Organic chemistry by clayden, greeves, warren and wothers

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 What is organic chemistry? Organic chemistry and you Organic compounds Organic chemistry and industry Organic chemistry and the periodic table 1 11 Organic chemistry and this book Connections Boxes and margin notes End-of-chapter problems Colour 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 chemists really call compounds? How should you name compounds? Problems 35 37 37 40 43 45 47 50 56 65 72 78 78 Organic reactions 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 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 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 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 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 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 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 32 Determination of stereochemistry by spectroscopic methods Introduction 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 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 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 1149 1156 1157 1159 1165 1169 1172 1174 1176 1176 1180 1182 44 Aromatic heterocycles 2: synthesis Thermodynamics is one our side 1185 Disconnect the carbon-heteroatom bonds first1 1186 Pyrroles, thiophenes, and furans from 1,4-dicarbonyl compounds 1188 How to make pyridines: the Hantzsch pyridine synthesis 1191 Pyrazoles and pyridazines from hydrazine and dicarbonyl compounds 1195 Pyrimidines can be made from 1,3-dicarbonyl compounds and amidines 1198 Unsymmetrical nucleophiles lead to selectivity questions 1199 Izoxazoles are made from hydroxylamine or by 1,3-dipolar cycloadditions 1200 Tetrazoles are also made by 1,3-dipolar cycloadditions 1202 The Fischer indole synthesis 1204 Quinolines and isoquinolines 1209 More heteroatoms in fused rings mean more choise in synthesis 1212 Summary: the three major approaches to the synthesisof aromatic heterocycles 1214 Problems 1217 45 Asymmetric synthesis Nature is asymmetrical – Nature in the looking-glass 1219 Resolution can be used to separateenantiomers 1221 The chiral pool – Nature’s ‘ready-made’ chiral centers 1222 Asymmetric synthesis Chiral reagents and chiral catalysts Problems 46 Organo-main-group sulfur 1225 1233 1244 chemistry 1: Sulfur: an element of contradictions Sulfur-stabilized anions Sulfonium salts Sulfonium ylids Thiocarbonyl compounds Sulfoxides Other oxidations with sulfur and selenium To conclude: the sulfur chemistry of onions and garlic Problems 47 Organo-main-group chemistry boron, silicon, and tin 1247 1251 1255 1258 1264 1265 1270 1272 1273 2: Organic chemists make extensive use of the periodic table Boron Silicon and carbon compared Organotin compounds Problems 1277 1278 1287 1304 1308 48 Organometallic chemistry Transition metals extend the range of organic reactions 1311 Transition metal complexes exibit special bonding 1315 Palladium (0) is most widely used in homogenous catalysis 1319 Alkenes are attacked by nucleophiles when coordinated to palladium (II) 1336 Palladium catalysis in the total synthesis of a natural alkaloid 1338 Other transition metals: cobalt 1339 Problems 1341 49 The chemistry of life Primary metabolism Life begins with nucleic acids Proteins are made of amino acids Sugars – just energy sources? Glycosides are everywhere in nature Most sugars are embedded in carbohydrates Lipids Bacteria and people have slightly different chemistry Problems 1388 1392 1397 1399 1400 1406 1411 51 Natural products Introduction Natural products come from secondary metabolism Alkaloids are basic compounds from amino acid metabolism Fatty acids and other poliketides are made from acetyl CoA Aromatic poliketides come in great variety Terpenes are volatile constituents of plant resins and essential oils Steroids are metabolites of terpene origin Biomimetic synthesis: learning from Nature Problems 1413 1414 1414 1425 1433 1437 1441 1446 1447 52 Polymerization Monomers, dimmers, and oligomers Polimerazation by carbonyl substitution reactions Polimerazation by electrophilic aromatic substitution Polimerazation by the SN2 reaction Polimerazation by nucleophilic attack on isocyanates Polimerazation of alkenes Co-polymerization Cross-linked polymers Reactions of polymers Biodedegradable polymers and plastics Chemical reagents can be bonded to polymers Problems 1451 1453 1455 1456 1458 1459 1464 1466 1468 1472 1473 1478 53 Organic chemistry today 1345 1347 1353 1359 1368 1372 1374 1377 1379 50 Mechanisms in biological chemistry Nature’s NaBH4 is a nucleotide: NADH or NADPH Reductive amination in nature Nature’s enols – lysine enamines and coenzyme A Nature’s acyl anion equivalent (d1 reagent) is thiamine pyrophosphate Rearrangements in the biosynthesis of valine and isoleucine Carbon dioxide is carried by biotin The shikimic acid pathway Haemoglobin carries oxygen as an iron (II) complex Problems 1381 1384 Modern science is based on interaction between disciplines The synthesis of Crixivan The future of organic chemistry Index 1481 1483 1487 1491 What is organic chemistry? Organic chemistry and you You are already a highly skilled organic chemist As you read these words, your eyes are using an organic compound (retinal) to convert visible light into nerve impulses When you picked up this book, your muscles were doing chemical reactions on sugars to give you the energy you needed As you understand, gaps between your brain cells are being bridged by simple organic molecules (neurotransmitter amines) so that nerve impulses can be passed around your brain And you did all that without consciously thinking about it You not yet understand these processes in your mind as well as you can carry them out in your brain and body You are not alone there No organic chemist, however brilliant, understands the detailed chemical working of the human mind or body very well We, the authors, include ourselves in this generalization, but we are going to show you in this book what enormous strides have been taken in the understanding of organic chemistry since the science came into being in the early years of the nineteenth century Organic chemistry began as a tentative attempt to understand the chemistry of life It has grown into the confident basis of vast multinational industries that feed, clothe, and cure millions of people without their even being aware of the role of chemistry in their lives Chemists cooperate with physicists and mathematicians to understand how molecules behave and with biologists to understand how molecules determine life processes The development of these ideas is already a revelation at the beginning of the twenty-first century, but is far from complete We aim not to give you the measurements of the skeleton of a dead science but to equip you to understand the conflicting demands of an adolescent one Like all sciences, chemistry has a unique place in our pattern of understanding of the universe It is the science of molecules But organic chemistry is something more It literally creates itself as it grows Of course we need to study the molecules of nature both because they are interesting in their own right and because their functions are important to our lives Organic chemistry often studies life by making new molecules that give information not available from the molecules actually present