CHEMISTRY 3300 Introduction to Heterocyclic ChemistryNOHONH2II-A. HETEROCYCLIC CHEMISTRYII. Special TopicsDr. P. WipfPage 1 of 624/2/2008Some useful references:Books:- Gilchrist, T. L. Heterocyclic chemistry; 3rd ed.; Addison Wesley Longman: Edinburgh Gate, 1997.- Joule, J. A.; Mills, K.; Heterocyclic chemistry; 4th ed.; Blackwell Science: Oxford, 2000.- Eicher, T.; Hauptmann, S. The chemistry of heterocycles; 2nd ed.; Thieme: Stuttgart, 2003.- Brown, E. G. Ring nitrogen and key biomolecules. The biochemistry of N-heterocycles; KluwerAcademic Publishers: 1998.- Conformational analysis of medium-sized heterocycles; Glass, R. S., Ed.; VCH: Weinheim, 1988.- Macrocycle synthesis; Parker, D., Ed.; Oxford: 1996.- 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: 1984. Padwa & Pearson, 2002.- Davies, D. T. Aromatic heterocyclic chemistry; Oxford University Press: Oxford, 1992.- Gupta, R. R.; Kumar, M.; Gupta, V. Heterocyclic chemistry; Springer: Berlin, 1998; Vol. I.- Katritzky, A. R.; Pozharskii, A. F. Handbook of heterocyclic chemistry; 2nd ed.; Pergamon: Oxford,2000.Series:- The Chemistry of Heterocyclic Compounds; Taylor, E. C.; Wipf, P., Eds.; Wiley. 64 volumes.- Comprehensive Heterocyclic Chemistry; 1st. ed.; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon:Oxford: 1984. 8 volumes.- Comprehensive Heterocyclic Chemistry; 2nd. ed.; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.,Eds.; Pergamon: Oxford: 1996. 11 volumes.- Progress in Heterocyclic Chemistry; Gribble, G. W.; Gilchrist, T. L., Eds.; Pergamon: Oxford. 19volumes.Published by the ISHC.- Hetarenes and Related Ring Systems; Houben-Weyl Methods of Molecular Transformations;Thieme: Stuttgart, 2001-2003. 8 volumes.Dr. P. WipfPage 2 of 624/2/2008Dr. P. WipfPage 3 of 624/2/2008Introduction Classification If the ring system is made up of carbons and at least one other element, the compound can be considered as heterocyclic. About 50% of all known organic compounds are heterocyclic. About 55% of organic chemistry publications are dedicated to this field. Uses of heterocyclic compounds • Pharmaceuticals: 8/10 top prescription drugs in 2006 Dr. P. WipfPage 4 of 624/2/2008Dr. P. WipfPage 5 of 624/2/2008Dr. P. WipfPage 6 of 624/2/2008- Agrochemicals- Veterinary products- Dyes and pigments, fluorescent agents- Antioxidants and food additives- Corrosion inhibitors- Intermediates in organic synthesis- Biological functions (pKa, metal binding, hydrogen bonding, hydrophilicity, - Fire retardant- Photographic materials- Organic conductorscf.: - Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles in life and society; Wiley: Chichester, 1997.Dr. P. WipfPage 7 of 624/2/2008Aro maticityQuantitative measurement of aromaticity from heats of combustion and hydrogenation:combustion(kcal/mol)36-3723-4324-3116-2314-31hydrogenation(kcal/mol)3629228-24128benzenepyridinethiophenefuranpyrrolepyrazinepyridazinepyrimidinesee also: Katritzky, A. R.; Jug, K.; Oniciu, D. C., "Quantitative measures of aromaticity for mono-, bi, and tricyclic penta- and hexaatomic heteroaromatic ring systems and their interrelationships." Chem. Rev. 2001, 101, 1421-1449.Dr. P. WipfPage 8 of 624/2/2008NomenclatureThe widely used Hantzsch-Widman nomenclature