1. Chapter 19 Aldehydes and Ketones: Nucleophilic Addition Reactions

2. Aldehydes and Ketones
Aldehydes (RCHO) and ketones (R2CO) are characterized by the carbonyl functional group (C=O)
Naming aldehydes and ketones+

3. Structure of the Carbonyl Group
Carbon is sp2 hybridized
C═O bond is shorter, stronger, and more polar than C═C bond in alkenes

4. Resonance First resonance Second resonance
All atoms complete the octet
No charges
Second resonance
Carbocation acts as an electrophile

5. Nomenclature

6. Ketone Nomenclature Number chain with lowest number on carbonyl carbon
Replace the alkane -e with -one
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7. Cyclic Ketone Nomenclature
Cyclic ketones carbonyl carbon is assigned the number 1
Carbonyl takes precedence over a double bond
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8. Aldehydes Nomenclature
Aldehyde carbon is number 1
Replace -e with -al.
Use suffix carbaldehyde when aldehyde is attached to a ring

9. Naming Aldehydes and Ketones
R–C=O as a substituent is an acyl group
Name substituent with suffix -yl added to the root name of the carboxylic acid
Naming aldehydes and ketones

10. Carbonyl as Substituent
Molecule has a higher priority functional group
Ketone is an oxo group
Aldehyde is a formyl group
Aldehydes have a higher priority than ketones

11. Worked Example Draw structures corresponding to the following names
a) 3-Methylbutanal
b) Cis-3-tert-Butylcyclohexanecarbaldehyde
Solution:
Naming aldehydes and ketones

12. Worked Example b) cis-3-tert-Butylcyclohexanecarbaldehyde
Naming aldehydes and ketones

13. Preparing Aldehydes and Ketones

14. Preparing Aldehydes From alcohols
Oxidize primary alcohols with Dess-Martin pyridinium reagent in dichloromethane solvent
Preparing aldehydes and ketones

15. Preparing Aldehydes From carboxylic acids
Partially reduce to yield aldehydes
Use diisobutylaluminum hydride (DIBAH)
Preparing aldehydes and ketones

16. Ozonolysis of Alkenes Reaction found in Previous Chapter
From alkenes
Double bond is oxidatively cleaved by ozone followed by reduction
Ketones and aldehydes can be isolated as products
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17. Worked Example
How is pentanal prepared from the following starting materials
a) CH3CH2CH2CH2CH2OH
b) CH3CH2CH2CH2CH=CH2
Solution: a) b)
Preparing aldehydes and ketones

18. Preparing Ketones
Prepare ketones by oxidization of a secondary alcohol
Use Dess–Martin periodinane or a Cr(VI) reagent
Preparing aldehydes and ketones

19. Preparing Ketones
Disubstitued alkenes yield ketones through ozonolysis
Preparing aldehydes and ketones

20. Preparing Ketones Friedel-Crafts acylation produces ketone
Reaction between an acyl halide and an aromatic ring
Use AlCl3 catalyst
Preparing aldehydes and ketones
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21. Preparing Ketones Reaction in Previous Chapter
Hydration of Alkynes
Initial product is Markovnikov hydration to an enol
Enol quickly tautomerizes to keto form
Internal alkynes form mixtures of ketones
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22. Worked Example How are the following reactions carried out? Solution:
a) 3-Hexyne → 3-Hexanone
b) Benzene → m-Bromoacetophenone
Solution: a) b)
Preparing aldehydes and ketones

23. Oxidation of Aldehydes and Ketones

24. Oxidation of Aldehydes and Ketones
Aldehydes oxidize to yield carboxylic acids
CrO3 in aqueous acid oxidizes aldehydes to carboxylic acids
Occur through intermediate 1,1-diols, or hydrates
Oxidation of aldehydes and ketones

25. Oxidation of Aldehydes and Ketones
Ketones undergo slow cleavage with hot, alkaline KMnO4
C–C bond next to C=O is broken to give carboxylic acids
Oxidation of aldehydes and ketones

26. Nucleophilic Addition Reactions

27. Nucleophilic Addition
A strong nucleophile attacks the carbonyl carbon
An alkoxide ion is formed
The alkoxide is protonated
Aldehydes are more reactive than ketones

