Chapter21TheChemistryofCarboxylicAcidDeriva7ves

Organic Chemistry, 5th ed. Marc Loudon

Eric J. Kantorowski California Polytechnic State University San Luis Obispo, CA

Chapter21Overview

•  21.1NomenclatureandClassifica5onofCarboxylicAcidDeriva5ves

•  21.2StructuresofCarboxylicAcidDeriva5ves•  21.3PhysicalProper5esofCarboxylicAcidDeriva5ves•  21.4SpectroscopyofCarboxylicAcidDeriva5ves•  21.5BasicityofCarboxylicAcidDeriva5ves•  21.6Introduc5ontoReac5onsofCarboxylicAcidDeriva5ves•  21.7HydrolysisofCarboxylicAcidDeriva5ves•  21.8Reac5onsofCarboxylicAcidDeriva5veswith

Nucleophiles•  21.9Reduc5onofCarboxylicAcidDeriva5ves

2

Chapter21Overview

•  21.10Reac5onsofCarboxylicAcidDeriva5veswithOrganometallicReagents

•  21.11SynthesisofCarboxylicAcidDeriva5ves•  21.12UseandOccurrenceofCarboxylicAcidsandTheir

Deriva5ves

3

CarboxylicAcidDeriva8ves

•  Acarboxylicacidderiva8veisacompoundthatcanbehydrolyzedunderacidicofbasiccondi5onstogivetherelatedcarboxylicacid

421.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

StructuresofCarboxylicAcidDeriva8ves

521.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

EstersandLactones

621.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

EstersandLactones

•  Cyclicestersarecalledlactones•  Thenameisderivedfromtheacidwiththesamenumberofcarbonsintheprinciplechain

•  TheringsizeisdenotedbyaGreekleUerindica5ngthepointofaUachment

721.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

AcidHalides

•  Replacetheicendingwithylfollowedbythenameofthehalide

821.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

Anhydrides

•  Thenameistheparentacidisfollowedbyanhydride

921.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

Nitriles

•  Droptheicoroicendingandaddonitrile•  Thenitrilecarboncountsaspartofthechainlength

1021.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

Amides,Lactams,andImides

•  Replacetheicoroicandaddamide

1121.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

Amides,Lactams,andImides

•  Amidesareclassifiedaccordingtothenumberofhydrogensontheamidenitrogen

•  UseNforsubs5tuentsonthenitrogen

1221.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

Amides,Lactams,andImides

•  Cyclicamidesarecalledlactams•  Thenomenclaturefollowsthatoflactones

1321.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

Amides,Lactams,andImides

•  Imidesarethenitrogenanalogsofanhydrides•  Cyclicimidesareofgreaterimportancethanopen‐chainimides

1421.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

NomenclatureofSubs8tuentGroups

•  Thepriori5esforci5ngprinciplegroupsinacarboxylicacidderiva5veare:

1521.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

NomenclatureofSubs8tuentGroups

1621.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

CarbonicAcidDeriva8ves

•  Estersofcarbonicacidarenamedlikeanyotherester

•  Otherimportantderiva5vesinclude:

1721.1NomenclatureandClassifica7onofCarboxylicAcidDeriva7ves

StructuresofCarboxylicAcidDeriva8ves

•  Thederiva5vesareverysimilartoothercarbonylcompounds(bondlengths,angles)

1821.2StructuresofCarboxylicAcidDeriva7ves

StructuresofCarboxylicAcidDeriva8ves

•  Becauseofthetrigonalplanargeometryatnitrogen,EandZconformersarepossible

•  Theinterconversionisrela5velyrapidatroomtemperature(~10s‐1,Ebarrier≈71kJmol‐1)

1921.2StructuresofCarboxylicAcidDeriva7ves

Esters

•  Polar;H‐bondacceptorsonly•  Typicallyvola5le,fragrantliquids•  Mostareinsolubleinwater

2021.3PhysicalProper7esofCarboxylicAcidDeriva7ves

AnhydridesandAcidChlorides

•  Loweranhydridesandacidchloridesaredense,water‐insolubleliquids

•  Typicallyhaveacrid,piercingodors

2121.3PhysicalProper7esofCarboxylicAcidDeriva7ves

Nitriles

•  Highlypolar(3.4DforH3C‐C≡N)

•  Nitrileslargerthanpropionitrilearewater‐insoluble

•  Acetonitrileisausefulpolar,apro5csolvent

2221.3PhysicalProper7esofCarboxylicAcidDeriva7ves

Amides

•  Polarwithhighboilingpoints•  Loweramidesarewater‐soluble

•  TendtoaggregateduetoH‐bonding

2321.3PhysicalProper7esofCarboxylicAcidDeriva7ves

IRSpectroscopy

2421.4SpectroscopyofCarboxylicAcidDeriva7ves

IRSpectroscopy:Esters

•  C=Ostretch:1735‐1745cm‐1

•  Readilydis5nguishesthemfromcarboxylicacids,aldehydes,andketones

2521.4SpectroscopyofCarboxylicAcidDeriva7ves

IRSpectroscopy:Anhydrides

•  TwoC=Ostretches(alsocommonforacidchlorides)

