1. Dr. Wolf's CHM 201 & 202 20-1 Chapter 20 Enols and Enolates

2. Dr. Wolf's CHM 201 & 202 20-2 Aldehyde, Ketone, and Ester Enolates

3. Dr. Wolf's CHM 201 & 202 20-3 The reference atom is the carbonyl carbon. Other carbons are designated , , , etc. on the basis of their position with respect to the carbonyl carbon. Hydrogens take the same Greek letter as the carbon to which they are attached. Terminology CH 3 CH 2 CH 2 CH O

4. Dr. Wolf's CHM 201 & 202 20-4 Acidity of  -Hydrogen + H + R2CR2CR2CR2C CR' O – R2CR2CR2CR2C CR' O – O R2CR2CR2CR2C CR' H pK a = 16-20 enolate ion

5. Dr. Wolf's CHM 201 & 202 20-5 Acidity of  -Hydrogen (CH 3 ) 2 CHCH O CCH 3 O pK a = 15.5 pK a = 18.3

6. Dr. Wolf's CHM 201 & 202 20-6 H3CH3CH3CH3C C CH 3 OC C O H H H3CH3CH3CH3C C O C C O H H+H+H+H+ + –  -Diketones are much more acidic pK a = 9

7. Dr. Wolf's CHM 201 & 202 20-7  -Diketones are much more acidic H3CH3CH3CH3C C CH 3 O C C O H – H3CH3CH3CH3C C CH 3 O C C O H– enolate of  -diketone is stabilized; negative charge is shared by both oxygens

8. Dr. Wolf's CHM 201 & 202 20-8  -Diketones are much more acidic H3CH3CH3CH3C C CH 3 O C C O H – – H3CH3CH3CH3C H C CH 3 O C C O H3CH3CH3CH3C C CH 3 O C C O H–

9. Dr. Wolf's CHM 201 & 202 20-9 Esters Hydrogens  to an ester carbonyl group are less acidic, pK a  24, than  of aldehydes and ketones, pK a  16-20. The decreased acidity is due the decreased electron withdrawing ability of an ester carbonyl. Electron delocalization decreases the positive character of the ester carbonyl group.

10. Dr. Wolf's CHM 201 & 202 20-10 Esters A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions. C CR C OR' HHOO

11. Dr. Wolf's CHM 201 & 202 20-11 C CR C OR' HHOO C CR C OR' HOO – pK a ~ 11 CH 3 CH 2 O –

12. Dr. Wolf's CHM 201 & 202 20-12 The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups. C CR C OR' H OO – C CR C OR' H OO –

13. Dr. Wolf's CHM 201 & 202 20-13 The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups. C CR C OR' H OO – C CR C OR' H OO–

14. Dr. Wolf's CHM 201 & 202 20-14 The Aldol Condensation

15. Dr. Wolf's CHM 201 & 202 20-15 A basic solution contains comparable amounts of the aldehyde and its enolate. Aldehydes undergo nucleophilic addition. Enolate ions are nucleophiles. What about nucleophilic addition of enolate to aldehyde? RCH 2 CH O+ OH – RCHCHO+HOH – pK a = 16-20 pK a = 16 Some thoughts...

16. Dr. Wolf's CHM 201 & 202 20-16 RCHCH O – RCH 2 CH O – RCH 2 CH O RCHCH O RCH 2 CH O RCHCH O H 2RCH 2 CH ONaOH RCH 2 CH OH CHCHOR

17. Dr. Wolf's CHM 201 & 202 20-17 product is called an "aldol" because it is both an aldehyde and an alcohol Aldol Addition RCH 2 CH OH CHCHOR

18. Dr. Wolf's CHM 201 & 202 20-18 Aldol Addition of Acetaldehyde Acetaldol (50%) NaOH, H 2 O 5°C 2CH 3 CH O CH 3 CH OH CH 2 CH O

19. Dr. Wolf's CHM 201 & 202 20-19 Aldol Addition of Butanal KOH, H 2 O 6°C 2CH 3 CH 2 CH 2 CH O (75%) CH 3 CH 2 CH 2 CH OH CHCHO CH 2 CH 3

20. Dr. Wolf's CHM 201 & 202 20-20 2RCH 2 CH ONaOH RCH 2 CH OH CHCHOR Aldol Condensation

21. Dr. Wolf's CHM 201 & 202 20-21 2RCH 2 CH ONaOH RCH 2 CH OH CHCH OR Aldol Condensation R heat RCH 2 CH CCH O NaOH heat

22. Dr. Wolf's CHM 201 & 202 20-22 Aldol Condensation of Butanal NaOH, H 2 O 80-100°C 2CH 3 CH 2 CH 2 CH O (86%) CH 3 CH 2 CH 2 CH CCHO CH 2 CH 3

23. Dr. Wolf's CHM 201 & 202 20-23 dehydration of  -hydroxy aldehyde can be catalyzed by either acids or bases Dehydration of Aldol Addition Product C O C C OH H C O C C

24. Dr. Wolf's CHM 201 & 202 20-24 in base, the enolate is formed Dehydration of Aldol Addition Product OH H C O C C NaOH OH C O C C –

