1. Chapter 18 Enols and Enolates

2. 18.1 The -Carbon Atom and its pKa5

3. The reference atom is the carbonyl carbon.
Terminology
CH3CH2CH2CH O   
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. 6

4. Acidity of -Hydrogen O R2C CR' H Enolate ion R2C CR' O – + H+ R2C CR'••
R2C
CR'
• • H
Enolate ion ••
R2C
CR' O
• • –
+ H+
R2C
CR' O ••
• • –
pKa = 16-20 35

5. Acidity of -Hydrogen
(CH3)2CHCH O
CCH3 O
pKa = 15.5
pKa = 18.3 40

6. -Diketones Are Much More Acidic
H3C C
CH3 O H
pKa = 9
H3C C
CH3 O H H+ + •• – 41

7. -Diketones Are Much More Acidic
H3C C
CH3 O H – ••
• •
Enolate of -diketone is stabilized; negative charge is shared by both oxygens.
H3C C
CH3 O H •• –
• • 41

8. -Diketones Are Much More Acidic
H3C C
CH3 O H – ••
• • –
H3C H C
CH3 O ••
• •
H3C C
CH3 O H •• –
• • 41

9. 18.2 The Aldol Condensation

10. A basic solution contains both the aldehyde and its enolate.
Some Thoughts...
RCH2CH O
RCHCH O •• OH
• • – ••
HOH + + •• –
pKa = 16-20
pKa = 15.7
A basic solution contains both the aldehyde and its enolate.
Aldehydes undergo nucleophilic addition.
Enolate ions are nucleophiles.
What about nucleophilic addition of enolate to aldehyde? 2

11. RCHCH O – – RCH2CH O RCHCH RCH2CH O RCHCH H RCH2CH O 2 RCH2CH O NaOH••
• • – –
RCH2CH O ••
• •
RCHCH ••
RCH2CH O
• •
RCHCH H ••
RCH2CH O ••
• •
2 RCH2CH O
NaOH
RCH2CH OH
CHCH R 3

12. Aldol Addition RCH2CH OH CHCH O R
Product is called an "aldol" because it is both an aldehyde and an alcohol. 5

13. Aldol Addition of Acetaldehyde
2 CH3CH O
CH3CH OH
CH2CH O
NaOH, H2O
5°C
Acetaldol (50%) 6

14. Aldol Addition of Butanal
2 CH3CH2CH2CH O
KOH, H2O
6°C
(75%)
CH3CH2CH2CH OH
CHCH O
CH2CH3 6

15. Aldol Condensation
2 RCH2CH O
RCH2CH OH
CHCH O R
NaOH 3

16. Aldol Condensation 2 RCH2CH O RCH2CH OH CHCH O R NaOH NaOH, heat R
CCH O 3

17. Aldol Condensation of Butanal
2 CH3CH2CH2CH O
NaOH, H2O
80-100°C
(86%)
CH3CH2CH2CH
CCH O
CH2CH3 6

18. Dehydration of Aldol Addition ProductOH H C O C O
Dehydration of -hydroxy aldehyde can be catalyzed by either acids or bases. 12

19. Dehydration of Aldol Addition ProductOH H C O OH C O
• • –
NaOH
In base, the enolate is formed. 12

20. Dehydration of Aldol Addition ProductOH H C O OH C O
• • –
NaOH
The enolate loses hydroxide to form the ,-unsaturated aldehyde. 12

21. Aldol Reactions of Ketones2%
98%
2 CH3CCH3 O
CH3CCH2CCH3 OH
CH3
The equilibrium constant for aldol addition reactions of ketones is usually unfavorable. 16

22. Intramolecular Aldol Condensation
(96%)
Na2CO3, H2O
heat O OH
via: 19

23. Intramolecular Aldol Condensation
(96%)
Na2CO3, H2O
heat
Even ketones give good yields of aldol condensation products when the reaction is intramolecular. 19

24. 18.3 Mixed Aldol Condensations

25. What Is the Product? O O NaOH + CH3CH2CH CH3CH
There are 4 possibilities because the reaction mixture contains the two aldehydes plus the enolate of each aldehyde. 21

26. What Is the Product? CH3CH O CH3CH2CH O + CH3CH OH CH2CH O CH2CH O O –
• • – –
CH3CHCH •• 21

27. What Is the Product? CH3CH O CH3CH2CH O + CH3CH2CH OH CHCH O CH3 CH2CH
• • – –
CH3CHCH •• 21

28. What Is the Product? CH3CH O CH3CH2CH O + CH3CH OH CHCH O CH3 CH2CH O
• • – –
CH3CHCH •• 21

29. What Is the Product? CH3CH O CH3CH2CH O + CH3CH2CH OH CH2CH O CH2CH O
• • – –
CH3CHCH •• 21

30. 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. 22

31. Formaldehyde cannot form an enolate.
HCH
Formaldehyde cannot form an enolate.
Formaldehyde is extremely reactive toward nucleophilic addition. 23

32. Formaldehyde O HCH (CH3)2CHCH2CH O (CH3)2CHCHCH O CH2OH + (52%) K2CO3
water- ether
(52%) 23

33. Aromatic aldehydes cannot form an enolate.
CH3O CH O
Aromatic aldehydes cannot form an enolate. 24

34. Aromatic Aldehydes CH3O CH O CH3CCH3 O + NaOH, H2O 30°C CH3O CH CHCCH3
(83%) 24

35. Converting Ketones to Enolates for Reaction with Aldehyde
Use very strong base like lithium diisopropylamide (LDA), then react with aldehyde. 24

36. 18.4 Alkylation of Enolate Anions

37. Enolate Ions in SN2 Reactions
Enolate ions are nucleophiles and react with alkyl halides.
With a very strong base like LDA, simple enolates can be alkylated without competition from aldol condensation.
Enolates derived from -diketones are more readily alkylated than simple enolates. 11

