Clayden - Organic chemistry - Jonathan Clayden(Mancheter...

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Unformatted text preview: Jonathan Clayden (Mancheter University) Nick Greevs (Liverpool University) Stuart Warren (Cambridge University) Peter Wothers (Cambridge University) ORGANIC CHEMISTRY C o n t e n t s 1. What is organic chemistry? 1 Organic chemistry and you Organic compounds Organic chemistry and industry Organic chemistry and the periodic table 1 1 6 11 Organic chemistry and this book Connections Boxes and margin notes End-of-chapter problems Colour 2. Organic structures 19 Hydrocarbon frameworks and functionalgroups Drawing molecules Hydrocarbon frameworks Functional groups Carbon atoms carrying functional groups can be classified byoxidation level Naming compounds Systematic nomenclature What do chemists really call compounds? How should you name compounds? Problems 3. 35 37 37 40 43 45 47 50 56 65 72 78 78 Organic reactions 6. 81 83 86 87 95 100 105 110 110 Nucleophilic addition carbonyl group to 113 123 127 133 the Molecular orbitals explain the rteactivityof the carbonyl group 135 Cyanohydrins from the attack of cyanide on aldehydes and ketones 137 The angle of nucleophilic attack on aldehydes and ketones 139 Nucleophilic attack by ”hydride” on aldehydes and ketones 139 Addition of organometallic reagents to aldehydes and ketones 142 Addition of water to aldehydes and ketones 143 Hemiacetals from reaction of alcohols withaldehydes and ketones 145 Acid and base catalysis of hemiacetal and hydrate formation 146 Bisulfite addition compounds 148 Problems 150 7. Delocalization and conjugation Introduction The structure of ethane (ethylene,CH2=CH2) Molecules with more than one C-C doublebond Conjugation The allyl system Other allyl-like system The conjugation of two π bonds UV and visible spectra Aromaticity Problems 8. Structure of molecules Introduction Atomic structure Summary of the importance of the quantum numbers Atomic orbitals Molecular orbitals – homonuclear diatomics Heteronuclear diatomics Hybridization of atomic orbitals Conclusion Problems 5. 20 21 26 31 Determining organic structures Introduction Mass spectrometry Nuclear magnetic resonance Infrared spectra Mass spectra, NMR, and IR combined make quick identification possible Looking forward to Chapter 11 and 14 Problems 4. 14 15 15 16 Chemical reactions Organic chemists use curly arrows to represent reaction mechanisms Drawing your own mechanisms with curlyarrows Problems Acidity, basicity, and pKa Introduction Acidity The definition of pKa Basicity Neutral nitrogen bases Neutral oxygen bases pKa in action – the development of the drug cimetidine Problems 9. 151 151 153 156 158 163 166 169 171 179 Using organometallic reagents to make C-C bonds 181 182 185 197 199 203 204 207 Introduction Organometallic compounds contain a carbon-metal bond Making organometallics Using organometallics to make organic molecules 218 A closer look at some mechanisms Problems 209 209 211 223 224 10. Conjugate addition Conjugation changes the reactivity of carbonyl group Alkenes conjugated with carbonyl groups are polarized Polarization is detectable spectroscopically Molecular orbitals control conjugate addition Ammonia and amines undergo conjugate addition Conjugate addition of alcohols can be catalysed by acid or base Conjugate addition or direct addition to the carbonyl group? Copper (I) salts have a remarkableeffect on organometallic reagents Conclusion Problems 227 229 229 230 231 233 234 239 240 241 11. Proton nuclear magnetic resonance The differences between carbon and protonNMR Integration tells us the number of hydrogen atoms in each peak Regions of the proton NMR spectrum Protons on saturated carbon atoms The alkene region and the benzene region The aldehyde region: unsaturated carbon bonded to oxygen Coupling in the proton NMR spectrum To conclude Problems 12. Nucleophilic substitution carbonyl (C=O) group at 243 244 245 246 251 255 258 274 275 the The product of nucleophilic addition to