25. Dr. Wolf's CHM 201 & 202 20-25 the enolate loses hydroxide to form the ,  -unsaturated aldehyde Dehydration of Aldol Addition Product OH H C O C C NaOH OH C O C C –

26. Dr. Wolf's CHM 201 & 202 20-26 Aldol reactions of ketones the equilibrium constant for aldol addition reactions of ketones is usually unfavorable 2% 98% 2CH 3 CCH 3 OO CH 3 CCH 2 CCH 3 OH CH 3

27. Dr. Wolf's CHM 201 & 202 20-27 Intramolecular Aldol Condensation Na 2 CO 3, H 2 O heatOO O(96%) OOH via:

28. Dr. Wolf's CHM 201 & 202 20-28 Intramolecular Aldol Condensation Na 2 CO 3, H 2 O heatOO O(96%) even ketones give good yields of aldol condensation products when the reaction is intramolecular

29. Dr. Wolf's CHM 201 & 202 20-29 Mixed Aldol Condensations

30. Dr. Wolf's CHM 201 & 202 20-30 What is the product? There are 4 possibilities because the reaction mixture contains the two aldehydes plus the enolate of each aldehyde. NaOH CH 3 CH O CH 3 CH 2 CH O+

31. Dr. Wolf's CHM 201 & 202 20-31 What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH OH CH 2 CH O

32. Dr. Wolf's CHM 201 & 202 20-32 What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH 2 CH OH CHCHO CH 3

33. Dr. Wolf's CHM 201 & 202 20-33 What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH OH CHCHO CH 3

34. Dr. Wolf's CHM 201 & 202 20-34 What is the product? CH 3 CH O CH 3 CH 2 CH O+ CH 2 CH O CH 3 CHCH O – – CH 3 CH 2 CH OH CH 2 CH O

35. Dr. Wolf's CHM 201 & 202 20-35 In order to effectively carry out a mixed aldol condensation: need to minimize reaction possibilities usually by choosing one component that cannot form an enolate

36. Dr. Wolf's CHM 201 & 202 20-36 Formaldehyde formaldehyde cannot form an enolate formaldehyde is extremely reactive toward nucleophilic addition OHCH

37. Dr. Wolf's CHM 201 & 202 20-37 FormaldehydeOHCH + (CH 3 ) 2 CHCH 2 CH O (CH 3 ) 2 CHCHCH O CH 2 OH (52%) K 2 CO 3 water- ether

38. Dr. Wolf's CHM 201 & 202 20-38 Aromatic Aldehydes CH 3 O CHO aromatic aldehydes cannot form an enolate

39. Dr. Wolf's CHM 201 & 202 20-39 Aromatic Aldehydes CH 3 O CHO+ CH 3 CCH 3 O NaOH, H 2 O 30°C CH 3 O CH CHCCH 3 O(83%)

40. Dr. Wolf's CHM 201 & 202 20-40 Deprotonation of Aldehydes, Ketones, and Esters Simple aldehydes, ketones, and esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original carbonyl, and Aldol or Claisen condensation occurs. Are there bases strong enough to completely deprotonate simple carbonyls, giving enolates quantitatively?

41. Dr. Wolf's CHM 201 & 202 20-41 Lithium diisopropylamide Lithium dialkylamides are strong bases (just as NaNH 2 is a very strong base). Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups. Li+ CNC HH CH 3 –

42. Dr. Wolf's CHM 201 & 202 20-42 Lithium diisopropylamide (LDA) Lithium diisopropylamide converts simple esters to the corresponding enolate. CH 3 CH 2 CH 2 COCH 3 O+ pK a ~ 22 LiN[CH(CH 3 ) 2 ] 2 CH 3 CH 2 CHCOCH 3 O+ HN[CH(CH 3 ) 2 ] 2 – + Li+ pK a ~ 36

43. Dr. Wolf's CHM 201 & 202 20-43 Lithium diisopropylamide (LDA) Enolates generated from esters and LDA can be alkylated. CH 3 CH 2 CHCOCH 3 O O – CH 3 CH 2 I CH 2 CH 3 (92%)

44. Dr. Wolf's CHM 201 & 202 20-44 Aldol addition of ester enolates Ester enolates undergo aldol addition to aldehydes and ketones. CH 3 COCH 2 CH 3 O 1. LiNR 2, THF 2. (CH 3 ) 2 C O 3. H 3 O + C H3CH3CH3CH3C CH 3 HO CH 2 COCH 2 CH 3 O(90%)

45. Dr. Wolf's CHM 201 & 202 20-45 Ketone Enolates Lithium diisopropylamide converts ketones quantitatively to their enolates. CH 3 CH 2 CC(CH 3 ) 3 O 1. LDA, THF 2. CH 3 CH 2 CH O 3. H 3 O + CH 3 CHCC(CH 3 ) 3 O HOCHCH 2 CH 3 (81%)

46. Dr. Wolf's CHM 201 & 202 20-46 The Claisen Condensation (gives  -keto esters)

47. Dr. Wolf's CHM 201 & 202 20-47 The Claisen Condensation  -Keto esters are made by the reaction shown, which is called the Claisen condensation. Ethyl esters are typically used, with sodium ethoxide as the base. 2RCH 2 COR' O 1. NaOR' 2. H 3 O + + R'OHOO RCH 2 CCHCOR' R

