reactions of enolate anions: enolates + electrophiles ii
DESCRIPTION
Reactions of Enolate Anions: Enolates + Electrophiles II. Condensations: Many Types, and (Other Reactions). Condensations: Aldol, Claisen, Dieckmann, Acetoacetic / Malonic esters, etc. (Decarboxylation) (Acylation) (Michael Addition) (Lithium cuprates). C. C. O. O. H. C. C. OH. - PowerPoint PPT PresentationTRANSCRIPT
Reactions of Enolate Anions:Reactions of Enolate Anions: Enolates + Electrophiles II Enolates + Electrophiles II
Condensations: Many Types, and (Other Reactions)Condensations: Many Types, and (Other Reactions)
Condensations:Condensations:
Aldol, Claisen, Dieckmann, Aldol, Claisen, Dieckmann,
Acetoacetic / Malonic esters, etc.Acetoacetic / Malonic esters, etc.
(Decarboxylation)(Decarboxylation)
(Acylation)(Acylation)
(Michael Addition)(Michael Addition)
(Lithium cuprates)(Lithium cuprates)
A chemical definition: Addition with subsequent loss of HA chemical definition: Addition with subsequent loss of H22OO
(eg. Dehydration of (eg. Dehydration of -hydroxy carbonyl compounds)-hydroxy carbonyl compounds)
CondensationCondensation
CC OO
CC
CCOHOH
HHCC OO
CC
CC
Acylation of Ketones with Esters
Acylation of Ketones with Esters
Esters that cannot form an enolate can be used to acylate ketone enolates.
Example
1. NaH1. NaH
2. H2. H33OO++
(60%)(60%)
++CHCH33CHCH22OOCCOCHOCH22CHCH33
OO OO
OO
CCOCHOCH22CHCH33
OO
Example
1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
(62-71%)(62-71%)
CCOCHOCH22CHCH33
OO
++
OO
CCHH33CC
OO
OO
CCCCHH22CC
Example
1. NaOCH1. NaOCH33
2. H2. H33OO++
(70-71%)(70-71%)
CHCH33CHCH22CCHCCH22CHCH22COCHCOCH22CHCH33
OO OO
OO
OO
CHCH33
Ketone Synthesis via -Keto Esters
Ketone Synthesis
-Keto acids decarboxylate readily to give ketones.
++
OO
RCHRCH22CCHCCH22RR
OO OO
RCHRCH22CCHCOHCCHCOH
RR
COCO22
Ketone Synthesis
-Keto acids decarboxylate readily to give ketones .-Keto acids are available by hydrolysis of -keto esters.
OO OO
RCHRCH22CCHCOR'CCHCOR'
RR
OO OO
RCHRCH22CCHCOHCCHCOH
RR
HH22OO++ R'OHR'OH
Ketone Synthesis
-Keto acids decarboxylate readily to give ketones .-Keto acids are available by hydrolysis of -keto esters.-Keto esters can be prepared by the Claisen condensation.
2RCH2RCH22COR'COR'
OO1. NaOR'1. NaOR'
2. H2. H33OO++++ R'OHR'OH
OO OO
RCHRCH22CCHCOR'CCHCOR'
RR
Example
1. NaOCH1. NaOCH22CHCH33
2. H2. H33OO++
(80%)(80%)
2 CH2 CH33CHCH22CHCH22CHCH22COCHCOCH22CHCH33
OO
CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33
OO OO
CHCH22CHCH22CHCH33
Example
1. KOH, H1. KOH, H22O, 70-80°CO, 70-80°C
2. H2. H33OO++
CHCH33CHCH22CHCH22CHCH22CCHCOCHCCHCOCH22CHCH33
OO OO
CHCH22CHCH22CHCH33
CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH
OO OO
CHCH22CHCH22CHCH33
Example
70-80°C70-80°C
(81%)(81%)
OO
CHCH33CHCH22CHCH22CHCH22CCHCCH22CHCH22CHCH22CHCH33
CHCH33CHCH22CHCH22CHCH22CCHCOHCCHCOH
OO OO
CHCH22CHCH22CHCH33
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Decarboxylation of 3-Oxocarboxylic Acids
The Acetoacetic Ester Synthesis
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.
