1. Chapter 12 (Part a) Reactions of Arenes: Electrophilic Aromatic Substitution+ Y d+ d–
Dr. Wolf's CHM 201 & 202
12-1 1

2. Representative Electrophilic Aromatic Substitution Reactions of Benzene+ Y d+ d–
Dr. Wolf's CHM 201 & 202
12-2 3

3. Electrophilic aromatic substitutions include:+ Y d+ d–
Electrophilic aromatic substitutions include:
Nitration
Sulfonation
Halogenation
Friedel-Crafts Alkylation
Friedel-Crafts Acylation
Dr. Wolf's CHM 201 & 202
12-3 5

4. Table 12.1: Nitration of BenzeneH
H2SO4
NO2 +
HONO2 +
H2O
Nitrobenzene (95%)
Dr. Wolf's CHM 201 & 202
12-4 6

5. Table 12.1: Sulfonation of BenzeneH
heat
SO2OH +
HOSO2OH +
H2O
Benzenesulfonic acid (100%)
Dr. Wolf's CHM 201 & 202
12-5 6

6. Table 12.1: Halogenation of Benzene
FeBr3 Br +
Br2 +
HBr
Bromobenzene (65-75%)
Dr. Wolf's CHM 201 & 202
12-6 6

7. Table 12.1: Friedel-Crafts Alkylation of BenzeneH
AlCl3
C(CH3)3 +
(CH3)3CCl +
HCl
tert-Butylbenzene (60%)
Dr. Wolf's CHM 201 & 202
12-7 6

8. Table 12.1: Friedel-Crafts Acylation of Benzene
CCH2CH3 O O
CH3CH2CCl H
AlCl3 + +
HCl
1-Phenyl-1-propanone (88%)
Dr. Wolf's CHM 201 & 202
12-8 6

9. Mechanistic Principles of Electrophilic Aromatic Substitution
Dr. Wolf's CHM 201 & 202
12-9 11

10. Step 1: attack of electrophile on p-electron system of aromatic ring+
highly endothermic
carbocation is allylic, but not aromatic
Dr. Wolf's CHM 201 & 202
12-10 12

11. Step 2: loss of a proton from the carbocation intermediate+ H H H H H H+
highly exothermic
this step restores aromaticity of ring
Dr. Wolf's CHM 201 & 202
12-11 12

12. H E + H
+ E+ E H
+ H+
Dr. Wolf's CHM 201 & 202
12-12 6

13. Based on this general mechanism:
what remains is to identify the electrophile in nitration, sulfonation, halogenation, Friedel-Crafts alkylation, and Friedel-Crafts acylation to establish the mechanism of specific electrophilic aromatic substitutions
Dr. Wolf's CHM 201 & 202
12-13 14

14. Nitration of Benzene
Dr. Wolf's CHM 201 & 202
12-14 15

15. Electrophile is nitronium ion
Nitration of Benzene H
H2SO4
NO2 +
HONO2 +
H2O O N •• + •
Electrophile is nitronium ion
Dr. Wolf's CHM 201 & 202
12-15 6

16. Step 1: attack of nitronium cation on p-electron system of aromatic ringH
NO2+ H
NO2 +
Dr. Wolf's CHM 201 & 202
12-16 12

17. Step 2: loss of a proton from the carbocation intermediate
NO2 H H H H
NO2 + H H H H H H+
Dr. Wolf's CHM 201 & 202
12-17 12

18. Where does nitronium ion come from?+ •• • – O N H + •• • –
H2SO4 H O •• O N •• + • +
Dr. Wolf's CHM 201 & 202
12-18 21

19. Sulfonation of Benzene
Dr. Wolf's CHM 201 & 202
12-19 22

20. Sulfonation of BenzeneH
heat
SO2OH +
HOSO2OH +
H2O O S + •• • –
Several electrophiles present:
a major one is sulfur trioxide
Dr. Wolf's CHM 201 & 202
12-20 6

21. Step 1: attack of sulfur trioxide on p-electron system of aromatic ringH
SO3 H
SO3– +
Dr. Wolf's CHM 201 & 202
12-21 12

