.
=>

26. Chapter 17 26
Summary of Deactivators
=>

27. Chapter 17 27
More Deactivators
=>

28. Chapter 17 28
Halobenzenes
• Halogens are deactivating toward
electrophilic substitution, but are ortho,
para-directing!
• Since halogens are very electronegative,
they withdraw electron density from the
ring inductively along the sigma bond.
• But halogens have lone pairs of electrons
that can stabilize the sigma complex by
resonance. =>

29. Chapter 17 29
Sigma Complex
for Bromobenzene
Br
E
+
Br
H
E
(+)
(+)
(+)
Ortho attack
+ Br
E
+
Br
H E
+
(+)
(+)
(+)
Para attack
Ortho and para attacks produce a bromonium ion
and other resonance structures.
=>
Meta attack
Br
E+
Br
H
H
E
+
(+)
(+)
No bromonium ion
possible with meta attack.

30. Chapter 17 30
Energy Diagram
=>

31. Chapter 17 31
Summary of
Directing Effects
=>

32. DIRECTIVITY OF SINGLE GROUPS

33. ortho, para - Directing Groups
X
Groups that donate
electron density
to the ring.
X
X :
+I Substituent +R Substituent
CH3-
R-
CH3-O-
CH3-N-
-NH2
-O-H
These groups also
“activate” the ring, or
make it more reactive.
E+
The +R groups activate
the ring more strongly
than +I groups.
..
..
..
..
..
..
increased
reactivity
PROFILE:

34. X Y
Y
meta - Directing Groups
X
Groups that withdraw
electron density from
the ring.
These groups also
“deactivate” the ring,
or make it less reactive.
E+
-I Substituent -R Substituent
d+ d-
C
O
R
C
O
OR
C
O
OH
C N
N
O
O
N
R
R
R
CCl3
-SO3H
+
decreased
reactivity
+
-
PROFILE:

35. Halides - o,p Directors / Deactivating
X
E+
: :
..
Halides represent a special case:
They are o,p directors (+R effect )
They are deactivating ( -I effect )
Most other other substituents fall
into one of these four categories:
1) +R / o,p / activating
2) +I / o,p / activating
3) -R / m / deactivating
4) -I / m / deactivating
+R / -I / o,p / deactivating
They are o,p directing groups
that are deactivating
-F
-Cl
-Br
-I
THE EXCEPTION

36. CH3
O CH3
NO2
C
O
O CH3
PREDICT !
o,p m
o,p m

37. DIRECTIVITY OF MULTIPLE GROUPS

38. GROUPS ACTING IN CONCERT
O CH3
NO2
m-director
o,p director
HNO3
H2SO4 O CH3
NO2
NO2
major
product
very
little
formed
O CH3
NO2
O2
N
steric
crowding
When groups direct to the
same positions it is easy to
predict the product.

39. GROUPS COMPETING
o,p-directing groups win
over m-directing groups
HNO3
H2SO4
O CH3
NO2
NO2
O CH3
NO2
O2
N
O CH3
NO2
too
crowded
X
+

40. HNO3
H2SO4
RESONANCE VERSUS INDUCTIVE EFFECT
O CH3
CH3
NO2
O CH3
CH3
+R
+I
resonance effects are more
important than inductive effects
major
product

41. SOME GENERAL RULES
1) Activating (o,p) groups (+R, +I) win over
deactivating (m) groups (-R,-I).
2) Resonance groups (+R) win over inductive (+I) groups.
3) 1,2,3-Trisubstituted products rarely form due to
excessive steric crowding.
4) With bulky directing groups, there will usually be more
p-substitution than o-substitution.
5) The incoming group replaces a hydrogen, it will not
usually displace a substituent already in place.

42. HOW CAN YOU MAKE ...
C
O
O CH3
NO2
CH3
NO2
NO2
NO2
O2
N
CH2
CH2
CH2
CH3
only,
no para

43. BROMINE - WATER REAGENT
PHENOLS AND ANILINES

44. H O
H
Br Br H O
H
Br Br
OMe
Br O
H
H
H
Br
OMe
..
..
.. .. ..
.. ..
..
..
..
..
..
..
:
: : : :
:
+
+
-
BROMINE IN WATER
+
This reagent works only with highly-activated rings
such as phenols, anisoles and anilines.
bromonium
ion
etc

