Solutions manual to accompany Clayden, Greeves, Warren, and Wothers aoe TASTUPaMElacae W)INNINSolutions manual to accompany Organic Chemistry by Clayden, Greeves, Warren, and Wothers, STUART WARREN University of Cambridge OXFORD UNIVERSITY PRESSOXFORD Geet Clarendon Set, Oxford OX2 6D? 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Diste ened cing nt sim rine sttccounon: wech Srer arzar:atares Haag (ea, Imarened, ard ic} pee tances, Draw molecule hased an gach framewors toni bath ketone and garbotnllc aolsrunctional grou, Purpose of the problem ‘Te: go me drewing Simple atiseines well and re ster yon seep Pom neles arc marras towns dealive sunita ica Suggested solution ‘me inesr atoratedlfyeicarhon witk sever esrhon atotrs hu there iy a wld chalice offer seme nexiilitias hut pac may-~wall have thocght of ether, Ther fr fi the rez. Ar ste Aa RAR sengel onus CoO Pre po fad & fe ye el ee Oe art CC Om Problem 2 ‘Scnay tn stucuoe of breselanih op 2. 33, hla a feo? ne ena pans oF mmiserag ‘evop tee ala Frage ia here er metry es aa of fa: enters a rus ot Sines, Finely, sendy che sabe areswees branche2 Organic Chemistry Solutions Manual Purpose of the problem ‘To petsuade you that functional groups are easily recognized even in complicated molecules and that, say, an ester is an ester whatever company it may keep. You were not expected to see the full implications of the carbon framework part of the question. That was to amuse and surprise you, Suggested solution ‘The ethers are all the unmarked oxygen atoms in the rings all are cyclic, seven in six-membered rings two in seven-membered rings, and one in an eight-membered ring, Tere are two carbonyl sroups, one an ester and one an aldehyde, and three alkenes. ‘The carbon chain is branched because it has seven methyl groups branching off it and the aldehyde is also a branch. Amazingly, under this disguise, you can detect a basically linear carbon chain, shown with a thick black line, although i twists and turns thoughout the entire molecule! Purpose of the problem To shock you with two dreadful siractures and to try and convince you that well drawn realistic structures are more attractive to the eye as well as easier to understandChapter 2 Suggested solutions for Chapter 2 Suggested solution The bond angles are grotesque with square planar saturated carbon, alkynes at 120°, alkenes at 180°, ‘onds coming off benzene rings at the wrong angle, and so on, The left-hand structure would be slearer if most of the hydrogens were omitted. Here are two possible hetter structures for each molecule, There are many other correct possibilities. ea ce Problem 4 Z Draw structures comesponding to these names. In each case sugges altemative names that might corwoy the strture more clearly to someone wo is istening to you speak. (a) 14-di(2.2-dimethylethybenzene (©) 3{pr0p-2enyoxyjorop-t-ene. (©) eyclohexe-1.3.5:riene Purpose of the problem ‘To help you appreciate the limitations of names, the usefulness of names for part structures, and, in the ase of (c), to amuse. Suggested solution (a) I-di-(1,1-dimethylethyDbenzene, More helpful name para 1 di-ter-butyl benzene, an equally helpful name. i--butyl benzene. It is sold as = the LL dimenicty soo b) 3+( prop-2-enyloxy)prop-I-ene. This name does not convey the simple symmetrical structure nor that it contains two allyl groups. Most chemists would call this ‘diallyl ether though it is sold as ‘ally ether’ (©) cyclohexs-1,3,5-trione. Tis is, of course, benzene, but even IUPAC has not tried to impose this ‘correct’ name for such an important compound, Pe, Problem 5: Draw one possible structure for each of these molecules, selecting any group of your choice ‘or the ‘wild card’ substituents.Organic Chemistry Solutions Manual Purpose of the problem . ‘To help you appreciate the wide range and versatility of general structures with X, RI, Ar!, ete ‘These become more important when you stata database search fora pat structure Suggested solution ‘There are, of course, many possible solutions. X could be a heteroatom or a structural fragment while Ar could be any of a very large number of substituted benzene rings or even other types of aromatic rings. Our frst two solutions in each case are ones you might have found and the rest are mote inventive. The four-membered ring could have X = NH or CO (a Ketone) while the substituents R! and R? could be the same (both methyl groups) or differen (a benzene ring and an ether) In the last two structures X itself cartes extra groups ~ the two oxygen atoms in the SOs group oran alkene while R' and R? could be ina ring orbe diferent highly functionalized groups Of course, there are also some things that R!, R®, and X cannot be. R’ and R® cannot be N or CH; while X cannot be Ph or Cl ‘The three aryl groups in the second example might all be different or some might be the same. In the last two structures we show some unusual aromatic rings including some linked together and. fone with a nitrogen atom in the ring A AL “yy Problem6 Bee Translate these vow poor ‘alagrams of molecules into more realistic stustues. Try to get ‘the angles about right and, whatever you do. don't include ary mua) Planar carbon atoms - “oF oter bond angles of 90: _ Saeco ton ene O(CH:CH;)20 _—~_(CHy0),CHCH=CHCH(OMe}2 Purpose of the problem [An exercise in interpretation and composition — this sor of ‘structure’, which i used hen sHructures must be represented by ordinary printing, gives no clue to the shape ofthe molecule and you must decide that for yours.Chapter 2 Suggested solutions for Chapter 2 Suggested solution ‘You probably needed a few tral and error drawings first, but simply drawing out the carbon chains ‘5 you the answers, The frst is straightforward though you may not previously have sen the dot ‘9a the mile ofthe formula. This does not represent any atom but simply shows thatthe atom aamediately belore the dot is not joined to that immediately after it The (OH) group is a substituent off the chain, not part ofthe chain itsel- The second has no ends (Me groups etc.) and © must be an unbroken ring. The third gives no clue as to the shape ofthe alkene and we have shosen tras. It also uses two ways to represent MeO. Either is correct but i is best to stick to one ‘representation in any given molecule. ‘CaMeCH(OM).(CH,),00CMy OfCH:CH.I:0 ——_(CHs0),CHCH=CHEHOMe, Scam aga cfferent stuctures that woule ae emia Cite. Make 3000 realistic diagrams of each one and say which functional groups) ae present Purpose of the problem ‘demtification and naming of functional groups is more important than the naming of sompounds. This was your chance to experiment with different functional groups as well as u= Purpose of the problem Just litle practice in converting verbal descriptions into {thea naming thetn is justified. We hope you agree that the diagrams are more the description in the question and more easly understood than the name, Suggested solution ‘The structures are uniquely described by the rather verbose conn [Naming the compounds requires (1) identi ‘goup, (2) numbering the skeleton, and (3) locating the functional group by name amd = The aromatic compound is 4 ketone with (wo carbon atoms ~ an ethanone ‘evem ‘eannot be 2 two-carbon Keetone!). ‘The carbonyl group is Cl. The aromatic vy its Cl at Cl and is numbered so as to give the smallest possible numbers to the I is (2.5-dichloro~ nitrophenyl)ethanone. “The aliphatic compound is a carboxylic acid which === CL The rest is straightforward. Groups are usualy named in alphabetical order. It is 2==— {6-triluorohex-4-ynoic acid. Ifyou don't agree with our names, don’t Worry. Ht gent => matter. What does mater is: did you draw clear comprehensible structure? Problem 9 Draw full structures for these compounds, displai-g v= ~c"3c=con framework clearly and ‘showing all the bonds present in the functional gowns. Name =e Functional groups. ‘AcO(CH NOs meo;0.0H,0c08% ‘cp=CH.CO.NH(CH):ON Purpose of the problem ‘This i rather like Problem 6 except that more thought is meeded forthe details of the functional {g70ups and you may have needed to check the ‘organic ements’ Ac, Es, and so on in the chapter. Suggested solution For once the solution can be simply stated as no variation & really possible The tricks for the ist ‘one ate to see that ‘AcO” represents an ester and to have only four bonds to nitrogen in NOs. The second has two ester groups on the central CH: group but nei joined to it by a CO bond and theChapter 2 Suggested solutions for Chapter 2 sxher by a CC bond. The las is straightforward except for the dots used to separate the substituents ‘explained in the answer to Problem 6). ‘AcO(CHaaNOs ‘me04e.cH, 0coet CHiz=CH.CO.NN(CH EN DAG RS doy Ay, Problem 10 Purpose of the problem TES important exercise is one you will et used to very quickly and, before long, do without ‘Hanking I you do, it wll sve you from many trivial erors. Remember that the oxidation state of ‘atbon is +4, oF C{1V), in all these compounds. The oxidation level of a functional group tll you ‘wih which oxygen-bosed functional group iti interchangeable without oxidation or reduction. Suggested solution vant the number of bonds to heterostoms. These can range from none to fou. The only tricky es ae alkenes and alkynes, which have no heteroatoms but are formed by dehydration of -deabols, aldehydes, or Ketones. There isa summary chart on p. 36 ofthe textbook, but brie: ‘eras to nerrostoms Oxdaton lve “pe struct ° ycrocarbon| a ‘eonot on In these cases we have examples ofall oxidation levels, Check the answer against yours and the ‘able. In the case of the alkene, formally a dehydration product from an alcohol, either but not both ef the C atoms is atthe alcohol oxidation level.Organic Chemistry Solutions Manual ea seo ce ils eee Be e ne iar rraneaeene ASAIN . ncrocaton etcne Seonat ten ane reise on pp. 23 (drawing ai es) 4 44 (ening soon re 1 ‘common compounds an three common solvents). Purpose of the problem These compounds are important so drawing them again is not just a useful exercise: it also helps reinforce your knowledge of these structures. Suggested solution Hire are the drawings we suggested for the amino acids on p, 23. There are other ways. sot yes Oe aie stents Qe. te te ‘The ‘ten common compounds’ and ‘three common solvents’ are specially important and we recommend that you learn these structures. We generally pour scorn on the idea of memorizing, things, so take note when we recommend itl plier ty td a) seston er sectcence mio ete acd (erp) dete ‘ahora neoursscmy ears acy Owego Coe ein ebera) ‘The three common solvents below join ether, acetone, ethyl acetate (ELOAc), toluene, and pyridine as commonly used solvents for organic reactions. One or other of these will dissolve almost any organic compound. e ple seem aimetrtomanice OME) sired (MSO)Suggested solutions for Chapter 3 Problem 4 é oe : 5 How doos the mass spectrum gives evidence ef isotopes in the compounds of bromine, hlorne, and carbon? Assuming the molecular jon of each of these compounds is of 100% sundance, what peeks (and in what intensity) would appear around that mass number? (a) C:HsBrO, (b) Ceo, (c) CoHuBrCI? Give In cages (a) and (o) a possible structure for the ompound. What compound is (b)? Purpose of the problem "9 ve you practic in spotting the important atoms that have isotopes and in interpreting multiple ‘Seiecular ions, The molecular ion isthe most important peak in the mass spectrum and is often the eiv peak to interest us. ‘Saggested solution Beomine has two isotopes, "Br and "Br, in about a I: ratio, chlorine has two, °°Cl and "Ch in about a 31 ratio and there is about 1.196 °C in normal compounds. Hence the molecular ions of ‘Se three compounds will be a fllows 2) GHsBrO, MW 124/126, There will also be weak peaks (2.2% of each main peak) at 125 and Compaunds containing Bor 127 forthe same ions with °C. seuss have thei ole ons Ca as a molecular ion at 720 witha stong peak at 721. The chance that one C atom is Cis Sosa ei. Te st ee simply 60 x 1.1% = 66% so the M + 1 peal more than half as strong as M* itelé The Shy, hance of two atoms i small <) GcH,BrCt is more complicated a the molecule ton will contain tl rata of Br and "ie, and a 3:1 ratio of $C and Cl. The molecu in consists of four peaks (ctios in brackets): CH BP"CL (G), CoHY"BC (3), CQHYBP"C (1), and Cele" Cl (1), The masses of these peaks are 190, 192, 182, and 19, The molecular ion wil therefore have thee peaks at 19, 192, and 194 in a ratio of Sl with peaks at 191, 193, and 195 at 6x 1.196 = 646% ofthe peak before it So the complete Picture is 190 (759%), 191 (59), 192 (L008), 195 (6.6%), 194 (259), and 195 (1.73). Compound (b) is of course, buckminsterfllerene and the other compounds might be isomers such as these o omar ene Sl lee le Problem 2 : : : i i The C NMR spectrum for ethyl benzoate contains these peaks: 17.3, 61.1, 100-150. oo ‘.p1m. (four peaks), and 166.8 p.p.m. Which peak belongs to which carbon atom? Purpose of the problem To familiarize you with the four main regions of the BC NMR spectrum: saturated carbons at 0-30 ppm, saturated carbons next to oxygen at 8 1-100 p.pam. alkenes and aromatic compounds1 We have ignored the effects of the c atoms on tho othe ¢ atom, but tay wil algo erase he ‘Shama! sit toa lesser extent, Organic Chemistry Solutions Manual with unsaturated carbon at 100-150 p.p.m., and unsaturated carbon next to oxygen (usually C=O} at 150-200 ppm. Suggested solution ‘There are four different types of carbon atom in the benzene ring (don't forget the ‘ipso’ carbon joined to the substituent) and it is not easy to say which is which. The rest can be deduced from the four main regions. Problem 3 The thinner used in typists comection fds a single compound, C2HsCls, having #C NVR ‘peaks at 45.1 and 95.0 p.o.m. What its stricture? A commercial paint thinner gives two spots on chromatogrephy and has 3¢ NWR pecks at 7.0, 27:5, 35.2, 46.3, 95.6, ond 206.3 p.pm. Suggest what compounds might be used to make up this thinner. Purpose of the problem To start you on the road of structure identification with one very simple problem and then some deductive reasoning. It is necessary to think about the size of chemical shifs inthis case. Suggested solution ‘There are only two possible structures for a compound C;HsCl ~ it must be trichloroethane and the chlorines can be distributed in these two ways. meh “ye ‘The frst isomer would have a peak for the methyl group in the region 0-50 ppm. and one for the CCls group at 2 much larger chemical shift because of the three chlorine atoms. The second jsomer would have a peak for CHCl in the 50-100 p.p.m. region and one for CHCl at a langer shift Dut the two shifts would not beso far apart. The observed shifts are 50 p.p.m. apart and, in fact, the ‘compound is 1,1,l-trichloroethane. The NMR specirum of the 11,2-richloro isomer has peaks at 50.5 and 70.7 p.pam. ~ much closer together. ‘The mixture probably contains the same trchloroethane as the peaks at 45.3 and 95.6 ppm, suggest (the chemical shifts of the mixture need not be quite the same as those ofthe pure compound. as each compound is effectively dissolved in the other). The remaining peaks at 7.0, 27.3, 35.2, and 20633 p.p.m. definitely belong to a carbonyl compound, probably a ketone since 206.3 p.pam. is so large. Butanone fits the bill a t has one methyl and one CH group on the carbonyl group and one ‘methyl away fom any electronegative atoms. There are other possibilities Problem 4 ‘The ‘normal’ O-H stretch (Le. without hydrogen bonding) comes at about 3600 em-. What Is the reduced mass (u) for 0-H? Wnat heppens to the reduced mass when you double the ‘atomic weight of each atom in tum, that is, what Is 4 for O-D and what isu for $-H? Infact, ‘both O-D and S-H stretches come at about 2500 om. Why? Purpose of the problem To get you thinking about the position of IR bands in terms of the two main influences ~ reduced mass and bond strength. The relationship between the frequency (v) of the vibration,Chapter 3 Suggested solutions for Chapter 3 a Se force constant f(more or less equals bond strength), and the reduced mass (j) is given by ‘aes cquation. eV Seggested solution ‘Tbe redaced mass) ofa vibrating bond i given by this equation, Se reduced mass of OH is 16/17 oF about 0.94. When you double the mass of H, the reduced ‘as of OD becomes 32/18 oF about 1.78 which is roughly double that for OH. But when you deste the mass of O, the reduced mass for SH is 32/33 or about 0.97 ~ hardly changed from O81 The change in reduced mass is enough to account forthe changed frequency of the OD bond ~ amps by about 2 — but cannot account for the change from OTT to SH as the two reduced ‘mmmees are bout the same. The only explanation of this can be thatthe SH bond is weaker than the 5 {OH bond by 2 factor of about 2. There isan important principe tobe deduced fram this problem. Very roughly, the reduced masses € a bonds involving heavier atoms (C, N, O, 5, et) are about the same and the differences in IR seething frequency are mostly due to changes in bond strength. This s most dramatic in comparing siege. double, and triple bonds. Only with bonds involving hydrogen does the reduced mass become ‘he more important factor, though i is also significant in comparing, sy, C-O with C-CL ‘wre: are their structiires? Without +#C NMR cata, it may be easier to tackle this: problem by. ‘es! Hriting down all the. possible siuctures for C3HaNO: In what tanec aye nou SAR eta help? i | One sharp band ave 3000 em ane ston bard at bout 1700 ei "= Two sharp bands above 3000 em” twa bands between 4600 and 1700 om“! “=! One strong broad bak above 3000 én~'; a hand at about 2200.m—" Purpose of the problem 2 Sow that IR alone has some usefulness in the identification of molecules but that NMR is ‘tecesy even with very simple molecules In answets to examination questions ofthis type itis «0 show how you interpret the data as well sto give a structure you get the answer right, tation is not so important, but if you get the answer wrong, you should still get some Se Sr your interpretation Seggested solution 4 Ore sharp band above 3000 cm“ must be an N-H and one strong band at about 1700 em~! is probably a C=O. That leaves CH, and so we might have one of these (there are other ls likely | ‘sractures). °C NMR would help because a(i) would have a carbonyl group and two signal for saturated € while ali) would aso have a C=O but only one signal for saturated carbon as the : sommpound is symmetricala2 Organic Chemistry Solutions Manual {h) Two sharp bandh above 3000 cm © must be an NIL, group ant wo bands between 16 ae 7mm ern! sugges C=O aad a C=C. This leaves jst three hydrogen atoms and yives us seu EE NMR would help because the -0 shift would show whether the compouend sos an amide or a aldshyde and the alkene shitis would reveal the presence of the NHe grou in i Ws, ~~ a wa ° 4c) One strong broad hand! shove MiOO emt mnast e an OL aids baad at about 2200 cm must hea tiple hond, presumably CX as there woul esherwise be NHS as well, That leaves CoH. again hut ke de nol need & rig and we hae suet two double bonds, presumably Tike thess Problem 6 Four compouncs having the molecular formuls CaMlsOr have the IR and "*C NMR spectra fiven below, How many OBEs (Double Bond Equivslents) are thore in CaHO2? What are the ‘structures of the four compounds? You mignt again find it helpful to draw aut some or all possibilities before you stan, NMR: 214, 82, 58, and 44 p.pm. 1300 (broad) cm’: "C NMR: 62 and 79 p.p-m. {e) IR: 1770 cm™': “C NMR: 178, 86, 40, and 27 p.pm. {@) IR: 1720 and 1650 (strong) cm '; “C NMR: 165, 131, 133, and 54 p.p.m, Purpose of the problem rst steps in eal identification using two diferent methods. Because the molecules ate vo small fonly four carbon atoms} drawing ut fee trial structes gives you some ideas 28 10 the 1ypES of -ompounds key to be fou Suggested solution Here are some posible structures for C.MQ.. I and a ring are likely wo feaure, The double bonds nave pot to be C20 or C=C tor both these isn ring’. Fanetional groups ae likely to ipdude alcohol, ldebyde, aid amd ketone °. ° WAA, Poo TS ‘oH Me Ile ot ketone). 82 and 58 one saturated carbon Bot next dear that two double bonds or one double bond Ga) METAS em oop: BC NMR: 214 ppm ppm, (to saturated atbons nent wo oxygen? and Al pspan twonygen bur nea some es must be a € tron: wtharawcing proxy. The secon! ase does not show Up i the IR so i must be an ether. As thete i only one double hond. there mst be a ring. This {yy He S00 rand cay mest ean OH, CNMI 92 aad “0 gay mest he a symmetrc anolecie with no alkenes and no C nana saturated carbon next to oxygen. Tica gies one struts. Nos 6 she ane des nat in the 18 because itis spmmetrica so it mast bea eipie borChapter 3 Suggested solutions for Chapter 3 {6} IR: 1770 cm! must be some sort of C=O; !°C NMR: 178 p.pm. (C=O of ac derivative), 86 p.pam. (saturated C next to 0), 40 and 27 ppm. (saturated Cs not next to 0). Again only one double bond so it must have a ring 100. Looks lke a close relative of ( 4) TR: 1720 and 1650 (strong) em must be conjugated C=C and C=O; "C NMR: 168 ppm, (C20 of acid derivative), 131 and 133 p.p.m, (alkene), and 54 p.p.m. (saturated C next to). ‘This defines all the carbon atoms and it must be a simple unsaturated ester. Notice that we cannot tell which signa corresponds to which alkene carbon but thet this does not affect our conclusion. Problem 7 Three compouncs of molecular formula CyHeO have the IR and *C NMR spectra given below. Suggest structute for each compound, explaining how you make your deductions. ‘compound AR: 1730 om; #9C NMR: 13.3, 15.7, 45.7, and 201.6 p.p.m. compound BR: 3200 (broad) cm”; °C NMR; 36.9, 61.3, 447.2, and 134.7 ppm. compound CIR: no peaks except CH and fingerprint; #0 NMR: 25.8 and 67.8 p.p.m. ‘The rest of the problem as stated in the text is given below in the ‘Suggested solution”) Purpose of the problem More practice in the same essential skill. Notice that we have two more H atoms in tis formula so = have either a ring or a double bond but not both. In adltion, a bit of chemistry is added. Suggested solution scpound A IR: 1730 cm” (C=O of some sort); C NMR: 13.3, 157, and 45.7 pppam. (three saturated carbon atoms with one next to some electron-withdrawing group but not oxygen), and 201.6 prpam. (aldehyde oF ketone). No symmetry. A ketone would hhave two Cs next to C=O so this is just butanal. Serpound BR: 3200 (broad) em™! (OH); #C NMR: 369 ppm. (saturated ©), 613 ppm. {saturated C next to 0), 117.2 and 1347 ppm alkene). There are two possibilities here eae aarzyssar ssempound CIR: no peaks except CH and fingerprint (oxygen must be ether; °C NMR: 258 ppm. (Gaturated © not next to O) and 67.9 ppm. (saturated C next to 0). Note symmetry. As there are no double bonds, there must be a ring and it can only be THR, Xow the extra bit of the orginal problem, which may resolve our doubts on the structure of Sepound B Compound A reacts with NaBH, to give compound D. Compound B reacts with hydrogen gas seer a palladium catalyst to give the same compound D. Compound C reacts with neither reagent. Seggsst structure for compound D from the data given and explain the reactions, (Note: He ‘Sikes alkenes to alkanes inthe presence of a palladium catalyst) ‘empound DIR: 3200 (broad) em! (OH); #C NMR: 15.2, 20.3, and 36.0 ppm. (three saturated Gs not next to O) and 62.9 p.pam, (saturated C next to 0). Must be n-butanol NaBH reduces the aldehyde to the alcohol and Hy/Pd would reduce the alkene in ether of our OH > NH > CH. Why? Purpose of the problem To encourage you to think about the energies of orbital as well as just about their quantum description. Suggested solution + orbitals and p omits can combine t frm o bonds. Inthe chapter (p. 108) we discussed the structure of PH, which has bond angles of about 90" and is made of bonds beoween Is) and 5p(P)onitals. There sno special problem in overlapping ether 2p or p oxi with Is orbitals though the 3p orbital are larger. a WA ‘The difference comes in the energy of the orbitals. The 2p orbitals are much closer in energy to the 1s orbital than the 3p orbitals and so the energy gain is greater on a bond formation. 