in living things This creation of new molecules has given us new materials such as plastics, new dyes to colour our clothes, new perfumes to wear, new drugs to cure diseases Some people think that these activities are unnatural and their products dangerous or unwholesome But these new molecules are built by humans from other molecules found on earth using the skills inherent in our natural brains Birds build nests; man makes houses Which is unnatural? To the organic chemist this is a meaningless distinction There are toxic compounds and nutritious ones, stable compounds and reactive ones—but there is only one type of chemistry: it goes on both inside our brains and bodies and also in our flasks and reactors, born from the ideas in our minds and the skill in our hands We are not going to set ourselves up as moral judges in any way We believe it is right to try and understand the world about us as best we can and to use that understanding creatively This is what we want to share with you Organic compounds Organic chemistry started as the chemistry of life, when that was thought to be different from the chemistry in the laboratory Then it became the chemistry of carbon compounds, especially those found in coal Now it is both It is the chemistry of the compounds of carbon along with other elements such as are found in living things and elsewhere H O 11-cis-retinal absorbs light when we see NH2 HO N H serotonin human neurotransmitter Ǡ We are going to give you structures of organic compounds in this chapter—otherwise it would be rather dull If you not understand the diagrams, not worry Explanation is on its way What is organic chemistry? í You will be able to read towards the end of the book (Chapters 49–51) about the extraordinary chemistry that allows life to exist but this is known only from a modern cooperation between chemists and biologists The organic compounds available to us today are those present in living things and those formed over millions of years from dead things In earlier times, the organic compounds known from nature were those in the ‘essential oils’ that could be distilled from plants and the alkaloids that could be extracted from crushed plants with acid Menthol is a famous example of a flavouring compound from the essential oil of spearmint and cis-jasmone an example of a perfume distilled from jasmine flowers O N HO OH cis-jasmone MeO menthol quinine N Even in the sixteenth century one alkaloid was famous—quinine was extracted from the bark of the South American cinchona tree and used to treat fevers, especially malaria The Jesuits who did this work (the remedy was known as ‘Jesuit’s bark’) did not of course know what the structure of quinine was, but now we The main reservoir of chemicals available to the nineteenth century chemists was coal Distillation of coal to give gas for lighting and heating (mainly hydrogen and carbon monoxide) also gave a brown tar rich in aromatic compounds such as benzene, pyridine, phenol, aniline, and thiophene NH2 OH S N benzene aniline phenol pyridine thiophene Phenol was used by Lister as an antiseptic in surgery and aniline became the basis for the dyestuffs industry It was this that really started the search for new organic compounds made by chemists rather than by nature A dyestuff of this kind—still available—is Bismarck Brown, which should tell you that much of this early work was done in Germany H2N NH2 N H2N NH2 N N N Bismarck Brown Y í You can read about polymers and plastics in Chapter 52 and about fine chemicals throughout the book CH3 (CH2)n CH3 n = an enormous number length of molecule is n + carbon atoms CH3 (CH2)n CH2 CH3 n = an enormous number length of molecule is n + carbon atoms In the twentieth century oil overtook coal as the main source of bulk organic compounds so that simple hydrocarbons like methane (CH4, ‘natural gas’) and propane (CH3CH2CH3, ‘calor gas’) became available for fuel At the same time chemists began the search for new molecules from new sources such as fungi, corals, and bacteria and two organic chemical industries developed in parallel—‘bulk’ and ‘fine’ chemicals Bulk chemicals like paints and plastics are usually based on simple molecules produced in multitonne quantities while fine chemicals such as drugs, perfumes, and flavouring materials are produced in smaller quantities but much more profitably At the time of writing there were about 16 million organic compounds known How many more are possible? There is no limit (except the number of atoms in the universe) Imagine you’ve just made the longest hydrocarbon ever made—you just have to add another carbon atom and you’ve made another This process can go on with any type of compound ad infinitum But these millions of compounds are not just a long list of linear hydrocarbons; they embrace all kinds of molecules with amazingly varied properties In this chapter we offer a selection Organic compounds What they look like? They may be crystalline solids, oils, waxes, plastics, elastics, mobile or volatile liquids, or gases Familiar ones include white crystalline sugar, a cheap natural compound isolated from plants as hard white crystals when pure, and petrol, a mixture of colourless, volatile, flammable hydrocarbons Isooctane is a typical example and gives its name to the octane rating of petrol The compounds need not lack colour Indeed we can soon dream up a rainbow of organic compounds covering the whole spectrum, not to mention black and brown In this table we have avoided dyestuffs and have chosen compounds as varied in structure as possible s HO HO HO Colour Description Compound red dark red hexagonal plates 3′-methoxybenzocycloheptatriene2′-one p O HO O OH HO O OH amber needles HO sucrose – ordinary sugar isolated from sugar cane or sugar beet white crystalline solid Structure O O dichloro dicyano quinone (DDQ) Cl CN e Cl CN O c yellow toxic yellow explosive gas diazomethane green green prisms with a steel-blue lustre 9-nitroso julolidine t CH2 N N N r NO blue deep blue liquid with a peppery smell azulene purple deep blue gas condensing to a purple solid nitroso trifluoromethane u F N C F O F m Colour is not the only characteristic by which we recognize compounds All too often it is their odour that lets us know they are around There are some quite foul organic compounds too; the smell of the skunk is a mixture of two thiols—sulfur compounds containing SH groups skunk spray contains: SH + SH CH3 CH3 MeO orange CH3 CH3 CH C C H2 CH3 isooctane (2,3,5-trimethylpentane) a major constiuent of petrol volatile inflammable liquid What is organic chemistry? S thioacetone ? S S S trithioacetone; Freiburg was evacuated because of a smell from the distillation this compound HS SH O HS 4-methyl-4sulfanylpentan2-one propane dithiol two candidates for the worst smell in the world no-one wants to find the winner! S S CH3 CH3 the divine smell of the black truffle comes from this compound O damascenone - the smell of roses But perhaps the worst aroma was that which caused the evacuation of the city of Freiburg in 1889 Attempts to make thioacetone by the cracking of trithioacetone gave rise to ‘an offensive smell which spread rapidly over a great area of the town causing fainting, vomiting and a panic evacuationºthe laboratory work was abandoned’ It was perhaps foolhardy for workers at an Esso research station to repeat the experiment of cracking trithioacetone south