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DerivativesofCarboxylicAcids
BuildingBridgestoKnowledge
FollowingareDerivativesofCarboxylicAcids.Thederivativesareobtainedbyreplacingthe“OH”groupwithothergroups:ReplacementoftheOHgroupwithahalogen-
whereX=F,Cl,Br,orIAcylChloridesAcylchloridesaremorecommonlyencounteredinthereactionsencounteredinanelementaryorganicchemistrycourse.
Acylhalidesarenamedbyreplacingthe“icacid”ofthecarboxylicacidwith“yl”followedbytheappropriatehalide.Forexample,
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wouldbebutanoicacidylchloride,butanoylchloride;
wouldbe3-pentenoicacidylchloride,3-pentenoylchloride;
wouldbep-methoxybenzoicacidylchloride,p-methoxybenzoylchloride;
wouldbecyclohexanecarboxylicacidnylchloride,cyclohexanecarbonylchloride.AnhydridesReplacingthe“OH”groupofacarboxylicacidwithanothercarboxylicacidwillformanhydrides.
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TheR’groupand/ortheRgroupcanalsobearomaticasillustratedinthefollowingtwoexamples.
or
whereZrepresentsavarietyofsubstituents,andthebargoingthroughthearomaticring,inthiscase,meansthatthesubstituentsattachedtotheringscouldbeintheorthoormetapositions.Anhydridesarenamedbyreplacingtheword“acid”ofthecarboxylicacidwiththeword“anhydride.”Forexample,
wouldbeaceticanhydride;
wouldbebenzoicanhydride;amixedanhydridesuchas
wouldhavethefollowingname:heptanoicp-methylbenzoicanhydride.
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EstersReplacingthe“OH”groupofacarboxylicacidwithanalkoxygroup,RO,willformesters.
Estersarenamedasalkylalkanoates.Forexample,
wouldbephenylacetateorphenylethanoate;and
wouldbemethylbenzoate.AmidesReplacingthe“OH”groupwithanaminegroup,NH2,willformaprimaryamide.
Aminesarenamedbyreplacingthe“oic”acidofthecarboxylicacidwithamide.Forexample,
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wouldbebenzoicacidamide,benzamide;
wouldbehexanoicacidamide,hexanamide;
wouldbe3-methylhexanoicacidamide,3-methylhexanamide.Amidesderivedfromacidswith“carboxylicacid”aspartoftheirnomenclaturearenamedbydroppingthe“ylicacid”partof“carboxylicacid”andadding“amide.”Forexampletheamideofcyclohexanecarboylicacid
wouldbecyclohexanecarboxylicacidamidecyclohexanecarboxamide.Whenanalkylsubstituentreplacesahydrogenatomattachedtothenitrogenatom,theresultingamideisasecondaryamide.
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TheethylgrouponthenitrogenisindicatedasN-ethyl;therefore,thenamefor
wouldbeN-ethyl-3-methylhexanamide.Whentwoalkylsubstituentsreplacethehydrogenatomsattachedtothenitrogenatom,theresultingamideisatertiaryamide.ThealkylgroupsattachedtothenitrogenatomareindicatedasN-alkylgroups.Forexample,
wouldbeN-ethyl-N-methyl3-methylhexanamide;and
wouldbeN,N-dimethyl-3-methylhexanamide;
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wouldbeN,N-dimethylcyclohexanecarboxamide.NitrilesNitrilesarenamedbyreplacingthe“icacid”with“nitrile”orreplacing“xylicacid”inacidswithcarboxylicacidaspartoftheirnomenclaturewith“nitrile.”Forexample,
derivedfrompropanoicacidwouldbepropanonitrile;
derivedfrombenzoicacidwouldbebenzonitrile;and
derivedfromcyclohexanecarboxylicacidwouldbecyclohexanecarbonitrile.ReactivityofCarboxylicAcidDerivativesCarboxylicAcidDerivativesundergonucleophilicreactions.Theorderofreactivitytowardnucleophilicreagentsis:
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Acylchloridesaremorereactivetowardnucleophilicreagentsthananhydrides,whicharemorereactivetowardnucleophilicreagentsthanesters,whicharemorereactivetowardnucleophilicreagentsthanamides.Acylchloridesarethemostreactivetowardnucleophilicreagentsbecausethechlorinehasunsharedelectronpairsthatarenoteasilyreleasedthroughresonance.Therefore,theincipientpositivechargeonthecarbonatomisnoteasilydelocalizedandismoresusceptibletonucleophilicattack.ThelongC-Clσ(2sp2+3p)bondingmolecularorbitalandthelone-pairofelectronsina3patomicorbitaloftheClatomcannoteasilyoverlaptoformtheπ(2p+3p)bond.
