1. © 2011 Pearson Education, Inc. 1 Organic Chemistry 6 th Edition Paula Yurkanis Bruice Chapter 18 Carbonyl Compounds II Reactions of Aldehydes and Ketones More Reactions of Carboxylic Acid Derivatives Reactions of ,  -Unsaturated Carbonyl Compounds

2. © 2011 Pearson Education, Inc. 2 Nomenclature of Aldehydes

3. © 2011 Pearson Education, Inc. 3 If the aldehyde group is attached to a ring,

4. © 2011 Pearson Education, Inc. 4 If a compound has two functional groups, the one with the lower priority is indicated by its prefix:

5. © 2011 Pearson Education, Inc. 5 Nomenclature of Ketones The carbonyl is assumed to be at the 1-position in cyclic ketones:

6. © 2011 Pearson Education, Inc. 6 If a ketone has a second functional group of higher priority… A few ketones have common names:

7. © 2011 Pearson Education, Inc. 7 An aldehyde has a greater partial positive charge on its carbonyl carbon than does a ketone: The partial positive charge on the carbonyl carbon causes that carbon to be attacked by nucleophiles:

8. © 2011 Pearson Education, Inc. 8 The carbonyl carbon of an aldehyde is more accessible to the nucleophile. Ketones have greater steric crowding in their transition states, so they have less stable transition states. Steric factors contribute to the reactivity of an aldehyde. Aldehydes Are More Reactive Than Ketones

9. © 2011 Pearson Education, Inc. 9 The reactivity of carbonyl compounds is also related to the basicity of Y – :

10. © 2011 Pearson Education, Inc. 10 Carboxylic acid derivatives undergo nucleophilic acyl substitution reactions with nucleophiles:

11. © 2011 Pearson Education, Inc. 11 Aldehydes and ketones undergo nucleophilic addition reactions with nucleophiles: This is an irreversible nucleophilic addition reaction if the nucleophile is a strong base

12. © 2011 Pearson Education, Inc. 12 A reversible nucleophilic addition reaction:

13. © 2011 Pearson Education, Inc. 13 Formation of a New Carbon–Carbon Bond Using Grignard Reagents Grignard reagents react with aldehydes, ketones, and carboxylic acid derivatives

14. © 2011 Pearson Education, Inc. 14 Grignard reagents are used to prepare alcohols:

15. © 2011 Pearson Education, Inc. 15 Mechanism for the reaction of an ester with a Grignard reagent:

16. © 2011 Pearson Education, Inc. 16 Examples of Grignard Reactions

17. © 2011 Pearson Education, Inc. 17 Reaction of Acetylide Ions with Carbonyl Compounds Na + + NH 3

18. © 2011 Pearson Education, Inc. 18 Reactions of Carbonyl Compounds with Hydride Ion

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20. © 2011 Pearson Education, Inc. 20 Mechanism for the reaction of an acyl chloride with hydride ion:

21. © 2011 Pearson Education, Inc. 21 Mechanism for the reaction of an ester with hydride ion: Esters and acyl chlorides undergo two successive reactions with hydride ion and Grignard reagents

22. © 2011 Pearson Education, Inc. 22 Utilization of DIBALH to Control the Reduction Reaction

23. © 2011 Pearson Education, Inc. 23 The reduction of a carboxylic acid with LiAlH 4 forms a single primary alcohol: Acyl chloride is also reduced by LiAlH 4 to yield an alcohol

24. © 2011 Pearson Education, Inc. 24 An amide is reduced by LiAlH 4 to an amine Mechanism for the reaction of an N-substituted amide with hydride ion:

25. © 2011 Pearson Education, Inc. 25 Hydride Reducing Agents

26. © 2011 Pearson Education, Inc. 26 Selectivity of Reductions

27. © 2011 Pearson Education, Inc. 27 Hydrogen cyanide adds to aldehydes and ketones to form cyanohydrins:

28. © 2011 Pearson Education, Inc. 28 Compared with Grignard reagents and hydride ion, CN – is a relatively weak base; therefore, in basic solution…

29. © 2011 Pearson Education, Inc. 29 Aldehydes and ketones react with a primary amine to form an imine: This is a pH-dependent nucleophilic addition– elimination reaction

30. © 2011 Pearson Education, Inc. 30 Dependence of the rate of the reaction of acetone with hydroxylamine on the pH of the reaction: a pH-rate profile Maximum rate is at pH = pK a of + NH 3 OH; at this pH, both [H + ] and [NH 2 OH] have the highest values Decreasing rate: [H + ] is decreasing Decreasing rate: [NH 2 OH] is decreasing Composition of the rate- determining step:

