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Chapter 23- Carbonyl Condensation Reactions

AshleyPiekarski,Ph.D.

Condensation Reactions

•  Carbonylcompoundsareboththeelectrophileandnucleophileincarbonylcondensa?onreac?ons

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Why this Chapter?

•  Carbonylcondensa?onreac?onsalsooccuro@eninmetabolicpathways.

•  AlsoonethegeneralmethodsusedtoformC-Cbonds.

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23.1 Carbonyl Condensation: The Aldol Reaction

•  Acetaldehydereactsinbasicsolu?on(NaOEt,NaOH)withanothermoleculeofacetaldhyde

•  Theβ-hydroxyaldehydeproductisaldol(aldehyde+alcohol)

•  Thisisageneralreac?onofaldehydesandketones

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The Equilibrium of the Aldol

•  Thealdolreac?onisreversible,favoringthecondensa?onproductonlyforaldehydeswithnoαsubs?tuent

•  Stericfactorsareincreasedinthealdolproduct

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Aldehydes and Ketones and the Aldol Equilibrium

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Mechanism of Aldol Reactions

•  Aldolreac?ons,likeallcarbonylcondensa?ons,occurbynucleophilicaddi?onoftheenolateionofthedonormoleculetothecarbonylgroupoftheacceptormolecule

•  Theaddi?onintermediateisprotonatedtogiveanalcoholproduct

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Mechanism of Aldol Reactions

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23.2 Carbonyl Condensation versus α-Substitution

•  Carbonylcondensa?onsandαsubs?tu?onsbothinvolveforma?onofenolateionintermediates

•  α-subs?tu?onreac?onsareaccomplishedbyconver?ngallofthecarbonylcompoundtoenolateformsoitisnotanelectrophile

•  Immediateaddi?onofanalkylhalidetocompletesthealkyla?onreac?on

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Conditions for Condensations

•  Asmallamountofbaseisusedtogenerateasmallamountofenolateinthepresenceofunreactedcarbonylcompound

•  A@erthecondensa?on,thebasiccatalystisregenerated

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23.3 Dehydration of Aldol Products: Synthesis of Enones

•  Theβ-hydroxycarbonylproductsdehydratetoyieldconjugatedenones

•  Theterm“condensa?on”referstothenetlossofwaterandcombina?onof2molecules

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Dehydration of β-Hydroxy Ketones and Aldehydes

•  Theαhydrogenisremovedbyabase,yieldinganenolateionthatexpelsthe-OHleavinggroup

•  Underacidiccondi?onsthe⎯OHgroupisprotonatedandwaterisexpelled

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Driving the Equilibrium

•  Removalofwaterfromthealdolreac?onmixturecanbeusedtodrivethereac?ontowardproducts

•  Eveniftheini?alaldolfavorsreactants,thesubsequentdehydra?onsteppushesthereac?ontocomple?on

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23.4 Using Aldol Reactions in Synthesis

•  Ifadesiredmoleculecontainseitheraβ-hydroxycarbonyloraconjugatedenone,itmightcomefromanaldolreac?on

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Extending the Synthesis

•  Subsequenttransforma?onscanbecarriedoutonthealdolproducts

•  Asaturatedketonemightbepreparedbycataly?chydrogena?onoftheenoneproduct

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23.5 Mixed Aldol Reactions

•  Amixedaldolreac?onbetweentwosimilaraldehydeorketonepartnersleadstoamixtureoffourpossibleproducts

•  Thisisnotuseful

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Practical Mixed Aldols

•  Ifoneofthecarbonylpartnerscontainsnoαhydrogensandthecarbonylisunhindered(suchasbenzaldehydeandformaldehyde)itisagoodelectrophileandcanreactwithenolates,thenamixedaldolreac?onislikelytobesuccessful

•  2-methylcyclohexanonegivesthemixedaldolproductonreac?onwithbenzaldehyde

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Practical Mixed Aldols

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Mixed Aldols With Acidic Carbonyl Compounds

•  Ethylacetoacetateiscompletelyconvertedintoitsenolateionunderlessbasiccondi?onsthanmonocarbonylpartners

•  Aldolcondensa?onswithethylacetoacetateoccurpreferen?allytogivethemixedproduct

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23.6 Intramolecular Aldol Reactions

•  Treatmentofcertaindicarbonylcompoundswithbaseproducescyclicproductsbyintramolecularreac?on

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Mechanism of Intramolecular Aldol Reactions

•  Boththenucleophiliccarbonylaniondonorandtheelectrophiliccarbonylacceptorarenowinthesamemolecule.

•  Theleaststrainedproductisformedbecausethereac?onisreversible

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Mechanism of Intramolecular Aldol Reactions

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23.7 The Claisen Condensation Reaction

•  Reac?onofanesterhavinganαhydrogenwith1equivalentofabasetoyieldaβ-ketoester

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Mechanism of the Claisen Condensation

•  Similartoaldolcondensa?on:nucleophilicacylsubs?tu?onofanesterenolateiononthecarbonylgroupofasecondestermolecule

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Mechanism of the Claisen Condensation

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Features of the Claisen Condensation

•  Ifthestar?ngesterhasmorethanoneacidicahydrogen,theproductβ-ketoesterhasadoublyac?vatedprotonthatcanbeabstractedbybase

•  Requiresafullequivalentofbaseratherthanacataly?camount

•  Thedeprotona?ondrivesthereac?ontotheproduct

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23.8 Mixed Claisen Condensations

•  Successfulwhenoneofthetwoestersactsastheelectrophilicacceptorinreac?onswithotheresteranionstogivemixedβ-ketoesters

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Esters and Ketones

•  Reac?onsbetweenestersandketones,resul?nginβ-diketones

•  Bestwhentheestercomponenthasnoαhydrogensandcan'tactasthenucleophilicdonor

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23.9 Intramolecular Claisen Condensations: The Dieckmann Cyclization

•  IntramolecularClaisencondensa?on•  Bestwith1,6-diesters(product:5-memberedβ-ketoester)and1,7-diesters(product:6-memberedβ-ketoester)

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Mechanism of the Dieckmann Cyclization

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Alkylation of Dieckmann Product

•  Thecyclicβ-ketoestercanbefurtheralkylatedanddecarboxylatedasintheacetoace?cestersynthesis

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23.10 Conjugate Carbonyl Additions: The Michael Reaction

•  Enolatescanaddasnucleophilestoα,β-unsaturatedaldehydesandketonestogivetheconjugateaddi?onproduct

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Best Conditions for the Michael Reaction

•  Whenapar?cularlystableenolateion•  Example:Enolatefromaβ-ketoesterorother1,3-dicarbonylcompoundaddingtoanunhinderedα,β-unsaturatedketone

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Mechanism of the Michael Reaction

•  Nucleophilicaddi?onofaenolateiondonortotheβcarbonofanα,β-unsaturatedcarbonylacceptor

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Mechanism of the Michael Reaction

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Generality of the Michael Reaction

•  Occurswithavarietyofα,β-unsaturatedcarbonylcompounds(aldehydes,esters,nitriles,amides,andnitrocompounds)

•  Donorsincludeβ-diketones,β-ketoesters,malonicesters,β-ketonitriles,andnitrocompounds

•  SeeTable23.1

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23.11 Carbonyl Condensations with Enamines: The Stork Reaction

•  Enaminesareequivalenttoenolatesintheirreac?onsandcanbeusedtoaccomplishthetransforma?onsundermildercondi?ons

•  Enaminesarepreparedfromaketoneandasecondaryamine

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Enamines Are Nucleophilic

•  Overlapofthenitrogenlone-pairorbitalwiththedouble-bondπorbitalsincreaseselectrondensityontheαcarbonatom

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Enamine Addition and Hydrolysis

•  Enamineaddstoanα,β-unsaturatedcarbonylacceptor

•  Theproductishydrolyzedtoa1,5-dicarbonylcompound

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23.12 The Robinson Annulation Reaction

•  Atwo-stepprocess:combinesaMichaelreac?onwithanintramolecularaldolreac?on

•  Theproductisasubs?tuted2-cyclohexenone

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Mechanism of the Robinson Annulation Reaction

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23.13 Some Biological Carbonyl Condensation Reactions

•  MalonylACPisdecarboxylatedandenolateisformed

•  Enolateisaddedtothecarbonylgroupofanotheracylgroupthroughathioesterlinkagetoasynthase

•  TetrahedralintermediategivesacetoacetylACP

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23.13 Some Biological Carbonyl Condensation Reactions

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