1. 16. Chemistry of Benzene: Electrophilic Aromatic Substitution

2. Substitution Reactions of Benzene and Its Derivatives
Benzene is aromatic: a cyclic conjugated compound with 6  electrons
Reactions of benzene lead to the retention of the aromatic core

3. Why this Chapter?
Continuation of coverage of aromatic compounds in preceding chapter…focus shift to understanding reactions
Examine relationship between aromatic structure and reactivity
Relationship critical to understanding of how biological molecules/pharmaceutical agents are synthesized

4. 16.1 Electrophilic Aromatic Substitution Reactions (EAS):
Reactions typical of addition to alkenes do not work on aromatic double bonds.
Need more electrophilic (more positive) halogen in order to break an aromatic double bond.

5. EAS: Bromination
EAS occurs in two steps: Addition followed by Elimination
FeBr3 acts as a catalyst to polarize the bromine reagent and so make it more positive (more electrophilic)
The  electrons of the aromatic ring act as a nucleophile toward the now more electrophilic Br2 (in the FeBr3 complex)
Addition
The cationic addition intermediate is called a sigma complex

6. EAS: Bromination
EAS occurs in two steps: Addition followed by Elimination
The cationic addition intermediate (sigma complex) transfers a proton to FeBr4- (from Br- and FeBr3)
Aromaticity is restored
(in contrast with addition in alkenes which is not followed by elimination)
Addition
Elimination

7. EAS: Bromination
EAS occurs in two steps: Addition followed by Elimination
The cationic addition intermediate (sigma complex) transfers a proton to FeBr4- (from Br- and FeBr3)
Aromaticity is restored
(in contrast with addition in alkenes which is not followed by elimination)
Elimination is driven by the stability of becoming aromatic

8. 16.2 Other Aromatic Substitutions
Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution products
Chlorination requires FeCl3
Iodine must be oxidized (with Cu+ or peroxide)
to form a more powerful I+ species

9. Example:
A common Amino Acid

10. Aromatic Nitration
The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion)
The reaction with benzene produces nitrobenzene

11. Reduction of Nitration Product:
To put an amino (NH2) group on an aromatic ring
first Nitrate
then reduce

12. Aromatic Sulfonation
Substitution of H by SO3 (sulfonation) with a mixture of sulfuric acid and SO3
Reactive species is sulfur trioxide or its conjugate acid
Reaction is Reversible:
Can remove sulfonyl group with H+,H2O, heat

13. Aromatic Hydroxylation
Hard to directly add –OH to an aromatic ring in lab.
Formation of Electrophile

14. Aromatic Hydroxylation
Biological systems use Enzymes to hydroxylate aromatics

15. 16.3 Alkylation of Aromatic Rings: The Friedel–Crafts Reaction
Electrophilic C+ forms
Alkylation (substitution of Carbon compounds) among most useful electrophilic aromatic subsitution reactions
Aromatic substitution of R+ for H+
Aluminum chloride promotes the formation of the carbocation
Addition
Elimination

16. Friedel-Crafts Alkylation: Limitations
Only alkyl halides can be used (F, Cl, I, Br)
Aryl halides (Ar-X) and vinylic halides (CH2=CH-X) do not react (their carbocations are too hard to form)
Will not work with rings containing an amino group substituent or a strongly electron-withdrawing group

17. Friedel-Crafts Alkylation: Control Problems
Multiple alkylations can occur because the first alkylation is activating (makes aromatic ring more nucleophilic so more likely to add again)

18. Friedel-Crafts Alkylation: Control Problems
Carbocation Rearrangements
Similar to those that occur during electrophilic additions to alkenes
Can involve H or alkyl shifts

19. Example:

20. Friedel-Crafts Acylation
Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, COR
Benzene with acetyl chloride yields acetophenone

21. Friedel-Crafts Acylation: Mechanism
Similar to alkylation
Reactive electrophile: resonance-stabilized acyl cation
An acyl cation does not rearrange
Electrophilic C+ forms
= Acylium ion
Addition
Elimination

22. EAS: Summary

23. 16.4 Substituent Effects
Nucleophile
Electrophile
Substituents that donate electrons make ring more nucleophilic
Electron donating groups (edg) activate the ring toward EAS
Substitutients that withdraw electrons make less nucleophilic
Electron withdrawing groups (ewg) deactivate the ring toward EAS

24. Substituent Effects Substituents influence by induction
edg activate the ring toward EAS
ewg deactivate the ring toward EAS
Halogens, C=O, CN, and NO2 withdraw electrons through s bond connected to ring
Alkyl groups donate electrons

25. Substituent Effects Substituents influence by resonance
Halogen, OH, alkoxyl (OR), and amino substituents donate electrons
edg activate the ring toward EAS

26. Substituent Effects Substituents influence by resonance
C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonance
ewg deactivate the ring toward EAS

27. Substituent Effects Substituents influence by resonance
edgs put negative character at o- and p- positions
(make o- and p- positions more nucleophilic)
Direct incoming electrophile into o- or p- spots
ewgs put positive character at o- and p- positions
(make o- and p- positions less nucleophilic)
Direct incoming electrophile into m- spots

