1. NUCLEOPHILIC ADDITION REACTION
CARBONYL COMPOUNDS:
NUCLEOPHILIC ADDITION REACTION
Lecture 6
ORGANIC CHEMISTRY 2

2. CARBONYL COMPOUNDS
ALDEHYDE
KETON
ESTHER
CARBOXILIC ACID

3. CARBONYL COMPOUNDS Formalin Ibuprofen Aspirin Asam cuka Asam semut
Perasa buah

4. CARBONYL COMPOUNDS

5. Preparation of Aldehydes and Ketones
Oxidation reactions
Hydrolysis of geminal dihalides
Hydration of alkynes
Reactions with acid derivatives and nitriles
Reaction with carboxylic acids
Reaction with thioacetals

6. 1. Aldehydes/Ketones via Oxidation Reactions
From Alcohols via PCC
From Alkenes via Ozonolysis
From Glycols via Periodic Acid Cleavage

7. Synthesis Mechanism a.1 Oxidation of 1˚ alcohols
a.2. Oxidation of 2° alcohols w/ PCC and base

8. b.1 Oxidative cleavage of alkenes w/ O3, Zn, CH3COOH

9. b.2.Ozonolysis of alkenes, if one of the unsaturated carbon atoms is disubstituted.

10. 2. Hydrolysis of Geminal Dihalides

11. 3. Hydration of Alkynes a. Markovnikov Addition
b. Anti-Markovnikov Addition

12. 3.a. Hydration of terminal alkynes methyl ketones

13. 4. Reactions with Acid Halides
a. Aldehydes via Selective Reduction
Lithium tri-tert-butoxyaluminum hydride
Rosenmund reduction
b. Ketones via Friedel-Crafts Acylation
c. Ketones via reaction with Organometallics
Gilman reagent (organocuprates)

14. 4.a. Aldehydes from Acid Chlorides
Lithium tri-t-butoxyaluminum hydride reduction
Rosenmund reduction

15. 4.b. Ketones via Friedel-Crafts Acylation
Friedel-Crafts acylation aryl ketones

16. 4.c.Ketones via Reaction with Organometallics
Use of Lithium dialkylcuprates

17. 5. Aldehydes from Esters and Amides
Diisobutylaluminum hydride (DIBAH or DIBAL-H)

18. 5.a. Partial reduction of certain carboxylic acid derivatives

19. Attack by Alkyl Lithium reagents
6. Ketones from Carboxylic Acids
Attack by Alkyl Lithium reagents

20. 8. Reactions with Nitriles
Grignard Addition to give Ketones
DIBAH Addition to give Aldehydes

21. 7. Ketones from Thioacetals
a. Thioacetal formation from an aldehyde precursor
b. Alkylation of the thioacetal intermediate using alkyl lithium reagents
c. Hydrolysis of the alkylated thioacetal to give ketone product

22. Characteristic Reactions of Aldehydes and Ketones
1. Reduction reactions
a. Alcohol formation
b. Alkane formation
2. Oxidation reactions
3. Nucleophilic addition reactions
a. Grignard additions to form alcohols
b. Addition of water (hydration) to form gem-diols
c. Addition of alcohols to form acetals/ketals
d. Addition of HCN to form cyanohydrins
e. Addition of ammonia and ammonia derivatives

23. Reduction Reactions of Aldehydes & Ketones
1. Alcohol formation
a. Hydrogenation
b. Hydride reduction
2. Alkane formation
a. Clemmensen reduction
b. Wolff-Kishner reduction

24. Oxidation of Aldehydes & Ketones
Conversion of aldehydes to carboxylic acids
Oxidation of aromatic aldehydes / ketones to benzoic acid derivatives
Haloform reaction of methyl carbonyls
Periodic acid cleavage of vicinal dials/diketones

25. Aldehyde / Ketone Oxidations1. 2. 3. 4.

26. Nucleophilic addition reactions

27. Structure of the Carbonyl Group
Hybridization of the carbonyl carbon is sp2.
Geometry of the carbonyl carbon is trigonal planar
Attack by nucleophiles will occur with equal ease from either the top or the bottom of the carbonyl group.
The carbonyl carbon is prochiral. That is, the carbonyl carbon is not the center of chirality, but it becomes chiral as the reaction proceeds.

28. Prochiral These two products are enantiomers.
In general, both enantiomers are formed in equal amount.

29. Reaction of the Carbonyl Group1. 2.

30. Nucleophilic Addition to Carbonyl: General Mechanism1.

31. 2.