2920 is wee otra’ to omar 1840 Sect 180 Bonds between H and C, N, O, and Farell stronger than bonds between H and Si , S, and CL ‘Thisisparly because 2p AOs ate used fr the fist but 3p AOS forthe second group. The ul story Includes the fat that CH, NHs, and H;0 are hybridized (so the lower energy 2s orbitals are used as wall wile PH, and H,S ae not hybridized. Sif, is, ofcourse, tetrahedral whl itis dificlt to ay ‘whether linear HP and HCl are hybridized or not ‘Within the group C, NO, and F, the energy ofthe 1s orbital stays the same but the energy ofthe 2p (or of the sp hybrid orbitals) drops as the elements get more electronegative. These orbitals gt closer in energy tothe 1s obital and the gain in bond formation is corespondingly grater.Chapter 4 Suggested solutions for Chapter 4 Problem 4 ‘Though no helium ‘molecule’ He> exists, an ion Hej does exist. Explain Purpose of the problem To encourage You to think aboot the filing of atonnx orbitals and to accept surprising conchasions. Suggested solution The orbitals of the He atom ans the fact that 0 Hes molecule exists sre diwused in the book an pp. 97-8, The prablen is that the 1s orbitals overlap te form a bonding tc) and an antibonding {e* orbital but hoth would be filled in the Hey molecule and the bond order i 70, If there sone fewer electron, only one cletrom need go into the antibonding order of oneshalf The ion Hey loos exist, orbital (a) and there isa boc Wes Ah emtsoning at He sreoning ot " On 9G +O tenses tb sews Problem 5 You may be surprised to know that the molecule CH, with divalent carbon, can exist tis, of ‘course, very unstable but Its Known and it can have two different stuuctures. One hes an H-G-H bone angle of 180 and the other an angle of 220°. Suggest structures for these species and say which orbitals will be occupeed by all bonding and ronbonding elections, Which structure is likely 0 be move stable? Purpose of the problem To demanstate that a simple MO treatment can be applied to strange and unknown molecules, Suggested solution The hasie arrangements of the orbitals w yet the H80 and 120° bond angles rust be an sp hybridized «case but ust one p wtbital and an sp* orbital in the second. oom for 1900 and am sp? carton for 120 . Thi leaves over two g orbitals im the fies “The orbitals for the @ structuse aze straightforward wg sestamsat tA) 18 There will he fru electrons in cach of these «bonds leaving exited (civalent cazbon has any’ valency eect {wo electsons to make up the six os and cannot achieve « noble pas structre) Inthe 18D case, the two remaining p orbitals are degenerate so we can pu one ebetzon in each, It lhe 120° case, the remaining spt orbital af lower ener ecto than the p orbital and will have bath 19Organic Chemistry Solutions Manual 1m You shoud nate tht onygen hae four 2 eectons ana wil have wo Ione portal an ene each nthe ‘other two fo avis repulsion, PR can, Gores Ay Sieh ta enon p ob Structures with unpaired degenerate electrons ate usually more stable than those with a full and an empty orbital. However, we have told you only part of the story and we shall return to these ‘carbenes” in Chapter 40. Problem 6 ji i “Consiruct an MO Giagfam for ne molecule LiH and suggest what typ of bond & might have. Purpose of the problem ‘To demonstrate that a simple MO treatment can be applied to ionic as well as covalent structures Suggested solution H has, ofcourse, only one electron ina 1s orbital Liha thtee~ a falls shell and one elton in the 2 orbital. Li isalso ver electroposiive so its 2 orbital is hgh in energy (much higher than that ‘of F~ see the answer to Problem 3) The results that lithium gives its 2s electron tothe Is orbital of 1H and an ionic compound results with both ions having the same electron configuration: 1s, The hhydrides of the alkali metals ae useful sources of hydride ion (H). un? 4O- 4O- “OF "Ot Problem 7 Deduice the MOS forthe angen molecule, What is the bond oe in onion and where are “the 2p electrons? Purpose of the problem To let you try out your sil in a simple diatomic molecule that has a curious structure. ‘Suggested solution Simply dock two oxygen atoms side by side and overlap the orbitals. The Is and 2s (only the shown below) interact as usual but both bonding and antibonding MOs are occupied so there is no bonding. When we overlap the parly filed p AOs we find we can make three bonds ~ one 2pcr and ‘two 2pm bonds. Now we have two electrons left over and they have to go into antibonding 2pm” (MO. The first two up are degenerate so itis better {0 put one electon in each and avoid the ‘repulsion from two electrons in the same orbital.Chapter 4 Suggested solutions for Chapter 4 Abin buenos Bie nc ke bya 0 td lw nh ese oped Sree stboig MO. The ek ht ond or snd espace Fees orks aed on oncck O nom Th eed Sues take oa ay wae ines neato, Parpose of the problem = 2ec easy to find molecules where you can construct MOs from AOs without hybridization but s=h v= = one such, You should not be ashamed if you failed to do this problem and you should be sseuily proud if you succeeded. We shall not in general construct MOs in this way a5 it is too ‘Sica bur if you simply set up an energy diagram ofthe AOs, in ascending order as usual, you can ee setstacory MOs. ‘Seggested solution ‘Etre (acctylene) has a C-C triple hond, Each carbon bonds to only two other atoms the other C ‘ax: -=: of the Hs, Using MO theory, we can see that only the carbon 2s and 2p, have the right s=meetr to bind to two atoms at ance which leaves the 2p, and 2p. to form & MOs with the 2 saris on the other carbon atom, —@ fh ot: = {0-Q-O-0 gos 2s 2s ts combination of As in ety tra he rise to bending MOsOrganic Chemistry Solutions Manual ‘The thre lowest orbitals are o MOs because they ae symmetrical about the line H-C-C-H. They are all bonding and al filled but they do not correspond to particular bonds in the molecule. The lowes is bonding right through, the second is bonding for both C-Hs but antibonding for C-C, and the third is ‘again bonding forall three bonds. The two top orbitals are x MOs because they have a node (zero clectron density) passing through the atoms. They are degenerate and correspond roughly to the two (CC mbonds. The total number of electrons (10) is right for $ bonds (2 CHs, 1 6 CC, and 2 x Cs). Purpose of the problem ‘To give you practice in selecting the right hybridization state for carbon atoms in molecules. ‘Suggested solution ‘Simply count the number of « bonds and hybridize that many AOs: if two, then the C atom is sp hybridized (linear; if three, sp* (trigonal); and, if four, sp? (tetrahedral). A simple statement of the answer should be enough. The atoms marked with an arrow are most likely to give you trouble: make sure you understand why they are as shown, oe 4 predet r ee ay te answer tothe Don’ se these sorts of rains in your answer. Purpose of the problem ‘To give you practice in selecting the right hybridization state fr carbon atoms and translating that information ino three-dimensional structures for molecules. Suggested solution ‘Carbon dione is linear as it has only two C-O o bonds and no lone pairs on C. The C atom must bbe p hybridized and the only tick sto get the two x bonds orthogonal to each other. They must be like that because the p orbitals on C involved in the two x bonds are themselves orthogonal (2p, and 2p.). Most people would draw the O atoms as sp* hybridized, rather than sp or even unhybridized, bur this is unimportant as you cant realy tll tetoobonds —— tietwoxbande sifu ge oe |e eco oe=0 = oes ecoChapter 4 Suggestec solutions for Chapter 4 The imine has a C=N double band so it must have sp! hybridized C and N. This means that the Jone pair on Nis in an sp orbital and aot in « p orbital, the molecule is planar (except for the oup which is of cours, tetrahedral) and bent atthe nitrogen ator, 4 wo “nN es so tetrahedral wih an sy! hybridized © atom, The serangement of rhe lone pairs stound the fluorine atoms imor shown! is also probably teteahedra x ‘Thifluoromethane is, of sours ‘he next molecule, CH, C2CH- is alone and it has the same shape as COs and for the same ‘eas, except that ve ean now be sure shat the end carbon atoms are 9p? ybridized as they are slanat. However, the ta planes are arthagonal so the mole as whole is mot planae Finally, (CH:),0 must be a three-membered ring and therefore the C-C-O skeleton of the snolecule must he phinat three paints are always ina planet, However, she two carbon atoms are 1p hybridized (four t bonds) and are approrimately tetrahedral with the H atoms above and below he plane. The oxygen atom might also be sp hybridized, but whe knows?Suggested solutions for Chapter 5 Problem” z een ee Eich of these molecules (s electootlé. loentiy the eletiopnilc, tom ena dana. __ Mechanism for action win a generalized nucleophile Nu”, gir ihe prot in each case. ee a ie 4 oer ese oe Purpose of the problem ‘The recognition of electrophilic sits is half the bale in starting to understand mechanisms. Here is some practice: later you will o this automatically. Suggested solution Here we have two cations, two compounds with x bonds, and two with nothing but & bonds. One ofthe cations has only three bonds to positively charged carbon soit will react by addition of the nucleophile. The other has thre-valent oxygen and so cannot add a nucleophile (four-valent ‘oxygen would have 10 valency electrons and is unknown). The nucleophile must attack the proton instead. Some nucleophiles might attack the carbon atom next to the oxygen “ “ r some — she s r Ys The ro carbonyl compounds will be atacked atthe carbon stom with clesvage of them bond. In general, x bonds are more easly broken than o bonds and negative charges end up on electronegative atoms. If you proposed that each compound reacted further, you were right, but the expected answers do not include these extra steps shovn in square brackets. A full discussion is found in Chapter 12 of the main text. et fe een Pel Ne [oe J - tam A at Re ss LU we ‘The last two molecules are forced to break o bonds. n the case of chlorine, the two ends are the same so you can attack either Cl atom. In MeSCI, the S-Cl bond is weaker than the C-S bond and (Cis the most electrophilic atom in the molecule. The $-Cl bond is broken and the negative charge ends up as chloride ion. oN mi Sel oe worse we,‘Chanter 5 Suaaested solutions for Chaprer 5 | tach of these molecules 1s migopiic, ently the muciopniic stam and craw a ones Tor reaction wih a geneaize lecvonie E, mina product lye Purpose of the problem “The recogion of micleophili sites isthe other half ofthe bt in starting to understand mechanisms. Here is some practic: later you wil do ths too automatically, Reactions occur when the two meet. Suggested solution, ‘This time there are three anions but only two of them (the alkyne and the sulfur anions) have lone pair electrons. We can start our arrows from these and they are the points where the electrophile will atach itself c i fe gt ie a potas Le oh ‘The last anion is like the BH, anion we discussed on p. 125 of the main text. The negative charge does not show a pair of elecizons on Al but just an imbalance of protons and electrons. ll the valency electrons are in the bonds and we must use these o electrons in the reaction. The arrow should stat halfway along the o bond and emerge through the Hf atom. roe ib = TT meoNome - E ‘One nucleophile has a x bond from C to N. The nitrogen atom also has a lone pair of electrons and you could stat your arrow either there or halfway down the t bond ~it doesn't matter which, ae " ner a Me me Me “The ening two nclophies have lone pair One syminetiel(NEy-Ny hyde) and will tack trough one nitrogen stom, You may have drawn the product sa cation or you may Ive removed «proton fom i Eder ane is correc F = Hani, “2 a we ri, | Finally, the phosphorus compound has four atoms with lone pits! There ate three OMe groups and the phosphorus atom il, However the lone parson the oxygen atoms are probably in 2sp* orbitals (and are certainly in some kind of orbital with the principal quantum number 2) while that fon the phosphorus atom is in a 3sp? orbital and is of higher energy. I eats, ae ad 1 Ts pois exred in Craper 7.Organic Chemistry Solutions Manual Purpose of the problem First practice in interpreting curly arrows and drawing the products. Once the arrows are drawn, there is no more scape for decision-making, You must draw the products. Suggested solution Just break the bonds that are being broken and make the bonds that are being formed. sas simple as that, though you might straighten out the products a it so that there aren't any funny angles. Ve 5 Purpose of the problem First practice in considering different posible reactions. One ofthe eatin might seem tivial but itis’ Suggested solution In each case one ofthe electrophilic sites isan acidic proton. There is also an electrophilic x bond in cach case (C=O of C=N+), We might as wel use the same abbreviation (Nu”) for the nucleophile that we used in Problem 1. For the frst case, we draw the two reactions separately Me meme me” MeChapter 5 Suggested solutions for Chapter 5 ‘The last compound also has an electrophilic P atom so there are three possibilities. Don't worry if you missed this last one but phosphorus comes below nitrogen in the periodic table and, unlike 2a ‘am have five & bonds as in PCI “wy mm pm wt Q, Problem 5 ‘Putin the arrows on these structures (which have been drawn with all the atoms in the right lacest) to give the products shown, A508 ‘oD — CKO Purpose of the problem To encourage you to draw arrows for unknown reactions and to show you how easy its Suggested solution ‘you have todo isto see which new bonds are formed and which old bonds are broken and draw “sows out ofthe one into the other. Which way should the arraws go? Take them from an eectron- ==nating atom (an anion in both these examples) towards an electron-accepting atom (O and Br ). In the fist example, a hydrogen atom has moved from the left- tothe righthand molecule 4 this is best shown by an atom-specific arrow. A ow | ee Don't worry if your arrows are not exactly the same as ours ~ as long as they stat and finish in the right place and move the right H atom, they're allright. The notes on the mechanism are for sour guidance ~ you should not usualy include them. The second reaction looks more complicated, but the problem is easier — just move electrons through the molecule, ear 7Organic Chemistry Solutions Manual Eide et ace nese tn wg ma have i ees ‘drawmin a ee a. Purpose of the problem To encourage you to draw arrows for unknown reactions without help. This time you have to decide how to draw the molecules so that reaction can occur. The compounds and the reactions are ‘much simpler than the last set. Suggested solution In the frst example, OH has replaced Br. The reagent NaOH is salt so the reactive species is the hydroxide anion, We can draw the mechanism in one step with HO as a nucleophile displacing stable Br from the organic molecule A» = ape goalie ‘The same reagents are used in the second example with the adltion of EtCH;SH’. This change is ‘obviously important because the product contains this unt rather than OH, We should first drave ‘out this compound and use NaOH as a base to remove a proton from the SH group. The second step is example (a) with a different nucleophile Bie IN A Example (6) uses HBr as the reagent. This isa strong acid with an electrophilic proton. The best nucleophile inthe organic compound isthe oxygen atom so the fist step isa proton transfer and the second step uses the bromide ion, as « nucleophile for the methyl group. Direct attack at O* ‘would give impossible four-valent oxygen. & on RCH SH = =Chapter 5 Suggested solutions for Chapter 5 Purpose of the problem "To develop your arow-drawing cil n a more dificult example. Suggested solution Best to follow the advice given in the hint, First, draw the molecules better. If NaHCO. isa salt we need draw only the anion, 2s the very table Na* won't do anything Ifthe anion is a weak base it can remove only the most acidic proton feom the organic molecule and that ‘must be the CO,H proton. ohhh Now we need to lose one Br atom ~ the one nearer to the benzene ring - and the whole CO ‘group which must falloff as CO,. We start our arrows on the negative charge, form the new x bond, and lose Bras the sable anion.Suggested solutions for Chapter 6 Problem 4 "Draw mechanisms for these reactions. — eo oe i OF Purpose of the problem Rehearsal ofa simple but important mechanism that works for all aldehydes and Ketones. Suggested solution Draw out the BH, or AIH, anion, and the compound if necessary, and transfer the hydride ion. A ‘second protonation step is also needed ~ during the work-up inthe second cas, It is not necessary to draw out the whole metal hydride anion but you must draw out one metal-hydrogen bond es you need to take electrons from that bond. ON = Og Purpose of the problem To get you thinking about equilibria and hence stability of compounds rather than reaction -mechanisms,Chapter 6 Suggested solutions for Chapter 6 34 Suggested solution Hydration isan equilibrium reaction so the mechanism isnot strictly relevant tothe question. If you have drawn the mechanism, you should be proud rather than ashamed because it isan important mechanism. To answer the question we must consider the effect ofthe theee-membered ving. All thre-membered rings are unstable because the ring angles are about 60” instead of the usual angle. Cjclopropanone is very stained because the trigonal (5p?) carbon would lke an angle of 120" and there is‘60" of stan’. Inthe hydrate the trigonal carbon setrahedrl (sp) and theres only 49! of strin'. The hydeat is more stable than the ketone The second casei totally diferent. The hydroxy-aldehyde isnot strained but the hemiacetal has 48° of strain at each corner. Even without strain, hydrates and hemiacetals ae normally less stable than aldehydes or Ketones because one C=O bond is worth more than two C-0 single bonds. In this case the hemiacetal is even less stable because of strain, Problem 3 (One way to make cyanohycrins is ilustrated here. Suggest a detaled mechanism forthe process. meson Purpose of the problem ‘To help you get used to mechanisms involving silicon and to revise an important way to promote Additions to C=O groups Suggested solution The sill eyane isan electrophile while the cyanide ion in the catalyst is a nucleophile. Cyanide adds to the carbonyl group and the oxyanion product is captured by silicon so liberating another cyanide ion for the next cycle. “Den oN en H oN Jo BO ge i Se Problem 4 There ate three possible products from the reduction of this compound with sodium. HW borohydride. What are their structures? How would you distinguish them spectroscopiclly, ‘assuming you can Isolate pure compounds? Purpose of the problem To et you think practically about reactions that may give more than one product Suggested solution The three compounds are easly drawn: one ot ther C=O of both may be reduced, yo eronyhtone aa15 0. Wians ana Fleming (1995), Spectroscopic methods in ‘ganic chemistry (Sted, MeGranis, London, Organic Chemistry Solutions Manual ‘The diol has no C=O group in the ""C NMR or infrared and has a molecular ion in the mass spectrum at two mass units higher than the other two products. Distinguishing them is more tricky. ‘The hydroxy-ketone has a conjugated carbonyl group (about 1680 cm! in the infrared) but the Ihydrony-aldehyde is not conjugated (about 1730 em™* in the infared). The chemical shift of the (C-OH carbon atoms in the 100-150 p.p.m. region will ls be different because the benzene ring is next to this atom in the hydroxy-Ketone. Calculations from tables in Williams and Fleming suggest about 80 ppm. for the hydroxy-ketone and about 60 p.p.m. for the hydroxy-aldehyde, The mass spectra will also be different ~ simple accleavage gives quite diferent fragments Problem 5 ‘The triketone shown here is called ‘ninhysrn’ and is used forthe detection of amino acids. It exists in equeous solution as @ monohydrate, Which of the three ketones Is hydrated and wy? Purpose of the problem ‘To start you thinking about why some carbonyl groups are more stable than others. Suggested solution ‘The two Ketones next to the benzene ring are conjugated with it and thereby stabilized though they ate also destabilized by the mide carbonyl group ~ two electron- withdrawing groups next to each ‘other is bad thing. The central carbonyl group has no stabilization from the benzene ring and a double dose of destabilization from its neighbours. Problem 6 ‘This hydrow-ketone shows no peaks in Is infrared spectrum between 1600 and 1809 em: * ‘butt does show a braad absorption at 3000 to 3400 om”*. Inthe “#C NMR spectrum, there ‘are no peaks above 150 p.p.m. but there is @ peak at 140 p.p-m. Suggest an explanation, Purpose of the problem Revision of Chapter 3 with & reaction from this chapter ‘Suggested solution ‘The evidence shows that there is no carbonyl group in this molecule but that there is an OH group. ‘The peak at 110 prp.m. looks at frst sight ike an alkene but that isnot possible (try to draw any alkene structures and you will see why) so it must be an unuswal saturated carbon atom (pesheps ‘one with two oxygen atoms). You might also argue that an alcohol and a ketone could react to give a hhemiacetal, and that, of course, is what its. The compound exists asthe stable cyclic hemiacetal ~ stable because ofthe ring size, MR heChapter 6 Suggested solutions for Chapter 6 Purpose of the problem ‘To give you practic in seeing the underlying structure of a hemiacetal Suggested solution Each OH group represents a carbonyl group in disguise (marked with a black blob). Just remove the ‘other oxygen atom with whatever i attached to it and you have the two components an alcohol and. an aldehyde or a ketone. The fist example shows how it is done. oaks on es eee ‘The next is similar but the alcohol is from a different molecule, So-7-70 Do not be deceived by the next: itis not symmetical. There is one hemicetal (two oxygens on te same carbon atom) but the other end of the molecule isa simple tertiary alcohol lege Similarly, the last two examples are not quite the same, The first is indeed symmetrical