Chapter 17 Aldehydes and Ketones. Nucleophilic Addition to the Carbonyl Group

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