Chapter 20 enols and enolates
This presentation is the property of its rightful owner.
Sponsored Links
1 / 190

Chapter 20 Enols and Enolates PowerPoint PPT Presentation


  • 77 Views
  • Uploaded on
  • Presentation posted in: General

Chapter 20 Enols and Enolates. Aldehyde , Ketone , and Ester Enolates. O. CH 3 CH 2 CH 2 CH. Terminology. The reference atom is the carbonyl carbon. Other carbons are designated  ,  ,  , etc. on the basis of their position with respect to the carbonyl carbon.

Download Presentation

Chapter 20 Enols and Enolates

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Chapter 20 enols and enolates

Chapter 20Enols and Enolates


Aldehyde ketone and ester enolates

Aldehyde, Ketone, and Ester Enolates


Terminology

O

CH3CH2CH2CH

Terminology

  • The reference atom is the carbonyl carbon.

  • Other carbons are designated , , , etc. on the basis of their position with respect to the carbonyl carbon.

  • Hydrogens take the same Greek letter as the carbon to which they are attached.


Acidity of hydrogen

••

••

O

O

••

••

R2C

R2C

CR'

CR'

••

H

enolate ion

••

O

pKa = 16-20

••

••

R2C

CR'

Acidity of -Hydrogen

+ H+


Acidity of hydrogen1

O

O

(CH3)2CHCH

CCH3

pKa = 15.5

pKa = 18.3

Acidity of -Hydrogen


Diketones are much more acidic

O

O

C

C

C

H3C

CH3

H

H

O

O

C

C

••

+

H+

C

H3C

CH3

H

-Diketones are much more acidic

pKa = 9


Diketones are much more acidic1

••

••

O

O

••

••

••

C

C

C

H3C

CH3

H

••

••

O

O

••

••

C

C

••

C

H3C

CH3

H

-Diketones are much more acidic

  • enolate of -diketone is stabilized; negative charge is shared by both oxygens


Diketones are much more acidic2

••

••

••

••

O

O

O

O

••

••

••

••

••

••

C

C

C

C

C

C

H3C

H3C

CH3

CH3

H

H

••

••

O

O

••

••

C

C

••

C

H3C

CH3

H

-Diketones are much more acidic


Esters

Esters

  • Hydrogens a to an ester carbonyl group are less acidic, pKa 24, than a of aldehydes and ketones, pKa 16-20.

  • The decreased acidity is due the decreased electron withdrawing ability of an ester carbonyl.

  • Electron delocalization decreases the positive character of the ester carbonyl group.


Esters1

O

O

C

C

R

C

OR'

H

H

Esters

  • A proton on the carbon flanked by the two carbonyl groups is relatively acidic, easily and quantitatively removed by alkoxide ions.


Chapter 20 enols and enolates

O

O

C

C

R

C

OR'

H

H

CH3CH2O

O

O

C

C

••

R

C

OR'

H

pKa ~ 11


Chapter 20 enols and enolates

••

••

••

••

O

O

O

O

••

••

••

••

••

C

C

C

C

••

R

C

OR'

R

C

OR'

H

H

  • The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups.


Chapter 20 enols and enolates

••

••

O

O

O

O

••

••

••

••

••

C

C

C

C

••

R

C

OR'

R

C

OR'

H

H

••

••

  • The resulting carbanion is stabilized by enolate resonance involving both carbonyl groups.


The aldol condensation

The Aldol Condensation


Some thoughts

O

O

••

••

RCH2CH

RCHCH

OH

HOH

••

••

••

Some thoughts...

+

+

  • A basic solution contains comparable amounts of the aldehyde and its enolate.

  • Aldehydes undergo nucleophilic addition.

  • Enolate ions are nucleophiles.

  • What about nucleophilic addition of enolate to aldehyde?