but the second has one oxygen atom in a different position, There is only one hemiscetal34 Organic Chemistry Solutions Manuel Reamer ao ome Bar BR & Oo ree Wan Purpose of the problem To help you detect bad mechanisms and find concealed good ones Suggested solution rere ‘The wrong mechanism, the one the question warns you to avoid, is shown in the margin just to clear the decks. If NaBH, doesn't displace like tis, then what does it do? We know it attacks carbonyl groups to give alcohols and to get trchlorocthanol we should have to reduce chloral and ‘we have chloral hydrate. Hydrates are in equiliorium with their carbonyl compounds, so this isthe “ fenas not deen allel pa pare the adducts ae simple lochs nt wre of Such ping cle onl Sow Purpose of the problem ‘More revision of equilibria to help you develop judgement about stability. Suggested solution “This time we need a mechanism so that we can work out what would be formed, Protonation of the carbonyl group and then nucleophilic addition of chloride ion gives the supposed product. Se — ‘There’s nothing wrong with the mechanism; it’s just that the reaction is an equilibrium that wil run backwards. Hemiacetals are unstable because they decompose back to carbonyl compound and alcohol. Chloride ion is very stable and this reaction will run backwards even ‘more readily.Chapter 6 Suggested solutions for Chapter 6 35 Problem 10, \What would be the products of these reactions? In eacn case give a mechanism to justify your predictions,» nach emer Nabi —-1 ee —+1 40, wet 0 Purpose of the problem “To give you practice in the at of predicting products, more dificult chan simply jusiping a known Suggested solution Each ofthese reactions is straight out of the textbook and each is simple addition tothe carbonyl soup. The ist is cyanohydrin formation and you need to draw out the aldehyde group to make a 00d job of the mechanism. AF" Jost we Ao ‘The second is a standard Grignard reaction and you just need to remember that the aqueous work-up step is not usualy written down but is still needed, e oes y aes ene ing none ‘The only tap isin the reduction of the eylic keto-ester where you need to recall that NaBHy reduces ketones but doesn't reduce esters. Correct identification of functional groups matters. Seu Pe on ath 0 aert. re Problem 44 i “The equilbxium constant Ko, for formation ofthe cyanohycrin of cyciopentanone and HCN is 667, while for butan-2ane and HON it is 28. Explain Purpose of the problem More revision of equilibria this time with some numbers,se 36 Organic Chemistry Solutions Manual ‘Suggested solution ‘We need fist to state the problem in chemistry rather than in writing Oreos ES SS The two Ketones are very similar, the ring being the main diference. The two equilibrium constants ae also very similar as Ke isa simple rato of [eyanohydrin] to [ketone] and is not on a log scale. There is a factor of about 2.5 between the two examples. There is, ofcourse, some strain in the five-membered ring (angle 108°) but only atthe carbonyl group (ideal angle 120°). Replacing ‘the trigonal centre by a tetrahedral centre so thatthe ideal angle (109°) is almost identical to the actual angle is enough to explain this small factor.Suggested solutions for Chapter 7 Problem 4. ‘Xe these molecules conjugated? Explain your ansiner in any reasonable way, My AAR. Purpose of the problem ‘evasion of the basic kinds of conjugation and how to show conjugation with curly arrows. gested solution £5 wo are straightforward with one conjugated system (an enone) in the first example and ‘ame (2 phenyl alkyne) in the second. OF course, the benzene ring is itself conjugated in the ssxoad example. You can show either or both with curly arrows: we have done so for the first exmnple only. The last three compounds obviously form a group with the same skeleton and only the alkene ‘mene around. There i, of course, ester conjugation in all three but this the only kind inthe last ‘sempound. The firs s most conjugated with the lone pair on nitrogen delocalized into the carbonyl pmep. The middle compound just has the alkene and the ester conjugated, This time we have used ‘amcty arrow representations for all three compounds and a dottedline electron distribution smmmnary forthe frst, ae meOrganic Chemistry Solutions Manual Problem 2 raw 2 full orbital diagram for all the bonding and ontibonding * orttals in the three ‘membered cylit cation shown here, The molecule is obviously very strained. Might it survive by also being aromatic? Purpose of the problem Revision of MO diagrams for conjugated systems with aromatic. Suggested solution ‘There are only two electrons inthis simple cation but we need to mix the 2 bond (mand x” orbitals) ‘withthe empty p orbital to gie the MOs, One MO will be bonding all ound the ring and this is the ‘only one that matters to the structure. The others may have given you problems. We can mix the p- ‘AO withthe #-MO as they have the same symmetry in a three-membered ring but we cannot mix P| with 27. So our three MOs are m+ p, x — py and “Se pec oT AC fm RA Hp ‘The cyclic cation is stable and can be made because of the gain in energy in populating only the lowest all-bonding orbital. As it happens ‘sand Ws are degenerate. Ifyou count the number of bonding and antibonding interactions in cach you will see that the net result is one antibonding interaction in both orbitals. I is also aromatic, having 4 + 2 n-electrons where n=0. ‘You get the same result if you mix three p-AOs, one an each carbon atom. Then its easier if we look down on the ting showing the top lobe ofthe p orbital at each atom, The lowest, all-bonding corbizal has no nodes (except the plane of the ring) and the two degenerate, antibonding, and unoccupied orbitals have one node exeh, aChapter 7 Suggested solutions for Chapter 7 Problem 3 How extensive are the conjugated systems in these molecules? OR saptecam arene o fae Purpose of the problem A chance to delve more deeply into what is meant by conjugation. Suggested solution ‘The B-lactam has ewo clearly deined conjugating systems: the amide and the more extended ‘unsaturated acid going right through tothe sulfur atom. These are shoven by culy arrows on the first diagram. These sysems are joined by a single bonds so they really are one system: all the p covbitals on the ringed atoms in the second diagram are more of less parallel and all are conjugated. B OH FE, EG rasliihedtrnoket tie) iipenbinaber wok de oplathgene (yea arrows on the first diggram, Each benzene ring has substituents with lone pairs shown on the second diagram so this molecule has no less than six lone pairs of electrons involved in extended ‘conjugation. There are three separate conjugated systems shown in boxes on the second diagram, moo ome m ‘ome ome ome Problem 4 Draw diagrams to jtustrate the conjugation present in these molecules. You should draw tee ‘ypes of diagram: (a) conjugation arrows to give at least two different ways of representing the ‘molecule joined by the corect ‘reaction’ arrow: (b) a diagram wih dotted ines and partial charges (i any to show the double bond and charge istibution (if any; and (c) 9 diagram of the atomic oritals that make up the lawestenergy bonding molecular orbital. SAECO10 Organic Chemistry Solutions Manual Purpose of the problem ‘A more exacting exploration of the precise details of conjugation. Suggested solution “Treating each molecule separately inthe styles demanded by the question. the first compound is the guanidinium ion, a very stable cation because of conjugation. The curly arzows in the frst set of diagrams show that each nitrogen hasan equal amount of postive charge and thsi reflected in the second diagram showing exactly one-third + on each N. The thd diagram, ofthe lowest-energy ‘MO, looks down on the molecule and shows the top lobe of the p orbital on each atom. cite is its “ee ® Ls ") ee ‘The second molecule is what we shall learn to call an enolate ion. The negative charge is delocalized throughout the conjugated system but is particularly on the two oxygen atoms and, to a lesser extent, ‘onthe central carbon atom. Is dificult to represent this accurately with partial changes but the charge ‘on each oxygen atom is nearly a half. The lowest-energy MO has all the p orbitals in phase ‘The third compound is naphthalene. The structure drawn isthe best; curly arrow diagrams do rot do this molecule justice and other versions are less convincing. In particular, they do not show that the middle bond common to both rings is the shortest bond. There are no charges anywhere and al the p orbitals are conjugated. This isthe basic ten-eleetron aromatic system. 08 -€9-CO OO thy Problem 5 \Which ofthese compounds are aromatic? Justiy your answer with some electron counting. You ‘ate welcome to treat each ring separately or two or more rings togetner, whichever you prefer. SOL ee) th 0 on oH siiaone: 9 wane aeoiote c0s4 of DH ome oR Vetote rg metore “"eetus used te taat aut ciliates ature Newer pmentChapter 7 Suggested solutions for Chapter 7 Purpose of the problem A simple explor Suggested solution “The frst three compounds ae straightforward providing you count lone pair electrons on atoms in the sing and donot count electrons outside the rng such a those in the carbonyl bond in the fst compound. Nor should you count the lone pair represented by the negative charge inthe third ‘compound. They are in an sp? orbital in the plane of the ring. ion ofthe idea of aromaticty: can you count to si? at 2lona pi tcrons arse oof Seine Ue ol. wen poe ‘The rest offer variations on the benzene ring and each ring must be considered separately. Methoxatin has five- and six-membered rings with nitsogen in them. Count the lone pair in @ P orbital on the nitrogen atom in the five-membered ring but not those in an sp! orbital in the six-membered ring (pyridine). Both are aromatic. Colchicine has an aromatic seven-membered ring with six electrons (don’t count the C=O group) while cllstephin has an interesting positively charged aromatic ring with three double bonds, We summarize these answers briefly by giving the ‘umber of electrons in each conjugated ring. 2lone par evens on bon on iainone: 9 teractneaiote1 19 you notice hat on one ‘dium on is necessary ae hee ls ‘ery one sive charge onthe Organic Chemistry Solutions Manual Purpose of the problem To get you thinking sbout the relationship between conjugation and light absorption. Suggested solution Each dyestuif has essentially the same conjugated system shown here isolated from extra substituents. The positive charge is shared between the two nitrogen atoms and the whole system is symmetrical. The colour is due to excitation of the lone pair electrons, which are delocalized over the whole system, into an antibonding x* orbital of the aromatic system. There will be many bonding x orbitals and the same number of antibonding x* orbitals. The lowest (the LUMO) willbe ‘unusually low in energy and the n, x* isin the visible region. me a CT Me ‘The substituent on the middle atom is iffrent inthe wo des and is als conjugating Tis extra conjugation decides the exact shade of colour wth the highly conjugating naphthalene rin in EL42 taking the absorption all the waytheough to red ight so the dye appears green tothe eye. The OH group also helps a lone par isalso conjugated into the aromatic ings. The sulfonate groups make the compound water-solubleChapter 7 Suggested solutions for Chapter 7 43 Purpose of the problem sher thoughts on the relationship between conjugation and light absorption plus revision of Chapter Suggested solution ~e of the dyestuffs in the shaving foam, Fast Green FCF, has a conjugated system very similar to 1 we have just been discussing in Problem 6, though it has extra solubilizing substituents on the Srogen atom, Fast een For eee congo sta ‘Saree cour ans “oso¢ ‘uy in er mv sly ater Quinoline yellow is quite different. It has two conjugated ring systems linked by a single bond. However, they are also linked by conjugation from the OH group in one ring tothe nitrogen atom the other. Infact, the whole molecule is conjugated. Because the conjugation is more limited, this snolecule absorbs violet light and so appears yellow. It has the usual sulfonate solubilizing groups. he ‘quinoline’ part of the name refers to the left-hand ring system. Qunotne tor Fay _/ ? a ‘0,08 ‘Soon ‘The compounds in the ‘spectrum of molecules’ are much simpler and you may well have been surprised after reading Chapter 7 that they are coloured at all ° —~ OOF ent rete uric oto You probably found ‘red’ easiest to deal with as there is an obvious extended conjugation throughout the whole molecule The conjugation in ‘blue is less obvious but clearly more effective blue compound absorbs longer wavelength light than a red compound) and relies on a redistribution of electrons that makes both rings aromatic. This compound is called azulene (an azure alkene) as a blue hydrocarbon is very remarkable.Organic Chemistry Solutions Manual The orange and yellow compounds owe their colour to functionality. ‘Orange’ is a quinone ~ 3 conjugated six-membered ring compound with four electrons — and has a low-energy unoccupied orbital (a x* orbital, the LUMO) from the two conjugated carbonyl groups, which is easily occupied by excitation of a x electron. 'Yellow’ is diazomethane, an unstable toxic and even explosive gas hich has some conjugation in its very small framework but owes its colour mainly to the N=N functionality which again has a low-energy 2” orbital. i\efs 2 8 oH, ae GEN ‘The green compound, delightfully named 9-nitrosojulolidine, has conventional conjugation of an eflicient sort between electton-donating Nand the electron-accepting nitroso group (N=0. Nitroso compounds can be brightly coloured without any conjugation asi the case with ‘purple’. It is very unusual to have blue or purple gases and this compound has a CF; group to stabilize the nitroso group which, when not conjugated, is an odd-electron compound. The colour comes from excitation of a lone pair electron into the N=O antibonding orbital Sean Go through the list of aromatic compounds at the end of the chapter and see how many. ‘electrons there are in the ings taken separately or taken together (if they are fused}. are al the numbers of the (4n ++ 2) kind? Purpose of the problem Revision of material in the chapter explored a litle more deeply to reinforce the concept of aromatic + Suggested solution The fst two compounds are straightforward providing you put lone pais in the right orbital and don’t count C=O groups. Gas Sigmar cee = Me rghctns frnoncangand tener, ios twotrom One par lb ings tage sence noi fe inne ine teen nrg Nain oatsspied ried NaN ofan :0). It the Chapter 7 Suggested solutions for Chapter 7 45 LSD and Omeprazole have in common a fused aromatic ring system with one benzene ring and sme heterocyclic ring. You can think of these as two sx-electron rings sharing two clectons oF as ome ten-cleciron system. Omeprazole has a pyridine ring as well nsgiew 9 enon a maingpeie. rine rng OMe Aa Ea. A Awe me a l mee fi) Ns cae COE Viagra has an ordinary benzene ring and an interesting double heterocyclic ring, You can simply “Sy that there are two fused rings with six electrons eack but a couple of delocalizations show clearly sebich lone pairs can be delocalized and that the resulting system has 10 electrons delocalized round ss rim, The final example, haem, was fully analysed in the chapter as an 18-electron aromaticSuggested solutions for Chapter 8 “Problem 4 It you wanted fo separate a mixture of naphthalene, pyridine, and prtoluc acid, how would you go about it? i oe o. Purpose of the problem Revision of simple acidity and basicity in a practical situation. Suggested solution 1 Thee a contves protien - Pyridine iva weak hase (pK 5.5) and can be dissolved in aqueous acd. p-Toluic acid isa weak acid Jou cannot uaaly separate (PK, about 4.5) and canbe dissolved in agucous base. Naphthalene is neither an acid nora base and eee ‘remains insoluble in water at any pH. So, dissolve the mixture in an organic solvent immiscible with water (say ether, Et:0, or CHsCh) and extract with aqueous acid (pH < 4); this will remove the pyridine as an aqueous solution of its protonated form. Then extract the remaining organic layer with aqueous base (pH > 6) which will extract the p-toluic acd as its anion. You now have three solutions. Braporate the organic solution of naphthalene and recrystllize it to get pure naphthalene. Aci the basic solution of p-toluic acd to precipitate the fce acid and recrysalize it. Finally, add base to the pyridine solution, extract the pyridine with an organic solvent, (say ether, Et,O, or CHCl), evaporate the solvent, and distil the pyridine. Itis just as good to extract with base first and acid second. © Problem 2 ae | in the separation of benzo acid from toluene we suggested using NaQH solution. How concentrated a solution woul bo necessary to ensure thatthe pH was above the OM of boenzoieecid (0K 4.2)? How would you estimate now much solution to Use? Purpose of the problem You can check your understanding ofthe relationship between pH and concentration Suggested solution Even avery weak solution of NaOH will have a pH > 4.2 By te calculation on p. 184 ofthe chapter, fora pH of 5 we should need [Hj0*] = 10° mol dma!, We know thatthe tonic product of waters {H,0"] (OH = 10-and so for pH 5 we need 10-* mol dm! of NaOH. This is very dite! The ‘rouble is that you need one hydroxide ion for every molecule of benzoic acid so if you had, say, 1.22 g PRCOLH (= 0.01 equi) you would need 1000 lies (d=) of your NaOH solution. It makes more sense to have a much more concentrated solution, say, 0.1M. This would give an unnecessarily high pH of 13 but you would need only 100 ml (cm*) to extract your benzoic acid,Chapter 8 Suggested solutions for Chapter 8 4a ° Problem 3 i \Whot species would be present you were to clsole this hyeron-ci na) water at pH (b) aqueous alkali at nH 42; or (c) @ concentrated solution of a mineral acid? Purpose of the problem Revision of simple acidity and basicity requiring pK; values ina practical situation, Suggested solution The COsH group will have a pK; of about 4-5 and the OH group a pK, of about 10. Tis gives a comfortable margin between the two ionization At pH 7 the acid willbe ionized an a pH 12 both cups wl be ionized. In concentrated mineral acid both wil have ther protons and te carboxylic ‘i will sart to be protonated. It is more readily protonated than the isolated OH group as it gives 4 delocalized cation “oh oh Tht Problem 4 ‘What would you expect to be the site of (a) protonation and (b) deprotonation if the compounds below were treated with an appropriate acid or base? In each case suggest & suitable acié or base for both purposes. ee Purpose of the problem Progressing towards more taxing judgements on more interesting molecules, Suggested solution The simple amine, piperidine, will have a normal amine pKus of about 11 so it will be easy £0 protonate with even very weak acids. Any mineral acid like HCl will do as would weaker acids ike RCOzH. Deprotonation will remove the NH proton as nitrogen is more electronegative than carbon but a very strong base such as BuLi wil be needed as the pK, willbe about 30-3. “~ ~ sean aii eae ne hae Qe = 4 ' ‘The next example is more complicated but actually contains 2 normal tertiary amine (pK about 11) and.a normal primary alcohol (pK, about 16). Protonation at nitrogen will occur with any acid = let’s choose TSOH this time ~ and deprotonation will occur at the OH group and will need a strong, base ~ let's say NaH. °°on —O ao we 239 wee Organic Chemistry Solutions Manual The final example isthe most complicated one. There sa normal OH geoup (PK; about 16) and a slightly acidic alkyne (pK, about 32) so the OH willbe deprotonatd frst The basic group isnot a normal amine but an amidine in which the two nitrogen atoms can combine (sc arzows) to capture 2 proton It wll hae a pK, of about 12 and so would even be protonated bya phenol though most chemists would use a carboxylic acd. i ee Stati Problem 5 ‘Suggest what species viould be formed ty each of these combinations of reagents. You ere ‘advised to use pK, values to help you and to beware of some cases where ‘no change’ might be the answer. ase den A. O le Purpose of the problem Learning to compare species of similar acidity or basicity. Suggested solution In each case one of the reagents might take a proton fiom the other. In example (a), would the anion of the phenol remove a proton fom the carboxylic acid? We can answer that by considering pK, values. The answer is yes. There ate five pH unis between the two acids so the equilibrium will be well to the right. The equilibrium constant is about 10°, Tos tear” Prout preavout10 Example (b) has a similar possible reaction. This time the difference is much smaller and the oer way. The carboxylic ac is slighty stronger than protonated imidazole and the equilibrium constant is about 1072, et Sen ww Lee oa seal Example (c) aso involves @ carboxylic acid but this one is rather different. The three fluorine atoms make CFsCO,H a very strong acid, comparable to mineral acids. This equilibrium is well lover to the lel Pk stout 5 pry anauroChapter 8 Suggested solutions for Chapter 8 49 Problem 6 What is the relationship between these two molecules? Discuss the structure ofthe anion ‘hat would be formed by the deprotonation of each compound. Purpose of the problem lp you recognize that conjugation may be at the back of some related stuetures. Suggested solution They are tautomers. They der only in the position of a proton. Each is an acid ~ the frst has an NH ‘poup a part of an amide and the second has an OH group. Deprotonation may at fist appear to ‘reduce two different anions but they are actually the same because of delocalization ofthe anion, 1. =—Qe ike ‘What species would be formed by treating this compound with: (a) one equivalent; b) WO yg, ‘cqulvalents of NaNH2 in quid ammonia? Purpose of the problem 4 simple problem to help you think about the possiblity of selective deprotonation Suggested solution ae more acidic group is the OH (PK; about 16) and the les acidic i the alkyne (PK, about 35). The alkoxide wil be formed first, and then a second deprotonation is posible because the (wo ‘ezative charges are far apart inthe dianion and wil not significantly destabilize each other. Was Sp tly 5p i a i Problem 8 ‘The carbon NMR spectra of these compounds could be run in D0 under the conditions. shown. Why were these conditions necessary and what spectrum would you expect to " dee ‘eepscvum nin 0CY/0;0 $C sesamin NoO0/%0 Purpose of the problem SMR revision and practice at judging the tates of compounds at different pH, Hidden symmetry ‘20m conjugationSuggested solution Both compounds are quite pola an not very soluble inthe usual organic NMR solvents in addition, they have NH or OH protons that exchange and broaden the signals Ifthe exchange is made rapid by acid or base catalysis andthe NHs and OHs exchanged for deuterium, al these problems disappear and clean sharp spect result The ist compound isa guanidine and forms a cation in ai The cation s symmetrical and avery simple spectrum results — just tre types of carbon inthe aromatic region and ne very low feld carbon (at age 6) forthe carbon in the mide of the eatin. 