Synthetic Routes to Aldehydes and Ketones: Efficient Methods and Reactions

1. Chapter 17Aldehydes and Ketones.Nucleophilic Additionto theCarbonyl Group

2. 17.4Sources of Aldehydes and Ketones

3. Synthesis of Aldehydes and Ketones A number of reactions alreadystudied provideefficient syntheticroutes to aldehydes and ketones. From alkenes: Ozonolysis (6.20) From alkynes: Hydration via enol (9.12) From arenes: Friedel-Crafts acylation (12.7) From alcohols: Oxidation (15.10)

4. O O C C R H R OH 1. LiAlH4 PDC, CH2Cl2 2. H2O RCH2OH What about Aldehydes from Carboxylic Acids?

5. O O COH CH 1. LiAlH4 PDCCH2Cl2 2. H2O CH2OH (83%) (81%) Example Benzaldehyde from benzoic acid

6. O O C C R R' R H 1. R'MgX OH PDC, CH2Cl2 2. H3O+ RCHR' What about Ketones from Aldehydes?

7. 17.5Reactions of Aldehydes and Ketones:A Review and a Preview

8. Reactions of Aldehydes and Ketones Already covered in earlier chapters: Reduction of C=O to CH2(12.8) Clemmensen reduction Wolff-Kishner reduction Reduction of C=O to CHOH (15.2) Addition of Grignard and organolithium reagents (14.6-14.7)

9. 17.6Principles of Nucleophilic Addition to Carbonyl Groups:Hydration of Aldehydes and Ketones

10. O C •• •• •• •• HO O H C •• •• Hydration of Aldehydes and Ketones H2O

11. OH O + C H2O R R' C R' R OH Substituent Effects on Hydration Equilibria Compared to H Electronic: Alkyl groups stabilize reactants Steric: Alkyl groups crowd product

12. Equilibrium Constants and Relative Ratesof Hydration C=O Hydrate K % Relative rate CH2=O CH2(OH)2 2300 >99.9 2200 CH3CH=O CH3CH(OH)2 1.0 50 1.0 (CH3)3CCH=O (CH3)3CCH(OH)2 0.2 17 0.09 (CH3)2C=O (CH3)2C(OH)2 0.0014 0.14 0.0018 Decreased hydration with greater alkyl substitution due to electron donation and steric crowding.

13. When Does Equilibrium Favor Hydrate? When carbonyl group is destabilized: electron-withdrawing groups destabilize C=O.

14. O Substituent Effects on Hydration Equilibria OH + C H2O R R C R R OH R = CH3: K = 0.000025 R = CF3: K = 22,000

15. H – – •• •• HO O C O O C •• •• •• •• •• •• •• •• Mechanism of Hydration (Base) Step 1: +

16. – •• •• HO O C •• •• •• H H O H •• – •• •• •• + HO OH C O •• •• •• •• •• Mechanism of Hydration (Base) Step 2:

17. H H O O C •• •• + •• H H + O + OH C •• •• •• H Mechanism of Hydration (Acid) Step 1: +

18. H H •• O OH C O •• •• •• + •• H H Mechanism of Hydration (Acid) Step 2: + + OH C ••

19. H H •• O H H + •• O •• H + H •• O OH C •• •• •• + •• O OH C •• H •• H Mechanism of Hydration (Acid) Step 3:

20. 17.7Cyanohydrin Formation

21. •• N C C O O H C •• •• •• •• Cyanohydrin Formation + HCN

22. – C O N C •• •• •• •• Cyanohydrin Formation

23. H – •• O H N C O C •• •• •• + •• H H •• O H N C O C •• •• •• •• H Cyanohydrin Formation Then acidify solution:

24. Cl Cl O OH Cl Cl CH CHCN Example NaCN, water then H2SO4 2,4-Dichlorobenzaldehyde cyanohydrin (100%)

25. OH O CH3CCH3 CH3CCH3 CN Example Acetone cyanohydrin is used in the synthesis of methacrylonitrile. NaCN, water then H2SO4 (77-78%)

26. 17.8Acetal Formation

27. Some Reactions of Aldehydes and Ketones ProgressBeyond the Nucleophilic Addition Stage Acetal formation Imine formation Compounds related to imines Enamine formation The Wittig reaction

28. HOCH2 O HO H H HOCH2 HO OCH3 O HO OH HO OH H OH HOCH2 HOCH2 H H O O O HO OH OH OH HO HO Hemiacetals and Acetals -D-Glucopyranose (a form of glucose), a hemiacetal Methyl--D-Glucopyranose, an acetal Polyoxymethylene, a polyacetal Lactose, an acetal and hemiacetal

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

30. 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.

31. 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. Hemiacetal R"OH, H+

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

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

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

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

36. Mechanism of Acetal Formation First stage is analogous to hydration andleads to hemiacetal: Acid-catalyzed nucleophilic addition of alcohol to C=O.

37. H •• O O H C •• •• + R Mechanism

38. Mechanism H •• + O O C •• •• H R

39. R O •• •• H Mechanism •• + O C H

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

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

42. Mechanism of Acetal Formation Second stage is hemiacetal-to-acetal conversion: Involves carbocation chemistry.

43. H R •• •• O H O O C •• •• + •• H R Hemiacetal-to-Acetal Stage

44. H R H •• •• O + O O C •• •• •• H R Hemiacetal-to-Acetal Stage

45. R H •• •• + O O C •• H Hemiacetal-to-Acetal Stage

46. R H •• •• O + C O •• •• H Hemiacetal-to-Acetal Stage

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

48. R R •• •• O + C O •• •• H Hemiacetal-to-Acetal Stage

49. R R •• •• + R O O C •• •• H O •• H Hemiacetal-to-Acetal Stage

50. R R •• •• R O O C •• •• •• H O + H Hemiacetal-to-Acetal Stage