Chapter 16 Ethers, Epoxides, and Sulfides

1. Chapter 16Ethers, Epoxides, and Sulfides

2. 16.5Preparation of Ethers

3. H2SO4, 130°C Acid-Catalyzed Condensation of Alcohols 2CH3CH2CH2CH2OH CH3CH2CH2CH2OCH2CH2CH2CH3 (60%)

4. Addition of Alcohols to Alkenes H+ (CH3)2C=CH2 + CH3OH (CH3)3COCH3 tert-Butyl methyl ether tert-Butyl methyl ether (MTBE) was produced on ascale exceeding 15 billion pounds per year in the U.S.during the 1990s. It is an effective octane rating booster ingasoline, but contaminates ground water if allowed toleak from storage tanks. Further use of MTBE is unlikely.

5. 16.6The Williamson Ether Synthesis Think SN2! Primary alkyl halide + alkoxide nucleophile.

6. Example CH3CH2CH2CH2ONa +CH3CH2I CH3CH2CH2CH2OCH2CH3+ NaI (71%)

7. Williamson Ether Synthesis Has Limitations 1) Alkyl halide must be primary (RCH2X). 2) Alkoxides can be derived from primary, secondary or tertiary alcohols.

8. CH3CHCH3 CH2Cl + ONa CH2OCHCH3 (84%) CH3 Williamson Ether Synthesis Has Limitations 1) Alkyl halide must be primary (RCH2X). 2) Alkoxides can be derived from primary, secondary or tertiary alcohols. The reaction works particularly well with benzyl and allyl halides, which are excellent alkylating agents.

9. CH3CHCH3 CH2OH OH HCl Na CH3CHCH3 CH2Cl + ONa CH2OCHCH3 (84%) CH3 Origin of Reactants

10. + CH3CHCH3 CH2ONa Br CHCH3 H2C + CH2OH Elimination by the E2 mechanism becomesthe major reaction pathway. What Happens if the Alkyl Halide Is Not Primary?

11. 16.7Reactions of Ethers:A Review and a Preview

12. Summary of Reactions of Ethers No reactions of ethers encountered to this point. Ethers are relatively unreactive. Their low level of reactivity is one reason why ethers are often used as solvents in chemical reactions. Ethers oxidize in air to form explosive hydroperoxides and peroxides.

13. 16.8Acid-Catalyzed Cleavage of Ethers

14. Example HBr CH3CHCH2CH3 CH3CHCH2CH3 + CH3Br heat OCH3 Br (81%)

15. CH3CHCH2CH3 CH3CHCH2CH3 O Br •• •• CH3 •• HBr Br H •• •• CH3CHCH2CH3 CH3CHCH2CH3 O •• + •• H – O •• •• CH3 •• H Br •• •• Br CH3 •• •• •• Mechanism

16. O Cleavage of Cyclic Ethers HI ICH2CH2CH2CH2I 150°C (65%)

17. ICH2CH2CH2CH2I O HI HI – •• •• I •• •• •• •• •• I •• + O •• O •• H H Mechanism •• ••

18. 16.9Preparation of Epoxides:A Review and a Preview

19. Preparation of Epoxides Epoxides are prepared by two major methods.Both begin with alkenes. Reaction of alkenes with peroxy acids(6.19). Conversion of alkenes to vicinalhalohydrins (6.18), followed by treatmentwith base (16.10).

20. 16.10Conversion of Vicinal Halohydrinsto Epoxides

21. H OH H Br •• – O via: •• •• H H Br •• •• •• Example H NaOH O H2O H (81%)

22. H3C H H3C H H CH3 CH3 H Epoxidation via Vicinal Halohydrins Br H3C Br2 H NaOH H2O H O CH3 OH Antiaddition Inversion Corresponds to overall syn addition ofoxygen to the double bond.

23. 16.11Reactions of Epoxides:A Review and a Preview

24. Reactions of Epoxides All reactions involve nucleophilic attack at carbon and lead to opening of the ring. An example is the reaction of ethylene oxide with a Grignard reagent (discussed in 15.4 as a method for the synthesis of alcohols).

