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hemistryJONATHAN CLUniversity of Manchester
NICK GREEVEiUniversity of Liverpool
STUART WARRUniversity of Cambridge
PETER WOTHEUniversity of Cambridge
OXFORDUNIVERSITY PRESS
AYDEN
S
EN
RS
Contents
1 What is organic chemistry?Organic chemistry and youOrganic compoundsOrganic chemistry and industry
Organic chemistry and the periodic table
Organic chemistry and this bookConnectionsBoxes and margin notes
End-of-chapter problemsColour
2 Organic structuresHydrocarbon frameworks and functionalgroupsDrawing moleculesHydrocarbon frameworks
Functional groupsCarbon atoms carrying functional groupscan be classified by oxidation levelNaming compounds
Systematic nomenclatureWhat do chemists really call compounds?How should you name compounds?
Problems
l
l
l
6
11
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26
31
35
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40
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45
Looking forward to Chapters 11and 14Problems
4 Structure of moleculesIntroductionAtomic structure
Summary of the importance of thequantum numbersAtomic orbitals
Molecular orbitals—homonucleardiatomicsHeteronudear diatomics
Hybridization of atomic orbitalsConclusion
Problems
5 Organic reactionsChemical reactions
Organic chemists use curly arrows torepresent reaction mechanisms
Drawing your own mechanisms withcurly arrowsProblems
6 Nucleophilic addition to thecarbonyl group
78
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81
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95
100
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135
3 Determining organic structures 47Introduction 47
Mass spectrometry 50
Nuclear magnetic resonance 56
Infrared spectra 65
Mass spectra, NMR, and IR combinedmake quick identification possible
of the carbonyl group
Cyanohydrins from the attack of cyanideon aldehydes and ketones
The angle of nucleophilic attack onaldehydes and ketones
Nucleophilic attack by 'hydride' onaldehydes and ketones
135
137
139
13972
Addition of organometallic reagents toaldehydes and ketones 142
Addition of water to aldehydes andketones 143
Hemiacetals from reaction of alcoholswith aldehydes and ketones 145
Acid and base catalysis of hemiacetal andhydrate formation 146
Bisulfite addition compounds 148
Problems 150
7 Delocalization andconjugationIntroduction
The structure of ethene (ethylene,CH2=CH2)Molecules with more than one C-Cdouble bondConjugationThe allyl system
Other allyl-like systemsThe conjugation of two 71 bonds
UV and visible spectraAromaticityProblems
151
151
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163
166
169
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179
8 Acidity, basicity, and plCa isiIntroduction 181
Acidity 182
The definition of p!Ca 185
Basicity 197
Neutral nitrogen bases 199
Neutral oxygen bases 203
pKa in action—the development of thedrugcimetidine 204
Problems 207
9 Using organometallic reagentsto make C-C bondsIntroduction
Organometallic compounds contain acarbon-metal bond
Making organometallics
Using organometallics to make organicmolecules
A closer look at some mechanismsProblems
10 Conjugate additionConjugation changes the reactivity ofcarbonyl groups
Alkenes conjugated with carbonyl groupsare polarizedPolarization is detectablespectroscopically
Molecular orbitals control conjugateadditions
Ammonia and amines undergo conjugateaddition
Conjugate addition of alcohols can becatalysed by acid or baseConjugate addition or direct addition tothe carbonyl group?Copper(I) salts have a remarkable effecton organometallic reagentsConclusion
Problems
11 Proton nuclear magneticresonanceThe differences between carbon andproton NMRIntegration tells us the number ofhydrogen atoms in each peakRegions of the proton NMR spectrumProtons on saturated carbon atoms
The alkene region and the benzene region 251
The aldehyde region: unsaturated carbonbonded to oxygen 255
Coupling in the proton NMR spectrum 258
To conclude 274
Problems 275
12 Nucleophilic substitution atthe carbonyl (C=O) group 279The product of nucleophilic addition to acarbonyl group is not always a stablecompound 279
Carboxylic acid derivatives 280
Not all carboxylic acid derivatives areequally reactive 286
Making other compounds by substitutionreactions of acid derivatives 297
Making ketones from esters: the problem 297
Making ketones from esters: the solution 299
To summarize...
And to conclude...
Problems
301
301
302
13 Equilibria, rates, andmechanisms: summary ofmechanistic principles 305How far and how fast? 305
How the equilibrium constant varieswith the difference in energy betweenreactants and products 307
How to make the equilibrium favourthe product you want 310
Entropy is important in determiningequilibrium constants 312
Equilibrium constants vary withtemperature ' 314
Making reactions go faster: the real reasonreactions are heated 315
Catalysis in carbonyl substitution reactions 323
The hydrolysis of amides can havetermolecular kinetics 325
The ci5-frans isomerization of alkenes 326
Kinetic versus thermodynamic products 328
Low temperatures prevent unwantedreactions from occurring 331
Solvents 332
Summary of mechanisms fromChapters 6-12 334
Problems 336
14 Nucleophilic substitution atC=O with loss of carbonyloxygen 339
Introduction
Aldehydes can react with alcohols toform hemiacetals
339
340
Kinetics 319
Acetals are formed from aldehydes orketones plus alcohols in the presence of
acid 342
Amines react with carbonyl compounds 348
Amines from imines: reductive amination 354
Substitution of C=O for C=C: a brief look
at the Wittig reaction 357
Summary 358
Problems 358
15 Review of spectroscopicmethods 36iThere are three reasons for this chapter 361
Does spectroscopy help with thechemistry of the carbonyl group? 361
Acid derivatives are best distinguished byinfrared ,„ 364
Small rings introduce strain inside thering and higher s character outside it 365
Simple calculations of C F O stretchingfrequencies in IR spectra 367
Interactions between different nuclei can
give enormous coupling constants 368
Identifying products spectroscopically 371
Tables 374
Problems 379
16 Stereochemistry 38iSome compounds can exist as a pair ofmirror-image forms 381
The rotation of plane-polarized light isknown as optical activity 388
Diastereoisomers are stereoisomers thatarenotenantiomers 390
Investigating the stereochemistry of acompound ' 397
Separating enantiomers is calledresolution 399
Problems 404
17 Nucleophilic substitution atsaturated carbon 407Nucleophilic substititution 407
Structure and stability of carbocations 407
The S^l and S^2 mechanisms fornucleophilic substitution 411
How can we decide which mechanism(SNI or Sjsf2) will apply to a given organiccompound? 414
The SN2 reaction 420
The leaving group 429
Nudeophiles 436
Nudeophiles in the S^2 reaction 437
Nudeophiles and leaving groupscompared 441
Looking forward: elimination andrearrangement reactions 443
Problems , 444
18 Conformational analysis 447Bond rotation allows chains of atoms toadopt a number of conformations 447
Conformation and configuration 448
Barriers to rotation 449
Conformations of ethane 450
Conformations of propane 450
Conformations of butane 450
Ring strain 452
A closer look at cydohexane 455
Substituted cydohexanes 460
Locking groups—f-butyl groups,decalins, and steroids 463
Axially and equatorially substituted ringsreact differently 464
Rings containing sp2 hybridized carbonatoms: cydohexanone and cyclohexene 471
Multiple rings 473
To conclude... 473
Problems 474
19 Elimination reactions 477Substitution and elimination 477
Elimination happens when thenucleophile attacks hydrogen instead ofcarbon 478
How the nucleophile affects eliminationversus substitution
El and E2 mechanisms
Substrate structure may allow El
The role of the leaving group
El reactions can be stereoselective
El reactions canberegioselective
E2 eliminations have anti-periplanartransition states
E2 eliminations can be stereospecific
E2 eliminations from cydohexanes
E2 elimination from vinyl halides: howtomakealkynes
The regioselectivity of E2 eliminations
Anion-stabilizing groups allow anothermechanism—ElcB
To conclude...
Problems
20 Electrophilic addition toalkenesAlkenes react with bromine
Oxidation of alkenes to form epoxides
Electrophilic addition to unsymmetricalalkenes is regioselective
Electrophilic addition to dienes
Unsymmetrical bromonium ions openregioselectively
Electrophilic additions to alkenes can bestereoselective
Electrophilic addition to alkenes canproduce stereoisomers
Bromonium ions as intermediates instereoselective synthesis
Iodolactonization andbromolactonization make new rings
How to add water across a double bond
To conclude...
