Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions McMurrayMcMurray TextText ChapterChapter 2121 Carboxylic Acid Derivatives O O R OH R X Acid Halide O O O O R OR' R NH2 Amide (1°) Ester R O R' Acid Anhydride NomenclatureNomenclature Acid Halides (Acyl Halides) ChangeChange “–“–icic acidacid”” inin thethe parentparent carboxyliccarboxylic acidacid toto “–yl” followedfollowed byby thethe halide. O O Cl H3C Cl Cl acetyl chloride O (from acetic acid) O hexanedioyl chloride (from hexanedioic acid) H3CH2CHC Cl 2-methylbutanoyl chloride CH3 (from 2-methylbutanoic acid) NomenclatureNomenclature Symmetrical Acid Anhydrides ChangeChange ““acidacid”” inin thethe parentparent carboxyliccarboxylic acidacid toto “anhydride.” O O O O O O acetic anhydride butanoic anhydride (from 2 acetic acids) (from 2 butanoic acids) NomenclatureNomenclature Unsymmetrical Acid Anhydrides NameName thethe twotwo acidsacids alphabeticallyalphabetically andand changechange ““acidacid”” toto “anhydride.” O O O O O O H acetic benzoic anhydride ethanoic methanoic anhydride NomenclatureNomenclature Esters Name R group bondedbonded toto O,O, followedfollowed byby replacingreplacing “–“–icic acidacid”” inin thethe parentparent acidacid withwith “–ate.” O O O O EtO OEt ethyl acetate diethyl propanedioate O O O O methyl butanoate isopentyl acetate NomenclatureNomenclature Amides 1° amides: ChangeChange “–“–oicoic acidacid”” (IUPAC)(IUPAC) oror ““--icic acidacid”” (common)(common) inin thethe parentparent acidacid toto “–amide.” O acetamide NH2 2° and 3° amides: FirstFirst identifyidentify thethe substituentsubstituent groupsgroups (preceded(preceded byby ““NN--””)and)and thenthen thethe parentparent amide.amide. O O H N H N N-Methylacetamide N,N-Dimethylformamide NucleophilicNucleophilic AcylAcyl SubstitutionSubstitution O O O + Nu + Lv R R Lv Nu Lv R Nu tetrahedral intermediate ReactivityReactivity ofof AcidAcid Derivatives:Derivatives: StericSteric EffectsEffects O O O O R H H H C < C < C C R < R H H R R R H Reactivity toward nucleophilic substitution Most Hindered Least Hindered ReactivityReactivity ofof AcidAcid Derivatives:Derivatives: ElectronicElectronic EffectsEffects O O O O O < < < R NH2 R OR' R O R' R X Amide Ester Acid Anhydride Acid Halide Reactivity toward nucleophilic substitution Carbonyl carbon Carbonyl carbon least electrophilic most electrophilic NucleophilicNucleophilic AcylAcyl SubstitutionSubstitution RxnsRxns O Alcoholysis O Reduction H- 1 R H R OR R1OH H- Grignard O O Reagent R1MgX 1 R R1 R Y R MgX O O Aminolysis Hydrolysis R OH R NH H O 2 NH3 2 PreparationPreparation ofof AcylAcyl HalidesHalides O SOCl2 O R Cl PBr R OH 3 O R Br Note: Acid fluorides are extremely reactive and require different preparation methods. PreparationPreparation ofof AnhydridesAnhydrides O O O Heat 2 R OH R O R + H2O Carboxylic Carboxylic acid acid Anhydride O COOH Heat O + H O Cyclic Anhydride COOH 2 O Succinic acid Succinic anhydride O O O O O R1 Cl NaOH Mixed Anhydride R OH R O-Na+ R O R1 PreparationPreparation ofof EstersEsters Fischer Esterification O O H+ R OH R OR1 + H2O R1OH + H H H O H O OH O R1 R1 R OH R OH R O R O HO H HO R1OH H H O O O -H O H Note: If one uses labeled alcohol, the 2 label is retained in the product. R OR1 R OR1 PreparationPreparation ofof AmidesAmides NoNo simplesimple methodmethod forfor thethe preparationpreparation ofof amidesamides fromfrom carboxyliccarboxylic acids!acids! AmidesAmides fromfrom acidsacids discusseddiscussed inin 26.1026.10 InterconversionInterconversion ofof DerivativesDerivatives AllAll acidacid derivativesderivatives cancan bebe convertedconverted toto carboxyliccarboxylic acids.acids. AA derivativederivative can bebe convertedconverted toto aa lessless reactivereactive derivative.derivative. AA derivativederivative cannot bebe convertedconverted toto aa moremore reactivereactive derivative.derivative. AnhydridesAnhydrides cancan bebe convertedconverted toto estersesters andand amides,amides, butbut notnot intointo acidacid halides.halides. InterconversionInterconversion LectureLecture 22 (with(with review)review) ReactivityReactivity ofof AcidAcid Derivatives:Derivatives: ElectronicElectronic EffectsEffects O O O O O < < < R NH2 R OR' R O R' R X Amide Ester Acid Anhydride Acid Halide Reactivity toward nucleophilic substitution Carbonyl carbon Carbonyl carbon least electrophilic most electrophilic NomenclatureNomenclature AcidAcid chloride:chloride: ““--ylyl chloridechloride”” Anhydride:Anhydride: ““anhydrideanhydride”” Ester:Ester: ““-ate-ate”” O Amide:Amide: ““amideamide”” O O isopentyl acetate H3C Cl acetyl chloride (from acetic acid) NucleophilicNucleophilic AcylAcyl SubstitutionSubstitution O O O + Nu + Lv R R Lv Nu Lv R Nu tetrahedral intermediate InterconversionInterconversion AcidAcid HalideHalide HydrolysisHydrolysis O O OH2 OH2 R Cl R Cl OH O O Acid H R OH R O H A base such as pyridine, triethylamine, or NaOH is used to remove the HCl that is formed. AcidAcid HalidesHalides intointo AnhydridesAnhydrides Acid chloride/carboxylate reaction useful for preparing either symmetrical or unsymmetrical anhydrides. O O O O O OH NaOH O-Na+ H3C Cl O CH3 Mixed Anhydride AcidAcid HalideHalide AlcoholysisAlcoholysis O OH N + + Cl O NH Cl + O Ester AcidAcid HalideHalide AminolysisAminolysis O O C 2 NH3 C Cl NH2 + NH4Cl Formation of a primary amide Benzoyl Chloride Benzamide O H O 2 H N C C H Cl CH3 N + CH3NH3Cl Formation of a secondary amide CH3 O 2 H N O C H - CH N + N Cl Formation of a tertiary amide C 3 H CH Cl CH3 3 NH O Cl Cl O N H m-toluyl chloride O N O N 3° amide! H Cl N,N-diethyl-m-toluamide (DEET) AcidAcid HalideHalide ReductionReduction O O H H 1. LAH LAH C 1 C C R OClR + R H R OH 2. H3O Ester Aldehyde Primary alcohol O O 1 R1 R R1MgX R1MgX C C 1 C R Cl R R R OH Grignard Reagent Ketone Tertiary alcohol AcidAcid HalidesHalides intointo KetonesKetones Gilman reagent: R2CuLi (lithium diorganocopper) O O C (CH ) CuLi C Cl 3 2 CH3 No overoxidation as opposed to Grignard reactions! Note: Carboxylic acids, esters, acid anhydrides, and amides do not react with Gilman reagents. AcidAcid AnhydrideAnhydride ReactionsReactions Less reactive than acid chlorides, but react in a similar fashion… HydrolysisHydrolysis React with water to form carboxylic acids AlcoholysisAlcoholysis React with alcohols to form esters AminolysisAminolysis React with amines to form amides ReductionReduction React with LiAlH4 to form 1° alcohols AcidAcid AnhydrideAnhydride Alcoholysis: Ester Aminolysis: Amide EsterEster HydrolysisHydrolysis base-catalyzed hydrolysis (saponification) O CH2O C (CH2)16CH3 CH2OH O O NaOH CHO C (CH2)16CH3 CHOH + 3 H3C(CH2)16 C ONa H2O O CH2O C (CH2)16CH3 CH2OH Triglyceride Glycerol Sodium Stearate Soap O O O O C C - 1 R OR1 R OR1 C + R1O C + R OH R OH R O OH OH EsterEster HydrolysisHydrolysis acid-catalyzed hydrolysis (reverse Fischer Esterification) H H H H O O O O O C 1 C 1 C C R1 C 1 R OR R OR R OR1 R O R OH + R OH O O H H H H O H H H H O O O H + C C + H3O R OH R OH Acid EsterEster AminolysisAminolysis Esters react with ammonia and with 1° and 2° amines to form amides. O Ph + NH3 OEt O Ph + EtOH NH2 EsterEster ReductionReduction O O H H 1. LAH LAH C 1 C C R OR + R H R OH 2. H3O Ester Aldehyde Primary alcohol O O 1 R1 R R1MgX R1MgX C C 1 C R ORCl R R R OH Grignard Reagent Ketone Tertiary alcohol AmideAmide HydrolysisHydrolysis O O Acid 1. HO C C R NH2 + R OH 2. H3O AmideAmide ReductionReduction AmidesAmides intointo AminesAmines usingusing LiAlHLiAlH4 ProductProduct ofof reductionreduction isis anan amine,amine, notnot anan alcoholalcohol asas withwith thethe otherother acidacid derivativesderivatives O 1. LAH H H C C R NH2 + R NH2 2. H3O Primary amine H H OAlH3 N O H H C C C C R NH2 R NH2 R H R NH2 H H H Primary amine NucleophilicNucleophilic SubstitutionSubstitution RxnsRxns SummarySummary Product Starting Acid Acid Carboxylic Ester Amide Material Chloride Anhydride Acid Acid Chloride - Rxn Rxn Rxn Rxn Acid Anhydride 0 - Rxn Rxn Rxn Carboxylic Acid Rxn Rxn - Rxn Rxn Ester 0 0 Rxn - Rxn Amide 0 0 Rxn 0 - 0 = No reaction.