a carbonyl group is notalways stable compound Carboxylic acid derivatives Not all carboxylic acid derivatives are equally reactive Making other compounds by substitution reaction of acid derivatives Making ketones from esters: the problem Making ketones from esters: the solution To summarize … Problems 279 280 286 297 297 299 301 302 13. Equilibria, rates and mechanisms: summary of mechanistic principles How far and how fast? 305 How the equilibrium constant varies withthe difference in energy between reactants and products 307 How to make the equilibrium favour the product you want 310 Entropy is important in determining equilibrium constant 312 Equilibrium constant vary with temperature 314 Making reactions go faster: the real reason reactions are heated 315 Kinetics 319 Catalysis in carbonyl substitution ractions 323 The hydrolysis of amides can have termolecular kinetics325 The cis-trans isomerization of alkenes 326 Kinetic versus thermodynamic products 328 Low temperatures prevent unwanted reations from occurring 331 Solvents 332 Summary of mechanisms from Chapters 6-12 334 Problems 336 14. Nucleophilic substitution at C=O with loss of carbonyl oxygen Introduction 339 Aldehydes can react with alcohols to form hemiacetrals 340 Acetals are formed from aldehydes or ketones plus alcohols in the presenceof acids 342 Amines react with carbonyl compounds 348 Amines from imines: reduction amination 354 Substitution of C=O for C=C: a brief look at the Wittig reation 357 Summary 358 Problems 358 15. Review of spectroscopic methods There are three reasons for this chapter Does spectroscopy help with the chemistry of the carbonyl group? Acid derivatives are best distinguished by infrared Small rings introduce strain inside the ring and higher s character outside it Simple calculations of C=O stretching frequencies in IR spectra Interactions between different nuclei can give enormous coupling constsants Identifying products spectroscopically Tables Problems 361 361 364 365 367 368 371 374 379 16. Stereochemistry Some compounds can exist as a pair of mirror-image forms 381 The rotation of plane-polarized light is known as optical activity 388 Diastereoisomers are stereoisomers that are not enantiomers 390 Investigating the stereochemistry of a compound 397 Separating enantiomers is called resolution 399 Problems 404 17. Nucleophilic substitution saturated carbon at Nucleophilic substitution Structure and stability of carbocations The SN1 and SN2 mechanisms for nucleophilic substitution How can we decide which mechanism(SN1 or SN2) will apply to a given organic compound? The SN2 reaction The leaving group Nucleophiles Nucleophiles in the SN2 reaction Nucleophile and leaving groups compared Looking forward: elimination and rearrangement reactions Problems 407 407 411 414 420 429 436 437 441 443 444 18. Conformational analysis Bond rotation allows chains of atoms to adopt a number of conformations Conformation and configuration Barriers to rotation Conformations of ethane Conformations of propane Conformations of butane Ring strain A closer look at cyclohexane Substituted cyclohexanes Looking groups – t-butyl groups, decalins, and steroids Axially and equatorially substituted rings react 447 448 449 450 450 450 452 455 460 463 differently Rings containing sp2 hybridized carbon atoms: cyclohexanone and cyclohexene Multiple rings To conclude Problems 464 471 473 473 474 19. Elimination reactions Substitution and elimination 477 Elimination happens when the nucleophilic attacks hydrogen instead of carbon 478 How the nucleophile affects elimination versus substitution 479 E1 and E2 mehanisms 480 Substrate structure may allow E1 482 The role of the leaving group 484 E1 reactions can be stereoselective 487 E1 reactions can be regioselective 489 E2 eliminations have anti-peroplanar transition state 490 E2 eliminations can be stereospecific 491 E2 eliminations from cyclohexanes 492 E2 elimination from vinyl halides: how to make alkynes493 The regioselectivity of E2 eliminations 494 