1. Chapter 23. Carbonyl Condensation Reactions
Why this Chapter?
Carbonyl condensation reactions also occur often in metabolic pathways.
Also one of the general methods used to form C-C bonds.

2. Condensation Reactions
Carbonyl compounds are both the electrophile and nucleophile in carbonyl condensation reactions

3. 23.1 Carbonyl Condensation: The Aldol Reaction
Acetaldehyde reacts in basic solution (NaOEt, NaOH) with another molecule of acetaldhyde
The b-hydroxy aldehyde product is aldol (aldehyde + alcohol)
This is a general reaction of aldehydes and ketones

4. General Condensations

5. Aldehydes & Ketones and Aldol Equilibrium
The aldol reaction is reversible, favoring the condensation product only for aldehydes with no  substituent
Steric factors are increased in the aldol product

6. Mechanism of Aldol Reactions
Aldol reactions, like all carbonyl condensations, occur by nucleophilic addition of the enolate ion of the donor molecule to the carbonyl group of the acceptor molecule
The addition intermediate is protonated to give an alcohol product

7. Predicting Aldol Products
The product will have an alcohol and a carbonyl in a 1,3 relationship (a beta-hydroxy carbonyl)

8. Learning Check: Know how to……
Predict the aldol reaction products of:

9. 23.2 Carbonyl Condensation versus Alpha-Substitution
Carbonyl condensations and  substitutions both involve formation of enolate ion intermediates
Alpha-substitution reactions are accomplished by converting all of the carbonyl compound to enolate form so it is not an electrophile
Immediate addition of an alkyl halide to completes the alkylation reaction

10. Conditions for Condensations
A small amount of base is used to generate a small amount of enolate in the presence of unreacted carbonyl compound
After the condensation, the basic catalyst is regenerated

11. 23.3 Dehydration of Aldol Products: Synthesis of Enones
The -hydroxy carbonyl products dehydrate to yield conjugated enones
The term “condensation” refers to the net loss of water and combination of 2 molecules

12. Dehydration of b-Hydroxy Ketones and Aldehydes
The  hydrogen is removed by a base, yielding an enolate ion that expels the OH leaving group
Under acidic conditions the OH group is protonated and water is expelled

13. Driving the Equilibrium
Removal of water from the aldol reaction mixture can be used to drive the reaction toward products
Even if the initial aldol favors reactants, the subsequent dehydration step pushes the reaction to completion

14. Learning Check:
What is the structure of the enone obtained from aldol condensation of acetaldehyde?

15. Solution:
What is the structure of the enone obtained from aldol condensation of acetaldehyde?

16. Learning Check: Know how to…
Predict the enone product from aldols of:

17. 23.4 Using Aldol Reactions in Synthesis
If a desired molecule contains either a -hydroxy carbonyl or a conjugated enone, it might come from an aldol reaction

18. Extending the Synthesis
Subsequent transformations can be carried out on the aldol products
A saturated ketone might be prepared by catalytic hydrogenation of the enone product

19. Learning Check: Know how to…
Prepare the following from an aldol condensation:

20. 23.5 Mixed Aldol Reactions
A mixed aldol reaction between two similar aldehyde or ketone partners leads to a mixture of four possible products
This is not useful

21. Practical Mixed Aldols
If one of the carbonyl partners contains no  hydrogens and the carbonyl is unhindered (such as benzaldehyde and formaldehyde) it is a good electrophile and can react with enolates, then a mixed aldol reaction is likely to be successful
2-methylcyclohexanone gives the mixed aldol product on reaction with benzaldehyde

22. Mixed Aldols With Acidic Carbonyl Compounds
Ethyl acetoacetate is completely converted into its enolate ion under less basic conditions than monocarbonyl partners
Aldol condensations with ethyl acetoacetate occur preferentially to give the mixed product

23. 23.6 Intramolecular Aldol Reactions
Treatment of certain dicarbonyl compounds with base produces cyclic products by intramolecular reaction

24. Mechanism of Intramolecular Aldol Reactions
Both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule.
The least strained product is formed because the reaction is reversible

25. Learning Check:
Which product would you expect to obtain from base treatment of the following?

26. Solution:
Which product would you expect to obtain from base treatment of the following?

27. 23.7 The Claisen Condensation Reaction
Reaction of an ester having an  hydrogen with 1 equivalent of a base to yield a -keto ester

