19 enolates enamines

19-19-11

Chapter 19Enolates and Enamines

19-19-22

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-HO

NaOH H C C-HO

HH C C-H

O Na+

HH2O+ +

An enolate anion

oxygen

Reactive carbon

19-19-33

Enolate AnionsEnolate Anions

Enolate anions are nucleophiles in SN2 reactions and carbonyl addition reactions,

An enolateanion

nucleophilic addition

A ketone A tetrahedral carbonyl addition intermediate

R R

R

O

+–R' R'

OO

RR

R

OR'

R'

An enolateanion

nucleophilicsubstitution

A 1° haloalkaneor sulfonate

R R

R

O

+–

R' Br

O

RR

RSN2R' + Br

SN2

Carbonyl addition

19-19-44

The Aldol ReactionThe Aldol Reaction

The most important reaction of enolate anions is nucleophilic addition to the carbonyl group of another molecule of the same or different compound.• Catalysis: Base catalysis is most common although

acid also works. Enolate anions only exist in base.

19-19-55

The Aldol ReactionThe Aldol Reaction

The product of an aldol reaction is:• a -hydroxyaldehyde.

• or a -hydroxyketone.

OCH3-C-CH3CH3-C-CH3

OCH2-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-HO

CH2-C-HH O NaOH

CH3-CH-CH2-C-H

OH O+

AcetaldehydeAcetaldehyde 3-Hydroxybutanal(a -hydroxyaldehyde;

racemic)

acid

acid

19-19-66

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

Base-catalyzed aldol reaction (good nucleophile)Step 1: Formation of a resonance-stabilized enolate

anion.

Step 2: Carbonyl addition gives a TCAI.

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

CH3-C-H

O

CH2-C-HO

CH3-CH-CH2-C-HOO -

A tetrahedal carbonyladdition intermediate

+

CH2=C-H

O

CH2-C-HO

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

+H-O

An enolate anionpKa 20(weaker acid)

pKa 15.7(stronger acid)

19-19-77

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 have

nucleophilic 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 sufficiently

reactive.

19-19-88

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

Acid-catalyzed aldol reaction (good electrophile)• Step 1: Acid-catalyzed equilibration of keto and enol

forms.

• Step 2: Proton transfer from HA to the carbonyl group of 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+ +

Nucleophilic carbon

Reactive carbonyl

19-19-99

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.

OCH3-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

19-19-1010

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.

• Keq for dehydration is generally large.

• If reaction conditions bring about dehydration, good yields of product can be obtained.

An -unsaturatedaldehyde

+

OOH O

CH3CHCH2CH CH3CH=CHCH H2 O

warm in eitheracid or base

19-19-1111

Crossed Aldol ReactionsCrossed Aldol Reactions

In a crossed aldol reaction, one kind of molecule provides the enolate anion and another kind provides the carbonyl group.

CH3CCH3

O

HCHO NaOH

CH3CCH2CH2OHO

4-Hydroxy-2-butanone+

acid Non-acidic, no alpha hydrogens

19-19-1212

Crossed Aldol ReactionsCrossed Aldol Reactions

Crossed aldol reactions are most successful if• one of the reactants has no -hydrogen and, therefore,

cannot form an enolate anion,•

• One reactant has a more acidic hydrogen than the other (next slide)

• One reactant is an aldehyde which has a more reactive carbonyl group.

HCH

OCHO

O CHO CHO

Formaldehyde Benzaldehyde Furfural 2,2-Dimethylpropanal

19-19-1313

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-NO

OH-O-H CH2-N

O

OCH2=N

O

O

Resonance-stabilized anion

+

NitromethanepKa 10.2

(stronger acid)

WaterpKa 15.7

(weaker acid)

+

O

CH3NO2NaOH

HO CH2NO2

H2, NiCH2NH2HO

1-(Aminomethyl)- cyclohexanol

1-(Nitromethyl)-cyclohexanol

Nitro-methane

Cyclohex-anone

(aldol)+

19-19-1414

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.

O

O

O

O

KOH

KOH

O

HO

O

OH

-H2O

-H2O

O

O2,7-Octanedione

(not formed)

(formed)

19-19-1515

SynthesisSynthesis: Retrosyntheic Analysis: Retrosyntheic Analysis

Two Patterns to look for

19-19-1616


Recognitionpattern

Analysis

19-19-1717


Example

Mixed aldol

BenzaldehydeNo alpha hydrogens

19-19-1818

Claisen Condensation, Claisen Condensation, EsterEster Substitution Substitution

Esters also form enolate anions which participate in nucleophilic acyl substitution.

• The product of a Claisen condensation is a -ketoester.