0s 0-0 ‘The second compound loses a proton from the OH group in bas to give a delocalized symmetrical anion. There willbe five signals in the NMR spectrum: the two methyl groups are the same and the two CCH, groups in the ring are equivalent, Thee is one unique carbon atom jained to the two methyl groups and another in the middle of the anion and, finally, the two carbonyl groups are equivalent. Problem 9 "The phenols shown here have approximate pk, values of 4, 7,9, 10, and 44. Suggest with ‘explanations which pK value belongs to which pheno}. cee Purpose of the problem [A problem requiring detailed interpretation of electronic effets. Suggested solution Hlecron-withdrawing groups (Gland even mote so NO,) make phenols more acidic but electron- donating groups (Me) make them less acd. The nito group is very effective if it can stabilize the anion by conjugation. A pk value of about 10 is normal for a phenol, o it is pheno tsef tht has that value. The compound less acidic than phenol (pK, 11) must be the timethyl compound. One chlorine atom will make phenol slightly more acidic 30 pK, 9 must be 3-chlorophenol and the compounds with one nitro group (pK. 7) oF two (PK, 4) must be the very acidic phenols. Problem 10 Discuss the stabilization of the anions formed by the deprotonation of (a) and (b) an the Cation formed bythe protonation of (c). Consider delocalization in general and the possibilty of aromaticty in particular. @ x ird a Chapter 8 Suggested solutions for Chapter 8 Purpose of the problem ‘To get you thinking about delocalized cations and anions. Soggested solution “Fee Js only one remotely acidic proton in (a), the NH proton, Removal of ths gives an anion that “sane delocalized on to all the four nitcogen atoms in the five-membered ring. The combination of © electronegative stoms, 2 delocalized anion, and an aromatic anion (see diagram in margin) srattes this a very stable anion and the original amine is areal acid witha pK, (5) about the same a5 p2 of a carboxylic acid (RCO,HD. CA 22 =O) ‘Tez most acidic proton in (b) is that of the phenol and the anion is delocalized round the ‘Seprene ring, into the fused five-membered ring, and even out onto the ketone axygen atom so its 4 Sol: anion. However, there are only cight delocalized electrons altogether so, although the esse ring remains aromatic, there is no extra stabilizaion from any aromaticity in the “Seocalized five-membered ring or in the system as a whole, It has a pK, value of about 8.5. “OO Gogh nee diamine (c) will be protonated on the trigonal (sp?) nitrogen using the delocalized lone pair “Meera shows both rings as aromatic) as there ae 12 electrons delocalized ~ six foreach ring. The ‘eer asa whole isn't aromatic because is not ane conjugated ring stem. PAR -OVQ- 2-0 ‘Parpose of the problem ‘See. ccvsion in thinking about the acidity and basicity of functional groups ~ amino acids are gretosbely important. ‘Seggred solution “Se world expect the NH; group to have a pyc of about 11 and the SH group a pK, of about 8 so “Se ook sll right. But you would also expect the CO:H group to have a pK, of about 5 and that ‘pets al crong! We need to stat at high pH and work downwards to see what exactly we have by Se Se come to pH 5, This is what happens.Organic Chemistry Solutions Manual wey ova al its “ By the time we want to protonate the COs ion, there is an NH group next door so it will be much more difficult to make the cation and the pX, value is lower because we must go to more acidic solutions to get protonation. The structure ofthe molecule at pHs 1 (cation), 5 (awitterion), 9 (monoanion, that is, dianion and monocation in the sime molectle), and 12 (dianion) is 3s shown. Coe es Purpose of the problem To get you thinking about carbon acids, how their anions are delocalized, and what makes the anions stable. Suggested solution All dhse carbon acids give anions whose negative charge is mainly on oxygen. Similar ones are described in the chapter (Table 82, p. 193) and we expect simple carbonyl compounds to have pK,s of about 15- 20 and 1,3-diearbonyl compounds to have pKys of about 5-15. The first three compounds are all ketones on the lft and have ketone, aldehyde, and ester groups on the right respectively. The charge is ‘delocalized over both cazbonyl groups. The aldehyde is most effective asi isa simple carbonyl group. ‘The Ketone has ¢-conjugation, which reduces the electiveness ofthe carbonyl delocalization, and the «ster is worst asi has competing conjugation from the ester oxygen ator, o 9 0 0° 80 o °0 8 Ad, =A A AL AR aH 4 “ 4 o rib apt os co pp tba a uO electronegative chlorine atom — it isa proton from that side ofthe ketone that is lost. Deloclizing the charge on to the carbon atoms shows this. ° a) ° Ae fe he = é Ss rtp pe ace red ve aa a RG SE and trifluoroacety. Delocalization is very effective and most ofthe negative charge will be on one of the two oxygen atoms. 8 ise. 2 oo 0 of Jobe ick sleetChapter 8 Suggested solutions for Chapter 8 53 Purpose of the problem you thinking about carbon acis, how their anions are delocalized, and what makes the szions sable 1 Note that at no pH dose Suggested solution ‘aan ci ex Be fom wo Tee thre pK, values for glutamic acd itself must be like this (the remote COsH group is normal _fetneen 22 and 42 ts fom 0 {Se che one near the amino group is unusual as we discussed in the answer to Problem 11). eau wth the zwtein ee a poo 9428 mee oar oe eth ont ons ont Ne esanic 8 Ia glutamine, the remote CO:H group is missing and the other two pK; values are hardy ‘Sunged. The dimethyl ster has only the amino group lft and its py value isles beause we ave slaved the wo CO} anions with eleeton-withdrawingester groups. The wo monoesters are most esting. The fis is essentially the same as glutamine ~ the remote ester has tle effect on the ‘ser ovo groups. The second has, a we should expect, a remote COsH group like that of glutaric 2 iselfbut an amino group lice that ofthe diester showing thatthe neaer of the two esgrgroups the diester has the bigger eect 0 Purpose of the problem ‘Ts belp you appreciate the disastrous effects that innocent-looking groups may have because of reir weak acidity. Suggested solution ‘The OH group is the Wicked Witch ofthe Westin this problem, Whoever planned these syntheses -xpected itto lie quitly and do nothing. Bu, although an OH group is only a weak acid (pK, about54 Organic Chemistry Solutions Manual 16) it will give up its proton to the very basic Grignard reagent. Inthe first case, one equivalent of Grignard reagent is destroyed but addition ofa second would save the day. wp nen ee ‘The second case is more serious as the Grignard reagent destroys itself as it s formed with the replacement of Br with H and then nothing can be done to rescue the synthesis. The only answer is to block the OH group with something non-acidic (see Chapter 24). An mgm ok ee ° Net sy SEB mesh 2°, Hao tSuggested solutions for Chapter 9 Problem 4. pose mechanisms for the frst four reactions in the chapter. je obS os Je Pode 2m Heo Purpose of the problem ‘zhearsal of the basic reactions of Chapter 8 Suggested solution A reaction simply involves the nucleophilic attack of the + Ketone followed by protonation. You may draw the intermediate as an anion or with an O-metal 1d as you please. Note the atom-specific arrows t0 show which atom is nucleophilic. Inthe second example the alyslthium might attack through its other end, 0 organometallic reagent on the aldehyde Problem 2 i \When this reaction is caried out with allyl bromide labelled as shown with #20, the label is ‘ound equally distibuted between the ends of the aly system in the product. Expain how this is possible, How would you detect the 1%C distrbution in the product? on Py Em, bs 2. Prono » Be awe FE Fe Purpose of the problem Reminder of the way ally-metals react and revision of NMR.Organic Chemistry Solutions Manual Suggested solution ‘One explanation is that allyl Grignard reagents might reat as nucleophiles at eit system, aay Sahn = = ‘The mechanism given in the chapter (p.224) suggest that allyl Grignards aways reat atthe rem: ced by a oyic mechanism, If that isthe case, the formation ofthe Grignard must occur at both ers os. met mene, ae eee eae y ‘This could occur during the formation by attack of the metal at the other end of the ally: system, of after formation by equilibration with the aly! anion ey ao ad, mat A MM Ay AS Gun = MA In either case the two ally] Grignard reagents would have equal energies and would be forme! = equal amounts. The reaction with benzaldehyde would then follow a cyclic mechanism, end of the ea tis Ts et See ‘Your explanation may not be exactly the same as either of these ~ the only important thing is thet you should have some way of getting the eacton to occur at the other end of the alli system. The '3¢ distribution in the product would be determined by NMR spectra. Each labelled atom woule appear as much stronger signal (the natural abundance of "Cis 1.19) and each signal will be in « different part of the spectrum. The chemical shits are more accurately estimated as 115-120 and 45-50 ppm. Purpose of the problem ‘The toughest test — predicting the product. The sooner you get practice the better.Chapter 9 Suggested solutions for Chapter 9 solution a ‘on harder than explanation, you should get these right frst ime as only the last, ~ «sina I the Bist example, ethyl Grignard reagent acts a a base to remove a ‘Sayne, Whether you draw the inteemediate as an alkyne anion or Grignard reagent 1 you need not necessarily include the mechanism for the protonation step. ee Seo example just make the organometallic compound and ad itt the carbonyl group _ssssess an electrophilic ketone because of the strain of a carbonyl group in a four-membered “Grignard eagent is vinyl and not ally so the ambiguities in Problem 2 donot aise. _ cf- 6 eg ao ‘cumple raises the question of halogen replacement or orholthiation and, if the former, hen bromine is one ofthe halogens, halogen replacements usualy the reaction which + did ortho-lthiation between Cl and Br, you should not be ashamed. be 4 sows [eR “oye “Y fee — o tar i 4 ty l. z ee eee aad Seabee rt ; : (Fee 2 216) : : 4 CL “sree of the problem Ms deere ©znals, you should have measured the J values. Coupling is measured in Hz and at 400 MHz ‘=h chemical shift unit of 1 p.m. is 400 He, so each subunit of 0. p.p-m. is 40 Hz. Out withthe vr the dividers and get measuring! Sm! shi, plum) Inlegation —_ Multipcty CCouping. He Comments = tH m > alkene region = aH wih fine soting 16.3. alkene region — HW doh tne spiting 10.4 akene reson 23 4 twtr ine spiting 65 heat 10 C=0 oF C=C? ae 2 tt fe soiting 6.5 ert © C=0 or C=C? in eT quit tne spiting 6.5 ext 10 0=0 or -07 an 2 oitn ine siting eat a C=0 oF C=C? an aw toad = S alge? = Fy a os Pot nest to arth ‘That gives us three protons inthe alkene region, five CH. groups, and one solitary proton, which <= © only the alkyne proton. Ifyou were surprised by its small chemical shift, check the tables and “5-21 sight. In the alkene region, the multiplet must be H? which couples to the CH at C3 and s-On Cl, H has a large iran coupling (16 Hz) to H? while H has a smaller cis coupling 98 £21, The coupling between H* and H'® is very small Tis suring rau was repo 8. Ant end A Hasenr. Sites 3076, 932. The expected eacton nse the Beckman rearangment (Chapter 37) ta what actly Insppenes was 2 Beckmann ‘ragrontaton (Chair 38) feowes by an nomoleulr Fede tytn (Chester 22), 9 Baorluenge4 Organic Chemistry Solutions Manual (Of the five CH, groups, the quintet at small chemical shift must be at C7. Those at C4, C6, and (C8 have two neighbours and are basically triplets, but that at C3 couples to three protons and must be the quartet at 6 2.32 ppm. Problem 8 A nitration product (CpH::NsO2) ofthis pyicine has been isolated which has 2 nitro (NOs) {g70up somewhere on the molecule. From the 90 MHz *H NMR spectrum, decuce whether the nitro group is (a) on the ring, (b} on the NH ritragen atom, or {c) on the aliphatic side chain land then exactly where iti. Give a full analysis ofthe spectrum, Purpose of the problem a er Ne ee Ne Pe al reasonably easily Suggested solution ‘The tre ype of compound under cansierton eh thee ate some ofthe est ands), ye eee Lear fl ‘Checking the itera wil deal with that problem. ‘The propyl side chain i ill there with a CHy Arplet a CH quintet and a CH; wilt wit a lage chemical shift The broad signal ati 59 ppam.is ‘ppial ofan NH group 50 no reaction has happened ther. The small signal les than a quarter of « proton ~at7.2 ppm, cannot be par ofthe molecule and must be CHI, The remaining signals inthe aromatic region at 63, 8.1, and 9.1 p.pm. must be tree protons on the pyridine ing, The nitro group thas replaced one ofthe orignal four and is somewhere onthe pyridine rng. These are the posits “The most significant feature of the aromatic region is a proton at very large chemical shift (9.1 ppm) with no coupling to speak of (there might be some long-range coupling). This proton has ‘no neighbours and that rules ou the S-ntro and 6 nitro compounds. Ifyou checkin tables you will se that protons an carbons next to strogen (C2 and C6) in peidine have very lage shifts as you would expect fiom thir aldehydelike nature, The nitro group also increases the shifts of protons on neighbouring carbon atoms, The compound must be S-nito andthe spectrum can be assigned like this. “The coupling inthe side chain is all about 7 Hz as expected and that between C3 and C4 in the pyridine ring is somewhat larger also as expected for an aromatic ring. The smaller chemical shift ofChapter 14 Suggested solutions for Chapter 14 15 the proton at C3 occurs because itis not affected by the nit group but it is affected by electron donation fom the amine nitrogen atom. Problem 9 ‘The netural product ullatenone was isolated in the 1950s from a New Zealand myrtle and assigned the structure 9A. Then compound 9A was synthesized and found not to be identical ‘with natural bulatenone. Predict the expected 4H NMR spectum of 9A. Given the full spectroscopic data available nowadays, but notin the 1950s, say why 9A is defnitely wrong, fend suggest a better structure for builatenone. Spectra of bullatenone: “Mass spectrum: m/z 188 (109) (high resolution confirms C,zH:02), 105 (2096), 102 (100%), and 77 (20%), Tnared: 1604 and 1705 em" THEN: ds (p.pim) 145 (6H, 9), 5.82 (1H, 6), 7.35 GH, m), and 7.68 (2H, m). Purpose of the problem Detecting wrong structures i fun and teaches us tobe alert to what the spectra are telling us rather than what we expect. Suggested solution The mass spectrum and infared are all ight for structure 9A but dhe NMR shows at once that bullatenone cannot be 9A. There is indeed s monosubstituted berzene ring (the 2H and 3H signals in the aromatic region confirm this) but the aliphatic protons consist of a 611 signal, almost certainly a CMe; group, and a 1H singlet inthe alkene region at 5.82 p.m. ‘The fagments we have are Ph, carbonyl and CMe, groups and an alkene with one H on it That, ads up to CHO and leaves only one oxygen atom to fit in. There must stil bea ring or else there will be 109 few hyrogen toms and the ring is five-membered (just cy other possiblities yoursel). There ae three bac rings we can choose and each can ave the phenyl group on ether nd ofthe double Bond making six possibile in all ey stogebiteroe ‘The last four ae all esters (ey estes or lactones) and they would ave IR casbony stretches at higher frequency in the 1745-17H0 em” range. The hydrogen on the alkene cannot be on the same carbon atom as the oxygen or it would beat avery lage shift indeed whereas iis coset the ‘norma atkene shift of 5.25 ppm, For 9C we coud estimate 5.25 + 064 ppm. for O, + 0.36 ppm. for Ph, and + 087 ppm. for C=O making 712 ppm. along way fom the observed 5 82 pp Structure 98 is correct and the spectra can be assigned. Compound 98 was synthesized and proved ientical to natural bullatenone. hh a 1 You can 2a the ful toy in W. Panter ota J: Chom, Soc. 1958, 3874: see also T. Resin ‘and P.M. Bel, Acta Chom. Scar, 43977, BuB, 127. Tevanecion Let, 1975, 489%, and RF W Jokson 0d R.A Rape, J Chom Soe omtin Tans 1.1984, 535,78 Organic Chemistry Solutions Manual coe Op 1 Top tip er exams — terete (ata evan ithe examiners ont ‘spectealy ask you to ‘Problem 10 Imei ihe 2H RAM Spectrum (se to. 277 fr he 80 NH NM of he compu n the margin.” j eS Purpose of the problem Further correlation of chemical shift and coupling with interpretation of longer-range coupling Suggested solution ‘The ethyl group is easy to find — atypical SH triplet at 1.2 ppm. and a 2H quaret at 4.3 ppm. — not just an ethyl group but an OFC group to get the age shift for the CH, group. The methyl group is also easy ~ a 3H singlet at 2.6 ppm. typical ofa methyl on an alkene. At the other end of the spectrum te broad signa at 11.0 p.psm. can be only the NH or the OFT ~one exchanges and is not seen, That leaves the three signals inthe aromatic region: 6x (p.pam.) 675 (IH, dd 19, 2H, 7.15 (1H d, 19 He), and 7.48 (1H, d 2 Ha). The larger coupling is atypical ortho and the smaller typical meta coupling so we can assign the whole spectrum, "Problem 14. * Susyest secures for he products ofthese reactions, ierreting te spectroscopic data. You ‘¢ not expected to write mechanisms forthe reactions and you should resist the temptation to "work out what ‘should happen’ rom the reactions. These are all unexpected products. 3 Mads An ein me ‘Aetp.pm.) 179,82, 38,27 ° st sip) 120104 9.387004 9) Beads ser 748,270 Sinpan)203,170,62,982228 pain) 228,941 37 221.0 82408 9.4 200H.6 JT neue se 90 seam) 20,88 22,15, ‘Mopm) 1121645. 280K s,.98.0K8) soc eM 2.10 Purpose of the problem Practice ofa favourite exam question as well as a common sination in red life — you carry outa reaction, isolate the product, and find i's something quite diferent from what you had expected. Wha isiChapter 14. Suggested solutions for Chapter 11 “Sospound A has a carbonyl group (IR) which isan acid derivative (179 ppm. in 8C NMR). The pe "= “aul in the proton NMR must be a tbutyl group and the 3H singlet at 3.67 p.p.m. must be an a a eatin esas os se eh TTL oe “Sesier (1715 + 30 = 1745 cme). ies nS ee res cakes gee af, J y eco pn hn (145 ca 17 ppm bata a rd 718" eM pe Tae ram sous horses om geet br cane a gat 2 nop) (MBG Ca aoicfae pas cere seca nes te ees ey (SMM gs) eo osha pg ty toe ora Cah i a tore inti tc Oona oom We ot or ncn OS AS “ex can only be th carbonyls so this CH, i between the two carbonyl groups and we have the ee Bad free, 2 BRO eee 32 2: ae © empound C has no formula given, just a molecular ion in the mass spectrum. You shoul “scecer why. The most obvious formula is Hey but sulfur is 32 while O is 16 0 two of those “e2e atoms could be one slfr atom. It might be CsHioOS. We must look at the rest of the scars for clarification. There is a carbonyl group (1730 cm™) which isan aldehyde or Ketone ‘BE ppm). The proton NMR shows a CMe: group (6H, 8), methy] group at 2.8 p.p.m. which ==" look like an OMe (expected shift about 3-3.5 pipsm.) but might be an SMe (the carbon ‘germ also suggests SMe rather than OMe at By 45 p.pm.)s and one hydrogen atom at 9.8 ‘525: which looks lke an aldehyde. We know we have these fragments. Me Me L 2.0 RN a) Home vu iw © % not possible to construct a molecule with two extra oxygen atoms but without an OMe S52. One possible structure is shown below but it does not fit the data very well. Other ‘Pasdilies include having a peroxide (O-O) link and are unlikely. ee ees SE ae ‘ound is possible if there isa sulfur atom ~ this is the data much better and i, in 4 the correct answer. It contains a genuine aldehyde (by expected about 10 p.pm.) not a formate feechanoste) ester (5y expected about & p.p.m.; see Problem 1), and $Me is better than OMe for “> ognal at by 28 ppm. and by 45 p.pan. inst 3, Laz.» ne dome S0Ch/EtN ete se ond riper ae a no Mas2P-cHO mes ~ovo i, SMe 1 er ee Be fh73 Organic Chemistry Solutions Manual rely Problem 12 pi Precogene Is # compound the couses insect aide to pupate arden also be found some _ plants (Ageratum sop) where it may act as an insecticide. It was isolated ih minute amounts "and has the following spectroscopic details. Propose a a Ee Spectra of precooene: ‘Mass spectrum: m/z (high resolution gives CzaHia02), M~15 (100%) and M-3O (weak) Inrareé: CH and Singers ony 7H NMR: 3, (B.0.m.) 1.34 (6H, s), 3.80 (3H, s), 3.82 (3H, s), 5.54 (1H, d, J 10 Hz), 6.37 (QH, d, 10 Ho), 642 UH, 5), nd 6.58 AH, 8). a Purpose of the problem Your first attempt at determining the structure of a natural product without any hints — not even & ‘wrong structure. Suggested solution ‘The mass spectrm gives us the formula (C)sHi¢O), which looks ike an aromatic compound as there ae 9 few hydrogens, an the base peak at M ~ 15 suggests that amethy group is lst rather easly. The infrared suggess that all three oxygen atoms are present as ethers. The NMR shows us these details 1.34 (6H, 5): two identical methyl groups, probably CMe. Rather large shift. 380 (3H, s) and 3.82 (3H, s): two different OMe groups. 554 (IH, d, 110 Hz) and 6.37 (1H, d, J10 Hr) two cis protons on an alkene, {6.42 (1H, s) and 6.58 (1H, 5}: two isolated protons on an aromatic ring, probably 14-related as ‘there is no coupling. Rather small shifts — electron-rich ring If allthis is tue, we have these fragments Ma Me rome KO a Y ome ff Y > This adds up 10 CH\4Os, so we have one more oxjgen atom to fit in somewhere, It is very ‘important that you now start to join up these fragments and see what you get. You quickly find that no chains of atoms are possible as there are not then enough substituents to go on the benzene ring (soe the structure in the margin). We must find four substituents for the ring and there are only four other pices to be joined up. The only chain-terminating units are the two OMe groups. The obvious solution is to put the cis double bond in another ring fused on to the benzene ring and hence making two ofthe required four substituents. We can then combine the other groups in various ways such as these ‘The five-membered ring is no good because the coupling constant between the alkene protons ‘would be much smaller than 10. The two six-membered rings are good because they make the benzene ring electron-rich (three OR substituents). The middle structure is not right because theChapter 14. Suggested solutions for Chapter 11 chemical shifts ofthe alkene protons would be very diferent: H* predicted to be about 45 ppm. ‘and H? about 5, 62 ppm, ra eo, " e Moor 1" $ ‘The thied structure (which is the correct one) fits all the data. The two alkene protons are at normal shifs for such protons (estimated from tables in Wiliams and Fleming: 635 p.p.m. for Hand 5.53 p.p.m. for H?), the two OMe groups on the ring are slighty different, and the loss of a ‘methyl group in the mass spectrum is easily explained by removal of an electron from oxygen followed by loss of Me* to form a stable aromatic cation. 