NotagoodcontributortoresonanceduetothedifficultyofformationAmidesaretheleasereactivetowardnucleophilicreagentsbecausethelonepairofelectronsonthenitrogenatomiseasilyreleasedintothecarbonylsystemtodelocalizetheincipientpositivechargeonthecarbonatom.Consequently,thepositivechargeonthecarbonatomislesssusceptibletotheincomingnucleophile.
AgoodcontributortoresonanceduetothedifficultyofformationFollowingisageneralmechanismforNucleophilicAcylSubstitution
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(1)
(2)
(3)
(4)
NucleophilicAcylSubstitutionsNucleophilicSubstitutionsinAcylChlorides
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Example
AcylChloridescanformacidanhydrides,esters,andamidesaswellascarboxylicacids.Formationofananhydride:
Formationofanester
Formationofanamide
Hydrolysis
Followingisamechanismforthehydrolysisreaction:
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(1)
(2)
(3)
NucleophilicsubstitutionofacylchloridesisfasterthananSN1reaction.Forexample,benzoylchloridereacts1,000timesfasterthanbenzylchloridewhentreatedwith80%ethanoland20%water.Therearetworeasonsforthisdifferenceinreactivity.Thefirstbeingthatthetetrahedralintermediateinnucleophilicacylsubstitutionhasastablearrangementofbonds,andsecondly,thetetrahedralarrangementcanbeformedthroughalowerenergytransitionstate.NucleophilicAcylSubstitutionsinAcidAnhydridesAnhydridesarenexttoacylchloridesinreactivitytowardnucleophiles.
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Anhydridesundergonucleophilicsubstitutiontoformacids,esters,andamides,butnotacylchlorides.FormationofesterandcarboxylicacidFormationofanester
Formationofanacid
Formationofanamideandanammoniumcarboxylatesalt
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Followingisamechanismofacidcatalyzedhydrolysisofananhydride.(1)
(2)
(3)
(4)
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(5)
(6)
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(7)
NucleophilicAcylSubstitutionofEstersManyesterscontributetopleasingodorsofoilsandfruits.Followingreactionsareexamplesofsynthesesofesters.Estersfromacylchlorides:
PyridinehelpsdrivestheformationoftheesterbytrappingtheHClintheformofpyridiniumchloride.Estersfromanhydrides
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EstersviatheBaeyer-VilligerOxidationofKetones
Thealkylgroupmigrateswithretentionofconfiguration;therefore,thereactionisstereospecific.(1)
(2)
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ReactionsofEsterEstersarecleavedinstrongacidsorstrongbasestoformcarboxylicacidsandcarboxylates.EstersreactwithGrignardreagentstoformtertiaryalcohols.EstersundergoreductionwithLiAlH4toformprimaryalcohols.Estersreactwithammonia,primary,andsecondaryaminestoformamides,secondaryamides,andtertiaryamides.Followingisamechanismfortheacid-catalyzedhydrolysisofesters:(1)
(2)
(3)
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(4)
(5)
(6)
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(7)
Followingisamechanismforthebased-catalyzedhydrolysisofesters.Labelingtechniquesshowedthatthereactionfollowsnucleophilicattackatthecarbonylcarbonoftheestersfollowingtheformationofanintermediatetetrahedralstructure.(1)
(2)
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Estersreactwithammonia,primaryamines,andsecondaryaminestoformprimaryamides,secondaryamides,andtertiaryamidesrespectively.
Asindicatedpreviously,thelonepairofelectronsonthenitrogencanbedelocalizedwiththecarbonylgroup.
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Themechanismofamideformationfromanestercanbeillustratedbythefollowingexample:(1)
(2)
(3)
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Amideswithhydrogenatomsattachedtonitrogenatomscanmolecularlyassociate.Thisistrueforprimaryandsecondaryamides,butnotfortertiaryamides.TheboilingpointofacetamideishigherthantheboilingpointofN-methylacetamide,andtheboilingpointofN-methylacetamideishigherthantheboilingpointofN,N-dimethylacetamide.Aspreviouslyindicated,amidesaretheleastreactivetowardnucleophilicacylsubstitutionreactionsascomparedtonucleophilicacylsubstitutionreactionsofester,anhydrides,andacylchlorides.Consequently,amidebondsarekeytotheformationofproteins.Thismakesamidebondsbiologicallysignificant.Amidebondsarestableinwater;however,amidebondsmaybecleavedonheatinginstrongacidorstrongbase.Cleavageinstrongbaseproducescarboxylatesandamines.Cleavageinstrongacidproducescarboxylicacidsandammoniumsalts.Cleavageoftheamidebondinstrongacidoccursinthefollowingmanner:
Cleavageofamidebondinstrongbase:
Followingisthemechanismforacid-catalyzedcleavageoftheamidebond.(1)
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(2)
(3)
(4)
(5)
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(6)
(7)
(8)
Followingisamechanismforbase-catalyzedcleavageoftheamidebond:(1)
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(2)
(3)
(4)
PreparationandreactionsofnitrilesNitrilescanbeformedfromprimaryalkylhalides.RCH2CH2CH2Br+NaCN→RCH2CH2CH2CN+NaBrNitrilescanbeformedfromaldehydesandketones.
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AromaticnitrilescanbeformedbytheSandmeyerReaction.
MechanismoftheformationofaromaticnitrilesbytheSandmeyerReaction(1)
(2)
(3)
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(4)
(5)
(6)
(7)
(8)
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(9)
ReductionofamidesAmidecanbedehydratedwithtetraphosphoruspentoxide,apowerfuldehydratingagent,toformnitriles.Forexample,tetraphosphoruspentoxide,P4O10,reactswithbenzamidetoformbenzonitrile.
benzamidebenzonitrileHydrolysisofNitrilesinmineralacidsleadstocarboxylicacids.Inaddition,hydrolysisofnitrilesinbaseleadstocarboxylates.Hydrolysisofnitrilesinacids
HydrolysisofNitrileswithbase
Usingbenzonitrileasanexample,thefollowingseriesofelementarystepsrepresentthemechanismfortheacid-catalyzedhydrolysisofnitriles.
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(1)
(2)
(3)
(4)
5)
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(6)
(7)
(8)
(9)
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(10)
Usingbenzonitrileasanexample,thefollowingseriesofelementarystepsrepresentthemechanismforthebase-catalyzedhydrolysisofnitriles.(1)
(2)
(3)
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(4)
(5)
(6)
(7)
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(8)
(9)
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Problems
CarboxylicAcidsDerivatives
1. Suggestproductsandgivenamestotheproductsresultingfromthereactionofbenzoicacidwith
(a) lithiumaluminumhydrideintetrahydrofuran,followedbyhydrolysis(b) thionylchloride(c) phosphoroustriiodide(d) 1-propanolinhydrochloricacid(e) acetylchloride(f) theproductof(e)withsodiumborohydrideinpyridine
2. Suggestaseriesofelementarystepsthatwouldrationalizethe
formationofproductinthefollowingreaction.
SuggestanIUPACnamefortheresultingproduct.
3. Suggestasynthesisforthefollowingmoleculefromtheindicatedstartingmaterialandanyothernecessaryinorganicmaterials.
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4. Suggestamechanismforthefollowingtransformation.
5. Suggestarationaleforthefollowingobservation.
6. Suggestamechanismforthefollowingtransformation.
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7. Thesynthesisofasexpheromonecanbeaccomplishedbythefollowingsequenceofreactions.
1.
Ethyl(E)-9-undecen-11-olate2.
3.
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WhatisthestructureofthesexhormonewiththemolecularformulaC14H24O2,andsuggestanameforthissexhormone?
8. Suggestamechanismforthefollowingreaction.
9. Suggestasynthesisforthefollowingfromthegivenstartingmaterialandanyothernecessaryorganicorinorganicmaterials.
andanyothernecessaryinorganicandorganicmaterials.
10. Suggestamechanismforthefollowingconversion.
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11. CompoundAexhibitsthefollowingH1NMR,13CNMR,andpartialmassspectrarespectively.
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WhencompoundAishydrolyzed,compoundBisproduced,CompoundBexhibitsthefollowingH1NMR,13CNMR,andpartialmassspectrarespectively.
SuggeststructuresforcompoundsAandB.
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12. Suggestamechanismforthefollowingconversion.
13. Writetheseriesofelementarystepstorationalizetheformationoftheproductinthefollowingreaction.
14. Writetheseriesofelementarystepstorationalizetheformationoftheacidinthefollowingreaction.
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15. SuggestastructureforcompoundIIproducedinthefollowingseriesofreactions.
16. (Achallengingproblem)
Compound16A,C10H14O,reactswithhydroxylaminetogiveC10H15NO,anoxime.Compound16Aisanα,β-unsaturatedketone.Therefore,itisnosurprisethatcompound16Aformsasemicarbozone,aphenyhydrazone,anda2,4-dinitrophenylhydrazone.Refluxingcompound16Ahydrazineandpotassiumhydroxide,resultsintheformationofcompound16B,C10H16.Compound16Bdecolorizesasolutionofbromineincarbontetrachloride.Catalytichydrogenationofcompound16BinNiconverts16BtoC10H18.Treating16BwithhotconcentratedKMnO4insulfuricacidresultsinconverting16Btocompound16C,C10H16O3.Compound16Cconvertstocompound16D,C10H18O2,withzincamalgaminconcentratedhydrochloricacid.Refluxingcompound16Dinethanolandsulfuricacidproducescompound16E,C12H22O2.Excessphenylmagnesiumbromideaddedtotheethersolutionof16Efollowedbyhydrolysisproducedcompound16F,C22H28O.Compound16Freactedwithconcentratedsulfuricacidtoformcompound16G,C22H26.Compound16GreactedhotconcentratedKMnO4insulfuricacidtoproducecompound16H,C13H10O,andcompound16I,C9H16O2.Compound16Iissolubleinsodium
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hydroxide.Compound16Hformsanoxime,C13H11NO,whentreatedwithhydroxylamine.TheinfraredspectrumofCompound16Hexhibitsastrongtransmittanceat1667cm-1.Followingistheprotonmagneticresonancespectrumofcompound16H.
1HNMRofCompoundCompound16Hexhibitedthreeprominentpeaksatm/e77,105,and182initsmassspectrum.Compound16IreactswithethanolinsulfuricacidtoformC11H20O2,andC11H20O2reactswithexcessphenylmagnesiumbromideinetherfollowedbyhydrolysistoproduceC21H26OwhichreactswithconcentratedsulfuricacidtoyieldC21H24.ReactionofC21H24withhotconcentratedKMnO4insulfuricacidproducescompound16Handcompound16J,C8H14O2.Compound16Jdissolvedinsodiumhydroxidesolution.Compound16JreactedwithethanolinacidtogiveC8H14O2.TreatingC8H14O2withexcessphenylmagnesiumbromide,followedbyheatingtheresultingproductinsulfuricacidproducedC20H22.OzonolysisofC20H22producedcompound16Handcompound16K,C7H12O.Compound16KreactedwithsodiumhydroxideiniodinetoproduceayellowprecipitateandC6H9O2Na.AcidificationofC6H9O2Naproducedcompound16L,C6H10O2.Compound16LreactedwithethanolinacidtogiveC8H14O2.TreatingC8H14O2withexcessphenylmagnesiumbromide,followedbyheatingtheresultingproductinsulfuricacidproducedC18H18.OzonolysisofC18H18producedcompound16Handcompound16M,C5H8O.Compound16Mformedaprecipitatewithphenylhydrazine.Followingarethe1HNMRand13CNMRspectraofcompound16M.
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1HNMRofcompound16M
13CNMRofcompound16M
Suggeststructuresforcompounds16A-16M.