45. OH
Br2
H2O
OH
Br
Br
Br
All available
positions are
bromiated.
NH2
CH3
NH2
CH3
Br
Br
Br2
H2O
PHENOLS AND ANILINES REACT

46. Chapter 17 46
Friedel-Crafts Alkylation
• Synthesis of alkyl benzenes from alkyl
halides and a Lewis acid, usually AlCl3.
• Reactions of alkyl halide with Lewis acid
produces a carbocation which is the
electrophile.
• Other sources of carbocations:
alkenes + HF or alcohols + BF3.
=>

47. Chapter 17 47
Examples of
Carbocation Formation
CH3 CH CH3
Cl
+ AlCl3
CH3
C
H3C H
Cl AlCl3
+ _
H2C CH CH3
HF
H3C CH CH3
F
+
_
H3C CH CH3
OH
BF3
H3C CH CH3
O
H BF3
+
H3C CH CH3
+
+ HOBF3
_
=>

48. Chapter 17 48
Formation of
Alkyl Benzene
C
CH3
CH3
H
+
H
H
CH(CH3)2
+
H
H
CH(CH3)2
B
F
F
F
OH
CH
CH3
CH3
+
HF
B
F
OH
F
=>
+
-

49. Chapter 17 49
Limitations of
Friedel-Crafts
• Reaction fails if benzene has a substituent
that is more deactivating than halogen.
• Carbocations rearrange. Reaction of
benzene with n-propyl chloride and AlCl3
produces isopropylbenzene.
• The alkylbenzene product is more reactive
than benzene, so polyalkylation occurs.
=>

50. Chapter 17 50
Friedel-Crafts
Acylation
• Acyl chloride is used in place of alkyl
chloride.
• The acylium ion intermediate is
resonance stabilized and does not
rearrange like a carbocation.
• The product is a phenyl ketone that is
less reactive than benzene.
=>

51. Chapter 17 51
Mechanism of Acylation
R C
O
Cl AlCl3 R C
O
AlCl3
Cl
+ _
R C
O
AlCl3
Cl
+ _
AlCl4 +
_ +
R C O R C O
+
C
O
R
+
H
C
H
O
R
+
Cl AlCl3
_
C
O
R +
HCl
AlCl3
=>

52. Chapter 17 52
Clemmensen Reduction
Acylbenzenes can be converted to
alkylbenzenes by treatment with
aqueous HCl and amalgamated zinc.
+ CH3CH2C
O
Cl
1) AlCl3
2) H2O
C
O
CH2CH3
Zn(Hg)
aq. HCl
CH2CH2CH3
=>

53. Chapter 17 53
Gatterman-Koch
Formylation
• Formyl chloride is unstable. Use a high
pressure mixture of CO, HCl, and catalyst.
• Product is benzaldehyde.
CO + HCl H C
O
Cl
AlCl3/CuCl
H C O
+
AlCl4
_
C
O
H
+ C
O
H
+ HCl
+
=>

54. Chapter 17 54
Chlorination of Benzene
• Addition to the benzene ring may occur
with high heat and pressure (or light).
• The first Cl2 addition is difficult, but the
next 2 moles add rapidly.
• The product, benzene hexachloride, is
an insecticide.
=>

55. Chapter 17 55
Catalytic Hydrogenation
• Elevated heat and pressure is required.
• Possible catalysts: Pt, Pd, Ni, Ru, Rh.
• Reduction cannot be stopped at an
intermediate stage.
=>
CH3
CH3
Ru, 100°C
1000 psi
3H2,
CH3
CH3

56. Chapter 17 56
Birch Reduction:
Regiospecific
• A carbon with an e--withdrawing group
is reduced.
• A carbon with an e--releasing group
is not reduced.
C
O
OH Na, NH3
CH3CH2OH
C
O
O
H
_
OCH3 Li, NH3
(CH3)3COH, THF
OCH3
=>

57. Chapter 17 57
Birch Mechanism
=>

58. Chapter 17 58
Side-Chain Oxidation
Alkylbenzenes are oxidized to benzoic
acid by hot KMnO4 or Na2Cr2O7/H2SO4.
CH(CH3)2
CH CH2
KMnO4, OH
-
H2O, heat
COO
COO
_
_
=>

59. Chapter 17 59
Side-Chain Halogenation
• Benzylic position is the most reactive.
• Chlorination is not as selective as
bromination, results in mixtures.
• Br2 reacts only at the benzylic position.
=>
CHCH2CH3
Br
h
Br2,
CH2CH2CH3