48. Dr. Wolf's CHM 201 & 202 20-48 Example Product from ethyl acetate is called ethyl acetoacetate or acetoacetic ester. 2CH 3 COCH 2 CH 3 O 1. NaOCH 2 CH 3 2. H 3 O + OO CH 3 CCH 2 COCH 2 CH 3 (75%)

49. Dr. Wolf's CHM 201 & 202 20-49 Mechanism Step 1: CH 3 CH 2 O – COCH 2 CH 3 O CH 2 H

50. Dr. Wolf's CHM 201 & 202 20-50 Mechanism Step 1: CH 3 CH 2 O – COCH 2 CH 3 O CH 2 H – COCH 2 CH 3 O CH 2 CH 3 CH 2 O H

51. Dr. Wolf's CHM 201 & 202 20-51 Mechanism Step 1: – COCH 2 CH 3 O CH 2 – COCH 2 CH 3 O CH 2 Anion produced is stabilized by electron delocalization; it is the enolate of an ester.

52. Dr. Wolf's CHM 201 & 202 20-52 Mechanism Step 2: – COCH 2 CH 3 O CH 2 CH 3 COCH 2 CH 3 O

53. Dr. Wolf's CHM 201 & 202 20-53 Mechanism Step 2: – COCH 2 CH 3 O CH 2 CH 3 COCH 2 CH 3 O CH 3 C – O COCH 2 CH 3 O CH 2 OCH 2 CH 3

54. Dr. Wolf's CHM 201 & 202 20-54 Mechanism Step 2: CH 3 C – O COCH 2 CH 3 O CH 2 OCH 2 CH 3

55. Dr. Wolf's CHM 201 & 202 20-55 Mechanism Step 3: CH 3 C – O COCH 2 CH 3 O CH 2 OCH 2 CH 3 – OCH 2 CH 3 CH 3 C O COCH 2 CH 3 O CH 2 +

56. Dr. Wolf's CHM 201 & 202 20-56 Mechanism– OCH 2 CH 3 CH 3 C O COCH 2 CH 3 O CH 2 + Step 3: The product at this point is ethyl acetoacetate. However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium constant for its formation is small. Something else does happen. Ethoxide abstracts a proton from the CH 2 group to give a stabilized anion. The equilibrium constant for this reaction is favorable.

57. Dr. Wolf's CHM 201 & 202 20-57 Mechanism– OCH 2 CH 3 CH 3 C O COCH 2 CH 3 O CH2CH2CH2CH2 + Step 4: + OCH 2 CH 3 H – COCH 2 CH 3 O CH 3 C O CHCHCHCH

58. Dr. Wolf's CHM 201 & 202 20-58 Mechanism Step 5: – COCH 2 CH 3 O CH 3 C O CHCHCHCH In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated product, ethyl acetoacetate.

59. Dr. Wolf's CHM 201 & 202 20-59 Mechanism + Step 5: – COCH 2 CH 3 O CH 3 C O CHCHCHCH + O H HH O H H CH 3 C O COCH 2 CH 3 O CHCHCHCH H

60. Dr. Wolf's CHM 201 & 202 20-60 Another example Reaction involves bond formation between the  - carbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other. 2 CH 3 CH 2 COCH 2 CH 3 O 1. NaOCH 2 CH 3 2. H 3 O + (81%)OO CH 3 CH 2 CCHCOCH 2 CH 3 CH 3

61. Dr. Wolf's CHM 201 & 202 20-61 Intramolecular Claisen Condensation: The Dieckmann Reaction

62. Dr. Wolf's CHM 201 & 202 20-62 CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 OO 1. NaOCH 2 CH 3 2. H 3 O + Example COCH 2 CH 3 OO(74-81%)

63. Dr. Wolf's CHM 201 & 202 20-63 CH 3 CH 2 OCCH 2 CH 2 CH 2 CH 2 COCH 2 CH 3 OO NaOCH 2 CH 3 via CH 3 CH 2 OCCH 2 CH 2 CH 2 CHCOCH 2 CH 3 OO –

64. Dr. Wolf's CHM 201 & 202 20-64 via CH 3 CH 2 OCCH 2 CH 2 CH 2 CHCOCH 2 CH 3 OO –

65. Dr. Wolf's CHM 201 & 202 20-65 via CH 3 CH 2 OCCH 2 CH 2 CH 2 CHCOCH 2 CH 3 OO – CHCOCH 2 CH 3 O – CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O CH 3 CH 2 O

66. Dr. Wolf's CHM 201 & 202 20-66 via CHCOCH 2 CH 3 O – CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O CH 3 CH 2 O

67. Dr. Wolf's CHM 201 & 202 20-67 via CHCOCH 2 CH 3 O – CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O CH 3 CH 2 O – CHCOCH 2 CH 3 O CH 2 H2CH2CH2CH2C H2CH2CH2CH2C C O +

68. Dr. Wolf's CHM 201 & 202 20-68 Mixed Claisen Condensations

69. Dr. Wolf's CHM 201 & 202 20-69 Mixed Claisen Condensations As with mixed aldol condensations, mixed Claisen condensations are best carried out when the reaction mixture contains one compound that can form an enolate and another that cannot.