22. Step 2: loss of a proton from the carbocation intermediate+ H H H H H H+
Dr. Wolf's CHM 201 & 202
12-22 12

23. Step 3: protonation of benzenesulfonate ionH
SO3–
H2SO4 H
SO3H
Dr. Wolf's CHM 201 & 202
12-23 12

24. Halogenation of Benzene
Dr. Wolf's CHM 201 & 202
12-24 24

25. Halogenation of Benzene
FeBr3 Br +
Br2 +
HBr
Electrophile is a Lewis acid-Lewis base complex between FeBr3 and Br2.
Dr. Wolf's CHM 201 & 202
12-25 6

26. The Br2-FeBr3 complex is more electrophilic than Br2 alone.• ••
FeBr3 – + • Br •• +
FeBr3
Lewis base
Lewis acid
Complex
The Br2-FeBr3 complex is more electrophilic than Br2 alone.
Dr. Wolf's CHM 201 & 202
12-26 21

27. Step 1: attack of Br2-FeBr3 complex on p-electron system of aromatic ring+ – Br Br
FeBr3 H Br + H H H H H H
+ FeBr4–
Dr. Wolf's CHM 201 & 202
12-27 12

28. Step 2: loss of a proton from the carbocation intermediateBr H H H H Br + H H H H H H+
Dr. Wolf's CHM 201 & 202
12-28 12

29. Friedel-Crafts Alkylation of Benzene
Dr. Wolf's CHM 201 & 202
12-29 27

30. Friedel-Crafts Alkylation of BenzeneH
AlCl3
C(CH3)3 +
(CH3)3CCl +
HCl C
CH3
H3C +
Electrophile is tert-butyl cation
Dr. Wolf's CHM 201 & 202
12-30 6

31. acts as a Lewis acid to promote ionization of the alkyl halide
Role of AlCl3
acts as a Lewis acid to promote ionization of the alkyl halide +
(CH3)3C Cl ••
AlCl3 – ••
(CH3)3C • Cl +
AlCl3 ••
Dr. Wolf's CHM 201 & 202
12-31 29

32. acts as a Lewis acid to promote ionization of the alkyl halide
Role of AlCl3
acts as a Lewis acid to promote ionization of the alkyl halide +
(CH3)3C Cl ••
AlCl3 – ••
(CH3)3C • Cl +
AlCl3 •• + Cl ••
AlCl3 – •
(CH3)3C +
Dr. Wolf's CHM 201 & 202
12-32 29

33. Step 1: attack of tert-butyl cation on p-electron system of aromatic ring
C(CH3)3 + H
C(CH3)3 + H H H H H H
Dr. Wolf's CHM 201 & 202
12-33 12

34. Step 2: loss of a proton from the carbocation intermediate
C(CH3)3 H H H H
C(CH3)3 + H H H H H H+
Dr. Wolf's CHM 201 & 202
12-34 12

35. Rearrangements in Friedel-Crafts Alkylation
Carbocations are intermediates.
Therefore, rearrangements can occur H
C(CH3)3
AlCl3 +
(CH3)2CHCH2Cl
Isobutyl chloride
tert-Butylbenzene (66%)
Dr. Wolf's CHM 201 & 202
12-35 34

36. Rearrangements in Friedel-Crafts Alkylation
Isobutyl chloride is the alkyl halide.
But tert-butyl cation is the electrophile. H
C(CH3)3
AlCl3 +
(CH3)2CHCH2Cl
Isobutyl chloride
tert-Butylbenzene (66%)
Dr. Wolf's CHM 201 & 202
12-36 34

37. Rearrangements in Friedel-Crafts Alkylation
CH2
H3C
CH3 H Cl ••
AlCl3 + – H + Cl ••
AlCl3 – •
H3C C +
CH2
CH3
Dr. Wolf's CHM 201 & 202
12-37 35

38. Reactions Related to Friedel-Crafts AlkylationH
H2SO4 +
Cyclohexylbenzene (65-68%)
Cyclohexene is protonated by sulfuric acid, giving cyclohexyl cation which attacks the benzene ring
Dr. Wolf's CHM 201 & 202
12-38 38