••

pKa = 16-20

pKa = 16


Chapter 20 enols and enolates

••

O

••

••

••

O

O

••

••

RCHCH

RCHCH

RCHCH

RCH2CH

RCH2CH

RCH2CH

O

O

••

H

O

••

••

••

••

••

••

O

O

NaOH

RCH2CH

CHCH

2RCH2CH

R

OH

••


Aldol addition

O

RCH2CH

CHCH

R

OH

Aldol Addition

  • product is called an "aldol" because it is both an aldehyde and an alcohol


Aldol addition of acetaldehyde

O

O

NaOH, H2O

2CH3CH

CH3CH

CH2CH

5°C

OH

Aldol Addition of Acetaldehyde

Acetaldol(50%)


Aldol addition of butanal

O

2CH3CH2CH2CH

O

CHCH

CH3CH2CH2CH

CH2CH3

OH

(75%)

Aldol Addition of Butanal

KOH, H2O

6°C


Aldol condensation

O

O

RCH2CH

CHCH

2RCH2CH

R

OH

Aldol Condensation

NaOH


Aldol condensation1

O

O

RCH2CH

CHCH

2RCH2CH

R

OH

heat

NaOHheat

O

RCH2CH

CCH

R

Aldol Condensation

NaOH


Aldol condensation of butanal

O

2CH3CH2CH2CH

O

CCH

CH3CH2CH2CH

CH2CH3

(86%)

Aldol Condensation of Butanal

NaOH, H2O

80-100°C


Dehydration of aldol addition product

C

C

O

O

H

C

C

OH

C

C

Dehydration of Aldol Addition Product

  • dehydration of -hydroxy aldehyde can becatalyzed by either acids or bases


Dehydration of aldol addition product1

C

C

O

O

H

C

C

••

OH

OH

C

C

Dehydration of Aldol Addition Product

  • in base, the enolate is formed

NaOH


Dehydration of aldol addition product2

C

C

O

O

H

C

C

••

OH

OH

C

C

Dehydration of Aldol Addition Product

  • the enolate loses hydroxide to form the ,-unsaturated aldehyde

NaOH


Aldol reactions of ketones

O

O

OH

2%

2CH3CCH3

CH3CCH2CCH3

98%

CH3

Aldol reactions of ketones

  • the equilibrium constant for aldol addition reactions of ketones is usually unfavorable


Intramolecular aldol condensation

O

O

O

O

(96%)

via:

OH

Intramolecular Aldol Condensation

Na2CO3, H2O

heat


Intramolecular aldol condensation1

O

O

O

(96%)

Intramolecular Aldol Condensation

  • even ketones give good yields of aldol condensation products when the reaction is intramolecular

Na2CO3, H2O

heat


Mixed aldol condensations

Mixed Aldol Condensations


What is the product

O

O

CH3CH2CH

CH3CH

What is the product?

  • There are 4 possibilities because the reaction mixture contains the two aldehydes plus the enolate of each aldehyde.

NaOH

+


What is the product1

O

O

CH3CH2CH

CH3CH

O

CH3CH

CH2CH

O

O

OH

CH2CH

••

What is the product?

+

CH3CHCH

••


What is the product2

O

O

CH3CH2CH

CH3CH

O

CH3CH2CH

CHCH

O

O

CH3

OH

CH2CH

••

What is the product?

+

CH3CHCH

••


What is the product3

O

O

CH3CH2CH

CH3CH

O

CH3CH

CHCH

O

O

CH3

OH

CH2CH

••

What is the product?

+

CH3CHCH

••


What is the product4

O

O

CH3CH2CH

CH3CH

O

CH3CH2CH

CH2CH

O

O

OH

CH2CH

••

What is the product?

+

CH3CHCH

••


In order to effectively carry out a mixed aldol condensation

In order to effectively carry outa mixed aldol condensation:

  • need to minimize reaction possibilities

  • usually by choosing one component that cannot form an enolate


Formaldehyde

O

HCH

Formaldehyde

  • formaldehyde cannot form an enolate

  • formaldehyde is extremely reactive toward nucleophilic addition


Formaldehyde1

O

O

O

HCH

(CH3)2CHCH2CH

(CH3)2CHCHCH

CH2OH

Formaldehyde

K2CO3

+

water-ether

(52%)


Aromatic aldehydes

O

CH3O

CH

Aromatic Aldehydes

  • aromatic aldehydes cannot form an enolate


Aromatic aldehydes1

O

O

CH3CCH3

CH3O

CH

O

CHCCH3

CH3O

CH

Aromatic Aldehydes

+

NaOH, H2O

30°C

(83%)


Deprotonation of aldehydes ketones and esters

Deprotonation of Aldehydes, Ketones, and Esters

  • Simple aldehydes, ketones, and esters (such as ethyl acetate) are not completely deprotonated, the enolate reacts with the original carbonyl, and Aldol or Claisen condensation occurs.

  • Are there bases strong enough to completely deprotonate simple carbonyls, giving enolates quantitatively?


Lithium diisopropylamide

CH3

CH3

+

••

Li

C

N

C

H

H

••

CH3

CH3

Lithium diisopropylamide

  • Lithium dialkylamides are strong bases (just as NaNH2 is a very strong base).

  • Lithium diisopropylamide is a strong base, but because it is sterically hindered, does not add to carbonyl groups.


Lithium diisopropylamide lda

O

CH3CH2CH2COCH3

O

+

Li

CH3CH2CHCOCH3

Lithium diisopropylamide (LDA)

  • Lithium diisopropylamide converts simple esters to the corresponding enolate.

+

LiN[CH(CH3)2]2

pKa ~ 22

+

+

HN[CH(CH3)2]2

••

pKa ~ 36


Lithium diisopropylamide lda1

O

CH3CH2CHCOCH3

Lithium diisopropylamide (LDA)

  • Enolates generated from esters and LDA can be alkylated.

O

CH3CH2CHCOCH3

CH2CH3

CH3CH2I

(92%)

••


Aldol addition of ester enolates

O

CH3COCH2CH3

2. (CH3)2C

O

O

HO

C

CH2COCH2CH3

H3C

CH3

Aldol addition of ester enolates

  • Ester enolates undergo aldol addition to aldehydes and ketones.

1. LiNR2, THF

3. H3O+

(90%)


Ketone enolates

O

CH3CH2CC(CH3)3

O

2. CH3CH2CH

O

CH3CHCC(CH3)3

HOCHCH2CH3

Ketone Enolates

  • Lithium diisopropylamide converts ketones quantitatively to their enolates.

1. LDA, THF

3. H3O+

(81%)


The claisen condensation gives keto esters

The Claisen Condensation(gives -keto esters)


The claisen condensation

O

O

O

2RCH2COR'

RCH2CCHCOR'

R

The Claisen Condensation

1. NaOR'

  • b-Keto esters are made by the reaction shown, which is called the Claisen condensation.

  • Ethyl esters are typically used, with sodium ethoxide as the base.

+

R'OH

2. H3O+


Example

O

O

O

2CH3COCH2CH3

CH3CCH2COCH2CH3

Example

1. NaOCH2CH3

  • Product from ethyl acetate is called ethylacetoacetateor acetoaceticester.

2. H3O+

(75%)


Mechanism

••

O

••

••

CH3CH2

CH2

O

H

COCH2CH3

••

••

Mechanism

Step 1:


Mechanism1

••

O

••

••

CH3CH2

CH2

O

H

COCH2CH3

••

••

O

••

CH3CH2

O

H

••

Mechanism

Step 1:

••

••

CH2

COCH2CH3

••


Mechanism2

••

O

••

••

CH2

COCH2CH3

••

O

••

CH2

COCH2CH3

••

Mechanism

Step 1:

  • Anion produced is stabilized by electron delocalization; it is the enolate of an ester.


Mechanism3

••

O

O

••

CH2

COCH2CH3

••

Mechanism

Step 2:

••

••

CH3COCH2CH3


Mechanism4

••

••

O

O

••

••

••

CH3C

CH2

COCH2CH3

••

O

O

••

CH2

COCH2CH3

••

Mechanism

Step 2:

OCH2CH3

••

••

••

••

CH3COCH2CH3


Mechanism5

••

••

O

O

••

••

••

CH3C

CH2

COCH2CH3

OCH2CH3

••

••

Mechanism

Step 2:


Mechanism6

••

••

O

O

••

••

••

CH3C

CH2

COCH2CH3

OCH2CH3

••

••

••

••

O

O

••

••

••

CH3C

CH2

OCH2CH3

COCH2CH3

••

••

Mechanism

Step 3:

+


Mechanism7

••

••

O

O

••

••

••

CH3C

CH2

OCH2CH3

COCH2CH3

••

••

Mechanism

Step 3:

  • The product at this point is ethyl acetoacetate.

  • However, were nothing else to happen, the yield of ethyl acetoacetate would be small because the equilibrium constant for its formation is small.

  • Something else does happen. Ethoxide abstracts a proton from the CH2 group to give a stabilized anion. The equilibrium constant for this reaction is favorable.