of Oxford in 1967 Let them take up the story ‘Recentlyºwe found ourselves with an odour problem beyond our worst expectations During early experiments, a stopper jumped from a bottle of residues, and, although replaced at once, resulted in an immediate complaint of nausea and sickness from colleagues working in a building two hundred yards away Two of our chemists who had done no more than investigate the cracking of minute amounts of trithioacetoneºfound themselves the object of hostile stares in a restaurant and suffered the humiliation of having a waitress spray the area around them with a deodorantº The odours defied the expected effects of dilution since workers in the laboratory did not find the odours intolerable and genuinely denied responsibility since they were working in closed systems To convince them otherwise, they were dispersed with other observers around the laboratory, at distances up to a quarter of a mile, and one drop of either acetone gem-dithiol or the mother liquors from crude trithioacetone crystallisations were placed on a watch glass in a fume cupboard The odour was detected downwind in seconds.’ There are two candidates for this dreadful smell—propane dithiol (called acetone gem-dithiol above) or 4-methyl-4-sulfanylpentan-2-one It is unlikely that anyone else will be brave enough to resolve the controversy Nasty smells have their uses The natural gas piped to our homes contains small amounts of deliberately added sulfur compounds such as tert-butyl thiol (CH3)3CSH When we say small, we mean very small—humans can detect one part in 50 000 000 000 parts of natural gas Other compounds have delightful odours To redeem the honour of sulfur compounds we must cite the truffle which pigs can smell through a metre of soil and whose taste and smell is so delightful that truffles cost more than their weight in gold Damascenones are responsible for the smell of roses If you smell one drop you will be disappointed, as it smells rather like turpentine or camphor, but next morning you and the clothes you were wearing will smell powerfully of roses Just like the compounds from trithioacetone, this smell develops on dilution Humans are not the only creatures with a sense of smell We can find mates using our eyes alone (though smell does play a part) but insects cannot this They are small in a crowded world and they find others of their own species and the opposite sex by smell Most insects produce volatile compounds that can be picked up by a potential mate in incredibly weak concentrations Only 1.5 mg of serricornin, the sex pheromone of the cigarette beetle, could be isolated from 65 000 female beetles—so there isn’t much in each beetle Nevertheless, the slightest whiff of it causes the males to gather and attempt frenzied copulation The sex pheromone of the Japanese beetle, also given off by the females, has been made by chemists As little as µg (micrograms, note!) was more effective than four virgin females in attracting the males OH O O O H serricornin japonilure the sex pheromone of the cigarette beetle Lasioderma serricorne the sex pheromone of the Japanese beetle Popilia japonica The pheromone of the gypsy moth, disparlure, was identified from a few µg isolated from the moths and only 10 µg of synthetic material As little as × 10–12 g is active as a lure for the males in field tests The three pheromones we have mentioned are available commercially for the specific trapping of these destructive insect pests Chemical reagents can be bonded to polymers 1475 Automated peptide synthesis uses polymer-bound reagents Automated polymer-based synthesis comes into its own when a stepwise polymerization is required with precise control over the addition of particular monomers in a specific sequence This is almost a definition of peptide synthesis Nature attaches each amino acid to a different ‘polymer’ (transfer RNA) and uses a ‘computer program’ (the genetic code) to assemble the polymers in the right order so that the amino acids can be joined together while bound to another polymer (a ribosome) No protection of any functional groups is necessary in this process Chemical synthesis of peptides uses a similar approach but our more primitive chemistry has not yet escaped from the need for full protection of all functional groups not involved in the coupling step The idea is that the first amino acid is attached to a polymer bead through its carboxyl group (and a spacer) and then each N-protected amino acid is added in turn After each addition, the Nprotection must be removed before the next amino acid is added The growing peptide chain is attached to the polymer so that all waste products, removed protecting groups, excess reagents, and inorganic rubbish can be washed out after each operation stage 1: attachment of the first (C-terminal) amino acid polymer bead R1 PG N H spacer CO2H removal of the N-protecting group wash out X residues wash out PG X O O R1 first amino acid added with Nprotection R1 O free amino group ready for next amino acid NH PG O NH2 Stage involves two chemical reactions—linking the first amino acid to the polymer and removing the N-protecting group—and two washing operations These four steps would take time if everything were in solution but, with the compounds attached to polystyrene beads, they can be carried out simply by packing the beads into a column chromatography-style and passing reagents and solvents through Stage involves the addition of the second N-protected amino acid with a reagent to couple it to the free amino group of the amino acid already in place Removal of the protecting group from the new amino acid is needed, followed by washes, as in stage stage 2: formation of the first peptide bond R2 PG N H CO2H removal of the N-protecting group coupling agent O O wash out X residues R1 O wash out PG R1 O R1 O NH2 O second amino acid PG added with Nprotection N H NH R2 O O free amino group ready for next H2N amino acid NH R2 í This subject was introduced in Chapter 25 and we will not repeat here all the details of how protecting groups are added and removed Please refer to that chapter if you need more explanations of the reactions We will concentrate here on the role of the polymer 52 Polymerization 1476 This process must now be repeated until all of the amino acids have been added Finally, all the side-chain protecting groups must be removed and the bond joining the peptide chain to the polymer must be broken to give the free peptide That is the process in outline, but we need now to look at some of the chemistry involved It is obviously important that all reactions are very efficient Suppose that the coupling step joining the second amino acid on to the first goes in 80% yield This may not seem bad for a chemical reaction, but it would mean that 20% of the chains consisted of only the first amino acid while 80% contained correctly both first and second Now what happens when the third amino acid is added? polymer and spacer 1 1 first coupling step 80% yield 1 1 1 2 2 1 1 2 2 3 3 second coupling step 75% yield polystyrene bead spacer O R1 O NH2 first amino acid polystyrene bead NH amide link must be stable to all reactions in peptide synthesis O 'Pam' linker or spacer O NH2 O R1 first amino acid The diagram shows that four out of five growing chains will be right (1–2) after the first coupling step, but after the second (we have put this one at 75% yield