Problems
493
494
495
500
501
503
503
505
509
510
Enolization is catalysed by acids andbasesThe intermediate in the base-catalysedreaction is the enolate ion
Summary of types of enol and enolate
Stable enols
Consequences of enolization
Reaction with enols or enolates asintermediates
Stable enolate equivalents
Enol and enolate reactions at oxygen:preparation of enol ethers
Reactions of enol ethers
To conclude...
Problems
526
527
528
531
534
535
540
541
542
544
544
512
514
515
516
517
518
520
520
2 1 Formation and reactions ofenols and enolates 523Would you accept a mixture of compoundsas a pure substance? 523
Tautomerism: formation of enols byproton transfer 524
Why don't simple aldehydes and ketonesexist as enols? 525
Evidence for equilibration of carbonylcompounds with enols 525
22 Electrophilic aromaticsubstitution 547Introduction: enols and phenols 547
Benzene and its reaction withelectrophiles 549
Electrophilic substitution on phenols 555
A nitrogen lone pair activates even morestrongly 558
Alkyl benzenes react at the ortho and parapositions: a donor substituents 561
Electronegative substituents give metaproducts 564
Halogens (F, Cl, Br, and I) both withdrawand donate electrons 566
Why do some reactions stop cleanly atmonosubstitution? 568
Review of important reactions includingselectivity 571
Electrophilic substitution is the usualroute to substituted aromaticcompounds '* 576
Problems 577
23 mectropmnc alkenesIntroduction—electrophilic alkenesNucleophilic conjugate addition toalkenesConjugate substitution reactionsNucleophilic epoxidationNucleophilic aromatic substitution
The addition-elimination mechanism
Some medicinal chemistry—preparationof an antibiotic
The Sjsjl mechanism for nucleophilicaromatic substitution—diazoniumcompoundsThe benzyne mechanismNucleophilic attack on allyliccompounds
To conclude...
Problems
24 Chemoselectivity: selectivereactions and protectionSelectivityReducing agentsReduction of carbonyl groups
Catalytic hydrogenationGetting rid of functional groups
Dissolving metal reductionsOne functional group may be morereactive than another for kinetic orfor thermodynamic reasonsOxidizing agents
To conclude...
Problems
25 Synthesis m actionIntroduction
Benzocaine
581
581
582
585
588
589
590
595
597
600
604
611
612
615
615
616
617
623
627
628
630
637
640
640
643
643
644
SaccharinSalbutamol
Thyroxine
Muscalure: the sexpheromone of thehouse-flyGrandisol: the sex pheromone of themale cotton boll weevilPeptide synthesis: carbonyl chemistryinactionThe synthesis of dofetilide, a drug tocombat erratic heartbeat
Looking forwardProblems
26 Alkylation of enolatesCarbonyl groups show diverse reactivity
Some important considerations thataffect all alkylationsNitriles and nitroalkanes can bealkylated
Choice of electrophile for alkylationLithium enolates of carbonyl compoundsAlkylations of lithium enolatesUsing specific enol equivalents toalkylate aldehydes and ketonesAlkylation of p-dicarbonyl compoundsKetone alkylation poses a problem inregioselectivityEnones provide a solution toregioselectivity problemsTo conclude...
Problems
27 Reactions of enolates with
aldehydes and ketones: thealdol reactionIntroduction: the aldol reactionCross-condensations
644
645
646
648
649
651
658
661
661
663
663
664
664
667
667
668
671
676
680
683
687
688
689
689
694
Compounds that can enolize but thatare not electrophilic 696
Controlling aldol reactions with specificenol equivalents 697
Specific enol equivalents for carboxylic acidderivatives 704
Specific enol equivalents for aldehydes 707
Specific enol equivalents for ketones 709
The Mannich reaction 712
Intramolecular aldol reactions 715
To conclude: a summary of equilibriumand directed aldol methods
Problems
718
721
28 Acylation at carbon 723Introduction: the Claisen estercondensation compared to the aldolreaction 723
Problems with acylation at carbon 725
Acylation of enolates by esters 726
Crossed ester condensations 728
Summary of preparation of keto-estersby the Claisen reaction
Intramolecular crossed Claisen estercondensations
Directed C-acylation of enols andenolates
The acylation of enamines
Acylation of enols under acidicconditions
Acylation at nucleophilic carbon (otherthan enols and enolates)
How Nature makes fatty acids
To conclude...