70. Dr. Wolf's CHM 201 & 202 20-70 Mixed Claisen Condensations These types of esters cannot form an enolate. HCOROROCOROROCOCOR O CORO

71. Dr. Wolf's CHM 201 & 202 20-71 Example 1. NaOCH 3 2. H 3 O + (60%) COCH 3 O+ CH 3 CH 2 COCH 3 O OO CCHCOCH 3 CH 3

72. Dr. Wolf's CHM 201 & 202 20-72 Acylation of Ketones with Esters

73. Dr. Wolf's CHM 201 & 202 20-73 Acylation of Ketones with Esters Esters that cannot form an enolate can be used to acylate ketone enolates.

74. Dr. Wolf's CHM 201 & 202 20-74 Example 1. NaH 2. H 3 O + (60%) + CH 3 CH 2 OCOCH 2 CH 3 O O O COCH 2 CH 3 O

75. Dr. Wolf's CHM 201 & 202 20-75 Example 1. NaOCH 2 CH 3 2. H 3 O + (62-71%) COCH 2 CH 3 O+ O CH3CCH3CCH3CCH3CO O CCH2CCCH2CCCH2CCCH2C

76. Dr. Wolf's CHM 201 & 202 20-76 Example 1. NaOCH 3 2. H 3 O + (70-71%) CH 3 CH 2 CCH 2 CH 2 COCH 2 CH 3 OO OO CH 3

77. Dr. Wolf's CHM 201 & 202 20-77 Alkylation of Enolate Anions

78. Dr. Wolf's CHM 201 & 202 20-78 Enolate ions are nucleophiles and react with alkyl halides. However, alkylation of simple enolates does not work well. Enolates derived from  -diketones can be alkylated efficiently. Enolate Ions in S N 2 Reactions

79. Dr. Wolf's CHM 201 & 202 20-79 Example CH 3 CCH 2 CCH 3 OO+ CH 3 I K 2 CO 3 CH 3 CCHCCH 3 OO CH 3 (75-77%)

80. Dr. Wolf's CHM 201 & 202 20-80 The Acetoacetic Ester Synthesis

81. Dr. Wolf's CHM 201 & 202 20-81 Acetoacetic Ester Acetoacetic ester is another name for ethyl acetoacetate. The "acetoacetic ester synthesis" uses acetoacetic ester as a reactant for the preparation of ketones. C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C

82. Dr. Wolf's CHM 201 & 202 20-82 Deprotonation of Ethyl Acetoacetate CH 3 CH 2 O C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C + – pK a ~ 11 Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.

83. Dr. Wolf's CHM 201 & 202 20-83 Deprotonation of Ethyl Acetoacetate pK a ~ 16 CH 3 CH 2 O C C C OCH 2 CH 3 HHOO H3CH3CH3CH3C + C C C HOO – H3CH3CH3CH3C + CH 3 CH 2 OH – pK a ~ 11 Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide. K ~ 10 5

84. Dr. Wolf's CHM 201 & 202 20-84 Alkylation of Ethyl Acetoacetate C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C The anion of ethyl acetoacetate can be alkylated using an alkyl halide (S N 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).RX

85. Dr. Wolf's CHM 201 & 202 20-85 Alkylation of Ethyl Acetoacetate C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C The anion of ethyl acetoacetate can be alkylated using an alkyl halide (S N 2: primary and secondary alkyl halides work best; tertiary alkyl halides undergo elimination).RX C C C OCH 2 CH 3 HOO H3CH3CH3CH3C R

86. Dr. Wolf's CHM 201 & 202 20-86 Conversion to Ketone Saponification and acidification convert the alkylated derivative to the corresponding  -keto acid. The  -keto acid then undergoes decarboxylation to form a ketone. C C C OCH 2 CH 3 HOO H3CH3CH3CH3C R C C C OH HOO H3CH3CH3CH3C R 1. HO –, H 2 O 2. H +

87. Dr. Wolf's CHM 201 & 202 20-87 Conversion to Ketone Saponification and acidification convert the alkylated derivative to the corresponding  -keto acid. The  -keto acid then undergoes decarboxylation to form a ketone. C C C OH HOO H3CH3CH3CH3C R C CH 2 R CO 2 O H3CH3CH3CH3C +

88. Dr. Wolf's CHM 201 & 202 20-88 Example 1. NaOCH 2 CH 3 2. CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CCH 2 COCH 2 CH 3

89. Dr. Wolf's CHM 201 & 202 20-89 Example (70%) 1. NaOCH 2 CH 3 2. CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CCH 2 COCH 2 CH 3 OO CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3

90. Dr. Wolf's CHM 201 & 202 20-90 Example (60%)O CH 3 CCH 2 CH 2 CH 2 CH 2 CH 3 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 OO CH 3 CCHCOCH 2 CH 3 CH 2 CH 2 CH 2 CH 3

91. Dr. Wolf's CHM 201 & 202 20-91 Example: DialkylationOO CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2

92. Dr. Wolf's CHM 201 & 202 20-92 Example: Dialkylation 1. NaOCH 2 CH 3 2. CH 3 CH 2 I OO CH 3 CCHCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CCCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CH 2 (75%)

93. Dr. Wolf's CHM 201 & 202 20-93 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 O CH 3 CCCOCH 2 CH 3 CH 2 CH CH 2 O CH 3 CH 2 Example: Dialkylation CH 3 CCH CH 2 CH CH 2 O CH 3 CH 2

94. Dr. Wolf's CHM 201 & 202 20-94 Another ExampleOO H COCH 2 CH 3  -Keto esters other than ethyl acetoacetate may be used.

