Chapter22TheChemistryofEnolateIons,Enols,andα,β‐UnsaturatedCarbonylCompounds

Organic Chemistry, 5th ed. Marc Loudon

Eric J. Kantorowski California Polytechnic State University San Luis Obispo, CA

Chapter22Overview

•  22.1AcidityofCarbonylCompounds

•  22.2Enoliza9onofCarbonylCompounds•  22.3α‐Halogena9onofCarbonylCompounds

•  22.4AldolAddi9onandAldolCondensa9on•  22.5Condensa9onReac9onsInvolvingEsterEnolateIons•  22.6BiosynthesisofFaHyAcids•  22.7Alkyla9onofEsterEnolates•  22.8Conjugate‐Addi9onReac9ons•  22.9Reduc9onofα,β‐UnsaturatedCarbonylCompounds•  22.10Reac9onsofα,β‐UnsaturatedCarbonylCompounds

withOrganometallicReagents

•  22.11OrganicSynthesiswithConjugate‐Addi9onReac9ons2

EnolatesandEnols

•  Theα‐Hofcarbonylcompoundsarerela9velyacidic

•  Theα‐Cofenolatesandenolscanserveasanucleophile

322.1AcidityofCarbonylCompounds

Forma6onofEnolateAnions

•  Theα‐Hofaldehydes,ketones,esters,andevennitrilescanbedeprotonated

422.1AcidityofCarbonylCompounds

Forma6onofEnolateAnions

•  Anesterα‐Hisabout1079meslessacidicthanaldehydesandketones(pKa≈25)

•  TheN‐Hofprimaryandsecondaryamidesismoreacidicthantheα‐H

522.1AcidityofCarbonylCompounds

AcidityandElectronDistribu6on

•  Theα‐Candcarbonyloxygenbearasignificantamountofelectrondensity

622.1AcidityofCarbonylCompounds

EnolateOrbitalDiagram

722.1AcidityofCarbonylCompounds

Reac6onsofEnolateIons

822.1AcidityofCarbonylCompounds

Reac6onsofEnolateIons

922.1AcidityofCarbonylCompounds

Enols

1022.2EnolizaAonofCarbonylCompounds

Enols

•  Someenolsaremorestablethantheircorrespondingcarbonylcompounds

1122.2EnolizaAonofCarbonylCompounds

Enols

•  Conversionofacarbonylcompoundintoitsenoliscalledenoliza6on

•  Theprocessisfacilitatedbyacidorbase•  Base‐catalyzedenoliza9on:

1222.2EnolizaAonofCarbonylCompounds

Enols

•  Acid‐catalyzedenoliza9on:

1322.2EnolizaAonofCarbonylCompounds

Enols

•  α‐Hexchangeandracemiza9onalsooccurunderacidiccondi9ons

1422.2EnolizaAonofCarbonylCompounds

Acid‐Catalyzedα‐Halogena6on

•  Enolsarethereac9veintermediates

1522.3α‐HalogenaAonofCarbonylCompounds

Acid‐Catalyzedα‐Halogena6on

•  Inacid,onlyasinglehalogena9onoccurs

1622.3α‐HalogenaAonofCarbonylCompounds

Halogena6onofAldehydesandKetones

•  Inbase,allα‐H’saresubs9tutedbyhalogens

•  Haloformreac6on:Whenacetaldehydeoramethylketoneareused,acarboxylicacidandhaloform(HCX3)areproduced

1722.3α‐HalogenaAonofCarbonylCompounds

TheHaloformReac6on

1822.3α‐HalogenaAonofCarbonylCompounds

TheHaloformReac6on

1922.3α‐HalogenaAonofCarbonylCompounds

α‐Bromina6onofCarboxylicAcids

•  ThisistheHell‐Volhard‐Zelinsky(orHVZ)reac9on

2022.3α‐HalogenaAonofCarbonylCompounds

α‐Bromina6onofCarboxylicAcids

2122.3α‐HalogenaAonofCarbonylCompounds

α‐Bromina6onofCarboxylicAcids

•  WhenasmallamountofPBr3catalystisused:

•  WhenonefullequivalentofPBr3isused:

