Nano product preview march 2009 the applause “ this is a fantastic effort”

21-1
Dr. Wolf's CHM 201 & 202
21.7
21.7
The Acetoacetic Ester Synthesis
The Acetoacetic Ester Synthesis
21-2
Dr. Wolf's CHM 201 & 202
Acetoacetic Ester
Acetoacetic Ester
Acetoacetic Ester
Acetoacetic Ester
Acetoacetic ester
Acetoacetic ester
is another name for
is another name for
ethyl
ethyl


acetoacetate
acetoacetate
.
.
The "acetoacetic ester synthesis" uses
The "acetoacetic ester synthesis" uses
acetoacetic ester as a
acetoacetic ester as a
reactant
reactant
for the

for the
preparation of ketones.
preparation of ketones.
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3
3
H
H
H
H
O
O
O
O
H
H
3
3
C

C
21-3
Dr. Wolf's CHM 201 & 202
Deprotonation of Ethyl Acetoacetate
Deprotonation of Ethyl Acetoacetate
Deprotonation of Ethyl Acetoacetate
Deprotonation of Ethyl Acetoacetate
CH
CH
3
3
CH
CH
2
2
O
O
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3

3
H
H
H
H
O
O
O
O
H
H
3
3
C
C
+
+
–
–
p
p
K
K
a
a
~ 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.
21-4
Dr. Wolf's CHM 201 & 202
Deprotonation of Ethyl Acetoacetate
Deprotonation of Ethyl Acetoacetate
Deprotonation of Ethyl Acetoacetate
Deprotonation of Ethyl Acetoacetate
p
p
K
K
a
a
~ 16
~ 16
CH
CH
3
3
CH
CH
2
2
O

O
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3
3
H
H
H
H
O
O
O
O
H
H
3
3
C
C
+

+
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3
3
H
H
O
O
O
O
••
••
–
–
H
H
3
3
C

C
+
+
CH
CH
3
3
CH
CH
2
2
OH
OH
–
–
p
p
K
K
a
a
~ 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.
K
K
~ 10
~ 10
5
5
21-5
Dr. Wolf's CHM 201 & 202
Alkylation of Ethyl Acetoacetate
Alkylation of Ethyl Acetoacetate
Alkylation of Ethyl Acetoacetate
Alkylation of Ethyl Acetoacetate
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3
3
H

H
O
O
O
O
••
••
–
–
H
H
3
3
C
C
The anion of ethyl
The anion of ethyl
acetoacetate can be
acetoacetate can be
alkylated using an
alkylated using an
alkyl halide (S
alkyl halide (S
N
N
2:
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).
R
R
X
X

21-6
Dr. Wolf's CHM 201 & 202
Alkylation of Ethyl Acetoacetate
Alkylation of Ethyl Acetoacetate
Alkylation of Ethyl Acetoacetate
Alkylation of Ethyl Acetoacetate
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH

3
3
H
H
O
O
O
O
••
••
–
–
H
H
3
3
C
C
The anion of ethyl
The anion of ethyl
acetoacetate can be
acetoacetate can be
alkylated using an
alkylated using an
alkyl halide (S
alkyl halide (S
N
N
2:
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).
R
R
X
X
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3
3
H
H

O
O
O
O
H
H
3
3
C
C
R
R
21-7
Dr. Wolf's CHM 201 & 202
Conversion to Ketone
Conversion to Ketone
Conversion to Ketone
Conversion to Ketone
Saponification and
Saponification and
acidification convert
acidification convert
the alkylated
the alkylated
derivative to the
derivative to the
corresponding
corresponding
β
β

-keto
-keto
acid.
acid.
The
The
β
β
-keto acid then
-keto acid then
undergoes
undergoes
decarboxylation to
decarboxylation to
form a ketone.
form a ketone.
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3
3

H
H
O
O
O
O
H
H
3
3
C
C
R
R
C
C
C
C
C
C
OH
OH
H
H
O
O
O
O
H
H

3
3
C
C
R
R
1. HO
1. HO
–
–
, H
, H
2
2
O
O
2. H
2. H
+
+
21-8
Dr. Wolf's CHM 201 & 202
Conversion to Ketone
Conversion to Ketone
Conversion to Ketone
Conversion to Ketone
Saponification and
Saponification and
acidification convert
acidification convert

the alkylated
the alkylated
derivative to the
derivative to the
corresponding
corresponding
β
β
-keto
-keto
acid.
acid.
The
The
β
β
-keto acid then
-keto acid then
undergoes
undergoes
decarboxylation to
decarboxylation to
form a ketone.
form a ketone.
C
C
C
C
C
C

