Chapter 21by

21-1Dr. Wolf's CHM 201 & 202

21.721.7The Acetoacetic Ester SynthesisThe Acetoacetic Ester Synthesis

21-2Dr. Wolf's CHM 201 & 202

Acetoacetic EsterAcetoacetic EsterAcetoacetic EsterAcetoacetic Ester

Acetoacetic ester Acetoacetic ester is another name for is another name for ethylethyl acetoacetateacetoacetate..

The "acetoacetic ester synthesis" uses The "acetoacetic ester synthesis" uses acetoacetic ester as a acetoacetic ester as a reactantreactant for the for the preparation of ketones.preparation of ketones.

CCCC

CCOCHOCH22CHCH33

HH HH

OO OO

HH33CC

21-3Dr. Wolf's CHM 201 & 202

Deprotonation of Ethyl AcetoacetateDeprotonation of Ethyl AcetoacetateDeprotonation of Ethyl AcetoacetateDeprotonation of Ethyl Acetoacetate

CHCH33CHCH22OOCCCC

CCOCHOCH22CHCH33

HH HH

OO OO

HH33CC++

––

ppKKaa ~ 11 ~ 11Ethyl acetoacetate Ethyl acetoacetate can be converted can be converted readily to its anion readily to its anion with bases such as with bases such as sodium ethoxide.sodium ethoxide.

21-4Dr. Wolf's CHM 201 & 202

Deprotonation of Ethyl AcetoacetateDeprotonation of Ethyl AcetoacetateDeprotonation of Ethyl AcetoacetateDeprotonation of Ethyl Acetoacetate

ppKKaa ~ 16 ~ 16

CHCH33CHCH22OOCCCC

CCOCHOCH22CHCH33

HH HH

OO OO

HH33CC

++

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC ++ CHCH33CHCH22OHOH

––

ppKKaa ~ 11 ~ 11

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

KK ~ 10 ~ 1055

21-5Dr. Wolf's CHM 201 & 202

Alkylation of Ethyl AcetoacetateAlkylation of Ethyl AcetoacetateAlkylation of Ethyl AcetoacetateAlkylation of Ethyl Acetoacetate

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC

The anion of ethyl The anion of ethyl acetoacetate can be acetoacetate can be alkylated using an alkylated using an alkyl halide (Salkyl halide (SNN2: 2:

primary and primary and secondary alkyl secondary alkyl halides work best; halides work best; tertiary alkyl halides tertiary alkyl halides undergo elimination).undergo elimination).

RR XX

21-6Dr. Wolf's CHM 201 & 202

Alkylation of Ethyl AcetoacetateAlkylation of Ethyl AcetoacetateAlkylation of Ethyl AcetoacetateAlkylation of Ethyl Acetoacetate

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC

The anion of ethyl The anion of ethyl acetoacetate can be acetoacetate can be alkylated using an alkylated using an alkyl halide (Salkyl halide (SNN2: 2:

primary and primary and secondary alkyl secondary alkyl halides work best; halides work best; tertiary alkyl halides tertiary alkyl halides undergo elimination).undergo elimination).

RR XX

CCCC

CCOCHOCH22CHCH33

HH

OO OO

HH33CC

RR

21-7Dr. Wolf's CHM 201 & 202

Conversion to KetoneConversion to KetoneConversion to KetoneConversion to Ketone

Saponification and Saponification and acidification convert acidification convert the alkylated the alkylated derivative to the derivative to the corresponding corresponding -keto -keto acid.acid.

The The -keto acid then -keto acid then undergoes undergoes decarboxylation to decarboxylation to form a ketone.form a ketone.

CCCC

CCOCHOCH22CHCH33

HH

OO OO

HH33CC

RR

CCCC

CCOHOH

HH

OO OO

HH33CC

RR

1. HO1. HO––, H, H22OO2. H2. H++

21-8Dr. Wolf's CHM 201 & 202

Conversion to KetoneConversion to KetoneConversion to KetoneConversion to Ketone

Saponification and Saponification and acidification convert acidification convert the alkylated the alkylated derivative to the derivative to the corresponding corresponding -keto -keto acid.acid.

The The -keto acid then -keto acid then undergoes undergoes decarboxylation to decarboxylation to form a ketone.form a ketone.