32. Relative Reactivity of Aldehydes & Ketones
Steric Reason
nucleophile is able to approach aldehydes more readily because it only has 1 large substituent bonded to the C=O carbon, vs. 2 in ketones.
transition state for the aldehyde rxn is therefore less crowded and has lower energy.
Aldehydes
Ketones

33. greater polarization of aldehyde carbonyl group
2. Electronic Reason
greater polarization of aldehyde carbonyl group
aldehyde is more electrophilic and more reactive than ketones.
1˚ carbocation
(less stable, more reactive)
2˚carbocation
(more stable, less reactive) ς- ς- ς+ ς+
Aldehyde
(less stabilization of ς+, more reactive)
Ketone
(more stabilization of ς+, less reactive)

34. Aliphatic aldehydes >>> Aromatic aldehydes
Relative Reactivity of Aldehydes & Ketones
Aliphatic aldehydes >>> Aromatic aldehydes
The electon-donating resonance effect of the aromatic ring
makes the carbonyl group less electrophilic than the carbonyl
group of the aliphatic aldehyde.

35. The carbocation intermediate
The positive charge character on carbon makes this an excellent site for attack by Lewis bases (nucleophiles).
Nucleophile attacks the electrophilic C=O carbon from a direction ~45˚ to the plane of the carbonyl group
At the same time: Rehybridization of the carbonyl carbon from sp2 to sp3 occurs.

36. Once we have the intermediate, what happens to it?

37. Case 1: The Addition Product is Stable.
The reaction stops here. This happens most often when the nucleophilic atom is carbon, oxygen, or sulfur.

38. Case 2: Addition-Elimination
The addition product is unstable with respect to loss of a molecule of water. This is observed most often when the nucleophilic atom is nitrogen or phosphorus.

39. Case 3: Loss of Leaving Group
This process is observed when X is a potential leaving group. In this case we have nucleophilic acyl substitution.

40. Nucleophilic Addition of H2O: Hydration
Aldehydes and ketones react with water to yield a geminal
diol. This hydration process is reversible.
Nucleophilic addition of water is catalyzed by acid and base.
1. Base-catalyzed

41. 2. Acid-catalized

42. Important only for low-molecular-weight aldehydes
Examples:

43. Nucleophilic Addition of Alcohols: Acetal Formation
Acetals and Ketals are formed by reacting two equivalents of an alcohol with an aldehyde or ketone, in the presence of an acid catalyst.
Hemiacetals and Hemiketals are formed by reacting only one equivalent of alcohol with the aldehyde or ketone in the presence of an acid catalyst. Further reaction with a second alcohol forms the acetal or ketal.
A diol, with two –OH groups on the same molecule, can be used to form cyclic acetals.
All steps in acetal/ketal formation are reversible.

44. Aldehydes form hemiacetals faster than ketones
This reaction is also reversible. But, in this case, the equilibrium can be driven to the right by an application of Le Châtelier’s Principle.

46. Mechanism of Acetal Formation:

47. Example Nucleophilic Addition of Alcohols
1. Formation of 2,2-Dimethoxy-propane
Dry acid =
HCl gas
HCl in methanol
HOTs
2. Formation of a Cyclic Acetal

48. 3. Cyclization of Monosaccharides
Carbohydrates contain the functional groups of alcohols and aldehydes or ketones in the same molecule. They are polyhydroxyaldehydes or polyhydroxyketones.
Thus they can form acetal-type products through the intramolecular interaction of these functional groups.
As a model, consider the reaction:

49. a pyranose
ring 6
a furanose
ring 5

50. Nucleophilic Addition of HCN
Aldehydes and unhindered ketones react with HCN to yield cyanohydrins. This formation is reversible and base-catalyzed.
Mechanism :
A cyanohydrin

51. Example
Notice that the cyanide ion and the acid are added in two separate steps!
Sodium carbonate is used to keep the reaction medium basic.

52. So, what’s it good for?
Cyanohydrins formation is unusual due to the addition of protic acid to a carbonyl group, but useful because of further chemistry.
This affords us with an important method of synthesizing a-hydroxy-carboxylic acids -- important intermediates in biochemical processes.
Reduced with LiAlH4, yielding primary amine.
Hydrolyzed with hot aqueous acid, yielding carboxylic acid.