39. Friedel-Crafts Acylation of Benzene
Dr. Wolf's CHM 201 & 202
12-39 39

40. Friedel-Crafts Acylation of BenzeneH
AlCl3
CCH2CH3 +
CH3CH2CCl +
HCl
Electrophile is an acyl cation ••
CH3CH2C O • +
CH3CH2C O • +
Dr. Wolf's CHM 201 & 202
12-40 6

41. Step 1: attack of the acyl cation on p-electron system of aromatic ring
CCH2CH3 + O
CCH2CH3 H H H H H H H + H H H H H
Dr. Wolf's CHM 201 & 202
12-41 12

42. Step 2: loss of a proton from the carbocation intermediate
CCH2CH3 O
CCH2CH3 H H H H H H + H H H H H H+
Dr. Wolf's CHM 201 & 202
12-42 12

43. can be used instead of acyl chlorides O
Acid Anhydrides
can be used instead of acyl chlorides O
CCH3 O
CH3COCCH3 H
AlCl3 +
Acetophenone (76-83%) O
CH3COH +
Dr. Wolf's CHM 201 & 202
12-43 43

44. Acylation-Reduction
Dr. Wolf's CHM 201 & 202
12-44
4 4

45. permits primary alkyl groups to be attached to an aromatic ring
Acylation-Reduction
permits primary alkyl groups to be attached to an aromatic ring O CR O H
RCCl
AlCl3
Zn(Hg), HCl
Reduction of aldehyde and ketone carbonyl groups using Zn(Hg) and HCl is called the Clemmensen reduction.
CH2R
Dr. Wolf's CHM 201 & 202
12-45 45

46. permits primary alkyl groups to be attached to an aromatic ring
Acylation-Reduction
permits primary alkyl groups to be attached to an aromatic ring O CR O H
RCCl
H2NNH2, KOH, triethylene glycol, heat
AlCl3
Reduction of aldehyde and ketone carbonyl groups by heating with H2NNH2 and KOH is called the Wolff-Kishner reduction.
CH2R
Dr. Wolf's CHM 201 & 202
12-46 45

47. Example: Prepare isobutylbenzene
(CH3)2CHCH2Cl
CH2CH(CH3)2
AlCl3
No! Friedel-Crafts alkylation of benzene using isobutyl chloride fails because of rearrangement.
Dr. Wolf's CHM 201 & 202
12-47 46

48. tert-Butylbenzene (66%)
Recall
C(CH3)3
AlCl3 +
(CH3)2CHCH2Cl
Isobutyl chloride
tert-Butylbenzene (66%)
Dr. Wolf's CHM 201 & 202
12-48 34

49. Use Acylation-Reduction Instead
(CH3)2CHCCl O +
AlCl3
CH2CH(CH3)2
Zn(Hg) HCl O
CCH(CH3)2
Dr. Wolf's CHM 201 & 202
12-49 34

50. Rate and Regioselectivity in Electrophilic Aromatic Substitution
A substituent already present on the ring can affect both the rate and regioselectivity of electrophilic aromatic substitution.
Dr. Wolf's CHM 201 & 202
12-50 1

51. Effect on Rate
Activating substituents increase the rate of EAS compared to that of benzene.
Deactivating substituents decrease the rate of EAS compared to benzene.
Dr. Wolf's CHM 201 & 202
12-51 2

52. Toluene undergoes nitration 20-25 times faster than benzene.
Methyl Group
Toluene undergoes nitration times faster than benzene.
A methyl group is an activating substituent.
CH3
Dr. Wolf's CHM 201 & 202
12-52 3

53. Trifluoromethyl Group
(Trifluoromethyl)benzene undergoes nitration 40, times more slowly than benzene .
A trifluoromethyl group is a deactivating substituent.
CF3
Dr. Wolf's CHM 201 & 202
12-53 3

54. Effect on Regioselectivity
Ortho-para directors direct an incoming electrophile to positions ortho and/or para to themselves.
Meta directors direct an incoming electrophile to positions meta to themselves.
Dr. Wolf's CHM 201 & 202
12-54 5

55. o- and p-nitrotoluene together comprise 97% of the product
Nitration of Toluene
CH3
NO2
CH3
NO2
CH3
NO2
CH3
HNO3
acetic anhydride + +
63% 3%
34%
o- and p-nitrotoluene together comprise 97% of the product
a methyl group is an ortho-para director
Dr. Wolf's CHM 201 & 202
12-55 6

