Chapter 21Chapter 21Ester EnolatesEster Enolates

IntroductionIntroduction

The preparation and reactions of The preparation and reactions of -dicarbonyl -dicarbonyl compounds, especially compounds, especially -keto esters, is the -keto esters, is the main focus of this chapter.main focus of this chapter.

A proton on the carbon flanked by the two A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions.quantitatively removed by alkoxide ions.

CCCCRR

CCOR'OR'

HH HH

OO OO

IntroductionIntroduction

CCCCRR

CCOR'OR'

HH HH

OO OO

CCCCRR

CCOR'OR'

HH

OO OO

••••––

ppKKaa ~ 11 ~ 11

CHCH33CHCH22OO––

IntroductionIntroduction

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

CCCCRR

CCOR'OR'

HH

OO OO

••••––

•••• ••••••••••••

CCCCRR

CCOR'OR'

HH

OO OO–– •••• ••••••••

••••••••

IntroductionIntroduction

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

CCCCRR

CCOR'OR'

HH

OO OO

••••––

•••• •••••••••••• •••• ••••

CCCCRR

CCOR'OR'

HH

OO OO––

•••• ••••••••

21.121.1

The Claisen CondensationThe Claisen Condensation

The Claisen CondensationThe Claisen Condensation

-Keto esters are made by the reaction shown, -Keto esters are made by the reaction shown, which is called the Claisen condensation.which is called the Claisen condensation.

Ethyl esters are typically used, with sodium Ethyl esters are typically used, with sodium ethoxide as the base.ethoxide as the base.

2RCH2RCH22COR'COR'

OO1. NaOR'1. NaOR'

2. H2. H33OO++++ R'OHR'OH

OO OO

RCHRCH22CCHCOR'CCHCOR'

RR

ExampleExample

Product from ethyl acetate is called Product from ethyl acetate is called ethylethyl acetoacetateacetoacetate or or acetoaceticacetoacetic esterester..

2CH2CH33COCHCOCH22CHCH33

OO1. NaOCH1. NaOCH22CHCH33

2. H2. H33OO++

OO OO

CHCH33CCHCCH22COCHCOCH22CHCH33

(75%)(75%)

MechanismMechanism

Step 1:Step 1:

CHCH33CHCH22 OO––•••• ••••

••••

••••

COCHCOCH22CHCH33

OO

CHCH22HH

••••

MechanismMechanism

Step 1:Step 1:

CHCH33CHCH22 OO––•••• ••••

••••

••••

COCHCOCH22CHCH33

OO

CHCH22HH

••••

––••••

••••

COCHCOCH22CHCH33

OO

CHCH22CHCH33CHCH22 OO••••

••••HH

••••

MechanismMechanism

Step 1:Step 1:

––••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

––••••

COCHCOCH22CHCH33

OO

CHCH22

•••• ••••

Anion produced is Anion produced is stabilized by electron stabilized by electron delocalization; it is the delocalization; it is the enolate of an ester.enolate of an ester.

MechanismMechanism

Step 2:Step 2:

––••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

CHCH33COCHCOCH22CHCH33

OO ••••••••

MechanismMechanism

Step 2:Step 2:

––••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

CHCH33COCHCOCH22CHCH33

OO ••••••••

CHCH33CC

––OO•••• ••••••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

OCHOCH22CHCH33••••••••

MechanismMechanism

Step 2:Step 2:

CHCH33CC

––OO•••• ••••••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

OCHOCH22CHCH33••••••••

MechanismMechanism

Step 3:Step 3:

CHCH33CC

––OO•••• ••••••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

OCHOCH22CHCH33••••••••

––OCHOCH22CHCH33••••

••••••••

CHCH33CC

OO•••• ••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

++

MechanismMechanism

––OCHOCH22CHCH33••••

••••••••

CHCH33CC

OO•••• ••••

••••

COCHCOCH22CHCH33

OO

CHCH22

••••

++

Step 3:Step 3:

The product at this point is ethyl acetoacetate.The product at this point is ethyl acetoacetate.

However, were nothing else to happen, the yield of ethyl However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium acetoacetate would be small because the equilibrium constant for its formation is small.constant for its formation is small.

Something else does happen. Ethoxide abstracts a Something else does happen. Ethoxide abstracts a proton from the CHproton from the CH22 group to give a stabilized anion. group to give a stabilized anion.

The equilibrium constant for this reaction is favorable. The equilibrium constant for this reaction is favorable.

MechanismMechanism

––OCHOCH22CHCH33••••

••••••••

CHCH33CC

OO•••• ••••

••••

COCHCOCH22CHCH33

OO

CCHH22

••••

++

Step 4:Step 4:

++ OCHOCH22CHCH33••••

••••HH

––

••••

COCHCOCH22CHCH33

OO ••••

CHCH33CC

OO•••• ••••

CCHH••••

MechanismMechanism

Step 5:Step 5:

––

••••

COCHCOCH22CHCH33

OO

CHCH33CC

OO•••• ••••

CCHH••••

In a separate operation, the reaction mixture is In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated acidified. This converts the anion to the isolated product, ethyl acetoacetate.product, ethyl acetoacetate.

MechanismMechanism

++

Step 5:Step 5:

––

••••

COCHCOCH22CHCH33

OO

CHCH33CC

OO•••• ••••

CCHH••••

++OOHH ••••

HH

HH

OO

HH

••••

HH

••••CHCH33CC

OO•••• ••••

••••

COCHCOCH22CHCH33

OO

CCHH

••••

HH

Another exampleAnother example

Reaction involves Reaction involves bond formation bond formation between the between the --carboncarbon atom of one atom of one ethyl propanoate ethyl propanoate molecule and the molecule and the carbonyl carbon carbonyl carbon of of the other.the other.

