1. Chapter 5-2. 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 p-system
Electrophilic aromatic substitution replaces a proton on benzene with another electrophile

4. Bromination of Aromatic Rings
Benzene’s  electrons participate as a Lewis base in reactions with Lewis acids
The product is formed by loss of a proton, which is replaced by bromine

5. Bromination of Aromatic Rings
FeBr3 is added as a catalyst to polarize the bromine reagent

6. Cationic Intermediate in Bromination
The addition of bromine occurs in two steps
In the first step the  electrons act as a nucleophile toward Br2 (in a complex with FeBr3)

7. This forms a cationic addition intermediate
The intermediate is not aromatic and therefore high in energy

8. Formation of Product from Intermediate
The cationic addition intermediate transfers a proton to FeBr4- (from Br- and FeBr3)
This restores aromaticity (in contrast with addition in alkenes)

10. Other Aromatic Substitutions
The reaction with bromine involves a mechanism that is similar to many other reactions of benzene with electrophiles
The cationic intermediate was first proposed by G. W. Wheland of the University of Chicago and is often called the Wheland intermediate

11. Aromatic Chlorination and Iodination
Chlorine and iodine (but not fluorine, which is too reactive) can produce aromatic substitution in the presence of Lewis acids.
Chlorination requires FeCl3

12. Aromatic Chlorination and Iodination
Iodine must be oxidized to form a more powerful I+ species (with Cu+ or peroxide)

13. Aromatic Nitration
The combination of nitric acid and sulfuric acid produces NO2+ (nitronium ion), which is isoelectronic with CO2

14. Aromatic Nitration
The reaction with benzene produces nitrobenzene

15. Reduction of nitro compounds to amines

16. Aromatic Sulfonation Substitution of H by SO3 (sulfonation)
Reaction with a mixture of sulfuric acid and SO3 (fuming sulfuric acid)
Reactive species is sulfur trioxide or its conjugate acid

17. Aromatic Sulfonation
Sulfur trioxide, or its conjugate acid, react by the usual mechanism:

18. Useful reactions of sulfonic acids
Sulfonic acids are useful as intermediates in the synthesis of sulfa drugs and phenols:

19. Alkylation of Aromatic Rings: The Friedel–Crafts Reaction
Aromatic substitution of “R+” for H, alkylating the ring

20. Alkylation of Aromatic Rings: The Friedel–Crafts Reaction
Aromatic substitution of a R+ for H
Aluminum chloride promotes the formation of the carbocation
Wheland intermediate forms

21. Limitations of the Friedel-Crafts Alkylation
Only alkyl halides can be used (F, Cl, I, Br)
Aryl halides and vinylic halides do not react (their carbocations are too hard to form)

22. Control Problems
Multiple alkylations can occur because the first alkylation is activating

23. Carbocation Rearrangements During Alkylation
Similar to those that occur during electrophilic additions to alkenes

25. Similar reactions:
Mechanism?

26. Solution:

27. Another variation:

28. Acylation of Aromatic Rings
Reaction of an acid chloride (RCOCl) and an aromatic ring in the presence of AlCl3 introduces acyl group, COR

29. Mechanism of Friedel-Crafts Acylation
Similar to alkylation; reactive electrophile is a resonance-stabilized acyl cation, which does not rearrange

30. Problem: acid chloride reactant?

31. Substituent Effects in Aromatic Rings
Substituents can cause a compound to be (much) more or (much) less reactive than benzene

32. Substituent Effects in Aromatic Rings
Substituents affect the orientation of the reaction – the positional relationship is controlled
ortho- and para-directing activators, ortho- and para-directing deactivators, and meta-directing deactivators

34. Origins of Substituent Effects
An interplay of inductive effects and resonance effects
Inductive effect - withdrawal or donation of electrons through a s bond
Resonance effect - withdrawal or donation of electrons through a  bond due to the overlap of a p orbital on the substituent with a p orbital on the aromatic ring

35. Inductive Effects
Controlled by electronegativity and the polarity of bonds in functional groups
Halogens, C=O, CN, and NO2 withdraw electrons through s bond connected to ring
Alkyl groups donate electrons

36. Resonance Effects – Electron Withdrawal
C=O, CN, NO2 substituents withdraw electrons from the aromatic ring by resonance

37. Resonance Effects – Electron Withdrawal

38. Resonance Effects – Electron Donation
Halogen, OH, alkoxyl (OR), and amino substituents donate electrons
Effect is greatest at ortho and para

39. Resonance Effects – Electron Donation

40. Contrasting Effects
Halogen, OH, OR, withdraw electrons inductively so that they deactivate the ring
Resonance interactions are generally weaker, affecting orientation
The strongest effects dominate

41. An 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

43. Electron Donation & Withdrawal from Benzene Rings

44. Ortho- and 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

46. 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

48. Ortho- and 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

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

52. Summary Table: Effect of Substituents in Aromatic Substitution

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

54. Substituents with Opposite Effects
If the directing effects of two groups oppose each other, the more powerful activating group decides the principal outcome

55. Meta-Disubstituted Compounds Are Unreactive between the two groups
The reaction site is too hindered

56. Prob.: Substitution at which positions?

57. Prob.: Major substitution product(s)?

58. Oxidation of Aromatic Compounds
Alkyl side chains can be oxidized to CO2H by strong reagents such as KMnO4 and Na2Cr2O7 if they have a C-H next to the ring
Converts an alkylbenzene into a benzoic acid

59. Prob.: Oxidation products?

60. Reduction of Aromatic Compounds
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
Reduction of an aromatic ring requires more powerful reducing conditions (high pressure or rhodium catalysts)

62. Reduction of Aryl Alkyl Ketones
Aromatic ring activates neighboring carbonyl group toward reduction
Ketone is converted into an alkylbenzene by catalytic hydrogenation over Pd catalyst

63. Synthesis Strategies
These syntheses require planning and consideration of alternative routes
Work through the practice problems in this section following the general guidelines for synthesis and retrosynthetic analysis.

64. Practice Problem:
Synthesize From Benzene:

65. Solutions:

66. Practice Problem:
Synthesize From Benzene:

68. How can we make m-chloropropylbenzene?

69. Putting it all together:

70. Prob.: What’s wrong with these syntheses?

71. Prob.: What’s wrong with these syntheses?

72. Prob.: Synthesize from benzene

73. Prob.: Identify the reagents