Chapter 12 Reactions of Arenes: Electrophilic Aromatic Substitution

1. H E d+ d– + + E Y H Y Chapter 12Reactions of Arenes:Electrophilic Aromatic Substitution

2. H E d+ d– + + E Y H Y 12.1Representative Electrophilic Aromatic Substitution Reactions of Benzene

3. H E d+ d– + + E Y H Y Electrophilic aromatic substitutions include: Nitration Sulfonation Halogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation

4. H NO2 Table 12.1: Nitration of Benzene H2SO4 + HONO2 + H2O Nitrobenzene(95%)

5. H SO2OH Table 12.1: Sulfonation of Benzene heat + HOSO2OH + H2O Benzenesulfonic acid(100%)

6. H Br2 Table 12.1: Halogenation of Benzene FeBr3 + Br2 + HBr Bromobenzene(65-75%)

7. H C(CH3)3 Table 12.1: Friedel-Crafts Alkylation of Benzene AlCl3 + (CH3)3CCl + HCl tert-Butylbenzene(60%)

8. O O H CCH2CH3 CH3CH2CCl Table 12.1: Friedel-Crafts Acylation of Benzene AlCl3 + + HCl 1-Phenyl-1-propanone(88%)

9. 12.2Mechanistic PrinciplesofElectrophilic Aromatic Substitution

10. E+ H H E H H H H H + H H H H H Step 1: attack of electrophileon p-electron system of aromatic ring highly endothermic carbocation is allylic, but not aromatic

11. Step 2: loss of a proton from the carbocationintermediate highly exothermic this step restores aromaticity of ring H H E H H H H E + H H H H H H+

12. H H E H + H H H H H H H + E+ + H+ H H H E H H H H

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

14. 12.3Nitration of Benzene

15. H NO2 + • • O N O • • •• •• Nitration of Benzene H2SO4 + HONO2 + H2O Electrophile isnitronium ion

16. NO2+ H H NO2 H H H H H + H H H H H Step 1: attack of nitronium cationon p-electron system of aromatic ring

17. Step 2: loss of a proton from the carbocationintermediate H H NO2 H H H H NO2 + H H H H H H+

18. – •• •• – •• •• • • O • O • O • O + • • + • •• •• N N + O • O • •• •• H H H •• + O • • O N O •• • • H H •• •• Where does nitronium ion come from? H2SO4 +

19. 12.4Sulfonation of Benzene

20. H SO2OH – •• •• • • O O • + • •• S • O • •• Sulfonation of Benzene heat + HOSO2OH + H2O Several electrophiles present: a major one is sulfur trioxide

21. SO3 H H SO3– H H H H H + H H H H H Step 1: attack of sulfur trioxideon p-electron system of aromatic ring

22. Step 2: loss of a proton from the carbocationintermediate H H SO3– H H H H SO3– + H H H H H H+

23. H H H H H SO3– H SO3H H H H H Step 3: protonation of benzenesulfonate ion H2SO4

24. 12.5Halogenation of Benzene

25. H Br2 Halogenation of Benzene FeBr3 + Br2 + HBr Electrophile is a Lewis acid-Lewis basecomplex between FeBr3 and Br2.

26. + – •• •• •• •• • • • Br Br Br Br FeBr3 • • • •• •• •• •• The Br2-FeBr3 Complex The Br2-FeBr3 complex is more electrophilic than Br2 alone. + FeBr3 Lewis base Lewis acid Complex

27. H H Br H + H H H Step 1: attack of Br2-FeBr3 complex on p-electron system of aromatic ring + – Br Br FeBr3 H H H H H H + FeBr4–

28. Step 2: loss of a proton from the carbocationintermediate H H Br H H H H Br + H H H H H H+

29. 12.6Friedel-Crafts Alkylation of Benzene

30. H C(CH3)3 H3C + CH3 C H3C Friedel-Crafts Alkylation of Benzene AlCl3 + (CH3)3CCl + HCl Electrophile is tert-butyl cation

31. + – •• • AlCl3 (CH3)3C Cl • •• Role of AlCl3 acts as a Lewis acid to promote ionizationof the alkyl halide •• + (CH3)3C Cl AlCl3 ••

32. + – •• • AlCl3 (CH3)3C Cl • •• – •• • AlCl3 Cl • •• Role of AlCl3 acts as a Lewis acid to promote ionizationof the alkyl halide •• + (CH3)3C Cl AlCl3 •• + + (CH3)3C

33. + C(CH3)3 H H C(CH3)3 H + H H H Step 1: attack of tert-butyl cationon p-electron system of aromatic ring H H H H H H

34. Step 2: loss of a proton from the carbocationintermediate H H C(CH3)3 H H H H C(CH3)3 + H H H H H H+

35. H C(CH3)3 AlCl3 Rearrangements in Friedel-Crafts Alkylation Carbocations are intermediates. Therefore, rearrangements can occur + (CH3)2CHCH2Cl Isobutyl chloride tert-Butylbenzene(66%)

36. H C(CH3)3 AlCl3 Rearrangements in Friedel-Crafts Alkylation Isobutyl chloride is the alkyl halide. But tert-butyl cation is the electrophile. + (CH3)2CHCH2Cl Isobutyl chloride tert-Butylbenzene(66%)

37. H •• AlCl3 H3C Cl C CH2 •• CH3 – •• • AlCl3 Cl • •• Rearrangements in Friedel-Crafts Alkylation + – H + + H3C C CH2 CH3

38. H Reactions Related to Friedel-Crafts Alkylation Cyclohexene is protonated by sulfuric acid, giving cyclohexyl cation which attacks the benzene ring H2SO4 + Cyclohexylbenzene(65-68%)

39. 12.7Friedel-Crafts Acylation of Benzene

40. H + + •• • • CH3CH2C O CH3CH2C O • • Friedel-Crafts Acylation of Benzene O O CCH2CH3 AlCl3 + CH3CH2CCl + HCl Electrophile is an acyl cation

41. O O CCH2CH3 + CCH2CH3 Step 1: attack of the acyl cationon p-electron system of aromatic ring H H H H H H H + H H H H H

42. O O CCH2CH3 CCH2CH3 Step 2: loss of a proton from the carbocationintermediate H H H H H H + H H H H H H+

43. O O O H CCH3 CH3COCCH3 O + CH3COH Acid Anhydrides can be used instead of acyl chlorides AlCl3 + Acetophenone(76-83%)

44. 12.8Acylation-Reduction

45. O O H CR Acylation-Reduction permits primary alkyl groups to be attachedto an aromatic ring Reduction of aldehyde and ketonecarbonyl groups using Zn(Hg) and HCl is called the Clemmensen reduction. RCCl AlCl3 Zn(Hg), HCl CH2R

46. O O H CR Acylation-Reduction permits primary alkyl groups to be attachedto an aromatic ring Reduction of aldehyde and ketonecarbonyl groups by heating with H2NNH2and KOH is called theWolff-Kishner reduction. RCCl H2NNH2, KOH,triethylene glycol,heat AlCl3 CH2R

47. Example: Prepare isobutylbenzene No! Friedel-Crafts alkylation of benzene using isobutyl chloride fails because of rearrangement. (CH3)2CHCH2Cl CH2CH(CH3)3 AlCl3

48. C(CH3)3 AlCl3 Recall + (CH3)2CHCH2Cl Isobutyl chloride tert-Butylbenzene(66%)

49. O (CH3)2CHCCl CH2CH(CH3)3 O CCH(CH3)2 Use Acylation-Reduction Instead + AlCl3 Zn(Hg)HCl