2222.3α‐HalogenaAonofCarbonylCompounds

Reac6onsofα‐HaloCarbonylCompounds

•  Mostα‐halocarbonylcompoundsarehighlyreac9veinSN2reac9ons

2322.3α‐HalogenaAonofCarbonylCompounds

Reac6onsofα‐HaloCarbonylCompounds

•  SN1reac9onsgenerallydonotoccur

2422.3α‐HalogenaAonofCarbonylCompounds

Base‐CatalyzedAldolReac6ons

•  Thetermaldolisalsousedgenericallyforβ‐hydroxyaldehydes

•  Aldolreac6on:Areac9onoftwoaldehydemoleculestoformaβ‐hydroxyaldehyde

2522.4AldolAddiAonandAldolCondensaAon

Base‐CatalyzedAldolReac6ons

•  Thealdoladdi9onisreversibleandmorefavorableforaldehydesthanketones

2622.4AldolAddiAonandAldolCondensaAon

TheAldolCondensa6on

•  Withhigherbaseconcentra9onand/orhighertemperaturesthealdolproductcandehydrate

2722.4AldolAddiAonandAldolCondensaAon

Acid‐CatalyzedAldolCondensa6on

•  Withacid,aldolcondensaAonproductsareformed;addi9onproductscannotbeisolated

2822.4AldolAddiAonandAldolCondensaAon

Acid‐CatalyzedAldolCondensa6on

2922.4AldolAddiAonandAldolCondensaAon

SpecialTypesofAldolReac6ons

•  Claisen‐Schmidtcondensa6on:AnexampleofacrossedaldolreacAon

•  Intramolecularaldolcondensa9ons

3022.4AldolAddiAonandAldolCondensaAon

SynthesiswiththeAldolCondensa6on

•  Recognizingthealdoldisconnec9onissynthe9callyuseful

3122.4AldolAddiAonandAldolCondensaAon

SomeCommonOrganicGroupAbbrevia6ons

3222.5CondensaAonReacAonsInvolvingEsterEnolateIons

ClaisenCondensa6on

•  Acondensa9onreac9oninvolvingesters

•  Theproductisaβ‐ketoester

3322.5CondensaAonReacAonsInvolvingEsterEnolateIons

ClaisenCondensa6on

3422.5CondensaAonReacAonsInvolvingEsterEnolateIons

ClaisenCondensa6on

•  Thereac9onisdriventocomple9onbyapplyingLeChâtelier’sprinciple

•  Onefullequivalentofthealkoxideisrequired

•  Atleastoneα‐Hisrequiredforsuccess

3522.5CondensaAonReacAonsInvolvingEsterEnolateIons

DieckmannCondensa6on

•  AnintramolecularClaisencondensa9on

3622.5CondensaAonReacAonsInvolvingEsterEnolateIons

CrossedClaisenCondensa6on

•  AClaisencondensa9onoftwodifferentesters•  Ifbothhaveα‐H’sthenamixtureoffourcompoundsresults

3722.5CondensaAonReacAonsInvolvingEsterEnolateIons

CrossedClaisenCondensa6on

•  Thereac9oncanbeusefulifoneesterisespeciallyreac9veorhasnoα‐H’s

3822.5CondensaAonReacAonsInvolvingEsterEnolateIons

SynthesiswiththeClaisenCondensa6on

3922.5CondensaAonReacAonsInvolvingEsterEnolateIons

SynthesiswiththeClaisenCondensa6on

4022.5CondensaAonReacAonsInvolvingEsterEnolateIons

BiosynthesisofFaMyAcids

•  Thestar9ngmaterial,acetyl‐coenzymeA,isathiolesteroface9cacid

4122.6BiosynthesisofFaOyAcids

BiosynthesisofFaMyAcids

•  Theacetyl‐CoAisconvertedintomalonyl‐CoA

4222.6BiosynthesisofFaOyAcids

BiosynthesisofFaMyAcids

4322.6BiosynthesisofFaOyAcids

MalonicEsterSynthesis

4422.7AlkylaAonofEsterEnolates

MalonicEsterSynthesis

•  Recognizinghowatargetcarboxylicacidcanbepreparedbythemalonicestersynthesisissynthe9callyuseful

