aldehydes and ketones - ashley piekarski · 2016. 2. 29. · aryl ketones by acylation •...
TRANSCRIPT
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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