ch19 of organic chemistry

7/28/2019 ch19 of Organic Chemistry

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Ch. 19 - 1

Condensation and ConjugateAddition Reactions of Carbonyl

Compounds

More Chemistry of Enolates


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Carbonyl condensation vs. addition reactions

R'

OR

O

R'

OR

O

H

+ R'

O

OR

O

R'

1. NaOR

2. H3O+ ROH

1,3-dicarbonyl

132

Claisen condensation

Aldol reaction

3-hydroxy-carbonyl

ester ester

R'

R

O

aldehyde or ketone

R'

R

O

H

(R = H, "C", "EWG")

with one or more hydrogens on!-carbon

+R'

HO

R

O

R'

132

R = H or "C"

!

+

!

BaseR

Addition

R'

R

O

R'

132

R

HOH

H H

H

+

Condensation


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Ch. 19 - 4Ch. 19 - 4

The Mannich Reaction


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Ch. 19 - 5

Conjugate addition reactions

R'

+

R

O

R'

1. Base

2. H+

1,5-dicarbonyl

12

Michael addition

!,"-unsaturatedcarbonyl

R'

R

O

H

(R = H, "C", "EWG")with one or morehydrogens on!-carbon

!

O

R'

O

34

5

H


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Ch. 19 - 6

2. The Claisen Condensation:

A Synthesis of-Keto Esters


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Ch. 19 - 7

Claisen condensationAn Acyl Substitution

(nucleophilic addition-eliminationreaction)

Useful for the synthesis of-ketoesters


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Ch. 19 - 8

Claisen condensation Esters that have only one hydrogen

do not undergo the usual Claisencondensation

e.g.The carbon has only

one hydrogen does not undergo

Claisencondensation

This is because an ester with only one

hydrogen will not have an acidic hydrogen whenstep 3 is reached, and step 3 promotes thefavorable equilibrium that ensures the forwardreaction


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Ch. 19 - 9

Examples of Claisen condensation


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Ch. 19 - 10

Examples of Claisen condensation


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Ch. 19 - 11

OCH2CH3

O

Question: The following compound gives a poor yield in the Claisencondensation with sodium ethoxide as base. What is the structure of the

expected Claisen product, and explain why a poor yield is obtained

O O

OCH2CH3

NaOEt


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Ch. 19 - 12

O

OCH2CH3

O

Question:What is the structure of the ester that you would use to prepare compound Ain a Claisen condensation reaction

Compound A

O

Review question:How would you convert compound A to compound B

Compound BSee problem 19.2


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Ch. 19 - 13

OCH2CH3

O

Question: Show all the steps in the following synthesis

O

R'OR

O

A general method for the synthesis of ketones

1. NaOR

2. H3O+

R'

O

OR

O

R'

2

R'

O

R'

1. NaOH, H2O

2. H3O+

3. heat (-CO2)

symmetrical ketone

R'

O

R'

unsymmetrical ketoneR

How?

See Q19.24a


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Ch. 19 - 14

See Q19.24b


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Ch. 19 - 16

Other examples


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Ch. 19 - 18

Question 19.31: In the presence of sodium ethoxide the followingtransformation occurs. Explain


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Crossed Claisen condensations arepossible when one estercomponent has no hydrogensand, therefore, is unable to form anenolate ion and undergo self-condensation


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Ch. 19 - 21

Question 23


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Ch. 19 - 22

R'

OR

O

R'

OR

O

H

+ R'

O

OR

O

R'

1. NaOR

2. H3O+ ROH

3-keto-ester

132


More general reaction

1,3-dicarbonyl

ester ester

Y X

O

carboxylic acid derivative

R'

R

O

H

aldehyde, ketoneor carboxylic acid derivative(R = H, "C", "EWG")with one or more hydrogens on!-carbon

+

Y

O

R

O

R'

132

Y = H, "C", electronwithdrawing group(EWG)X = EWG

!

XH

+

+

!


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Ch. 19 - 24

Recall: esters that have only one hydrogen cannot undergoClaisen Condensation by using

sodium alkoxide

However, they can be converted to the-keto esters by reactions that usevery strong bases such as lithium

diisopropyamide (LDA)


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Ch. 19 - 26Ch. 19 - 26

Carbonyl condensation reactions

https://www.concursolutions.com

R'

OR

O

R'

OR

O

H

+ R'

O

OR

O

R'

1. NaOR

2. H3O+ ROH

3-keto-ester

132


More general reaction

1,3-dicarbonyl

ester ester

Y X

O

carboxylic acid derivative

R'

R

O

H

aldehyde, ketoneor carboxylic acid derivative(R = H, "C", "EWG")with one or more hydrogens on!-carbon

+

Y

O

R

O

R'

132

Y = H, "C", electronwithdrawing group(EWG)X = EWG

!

