Chapter 12 Electrophilic and Nucleophilic Aromatic Substitution

1. H X E Nu + – + + + + E :Nu- Y :X- H Y Chapter 12Electrophilic and NucleophilicAromatic Substitution

2. 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 Nitration of Benzene H2SO4 + HONO2 + H2O Nitrobenzene(95%) Nitric acid : HNO3

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

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

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

8. O O H CCH2CH3 CH3CH2CCl 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. 12.3Nitration of Benzene

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

15. 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

16. H H H NO2 H H H+ Step 2: Loss of a proton from the carbocationintermediate H H NO2 H + H H H

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

18. 12.4Sulfonation of Benzene

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

20. 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

21. H H H SO3– H H H+ Step 2: Loss of a proton from the carbocationintermediate H H SO3– H + H H H

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

23. 12.5Halogenation of Benzene

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

25. + – •• •• •• •• • • • 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

26. 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

27. H H H Br H H H+ Step 2: Loss of a proton from the carbocationintermediate H H Br H + H H H

28. 12.6Friedel-Crafts Alkylation of Benzene

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

30. + – •• • 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 ••

31. + 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

32. 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

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

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

35. 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%)

36. 12.7Friedel-Crafts Acylation of Benzene

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

38. 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

39. 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

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

41. 12.8Synthesis of Alkylbenzenes by Acylation-Reduction

42. 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

43. 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

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

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

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

47. 12.9Rate and Regioselectivity in Electrophilic Aromatic Substitution A substituent already present on the ring can affect both the rate and regioselectivityof electrophilic aromatic substitution. EAS or SEAr

48. 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. Electron Donating Group : EDG Electron Withdrawing Group : EWG

49. CH3 Methyl Group Toluene undergoes nitration 20-25 times faster than benzene. A methyl group is an activating substituent. : EDG or ERG

50. CF3 Trifluoromethyl Group (Trifluoromethyl)benzene undergoes nitration 40,000 times more slowly than benzene . A trifluoromethyl group is adeactivating substituent : EWG