29. Explanation of Substituent Effects
Activating groups donate electrons to the ring, stabilizing the Wheland intermediate (carbocation)
Deactivating groups withdraw electrons from the ring, destabilizing the Wheland intermediate

30. 16.5 Ortho- & Para-Directing Activators: Alkyl Groups
Alkyl groups activate: direct further substitution to positions ortho and para to themselves
Alkyl group is most effective in the ortho and para positions

31. Ortho- and Para-Directing Activators: OH and NH2
Alkoxyl, and amino groups have a strong, electron-donating resonance effect
Most pronounced at the ortho and para positions

32. Ortho- & Para-Directing Deactivators: Halogens
Electron-withdrawing inductive effect outweighs weaker electron-donating resonance effect
Resonance effect is only at the ortho and para positions, stabilizing carbocation intermediate

33. Meta-Directing Deactivators
Inductive and resonance effects reinforce each other
Ortho and para intermediates destabilized by deactivation of carbocation intermediate
Resonance cannot produce stabilization

34. Summary:

35. Another Summary:

36. 16.6 Trisubstituted Benzenes: Additivity of Effects
If the directing effects of the two groups are the same, the result is additive

37. Learning Check:
Br2, FeBr3 ?

38. Solution:
Br2, FeBr3 ?

40. Substituents with Opposite Effects
If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome
Usually gives mixtures of products

41. Meta-Disubstituted Compounds
The reaction site is too hindered
To make aromatic rings with three adjacent substituents, it is best to start with an ortho-disubstituted compound

42. 16.7 Nucleophilic Aromatic Substitution
Aryl halides with ewg’s o- and p- react with nucleophiles
Sanger’s reagent: For labeling proteins in biochemistry

43. Nucleophilic Aromatic Substitution

44. Nucleophilic Aromatic Substitution

45. Nucleophilic Aromatic Substitution
ewg’s o- and p- stabilize the intermediate
Intermediate Meisenheimer complex is stabilized by electron-withdrawal
Halide ion is lost to give aromatic ring

46. 16.8 Benzyne
Phenol is prepared on an industrial scale by treatment of chlorobenzene with dilute aqueous NaOH at 340°C under high pressure
Elimination reaction gives a triple bond intermediate called benzyne

47. Evidence for Benzyne
Bromobenzene with 14C* only at C1 gives substitution product with label scrambled between C1 and C2
Reaction proceeds through a symmetrical intermediate in which C1 & C2 are equivalent— must be benzyne

48. Structure of Benzyne Benzyne is a highly distorted alkyne
The triple bond uses sp2-hybridized carbons, not the usual sp
The triple bond has one  bond formed by p–p overlap and another by weak sp2–sp2 overlap

49. 16.9 Benzylic Oxidation
Alkyl side chains with a C-H next to the ring can be oxidized to CO2H by strong reagents such as
KMnO4 and
Na2Cr2O7
O2, Co(III)
Converts an alkylbenzene into a benzoic acid,
ArR  ArCO2H

50. Examples:

51. Benzylic Bromination
Reaction of an alkylbenzene with N-bromo-succinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain

52. Mechanism of NBS (Radical) Reaction
Abstraction of a benzylic hydrogen atom by a bromine radical generates an intermediate benzylic radical which reacts with Br2 to yield product
Br· radical cycles back into reaction to carry chain

53. Mechanism of NBS (Radical) Reaction
Benzylic radical is stabilized by resonance

54. 16.10 Aromatic Reductions
Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds
Can selectively reduce an alkene double bond in the presence of an aromatic ring

55. Aromatic Reductions
Reduction of aromatic ring requires more powerful reducing conditions
high pressure
rhodium catalysts

56. Reduction of Aryl Alkyl Ketones
Aromatic ring activates neighboring carbonyl group toward reduction
Ketone is converted into an alkylbenzene by cat H2/Pd

57. Examples:

58. Learning Check: Synthesize para-chlorobenzoic acid from benzene.
Synthesize meta-chlorobenzoic acid from benzene.

59. Solution: Synthesize para-chlorobenzoic acid from benzene.
Synthesize meta-chlorobenzoic acid from benzene.

60. 16.11 Synthesis of Trisubstituted Benzenes
plan a sequence of reactions in right order is valuable to synthesis of substituted aromatic rings

61. Synthesis of Trisubstituted Benzenes
Work Backwards

62. Synthesis of Trisubstituted Benzenes
Work Backwards

63. Synthesis of Trisubstituted Benzenes

64. Learning Check:
Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.

65. Solution:
Synthesize 4-chloro-2-propylbenzenesulfonic acid from benzene.

66. Learning Check:
Which of the following groups is an activator?

67. Solution: Which of the following groups is an activator?
Generally and except for the halogens, groups with lone pairs of electrons adjacent to the ring are activators.

68. Learning Check:
Which of the following groups is an ortho- para- director?
-Cl
-CHO
-CN
-NO2
None of the above

69. Solution: Which of the following groups is an ortho- para- director?
-Cl
-CHO
-CN
-NO2
None of the above
Although –Cl is a deactivator, it’s lone pairs of electrons stabilize electrophilic aromatic substitution reactions and it is an o- p- director.