O

2CH3COEt1. EtO

- Na

+

2. H2O, HCl

O O

CH3CCH2COEt EtOHEthanolEthyl 3-oxobutanoate

(Ethyl acetoacetate)Ethyl ethanoate(Ethyl acetate)

+

CC C C OR

O O

A -ketoester

Recognition Element

19-19-1919

Claisen CondensationClaisen Condensation

• Claisen condensation of ethyl propanoate

OEt

O

OEt

O1. EtO

- Na

+

2. H2O, HClOEt

OO

EtOH+

Ethyl propanoate

Ethyl 2-methyl-3-oxopentanoate

(racemic)

+

Ethyl propanoate

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

19-19-2020

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-COEtHO

EtOH CH2-COEtO O -

CH2=COEtpKa = 22

(weaker acid)pKa 15.9(stronger

acid)

Resonance-stabilized enolate anion

-++

CH3-C-OEt

O OCH2-COEt

O - O

OEtCH3-C-CH2-C-OEt+

A tetrahedral carbonyladdition intermediate

19-19-2121

Mechanism: Mechanism: Claisen CondensationClaisen CondensationStep 3: Collapse of the TCAI gives a -ketoester and an

alkoxide ion.

Step 4: An acid-base reaction drives the reaction to completion. This consumption of base must be anticipated.

EtOCH3-C-CH2-C-OEt

O OOCH3-C-CH2-C-OEt

O

OEt

+

EtO

H

CH3-C-CH-C-OEtO O

CH3-C-CH-C-OEt

OO

EtOH

pKa 15.9(weaker acid)

pKa 10.7(stronger acid)

++

19-19-2222

Intramolecular Claisen condensation: Intramolecular Claisen condensation: Dieckman CondensationDieckman Condensation

+

Diethyl hexanedioate(Diethyl adipate)

Ethyl 2-oxocyclo-pentanecarboxylate

1. EtO-

Na+

2. H2O, HCl

EtOH

OEt

OEtO

O

OEt

O O

Acidic

19-19-2323

Crossed Claisen CondsnsCrossed Claisen Condsns

Crossed Claisen condensations between two different esters, each with -hydrogens, give mixtures of products and are usually not useful.

But if one ester has no -hydrogens crossed Claisen is useful.

O

HCOEt EtOCOEtO

COEt

OO

EtOC-COEt

Diethyl ethanedioate (Diethyl oxalate)

Diethylcarbonate

Ethylformate

Ethyl benzoate

O

No -hydrogens

19-19-2424

Crossed Claisen CondsnsCrossed Claisen Condsns

• The ester with no -hydrogens is generally used in excess.

Ph OCH3

O

OCH3

O1. CH3O

- Na

+

2. H2O, HCl Ph OCH3

O O

Methylpropanoate

Methylbenzoate

+

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

(racemic)Used in excess

19-19-2525

Claisen condensations are a route to ketones via decarboxylation

OEt

O

OEt

OO

1. EtO-

Na+

2. H2O, HCl

3. NaOH, H2O, heat

OEt

OO

4. H2O, HCl

5. heatO

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

19-19-2626

Synthesis: Synthesis: Claisen CondensationClaisen Condensation

The result of Claisen condensation, saponification, acidification, and decarboxylation is a ketone.

R-CH2-COR'

O

R

O

CH2-C-OR' R-CH2-C-CH2-RO

2HOR' CO2++

severalsteps

+

from the esterfurnishing theenolate anion

from the esterfurnishing the carbonyl group

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

19-19-2727

Synthesis: Synthesis: Retrosynthetic AnalysisRetrosynthetic Analysis

Site of acidic hydrogen, nucleophile

Site of substitution, electrophile

New bond

19-19-2828

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

Recall primary amines react with carbonyl compounds to give Schiff bases (imines), RN=CR2.

Primary amine

Secondary Amine

But secondary amines react to give enamines

19-19-2929

Formation of EnaminesFormation of Enamines

Again, enamines are formed by the reaction of a 2° amine with the carbonyl group of an aldehyde or ketone.• The 2° amines most commonly used to prepare

enamines are pyrrolidine and morpholine.

Pyrrolidine Morpholine

N

O

N

HH

19-19-3030

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+

-H2OH

+

19-19-3131

Enamines – Alkylation at Enamines – 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 of

cyclohexanone

+

Br••N

O

BrSN2 N

O

3-Bromopropene(Allyl bromide)

19-19-3232

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

OCH3-C-H

H

CH2=C-H

HO

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

OH O

H-A+ ++

(racemic)

An iminiumbromide(racemic)

The morpholineenamine of

cyclohexanone

+

Br••N

O

BrSN2 N

O

3-Bromopropene(Allyl bromide)

19-19-3333

Enamines - AlkylationEnamines - Alkylation

• Hydrolysis of the iminium halide gives an alkylated aldehyde or ketone.