56. Nitration of (Trifluoromethyl)benzene
CF3
NO2
CF3
NO2
CF3
NO2
CF3
HNO3
H2SO4 + + 6%
91% 3%
m-nitro(trifluoromethyl)benzene comprises 91% of the product
a trifluoromethyl group is a meta director
Dr. Wolf's CHM 201 & 202
12-56 6

57. Rate and Regioselectivity in the Nitration of Toluene
Dr. Wolf's CHM 201 & 202
12-57 8

58. Carbocation Stability Controls Regioselectivity+ H
CH3
NO2 + H
NO2
CH3 + H
NO2
CH3
gives ortho
gives para
gives meta
Dr. Wolf's CHM 201 & 202
12-58 10

59. Carbocation Stability Controls Regioselectivity+ H
CH3
NO2 + H
NO2
CH3 + H
NO2
CH3
gives ortho
gives para
gives meta
more stable
less stable
Dr. Wolf's CHM 201 & 202
12-59 10

60. ortho Nitration of Toluene
CH3 +
NO2 H H H H H
Dr. Wolf's CHM 201 & 202
12-60 12

61. ortho Nitration of Toluene
CH3
CH3 +
NO2
NO2 H H H H + H H H H H H
Dr. Wolf's CHM 201 & 202
12-61 12

62. ortho Nitration of Toluene
CH3
CH3
CH3 +
NO2
NO2
NO2 H H H + H H H + H H H H H H H H H
this resonance form is a tertiary carbocation
Dr. Wolf's CHM 201 & 202
12-62 12

63. ortho Nitration of Toluene
CH3
CH3
CH3 +
NO2
NO2
NO2 H H H + H H H + H H H H H H H H H
the rate-determining intermediate in the ortho nitration of toluene has tertiary carbocation character
Dr. Wolf's CHM 201 & 202
12-63 12

64. para Nitration of Toluene+ H
NO2
CH3
Dr. Wolf's CHM 201 & 202
12-64 12

65. para Nitration of TolueneH
NO2
CH3 H
NO2
CH3 + +
this resonance form is a tertiary carbocation
Dr. Wolf's CHM 201 & 202
12-65 12

66. para Nitration of TolueneH
NO2
CH3 H
NO2
CH3 H
NO2
CH3 + + +
this resonance form is a tertiary carbocation
Dr. Wolf's CHM 201 & 202
12-66 12

67. para Nitration of TolueneH
NO2
CH3 H
NO2
CH3 H
NO2
CH3 + + +
the rate-determining intermediate in the para nitration of toluene has tertiary carbocation character
Dr. Wolf's CHM 201 & 202
12-67 12

68. meta Nitration of TolueneH
NO2
CH3 +
Dr. Wolf's CHM 201 & 202
12-68 14

69. meta Nitration of TolueneH
NO2
CH3 H
NO2
CH3 + +
Dr. Wolf's CHM 201 & 202
12-69 14

70. meta Nitration of TolueneH
NO2
CH3 H
NO2
CH3 H
NO2
CH3 + + +
all the resonance forms of the rate-determining intermediate in the meta nitration of toluene have their positive charge on a secondary carbon
Dr. Wolf's CHM 201 & 202
12-70 14

71. Nitration of Toluene: Interpretation
The rate-determining intermediates for ortho and para nitration each have a resonance form that is a tertiary carbocation. All of the resonance forms for the rate-determining intermediate in meta nitration are secondary carbocations.
Tertiary carbocations, being more stable, are formed faster than secondary ones. Therefore, the intermediates for attack at the ortho and para positions are formed faster than the intermediate for attack at the meta position. This explains why the major products are o- and p-nitrotoluene.
Dr. Wolf's CHM 201 & 202
12-71 15

72. Nitration of Toluene: Partial Rate Factors
The experimentally determined reaction rate can be combined with the ortho/meta/para distribution to give partial rate factors for substitution at the various ring positions.
Expressed as a numerical value, a partial rate factor tells you by how much the rate of substitution at a particular position is faster (or slower) than at a single position of benzene.
Dr. Wolf's CHM 201 & 202
12-72 15