Problems
733
734
736
739
740
742
743
746
746
29 Conjugate addition ofenolatesIntroduction: conjugate addition of
enolates is a powerful synthetictransformation 749
Conjugate addition of enolates is theresult of thermodynamic control 749
A variety of electrophilic alkenes willaccept enol(ate) nudeophiles 757
Conjugate addition followed bycydization makes six-membered rings 760
Nitroalkanes are superb at conjugateaddition 766
Problems 768
30 Retrosynthetic analysis 771Creative chemistry 771
Retrosynthetic analysis: synthesisbackwards 772
Disconnections must correspond to
known, reliable reactions 773
Synthons are idealized reagents 773
Choosing a disconnection 775
Multiple step syntheses: avoid
chemoselectivity problems 776
Functional group interconversion 777
Two-group disconnections are better
than one 780
C-C disconnections 784
Donor and acceptor synthons 791
Two-group C-C disconnections 791
1,5 Related functional groups 798
'Natural reactivity' and 'umpolung' 798
Problems 801^
31 Controlling the geometry ofdouble bonds 803
749
The properties of alkenes depend on theirgeometry '* 803
Elimination reactions are oftenunselective 805
The Julia olefination is regiospecific and
connective 8io
Stereospecific eliminations can give puresingle isomers of alkenes 812
The Peterson reaction is a stereospecificelimination 812
Perhaps the most important way ofmaking alkenes—the Wittig reaction 814
E- and Z-alkenes can be made bystereoselective addition to alkynes 818
Problems 821
32 Determination ofstereochemistry byspectroscopic methodsIntroduction3/values vary with H-C-C-H dihedralangleStereochemistry of fused ringsThe dihedral angle is not the only angleworth measuringVicinal ( J) coupling constants in otherring sizesGeminal (2J) couplingDiastereotopic CH2 groupsGeminal coupling in six-memberedringsA surprising reaction productThe 71 contribution to geminal coupling
The nuclear Overhauser effect
To conclude...Problems
823
823
824
828
830
831
834
835
841
842
844
844
848
848
33 Stereoselective reactions ofcyclic compoundsIntroduction
Reactions on small ringsStereochemical control in six-memberedrings
851
852
856
Conformational control in the formationof six-membered ringsStereochemistry of bicydic compoundsFused bicydic compoundsSpirocyclic compounds
Reactions with cyclic intermediates orcyclic transition statesTo conclude...
