Chapter 22 · Chapter 22 The Chemistry of Enolate Ions, Enols, and α,β ... • 22.11 Organic...

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


Forma6onofEnolateAnions

•  Anesterα‐Hisabout1079meslessacidicthanaldehydesandketones(pKa≈25)

•  TheN‐Hofprimaryandsecondaryamidesismoreacidicthantheα‐H


AcidityandElectronDistribu6on

•  Theα‐Candcarbonyloxygenbearasignificantamountofelectrondensity


EnolateOrbitalDiagram


Reac6onsofEnolateIons


Enols

1022.2EnolizaAonofCarbonylCompounds

Enols

•  Someenolsaremorestablethantheircorrespondingcarbonylcompounds


Enols

•  Conversionofacarbonylcompoundintoitsenoliscalledenoliza6on

•  Theprocessisfacilitatedbyacidorbase•  Base‐catalyzedenoliza9on:


Enols

•  Acid‐catalyzedenoliza9on:


Enols

•  α‐Hexchangeandracemiza9onalsooccurunderacidiccondi9ons


Acid‐Catalyzedα‐Halogena6on

•  Enolsarethereac9veintermediates

1522.3α‐HalogenaAonofCarbonylCompounds

Acid‐Catalyzedα‐Halogena6on

•  Inacid,onlyasinglehalogena9onoccurs


Halogena6onofAldehydesandKetones

•  Inbase,allα‐H’saresubs9tutedbyhalogens

•  Haloformreac6on:Whenacetaldehydeoramethylketoneareused,acarboxylicacidandhaloform(HCX3)areproduced


TheHaloformReac6on


α‐Bromina6onofCarboxylicAcids

•  ThisistheHell‐Volhard‐Zelinsky(orHVZ)reac9on



•  WhenasmallamountofPBr3catalystisused:

•  WhenonefullequivalentofPBr3isused:


Reac6onsofα‐HaloCarbonylCompounds

•  Mostα‐halocarbonylcompoundsarehighlyreac9veinSN2reac9ons


Reac6onsofα‐HaloCarbonylCompounds

•  SN1reac9onsgenerallydonotoccur


Base‐CatalyzedAldolReac6ons

•  Thetermaldolisalsousedgenericallyforβ‐hydroxyaldehydes

•  Aldolreac6on:Areac9onoftwoaldehydemoleculestoformaβ‐hydroxyaldehyde

2522.4AldolAddiAonandAldolCondensaAon

Base‐CatalyzedAldolReac6ons

•  Thealdoladdi9onisreversibleandmorefavorableforaldehydesthanketones


TheAldolCondensa6on

•  Withhigherbaseconcentra9onand/orhighertemperaturesthealdolproductcandehydrate


Acid‐CatalyzedAldolCondensa6on

•  Withacid,aldolcondensaAonproductsareformed;addi9onproductscannotbeisolated


Acid‐CatalyzedAldolCondensa6on


SpecialTypesofAldolReac6ons

•  Claisen‐Schmidtcondensa6on:AnexampleofacrossedaldolreacAon

•  Intramolecularaldolcondensa9ons


SynthesiswiththeAldolCondensa6on

•  Recognizingthealdoldisconnec9onissynthe9callyuseful


SomeCommonOrganicGroupAbbrevia6ons

3222.5CondensaAonReacAonsInvolvingEsterEnolateIons

ClaisenCondensa6on

•  Acondensa9onreac9oninvolvingesters

•  Theproductisaβ‐ketoester


ClaisenCondensa6on


ClaisenCondensa6on

•  Thereac9onisdriventocomple9onbyapplyingLeChâtelier’sprinciple

•  Onefullequivalentofthealkoxideisrequired

•  Atleastoneα‐Hisrequiredforsuccess


DieckmannCondensa6on

•  AnintramolecularClaisencondensa9on


CrossedClaisenCondensa6on

•  AClaisencondensa9onoftwodifferentesters•  Ifbothhaveα‐H’sthenamixtureoffourcompoundsresults


CrossedClaisenCondensa6on

•  Thereac9oncanbeusefulifoneesterisespeciallyreac9veorhasnoα‐H’s


SynthesiswiththeClaisenCondensa6on


BiosynthesisofFaMyAcids

•  Thestar9ngmaterial,acetyl‐coenzymeA,isathiolesteroface9cacid

4122.6BiosynthesisofFaOyAcids


•  Theacetyl‐CoAisconvertedintomalonyl‐CoA


MalonicEsterSynthesis

4422.7AlkylaAonofEsterEnolates

MalonicEsterSynthesis

•  Recognizinghowatargetcarboxylicacidcanbepreparedbythemalonicestersynthesisissynthe9callyuseful


DirectAlkyla6onofEnolateIons

•  Highlybranchednitrogenbasesarecommonlyused


DirectAlkyla6onofEnolateIons


Acetoace6cEsterSynthesis



•  Recognizinghowatargetketonecanbepreparedbytheacetoace9cestersynthesisissynthe9callyuseful


ConjugateAddi6on

•  Auniquereac9vityisobservedforalkenesthatareconjugatedwithcarbonyls(C=C–C=O)

•  Theseconjugatedcompoundsaregenerallycalledα,β‐unsaturatedcarbonylcompounds

5122.8Conjugate‐AddiAonReacAons

ConjugateAddi6on


ConjugateAddi6on

•  Withα,β‐unsaturatedesters:

•  Withα,β‐unsaturatedketones:

•  Withα,β‐unsaturatednitriles:


ConjugateAddi6onvsCarbonyl‐GroupAddi6on

•  Forketonesandaldehydes,rela9velyweakbasesthatgivereversiblecarbonyl‐addi9ontendtogiveconjugateaddi9on


ConjugateAddi6onvsCarbonyl‐GroupAddi6on

•  Forestersconjugateaddi9oncompeteswithnucleophilicacylsubs9tu9on


ConjugateAddi6onofEnolateIons

•  Commonforenolateionsderivedfrommalonicesterderiva9vesandβ‐ketoesters

•  Conjugateaddi9onstoα,β‐unsaturatedcarbonylcompoundsarecalledMichaeladdi6ons


TheRobinsonAnnula6on

•  Asynthe9callyusefulvariantthatu9lizesaMichaeladdi9onfollowedbyanaldolcondensa9on


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


Addi6onofLithiumDialkylcuprateReagents

•  Theaddi9onofthenucleophilicreagentresultsintheforma9onofanenolateion


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

Chapter 22 · Chapter 22 The Chemistry of Enolate Ions, Enols, and α,β ... • 22.11 Organic...

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