Chapter 12 Reactions of Arenes: Electrophilic Aromatic Substitution

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

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

3. H E + – + + 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 Br 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 -electron system of aromatic ring highly endothermic carbocation is allylic, but not aromatic

11. H H H E H H H+ Step 2: loss of a proton from the carbocationintermediate highly exothermic this step restores aromaticity of ring H H E 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 + Electrophile isnitronium ion • • O N O • • •• •• Nitration of Benzene H2SO4 + HONO2 + H2O

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

17. H H H NO2 H H H+ Step 2: loss of a proton from the carbocationintermediate H H NO2 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 • + • •• Several electrophiles present: a major one is sulfur trioxide S • O • •• Sulfonation of Benzene heat + HOSO2OH + H2O

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

22. H H H SO3– H H H+ Step 2: loss of a proton from the carbocationintermediate H H SO3– 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 Br Halogenation of Benzene FeBr3 + Br2 + HBr Electrophile is a Lewis acid-Lewis basecomplex between FeBr3 and Br2.

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

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

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

29. 12.6Friedel-Crafts Alkylation of Benzene

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

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

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

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

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

35. 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%)

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

37. 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%)

38. 12.7Friedel-Crafts Acylation of Benzene

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

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

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

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

43. 12.8Acylation-Reduction

44. O O H CR Zn(Hg), HCl CH2R 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

45. 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

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

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

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