Essentials of Organic Chemistry: For Students of Pharmacy, Medicinal Chemistry and Biological Chemistry

711 Pages·2006·7.29 MB·English

by  Paul M. Dewick

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
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ISBN-13:978-0-470-01665-7 (HB) 978-0-470-01666-4 (PB)
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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