for convenience) only three of the five are correct (1–2–3) One of the others has the sequence 1–2 and the other 1–3 This situation will rapidly deteriorate and the final peptide will be a mixture of thousands of different peptides So, for a start, each reaction must occur in essentially 100% yield This can be achieved with efficient reactions and an excess of reagents (which are not a problem in polymer-supported reactions as the excess is washed away) Now some detail—and we will discuss the Merrifield version of peptide synthesis Spherical crosslinked polystyrene beads of about 50 µm in diameter are used and attached to various spacers of which the simplest is just a CH2 group from the chloromethylated polystyrene we have just discussed The caesium (Cs) salt of the amino acid is used to displace the chloride as it is a better nucleophile than the Na or K salts A better alternative is ‘Pam’ (shown in the margin) It can be used as the nucleophile to displace the chloride first The amino acid is then added after purification No chloromethyl groups can remain on the polymer with this spacer The next stage is to link the carboxyl group of the second amino acid on to the amino group of the first The Boc group (Chapter 24) is usually used for amino group protection in the Merrifield method and DCC (dicyclohexylcarbodiimide) is used to activate the new amino acid Here is a summary of this step, using symbols again for polymer and spacer Chemical reagents can be bonded to polymers 1477 Boc protecting group R2 O O CO2H N H O O R N C N R1 O O H2N DCC dicyclohexylcarbodiimide O NH N H R2 Boc The details of the reaction mechanism with DCC were given in Chapter 43, p 000, and can be shown more easily if we mark the polymer and spacer as ‘P’ and the cyclohexyl groups as ‘R’ The DCC is protonated by the free carboxylic acid and is then attacked by the carboxylate anion The intermediate is rather like an anhydride with a C=NR group replacing one of the carbonyl groups It is attacked by the amino group of the polymer-bound amino acid The by-product is dicyclohexylurea, which is washed off the column of resin OP H N R2 C R R O H2N H O O R O BocHN OP R1 N O O N C O NH R R2 BocHN BocHN R2 NR dicyclohexylurea + R N R O H N O BocHN R2 H H N H N R R O Now the Boc group must be removed with acid (such as CF3CO2H in CH2Cl2) and washed off the column leaving the free NH2 group of amino acid number two ready for the next step OP R1 O O O O NH O CF3CO3H N H R2 The mechanism of this reaction is discussed in Chapter 25 OP R1 O NH H2N R2 í The synthesis continues with repetition of these two steps until the peptide chain is complete The peptide is cleaved from the resin, usually with HF in pyridine or CF3SO2OH in CF3CO2H and given a final purification from small amounts of peptides of the wrong sequence by chromatography, usually HPLC This process is routinely automated in commercially available machines Solutions of all of the protected amino acids required are stored in separate containers and a programmed sequence of coupling and deprotection leads rapidly to the complete peptide in days rather than the years needed for solution chemistry The most dramatic illustration of this came with the publication of a heroic traditional synthesis of bovine pancreatic ribonuclease A (an enzyme with 124 amino acids) by Hirschmann, side-byside with one by Merrifield using functionalized polystyrene as we have described The traditional method required 22 co-workers, while the Merrifield method needed only one Peptide synthesis on polyacrylamide gel Another method of polymer-supported peptide synthesis has been developed by Sheppard Most things are different in this approach, which is better adapted for polar solvents and automated 52 Polymerization 1478 operation The polymer is a polyacrylamide cross-linked with bis-acrylamides joined by –NCH2CH2N– groups NMe2 Me2NOC monomer O O NH CONMe2 O H N HN N H O Me2NOC CONMe2 O cross-linking monomer Polar solvents such as water or DMF penetrate the beads, making them swell much more than the polystyrene resins This exposes more reactive groups and increases the loading of peptide chains on each bead The first amino acid is attached through its carboxyl group to an amino group on the polymer, added during or after polymerization by incorporating more 1,2-diaminoethane The favoured amino protecting group is now Fmoc (see Chapter 24), which has the advantage that it can be removed under basic conditions (piperidine) which not affect acid-labile side-chain protecting groups Methods like these have made polymer-supported synthesis so valuable a method that it is now being developed for many reactions old and new A recent (1999) issue of the journal Perkin Transactions reported two syntheses of natural products in which every step was carried out using a polymer-supported reagent Polymers are vital to us in everyday life in a multitude of ways and new polymers are being invented all the time We have done no more than scratch the surface of this subject and you should turn to more specialized books if you want to go further Problems The monomer bisphenol A is made by the following reaction NH2 Suggest a detailed mechanism N heat O H2N N N H2N cyanamide NH2 N melamine HO HO H OH bisphenol A hint about the first step: NH2 H2N N An alternative synthesis of 18-crown-6 to the one given in the chapter is outlined below How would you describe the product in polymer terms? What is the monomer? How would you make 15crown-5? H2SO4 OH O Cl Cl HO O OH O O O Cl Cl Cl KOH, THF Melamine is formed by the trimerization of cyanamide and a hint was given in the chapter as to the mechanism of this process Expand that hint into a full mechanism NH • H2N NH Melamine is polymerized with formaldehyde to make formica Draw a mechanism for the first step in this process NH2 NH2 melamine N + CH2=O 18-crown-6 (30% yield) N N H2N N N N N H N H N N NH2 An acidic resin can be made by the polymerization of 4vinylpyridine initiated by AIBN and heat followed by treatment of the polymer with bromoacetate Explain what is happening and give a representative part structure of the acidic resin Problems Br AIBN What would be the advantage of the polymer-bound reagent over normal PCC? CO2 polymer acidic resin O then acid heat PCC pyridinium chlorochromate Cl Cr N N An artificial rubber may be made by cationic polymerization of isobutene using acid initiation with BF3 and water What is the mechanism of the polymerBF3, H2O ization, and what is the strucpolymer ture of the polymer? This rubber is too weak to be used commercially and 5–10% isoprene is incorporated into the polymerizing mixture to give a different polymer that can be cross-linked by heating with sulfur (or other radical generators) Draw representative structures for sections of the new polymer and show how it can be cross-linked with sulfur BF3, H2O + 1479 O O H A polymer that might bind specifically to metal ions and be able to extract them from solution would be based on a crown ether How would you make a polymer such as this? O polymer chain O O O O S8 O ‘rubber’ polymer heat When sodium metal is dissolved in a solution of naphthalene in THF, a green solution of a radical anion is produced What is its structure? 