21 6 the acetoacetic ester synthesis
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21.6 The Acetoacetic Ester Synthesis PowerPoint PPT Presentation


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21.6 The Acetoacetic Ester Synthesis. O. O. C. C. H 3 C. C. OCH 2 CH 3. H. H. 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. O. O. C. C. H 3 C.

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21.6 The Acetoacetic Ester Synthesis

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21 6 the acetoacetic ester synthesis

21.6The Acetoacetic Ester Synthesis


Acetoacetic ester

O

O

C

C

H3C

C

OCH2CH3

H

H

Acetoacetic Ester

  • Acetoacetic ester is another name for ethylacetoacetate.

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


Deprotonation of ethyl acetoacetate

O

O

C

C

H3C

C

OCH2CH3

H

H

Deprotonation of Ethyl Acetoacetate

+

CH3CH2O

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

pKa ~ 11


Deprotonation of ethyl acetoacetate1

O

O

C

C

H3C

C

OCH2CH3

H

H

O

O

C

C

••

H3C

C

OCH2CH3

H

Deprotonation of Ethyl Acetoacetate

+

CH3CH2O

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

pKa ~ 11

K ~ 105

CH3CH2OH

+

pKa ~ 16


Alkylation of ethyl acetoacetate

O

O

C

C

••

H3C

C

OCH2CH3

H

R

X

Alkylation of Ethyl Acetoacetate

  • 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 acetoacetate1

O

O

C

C

••

H3C

C

OCH2CH3

H

R

X

O

O

C

C

H3C

C

OCH2CH3

H

R

Alkylation of Ethyl Acetoacetate

  • 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

O

C

C

H3C

C

OH

H

R

O

O

C

C

H3C

C

OCH2CH3

H

R

Conversion to Ketone

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

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

1. HO–, H2O

2. H+


Conversion to ketone1

O

O

C

C

H3C

C

OH

H

R

O

Conversion to Ketone

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

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

+

C

CO2

H3C

CH2R


Example

O

O

CH3CCH2COCH2CH3

Example

1. NaOCH2CH3

2. CH3CH2CH2CH2Br


Example1

O

O

CH3CCH2COCH2CH3

O

O

CH3CCHCOCH2CH3

CH2CH2CH2CH3

Example

1. NaOCH2CH3

2. CH3CH2CH2CH2Br

(70%)


Example2

O

CH3CCH2CH2CH2CH2CH3

1. NaOH, H2O

2. H+

3. heat, -CO2

O

O

CH3CCHCOCH2CH3

CH2CH2CH2CH3

Example

(60%)


Example dialkylation

O

O

CH3CCHCOCH2CH3

CH2

CH2CH

Example: Dialkylation


Example dialkylation1

O

O

CH3CCHCOCH2CH3

CH2

CH2CH

O

O

CH3CCCOCH2CH3

CH2

CH2CH

CH3CH2

Example: Dialkylation

1. NaOCH2CH3

2. CH3CH2I

(75%)


Example dialkylation2

O

CH3CCH

CH2

CH2CH

CH3CH2

1. NaOH, H2O

2. H+

3. heat, -CO2

O

O

CH3CCCOCH2CH3

CH2

CH2CH

CH3CH2

Example: Dialkylation


Another example

O

O

COCH2CH3

H

Another Example

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


Another example1

O

O

COCH2CH3

H

CHCH2Br

2. H2C

O

O

COCH2CH3

CH2

CH2CH

Another Example

1. NaOCH2CH3

(89%)


Another example2

O

CH2

CH2CH

Another Example

O

COCH2CH3


Another example3

CH2

CH2CH

1. NaOH, H2O

2. H+

3. heat, -CO2

O

CH2

CH2CH

Another Example

O

H

(66%)

O

COCH2CH3


21 7 the malonic ester synthesis

21.7The Malonic Ester Synthesis


Malonic ester

O

O

C

C

C

OCH2CH3

CH3CH2O

H

H

Malonic Ester

  • Malonic ester is another name for diethylmalonate.

  • 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

An Analogy

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


Example3

O

O

CH3CH2OCCH2COCH2CH3

H2C

CHCH2CH2CH2Br

O

O

CH3CH2OCCHCOCH2CH3

CH2

CH2CH2CH2CH

Example

1. NaOCH2CH3

2.

(85%)


Example4

O

HOCCH2CH2CH2CH2CH

CH2

1. NaOH, H2O

2. H+

3. heat, -CO2

O

O

CH3CH2OCCHCOCH2CH3

CH2

CH2CH2CH2CH

Example

(75%)


Dialkylation

O

O

CH3CH2OCCH2COCH2CH3

O

O

CH3CH2OCCHCOCH2CH3

CH3

Dialkylation

1. NaOCH2CH3

2. CH3Br

(79-83%)


Dialkylation1

O

O

O

O

CH3CH2OCCHCOCH2CH3

CH3

Dialkylation

CH3CH2OCCCOCH2CH3

CH3(CH2)8CH2

CH3

1. NaOCH2CH3

2. CH3(CH2)8CH2Br


Dialkylation2

O

O

O

Dialkylation

CH3CH2OCCCOCH2CH3

CH3(CH2)8CH2

CH3

1. NaOH, H2O

2. H+

3. heat, -CO2

(61-74%)

CH3(CH2)8CH2CHCOH

CH3


Another example4

O

O

CH3CH2OCCH2COCH2CH3

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CH2Br

Another Example

1. NaOCH2CH3

2. BrCH2CH2CH2Br


Another example5

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CH2Br

Another Example

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


Another example6

O

O

CH3CH2OCCCOCH2CH3

H2C

CH2

CH2

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CH2Br

Another Example

(60-65%)

NaOCH2CH3


Another example7

O

O

CH3CH2OCCCOCH2CH3

H2C

CH2

CH2

H

CO2H

C

H2C

CH2

CH2

Another Example

1. NaOH, H2O

2. H+

3. heat, -CO2

(80%)


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