Essentials of Organic Chemistry Essentials of Organic Chemistry For students of pharmacy, medicinal chemistry and biological chemistry Paul M Dewick School of Pharmacy University of Nottingham, UK Copyright2006 JohnWiley&SonsLtd,TheAtrium,SouthernGate,Chichester, WestSussexPO198SQ,England Telephone(+44)1243779777 Email(forordersandcustomerserviceenquiries):[email protected] VisitourHomePageonwww.wiley.com ReprintedwithcorrectionsJune2006. 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BritishLibraryCataloguinginPublicationData AcataloguerecordforthisbookisavailablefromtheBritishLibrary ISBN-13:978-0-470-01665-7 (HB) 978-0-470-01666-4 (PB) ISBN-10:0-470-01665-5(HB) 0-470-01666-3(PB) Contents Preface xiii 1 Molecular representations and nomenclature 1 1.1 Molecularrepresentations 1 1.2 Partialstructures 3 1.3 Functionalgroups 4 1.4 Systematicnomenclature 6 1.5 Commongroupsandabbreviations 14 1.6 Common,non-systematicnames 15 1.7 Trivialnamesforcomplexstructures 15 1.8 Acronyms 15 1.9 Pronunciation 16 2 Atomic structure and bonding 19 2.1 Atomicstructure 19 2.2 Bondingandvalency 19 2.3 Atomicorbitals 20 2.4 Electronicconfigurations 23 2.5 Ionicbonding 23 2.6 Covalentbonding 24 2.6.1 Molecularorbitals:σandπbonds 24 2.6.2 Hybridorbitalsincarbon 26 2.6.3 Hybridorbitalsinoxygenandnitrogen 33 2.7 Bondpolarity 35 2.8 Conjugation 37 2.9 Aromaticity 41 2.9.1 Benzene 41 2.9.2 Cyclooctatetraene 42 2.9.3 Hu¨ckel’srule 42 2.9.4 Kekule´ structures 44 2.9.5 Aromaticityandringcurrents 44 vi CONTENTS 2.9.6 Aromaticheterocycles 44 2.9.7 Fusedrings 44 2.10 Resonancestructuresandcurlyarrows 45 2.11 Hydrogenbonding 49 2.12 Molecularmodels 51 3 Stereochemistry 55 3.1 Hybridizationandbondangles 55 3.2 Stereoisomers 56 3.3 Conformationalisomers 57 3.3.1 Conformationsofacycliccompounds 57 3.3.2 Conformationsofcycliccompounds 60 3.4 Configurationalisomers 73 3.4.1 Opticalisomers:chiralityandopticalactivity 73 3.4.2 Cahn–Ingold–Prelogsystemtodescribeconfiguration atchiralcentres 80 3.4.3 Geometricisomers 83 3.4.4 Configurationalisomerswithseveralchiralcentres 85 3.4.5 Mesocompounds 90 3.4.6 Chiralitywithoutchiralcentres 92 3.4.7 Prochirality 94 3.4.8 Separationofenantiomers:resolution 99 3.4.9 Fischerprojections 100 3.4.10 DandLconfigurations 103 3.5 Polycyclicsystems 106 3.5.1 Spirosystems 106 3.5.2 Fusedringsystems 107 3.5.3 Bridgedringsystems 116 4 Acids and bases 121 4.1 Acid–baseequilibria 121 4.2 AcidityandpK values 122 a 4.3 Electronicandstructuralfeaturesthatinfluenceacidity 125 4.3.1 Electronegativity 125 4.3.2 Bondenergies 125 4.3.3 Inductiveeffects 125 4.3.4 Hybridizationeffects 128 4.3.5 Resonance/delocalizationeffects 129 4.4 Basicity 135 4.5 Electronicandstructuralfeaturesthatinfluencebasicity 136 4.5.1 Electronegativity 136 4.5.2 Inductiveeffects 137 4.5.3 Hybridizationeffects 138 4.5.4 Resonance/delocalizationeffects 139 4.6 