15D. 1. Witlans and Reming, Soecvoscon methods inorganic ‘poms (3th ear, MeGrow Hl {London (1996 1 Mere doa of te aiscoven. ‘olga! acy, and stuctural cuciation of seeacore ae gen DW. S. Bowes e a Sence, Peace se OA OL 134,0H,5 Meo” e Meo” ¢ Problem 13 ‘Suggest structures for the products of these reactions, interpreting the spectroscopic data, ‘Though these products, unlike those in Problem 1, are reasonably logical, you wil not meet ‘the mechanisms for the reactions until Chapters 22, 29, and 23, respectively, and you are ‘2evised to sot the structures through the spectra. Bee Beha ke) 148, 1790 ‘do. p) 22, 478, €2, 48, 34.72.18, iam) 1.2 (6) 2.804 17H, 224,24, ITH 4.3. 08,9 1008 0 6.eMOy alo) $730 im) 291 206, 122 190,115,644, 28 yom) 232(0H ak 308 2, JHA, “420(214, 169 697M. 7 9. Tiana, 17 ma, 297 Purpose of the problem Your second attempt at determining the structures of reaction products, now of moderate : sgullibrium is [R'OH|IMeCO,R'] (woHIpMeCO.|*Organic Chemistry Solutions Manual So, if the available concentrations of [R!OH}{R4OH]} are about 25, the ratio of esters must be about 25 the other way with a 25-fold excess of MeCO;R*. The mixture contains about 96% ‘MeCO;R? and about 4% MeCOpR!. This is quite enough to make ester exchange a practical method. Problem 4 _Wte a mechanism for the reaction to give HCI on alumina. You do not seed a orl te (le ote tuna, io Ae he fee cy cnr Purpose of the problem Practice at writing mechanisms of new reactions Suggested solution “The first step must surely be attack of water on one of the very reactive acd chlorides. - ager sre wh < ‘This intermediate, which is half acid and half acid chloride, can now decompose to produce all the products in a step greatly favoured by entropy. Ha, —= Ws co + co + ai® o 7 Propose a mechanism fer tne formation ofthe clazonium sat rete to inthe cha “frst step is be formation of nivous acid HONO. He NaNO, HCL ra OF Purpose of the problem Practice at writing the complicated mechanism of an important reaction that we shall need later. Suggested solution ‘The fist step isthe formation of HONO, we are told, and itis clear that the amine must be @ nucleophile as amines can only play that role. HONO must be the electrophile so we had better ‘combine them to form an N-N bond a that is present in the produc. ooo ot orabe we ial Chapter 13 Suggested solutions for Chapter 13 ‘We need to lose two OH groups ftom this intermediate so we must protonate it on each oxygen ‘224 use the lone pair electrons ftom the nitrogen atom to expel two molecules of water Purpose of the problem lerpretaion of unlikely kinetics in «reaction seated to some in the chapter. Suggested solution "ae hydroxide on must atack the Ketone to form a tetrahedral intermediate, The best leaving ‘evap from this intermediate is the hydroxide ion that has just come in (PK 15) rather than the Syne anion (pKa about 35). I'we use the second hydroxide ion to deprotonate the intermediate ‘fave only one possible leaving group, though itis a bad one, and the decomposition of the 2 must be the rate-determining step. This mechanism is usally found for nucleophilic -etstituton at a carbonyl group with a very bad leaving group such as amide hydrolysis. Som oe EOL ee a The benzoate ion is the product under the reaction conditions but the alkyne anion collects a ‘oton from a water molecule, eenerating the second hydroxide ion, which therefore is a base cory. Purpose of the problem atice at drawing energy profile diagrams as one way to present the energetics of mechanisms: ‘Cigars Carshetny ciation bac, Suggested solution ‘The first thing isto draw the mechanism: this reaction was discussed in Chapter 6 proton transfer between oxygen atoms and is certainly fast. The frst step must be the rat determining step and the intermediate will hve a higher energy than the starting material or t= ‘product asi isan anion. Jn this answer we have used the style of energy profile diagrams used in tee chapter but there is nothing sacred about this ~ any similar diagram is fine. Purpose of the problem Practice at drawing energy profile diagrams to show the relationship between the same reacties different compounds Suggested solution “This is an equilibrium so the mechanism is irrelevant. The two five-membered ings ate both stable than the two three-membered rings but the important thing to express is thatthe =Chapter 13 Suggested solutions for Chapter 13 95 ‘membered cyclic hydrate is es stable than cyclopentanone but the three-membered cyclic hydrate ‘© more stable than cyclopropanone. ‘hate be ta tron oe 5? woud nye ce bis ee 3 Purpose of the problem Sesstice at assessing the likely effect of solvent polarity in terms of the mechanism of reactions Suggested solution, #5 essential first to draw a mechanism for each reaction and to identify the ratedetermining step cach case. The first two reactions are one-step processs so that atleast makes life easier. navel endows Dh catia ‘Now we need to draw the transition state for each reaction so that we can assess whether it is more ‘loss polar than the starting materials. The way to do this is described on p. 318 in the text. par? orbs emit oe ae. ‘othe frst reaction, uncharged starting materials form a partly charged transition sate. A polar xt will sbilize the tanston sate and speed up the reaction. In the second case, a flly ‘Sesed (ewiteroni) starting material gives a partly charged transition tate. A pola solvent will Hc both stating material and tramsiion sat but twill stabilize the starting materials ore ie ergy gap (AGF) will ncease andthe reaction wil go more slowly.Organic Chemistry Solutions Manual ‘The third reaction is different because it has more than one step. tis a carbonyl substitution the kind we met in Chapter 12. The nucleophile (ammonia) attacks the carbonyl group to for » teirahedral intermediate that decomposes with the loss ofthe better leaving group. Sora oR OMe "Nie We have marked two steps fast because they are just proton transfers between nitrogen ‘oxygen atoms. Either of the other two steps might be rate-determining. In this substitution leaving group is relatively good (compare Problem 6) and the rate-determining step is the fis ~ usual one for carbonyl substitutions. In this step, neutral starting materials become 2 cin = (awiterionic) intermediate so the transition state is becoming more charged and the reac: « accelerated by more polar solvents I Problem 10 ‘Comment on the Ukely effect of acid or base on these equilbria, Lape bees Purpose of the problem Practice at assessing the likely effect of acid and base on particular examples of equilibria Suggested solution ‘The first example is an esterification (or lactonzation as the product isa cyclic ester or lactone’ + the forwards direction and an ester hydrolysis in the backwards direction. Ester hydrolysis catalysed by acid or base but esterification by acid only In addition, even a weak base will be enough to urn the starting material into the carboxylate anion, which will nt cyliz. The equilibrium isto the right in acid solution and to the left in basic solution, ‘The second example is the familiar one of cyanobydrin formation from a ketone. The reaction is indeed reversible but in basic solution the cyanide anion is more stable than the oxyanion in the product and the carbonyl group is very table too. In acidic solution (at pHs less than about 12) the ‘oxyanion will be protonated and the reaction driven over to the Problem 14. Elemental sufur normally exists as an eight membered ring (Ss), but itcan also be found in a number of other states. How would entropy and enthalpy affect the equilibrium between sulfur in these two forms? ek so Lohag tt 9 Purpose of the problem eee eeeChapter 13 Suggested solutions for Chapter 13 97 Suggested solution The equilibrium position is determined both by enthalpy and entropy as discussed on p. 312 of the chapter Entropy favours the larger number of molecules as they have greater randomness so heat ‘i drive the equilbsium to the right. Enthalpy will favour the eight-membered ting as it has no cing sttain and so lower temperatutes favour the lefi-hand side. Problem 12 Draw transition states and intermediates for this reaction and fit each on an energy profile diagram, Be careful to distinguish between transition states and intermediates. : ° G 7 Cs °° , ° Purpose of the problem Constructing an enecgy profile diagram for a multistep proces Suggested solution :sta meshanism is essceal, This i quite long job as there are several steps so we must patiently ‘ork our way through them, And no short cuts are allowed! ; Yon Low bon L, on ore. =OS Step 3 must be fast a8 isu proton transfer between oxygen atoans, The decomposition of the hedral intermediate is likely to be fast as the leaving group ‘carboxylate ion, pK about 5) is sash a good ene. The first step, the bimolecular attack of hydroxide on the anhydride, will be the “ate-determining step. We need only drave the structures of the transition states and we can ‘onsiruct our diagram,Suggested solutions for Chapter 14 14 "the gelatin of ne openhaifor of ucose to othe tale cata i be "afgut to work out wriat nas happened. Number the carton atoms in the optichain form ee ee a es carton aon Then ara 9 mechanism fr the eacin: ne Purpose of the problem First trial of a simple method to follow complicated locking reactions plus some revision o: carbonyl addition reactions. Suggested solution Just do what the question says! The starting material is numbered from the aldehyde group. We started numbering the product with Cé as that isthe only CH, group and then followed the earbor chain back to CI which is now the hemiacetal carbon. Q tees wo RSH epee eal eo coats wo"2"on an bn ou Numbering the carbon atoms makes it clear thatthe hydroxyl group on CS has cyclized. To draw ‘the mechanism, we need to redraw the starting material so that the reaction is possible and ti casiest way todo that i to draw it ike the product. Don’t forget to change the thick and thn lines = necessary when you flip a C atom over! ‘The mechanism is just a nucleophilic addition to t= aldehyde as described in Chapter 6 and isthe first step of the reactions in this chapter.Chapter 14 Suggested solutions for Chapter 14 Purpose of the problem see if you can daw mechanisms fortwo of the main types of reactions inthe chapter. ‘Suggested solution “+ MeOH is the solvent and present in large excess, it probably adds fist. This also makes the mediate in the addition of chloride a more stable oxonium ion. This mechanism is very ike ‘+= of acetal formation and, if you added chloride is, that isa good mechanism too. BS Fj Og cond example is imine formation ~ attack by an amine nucleophile and dehydration ofthe “ate, Don't forget to protonate the OF group so that it can leave as a water molecule. lem3 Z "1507 of these molecules is an acetal, that is, a ompounc made from an aldehyde 0 ketone £3 two aleohol groups. Which compounds were used to make these acetals? SE hw Purpose of the problem tice a the recognition of acetals and working out how to make them, Suggested solution 22 we have 1 doi to identify the hidden carbonyl group by loking fr the only carbon atom having ~>C-O bonds. This stom is marked with a lack blob in the answer below. Those ae the bonds nade ng acetal formation so, if we imagine breaking therm, we can se the alcool or dl needed. Ct ore Or Odes GoaOrganic Chemistry Solutions Manual Purpose of the problem Practice at drawing mechanisms for acetal exchange rather than straightforward acetal synthesis Suggested solution In each case the acetal provided reacts with the acid catalyst to create an oxonium jon and ar alcohol. Each has a vital part to play in the rest ofthe reaction. “ome + Moot By the usual acetal mechanism the alcotiol and the ketone combine to form a hemiacetal, which i dehydrated either by acid or by the oxonium ion. If water is lost, i is captured by the oxonium ior and the end result is the same. 8 Mog oH yo pts + meow ss Ay Enough methanol is formed in these eactions to make the final acetal and the water is consumeé in this process to give acetone as the other product. So both Ketones and both acetals are i= equilibrium but the most volatile component is acetone and this is distilled off, driving equilibrium over to the right. ‘The third example is essentially the same except that the reagent is one orthoester and product is another. The volatile by-product is methanol and disilation of this pushes t= ‘equilibrium across. The mechanism is very similar to the first example with the formation = ‘methanol and an oxonium ion starting the process off. Ths time, an oxonium ion must be involr=! in the capture of each alcohol +eChapter 14 Suggested solutions for Chapter 14 ‘The second example is different because no volatile by-product is removed and the position of -guilbrium must represent a genuine difference in stabilities of the two acetals. Some water is seeded as the first acetal must be wholly or partially hydrolysed and the water appears when the ‘ond acetal is formed, The exact details of this mechanism are uncertain but the whole process is ‘scler thermodynamic control: the ketone is more stable than the aldehyde. re es Purpose of the problem ‘Scension of simple acetal chemistry into related reactions with nitrogen. Suggested solution ‘Sith reactions start inthe same way by attack of a nitrogen nucleophile on formaldehyde, Acid “rly is not necessay for this fst step. The ist reaction ends with the formation of an iiniam fon by acid-atalyed loss of water OP a Oe =O OL = Oh In the second reaction a second amino group is wating to capture this intermediate by cyclization form a stable five-membered ring. The stereochemistry does not change but the central bond of “Se molecule has to be rotated through 180° before the cyclization can occur. ae Aisesy tse a wo? “ back into this reactive electrophile 1 give the final preduct. This is loss uf carbonyl oxygen in an unusual setting as the carbonyl group is not ‘here atthe start, a me NN Problem 8 Suggest a detailed mechanism for the acetal exchange used in this chapter to make any ‘acetal of @ ketone from an orthoester. SO te ‘emety orate seh erate Purpose of the problem Seminder of chemistry from this chapter ~ making acetals fom ketones is diffcult~ and drawing “echanism related to, bu diferent from, one in Problem 4 Suggested solution he equilibrium berween a ketone and an alcohol on the one hand and the dimethyl acetal on the ther is unfavourable and must be driven over by devices such as this. The orthoformate is even ore unstable than the acetal (three C-O bonds insiead of tw atthe same carbon atom) and the ster even more stable, because of conjugation, than the Ketone. There are various mechanisms you ight have drawn, which differ only in details such as the order of the steps. Here s one such 4 CR-Cr-Or - CO" Jinn Be LO Oe Se am “The frst line shows the normal mechanism for acetal formation snd points out the by-product, -rolecule of water. This water is consumed in the hydrolysis of the orthoformate (by an acetal =drolysis mechanism) to give a stable ordinary ester. The favourable second equilibrium pulls the ist across to the right.Organic Chemistry Solutions Manual “When we introduced eyelio acetals, we showed you this reaction. : eryco.n m0 me Ga oven orean ) 6 ~ What are te ta functional gouns nt afectedby tis acon? How weuld you hserobse then? Purpose of the problem Revision ofthe different types of acetals and their relative reactivity. Suggested solution ‘This question develops immediately from the last. The noneyclc acetal hydrolyses easily because the equilibrium favours the three molecules (one aldehyde and two alcohols). The two remaining acetals are a cyclic acetal or dioxolane and a cyclic dthioacetal or dithiane. The cyclic acetal just needs more vigorous acidic conditions but the dithiane needs a Lewis acid that likes sulfur, Mercurr ~ Hl) ~ is a good example. The precise reagents and conditions are not important. “anor oe Maone), a a non eta ‘eno “aoe noo Problem 40 eis i Wet would actualy hapoen i you tied io make the unrotected Grignard reagent shown here? Purpose of the problem Revision ofthe danger of mutually destructive functional groups ‘Suggested solution “The Grignard reagent would attack the carbonyl group inthe same molecu or in another molecule with ireversible formation of a carbon-carbon bond. The intramolecular reaction forms a fou membered ring and so may not be favoured. There are other possibilities 100 such as radical reactions (Chapter 39) or polymerization (Chapter 52). = 0 omeous workupoe Chapter 14 Suggested solutions for Chapter 14 tp ease ” is Fad the acetals in celiulose (see the answer below for he structure of cellulose). -2zrpose of the problem ‘iecznder that functional groups are the same no matter how complex the strcture. Acetals can be ete! ‘Sezgested solution “£5 Took for the carbon atoms (marked with a bab) having two C-O single bonds. Problem 12 pat | stable product can be isolated from the fea between bensaideyoe ‘and ammonia _ Sevssedin this chapter, Suggest a mechanism for ts formation. ‘Parpose of the problem "2 on of aminal formation ~ the all-nitrogen version of acetal formation. Sezgested solution “S.ce formation follows its usual course but the imine is unstable and reacts with more benzaldehyde OMto*-ot- or 2£0~ The reaction with benzaldehyde starts normally enough but the oe of the first “seemediate produces a strange looking cation with two adjacent double bonds to the same ‘seezin atom, Since the benzene rings play no part in the reaction, we abbreviate them to ‘Ph’. a ae 4 © aus per wed, I ~ oxen 205Purpose of the problem Extension of acta and aminal formation into examples where the intermediate i trapped by Aitferent nucleophile. Suggested solution ‘The first reaction starts with the usual attack of an aleohol on an aldehyde but the ‘nucleophile isa carboxylic acid. Though a poor nucleophile, itis good enough to react with ‘oxonium ion, especially when the product is eylic. eee ee “The second reaction stats with nucleophilic attack by the amine on the more carbonyl group ~ the Ketone. Ine formation is followed by cyclization and thi second te i ‘normal nudeophili substitution at the carbonyl group ofan exter (Chapter 12). The imine ‘bond moves into the ring to secure conjugation with the ester, 190.5. Fumie ot, voeo's vif 1 ‘ium ion a cere pile that captures the iin ‘and 4 second imine formation completes 3969,» 753. ‘mechanism,Chapter 14 Suggested solutions for Chapter 14 207 Purpose of the problem Extension of the mechanism for acetal formation into dithiacstal(dithiane) formation. Suggested solution. ‘The mechanism is @ direct analogue of acetal formation, The debydeation step is more dificult because the C=5 bond is less stable than the C=O bond hecause overlap of 2p and 3p orbitals is not as good as overlap of orbitals (for example, two 2px) of the same size and energy. BeseSuggested solutions for Chapter 15 j 5 Problem 2. j ‘compound CalsFO has a brood peak in the inrared at about 3100-3400 em-* and the following signals i its (oroton decoupled) “C NMR spectrum. Suggest @ stuctue forthe compound and interpret the soecta i “Bo (ppm) 157,38 (doublet, coupling constant) 229 Hz), 154.24 (single), 116.32 + (Goublet, coupling constant 7-5 Hz), 446.02 (doublet. coupling constant 23.2 Ha) Purpose of the problem Just to remind you thet coupling occurs in carbon spectra too and is useful Suggested solution All the signals are in the sp* region and two (at > 150 p.pm.) are attached to electronegative clements. As the formula is Cy, 2 benzene ring is strongly suggested. The IR peak tells us we have a OH group s0 the compound is one of these. enlaces ‘The symmety of the spectrum (only four signals) suggest the third compound asthe athe two would have six different carbon atoms inthe ring. We can therefore assign the spectrum by saying that the very large coupling (229 Hz) must be a"Jcs andthe zero coupling must be the carbor attached to the OH. The other two signals are the carbons in between and we can assume that, the laegr the coupling, the nearer the carbon isto fluorine. . siesa@sisny oe NST ase sou apse oe ene “Problem 2 Suggest structures forthe products of these reactions. © Compound 28s C:Hi202 and nas R 2725 om * {ip 1.02 (6H, 5), 1.66 (2H, t, 17 HE), 2.59 (2H, t, J7 Ha, anB 3.9 2H, sh ‘Compound 28 has: m/z 149/154 (M’ ratio 3:1}; IR 2250 cm-*, {4 (0-D.m): 2.0 (2H, quintet, J7 Hz), 2.5 (2H, t, 47 Ha), 2.9 (2H, 1,17 Ha), and 4.6 (2H, s)Chapter 18 Suggested solutions for Chapter 15 109 ezpose of the problem “dession of Chapter 11 and the frst example of total structure determination “Sezgested solution “Phe arting material for 2A is CpH:Os and has apparently lost an oxygen atom. As the reagent is 02s, 390%.) “SSE, itis more likely to have gained two hydrogen atoms and lost a water molecule. The IR ‘gem shows « C=O group and suggests an exter oF a stained Ketone. The NMIR shows two t ‘son! CH, groups, one (at 251 ppm.) next ta functional group but not oxygen, so presumably +4°2%.0 . =, ve intact CMe, group, and an isolated CH. group next to oxygen at 3.9 ppm. Theres only astiann “oe Fssonable structure. “Th: mass spectrum of compound 2B shows that thas chlorine in tthe IR shows aN group, | Bp asc) “et “he proton NMR shows eight Hs. If we assume that no C atoms have been lost, the mast ‘sSssble formula is CsHCINS. The compound has lost a water molecule. The proton NMR ‘Sor three linked CH: groups, a quintet in the middle , and two triplets atthe ends. The shifts of Bind cing (25 a 23 ppin) dow hay seas we cial gmp bo wc. 22% ie 2st “Ser és no oxygen in the molecule). This must mean that we have @ units SCHsCHCH,CN. All 2.024, aint) “Set remains is an isolated CH, group with a large shift and the chlorine atom so they must be “sees to S, The large shift (4.9 ppm.) comes from 1.3 + 1 (S) + 2 (Cl) = 45 ppm. Again one “sevcrure emerges. oe Soe Ms=pose of the problem 2 you thinking the other way round — from structure to data, What aze the important pieces of omen? ‘Seggested solution "ip are many acceptable ways in which you could answer this question ranging from choosing Se ome vital statistic for cach pair to analysing all the data for each compound. We'll adopt “=85 way and point out several important distinctions. In te ist example, one main difference is “Sp sie, sen mainly in the IR. Both ae esters (ahout 1745 em") but we should add 30 em”! ‘f % five-membered ring. The functional group next to the OCH: group is different ~ an OH “05p in one case and an ester in the othe. There are other diferences.Organic Chemistry Solutions Manual In the second case there are also differences in the IR C=O stretch between the aldehyde (about 1730 em!) and the conjugated ketone (about 1680 cm!) but the main difference isin the proton NMR. The aldehyde proton and the number of protons next to oxygen make a clear distinction. There will also be differences in the 'H and °C NMR spectra of the benzene rings since one is conjugated with a C=O group and the other is not. The reaction actually gives a z oe aan ee me Problem 4 ‘The following products might possibly be formed from the reaction of MeMgBr with the gyclic anhydride shown. How would you tell the difference between these