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Lecture Organic chemistry - Chapter 25: Heterocycles

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Lecture Organic chemistry - Chapter 25: Heterocycles. In this chapter, the following content will be discussed: Intramolecular SN2 reaction, special reaction for oxacyclopropanes, heterocyclopentadienes: pyrrole, furan, and thiophene; synthesis of heterocyclopentadienes,.and other contents. | Cyclic molecules that contain at least 1 heteroatom Oxacyloalkane: Oxygen-containing heterocycle Azacycloalkane: Nitrogen-containing heterocycle Thiacyloalkane: Sulfur-containing heterocycle Chapter 25: Heterocycles Numbering starts at heteroatom Intramolecular SN2 reaction X : CH2− L (CH2)n 2. Special reaction for oxacyclopropanes Preparation of Heterocloalkanes Three- and four-membered rings open: ring strain Reactions Usual conditions are basic. For rings larger than four, no ring strain: Need strong acid Heterocyclopentadienes: Pyrrole, Furan, and Thiophene The lone pairs participate in the aromatic cyclic six e system: Like the cyclopentadienyl anion Pyrrole Furan Thiophene The distribution of 6 π electrons over five atoms makes these systems relatively e-rich, compared to benzene. Cyclopentadienyl anion sp2 sp2 sp2 Resonance: recall enamines Orbitals Relative to benzene: electron rich Paal-Knorr synthesis of pyrroles and its variations Synthesis of Heterocyclopentadienes 75% . | Cyclic molecules that contain at least 1 heteroatom Oxacyloalkane: Oxygen-containing heterocycle Azacycloalkane: Nitrogen-containing heterocycle Thiacyloalkane: Sulfur-containing heterocycle Chapter 25: Heterocycles Numbering starts at heteroatom Intramolecular SN2 reaction X : CH2− L (CH2)n 2. Special reaction for oxacyclopropanes Preparation of Heterocloalkanes Three- and four-membered rings open: ring strain Reactions Usual conditions are basic. For rings larger than four, no ring strain: Need strong acid Heterocyclopentadienes: Pyrrole, Furan, and Thiophene The lone pairs participate in the aromatic cyclic six e system: Like the cyclopentadienyl anion Pyrrole Furan Thiophene The distribution of 6 π electrons over five atoms makes these systems relatively e-rich, compared to benzene. Cyclopentadienyl anion sp2 sp2 sp2 Resonance: recall enamines Orbitals Relative to benzene: electron rich Paal-Knorr synthesis of pyrroles and its variations Synthesis of Heterocyclopentadienes 75% Mechanism: Driven by aromatization Mechanism: Goes via enamine 1. Electrophilic Aromatic Substitution: Activated! Attack at C2 is preferred generally But often also attack at C3 Reactions Examples: Relative reactivity: Benzene << thiophene < furan < pyrrole Mixture 11/27/2014 10 Pauling 3.0 N 3.4 O 2.6 S 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 ~8 3. Pyrrole is quite acidic Reason is sp2-hybridization and cyclic delocalization of charge. Like cyclopentadienyl anion Compare: Benzofusion: Indole EAS occurs at more e-rich pyrrole ring and at C3: Allows for resonance forms which do not disrupt the benzene ring Leaves aromaticity Disrupts aromaticity Attack at C3: Attack at C2: turkey Pyridine: Azabenzene Can be viewed as a cyclic aromatic imine: The nitrogen is sp2-hybridized, the lone pair is perpendicular to the aromatic π .