1. Reactions of Enolate Anions: Enolates + Electrophiles II1

2. Condensations: Many Types, and (Other Reactions)
Aldol, Claisen, Dieckmann,
Acetoacetic / Malonic esters, etc.
(Decarboxylation)
(Acylation)
(Michael Addition)
(Lithium cuprates) 22

3. Condensation OH H C O C O
A chemical definition: Addition with subsequent loss of H2O
(eg. Dehydration of b-hydroxy carbonyl compounds) 12

4. Acylation of Ketones with Esters3

5. Acylation of Ketones with Esters
Esters that cannot form an enolate can be used to acylate ketone enolates. 6

6. Example O
CH3CH2OCOCH2CH3 O +
1. NaH
2. H3O+ O
COCH2CH3
(60%) 6

7. Example
COCH2CH3 O
CH3C O +
1. NaOCH2CH3
2. H3O+ O
CCH2C O
(62-71%) 6

8. Example
CH3CH2CCH2CH2COCH2CH3 O
1. NaOCH3
2. H3O+ O
CH3
(70-71%) 6

9. Ketone Synthesis via b-Keto Esters3

10. Ketone Synthesis O RCH2CCHCOH R O RCH2CCH2R + CO2
b-Keto acids decarboxylate readily to give ketones. 6

11. Ketone Synthesis O RCH2CCHCOR' R O RCH2CCHCOH R H2O + R'OH
b-Keto acids decarboxylate readily to give ketones .
b-Keto acids are available by hydrolysis of b-keto esters. 6

12. Ketone Synthesis 2RCH2COR' O O RCH2CCHCOR' R 1. NaOR' + R'OH 2. H3O+
b-Keto acids decarboxylate readily to give ketones .
b-Keto acids are available by hydrolysis of b-keto esters.
b-Keto esters can be prepared by the Claisen condensation. 6

13. Example O 2 CH3CH2CH2CH2COCH2CH3 1. NaOCH2CH3 2. H3O+ O
CH3CH2CH2CH2CCHCOCH2CH3 O
CH2CH2CH3
(80%) 6

14. Example O CH3CH2CH2CH2CCHCOH CH2CH2CH3 1. KOH, H2O, 70-80°C 2. H3O+ O
CH3CH2CH2CH2CCHCOCH2CH3 O
CH2CH2CH3 6

15. Example O CH3CH2CH2CH2CCHCOH CH2CH2CH3 70-80°C O
CH3CH2CH2CH2CCH2CH2CH2CH3
(81%) 6

16. 3

17. Decarboxylation of
3-Oxocarboxylic Acids

18. The Acetoacetic Ester Synthesis3

19. Acetoacetic Ester O C H3C OCH2CH3 H
Acetoacetic ester is another name for ethyl acetoacetate.
The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones. 6

20. Deprotonation of Ethyl Acetoacetate
OCH2CH3 H O
H3C – +
CH3CH2O
Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
pKa ~ 11 6

21. Deprotonation of Ethyl Acetoacetate
OCH2CH3 H O
H3C – +
CH3CH2O
Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
pKa ~ 11
K ~ 105 C
OCH2CH3 H O •• –
H3C +
CH3CH2OH
pKa ~ 16 6

22. Alkylation of Ethyl Acetoacetate
OCH2CH3 H O •• –
H3C
The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination). R X 6

23. Alkylation of Ethyl Acetoacetate
OCH2CH3 H O •• –
H3C
The anion of ethyl acetoacetate can be alkylated using an alkyl halide (SN2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination). R X C
OCH2CH3 H O
H3C R 6

24. Conversion to Ketone C OH H O H3C R
Saponification and acidification convert the alkylated derivative to the corresponding b-keto acid.
The b-keto acid then undergoes decarboxylation to form a ketone.
1. HO–, H2O
2. H+ C
OCH2CH3 H O
H3C R 6

25. Conversion to Ketone C OH H O H3C R
Saponification and acidification convert the alkylated derivative to the corresponding b-keto acid.
The b-keto acid then undergoes decarboxylation to form a ketone. O C +
CO2
H3C
CH2R 6

26. Example O
CH3CCH2COCH2CH3
1. NaOCH2CH3
2. CH3CH2CH2CH2Br 6

27. Example O CH3CCH2COCH2CH3 1. NaOCH2CH3 2. CH3CH2CH2CH2Br O
(70%) 6

28. Example O (60%) CH3CCH2CH2CH2CH2CH3 1. NaOH, H2O 2. H+ 3. heat, -CO2 O
CH3CCHCOCH2CH3
CH2CH2CH2CH3 6

29. Example: Dialkylation
CH3CCHCOCH2CH3
CH2CH
CH2 6

30. Example: Dialkylation
CH3CCHCOCH2CH3
CH2CH
CH2
1. NaOCH2CH3
2. CH3CH2I O
CH3CCCOCH2CH3
CH2CH
CH2
CH3CH2
(75%) 6

31. Example: Dialkylation
CH3CCH
CH2CH
CH2 O
CH3CH2
Example: Dialkylation
1. NaOH, H2O
2. H+
3. heat, -CO2 O
CH3CCCOCH2CH3
CH2CH
CH2
CH3CH2 6

32. Another Example O COCH2CH3 H
b-Keto esters other than ethyl acetoacetate may be used. 6

33. Another Example O COCH2CH3 H 1. NaOCH2CH3 2. H2C CHCH2Br O COCH2CH3
(89%) 6

34. Another Example O O
COCH2CH3
CH2CH
CH2 6

35. Another Example O H (66%) CH2CH CH2 1. NaOH, H2O 2. H+ 3. heat, -CO2 O
COCH2CH3
CH2CH
CH2 6

36. The Malonic Ester Synthesis3

37. Malonic Ester O C CH3CH2O OCH2CH3 H
Malonic ester is another name for diethyl malonate.
The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids. 6