73. Nitration of Toluene: Partial Rate Factors
CH3 1 1 1 42 42 1 1
2.5
2.5 1 58
All of the available ring positions in toluene are more reactive than a single position of benzene.
A methyl group activates all of the ring positions but the effect is greatest at the ortho and para positons.
Steric hindrance by the methyl group makes each ortho position slightly less reactive than para.
Dr. Wolf's CHM 201 & 202
12-73 15

74. Nitration of Toluene vs. tert-Butylbenzene
CH3 75 3
4.5 C
H3C
CH3 42
2.5 58
tert-Butyl is activating and ortho-para directing
tert-Butyl crowds the ortho positions and decreases the rate of attack at those positions.
Dr. Wolf's CHM 201 & 202
12-74 15

75. all alkyl groups are activating and ortho-para directing
Generalization
all alkyl groups are activating and ortho-para directing
Dr. Wolf's CHM 201 & 202
12-75 17

76. Theory of Directing Effects

77. Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene
Dr. Wolf's CHM 201 & 202
12-76 8

78. A methyl group is electron-donating and stabilizes a carbocation.
A Key Point C +
H3C C +
F3C
A methyl group is electron-donating and stabilizes a carbocation.
Because F is so electronegative, a CF3 group destabilizes a carbocation.
Dr. Wolf's CHM 201 & 202
12-77 17

79. Carbocation Stability Controls Regioselectivity+ H
CF3
NO2 + H
NO2
CF3 + H
NO2
CF3
gives ortho
gives para
gives meta
Dr. Wolf's CHM 201 & 202
12-78 10

80. Carbocation Stability Controls Regioselectivity+ H
CF3
NO2 + H
NO2
CF3 + H
NO2
CF3
gives ortho
gives para
gives meta
less stable
more stable
Dr. Wolf's CHM 201 & 202
12-79 10

81. ortho Nitration of (Trifluoromethyl)benzene
CF3 +
NO2 H H H H H
Dr. Wolf's CHM 201 & 202
12-80 12

82. ortho Nitration of (Trifluoromethyl)benzene
CF3
CF3 +
NO2
NO2 H H H H + H H H H H H
Dr. Wolf's CHM 201 & 202
12-81 12

83. ortho Nitration of (Trifluoromethyl)benzene
CF3
CF3
CF3 +
NO2
NO2
NO2 H H H + H H H + H H H H H H H H H
this resonance form is destabilized
Dr. Wolf's CHM 201 & 202
12-82 12

84. ortho Nitration of (Trifluoromethyl)benzene
CF3
CF3
CF3 +
NO2
NO2
NO2 H H H + H H H + H H H H H H H H H
one of the resonance forms of the rate-determining intermediate in the ortho nitration of (trifluoromethyl)benzene is strongly destabilized
Dr. Wolf's CHM 201 & 202
12-83 12

85. para Nitration of (Trifluoromethyl)benzene+ H
NO2
CF3
Dr. Wolf's CHM 201 & 202
12-84 12

86. para Nitration of (Trifluoromethyl)benzene
CF3 H
NO2
CF3 + +
this resonance form is destabilized
Dr. Wolf's CHM 201 & 202
12-85 12

87. para Nitration of (Trifluoromethyl)benzene
CF3 H
NO2
CF3 H
NO2
CF3 + + +
this resonance form is destabilized
Dr. Wolf's CHM 201 & 202
12-86 12

88. para Nitration of (Trifluoromethyl)benzene
CF3 H
NO2
CF3 H
NO2
CF3 + + +
one of the resonance forms of the rate-determining intermediate in the para nitration of (trifluoromethyl)benzene is strongly destabilized
Dr. Wolf's CHM 201 & 202
12-87 12

89. meta Nitration of (Trifluoromethyl)benzene
CF3 +
Dr. Wolf's CHM 201 & 202
12-88 14

90. meta Nitration of (Trifluoromethyl)benzene
CF3 H
NO2
CF3 + +
Dr. Wolf's CHM 201 & 202
12-89 14

91. meta Nitration of (Trifluoromethyl)benzene
CF3 H
NO2
CF3 H
NO2
CF3 + + +
none of the resonance forms of the rate-determining intermediate in the meta nitration of (trifluoromethyl)benzene have their positive charge on the carbon that bears the CF3 group
Dr. Wolf's CHM 201 & 202
12-90 14

