1. Chapter 17 Aldehydes and Ketones
Chapter 17 Aldehydes and Ketones. Nucleophilic Addition to the Carbonyl Group 1

2. 17.4 Sources of Aldehydes and Ketones14

3. Synthesis of 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)
A number of reactions already studied provide efficient synthetic routes to aldehydes and ketones. 17

4. What about Aldehydes from Carboxylic Acids?OH H C O R
RCH2OH
1. LiAlH4
2. H2O
PDC, CH2Cl2 18

5. Benzaldehyde from benzoic acid
Example
Benzaldehyde from benzoic acid
COH O CH O
1. LiAlH4
2. H2O
PDC CH2Cl2
CH2OH
(81%)
(83%) 18

6. What about Ketones from Aldehydes?C O R H R' C O R
PDC, CH2Cl2
1. R'MgX
2. H3O+
RCHR' OH 18

7. 17.5 Reactions 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 ( ) 2

9. 17.6 Principles of Nucleophilic Addition to Carbonyl Groups: Hydration of Aldehydes and Ketones4

10. Hydration of Aldehydes and KetonesC •• O
• •
H2O HO C O H •• 5

11. Substituent Effects on Hydration EquilibriaOH R R' +
H2O C O
Compared to H
Electronic: Alkyl groups stabilize reactants
Steric: Alkyl groups crowd product 6

12. Equilibrium Constants and Relative Rates of Hydration
C=O Hydrate K % Relative rate
CH2=O CH2(OH) >
CH3CH=O CH3CH(OH)
(CH3)3CCH=O (CH3)3CCH(OH)
(CH3)2C=O (CH3)2C(OH)
Decreased hydration with greater alkyl substitution due to electron donation and steric crowding. 7

13. When Does Equilibrium Favor Hydrate?
When carbonyl group is destabilized:
electron-withdrawing groups destabilize C=O. 8

14. Substituent Effects on Hydration EquilibriaOH O +
H2O R C R C R R OH
R = CH3: K =
R = CF3: K = 22,000 9

15. Mechanism of Hydration (Base)
Step 1:
• • O H •• – •• HO C O
• • – C •• O
• • + 10

16. Mechanism of Hydration (Base)
Step 2: •• HO C O
• • – + ••
• • O H – HO C OH
• • O H •• 10

17. Mechanism of Hydration (Acid)
Step 1:
• • H O + C •• O
• • + C •• OH
• • H O + 10

18. Mechanism of Hydration (Acid)
Step 2:
• • H O +
• • H O •• C OH + + C OH •• 10

19. Mechanism of Hydration (Acid)
Step 3:
• • O H •• C OH + H O •• +
• • H O •• C OH 10

20. 17.7 Cyanohydrin Formation

21. Cyanohydrin Formation••
• • C O H C O N
• • •• +
HCN 18

22. Cyanohydrin Formation– N
• • ••
• • C O 18

23. Cyanohydrin Formation+ O
• •
Then acidify solution: – O N C ••
• • H O
• • N C •• 18

24. 2,4-Dichlorobenzaldehyde
Example Cl CH O Cl
CHCN OH
NaCN, water
then H2SO4
2,4-Dichlorobenzaldehyde
cyanohydrin (100%) 20

25. Acetone cyanohydrin is used in the synthesis of methacrylonitrile.
Example
CH3CCH3 O
CH3CCH3 OH CN
NaCN, water
then H2SO4
(77-78%)
Acetone cyanohydrin is used in the synthesis of methacrylonitrile. 21

26. 17.8 Acetal Formation 1

27. Compounds related to imines Enamine formation The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamine formation
The Wittig reaction 22

28. Hemiacetals and AcetalsOH H HO
HOCH2 O O
OCH3 OH HO
HOCH2
-D-Glucopyranose (a form of glucose), a hemiacetal
Methyl--D-Glucopyranose,
an acetal O
HOCH2 OH HO
Polyoxymethylene,
a polyacetal
Lactose,
an acetal and hemiacetal 5

29. Recall Hydration of Aldehydes and Ketones
HOH C •• O
• • HO H R R' 5

30. Alcohols Under Analogous Reaction with Aldehydes and Ketones
R"OH C •• O
• • R R'
R"O H
Product is called a hemiacetal. 5

31. Hemiacetal Reacts Further in Acid to Yield an Acetal
R"O C O H •• R R'
Hemiacetal
R"OH, H+
R"O C
OR" •• R R'
Product is called an acetal. 5

32. Benzaldehyde diethyl acetal (66%)
Example CH O +
2CH3CH2OH
HCl
CH(OCH2CH3)2
+ H2O
Benzaldehyde diethyl acetal (66%) 6

33. Diols Form Cyclic Acetals
CH3(CH2)5CH +
HOCH2CH2OH
p-toluenesulfonic acid,
benzene H
(CH2)5CH3
H2C
CH2 O C +
H2O
(81%) 7

34. Important exception: Cyclic acetals can be prepared from ketones.
In General:
Position of equilibrium is usually unfavorable for acetal formation from ketones.
Important exception: Cyclic acetals can be prepared from ketones. 8

35. p-toluenesulfonic acid,
Example O
C6H5CH2CCH3 +
HOCH2CH2OH
p-toluenesulfonic acid,
benzene
H2C
CH2 O O +
H2O
(78%) C
C6H5CH2
CH3 7

36. Mechanism of Acetal Formation
First stage is analogous to hydration and leads to hemiacetal:
Acid-catalyzed nucleophilic addition of alcohol to C=O. 10

37. Mechanism H R + O
• • C O ••
• • 10

38. Mechanism H •• + C O O
• •
• • H R 10

39. Mechanism R H O
• • •• + C O H 10

40. Mechanism R •• •• O C O O R H ••
• • + H H 10

41. Mechanism C O ••
• • H R + H O R •• 10

42. Mechanism of Acetal Formation
Second stage is hemiacetal-to-acetal conversion:
Involves carbocation chemistry. 15

43. Hemiacetal-to-Acetal StageR + O
• • C O ••
• • H R 16

44. Hemiacetal-to-Acetal StageR O
• • C O •• H R + 16

45. Hemiacetal-to-Acetal Stage•• H R + C 16

46. Hemiacetal-to-Acetal Stage•• R + O •• H
• • 16

47. Hemiacetal-to-Acetal Stage•• R + C O R •• +
Carbocation is stabilized by delocalization of unshared electron pair of oxygen. 16

48. Hemiacetal-to-Acetal Stage•• R + O •• H R
• • 16

49. Hemiacetal-to-Acetal Stage•• R + H O •• H R
• • 16

50. Hemiacetal-to-Acetal Stage•• R + H O •• R 16

51. Reverse of acetal formation; hemiacetal is intermediate.
Hydrolysis of Acetals
OR" R R' C
+ H2O C R R' O
2R"OH +
Mechanism:
Reverse of acetal formation; hemiacetal is intermediate.
Application:
Aldehydes and ketones can be "protected" as acetals. 26

52. 17.9 Acetals as Protecting Groups28

53. The conversion shown cannot be carried out directly...
Example
The conversion shown cannot be carried out directly... CH
CH3CCH2CH2C O
1. NaNH2 2. CH3I
CCH3
CH3CCH2CH2C O 29

54. Because the carbonyl group and the carbanion are incompatible functional groups.
CH3CCH2CH2C O – 31

55. Strategy
1) Protect C=O
2) Alkylate
3) Restore C=O 32

56. Example: Protect O + CH3CCH2CH2C CH HOCH2CH2OH H2C CH2 O C CH2CH2C CH
p-toluenesulfonic acid,
benzene
H2C
CH2 O C
CH3
CH2CH2C CH 7