38. An Analogy O CH3CCH2COCH2CH3 O CH3CH2OCCH2COCH2CH3 O CH3CCH2R O
HOCCH2R
The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids. 6

39. Example O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. H2C CHCH2CH2CH2Br CH2
(85%) 6

40. Example O HOCCH2CH2CH2CH2CH CH2 (75%) 1. NaOH, H2O 2. H+ 3. heat, -CO2
CH3CH2OCCHCOCH2CH3 6

41. 3

42. Dialkylation O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. CH3Br CH3 O
(79-83%) 6

43. Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOCH2CH3
2. CH3(CH2)8CH2Br
CH3 O
CH3CH2OCCHCOCH2CH3 6

44. Dialkylation O O CH3CH2OCCCOCH2CH3 CH3(CH2)8CH2 CH3 1. NaOH, H2O 2. H+
3. heat, -CO2 O
CH3(CH2)8CH2CHCOH
(61-74%)
CH3 6

45. Another Example O CH3CH2OCCH2COCH2CH3 1. NaOCH2CH3 2. BrCH2CH2CH2Br O6

46. Another Example
This product is not isolated, but cyclizes in the presence of sodium ethoxide.
CH2CH2CH2Br O
CH3CH2OCCHCOCH2CH3 6

47. Another Example O CH3CH2OCCCOCH2CH3 H2C CH2 C H2 (60-65%) NaOCH2CH3
CH2CH2CH2Br O
CH3CH2OCCHCOCH2CH3 6

48. Another Example O CH3CH2OCCCOCH2CH3 H2C CH2 C H2 1. NaOH, H2O 2. H+
3. heat, -CO2
H2C
CH2
C H2 C H
CO2H
(80%) 6

49. Barbiturates 3

50. Barbituric acid is made from diethyl malonate and urea
H2C O
COCH2CH3 C
H2N O + 6

51. Barbituric acid is made from diethyl malonate and urea
H2C O
COCH2CH3 C
H2N O +
H2C O C N H
1. NaOCH2CH3
2. H+
(72-78%) 6

52. Barbituric acid is made from diethyl malonate and urea
H2C O
COCH2CH3 C
H2N O + H O N
1. NaOCH2CH3
2. H+ O N O
(72-78%) H 6

53. Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate
H2C O
COCH2CH3 C O
COCH2CH3 R R'
1. RX, NaOCH2CH3
2. R'X, NaOCH2CH3 6

54. Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate
COCH2CH3 R R' O N H R R'
(H2N)2C O 6

55. 5,5-Diethylbarbituric acid (barbital; Veronal)
Examples O N H
CH3CH2
5,5-Diethylbarbituric acid (barbital; Veronal) 6

56. 5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal)
Examples
CH3CH2CH2CH
H3C O H N O
CH3CH2 N H O
5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) 6

57. 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal)
Examples
CH3CH2CH2CH
H3C O H N O
CHCH2
H2C N H O
5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) 6

58. Addition of Carbanions to a,b-Unsaturated Carbonyl Compounds: The Michael Reaction1

59. Michael Addition
Stabilized carbanions, such as those derived from b-diketones undergo conjugate addition to a,b-unsaturated ketones. 11

60. Example
CH3 O O
H2C
CHCCH3 +
KOH, methanol O
CH3
CH2CH2CCH3
(85%) 20

61. The Stork Enamine Reaction
Enamines are used in place of enolates in Michael
reactions

62. Michael Addition
The Michael reaction is a useful method for forming carbon-carbon bonds.
It is also useful in that the product of the reaction can undergo an intramolecular aldol condensation to form a six-membered ring. One such application is called the Robinson annulation. 11

63. not isolated; dehydrates under reaction conditions
Example O
CH3
CH2CH2CCH3 OH O
CH3
NaOH heat
not isolated; dehydrates under reaction conditions 20

64. Example O
CH3
CH2CH2CCH3 OH O
CH3
NaOH heat O
CH3
(85%) 20

65. 3

66. Michael Additions of Stabilized Anions3

67. 3

68. Stabilized Anions
The anions derived by deprotonation of b-keto esters and diethyl malonate are weak bases.
Weak bases react with a,b-unsaturated carbonyl compounds by conjugate addition. C
OCH2CH3 H O •• –
H3C C
OCH2CH3 H O
CH3CH2O •• – 6

69. Example O
CH3CH2OCCH2COCH2CH3
H2C
CHCCH3 O + 6

70. Example O CH3CH2OCCH2COCH2CH3 H2C CHCCH3 O + KOH, ethanol CH2CH2CCH3 O
(85%) 6

71. Example CH3CCH2CH2CH2COH O O (42%) 1. KOH, ethanol-water 2. H+ 3. heat
CH2CH2CCH3 O
CH3CH2OCCHCOCH2CH3 6

72. 3

73. Conjugate Addition of Organocopper Reagents to a,b-Unsaturated Carbonyl Compounds1

74. Addition of Organocopper Reagents to a,b-Unsaturated Aldehydes and Ketones
The main use of organocopper reagents is to form carbon-carbon bonds by conjugate addition to a,b-unsaturated ketones. 11

75. O
CH3
Example +
LiCu(CH3)2
1. diethyl ether
2. H2O O
CH3
(98%) 21