10 What is a ‘block co-polymer’? What polymer would be produced by this sequence of reactions? What special physical properties would it have? H2O O Na polymer A controlled amounts radical anion THF This green solution initiates the polymerization of butadiene to give a ‘living polymer’ What is the structure of this polymer and why is it called ‘living’? radical anion OCN NCO in excess polymer B ‘living’ polymer H2N We introduced the idea of a spacer between a benzene ring (in a polystyrene resin) and a functional group in the chapter If a polymer is being designed to Wittig reactions, why would it be better to have a Ph2P group joined directly to the benzene ring than to have a CH2 spacer between them? polymer polymer NH2 polymer C 11 Why does polymerization occur only at relatively low temper- atures often below 200 °C? What occurs at higher temperatures? Formaldehyde polymerizes only below about 100 °C but ethylene still polymerizes up to about 500 °C Why the difference? 12 Poly(vinyl chloride) (PVC) is used for rigid structures like window frames and gutters with only small amounts of additives such as pigments If PVC is used for flexible things like plastic bags, about 20–30% of dialkyl phthalates such as the compound below are incorporated during polymerization Why is this? PPh2 useful for Wittig reactions PPh2 useless for Wittig reactions O If you need a hint, draw out the reagents that you would add to the polymer to a Wittig reaction and work out what you would get in each case A useful reagent for the oxidation of alcohol is ‘PCC’ (pyridinium chlorochromate) Design a polymeric (or at least polymer-bound) reagent that should show similar reactivity O dialkyl phthalate O O 53 Organic chemistry today 1482 On the left is a section of normal protein with glycine and phenylalanine residues (Chapter 49) In the middle is the intermediate formed when a molecule of water attacks the amide carbonyl group On the right is a piece of the HIV protease inhibitor The amide nitrogen atom has been replaced by a CH2 group (ringed in black) so that no ‘hydrolysis’ of the C–C bond can occur The inhibitor may bind but it cannot react Enzymes ideally bind their substrates strongly and the product of the reaction much more weakly If they are to accelerate the reaction they need to lower the energy of the transition state (Chapters 13 and 41) and they can this by binding the transition state of the reaction strongest of all We cannot literally synthesize a transition state analogue because transition states are by definition unstable, but intermediate analogues can be synthesized The inhibitor above has one OH group instead of the two in the genuine intermediate but this turns out to be the vital one This knowledge was acquired from an X-ray crystal structure showing how the enzyme binds the substrate The inhibitor binds well to the enzyme but cannot react so it blocks the active site These compounds are a good deal more sophisticated than this simple analysis suggests For example, HIV protease is a dimeric enzyme and experience with this class of protease suggested correctly that more or less symmetrically placed heterocyclic rings (Chapters 42–44) would greatly improve binding Here are two of the inhibitors with the active site binding portion framed in black and the heterocyclic binding portions framed in green Ph N OH OH H N N enzyme binding groups N t-Bu O N H O Crixivan (Merck) Ph N S H N O OH O N H O Ph Norvir (Abbott) NH2 N O HO N O deoxycytidine a nucleoside of DNA HO NH2 N HO N O S O 3-TC Lamivudine anti-AIDS drug Me H N N O S N hydrolysis intermediate mimics These developments looked so promising that Merck even set up a completely new research station at West Point, Pennsylvania, dedicated to this work The biochemist in charge, Dr Irving Segal, was one of the victims of the Lockerbie bombing in 1988 but his work lives on as Crixivan (indinavir) is now one of the cocktail of three drugs (AZT and 3TC, shown with the nucleoside it imitates, are the others) that has revolutionized the treatment of HIV Before this treatment most HIV victims were dead within years Now no one knows how long they will survive as the combination of the three drugs reduces the amount of virus below detectable levels Crixivan was not the first compound that Merck discovered Many others fell by the wayside because they were not active enough, were too toxic, didn’t last long enough in the body, or for other reasons Crixivan was developed from cooperation between biochemists, virologists, X-ray crystallographers, and molecular modellers as well as organic chemists When the choice of Crixivan from the various drug candidates had been made and the chemists were trying to make enough of it for trials and use, theirs was an exceptionally urgent task They knew that a kilo of compound was needed to keep each patient alive and well for a year Merck built a dedicated plant for the manufacture of Crixivan at Elkton, Virginia, in 1995 Within year, production was running at full blast and there are thousands of people alive today as a result The AIDS crisis led to cooperation between the pharmaceutical companies unparalleled since the development of penicillin during the Second World War Fifteen companies set up an AIDS drug development collaboration programme and government agencies and universities have all joined in The synthesis of Crixivan The battle is not yet won, of course, but the HIV protease inhibitors are being followed by a new generation of nonnucleoside reverse transcriptase inhibitors, which promise to be less toxic to humans An example is the DuPont–Merck compound DMP-266, made as a single enantiomer and now under clinical trials This compound, though it contains a most unusual cyclopropane and alkyne combination, is nevertheless a much simpler compound than Crixivan We shall devote most of this final chapter to the synthesis of the established and chemically more interesting drug Crixivan Crixivan is a formidable synthetic target It is probably the most complex compound ever made in quantity by organic synthesis and very large amounts must be made because one kilo is needed per patient per year The complexity largely arisPh N OH OH es from the stereochemistry There are five H stereogenic centres, marked with coloured N N N circles on this diagram, and their disposition t-Bu O means that three separate pieces of asymN O metric synthesis must be devised There are, H Crixivan (Merck) of course, also many functional groups and stereogenic centres Crixivanmarked (Merck)with circles four different rings The two black centres are 1,2-related and we have already discussed them in part at the end of Chapter 41 The green centres are 1,3-related and we saw in Chapter 45 that this type of control is possible though difficult The orange centre is 1,4-related to the nearer green centre and must be considered separately two amine alkylations (disconnection next to heteroatom) amide formation (disconnection next to heteroatom) Ph OH OH H N N N t-Bu O N H O enolate alkylation (creates ringed stereogenic centre) OH HN H2N Ph NH OH t-Bu N H N —use Cl N the piperazine fragment F3C Cl O N H The synthesis of Crixivan N 1483 O O —use cis amino indanol —use O Ph TsO the central epoxide Cl O The challenge with Crixivan, as with any drug, is to make it efficiently—high yields; few steps It has five stereogenic centres, so the chemists developing the synthesis needed to address the issue of diastereoselectivity And it is a single enantiomer, so an asymmetric synthesis was required We can start by looking