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

2. About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

3. Introduction Carbonyl condensation reactions Claisen condensation
Introduction
Carbonyl condensation reactions
Claisen condensation

4. Aldol addition and condensation

5. Conjugate addition reactions
e.g.

6. The Claisen Condensation: A Synthesis of b-Keto Esters

7. Mechanism
Step 1

8. Mechanism
Step 2

9. Mechanism
Step 3

11. Mechanism
Step 4

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

13. 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 Claisen condensation
 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

14. Examples of Claisen condensation

15. Examples of Claisen condensation

16. 2A. Intramolecular Claisen Condensations: The Diekmann Condensation
Useful for the synthesis of five- and six-membered rings

17. Mechanism
(This favorable
equilibrium drives the reaction)

18. Other examples

19. Other examples
Why?

20. 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

21. Mechanism

22. Mechanism
(This favorable equilibrium
drives the reaction)

23. Other examples

24. 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)

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

27. Intramolecular example
The product was formed by deprotonation of Hb, the enolate formed at C5 and then adding to C1

28. 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.

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

30. 4A. Aldol Addition Reactions
Mechanism of the aldol addition

31. 4B. The Retro-Aldol Reaction
Mechanism

32. 4C. Aldol Condensation Reactions: Dehydration of the Aldol Addition Product

33. 4C. Acid-Catalyzed Aldol Condensations

34. Mechanism

35. 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

37. Crossed Aldol Condensations

38. 5A. Crossed Aldol Condensations Using Weak Bases
addition
dehydration

40. 5B. Crossed Aldol Condensations Using Strong Bases: Lithium Enolates and Directed Aldol Reactions
Directed Aldol Synthesis using a strong base, iPr2NLi (LDA)

41. The use of a weaker base under protic conditions
Formation of both kinetic and thermodynamic enolates
Results in mixture of crossed aldol products

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

44. Synthesis

45. 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

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

50. 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

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

53. nucleophiles attack the carbonyl carbon or the b carbon

54. Conjugate addition of HCN

55. Conjugate addition of an amine

56. 7A. Conjugate Additions of Enolates: Michael Additions

57. Other examples of Michael additions

58. 7B. The Robinson Annulation

59. Mechanism of the Robinson Annulation

60. Mechanism of the Robinson Annulation

61. The Mannich Reaction

62. Mechanism of the Mannich Reaction

63. Other examples of the Mannich Reaction

64. Summary of Important Reactions
Claisen Condensations

65. Aldol Condensations

66. Simple & Conjugate (Michael) additions

67. Mannich reaction

68.  END OF CHAPTER 19 