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Chapter 21- Carboxylic Acid Derivatives: NucleophilicAcyl Substitution Reactions

Carboxylic Compounds

• Acylgroupbonded toX,anelectronegativeatomorleavinggroup

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General Reaction Pattern

• Nucleophilic acylsubstitution

Why do I care, Dr. P?

• Carboxylicacidsareamongthemostwidespreadofmolecules.

• Astudyofthemandtheirprimaryreaction“nucleophilic acylsubstitution” isfundamentaltounderstandingorganicchemistry

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Nomenclature

• AcidHalides,RCOX• Derived from the carboxylic acid name by

replacing the -ic acid ending with -yl or the -carboxylic acid ending with –carbonyl and specifying the halide

Naming Acid Anhydrides, RCO2COR'

• Ifsymmetricalreplace“acid”with“anhydride”basedontherelatedcarboxylicacid

• Fromsubstitutedmonocarboxylicacids:usebis- aheadoftheacidname

• Unsymmetricalanhydrides— citethetwoacidsalphabetically

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Naming Amides, RCONH2

• Withunsubstituted ⎯NH2 group.replace-oic acidor-ic acidwith-amide,orbyreplacingthe-carboxylicacidendingwith–carboxamide

• IftheNisfurthersubstituted, identifythesubstituent groups(precededby“N”)andthentheparentamide

Naming Esters, RCO2R’

• NameR’andthen,afteraspace,thecarboxylicacid(RCOOH),withthe“-icacid”endingreplacedby“-ate”

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NucleophilicAcyl Substitution-Mechanism

Relative Reactivity of Carboxylic Acid Derivatives

• Nucleophilesreactmorereadilywithunhinderedcarbonylgroups

• Moreelectrophiliccarbonylgroupsaremorereactivetoaddition(acylhalidesaremostreactive,amidesareleast)

• Theintermediatewiththebestleavinggroupdecomposesfastest

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Relative Reactivity of Carboxylic Acid Derivatives

Substitution in Synthesis

• Wecanreadilyconvertamorereactiveacidderivativeintoalessreactiveone

• Reactionsintheoppositesensearepossiblebutrequiremorecomplexapproaches

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General Reactions of Carboxylic Acid Derivatives

• waterà carboxylicacid• alcoholsà esters• ammoniaoranamineà anamide• hydridesourceà analdehydeoranalcohol• Grignardreagentà aketoneoranalcohol

NucleophilicAcyl Substitution Reactions of Carboxylic Acids

• Mustenhancereactivity• Convert⎯OHintoabetterleavinggroup• Specificreagentscanproduceacidchlorides,anhydrides,esters,amides

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Conversion of Carboxylic Acids into Acid Chlorides

• Reactionwiththionyl chloride,SOCl2

Mechanism of Thionyl Chloride Reaction

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Conversion of Carboxylic Acids into Acid Anhydrides

• Acidanhydridescanbederivedfromtwomoleculesofcarboxylicacidbystrongheatingtoremovewater

Acid Anhydride Mechanism

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Conversion of Carboxylic Acids into Esters

• Methods includereactionofacarboxylateanionwithaprimaryalkylhalide

Fischer Esterification

• Heatingacarboxylicacidinanalcoholsolventcontainingasmallamountofstrongacidproducesanesterfromthealcoholandacid

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Mechanism of the Fischer Esterification

Conversion of Carboxylic acids into Amides

• Amidesaredifficulttopreparedirectlywithaminesbecauseaminesactlikebaseswhichconvertthecarboxylicacidintothecarboxylateanion

• Toprepareamidesfromcarboxylicacids,DCCisused

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Reduction of Carboxylic Acids in Alcohols

• Convertscarboxylicacidsinto1oalcohols• Limitation:requireshightemperaturesandlongreactiontimes

• Alternativemethod: BH3/THF

Reduction of Carboxylic Acids in Alcohols

• Convertscarboxylicacidsinto1o alcohols• Limitation:requireshightemperaturesandlongreactiontimes

• Alternativemethod: BH3/THF

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Chemistry of Acid Halides

• AcidchloridesarepreparedfromcarboxylicacidsbyreactionwithSOCl2

• ReactionofacarboxylicacidwithPBr3 yieldstheacidbromide

Reactions of Acid Halides

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Hydrolysis: Conversion of Acid Halides into Acids

• Acidchloridesreactwithwatertoyieldcarboxylicacids

Acid chloride to Acid Anhydride

• Reactionofacarboxylateanionandanacidchlorideyieldstheacidanhydride

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Conversion of Acid Halides to Esters

• EstersareproducedinthereactionofacidchlorideswithalcoholsinthepresenceofpyridineorNaOH.ThisiscalledAlcoholysis

• Thereactionisbetterwith lessstericbulk

Mechanism

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Aminolysis: Conversion of Acid Halides into Amides

• AmidesresultfromthereactionofacidchlorideswithNH3,primary(RNH2)andsecondaryamines(R2NH)

• Thereactionwithtertiaryamines(R3N)givesanunstablespeciesthatcannotbeisolated

• HCl isneutralizedbytheamineoranaddedbase

Aminolysis: Conversion of Acid Halides into Amides

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Reduction: Conversion of Acid Chlorides into Alcohols

• LiAlH4 reducesacidchloridestoyieldaldehydesandthenprimaryalcohols

Reaction of Acid Chlorides with Organometallic Reagents

• Grignardreagentsreactwithacidchloridestoyieldtertiaryalcoholsinwhichtwoofthesubstituents arethesame

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Reaction of Acid Chlorides with Organometallic Reagents

Formation of Ketones from Acid Chlorides

• Reactionofanacidchloridewithalithiumdiorganocopper (Gilman)reagent,Li+ R2Cu−

• Additionproducesanacyldiorganocopperintermediate,followedbylossofRʹCu andformationoftheketone

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Chemistry of Acid Anhydrides

• Preparedbynucleophilicacylsubstitution ofacarboxylatewithanacidchloride

Reactions of Acid Anhydrides

• Similartoacidchloridesinreactivity

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Acetylation

• AceticanhydrideformsacetateestersfromalcoholsandN-substituted acetamidesfromamines

Mechanism forming Aspirin

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Mechanism forming Acetaminophen

Chemistry of Esters

• Manyestersarepleasant-smellingliquids:fragrantodorsoffruitsandflowers

• Alsopresentinfatsandvegetableoils

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Preparation of Esters

• Estersareusuallypreparedfromcarboxylicacids

Reactions of Esters

• Lessreactivetowardnucleophilesthanareacidchloridesoranhydrides

• Cyclicestersarecalledlactonesandreactsimilarlytoacyclicesters

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Hydrolysis: Conversion of Esters into Carboxylic Acids

• Anesterishydrolyzedbyaqueousbaseoraqueousacidtoyieldacarboxylicacidplusanalcohol

Mechanism of Ester Hydrolysis

• Base-catalyzed

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Mechanism of Ester Hydrolysis

• Acid-catalyzed

Aminolysis of Esters

• Ammoniareactswithesterstoformamides

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Aminolysis of Esters

• Ammoniareactswithesterstoformamides

Reduction: Conversion of Esters into Alcohols

• ReactionwithLiAlH4 yieldsprimaryalcohols

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Mechanism of Reduction of Esters

• Hydrideionaddstothecarbonylgroup,followedbyeliminationofalkoxideiontoyieldanaldehyde

• Reductionofthealdehydegivestheprimaryalcohol

Reaction of Esters with Grignard Reagents

• Reactwith2equivalentsofaGrignardreagenttoyieldatertiaryalcohol

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Reaction of Esters with Grignard Reagents

Chemistry of Amides

• Amidesareabundant inalllivingorganisms…proteins,nucleicacids,andotherpharmaceuticalshaveamidefunctionalgroups

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Preparation of Amides

• Preparedbyreactionofanacidchloridewithammonia,monosubstituted amines,ordisubstituted amines

Reactions of Amides

• Heatingineitheraqueous acidoraqueousbaseproducesacarboxylicacidandamine

• Acidichydrolysisbynucleophilicadditionofwatertotheprotonatedamide,followedbylossofammonia

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Reactions of Amides

• Base-catalyzedmechanism

Reactions of Amides

• Acid-catalyzedmechanism

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Reduction: Conversion of Amides into Amines

• ReducedbyLiAlH4 toanamineratherthananalcohol

• ConvertsC=O→ CH2

Mechanism of Reduction

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Uses of Reduction of Amides

• Workswithcyclicandacyclic• Goodroutetocyclicamines

Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives

• Nucleophilic carboxylsubstitution innatureoften involvesathioester oracylphosphate

• AcetylCoA’saremostcommonthioesters innature

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Chemistry of Thioesters and Acyl Phosphates: Biological Carboxylic Acid Derivatives

Polyamides and Polyesters: Step-Growth Polymers

• Reactionsoccurindistinctlinearsteps,notaschainreactions

• Reactionofadiamineandadiacidchloridegivesanongoingcyclethatproducesapolyamide

• Adiolwithadiacidleadstoapolyester

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Polyamides (Nylons)

• HeatingadiaminewithadiacidproducesapolyamidecalledNylon®

• Nylon66®isfromadipicacidandhexamethylene-diamineat280°C

Polyesters

• ThepolyesterfromdimethylterephthalateandethyleneglycoliscalledDacron®andMylar®tomakefibers

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Spectroscopy of Carboxylic Acid Derivatives

• InfraredSpectroscopy• Acid chlorides absorb near 1800 cm−1

• Acid anhydrides absorb at 1820 cm−1 and also at 1760 cm−1

• Esters absorb at 1735 cm−1, higher than aldehydes or ketones

• Amides absorb near the low end of the carbonyl region

Nuclear Magnetic Resonance Spectroscopy

• Hydrogens onthecarbonnexttoaC=Oarenearδ2inthe1HNMRspectrum.

• AllacidderivativesabsorbinthesamerangesoNMRdoesnotdistinguishthemfromeachother

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13C NMR

• 13CNMRisusefulfordeterminingthepresenceorabsenceofacarbonylgroupinamoleculeofunknown structure

• Carbonylcarbonatomsofthevariousacidderivativesabsorbfromδ160toδ180