compounds using IR and "°C NMR spectra? With *H NMR available as well, how would your task be easier? GEG AY tr be Purpose of the problem Farther thinking the other way round — from structure to data. Contrasting the limitations of IR and °C NMR with the data from 'H NMR spectra. Suggested solution ‘The molecular formula ofthe compounds varies so mass spectra would also be useful, but inthe [R the compounds with an OH group vould show a strong broad U-shaped band at above 3000 cm ‘The cyclic ester would have a C=O stretch at about 1775 em”, the ketones a band at abou: 1715 em", and the CO;H group a broad band at about 1715 cm~! as well as avery broad V-shaped ‘band from 2500 to 3800 em", In the C NMR the ester and acid would have @ carbonyl group at about 170-180 ppm. but the ketones would have one at about 200 pp.m. The number and positon of the other signals would also vary Eales ae In the proton NMR, all compounds would show the two linked CH groups a a pair of tiple ‘except in the second compound where they have the same chemical shift and do not couple. AE Ihave a GH singlet, for the CMe: group in all cates except the second where itis the two identical COME groups, The last has an isolated Me group. The OH and CO,H protons might show up as broad signals at any chemical shift.Chapter 45 Suggested solutions for Chapter 15 semeeeetindimteadie <> :oupling to luorine i fine. The carbon NMR shows the carboxylate carbon at 176 p.p.m. « small coupling to F as itis far away and the CH carbon at 86.1 p.p.m. with an enormous it is joined directly to F. But where is the ketone? We should expect it at about ‘pm. but itis at 83.5 p.pam, with the expected intermediate coupling. It cannot be a carbonyl al. So what could have happened in D,O solution? The obvious answer is that a hydrate is 13 (Chapter 6). ane) pci ayhe meme oe nee pect: 182 A Gomdin| aa ee for ‘Seactuce determination of a compound with biological activity isolated from & natural source. ‘Sepgested solution ‘Te solubility and sale formation data suggest the presence of acidic and basic groups, probably 7H and NH; as ths is @ natural compound. Ifo, the #'C peak at 170.2 p.p.m. is the COsH ‘peep. The five carbons in the sp* region and protons at 8.0 and 8.4 pp.m. suggest an ‘=>catic ving. There cannot be just one nitrogen atom as M* is an even number and that looks very like a pyridine ring (typical dy about 7-8 p.p.m. but the N atom will be Scvonated at pH < 1). The two sets of aliphatic protons aze coupled and the large shift ofthe © vgnal at 4.57 p.p.m. suggests proton between CO:H and NH (pH < 1), We have these Segnents112 1a Tre dais ofthe stuctue and spect ate in , inoue eta (hem. Pham. Bil, 1975, 23, ‘2669; S, R. Scho ota, 1. One ‘Chem, 1984, 88,6850; and B. Ye sand. Burke, J. Org. Chom, 43995, 60,2640. Organic Chemistry Solutions Manual Presumably, the aliphatic part must be X or Y and that leaves just one oxygen atom fora forms ‘of CHoN2Os = 182, Only sx ofthe ten H atoms show up in the NMR because the OH, CO-E and NH protons all exchange rapidly at pH < 1 and do not show up. Thee are vatious isome= possible and the compound is actually ‘azatrosine’ though you cannot be expected to deduce ths ‘The second diagram shows the structure in soltion at pH < 1 8 3.02 (24, m) Ho. He ~ em wot oe satin |W Problem 7 Suggest structures for the products of these two reactions. ee. ‘Compound 7A, m/z: 170 (M“, 1%), 84 (77%), and 66 (400%); IR: 1773, 1754 em-*: (ppm; CDCI): 4.82 6H, sand 4.97 (4H, 5). dc (.pm.; CDCIs): 22, 23, 28, 105, and 169 {the signals at 22 and 105 p.p.m, ere weak). ‘Compound 78. m/z: 205 (M' , 40%), 164 (50%), 160 (35%), 106 (100%), and 77 (42%) IR: 41670, 1720 om; Bx (p.p.m.; CDCl: 2.55 (2H, m), 3.74 (4H, t, J6 He), 3.92 2H, m), 7.21 (2H, d, J8 Ha), 7,35 (4H, t, 18 Hz), and 7.62 (2H, d, 18 Hz); bo (9-p.m.; CDC}: 24, 47, 48, 424, 427, 130, 198, 170, and 172 pam. Purpose of the problem ‘The other important kind of structure determination: compound Suggested solution Compound 74 is much the simpler 0 we start with that. The two reagents are CsHsOs 2 HO» which adds up t0 CioHisO¢ oF 230 50 60 has been lst. That looks like C3HjO> oF le likely CsHO (because itis saturated). Ifthe fist is right, 7A is CubfoOe which atleast fis proton NMR, ‘The IR suggests two carbonyl groups, though the !™C NMR suggests one only, but the molec: ‘must have some symmetry as there are only five signals fr eight carbon atoms. The proton N\!= shows a CMe; group and four identieal protons, which ean only be two identical CH, groups. The nly unsaturation isthe two carbonyl groups so the °C signal a 105 p.p.m. is wey strange. hike the signal at 22 pipam, is probably a quaternary carbon as tis weak and it must be next to: oxygen atoms to have such a large shift. Either 22 or 105 p.m. must be C of CMe. The last degrees of unsaturation must be rings. The cyclopropane would supply one ring and the two link== and symmetrical CH groups andthe carbon at 22 p.p.m. would be the atom joining that ring to two carbonyl groups leaving 105 ppm. tobe C of CMes. So we have: Isolated from a chemi 2 196 mt A AK PGChapter 45 Suggested solutions for Chapter 15 ‘Tat actually accounts forall the atoms so 7A must be what you get when you join these two ‘Syprents together. The carbonyls are arranged rather ike those in aeelic anhydride and the two 5 sectches must be the symmetrical and antisyrmmetrical combinations 405 192 (64.8) zaraeyo, 23728 Vv ~ AB Ak 25728 sori) “Sd, ‘Compound 7B has nitrogen in it (odd MW) and clearly has the benzene ring too from the NMR se ws can put down PHN (= 91) as part ofthe structure. Italso has two carbonyl groups (in IR, the ‘9 +t 1670 cm" looks like an amide) and they are both acid derivatives ("°C NMR). There are “Se aliphatic carbons, two CHs and one CH. Adding these together gives us C), HNO: = 188 50 “tes is 17 missing which looks like OH. Since we need a secon acid derivative and the OH is the ‘only remaining heteroatom, it must be a carboxylic acid. Given thatthe CH is a triplet, it must be +2e<:t0 one of the CHas and, a they are both multiplets, they must be joined to each other. There is ‘ace more degree of unsaturation so there isa ring, So we haves ue x { ee Zh OT OM ‘sescrved value of 3.92 p.pum. fits the fist better. A similar estimate for the CH also suggests the ‘Sew structure. This is indeed the correct answer. ‘n/a: 281 (60%) 90 400%), 691629) jes (il a9 Ho, 734 GH, 9) oe ie COLIg 62: 64, 222, 429, 126, 127,4 Purpose of the problem Perther practice at structure determination, adding ideas ofthe size ofthe coupling constant, 18 See 5, Daisetsty ant RK Singh, J. Am. Chem. Soe, 1975.97, 3258. 15 From now on. axing estabishs the general method and apoe2ch, we shal simply ge the ansners wn ary special pins apoing to ‘he question under seuss.‘Suggested solution “The compound 1 ai epoxide: th Coupling cooks ‘aftind th’ vng an! mall (Hz, cone 10 Ha in the benzene ring) because of rng size and the electronegative oxen atom, Al the Hs ‘the Ph group happen to come at the same sh but those in the nitrated ing are at ower Beld and separated bythe NO; group. | aaa Organic Chemistry Solutions Manual | | areas | | ae ase \ l : é 4 fe along 4 7ai(shs~ se0aHe TS4AKe ra < ‘, é Purpose of the problem ~ Further practice at structure determination, adding a carious chemical shi Suggested solution im See A Eschenmoser 94 8049, The compound is an alkyne formed by the Eschenmoser fragmentation (Chapter 38). It is ne= Heme Ci Aes 29744 Ar 2828. be o assign all the °C NMR with certainty but the alkyne Cs come in the region 70-85 pp. safes eran pete os ae Seat Wein soare 2115 (6-C ston (od aut) eae 298,48) | Purpose of the problem Further practice at structure determination including a change in the carbon skeleton ~ a ries contraction,Chapter 15 Suggested solutions for Chapter 15 335 Suggested solution Te compound isa simple eyclopentensl, The ®C NMR assignment is not all certain 18.6, Magnusson ana 8. Trt 4.018. Chem. 1973, 38, 1380. Wo Seno. ereahy — SatHs) Problem 44. Female boll weevils (2 cotton pest) produce two Isomeric compounds that aggregate the ‘rales for food and sex. A few mg of two isomeric active compounds, gandiso! end Zochtodencl, were ‘isolated trom 4.5 milin insects. Suggest structures for these compounds from the spectroscopic data below. Signels marked * exchange with D2O. ZOchtodenol. m/z: 154 (CyoHsa0), 139, 136, 121, 107, 69 (100%, Sax {om}; 3350, 1660. 5a (p-p.m: 0.89 (6H, s), 1.351.70 (4H, broad m), 1.41 (14, s"), 1.96 (2H, s), 2.06 (2H, t, 16 He), 4.44 (2H, d, 17 Ha), and 5.48 (1H, t, J7 Ha). Grandisol. m/z: 184 (CioHix0), 199, 136, 121, 109, 68 (100%). nx (om-*; 3630, 32503550, and 1642. 34 (o.p.m)}: 1.15 (BH, 8), 1.42 (AM, ddd, J 1.2, 6.2, 9.4, 13.4 Hz), 1.95.45 (1H, m), 1,551.67 (2H, m), 2.65 (SH, s). 1.70.84 (2H, m), 1.94.99 (4H, m), 2.52" (4H, broadt, J 9.0 Hz), 3.68 (1H, ddd, J5.6, 9.4, 10.2 Hz), 3.66 (1H, ddd, J6.2, 9.4, 10.2 Hr), 4.62 (28, road §), and 4.81 (2H, broads) 4 (ppm): 19.1, 23.4, 28.3, 29.2, 96.8, 41.2, 52.4, 59.8, 109.6, and 145.1 Purpose of the problem ther practice at struct determination of natural products wit al the data properly presented. Suggested solution structures are shown below. 18 J.M-Tumingon otal, Setnce, 1960, 266, 10:0, but soe K. Mot 3 at at Li's donate, 1969, 909 low forthe spect of eenadenet snd osm pret inate a, Bu Crem. So. phe Jn, 3991. 68,1871 forte ty secre of ganden Problem 12 Suggest structures for the products of these reactions. ° BA A.meP-et_ Aven it LI ae Ae Ser Data for compound 12h: CyoHs30P, IR (em-4): 1610, 1235; dy (p.p-m.): 6.57.5 (SH, m), 6.42 (AM, t, J27 Ha), 7.47 (AH, dd, J47, 23 Hz), and 2.43 (6H, d, J 25 Hz). Data for compound 128: Cs2HseOz: IR: CH and fingerprint ony; 8y (ppm): 7.25 (BH, 8) 4.28 (1M, d, J4.8 Ha), 3.91 (1H, d, J 4.8 H), 2.96 (3H, s), 1.26 (BH, 5), and 0.76 (3H, 5)Organic Chemistry Solutions Manual 1 S00 F. Nrdol et al, Tetrahedron tet, 1968, 5751. ae Purpose of the problem ‘Structure determination of reaction products by proton NMR alone with extra twists ~ an elemen: with spin (P) and protons on the same carbon atom that are different in the NMR. Suggested solution ‘The coupling constants Jp) across the double bond in 124 are very large. Typically is Jp shout 20 Hz and rns "J is about 40 Hz, Geminal Fp) coupling constants are also large bs ‘mote vatable. In 128 thee is a stereogenic centre so that the hydrogen atoms and methyl groups = te rng ae either onthe same side as MeO or the same side as Ph, They are diastereotopic with different chemical shifts and the Hs couple 7). We cannot say which is which 0? -sy--— zara, °. eee Pty neste amor — 243.9)-~ mee as nt 05-75 64m) @ W428 046 148) aoa gf -MSotCNe 148) Mo l Pa sana ie 276,48) Problem 43 Identity the compounds pracuced in these reactions. Warning! Do not attempt to deduce the ‘structures from the starting materials but use the datal These molecules are so smal that you can identity them from *H NMR alone. Oe hog tt te = Data for compound 13A (C,He): 54 (p.p.m.): 5.35 (2H, 8) and 1.00 (4H, s) Data for compound 138 (C Ch Gly aC a a Ce a = = OO == OL eats oS The trina ps pe 1) qu ag Te | leaving groups (HO™ and MeO) are about equally good but the formation ofthe carboxylate anion tunder the reaction conditions drives the equilibrium to the right. one mas ool =O0y- = eaten ‘or these reactions, commeriing on the choice of sates and solvents. How woul you Ha cicra Couey? Purpose of the problem Dravwing mechanisms for uscful substitutions and extending the saquence by other reactionsChapter 47 Suggested solutions for Chapter 17 ‘Suggested solution “Se at standard Sy2 reactions at primary carbon atoms. Inthe first case, the OH group has to be ced into a good leaving group. We show one reaction of each kind, though actually everything ‘pens twice. The dinitrile is converted into the diester by treatment with ethanol in acid solution; se Problem 9 in Chapter 12. Problem 6 as eS ‘raw mechanisms fr tese reactions and describe the echo o tho pec Purpose of the problem esving mechanisms for two types of substtmions in the same sequence to make a useful ioreule, Suggested solution The two reactions are an Sy2 at primary carbon and a nucleophilic substitution at the carbonyl ‘ae-9 with the amino group as the nucleophile in both cases. Substitution atthe carbony! group ‘=>bably happens first. Don't worry if you didn't draw the deprotonation of the amide and the $2 22ck of nitrogen exactly as we di The stereochemistry ofthe product isthe same as that ofthe fearing material (CO;Et group up) as no change has occurred atthe chiral centre, Purpose of the problem Aevsion of Chapter 2 and practice at drawing mechanisms of nonstandard reactions.Organic Chemistry Solutions Manual Suggested solution First draw good diagrams ofthe molecules as the question a; Me sens oe ae — ye I. at oe vi babs roto bs bolt nadie ad eephg a we sl happens when we unite them. The nitrogen atom is obviously the aucleoptile and one of Se carbony groups ofthe anhydride must be the elctrophile as nitrogen is Bonded to an acetyl = in one of the products. ‘We must lose @ -butyl group from this intermediate to give one ofthe products and unit: = the acetate anion to give the other. This must be an Sy rather than an Sy2 reaction at © Purpose of the problem Revision of stereochemistry from Chapter 16 and practice at applying i to substitution Suggested solution ‘The two sides ofthe epoxide in example (a) ate the same as the molecule has a plane of =) ‘Attack at cither side by the Sy2 mechanism must occur from the bottom face ofthe that inversion occurs, The product is a single diastereoisomer but cannot, of co=ne ‘The stereochemistry ofthe starting material in (b) was discussed in the soln = (Chapter 16. The starting material has a plane of symmetry but is a single diaste-=0iseme= centres are inverted during the double displacement by sulfur. You must be Jem =Chapter 47 Suggested solutions for Chapter 17 133 ‘sereochemistry right when twisting the molecule round to draw it as a sing, The product is a single Bastereoisomer but is not chiral. Problem 9. ‘What are the mechanisms ofthese reactions, and what is the role ofthe ZnCl, in the frst step and the Nal in the second? cl alo = soy ee h(n 6 Purpose of the problem Exploration of the roles of two different kinds of catalysts in substitution reactions. Suggested solution The ZnCl, acts as a Lewis acid and can be used either to remove chloride from MeCOCI or to ‘complex wit its carbonyl oxygen atom, in either case making ita better electrophile so that it can smzuck the unreactive oxygen atom of the cylic ether. Ring cleavage by chloride follows. ° Gj a yO a. o. eee LO ay YO. 18 You can read more about is in The second reaction is an $2 displacement ofa reasoneble leaving group (chloride) by a rather 8.5. rumise et at, Vogel's ebook ‘weak nucleophile (acetate). The reaction is very slow unless catalysed by iodide ~ a better of ogni chemist (nec, amaceophile than acetate and a better leaving group than chloride. It isa nucleophilic catalyst. Lone™ans, Haxow, 1989p. 492 Brn ey yey Problem 10. t oe ‘escrb the sterecchemisty ofthe produts ofthese reactions. el wt =oOrganic Chemistry Solutions Manual Purpose of the problem Time for nucleophilic substitution and stereochemistry again with afew exta twists this tard Suggested solution ‘The ester in the fist example is removed by reduction, leaving an oxyanion that cycizes intramolecular Sy2 reaction with inversion of configuration giving a ci-fused product. Gon CBO ‘The second case involves an intramolecular Sy2 reaction by a sulfur anion on one end of he epoxide. The reaction occurs stereospecitically with inversion and so one enantiomer of ca diastereoisomer of the product is formed. Some redrawing is needed and we have kept the epaxide ofthe starting material in its original postion to avoid mistakes, Purpose of the problem ‘Trying out substitution reactions in synthesis. Suggested solution Sequence (a) starts with a displacement of the carboxylate anion followed by acid-catalr Ihydrolysis of the nitrile to give the second carboxylic aci, Full details of the second step Chapter 12 (p. 294). (vm a ws OS OC - OCF Reaction (b) starts with two consecutive Sy2 reactions of the amine on the epoxide. At that p: there are no more NH protons to be replaced. The diol intermediate cyelizes by an intramolecd ‘Sq2 reaction with one of the primary alcohols displacing the other after protonation.Chapter 17 Suggested solutions for Chapter 17 Problem 12 ate with reasons whether these reactions wil be either Syd oF Sy2. mye 2 at so oY = oF Purpose of the problem examples of choice between our two main mechanisms with (c) and (A) difering only in Scegested solution =nple (a offers a choice between an Sy2 reaction ata tertiary carbon atom or an Syl reaction next 0 Sonyl group. In fact, thes ae about the only known examples of Ss2 reations at tertiary carbon cerk because the carbonyl group aeeerates $2 reactions so much The diagram ofthe transition ‘shows how the p orbitals on the carbonyl group are parallel tothe p orbital n the Sy2 transition SS. Auide is also an excellent nucleophile being sharp and nacrow and not afected much by steric “ance. We know the reaction is Sx2 because we find inversion of configuration. ap Ht | “ES es) o is = the chemistry described in Chapter 14 and particularly with Problems 4 and 8 atthe end of that ser. The replacement of OMe by the primary OH isa nucleophilic substitution at saturated carbon «goes by the Sx] route because ofthe caion-sabilzing effect ofthe other two oxygen atoms. amples (c) and (d) add the same group (PrO) tothe same starting material (an epoxide) under © =zrent conditions. We can tel that (c) must be Sx because the nucleophile has added to the rv rather than the secondary end ofthe epoxide and that (d) must be Sx2 because of the reverse -clectvity. Acid catalysis makes Sy better by improving the leaving group and base catalysis, 5x2 better by improving the mucleophile. Notice that inversion of configuration occurs in + reactions. This is expected in Sy2 and may be the case in Sy1 because the underside of theSuggested solutions for Chapter 18 j 8 Problem 1. Ident the char of boat sbomemaerd rings nthe following sttures and say why that particular shape is adopted. Purpose of the problem Simple examples of chair and boat forms. Suggested solution ‘The first three are relatively simple ‘oa roca maa eaistra! (ho mpsesoie ene ‘The next two have several rings each, all boat i the first. We'll link that to the sixth molecule as also has a boat and neither of these cage structures has any choice. ‘The rings are all chairs in the fifth molecule adamantane — a tiny fragment of a diamon? ‘molecule. ‘The rings don't all look very chair-like in these diagrams - making a model o= adamantane isthe only way to appreciate this beautiful and symmetrical structure and to see all the BHD Problem 2 i Draw lear confrinaina! see te these molecules, tepelng each salient as axialChapter 18 Suggested solutions for Chapter 18 137 ‘Purpose of the problem ‘Seep practic at drawing chair cyelohexanes with axial and equatorial substituents. ‘Segzested solution Bee drawings may look different from ours but make sure the rings have parallel sides and don't ‘Mew upstairs. Make sure that the axil bonds ae vertical ané the equatorial bonds paalle! tothe ‘m= ring bond-but-one. The first molecule has a fee choice soit puts both substituents equatorial. “Whe as Geo molecules are dominated by the Futyl groups, which insist on being equatorial Re eR oases tot oo! Problem 3 ‘Would the substituents in these molecules be axial or equatorial or a mixture of the two? eee *-pose of the problem practice at drawing chair cylohexanes and deciding whether the substituents are axial or sorul, Remember to decide by drawing and not by some memory trick like trans means “scvorial’ or any such nonsense Seszested solution <4 se molecules have a fiee choice asthe substitutents aren't large and are about the same sie. ‘oc: that trans means diequatorial in two cases and axiallequatorial in the third. Sei ost ag so80 = oH iat extort Problem 4 “sis it alificult for cyciohexy bromide to undergo an E2 reaction? When its treated with 23e, it does undergo an £2 reaction to glve cyclohexene, What conformational changes, '~st occur during this reaction?Organic Chemistry Solutions Manual Suggested solution CCyclohexyi bromide has the chair conformation with the bromine atom equatorial. It cannot do an E2 reaction (Chapter 19) in this conformation as £2 require the reacting C-H and C-Br bonds to be anti- periplanar. This can be achieved ifthe molecule first fips to an unfavourable axial conformation. y Sa ae Problem 5 A he “TWeetment ofthis aketosiconl win base cess an elimination feecton. Wnts the Apeeheriem, end | which conformation must the molecule adont for oe eeah enue Purpose of the problem Exploration of the relationship between conformation and mechanism in ales simple example. Suggested solution Since this is a multistep mechanism, it is best to draw the mechanism first before considering conformation. In the deprotonation step, the axial proton will be lost, though this doesn't affect the conformation ofthe molecule. Inthe elimination step the OH group enust be axial 0 that the C=O ‘bond is paral! tothe p orbitals inthe system. The molecule isa ci-decaln soit as a choice of conformations. Don’t be disheartened if you got the wrong conformation first time ~ we took several tries before geting it right 0,Chapter 18 Suggested solutions for Chapter 18 139 Purpose of the problem Zapioration of the relationship between conformation of important frans-decalins and mechanism, Seagested solution mechanism is easy and the conformations of trans-decalns ae fixed, so we can start with the Only the first compound can get the necessary ‘attack from the back’ angle of 180° between ‘wackophile (O~), carbon atom, and leaving group (Br) for the intramolecular Sy2 reaction to make ‘Be epoxide. Problem 7 ‘ew conformations! diagrams for these compounds. State in each case why the substituents "ave the positions you state, To what extent could you confinn your predictions experimentally? ; Soy tee SENS Perpose of the problem “Ser exploration of conformation and establishing the link wit cn 15 Tis poner unos materia tom ploration of conformation and establishing the link with NMR spect pi eels eee we suggest you come bark to it Sezgested solution When you have ea hat chapter. frst rwo molecules have no choice about their conformation but the third does. Canfieming the conformations experimentally means measuring coupling constants in the Soren NMR 10 we need to Took atthe vital protons (marked ‘HT on the diagrams below) and “ier whether they canbe seen inthe spectrum, Fortunately, the intresting protons are all next ~ “cnctional groups so they can be seen. We probably can't sce the axial proton atthe ring junction “first example but trans-decalins must have axial protons there, so that is not so important,140 Organic Chemistry Solutions Manual In the fist molecule, proton H has two neighbours, oe axial (H*) and one equatorial (1H®) and will appear as a double doublet with characteristic avial/axial and