Chapter 1. Chapte r 2. Chapter 3. Chapter 4. Chapter 5. Chapter 6. Chapter 7.
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21-1Dr. Wolf's CHM 201 & 202
21.721.7The Acetoacetic Ester SynthesisThe Acetoacetic Ester Synthesis
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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
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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.
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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
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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
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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
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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++
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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++
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21-9Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCCCHH22COCHCOCH22CHCH33
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21-10Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
(70%)(70%)
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCCCHH22COCHCOCH22CHCH33
OO OO
CHCH33CCCCHCOCHHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
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21-11Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
(60%)(60%)
OO
CHCH33CCCCHH22CHCH22CHCH22CHCH22CHCH33
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
OO OO
CHCH33CCCCHCOCHHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
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21-12Dr. Wolf's CHM 201 & 202
Example: Example: DialkylationDialkylationExample: Example:
DialkylationDialkylation OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
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21-13Dr. Wolf's CHM 201 & 202
Example: Example: DialkylationDialkylationExample: Example:
DialkylationDialkylation
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22II
OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
(75%)(75%)
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21-14Dr. Wolf's CHM 201 & 202
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
Example: Example: DialkylationDialkylationExample: Example:
DialkylationDialkylationCHCH33CCHCCH CHCH22CHCH CHCH22
OO
CHCH33CHCH22
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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.
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21-16Dr. Wolf's CHM 201 & 202
Another Another ExampleExampleAnother Another ExampleExample OO OO
HH
COCHCOCH22CHCH33
1. NaOCH1. NaOCH22CHCH33
2. 2. HH22CC CHCHCHCH22BrBr
OO OOCHCH22CHCH
COCHCOCH22CHCH33
CHCH22(89%)(89%)
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21-17Dr. Wolf's CHM 201 & 202
Another Another ExampleExampleAnother Another ExampleExample
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
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21-18Dr. Wolf's CHM 201 & 202
Another Another ExampleExampleAnother Another ExampleExample OO
HH
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH CHCH22 (66%)(66%)
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21-19Dr. Wolf's CHM 201 & 202
21.821.8The Malonic Ester SynthesisThe Malonic Ester Synthesis
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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
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21-21Dr. Wolf's CHM 201 & 202
An AnalogyAn AnalogyAn AnalogyAn Analogy
OO OO
CHCH33CCCCHH22COCHCOCH22CHCH33
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.
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21-22Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
HH22CC CHCHCHCH22CHCH22CHCH22BrBr2.2.
CHCH22CHCH22CHCH22CHCH22CHCH
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
(85%)(85%)
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21-23Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
(75%)(75%)
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH22CHCH22CHCH CHCH22
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
HOCCHHOCCH22CHCH22CHCH22CHCH22CHCH CHCH22
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21-24Dr. Wolf's CHM 201 & 202
DialkylationDialkylationDialkylationDialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. 2. CHCH33BrBr
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33 (79-83%)(79-83%)
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21-25Dr. Wolf's CHM 201 & 202
DialkylationDialkylationDialkylationDialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
2. 2. CHCH33(CH(CH22))88CHCH22BrBr
CHCH33CHCH33(CH(CH22))88CHCH22
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
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21-26Dr. Wolf's CHM 201 & 202
DialkylationDialkylationDialkylationDialkylation OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
CHCH33
OO
CHCH33(CH(CH22))88CHCH22CHCOHCHCOH
CHCH33CHCH33(CH(CH22))88CHCH22
1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
(61-74%)(61-74%)
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21-27Dr. Wolf's CHM 201 & 202
Another Another ExampleExampleAnother Another ExampleExample
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. Br2. BrCHCH22CHCH22CHCH22BrBr
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
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21-28Dr. Wolf's CHM 201 & 202
Another Another ExampleExampleAnother Another ExampleExample
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.
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
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21-29Dr. Wolf's CHM 201 & 202
Another Another ExampleExampleAnother Another ExampleExample
NaOCHNaOCH22CHCH33
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HH22CC CHCH22
CCHH22
(60-65%)(60-65%)
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21-30Dr. Wolf's CHM 201 & 202
Another Another ExampleExampleAnother Another ExampleExample
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HH22CC CHCH22
CCHH22 1. NaOH, H1. NaOH, H22OO
2. H2. H++
3. heat, -CO3. heat, -CO22
HH22CC CHCH22
CCHH22
CC
HH COCO22HH
(80%)(80%)
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21-31Dr. Wolf's CHM 201 & 202
BarbituratesBarbiturates
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21-32Dr. Wolf's CHM 201 & 202
Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea
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
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21-33Dr. Wolf's CHM 201 & 202
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
1. NaOCH1. NaOCH22CHCH33
2. H2. H++
HH22CC
OO
CC
CC
OO
CC
NN
OO
NN
HH
HH
(72-78%)(72-78%)
Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea
Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea
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21-34Dr. Wolf's CHM 201 & 202
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
1. NaOCH1. NaOCH22CHCH33
2. H2. H++
OO
OO
NN
OO
NN
HH
HH
(72-78%)(72-78%)
Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea
Barbituric acid Barbituric acid is made from is made from diethyl diethyl malonate and malonate and ureaurea
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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
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'
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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
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
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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)
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21-38Dr. Wolf's CHM 201 & 202
ExamplesExamplesExamplesExamples OOOO
NNOO
NN
HH
HH
CHCH33CHCH22
5-Ethyl-5-(1-methylbutyl)barbituric acid5-Ethyl-5-(1-methylbutyl)barbituric acid(pentobarbital; Nembutal)(pentobarbital; Nembutal)
CHCH33CHCH22CHCH22CHCH
HH33CC
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21-39Dr. Wolf's CHM 201 & 202
ExamplesExamplesExamplesExamples OOOO
NNOO
NN
HH
HH
5-Allyl-5-(1-methylbutyl)barbituric acid5-Allyl-5-(1-methylbutyl)barbituric acid(secobarbital; Seconal)(secobarbital; Seconal)
CHCH33CHCH22CHCH22CHCH
HH33CC
CHCHCHCH22HH22CC
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21-40Dr. Wolf's CHM 201 & 202
21.921.9
Michael Additions of Stabilized Michael Additions of Stabilized
AnionsAnions
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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••••
––
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21-42Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33++ HH22CC CHCCHCHCCH33
OO
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21-43Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
KOH, ethanolKOH, ethanol
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
(85%)(85%)
++ HH22CC CHCCHCHCCH33
OO
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
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21-44Dr. Wolf's CHM 201 & 202
ExampleExampleExampleExample
1. KOH, ethanol-water1. KOH, ethanol-water
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
2. H2. H++
3. heat3. heat
CHCH33CCHCCH22CHCH22CHCH22COHCOH
OOOO
(42%)(42%)
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21-45Dr. Wolf's CHM 201 & 202
21.10
Reactions of LDA-Generated Ester Enolates
Lithium diisopropylamide (LDA)
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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?
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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
••••
••••
––
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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
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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.
CHCH33CHCH22CHCOCHCHCOCH33
OO
CHCH33CHCH22CHCOCHCHCOCH33
OO
••••
––
CHCH33CHCH22II
CHCH22CHCH33
(92%)(92%)
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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%)
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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%)
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Dr. Wolf's CHM 201 & 202 21-52
End of Chapter 21End of Chapter 21