1. Condensation and Conjugate Addition Reactions of Carbonyl Compounds
Chapter 19
Condensation and Conjugate Addition Reactions of Carbonyl Compounds
More Chemistry of Enolates

2. Introduction Carbonyl condensation reactions. Claisen condensation:
Introduction
Carbonyl condensation reactions.
Claisen condensation:
An a carbon anion
(enolate) from one
ester attacks the
carbonyl of the other.

3. Aldol addition and condensation:
An a carbon anion
(enolate) from one
attacks the carbonyl
of the other followed
by dehydration.

4. Conjugate addition reaction:. e. g
Conjugate addition reaction: e.g. to an alkene conjugated to a carbonyl.
A nucleophile (could be an enolate) attacks
the b carbon of the a-b unsaturated carbonyl.
Where Nu: is an enolate it is called a Michael
addition.

5. The Claisen Condensation: A Synthesis of b-Keto Esters
An a carbon anion
(enolate) from one
ester attacks the
carbonyl of the other.

6. Mechanism: Step 1 Base removes an a hydrogen
forming an enolate from one
ester.

7. Mechanism: Step 2 The enolate attacks the carbonyl of another ester
with loss of -OR.

8. Mechanism:
Step 3

10. Mechanism:
Step 4

11. Claisen condensation:
An Acyl Substitution:
(nucleophilic addition-elimination reaction).
Useful for the synthesis of b-keto esters.

12. Claisen condensation:
Esters that have only one a hydrogen do not undergo the usual Claisen condensation.
e.g.
The a carbon has only one
a hydrogen does not undergo the Claisen condensation using RO- (alkoxide). Use LDA, a stronger base, see slide 23.
 This is because an ester with only one hydrogen will not have an acidic hydrogen when step 3 is reached, and step 3 promotes the favorable equilibrium that ensures the forward reaction.

13. Examples of Claisen condensation:

14. Examples of Claisen condensation:

15. 2A. Intramolecular Claisen Condensations: The Dieckmann Condensation
Intramolecular (cyclic) Claisen condensation:
Dieckmann condensation.
Useful for the synthesis of five- and six-membered rings.

16. Mechanism:
(This favorable
equilibrium drives the reaction)

17. Other examples:

18. Other examples:
Why?

19. 2B. Crossed Claisen Condensations
Crossed Claisen condensations are possible when one ester component has no a hydrogens and, therefore, is unable to form an enolate ion and undergo self-condensation.

20. Mechanism:

21. Mechanism:
(This favorable equilibrium
drives the reaction)

22. Other examples:

23. Recall:. esters that have only one a. hydrogen cannot undergo
Recall: esters that have only one a hydrogen cannot undergo Claisen Condensation by using sodium alkoxide.
However, they can be converted to the b-keto esters by reactions that use very strong bases such as lithium diisopropyamide (LDA). LDA is strong enough to retain the anion.

25. b-Dicarbonyl Compounds by Acylation of Ketone Enolates
slightly more acidic

26. Intramolecular example:
The product was formed by deprotonation of Hb, the enolate formed at C5 and then adding to C1. A five membered ring is more stable than a seven membered ring.

27. Questions:
Give the structure of the product by deprotonation of Ha, and adding the resulting enolate (at C7) to C1. Explain why this product is not formed.
Give the structure of the product by deprotonation of Hc, and adding the resulting enolate (at C2) to C6. Explain why this product is not formed.

28. Aldol Reactions: Addition of Enolates and Enols to Aldehydes and Ketones
 The product contains both an aldehyde and an alcohol functional group.
 Therefore: aldol addition

29. 4A. Aldol Addition Reactions Mechanism of the aldol addition:
Shown on slide 3.

30. 4B. The Retro-Aldol Reaction
Mechanism for reverse aldol:

31. Dehydration of the aldol product. Base catalyzed aldol condensation:
4C. Aldol Condensation Reactions: Dehydration of the Aldol Addition Product
Dehydration of the aldol product.
Base catalyzed aldol condensation:
This dehydration is easier than normal because the double bond is conjugated with the carbonyl.
Aldol product.

32. 4C. Acid-Catalyzed Aldol Condensations

33. Mechanism:
Followed by dehydration of the aldol product.

34. 4E. Synthetic Applications of Aldol Reactions
Aldol additions and aldol condensations:
Important methods for carbon-carbon bond formation.
Useful synthesis for:
b-hydroxyl carbonyl compounds
a,b-unsaturated carbon compounds

36. Crossed Aldol Condensations
Works best when one
reactant does not have
an a hydrogen.

37. 5A. Crossed Aldol Condensations Using Weak Bases
addition
No a hydrogen
dehydration

38. No a hydrogen

39. 5B. Crossed Aldol Condensations Using Strong Bases: Lithium Enolates and Directed Aldol Reactions
Directed Aldol Synthesis using a strong base, iPr2NLi (LDA).

40. The use of a weaker base under protic conditions:
Results in formation of both kinetic and thermodynamic enolates,
Therefore, a mixture of crossed aldol products.

42. Retrosynthetic analysis:
Suggest a synthesis of the following compound using a directed aldol synthesis.
Retrosynthetic analysis:
disconnection

43. Synthesis:

44. Cyclizations via Aldol Condensations
Intramolecular Aldol condensation:
Useful for the synthesis of five- and six-membered rings.
Using a dialdehyde, a keto aldehyde, or a diketone.

48. Although three different enolates are formed, cyclization usually occurs with an enolate of the ketone adding to the aldehyde.
 Path c is least favorable.

49. Path b is more favorable than path a because six-membered rings are thermodynamically more favorable to form than eight-membered rings.
Likewise, five-membered rings form far more readily than seven-membered rings.

50. Additions to a,b-Unsaturated Aldehydes and Ketones

51. Stronger Nu: attacks the C=O.

52. nucleophiles attack the carbonyl carbon or the b carbon

53. Conjugate addition of HCN:
Weaker Nu: attacks b to the C=O.

54. Conjugate addition of an amine:

55. 7A. Conjugate Additions of Enolates: Michael Additions

56. Other examples of Michael additions:

57. 7B. The Robinson Annulation

58. Mechanism of the Robinson Annulation:

59. Mechanism of the Robinson Annulation:

60. The Mannich Reaction
A 1o or 2o amine reacts with formaldehyde to form an imine (schiff base). The enol then reacts with the imine.
Mannich base

61. Mechanism of the Mannich Reaction:
The imine reacts with an enol producing a Mannich base.

62. Other examples of the Mannich Reaction:

63. Summary of Important Reactions
Claisen Condensations:

64. Aldol Condensations:

65. Simple & Conjugate (Michael) additions:

66. Mannich reaction:

67.  END OF CHAPTER 19 