Morpholinium chloride

2-Allylcyclo-hexanone

+HCl/ H2O

+Br-N

OO

+Cl-N

O

H H

Overall process is to render the alpha carbonss of ketone nucleophilic enough so that substitution reactions can occur.

19-19-3434

Enamines – Acylation at Enamines – Acylation at position position

• Enamines undergo acylation when treated with acid chlorides and acid anhydrides.

N

CH3CClO

Cl- N OHCl

O O

NH H

Cl-

+

Acetyl chloride

An iminiumchloride(racemic)

2-Acetylcyclo-hexanone(racemic)

++

+

H2O

O

Could this be made via a crossed Claisen followed by decarboxylation.

19-19-3535

Overall, Acetoacetic Ester SynthesisOverall, Acetoacetic Ester Synthesis

The acetoacetic ester (AAE) synthesis is useful for the preparation of mono- and disubstituted acetones of the following types:

CH3CCH2COEtO O

R'

CH3CCHRO

CH3CCH2RO

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

19-19-3636

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 -diester rather than a -ketoester.

O

EtOCCH2COEt

O

OR

RCHCOH

RCH2COHO

A disubstitutedacetic 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

19-19-3737

Malonic Ester SynthesisMalonic Ester Synthesis

Consider the synthesis of this target molecule:

MeO OH

O

5-Methoxypentanoic acid

These two carbonsare from diethyl malonate

Recognize as substituted acetic acid. Malonic Ester Synthesis

19-19-3838

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

EthanolpKa 15.9

(weaker acid)

Sodium ethoxide

Sodium salt of diethyl malonate

+

Diethyl malonatepKa 13.3

(stronger acid)

MeO Br

Na+

COOEt

COOEt

COOEt

COOEtMeO Na+ Br-++

SN2

19-19-3939

Malonic Ester SynthesisMalonic Ester Synthesis

3. Saponify and acidify.

4. Decarboxylation.

2EtOH+COOEt

COOEtMeO

3. NaOH, H2O

4. HCl, H2OCOOH

COOHMeO

COOH

COOHMeO

heatMeO

COOH CO2+

5-Methoxypentanoic acid

19-19-4040

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

Michael reaction:Michael reaction: the nucleophilic addition of an enolate anion to an ,-unsaturated carbonyl compound.• Example:

COOEt

EtOOCO

EtO- Na

+

EtOHCOOEt

EtOOCO

+

3-Buten-2-one(Methyl vinyl

ketone)

Diethylpropanedioate

(Diethyl malonate)

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

19-19-4141

CH2=CHCCH3

O

CH2=CHCOEtO

CH2=CHCNR2

O

CH3CCH2CCH3

O O

CH2=CHNO2

CH2=CHC N

CH2=CHCHO

CH3CCH2COEtO O

O

EtOCCH2COEtO

NCH3C=CH2

CH3CCH2CNO

NH3, RNH2, R2NH

These Types of -Unsaturated Compounds are Nucleophile Acceptors in Michael Reactions

These Types of CompoundsProvide Effective Nucleophilesfor Michael Reactions

-Ketoester

-Diketone

-Diester

Enamine

-Ketonitrile

Aldehyde

Ketone

Ester

Amide

Nitrile

Nitro compound

Amine

Michael ReactionMichael Reaction

19-19-4242

Michael Reaction in baseMichael Reaction in base

Example:

• The double bond of an ,-unsaturated carbonyl compound 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

19-19-4343

Mechanism: Mechanism: Michael ReactionMichael Reaction

Mechanism1: Set up of nucleophile; Proton transfer to the base.

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

Base+ +Nu-H :B- Nu:- H-B

+ C C C

O

CCNu C

O

CCNu C

O

Resonance-stabilized enolate anion

Nu

19-19-4444

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.

CCNu CO

H-B+ CCNu C

O-H

BB

An enol(a product of 1,4-addition)

1

4 3 2+

CCNuO-H

C CCNu CH O

More stable keto formLess stable enol form

19-19-4545

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, and give 1,4-addition products.

• Organolithium and Grignard reagents, on the other hand, are strong bases, add rapidly to carbonyl groups, and given primarily 1,2-addition.