28. Nucleophilic Addition
Nucleophiles can be
Negatively charged (:Nu-)
Neutral (:Nu)
Nucleophilic addition reactions of aldehydes and ketones

29. Nucleophilic Addition
Nucleophilic additions has two general variations
Product is a result of a tetrahedral intermediate being protonated by water or acid
Carbonyl oxygen is protonated then eliminated as HO- or H2O where product is a C=Nu double bond
Nucleophilic addition reactions of aldehydes and ketones

30. Nucleophilic Addition
Aldehydes are more reactive than ketones
Aldehydes have one substituent bonded to the C=O
Ketones have two substituent bonded to the C=O
Transition state for addition is less crowded and lower in energy for an aldehyde than for a ketone
Nucleophilic addition reactions of aldehydes and ketones

31. Nucleophilic Addition
Aldehydes are more reactive than ketones
Aldehydes are more polarized than ketones
More alkyl groups stabilize the carbocation inductively
Nucleophilic addition reactions of aldehydes and ketones

32. Nucleophilic Addition
Aromatic aldehyde is less reactive than aliphatic aldehydes
Aromatic aldehyde is less positive than non aromatic aldehyde
Nucleophilic addition reactions of aldehydes and ketones

33. Worked Example
Treatment of an aldehyde or ketone with cyanide ion (–:C≡N), followed by protonation of the tetrahedral alkoxide ion intermediate, gives a cyanohydrin
Show the structure of the cyanohydrin obtained from cyclohexanone
Nucleophilic addition reactions of aldehydes and ketones

34. Worked Example Solution:
Step 1 - Cyanide anion adds to the carbonyl carbon to form a tetrahedral intermediate
Step 2 - Intermediate is protonated to yield the cyanohydrin
Nucleophilic addition reactions of aldehydes and ketones

35. Nucleophilic Addition: Hydration
Aldehydes and ketones react with water to yield 1,1-diols or geminal diols
Hydration is reversible
Equilibrium depends on structure of carbonyl compound
Nucleophilic addition of H2O: Hydration

36. Nucleophilic Addition: Hydration
A ketone or an aldehyde in aqueous solution is in equilibrium with its hydrate
Ketones equilibrium favors the unhydrated keto form

37. Nucleophilic Addition: Acid-Catalyzed Hydration
Hydration occurs through the nucleophilic addition mechanism
Protonation converts carbonyl compound into an electrophile
Increases electrophilicity of carbonyl group

38. Nucleophilic Addition: Base-Catalyzed Hydration
The hydroxide ion attacks the carbonyl group
Protonation of the intermediate gives the hydrate
Water is converted into hydroxide ion
Better nucleophile

39. Worked Example
When dissolved in water, trichloroacetaldehyde exists primarily as its hydrate, called chloral hydrate
Show the structure of chloral hydrate
Solution:
Nucleophilic addition of H2O: Hydration

40. Cyanohydrin Formation
Nucleophilic addition of HCN
Base-catalyzed nucleophilic addition:
Cyanide ion attacks the carbonyl group yielding a tetrahedral intermediate
Protonation of the intermediate yields product
Equilibrium favors cyanohydrin adduct
HCN is highly toxic

41. Uses of Cyanohydrins The nitrile group (R–C≡N) can be
Reduced with LiAlH4 to yield a primary amine
Hydrolyzed by hot acid to yield a carboxylic acid
Nucleophilic addition of HCN: Cyanohydrin formation

42. Worked Example
Cyclohexanone forms a cyanohydrin in good yield but 2,2,6-trimethylcyclohexanone does not Explain
Solution:
Cyanohydrin formation is an equilibrium process
Addition of –CN to 2,2,6-trimethylcyclohexanone is sterically hindered by 3 methyl groups, equilibrium lies toward the side of unreacted ketone
Nucleophilic addition of HCN: Cyanohydrin formation

43. Nucleophilic Addition of Hydride: Alcohol Formation
Addition of hydride reagents produce alcohols
Alcohols prepared by reduction of a carbonyl
Occurs by basic nucleophilic addition mechanism
Protonation after addition yields the alcohol
Reduction by hydride is irreversible
LiAlH4 and NaBH4 act as donors of hydride ion
Nucleophilic addition of hydride and grignard reagents: Alcohol formation

