Chapter 19 Enolates and Enamines

1. Chapter 19 Enolates and Enamines

2. Formation of an Enolate Anion • Enolate anions are formed by treating an aldehyde, ketone, or ester, which has at least one a-hydrogen, with base, • Most of the negative charge in an enolate anion is on oxygen. oxygen Reactive carbon

3. Enolate Anions • Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions, SN2 Carbonyl addition

4. The Aldol Reaction • The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound. • Catalysis: Base catalysis is most common although acid also works. Enolate anions only exist in base.

5. The Aldol Reaction • The product of an aldol reaction is: • a -hydroxyaldehyde. • or a -hydroxyketone. acid acid

6. Mechanism: the Aldol Reaction, Base • Base-catalyzed aldol reaction (good nucleophile) Step 1: Formation of a resonance-stabilized enolate anion. Step 2: Carbonyl addition gives a TCAI. Step 3: Proton transfer to O- completes the aldol reaction.

7. Mechanism: the Aldol Reaction: Acid catalysis • Before showing the mechanism think about what is needed. • On one molecule the beta carbon must have nucleophilic capabilities to supply an electron pair. • On the second molecule the carbonyl group must function as an electrophile. • One or the other molecules must be sufficiently reactive.

8. Mechanism: the Aldol Reaction: Acid catalysis • Acid-catalyzed aldol reaction (good electrophile) • Step 1: Acid-catalyzed equilibration of keto and enol forms. • Step 2: Proton transfer from HA to the carbonyl group of a second molecule of aldehyde or ketone. Nucleophilic carbon Reactive carbonyl

9. Mechanism: the Aldol Reaction: Acid catalysis • Step 3: Attack of the enol of one molecule on the protonated carbonyl group of the other molecule. • Step 4: Proton transfer to A- completes the reaction. This may look a bit strange but compare to

10. The Aldol Products: Dehydration to alkene • Aldol products are very easily dehydrated to ,-unsaturated aldehydes or ketones. • Aldol reactions are reversible and often little aldol is present at equilibrium. • Keq for dehydration is generally large. • If reaction conditions bring about dehydration, good yields of product can be obtained.

11. Crossed Aldol Reactions • In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group. acid Non-acidic, no alpha hydrogens

12. Crossed Aldol Reactions • Crossed aldol reactions are most successful if • one of the reactants has no -hydrogen and, therefore, cannot form an enolate anion, • One reactant has a more acidic hydrogen than the other (next slide) • One reactant is an aldehyde which has a more reactive carbonyl group.

13. Crossed Aldol Reactions, Nitro activation • Nitro groups can be introduced by way of an aldol reaction using a nitroalkane. • Nitro groups can be reduced to 1° amines.

14. IntramolecularAldol Reactions • Intramolecular aldol reactions are most successful for formation of five- and six-membered rings. • Consider 2,7-octadione, which has two a-carbons.

15. Synthesis: Retrosyntheic Analysis Two Patterns to look for

16. Synthesis: Retrosyntheic Analysis Recognition pattern Analysis

17. Synthesis: Retrosyntheic Analysis Example Mixed aldol Benzaldehyde No alpha hydrogens

18. Claisen Condensation, Ester Substitution • Esters also form enolate anions which participate in nucleophilic acyl substitution. • The product of a Claisen condensation is a -ketoester. Recognition Element

19. Claisen Condensation • Claisen condensation of ethyl propanoate Here the enolate part of one ester molecule has replaced the alkoxy group of the other ester molecule.

20. Mechanism: Claisen Condensation Step 1: Formation of an enolate anion. Step 2: Attack of the enolate anion on a carbonyl carbon gives a TCAI.

21. Mechanism: Claisen Condensation Step 3: Collapse of the TCAI gives a -ketoester and an alkoxide ion. Step 4: An acid-base reaction drives the reaction to completion. This consumption of base must be anticipated.

22. IntramolecularClaisen condensation: Dieckman Condensation Acidic

23. Crossed Claisen Condsns • Crossed Claisen condensations between two different esters, each with -hydrogens, give mixtures of products and are usually not useful. • But if one ester has no -hydrogens crossed Claisen is useful. No -hydrogens

24. Crossed Claisen Condsns • The ester with no -hydrogens is generally used in excess. Used in excess

25. Synthesis: Claisen Condensation • Claisen condensations are a route to ketones via decarboxylation

26. Synthesis: Claisen Condensation The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone. Note that in this Claisen (not crossed) the ketone is symmetric. Crossed Claisen can yield non symmetric ketones.

