Ester Enolates

1
Chapter 21

• Ester Enolates

2
Introduction

• The preparation and reactions of ?-dicarbonyl
  compounds, especially ?-keto esters, is the main
  focus of this chapter.
• A proton on the carbon flanked by the two
  carbonyl groups is relatively acidic, easily and
  quantitatively removed by alkoxide ions.

3
Introduction
pKa 11
4
Introduction

• The resulting carbanion is stabilized by enolate
  resonance involving both carbonyl groups.

5
The Claisen Condensation
1. NaOR'

R'OH
2. H3O

• ?-Keto esters are made by the reaction shown,
  which is called the Claisen condensation.
• Ethyl esters are typically used, with sodium
  ethoxide as the base.

6
Example
1. NaOCH2CH3
2. H3O
(75)

• Product from ethyl acetate is called ethyl
  acetoacetate or acetoacetic ester.

7
Mechanism

• 1. Abstraction of a proton. (Enolate)
• 2. Nucleophilic attach of carbonyl carbon.
  (Nucleophilic Acyl Substitution)
• 3. Loss of alkoxide/abstraction of proton.
• 4. Acidification to form product.

8
The Intermolecular Claisen Condensation is called
the Dieckmann Reaction
CH3CH2OCCH2CH2CH2CH2COCH2CH3
9
Mixed Claisen Condensations

• As with mixed aldol condensations, mixedClaisen
  condensations are best carried outwhen the
  reaction mixture contains one compound that can
  form an enolate and another that cannot.

10
Mixed Claisen Condensations

• These types of esters cannot form an enolate.

11
Example

1. NaOCH3
2. H3O
12
Acylation of Ketones with Esters

• Esters that cannot form an enolate can be used
  to acylate ketone enolates.

13
Example

14
Ketone Synthesis

RCH2CCH2R
CO2

• ?-Keto acids decarboxylate readily to give
  ketones (Section 19.17).

15
Ketone Synthesis
H2O

R'OH

• ?-Keto acids decarboxylate readily to give
  ketones (Section 19.17).
• ?-Keto acids are available by hydrolysis of
  ?-keto esters.

16
Ketone Synthesis
1. NaOR'

R'OH
2. H3O

• ?-Keto acids decarboxylate readily to give
  ketones (Section 19.17).
• ?-Keto acids are available by hydrolysis of
  ?-keto esters.
• ?-Keto esters can be prepared by the Claisen
  condensation.

17
Example
1. NaOCH2CH3
2. H3O
(80)
18
Example
19
Example
70-80C
(81)
20
Acetoacetic Ester

• Acetoacetic ester is another name for ethyl
  acetoacetate.
• The "acetoacetic ester synthesis" uses
  acetoacetic ester as a reactant for the
  preparation of ketones.

21
Deprotonation of Ethyl Acetoacetate


CH3CH2O

• Ethyl acetoacetate can be converted readily to
  its anion with bases such as sodium ethoxide.

pKa 11
22
Alkylation of Ethyl Acetoacetate

• The anion of ethyl acetoacetate can be alkylated
  using an alkyl halide (SN2 primary and
  secondary alkyl halides work best tertiary
  alkyl halides undergo elimination).

23
Conversion to Ketone

• Saponification and acidification convert the
  alkylated derivative to the corresponding ?-keto
  acid.
• The ?-keto acid then undergoes decarboxylation to
  form a ketone.

24
Conversion to Ketone

• Saponification and acidification convert the
  alkylated derivative to the corresponding ?-keto
  acid.
• The ?-keto acid then undergoes decarboxylation to
  form a ketone.

C
CO2
H3C
CH2R
25
Malonic Ester

• Malonic ester is another name for diethyl
  malonate.
• The "malonic ester synthesis" uses diethyl
  malonate as a reactant for the preparation of
  carboxylic acids.

26
An Analogy

• The same procedure by which ethyl acetoacetate
  is used to prepare ketonesconverts diethyl
  malonate to carboxylic acids.

27
Example
28
Example
29
Dialkylation
1. NaOCH2CH3
2. CH3Br
(79-83)
30
Dialkylation
31
Dialkylation
CH3CH2OCCCOCH2CH3
CH3(CH2)8CH2
CH3
32
Barbituric acid is made from diethyl malonate and
urea

33
Substituted derivatives of barbituric acid are
madefrom alkylated derivatives of diethyl
malonate
34
Substituted derivatives of barbituric acid are
madefrom alkylated derivatives of diethyl
malonate
35
Examples
36
Stabilized Anions

• The anions derived by deprotonation of ?-keto
  esters and diethyl malonate are weak bases.
• Weak bases react with ?,?-unsaturated carbonyl
  compounds by conjugate addition.

37
Example

38
Deprotonation of Simple Esters

• Ethyl acetoacetate (pKa 11) and diethyl malonate
  (pKa 13) are completely deprotonated by alkoxide
  bases.
• Simple esters (such as ethyl acetate) are not
  completely deprotonated, the enolate reacts with
  the original ester, and Claisen condensation
  occurs.
• Are there bases strong enough to completely
  deprotonate simple esters, giving ester enolates
  quantitatively?

39
Lithium diisopropylamide

• Lithium dialkylamides are strong bases (just as
  NaNH2 is a very strong base).
• Lithium diisopropylamide is a strong base, but
  because it is sterically hindered, does not add
  to carbonyl groups.

40
Lithium diisopropylamide (LDA)

• Lithium diisopropylamide converts simple esters
  to the corresponding enolate.

LiNCH(CH3)22
pKa 22
41
Lithium diisopropylamide (LDA)

• Enolates generated from esters and LDA can be
  alkylated.

42
Aldol addition of ester enolates

• Ester enolates undergo aldol addition to
  aldehydes and ketones.

1. LiNR2, THF
3. H3O
(90)
43
Ketone Enolates

• Lithium diisopropylamide converts ketones
  quantitatively to their enolates.

1. LDA, THF
3. H3O
(81)