AROMATIC COMPOUNDS

1. Chemistry of Aromatic
Compounds
Electrophilic Aromatic Substitution
Directing Effects
Side-chain Reactions
Synthesis
Nucleophilic Aromatic Substitution

2. Electrophilic Aromatic
Substitution
H
E
E
H
E
+ H-base
:base

3. EAS Reactions of Benzene
Br
NO2
SO3H
CR
O
Cl
IR
CHO

4. Bromination / Chlorination
H Br
Br2, FeBr3
+ HBr
H Cl
Cl2, FeCl3
+ HCl

5. Bromination Mechanism

6. Reaction Profile

7. Nitration
HNO3, H2SO4
NO2
+ H2O
HNO3 + H2SO4 NO2
+
+ H2O + HSO4
-
Formation of electrophile

8. Nitration Mechanism

9. Nitration of Toluene

10. Sulfonation is Reversible
H
SO3, H2SO4
SO3H
fuming sulfuric acid
S
O
OO H OSO3H
SO3H
H
OSO3H

11. Desulfonation

12. Friedel-Crafts Acylation
RCCl, AlCl3
O C
O
R
+ HCl

14. 1st
, Formaton of Electrophile
C
O
R Cl AlCl3
δ δ
+ -
R
C
O
R C O AlCl4
acylium ion

15. Acylation Mechanism
C
O
R
C
O
R
H Cl AlCl3
C
R
O
+ HCl

16. Intermediate is
Resonance-Stabilized
C
O
R
H
C
O
R
H
C
O
R
H

17. An Acylation
CH3
CH3
CH3CH2CH2CH2CCl
O
TiCl4 in CH2Cl2
CCH2CH2CH2CH3
OCH3
CH3
+ HCl

18. Friedel-Crafts Alkylation
many more limitations
RX, AlCl3
R
+ HCl

20. Mechanism
CH3 C
CH3
CH3
Cl AlCl3 C
CH3
CH3
CH3
t-butyl carbocation
AlCl4
CH3 C
CH3
CH3
(CH3)3C
H
(CH3)3C (CH3)3C
resonance stabilized intermediate
Cl AlCl3
(CH3)3C
+ HCl
(+ AlCl3)

21. Carbocation Generated From
Alkene

22. Unexpected Product?
CH3CH2CH2CH2Cl, AlCl3
CH2CH2CH2CH3
CHCH2CH3
CH3
minor product
major product

23. Carbocations Rearrange…
CH3CH2CH2CH2 Cl AlCl3 CH3CH2CHCH2
H
CH3CH2CHCH3
hydride shift
2o
1
o

24. 1o
RX Typically Undergoes Shift

25. Side Chain Reactions
O
H2, Pd/C
in ethanol
1) Reduction of Aromatic Ketones

26. Straight-chain Alkylation can
be Accomplished in 2 steps:
Acylation, then Reduction
CH2CH2CH3
CCH2CH3
O
CH3CH2CH2Cl
AlCl3 minor
CH(CH3)2
+
CH3CH2CCl
AlCl3
O
major
H2, Pd/C

27. 2) Oxidation of Alkyl Substituents
CH3
KMnO4, H2O
COH
O
KMnO4
H2O
CO2H
CH3
CH(CH3)2
KMnO4, H2O
CO2H
CO2H

28. 3) Benzylic Bromination with NBS
H
NBS, CCl4, hν
Br
NBr
O
O
NBS
benzylic hydrogen

29. 4) Alkali Fusion of Sulfonic Acids
phenol
SO3H
1) NaOH, 300 C
2) H3O
+
OH
o

30. 5) Reduction of Nitro Groups
NO2
1) SnCl2, HCl
2) NaOH
or H2 on Pt
NH2

31. Directing Effects
EDG EWG
electron donating groups electron withdrawing groups
activate ring deactivate ring
atom attached is
usually sp3
atom attached is
usually sp or sp2

32. ortho/para-Directing
Activating Groups
OCH3 OCH3 OCH3 OCH3
OCH3
δ
δ
δ
δ
+
- -
-