CCCC
CCOCHOCH22CHCH33
HH HH
OO OO
HH33CC
Deprotonation of Ethyl Acetoacetate
CHCH33CHCH22OOCCCC
CCOCHOCH22CHCH33
HH HH
OO OO
HH33CC++ ––
ppKKaa ~ 11 ~ 11Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
Deprotonation of Ethyl Acetoacetate
ppKKaa ~ 16 ~ 16
CHCH33CHCH22OOCCCC
CCOCHOCH22CHCH33
HH HH
OO OO
HH33CC++
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC ++ CHCH33CHCH22OHOH
––
ppKKaa ~ 11 ~ 11Ethyl acetoacetate can be converted readily to its anion with bases such as sodium ethoxide.
KK ~ 10 ~ 1055
Alkylation of Ethyl Acetoacetate
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC
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).
RR XX
Alkylation of Ethyl Acetoacetate
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC
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).
RR XX
CCCC
CCOCHOCH22CHCH33
HH
OO OO
HH33CC
RR
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.
CCCC
CCOCHOCH22CHCH33
HH
OO OO
HH33CC
RR
CCCC
CCOHOH
HH
OO OO
HH33CC
RR1. HO1. HO––, H, H22OO2. H2. H++
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.
CCCC
CCOHOH
HH
OO OO
HH33CC
RR
CCCHCH22RR
COCO22
OO
HH33CC++
Example
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCHCCH22COCHCOCH22CHCH33
Example
(70%)(70%)
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CCHCCH22COCHCOCH22CHCH33
OO OO
CHCH33CCHCOCHCCHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
Example
(60%)(60%)
OO
CHCH33CCHCCH22CHCH22CHCH22CHCH22CHCH33
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
OO OO
CHCH33CCHCOCHCCHCOCH22CHCH33
CHCH22CHCH22CHCH22CHCH33
Example: Dialkylation OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
Example: Dialkylation
1. NaOCH1. NaOCH22CHCH33
2. 2. CHCH33CHCH22II
OO OO
CHCH33CCCCHHCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
(75%)(75%)
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
OO
CHCH33CCCOCHCCCOCH22CHCH33
CHCH22CHCH CHCH22
OO
CHCH33CHCH22
Example: Dialkylation CHCH33CCHCCH CHCH22CHCH CHCH22
OO
CHCH33CHCH22
Another Example OO OO
HH
COCHCOCH22CHCH33
-Keto esters other than ethyl acetoacetate may be used.
Another Example OO OO
HH
COCHCOCH22CHCH33
1. NaOCH1. NaOCH22CHCH33
2. 2. HH22CC CHCHCHCH22BrBr
OO OO
CHCH22CHCH
COCHCOCH22CHCH33
CHCH22(89%)(89%)
Another Example
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
Another Example OO
HH
OO OOCOCHCOCH22CHCH33
CHCH22CHCH CHCH22
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH CHCH22 (66%)(66%)
The Malonic Ester Synthesis
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.
CCCC
CCOCHOCH22CHCH33
HH HH
OO OO
CHCH33CHCH22OO
An Analogy
OO OO
CHCH33CCHCCH22COCHCOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
OO
CHCH33CCHCCH22RR
OO
HOCCHHOCCH22RR
The same procedure by which ethyl acetoacetate is used to prepare ketones converts diethyl malonate to carboxylic acids.
Example
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
HH22CC CHCHCHCH22CHCH22CHCH22BrBr2.2.
CHCH22CHCH22CHCH22CHCH22CHCH
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
(85%)(85%)
Example
(75%)(75%)
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
CHCH22CHCH22CHCH22CHCH CHCH22
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
HOCCHHOCCH22CHCH22CHCH22CHCH22CHCH CHCH22
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Dialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. 2. CHCH33BrBr
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33 (79-83%)(79-83%)
Dialkylation
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
2. 2. CHCH33(CH(CH22))88CHCH22BrBr
CHCH33CHCH33(CH(CH22))88CHCH22
CHCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
Dialkylation OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
CHCH33
OO
CHCH33(CH(CH22))88CHCH22CHCOHCHCOH
CHCH33CHCH33(CH(CH22))88CHCH22
1. NaOH, H1. NaOH, H22OO2. H2. H++
3. heat, -CO3. heat, -CO22
(61-74%)(61-74%)
Another Example
1. NaOCH1. NaOCH22CHCH33
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
2. Br2. BrCHCH22CHCH22CHCH22BrBr
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
Another Example
This product is not isolated, but cyclizes in the presence of sodium ethoxide.