28. Mechanism of the Claisen Condensation
Similar to aldol condensation: nucleophilic acyl substitution of an ester enolate ion on the carbonyl group of a second ester molecule
See the simulation at
If the starting ester has more than one acidic a hydrogen, the product -keto ester has a doubly activated proton that can be abstracted by base
Requires a full equivalent of base rather than a catalytic amount
The deprotonation drives the reaction to the product

29. Learning Check:
Predict the product of Claisen condensation of ethyl propanoate

30. Solution:
Predict the product of Claisen condensation of ethyl propanoate

31. 23.8 Mixed Claisen Condensations
Successful when one of the two esters acts as the electrophilic acceptor in reactions with other ester anions to give mixed -keto esters

32. Esters and Ketones
Reactions between esters and ketones, resulting in - diketones
Best when the ester component has no  hydrogens and can't act as the nucleophilic donor

33. Learning Check: Know how to…
Predict the product of the following reaction:

34. 23.9 Intramolecular Claisen Condensations: The Dieckmann Cyclization
Best with 1,6-diesters (product: 5-membered -ketoester) and 1,7-diesters (product: 6-membered -ketoester)

35. Mechanism of the Dieckmann Cyclization

36. Alkylation of Dieckmann Product
The cyclic -keto ester can be further alkylated and decarboxylated as in the acetoacetic ester synthesis

37. Learning Check: Know how to…
Predict the product:

38. 23.10 Conjugate Carbonyl Additions: The Michael Reaction
Enolates can add as nucleophiles to ,-unsaturated aldehydes and ketones to give the conjugate addition product

39. Best Conditions for the Michael Reaction
When a particularly stable enolate ion
Example: Enolate from a -keto ester or other 1,3- dicarbonyl compound adding to an unhindered ,- unsaturated ketone

40. Mechanism of the Michael
Nucleophilic addition of a enolate ion donor to the  carbon of an ,-unsaturated carbonyl acceptor

41. Generality of the Michael Reaction
Occurs with a variety of ,-unsaturated carbonyl compounds (aldehydes, esters, nitriles, amides, and nitro compounds)
Donors include - diketones, -keto esters, malonic esters, - keto nitriles, and nitro compounds

42. Learning Check:
Make the following using a Michael Reaction:

43. Solution:
Make the following using a Michael Reaction:

44. 23.11 Carbonyl Condensations with Enamines: The Stork Reaction
Enamines are equivalent to enolates in their reactions and can be used to accomplish the transformations under milder conditions
Enamines are prepared from a ketone and a secondary amine

45. Enamines Are Nucleophilic
Overlap of the nitrogen lone-pair orbital with the double- bond π orbitals increases electron density on the  carbon atom

46. Enamine Addition and Hydrolysis
Enamine adds to an ,-unsaturated carbonyl acceptor
The product is hydrolyzed to a 1,5-dicarbonyl compound

47. Learning Check:
Prepare Using a Stork Enamine Reaction

48. Solution:
Prepare Using a Stork Enamine Reaction

49. Learning Check: Know how to…
Prepare Using a Stork Enamine Reaction

50. 23.12 The Robinson Annulation Reaction
A two-step process: combines a
Michael reaction with an
intramolecular aldol reaction
The product is a substituted 2-cyclohexenone

51. Robinson Annulation Example
Synthesis of estrone

52. Learning Check: Know how to..
Prepare via a Robinson Annulation:

53. 23.13 Some Biological Carbonyl Condensation Reactions
Malonyl ACP is decarboxylated and enolate is formed
Enolate is added to the carbonyl group of another acyl group through a thioester linkage to a synthase
Tetrahedral intermediate gives acetoacetyl ACP

54. Learning Check:
Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself?
The benzene ring makes the carbonyl group unreactive towards aldol reactions.
A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction.
The molecule does not possess any hydrogens α to the carbonyl group.
Electrophilic aromatic substitution competes favorably with the aldol reaction.
Nucleophilic acyl substitution competes favorably with the aldol reaction.

55. Solution:
Which of the following statements explains why the following aldehyde will not undergo an aldol reaction with itself?
The benzene ring makes the carbonyl group unreactive towards aldol reactions.
A carbonyl group must be connected to two alkyl groups in order to undergo an aldol reaction.
The molecule does not possess any hydrogens α to the carbonyl group.
Electrophilic aromatic substitution competes favorably with the aldol reaction.
Nucleophilic acyl substitution competes favorably with the aldol reaction.

