Bài giảng Organic Chemistry - Chapter 20: Carboxylic Acid Derivatives

Chapter 20: Carboxylic Acid DerivativesOH bad leaving groupWhat is the relative reactivity of these carboxylic acid derivatives? Most reactiveLeast reactiveL to the right, when acting as Nu, displaces L to the left= LNo catalyst neededNo catalyst neededOrigins of Reactivity TrendsInductive effectsElements to the right in a row of Periodic Table are more electronegative (nuclear charge increase).Donating ability of L increases from right to left in the periodic table. 2. Resonance effectsAcetyl chlorideAcetamideDifferences reflected in pKa valuesBasicityProtonation gets easier from L = X to O to NFor the same reason, deprotonation gets more difficultA. Acyl HalidesNames:Alkanoic acid → alkanoyl halideCyclohexanecarbonyl fluorideCycloalkanecarboxylic acid → cycloalkanecarbonyl halideMechanism:Example:1. Water: Hydrolysis gives RCOOHReactionsGeneral ReactionExample:60%2. Alcohols: R’OH converts acyl chlorides into esters, -SO2Works for NH3, RNH2, and RNHR’Reaction:3. Amines turn acyl chlorides into amidesMechanism:One equiv used up as baseR2CuLi4. Organocuprates transform acyl chlorides into ketonesExamples:1. THF2. H+, H2ODoes not add to ketone carbonyl5. Reduction of acyl chlorides results in aldehydesUse modified (less reactive form of) LiAlH4:Does not touch the aldehyde productVia addition-eliminationB. AnhydridesNames: Add anhydride to the alkanoic acid nameAcetic anhydridePentanedioic anhydride= Leaving group++Reactions:Similar to acyl halides, but anhydrides are less corrosive, cheaperMechanism:Examples:Regioselective reaction?Cyclic anhydrides react by ring opening: Allows the regioselective functionalization of a dioic acid.For example, problem:Heating the dioic acid or SOCl2 produces the cyclic anhydride:ΔNow, treat with nucleophile to ring open:Friedel-Crafts ReactivityC. EstersNames: Alkyl alkanoate Methyl acetateCyclic: Lactoneβ-Propiolactone Common name1,1-Dimethylethyl butanoateNote space-COR substituent called alkoxycarbonylOMechanisms: a. Acid-mediated1. Water: Hydrolysis gives carboxylic acidsReactions of Estersb. Base-mediatedWork up with acidic water gives RCOOHExample:Work up with acidic water gives RCOOH2. Alcohols effect transesterificationThis specific example works only with acid. Why?3. Amines convert esters into amidesExample:Use 2 equivalents of Grignard reagent4. Grignard reagents: Esters turn into alcoholsMechanism:5. Hydride reagents: Reduce esters to alcohols or aldehydesLiAlH4 goes all the way (same as for RCOOH):The milder DIBAL stops at aldehyde stage:NaBH4 is too unreactive.Not really a “hydride”, but an “alane”, R2AlH, like an alkylborane”, R2BH, Mechanisms:Double or single hydride additions6. Ester enolates can be alkylatedSimilar to aldehyde and ketone enolates. Limitation: Basic!Other alkylating agents:-Aldol-likeIntramolecular transesterificationCompare aldehydes and ketones: pKa = 16-20D. AmidesProteins are poly(amino acids):Names: Alkane → Alkanamide Substituents on N labeled N -or N,N - Cycloalkane amides: Cycloalkanecarboxamide Cyclic amides: LactamsFormamidePrimarySecondaryN-MethylacetamideTertiary4-Bromo-N-ethyl-N-methylpentanamide1. Hydrolysis to component carboxylic acid and amineBase:Acid: (Mechanism Problem 51)Mechanism of hydrolysis by aqueous base:Neutralized by aqueous work-up2. Reduction to an amineMechanism:This is different from esters, where RO− is leaving (with LiAlH4). The lone pair on N pushes out R2AlO-.Hemiaminalaluminum complex3. With DIBAL, reduction to an aldehydeSimilar to esters with DIBAL: stops at hemiacetal stage, and hydrolysis also gives an aldehyde.Mechanism goes by single hydride addition to hemiaminal stage, then hydrolysis:Acidic, like carboxylic acidpKa Values higher because amide carbonyl is relatively stabilized by resonance and N is less e-negative than O.Amide Enolates and AmidatesAcidic, like other carbonyl compoundsAllows alkylation at N or C (if N is blocked):Only for primary amides:This constitutes a one-carbon degradation of a chain: Topologically, CO is excised.4. Hofmann rearrangementExample:August Wilhelm von Hofmann 1818-1892Mechanism:Note similarity to carbonic acid:E. Alkanenitriles: RCNNames: Alkanoic acid → alkanenitrileRetained by IUPACCyclic systems are called cycloalkanecarbonitrilesCN substituent is termed cyanoStructureC and N sp-hybridized like C in alkynesNitriles are Acidic and BasicpKa~ < -5RCH2CNpKa ~ 25(like esters)Alkylation of anion with RX, RC(O)H is possible: Like enolatesAcidic:BasicExample:Hydrolysis: H+ or HO- to carboxylic acidsRecall:General: RH  RX  RCN  RCOOHMechanisms: H+-catalyzedHO--”catalyzed” (actually need stoichiometric base, because it makes carboxylate first, before acidic work-up)Amide+(Section 20-6)Use R’Li or R’MgX reagentsOrganometallic reagents attack nitriles to give ketonesGeneral:Ketone synthesisExample:RXCNRROR'R'XGeneral: RX  RCN  RCHOUse LiAlH(OR)3 or DIBAL: Reduction of nitriles by modified hydrides leads to aldehydesExample:LiAlH4 + RCN  RCH2NH2H2 + RCN RCH2NH2General: RX  RCN  RCH2NH2Reduction of nitriles by LiAlH4 or catalytic hydrogenation leads to aminesPtO2Examples: Exam 2