Bài giảng Organic Chemistry - Chapter 19: Carboxylic Acids

Chapter 19: Carboxylic AcidsCarboxy group: -COOH, -CO2H, Carboxylic acids take precedence over other groups:Naming: Alkanoic AcidsIUPAC: Replace –e of alkane name with –oic acid4-Methylhexanoic acidC1Cyclic: Cycloalkanecarboxylic acidsCyclohexanecarboxylic acid1-Naphthalenecarboxylic acidC1, as in cyclic aldehydesHCOOH Methanoic acid—Formic acid acceptedCH3COOH Ethanoic acid—Acetic acid acceptedCH3CH2COOH Propanoic acidEtc.ResonanceKetones versus Carboxylic Acids:AcidityThe carboxy group is relatively acidic:Acetate ionReasons: 1. Carbonyl carbon is inductively strongly electron withdrawing, 2. Carboxylate ion is stabilized by resonanceCompare 2-Propenyl (allyl)BH +pKa ~ 40+Electron withdrawing groups increase the acidity (decrease pKa): Distance affects acidity:pKa 4.19pKa 3.98CH3COOH pKa = 4.76 CF3COOH pKa = 0.23BasicityProtonated on the carbonyl oxygen: Allows for allylic resonance1. Oxidation of primary alcohols and aldehydesWith KMnO4; or CrO3, H2O; or HNO3; or H2O2Recall Cr(VI) oxidation:PreparationIn H2O: Forms hydrate, which oxidizes to acid2. Carbonation: Organometallic reagents and carbon dioxideExample: Synthetic strategy: RH → RX → RMgBr → RCO2H3. Nitrile hydrolysisMechanisms later, but for the time being, think of it as a triple hydration of CN:With aqueous acid or base, e.g. NaOH, H2O:Cyanohydrin-hydrolysis: 2-Hydroxy acidsReactions Nucleophilic substitution occurs by addition-eliminationLead to carboxylic acid derivatives:General::NuE+Leaving groupEliminationNucleophilic Substitution by Addition- EliminationTetrahedral intermediateAddition::Potential problem: AcidityAcid or base catalyzedNu- acting as a baseBase Catalyzed MechanismMust not compete with :Nu-Acid Catalyzed Mechanism1. –H+2. +H+Synthesis of Carboxylic Acid DerivativesA. Acyl Halides:+ -Cl+ -OHMore stableLess stablePoor NuBad leaving group, strong base, good NuuphillTherefore use other reagents: SOCl2, PCl5, PBr3SOCl2: Mechanism: First step is to convert the bad leaving group OH into a good oneGood leaving groupExercise 19-12Same as ROH  RCl, except addition-elimination and not SN2Then it is addition-elimination:PCl5:90%PBr3:B. AnhydridesCyclic anhydrides: Just heat, or SOCl2Mechanism: Exercise 19-15C. Esters:Alcohols + carboxylic acids, cat. mineral acid, reversibleExample:ΔH º ~ 0, ΔS º ~ 0, ΔG º ~ 0Reverse: Ester hydrolysis, driven by excess H2O. Mechanism: H+ mineral acid, e.g., H2SO4, HCl, proceeds initially like hemiacetalization of aldehydes and ketonesNote: Carbonyl oxygen is always more basic than hydroxy oxygen, because of resonance in the protonated product.EsterEster hydrolysis can also be effected by aqueous NaOH. Chapter 8: RX + Na+-O2CR on the way to ROHIntramolecular esterification: LactonesEven without removing the water, the equilibrium is favorable because of entropy (positive). As always in reversible reactions (thermodynamic control), cyclization is best for five and six membered rings.D. AmidesThis method is rarely used. Problem: Fast (although reversible) salt formation (reverse is slow, hence Δ needed)Heat carboxylic acid with an amine:Note: M+ –NH2 are also called amides.Mechanism:Highly pH dependent profile. We shall see in Chapter 20 that amide formation is better accomplished by “activation” of the carboxy group, as in acyl halides or anhydrides or even esters.Cyclic amides: Imides from dioic acids, or lactams fom amino acidsImide formation:Mechanism: Exercise 19-21RecallLactam formation:Famous lactams: penicillins R’OH stands for transpeptidase, the enzyme necessary for all cell wall construction. Osmotic pressure in a cell is enormous, 10-20 atm. Penicillin causes literally an explosion. Other Reactions of Carboxylic Acids1. Reduction by LiAlH4Mechanism complex, not clear, possibly via:2. Hell-Volhard-Zelinsky Reaction: Makes α-bromocarboxylic acidsP + Br2  PBr3Important functionalization; can be exploited to access α-amino acids. Mechanism is reminiscent of acid catalyzed halogenation of aldehydes and ketones.Jakob Volhard (1834-1910)Nikolaj Zelinski (1861-1953) Carl Magnus von Hell (1849-1926) Mechanism:As in the acid catalyzed halogenation of aldehydes and ketones, this needs enolization of RCH2COOH. However, the COOH group is too stable to enolize sufficiently, hence it requires activation to RCH2CBr.llOMechanism: Chapter Integration Problem 19-25apKa ~ 16!Mechanisms: Exercise 19-23SummaryNucleophilic substitution occurs by addition- elimination:NuE+Leaving group