25. R MgX R CH2 CH2 CH2 OMgX H2C O H3O+ RCH2CH2OH Reaction of Grignard Reagentswith Epoxides

26. CH2MgCl CH2CH2CH2OH Example CH2 H2C + O 1. diethyl ether 2. H3O+ (71%)

27. CH2 H2C O Nu—CH2CH2O—H In General... Reactions of epoxides involve attack by anucleophile and proceed with ring-opening.For ethylene oxide: + Nu—H

28. Nucleophiles attack herewhen the reaction iscatalyzed by acids. Anionic and other good nucleophiles in non-acidic conditions attack here. R CH2 C H O In General... For epoxides where the two carbons of thering are differently substituted:

29. 16.12Nucleophilic Ring-OpeningReactions of Epoxides

30. CH2 H2C O CH3CH2O CH2CH2OH Example NaOCH2CH3 CH3CH2OH (50%)

31. – •• CH3CH2 O •• •• CH2 H2C O •• •• •• O CH2CH3 •• – •• •• CH3CH2 O O CH2CH2 H •• •• •• – •• •• •• CH3CH2 O O CH2CH2 O CH2CH3 H •• •• •• •• Mechanism

32. CH2 H2C O CH3CH2CH2CH2S CH2CH2OH (99%) Example KSCH2CH2CH2CH3 ethanol-water, 0°C

33. H NaOCH2CH3 H CH3CH2OH O Stereochemistry Inversion of configuration at carbon being attacked by nucleophile. Suggests SN2-like transition state. OCH2CH3 H H OH (67%)

34. Stereochemistry CH3 H3C Inversion of configuration at carbon being attacked by nucleophile. Suggests SN2-like transition state. R R H NH3 H OH O H2N H R H2O S H H3C CH3 (70%)

35. Stereochemistry CH3 H3C R R H NH3 H OH O H2N H R H2O S H H3C CH3 (70%) H3C H - O H3N H H3C

36. CH3O CH3 H3C CH3 CH3CH CCH3 C C OH H CH3 O Good Nucleophiles Attack Less-Crowded Carbon Consistent with SN2-like transition state. NaOCH3 CH3OH (53%)

37. MgBr CHCH3 H2C O CH2CHCH3 OH (60%) Good Nucleophiles Attack Less-Crowded Carbon + 1. diethyl ether 2. H3O+

38. CH(CH2)7CH3 H2C O CH(CH2)7CH3 H3C OH (90%) Lithium Aluminum Hydride Reduces Epoxides 1. LiAlH4, diethyl ether 2. H2O Hydride anion attacksless-crowdedcarbon.

39. 16.13Acid-Catalyzed Ring-OpeningReactions of Epoxides

40. CH2 H2C O Example CH3CH2OCH2CH2OCH2CH3 formed only on heating and/or longer reaction times. CH3CH2OH CH3CH2OCH2CH2OH H2SO4, 25°C (87-92%)

41. CH2 H2C O Example BrCH2CH2Br formed only on heating and/or longer reaction times with excess HBr. HBr BrCH2CH2OH 10°C (87-92%)

42. – •• Br •• •• •• CH2 H2C CH2 H2C + O O •• •• •• Br H H •• •• •• Br •• •• •• H O CH2CH2 •• Mechanism ••

43. CH2 H2C + O H •• H H O H O •• + •• •• H H Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 1 CH2 H2C O •• ••

44. H O H •• •• CH2 H2C + O •• H H + O H •• •• H O CH2CH2 •• Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 2

45. H + O H •• H H H O •• •• O H •• •• •• H H O CH2CH2 •• + O H •• •• H O CH2CH2 Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 3 ••

46. Acid-Catalyzed Ring Opening of Epoxides Characteristics: Nucleophile attacks more substituted carbon of protonated epoxide. Inversion of configuration at site of nucleophilic attack.

47. OCH3 H3C CH3 CH3CH CCH3 C C CH3 OH H CH3 O (76%) Nucleophile Attacks More-Substituted Carbon Consistent with carbocation character of transition state. CH3OH H2SO4

48. H O H Stereochemistry H Inversion of configuration at carbon being attacked by nucleophile. OH HBr H Br (73%)

49. CH3OH H2SO4 Stereochemistry CH3 H3C Inversion of configuration at carbon being attacked by nucleophile. R R H H OH O CH3O H R S H H3C CH3 (57%)

50. CH3OH H2SO4 Stereochemistry CH3 H3C R R H H OH O CH3O H R S H H3C CH3 H3C H + + + H O CH3O H H H3C