Chapter 1a - Alpha Carbon Enol Enolate (Part 2)

8/10/2019 Chapter 1a - Alpha Carbon Enol Enolate (Part 2)

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( ),

.

I , .

.

H .

A The characteristic reaction of aldehydes and ketones is

nucleophilic addition.

An aldol reaction is a nucleophilic addition in which an

enolate is the nucleophile.

Nucleophilic Addition of Enolates

:

A

42

A second example of an aldol reaction is shown with propanalas the starting material.

The two molecules of the aldehyde that participate in the aldol

reaction react in opposite ways.

One molecule becomes an enolatean electron-richnucleophile.

One molecule serves as the electrophilebecause its

carbonyl is electron deficient.

Aldol Reaction with Propanal


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The carbon of one carbonyl component becomes bondedto the carbonyl carbon of the other component.

Joining Carbons to Form Aldol Products

:

A

A .

G

.

: A

G

A: A


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, . B .

: A

, . B

B ,

A: A

, , .

ALDL CDEAI, .

,

. H? C .

A

.

G :

: A


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G

A: A

, .

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A

B ,

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C .

A

A , ,

.

A


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. B .

: A

. B

B ,

A: A

Sometimes it is possible to carry out an aldol reactionbetween two different carbonyl compounds.

Such reactions are called crossed or mixed aldol reactions.

Crossed Aldol Reactions

CED :

1.

.

A


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1.

.

A CED

:

2. LDA

.

.

A

61

In this type of crossed aldol reaction, the initial -hydroxycompound always loses water to form the highly conjugatedproduct.

Example of Crossed Aldol Reactions

D .

: A


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D

A: A C

.

.

5 6 . H?

A

Under the basic reaction conditions, the initial aldol productis often not isolated.

Instead, it loses the elements of H2O from the and carbons to form an ,-unsaturated carbonyl compound.

Dehydration of the Aldol Product

66

In the Claisen reaction, two molecules of an ester react witheach other in the presence of an alkoxide base to form a-keto ester.

Unlike the aldol reaction which is base-catalyzed, a fullequivalent of base is needed to deprotonate the -keto esterformed in Step [3] of the Claisen reaction.

Since esters have a leaving group on the carbonyl carbon,loss of the leaving group occurs to form the product ofsubstitution, not addition.

The Claisen Reactions


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The characteristic reaction of esters is nucleophilicsubstitution.

A Claisen reaction is a nucleophilic substitution in which anenolate is the nucleophile.

Claisen ReactionExample ofNucleophilic Substitution

C :

1.

.

2. H C

.

3. A

.

C C Like the aldol reaction, it is sometimes possible to carry out

a Claisen reaction with two different carbonyl components asstarting materials.

A Claisen reaction between two different carbonylcompounds is called a crossed Claisen reaction.

A crossed Claisen is synthetically useful in two differentinstances:

[1] Between two different esters when only one has hydrogens, one product is usually formed.

Crossed Claisen Reaction


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G

C C An intramolecular Claisen reaction is called a Dieckmann

reaction.

Two types of diesters give good yields of cyclic products.

The Dieckmann Reaction

77

.

2 .

A A


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2 3 , E2 . H .

, LDA .

.

I , .

A A

?

A A

A A

F , .

E .

LDA , , .

H , , .

A A


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G

.

: A A

G 5

A: A A

.

D .

E

.

, .

E


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DECABLAED

.

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E

H .

A A

D :

.

E

90

The malonic ester synthesis results in the preparation ofcarboxylic acids having two general structures:

The malonic ester synthesis is a stepwise method for convertingdiethyl malonate into a carboxylic acid having one or two alkylgroups on thecarbon.

Malonic Ester Synthesis


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91

Heating diethyl malonate with acid and water hydrolyzes bothesters to carboxy groups, forming a -diacid (1,3-diacid).

-Diacids are unstable to heat and decarboxylate resulting incleavage of a CC bond and formation of a carboxylic acid.

Decarboxylation of Malonic Esters

92

The net result of decarboxylation is cleavage of a CC bond onthecarbon, with loss of CO2.

Decarboxylation occurs readily whenever a carboxy group

(COOH) is bonded to thecarbon of another carbonyl group.

Decarboxylation Result

This can also occur with -keto acids, forming a ketone.

93

Thus, the malonic ester synthesis converts diethyl malonate to acarboxylic acid in three steps.

Path of Malonic Ester Synthesis

94

The synthesis of 2-butanoic acid (CH3CH2CH2COOH) from diethylmalonate illustrates the basic process:

Example of Malonic Ester Synthesis


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95

If the first two steps of the reaction sequence are repeated prior tohydrolysis and decarboxylation, then a carboxylic acid having twonew alkyl groups on thecarbon can be synthesized.

This is illustrated in the synthesis of 2-benzylbutanoic acid[CH3CH2CH(CH2C6H5)COOH] from diethyl malonate.

Repeated Malonic Ester Synthesis

96

An intramolecular malonic ester synthesis can be used to formrings having three to six atoms, provided the appropriate dihalideis used as starting material.

For example, cyclopentanecarboxylic acid can be prepared fromdiethyl malonate and 1,4-dibromobutane (BrCH2CH2CH2CH2Br)by the following sequence of reactions.

Intramolecular Malonic Ester Synthesis

97

To use the malonic ester synthesis, you must be able to determinewhat starting materials are needed to prepare a givencompoundthat is, you must work backwards in theretrosynthetic direction.

This involves a two-step process:

Retrosynthetic Analysis of Malonic Esters

G .

: E


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G

A: E

100

The addition of one Br atom stabilizes the second enolate due tothe electron-withdrawinginductive effect of Br.

As a result, theH of -bromopropiophenone is more acidic thantheH atoms of propiophenone, making it easier to remove withbase.

Halogenation of a methyl ketone with excess halogen, called thehaloform reaction, results in the cleavage of a CCbond and formation of two products, a carboxylate anion andCHX3(commonly called haloform).

The final cleavage step is actually a nucleophilic substitution,made possible by the fact that the tri-substituted CX3 is now agood leaving group.

Haloform Reaction

101

In the haloform reaction, the three H atoms of the CH 3group aresuccessively replaced by X to form an intermediate that is oxidativelycleaved with base.

Methyl ketones form iodoform (CHI3), a pale yellow solid thatprecipitates from the reaction mixture.

This reaction is the basis of the iodoform test to detect methylketones.

Methyl ketones give a positive iodoform test (appearance of a yellowsolid) whereas other ketones give a negative iodoform test (nochange in the reaction mixture).

Haloform Reaction


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-Dicarbonyl compounds are also prepared by reacting anenolate with ethyl chloroformate or diethyl carbonate.

Forming -Dicarbonyl Compounds

104

Reaction [2] is noteworthy because it provides easy accessto -keto esters, which are useful starting materials in theacetoacetic ester synthesis.

In this reaction, Cl is eliminated rather than OEt in Step [3]because Cl is a better leaving group, as shown in thefollowing steps.

Preparing -Keto Esters

105

The Michael reaction involves two carbonyl componentsthe enolate of one carbonyl compound and an,-unsaturated carbonyl compound.

Recall that ,-unsaturated carbonyl compounds areresonance stabilized and have two electrophilic sitesthecarbonyl carbon and the carbon.

The Michael Reaction

The ,-unsaturated carbonyl component is often called aMichael acceptor.

Michael Acceptors


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, .

C A

When the product of a Michael reaction is also a -keto ester,it can be hydrolyzed and decarboxylated by heating inaqueous acid.

This forms a 1,5-dicarbonyl compound.

1,5-dicarbonyl compounds are starting materials for

intramolecular aldol reactions.

Michael Reaction Products Using the Michael Reaction


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G , 1,2 .

I , G 1,4 , CJGAE ADDII.

C , .

Chapter 1a - Alpha Carbon Enol Enolate (Part 2)

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Transcript of Chapter 1a - Alpha Carbon Enol Enolate (Part 2)