17.8 Acetal Formation

1. 17.8Acetal Formation

2. Some reactions of aldehydes and ketones progressbeyond the nucleophilic addition stage • Acetal formation • Imine formation • Enamine formation • Compounds related to imines • The Wittig reaction

3. R O C •• •• R' HOH R •• •• HO O H C •• •• R' Recall Hydration of Aldehydes and Ketones

4. R O C •• •• R' R"OH R •• •• R"O O H C •• •• R' Alcohols Under Analogous Reactionwith Aldehydes and Ketones • Product is called a hemiacetal.

5. R •• •• R"O OR C •• •• R' R •• •• R"O O H C •• •• R' Hemiacetal reacts further in acid to yield an acetal • Product is called an acetal. ROH, H+ Product is called a hemiacetal.

6. O CH CH(OCH2CH3)2 Example + 2CH3CH2OH HCl + H2O Benzaldehyde diethyl acetal (66%)

7. O H2C CH2 O O C (CH2)5CH3 H Diols Form Cyclic Acetals + CH3(CH2)5CH HOCH2CH2OH benzene p-toluenesulfonic acid + H2O (81%)

8. In general: • Position of equilibrium is usually unfavorablefor acetal formation from ketones. • Important exception: Cyclic acetals can be prepared from ketones.

9. O Example C6H5CH2CCH3 + HOCH2CH2OH benzene p-toluenesulfonic acid H2C CH2 O + O H2O (78%) C CH3 C6H5CH2

10. Mechanism of Acetal Formation • First stage is analogous to hydration andleads to hemiacetal • acid-catalyzed nucleophilic addition of alcohol to C=O

11. H •• O O H C •• •• + R Mechanism

12. Mechanism H •• + O O C •• •• H R

13. R O •• •• H Mechanism •• + O C H

14. •• O •• R H Mechanism R •• •• O O C •• + H H

15. R •• •• O O C •• •• H H + O •• R H Mechanism

16. Mechanism of Acetal Formation • Second stage is hemiacetal-to-acetal conversion • involves carbocation chemistry

17. H R •• •• O H O O C •• •• + •• H R Hemiacetal-to-acetal Stage

18. H R H •• •• O + O O C •• •• •• H R Hemiacetal-to-acetal Stage

19. R H •• •• + O O C •• H Hemiacetal-to-acetal Stage

20. R H •• •• O + C O •• •• H Hemiacetal-to-acetal Stage

21. R R + •• O + O C C •• •• Hemiacetal-to-acetal Stage Carbocation is stabilized by delocalizationof unshared electron pair of oxygen

22. R R •• •• O + C O •• •• H Hemiacetal-to-acetal Stage

23. R R •• •• + R O O C •• •• H O •• H Hemiacetal-to-acetal Stage

24. R R •• •• R O O C •• •• •• H O + H Hemiacetal-to-acetal Stage

25. OR" O + C 2R"OH R C R' + H2O R R' OR" Hydrolysis of Acetals • mechanism: • reverse of acetal formation;hemiacetal is intermediate • application: • aldehydes and ketones can be "protected" as acetals.

26. 17.9Acetals as Protecting Groups

27. O CH CH3CCH2CH2C O CCH3 CH3CCH2CH2C Example • The conversion shown cannot be carried outdirectly... 1. NaNH22. CH3I

28. O C: CH3CCH2CH2C because the carbonyl group and thecarbanion are incompatible functionalgroups. –

29. Strategy • 1) protect C=O • 2) alkylate • 3) restore C=O

30. O CH H2C CH2 O O C CH CH3 Example: Protect + HOCH2CH2OH CH3CCH2CH2C benzene p-toluenesulfonic acid CH2CH2C

31. H2C CH2 O O C CH2CH2C CCH3 CH3 H2C CH2 O O C CH CH3 Example: Alkylate 1. NaNH22. CH3I CH2CH2C

32. H2C CH2 O O C CH2CH2C CCH3 CH3 O CCH3 CH3CCH2CH2C Example: Deprotect H2O HCl + HOCH2CH2OH (96%)

33. 17.10Reaction with Primary Amines:Imines

34. Some reactions of aldehydes and ketones progressbeyond the nucleophilic addition stage • Acetal formation • Imine formation • Compounds related to imines • Enamines • The Wittig reaction

35. Some reactions of aldehydes and ketones progressbeyond the nucleophilic addition stage • Acetal formation • Imine formation • Compounds related to imines • Enamines • The Wittig reaction

36. •• •• + H H2N HN C O C O •• •• •• •• R R a carbinolamine •• N + H2O C (imine) R Imine (Schiff's Base) Formation

37. O CH Example + CH3NH2 CH=NCH3 + H2O N-Benzylidenemethylamine (70%)

38. O CH OH CH NHCH3 Example + CH3NH2 CH=NCH3 + H2O N-Benzylidenemethylamine (70%)

39. Example + (CH3)2CHCH2NH2 O NCH2CH(CH3)2 + H2O N-Cyclohexylideneisobutylamine (79%)

40. Example + (CH3)2CHCH2NH2 O OH NHCH2CH(CH3)2 NCH2CH(CH3)2 + H2O N-Cyclohexylideneisobutylamine (79%)

41. Some reactions of aldehydes and ketones progressbeyond the nucleophilic addition stage • Acetal formation • Imine formation • Compounds related to imines • Enamines • The Wittig reaction

42. Some reactions of aldehydes and ketones progressbeyond the nucleophilic addition stage • Acetal formation • Imine formation • Compounds related to imines • Enamines • The Wittig reaction

43. + NG + R2C H2O H2N G O R2C NOH R2C H2N OH hydroxylamine oxime Reaction with Derivatives of Ammonia

44. O CH3(CH2)5CH + H2NOH NOH CH3(CH2)5CH + H2O Example (81-93%)

45. + NG + R2C H2O H2N G O R2C NOH R2C H2N OH hydroxylamine oxime NNH2 R2C H2N NH2 hydrazine hydrazone etc. Reaction with Derivatives of Ammonia

46. O C NNH2 C Example + H2NNH2 + H2O (73%)

47. O + H2NNH NNH CCH3 + H2O a phenylhydrazone (87-91%) Example CCH3 phenylhydrazine

48. O O NNHCNH2 + CH3(CH2)9CCH3 H2O Example O + CH3(CH2)9CCH3 H2NNHCNH2 semicarbazide a semicarbazone (93%)

49. 17.11Reaction with Secondary Amines:Enamines

50. Some reactions of aldehydes and ketones progressbeyond the nucleophilic addition stage • Acetal formation • Imine formation • Compounds related to imines • Enamines • The Wittig reaction