+


Mechanism8

••

••

O

O

••

••

••

OCH2CH3

CH3C

CH

H

COCH2CH3

••

••

••

••

O

O

••

••

••

CH3C

CH2

OCH2CH3

COCH2CH3

••

••

Mechanism

Step 4:

+

+


Mechanism9

••

O

O

••

CH3C

CH

Mechanism

Step 5:

••

  • In a separate operation, the reaction mixture is acidified. This converts the anion to the isolated product, ethyl acetoacetate.

COCH2CH3

••


Mechanism10

••

H

O

O

••

+

O

CH3C

CH

H

••

H

••

••

O

H

O

••

••

CH3C

CH

O

COCH2CH3

••

••

H

H

Mechanism

Step 5:

••

COCH2CH3

••

+


Another example

O

1. NaOCH2CH3

2. H3O+

O

O

CH3CH2CCHCOCH2CH3

CH3

Another example

2 CH3CH2COCH2CH3

  • Reaction involves bond formation between the a-carbon atom of one ethyl propanoate molecule and the carbonyl carbon of the other.

(81%)


Intramolecular claisen condensation the dieckmann reaction

Intramolecular Claisen Condensation:The Dieckmann Reaction


Example1

O

O

1. NaOCH2CH3

2. H3O+

O

O

COCH2CH3

Example

CH3CH2OCCH2CH2CH2CH2COCH2CH3

(74-81%)


Chapter 20 enols and enolates

••

O

O

••

••

••

O

O

••

••

CH3CH2OCCH2CH2CH2CHCOCH2CH3

••

via

CH3CH2OCCH2CH2CH2CH2COCH2CH3

NaOCH2CH3


Chapter 20 enols and enolates

••

••

O

O

••

••

CH3CH2OCCH2CH2CH2CHCOCH2CH3

••

via


Chapter 20 enols and enolates

••

••

O

CH3CH2O

••

••

••

••

O

••

C

CHCOCH2CH3

H2C

H2C

CH2

••

••

O

O

••

••

CH3CH2OCCH2CH2CH2CHCOCH2CH3

••

via


Chapter 20 enols and enolates

••

••

O

CH3CH2O

••

••

••

••

O

••

C

CHCOCH2CH3

H2C

H2C

CH2

via


Chapter 20 enols and enolates

••

••

O

CH3CH2O

••

••

••

••

O

••

C

CHCOCH2CH3

H2C

H2C

CH2

••

O

••

••

O

••

C

••

CH3CH2O

CHCOCH2CH3

H2C

••

••

H2C

CH2

via

+


Mixed claisen condensations

Mixed Claisen Condensations


Mixed claisen condensations1

Mixed Claisen Condensations

  • As with mixed aldol condensations, mixedClaisen condensations are best carried outwhen the reaction mixture contains one compound that can form an enolate and another that cannot.


Mixed claisen condensations2

O

O

O

O

HCOR

ROCOR

ROC

COR

O

COR

Mixed Claisen Condensations

  • These types of esters cannot form an enolate.


Example2

O

O

COCH3

CH3CH2COCH3

O

O

CCHCOCH3

CH3

Example

+

1. NaOCH3

2. H3O+

(60%)


Acylation of ketones with esters

Acylation of Ketones with Esters


Acylation of ketones with esters1

Acylation of Ketones with Esters

  • Esters that cannot form an enolate can be used to acylateketoneenolates.


Example3

O

O

CH3CH2OCOCH2CH3

O

O

COCH2CH3

Example

+

1. NaH

2. H3O+

(60%)


Example4

O

O

COCH2CH3

CH3C

O

CCH2C

Example

+

1. NaOCH2CH3

2. H3O+

O

(62-71%)


Example5

O

O

CH3CH2CCH2CH2COCH2CH3

O

O

CH3

Example

1. NaOCH3

2. H3O+

(70-71%)


Alkylation of enolate anions

Alkylation of Enolate Anions


Enolate ions in s n 2 reactions

Enolate Ions in SN2 Reactions

  • Enolate ions are nucleophiles and react withalkyl halides.

  • However, alkylation of simple enolates does not work well.

  • Enolates derived from -diketones can bealkylated efficiently.