Basicityofnitrogenheterocycles 143 4.7 Polyfunctionalacidsandbases 144 4.8 pH 146 4.9 TheHenderson–Hasselbalchequation 149 CONTENTS vii 4.10 Buffers 152 4.11 UsingpK values 155 a 4.11.1 Predictingacid–baseinteractions 155 4.11.2 Isotopiclabellingusingbasicreagents 157 4.11.3 Amphotericcompounds:aminoacids 159 4.11.4 pK anddrugabsorption 164 a 5 Reaction mechanisms 167 5.1 Ionicreactions 167 5.1.1 Bondpolarity 170 5.1.2 Nucleophiles,electrophiles,andleavinggroups 171 5.2 Radicalreactions 171 5.3 Reactionkineticsandmechanism 173 5.4 Intermediatesandtransitionstates 173 5.5 Typesofreaction 174 5.6 Arrows 175 6 Nucleophilic reactions: nucleophilic substitution 183 6.1 TheS 2reaction:bimolecularnucleophilicsubstitution 183 N 6.1.1 Theeffectofsubstituents 184 6.1.2 Nucleophiles:nucleophilicityandbasicity 185 6.1.3 Solventeffects 187 6.1.4 Leavinggroups 188 6.1.5 S 2reactionsincyclicsystems 190 N 6.2 TheS 1reaction:unimolecularnucleophilicsubstitution 191 N 6.2.1 Theeffectofsubstituents 193 6.2.2 S 1reactionsincyclicsystems 195 N 6.2.3 S 1orS 2? 195 N N 6.3 Nucleophilicsubstitutionreactions 198 6.3.1 Halideasanucleophile:alkylhalides 198 6.3.2 Oxygenandsulfurasnucleophiles:ethers,esters,thioethers, epoxides 198 6.3.3 Nitrogenasanucleophile:ammoniumsalts,amines 201 6.3.4 Carbonasanucleophile:nitriles,Grignardreagents,acetylides 204 6.3.5 Hydrideasnucleophile:lithiumaluminiumhydrideandsodium borohydridereductions 205 6.3.6 Formationofcycliccompounds 206 6.4 Competingreactions:eliminationsandrearrangements 206 6.4.1 Eliminationreactions 207 6.4.2 Carbocationrearrangementreactions 214 7 Nucleophilic reactions of carbonyl groups 221 7.1 Nucleophilicadditiontocarbonylgroups:aldehydesandketones 221 7.1.1 Aldehydesaremorereactivethanketones 222 7.1.2 Nucleophilesandleavinggroups:reversibleadditionreactions 223 7.2 Oxygenasanucleophile:hemiacetals,hemiketals,acetalsandketals 224 7.3 Waterasanucleophile:hydrates 234 7.4 Sulfurasanucleophile:hemithioacetals,hemithioketals,thioacetals andthioketals 235 viii CONTENTS 7.5 Hydrideasanucleophile:reductionofaldehydesandketones, lithiumaluminiumhydrideandsodiumborohydride 235 7.6 Carbonasanucleophile 238 7.6.1 Cyanide:cyanohydrins 238 7.6.2 Organometallics:Grignardreagentsandacetylides 240 7.7 Nitrogenasanucleophile:iminesandenamines 242 7.7.1 Imines 242 7.7.2 Enamines 247 7.8 Nucleophilicsubstitutiononcarbonylgroups:carboxylicacidderivatives 248 7.9 Oxygenandsulfurasnucleophiles:estersandcarboxylicacids 252 7.9.1 Alcohols:esterformation 252 7.9.2 Water:hydrolysisofcarboxylicacidderivatives 256 7.9.3 Thiols:thioacidsandthioesters 261 7.10 Nitrogenasanucleophile:amides 262 7.11 Hydrideasanucleophile:reductionofcarboxylicacidderivatives 267 7.12 Carbonasanucleophile:Grignardreagents 271 7.13 Nucleophilicsubstitutiononderivativesofsulfuricandphosphoricacids 272 7.13.1 Sulfuricacidderivatives 272 7.13.2 