CCCC

CCOHOH

HH

OO OO

HH33CC

RR

CCCHCH22RR

COCO22

OO

HH33CC++

21-9Dr. Wolf's CHM 201 & 202

ExampleExampleExampleExample

1. NaOCH1. NaOCH22CHCH33

2. 2. CHCH33CHCH22CHCH22CHCH22BrBr

OO OO

CHCH33CCCCHH22COCHCOCH22CHCH33

21-10Dr. Wolf's CHM 201 & 202


(70%)(70%)


2. 2. CHCH33CHCH22CHCH22CHCH22BrBr

OO OO


OO OO

CHCH33CCCCHCOCHHCOCH22CHCH33

CHCH22CHCH22CHCH22CHCH33

21-11Dr. Wolf's CHM 201 & 202


(60%)(60%)

OO

CHCH33CCCCHH22CHCH22CHCH22CHCH22CHCH33

1. NaOH, H1. NaOH, H22OO

2. H2. H++

3. heat, -CO3. heat, -CO22

OO OO

CHCH33CCCCHCOCHHCOCH22CHCH33

CHCH22CHCH22CHCH22CHCH33

21-12Dr. Wolf's CHM 201 & 202

Example: Example: DialkylationDialkylationExample: Example:

DialkylationDialkylation OO OO

CHCH33CCCCHHCOCHCOCH22CHCH33

CHCH22CHCH CHCH22

21-13Dr. Wolf's CHM 201 & 202


DialkylationDialkylation


2. 2. CHCH33CHCH22II

OO OO

CHCH33CCCCHHCOCHCOCH22CHCH33

CHCH22CHCH CHCH22

OO

CHCH33CCCOCHCCCOCH22CHCH33

CHCH22CHCH CHCH22

OO

CHCH33CHCH22

(75%)(75%)

21-14Dr. Wolf's CHM 201 & 202


2. H2. H++


OO

CHCH33CCCOCHCCCOCH22CHCH33

CHCH22CHCH CHCH22

OO

CHCH33CHCH22


DialkylationDialkylationCHCH33CCHCCH CHCH22CHCH CHCH22

OO

CHCH33CHCH22

21-15Dr. Wolf's CHM 201 & 202

Another Another ExampleExampleAnother Another ExampleExample OO OO

HH

COCHCOCH22CHCH33

-Keto esters other than ethyl acetoacetate -Keto esters other than ethyl acetoacetate may be used.may be used.

21-16Dr. Wolf's CHM 201 & 202

Another Another ExampleExampleAnother Another ExampleExample OO OO

HH

COCHCOCH22CHCH33


2. 2. HH22CC CHCHCHCH22BrBr

OO OOCHCH22CHCH

COCHCOCH22CHCH33

CHCH22(89%)(89%)

21-17Dr. Wolf's CHM 201 & 202

Another Another ExampleExampleAnother Another ExampleExample

OO OOCOCHCOCH22CHCH33

CHCH22CHCH CHCH22

21-18Dr. Wolf's CHM 201 & 202

Another Another ExampleExampleAnother Another ExampleExample OO

HH

OO OOCOCHCOCH22CHCH33

CHCH22CHCH CHCH22


2. H2. H++


CHCH22CHCH CHCH22 (66%)(66%)

21-19Dr. Wolf's CHM 201 & 202

21.821.8The Malonic Ester SynthesisThe Malonic Ester Synthesis

21-20Dr. Wolf's CHM 201 & 202

Malonic EsterMalonic EsterMalonic EsterMalonic Ester

Malonic ester Malonic ester is another name for is another name for diethyldiethyl malonatemalonate..

The "malonic ester synthesis" uses diethyl The "malonic ester synthesis" uses diethyl malonate as a malonate as a reactantreactant for the preparation of for the preparation of carboxylic acids.carboxylic acids.

CCCC

CCOCHOCH22CHCH33

HH HH

OO OO

CHCH33CHCH22OO

21-21Dr. Wolf's CHM 201 & 202

An AnalogyAn AnalogyAn AnalogyAn Analogy

OO OO


OO OO

CHCH33CHCH22OCOCCCHH22COCHCOCH22CHCH33

OO

CHCH33CCCCHH22RR

OO

HOCHOCCCHH22RR

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

21-22Dr. Wolf's CHM 201 & 202



OO OO

CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33

HH22CC CHCHCHCH22CHCH22CHCH22BrBr2.2.

