Solomon Organic Chemistry Chapter 19 Slides

8/11/2019 Solomon Organic Chemistry Chapter 19 Slides

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Chapter 19

Condensation and Conjugate Addition

Reaction of Carbonyl Compounds

- More Chemistry of Enolates -

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The Claisen Condensation: Formation of -Ketoestersfrom Esters with Enolizable Hydrogens

Esters with enolizable Hundergo a reaction similar to the aldolcondensation in the presence of alkoxide bases.

Alkoxide bases are used so that competing nucleophilic additiontothe acyl carbon does not destroy or change the ester function.

-C-C-OR

H

:O:=

pKa 25~~

+ B:- -C-C-OR

:O:=

:

--C=C-OR

:O:: -

enolate anion of ester

-C C OR

O

hybrid

-C-C-OR

O=

H

+ RO-

Na+

-C-C-OR

OR

O-

H

Na+

competing nucleophilic addition

-C-C-ORO=

H

+ RO- Na+

no change

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Condensation Step

The enolate anion of an ester reacts as a nucleophileby way of the

carbanion center in adding to the acyl carbon of a second ester:

-C-C-OR

H

:O:=

-C-C-OR

O=

:

-

+

enolate anion

-C C-OR

:O:

: -

H C-C-OR

O=

reversible nucleophilic addition

tetrahedral intermediate

-C C-OR

:O:

: -

HC-C-OR

O

=

cleavage

-C-C C-C-OR

O

=

O=

H

-keto ester

+ RO-

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Example: The Condensation of Ethyl Acetate.Ludwig Claisen (1851-1930)

The recommended procedure involves dissolving one equivalent ofsodium metal slowly in absolute (dry) ethanol. An immediate redoxreaction generates one equivalent of sodium ethoxide. Twoequivalents of ethyl acetate are added, and the mixture is heated forseveral hours. Acidification of the reaction mixture yields thecondensation product ethyl acetoacetate.

2 CH3COC2H5

O=

ethyl acetate pKa = 25

+ Na+ -OC2H5

overall reaction

CH3CCHCOC2H5

O= O=

:

-

Na++ C2H5O

sodium ethyl acetoacetate

CH3CCHCOC2H5

O=

:

-

Na+

workup

H+ CH3CCH2COC2H5

O= O=

ethyl acetoacetate pKa = 11

O=

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Some Observations

One full equivalent of base (NaOEt) is consumed in the reaction.

The product is the sodium salt of ethyl acetoacetate whichaccumulates as the condensation reaction proceeds.

The relative aciditiesof key compounds in this reaction are:

CH3CCH2COC2H5

O= O=

ethyl acetoacetate pKa = 11

> CH3CH2OH

ethyl alcohol pKa = 16

> CH3COC2H5

O=

ethyl acetate pKa = 25

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A Mechanism for the Claisen Condensation of Esters

formation of the enolate anion in low concentration

CH3COC2H5O=

pKa = 25

+ Na+ -OC2H5 :CH2COC2H5Na+ - + C2H5OH

pKa = 16

O=

addition to acyl carbon

:CH2COC2H5-CH3COC2H5

O=

+

O=

CH3C-OC2H5

O-

CH2CO2C2H5

Na+

cleavage and deprotonation

CH3C-OC

2H

5

O-

CH2CO2C2H5

Na+

CH3CCH2CO2C2H5

O=

pKa = 11

+ NaOC2H5

fast

CH3CCHCO2C2H5

O=

:

-Na+

+ C2H5O

pKa = 16

Although the Claisen condensation is areversible reaction, it is driven to completionby essentially irreversible formation of theanion of ethyl acetoacetate.

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The Claisen Condensation of Ethyl Propanoate

2 CH3CH2CO2C2H5NaOC2H5

ethanol, heat

CH3CH2CCCO2C2H5

O=

CH3

:-Na

+

+ C2H5O

CH3CH2CCCO2C2H5

O=

CH3

:-Na+

workup

H+

CH3CH2CCHCO2C2H5

CH3

O=

ethyl 3-oxo-2-methylpentanoate

Note the overall syntheticstrategy of the Claisencondensation of esters toyield ketoesters:

RCH2C CHCO2Et

R

O=

RCH2C CH2CO2Et

O=

OEt R

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Limitations of the Claisen Condensation

Esters with only one enolizable H do not give condensation

products under the usual conditions. Because the condensationproduct is not protected by deprotonation to the stable anion, a"reverse Claisen reaction" can occur thatlimits the amount ofproduct formed.