44. Nucleophilic Addition of Hydride: Alcohol Formation
Addition of hydride reagents produce alcohols
Aldehyde reduction by NaBH4 yields 1o alcohols
Ketone reduction by NaBH4 yields 2° alcohols
Nucleophilic addition of hydride and grignard reagents: Alcohol formation

45. Nucleophilic Addition of Grignard Reagents: Alcohol Formation
Grignard reagents react with carbonyl groups to yield an alcohol
Nucleophilic addition of hydride and grignard reagents: Alcohol formation

46. Nucleophilic Addition of Grignard Reagents: Alcohol Formation
Mechanism
Nucleophilic addition of hydride and grignard reagents: Alcohol formation

47. Nucleophilic Addition of Amines
RNH2 adds to aldehydes and ketones to form imines, R2C=NR
Called Schiff bases
Common as intermediates in biological pathways
R2NH adds similarly to yield enamines, R2N–CR=CR2
Nucleophilic addition of amines: Imine and enamine formation

48. Nucleophilic Addition of Amines: Imine Formation Mechanism
Nucleophilic addition of amines: Imine and enamine formation

49. Nucleophilic Addition of Amines: Imine Formation Mechanism
Nucleophilic addition of amines: Imine and enamine formation

50. Nucleophilic Addition of Amines: Enamine Formation Mechanism
Nucleophilic addition of amines: Imine and enamine formation

51. Nucleophilic Addition of Amines: Enamine Formation Mechanism
Nucleophilic addition of amines: Imine and enamine formation

52. Worked Example
Show the products you would obtain by acid-catalyzed reaction of cyclohexanone with ethylamine, CH3CH2NH2 and with diethylamine, (CH3CH2)2NH
Solution:
Nucleophilic addition of amines: Imine and enamine formation

53. Nucleophilic Addition of Hydrazine: The Wolff-Kishner Reaction
Aldehyde or ketone react with hydrazine, H2NNH2, and KOH to produce an alkane
More useful than catalytic hydrogenation
Nucleophilic addition of hydrazine: The Wolff-Kishner Reaction

54. Nucleophilic Addition of Hydrazine: The Wolff-Kishner Reaction
Aldehyde or ketone react with hydrazine, H2NNH2, and KOH to produce an alkane
More useful than catalytic hydrogenation
Nucleophilic addition of hydrazine: The Wolff-Kishner Reaction

55. Worked Example
Show how you could prepare the following compounds from 4-methyl-3-penten-2-one, (CH3)2C=CHCOCH3 a) b)
Nucleophilic addition of hydrazine: The Wolff– Kishner Reaction

56. Worked Example Solution: a) b)
Nucleophilic addition of hydrazine: The Wolff– Kishner Reaction

57. Nucleophilic Addition of Alcohols: Acetal Formation
Aldehydes and ketones react reversibly with 2 equivalents of an alcohol in the presence of an acid catalyst to yield acetals, R2C(OR’)2
Called ketals if derived from a ketone
Under acidic conditions reactivity of the carbonyl group is increased by protonation
Nucleophilic addition of alcohols: Acetal formation

58. Nucleophilic Addition of Alcohols: Acetal Formation
Acetals can serve as protecting groups for aldehydes and ketones
Nucleophilic addition of alcohols: Acetal formation

59. Nucleophilic Addition of Alcohols: Acetal Formation
Mechanism
Nucleophilic addition of alcohols: Acetal formation

60. Nucleophilic Addition of Alcohols: Acetal Formation
Mechanism
Nucleophilic addition of alcohols: Acetal formation

61. Worked Example
Show the structure of the acetal obtained by acid-catalyzed reaction of 2-pentanone with 1,3-propanediol
Solution:
Nucleophilic addition of alcohols: Acetal formation

62. Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
Wittig reaction converts aldehydes and ketones into alkenes by nucleophilic addition
Triphenylphosphorus ylide adds to a carbonyl group to yield a four-membered cyclic intermediate called an oxaphosphetane
Oxaphosphetane spontaneously decomposes to give an alkene plus triphenylphosphine oxide
Nucleophilic addition of phosphorus ylides: The Wittig Reaction

63. Mechanism of the Wittig Reaction
Nucleophilic addition of phosphorus ylides: The Wittig Reaction

64. Worked Example
What carbonyl compound and what phosphorus ylide might be used to prepare the following compounds a) b)
Nucleophilic addition of phosphorus ylides: The Wittig Reaction