PhLi

O O-Li

+Ph

H2OHCl

OHPh

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

4-Methyl-3-penten-2-one

+

Phenyl-lithium

19-19-4646

Michael Reaction: Thermodynamic vs KineticMichael Reaction: Thermodynamic vs Kinetic

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

COCC

Nu

ROHC C C

OH

Nu

Nu:

RO-

C C CO

ROHCCNu C

OC C

H

Nu CO

RO-

-

- +

-

+

+

fast

slow

1,2-Addition(less stable product)

1,4-Addition(more stable product)

19-19-4747

Micheal-Aldol CombinationMicheal-Aldol Combination

+

Ethyl 2-oxocyclohex- anecarboxylate

3-Buten-2-one(Methyl vinyl

ketone)

1. NaOEt, EtOH

(Michael reaction)

2. NaOEt, EtOH

(Aldol reaction)

COOEt

O O

COOEt

OO O

COOEt

Carbanion siteunsaturated

Dieckman

19-19-4848

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

O O O O

COOH

O

COOEt

O

this carbonlost by decarboxylation

this bond formedin a Michael reaction

Ethyl acetoacetate

Methyl vinyl ketone

these three carbons fromacetoacetic ester

+

Recognize as substituted acetone, aae synthesis

Recognize as Nucleophile – C – C – COMichael

19-19-4949

Michael ReactionsMichael Reactions

• Enamines also participate in Michael reactions.

N 1. CH2=CHCN

2. H2O, HCl

OCN

NHHCl-

+ +

Pyrrolidine enamineof cyclohexanone

(racemic)

19-19-5050

Gilman Reagents vs other organometallicsGilman Reagents vs other organometallics

Gilman reagents undergo conjugate addition to ,-unsaturated aldehydes and ketones in a reaction 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 Grignard reagents, add to the carbonyl carbon by 1,2-addition.

O

1. (CH3)2CuLi, ether, -78°C

2. H2O, HCl

O

3-Methyl-2-cyclohexenone

3,3-Dimethyl-cyclohexanone

CH3 CH3

CH3

19-19-5151

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 purpose is lithium diisopropylamide , LDA.

LDA is prepared by dissolving diisopropylamine in THF and treating the solution with butyl lithium.

[(CH3)2CH]2N-Li+

Lithium diisopropylamde(weaker base)

[(CH3)2CH]2NH + CH3(CH2)3Li + CH3(CH2)2CH3

ButanepKa 50

(weaker acid)

Butyllithium(stronger base)

Diisopropylamine(pKa 40

(stronger acid)

LDA

19-19-5252


The crossed aldol reaction between acetone and an aldehyde can be carried out successfully by adding acetone to one equivalent of LDA to completely preform its enolate anion, which is then treated with the aldehyde.

O LDA

-78°C

O-Li+ C6H5CH2CHO

1.

2. H2O

OOHC6H5

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

Acetone Lithiumenolate

19-19-5353

Examples using LDAExamples using LDA

Crossed aldol

Michael

Alkylation

Acylation

19-19-5454


Question: For ketones with nonequivalent -hydrogens, can we selectively utilize the nonequivalent sites?

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

19-19-5555


• When 2-methylcyclohexanone is treated with a slight excess of LDA, the enolate is almost entirely the less substituted enolate anion.

• When 2-methylcyclohexanone is treated with LDA where the ketone is in slight excess, the product is richer in the more substituted enolate.

O

+ LDA0°C

O-Li+ O-Li+

[(CH3)2CH]2NH

(racemic) 10% 90%

++

slight excess of the ketone

O

+ LDA0°C

O-Li+ O-Li+

[(CH3)2CH]2NH

(racemic) 99% 1%

++

slight excess of base

19-19-5656


The most important factor determining the composition of the enolate anion mixture is whether the reaction is under kinetic (rate) or thermodynamic (equilibrium) control.

Thermodynamic Control: Experimental conditions that permit establishment of equilibrium between two or more products of a reaction.The composition of the mixture is determined by the relative stabilities of the products.

19-19-5757


• Equilibrium among enolate anions is established when the ketone is in slight excess, a condition under which it is possible for proton-transfer reactions to occur between an enolate and an -hydrogen of an unreacted ketone. Thus, equilibrium is established between alternative enolate anions.

OH

+CH3

O Li+ O-Li+ O

+

(racemic)More stableenolate anion

(racemic) Less stableenolate anion

(racemic)

19-19-5858


Kinetic control: Experimental conditions under which the composition of the product mixture is determined by the relative rates of formation of each 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 hindered hydrogen is removed more rapidly, and the major product is the less substituted enolate anion.

• No equilibrium among alternative structures is set up.

19-19-5959

ExampleExample

1. 1.01 mol LDA, kinetic control

1. 0.99 mol LDA, thermodynamic control

19 enolates enamines

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