2CH2CH33CHCH22COCHCOCH22CHCH33

OO

1. NaOCH1. NaOCH22CHCH33

2. H2. H33OO++

(81%)(81%)

OO OO

CHCH33CHCH22CCCCHCOCHHCOCH22CHCH33

CHCH33

21.221.2

Intramolecular Claisen Intramolecular Claisen

Condensation:Condensation:

The Dieckmann ReactionThe Dieckmann Reaction

CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CHCH22COCHCOCH22CHCH33

OO OO

1. NaOCH1. NaOCH22CHCH33

2. H2. H33OO++

ExampleExample

COCHCOCH22CHCH33

OO OO

(74-81%)(74-81%)

CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHH22COCHCOCH22CHCH33

OO OO

NaOCHNaOCH22CHCH33

viavia

CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHHCOCHCOCH22CHCH33

OO OO

••••

––

•••• ••••

•••• ••••

•••• ••••

viavia

CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHHCOCHCOCH22CHCH33

OO OO

••••

––

•••• •••••••• ••••

viavia

CHCH33CHCH22OCCHOCCH22CHCH22CHCH22CCHHCOCHCOCH22CHCH33

OO OO

••••

––

•••• •••••••• ••••

CCHHCOCHCOCH22CHCH33

OO

––•••• ••••

CHCH22HH22CC

HH22CC

CC

OO•••• ••••••••CHCH33CHCH22OO

••••

••••

viavia

CCHHCOCHCOCH22CHCH33

OO

––•••• ••••

CHCH22HH22CC

HH22CC

CC

OO•••• ••••••••CHCH33CHCH22OO

••••

••••

viavia

CCHHCOCHCOCH22CHCH33

OO

––•••• ••••

CHCH22HH22CC

HH22CC

CC

OO•••• ••••••••CHCH33CHCH22OO

••••

••••

CHCH33CHCH22OO••••

••••••••––

•••• ••••

CCHHCOCHCOCH22CHCH33

OO

CHCH22HH22CC

HH22CC

CC

OO••••••••

++

21.321.3

Mixed Claisen CondensationsMixed Claisen Condensations

Mixed Claisen CondensationsMixed Claisen Condensations

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

Mixed Claisen CondensationsMixed Claisen Condensations

These types of esters cannot form an enolate.These types of esters cannot form an enolate.

HCORHCOR

OO

ROCORROCOR

OO

ROCROC

OO

CORCOR

OO

CORCOR

OO

ExampleExample

1. NaOCH1. NaOCH33

2. H2. H33OO++

(60%)(60%)

CCOCHOCH33

OO

++ CHCH33CCHH22COCHCOCH33

OO

OO OO

CCCCHCOCHHCOCH33

CHCH33

21.421.4

Acylation of Ketones with EstersAcylation of Ketones with Esters

Acylation of Ketones with EstersAcylation of Ketones with Esters

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

ExampleExample

1. NaH1. NaH

2. H2. H33OO++

(60%)(60%)

++CHCH33CHCH22OOCCOCHOCH22CHCH33

OO OO

OO

CCOCHOCH22CHCH33

OO

ExampleExample

1. NaOCH1. NaOCH22CHCH33

2. H2. H33OO++

(62-71%)(62-71%)

CCOCHOCH22CHCH33

OO

++

OO

CCHH33CC

OO

OO

CCCCHH22CC

ExampleExample

1. NaOCH1. NaOCH33

2. H2. H33OO++

(70-71%)(70-71%)

CHCH33CHCH22CCHCCH22CHCH22COCHCOCH22CHCH33

OO OO

OO

OO

CHCH33

21.521.5

Ketone Synthesis via Ketone Synthesis via -Keto -Keto

EstersEsters

Ketone SynthesisKetone Synthesis

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

++

OO

RCHRCH22CCHCCH22RR

OO OO

RCHRCH22CCHCOHCCHCOH

RR

COCO22

Ketone SynthesisKetone Synthesis

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

-Keto acids are available by hydrolysis of -Keto acids are available by hydrolysis of --keto esters.keto esters.

OO OO

RCHRCH22CCHCOR'CCHCOR'

RR

OO OO

RCHRCH22CCHCOHCCHCOH

RR

HH22OO++ R'OHR'OH

Ketone SynthesisKetone Synthesis

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

-Keto acids are available by hydrolysis of -Keto acids are available by hydrolysis of --keto esters.keto esters.

-Keto esters can be prepared by the Claisen -Keto esters can be prepared by the Claisen condensation.condensation.

2RCH2RCH22COR'COR'

OO1. NaOR'1. NaOR'

2. H2. H33OO++++ R'OHR'OH

OO OO

RCHRCH22CCHCOR'CCHCOR'

RR

ExampleExample

1. NaOCH1. NaOCH22CHCH33

2. H2. H33OO++

(80%)(80%)

2 CH2 CH33CHCH22CHCH22CHCH22COCHCOCH22CHCH33

OO

CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33

OO OO

CHCH22CHCH22CHCH33

ExampleExample

1. KOH, H1. KOH, H22O, 70-80°CO, 70-80°C

2. H2. H33OO++

CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33

OO OO

CHCH22CHCH22CHCH33

CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH

OO OO

CHCH22CHCH22CHCH33

ExampleExample

70-80°C70-80°C

(81%)(81%)

OO

CHCH33CHCH22CHCH22CHCH22CCHCCH22CHCH22CHCH22CHCH33

CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH

OO OO

CHCH22CHCH22CHCH33