Aromatic Heterocyclic Chemistry PDF
Preview Aromatic Heterocyclic Chemistry
Short Course Aromatic Heterocyclic Chemistry An Outline of Fundamental Reactivity of Thiophenes, Furans, Pyrroles, Indole and Pyridine Professor Daniel L. Comins Department of Chemistry North Carolina State University N N Raleigh, North Carolina USA H Scheme 1. Typical Reactivity of Thiophenes, Furans and Pyrroles D.Comins-2 Electrophilic Aromatic Substitution: α-Attack Predominates β E E E E α Z Z H Z H Z H Z = S, O, NH, NR H Electron rich heterocycles The heteroatom activates the ring toward electrophilic substitution; mild conditions are generally required. Since these heterocycles are electron rich, they are not E prone to nucleophilic attack. Z Electrophilic Aromatic Substitution: Effect of Substituents major R electron R electron minor minor minor donating withdrawing minor R R Z Z Z Z electron electron major major major donating withdrawing Further information, see: (1) Handbook of Heterocyclic Chemistry, Katritzky and Pozharskii, p. 302-304; (2) Heterocyclic Chemistry, J. A. Joule and K. Mills, 5th Ed., Wiley, 2010. D. Comins-3 Scheme 2. Typical Reactivity of Thiophenes, Furans and Pyrroles Substitution via Ring Metalation: α-Deprotonation Predominates β R-Li E α Li E Z Z Z Z = S, O, NR Electron rich heterocycles Since these heterocycles are electron rich, they undergo deprotonation instead of nucleophilic attack with alkyllithiums. Substitution via Ring Metalation: Effect of Directing Groups DG minor major minor minor DG Z Z major D.Comins-4 Scheme 3. General Synthesis of Thiophenes, Furans and Pyrroles Preparation from 1,4-Dicarbonyl Compounds: The Paal-Knorr Synthesis The Paal-Knorr Synthesis is a synthetically valuable method that generates either furans, pyrroles, or thiophenes from 1,4-diketones. H+ R R R R O O O R'-NH 2 R R R R N O O R' P S 4 10 R R R R S O O Scheme 4. Reactions of Thiophenes D. Comins-5 Electrophilic Aromatic Substitution: Nitration NO 2 β conc. HNO , Ac O 3 2 α AcOH, 0 °C NO S S 2 S 70 % 6 : 1 acetyl nitrate O N 2 NO 2 NO O N NO 2 NO 2 2 S 2 S S 1 : 1 conc. HNO 3 (CF CO) O S 3 2 NO2 S 78 % Katritzky, et. al., ARKIVOC, 2005, 179. D. Comins-6 Scheme 5. Reactions of Thiophenes Electrophilic Aromatic Substitution: Nitration-cont. O N NO 2 2 NO 2 Me Me Me S S S major minor Me Me Me NO 2 O N NO 2 2 S S S minor major D. Comins-7 Scheme 6. Reactions of Thiophenes Electrophilic Aromatic Substitution: Sulfonation ClSO H, PCl , rt 3 5 70% SO Cl 2 S S Scheme 7. Reactions of Thiophenes D. Comins-8 Electrophilic Aromatic Substitution: Halogenation The rate of halogenation of thiophene at rt is about 108 x that of benzene. 1 eq. NCS, cat. HClO 4 Cl hexane, rt, 12 h S S 88% 1 eq. NBS, cat. HClO 4 hexane, rt, 1 h Br S S 90% 2 eq. NBS, cat. HClO 4 Br Br hexane, rt, 24 h S S 95% Reference: Goldberg and Alper, J. Org. Chem. 1993, 58, 3072. Scheme 8. Reactions of Thiophenes D. Comins-9 Electrophilic Aromatic Substitution: Halogenation-cont. 1 eq. NBS, cat. HClO 4 Br Me Me hexane, rt, 18 h S S 80% 1 eq. NCS, cat. HClO 4 I hexane, rt, 24 h Cl I S S 70% Br Br 1 eq. NBS, cat. HClO 4 Br hexane, rt, 24 h S S 93% Reference: Goldberg and Alper, J. Org. Chem. 1993, 58, 3072. Scheme 9. Reactions of Thiophenes D. Comins-10 Electrophilic Aromatic Substitution: Halogenation-cont. Br 3 eq Br , 48% HBr 2 Br Br rt to 75 °C S S 75% Br Zn/AcOH, heat Br 90% S Br Br Br NaBH , Pd cat. S 4 MeCN, reflux Br S 83% Note: Zinc/AcOH will selectively remove α-halogens from polyhalothiophenes. Reference: See: Heterocyclic Chemistry, J. A. Joule and K. Mills, 5th Ed., Wiley, 2010.
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