Example6

O

O

O

O

CH3CCH2CCH3

CH3

Example

K2CO3

+

CH3I

CH3CCHCCH3

(75-77%)


The acetoacetic ester synthesis

The 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

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

+

CH3CH2O

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


Example7

O

O

CH3CCH2COCH2CH3

Example

1. NaOCH2CH3

2. CH3CH2CH2CH2Br


Example8

O

O

CH3CCH2COCH2CH3

O

O

CH3CCHCOCH2CH3

CH2CH2CH2CH3

Example

1. NaOCH2CH3

2. CH3CH2CH2CH2Br

(70%)


Example9

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 example1

O

O

COCH2CH3

H

Another Example

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


Another example2

O

O

COCH2CH3

H

CHCH2Br

2. H2C

O

O

COCH2CH3

CH2

CH2CH

Another Example

1. NaOCH2CH3

(89%)


Another example3

O

CH2

CH2CH

Another Example

O

COCH2CH3


Another example4

CH2

CH2CH

1. NaOH, H2O

2. H+

3. heat, -CO2

O

CH2

CH2CH

Another Example

O

H

(66%)

O

COCH2CH3


The malonic ester synthesis

The 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.


Example10

O

O

CH3CH2OCCH2COCH2CH3

H2C

CHCH2CH2CH2Br

O

O

CH3CH2OCCHCOCH2CH3

CH2

CH2CH2CH2CH

Example

1. NaOCH2CH3

2.

(85%)


Example11

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 example5

O

O

CH3CH2OCCH2COCH2CH3

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CH2Br

Another Example

1. NaOCH2CH3

2. BrCH2CH2CH2Br


Another example6

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CH2Br

Another Example

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


Another example7

O

O

CH3CH2OCCCOCH2CH3

H2C

CH2

CH2

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CH2Br

Another Example

(60-65%)

NaOCH2CH3


Another example8

O

O

CH3CH2OCCCOCH2CH3

H2C

CH2

CH2

H

CO2H

C

H2C

CH2

CH2

Another Example

1. NaOH, H2O

2. H+

3. heat, -CO2

(80%)


Barbiturates

Barbiturates


Barbituric acid is made from diethyl malonate

O

COCH2CH3

H2N

H2C

C

O

COCH2CH3

H2N

O

Barbituric acid is made from diethyl malonate

+


Barbituric acid is made from diethyl malonate and urea

O

COCH2CH3

H2N

H2C

C

O

COCH2CH3

H2N

O

O

H

N

C

C

O

H2C

N

C

O

H

Barbituric acid is made from diethyl malonate and urea

+

1. NaOCH2CH3

2. H+

(72-78%)


Barbituric acid is made from diethyl malonate and urea1

O

COCH2CH3

H2N

H2C

C

O

COCH2CH3

H2N

O

Barbituric acid is made from diethyl malonate and urea

+

H

O

1. NaOCH2CH3

N

2. H+

O

N

O

(72-78%)

H


Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate

O

O

COCH2CH3

COCH2CH3

R

H2C

C

R'

COCH2CH3

COCH2CH3

O

O

Substituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonate

1. RX,NaOCH2CH3

2. R'X,NaOCH2CH3


Substituted derivatives of barbituric acid are made from alkylated derivatives of diethyl malonate1

O

O

H

COCH2CH3

N

O

(H2N)2C

R

R

C

O

R'

R'

N

COCH2CH3

H

O

O

Substituted derivatives of barbituric acid are madefrom alkylated derivatives of diethyl malonate


Examples

O

H

N

CH3CH2

O

CH3CH2

N

H

O

5,5-Diethylbarbituric acid(barbital; Veronal)

Examples


Examples1

H3C

CH3CH2CH2CH

Examples

O

H

N

O

CH3CH2

N

H

O

5-Ethyl-5-(1-methylbutyl)barbituric acid(pentobarbital; Nembutal)


Examples2

H3C

CH3CH2CH2CH

CHCH2

H2C

Examples

O

H

N

O

N

H

O

5-Allyl-5-(1-methylbutyl)barbituric acid(secobarbital; Seconal)


Enolization and enol content

Enolization and Enol Content


Mechanism of enolization in general

H

••

O

H

O

••

••

••

R2C

CR'

H

O

H

••

••

H

••

O

H

••

R2C

CR'

Mechanism of Enolization(In general)


Mechanism of enolization base catalyzed

Mechanism of Enolization(Base-catalyzed)

••

O

••

R2C

CR'

••

O

H

••

••

H


Mechanism of enolization base catalyzed1

H

••

O

H

O

••

••

••

••

R2C

CR'

Mechanism of Enolization(Base-catalyzed)

••

O

H

••

H


Mechanism of enolization base catalyzed2

H

••

O

H

O

••

••

••

R2C

CR'

Mechanism of Enolization(Base-catalyzed)

••


Mechanism of enolization base catalyzed3

H

O

••

••

••

Mechanism of Enolization(Base-catalyzed)

••

O

H

••

R2C

CR'


Mechanism of enolization acid catalyzed

H

••

O

H

O

••

••

+

H

R2C

CR'

H

Mechanism of Enolization(Acid-catalyzed)


Mechanism of enolization acid catalyzed1

Mechanism of Enolization(Acid-catalyzed)

H

+

••

H

O

O

••

••

H

R2C

CR'

H


Mechanism of enolization acid catalyzed2

H

O

••

••

H

Mechanism of Enolization(Acid-catalyzed)

+

••

H

O

R2C

CR'

H


Mechanism of enolization acid catalyzed3

••

H

O

••

R2C

CR'

H

+

O

H

••

H

Mechanism of Enolization(Acid-catalyzed)


Enol content

OH

O

R2CHCR'

R2C

CR'

Enol Content

  • percent enol is usually very small

  • keto form usually 45-60 kJ/mol more stablethan enol

keto

enol


Enol content1

OH

O

CH3CH

H2C

CH

OH

O

Acetone

CH3CCH3

H2C

CCH3

K = 6 x 10-9

Enol Content

Acetaldehyde

K = 3 x 10-7


Halogenation of aldehydes and ketones

Halogenation ofAldehydes and Ketones


General reaction

O

O

H+

R2CCR'

R2CCR'

H

X

General Reaction

+

+

X2

HX

  • X2 is Cl2, Br2, or I2.

  • Substitution is specific for replacement of hydrogen.

  • Catalyzed by acids. One of the products is an acid (HX); the reaction is autocatalytic.

  • Nota free-radical reaction.


Example12

O

O

Cl

+

HCl

+

Cl2

Example

H2O

(61-66%)


Example13

O

O

CH

CH

H

Br

Example

  • Notice that it is the proton on the  carbon that is replaced, not the one on the carbonyl carbon.

CHCl3

+

HBr

+

Br2

(80%)


Mechanism of halogenation

Interpretation

no involvement of halogen until after therate-determining step

Mechanism of  Halogenation

Experimental Facts

  • specific for replacement of H at the  carbon

  • equal rates for chlorination, bromination, and iodination

  • first order in ketone; zero order in halogen


Mechanism of halogenation1

Mechanism of  Halogenation

Two stages:

  • first stage is conversion of aldehyde or ketone to the corresponding enol; is rate-determining

  • second stage is reaction of enol with halogen; is faster than the first stage


Mechanism of halogenation2

OH

O

O

slow

X2

RCH2CR'

RCHCR'

RCH

CR'

fast

X

enol

Enol is key intermediate

Mechanism of  Halogenation


Mechanism of halogenation3

Mechanism of  Halogenation

Two stages:

  • first stage is conversion of aldehyde or ketone to the corresponding enol; is rate-determining

  • second stage is reaction of enol with halogen; is faster than the first stage

examine second stage now


Reaction of enol with br 2

••

••

OH

OH

••

••

R2C

R2C

+

CR'

CR'

+

Br

••

••

••

••

••

Br

Br

••

••

••

••

••

Br

••

••

••

+

OH

••

R2C

CR'

Br

••

••

••

Reaction of enol with Br2

  • carbocation is stabilized by electron release from oxygen


Loss of proton from oxygen completes the process

••

••

Br

Br

H

••

••

••

••

••

••

+

H

O

O

••

R2C

R2C

CR'

CR'

Br

Br

••

••

••

••

••

••

Loss of proton from oxygen completes the process

••


A halogenation of carboxylic acids the hell volhard zelinsky reaction

a-Halogenation of Carboxylic Acids:The Hell-Volhard-Zelinsky Reaction


A halogenation of carboxylic acids

O

O

R2CCOH

R2CCOH

H

X

a -Halogenation of Carboxylic Acids

  • analogous to a-halogenation of aldehydes and ketones

  • key question: Is enol content of carboxylic acids high enough to permit reaction to occur at reasonable rate? (Answer is NO)

+

+

X2

HX


Chapter 20 enols and enolates

O

O

R2CCOH

R2CCOH

H

X

But...

  • reaction works well if a small amount ofphosphorus or a phosphorus trihalide is added tothe reaction mixture

  • this combination is called the Hell-Volhard-Zelinsky reaction

P or PX3

+

+

X2

HX


Example14

O

CH2COH

O

CHCOH

Br

Example

+

Br2

PCl3

benzene80°C

(60-62%)


Value

O

O

CH3CH2CH2COH

CH3CH2CHCOH

Br

Value

Br2

  • a-Halogen can be replaced by nucleophilic substitution

P

(77%)


Value1

O

O

CH3CH2CH2COH

CH3CH2CHCOH

Br

O

CH3CH2CHCOH

OH

Value

Br2

P

(77%)

K2CO3H2Oheat

(69%)


Synthesis of a amino acids

O

O

(CH3)2CHCHCOH

Br

O

(CH3)2CHCHCOH

NH2

Synthesis of a -Amino Acids

Br2

(CH3)2CHCH2COH

PCl3

(88%)

NH3H2O

(48%)


The haloform reaction

The Haloform Reaction

  • Under basic conditions, halogenation of a methyl ketone often leads to carbon-carbon bond cleavage.

  • Such cleavage is called the haloform reaction because chloroform, bromoform, or iodoform is one of the products.


Example15

O

(CH3)3CCCH3

O

(CH3)3CCONa

O

(CH3)3CCOH

Example

Br2, NaOH, H2O

+

CHBr3

H+

(71-74%)


The haloform reaction1

O

O

O

ArCCH3

(CH3)3CCCH3

RCH2CCH3

The Haloform Reaction

  • The haloform reaction is sometimes used as a method for preparing carboxylic acids, but works well only when a single enolate can form.

yes

yes

no


Mechanism11

O

O

RCCH3

RCCX3

O

O

RCCH2X

RCCHX2

Mechanism

  • First stage is substitution of all available hydrogens by halogen

X2, HO–

X2, HO–

X2, HO–


Mechanism12

••

••

O

O

••

••

••

••

CX3

CX3

HO

RC

RC

••

••

HO

••

••

••

••

O

O

••

••

••

••

+

+

HCX3

CX3

RC

RC

O

OH

••

••

••

••

Mechanism

  • Formation of the trihalomethyl ketone is followed by its hydroxide-induced cleavage

+


Some chemical and stereochemical consequences of enolization

Some Chemical and StereochemicalConsequences of Enolization


Hydrogen deuterium exchange

O

H

H

H

H

O

D

D

D

D

Hydrogen-Deuterium Exchange

+

4D2O

KOD, heat

+

4DOH


Mechanism13

••

O

••

H

H

••

OD

••

H

H

••

••

O

••

••

H

H

••

+

HOD

H

••

Mechanism

+


Mechanism14

••

O

••

H

D

••

+

OD

••

H

H

••

••

O

••

••

H

••

H

OD

D

H

••

Mechanism


Stereochemical consequences of enolization

H

O

H3C

CC6H5

C

CH3CH2

Stereochemical Consequences of Enolization

H3O+

50% R50% S

50% R50% S

100% R

H2O, HO–


Enol is achiral

H

H3C

OH

O

H3C

C

CC6H5

CC6H5

C

CH3CH2

CH3CH2

Enol is achiral

R


Enol is achiral1

O

C

H3C

OH

C

CC6H5

H

CH3CH2

O

H3C

CC6H5

C

CH3CH2

Enol is achiral

H3C

H

CC6H5

S

50%

CH3CH2

50%

R


Results of rate studies

H

O

H3C

CC6H5

C

CH3CH2

Results of Rate Studies

  • Equal rates for:racemizationH-D exchangebrominationiodination

  • Enol is intermediate and its formation is rate-determining


Effects of conjugation in unsaturated aldehydes and ketones

Effects of Conjugation in -Unsaturated Aldehydes and Ketones


Relative stability

Relative Stability

  • aldehydes and ketones that contain a carbon-carbon double bond are more stable when the double bond is conjugated with the carbonyl group than when it is not

  • compounds of this type are referred to as , unsaturated aldehydes and ketones


Relative stability1

O

CH3CH

CHCH2CCH3

(17%)

K = 4.8

O

(83%)

CHCCH3

CH3CH2CH

Relative Stability


Acrolein

O

H2C

CHCH

Acrolein


Acrolein1

O

H2C

CHCH

Acrolein


Acrolein2

O

H2C

CHCH

Acrolein


Acrolein3

O

H2C

CHCH

Acrolein


Resonance description

••

••

O

O

C

C

••

••

••

C

C

C

C

+

••

O

C

••

••

C

C

+

Resonance Description


Properties

••

O

C

••

C

C

Properties

  • -Unsaturated aldehydes and ketones are more polar than simple aldehydes and ketones.

  • -Unsaturated aldehydes and ketones contain two possible sites for nucleophiles to attack

    • carbonyl carbon

    • -carbon


Dipole moments

O

O

 = 2.7 D

 = 3.7 D

Dipole Moments

–

–

  • greater separation of positive and negative charge

+

+

+

Butanal

trans-2-Butenal


Conjugate addition to unsaturated carbonyl compounds

Conjugate Addition to -Unsaturated Carbonyl Compounds


Nucleophilic addition to unsaturated aldehydes and ketones

Nucleophilic Addition to -Unsaturated Aldehydes and Ketones

  • 1,2-addition (direct addition)

    • nucleophile attacks carbon of C=O

  • 1,4-addition (conjugate addition)

    • nucleophile attacks -carbon


Kinetic versus thermodynamic control

Kinetic versus Thermodynamic Control

  • attack is faster at C=O

  • attack at -carbon gives the more stable product


Chapter 20 enols and enolates

O

C

C

C

H

Y

H

O

Y

C

C

C

+

  • formed faster

  • major product under conditions of kinetic control (i.e. when addition is not readily reversible)

1,2-addition


Chapter 20 enols and enolates

O

C

C

C

H

Y

H

O

C

Y

C

C

+

  • enol

  • goes to keto form under reaction conditions

1,4-addition


Chapter 20 enols and enolates

O

C

C

C

H

Y

O

C

Y

H

C

C

+

  • keto form is isolated product of 1,4-addition

  • is more stable than 1,2-addition product

1,4-addition


Chapter 20 enols and enolates

O

C

C

C

H

Y

O

H

O

C

Y

C

Y

H

C

C

C

C

+

1,2-addition

1,4-addition

C=O is stronger than C=C


Addition of carbanions to unsaturated carbonyl compounds the michael reaction

Addition of Carbanions to-Unsaturated Carbonyl Compounds:The Michael Reaction


Michael addition

Michael Addition

  • Stabilized carbanions, such as those derived from -diketones undergo conjugateaddition to ,-unsaturated ketones.


Example16

O

O

CH3

H2C

CHCCH3

O

O

O

CH3

CH2CH2CCH3

O

Example

+

KOH, methanol

(85%)


Michael addition1

Michael Addition

  • 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.


Example17

O

O

CH3

O

CH3

CH2CH2CCH3

O

O

OH

O

CH3

(85%)

O

Example

NaOHheat

not isolated;dehydrates under reaction conditions


Stabilized anions

O

O

C

C

••

H3C

C

OCH2CH3

H

O

O

C

C

••

C

OCH2CH3

CH3CH2O

H

Stabilized Anions

  • The anions derived by deprotonation of b-keto esters and diethyl malonate are weak bases.

  • Weak bases react with a,b-unsaturated carbonyl compounds by conjugate addition.


Example18

O

O

O

H2C

CHCCH3

CH3CH2OCCH2COCH2CH3

Example

+


Example19

O

O

O

H2C

CHCCH3

CH3CH2OCCH2COCH2CH3

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CCH3

O

Example

+

KOH, ethanol

(85%)


Example20

O

CH3CCH2CH2CH2COH

O

O

CH3CH2OCCHCOCH2CH3

CH2CH2CCH3

O

O

Example

(42%)

1. KOH, ethanol-water

2. H+

3. heat


Conjugate addition of organocopper reagents to unsaturated carbonyl compounds

Conjugate Addition of Organocopper Reagentsto -Unsaturated Carbonyl Compounds


Addition of organocopper reagents to unsaturated aldehydes and ketones

Addition of Organocopper Reagents to-Unsaturated Aldehydes and Ketones

  • The main use of organocopper reagents is toform carbon-carbon bonds by conjugate addition to ,-unsaturated ketones.


Example21

O

CH3

1. diethyl ether

2. H2O

O

CH3

CH3

Example

+

LiCu(CH3)2

(98%)


End of chapter 20

End of Chapter 20


  • Login