Problems
879
879
34 DiastereoselectivityLooking back
Making single diastereoisomers usingstereospecific reactions of alkenesStereoselective reactionsProchiralityAdditions to carbonyl groups can bediastereoselective even without ringsChelation can reverse stereoselectivity
Stereoselective reactions of acyclicalkenesAldol reactions can be stereoselective
Problems
35 Pericyclic reactions 1:cydoadditionsA new sort of reactionGeneral description of the Diels-AlderreactionThe frontier orbital description ofcydoadditionsThe Diels-Alder reaction in more detailRegioselectivity in Diels-Alder reactionsThe Woodward-Hoffmann descriptionof the Diels-Alder reactionTrapping reactive intermediates byDiels-Alder reactionsOther thermal cydoadditionsPhotochemical [2 + 2] cydoadditions
Thermal [2 + 2] cydoadditions 929Making five-membered rings—1,3-dipolar cydoadditions 932Two very important synthetic reactions:cydoaddition of alkenes with osmiumtetroxide and with ozone 936
Summary of cydoaddition reactions 940
Problems 940
36 Pericyclic reactions 2:sigmatropic and electrocyclicreactions 943Sigmatropic rearrangements 943
Orbital descriptions of [3,3] -sigmatropicrearrangements 946
The direction of [3,3] -sigmatropicrearrangements 947
[2,3] -Sigmatropic rearrangements 951
[1,5] -Sigmatropic hydrogen shifts 953
Electrocyclic reactions 956
Problems 966
37 Rearrangements 969Neighbouring groups can acceleratesubstitution reactions 969
Rearrangements occur when aparticipating group ends up bonded to adifferent atom 975
Ring expansion means rearrangement 982
Carbocation rearrangements: blessing or
curse? 983
The pinacol rearrangement 984
The dienone-phenol rearrangement 988
The benzilic acid rearrangement 989
The Favorskii rearrangement 990
Migration to oxygen: the Baeyer-Villiger
reaction 992
The Beckmann rearrangement 997
Problems 1000
38 Fragmentation 1003Polarization of C-C bonds helpsfragmentation 1003
Fragmentations are controlled bystereochemistry 1005
A second synthesis of longifolene 1010
The synthesis of nootkatone 1011
A revision example: rearrangements andfragmentation 1014
Problems 1017
39 Radical reactions 1021Radicals contain unpaired electrons 1022
Most radicals are extremely reactive... 1024
How to analyse the structure of radicals:electron spin resonance 1024
Radicals have singly occupied molecularorbitals 1025
Radical stability 1026
How do radicals react? 1029
Titanium promotes the pinacol couplingthen deoxygenates the products: theMcMurry reaction 1031
Radical chain reactions
Selectivity in radical chain reactions
Selective radical bromination: allylicsubstitution of H by Br 1039
Controlling radical chains 1041
. The reactivity pattern of radicals is quitedifferent from that of polar reagents 1047
An alternative way of making alkylradicals: the mercury method 1048
Intramolecular radical reactions are moreefficient that intermolecular ones 1049
Problems
1033
1035
1051
40 Synthesis and reactions ofcarbenes 1053
Diazomethane makes methyl esters fromcarboxylic acids 1053
Photolysis of diazomethane produces a
carbene 1055
How are carbenes formed? 1056
Carbenes can be divided into two types 1060
How do carbenes react? 1063
Alkene (olefin) metathesis 1074
Summary 1076
Problems 1076
41 Determining reactionmechanismsThere are mechanisms and there aremechanismsDetermining reaction mechanisms—the Cannizzaro reaction
1079
1079
1081
Be sure of the structure of the product 1084
Systematic structural variation 1089
The Hammett relationship 1090
Other kinetic evidence 1100
Acid and base catalysis 1102
The detection of intermediates 1109
Stereochemistry and mechanism 1113
Summary of methods for the investigationofmechanism 1117
Problems 1118
42 Saturated heterocydes andstereoelectronics 1121
1121
1122
Introduction
Reactions of heterocydes
Conformation of saturated heterocydes:the anomeric effect 1128Making heterocydes: ring-dosingreactions
Problems
1134
1144
43 Aromatic heterocydes 1:structures and reactions 114
114IntroductionAromatidty survives when parts of benzene'sring are replaced by nitrogen atoms 114
Pyridine is a very unreactive aromaticinline 114
Six-membered aromatic heterocydes canhave oxygen in the ring 115Five-membered heterocydes are goodnudeophiles 115Furan and thiophene are oxygen andsulfur analogues of pyrrole 115More reactions of five-memberedheterocydes 116
Five-membered rings with two or morenitrogen atoms 116Benzo-fused heterocydes 116Putting more nitrogen atoms in asix-membered ring 117
Fusing rings to pyridines: quinolinesandisoquinolines 117
Heterocydes can have many nitrogens butonly one sulfur or oxygen in any ring 117There are thousands more heterocydesout there 117Which heterocydic structures shouldyou learn?