avial/equatorial coupling constants. By contrast, the two equatorial Hs inthe second compound have each got two axial and two equacoril neighbours (not shown) and all the coupling constants will be the same. They will both appear as narzow triplets of triplets. The two axil protons in the third example have each got {wo axial and two equatorial neighbours (one pair shown) and will appear again as approximate ts, Dut this time one cripet will have a large axial/axial coupling constant. sone Purpose of the problem Exploration ofthe effect of conformation on equilibria in thermodynamically controled reactions Suggested solution ‘The mechanism of these reaction is normal acetal formation as described in Chapter 14 and is irrelevant to this question as we are dealing only with stabilities in this thermodynamicall ‘We need to look at the conformations of the molecules. Axial groups in the ketones are not very important as there is no 1,3-diaial interaction with the ketone itself. But 1,3-dixial interactions with the acetal are bad because one ofthe the acetal oxygen atoms has to be axial, Though the ketone 8A is slightly less stable than 8B, the acetal of 8A is much less stable than the acetal of 8B. Purpose of the problem Practice at choosing the correc regiochemistry of a conformationally controlled epoxide opening. Suggested solution ‘The opening of cyclohexene epoxides is controlled by the need to get tras diasial products. This is the reverse ofthe reaction discussed in Problem 6 and is described in fll in the text on pp 468-70,Chapter 48 Suggested solutions for Chapter 18 144. ‘ get the right answer we need merely to draw the only possible trans diaval product from each of We desuces he structure of he ‘es conformationally fixed trans-decalins, Cyanide must, of course, open the epoxide wih omic coniomatons “ecsion so the OH group in the products is on the same side asthe original epoxide, saa HEE tonetsyie we ‘hat ofthe sarting material. eat of he stuctire of wo, ae Le Unis Purpose of the problem “Scploretion of conformations in natural products with many substituents, ‘Sezgested solution nd error gives the conformations with the most equatorial substituents. The first compound —w this OM group acuay prefers to “= Zave all its groups equatorial and the second can have three equatorial and only one axial. be an se tent. 1128. arpose of the problem -Aow the conformation ofa trcylic sytem and that conformation ca control stereochemistry S01 reactions142 Organic Chemistry Solutions Manual Suggested solution ‘The mechanism of hydrolysis ofthis tertiary bromide is obviously Sy 50 the water molecule can approach from either sie ofthe planar cation intermediate. Infact, there is a unigue conformation ofthe (achiral) starting material with all three rings in a chair conformation and this will be muck preferred in the product. The reaction goes with retention. Purpose of the problem More revision of acetal formation with extra selectivity conteoled by conformation, Suggested solution -Acetal formation is thermodynamiclly controlled so we ned loak only forthe mos table posi acetal. The one that is not formed is a cisdeclin~ significantly les stable than the tans (128) that is formed. The equatorial conformation of the phenyl group wil decide it configuratio= 2 all the acetals are in equiibrium,Suggested solutions for Chapter 19 19 Problem 4. Draw mechanisms for hese reactions, wen were listed in he chapter. SSeS, whe T ee Purpose of the problem ‘Simple examples of elimination mechanisms, Suggested solution om meat pen ges a hoee | ESSE . wpm Sry eau Problem 2 ‘The leaving group is on a primary carbon atom in both cases so these must be E2 reactions Purpose of the problem {ering you switch from E2 to F1 witha bit of evidence to help you. Suggested solution Tre teary alcool leaving group, the aid catalyst, and the mixture of alkenes ll suggest El rather an 12. There is only one proton that can be lost and, depending on the conformation ofthe spolecule at that moment, we may ge the cs or trans alkene 804Purpose of the problem 144 Organic Chemistry Solutions Manual | Revision of conformational analysis in the context of elimination reactions. ‘Suggested solution ‘The only difference between the two molecules is stereochemistry and, as these are t-butyl ‘eyclohexanes, the conformation of each molecule is determined by putting the t-butyl group ‘equatorial. In each case itis the group ant-perplanar to the bromine that is lost. son fe Purpose of the problem Finding the mechanism of less obvious elimination reactions. Suggested solution ‘The first mechanism is not to dificult to find ~ just lose a proton from the methyl group in an E2 PD ‘The second mechanism also involves opening an epoxide, but in acid solution the mote stable cation is formed and we can see from the structure of the product that CO; is lost a in Problem 3Chapter 19 Suggested solutions for Chapter 19 445 “Onvy gf the alatereemerc rom Patna ie se ee Cane cm Purpose of the problem 1 0 appreciate that cage molecules often have restricted opportunities for eliminations Suggested solution ‘The first molecule has one ant-periplanar Hand Br so elimination can occur. The second has no “Snlcogens in the right place, Alkene B is a bridgehead alkene and could not exist Purpose of the problem ‘sploiting multiple eliminations, Suggested solution ‘he first compound is an amide and hydeolyses in base to a nitrogen anion that can lose one Rea ebut sn B.S uss Sromide second elimination then expel the remaining bromide and emlecle of nitrogen. Sl 8 xBook zone m oP (eee Hato, 1989, 5.764 ee oP gp Zeno : ou nat ‘The second example incudes a cyclization and an elimination. They could occur in either order Pied about this BS. Fuss ‘ut starting with the cyclization removes any difficulty about the geometry of the alkene. In 213 Yael textbook of gene ‘whichever order you do the reactions, the elimination should be by the El petepe cies pei g og sR sR ‘sR I ib ‘er of ‘or ‘The hydrolysis of the thiolester occurs by simple substitution at the carbonyl group (Chapter 12) Since a thiol i a good leaving group (pX, RSH about 7) no strong acid or base is needed. The two bromine atoms will also accelerate nucleophilic attack both because they are electron-withdrawing and because they prevent enoliation Ree en ae Decatboxylation occurs by the cyclic mechanism explained on p. 678 to give the enol of the product, which is brominated again by the biological brominating agent. : oe ks . Ag we ed w Dee lw Te UE Tasted, v jargon tetrahedral intermediate with C-C bond cleavage (cf. the bromination reaction, p. 537). The anion is protonated by water as it goes. Ag ee a aChapter 24 Suggested solutions for Chapter 21. Problem 8 ‘Suegest mechanisms ‘or these reactions and explanations as to why these products are forme Opa ht err Purpose of the problem Making sure that you understand the reasons why enols sometimes attack through oxygen and sometimes through carbon. Suggested solution “The same ketone reacts in similar (acidic) conditions with different electrophiles and with diferent selectivity. The selectivity must come from the nature of the eletrophile. First, we should draw mechanisms. Note that these reactions must occur through the enol and not the enolate as the Chapter 24 Suggested solutions for Chapter 21 Purpose of the problem Sesion of the material of Chapter 13 to enol chemistry. “Suggested solution “+> seed to draw the mechanism out in fll with no short cuts. I has four steps (A-D). Steps A and © or merely proton transfers between oxygen atoms and cannot be slow. The rat-determining step = be either B oC. Ithe rat isnot proportional tothe concentration of bromine, then the rate- ccermining step must be B= a step before bromine gets involved. Step B is also just a proton De ial coms nteae oer ear ee como ka eee 7 iw 8 ro chies | th : we ° bbromination is carried out in acidic solution to prevent multiple bromination, There is fll “amibsis of this problem in the chapter (p. 536). ce >Suggested solutions for Chapter 22 22 Problem 2 : Be es Al you have t dois to spot the aromatic ings i these compounds lt ay not be as easy as you tink ane you should stes some reasons for your cholcel cochene alien ‘tt _pempound from sulunn roca. ‘atic od ower pigment “coerayme from bacteda aarti eee ih oy Purpose of the problem ‘Simple exercise in counting electrons with a few hidden tricks. Suggested solution ‘Truly aromatic rings are marked with thick lines. Thyroxine has two benzene sings, whieh <= aromatic and that i that. AKavinone has again two aromatic rings, one defintely nonaromatic = {D), and one (B) that we might argue about. However, try as you may you can't gets eecton= {nto ring B (one extreme delocalized version is shown). “Tetracyclne’ because of the four tins 9 goxme hn 8D on on Colchicine has one benzene ring and one aromatic seven-membered ring with six electrons (8:2 count the electrons in the C=O bond) as the delocalized structure makes clear. Callistephin has benzene rng anda two-ring exygen-based cation, which slike a naphthalene, You can count it ase ten-electron system or as fo ised sx-electron systems sharing one C=C bond, whichever you pri Meo!Chapter 22 Suggested solutions for Chapter 22 167 ‘Methoxatin has an aromatic pyridine ring (don’t count the lone pair as itis in an sp* orbital) and 2 aromatic pyrrole ring (do count the lone pair ait sina p orbital) but the middle ring cannot be sven six electrons even if you try delocalization (example given) Wor, W030, woe it cont incon oe goa [ l | nF con or neon“ nog 6 6 ° Problem 2 Just to remind you - write out a detailed mechanism for these steps. worn = fm) Sys In a standard nitration reaction with, say, HNO3 and HS0s, e2ch of these compounds forms ‘single manonitation product. What i its structure? Justify your answer with amecnanism. om OQ 07 Ox Purpose of the problem Pevision ofthe bas tration mechanism and extension to compounds where selectivity is an issue. Suggested solution he basic mechanism involves the formation ofthe active nitrating species, NOS, and adding it Dbenzene. Don't forget to deaw in the hydrogen atom at the point of substitution in the ‘termediate. The frst compound has one electron-withdrawing substituent (CO3H), which is meta-directing and deactivating, The second has two identical ortho, para-directing substituents (alkyl groups), “ich activate all positions. Steric hindrance decides where the nitro group will go. ena cone ‘The remaining two compounds have two competing ortho, para-drecting substituents, but in «ach case the one with lone pair electrons (NHAc or OR) beats the simple alkyl group. In the firstOrganic Chemistry Solutions Manual ‘ase, that alone defines the position of nitration ~ ortho to NHIAc. In the second, steric hindran. 'makes the postion para to OR the more attractive, JO ox Ox Purpose of the problem ‘Making you draw mechanisms fortwo other important reactions and discos selectivity futher. Suggested solution ‘Reaction (i is ke the last one in Problem 2: NHAc dominates Me because it has alone prof electrons Chlorine is small andl goes in twice: it doesn't matter whether you substitute oro or para frst PY gl Sigh lg “The nitration in reaction (i) goes para because of the large electron-donating OFt group. The ‘details of the second stage ~ chloromethylation — are on p.575 ofthe chapter so we give just the ke:Chapter 22 Suggested solutions for Chapter 22 169 Purpose of the problem 4 more quantitative assessment ofthe relative reactivities of the vatious positions in an aromatic = Suggested solution are two ortho and two meta sites but only one para site 0 the ratio would be 22:1 camp if + were equally reactive. It is actully 30:2:37 or 15:1:18 or 43:354 depending on how you =ressed i, The ortho and para positions are roughly equally reactive because the alkyl group is donating The paras slightly more reactive than the ortho because of steric hindrance. The san order of magnitade less reactive hecause the intermediate cation isnot so stabilized by Problem 5 Revision probiem. The local anaesthetic proparacaine Is made by this sequence of reactions. Deduce a structure for each product. Draw @ mechanism for each step and explain why it _zNes that particular product. BOs A BH, tree, a Purpose of the problem ‘son of Chapters 12 and 17 with a bit of aromatic substitution to start with. Saggested solution answer is set out below. The nitration occurs ortho to the OH group, which, being strongly sdectron-donatng, dominates the CO;H group. The ret i tevision, The steps to make 4 and 6 are saceophilie substitution a C=O. LOW =O ae te on — 8 ee Ag che SPH raane170 Organic Chemistry Solutions Manual Problom 6 tine feaction ifthe nitration of tituoromety| benzene. Dra out the detailed mechanism for this reaction and iso for a reaction that does not hapgen ~ the nitration of the same ‘compound in thie cara position. Oraw all the delocalized structures of the intermediates anc Purpose of the problem Making sue that you really do understand why groups lke CF; are meta- directing Suggested solution Just do what the question says! You need to do this once to convince yourself Inthe mechanisen for ‘meta substitution, the positive charge in the intermediate is not delocalized to the carbon ator: carrying the CF; group. Oe a ee, In the mechanism for para substitution, the postive charge in the intermediate is delocalized te the carbon atom carrying the electron-withdrawing CF; group, This intermediate is unstable and is not formed. SO LI LPL ‘Problem 7 raw mechenisms for the following reactions and explain the position(s) of substitution, 3S eae Purpose of the problem Further exercises in explaining the postion of substitution.Chapter 22 Suggested solutions for Chapter 22 am Suggested solution ‘The OH group has a lone par of electrons and dominates both reactions. Steric hindrance favours ‘© para product inthe first reaction. Ortho substitution has to occur in the second because the para The second example has two Friedel-Crafts alkylations with tertiary alkyl halides. The first ‘curs para to Br, a deactivating but ortho,para-directing group (pp. 566-8 of the chapter), ‘ecause of steric hindrance and the second has to occur ortho to the first as the new ring cannot sscetch any further. Problem 8 Nitration of these compounds gives products withthe proton NMR spectra shown, Deduce the structures ofthe products ‘rom the NMR and explain the position of substitution. Se be. a z OO dee oo S300aH a 268) e251am 8130) er Purpose of the problem ossion of the relationship between substitution pattern and proton NMR spectra, Suggested solution Fst product as only eight hydrogen atoms and is symmetrical so two nitro groups must have _m Sty ofcourse, you cant tet ‘ren added. Each benzene ring acts as an orth, para-diresting group on the other so that the = 0y NMR -meeiate cation can be delocalized round both rings. Steric hindrance favours the para product «= Soth rings. DOSS ROSO) EHO. thy DO * ‘t= the one hydrogen (at 83) which is ortho to the nitro group and has no coupling to an ortho gen. The two chlorine atoms axe ortho, part-drecting and steric hindrance favours the 1,24472 Organic Chemistry Solutions Manual pattern rather than the 1,23. The symmetry ofthe NMR shows thatthe fluoro compound gives *= ‘para product. Fluorine is also ortho, par-directing, The 8 Hz coupling is between neighbouring = and the 6 and 7 Hz couplings are to the fluorine ator. ean 1) W725 (2H, 178) OS. OA 16.aH 4, 140) Problem 9 Attempted Friedel-Crafts acylation of benzene with #BUCOCI gives some of the expectes ketone, 28 2 minor product, and also some fbutyl benzene, but the major product is the substituted compound C. Explain how these compounds are formed and suggest the order In which the two substituents are added to form compound C. Purpose of the problem ens euler ee Suggested solution ‘The expected reaction to give A isa simple Friedel-Crafts acylation withthe usual acylium fon (tex: 1. $54) as the reactive intermediate fom Fg Product B must arise from a Friedel-Crafts alkylation with the t-butyl cation as intermediate ‘This comes from the loss of carbon monoxide from the acylium ion, Such a reaction happens on: ‘when the simple carbocation is stable. fe ‘The main product, C, comes from the addition of both these electrophiles, but which adds fr" ‘The Ketone in A is meta-directing but the -butyl group in Bis para-drecting, Product C has a par: ‘lationship and must come from Friedel-Cralts acylation of B withthe acylium cation. Oaha AD aDthe He ae Chapter 22 Suggested solutions for Chapter 22 173 ‘We have now answered the question but you might like to go 2 stage further. Both A and C ste formed with alkylation of benzene as the first step. The decomposition of the acylium ion is “cvidently faster than the acylation of benzene. However, when B reacts further, it is scylated (only ¢ small amount of di--butyl benzene is formed). Evidently, the decomp he acylium ion is slower than the acylation of B! This is not, in fact, unreasonable as the f-Bu B accelerates electrophilic attack ~ it is just a dramatic demonstration of that Problem 10 Draw machanisms for the following reactions. Purpose of the problem sing mechanisms fora variety ofelectrophi Suggested solution, Example () isthe same asthe fist part of Problem 9 and the orientation was explained there. Parts 4 and (b) raise no orientation questions and ortho atack in () is simply because the chain cannot seach any further round the benzene ring. substitutions « Cue o, 7474 Organic Chemistry Solutions Manual Purpose of the problem Revision of NMR and an attempt to convince you that the principles of Chapter 22 can eas be applied to molecules you haven't met before Suggested solution “The two 2H triplets and the broad NH show that the saturated ring is intact so one nitro group 3s: been added to the benzene ring, The proton at 7.81 p.pm. with only one small (meta) coup’ ‘ust be between the nitro group and the ring and is marked in each structure, There are = possible structures. Op 2 “Op - 49 ‘Though both NH and CH: are ortho, pare-dizecting, we should expect NH to win as it has alee pal of electrons. This would favour the fist steuture, but is not evidence, Caleulation of = ‘expected chemical shifts of protons inthe to structures gives a more reliable answer. For exam the two marked hydrogen atoms are predicted to come at: ihe ae Preeti (Rpm Om = 0a N= 0.25 773 N¥=-075, Os =-008 734 “The observed valu of 7.81 ppm. clearly ts H® better than HE The main difference betwee ‘so comes from the NH group and the result favours the compound predicted from the expects! ‘mechanism. This one i correct.Chapter 22 Suggested solutions for Chapter 22 175 Problem 12 i it ronan isi alone pit We NOEL Se ONCE Ven ste A seh eer poe “OIE = ApS Oe Perpose of the problem + exploration of important synthetic reactions: Friedel-Crafts and bromination. Seggested solution deacon (a) is an intramolecular Friedel-Crafts alkylation at an activated position. Eocene SR =O Scection (b) starts with a Friedel-Crafts acylation para to the large orthapara-directng isopropyl bei teo., omination in part (a) will also be directed by the delocalized electrons of the OMe group and hose the less hindered of the two positions ortho to OMe. In the second part the activating = group and the deactivating acyl group both direct bromination to the same position: ortho to and meta to acyl. No Lewis ac is needed in (a) asthe ring is activated and the reaction is ‘>-molecular, whereas in (b) the ring is weakly activated by #-Pr, more strongly deactivated by the “= group, and the reaction is intermolecular. ERR “OR ~ DOR 200, Problem 13 ‘Suggest mechanisms for the methylation step at the end of the synthesis which concludes: ‘echo. Why i necessary to gow these lenin rather han ust react ih Mel? 8 meet (er040176 Organic Chemistry Solutions Manual Purpose of the problem Revision of Chapters 12 and 17. Suggested solution ‘The acylation isa straightforward nucleophilic substitution at the carbonyl group and the CFs ‘s10up is chosen to make the anion at nitrogen more stable. Alkylation can occur only once where direct alkylation with Mel could occur several times. Hydrolysis of the amide is also easier with "= CHCO gow, ar wor Ane fe JP Ren on Cte x t ap: i. ig Ce hci eh em I enon o ‘on Ho 0° Problem 14 — ee So what happens if we force phenol to react again with bromine? Will reaction then occurin the meta positions? tis possible to brominate 2,4.6tnbromophenol if we use bromine in ‘s0etc act. Aecount forthe formation of he product Oey ‘This product can be used for bromination asin the monobromination of this amine. Suggest 2 mechanism and explain the selectivity SNe Purpose of the problem Revision of Chapters 12 and 17, ‘Suggested solution ‘The first step is surprising but simple. Electrophilic attack occurs in the para postion to the activating OH group. The intermediate cannot lose a proton from the tetrahedral centre sit oss the OH proton instead. The phenol would rather lose its aromaticty than react inthe meta postior. eyChapter 22 Suggested solutions for Chapter 22 a7 second reaction uses the compound we have just made to brominate another organic _Serale. One of the bromine atoms in the para position is used ~ a case of las in, fist out. The “and steongly activating NMep group directs the reaction both electronically and sterically. ‘that in the intermediate the two Me groups on nitrogen ae fixed inthe plane of the ring and “ss clash sterically with an ortho substituent. aC aeSuggested solutions for Chapter 23 23 cg, Mona sc0: 90. ot a “eiwos Games toma ome iin "aolauusonaaar owes? ene | aaa irineerc Purpose of the problem Revision of NMR with an exercise in nucleophilic aromatic substitution. Suggested solution “This i the answer. You should, of course, work out the structure from the spectra in the style We ‘used in the solutions for Chapters 11 and 15. ae © i ee et hy wane PEE ates wet Ay ear aa. s7H) ° ° 139/130/128 J 191 420,244 76H " eet H sara ne aoe mat A, W782 i237 B08.2He 46h Purpose of the problem ‘Simple example of conjugate addition with a ncleophile from the second row ofthe periodic table ‘Suggested solution ‘The phosphine is a good soft nucleophile with a high-energy lone pai, well able to add in | ‘conjugate fashion without help. In particular, the neutral phosphine is a good nucleophile andChapter 23 Suggested solutions for Chapter 23 179 's not need to be converted into the anion fist. The proton transfer accurs after the conjugate «ition and need not be intramolecular. Purpose of the problem Do you understand the essentials of conjugate addition and can you say when it wor’ happen? Suggested solution “The chloride must add in a conjugate fashion and the ethyl Grignard in a direct fshion that semoves the carbonyl group. Conjugate addition can happen only ifthe carbonyl group is intact 0 “must happen first and the lower suggestion will work. lies BESS ee ee amas Cee In the other sequence, EtMgBr is likely to add to the carbonyl direct and the further addition of ICI may either substitute on the allylic aleahol or add the ‘wrong way round? to the alkene. SOS Problem 4 Purpose of the problem A reminder of the reactions possible with enones.Organic Chemistry Solutions Manual Suggested solution ‘The three reactions are: enolization and trapping with silicon (Chapter 21); direct addition with « hard irreversible nucleophile; and conjugate addition by a softer reversible nucleophile. Purpose of the problem Revision of conjugate addition (Chapter 10 and this chapter, nucleophilic substitution at the carbonyl group (Chapter 14), and decarborylation of malonates (Chapter 21. Suggested solution The first sep is conjugate adltion promoted by two elctron-acceptng groups at one end of the alkene. We show the involvement of only one of them in the mechanism ; =e a Dok, rp Eh a Rae Cie: Oe: sarah aca aay mo eae vet de vere are in Chapter 14 — make sure you can draw them. Finally, the triaid loses a molecule of CO, by the cyclic mechanism introduced in Chapter 21. 