at some likely disconnections, summarized in the scheme above They are all disconnections of the sorts you met in Chapter 30, and they all correspond to reliable reactions These disconnections split the molecule into five manageable chunks (synthons), three of which contain stereogenic centres and will have to be made as single enantiomers The final stereogenic DMP-266 O 53 Organic chemistry today 1484 centre (ringed in the disconnection diagram) would have to be made in the enolate alkylation step, so this step will have to be done diastereoselectively Let’s take these three chiral synthons in turn First, the simplest one: the central epoxide The reagent we need here will carry a leaving group, such as a tosylate, and it can easily be made from the epoxy-alcohol This gives a very good way of making this compound as a single enantiomer—a Sharpless asymmetric epoxidation of allyl alcohol retrosynthetic analysis O sulfonate ester formation Sharpless asymmetric epoxidation O TsO HO synthesis HO t-BuOOH, Ti(OiPr)4 TsCl O HO HO pyridine D-(–)-diethyl tartrate Next, the piperazine fragment This has two nucleophilic nitrogen atoms and they will both need protecting with different protecting groups to allow them to be revealed one at a time It will also need to be made as a single enantiomer In an early route to Crixivan, this was done by resolution, but enantioselective hydrogenation provides a better alternative Starting from a pyridine derivative, a normal hydrogenation over palladium on charcoal could be stopped at the tetrahydropyrazine stage The two nitrogens in this compound are quite different because one is conjugated with the amide while one is not (the curly arrows in the margin show this) The more nucleophilic nitrogen— the one not conjugated with the amide—was protected with benzyl chloroformate to give the Cbz derivative Now the less reactive nitrogen can be protected with a Boc group, using DMAP as a O nucleophilic catalyst O H N NH t-Bu N H O TsO O N N HN H2 Pd/C Cl OBn t-BuO NH N O N H O N H O OBn O t-Bu t-Bu N t-Bu t-BuO O Ot-Bu DMAP O N H O You met asymmetric hydrogenation using BINAP–metal complexes in Chapter 45 as a method for the synthesis of amino acids The substrate and catalyst are slightly different here, but the principle is the same: the chiral ligand, BINAP, directs addition of hydrogen across the double bond with almost perfect enantioselectivity and in very high yield In Chapter 45 we described this as addition to one enantiotopic face of the alkene A further hydrogenation step allowed selective removal of the Cbz group, preparing one of the two nitrogen atoms for alkylation í COD = cyclooctadiene H2 [(R)-BINAP(COD)Rh]OTf N t-BuO O O O N t-Bu O N OBn O N H H2, Pd/C MeOH N t-BuO t-Bu N NH OBn O N H t-BuO O t-Bu N H O 96% yield; 99% ee Ǡ H2O2 and MeCN react to give a ‘peroxyimidic acid’—the C=N analogue of a peroxy-acid—as the true epoxidizing agent NH H O O peroxyimidic acid The remaining chiral fragment is a compound whose synthesis was discussed in Chapter 41, and you should turn to p 000 for more details of the mechanisms in the reaction sequence It can be made on a reasonably large scale (600 kg) in one reaction vessel, starting from indene First, the double bond is epoxidized, not with a peroxy-acid but with the cheaper hydrogen peroxide in an acetonitrile–methanol mixture Acid-catalysed opening of the epoxide leads to a cation, which takes part in a reversible Ritter reaction with the acetonitrile solvent, leading to a single diastereoisomer of a heterocyclic intermediate which is hydrolysed to the amino-alcohol The synthesis of Crixivan H 2O MeCN MeOH NH2 N H2SO4 MeCN O H 2O O (±) OH (±) (±) The product is, of course, racemic but, as it is an amine, resolution with an acid should be straightforward Crystallization of its tartrate salt, for example, leads to the required single enantiomer in 99.9% ee With such cheap starting materials, resolution is just about acceptable, even though it wastes half the material It would be better to oxidize the indene enantioselectively, and retain the enantiomeric purity through the sequence: it is indeed possible to carry out a very selective Sharpless asymmetric dihydroxylation (Chapter 45) of indene, and the diol serves as an equally good starting material for the Ritter reaction The stereogenic centre carrying the green hydroxyl group remains firmly in place throughout the route, and controls the absolute configuration of the final product H N OH Sharpless asymmetric dihydroxylation 1485 N The Ritter reaction was described in Chapter 16, p 000 The reason for the formation of the cis diastereoisomer in this example is discussed in Chapter 41, p 000 OTf NH2 H 2O O OH í OH CF3CO2H –40 to 25°C 87% yield >99% ee Both resolution and Sharpless asymmetric dihydroxylation were successful in the synthesis of Crixivan but the best method is one we shall keep till later Only one stereogenic centre remains, and its stereoselective formation turns out to be the most remarkable reaction of the whole synthesis The centre is the one created in the planned enolate alkylation step O Ph Ph HN O HN O base Y R O X Y R O new stereogenic centre protected amino-alcohol Evans' phenylalanine-derived oxazolidinone auxiliary The obvious way to make this centre is to make Y a chiral auxiliary; the required acyl chloride could be used to acylate the auxiliary, which would direct a diastereoselective alkylation, before being removed and replaced with the amino-alcohol portion But the amino-alcohol itself, certainly once protected, has a remarkable similarity to Evans’ oxazolidinone auxiliaries (Chapter 45), and it turns out that this amino-alcohol will function very successfully as a chiral auxiliary, which does not need to be removed, avoiding waste and saving steps! The amino-alcohol was acylated with the acyl chloride, and the amide was protected as the nitrogen analogue of an acetonide by treating with 2-methoxypropene (the methyl enol ether of acetone) and an acid catalyst The enolate of this amide reacts highly diastereoselectively with alkylating agents, including, for example, allyl bromide O H 2N O OH O Ph N O Ph N O Ph Cl OMe base Br H+ cat 96:4 ratio of diastereoisomers 53 Organic chemistry today 1486 E N Li The reason for the stereoselectivity is not altogether clear, but we would expect the bulky nitrogen substituents to favour formation of the cis enolate With the amino-alcohol portion arranged as shown, the top face is more open to attack by electrophiles electrophiles attack from above H H O O OLi O Ph N LiNR2 O Ph O N O Ph N O Br bottom face crowded í The enolate also reacted diastereoselectively with the epoxy-tosylate prepared earlier The epoxide, being more electrophilic than the tosylate, is opened first, giving an alkoxide, which closes again to give a new epoxide How we know that this happens, and that the reaction does not go simply via direct displacement of tosylate? O O Ph N O Ph base O N O Ph N O TsO O TsO O O The absolute configuration at the stereogenic centre in the epoxide was, of course, already fixed (by the earlier enantioselective Sharpless epoxidation) However, it also turned out to be possible to make this compound by a different route involving a diastereoselective reaction of the alkylation product from allyl bromide, again directed by the amino-alcohol-derived auxiliary The reagents make the reaction look like an