CH3CHCO2C2H5

CH3

+ CH3CCO2C2H5

CH3

:- Na+

CH3CHCO2C2H5

CH3ethyl 2-methylpropanoate

+ NaOEt CH3CCO2C2H5

CH3

:- Na+

+ EtOH

enolate anion

CH3CHC-C-CO2C2H5

O= CH3

CH3

+ NaOC2H5

CH3

reverse Claisen cleaves condensation product

CH3CHC-C-CO2C2H5

O= CH3

CH3

+-OC2H5

CH3

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Variations of the Claisen Condensation Reaction

The Dieckmann Condensation (1894): An IntramolecularClaisen Condensation

CH2

CH2

CH

CO2C2H5

CH2

C

OC2H5

O- Na

+

CH2CH2

CH2CO2C2H5

CH2CO2C2H5

diethyl adipate

+ NaOEtCH2

CH2

CHCO2C2H5

CH2CO2C2H5

:- Na+

+ EtOH

CH2

CH2

CHCO2C2H5

CH2C-OC2H5

:- Na+

intramolecular acyl addition

O

=

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CH2

CH2

CH

CO2C2H5

CH2

C

OC2H5

O- Na+

cleavage

CH2

CH2

CH

CO2C2H5

CH2

C=O + NaOEt

fast deprotonation

CH2

CH2

C:-

CO2C2H5

CH2

C=O

Na+

+ EtOH

workup

CH2

CH2

C:-

CO2C2H5

CH2

C=O

Na+

H+

CH2CH2

CHCO2C2H5

CH2

C=O

ethyl 2-oxocyclopentanecarboxylate10


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The Crossed Claisen Condensation

The condensation reaction of one ester with a second ester, orwith an aldehyde or ketone is called a crossed Claisen. As withthe crossed aldol condensation, it is a synthetically useful reactiononly when it is directedtowards one product.

The reaction may be directed by:

using two different esters where only onehas enolizable H.

reacting an an ester with aldehydes or ketones with enolizableH and exploiting the greater acidity of these compounds.

Examples of Crossed Claisen Reactions

COC2H5O=

+ CH3CO2C2H5

ethyl benzoate(no enolizable H)

(i) NaOEt/EtOH(ii) H+

C-CH2CO2C2H5

O=

ethyl 3-oxo-3-phenylpropanoate

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The Aldol Reaction: Addition of EnolateAnions to Aldehydes and Ketones

Aldehydes and ketones with enolizable hydrogens (

-H) undergo aself-reaction to give a -hydroxyaldehyde or -hydroxyketone in thepresence of base. This reaction is called the aldol condensation.

Requirements for an aldol reaction:

-H

Dilute solution of base-usually HO-

2 CH3CHO=

acetaldehyde

10% NaOH, H2O

5oCCH3CHCH2CH

O=OH

3-hydroxbutanal

an "aldol"

The aldol reaction does not occur with

ArCHO HCHO (CH3)3CCH

O=

ArCAr'

O=

ArCCR3

O=

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Aldol additon is reversible14


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Dehydration of Aldol Products

The -hydroxyaldehyde and-ketone aldol condensation products,when isolated, dehydrate very easily to

#

unsaturated carbonyl

compoundsbecause of the stability inherent in the conjugatedenone structures.

When R = aryl,dehydration occursduring the aldolcondensation:

RCCH3

O=

2

HO-

or RO-CH3CCH2CR

R

OH O=

-hydroxyaldehyde

or -ketone

dil. HCl

heat

fast(-H2O)

CH3C=CHCR

O=

R

#unsaturated

aldehyde or ketone

The dehydration yields an

extended system withresonance stabilization:

CH3C=CHCR

:O:=

R

CH3C-CH=CR

R

:O::

+-

acetophenone

C=C

CH3

H

C-O=

CCH3

O=

1,3-diphenyl-2-buten-1-one

NaOEt

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The Crossed Aldol Condensation

An aldol reaction using two different carbonyl compounds is acrossed aldol condensation. Because of the possibility of four

different condensation products, this reaction is not syntheticallyuseful unless it is carefully designed.

Directed Crossed Aldol Condensations

A simple designed synthesis includes one carbonyl compoundwith no -H, which eliminates two of the possible products. An

example is the crossed aldol condensation of benzaldehydeandacetaldehyde.

To minimize self-condensation of

acetaldehyde, the enolizable carbonyl

is slowly added to a mixture of

benzaldehyde and dilute HO-.

CH

O=

benzaldehyde

(no enolizable H)

+ CH3CHO= dil. HO-

CHCH2CH

O=OH

a directed aldol product

fast

(-H2O)

CH=CHCH

O=

cinnamaldehyde(3-phenyl-2-propen-1-one)

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Additional examples of directed crossed aldolreactions using benzaldehyde:

CH

O=

+ HO-

benzaldehyde(no enolizable H)

slowly add

CH3CCH3

O=

(-H2O)

CH=CHCCH3

O=

4-phenyl-3-buten-2-one

slowly add

C6H5CCH3

O=

(-H2O)

CH=CHC

O=

1,3-diphenyl-2-propenone

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The Acid-Catalyzed Aldol Condensation

The self-aldol reaction of aldehydes and ketones with enolizable-Halso occurs under acid-catalyzed conditions. The nucleophile in the

addition reaction is the enol (not the enolate anion), and the rate ofthe addition step is increased by acid catalysis, as shown below.

A Mechanism

acid-catalyzed enol formation

RCCH3

:O:=

+ H-B+ fast RCCH3

:O-H=

+ B:

+

While only a lowconcentration of enol ispresent under equilibriumconditions, it is a reactivenucleophile.

Overall Reaction

2 RCCH3

O= H+

heat RCCH2CCH3

O=

R

OH

(-H2O)RCCH=CCH3

O=

R

RCCH3

:O-H=

+ B:

+slow

RC=CH2

:O-H

:

+ H-B+

enol

low conc.

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In general the dehydration

product is formed in the acidcatalyzed mechanism

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A Directed Intramolecular Aldol Reaction

O

CH2CH2CCH3

O=

H+

O

To understand the selectivity of this reaction, the four possiblereaction pathways need to be evaluated. Also, favorableintramolecular reactions proceed much faster than comparableintermolecular reactions.

The acid-catalyzed intramolecular aldol reaction of the diketone

below yields a single product even though four different reactionpathways are possible.

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Four Intramolecular Aldol Pathways

OH

CH2CH

2CCH

3

O=O

CH3

OH

strained bicyclicring system

OH

CH2CH2CCH3

O=

O

CH2

CH2C

CH3

OH

highly strainedspiran system

O

CH2CH=CCH3

OH

CH2

CH

HO C=OCH3

highly strainedcyclobutane

O

CH2CHC=CH2

OH

OH O

stable product

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Claisen-Schmidt Reactions: -Unsaturated Ketones

Crossed aldol reactions where ketones are one component are called

Claisen-Schmidt reactions. These reactions were discovered anddeveloped by two Germans chemists in the 1880s: J.G. Schmidt andLudwig Claisen.

The crossed aldol product is favored over the self-reaction of theketones because of the irreversibility of the cross product (aconjugated enone), while the self-reaction of the ketones is

reversible.

C6H5CH

O=

benzaldehyde

+ CH3CCH3

O= HO-

100oCC6H5CH=CHCCH3

O=

4-phenyl-3-buten-2-one(benzalacetone) 70%

acetone

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A Mechanism for the Claisen-Schmidt Reaction ofBenzaldehyde and Acetone

enolate anion formation

CH3CCH3

O=

+ HO- :CH2CCH3

:O:=-

CH2=CCH3

:O:

:

-

+ H2O

C6H5CH

=

+ :CH2CCH3

:O:=-

:O:

nucleophilic addition

C6H5CH-CH2CCH3

:O:=:O:

: -

H2O

C6H

5CH-CH

2CCH

3

=OOH

+ HO-

aldoldehydration

C6H5CH-CHCCH3

=OOH

+ HO-

HC6H5CH=CHCCH3

O=+ H2O + HO

-

The dehydration step occurs readily.

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Additions to -Unsaturated Aldehydes and Ketones

C=C-C-

:O:=C=C-C-

:O:

:

+

-

C-C=C-

:O:

:

+

-

C C C

O!"

!+!+

Nu:-

modes of nucleophilic attack

-Unsaturated aldehydes and ketones react with nucleophiles bysimple(1,2) addition, and/or conjugate(1,4) addition. These twomodes of reaction are understandable from an examination of theresonance structures for a conjugated enone system that shows twoelectropositive carbon centers.

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Reaction Schemes for Simple and Conjugate Additions

C=C-C-O=

+ Nu:-

+H+simple addition

(1,2-addition)

+H+conjugate addition

(1,4-addition)

C=C-C-

O-H

Nu

C-C=C-

O-H

Nu enol

(initial product)

C-C-C-

Nu

O=H

ketone

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Examples

Often both modes of addition compete giving a mixture of 1,2-and 1,4-addition products.

CH3CH=CHCCH3

O= (i) CH3MgBr

(ii) H3O+

3-penten-2-one

CH3CH=CHCCH3CH3

OH

+ CH3CHCH2CCH3

O=

CH31,2-addition product

72%

1,4-addition product 20%

While Grignard reagents give mixtures from both addition modes,organocopper reagents tend to give conjugate addition products.

O=

CH3

4-methyl-2-cyclohexen-1-one

(i) (CH3)2CuLi

(ii) H3O+

O=

CH3

CH3

O=

CH3

CH3

+

98% 2%

(two diastereomers of 1,4-addition)

Only products from conjugate addition are found as a mixture ofdiastereomers. The dominant product results from addition fromthe less hindered side away from the methyl group in the

4-position.

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The Michael Addition of Diethyl Malonate to 3-Buten-2-one

H2C

CO2Et

CO2Et

diethyl malonate pKa = 12.9

+ CH2=CHCCH3

O=

3-buten-2-one(methyl vinyl ketone)

cat. NaOEt

EtOH CH2-CH2CCH3

O=

CH

EtOOC

EtOOC65%

A Mechanism

A catalytic amount of NaOEt produces a lowconcentration of the anion of diethyl malonate.

CH2(CO2Et)2 + NaOEt

pKa = 12.9

Na+ -CH(CO2Et)2 + HOEtpKa = 15.9

generation of nucleophile

CH2-CH-CCH3

O

CHEtOOC

EtOOC

-

simple enolate anion

conjugate addition

Na+ -CH(CO2Et)2 + CH2=CH-CCH3

O=

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The overall energetics for the Michael addition arefavorable, and the reaction goes to completion,because the carbon-carbon -bond formed isstronger than the carbon-carbon -bond that is lost.

protonation and regeneration of nucleophile

CH2-CH-CCH3

O

CHEtOOC

EtOOC

-

+ CH2(CO2Et)2

pKa = 12.9

CH2-CH=CCH3CHEtOOC

EtOOC

OH

enol+

Na+ -CH(CO2Et)2nucleophile regenerated

CH2-CH=CCH3CHEtOOC

EtOOC

OH

enol

ketone-enol equilibration

CH2-CH2CCH3O=

CHEtOOCEtOOC

ketone(stable product)

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The Robinson Annulation

CH3H

O=

2-methyl-1,3-cyclohexadione

+ CH2=CHCCH3O=

HO-

CH3OH

CH3O=

CH2CH2CCH3O=

Michael addition

O O

The addition product reacts further by way of anintramolecular aldol condensation:

CH3

O=

CH2CH2

C=O

CH3

+ HO-

O

CH3O=

CH2-CH2

C=O

CH2:-

enolate anion

O

CH3O=

O

CH2-CH2

C=OCH2-

CH3O=

O

CH2-CH2

C=OCH2H

CH3OH

(-H2O)

O=

CH3

65%

dehydrationO

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Solomon Organic Chemistry Chapter 19 Slides

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