92. Nitration of (Trifluoromethyl)benzene: Interpretation
The rate-determining intermediates for ortho and para nitration each have a resonance form in which the positive charge is on a carbon that bears a CF3 group. Such a resonance structure is strongly destabilized. The intermediate in meta nitration avoids such a structure. It is the least unstable of three unstable intermediates and is the one from which most of the product is formed.
Dr. Wolf's CHM 201 & 202
12-91 15

93. Nitration of (Trifluoromethyl)benzene: Partial Rate Factors
CF3
4.5 x 10-6
67 x 10-6
All of the available ring positions in (trifluoromethyl)benzene are much less reactive than a single position of benzene.
A CF3 group deactivates all of the ring positions but the degree of deactivation is greatest at the ortho and para positons.
Dr. Wolf's CHM 201 & 202
12-92 15

94. Theory of Directing Effects

95. Substituent Effects in Electrophilic Aromatic Substitution: Activating Substituents
Dr. Wolf's CHM 201 & 202
12-93 8

96. Very strongly activating Strongly activating Activating
Table 12.2
Classification of Substituents in Electrophilic Aromatic Substitution Reactions
Very strongly activating
Strongly activating
Activating
Standard of comparison is H
Deactivating
Strongly deactivating
Very strongly deactivating
Dr. Wolf's CHM 201 & 202
12-94 1

97. 1. All activating substituents are ortho-para directors.
Generalizations
1. All activating substituents are ortho-para directors.
2. Halogen substituents are slightly deactivating but ortho-para directing.
3. Strongly deactivating substituents are meta directors.
Dr. Wolf's CHM 201 & 202
12-95 23

98. Electron-Releasing Groups (ERGs)
are ortho-para directing and activating
ERG
ERGs include —R, —Ar, and —C=C
Dr. Wolf's CHM 201 & 202
12-96 25

99. Electron-Releasing Groups (ERGs)
are ortho-para directing and strongly activating
ERG
ERGs such as —OH, and —OR are strongly activating
Dr. Wolf's CHM 201 & 202
12-97 25

100. occurs about 1000 times faster than nitration of benzene
Nitration of Phenol
occurs about 1000 times faster than nitration of benzene OH OH
NO2 OH
NO2
HNO3 +
44%
56%
Dr. Wolf's CHM 201 & 202
12-98 26

101. Bromination of Anisole
FeBr3 catalyst not necessary
OCH3
OCH3 Br
Br2
acetic acid
90%
Dr. Wolf's CHM 201 & 202
12-99 26

102. Oxygen Lone Pair Stabilizes Intermediate
OCH3 •• • H Br +
OCH3 •• • •• H Br +
OCH3 + H H H H H Br
all atoms have octets
Dr. Wolf's CHM 201 & 202
12-100 26

103. Electron-Releasing Groups (ERGs)•
ERG
ERGs with a lone pair on the atom directly attached to the ring are ortho-para directing and strongly activating
Dr. Wolf's CHM 201 & 202
12-101 25

104. Examples O OH OR OCR ERG = NHCR O NH2 NHR NR2•• OR • ••
OCR • ••
ERG = • •
NHCR • O •
NH2 •
NHR •
NR2
All of these are ortho-para directing and strongly to very strongly activating
Dr. Wolf's CHM 201 & 202
12-102 25

105. Lone Pair Stabilizes Intermediates for ortho and para SubstitutionX +
ERG H X +
ERG
comparable stabilization not possible for intermediate leading to meta substitution
Dr. Wolf's CHM 201 & 202
12-103 26

106. Substituent Effects in Electrophilic Aromatic Substitution: Strongly Deactivating Substituents
Dr. Wolf's CHM 201 & 202
12-104 8

107. ERGs Stabilize Intermediates for ortho and para SubstitutionX +
ERG • H X +
ERG •
Dr. Wolf's CHM 201 & 202
12-105 26

108. —CF3 is a powerful EWG. It is strongly deactivating and meta directing
Electron-withdrawing Groups (EWGs) Destabilize Intermediates for ortho and para Substitution
EWG
EWG X H H H + + H H H H H H X H
—CF3 is a powerful EWG. It is strongly deactivating and meta directing
Dr. Wolf's CHM 201 & 202
12-106 26