iodolactonization—and, indeed, there are many similarities with the diastereoselective iodolactonizations of Chapter 33 NIS (N-iodosuccinimide, the iodine analogue of NBS) provides an ‘I+’ source, reacting reversible and non-stereoselectively with the alkene Of the two diastereoisomeric iodonium ions, one may cyclize rapidly by intramolecular attack of the amide carbonyl group Cyclization of the other diastereoisomer is prevented by steric hindrance between the parts of the molecule coloured green Opening of the five-membered ring gives a single diastereoisomer of the iodoalcohol, which was closed to the epoxide by treatment with base O Ph O N O NIS NaHCO3 Ph Ph N O I O N (redraw) I HO Ph O (+) O I N O OH (+) I O OH Ph OH Ph NR2 I O NR2 green groups on opposite sides of ring continued opposite O The future of organic chemistry Ph OH 1487 O Ph O I O O N Ph N NaOMe O (redraw) O N O O Three of the five fragments have now been assembled, and only the two amine alkylations remain The first alkylation makes use of the epoxide to introduce the required 1,2-amino-alcohol functionality The protected enantiomerically pure piperazine reacted with the epoxide, and the product was treated with acid to deprotect both the second piperazine nitrogen and the ‘acetonide’ group left over from the earlier chiral auxiliary step The newly liberated secondary amine was alkylated with the reactive electrophile 3-chloromethyl pyridine, and the final product was crystallized as its sulfate salt O Ph t-BuO Ph O N HN O OH heat N H N N OH NH M HCl 83°C 24 h t-Bu O N H O N H t-Bu O O Ph N OH H N N OH N Cl t-Bu N O N H O Crixivan The future of organic chemistry Not all organic chemists can be involved in such exciting projects as the launching of a new antiAIDS drug But the chemistry used in this project was invented by chemists in other institutions who had no idea that it would eventually be used to make Crixivan The Sharpless asymmetric epoxidation, the catalytic asymmetric reduction, the stereoselective enolate alkylation, and the various methods tried out for the enantiomerically pure amino indanol (resolution, enzymatic kinetic resolution) were developed by organic chemists in research laboratories Some of these famous chemists like Sharpless invented new methods, some made new compounds, some studied new types of molecules, but all built on the work of other chemists In 1980 Giovanni Casiraghi, a rather less famous chemist from the University of Parma, published a paper in the Journal of the Chemical Society about selective reactions between phenols and formaldehyde He and his colleagues made the modest discovery that controlled reactions to give salicylaldehydes could be achieved in toluene with SnCl4 as catalyst The reaction is regioselective for the ortho isomer and the paper described the rather precise conditions needed to get a good yield O (CH2)n [paraformaldehyde] OH OH SnCl4, R3N, PhCH3 phenol salicylaldehyde í In Chapter 52 you met Bakelite, the first synthetic polymer, which results from unselective reactions between these two compounds 1488 53 Organic chemistry today The reaction was also successful for substituted salicylaldehydes When Jacobsen came to develop his asymmetric epoxidation, which, unlike the Sharpless asymmetric epoxidation, works for simple alkenes and not just for allylic alcohols, he chose ‘salens’ as his catalysts, partly because they could be made so easily from salicylaldehydes For example: O t-Bu H2N OH NH2 N K2CO3, H2O, EtOH t-BuO t-Bu N OH HO t-Bu 80°C t-Bu t-Bu This ‘salen’ is the ligand for manganese in the asymmetric epoxidation The stable brown Mn(III) complex can be made from it with Mn(OAc)3 in excellent yield and this can be oxidized to the active complex used above with domestic bleach (NaOCl) N Mn(OAc)3·4H2O N Mn the salen NaCl, H2O t-BuO O Cl O t-Bu 85°C, air t-Bu t-Bu stable Mn(III) complex Jacobsen epoxidation turned out to be the best large-scale method for preparing the cis-aminoindanol for the synthesis of Crixivan This process is very much the cornerstone of the whole synthesis During the development of the first laboratory route into a route usable on a very large scale, many methods were tried and the final choice fell on this relatively new type of asymmetric epoxidation The Sharpless asymmetric epoxidation works only for allylic alcohols (Chapter 45) and so is no good here The Sharpless asymmetric dihydroxylation works less well on cis-alkenes than on transalkenes The Jacobsen epoxidation works best on cis-alkenes The catalyst is the Mn(III) complex easily made from a chiral diamine and an aromatic salicylaldehyde (a 2-hydroxybenzaldehyde) N O H2N t-Bu N Mn NH2 OH R t-BuO O O O t-Bu then Mn(III) then NaOCl t-Bu t-Bu t-Bu The chirality comes from the diamine and the oxidation from ordinary domestic bleach (NaOCl), which continually recreates the Mn=O bond as it is used in the epoxidation Only 0.7% catalyst is needed to keep the cycle going efficiently The epoxide is as good as the diol in the Ritter reaction and the whole process gives a 50% yield of enantiomerically pure cis-amino-indanol on a very large scale Jacobsen asymmetric epoxidation Me N O N Me oleum [H2SO4 + SO3] O NH2 H2O OH tartaric acid 50% yield from indene >99% ee 53 Organic chemistry today Connections Building on: Arriving at: • The rest of the book ch1–ch52 Looking forward to: • How organic chemistry produced an • Life as a chemist AIDS treatment in collaboration with biologists Modern science is based on interaction between disciplines Organic chemistry has transformed the materials of everyday life, as we have seen in Chapter 52, but this is merely a glimpse of the future of organic materials where light-emitting polymers, polymers that conduct electricity, self-reproducing organic compounds, molecules that work (nano-engineering), and even molecules that think may transform our world in ways not yet imagined These developments are the result of cooperation between organic chemists and physicists, engineers, material scientists, computer experts, and many others The most dramatic developments at the beginning of the twenty-first century are new methods in medicine from collaborations between organic chemists and biologists (The biochemical background is sketched out in Chapters 49–51.) The media’s favourite ‘a cure for cancer’ is already not just ‘a cure’ but hundreds of successful cures for the hundreds of diseases collectively called ‘cancer’ A newspaper headline in 1999 revealed that there was some chance of survival for all known types of childhood cancer We are going to discuss just one equally dramatic medical development, the treatment of AIDS Like the treatment of cancer, this is a story that is only just starting, but enough is known to make it a gripping story full of hope When AIDS (Acquired Immune Deficiency Syndrome) first came into the news in the 1980s it was a horror story of mysterious deaths from normally harmless diseases after the patient’s immune system had been weakened and eventually destroyed The cause was identified by biologists as a new virus: HIV (Human Immunodeficiency Virus) and antiviral drugs, notably AZT (Chapter 49), were used with some success These drugs imitate natural nucleosides (AZT imitates deoxythymidine) and inhibit the virus from copying its RNA into DNA inside human cells by inhibiting the enzyme ‘reverse transcriptase’ These drugs also inhibit