Bài giảng Organic Chemistry - Chapter 21: Amines and Their Derivatives

Chapter 21: Amines and Their DerivativesMedicines, amino acids, peptides, proteins, alkaloids, industrial materialsFluoxetin (Prozac)OFFFPolypeptideNAmphetamineMescalineEpinephrine(Adrenaline)Alkaloids (natural amines)EcstasyAmines in Industry: NylonNylon 6,6Hosiery, gears, textile fiber,.......Primary aminesSecondary aminesTertiary aminesNaming: AlkanaminesN-alkyl, as in amidesSubstituent name: Amino-Common names: Alkylamine4-(2-Aminoethyl)benzoic acidPhysical PropertiesTetrahedral structureBasicEa = 5-7 kcal mol-1Inversion3. Basicity-NucleophilicityRNH2 :HClRNH3 + Cl-+Primary ammonium chloride::::RNH2 :CH3IRNH2CH3 + I+::::-Secondary ammonium iodide2. Chiral amines racemizeAmmonium salts are configurationally stableCan be resolved, e.g, by fractional crystallization of a salt with optically active anion4. Weaker hydrogen bonds than OHOnly primary and secondary amines can function as proton donorsLess electronegativethan oxygenNH3 b.p. –33.4 CAcidity and BasicityAcidity:Acid dissociation constant Preparation of Sodium Amide: Preparation of LDA:Needs strong basepKa ~ 36Compare:Basicity is best assessed by pKa values of conjugate acid:pKa = -3Reminder: The weaker the conjugate acid,the higher its pKa and the stronger the corresponding baseCompare: oxonium ionBasicity Decreases When the Lone Pair is Less Availablee-negativesp2In the free amine: lone pair delocalized sp2spSynthesis Alkylation of NH3, primary, and secondary amines Problem: Overalkylation: Even though amine gets more hindered, it also gets more nucleophilic One solution is to have excess of RNH2 and use RX as limiting reagent2. Via nitriles3. Arenamine via nitroarene1,3-Benzenediamine4. Gabriel Synthesis ( RX  RNH2)Solves problem of overalkylationSiegmund Gabriel1851-19245. Reductive AminationUse catalytic hydrogenation or NaBH3CN. Both stepsare run simultaneously (one-pot reaction).NaBH3CNPrimary amineSecondary amineTertiary amineGoes through iminium ionGoes through iminium ionFormaldehyde and a secondary amine:Use of formaldehyde effects monomethylation of an amine.RedAmin6. Reduction of amidesRCNHR’LiAlH4ORCH2NHR’Recall: 7. Hofmann RearrangementReactions of Amines Hofmann EliminationRecall: ::Oxonium ionAnalogous (but attenuated) behavior in quaternary ammonium ions. Works for E2Procedure: 1. methylate exhaustively to the quaternary ammonium salt; 2. treat with base. Best with Ag2O, H2O (i.e. AgOH), because Ag+ forms amine complexes, Ag(NR3)2+.Hofmann eliminations are often used to chop alkaloids into smaller fragments for structure proof. Degradation of a simple alkaloid:2. Mannich ReactionAlkylation of Enols by Iminium IonsThe enol is derived from an enolizable ketone/aldehyde and the iminium ion is formed in situ by condensation of a second, more reactive carbonyl component with an amine. The outcome is a β-aminocarbonyl product.Form iminium ionForm iminium ionCarl Ulrich Franz Mannich 1877-1947This is an “aldol” addition using an imineNet: α–Amino- methylation of enolizable alde- hydeMannichMechanism:3. Reaction with Nitrous Acid Nitrosyl cation: like C O , but more electrophilic (charged) and gets attacked by amines:+:Tertiaryamine (stable)Secondary amineN –Nitrosamines are implicated in the carcinogenicity of cured meats-Primary N -nitrosamines decompose R = Alkyl  mess, R = Arene  stable (Chapter 22)(Tautomer ofN-nitroso precursor)