3H 0m on co = — i = conn a ryChapter 23 Suggested solutions for Chapter 23 Purpose of the problem ‘Fombination of conjugate adltion and electrophilic aromatic substitution (Chapter 22). Suggested solution ‘=e weakly nucleophilic benzene ring has evidently added in conjugate fashion to the enone in a ‘ead of Friedel-Crafts reaction and we can use the Lewis acid to make the electrophile into the secessary cation. CAE GLH i iy spin ee Suegest 2 mechanism for his reacton explaining he sl per ae eee ‘Purpose of the problem Jtooduction tothe mechaniam and selectivity of nucleophilic aromatic substitution. Suggested solution ‘The amine atacks in the para position so that the intermediate anion is stabilized by conjugation ‘vith the ketone and by the five electronegative fliorine atoms.Organic Chemistry Solutions Manual Purpose of the problem Revision of electrophilic substitution and a probes nucleophilic aromatic substitution, Suggested solution ‘The first reaction is standard nitration of benzene with an ortho, paradirecting group (Chapter 2), ‘The frst nitration can go ether 2- oF 4 tothe chlorine and the second goes mea tothe fist. - Ba $ eI as si, Nos "Wo Nos ‘The reaction with hydrazine is a nucleophilic substitution activated by two nitro groups. Purpose of the problem retin of the ext on muckopbié erate oben into new compounds Suggested solution The mln er i find wire ope nese carga thle Te oy ae fe vec rai Pepe pel Wc GaP areca Ue sone Back 2 or #clorprtitng, but ot wien we do the same thing with -cloropyriine Ty for yours Qo-Qe -O, FLO ‘The amine formation given in the question is just one important example ofthis reaction. 0-08. -C Oy 4 l <1 «EON chlorine iChapter 23 Suggested solutions for Chapter 23 Problem 10 ‘230 detailed mechanisms for the last two steps in the ranitidine synthesis that involve ‘== gate substitution. Why is it possible to replace one MeS group ata time? bs ea es enon oe i Nos Serpose of the problem | Lance to explore the details of a rare but important conjugate substitution, Sezzested solution egate addition of the mucleophile is possible because of the nitro group. After the first --~cution the compound gains extra stabilization from conjugation ofthe amino and the nitro ‘oer (in frame in margin). This conjugation is interrupted during the second substitution so itis + but follows the same mechanism. in) + “Et Ga Ue o> Problem 14. How would you convert this aromatic compound into the two derivatives shown? EE Purpose of the problem ‘pplication of nucleophilic aromatic substitution tothe synthesis of aromatic compounds Suggested solution “2 want to introduce both CN and NH; as nucleophiles but the ring is unactivated so we must use ‘>-sial methods. The most obvious are a benzyne route forthe amine and a diazonium route for the vile. Inthe second example the amide anion attacks the benzyne so that the negative charge ends © ortho to the OMe group (p. 603) eee er paarOrganic Chemistry Solutions Manual Purpose of the problem eample of aly Fubadinion ester > amide) but the ketone and amide groups are on adjacent cee atoms (a-keto-aride) o both are more reactive than normal The ketone isthe most reactive: ests amides are not usually reduced by NaBH. The second example has a ketone and an aldehy Aldehyde is more reactive. If we used NaBH, asthe reagent it would probably reduce both, so reactive modified borohydride NaB(OAOsH, sodium tacetoxyorohyéride, i used instead. Purpose of the problem Further examples of chemoselectvity between diffrent functional groups with danger == overreaction, Suggested solution ‘We need to reduce the first ester, convert the OH group to an SH, couple it with a two-car lectrophilic fragment suchas an epoxide, and convert OH to NH). The plan is something on these lisss i oe oe “aga coe 15 Tiss part ofthe sythossc the antulercug cet. The reduction is simple (LiAIH, will reduce the ester and won't affect the aromatic ring) bux the conversion of OH to SH requires care to stop the sulfide forming. We suggest one possibib= ‘Similarly, the conversion of OH to NH, requies a nitrogen nucleophile that will react once ox (Chapter 17, p. 437) and again we offer one suggestion. Cte ee " Lem yee eee) eee Uaead te = Chapter 24 Suggested solutions for Chapter 24 193 “The second example requires reduction of the ketone ~ no problem ~ and the chemoselective eavage of one of two ethers ~ chemoseectvity problem! ust NOT be esucteyceved ere: Fortunately, the ether that must he cleaved is a benzyl ether and the C-O bond can be reduced by ‘cralytic hydrogenation using hydrogen and palladium (p. 621 of text). The ketone can be reduced, sth NaBH.Suggested solutions for Chapter 25 25 18 Sever! problems inthis enaoter ask you to suggest ways to cary ost ‘onersions of one reece to ‘nother. We ghe one possible ‘none and somenes comment on ‘teratves but you sould realize ‘hat tere are any possible rt ‘nwo to tis sor of question. Make sure you have understood the priniles behind each question ‘nd, f your answers ferent fom tur, check f th someone wna vows hes Problem 1. Sugest wo cferent syntheses forthe thos ang say which you prefer (and why). Purpose of the problem [An exercise in choosing good routes to simple compounds, Suggested solution ‘You willbe making C-O bonds in making these ethers and the choice hinges on which C-O bone You think can be made more eal or without selectivity problems, Inthe ist cae ether route wil ‘or theatomati substitution i all right because of the para-niteo group and an epoxide canbe uiez as the electrophile in the alternative, ice A Soe LY aes on on allylic halide, There is no problem with the allylic alcohol, but we need to be sure thatthe allyic halide will react at the right end. Compound A has two sites for atack marked with a black blob ‘Attack at ether leads to the same product (work it out for yourselves!) In compound B they a different but attack at the primary centre will be much preferred. Either route is fin. In ba! cases we now know that we can choose cither route because we have analysed ther: mechanistically. ts acee ge Bt behon oho Problem 2 es tnese esters, The stots rigs ade nll aChapter 25 Suggested solutions for Chapter 25 495 Purpose of the problem “2s steps in making C-C bonds as a preliminary to joining molecules together. ‘Seggested solution ‘sce are made from acid derivatives and alcohols so we need first f0 look at those starting als. a ic ce is de, Acid A can be made by alkyne chemistry, adding the alkyl group frst and CO second. Alcohol A » ssilble. Acid B is available phthalic acid and alcoho! B can be made by Phi or PhMgBr addition “© es available ketone. Acid A can be joined to alcohol A via the ac chloride but acid Bis best used ‘=e cyclic anhydride to get the monoester. 7 ae a ss EM EM co rca eapaaeeh a es sineia see i P ° Ph nat yn nen NY pi mw OV en ake cout Problem 3 i He Suggest a sythesis for his local aneesthetc, s —™ f arpose of the problem Azother exercise ip making C-O and C-N bonds but with selectivity required. ‘Suggested solution ester willbe made from an alcohol (made in turn from an epoxide and an amine) and an acid. “= che para positon, the amine can be made from ether an amide or an imine by reduction. There ‘3 slight problem in doing the reactions inthe right order as we must avoid a reduction step that ‘d reduce too many groups. Coupling the alcohol and the acid in acidic solution will avoid “anted reactions atthe amino group as the nitrogen atom will be protonsted,Organic Chemistry Solutions Manual Purpose of the problem {A simple synthesis with many solutions Suggested solution ‘This another ether and there are two obvious ways to make i, each involving the formation of one of the C-O bonds. or a a os =o" rm In both cases we must consider the danger of enolate formation from the ketone. In the first case the alcohol might displace the bromide or attack the ketone and in the second the allylic bromide ‘might be attacked atthe alkene though this makes no difference as the allylic system i symmetrical ‘The fist approach is easier as the bromoketone is easly made from acetone (Chapter 21) and the allylic halide in the second approach would probably be made from the alcohol used in the firs: synthesis nce Purpose of the problem ‘More advanced synthesis planning with mote steps in the synthesis, Suggested solution, ‘The amide must be made from the amine and an acid derivative and any ofthe methods describe in the chapter could be used though we must be suze that the amine wil attack the carbonyl group and not do conjugate addition. The acid can be made by 2 Witig reaction (Chapter 14) from the available aldchyde ‘piperonaY’ Ifthe amine does conjugate addition tothe ester, change to the aciz chloride by hyérolysis to the acid and treatment with SOC first. Cres StesChapter 25 Suggested solutions for Chapter 25 197 “Seeese of the problem "==> into counting the relationship between functional groups “megsited solution “Tie seizy alcohol comes from addition of PhLi or PhMgX to a ketone, and the relationship ‘seers the ketone carbonyl and the amine is just right for conjugate addition (Chapter 10). geo sd <-ezond compound arises in much the same way except that cyclopentanol can be added to “<= -‘nile in conjugate fashion and the primary amine derived by reduction ofthe nitrile. Chiwe Oa SC ‘7s hexealoohol can be deprotected, one OH at a time, by the sequence of reagents shown ‘ze'ow. Explain how each reagent works, stating, of course, which protecting group it “=70ves! Would any other order of events be successful? Me me es eye” “* See 2. HORC, HO Cra ek Tal see LL Ge Purpose of the problem Ses cei enn eee area Saggested solution ‘sp I: Fluoride attacks silicon and releases the OH group on C4, Step 2: Mild acidic conditions “rdrolyse the only acetal, a THP derivative at C5. Step 3: Zinc is a two-electron donor that atacks198 Organic Chemistry Solutions Manual 1 Deine ofa teste reactions halogens and releases the OH on C2 by an elimination reaction. Step 4: These are the ei (ieee oureed conditions and are ideal for ester hydrolysis, releasing the OH on Cl. Step 5: The only pro“ ‘verhteswon, Jn Chen. SfOUp susceptible ohydrogenlysis isthe benzyl ether a C3. Step 6: The most robust group a> Sec, 1972, 94, 6191. ‘most difficult to cleave is the methyl ether at C6. Several other orders of events are possibie = step 6 is very vigorous and would cleave the acetal at C5 for example. Problem 8 Suggest 5 synthesis of the starting material and give mechanisms for the reactions. Wh: ‘Goes the last step go under such unusual concltions? Oe Fae ae Purpose of the problem Learning to make C-C bonds and revision of Chapters 12 and 22, Suggested solution “The CH,CH;OH group inthe starting material suggests the addition of PAL or PhMgBr to et oxide, The next reaction i ike acetal formation with te intermediate oxonium ion eapeure® = chloride. Br a. mg. Eto aN an? ee reeset cs a Grae “ ‘The lst step is an electrophilic aromatic substitution with base! Presumably, the easily for ‘ation (the same one that was involved in the previous reaction) cylizes rapidly and reversible it is the deprotonation of the intermediate that makes the reaction go. Ove —Ocr— Ga — Og wo FR ' Problem 9, Esters are normally made from elcohols and activated acids. This one Is made ‘completely cifferent method. Wry? goChapter 25 Suggested solutions for Chapter 25 of the problem * put mechanistic thinking into the solution to problems in synthesis. ‘ed solution “se & clearly made by an $y2 reaction (Chapter 17) rather than nucleophilic attack by an an acid derivative. The base creates the carboxylate anion and the $y2 reaction next to a2 carbonyl is such a good reaction that even this weak nucleophiles enough. The bromide © ruake from the ketone by bromination ofthe enol and the alcohol would be made in turn ‘+ bromide, So why bother with the usual method? a es a ee lem 40 i i i a synthesis of this non-protein peptide, emphasizing the choice of protecting of the problem sare you understand the approach to peptide synthesis explained in the chapter. «sted solution ‘See amino acids (serine, glycine, and Ipsine) need to be coupled together, and the other “= groups (ringed) need tobe protected. In principle, you can start tether end and there ‘S22: good answers to this problem but we shall give the method used in the chapter NA ee aed vocste "ag "sng a Che protecting group forthe terminal amino group and any protecting group you = om the list on p. 657, we conver serine into an aryl ester (Ar = p-nitrophenyl o 2, henyl) and react the aryl ester with glycine protected as its t-huty ester. Simple removes the t-butyl group and the process is repeated, this time with Isine having -the.Organic Chemistry Solutions Manual Purpose of the problem Straightforward exam-stye synthesis question, Suggested solution ‘One possible synthesis of each compound follows: there are many moze correct answers. _~_ eee ges elena| ‘ ‘ ; Ss =~ . : 1 Sever grobions nis chapter ; lem 1 Sek yout Suggest way to cary out Esz:st te following compounds might le medeby the allfation of anenotorenolate, Srnec os rae : ‘We ge one posible anawer and So Ss eee i ‘bayou should eats at he oe ran posse et rons queso. Make ue Ou ose of the problem ove uncerstood the pipes {=2>se in choosing good routes to simple compounds st set oes scested solution a - ssc the enolate inside these molecules s its obvious which elecrophiles to use. In both cases, = ssmmetial ally halides, These ae good lecrophiles for an Sx2 reaction. We need to use the Se twice in the frst case and to use an enol or enolate equivalent that wll not se-condense in second. You might have chosen a seas compound, a ae ‘enol ether, oF an enamine, seemed 2 nly functional group in both molecules is an acetal. Cylic acetals are made from diols and {2 compounds so we need to hve aloo atthe ‘protected molecules before taking any Z- decision a.Organic Chemistry Solutions Manual In both cases the carbonyl compound is acetone, but we have to make the diol. Each diol sas» 1.3-telationship between the two OH groups so we could make the diols by reduction of |» dicarbonyl compounds and use stable enolates in any alkylation steps, We can abbreviate = benzene rings for clarity. Se sae [Now the alkylation steps are clear: we need to add two benzyl groups to diethyl malonate is. fist case and an ethyl group to the available five-ring ketovester in the second, In both cases >= ‘ethoxide as base avoids substitution problems. Purpose of the problem [An exercise in using enolate chemistry to make carbonyl compounds disguised as amines. Suggested solution The first amine could be made by reduction of a nitrile and that could be made by alkylatio: = benzyl eyanide (PhCH:CN). Ce ae z. cro Marae ems ‘The second amine can be made by reductive amination of a ketone so we need to think how ketone might be made by enolate alkylation. {ti ideal for alkylation of an enol or enolate wit: = benzyl electrophile. You could have chosen a numberof specific enol equivalents for this, we use Awe dS ay EFarr Ue = 4 sey a =Chapter 26 Suggested solutions for Chapter 26 205 Sorted eae ation ses ot ge he egured rod, Whe ons won? croducts would be expected from the action? = - of the problem “rter that enolate-like intermediates can be formed at nitrogen as well as at carbon. the NH proton to make an enolateslke intermediate that reacts ‘seven. Now that the NH is blocked, the second molecule of base makes the amide enolate, © alkylated at carbon.210 Organic Chemistry Solutions Manual Purpose of the problem [A simple exercise to revise the material of this chapter in the context of synthesis. Suggested solution ‘The tutyl group can be added only throug the silyl enol ether while the benzyl group a= ‘xided in almost any way. The second molecule must be made bya cyclization. The third mol requires the crzation of a quaternary centre which limits the option. Here is one posible sl Mo sis 4. MesSic), Et CHO 2 Nay 40 Lepage tty se |Suggested solutions for Chapter 27 27 Problem 1. wy __sunnests presented inthe chapter. on i 2 ‘CHAO: ae Bee Came Pe oH Nome so hee tee Purpose of the problem Session of elimination reactions (Chapter 19) and the mechanism for an ‘aldol reaction that can't eve. Scggested solution ‘nitro group is worth two carbonyl groups so it will be the nitromethane that forms an ‘enolate™ >. The aldehyde is more electrophilic than the nitro compound. Elimination is by the EleB seevhaniam after a second ‘enoization Snsotutted Eero combo “ahy you think this product is formed. Purpose of the problem eswing mechanisms for the simplest aldol —celf-condensations of aldehydes and ketones. 1 Several prebioms inthis chapter ‘28k yu to suggest ways to make molecules scot reactions, We {ve oe possible answer and Dulyou should ele tat Hee ae ‘many posse ght answers to this ‘sof auesion. Make sie you ‘ve unaersteca te principes ‘etn each question and, your ‘answer i erent rom es, check fet eomeone who knows,Organic Chemistry Solutions Manual Suggested solution Only one compound can form an enolate and only one compound (the same) can be Se clectrophile, The ketone can lose a proton from either side but it can produce an en-ae ‘only if the enolate is formed into the methyl group. The climination is again by the Eick mechanism. ae Purpose of the problem Extending the lst problem so that you Took at the aldol reaction asa way to make unsaturse «carbonyl compounds Suggested solution Just find the conjugated alkene and ‘se’ the enolate there. Inthe first case, cyclohexanone proviss= tho enolate to react with two molecules of unenolizable benzaldehyde stipe sere 1 ' 5 2 3 dbase In the second case, two aldol-style reactions must be used, one alter the other. The emit ‘required for the first aldo is an aldehyde but, for the second, an acid derivative must be used 25 ‘the best is probably malonic acid so that no hydrolysis is needed and decarboxylation occurs unit the conditions of the reaction. 7. ee compensa satteandesation)Chapter 27 Suggested solutions for Chapter 27 lem 4 ‘sould you use a Syl anol ether to make this aldol product? Why is it necessary to use + sartoular Intermediate? What would the products be if the two carbonyl compounds ‘simply mixed and treated with base? Sa of the problem the last problem so that you are forced to use silyl enol ethers and appreciate their ted solution “= shout the most difficult type of aldol reaction to do: two slightly different aldehydes, both =e. both electrophilic, both capable of self-condensation. The only solution isto couple the == ther of one with the other aldehyde under the influence of a Lewis acid. This gives the " svoduct which can be dehydrated to the enal me ee “© this conteol, each aldehyde would self-condense and each would react with the other. wold be the products. gy gh day evescandensatn A+ 8 cevencansenstian 8+ nl Be a ay dos hs reaction estmibe an aol acon? How could the seme product be “aithout using phosphorus chemisty? Comment on the choice of base, of the problem "sat there are reactions closely related tothe aldl that produce si ted solution: ‘oveephonate ester acts rather like the extra CO;Et group in malonate to stabilize the enolate. “5205 of the enolate to EtCHO is very like the first step ofan aldol reaction and the second lar products,Organic Chemistry Solutions Manual step isthe loss of phosphate instead of water. The very weak base (pK, about 10) shows how == is to make the enolate ‘The same product could be made by an aldol condensation between the enolate of a ketone the same aldehyde (EtCHO) but some other method would have to be used to ensure enolir i= the ketone om the right side and to prevent selcondensation of the aldehyde. A silyl eat =e produced via the kinetic enolate would do the trick. Purpose of the problem [A demonstration of one reason why aldol reactions with formaldehyde (methanal) can Suggested solution ‘The aldol reaction appears to have taken place but there has been reduction of the Ketone s= product. The only possible reducing agent is more formaldehyde and reduction is by the Ce reaction (p. 1081), The aldol can be successful if a weaker base (NazCOs will do) is used = Cannizaro reaction requires dianion. ce es ae omc Se | Problem 7 What are te sructres ofthe intermedictes and the mechanisms f the reactions this simple cjtohexenone? zChapter 27 Suggested solutions for Chapter 27 of the problem esonstration ofthe problems with formaldehyde but this time they are put to good use. solution ~ s40 molecules ofthe keto-ester have combined with one molecule of formaldehyde to ©: product (margin). Initially a Mannich product mus be formed, which loses MeNH © <3 elimination, and conjugate addition of the second keto-ester follows. Finally, an “lar aol gives the six-membered zing 2 aes a A, 20s —— . come ro sn Weg t 0 ° =. 10,0. 0,0. 10,0. Shar ° >) \4« Gone es come cose onl of the two ester groups by standard ester hydlys, decarboxylation ofthe B- Sethe usual mechanism, and decarboxylation of the 7-keto-acid by an extended version se thing. cation of alkenes is normally caried out with electophic prony-acids such as m-CPBA, “ene is elf ectopic and a beter reagent isthe nacleophilic anion from hydrogen sual Conjugte ation is followed by cleavage of the weak O-O bund wo give the epoxide Loo : i Ota Che Oe itrestr © ee | sictvce | Cogee tester,Organic Chemistry Solutions Manual ‘The conjugate addition of 'R’ is best accomplished with an organacopper reagent 10 conjugate rather than direct addition. You might choose RMgBr with catalytic Cull) or Rest. the reagent, These methods are described in Chapter 23. Purpose of the problem [An exploration of selectivity in the context of intramolecular aldol chemistry Suggested solution ‘The first example is the completion of the Robinson annelation (p. 761). There are four > sites of enolization (1-4) though two are the same (3 and 4). Enolization at C2 can lead or! unstable four-memiered ring and is reversible. } Enolization at C3 or C4 leads to a six-membered ring, but it is bridged and cannot dehyde give a stable enone. This too is reversible. 2 ne 6 Finally, enolzation at C1 and cyclization to either of the ketones in the ring gives a ss ‘membered ring that can dehydrate to give an even mare stable conjugated enone and ths = ‘The second case must start with an intermolecular aldol reaction, