Transcript Document

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)
Condensation
C
H
C
O
C
O
C
C
OH
C
A chemical definition: Addition with subsequent loss of H2O
(eg. Dehydration of b-hydroxy carbonyl compounds)
Acylation of Ketones with Esters
Acylation of Ketones with Esters
Esters that cannot form an enolate can be
used to acylate ketone enolates.
Example
O
O
CH3CH2OCOCH2CH3
+
1. NaH
2. H3O+
O
O
COCH2CH3
(60%)
Example
O
O
COCH2CH3
+
CH3C
1. NaOCH2CH3
2. H3O+
O
O
CCH2C
(62-71%)
Example
O
O
CH3CH2CCH2CH2COCH2CH3
1. NaOCH3
2. H3O+
O
O
CH3
(70-71%)
Ketone Synthesis via b-Keto Esters
Ketone Synthesis
O
O
RCH2CCHCOH
O
RCH2CCH2R + CO2
R
b-Keto acids decarboxylate readily to give
ketones.
Ketone Synthesis
O
O
RCH2CCHCOR'
O
H2O
O
RCH2CCHCOH + R'OH
R
R
b-Keto acids decarboxylate readily to give
ketones .
b-Keto acids are available by hydrolysis of bketo esters.
Ketone Synthesis
O
O
1. NaOR'
2RCH2COR'
2. H3O+
O
RCH2CCHCOR' + R'OH
R
b-Keto acids decarboxylate readily to give
ketones .
b-Keto acids are available by hydrolysis of bketo esters.
b-Keto esters can be prepared by the Claisen
condensation.
Example
O
2 CH3CH2CH2CH2COCH2CH3
1. NaOCH2CH3
2. H3O+
O
O
CH3CH2CH2CH2CCHCOCH2CH3
CH2CH2CH3
(80%)
Example
O
O
CH3CH2CH2CH2CCHCOH
CH2CH2CH3
1. KOH, H2O, 70-80°C
2. H3O+
O
O
CH3CH2CH2CH2CCHCOCH2CH3
CH2CH2CH3
Example
O
O
CH3CH2CH2CH2CCHCOH
CH2CH2CH3
70-80°C
O
CH3CH2CH2CH2CCH2CH2CH2CH3
(81%)
QuickTime™ and a
Graphics decompressor
are needed to see this picture.
Decarboxylation of
3-Oxocarboxylic Acids
The Acetoacetic Ester Synthesis
Acetoacetic Ester
H3C
O
O
C
C
H
C
OCH2CH3
H
Acetoacetic ester is another name for ethyl
acetoacetate.
The "acetoacetic ester synthesis" uses
acetoacetic ester as a reactant for the
preparation of ketones.
Deprotonation of Ethyl Acetoacetate
O
H3C
C
O
C
C
H
H
pKa ~ 11
+
OCH2CH3
CH3CH2O
–
Ethyl acetoacetate
can be converted
readily to its anion
with bases such as
sodium ethoxide.
Deprotonation of Ethyl Acetoacetate
O
H3C
C
O
+
C
C
OCH2CH3
H
H
pKa ~ 11
K ~ 105
O
H3C
C
O
••
–C
H
C
CH3CH2O
–
Ethyl acetoacetate
can be converted
readily to its anion
with bases such as
sodium ethoxide.
OCH2CH3 + CH3CH2OH
pKa ~ 16
Alkylation of Ethyl Acetoacetate
O
H3C
C
O
••
–C
C
OCH2CH3
H
R
X
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).
Alkylation of Ethyl Acetoacetate
O
H3C
O
••
C
–C
C
OCH2CH3
H
R
H3C
O
O
C
C
C
H
R
X
OCH2CH3
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).
Conversion to Ketone
O
H3C
C
O
C
H
H3C
C
R
1. HO–, H2O
2. H+
O
O
C
C
C
H
OH
R
OCH2CH3
Saponification and
acidification convert
the alkylated
derivative to the
corresponding b-keto
acid.
The b-keto acid then
undergoes
decarboxylation to
form a ketone.
Conversion to Ketone
O
H3C
C
O
C
H
C
OH
R
O
H3C
C
+
CH2R
CO2
Saponification and
acidification convert
the alkylated
derivative to the
corresponding b-keto
acid.