38. Example
CH3CCH2CCH3 O O O
K2CO3 +
CH3I
CH3CCHCCH3
CH3
(75-77%) 11

39. 18.5 Enolization and Enol Content

40. Enolization (or Keto-Enol Tautomerism)H
• • •• O ••
CR'
• •
R2C H O H
• •
Ketone or aldehyde
(keto form)
R2C
CR' O ••
• • H
Note: keto and enol forms are constitutional isomers.
Enol 6

41. Mechanism of Enolization (Base-Catalyzed)•• O
• •
R2C
CR' – •• O H
• •
• • H 6

42. Mechanism of Enolization (Base-Catalyzed)
• • •• O ••
R2C
CR' –
• • •• O H
• • H 6

43. Mechanism of Enolization (Base-Catalyzed)
• • O ••
R2C
CR' –
• • •• 6

44. Mechanism of Enolization (Base-Catalyzed)
• • – •• •• O H
• •
R2C
CR' 6

45. Mechanism of Enolization (Acid-Catalyzed)
• •
R2C H O ••
CR'
• • + 6

46. Mechanism of Enolization (Acid-Catalyzed)+ •• O H O
• •
• •
R2C
CR' H H 6

47. Mechanism of Enolization (Acid-Catalyzed)+ •• O H O H
• •
R2C
CR' H 6

48. Mechanism of Enolization (Acid-Catalyzed)••
R2C
CR' H
• • H O
• • + 6

49. Percent enol is usually very small.
Enol Content
R2CHCR' O
R2C
CR' OH
keto
enol
Percent enol is usually very small.
Keto form usually kJ/mol more stable than enol.
C=O is stronger than C=C. 27

50. Enol Content Acetaldehyde CH3CH O H2C CH OH K = 3 x 10-7 Acetone
CH3CCH3 O
H2C
CCH3 OH
K = 6 x 10-9 27

51. 18.11 Effects of Conjugation in -Unsaturated Aldehydes and Ketones

52. 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. 2

53. Relative Stability CH3CH O CHCH2CCH3    (17%) K = 4.8 (83%) O
CH3CH2CH
CHCCH3    2

54. Acrolein
H2C
CHCH O 3

55. Acrolein
H2C
CHCH O 3

56. Acrolein
H2C
CHCH O 3

57. Resonance Description••
• • + – C O ••
• • + – C O ••
• • 7

58. Properties
-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 C O ••
• •  8

59. Greater separation of positive and negative charge
Dipole Moments – – O O + + +
 = 2.7 D
 = 3.7 D
Butanal
trans-2-Butenal
Greater separation of positive and negative charge 9

60. 18.12 Conjugate Addition to -Unsaturated Carbonyl Compounds

61. Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
1,2-Addition (direct addition):
Nucleophile attacks carbon of C=O
1,4-Addition (conjugate addition):
Nucleophile attacks -carbon 11

62. Kinetic versus Thermodynamic Control
Attack is faster at C=O.
Attack at -carbon gives the more stable product. 11

63. C O + H Y
1,2-addition
Formed faster.
Major product under conditions of kinetic control (i.e., when addition is not readily reversible). C O H Y 13

64. Enol form goes to keto form under reaction conditions.+ H Y
1,4-addition C O H Y
Enol form goes to keto form under reaction conditions. 13

65. C O + H Y
1,4-addition
Keto form is isolated product of 1,4-addition. Major product under conditions of thermodynamic control.
More stable than 1,2-addition product. C O H Y 13

66. C=O is stronger than C=C+ H Y
1,2-addition
1,4-addition
C=O is stronger than C=C C O H Y C O H Y 13

67. 13

68. Observed with strongly basic nucleophiles: Grignard reagents LiAlH4
1,2-Addition
Observed with strongly basic nucleophiles:
Grignard reagents
LiAlH4
NaBH4
Sodium acetylide
Strongly basic nucleophiles add “irreversibly.” 17

69. Example O CH3CH CHCH + HC CMgBr 1. THF 2. H3O+ OH CH3CH CHCHC CH (84%)18

70. Observed with weakly basic nucleophiles: Cyanide ion (CN–)
1,4-Addition
Observed with weakly basic nucleophiles:
Cyanide ion (CN–)
Thiolate ions (RS–)
Ammonia and amines (NH3, RNH2, R2NH)
Azide ion (N3–)
Weakly basic nucleophiles add reversibly. 17

71. Example via C6H5CH CC6H5 CN – O CH O C6H5CH CHCC6H5 KCN O•• – O
• • CH O
C6H5CH
CHCC6H5
KCN
ethanol, acetic acid O
C6H5CHCH2CC6H5 CN
(93-96%) 20

72. via – O CH3 SCH2C6H5 Example O CH3 O CH3 SCH2C6H5 (58%) •• • •
C6H5CH2SH
HO–, H2O O
CH3
SCH2C6H5
(58%) 21

73. 18.13 Addition of Carbanions to -Unsaturated Carbonyl Compounds: The Michael Reaction

74. Michael Addition
Stabilized carbanions, such as those derived from -diketones, undergo conjugate addition to ,-unsaturated ketones. 11

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

76. 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

77. Example: Robinson Annulation
CH3
CH2CH2CCH3 OH O
CH3
NaOH heat
(85%) O
CH3
Not isolated; dehydrates under reaction conditions. 20

78. 18.14 Conjugate Addition of Organocopper Reagents to -Unsaturated Carbonyl Compounds

79. Addition of Organocopper Reagents to -Unsaturated Aldehydes and Ketones
The main use of organocopper reagents is to form carbon-carbon bonds by conjugate addition to ,-unsaturated ketones. 11

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