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Chapter 19- Aldehydes and Ketones: NucleophilicAddition Reactions

Aldehydes and Ketones

• Aldehydes(RCHO)andketones (R2CO)arecharacterizedbythethecarbonylfunctionalgroup(C=O)

• Thecompounds occurwidelyinnatureasintermediatesinmetabolismandbiosynthesis

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Why do I care, Dr. P?

• Muchoforganicchemistryinvolvesthechemistryofcarbonylcompounds

• Aldehydes/ketones areintermediatesinsynthesisofpharmaceuticalagents,biologicalpathways,numerous industrialprocesses

• Anunderstandingoftheirpropertiesisessential

Nomenclature

• Aldehydesarenamedbyreplacingtheterminal-eofthecorrespondingalkanenamewith–al

• Theparentchainmustcontainthe⎯CHOgroup• The ⎯CHO carbon is numbered as C1

• Ifthe⎯CHOgroupisattachedtoaring,usethesuffixcarbaldehyde.

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Nomenclature examples

Nomenclature- Common names

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Naming Ketones

• Replacetheterminal-eofthealkanenamewith–one

• Parentchainisthe longestonethatcontainstheketone group• Numbering begins at the end nearer the

carbonyl carbon

Ketones with Common Names

• IUPACretainswell-usedbutunsystematicnamesforafewketones

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Ketones and Aldehydes as Substituents

• TheR–C=Oasasubstituent isanacylgroup,usedwiththesuffix-yl fromtherootofthecarboxylicacid

• Theprefixoxo- isusedifotherfunctionalgroupsarepresentandthedoubly bondedoxygenislabeledasasubstituent onaparentchain

Ketones and Aldehydes as Substituents

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Preparation of Aldehydes

• Oxidizeprimaryalcoholsusingpyridiniumchlorochromate

Preparation of Aldehydes

• Alkeneswithavinylic hydrogencanundergooxidativecleavagewhentreatedwithozone,yieldingaldehydes

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Preparation of Aldehydes

• Reduceanesterwithdiisobutylaluminumhydride(DIBAH)

Preparing Ketones

• Oxidizea2° alcohol• Manyreagentspossible:chooseforthespecificsituation(scale,cost,andacid/basesensitivity)

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Ketones from Ozonolysis

• Ozonolysisofalkenesyieldsketones ifoneoftheunsaturatedcarbonatomsisdisubstituted

Aryl Ketones by Acylation

• Friedel–CraftsacylationofanaromaticringwithanacidchlorideinthepresenceofAlCl3catalyst

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Methyl Ketones by Hydrating Alkynes

• HydrationofterminalalkynesinthepresenceofHg2+

Oxidation of Aldehydes and Ketones

• CrO3 inaqueousacidoxidizesaldehydestocarboxylicacidsefficiently

• Silveroxide,Ag2O,inaqueousammonia(Tollens’ reagent)oxidizesaldehydes(noacid)

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Hydration of Aldehydes

• Aldehydeoxidationsoccurthrough1,1-diols(“hydrates”)

• Reversibleadditionofwatertothecarbonylgroup

• Aldehydehydrateisoxidizedtoacarboxylicacidbyusualreagentsforalcohols

Ketones Oxidize with Difficulty

• Undergoslowcleavagewithhot,alkalineKMnO4

• C–CbondnexttoC=Oisbrokentogivecarboxylicacids

• Reactionispracticalforcleavingsymmetricalketones

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NucleophilicAddition Reactions of Aldehydes and Ketones

• Nu- approaches75° totheplaneofC=OandaddstoC

• Atetrahedralalkoxide ionintermediateisproduced

Nucleophiles

• Nucleophilescanbenegativelycharged(:Nu−)orneutral(:Nu)atthereactionsite

• Theoverallchargeonthenucleophilic speciesisnotconsidered

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Nucleophiles- examples

Relative Reactivity of Aldehydes and Ketones

• Aldehydesaregenerallymorereactivethanketones innucleophilic additionreactions

• Whydoyouthinkthishappens?

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Relative Reactivity of Aldehydes and Ketones

• Thetransitionstateforaddition islesscrowdedandlowerinenergyforanaldehyde(a)thanforaketone(b)

• AldehydeshaveonelargesubstituentbondedtotheC=O:ketoneshavetwo- aldehydesaremorepolarized

Electrophilicity of Aldehydes and Ketones

• AldehydeC=OismorepolarizedthanketoneC=O

• Asincarbocations,morealkylgroupsstabilize+character

• Ketonehasmorealkylgroups,stabilizingtheC=Ocarboninductively

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Electrophilicity of Aldehydes and Ketones

Reactivity of Aromatic Aldehydes

• Lessreactiveinnucleophilicadditionreactionsthanaliphaticaldehydes

• Electron-donatingresonanceeffectofaromaticringmakesC=Olessreactiveelectrophilethanthecarbonylgroupofanaliphaticaldehyde

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Reactivity of Aromatic Aldehydes

Nucleophilic Addition of H2O: Hydration

• Aldehydesandketonesreactwithwatertoyield1,1-diols(geminal (gem)diols)

• Hydrationisreversible:agemdiol caneliminatewater

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Base-Catalyzed Addition of Water

• Additionofwateriscatalyzedbybothacidandbase

• Thebase-catalyzedhydrationnucleophileisthehydroxideion,which isamuchstrongernucleophilethanwater

Base-Catalyzed Addition of Water

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Acid-Catalyzed Addition of Water

• ProtonationofC=Omakesitmoreelectrophilic

Addition of H-Y to C=O

• ReactionofC=OwithH-Y,whereYiselectronegative,givesanadditionproduct(“adduct”)

• Formationisreadilyreversible

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NucleophilicAddition of HCN: Cyanohydrin Formation

• Aldehydesandunhinderedketones reactwithHCNtoyieldcyanohydrins,RCH(OH)C≡N

• AdditionofHCNisreversibleandbase-catalyzed,generatingnucleophilic cyanideion,CN-

• AdditionofCN− toC=Oyieldsatetrahedralintermediate,whichisthenprotonated

• Equilibriumfavorsadduct

NucleophilicAddition of HCN: Cyanohydrin Formation

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Uses of Cyanohydrins

• Thenitrilegroup(⎯C≡N)canbereducedwithLiAlH4 toyieldaprimaryamine(RCH2NH2)

• Canbehydrolyzedbyhotacidtoyieldacarboxylicacid

Nucleophilic Addition of Grignard Reagents and Hydride Reagents: Alcohol Formation

• TreatmentofaldehydesorketoneswithGrignardreagentsyieldsanalcohol• Nucleophilic addition of the equivalent of a

carbon anion, or carbanion. A carbon–magnesium bond is strongly polarized, so a Grignard reagent reacts for all practical purposes as R : − MgX +.

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Mechanism of Addition of Grignard Reagents

Hydride Addition

• ConvertC=OtoCH-OH• LiAlH4 andNaBH4 reactasdonorsofhydrideion

• Protonationafteradditionyieldsthealcohol

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NucleophilicAddition of Amines: Imine and Enamine Formation

• RNH2 addstoC=Otoformimines,R2C=NR(afterlossofHOH)

• R2NHyieldsenamines,R2N⎯CR=CR2 (afterlossofHOH)

Mechanism of Formation of Imines

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Imine Derivatives

• Additionofamineswithanatomcontainingalonepairofelectronsontheadjacentatomoccursveryreadily,givinguseful,stableimines

• Forexample,hydroxylamineformsoximesand2,4-dinitrophenylhydrazinereadilyforms2,4-dinitrophenylhydrazones• These are usually solids and help in

characterizing liquid ketones or aldehydes by melting points

Imine Derivatives

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Enamine Formation

NucleophilicAddition of Hydrazine: The Wolff–Kishner Reaction

• Treatmentofanaldehydeorketonewithhydrazine,H2NNH2 andKOHconvertsthecompound toanalkane

• Originallycarriedoutathightemperaturesbut withdimethylsulfoxide assolventtakesplacenearroomtemperature

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NucleophilicAddition of Alcohols: AcetalFormation

• AlcoholsareweaknucleophilesbutacidpromotesadditionformingtheconjugateacidofC=O

• Additionyieldsahydroxy ether,calledahemiacetal (reversible);furtherreactioncanoccur

• Protonationofthe⎯OHandlossofwaterleadstoanoxonium ion,R2C=OR+towhichasecondalcoholaddstoformtheacetal

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Uses of Acetals

• Acetals canserveasprotectinggroupsforaldehydesandketones

• Itisconvenienttouseadiol,toformacyclicacetal (thereactiongoesevenmorereadily)

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NucleophilicAddition of Phosphorus Ylides: The Wittig Reaction

• ThesequenceconvertsC=OistoC=C• Aphosphorus ylide addstoanaldehydeorketonetoyieldadipolarintermediatecalledabetaine

• Theintermediatespontaneously decomposesthroughafour-memberedringtoyieldalkeneandtriphenylphosphine oxide,(Ph)3P=O

NucleophilicAddition of Phosphorus Ylides: The Wittig Reaction

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Mechanism of the Wittig Reaction

Uses of the Wittig Reaction

• Canbeusedformonosubstituted,disubstituted, andtrisubstituted alkenesbutnottetrasubstituted alkenes

• Thereactionyieldsapurealkeneofknownstructure

• Forcomparison,additionofCH3MgBrtocyclohexanone anddehydrationwith,yieldsamixtureoftwoalkenes

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Uses of the Wittig Reaction

The Cannizaro Reaction

• TheadductofanaldehydeandOH− cantransferhydrideiontoanotheraldehydeC=Oresultinginasimultaneousoxidationandreduction(disproportionation)

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Conjugate NucleophilicAddition to α,β-Unsaturated Aldehydes and Ketones

• AnucleophilecanaddtotheC=Cdoublebondofanα,b-unsaturatedaldehydeorketone(conjugateaddition,or1,4addition)

• Theinitialproductisaresonance-stabilizedenolateion,whichisthenprotonated

Conjugate NucleophilicAddition to α,β-Unsaturated Aldehydes and Ketones

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Conjugate Addition of Amines

• Primaryandsecondaryaminesaddtoα,b-unsaturatedaldehydesandketonestoyieldb-aminoaldehydesandketones

Conjugate Addition of Alkyl Groups: Organocopper Reactions

• Reactionofanα,b-unsaturatedketonewithalithiumdiorganocopperreagent

• Diorganocopper(Gilman)reagentsformbyreactionof1equivalentofcuprous iodideand2equivalentsoforganolithium

• 1°,2°,3° alkyl,arylandalkenylgroupsreactbutnotalkynylgroups

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Conjugate Addition of Alkyl Groups: Organocopper Reactions

Mechanism of Alkyl Conjugate Addition

• Conjugatenucleophilic additionofadiorganocopper anion,R2Cu−,toanenone

• TransferofanRgroupandeliminationofaneutralorganocopper species,RCu

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Spectroscopy of Aldehydes and Ketones

• InfraredSpectroscopy• Aldehydesandketonesshow astrongC=Opeak1660to1770cm−1

• aldehydesshowtwocharacteristicC–Habsorptions inthe2720to2820cm−1range.

C=O Peak Position in the IR Spectrum

• Theprecisepositionofthepeakrevealstheexactnatureofthecarbonylgroup

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NMR Spectra of Aldehydes

• Aldehydeprotonsignalsareatδ 10in1HNMR- distinctivespin–spincouplingwithprotonsontheneighboringcarbon,J≈ 3Hz

13C NMR of C=O

• C=Osignalisatδ 190toδ 215• Nootherkindsofcarbonsabsorb inthisrange

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Mass Spectrometry – McLafferty Rearrangement

• Aliphaticaldehydesandketonesthathavehydrogensontheirgamma(γ)carbonatomsrearrangeasshown

Mass Spectroscopy: α-Cleavage

• Cleavageofthebondbetweenthecarbonylgroupandtheα carbon

• Yieldsaneutralradicalandanoxygen-containingcation