Anion-stabilizing groups allow another mechanism E1cB 495 To conclude … 500 Problems 501 20. Electrophilic addition to alkenes Alkenes react with bromine Oxidation of alkenes to form epoxides Electrophilic addition to unsymmetrical alkenes is regioselective Eletrophilic addition to dienes Unsymmetrical bromonium ions open regioselectively Eletrophilic additions to alkenes can be tereoselctive Bromonium ions as intermediates in stereoselective synthesis Iodolactonization and bromolactonization make new rings How to add water across a double bond To conclude … Problems 503 505 509 510 512 514 516 517 518 520 520 21. Formation and reactions of enols and enolates Would you accept a mixture of compounds as a pure substance? 523 Tautomerism: formation of enols by transfer proton 524 Why don’t simple aldehydes and ketones exist as enols?525 Evidence for equilibriation of carbonyl compounds with enols 525 Enolization is catalysed by acids and bases 526 The intermediate in the base-catalysed reaction is the enolate ion 527 Summary of types of enol and enolate 528 Stable enols 531 Consequences of enolization 534 Reaction with enols or enolates as intermediates 535 Stable enolate equivalents 540 Enol and enolate reactions of oxygen: preparation of enol ethers 541 Reaction of enol ethers 542 To conclude … 544 Problems 544 22. Electrophilic aromatic substitution Introduction: enols and phenols Benzene and its reaction with electrophiles Electrophilic substitution of phenols A nitrogen lone pair activates even more strongly Alkyl benzenes react at the orto and para positions: 547 549 555 558 α donor substituents 561 Electronegative substituents give meta products 564 Halogens (F, Cl, Br, and I) both withdraw and donate electrons 566 Why do some reactions stop cleantly at monosubstitution? 568 Rewiew of important reactions including selectivity 571 Electrophilic substitution is the usual route to substituted aromatic compounds 576 Problems 577 23. Electrophilic alkenes Introduction – electrophilic alkenes 581 Nucleophilic conjugate addition to alkenes 582 Conjugate substitution reactions 585 Nucleophilic epoxidation 588 Nucleophilic aromatic substitution 589 The addition–elimination mechanism 590 Some medicinal chemistry – preparation of an antibiotic595 The SN1 mechanism for nucleophilic aromatic substitution–diazonium compounds 597 The benzyne mechanism 600 Nucleophilic attack on allylic compounds 604 To conclude … 611 Problems 612 24. Chemoselectivity: selective reactions and protection Selectivity Reducing agents Reduction of carbonyl groups Catalytic hydrogenation Getting rid of functional groups Dissolving metal reduction One functional group may be more reactive than another for kineticor forthermodynamic reasons Oxidizing agents To conclude Problems 615 616 617 623 627 628 630 637 640 640 25. Synthesis in action Introduction Benzocaine Saccharin Salbutamol Thyroxine 646 Muscalure: the sex pheromone of the house-fly Grandisol: the sex pheromoneof the male cotton boll weevil Peptide synthesis: carbonyl chemistry in action The synthesisi of dofetilide, a drug to combat erratic heartbeat Looking forward Problems 643 644 644 645 648 649 651 658/ 661 661 26. Alkylation of enolates Carbonyl groups show diverse reactivity 663 Some important considerations that affect all alkylations664 Nitriles and nitrolkenes can be alkylated 664 Choise of electrophile for alkylation 667 Lithium enolates of carbonyl compounds 667 Alkylations of lithium enolates 668 Using specific enol equivalents to alkylate aldehydes and ketones 671 Alkylation of β-dicarbonyl compounds 676 Ketone alkylation poses a problem in regioselectivity 680 Enones provide a solution to regioselectivity problems 683 To conclude … 687 Problems 688 27. Reactions of enolates with aldehydes and ketones: the aldol reaction Introduction: the aldol reaction 689 Cross-condensation 694 Compounds that can enolize but that are not electrophilic 696 Controlling aldol reaction with specific enol equivalents 697 Specific enol equivalents