Heterocycles 2.pptx PDF

Five Membered Aromatic Heterocycles N O S X H pyrrole furan thiophene (Appear to have only 4 p-electrons) Each ring has 3 pairs of delocalized p electrons They  obey the 4n+2 Hückel rule for aromaticity...

Five Membered Aromatic Heterocycles N O S X H pyrrole furan thiophene (Appear to have only 4 p-electrons) Each ring has 3 pairs of delocalized p electrons They  obey the 4n+2 Hückel rule for aromaticity They are all planar in shape  These e-’s are These e ’s are - part of the p- part of the p- cloud cloud These e-’s are in an sp2 orbital N H O orthogonal to the p orbitals Orbital structure of pyrrole Orbital structure of furan The lone pair of electrons in the p- cloud are involved in aromaticity. They  are not available for bonding (unlike pyridine). As a result, theses molecules are not basic.  Pyrrole and its Resonance Contributors - - + - + + - + N N N N N H H H H H Electron density is drawn away from N. Heterocycles such as pyrrole are  referred to as “electron rich” or p-excessive. Important to remember that the N lone pair form part of the aromatic 6-electron system.  Reactivity Pyrrole, Furan & Thiophene Because pyrrole, furan & thiophene are all aromatic, they readily undergo electrophilic aromatic substitution + + H + H+ +Y X X Y X Y Electrophilic substitution occurs mainly at the C-2 position (C-5) unless it is already substituted.  Relative Resonance/ Relative Reactivity ResonanceEnergy: the more delocalized the e-’s, the more stable the compound is _ O N S H Increasing Resonance Energy Relative reactivity toward electrophilic aromatic substitution S O N H Increasing Relative Reactivity  Drugs containing pyrrole, furan & thiophene NH N O O N N O N NH N HN O Nitrofurantoin O (antibiotic for UTI Porphyrin – planar macrocycle destroys E-coli) Coordinated with Fe2+ haemoglobin Mg2+ chlorophyll O Co2+ vitamin B12 S O OH Suprofen - Profenal (NSAID, topical opthalmic solution prevents miosis  Fused 6-Membered Rings Benzopyridines benzene ring pyridine ring 5 4 6 3 + H+ 7 2 8 N +N 1 H quinoline pKa = 4.85 + H+ N NH 2 + 1 isoquinoline pKa = 5.14 Planar aromatic compounds (obey Hückel’s rule) Weak base – can deprotonate to give the quaternary salt  Relative Resonance/ Relative Reactivity N N Increasing Resonance Energy Electrophilic Aromatic substitution The benzene ring will undergo electrophilic aromatic substitution in preference to the pyridine ring at the C-5 & C-8 position. E + E+ + N N N E Nucleophilic aromatic substitution Quinoline & isoquinoline undergo nucleophilic aromatic substitution on the pyridine ring: Quinoline at the C-2 & C-4 position Nu + Nu- + N N Nu N Isoquinoline at the C-1 position only - N + Nu N Nu Pharmaceutical Importance Alkaloid Drugs: RO OMe N O OH NMe H H N MeO R'O Quinine N Morphine (R = R’ = H) MeO Codeine (R = Me, R’ = H) (anti-malarial) MeO Heroin (R = R’ = acetate) Opium alkaloids MeO Papaverine (vasodilator) Opium alkaloid  ACRIDINES Linear tricyclic system Single N heteroatom N 14 p-electron system → aromatic like anthracene (4n + 2) Basic – lone pair do not contribute to bonding and can deprotonate as a base N HN O H2 N N NH2 Cl N Proflavine (acridine-3,6-diamine) Quinacrine Antibacterial, topical antiseptic Synthetic antimalarial  Fused 6-Membered Rings CONTAINING OXYGEN O O pyran pyrylium cation + O O O O Benzopyran 1- Benzopyrylium Coumarin (not aromatic) chromylium (benzopyrone) (aromatic) Sweet clover Widely distributed throughout the plant +O O kingdom as anthocyanins Isochromylium O Isocoumarin & flavones 2-benzopyrylium (benzopyrone)  Pharmaceutical Importance OH O OH OH O HO O O O OH Quercetin (flavonoid) Warfarin (coumarin) OH Antioxidant Anticoagulant O--D-glucose O--D-glucose + OH HO O Cl- Cyanin chloride OH (anthocyanine) Antioxidant