16.9 Preparation of Epoxides: A Review and a Preview

1. 16.9Preparation of Epoxides:A Review and a Preview

2. Preparation of Epoxides Epoxides are prepared by two major methods.Both begin with alkenes. reaction of alkenes with peroxy acids(Section 6.18) conversion of alkenes to vicinalhalohydrins, followed by treatmentwith base (Section 16.10)

3. 16.10Conversion of Vicinal Halohydrinsto Epoxides

4. H OH H Br Example H NaOH O H2O H (81%)

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

6. Epoxidation via Vicinal Halohydrins Br Br2 H2O OH antiaddition

7. Epoxidation via Vicinal Halohydrins corresponds to overall syn addition ofoxygen to the double bond Br Br2 NaOH H2O O OH antiaddition inversion

8. Epoxidation via Vicinal Halohydrins corresponds to overall syn addition ofoxygen to the double bond Br H3C Br2 H NaOH H3C H CH3 H H2O H O CH3 OH antiaddition inversion

9. Epoxidation via Vicinal Halohydrins corresponds to overall syn addition ofoxygen to the double bond Br H3C Br2 H3C H H NaOH H3C H H CH3 CH3 H H2O H O CH3 OH antiaddition inversion

10. 16.11Reactions of Epoxides:A Review and a Preview

11. 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 Section 15.4 as a method for the synthesis of alcohols).

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

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

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

15. R CH2 C H O In general... For epoxides where the two carbons of thering are differently substituted: Nucleophiles attack herewhen the reaction iscatalyzed by acids: Anionic nucleophilesattack here:

16. 16.12Nucleophilic Ring-OpeningReactions of Epoxides

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

18. – •• CH3CH2 O •• •• CH2 H2C O Mechanism •• ••

19. – •• CH3CH2 O •• •• CH2 H2C O •• •• CH3CH2 O O CH2CH2 •• •• •• Mechanism •• •• –

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

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

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

23. 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%)

24. 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%)

25. Stereochemistry CH3 H3C R R H NH3 H OH O H2N H R H2O S H H3C CH3 (70%) H3C H d+ d- O H3N H H3C

26. CH3O CH3 H3C CH3 CH3CH CCH3 C C OH H CH3 O Anionic nucleophile attacks less-crowded carbon consistent with SN2-like transition state NaOCH3 CH3OH (53%)

27. MgBr CHCH3 H2C O CH2CHCH3 OH Anionic nucleophile attacks less-crowded carbon + 1. diethyl ether 2. H3O+ (60%)

28. CH(CH2)7CH3 H2C O CH(CH2)7CH3 H3C OH Lithium aluminum hydride reduces epoxides Hydride attacksless-crowdedcarbon 1. LiAlH4, diethyl ether 2. H2O (90%)

29. 16.13Acid-Catalyzed Ring-OpeningReactions of Epoxides

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

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

32. CH2 H2C CH2 H2C + + O O •• •• – •• •• Br Br H H •• •• •• •• •• Mechanism ••

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

34. H O H •• + H Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 1 CH2 CH2 H2C H2C + + O O •• •• H •• H O •• •• H

35. H O H •• •• CH2 H2C + O •• H H + O H •• •• H O CH2CH2 Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 2 ••

36. H + O H •• H H H O •• •• O H •• •• •• H H O CH2CH2 + O H •• •• H O CH2CH2 Figure 16.6 Acid-Catalyzed Hydrolysis of Ethylene Oxide Step 3 •• ••

37. Acid-Catalyzed Ring Opening of Epoxides Characteristics: nucleophile attacks more substituted carbon of protonated epoxide inversion of configuration at site of nucleophilic attack

38. H3C CH3 C C H CH3 O Nucleophile attacks more-substituted carbon consistent with carbocation character at transition state OCH3 CH3OH CH3CH CCH3 H2SO4 CH3 OH (76%)

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

40. 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%)

41. CH3OH H2SO4 Stereochemistry CH3 H3C R R H H OH O CH3O H R S H H3C CH3 H3C H d+ d+ d+ H O CH3O H H H3C

42. H O H CH3COOH O H H anti-Hydroxylation of Alkenes H2O HClO4 H OH H OH (80%)