31. © 2011 Pearson Education, Inc. An enamine undergoes an acid-catalyzed hydrolysis to form a carbonyl compound and a secondary amine 31 Aldehydes and ketones react with secondary amines to form enamines:

32. © 2011 Pearson Education, Inc. 32 Enamine Reactions

33. © 2011 Pearson Education, Inc. 33 Formation of Imine Derivatives

34. © 2011 Pearson Education, Inc. 34 Types of Amine–Carbonyl Addition Products

35. © 2011 Pearson Education, Inc. 35 Reductive Amination

36. © 2011 Pearson Education, Inc. 36 Deoxygenation of the Carbonyl Group Called the Wolff–Kishner reduction

37. © 2011 Pearson Education, Inc. 37 Water adds to an aldehyde or ketone to form a hydrate:

38. © 2011 Pearson Education, Inc. 38 Mechanism for acid-catalyzed hydrate formation:

39. © 2011 Pearson Education, Inc. 39 Why is there such a difference in the K eq values?

40. © 2011 Pearson Education, Inc. 40 The equilibrium constant for the reaction depends on the relative stabilities of the reactants and products:

41. © 2011 Pearson Education, Inc. 41 Addition of an Alcohol to an Aldehyde or a Ketone

42. © 2011 Pearson Education, Inc. 42 Mechanism for acid-catalyzed acetal or ketal formation:

43. © 2011 Pearson Education, Inc. 43 Utilization of Protecting Groups in Synthesis LiAlH 4 will reduce the ester to yield an alcohol, but the keto group will also be reduced

44. © 2011 Pearson Education, Inc. 44 The keto group is protected as a ketal in this synthesis: The more reactive aldehyde is protected with the diol before reaction with the Grignard reagent:

45. © 2011 Pearson Education, Inc. 45 An OH group can be protected as a trimethylsilyl (TMS) ether:

46. © 2011 Pearson Education, Inc. 46 Protection of an OH group in a carboxylic acid as the ester:

47. © 2011 Pearson Education, Inc. 47 Protection of an amino group as the amide:

48. © 2011 Pearson Education, Inc. 48 Addition of Sulfur Nucleophiles

49. © 2011 Pearson Education, Inc. 49 Desulfurization replaces the C—S bonds with C—H bonds:

50. © 2011 Pearson Education, Inc. 50 The synthetically useful aldehyde anion does not exist But its equivalent is accessible via the thioacetal:

51. © 2011 Pearson Education, Inc. 51 Formation of Alkenes: The Wittig Reaction

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53. © 2011 Pearson Education, Inc. 53 Preparation of the Phosphonium Ylide The phosphonium ylide should be prepared from sterically hindered alkyl halide: Synthetic target: Preferred synthetic approach:

54. © 2011 Pearson Education, Inc. 54 The Wittig reaction is completely regioselective. This reaction is the best way to make a terminal alkene. Stable ylides form primarily E isomers, and unstabilized ylides form primarily Z isomers. Stable ylides have a group (C=O) that can share the carbanion’s negative charge. Example:

55. © 2011 Pearson Education, Inc. 55 Stereochemistry of Nucleophilic Addition Reaction

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59. © 2011 Pearson Education, Inc. 59 Disconnections, Synthons, and Synthetic Equivalents

60. © 2011 Pearson Education, Inc. 60 A synthetic equivalent is the reagent that is actually used as the source of a synthon

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64. © 2011 Pearson Education, Inc. 64 Nucleophilic Addition to ,  - Unsaturated Aldehydes and Ketones

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66. © 2011 Pearson Education, Inc. 66 Nucleophiles that form unstable addition products form conjugated addition products, because the conjugate addition is not reversible. Nucleophiles that form stable addition products can form direct addition products or conjugate addition products. If the rate of direct addition is slowed down by steric hindrance, a Grignard reagent will form the conjugate addition product.

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68. © 2011 Pearson Education, Inc. 68 Strong bases form direct addition products with reactive carbonyl groups and conjugate addition products with less reactive carbonyl groups:

69. © 2011 Pearson Education, Inc. 69 Weak bases form conjugate addition products:

70. © 2011 Pearson Education, Inc. 70 Nucleophilic Addition to ,  -Unsaturated Carboxylic Acid Derivatives

71. © 2011 Pearson Education, Inc. 71 Enzyme-Catalyzed Additions to ,  - Unsaturated Carbonyl Compounds

72. © 2011 Pearson Education, Inc. 72 Addition Reactions to ,  -Unsaturated Carbonyls Michael addition nucleophiles: Cyanide Sulfide Organocuprate Amine Halides Direct addition nucleophiles: Grignard LAH Organolithiums

73. © 2011 Pearson Education, Inc. 73 Metabolism of acetaminophen involves conjugate addition: