chapter 20 enols and enolates
Download
Skip this Video
Download Presentation
Chapter 20 Enols and Enolates

Loading in 2 Seconds...

play fullscreen
1 / 190

Chapter 20 Enols and Enolates - PowerPoint PPT Presentation


  • 126 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Chapter 20 Enols and Enolates' - cora-vinson


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
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.
slide11
O

O

C

C

R

C

OR'

H

H

CH3CH2O

O

O

C

C

••

R

C

OR'

H

pKa ~ 11

slide12
••

••

••

••

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.
slide13

••

••

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.
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

slide16
••

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

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
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%)

example1
O

O

1. NaOCH2CH3

2. H3O+

O

O

COCH2CH3

Example

CH3CH2OCCH2CH2CH2CH2COCH2CH3

(74-81%)

slide63
••

O

O

••

••

••

O

O

••

••

CH3CH2OCCH2CH2CH2CHCOCH2CH3

••

via

CH3CH2OCCH2CH2CH2CH2COCH2CH3

NaOCH2CH3

slide64
••

••

O

O

••

••

CH3CH2OCCH2CH2CH2CHCOCH2CH3

••

via
slide65
••

••

O

CH3CH2O

••

••

••

••

O

••

C

CHCOCH2CH3

H2C

H2C

CH2

••

••

O

O

••

••

CH3CH2OCCH2CH2CH2CHCOCH2CH3

••

via
slide66
••

••

O

CH3CH2O

••

••

••

••

O

••

C

CHCOCH2CH3

H2C

H2C

CH2

via
slide67
••

••

O

CH3CH2O

••

••

••

••

O

••

C

CHCOCH2CH3

H2C

H2C

CH2

••

O

••

••

O

••

C

••

CH3CH2O

CHCOCH2CH3

H2C

••

••

H2C

CH2

via

+

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 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%)

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%)

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

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%)

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)

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

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

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

slide143
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

+

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
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

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
slide174
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

slide175
O

C

C

C

H

Y

H

O

C

Y

C

C

+

  • enol
  • goes to keto form under reaction conditions

1,4-addition

slide176
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

slide177
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

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%)

ad