Bài giảng Organic Chemistry - Chapter 25: Heterocycles

Cyclic molecules that contain at least 1 heteroatom Oxacyloalkane: Oxygen-containing heterocycle Azacycloalkane: Nitrogen-containing heterocycle Thiacyloalkane: Sulfur-containing heterocycleChapter 25: HeterocyclesNumbering starts at heteroatomIntramolecular SN2 reactionX:CH2− L(CH2)n2. Special reaction for oxacyclopropanesPreparation of HeterocloalkanesThree- and four-membered rings open: ring strainReactionsUsual conditions are basic.For rings larger than four, no ring strain: Need strong acidHeterocyclopentadienes: Pyrrole, Furan, and ThiopheneThe lone pairs participate in the aromatic cyclic six e system: Like the cyclopentadienyl anionPyrroleFuranThiopheneThe distribution of 6 π electrons over five atoms makes these systems relatively e-rich, compared to benzene.Cyclopentadienyl anionsp2sp2sp2Resonance: recall enaminesOrbitalsRelative to benzene: electron rich Paal-Knorr synthesis of pyrroles and its variationsSynthesis of Heterocyclopentadienes75%Mechanism:Driven by aromatizationMechanism:Goes via enamine1. Electrophilic Aromatic Substitution: Activated!Attack at C2 is preferred generally But often also attack at C3ReactionsExamples: Relative reactivity: Benzene << thiophene < furan < pyrroleMixture Recall:2. Basicity of pyrrole (and other heterocyclopentadienes)Relatively (cf. normal amines) nonbasic: Lone pair is tied up by resonance. Protonation occurs on carbon!Or:pKa of ammonium ~ 10;iminium ~83. Pyrrole is quite acidicReason is sp2-hybridization and cyclic delocalization of charge.Like cyclopentadienyl anionCompare:Benzofusion: IndoleEAS occurs at more e-rich pyrrole ring and at C3: Allows for resonance forms which do not disrupt the benzene ringLeavesaromaticityDisruptsaromaticityAttack at C3:Attack at C2:turkeyPyridine: AzabenzeneCan be viewed as a cyclic aromatic imine:The nitrogen is sp2-hybridized, the lone pair is perpendicular to the aromatic π system. ImineThe N does not donate e-density; rather, it withdraws by inductionCf. benzenePyridine is a (weak) basePyridinePyridinium ionpKa = 5.29Compare pKa of R3NH ~ 9-10+Reactions of PyridinePyridine is relatively (to benzene) electron poor, therefore EAS only under extreme conditions and only at C3Nitration of PyridineActivating substituents improve yieldsPyridine undergoes relatively easy nucleophilic aromatic substitutionLeaving groups are typically halides;2- and 4-halopyridines are particularlyreactiveNucleophilic Attack on Pyridineturkey