Chapter 19

1. 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 1995. 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. https://www.concursolutions.com 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 • Intramolecular Claisen condensation • 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 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 • Dehydration of the aldol addition product • Aldol condensation

33. 4C. Acid-Catalyzed AldolCondensations

34. Mechanism

35. 4E. Synthetic Applications of AldolReactions • 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 aldol addition dehydration

40. 5B. Crossed Aldol Condensations UsingStrong 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. Suggest a synthesis of the following compound using a directed aldol synthesis • Retrosynthetic analysis disconnection

44. Synthesis

45. Cyclizations via AldolCondensations • 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