70. Learning Check:
Which of the following groups most strongly activates an aromatic ring toward Friedel-Crafts acylation?
-NH2
-OCH3
-O-C(=O)CH3
NO2 H

71. Solution:
Which of the following groups most strongly activates an aromatic ring toward Friedel-Crafts acylation?
Although the –NH2 group is a stronger activator it complexes with AlCl3 to form a strongly deactivating ammonium group. Consequently, the methoxy is a better activator.
-NH2
-OCH3
-O-C(=O)CH3
NO2 H

72. Learning Check:
Which compound is the major product of the chlorination shown below?

73. Solution:
Which compound is the major product of the chlorination shown below?
The nitrogen is an activator and o- p- director. The C=O is a deactivator.

74. Learning Check:
Which step in the following reaction will cause the proposed synthesis to fail?

75. Solution:
Which step in the following reaction will cause the proposed synthesis to fail?
Addition of water in step “D” occurs with Markovnikov selectivity.

76. What is the major product of the reaction of nitrobenzene with Br2/FeBr3?1. 2. 3. 4. 5. 1 2 3 4 5

77. Which of the following compounds would react fastest with HNO3/H2SO4?
nitrobenzene (PhNO2)
toluene (PhCH3)
bromobenzene (PhBr)
anisole (PhOCH3)
benzoic acid (PhCOOH)

78. Which structure is a major intermediate formed in the electrophilic nitration of chlorobenzene?1. 2. 3. 5. 4. 1 2 3 4 5

79. Which series of reactions will convert benzene into p-nitrobenzoic acid?
CH3Br/AlBr3 followed by HNO3/H2SO4 followed by KMnO4/H2O
HNO3/H2SO4 followed by KMnO4/H2O followed by CH3Br/AlBr3
KMnO4/H2O followed by CH3Br/FeBr3 followed by HNO3/H2SO4
CH3Br/AlBr3 followed by KMnO4/H2O followed by HNO3/H2SO4
HNO3/H2SO4 followed by CH3Br/AlBr3 followed by KMnO4/H2O

80. Select the major product of the following reaction.1. 2. 3. 4. 5. 1 2 3 4 5

81. What is the electrophile in the following aromatic substitution?2. 1. 3. 5. 4. 1 2 3 4 5

82. What is the best sequence of reactions to synthesize the desired product (Pr = propyl)?
Step 1
Step 2
Step 3 1
HNO3/H2SO4
PrMgBr/H3O+
H2/Pd 2
AlCl3/PrBr 3
AlCl3/PrCl 4 5
AlCl3/CH3CH2COCl X

83. What are the reagents necessary for step 3 in the following transformation?
CH3COCl/AlCl3
CH3CH2Br/AlBr3
SO3/H2SO4
H2/Pd
SOCl2/AlCl3

84. Which of the following carbons of the benzyl radical has the smallest unpaired electron density?1 2 3 4 5

85. What would be the main product of nitration of benzenesulfonic acid?
o-nitrobenzenesulfonic acid
p-nitrobenzenesulfonic acid
2-nitrobenzoic acid
m-nitrobenzenesulfonic acid
m-nitrobenzoic acid

86. Fluorine is less deactivating than chlorine in the aromatic electrophilic substitution reactions. What is the main reason for this reactivity trend?
Fluorine forms stronger π bonds than chlorine, providing more resonance stabilization.
Chlorine is more electronegative than fluorine.
Because of it size chlorine has stronger inductive influence than fluorine.
Fluorine is smaller, making the entry of electrophiles easier.
Chlorine forms complexes with electrophiles, diminishing their reactivity.

87. Which of the following represent the intermediate formed in the reaction between p-chloronitrobenzene and hydroxide ion? 1. 2. 3. 4. 5. 1 2 3 4 5

88. Based on the electronic structure, what kind of substituent effect would you expect from the nitroso group?
o,p-directing, deactivating
o,p-directing activating
m-directing, activating
m-directing, deactivating

89. Which one is not a limitation of Friedel-Crafts alkylations?
carbocation rearrangements may occur
polyalkylation products are possible
only substrates with selected activating groups can be used
vinyl halides cannot be used to generate electrophiles
the halogen in the aluminum halide must match one in the alkyl halide

90. What is the major product of the following reaction?1. 2. 3. 5. 4. 1 2 3 4 5

91. What is the result of the reaction between m-bromotoluene and sodium amide?
2-aminotoluene
3-aminotoluene
4-aminotoluene
all of these
none of these

92. Aromatic compounds can be oxidized to their radical cations by removal of just one electron. Which of the following will be the easiest to oxidize to a radical cation? 1. 2. 3. 5. 4. 1 2 3 4 5

93. HNO3/H2SO4 Cl2/FeBr3 I2/CuCl2 SO3/H2SO4 CH3COCl/AlBr3
Which of the following is not a practical method to generate an electrophile for aromatic substitution reaction?
HNO3/H2SO4
Cl2/FeBr3
I2/CuCl2
SO3/H2SO4
CH3COCl/AlBr3