systemspecifies the ring size and the nature, type, and position of theheteroatom(s).Dr. P. WipfPage 9 of 624/2/2008Note: the stem –irine is used for three-membered nitrogen-containing unsaturated heteromonocycles, and the stems –iridine, -etidine, and –olidine, are used for nitrogen-containing saturated 3-, 4-, and 5-membered heteromonocycles, respectively. Trivial names such as pyrrole, pyrazole, imidazole, pyridine, pyridazine, pyrimidine, etc. are preferred over the systematic names.OOxa + irane = oxiraneHNAza + iridine = aziridineHNAza + irine = azirineNHOOxa + aza + iridine = oxaziridineHNAza + etidine = azetidineNNAza + ete = azeteSThia + etane = thietanePPhospha + ole = phospholeDr. P. WipfPage 10 of 624/2/2008SThia + epane = thiepaneNHAza + epine = azepineOOxa + epine = oxepineNAza + ocine = azocineOO1,3-dioxolaneNNNH1,2,4-triazoleN NN1,3,5-triazineNSThia + aza + ole = 1,3-thiazoleOHNOxa + aza + ine = 1,4-oxazinefor the numbering sequence, O > S > NDr. P. WipfPage 11 of 624/2/2008SHN4H-1,4-thiazineON6H-1,3-oxazineN2H-pyrroleN3H-azepineNHOpyridin-2(1H)-oneNNOpyrazin-2(3H)-oneDr. P. WipfPage 12 of 624/2/2008- The bonds of the base component are alphabetized withconsecutive italic letters, starting with ‘a’ for the 1,2-bond, ‘b’for the 2,3-bond, etc.- The atoms of the ring system of the attached component arenumbered 1, 2, 3, … observing the principle of lowest possiblenumbering.- Atoms common to both rings (site of fusion) are indicated bythe appropriate letters and numbers and are placed in a squarebracket immediately after the prefix of the attached component.SOThieno[2,3-b]furanSO12345+abcdeNNNNNNOPyrazino[2,3-c]pyridazineImidazo[2,1-b]oxazoleDr. P. WipfPage 13 of 624/2/2008Trivial names:NHPyrrole12345O12345S12345Se12345Te12345NHN12345FuranThiopheneSelenopheneTellurophenePyrazole(1H-isomer)NHN12345(1H-isomer )ImidazoleON12345IsoxazoleNPyridine123456Dr. P. WipfPage 14 of 624/2/2008PyridazineNN123456PyrimidineNNN123456PyrazineNN123456CH2O123456Pyran(2H-isomer)PyrrolizineN1234567(1H-isomer)IndoleNH1234567(1H-isomer)IsoindoleNH1234567(2H-isomer)Dr. P. WipfPage 15 of 624/2/2008PH1234567(1H-isomer)PhosphindoleIsophosphindolePH1234567(2H-isomer)AsH1234567(1H-isomer)ArsindoleAsH1234567(2H-isomer)IsoarsindoleNNH1234567(1H-isomer)IndazoleO1234567IsobenzofuranN1238567Indolizine4NNHNN1234567(exception to systematicnumbering)89PurineDr. P. WipfPage 16 of 624/2/2008QuinolineN13245678N13245678IsoquinolineP13245678PhosphinolineAs13245678ArsinolineP13245678IsophosphinolineNN13245678PhthalazineAs13245678IsoarsinolineNN13245678QuinazolineNN13245678CinnolineNN13245678QuinoxalineDr. P. WipfPage 17 of 624/2/2008N132456789QuinolizineO13245678Chromene(4H- isomer)(2H- isomer)O13245678(1H- isomer)IsochromeneNN13245678(1,8- isomer)1,8-NaphthyridineNNNN13245678PteridineCarbazoleNH981234567(9H- isomer)(exception to systematic numbering)OO2H-Chromen-2-one(aka Coumarin)Dr. P. WipfPage 18 of 624/2/2008NHN981234567(9H- isomer)!-CarbolineAcridineN1012458679(exception to systematic numbering)NN1012458679PhenazineAs1012458679AcridarsinePhenanthridineN51032169 487As51032169 487ArsanthridineO1012458679Xanthene(9H- isomer)(exception to systematic numbering)(exception to
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