65. Worked Example Solution: a) b)
Nucleophilic addition of phosphorus ylides: The Wittig Reaction

66. 1,2-addition: Addition of a nucleophile directly to the carbonyl group
Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
1,2-addition: Addition of a nucleophile directly to the carbonyl group
Biological reductions

67. Conjugate addition (1,4-addition):
Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
Conjugate addition (1,4-addition):
Adds a nucleophile to the C=C double bond of an -unsaturated aldehyde or ketone
Biological reductions

68. Conjugate addition of amines
Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
Conjugate addition of amines
Primary and secondary amines add to   -unsaturated aldehydes and ketones to yield -amino aldehydes and ketones
Conjugate nucleophilic addition to -unsaturated aldehydes and ketones

69. Conjugate addition of water
Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
Conjugate addition of water
Yields -hydroxy aldehydes and ketones,
Adds reversibly to -unsaturated aldehydes and ketones
Position of the equilibrium generally favors unsaturated reactant
Conjugate nucleophilic addition to -unsaturated aldehydes and ketones

70. Conjugate Nucleophilic Addition to -Unsaturated Aldehydes and Ketones
Organocopper reactions with -unsaturated ketone adds conjugate addition products
1, 2, 3 alkyl, aryl, and alkenyl groups react
Alkynyl groups react poorly
Mechanism
Conjugate nucleophilic addition of a diorganocopper anion, R2Cu–, to a ketone
Transfer of an R group and elimination of a neutral organocopper species, RCu, gives the final product
Conjugate nucleophilic addition to -unsaturated aldehydes and ketones

71. Worked Example
How might conjugate addition reactions of lithium diorganocopper reagents be used to synthesize
Solution:
Conjugate nucleophilic addition to -unsaturated aldehydes and ketones

72. Spectroscopy of Aldehydes and Ketones
Infrared Spectroscopy
Aldehydes and ketones show a strong C=O peak from 1660 to 1770 cm-1
Aldehydes show two characteristic C–H absorptions in the 2720 to 2820 cm-1 range
Spectroscopy of aldehydes and ketones

73. Spectroscopy of Aldehydes and Ketones
Nuclear magnetic resonance spectroscopy
Aldehyde proton signals absorb near 10  in 1H NMR
Spectroscopy of aldehydes and ketones

74. Spectroscopy of Aldehydes and Ketones
Carbonyl-group carbon atoms of aldehydes and ketones signal is at 190  to 215 
No other kinds of carbons absorb in this range
Saturated aldehyde or ketone carbons absorb in the region from 200  to 215 
Spectroscopy of aldehydes and ketones

75. Spectroscopy of Aldehydes and Ketones
Mass spectrometry - McLafferty rearrangement
Aliphatic aldehydes and ketones that have hydrogens on their gamma () carbon atoms rearrange as shown
Spectroscopy of aldehydes and ketones

76. Mass Spectroscopy: -Cleavage
Cleavage of the bond between the carbonyl group and the  carbon
Yields a neutral radical and an oxygen-containing cation
Spectroscopy of aldehydes and ketones

77. Worked Example
Describe the prominent IR absorptions and mass spectral peaks expected for the following compound:
Spectroscopy of aldehydes and ketones

78. Worked Example Solution:
The important IR absorption for the compound is seen at 1750 cm-1
Products of alpha cleavage, which occurs in the ring, have the same mass as the molecular ion
Spectroscopy of aldehydes and ketones

79. Worked Example The McLafferty rearrangement appears at m/z = 84
Spectroscopy of aldehydes and ketones

80. Summary
Most common general reaction type for aldehydes and ketones is nucleophilic addition reaction
Addition of HCN to aldehydes and ketones yields cyanohydrins
Primary amines add to carbonyl compounds yielding imines, or Schiff bases, and secondary amines yield enamines
Wolff-Kishner reaction is the reaction of an aldehyde or a ketone with hydrazine and base to give an alkane

81. Summary
Acetals, valuable protecting groups, are produced by adding alcohols to carbonyl groups
Phosphorus ylides add to aldehydes and ketones in the Wittig reaction to give alkenes
-unsaturated aldehydes and ketones react with nucleophiles to give product of conjugate addition, or 1,4-addition