27. Synthesis: Retrosynthetic Analysis New bond Site of acidic hydrogen, nucleophile Site of substitution, electrophile

28. Enamines (and imines, Schiff bases) Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2. Primary amine But secondary amines react to give enamines Secondary Amine

29. Formation of Enamines • Again, enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone. • The 2° amines most commonly used to prepare enamines are pyrrolidine and morpholine.

30. Formation of Enamines • Examples:

31. Enamines – Alkylation at a position. • The value of enamines is that the -carbon is nucleophilic. • Enamines undergo SN2 reactions with methyl and 1° haloalkanes, -haloketones, and -haloesters. • Treatment of the enamine with one equivalent of an alkylating agent gives an iminium halide.

32. Compare mechanisms of acid catalyzed aldol and enamine

33. Enamines - Alkylation • Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone. Overall process is to render the alpha carbonss of ketone nucleophilic enough so that substitution reactions can occur.

34. Enamines – Acylation at a position • Enamines undergo acylation when treated with acid chlorides and acid anhydrides. Could this be made via a crossed Claisen followed by decarboxylation.

35. Overall, Acetoacetic Ester Synthesis • The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types: RX • Main points • Acidic hydrogen providing a nucleophilic center. • Carboxyl to be removed thermally • Derived from a halide

36. Overall, Malonic Ester Synthesis • The strategy of a malonic ester (ME) synthesis is identical to that of an acetoacetic ester synthesis, except that the starting material is a -diester rather than a -ketoester. RX • Main points • Acidic hydrogen providing a nucleophilic center • Carboxyl group removed by decarboxylation • Introduced from alkyl halide

37. Malonic Ester Synthesis • Consider the synthesis of this target molecule: Recognize as substituted acetic acid. Malonic Ester Synthesis

38. Malonic Ester Synthesis Steps • Treat malonic ester with an alkali metal alkoxide. 2. Alkylate with an alkyl halide.

39. Malonic Ester Synthesis 3. Saponify and acidify. 4. Decarboxylation.

40. Michael Reaction, addition to ,-unsaturated carbonyl • Michael reaction: the nucleophilic addition of an enolate anion to an ,-unsaturated carbonyl compound. • Example: Recognition Pattern: Nucleophile – C – C – CO (nitrile or nitro)

41. Michael Reaction

42. Michael Reaction in base Example: • The double bond of an a,b-unsaturated carbonyl compound is activated for attack by nucleophile. More positive carbon

43. Mechanism: Michael Reaction • Mechanism 1: Set up of nucleophile; Proton transfer to the base. 2: Addition of Nu:- to the  carbon of the ,-unsaturated carbonyl compound.

44. Michael Reaction Step 3: Proton transfer to HB gives an enol. Step 4: Tautomerism of the less stable enol form to the more stable keto form.

45. Michael Reaction, Cautions 1,4 vs 1,2 • Resonance-stabilized enolate anions and enamines are weak bases, react slowly with a,b-unsaturated carbonyl compounds, and give 1,4-addition products. • Organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and given primarily 1,2-addition.

46. Michael Reaction: Thermodynamic vs Kinetic Addition of the nucleophile is irrevesible for strongly basic carbon nucleophiles (kinetic product)

47. Micheal-Aldol Combination a, b unsaturated Carbanion site Dieckman

48. Retrosynthesis of 2,6-Heptadione Recognize as substituted acetone, aae synthesis Recognize as Nucleophile – C – C – CO Michael

49. Michael Reactions • Enamines also participate in Michael reactions.

50. Gilman Reagents vs other organometallics • Gilman reagents undergo conjugate addition to ,-unsaturated aldehydes and ketones in a reaction closely related to the Michael reaction. • Gilman reagents are unique among organometallic compounds in that they give almost exclusively 1,4-addition. • Other organometallic compounds, including Grignard reagents, add to the carbonyl carbon by 1,2-addition.