95. Dr. Wolf's CHM 201 & 202 20-95 Another ExampleOO H COCH 2 CH 3 1. NaOCH 2 CH 3 2. H 2 C CHCH 2 Br OO CH 2 CH COCH 2 CH 3 CH 2 (89%)

96. Dr. Wolf's CHM 201 & 202 20-96 Another ExampleOO COCH 2 CH 3 CH 2 CH CH 2

97. Dr. Wolf's CHM 201 & 202 20-97 Another Example O HOO COCH 2 CH 3 CH 2 CH CH 2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 CH 2 CH CH 2 (66%)

98. Dr. Wolf's CHM 201 & 202 20-98 The Malonic Ester Synthesis

99. Dr. Wolf's CHM 201 & 202 20-99 Malonic Ester Malonic ester is another name for diethyl malonate. The "malonic ester synthesis" uses diethyl malonate as a reactant for the preparation of carboxylic acids. C C C OCH 2 CH 3 HHOO CH 3 CH 2 O

100. Dr. Wolf's CHM 201 & 202 20-100 An AnalogyOO CH 3 CCH 2 COCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 O CH 3 CCH 2 R O HOCCH 2 R The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids.

101. Dr. Wolf's CHM 201 & 202 20-101 Example 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 H2CH2CH2CH2C CHCH 2 CH 2 CH 2 Br 2. CH 2 CH 2 CH 2 CH 2 CH OO CH 3 CH 2 OCCHCOCH 2 CH 3 (85%)

102. Dr. Wolf's CHM 201 & 202 20-102 Example (75%) 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 CH 2 CH 2 CH 2 CH CH 2 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O HOCCH 2 CH 2 CH 2 CH 2 CH CH 2

103. Dr. Wolf's CHM 201 & 202 20-103 Dialkylation 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 2. CH 3 Br CH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 (79-83%)

104. Dr. Wolf's CHM 201 & 202 20-104 Dialkylation 1. NaOCH 2 CH 3 O O CH 3 CH 2 OCCCOCH 2 CH 3 2. CH 3 (CH 2 ) 8 CH 2 Br CH 3 CH 3 (CH 2 ) 8 CH 2 CH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3

105. Dr. Wolf's CHM 201 & 202 20-105 DialkylationO O CH 3 CH 2 OCCCOCH 2 CH 3 CH 3 O CH 3 (CH 2 ) 8 CH 2 CHCOH CH 3 CH 3 (CH 2 ) 8 CH 2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 (61-74%)

106. Dr. Wolf's CHM 201 & 202 20-106 Another Example 1. NaOCH 2 CH 3 OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 2. BrCH 2 CH 2 CH 2 Br CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3

107. Dr. Wolf's CHM 201 & 202 20-107 Another Example This product is not isolated, but cyclizes in the presence of sodium ethoxide. CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3

108. Dr. Wolf's CHM 201 & 202 20-108 Another Example NaOCH 2 CH 3 CH 2 CH 2 CH 2 Br OO CH 3 CH 2 OCCHCOCH 2 CH 3 OO CH 3 CH 2 OCCCOCH 2 CH 3 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 (60-65%)

109. Dr. Wolf's CHM 201 & 202 20-109 Another ExampleOO CH 3 CH 2 OCCCOCH 2 CH 3 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 1. NaOH, H 2 O 2. H + 3. heat, -CO 2 H2CH2CH2CH2C CH 2 CH2CH2CH2CH2 CH CO 2 H (80%)

110. Dr. Wolf's CHM 201 & 202 21-110 Barbiturates

111. Dr. Wolf's CHM 201 & 202 21-111 Barbituric acid is made from diethyl malonate H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N

112. Dr. Wolf's CHM 201 & 202 21-112 H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N 1. NaOCH 2 CH 3 2. H + H2CH2CH2CH2COC C O C N O N H H (72-78%) Barbituric acid is made from diethyl malonate and urea

113. Dr. Wolf's CHM 201 & 202 21-113 H2CH2CH2CH2CO COCH 2 CH 3 O + C H2NH2NH2NH2N O H2NH2NH2NH2N 1. NaOCH 2 CH 3 2. H + O O N O N H H (72-78%) Barbituric acid is made from diethyl malonate and urea

114. Dr. Wolf's CHM 201 & 202 21-114 Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate H2CH2CH2CH2CO COCH 2 CH 3 O 1. RX, NaOCH 2 CH 3 2. R'X, NaOCH 2 CH 3 CO COCH 2 CH 3 O R R'

115. Dr. Wolf's CHM 201 & 202 21-115 Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonateOO N O N H H R R' CO COCH 2 CH 3 O R R' (H 2 N) 2 C O