56. Predict the aldol reaction product of the following ketone.
Learning Check:
Predict the aldol reaction product of the following ketone. 1. 2. 3. 4. 5. 1 2 3 4 5

57. Predict the aldol reaction product of the following ketone.
Solution:
Predict the aldol reaction product of the following ketone. 1. 2. 3. 4. 5. 1 2 3 4 5

58. Learning Check:
Which starting material(s) will produce the following aldol reaction product? 1. 2. 3. 5. 4. 1 2 3 4 5

59. Solution:
Which starting material(s) will produce the following aldol reaction product? 1. 2. 3. 5. 4. 1 2 3 4 5

60. Select the correct aldol reaction product for the following reaction.
Solution:
Select the correct aldol reaction product for the following reaction. 2. 1. 3. 5. 4. 1 2 3 4 5

61. Solution:
Which pair of compounds would be required to prepare the following aldol product? 1. 2. 3. 5. 4. 1 2 3 4 5

62. Which of the following reactions will yield the compound shown below?
Learning Check:
Which of the following reactions will yield the compound shown below? 1. 2. 3. 4. 5. 1 2 3 4 5

63. Which of the following reactions will yield the compound shown below?
Solution:
Which of the following reactions will yield the compound shown below? 1. 2. 3. 4. 5. 1 2 3 4 5

64. Learning Check:
Which of the following would not be produced in the aldol reaction between 2-butanone and acetophenone? 1. 2. 3. 5. 4. 1 2 3 4 5

65. Solution:
Which of the following would not be produced in the aldol reaction between 2-butanone and acetophenone? 1. 2. 3. 5. 4. 1 2 3 4 5

66. Predict the aldol reaction product(s) of the following ketone.
Learning Check:
Predict the aldol reaction product(s) of the following ketone. A B
Both A and C
Both B and D
A, B, and C

67. Predict the aldol reaction product(s) of the following ketone.
Solution:
Predict the aldol reaction product(s) of the following ketone. A B
Both A and C
Both B and D
A, B, and C

68. Learning Check:
Which of the following is the best candidate for a crossed Claisen reaction with ethyl acetate? 2. 3. 1. 5. 4. 1 2 3 4 5

69. Solution:
Which of the following is the best candidate for a crossed Claisen reaction with ethyl acetate? 2. 3. 1. 5. 4. 1 2 3 4 5

70. What type of reaction occurs in a Claisen condensation?
Learning Check:
What type of reaction occurs in a Claisen condensation?
electrophilic aromatic substitution
nucleophilic addition
hydrolysis
nucleophilic acyl substitution
decarboxylation

71. What type of reaction occurs in a Claisen condensation?
Solution:
What type of reaction occurs in a Claisen condensation?
electrophilic aromatic substitution
nucleophilic addition
hydrolysis
nucleophilic acyl substitution
decarboxylation

72. Learning Check:
Select the correct Claisen condensation product for the following reaction. 1. 2. 3. 5. 4. 1 2 3 4 5

73. Solution:
Select the correct Claisen condensation product for the following reaction. 1. 2. 3. 5. 4. 1 2 3 4 5

74. Predict the outcome of the following reaction.
Learning Check:
Predict the outcome of the following reaction. 1. 2. 3. 5. 4. 1 2 3 4 5

75. Predict the outcome of the following reaction.
Solution:
Predict the outcome of the following reaction. 1. 2. 3. 5. 4. 1 2 3 4 5

76. What is the expected major product of the following reaction?
Learning Check:
What is the expected major product of the following reaction? 1. 2. 3. 4. 5. 1 2 3 4 5

77. What is the expected major product of the following reaction?
Solution:
What is the expected major product of the following reaction? 1. 2. 3. 4. 5. 1 2 3 4 5

78. Predict the outcome of the following reaction.
Learning Check:
Predict the outcome of the following reaction. 1. 3. 2. 5. 4. 1 2 3 4 5

79. Predict the outcome of the following reaction.
Solution:
Predict the outcome of the following reaction. 1. 3. 2. 5. 4. 1 2 3 4 5

80. What type of reaction has occurred in the given biological process?
Learning Check:
What type of reaction has occurred in the given biological process?
Claisen condensation
aldol reaction
nucleophilic acyl substitution
β-elimination
both Claisen condensation and nucleophilic acyl substitution

81. What type of reaction has occurred in the given biological process?
Solution:
What type of reaction has occurred in the given biological process?
Claisen condensation
aldol reaction
nucleophilic acyl substitution
β-elimination
both Claisen condensation and nucleophilic acyl substitution