XH

+

+

!


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Ch. 19 - 27

3. -Dicarbonyl Compounds byAcylation of Ketone Enolates

slightlymoreacidic


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Ch. 19 - 28

Question 23


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Claisen condensation - Summary

1. General reaction: nucleophilic carbon of an an enolate froman ester reacts with a carboxylic acid derivative to give a1,3 dicarbonyl compound

2. Ketones can be used as the precursor to the enolate.3.

With weak bases (e.g. alkoxides), no reaction/poor yieldwhen alpha-carbon of the enolate precursor has only onehydrogen.

4. High yields of Crossed Claisen Condensations are possiblewhen one ester component has no alpha hydrogens.

5. Intramolecular cyclization of di-esters and keto esters6. More complex synthesis: Combine Claisen Condensation

with Malonic & Acetoacetic acid ester synthesis


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Ch. 19 - 32

Carbonyl condensation vs. addition reactions

R'

OR

O

R'

OR

O

H

+ R'

O

OR

O

R'

1. NaOR

2. H3O+ ROH

1,3-dicarbonyl

132


Aldol reaction

3-hydroxy-carbonyl

ester ester

R'

R

O

aldehyde or ketone

R'

R

O

H

(R = H, "C", "EWG")

with one or more hydrogens on!-carbon

+R'

HO

R

O

R'

132

R = H or "C"

!

+

!

BaseR

Addition

R'

R

O

R'

132

R

HOH

H H

H

+

Condensation


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Ch. 19 - 33

4. Aldol Reactions: Addition of

Enolates and Enols toAldehydes and Ketones

contains both analdehyde and an

alcohol functionalgroup

aldol addition


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Ch. 19 - 35

Question:Give the two reactants in the Aldol reaction that leads to thefollowing product

HOCH2

CH2OH

OHH

HO H

HO H

O

2-

O3POCH2

CH2OPO32-

OHH

HO H

HO H

O

Fructose 1,6-biphosphate

2-O3POCH2

HO

OCH2OPO3

2-

OHH

O

H

Dihydroxyacetonephosphate

Glyceraldehye-3-phosphate

Aldolase

Biological Retro Aldol & Aldol reactions : Glycolysis & Glucogenesis


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Ch. 19 - 37


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Ch. 19 - 38Ch. 19 - 38

Question:Biochemists studying the structure of collagen (a fibrous protein inconnective tissue) found cross-links containing!,"-unsaturated aldehydesbetween protein chains. Show the structures of the side chains ("R") thatreact to form these cross-links, and propose a mechanism for their formation

in a weakly acidic solution

N

C

H

H R

CO

N

C

H

R H

C O

protein chain protein chain

N

C

H

H CH2

CO

N

C

H

H

C O

CH2 CH C

CHO

CH2 CH2CH2

+


1

23

N

C

H

H CH2

CO

NC

HH

C O

CH2CHO H2C

CHO

CH2 CH2CH2

+



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Ch. 19 - 41


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Ch. 19 - 43


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Ch. 19 - 46Ch. 19 - 46Ch. 19 - 46

Aldol additions and aldol condensations Important methods for carbon-

carbon bond formation Useful synthesis for

-hydroxyl carbonyl compounds ,-unsaturated carbon

compounds


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Review Question 19.10: Show how each of the following products can besynthesized using an Aldol reaction

CHO

HO

CH3

CH2OH

CH3

CH2OH

CH3

CH2OH

CH3

HO


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Ch. 19 - 51

Path a

Path b

Path c


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Ch. 19 - 60

Conjugate addition of HCN

Conjugate addition of an amine


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Ch. 19 - 61


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Other examples of Michael additions


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8. The Mannich Reaction


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Ch. 19 - 66

Other examples of the Mannich Reaction


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Ch. 19 - 67

NO

O

O

O

Cocaine


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Ch. 19 - 68

9. Summary of Important Reactions

Claisen Condensations


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Aldol Condensations


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Simple & Conjugate (Michael) additions


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ch19 of organic chemistry

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