1. Enolate Anions
Chapter 19
Chapter 19

2. Reactions of Chapter 19 Aldol reaction (aldehyde or ketone)
Crossed Aldol
Intramolecular Aldol (cyclic)
Claisen reaction (esters)
Crossed Claisen
Dieckmann (cyclic)
Enamines (2o amine + aldehyde or ketone)
Acetoacetic ester reaction
Malonic ester reaction
Michael addition (,  -unsaturated carbonyl)
Robinson Annulation (cyclic from Michael + aldol)
Gilman alkylation (Michael)

3. 19.1 Formation of an Enolate Anion
Enolate anions are formed by treating an aldehyde or ketone with base.
most of the negative charge in an enolate anion is on oxygen.

4. Reaction Types with Enolate Anions
Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions. 1. 2.

5. The Hell-Volhard-Zelinsky reaction
This reaction is a synthesis of -haloacids.
The starting acid must have an -hydrogen. It is treated with Br2 and PBr3 then hydrolyzed.
Remember we had -halogenation of ketones in chapter 16. OH O O
Br2 C H 3 - OH C H 3 - Br C H 2 = - Br
PBr3 OH O O
HOH C H 2 = - Br
Br-CH2-C-Br
Br-CH2-C-OH

6. 19.2 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.
This reaction with aldehydes or with ketones is an Aldol reaction.
although these reactions may be catalyzed by either acid or base, base catalysis is more common.

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

8. The Aldol Reaction Base-catalyzed aldol reaction:
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.

9. The Aldol Reaction: acid
Acid-catalyzed aldol reaction:
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.

10. The Aldol Reaction: acid
Step 3: attack of the enol of one molecule on the protonated carbonyl group of another molecule.
Step 4: proton transfer to A- completes the reaction.

11. The Aldol Products: -H2O
aldol products are very easily dehydrated to ,-unsaturated aldehydes or ketones.
aldol reactions are reversible and often little aldol present at equilibrium.
Keq for dehydration is generally large.
if reaction conditions bring about dehydration, good yields of product can be obtained.

12. Crossed Aldol Reactions
In a Crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group.
Note: Formaldehyde has no -carbon.
To be useful the electrophile must not have a hydrogen on the -carbon.

13. Crossed Aldol Reactions
Crossed aldol reactions are most successful if
one of the reactants has no -hydrogen and, therefore, cannot form an enolate anion and
the other reactant has a more reactive carbonyl group, namely an aldehyde.
Aldehydes without an -H

14. Crossed Aldol Reactions
Nitro groups can be introduced by way of an aldol reaction using a nitroalkane.
nitro groups can be reduced to 1° amines.

15. 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.

16. Cannizzaro Reaction
An aldehyde which has no a-hydrogens undergoes oxidation-reduction when treated with base: - O O
R3C-C-H + N a O H
R3C-C-H A c e t a l d h y OH - O O O -
R3C-C-O +
R3C-CH2-OH
R3C-C-H +
R3C-C-H OH
oxidized
reduced

17. 19.3 A. Claisen Condensation
Esters also form enolate anions which condense in a Claisen condensation.
the product of a Claisen condensation is a -ketoester.

18. Claisen Condensation
Claisen condensation of ethyl propanoate gives this -ketoester. The base generally used is the alkoxide corresponding to the alcohol moiety of the ester.

19. Claisen Condensation Step 1: formation of an enolate anion.
Step 2: attack of the enolate anion on a carbonyl carbon gives a TCAI.

20. 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.

21. B. Dieckman Condensation
A Dieckman condensation is an intramolecular Claisen condensation (forms a cyclic product).

22. C. Crossed Claisen Condsns
Crossed Claisen condensations between two different esters, each with -hydrogens, give mixtures of products and are not useful.
useful crossed Claisen condensations are possible, however, if there is an appreciable difference in reactivity between the two esters; that is, when one of them has no -hydrogens.
Esters without an -H

23. Crossed Claisen Condensations
the ester with no -hydrogens is generally used in excess.

24. D. Use of the Claisen Condensation
Claisen condensations are a route to ketones.

25. Claisen Condensation
The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.

26. 19.4 From Acetyl Coenzyme A
Carbonyl condensations are among the most widely used reactions in the biological world for formation of new carbon-carbon bonds in such biomolecules as:
fatty acids
cholesterol, bile acids, and steroid hormones
terpenes
One source of carbon atoms for the synthesis of these biomolecules is acetyl coenzyme A (acetyl-CoA).