our own enzymes and are very toxic Biologists then discovered an alternative point of attack An enzyme unique to the virus cuts up long proteins into small pieces essential for the formation of new HIV particles If this enzyme could be inhibited, no new viruses would be formed, and the inhibitor should not damage human chemistry Several companies invented HIV protease inhibitors, which looked more like small pieces of proteins with the weak link of the amide bond replaced by a more stable C–C bond Real peptides are usually poor drugs because we have our own peptidases which quickly cut up ingested proteins into their constituent amino acids by hydrolysis of the amide link Drugs that imitate peptides may avoid this ignominious fate by replacing the amide bond with another bond less susceptible to hydrolysis This part structure of one HIV protease inhibitor makes the point Ph H N O H N N H O section of protein H N OH N H HN N O HO O HO deoxythymidine— a nucleoside of DNA O HN O HO N O Ph Ph HO O H N H N OH H N N N O intermediate in amide hydrolysis O section of inhibitor N AZT azidothymidine anti-AIDS drug The future of organic chemistry In the same year (1990) that Jacobsen reported his asymmetric epoxidation, a group led by Tsutomu Katsuki at the University of Kyushu in Japan reported a closely related asymmetric epoxidation The chiral catalyst is also a salen and the metal manganese The oxidant is iodosobenzene (PhI=O) but this method works best for E-alkenes It is no coincidence that Katsuki and Jacobsen both worked for Sharpless It is not unusual for similar discoveries to be made independently in different parts of the world Ph the Katsuki manganese salen complex Ph Ph Ph N O H2N N Mn NH2 OH O O Mn(OAc)2·4H2O O2 Ph Ph Ph AcO It did not enter Casiraghi’s wildest dreams that his work might some day be useful in a matter of life and death Nor did his four co-workers nor Jacobsen’s more numerous co-workers see clearly the future applications of their work By its very nature it is impossible to predict the outcome or the applications of research But be quite sure of one thing Good research and exciting discoveries come from a thorough understanding of the fundamentals of organic chemistry and require chemists to work as a team The Italian work is a model of careful experimentation and a thorough study of reaction conditions together with sensible explanations of their discoveries using the same curly arrows we have been using The Harvard team probably had a clearer idea that they were into something significant and worked with equal care and precision Jacobsen’s name is famous but both teams at Parma and Harvard Universities were needed to make the work available to Merck Hexamethylenetetramine Hexamethylenetetramine is a co-polymer (oligomer really such as those we met in Chapter 52) of formaldehyde and ammonia containing six formaldehyde and four ammonia molecules It has a beautifully symmetrical cage structure belonging to the adamantane series Hexamethylenetetramine is a crystalline compound used as a convenient source of formaldehyde for, among other things, polymerization reactions It has a tetrahedral symmetry, as does adamantane, which might be regarded CH2 O N NH3 N N N hexamethylenetetramine adamantane as the basic structural unit (not the same as the monomer!) of diamonde Diamond is of course a polymer of carbon atoms When Jacobsen’s epoxidation was fully described in 1998–99, the Casiraghi method was abandoned in favour of an even older method discovered in the 1930s by Duff The remarkable Duff reaction uses hexamethylenetetramine, the oligomer of formaldehyde and ammonia, to provide the extra carbon atom The otherwise unknown Duff worked at Birmingham Technical College Later in 1972, a William E Smith, working in the GEC chemical laboratories at Schenectady, New York, found how to make the Duff reaction more general and better yielding by using CF3CO2H as catalyst Even so, this method gives a lower yield than the Casiraghi method but it uses no dangerous reagents (particularly no stoichiometric tin) and is more suitable for large-scale work When Duff was inventing his reaction or Smith was modifying the conditions, asymmetric synthesis was not even a gleam in anyone’s eyes It is impossible even for the inventor to predict whether a discovery is important or not the Duff reaction t-Bu O N OH t-Bu + N N N hexamethylenetetramine CF3CO2H t-Bu OH 100°C t-Bu 1489 1490 í If you want to read more about these discoveries we suggest: ‘Practical asymmetric synthesis’, I W Davies and P J Reider, Chemistry and Industry (London), 1996, 412–15 The reference for the Parma work is: G Casiraghi, G Casnati, G Puglia, and G Terenghi, J Chem Soc., Perkin Trans 1, 1980, 1862–65 These journals will be in your department or university library 53 Organic chemistry today The Sharpless asymmetric dihydroxylation works best for trans disubstituted alkenes, while the Jacobsen epoxidation works best for cis disubstituted alkenes Even in this small area, there is a need for better and more general methods Organic chemistry has a long way to go If you continue your studies in organic chemistry beyond the scope of this book, you will want to read of modern work in more specialized areas Your university library should have a selection of books on topics such as: orbitals and chemical reactions; NMR spectroscopy; enzyme mechanisms; organometallic chemistry; biosynthesis; asymmetric synthesis; combinatorial chemistry; and molecular modelling This book should equip you with enough fundamental organic chemistry to explore these topics with understanding and enjoyment and, perhaps, to discover what you want to for the rest of your life All of the chemists mentioned in this chapter and throughout the book began their careers as students of chemistry at universities somewhere in the world You have the good fortune to study chemistry at a time when more is understood about the subject than ever before, when information is easier to retrieve than ever before, and when organic chemistry is more interrelated with other disciplines than ever before Duff, Smith, and Casiraghi felt themselves part of an international community of organic chemists in industry and universities but never has that community been so well founded as it is nowadays Travel to laboratories in other countries is commonplace for students of organic chemistry now and even at home you can travel on the internet to other countries and see what is going on in chemistry there You might try the web pages of our institutions for a start: Cambridge is http://www.ch.cam.ac.uk/; Liverpool is http://www.liv.ac.uk/Chemistry/; and Manchester is http://www.ch.man.ac.uk/ There is a general index to chemistry all over the world on http://www.ch.cam.ac.uk/ChemSitesIndex.html ... boundaries between organic chemistry and inorganic chemistry on the one side and organic chemistry and biochemistry on the other Be glad that the boundaries are indistinct as that means the chemistry. .. to try and understand the world about us as best we can and to use that understanding creatively This is what we want to share with you Organic compounds Organic chemistry started as the chemistry. .. synthesis of Crixivan The future of organic chemistry Index 1481 1483 1487 1491 What is organic chemistry? Organic chemistry and you You are already a highly skilled organic chemist As you read these