116. Dr. Wolf's CHM 201 & 202 21-116 ExamplesOO N O N H H CH 3 CH 2 5,5-Diethylbarbituric acid (barbital; Veronal)

117. Dr. Wolf's CHM 201 & 202 21-117 Examples O O N O N H H CH 3 CH 2 5-Ethyl-5-(1-methylbutyl)barbituric acid (pentobarbital; Nembutal) CH 3 CH 2 CH 2 CH H3CH3CH3CH3C

118. Dr. Wolf's CHM 201 & 202 21-118 Examples O O N O N H H 5-Allyl-5-(1-methylbutyl)barbituric acid (secobarbital; Seconal) CH 3 CH 2 CH 2 CH H3CH3CH3CH3C CHCH 2 H2CH2CH2CH2C

119. Dr. Wolf's CHM 201 & 202 20-119 Enolization and Enol Content Enolization and Enol Content

120. Dr. Wolf's CHM 201 & 202 20-120 Mechanism of Enolization (In general) OCR' R2CR2CR2CR2C H OHH OHH R2CR2CR2CR2C CR' O H

121. Dr. Wolf's CHM 201 & 202 20-121 Mechanism of Enolization (Base-catalyzed) O R2CR2CR2CR2C CR' H O H –

122. Dr. Wolf's CHM 201 & 202 20-122 Mechanism of Enolization (Base-catalyzed) H O H O R2CR2CR2CR2C CR'– OHH

123. Dr. Wolf's CHM 201 & 202 20-123 Mechanism of Enolization (Base-catalyzed) OHH O R2CR2CR2CR2C CR'–

124. Dr. Wolf's CHM 201 & 202 20-124 Mechanism of Enolization (Base-catalyzed) HO R2CR2CR2CR2C CR' OH –

125. Dr. Wolf's CHM 201 & 202 20-125 Mechanism of Enolization (Acid-catalyzed) OHH H R2CR2CR2CR2C H O CR' +

126. Dr. Wolf's CHM 201 & 202 20-126 Mechanism of Enolization (Acid-catalyzed) O R2CR2CR2CR2C CR' H O H H H +

127. Dr. Wolf's CHM 201 & 202 20-127 Mechanism of Enolization (Acid-catalyzed) O R2CR2CR2CR2C CR' H H + O H H

128. Dr. Wolf's CHM 201 & 202 20-128 Mechanism of Enolization (Acid-catalyzed) H OHH + O R2CR2CR2CR2C CR' H

129. Dr. Wolf's CHM 201 & 202 20-129 percent enol is usually very small keto form usually 45-60 kJ/mol more stable than enol Enol Content R 2 CHCR' O R2CR2CR2CR2C CR'OHenolketo

130. Dr. Wolf's CHM 201 & 202 20-130 Enol Content CH 3 CH O H2CH2CH2CH2C CHOH K = 3 x 10 -7 Acetaldehyde CH 3 CCH 3 O H2CH2CH2CH2C CCH 3 OH K = 6 x 10 -9 Acetone

131. Dr. Wolf's CHM 201 & 202 20-131  Halogenation of Aldehydes and Ketones  Halogenation of Aldehydes and Ketones

132. Dr. Wolf's CHM 201 & 202 20-132 X 2 is Cl 2, Br 2, or I 2. Substitution is specific for replacement of  hydrogen. Catalyzed by acids. One of the products is an acid (HX); the reaction is autocatalytic. Not a free-radical reaction. General Reaction O R 2 CCR' H + X2X2X2X2O X + HXHXHXHX H+H+H+H+

133. Dr. Wolf's CHM 201 & 202 20-133 Example H2OH2OH2OH2O (61-66%) Cl 2 +O HCl OCl +

134. Dr. Wolf's CHM 201 & 202 20-134 Example CHCl 3 (80%) Br 2 + HBr + H CHOBr CHO Notice that it is the proton on the  carbon that is replaced, not the one on the carbonyl carbon.

135. Dr. Wolf's CHM 201 & 202 20-135 specific for replacement of H at the  carbon equal rates for chlorination, bromination, and iodination first order in ketone; zero order in halogen Mechanism of  Halogenation Experimental Facts Interpretation no involvement of halogen until after the rate-determining step

136. Dr. Wolf's CHM 201 & 202 20-136 first stage is conversion of aldehyde or ketone to the corresponding enol; is rate- determining second stage is reaction of enol with halogen; is faster than the first stage Mechanism of  Halogenation Two stages:

137. Dr. Wolf's CHM 201 & 202 20-137 Mechanism of  Halogenation RCH 2 CR' O X2X2X2X2 fast RCHCR'OX RCH CR'OHslow enol Enol is key intermediate

138. Dr. Wolf's CHM 201 & 202 20-138 first stage is conversion of aldehyde or ketone to the corresponding enol; is rate- determining second stage is reaction of enol with halogen; is faster than the first stage Mechanism of  Halogenation Two stages: examine second stage now

139. Dr. Wolf's CHM 201 & 202 20-139 Reaction of enol with Br 2 carbocation is stabilized by electron release from oxygen BrBr R2CR2CR2CR2C CR' OH Br R2CR2CR2CR2C CR' OH + Br – + Br R2CR2CR2CR2C CR' OH +