27. Acetyl-CoA
Claisen condensation of acetyl-CoA is catalyzed by the enzyme thiolase.

28. Acetyl-CoA
this is followed by an aldol reaction with a second molecule of acetyl-CoA.

29. Acetyl-CoA enzyme-catalyzed reduction of thioester group.
phosphorylation by ATP followed by -elimination.

30. Acetyl-CoA
isopentenyl pyrophosphate has the carbon skeleton of isoprene and is a key intermediate in the synthesis of these classes of biomolecules.

31. 19.5 Enamines
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. O N N H H
Pyrrolidine M
orpholine

32. Enamines
Examples:

33. A. Enamines – The Stork Reaction
The value of enamines is that the -carbon is nucleophilic and gives an SN2 alkylation.
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.

34. Enamines - Alkylation
hydrolysis of the iminium halide (Schiff base) gives an alkylated aldehyde or ketone. O O O + B r - N + H C l / 2 O + N C l - H H
2-Allylcyclo-
hexanone
Morpholinium
chloride
Remember, a C=N
is a Schiff base. These
will hydrolyze in acid
to give the amine and
carbonyl.

35. B. Enamines - Acylation
enamines undergo acylation when treated with acid chlorides and acid anhydrides.

36. 19.6 Acetoacetic Ester Synthesis
The acetoacetic ester (AAE) synthesisis useful for the preparation of mono- and disubstituted acetones of the following types.

37. Acetoacetic Ester Synthesis
this occurs by alkyation of the carbon between the carbonyl groups followed by hydrolysis of the ester then decarboxylation of the -ketoacid
consider the AAE synthesis of this target molecule, which is a monosubstituted acetone.

38. Acetoacetic Ester Synthesis
Step 1: formation of the enolate anion of AAE.
Step 2: alkylation with allyl bromide.

39. Acetoacetic Ester Synthesis
Steps 3 & 4 saponification followed by acidification.
Step 5: thermal decarboxylation.

40. Acetoacetic Ester Synthesis
to prepare a disubstituted acetone, treat the monoalkylated AAE with a second mole of base, etc.

41. 19.7 Malonic Ester Synthesis
The strategy of a Malonic ester (ME) synthesis is similar to that of an acetoacetic ester synthesis. The starting material is a -diester rather than a -ketoester.

42. Malonic Ester Synthesis
is useful for the preparation of mono- and disubstituted acetic acids.
Consider the synthesis of this target molecule.
This is the R group from
alkylation of malonic ester

43. Malonic Ester Synthesis
treat malonic ester with an alkali metal alkoxide.
alkylate with 1-bromo-3-methoxypropane.

44. Malonic Ester Synthesis
saponify and acidify.
decarboxylation.
Disubstitution can be obtained in the same manner as used with acetoacetic ester

45. 19.8 A. Michael Reaction
Michael reaction: the nucleophilic addition of an enolate anion to an ,-unsaturated carbonyl compound.
Example:
Electron donor
Electron recipient

46. Michael Reaction, Table 19.1

47. Michael Reaction Example:
the double bond of an a,b-unsaturated carbonyl compound is activated for nucleophilic attack.

48. Michael Reaction Mechanism: Step 1: proton transfer to the base.
Step 2: addition of Nu:- to the  carbon of the ,-unsaturated carbonyl compound.

49. 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.

50. Michael Reaction
**A final word about nucleophilic addition to a,b-unsaturated carbonyl compounds.
resonance-stabilized enolate anions and enamines are weak bases, react slowly with a,b-unsaturated carbonyl groups, and instead give 1,4-addition products.
organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and give primarily 1,2-addition.

51. Michael Reaction
Thermodynamic versus kinetic control.

52. Michael Reactions
enamines also participate in Michael reactions.

53. B. Robinson Annulation A Michael reaction followed by a cyclic aldol.1 . N a O E t , H + C O E t
(Michael reaction)
Ethyl 2-oxocyclohexane
carboxylate
3-Buten-2-one
(Methyl vinyl
ketone) O O O 2 . N a O E t , H
(Aldol reaction) C O E t C O E t

54. Another example: Michael addition followed by an aldol condensation. O
- OH
CH2-CH2-C-CH3 +
CH2=CH-C-CH3
Michael O O
- OH O
CH2-CH2-C-CH3
Aldol

55. C. Gilman Reagents
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.

56. Retrosynthesis of 2,6-Heptadione

57. Enolate Anions
End Chapter 19