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. Intramolecular Aldol 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. Intramolecular Claisen 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
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.

51. Crossed Enolate Reactions using LDA
With a strong enough base, enolate anion formation can be driven to completion.
The base most commonly used for this purpose is lithium diisopropylamide , LDA.
LDA is prepared by dissolving diisopropylamine in THF and treating the solution with butyl lithium.
LDA

52. Crossed Enolate Reactions using LDA
The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to completely preform its enolate anion, which is then treated with the aldehyde.

53. Examples using LDA
Crossed aldol
Michael
Alkylation
Acylation

54. Crossed Enolate Reactions using LDA
Question: For ketones with nonequivalent a-hydrogens, can we selectively utilize the nonequivalent sites?
Answer: A high degree of regioselectivity exists and it depends on experimental conditions.

55. Crossed Enolate Reactions using LDA
When 2-methylcyclohexanone is treated with a slight excess of LDA, the enolate is almost entirely the less substituted enolate anion.
When 2-methylcyclohexanone is treated with LDA where the ketone is in slight excess, the product is richer in the more substituted enolate.

56. Crossed Enolate Reactions using LDA
The most important factor determining the composition of the enolate anion mixture is whether the reaction is under kinetic (rate) or thermodynamic (equilibrium) control.
Thermodynamic Control: Experimental conditions that permit establishment of equilibrium between two or more products of a reaction.The composition of the mixture is determined by the relative stabilities of the products.

57. Crossed Enolate Reactions using LDA
Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate and an a-hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.

58. Crossed Enolate Reactions using LDA
Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each product. First formed dominates.
In the case of enolate anion formation, kinetic control refers to the relative rate of removal of alternative a-hydrogens.
With the use of a bulky base, the less hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion.
No equilibrium among alternative structures is set up.

59. Example 1. 1.01 mol LDA, kinetic control
mol LDA, thermodynamic control