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Chapter 19

Chapter 19. Condensation and Conjugate Addition Reactions of Carbonyl Compounds More Chemistry of Enolates. https://www.concursolutions.com. Introduction. Carbonyl condensation reactions. Claisen condensation:. An a carbon anion (enolate) from one ester attacks the

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Chapter 19

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  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

  9. Mechanism: • Step 4

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

  11. 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.

  12. Examples of Claisen condensation:

  13. Examples of Claisen condensation:

  14. 2A. Intramolecular Claisen Condensations:The Dieckmann Condensation Intramolecular (cyclic) Claisen condensation: • Dieckmann condensation. • Useful for the synthesis of five- and six-membered rings.

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

  16. Other examples:

  17. Other examples: Why?

  18. 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.

  19. Mechanism:

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

  21. Other examples:

  22. 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.

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

  24. 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.

  25. 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.

  26. 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

  27. 4A. Aldol Addition Reactions • Mechanism of the aldol addition: Shown on slide 3.

  28. 4B. The Retro-Aldol Reaction • Mechanism for reverse aldol:

  29. 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.

  30. 4C. Acid-Catalyzed AldolCondensations

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

  32. 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

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

  34. 5A. Crossed Aldol Condensations Using Weak Bases aldol addition No a hydrogen dehydration

  35. No a hydrogen

  36. 5B. Crossed Aldol Condensations UsingStrong Bases: Lithium Enolates and Directed Aldol Reactions • Directed Aldol Synthesis using a strong base, iPr2NLi (LDA).

  37. 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.

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

  39. Synthesis:

  40. 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.

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

  42. 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.

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

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