CHCH22CHCH22CHCH22CHCH22CHCH

OO OO

CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33

(85%)(85%)

21-23Dr. Wolf's CHM 201 & 202


(75%)(75%)


2. H2. H++


CHCH22CHCH22CHCH22CHCH CHCH22

OO OO


OO

HOCCHHOCCH22CHCH22CHCH22CHCH22CHCH CHCH22

21-24Dr. Wolf's CHM 201 & 202

DialkylationDialkylationDialkylationDialkylation


OO OO


2. 2. CHCH33BrBr

CHCH33

OO OO

CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33 (79-83%)(79-83%)

21-25Dr. Wolf's CHM 201 & 202

DialkylationDialkylationDialkylationDialkylation


OO OO

CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33

2. 2. CHCH33(CH(CH22))88CHCH22BrBr

CHCH33CHCH33(CH(CH22))88CHCH22

CHCH33

OO OO


21-26Dr. Wolf's CHM 201 & 202

DialkylationDialkylationDialkylationDialkylation OO OO


CHCH33

OO

CHCH33(CH(CH22))88CHCH22CHCOHCHCOH

CHCH33CHCH33(CH(CH22))88CHCH22


2. H2. H++


(61-74%)(61-74%)

21-27Dr. Wolf's CHM 201 & 202



OO OO


2. Br2. BrCHCH22CHCH22CHCH22BrBr

CHCH22CHCH22CHCH22BrBr

OO OO


21-28Dr. Wolf's CHM 201 & 202


This product is not isolated, but cyclizes in the This product is not isolated, but cyclizes in the presence of sodium ethoxide.presence of sodium ethoxide.


OO OO


21-29Dr. Wolf's CHM 201 & 202


NaOCHNaOCH22CHCH33


OO OO


OO OO


HH22CC CHCH22

CCHH22

(60-65%)(60-65%)

21-30Dr. Wolf's CHM 201 & 202


OO OO


HH22CC CHCH22

CCHH22 1. NaOH, H1. NaOH, H22OO

2. H2. H++


HH22CC CHCH22

CCHH22

CC

HH COCO22HH

(80%)(80%)

21-31Dr. Wolf's CHM 201 & 202

BarbituratesBarbiturates

21-32Dr. Wolf's CHM 201 & 202

Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea


HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN

21-33Dr. Wolf's CHM 201 & 202

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN


2. H2. H++

HH22CC

OO

CC

CC

OO

CC

NN

OO

NN

HH

HH

(72-78%)(72-78%)



21-34Dr. Wolf's CHM 201 & 202

HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

++ CC

HH22NN

OO

HH22NN


2. H2. H++

OO

OO

NN

OO

NN

HH

HH

(72-78%)(72-78%)



21-35Dr. Wolf's CHM 201 & 202

Substituted derivatives of barbituric acid are madeSubstituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonatefrom alkylated derivatives of diethyl malonate


HH22CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

1. 1. RRX,X,NaOCHNaOCH22CHCH33

2. 2. R'R'X,X,NaOCHNaOCH22CHCH33

CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

RR

R'R'

21-36Dr. Wolf's CHM 201 & 202


Substituted derivatives of barbituric acid are madeSubstituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonatefrom alkylated derivatives of diethyl malonate OO

OO

NNOO

NN

HH

HH

RR

R'R'CC

OO

COCHCOCH22CHCH33

COCHCOCH22CHCH33

OO

RR

R'R'

(H(H22N)N)22CC OO

21-37Dr. Wolf's CHM 201 & 202

ExamplesExamplesExamplesExamples OOOO

NNOO

NN

HH

HH

CHCH33CHCH22

CHCH33CHCH22

5,5-Diethylbarbituric acid5,5-Diethylbarbituric acid(barbital; Veronal)(barbital; Veronal)

21-38Dr. Wolf's CHM 201 & 202


NNOO

NN

HH

HH

CHCH33CHCH22

5-Ethyl-5-(1-methylbutyl)barbituric acid5-Ethyl-5-(1-methylbutyl)barbituric acid(pentobarbital; Nembutal)(pentobarbital; Nembutal)

CHCH33CHCH22CHCH22CHCH

HH33CC

21-39Dr. Wolf's CHM 201 & 202


NNOO

NN

HH

HH

5-Allyl-5-(1-methylbutyl)barbituric acid5-Allyl-5-(1-methylbutyl)barbituric acid(secobarbital; Seconal)(secobarbital; Seconal)

CHCH33CHCH22CHCH22CHCH

HH33CC

CHCHCHCH22HH22CC

21-40Dr. Wolf's CHM 201 & 202

21.921.9

Michael Additions of Stabilized Michael Additions of Stabilized

AnionsAnions

21-41Dr. Wolf's CHM 201 & 202

Stabilized AnionsStabilized AnionsStabilized AnionsStabilized Anions The anions The anions derived by derived by deprotonation of deprotonation of -keto esters -keto esters and diethyl and diethyl malonate are malonate are weak bases.weak bases.

Weak bases Weak bases react with react with ,,--unsaturated unsaturated carbonyl carbonyl compounds by compounds by conjugate conjugate addition.addition.