for carboxylic acid derivatives704 Specific enol equivalents for aldehydes 707 Specific enol equivalents for ketones 709 The Mannich reaction 712 Intramolecular aldol reaction 715 To conclude: a summary of equilibrium and directed aldol methods 718 Problems 721 28. Acylation at carbon Introduction: the Claisen ester condensation compared to the aldol reaction Problems with acylation at carbon Acylation of enolates by esters Crossed ester condensations Summary of preparation of keto-esters by Claisen reaction Intramolecular crossed Claisen ester condensations Directed C-acylation of enols and enolates The acylation of enamines ` Acylation of enols under acidic conditions Acylation at nucleophilic carbon (other than enols and enolates) How nature makes fatty acids To conclude … Problems 723 725 726 728 733 734 736 739 740 742 743 746 746 29. Conjugate addition of enolates Introduction: conjugate addition of enolates is a Powerful synthetic transformation Conjugate addition of enolates is the result of thermodynamic control A variety of electrophilic alkenes will accept enol(ate) nucleophiles Conjugate addition followed by cyclization makes six–membered rings Nitroalkanes are superb at conjugate addition Problems 749 749 757 760 766 768 30. Retrosynthetic analysis Creative chemistry Retrosynthetic analysis: synthesis backward Disconnections must correspond to known, reliabile reactions Synthons are idealized reagents Choosing a disconnection Multiple step syntheses: avoid chemoselectivity problems Functional group interconversion Two-group disconnections are better than one C-C disconnections Donor and acceptor synthons Two-group C-C disconnections 1,5 Related functional groups Natural activity’ and ‘umpolung’ Problems 771 772 773 773 775 776 777 780 784 791 791 798 798 801 31. Controlling the geometry of double bonds The properties of alkenes depend on their geometry 803 Elimination reations are often unselective 803 The Julia olefination is regiospecific and connective 810 Stereospecific eliminations can give pure single isomers of alkenes 812 The Peterson reaction is a stereospecific elimination Perhaps the most important way of making alkenes – the Wittig reaction E- and Z- alkenes can be made by stereoselective alkynes 818 Problems 1 32. Determination of stereochemistry by spectroscopic methods Introduction 3 J values vary with H-C-C-H dihedral angle Stereochemistry of fused rings The dihedral angle is not the only angle worth measuring Vicinal (3J) coupling constants in other ring sizes Geminal (2J) coupling Diastereotopic CH2 groups Geminal coupling in six-membered rings A surprising reaction product The π contribution to geminal coupling The nuclear Overhauser effect To conclude … Problems 812 814 addition to 82 823 824 828 830 831 834 835 841 842 844 844 848 848 33. Stereoselective reactions of cyclic compounds Introduction Reations of small rings Stereochemical control in six-membered rings Conformational control in the formation of sixmembered rings Stereochemistry of bicyclic compounds Fused bicyclic compounds Spirocyclic compounds Reactions with cyclic intermediates or cyclic transition states To conclude … Problems 851 852 856 861 862 863 870 871 879 879 34. Diastereoselectivity Looking back 881 Making single diastereoisomers using stereospecific reactions of alkenes 882 Stereoselective reactions 884 Prochirality 884 Additions to carbonyl groups can be diastereoselective even without rings 887 Chelation can reverse stereoselectivity 892 Stereoselective reactions of acyclic alkenes 895 Aldol reactions can be stereoselective 898 Problems 903 35. Pericyclic reactions 1: cycloadditions A new sort of reation General description of the Diels-Alderreaction The frontier orbital description of cycloadditions The Diels-Alder reaction in more detail Regioselectivity in Diels-Alder reactions The Woodward-Hoffmann description of the DielsAlder reaction Trapping reactive intermediates by Diels-Alder reactions Other thermal cycloadditions Photochemical [2+2] cycloadditions Thermal [2+2] cycloadditions Making five-membered rings – 1,3-dipolar cycloadditions Two very important synthetic reactions: cycloaddition of alkenes with osmium tetroxide and with ozone Summary of cycloaddition reactions Problems 905 907 914 916 919 922 923 924 927 929 932 936 940 940 36. Pericyclic reactions 2: sigmatropic and electrocyclic reactions Sigmatropic rearrangements Orbital description of [3,3]- sigmatropic rearrangements The direction of [3,3]- sigmatropic rearrangements [2,2]- Sigmatropic rearrangements [1,3]- Sigmatropic hydrogen shifts Electrocyclic reactions Problems 943 946 947 951 953 956 966 37. Rearrangements Neighbouring groups can accelerate substitution reactions Rearrangements occurs when a participatinggroups ends up bonded to a different atom Ring expansion means rearrangement Carbocations rearrangements: blessing or course? The pinacol rearrangement The dienone-phenol rearrangement The benzilic acid rearrangement The Favorskii rearrangement Migration to oxygen: the Baeyer-Villigerreaction The Beckmann rearrangement Problems 969 975 982 983 984 988 989 990 992 997 1000 38. Fragmentation Polarization of C-C bonds helps fragmentation Fragmentations are controlled by stereochemistry A second synthesis of longifolene The synthesis of nootkatone A revision example: rearrangements and fragmentation Problems 1003 1005 1010 1011 1014 1017 39. Radical reactions Radicals contain unpaired electrons 1021 Most radicals are extremely reactive … 1022 How to analyse the structure of radicals: electron spin resonance 1024 Radicals have singly occupied molecular orbitals 1025 Radical stability 1026 How do radicals react? 1029 Titanium promotes the pinacol couplingthen deoxygenates the products: the McMurry reaction 1031 Radical chain reactions 1033 Selectivity in radical chain reactions 1035 Selective radical bromination: allylic substitution of H by Br 1039 Controlling radical chains 1041 The reactivity pattern of radicals is quite different from that of polar reagents 1047 An alternative way of making alkyl radicals: the mercury method 1048 Intramolecular radical reactions are moreefficient that intermolecular ones 1049 Problems 1051 40. Synthesis and reactions of carbenes Diazomethane makes methyl esters from carboxylic Acids Photolysis of diazomethane produces a carbene How are carbenes formed? Carbenes can be devided into two types How do carbenes react? Alkene (olefin) metathesis Summary Problems 1053 1055 1056 1060 1063 1074 1076 1076 41. Determining reaction mechanisms There are mechanisms and there are mechanisms 1079 Determinating reaction mechanisms – the Cannizzaro reaction Be sure of the structure of the product Systematic structural variation The Hammett relationship Other kinetic evidence Acid and base catalysis The detection of intermediates Stereochemistry and mechanism Summary of methods for the investigation of mechanism Problems 42. Saturated heterocycles stereoelectronics 1081 1084 1089 1090 1100 1102 1109 1113 1117 1118 and Introduction Reactions of heterocycles Conformation of saturated heterocycles: the anomeric effect Making heterocycles: ring-closing reactions Problems 1121 1121 1128 1134 1144 43. Aromatic heterocycles 1: structures and reations Introduction Aromatcity survives when parts of benzene’s ring are replaced by nitrogen atoms Pyridine is a very unreactive aromatic imine Six-membered aromatic heterocycles can have oxygen in the ring Five-membered heterocycles are good nucleophiles Furan and thiophene are oxygen and sulfur analogues of pyrrole More reactions of five-membered heterocycles1162 Five-membered rings with two or more nitrogen atoms Benzo-fused heterocycles Putting more nitrogen atoms in a six-membered ring Fusing rings to pyridines: quinolines andisoquinolines Heterocycles can have many nitrogens but only one sulfur or oxygen in any ring There are thousands more heterocycles out there Which heterocyclic structures should you learn? Problems 1147 1148...
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