The b-keto acid then
undergoes
decarboxylation to
form a ketone.
Example
O
O
CH3CCH2COCH2CH3
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
Example
O
O
CH3CCH2COCH2CH3
1. NaOCH2CH3
2. CH3CH2CH2CH2Br
O
O
CH3CCHCOCH2CH3
CH2CH2CH2CH3
(70%)
Example
O
CH3CCH2CH2CH2CH2CH3
1. NaOH, H2O
2. H+
3. heat, -CO2
O
O
CH3CCHCOCH2CH3
CH2CH2CH2CH3
(60%)
Example:
Dialkylation
O
O
CH3CCHCOCH2CH3
CH2CH
CH2
Example:
Dialkylation
O
O
CH3CCHCOCH2CH3
CH2CH
CH2
1. NaOCH2CH3
2. CH3CH2I
O O
CH3CCCOCH2CH3
CH3CH2
CH2CH
(75%)
CH2
Example:
Dialkylation
O
CH3CCH
CH2CH
CH2
CH3CH2
1. NaOH, H2O
2. H+
3. heat, -CO2
O O
CH3CCCOCH2CH3
CH3CH2
CH2CH
CH2
Another
Example
O
O
COCH2CH3
H
b-Keto esters other than ethyl acetoacetate
may be used.
Another
Example
O
O
COCH2CH3
H
1. NaOCH2CH3
2. H2C CHCH2Br
O
O
COCH2CH3
CH2CH
CH2
(89%)
Another
Example
O
O
COCH2CH3
CH2CH
CH2
Another
Example
O
H
CH2CH
O
CH2 (66%)
1. NaOH, H2O
2. H+
3. heat, -CO2
O
COCH2CH3
CH2CH
CH2
The Malonic Ester Synthesis
Malonic Ester
O
O
C
C
CH3CH2O
H
C
OCH2CH3
H
Malonic ester is another name for diethyl
malonate.
The "malonic ester synthesis" uses diethyl
malonate as a reactant for the preparation of
carboxylic acids.
An Analogy
O
O
O
O
CH3CCH2COCH2CH3
CH3CH2OCCH2COCH2CH3
O
O
CH3CCH2R
HOCCH2R
The same procedure by which ethyl
acetoacetate is used to prepare ketones
converts diethyl malonate to carboxylic acids.
Example
O
O
CH3CH2OCCH2COCH2CH3
1. NaOCH2CH3
2. H2C
O
CHCH2CH2CH2Br
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2CH
(85%)
CH2
Example
O
HOCCH2CH2CH2CH2CH
CH2 (75%)
1. NaOH, H2O
2. H+
3. heat, -CO2
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2CH
CH2
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Dialkylation
O
O
CH3CH2OCCH2COCH2CH3
1. NaOCH2CH3
2. CH3Br
O
O
CH3CH2OCCHCOCH2CH3
CH3
(79-83%)
Dialkylation
O O
CH3CH2OCCCOCH2CH3
CH3
CH3(CH2)8CH2
1. NaOCH2CH3
2. CH3(CH2)8CH2Br
O
O
CH3CH2OCCHCOCH2CH3
CH3
Dialkylation
O O
CH3CH2OCCCOCH2CH3
CH3(CH2)8CH2
CH3
1. NaOH, H2O
2. H+
3. heat, -CO2
O
CH3(CH2)8CH2CHCOH
CH3
(61-74%)
Another
Example
O
O
CH3CH2OCCH2COCH2CH3
1. NaOCH2CH3
2. BrCH2CH2CH2Br
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2Br
Another
Example
This product is not isolated, but cyclizes in the
presence of sodium ethoxide.