CCCC

CCOCHOCH22CHCH33

HH

OO OO

••••––HH33CC

CCCC

CCOCHOCH22CHCH33

HH

OO OO

CHCH33CHCH22OO••••

––

21-42Dr. Wolf's CHM 201 & 202


OO OO

CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33++ HH22CC CHCCHCHCCH33

OO

21-43Dr. Wolf's CHM 201 & 202


KOH, ethanolKOH, ethanol

OO OO


(85%)(85%)

++ HH22CC CHCCHCHCCH33

OO

CHCH22CHCH22CCHCCH33

OO OO


OO

21-44Dr. Wolf's CHM 201 & 202


1. KOH, ethanol-water1. KOH, ethanol-water

CHCH22CHCH22CCHCCH33

OO OO


OO

2. H2. H++

3. heat3. heat

CHCH33CCHCCH22CHCH22CHCH22COHCOH

OOOO

(42%)(42%)

21-45Dr. Wolf's CHM 201 & 202

21.10

Reactions of LDA-Generated Ester Enolates

Lithium diisopropylamide (LDA)

21-46Dr. Wolf's CHM 201 & 202

Deprotonation of Simple EstersDeprotonation of Simple EstersDeprotonation of Simple EstersDeprotonation of Simple Esters

Ethyl acetoacetate (pKa ~11) and diethyl Ethyl acetoacetate (pKa ~11) and diethyl malonate (pKa ~13) are completely malonate (pKa ~13) are completely deprotonated by alkoxide bases.deprotonated by alkoxide bases.

Simple esters (such as ethyl acetate) are not Simple esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts completely deprotonated, the enolate reacts with the original ester, and Claisen with the original ester, and Claisen condensation occurs.condensation occurs.

Are there bases strong enough to completely Are there bases strong enough to completely deprotonate simple esters, giving ester enolates deprotonate simple esters, giving ester enolates quantitatively?quantitatively?

Dr. Wolf's CHM 201 & 202 21-47

Lithium diisopropylamideLithium diisopropylamideLithium diisopropylamideLithium diisopropylamide

Lithium dialkylamides are strong bases (just as Lithium dialkylamides are strong bases (just as NaNHNaNH22 is a very strong base). is a very strong base).

Lithium diisopropylamide is a strong base, but Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to because it is sterically hindered, does not add to carbonyl groups.carbonyl groups.

LiLi++

CC NN CC HHHH

CHCH33

CHCH33

CHCH33

CHCH33

••••

••••

––

Dr. Wolf's CHM 201 & 202 21-48

Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)

Lithium diisopropylamide converts simple esters Lithium diisopropylamide converts simple esters to the corresponding enolate.to the corresponding enolate.

CHCH33CHCH22CHCH22COCHCOCH33

OO

++

ppKKaa ~ 22 ~ 22

LiN[CH(CHLiN[CH(CH33))22]]22

CHCH33CHCH22CHCOCHCHCOCH33

OO

++ HN[CH(CHHN[CH(CH33))22]]22••••

––++ LiLi+

+

ppKKaa ~ 36 ~ 36

Dr. Wolf's CHM 201 & 202 21-49

Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)Lithium diisopropylamide (LDA)

Enolates generated from esters and LDA can be Enolates generated from esters and LDA can be alkylated.alkylated.


OO


OO

••••

––

CHCH33CHCH22II

CHCH22CHCH33

(92%)(92%)

Dr. Wolf's CHM 201 & 202 21-50

Aldol addition of ester enolatesAldol addition of ester enolatesAldol addition of ester enolatesAldol addition of ester enolates

Ester enolates undergo aldol addition to Ester enolates undergo aldol addition to aldehydes and ketones.aldehydes and ketones.

CHCH33COCHCOCH22CHCH33

OO1. LiNR1. LiNR22, THF, THF

2. 2. (CH(CH33))22CC OO

3. H3. H33OO++

CCHH33CC

CHCH33

HOHO

CHCH22COCHCOCH22CHCH33

OO

(90%)(90%)

Dr. Wolf's CHM 201 & 202 21-51

Ketone EnolatesKetone EnolatesKetone EnolatesKetone Enolates

Lithium diisopropylamide converts ketones Lithium diisopropylamide converts ketones quantitatively to their enolates.quantitatively to their enolates.

CHCH33CHCH22CC(CHCC(CH33))33

OO1. LDA, THF1. LDA, THF

2. 2. CHCH33CHCH22CHCH OO

3. H3. H33OO++

CHCH33CHCC(CHCHCC(CH33))33

OO

HOCHCHHOCHCH22CHCH33(81%)(81%)

Dr. Wolf's CHM 201 & 202 21-52

End of Chapter 21End of Chapter 21

Chapter 21by

Documents

Transcript of Chapter 21by