140. Dr. Wolf's CHM 201 & 202 20-140 Loss of proton from oxygen completes the process Br – O CR' Br R2CR2CR2CR2C H Br HBr R2CR2CR2CR2C CR' O +

141. Dr. Wolf's CHM 201 & 202 20-141  -Halogenation of Carboxylic Acids: The Hell-Volhard-Zelinsky Reaction

142. Dr. Wolf's CHM 201 & 202 20-142 analogous to  -halogenation of aldehydes and ketones key question: Is enol content of carboxylic acids high enough to permit reaction to occur at reasonable rate? (Answer is NO)  -Halogenation of Carboxylic Acids + X2X2X2X2 + HXHXHXHX R 2 CCOH OH OX

143. Dr. Wolf's CHM 201 & 202 20-143 reaction works well if a small amount of phosphorus or a phosphorus trihalide is added to the reaction mixture this combination is called the Hell-Volhard- Zelinsky reaction But... + X2X2X2X2 + HXHXHXHX R 2 CCOH OH OX P or PX 3

144. Dr. Wolf's CHM 201 & 202 20-144 Example CH 2 COH O PCl 3 benzene 80°C CHCOHOBr (60-62%) + Br 2

145. Dr. Wolf's CHM 201 & 202 20-145 Value CH 3 CH 2 CH 2 COH O Br 2 P CH 3 CH 2 CHCOH OBr (77%)  -Halogen can be replaced by nucleophilic substitution

146. Dr. Wolf's CHM 201 & 202 20-146 Value CH 3 CH 2 CH 2 COH O Br 2 P CH 3 CH 2 CHCOH OBr OOH (77%) (69%) K 2 CO 3 H 2 O heat

147. Dr. Wolf's CHM 201 & 202 20-147 Synthesis of  -Amino Acids (CH 3 ) 2 CHCH 2 COH O Br 2 PCl 3 (CH 3 ) 2 CHCHCOH OBr O NH 2 (88%) (48%) NH 3 H 2 O

148. Dr. Wolf's CHM 201 & 202 20-148 Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage. Such cleavage is called the haloform reaction because chloroform, bromoform, or iodoform is one of the products. The Haloform Reaction

149. Dr. Wolf's CHM 201 & 202 20-149 Example (CH 3 ) 3 CCCH 3 O Br 2, NaOH, H 2 O CHBr 3 + (CH 3 ) 3 CCONa O (CH 3 ) 3 CCOH O H+H+H+H+ (71-74%)

150. Dr. Wolf's CHM 201 & 202 20-150 The haloform reaction is sometimes used as a method for preparing carboxylic acids, but works well only when a single enolate can form. The Haloform Reaction ArCCH 3 O (CH 3 ) 3 CCCH 3 O RCH 2 CCH 3 Oyesyesno

151. Dr. Wolf's CHM 201 & 202 20-151 RCCH 3 O X 2, HO – RCCH 2 X O X 2, HO – RCCHX 2 O X 2, HO – RCCX 3 OMechanism First stage is substitution of all available  hydrogens by halogen

152. Dr. Wolf's CHM 201 & 202 20-152 Mechanism Formation of the trihalomethyl ketone is followed by its hydroxide-induced cleavage HO – RC O CX3CX3CX3CX3 –RC O HO CX3CX3CX3CX3 + – HCX 3 RC O O + – CX3CX3CX3CX3 RC O OH +

153. Dr. Wolf's CHM 201 & 202 20-153 Some Chemical and Stereochemical Consequences of Enolization

154. Dr. Wolf's CHM 201 & 202 20-154 Hydrogen-Deuterium Exchange OH HH H + 4D2O4D2O4D2O4D2OOD DD D + 4DOH KOD, heat

155. Dr. Wolf's CHM 201 & 202 20-155 Mechanism ODODODOD – + HOD + H O H H – O H H H H

156. Dr. Wolf's CHM 201 & 202 20-156 Mechanism H O H H – ODODODOD – + O H H D H ODODODOD D

157. Dr. Wolf's CHM 201 & 202 20-157 Stereochemical Consequences of Enolization C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C 100% R H3O+H3O+H3O+H3O+ H 2 O, HO – 50% R 50% S

158. Dr. Wolf's CHM 201 & 202 20-158 Enol is achiral C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C R R CC 6 H 5 OH C H3CH3CH3CH3C CH 3 CH 2

159. Dr. Wolf's CHM 201 & 202 20-159 Enol is achiral C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C R R CC 6 H 5 OH C H3CH3CH3CH3C CH 3 CH 2 C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C S S 50% 50%

160. Dr. Wolf's CHM 201 & 202 20-160 Results of Rate Studies C CC 6 H 5 OH CH 3 CH 2 H3CH3CH3CH3C Equal rates for: racemization H-D exchange bromination iodination Enol is intermediate and its formation is rate- determining

161. Dr. Wolf's CHM 201 & 202 20-161 Effects of Conjugation in  -Unsaturated Aldehydes and Ketones

162. Dr. Wolf's CHM 201 & 202 20-162 Relative Stability aldehydes and ketones that contain a carbon- carbon double bond are more stable when the double bond is conjugated with the carbonyl group than when it is not compounds of this type are referred to as ,  unsaturated aldehydes and ketones