109. Many EWGs Have a Carbonyl Group Attached Directly to the Ring
—CR
—EWG = O
—COH O
—COR O
—CCl
All of these are meta directing and strongly deactivating
Dr. Wolf's CHM 201 & 202
12-107 25

110. All of these are meta directing and strongly deactivating
Other EWGs Include:
—EWG =
—NO2
—SO3H —C N
All of these are meta directing and strongly deactivating
Dr. Wolf's CHM 201 & 202
12-108 25

111. Nitration of BenzaldehydeCH O
O2N CH O
HNO3
H2SO4
75-84%
Dr. Wolf's CHM 201 & 202
12-109 26

112. Problem 12.14(a); page 468 Cl O O Cl2 CCl CCl FeCl3 62% 12-110 26
Dr. Wolf's CHM 201 & 202
12-110 26

113. Disulfonation of Benzene
HO3S
SO3
SO3H
H2SO4
90%
Dr. Wolf's CHM 201 & 202
12-111 26

114. Bromination of NitrobenzeneFe
60-75%
Dr. Wolf's CHM 201 & 202
12-112 26

115. Substituent Effects in Electrophilic Aromatic Substitution: Halogens
F, Cl, Br, and I are ortho-para directing, but deactivating
Dr. Wolf's CHM 201 & 202
12-113 8

116. Nitration of ChlorobenzeneCl
NO2 Cl
NO2 Cl
NO2 Cl
HNO3 + +
H2SO4
30% 1%
69%
The rate of nitration of chlorobenzene is about 30 times slower than that of benzene.
Dr. Wolf's CHM 201 & 202
12-114 6

117. Nitration of Toluene vs. Chlorobenzene42
2.5 58 Cl
0.029
0.029
0.009
0.009
0.137
Dr. Wolf's CHM 201 & 202
12-115 15

118. Halogens
thus, for the halogens, the inductive and resonance effects run counter to each other, but the former is somewhat stronger
the net effect is that halogens are deactivating but ortho-para directing 41 41 41

119. Multiple Substituent Effects
Dr. Wolf's CHM 201 & 202
12-116 1

120. all possible EAS sites may be equivalent
The Simplest Case
all possible EAS sites may be equivalent
CH3
CH3 O O
CH3COCCH3
CCH3
AlCl3 +
CH3
99%
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121. Another Straightforward Case
CH3
NO2
CH3 Br
Br2 Fe
NO2
86-90%
directing effects of substituents reinforce each other; substitution takes place ortho to the methyl group and meta to the nitro group
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122. regioselectivity is controlled by the most activating substituent
Generalization
regioselectivity is controlled by the most activating substituent
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12-119 6

123. all possible EAS sites may not be equivalent
The Simplest Case
all possible EAS sites may not be equivalent
strongly activating
NHCH3 Cl
NHCH3 Cl Br
Br2
acetic acid
87%
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124. When activating effects are similar...
CH3
C(CH3)3
CH3
HNO3
H2SO4
NO2
C(CH3)3
88%
substitution occurs ortho to the smaller group
Dr. Wolf's CHM 201 & 202
12-121 5

125. position between two substituents is last position to be substituted
Steric effects control regioselectivity when electronic effects are similar
CH3
NO2
CH3
HNO3
H2SO4
98%
position between two substituents is last position to be substituted
Dr. Wolf's CHM 201 & 202
12-122 5

126. Regioselective Synthesis of Disubstituted Aromatic Compounds
Dr. Wolf's CHM 201 & 202
12-123 7

127. order of introduction of substituents to ensure correct orientation
Factors to Consider
order of introduction of substituents to ensure correct orientation
Dr. Wolf's CHM 201 & 202
12-124 6

128. Synthesis of m-Bromoacetophenone
Which substituent should be introduced first?
CCH3 O
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12-125 8

129. Synthesis of m-Bromoacetophenone
para
If bromine is introduced first, p-bromoacetophenone is major product.
CCH3 O
meta
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12-126 8