•  Duetosymmetricandasymmetricstretching

2621.4SpectroscopyofCarboxylicAcidDeriva7ves

IRSpectroscopy:Amides

•  C=Ostretch:1650‐1675cm‐1

•  MuchlowerthanotherC=Ostretches

2721.4SpectroscopyofCarboxylicAcidDeriva7ves

IRSpectroscopy:Amides

•  Primary,secondary,andter5aryamidesmayalsobedifferen5ated

2821.4SpectroscopyofCarboxylicAcidDeriva7ves

IRSpectroscopy:Nitriles

•  C≡Nstretch:2200‐2250cm‐1

•  NormallymuchstrongerthanC≡Cstretchduetothelargebonddipole

2921.4SpectroscopyofCarboxylicAcidDeriva7ves

1HNMRSpectroscopy

•  α‐Hydrogensnexttocarbonyl:δ1.9‐3•  HydrogensoncarbonnexttoalkoxyO:~+0.6ppmmorethanforthatofalcoholsandethers

3021.4SpectroscopyofCarboxylicAcidDeriva7ves

1HNMRSpectroscopy

•  Amidesdisplaynon‐equivalencyforthetwogroupsaUachedtothenitrogen

•  Theyarediastereotopic•  Althoughtheserotateat~10s‐1,ontheNMR5mescalethesegroupsappearfrozeninposi5on

3121.4SpectroscopyofCarboxylicAcidDeriva7ves

13CNMRSpectroscopy

•  C=O:δ165‐180

•  C≡N:δ115‐120

3221.4SpectroscopyofCarboxylicAcidDeriva7ves

BasicityofCarboxylicAcidDeriva8ves

•  Likecarboxylicacids,theirderiva5vesarealsoweaklybasic

•  Protona5onoccursonthecarbonyloxygen

3321.5BasicityofCarboxylicAcidDeriva7ves

BasicityofCarboxylicAcidDeriva8ves

•  Amidesareconsiderablymorebasic

•  Nitrilesareextremelyweakbases

3421.5BasicityofCarboxylicAcidDeriva7ves

Reac8onsofCarboxylicAcidDeriva8ves

•  Therearethreegeneralcategories:1.Reac5onsatthecarbonyl(orcyano)group

a.attheC=OoxygenorC≡Nnitrogen

b.attheC=OcarbonorC≡Ncarbon

2.Reac5onsinvolvingtheα‐carbon

3.Reac5onsatthenitrogenofamides

3521.6Introduc7ontotheReac7onsofCarboxylicAcidDeriva7ves

Reac8onsofCarboxylicAcidDeriva8ves

•  Acylsubs8tu8on:Subs5tu5onatthecarbonyl

•  Addi7onisatypicalreac5onofnitriles

3621.6Introduc7ontotheReac7onsofCarboxylicAcidDeriva7ves

HydrolysisofEsters

•  Saponifica8on

•  Saponifica5oniseffec5velyirreversible•  Classifiedasanucleophilicacylsubs8tu8on

3721.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisofEsters

3821.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisofEsters

•  Acid‐catalyzedhydrolysis•  Thereac5onisslowandrequiresanexcessofwater

3921.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisofEsters

•  Classifiedasanucleophilicacylsubs8tu8on

4021.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisandForma8onofLactones

4121.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisofAmides

4221.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisofNitriles

•  Moreextremecondi5onsarerequiredcomparedtothoseofestersandamides

4321.7HydrolysisofCarboxylicAcidDeriva7ves

•  Imidicacidscanbeviewedasthenitrogen‐analogsofenols

HydrolysisofNitriles

4421.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisofNitriles

•  Base‐promotedhydrolysisisalsopossible

4521.7HydrolysisofCarboxylicAcidDeriva7ves

HydrolysisofAcidChloridesandAnhydrides

•  Bothreactrapidlywithwater

4621.7HydrolysisofCarboxylicAcidDeriva7ves

NucleophilicAcylSubs8tu8onReac8ons

•  Thecondi7onsforhydrolysisforthesederiva5vescandifferconsiderably

4721.7HydrolysisofCarboxylicAcidDeriva7ves

NucleophilicAcylSubs8tu8onReac8ons

4821.7HydrolysisofCarboxylicAcidDeriva7ves

NucleophilicAcylSubs8tu8onReac8ons

•  Energiesinthereac5oncoordinatediagramareaffectedby:

•  Stabilityofthecarbonylcompound

•  TheleavinggroupabilityofX:‐

4921.7HydrolysisofCarboxylicAcidDeriva7ves

NucleophilicAcylSubs8tu8onReac8ons

5021.7HydrolysisofCarboxylicAcidDeriva7ves

Reac8onsofAcidChlorideswithNucleophiles

5121.8Reac7onsofCarboxylicAcidDeriva7veswithNucleophiles

Reac8onsofAcidChlorideswithNucleophiles

5221.8Reac7onsofCarboxylicAcidDeriva7veswithNucleophiles

Reac8onsofAcidChlorideswithNucleophiles

•  Relatedreac5onsofsulfonylchlorides

5321.8Reac7onsofCarboxylicAcidDeriva7veswithNucleophiles

Reac8onsofAnhydrideswithNucleophiles

5421.8Reac7onsofCarboxylicAcidDeriva7veswithNucleophiles

Reac8onsofEsterswithNucleophiles

•  Transesterifica8on:

5521.8Reac7onsofCarboxylicAcidDeriva7veswithNucleophiles

Reduc8onofEsterstoPrimaryAlcohols

5621.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofAmidestoAmines

•  NotethataprotonolysisstepwithaqueousacidfollowstheLiAlH4reduc5on

•  Thisisfollowedbybasetofreetheamine

5721.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofAmidestoAmines

•  Notehowtheamidereduc5ondiffersfromthatofesterreduc5on

5821.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofAmidestoAmines

5921.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofAmidestoAmines

6021.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofNitrilestoPrimaryAmines

•  Twosuccessivenucleophilicaddi5onsoccur

6121.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofNitrilestoPrimaryAmines

6221.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofAcidChloridestoAldehydes

•  TheRosenmundreduc8on:

6321.9Reduc7onofCarboxylicAcidDeriva7ves

Reduc8onofAcidChloridestoAldehydes

•  Useofderiva5vesofLiAlH4:

6421.9Reduc7onofCarboxylicAcidDeriva7ves

Rela8veReac8vi8es

6521.9Reduc7onofCarboxylicAcidDeriva7ves

Reac8onsofEsterswithGrignardReagents

6621.10Reac7onsofCarboxylicAcidDeriva7veswithOrganometallicReagents

Reac8onsofAcidChlorideswithR2CuLi

•  Dialkylcupratesarelessreac5vethanGrignardreagents

6721.10Reac7onsofCarboxylicAcidDeriva7veswithOrganometallicReagents

SummaryofC.A.Deriva8vePrepara8on

Synthesisofesters:•  Acid‐catalyzedesterifica5onofRCO2H

•  Alkyla5onofRCO2HorRCO2‐

•  AcidchloridesoranhydrideswithROH•  Transesterifica5on

Synthesisofacidchlorides:

•  RCO2HwithSOCl2orPCl3

6821.11SynthesisofCarboxylicAcidDeriva7ves

SummaryofC.A.Deriva8vePrepara8on

Synthesisofanhydrides:•  RCO2Hwithdehydra5ngagents

•  AcidchlorideswithRCO2‐

Synthesisofamides:

•  Acidchlorides,anhydrides,oresterswithamines

6921.11SynthesisofCarboxylicAcidDeriva7ves

SummaryofC.A.Deriva8vePrepara8on

Synthesisofnitriles:•  Cyanohydrinforma5on

•  SN2reac5onofcyanideionwithalkylhalidesorsulfonateesters

7021.11SynthesisofCarboxylicAcidDeriva7ves

NylonandPolyesters

•  Nylonisagenericnamegiventopolyamides

7121.12UseandOccurrenceofCarboxylicAcidsandTheirDeriva7ves

NylonandPolyesters

•  Polyestersarecondensa8onpolymersderivedfromdiolsanddicarboxylicacids

7221.12UseandOccurrenceofCarboxylicAcidsandTheirDeriva7ves

Waxes,Fats,andPhospholipids

•  AwaxisanesterofafaUyacidanda“faUyalcohol”

7321.12UseandOccurrenceofCarboxylicAcidsandTheirDeriva7ves

•  AfatisderivedformamoleculeofglycerolandthreemoleculesoffaUyacid

Waxes,Fats,andPhospholipids

•  Fatswithnodoublebondsarecalledsaturatedfats

•  Fatscontainingdoublebondsarecalledunsaturatedfats

•  TreatmentoffatswithKOHorNaOHgivesglycerolandthesaltofthefaUyacid(asoap)

•  Thisreac5onistheoriginofthetermsaponifica8on

7421.12UseandOccurrenceofCarboxylicAcidsandTheirDeriva7ves

Waxes,Fats,andPhospholipids

•  Phospholipidsarealsoestersofglycerol•  Thekeystructuraldifferenceisthepresenceofapolarphosphoricacidderiva5ve

7521.12UseandOccurrenceofCarboxylicAcidsandTheirDeriva7ves