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
Another Example
NaOCHNaOCH22CHCH33
CHCH22CHCH22CHCH22BrBr
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO OO
CHCH33CHCH22OCCCOCHOCCCOCH22CHCH33
HH22CC CHCH22
CCHH22
(60-65%)(60-65%)
Another Example
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%)
Barbiturates
Barbituric acid is made from diethyl malonate and urea
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
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 is made from diethyl malonate and urea
HH22CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
++ CC
HH22NN
OO
HH22NN
1. NaOCH1. NaOCH22CHCH33
2. H2. H++
OO
OONN
OO
NN
HH
HH
(72-78%)(72-78%)
Barbituric acid is made from diethyl malonate and urea
Substituted derivatives of barbituric acid are madefrom 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'
Substituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonate
OO
OONN
OONN
HH
HHRR
R'R'CC
OO
COCHCOCH22CHCH33
COCHCOCH22CHCH33
OO
RR
R'R'
(H(H22N)N)22CC OO
Examples
OO
OONN
OONN
HH
HHCHCH33CHCH22
CHCH33CHCH22
5,5-Diethylbarbituric acid5,5-Diethylbarbituric acid(barbital; Veronal)(barbital; Veronal)
Examples
OO
OONN
OONN
HH
HH
CHCH33CHCH22
5-Ethyl-5-(1-methylbutyl)barbituric acid5-Ethyl-5-(1-methylbutyl)barbituric acid(pentobarbital; Nembutal)(pentobarbital; Nembutal)
CHCH33CHCH22CHCH22CHCH
HH33CC
Examples
OO
OONN
OONN
HH
HH
5-Allyl-5-(1-methylbutyl)barbituric acid5-Allyl-5-(1-methylbutyl)barbituric acid(secobarbital; Seconal)(secobarbital; Seconal)
CHCH33CHCH22CHCH22CHCH
HH33CC
CHCHCHCH22HH22CC
Addition of Carbanions toAddition of Carbanions to-Unsaturated Carbonyl Compounds:-Unsaturated Carbonyl Compounds:
The Michael ReactionThe Michael Reaction
Stabilized carbanions, such as those derived from -diketones undergo conjugateaddition to ,-unsaturated ketones.
Michael AdditionMichael Addition
ExampleExample
(85%)(85%)
OO
HH22CC CHCCHCHCCH33
CHCH33
OO
OO
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
KOH, methanolKOH, methanol
++
The Stork Enamine Reaction
Enamines are used in place of enolates in Michael reactions
The Michael reaction is a useful method forforming carbon-carbon bonds.
It is also useful in that the product of the reaction can undergo an intramolecularaldol condensation to form a six-membered ring. One such application is called the Robinsonannulation.
Michael AdditionMichael Addition
ExampleExample
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
NaOHNaOHheatheat
OHOH
OO CHCH33
OO
not isolated;not isolated;dehydrates under dehydrates under reaction conditionsreaction conditions
ExampleExample
(85%)(85%)
OO
CHCH33
OO
OO
CHCH22CHCH22CCHCCH33
NaOHNaOHheatheat
OO
OO
CHCH33
OHOH
OO CHCH33
OO
Michael Additions of Stabilized Anions
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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.
CCCC
CCOCHOCH22CHCH33
HH
OO OO
••••––HH33CC
CCCC
CCOCHOCH22CHCH33
HH
OO OO
CHCH33CHCH22OO••••
––
Example
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33 ++ HH22CC CHCCHCHCCH33
OO
Example
KOH, ethanolKOH, ethanol
OO OO
CHCH33CHCH22OCCHOCCH22COCHCOCH22CHCH33
(85%)(85%)
++ HH22CC CHCCHCHCCH33
OO
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
Example
1. KOH, ethanol-water1. KOH, ethanol-water
CHCH22CHCH22CCHCCH33
OO OO
CHCH33CHCH22OCCHCOCHOCCHCOCH22CHCH33
OO
2. H2. H++
3. heat3. heat
CHCH33CCHCCH22CHCH22CHCH22COHCOH
OOOO
(42%)(42%)
Conjugate Addition of Organocopper Conjugate Addition of Organocopper Reagents to Reagents to
-Unsaturated Carbonyl Compounds-Unsaturated Carbonyl Compounds
The main use of organocopper reagents is toform carbon-carbon bonds by conjugate addition to ,-unsaturated ketones.
Addition of Organocopper Reagents toAddition of Organocopper Reagents to-Unsaturated Aldehydes and Ketones-Unsaturated Aldehydes and Ketones
ExampleExampleOO
CHCH33
(98%)(98%)
++ LiCu(LiCu(CHCH33))22
OO
CHCH33
CHCH33
1. diethyl ether1. diethyl ether2. H2. H22OO