53. Addition of Organometallic Reagents
The products of the addition are always alcohols.

54. Whatever is attached to the carbonyl group will be attached to the resulting alcohol carbon.

55. Nucleophilic Addition of Grignard (R-MgX)
Grignard reagents R-MgX, strongly polarized reacts with an acid-base behavior. Nucleophilic addition of a carbanion to an aldehyde or ketone, followed by protonation of alkoxide intermediate, yields an alcohol.

56. Addition of Hydride Reagents
Addition of hydride ion, from LiAlH4 or NaBH4, and water or aqueous acid yields an alcohol.

57. Compounds that bear an amino group
Form Imines
The G group can be one of many different possibilities

58. Addition-Elimination: The Formation of Imines
All of the imine reactions, regardless of G, go by the same mechanism.

59. Mechanism of Imine Formation:

60. Formation of Simple Imines
A. Simple primary amines
Aldehydes and ketones react with simple primary amines to yield imines.
The equilibrium is unfavorable; the products are much less stable than the reactants.

61. B. Simple secondary amines
When secondary amines are allowed to react with aldehydes or ketones, dehydration of the type shown in the elimination step cannot take place (there is no labile hydrogen on the nitrogen atom of the addition product).

62. If the starting aldehyde or ketone has an α -hydrogen, however, dehydration toward the α -carbon can occur, yielding an enamine.
The acid catalyst is generally a dry acid, such as p-toluene sulfonic acid (HOTs)

63. Amines that are used typically to form enamines:

64. Enamine Formation

66. Formation of Oximes
hydroxylamine
Aldehydes and ketones react with hydroxylamine to yield oximes.
Oximes are important derivatives in qualitative organic analysis.

67. Formation of Hydrazones
a hydrazine
Aldehydes and ketones react with substituted hydrazines to yield substituted hydrazones.
The equilibrium is generally unfavorable.
Exception: when R is an aromatic ring.

68. Wolff-Kishner Reaction: Nu- Addition of Hydrazine
Addition of hydrazine converts aldehyde/ketone to an alkane. An intermediate hydrazone forms, followed by base catalyzed double bond migration, loss of N2 gas, finally protonation yields an alkane.

69. Formation of Semicarbazones
semicarbazide
Aldehydes and ketones react with semicarbazide to yield semicarbazones.
Semicarbazones are the second-most important of the derivatives of aldehydes and ketones.

70. The enamine is quite nucleophilic, owing to resonance of the type:
As a consequence of this resonance, the α-carbon of an enamine has a great deal of carbanion-like (nucleophilic) character.

71. Reactions of Enamines as Nucleophiles

72. Hydrolysis of Iminium Salts

73. Enamines can react with alkyl halides -- Here’s an example.

74. Nucleophilic Addition of Phosphorus Ylides: The Wittig Reaction
Converts an aldehyde/ketone into an alkene.
A phosphorus ylide(aka phosphorane), acts as the Nu-
Ylide : A compound or intermediate with both a positive and a negative formal charge on adjacent atoms.
The ylide is nucleophilic, owing to the negative charge character on carbon (structure on the right).

75. A phosphorus ylide(aka phosphorane), acts as the Nu- to attack the carbonyl carbon and yields a four-membered ring, dipolar intermediate called the betaine.
The betaine decomposes spontaneously to yield an alkene and a triphenylphosphine oxide.
Can produce monosubstituted, disubstituted, and trisubstituted alkenes.
This is a type of condensation reaction -- we use it to “dock” to large structures together.
This is another example of addition-elimination.

76. Mechanism of the Witting Reaction:

77. Conjugate Nucleophilic Addition to α-β-Unsaturated Aldehydes and Ketones
Direct addition (aka 1,2 addition) occurs when a nucleophile attacks the carbon in the carbonyl directly.
Conjugate addition (aka 1,4 addition) occurs when the nucleophile attacks the carbonyl indirectly by attacking the second carbon away from the carbonyl group, called the beta carbon, in an unsaturated aldehyde or ketone.
Conjugate addition reactions form an initial product called an enolate, which is protonated on the carbon next to the carbonyl, the alpha carbon, to give the final saturated aldehyde/ketone product.
Conjugate addition can be carried out with nucleophiles such as primary amines, secondary amines, and even alkyl groups like in organocopper reactions.
It is the carbonyl that activates the conjugated C=C double bond for addition which would otherwise not react.

78. Conjugate (1,4) addition mechanism: