19 enolates enamines-2

7/25/2019 19 Enolates Enamines-2

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Chapter 19

Enolates and Enamines


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Formation of an Enolate AnionFormation of an Enolate Anion

Enolate anions are formed by treating an

aldehyde, ketone, or ester, which has at least one-hydrogen, with base,

Most of the negative charge in an enolate anion is on

oxygen.

CH3-C-H

O

NaOH H C C-H

O

H

H C C-H

O Na+

H

H2O+ +

An enolate anion

oxygen

Reactive carbon


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Enolate AnionsEnolate Anions

Enolate anions are nucleophiles inSN2 reactions

andcarbonyl addition reactions,

An enolateanion

nucleophilicaddition

A ketone A tetrahedral carbonyl

addition intermediate

R R

R

O

+R' R'

O

O

R

R

R

O

R'R'

An enolateanion

nucleophilicsubstitution

A 1 haloalkaneor sulfonate

R R

R

O

+

R' Br

O

R

R

RSN2R' + Br

SN2

Carbonyl

addition


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The Aldol ReactionThe Aldol Reaction

The most important reaction of enolate anions is

nucleophilic addition to the carbonyl group ofanother molecule of the same or differentcompound.

Catalysis: Base catalysis is most common althoughacid also works. Enolate anions only exist in base.


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The Aldol ReactionThe Aldol Reaction

The product of an aldol reaction is:

a -hydroxyaldehyde.

or a -hydroxyketone.O

CH3-C-CH3CH3-C-CH3

O

CH2-C-CH3

OH Ba(OH)2Ba(OH)2

OH

CH3

CH3-C-CH2-C-CH3

CH3

CH3-C-CH2-C-CH3

O

Acetone

+

4-Hydroxy-4-methyl-2-pentanone(a -hydroxyketone)

+

Acetone

CH3-C-H

O

CH2-C-H

H ONaOH

CH3-CH-CH2-C-H

OH O

+

Acetaldehyde Acetaldehyde 3-Hydroxybutanal

(a -hydroxyaldehyde;racemic)

acid

acid


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MechanismMechanism: the Aldol Reaction, Base: the Aldol Reaction, Base

Base-catalyzed aldol reaction (good nucleophile)

Step 1: Formation of a resonance-stabilized enolateanion.

Step 2: Carbonyl addition gives a TCAI.

Step 3: Proton transfer to O-completes the aldol reaction.

CH3-C-H

O

CH2-C-H

O

CH3-CH-CH2-C-H

OO-

A tetrahedal carbonyladdition intermediate

+

CH2=C-H

O

CH2-C-H

O

H-O-H+H-CH2-C-H

O

+H-O

An enolate anionpKa20

(weaker acid)pKa15.7

(stronger acid)


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MechanismMechanism: the Aldol Reaction:: the Aldol Reaction:Acid catalysisAcid catalysis

Before showing the mechanism think about what

is needed.On one molecule the beta carbon must havenucleophilic capabilities to supply an electron pair.

On the second molecule the carbonyl group must

function as an electrophile.

One or the other molecules must be sufficientlyreactive.


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MechanismMechanism: the Aldol Reaction:: the Aldol Reaction:Acid catalysisAcid catalysis

Acid-catalyzed aldol reaction (good electrophile)

Step 1: Acid-catalyzed equilibration of keto and enolforms.

Step 2: Proton transfer from HA to the carbonyl groupof a second molecule of aldehyde or ketone.

O OH

CH3-C-H CH2=C-HHA

CH3-C-H

O

H A

O

CH3-C-H

H

A+ +

Nucleophiliccarbon

Reactive carbonyl


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Mechanism: the Aldol Reaction:Mechanism: the Aldol Reaction:Acid catalysisAcid catalysis

Step 3: Attack of the enol of one molecule on the

protonated carbonyl group of the other molecule.Step 4: Proton transfer to A-completes the reaction.

O

CH3-C-H

H

CH2=C-H

HO

:A- CH3-CH-CH2-C-H

OH O

H-A+ ++

(racemic)

This may look a bit strange but compare to


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The Aldol Products: Dehydration to alkeneThe Aldol Products: Dehydration to alkene

Aldol products are very easily dehydrated to ,-

unsaturated aldehydes or ketones.

Aldol reactions are reversible and often little aldol is

present at equilibrium.

K

eqfor dehydration is generally large.If reaction conditions bring about dehydration, goodyields of product can be obtained.

An

-unsaturated

aldehyde

+

OOH O

CH3CHCH2CH CH3CH=CHCH H2 O

warm in eitheracid or base


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Crossed Aldol ReactionsCrossed Aldol Reactions

In a crossed aldol reaction, one kind of molecule

provides the enolate anion and another kindprovides the carbonyl group.

CH3CCH3

O

HCH

ONaOH

CH3CCH2CH2OH

O

4-Hydroxy-2-butanone

+

acid Non-acidic, noalpha

hydrogens


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Crossed Aldol ReactionsCrossed Aldol Reactions

Crossed aldol reactions are most successful if

one of the reactants hasno -hydrogenand, therefore,cannot form an enolate anion,

One reactant has amore acidic hydrogenthan theother (next slide)

One reactant is an aldehydewhich has a more reactivecarbonyl group.

HCH

OCHO

O CHO CHO

Formaldehyde Benzaldehyde Furfural 2,2-Dimethylpropanal


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Crossed Aldol Reactions, Nitro activationCrossed Aldol Reactions, Nitro activation

Nitro groups can be introduced by way of an

aldol reaction using a nitroalkane.

Nitro groups can be reduced to 1 amines.

HO H-CH2-N

O

OH-O-H CH2-N

O

O

CH2=N

O

O

Resonance-stabilized anion

+

NitromethanepKa10.2(stronger acid)

WaterpKa15.7(weaker acid)

+

O

CH3NO2NaOH

HO CH2NO2H2, Ni

CH2NH2HO

1-(Aminomethyl)-cyclohexanol

1-(Nitromethyl)-cyclohexanol

Nitro-methane

Cyclohex-anone

(aldol)+


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Intramolecular Aldol ReactionsIntramolecular Aldol Reactions

Intramolecular aldol reactions are most successful for

formation of five- and six-membered rings.Consider 2,7-octadione,which has two -carbons.

3

3

O

O

O

O

1

1

KOH

KOH

O

HO

O

OH

-H2O

-H2O

O

O

2,7-Octanedione

(not formed)

(formed)


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SynthesisSynthesis: Retrosyntheic Analysis: Retrosyntheic Analysis

Two Patterns to look for


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Recognition

pattern

Analysis


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Example

Mixedaldol

BenzaldehydeNo alphahydrogens


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Claisen Condensation,Claisen Condensation,EsterEsterSubstitutionSubstitution

Esters also form enolate anions which participate

innucleophilic acyl substitution.

The product of a Claisen condensation is a -ketoester.

O

2CH3COEt1. EtO

-Na

+

2. H2O, HCl

O O

CH3CCH2COEt EtOH

EthanolEthyl 3-oxobutanoate

(Ethyl acetoacetate)

Ethyl ethanoate

(Ethyl acetate)

+

CC C C ORO O

A -kto!tr

RecognitionElement


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Claisen CondensationClaisen Condensation

Claisen condensation of ethyl propanoate

OEt

O

OEt

O1. EtO

-Na

+

2. H2O, HClOEt

OO

EtOH+

Ethylpropanoate Ethyl 2-methyl-3-oxopentanoate(racemic)

+

Ethylpropanoate

Here the enolate part of one ester molecule hasreplaced the alkoxy group of the other ester molecule.


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MechanismMechanism::Claisen CondensationClaisen Condensation

Step 1: Formation of an enolate anion.

Step 2: Attack of the enolate anion on a carbonyl carbon

gives a TCAI.

EtO-

CH2-COEtH

O

EtOH CH2-COEt

O O -

CH2=COEt

pKa= 22(weaker acid)

pKa15.9(strongeracid)

Resonance-stabilized enolate anion

-++

CH3-C-OEtO O

CH2-COEt

O-

O

OEt

CH3-C-CH2-C-OEt+

A tetrahedral carbonyladdition intermediate


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Mechanism:Mechanism:Claisen CondensationClaisen CondensationStep 3: Collapse of the TCAI gives a -ketoester and analkoxide ion.

Step 4: An acid-base reaction drives the reaction tocompletion. This consumption of base must beanticipated.

EtOCH3-C-CH2-C-OEt

O OO

CH3-C-CH2-C-OEt

O

OEt

+

EtO

H

CH3-C-CH-C-OEt

O O

CH3-C-CH-C-OEt

OO

EtOH

pKa15.9(weaker acid)

pKa10.7(stronger acid)

++


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Intramolecular Claisen condensation:Intramolecular Claisen condensation:Dieckman CondensatioDieckman Condensation

+

Diethyl hexanedioate

(Diethyl adipate)

Ethyl 2-oxocyclo-pentanecarboxylate

1. EtO-

Na+

2. H2O, HCl

EtOH

OEt

O

EtO

O

OEt

O O

Acidic


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Crossed Claisen CondsnsCrossed Claisen Condsns

Crossed Claisen condensations between two

different esters, each with -hydrogens, givemixtures of products and are usuallynot useful.

But if one ester has no -hydrogens crossed

Claisen is useful.

O

HCOEt EtOCOEt

O

COEt

OO

EtOC-COEt

Diethyl ethanedioate(Diethyl oxalate)

Diethylcarbonate

Ethylformate

Ethyl benzoate

O

No -hydrogens


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Crossed Claisen CondsnsCrossed Claisen Condsns

The ester with no -hydrogens is generally used in

excess.

"# OCH3

O

OCH3

O1. CH3O

-Na

+

2. H2O, HCl"# OCH3

O O

Methylpropanoate

Methylbenzoate

+

Methyl 2-methyl-3-oxo-3-phenylpropanoate

(racemic)

Used inexcess


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Claisen condensations are a route to ketones via

decarboxylation

OEt

O

OEt

OO

1. EtO-

Na+

2. H2O, HCl

3. NaOH, H2O, #at

OEt

OO

$. H2O, HCl

%. #atO

OH

O O

CO2

OH

OO

EtOH

EtOH

+

+

Reactions 1 & 2: Claisen condensation followed by acidification.

Reactions 3 & 4: Saponification and acidification

Reaction 5: Thermal decarboxylation.

+

Synthesis:Synthesis:Claisen CondensationClaisen Condensation


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Synthesis:Synthesis:Claisen CondensationClaisen Condensation

The result of Claisen condensation, saponification,

acidification, and decarboxylation is a ketone.

R-CH2-C

OR'

O

R

OCH2-C-OR' R-CH2-C-CH2-R

O2HOR' CO2++

severalsteps+

from the esterfurnishing theenolate anion

from the esterfurnishing thecarbonyl group

Note that in this Claisen (not crossed) the ketone issymmetric. Crossed Claisen can yield non symmetricketones.


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Synthesis:Synthesis:Retrosynthetic AnalysisRetrosynthetic Analysis

Site of acidic

hydrogen,nucleophile

Site ofsubstitution,electrophile

Newbond


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Enamines (and imines, Schiff bases)Enamines (and imines, Schiff bases)

Recallprimary aminesreact with carbonylcompounds to give Schiff bases (imines), RN=CR2.

Primaryamine

SecondaryAmine

Butsecondary aminesreact to give enamines


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Formation of EnaminesFormation of Enamines

Again, enamines are formed by the reaction of a

2 amine with the carbonyl group of an aldehydeor ketone.

The 2 amines most commonly used to prepareenamines are pyrrolidine and morpholine.

Pyrrolidine Morpholine

N

O

N

HH


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Formation of EnaminesFormation of Enamines

Examples:

+H

+

N

H

O

An enamine

-H2ON

OHN

+

O

An enamine

N

O

OHN

O

N

O

H

H+

H+

-H2O

H+


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Enamines Alkylation atEnamines Alkylation at position.position.

The value of enamines is that the -carbon is

nucleophilic.Enamines undergo SN2 reactions with methyl and

1 haloalkanes, -haloketones, and -haloesters.

Treatment of the enamine with one equivalent of an

alkylating agent gives an iminium halide.

An iminiumbromide(racemic)

The morpholineenamine ofcyclohexanone

+

BrN

O

BrSN2

N

O

3-Bromopropene(Allyl bromide)


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Compare mechanisms of acid catalyzed aldol and enamineCompare mechanisms of acid catalyzed aldol and enamine

O

CH3-C-H

H

CH2=C-H

HO

:A-

CH3-CH-CH2-C-H

OH O

H-A+ ++

(racemic)

An iminiumbromide(racemic)

The morpholineenamine ofcyclohexanone

+

BrN

O

BrSN2

N

O

3-Bromopropene(Allyl bromide)


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Enamines - AlkylationEnamines - Alkylation

Hydrolysis of the iminium halide gives an alkylated

aldehyde or ketone.

Morpholinium chloride

2-Allylcyclo-hexanone

+HCl& H2O

+Br-

N

O

O

+Cl-

N

O

H H

Overall process is to render the alpha carbonss of

ketone nucleophilic enough so that substitutionreactions can occur.


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Enamines Acylation atEnamines Acylation at positionposition

Enamines undergo acylation when treated with acid

chlorides and acid anhydrides.

N

CH3CCl

O

Cl- N O

HCl

O O

NH HCl-

+

Acetyl chloride

An iminiumchloride(racemic)

2-Acetylcyclo-hexanone(racemic)

++

+

H2O

Could this be made via acrossed Claisen followedby decarboxylation.


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Overall, Acetoacetic Ester SynthesisOverall, Acetoacetic Ester Synthesis

The acetoacetic ester (AAE) synthesis is useful

for the preparation of mono- and disubstitutedacetones of the following types:

CH3CCH2COEt

O O

R'

CH3CCHR

O

CH3CCH2R

O

A disubstitutedacetone

A monosubstituted

acetone

Ethyl acetoacetate(Acetoacetic ester)

Main points1.Acidic hydrogen providing a nucleophilic center.2.Carboxyl to be removed thermally3.Derived from a halide

RX


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Overall, Malonic Ester SynthesisOverall, Malonic Ester Synthesis

The strategy of a malonic ester (ME) synthesis is

identical to that of an acetoacetic ester synthesis,except that the starting material is a-diesterrather than a -ketoester.

O

EtOCCH2COEt

O

OR

RCHCOH

RCH2COH

O

A disubstituted

acetic acid

A monosubstitutedacetic acid

Diethyl malonate(Malonic ester)

Main points1.Acidic hydrogen providing a nucleophilic center2.Carboxyl group removed by decarboxylation3.Introduced from alkyl halide

RX


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Malonic Ester SynthesisMalonic Ester Synthesis

Consider the synthesis of this target molecule:

O OH

O

5-Methoxypentanoic acid

These two carbonsare from diethyl malonate

Recognize as substituted acetic acid.Malonic Ester Synthesis


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Malonic Ester Synthesis StepsMalonic Ester Synthesis Steps

1.Treat malonic ester with an alkali metal alkoxide.

2. Alkylate with an alkyl halide.

COOEt

COOEtEtO

-Na

++

Na+

COOEt

COOEtEtOH

EthanolpKa15.9

(weaker acid)

Sodiumethoxide

Sodium salt ofdiethyl malonate

+

Diethyl malonatepKa13.3

(stronger acid)

O Br

Na+

COOEt

COOEt

COOEt

COOEt

O Na+

Br-++

N2

i i


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Malonic Ester SynthesisMalonic Ester Synthesis

3. Saponify and acidify.

4. Decarboxylation.

2EtOH+

COOEt

COOEtO

3. NaOH, H2O

$. HCl, H2OCOOH

COOHO

COOH

COOHO

#atO

COOH CO2+

5-Methoxypentanoic acid

Mih lR i ddii d b

l


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Michael Reaction, addition toMichael Reaction, addition to ,,-unsaturated carbonyl-unsaturated carbonyl

Michael reaction:Michael reaction:the nucleophilic addition of an

enolate anion to an ,-unsaturated carbonylcompound.

Example:

COOEtEtOOC

O

EtO

-

Na

+

EtOHCOOEt

EtOOC

O

+

3-Buten-2-one(Methyl vinylketone)

Diethylpropanedioate(Diethyl malonate)

Recognition Pattern:Nucleophile C C CO (nitrile or nitro)

Mih lR i


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CH2

=CHCCH3

O

CH2=CHCOEt

O

CH2=CHCNR2

O

CH3CCH2CCH3

O O

CH2=CHNO2

CH2=CHC N

CH2=CHCH

O

CH3CCH2COEt

O O

O

EtOCCH2COEt

O

N

CH3C=CH2

CH3CCH2CN

O

NH3, RNH2, R2NH

These Types of

-UnsaturatedCompounds are NucleophileAcceptors in Michael Reactions

These Types of Compounds

Provide Effective Nucleophilesfor Michael Reactions

-Ketoester

-Diketone

-Diester

Enamine

-Ketonitrile

Aldehyde

Ketone

Ester

Amide

NitrileNitro compound

Amine

Michael ReactionMichael Reaction

i i iMih lR i ib


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Michael Reaction in baseMichael Reaction in base

Example:

The double bond of an ,-unsaturated carbonylcompound is activated for attack by nucleophile.

COOEt

OO

EtO- Na+

EtOH

O

COOEt

O

2-CyclohexenoneEthyl 3-oxobutanoate(Ethyl acetoacetate)

+

O O

+

O

+

More positive carbon

M h iM h i Mih lR iMih lR ti


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Mechanism:Mechanism:Michael ReactionMichael Reaction

Mechanism

1: Set up of nucleophile; Proton transfer to the base.

2: Addition of Nu:-to the carbon of the ,-unsaturatedcarbonyl compound.

Base+ +N-H :B- N:- H-B

+ C C C

O

CCN C

O

CCN C

O

Resonance-stabilized enolate anion

N

Mih lR iMih lR ti


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Michael ReactionMichael Reaction

Step 3: Proton transfer to HB gives an enol.

Step 4: Tautomerism of the less stable enol form to the

more stable keto form.

CCN C

O

H-B+ CCN C

O-H

BB

An enol

(a product of 1,4-addition)

1

$ 3 2+

CCN

O-H

C CCN C

H O

More stable keto formLess stable enol form

Mih lR i C i 14 12Mih lR ti C ti 14 12


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Michael Reaction, Cautions 1,4 vs 1,2Michael Reaction, Cautions 1,4 vs 1,2

Resonance-stabilized enolate anions and

enamines are weak bases, react slowly with,-unsaturated carbonyl compounds, andgive 1,4-addition products.

Organolithium and Grignard reagents, on theother hand, are strong bases, add rapidly tocarbonyl groups, and given primarily 1,2-addition.

"#*iO O

-

*i

+

"# H2O

HCl

OH"#

4-Methyl-2-phenyl-3-penten-2-ol

4-Methyl-3-penten-2-one

+

Phenyl-lithium

Mih lR ti Th d i Ki tiMih lR ti Th d i Ki ti


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Michael Reaction: Thermodynamic vs KineticMichael Reaction: Thermodynamic vs Kinetic

Addition of the nucleophile is irrevesible for strongly basiccarbon nucleophiles (kinetic product)

C

O

CC

N

ROHC C C

OH

N

N:

RO-

C C C

O

ROH

CCN C

O

C C

H

N C

O

RO-

-

- +

-

+

+

fast

slow

1,2-Addition(less stable product)

1,4-Addition(more stable product)

Mih lAldlC bi tiMih lAldlC bi ti


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19-19-4747

Micheal-Aldol CombinationMicheal-Aldol Combination

+

Ethyl 2-oxocyclohex-anecarboxylate

3-Buten-2-one(Methyl vinylketone)

1. NaOEt, EtOH

(Michael reaction)

2. NaOEt, EtOH

(Aldol reaction)

COOEt

O O

COOEt

OO O

COOEt

Carbanion site unsaturated

Dieckman

Rt th i f26H tdiRt th i f26H tdi


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Retrosynthesis of 2,6-HeptadioneRetrosynthesis of 2,6-Heptadione

O O O O

COOH

O

COOEt

O

this carbonlost bydecarboxylation

this bond formed

in a Michael reaction

Ethylacetoacetate

Methyl vinylketone

these threecarbons from

acetoacetic ester

+

Recognize as substitutedacetone, aae synthesis

Recognize as Nucleophile C C COMichael

Mih lR tiMih lR ti


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Michael ReactionsMichael Reactions

Enamines also participate in Michael reactions.

