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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.