57. Example: Alkylate H2C CH2 O C CH2CH2C CCH3 CH3 H2C CH2
1. NaNH2 2. CH3I
CH2CH2C CH 7

58. Example: Deprotect H2C CH2 O C CH3 CH2CH2C CCH3 H2O HCl CCH3
CH3CCH2CH2C O +
HOCH2CH2OH
(96%) 7

59. 17.10 Reaction with Primary Amines: Imines2

60. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

61. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

62. Imine (Schiff's Base) Formation
H2N R C O •• +
• • H
Carbinolamine
intermediate C O HN R ••
Primary amine •• N C
+ H2O R
Imine 3

63. N-Benzylidenemethylamine (70%)
Example CH O
Methylamine +
CH3NH2
Benzaldehyde
CH=NCH3
+ H2O
N-Benzylidenemethylamine (70%) 4

64. N-Benzylidenemethylamine (70%)
Example
Carbinolamine
intermediate CH O +
CH3NH2 CH OH
NHCH3
CH=NCH3
+ H2O
N-Benzylidenemethylamine (70%) 4

65. N-Cyclohexylideneisobutylamine (79%)
Example O +
(CH3)2CHCH2NH2
Isobutylamine
Cyclohexanone
NCH2CH(CH3)2
+ H2O
N-Cyclohexylideneisobutylamine (79%) 5

66. N-Cyclohexylideneisobutylamine (79%)
Example O +
(CH3)2CHCH2NH2
Carbinolamine
intermediate OH
NHCH2CH(CH3)2
NCH2CH(CH3)2
+ H2O
N-Cyclohexylideneisobutylamine (79%) 5

67. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

68. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

69. Reaction with Derivatives of Ammonia
H2N G +
R2C O NG
H2O
H2N OH
R2C
NOH
Hydroxylamine
Oxime 14

70. Example CH3(CH2)5CH + H2NOH O Hydroxylamine Heptanal CH3(CH2)5CH + H2O
Heptanal oxime (81-93%) 15

71. Reaction with Derivatives of Ammonia
H2N G +
R2C O NG
H2O OH
NOH
Hydroxylamine
Oxime
H2N
NH2
R2C
NNH2
Hydrazine
Hydrazone
etc. 14

72. Benzophenone hydrazone (73%)
Example O C
+ H2NNH2
Hydrazine
Benzophenone
NNH2 C
+ H2O
Benzophenone hydrazone (73%) 16

73. Acetophenone phenylhydrazone (87-91%)
Example O
+ H2NNH
CCH3
Acetophenone
Phenylhydrazine
+ H2O
CCH3
NNH
Acetophenone phenylhydrazone (87-91%) 17

74. 2-Dodecanone semicarbazone (93%)
Example O O +
CH3(CH2)9CCH3
H2NNHCNH2
Semicarbazide
2-Dodecanone
H2O
CH3(CH2)9CCH3
NNHCNH2 O +
2-Dodecanone semicarbazone (93%) 18

75. 17.11 Reaction with Secondary Amines: Enamines20

76. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

77. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

78. Enamine Formation C O R2N H Carbinolamine intermediate C O H R2NH•• O
R2N H
Carbinolamine
intermediate C O •• H
• •
R2NH ••
Secondary amine
+ H2O
Secondary enamine C ••
R2N 21

79. Example O N + N H N OH p-toluenesulfonic acid, benzene, heat
Cyclopentanone
Pyrrolidine OH N
via carbinolamine intermediate
N-(1-Cyclopentyl)-
pyrrolidine
(a secondary enamine)
(80-90%) 22

80. Example of the Importance of Imines and Enamines
Protonated imine
Primary enamine
Biochemical reaction catalyzed by acetoacetate decarboxylase 21

81. 17.12 The Wittig Reaction 20

82. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

83. Compounds related to imines Enamines The Wittig reaction
Some Reactions of Aldehydes and Ketones Progress Beyond the Nucleophilic Addition Stage
Acetal formation
Imine formation
Compounds related to imines
Enamines
The Wittig reaction 22

