The Aldol Condensation

1. The Aldol Condensation • In the presence of a strong base, two molecules of aldehyde or ketone may combine to form a b-hydroxyaldehyde or a b-hydroxyketone. • This reaction is called the aldol condensation.

2. The Aldol Condensation

3. Example

4. Another Example

5. One More:

6. The Aldol Condensation Reaction: Mechanism

7. The Aldol Condensation Reaction: Mechanism • The enolate ion (carbanion) is the actual nucleophilic reagent. • The reaction breaks down to the following:The a-carbon of the donor attaches itself to the carbonyl carbon of the acceptor

8. The “Heart” of the Mechanism

9. The Aldol Condensation • The carbonyl group plays two roles in this reaction: • 1. It provides a site for nucleophilic attack by the enolate ion. • 2. It makes the a-hydrogens sufficiently acidic to enable the formation of reasonable concentrations of enolate ion.

10. The Aldol Condensation • NOTE: The must be a-hydrogens in order to have an aldol condensation. • Without a-hydrogens, the only possible reaction is the Cannizarro reaction (Chapter 17, Section 17.3 -- we skipped this) • NOTE ALSO: The aldol condensation is notan end-to-end condensation!

11. Synthesis Problem

12. Synthesis Problem

13. Dehydration of Aldol Products • Aldol products are often very easily dehydrated, yielding a,b-unsaturated aldehydes or ketones. • After dehydration, the a,b-unsaturated aldehydes and ketones are stabilized by resonance, thereby providing a driving force for the dehydration.

14. Dehydration of Aldol Products

15. Dehydration of Aldol Products Note here that iodine is a sufficiently strong Lewis acid to bring about dehydration.

16. Chalcone Formation (formed from an aldol condensation)

17. Dehydration of Aldol Products • The mechanism for the dehydration is E1. • The dehydration happens because the product is conjugated (i.e., resonance-stabilized)

18. Dehydration Products

19. Dehydration of Aldol Products

20. Preparation via Aldol Condensation

21. Preparation via Aldol Condensation

22. Also:

23. Synthesis of:

24. The Crossed Aldol Condensation • What if we tried mixing two different aldehydes (or ketones) together?

25. Argh!!!

26. Crossed Aldol Condensation • If both carbonyl compounds have a-hydrogens, then we can’t control which is the donor and which is the acceptor. • But if we choose one carbonyl compound that does not have a-hydrogens, it can only act as an acceptor. • Then, but adding the donor to a dilute solution of acceptor, we can control the reaction to give only one product.

27. Crossed Aldol Condensations acceptor donor

28. From Experiment 35

29. Do the synthesis of:

30. Uses of the Aldol Condensation • The aldol condensation is very useful in the preparation of large molecules from simple starting materials. • In biosynthesis, where large molecules are products, condensation reactions provide the only reasonable route, since all of the starting materials are small molecules containing only two or three carbons.

31. Synthesis of an Insect Repellent

32. Synthesis of a Compound used in Perfumery

33. Biological Synthesis of Fructose

34. Condensation Reactions • The aldol condensation serves as the prototype for a large number of condensation reactions. • In virtually every case, a carbanion is generated, usually by the action of a base to remove an a-hydrogen that has been activated by a near-by group (C=O, CºN, NO2)

35. Condensation Reactions • The carbanion then acts as a nucleophile to attack the carbonyl carbon of the other reagent used in the reaction. • This is an important process in biosynthesis, where large and complex molecules can be built from simple precursors.

36. Condensation Reactions • We will not examine all of the other possible reactions that follow this general pathway, with one exception: • We will examine the Claisen ester condensation.