OH
OH
H
H
O
O
O
O
H
H
3
3
C
C
R
R
C
C
CH
CH
2
2
R
R
CO
CO
2
2
O
O

H
H
3
3
C
C
+
+
21-9
Dr. Wolf's CHM 201 & 202
Example
Example
Example
Example
1. NaOCH
1. NaOCH
2
2
CH
CH
3
3
2.
2.
CH
CH
3
3
CH
CH

2
2
CH
CH
2
2
CH
CH
2
2
Br
Br
O
O
O
O
CH
CH
3
3
C
C
C
C
H
H
2
2
COCH
COCH

2
2
CH
CH
3
3
21-10
Dr. Wolf's CHM 201 & 202
Example
Example
Example
Example
(70%)
(70%)
1. NaOCH
1. NaOCH
2
2
CH
CH
3
3
2.
2.
CH
CH
3
3
CH
CH

2
2
CH
CH
2
2
CH
CH
2
2
Br
Br
O
O
O
O
CH
CH
3
3
C
C
C
C
H
H
2
2
COCH
COCH

2
2
CH
CH
3
3
O
O
O
O
CH
CH
3
3
C
C
C
C
HCOCH
HCOCH
2
2
CH
CH
3
3
CH
CH
2
2

CH
CH
2
2
CH
CH
2
2
CH
CH
3
3
21-11
Dr. Wolf's CHM 201 & 202
Example
Example
Example
Example
(60%)
(60%)
O
O
CH
CH
3
3
C
C
C
C

H
H
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH
3
3
1. NaOH, H
1. NaOH, H
2
2
O
O
2. H
2. H
+
+

3. heat, -CO
3. heat, -CO
2
2
O
O
O
O
CH
CH
3
3
C
C
C
C
HCOCH
HCOCH
2
2
CH
CH
3
3
CH
CH
2
2
CH
CH

2
2
CH
CH
2
2
CH
CH
3
3
21-12
Dr. Wolf's CHM 201 & 202
Example:
Example:
Dialkylation
Dialkylation
Example:
Example:
Dialkylation
Dialkylation
O
O
O
O
CH
CH
3
3
CC
CC

H
H
COCH
COCH
2
2
CH
CH
3
3
CH
CH
2
2
CH
CH
CH
CH
2
2
21-13
Dr. Wolf's CHM 201 & 202
Example:
Example:
Dialkylation
Dialkylation
Example:
Example:
Dialkylation
Dialkylation

1. NaOCH
1. NaOCH
2
2
CH
CH
3
3
2.
2.
CH
CH
3
3
CH
CH
2
2
I
I
O
O
O
O
CH
CH
3
3
CC
CC

H
H
COCH
COCH
2
2
CH
CH
3
3
CH
CH
2
2
CH
CH
CH
CH
2
2
O
O
CH
CH
3
3
CCCOCH
CCCOCH
2
2

CH
CH
3
3
CH
CH
2
2
CH
CH
CH
CH
2
2
O
O
CH
CH
3
3
CH
CH
2
2
(75%)
(75%)
21-14
Dr. Wolf's CHM 201 & 202
1. NaOH, H
1. NaOH, H

2
2
O
O
2. H
2. H
+
+
3. heat, -CO
3. heat, -CO
2
2
O
O
CH
CH
3
3
CCCOCH
CCCOCH
2
2
CH
CH
3
3
CH
CH
2
2

CH
CH
CH
CH
2
2
O
O
CH
CH
3
3
CH
CH
2
2
Example:
Example:
Dialkylation
Dialkylation
Example:
Example:
Dialkylation
Dialkylation
CH
CH
3
3
CCH
CCH

CH
CH
2
2
CH
CH
CH
CH
2
2
O
O
CH
CH
3
3
CH
CH
2
2
21-15
Dr. Wolf's CHM 201 & 202
Another
Another
Example
Example
Another
Another
Example
Example

O
O

O
O
H
H
COCH
COCH
2
2
CH
CH
3
3
 β
 β
-Keto esters other than ethyl acetoacetate
-Keto esters other than ethyl acetoacetate
may be used.
may be used.
21-16
Dr. Wolf's CHM 201 & 202
Another
Another
Example
Example
Another
Another
Example

Example
O
O

O
O
H
H
COCH
COCH
2
2
CH
CH
3
3
1. NaOCH
1. NaOCH
2
2
CH
CH
3
3
2.
2.
H
H
2
2

C
C
CHCH
CHCH
2
2
Br
Br
O
O

O
O
CH
CH
2
2
CH
CH
COCH
COCH
2
2
CH
CH
3
3
CH
CH
2

2
(89%)
(89%)
21-17
Dr. Wolf's CHM 201 & 202
Another
Another
Example
Example
Another
Another
Example
Example
O
O