130. Synthesis of m-Bromoacetophenone
CCH3 O Br O
CH3COCCH3
Br2
AlCl3
CCH3 O
AlCl3
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131. order of introduction of substituents to ensure correct orientation
Factors to Consider
order of introduction of substituents to ensure correct orientation
Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics
Dr. Wolf's CHM 201 & 202
12-128 6

132. Synthesis of m-Nitroacetophenone
Which substituent should be introduced first?
CCH3 O
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12-129 8

133. Synthesis of m-Nitroacetophenone
If NO2 is introduced first, the next step (Friedel-Crafts acylation) fails.
CCH3 O
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12-130 8

134. Synthesis of m-Nitroacetophenone
CCH3 O O
CH3COCCH3
HNO3
H2SO4
CCH3 O
AlCl3
Dr. Wolf's CHM 201 & 202
12-131 8

135. order of introduction of substituents to ensure correct orientation
Factors to Consider
order of introduction of substituents to ensure correct orientation
Friedel-Crafts reactions (alkylation, acylation) cannot be carried out on strongly deactivated aromatics
sometimes electrophilic aromatic substitution must be combined with a functional group transformation
Dr. Wolf's CHM 201 & 202
12-132 6

136. Synthesis of p-Nitrobenzoic Acid from Toluene
CO2H
CH3
Which first? (oxidation of methyl group or nitration of ring)
NO2
CH3
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12-133 8

137. Synthesis of p-Nitrobenzoic Acid from Toluene
CO2H
nitration gives m-nitrobenzoic acid
CH3
NO2
CH3
oxidation gives p-nitrobenzoic acid
Dr. Wolf's CHM 201 & 202
12-134 8

138. Synthesis of p-Nitrobenzoic Acid from Toluene
NO2
CO2H
CH3
NO2
CH3
HNO3
Na2Cr2O7, H2O
H2SO4, heat
H2SO4
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139. Substitution in Naphthalene
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12-136 1

140. two sites possible for electrophilic aromatic substitution
Naphthalene H H 1 H H 2 H H H H
two sites possible for electrophilic aromatic substitution
all other sites at which substitution can occur are equivalent to 1 and 2
Dr. Wolf's CHM 201 & 202
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141. is faster at C-1 than at C-2
EAS in Naphthalene
CCH3 O O
CH3CCl
AlCl3
90%
is faster at C-1 than at C-2
Dr. Wolf's CHM 201 & 202
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142. carbocation is stabilized by allylic resonance
EAS in Naphthalene E H E H + +
when attack is at C-1
carbocation is stabilized by allylic resonance
benzenoid character of other ring is maintained
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12-139 2

143. EAS in Naphthalene E H + E H + when attack is at C-2
in order for carbocation to be stabilized by allylic resonance, the benzenoid character of the other ring is sacrificed
Dr. Wolf's CHM 201 & 202
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144. Substitution in Heterocyclic Aromatic Compounds
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12-141 1

145. Generalization There is none.
There are so many different kinds of heterocyclic aromatic compounds that no generalization is possible.
Some heterocyclic aromatic compounds are very reactive toward electrophilic aromatic substitution, others are very unreactive..
Dr. Wolf's CHM 201 & 202
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146. Pyridine N
Pyridine is very unreactive; it resembles nitrobenzene in its reactivity.
Presence of electronegative atom (N) in ring causes p electrons to be held more strongly than in benzene.
Dr. Wolf's CHM 201 & 202
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147. Pyridine can be sulfonated at high temperature.
SO3, H2SO4
SO3H N N
HgSO4, 230°C
71%
Pyridine can be sulfonated at high temperature.
EAS takes place at C-3.
Dr. Wolf's CHM 201 & 202
12-144 2

148. Pyrrole, Furan, and Thiophene•• O •• S ••
Have 1 less ring atom than benzene or pyridine to hold same number of p electrons (6).
p electrons are held less strongly.
These compounds are relatively reactive toward EAS..
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149. undergoes EAS readily C-2 is most reactive position
Example: Furan O
CH3COCCH3 O
BF3 +
CCH3 O O
75-92%
undergoes EAS readily C-2 is most reactive position
Dr. Wolf's CHM 201 & 202
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150. End of Chapter 12 (Part a)
Dr. Wolf's CHM 201 & 202