33. Nitration of Anisole

34. Nitration Affords
ortho and para Products
OCH3
HNO3, H2SO4
OCH3
NO2
OCH3
NO2
+
ortho para

35. Activating ortho/para directors

36. Nitration of Toluene

37. meta-Directing
Deactivating Groups
CH
O
CH
O
CH
O
CH
O
CH
O
δ
δ δ
δ
+
+ +
-
ortho and para positions
are deactivated toward
EAS

38. Electron-Withdrawing Nitro
Group Directs meta

40. meta Directors

41. Comparison
CH3
CF3
Br2, FeBr3
ortho meta para
Brominated product
63 3 34
6 91 3
ortho meta para
rel. rate
25
0.000025
rate rel. to
benzene

42. More Limitations with
Friedel Crafts Reactions
Cl
Ring must be at least as
activated (reactive) as
NO2 ClCCH3, AlCl3
O
No Reaction
Cl
CH2CH3
+ orthoCH3CH2Cl, TiCl4

43. Substituent Summary

44. Halogens are the Anomoly
Deactivators and o,p-Directors
Br
CH3CH2Cl
AlCl3
Br
CH2CH3
CH2CH3
Br
+
rel. rate = 0.5
Inductively withdrawing, hence deactivating
Resonance donation causes o,p directing

45. Reactions of Rings With
Two or More Substituents
NO2
OCH3 OCH3
NO2
Cl
Cl2, FeCl3
Activating Group Controls Reaction

46. The (More) Activated Ring Reacts
CO
O
H2SO4
SO3
CO
O
SO3H
deactivated activated
(+ some ortho)
*

47. Mixtures with Conflicting
Directing Effects

48. Provide the Reagents
NH2
C(CH3)3
Br

49. Must Acylate First
NH2
ClCCH2CH2CH2CH3
O
AlCl3
O meta director
HNO3
H2SO4
O
NO2
H2, Pt/C

50. Sulfonic Acid Blocks para
Position C(CH3)3
Br
H(CH3)3CBr
AlCl3
C(CH3)3
SO3, H2SO4
SO3H
C(CH3)3
Br2, FeBr3
C(CH3)3
SO3H
Br
H3O
+
blocks para

51. Give the Reagents
CO2H
O
CH3
Cl

52. Provide the Reagents
CH2CH3
OHBr

53. CH2CH3
OHBr
1) ClCCH3, AlCl3
O
2) SO3, H2SO4
3) Br2, FeBr3
4) H2 Pd/C
5) NaOH, 300 C
o
6) H3O
+
O O
SO3H
O
SO3HBr SO3HBr
1)
2) 3) 4)
5,6)

54. Provide the Reagents
HO2C

55. HO2C1)
Cl
AlCl3
2) Cl
O AlCl3
3) KMnO4, H2O
4) H2, Pd/C
5) NBS, hν
6) NaOCH3 in CH3OH, heat
(E2 elim of HBr)
1)
O
2)
O
HO2C
3)
HO2C
HO2C
Br
4)
5)
6) workup w/
H3O
+

56. Nucleophlic Aromatic
Substitution

57. Not an SN1

58. Not an SN2

61. “SNA” criteria:
• Strongly deactivated ring
• Leaving group
• Deactivating group(s) ortho &/or para to
leaving group (preferably)
• Strong base (nucleophile) such as RO-
, NH2
-

62. Methoxide as a nucleophile

63. Mechanism
Cl
O
O
OCH3
Cl
O
O OCH3
Cl
O
O OCH3
OCH3
O
O
+ Cl

64. With no EWG, reaction
conditions are more extreme
Elimination/Addition Mechanism

65. “Benzyne” Intermediate

66. Carbons are sp2
(not a second π bond)

67. Benzyne can be trapped by a Diene:
Undergoes a Diels-Alder rxn

68. Benzyne intermediate has 2
reactive sites

69. Mixture of Regioisomers
Br
OCH3
NaNH2, NH3
NH2
OCH3
+
OCH3
H2N
majorminor
+ NaBr