163. Dr. Wolf's CHM 201 & 202 20-163 Relative Stability CH 3 CH O CHCH 2 CCH 3 (17%) K = 4.8 (83%)  O CH 3 CH 2 CH CHCCH 3 

164. Dr. Wolf's CHM 201 & 202 20-164 Acrolein H2CH2CH2CH2C CHCHO

165. Dr. Wolf's CHM 201 & 202 20-165 Acrolein H2CH2CH2CH2C CHCHO

166. Dr. Wolf's CHM 201 & 202 20-166 Acrolein H2CH2CH2CH2C CHCHO

167. Dr. Wolf's CHM 201 & 202 20-167 Acrolein H2CH2CH2CH2C CHCHO

168. Dr. Wolf's CHM 201 & 202 20-168 Resonance Description C O C C +–C O C C + – C O C C

169. Dr. Wolf's CHM 201 & 202 20-169  -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones.  -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack carbonyl carbon  -carbon Properties C O C C 

170. Dr. Wolf's CHM 201 & 202 20-170 Dipole Moments Butanal trans-2-Butenal  = 2.7 D  = 3.7 D O O –––– –––– ++++ ++++ ++++ greater separation of positive and negative charge

171. Dr. Wolf's CHM 201 & 202 20-171 Conjugate Addition to  -Unsaturated Carbonyl Compounds

172. Dr. Wolf's CHM 201 & 202 20-172 1,2-addition (direct addition) nucleophile attacks carbon of C=O 1,4-addition (conjugate addition) nucleophile attacks  -carbon Nucleophilic Addition to  -Unsaturated Aldehydes and Ketones

173. Dr. Wolf's CHM 201 & 202 20-173 attack is faster at C=O attack at  -carbon gives the more stable product Kinetic versus Thermodynamic Control

174. Dr. Wolf's CHM 201 & 202 20-174HY+ C C CO1,2-addition C C C OHY formed faster major product under conditions of kinetic control (i.e. when addition is not readily reversible)

175. Dr. Wolf's CHM 201 & 202 20-175HY+ C C CO1,4-addition C C C OHY enol goes to keto form under reaction conditions

176. Dr. Wolf's CHM 201 & 202 20-176HY+ C C CO1,4-addition keto form is isolated product of 1,4-addition is more stable than 1,2-addition product C C COH Y

177. Dr. Wolf's CHM 201 & 202 20-177HY+ C C CO1,2-addition C C C OHY 1,4-addition C C COH Y C=O is stronger than C=C

178. Dr. Wolf's CHM 201 & 202 20-178 Addition of Carbanions to  -Unsaturated Carbonyl Compounds: The Michael Reaction

179. Dr. Wolf's CHM 201 & 202 20-179 Stabilized carbanions, such as those derived from  -diketones undergo conjugate addition to ,  -unsaturated ketones. Michael Addition

180. Dr. Wolf's CHM 201 & 202 20-180 Example (85%)O H2CH2CH2CH2C CHCCH 3 CH 3 OO O OO CH 2 CH 2 CCH 3 KOH, methanol +

181. Dr. Wolf's CHM 201 & 202 20-181 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. Michael Addition

182. Dr. Wolf's CHM 201 & 202 20-182 Example O CH 3 OO CH 2 CH 2 CCH 3 NaOH heat (85%) O O CH 3 OHO O not isolated; dehydrates under reaction conditions

183. Dr. Wolf's CHM 201 & 202 20-183 Stabilized Anions The anions derived by deprotonation of  -keto esters and diethyl malonate are weak bases. Weak bases react with ,  - unsaturated carbonyl compounds by conjugate addition. C C C OCH 2 CH 3 HOO – H3CH3CH3CH3C C C C HOO CH 3 CH 2 O –

184. Dr. Wolf's CHM 201 & 202 20-184 ExampleOO CH 3 CH 2 OCCH 2 COCH 2 CH 3 + H2CH2CH2CH2C CHCCH 3 O

185. Dr. Wolf's CHM 201 & 202 20-185 Example KOH, ethanol OO CH 3 CH 2 OCCH 2 COCH 2 CH 3 (85%) + H2CH2CH2CH2C CHCCH 3 O CH 2 CH 2 CCH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O

186. Dr. Wolf's CHM 201 & 202 20-186 Example 1. KOH, ethanol-water CH 2 CH 2 CCH 3 OO CH 3 CH 2 OCCHCOCH 2 CH 3 O 2. H + 3. heat CH 3 CCH 2 CH 2 CH 2 COH OO (42%)

187. Dr. Wolf's CHM 201 & 202 20-187 Conjugate Addition of Organocopper Reagents to  -Unsaturated Carbonyl Compounds

188. Dr. Wolf's CHM 201 & 202 20-188 The main use of organocopper reagents is to form carbon-carbon bonds by conjugate addition to ,  -unsaturated ketones. Addition of Organocopper Reagents to  -Unsaturated Aldehydes and Ketones

189. Dr. Wolf's CHM 201 & 202 20-189 ExampleO CH 3 (98%) + LiCu(CH 3 ) 2 O CH 3 1. diethyl ether 2. H 2 O

190. Dr. Wolf's CHM 201 & 202 20-190 End of Chapter 20