N 1. CH2=CHCN

2. H2O, HCl

O

CN

N

HH

Cl-+ +

Pyrrolidine enamineof cyclohexanone

(racemic)

GilmanReagents sotherorganometallicsGilmanReagentsvsotherorganometallics


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Gilman Reagents vs other organometallicsGilman Reagents vs other organometallics

Gilman reagents undergo conjugate addition to

,-unsaturated aldehydes and ketones in areaction closely related to the Michael reaction.

Gilman reagents are unique among organometallic

compounds in that they give almost exclusively 1,4-addition.

Other organometallic compounds, including Grignardreagents, add to the carbonyl carbon by 1,2-addition.

O

1. (CH3)2C*i, ether, -78C

2. H2O, HCl

O

3-Methyl-2-cyclohexenone

3,3-Dimethyl-cyclohexanone

CH3 CH3

CH3

C dE ltR ti i LDACrossedEnolateReactionsusingLDA


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Crossed Enolate Reactions using LDACrossed Enolate Reactions using LDA

With a strong enough base, enolate anion

formation can be driven to completion. The base most commonly used for this purposeis lithium diisopropylamide , LDA.

LDA is prepared by dissolving diisopropylaminein THF and treating the solution with butyllithium.

(CH3)2CH2N-*i+

Lithium diisopropylamde(weaker base)

(CH3)2CH2NH+CH3(CH2)3*i +CH3(CH2)2CH3

ButanepKa50(weaker acid)

Butyllithium(stronger base)

Diisopropylamine(pKa40

(stronger acid)

LDA

C dE ltR ti i LDACrossedEnolateReactionsusingLDA


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The crossed aldol reaction between acetone and

an aldehyde can be carried out successfully byadding acetone to one equivalent of LDA tocompletely preform its enolate anion, which isthen treated with the aldehyde.

OLDA

-78C

O-Li+

C6H5CH2CHO

1.

2. H2O

OOH

C6H5

4-Hydroxy-5-phenyl-2-pentanone(racemic)

Acetone Lithiumenolate

ExamplesusingLDAExamplesusingLDA


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Examples using LDAExamples using LDA

Crossed aldol

Michael

Alkylation

Acylation

CrossedEnolateReactionsusingLDACrossedEnolateReactionsusingLDA


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Question: For ketones withnonequivalent -

hydrogens, can we selectively utilize thenonequivalent sites?

Answer: A high degree of regioselectivity existsand it depends on experimental conditions.



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When 2-methylcyclohexanone is treated with a slight

excess of LDA, the enolate is almost entirely the lesssubstituted enolate anion.

When 2-methylcyclohexanone is treated with LDA

where the ketone is in slight excess, the product isricher in the more substituted enolate.

O

+ LDA0C

O-*i+ O-*i+

(CH3)2CH2NH

(racemic)10% 90%

++

slight excessof the ketone

O

+ LDA0C

O-*i+ O-*i+

(CH3)2CH2NH

(racemic)99% 1%

++

slight excessof base



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The most important factor determining the

composition of the enolate anion mixture iswhether the reaction is under kinetic (rate) orthermodynamic (equilibrium) control.

Thermodynamic Control: Experimentalconditions that permit establishment ofequilibrium between two or more products of areaction.The composition of the mixture is

determined by the relative stabilities of theproducts.



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Equilibrium among enolate anions is established when

the ketone is in slight excess, a condition under whichit is possible for proton-transfer reactions to occurbetween an enolate and an -hydrogen of anunreacted ketone. Thus, equilibrium is establishedbetween alternative enolate anions.

O

H

+CH3

O *i+ O-*i+ O

+

(racemic)More stableenolate anion(racemic) Less stableenolate anion(racemic)



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Kinetic control: Experimental conditions under

which the composition of the product mixture isdetermined by the relative rates of formation ofeach product. First formed dominates.

In the case of enolate anion formation, kinetic control

refers to the relative rate of removal of alternative-hydrogens.

With the use of a bulky base, the less hinderedhydrogen is removed more rapidly, and the major

product is the less substituted enolate anion.No equilibrium among alternative structures is set up.

ExampleExample


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ExampleExample

1. 1.1 ol */A, ki0ti

o0trol

1. . ol */A,t#rod0ai o0trol

19 enolates enamines-2

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