4522.7AlkylaAonofEsterEnolates

DirectAlkyla6onofEnolateIons

•  Highlybranchednitrogenbasesarecommonlyused

4622.7AlkylaAonofEsterEnolates

DirectAlkyla6onofEnolateIons

4722.7AlkylaAonofEsterEnolates

Acetoace6cEsterSynthesis

4822.7AlkylaAonofEsterEnolates

Acetoace6cEsterSynthesis

4922.7AlkylaAonofEsterEnolates

Acetoace6cEsterSynthesis

•  Recognizinghowatargetketonecanbepreparedbytheacetoace9cestersynthesisissynthe9callyuseful

5022.7AlkylaAonofEsterEnolates

ConjugateAddi6on

•  Auniquereac9vityisobservedforalkenesthatareconjugatedwithcarbonyls(C=C–C=O)

•  Theseconjugatedcompoundsaregenerallycalledα,β‐unsaturatedcarbonylcompounds

5122.8Conjugate‐AddiAonReacAons

ConjugateAddi6on

5222.8Conjugate‐AddiAonReacAons

ConjugateAddi6on

•  Withα,β‐unsaturatedesters:

•  Withα,β‐unsaturatedketones:

•  Withα,β‐unsaturatednitriles:

5322.8Conjugate‐AddiAonReacAons

ConjugateAddi6onvsCarbonyl‐GroupAddi6on

•  Forketonesandaldehydes,rela9velyweakbasesthatgivereversiblecarbonyl‐addi9ontendtogiveconjugateaddi9on

5422.8Conjugate‐AddiAonReacAons

ConjugateAddi6onvsCarbonyl‐GroupAddi6on

•  Forestersconjugateaddi9oncompeteswithnucleophilicacylsubs9tu9on

5522.8Conjugate‐AddiAonReacAons

ConjugateAddi6onofEnolateIons

•  Commonforenolateionsderivedfrommalonicesterderiva9vesandβ‐ketoesters

•  Conjugateaddi9onstoα,β‐unsaturatedcarbonylcompoundsarecalledMichaeladdi6ons

5622.8Conjugate‐AddiAonReacAons

TheRobinsonAnnula6on

•  Asynthe9callyusefulvariantthatu9lizesaMichaeladdi9onfollowedbyanaldolcondensa9on

5722.8Conjugate‐AddiAonReacAons

Reduc6onofα,β‐UnsaturatedCarbonyls

•  Carbonylreduc9onisnotonlyfaster,butisalsoirreversible(i.e.,kineAcallycontrolled)

5822.9ReducAonofα,β‐UnsaturatedCarbonylCompounds

Reduc6onofα,β‐UnsaturatedCarbonyls

•  TheC=Cofα,β‐unsaturatedcarbonylscanbeselec9velyreducedbycataly9chydrogena9on

5922.9ReducAonofα,β‐UnsaturatedCarbonylCompounds

Addi6onofOrganolithiumReagents

•  Addi9onofR‐Liresultsincarbonyladdi9on

6022.10ReacAonsofα,β‐UnsaturatedCarbonylCompoundswithOrganometallics

Addi6onofLithiumDialkylcuprateReagents

•  Addi9onofR2CuLiresultsinconjugateaddi9on

6122.10ReacAonsofα,β‐UnsaturatedCarbonylCompoundswithOrganometallics

Addi6onofLithiumDialkylcuprateReagents

•  Theaddi9onofthenucleophilicreagentresultsintheforma9onofanenolateion

6222.10ReacAonsofα,β‐UnsaturatedCarbonylCompoundswithOrganometallics

ConjugateAddi6oninOrganicSynthesis

•  Consideranygroupattheβ‐posi9onofacarbonyl(ornitrile)asanucleophileinaconjugateaddi9onreac9on

6322.11OrganicSynthesiswithConjugate‐AddiAonReacAons

SummaryofC‐CBondFormingReac6ons

1.Aldoladdi9onandcondensa9on2.ClaisenandDieckmanncondensa9ons

3.Malonicestersynthesis

4.Alkyla9onofesterenolates

5.Acetoace9cestersynthesis

6.Conjugateaddi9onofcyanideionsandenolateions

7.Conjugateaddi9onofR2CuLi

6422.11OrganicSynthesiswithConjugate‐AddiAonReacAons