84. Synthetic method for preparing alkenes.
The Wittig Reaction
Synthetic method for preparing alkenes.
One of the reactants is an aldehyde or ketone.
The other reactant is a phosphorus ylide.
(C6H5)3P C + A B
• • –
A key property of ylides is that they have a negatively polarized carbon and are nucleophilic. 22

85. Charge Distribution in an Ylide22

86. The Wittig Reaction C O R R' (C6H5)3P C + A B – + + C R R' A B••
(C6H5)3P C + A B
• • – + + C R R' A B
(C6H5)3P O
• • – •• 22

87. Example + – O + (C6H5)3P CH2 DMSO + – CH2 + (C6H5)3P O (86%)••
(C6H5)3P
CH2 + – •• +
DMSO
CH2
(C6H5)3P O +
• • – •• +
(86%)
Dimethyl sulfoxide (DMSO) or tetrahydrofuran (THF) is the customary solvent. 22

88. Mechanism Step 1 C O R R' O C P(C6H5)3 R R' B A P(C6H5)3 + C A B – ••
• •
P(C6H5)3 + C A B – •• 22

89. Mechanism Step 2 O C P(C6H5)3 R R' B A P(C6H5)3 + – O R' R A B C •• ••22

90. 17.13 Planning an Alkene Synthesis via the Wittig Reaction20

91. Retrosynthetic AnalysisB
There will be two possible Wittig routes to an alkene.
Analyze the structure retrosynthetically.
Disconnect the doubly bonded carbons. One will come from the aldehyde or ketone, the other from the ylide. 22

92. Retrosynthetic Analysis of Styrene
C6H5CH O +
(C6H5)3P
CH2 – ••
Both routes are acceptable.
C6H5CH
CH2
HCH O +
(C6H5)3P
CHC6H5 – •• 22

93. Ylides are prepared from alkyl halides by a two-stage process.
Preparation of Ylides
Ylides are prepared from alkyl halides by a two-stage process.
The first step is a nucleophilic substitution. Triphenylphosphine is the nucleophile. +
(C6H5)3P
+ X– CH A B
(C6H5)3P
• • + CH A B X 22

94. Preparation of Ylides
In the second step, the phosphonium salt is treated with a strong base in order to remove a proton from the carbon bonded to phosphorus.
(C6H5)3P C A B + H
base
• • –
(C6H5)3P C A B +
• • – H
base 22

95. Preparation of Ylides
Typical strong bases include organolithium reagents (RLi) and the conjugate base of dimethyl sulfoxide as its sodium salt [NaCH2S(O)CH3].
(C6H5)3P C A B + H A + –
(C6H5)3P C
• • B – H
base
base
• • 22

96. Section 17.17 Spectroscopic Analysis of Aldehydes and Ketones

97. Infrared Spectroscopy
Presence of a C=O group is readily apparent in infrared spectrum.
C=O stretching gives an intense absorption at cm-1.
In addition to peak for C=O, aldehydes give two weak peaks near 2720 and 2820 cm-1 for H—C=O. 6

98. Infrared Spectrum of Butanal8

99. Aldehydes: H—C=O proton is at very low field ( 9-10 ppm).
1H NMR
Aldehydes: H—C=O proton is at very low field ( 9-10 ppm).
Methyl ketones: CH3 singlet near  2 ppm.
More substituted ketones: methylene CH2 around around  2.4 ppm and methine CH around  2.5. 6

100. 2-Butanone CH3 C O CH3CH2 1 Chemical shift (, ppm) 1.0 2.0 3.0 4.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
Chemical shift (, ppm) 1

101. Isobutyraldehyde H C O CH(CH3)2 1 Chemical shift (, ppm) 1.0 2.0 3.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
Chemical shift (, ppm) 1

102. 13C NMR
Carbonyl carbon is at extremely low field-near  200 ppm.
Intensity of carbonyl carbon is usually weak.

103. 3-Heptanone O CH3CH2CCH2CH2CH2CH3 Chemical shift (, ppm) 1 20 40 6020 40 60 80
100
120
140
160
180
200
Chemical shift (, ppm) 1