Phosphoricacidderivatives 275 8 Electrophilic reactions 283 8.1 Electrophilicadditiontounsaturatedcarbon 283 8.1.1 Additionofhydrogenhalidestoalkenes 284 8.1.2 Additionofhalogenstoalkenes 286 8.1.3 Electrophilicadditionstoalkynes 292 8.1.4 Carbocationrearrangements 296 8.2 Electrophilicadditiontoconjugatedsystems 296 8.3 Carbocationsaselectrophiles 299 8.4 Electrophilicaromaticsubstitution 304 8.4.1 Electrophilicalkylations:Friedel–Craftsreactions 306 8.4.2 Electrophilicacylations:Friedel–Craftsreactions 308 8.4.3 Effectofsubstituentsonelectrophilicaromaticsubstitution 309 8.4.4 Electrophilicsubstitutiononpolycyclicaromaticcompounds 315 9 Radical reactions 319 9.1 Formationofradicals 319 9.2 Structureandstabilityofradicals 321 9.3 Radicalsubstitutionreactions:halogenation 322 9.3.1 Stereochemistryofradicalreactions 325 9.3.2 Allylicandbenzylicsubstitution:halogenationreactions 325 9.4 Radicaladditionreactions:additionofHBrtoalkenes 328 9.4.1 RadicaladditionofHBrtoconjugateddienes 330 9.4.2 Radicalpolymerizationofalkenes 331 9.4.3 Additionofhydrogentoalkenesandalkynes:catalytic hydrogenation 332 9.5 Radicaladditionofoxygen:autoxidationreactions 333 9.6 Phenolicoxidativecoupling 340 CONTENTS ix 10 Nucleophilic reactions involving enolate anions 347 10.1 Enolsandenolization 347 10.1.1 Hydrogenexchange 351 10.1.2 Racemization 352 10.1.3 Conjugation 354 10.1.4 Halogenation 356 10.2 Alkylationofenolateanions 357 10.3 Addition–dehydration:thealdolreaction 360 10.4 Otherstabilizedanionsasnucleophiles:nitrilesandnitromethane 365 10.5 Enaminesasnucleophiles 366 10.6 TheMannichreaction 369 10.7 Enolateanionsfromcarboxylicacidderivatives 372 10.8 Acylationofenolateanions:theClaisenreaction 379 10.8.1 ReverseClaisenreactions 386 10.9 Decarboxylationreactions 387 10.10 Nucleophilicadditiontoconjugatedsystems:conjugateaddition andMichaelreactions 393 11 Heterocycles 403 11.1 Heterocycles 403 11.2 Non-aromaticheterocycles 403 11.3 Aromaticityandheteroaromaticity 405 11.4 Six-memberedaromaticheterocycles 407 11.4.1 Pyridine 407 11.4.2 Nucleophilicadditiontopyridiniumsalts 414 11.4.3 Tautomerism:pyridones 416 11.4.4 Pyryliumcationandpyrones 418 11.5 Five-memberedaromaticheterocycles 420 11.5.1 Pyrrole 420 11.5.2 Furanandthiophene 426 11.6 Six-memberedringswithtwoheteroatoms 427 11.6.1 Diazines 427 11.6.2 Tautomerisminhydroxy-andamino-diazines 429 11.7 Five-memberedringswithtwoheteroatoms 432 11.7.1 1,3-Azoles:imidazole,oxazole,andthiazole 432 11.7.2 Tautomerisminimidazoles 433 11.7.3 Reactivityof1,3-azoles 436 11.7.4 1,2-Azoles:pyrazole,isoxazole,andisothiazole 438 11.8 Heterocyclesfusedtoabenzenering 438 11.8.1 Quinolineandisoquinoline 440 11.8.2 Indole 443 11.9 Fusedheterocycles 448 11.9.1 Purines 449 11.9.2 Pteridines 452 11.10 Someclassicaromaticheterocyclesyntheses 457 11.10.1 Hantzschpyridinesynthesis 458 11.10.2 Skraupquinolinesynthesis 458