Chapter 19

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

2. https://www.concursolutions.com 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. 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 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. 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 AldolCondensations

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

34. 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

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

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

38. No a hydrogen

39. 5B. Crossed Aldol Condensations UsingStrong 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. Suggest a synthesis of the following compound using a directed aldol synthesis. • Retrosynthetic analysis: disconnection

43. Synthesis:

44. 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.

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