Problems
118
118
44 Aromatic heterocydes 2:synthesisThermodynamics is on our sideDisconnect the carbon-heteroatombonds first
Pyrroles, thiophenes, and furans from1,4-dicarbonyl compoundsHowtp make pyridines: the Hantzschpyridine synthesis 119Pyrazoles and pyridazines from hydrazine
118
118
118
118
- i f
and dicarbonyl compoundsPyrimidines can be made from1,3-dicarbonyl compounds and amidinesUnsymmetrical nudeophiles lead toselectivity questionsIsoxazoles are made from hydroxylamineor by 1,3-dipolar cydoadditionsTetrazoles are also made by 1,3-dipolarcydoadditionsThe Fischer indole synthesisQuinolines and isoquinolines
More heteroatoms in fused rings meanmore choice in synthesisSummary: the three major approaches tothe synthesis of aromatic heterocydesProblems
45 Asymmetric synthesisNature is asymmetrical—Nature in thelooking-glassResolution can be used to separateenantiomersThe chiral pool—Nature's 'ready-made'chiral centresAsymmetric synthesisChiral reagents and chiral catalystsProblems
46 Organo-main-groupchemistry 1: sulfurSulfur: an element of contradictionsSulfur-stabilized anionsSulfonium salts
SulfoniumylidsSulfur-stabilized cationsThiocarbonyl compoundsSulfoxides
1195
1198
1199
1200
1202
1204
1209
1212
1214
1217
1219
1219
1221
1222
1225
1233
1244
1247
1247
1251
1255
1258
1261
1264
1265
seleniumTo conclude: the sulfur chemistry ofonions and garlicProblems
47 Organo-main-groupchemistry 2: boron, silicon,andtmOrganic chemists make extensive use ofthe periodic table
BoronSilicon and carbon comparedOrganotin compoundsProblems
48 Organometallic chemistryTransition metals extend the range oforganic reactionsTransition metal complexes exhibitspecial bondingPalladium (0) is most widely used inhomogeneous catalysisAlkenes are attacked by nudeophileswhen coordinated to palladium (II)Palladium catalysis in the total synthesisof a natural alkaloidOther transition metals: cobalt
Problems
49 The chemistry of lifePrimary metabolism
Life begins with nucleic acidsProteins are made of amino acids
Sugars—just energy sources?Glycosides are everywhere in nature
Compounds derived from sugars
1270
1272
1273
1277
1277
1278
1287
1304
1308 '
1311
1311
1315
1319
1336
1338
1339
1341
1345*^,
1345
1347
1353
1359
1367
1368
Other oxidations with sulfur and Most sugars are embedded incarbohydrates 1372
Lipids 1374
Bacteria and people have slightly differentchemistry 1377
Problems 1379
50 Mechanisms in biologicalchemistry 1381
Nature's NaBH4 is a nudeotide: NADHorNADPH 1381
Reductive animation in nature 1384
Nature's enols—lysine enamines andcoenzymeA 1388
Nature's acyl anion equivalent (d1
reagent) is thiamine pyrophosphate 1392
Rearrangements in the biosynthesis ofvaline and isoleucineCarbon dioxide is carried by bio tin
The shikimic acid pathway
Haemoglobin carries oxygen as aniron(II) complex
Problems
51 Natural productsIntroduction
1397
1399
1400
1406
1411
1413
1413
Natural products come from secondarymetabolism 1414
Alkaloids are basic compounds fromamino acid metabolism 1414
Fatty acids and other polyketides are madefromacetylCoA 1425
Aromatic polyketides come in greatvariety 1433
Terpenes are volatile constituents of plantresins and essential oils 1437-
Steroids are metabolites of terpene origin 144
Biomimetic synthesis: learning fromNature
Problems144
144
52 PolymerizationMonomers, dimers, and oligomers
145
145
Polymerization by carbonyl substitutionreactions 145
Polymerization by electrophilic aromatic
substitution 145
Polymerization by the SN2 reaction 145
Polymerization by nucleophilic attack
onisocyanates 145
Polymerization of alkenes 145
Co-polymerization 146
Cross-linked polymers 146
Reactions of polymers 146
Biodegradable polymers and plastics 147
Chemical reagents can be bonded topolymers 147Problems 147
53 Organic chemistry todayModern science is based on interactionbetween disciplines
The synthesis of Crixivan
The future of organic chemistry
Index
148
148
148
148
149