O
O
COCH
COCH
2
2
CH
CH
3
3
CH
CH
2
2

CH
CH
CH
CH
2
2
21-18
Dr. Wolf's CHM 201 & 202
Another
Another
Example
Example
Another
Another
Example
Example

O
O
H
H
O
O

O
O
COCH
COCH
2
2

CH
CH
3
3
CH
CH
2
2
CH
CH
CH
CH
2
2
1. NaOH, H
1. NaOH, H
2
2
O
O
2. H
2. H
+
+
3. heat, -CO
3. heat, -CO
2
2
CH
CH

2
2
CH
CH
CH
CH
2
2
(66%)
(66%)
21-19
Dr. Wolf's CHM 201 & 202
21.8
21.8
The Malonic Ester Synthesis
The Malonic Ester Synthesis
21-20
Dr. Wolf's CHM 201 & 202
Malonic Ester
Malonic Ester
Malonic Ester
Malonic Ester
Malonic ester
Malonic ester
is another name for
is another name for
diethyl
diethyl

malonate
malonate
.
.
The "malonic ester synthesis" uses diethyl
The "malonic ester synthesis" uses diethyl
malonate as a
malonate as a
reactant
reactant
for the preparation of
for the preparation of
carboxylic acids.
carboxylic acids.
C
C
C
C
C
C
OCH
OCH
2
2
CH
CH
3
3
H
H

H
H
O
O
O
O
CH
CH
3
3
CH
CH
2
2
O
O
21-21
Dr. Wolf's CHM 201 & 202
An Analogy
An Analogy
An Analogy
An Analogy
O
O
O
O
CH
CH
3
3

C
C
C
C
H
H
2
2
COCH
COCH
2
2
CH
CH
3
3
O
O
O
O
CH
CH
3
3
CH
CH
2
2
OC
OC

C
C
H
H
2
2
COCH
COCH
2
2
CH
CH
3
3
O
O
CH
CH
3
3
C
C
C
C
H
H
2
2
R
R

O
O
HOC
HOC
C
C
H
H
2
2
R
R
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.
21-22
Dr. Wolf's CHM 201 & 202
Example
Example
Example
Example
1. NaOCH
1. NaOCH
2
2
CH
CH

3
3
O
O
O
O
CH
CH
3
3
CH
CH
2
2
OCCH
OCCH
2
2
COCH
COCH
2
2
CH
CH
3
3
H
H
2
2

C
C
CHCH
CHCH
2
2
CH
CH
2
2
CH
CH
2
2
Br
Br
2.
2.
CH
CH
2
2
CH
CH
2
2
CH
CH
2
2

CH
CH
2
2
CH
CH
O
O
O
O
CH
CH
3
3
CH
CH
2
2
OCCHCOCH
OCCHCOCH
2
2
CH
CH
3
3
(85%)
(85%)
21-23
Dr. Wolf's CHM 201 & 202

Example
Example
Example
Example
(75%)
(75%)
1. NaOH, H
1. NaOH, H
2
2
O
O
2. H
2. H
+
+
3. heat, -CO
3. heat, -CO
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH

2
2
CH
CH
CH
CH
2
2
O
O
O
O
CH
CH
3
3
CH
CH
2
2
OCCHCOCH
OCCHCOCH
2
2
CH
CH
3
3
O
O

HOCCH
HOCCH
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH
2
2
CH
CH
CH
CH
2
2
21-24
Dr. Wolf's CHM 201 & 202
Dialkylation
Dialkylation
Dialkylation
Dialkylation
1. NaOCH
1. NaOCH

2
2
CH
CH
3
3
O
O
O
O
CH
CH
3
3
CH
CH
2
2
OCCH
OCCH
2
2
COCH
COCH
2
2
CH
CH
3
3

2.
2.
CH
CH
3
3
Br
Br
CH
CH
3
3
O
O
O
O
CH
CH
3
3
CH
CH
2
2
OCCHCOCH
OCCHCOCH
2
2
CH
CH

3
3
(79-83%)
(79-83%)
21-25
Dr. Wolf's CHM 201 & 202
Dialkylation
Dialkylation
Dialkylation
Dialkylation
1. NaOCH
1. NaOCH
2
2
CH
CH
3
3
O
O
O
O
CH
CH
3
3
CH
CH
2
2

OCCCOCH
OCCCOCH
2
2
CH
CH
3
3
2.
2.
CH
CH
3
3
(CH
(CH
2
2
)
)
8
8
CH
CH
2
2
Br
Br
CH
CH

3
3
CH
CH
3
3
(CH
(CH
2
2
)
)
8
8
CH
CH
2
2
CH
CH
3
3
O
O
O
O
CH
CH
3
3

CH
CH
2
2
OCCHCOCH
OCCHCOCH
2
2
CH
CH
3
3