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2Br
Another
Example
O O
CH3CH2OCCCOCH2CH3
H2C
CH2
(60-65%)
C
H2
NaOCH2CH3
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CH2Br
Another
Example
O O
CH3CH2OCCCOCH2CH3
H2C
CH2
C
H2
H
1. NaOH, H2O
2. H+
3. heat, -CO2
CO2H
C
H2C
CH2
C
H2
(80%)
Barbiturates
Barbituric acid
is made from
diethyl
malonate and
urea
O
COCH2CH3
H2N
+
H2C
COCH2CH3
O
C
H2 N
O
Barbituric acid
is made from
diethyl
malonate and
urea
O
COCH2CH3
COCH2CH3
C
C
O
N
H
C
O
H2 N
O
N
H2C
H2N
+
H2C
H
C
O
O
(72-78%)
1. NaOCH2CH3
2. H+
Barbituric acid
is made from
diethyl
malonate and
urea
O
COCH2CH3
+
H2C
COCH2CH3
O
N
H
O
H2 N
1. NaOCH2CH3
2. H+
N
O
C
O
H
O
H2N
(72-78%)
Substituted derivatives of barbituric acid are made
from alkylated derivatives of diethyl malonate
O
COCH2CH3
H2C
COCH2CH3
O
O
1. RX,
NaOCH2CH3 R
2. R'X,
R'
NaOCH2CH3
COCH2CH3
C
COCH2CH3
O
Substituted derivatives of barbituric acid are made
from alkylated derivatives of diethyl malonate
O
O
R
H
N
(H2N)2C
O
R
C
O
R'
O
N
H
COCH2CH3
R'
COCH2CH3
O
Examples
O
CH3CH2
H
N
O
CH3CH2
O
N
H
5,5-Diethylbarbituric acid
(barbital; Veronal)
Examples
H3C
O
CH3CH2CH2CH
H
N
O
CH3CH2
O
N
H
5-Ethyl-5-(1-methylbutyl)barbituric acid
(pentobarbital; Nembutal)
Examples
H3C
O
CH3CH2CH2CH
H2C
H
N
O
CHCH2
O
N
H
5-Allyl-5-(1-methylbutyl)barbituric acid
(secobarbital; Seconal)
Addition of Carbanions to
a,b-Unsaturated Carbonyl Compounds:
The Michael Reaction
Michael Addition
Stabilized carbanions, such as those
derived from b-diketones undergo conjugate
addition to a,b-unsaturated ketones.
Example
O
O
CH3
+
H2C
CHCCH3
O
KOH, methanol
O
CH3
O
CH2CH2CCH3
O
(85%)
The Stork Enamine Reaction
Enamines are used in place of enolates in Michael
reactions
Michael Addition
The Michael reaction is a useful method for
forming carbon-carbon bonds.
It is also useful in that the product of the
reaction can undergo an intramolecular
aldol condensation to form a six-membered
ring. One such application is called the Robinson
annulation.
Example
O
CH3
O
NaOH
heat
O CH
3
CH2CH2CCH3
O
O
OH
not isolated;
dehydrates under
reaction conditions
Example
O
CH3
O
NaOH
heat
O CH
3
CH2CH2CCH3
O
O
OH
O CH
3
(85%)
O
Michael Additions of Stabilized Anions
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Stabilized Anions
O
H3C
C
O
••
–C
C
OCH2CH3
H
O
C
CH3CH2O
O
••
–C
H
C
OCH2CH3
The anions
derived by
deprotonation of
b-keto esters
and diethyl
malonate are
weak bases.
Weak bases
react with a,bunsaturated
carbonyl
compounds by
conjugate
addition.
Example
O
O
O
CH3CH2OCCH2COCH2CH3 +
H2C
CHCCH3
Example
O
O
O
CH3CH2OCCH2COCH2CH3 +
H2C
CHCCH3
KOH, ethanol
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CCH3
O
(85%)
Example
O
O
CH3CCH2CH2CH2COH
(42%)
1. KOH, ethanol-water
2. H+
3. heat
O
O
CH3CH2OCCHCOCH2CH3
CH2CH2CCH3
O
Conjugate Addition of Organocopper Reagents to
a,b-Unsaturated Carbonyl Compounds
Addition of Organocopper Reagents to
a,b-Unsaturated Aldehydes and Ketones
The main use of organocopper reagents is to
form carbon-carbon bonds by conjugate
addition to a,b-unsaturated ketones.
O
Example
+ LiCu(CH3)2
CH3
1. diethyl ether
2. H2O
O
CH3
CH3
(98%)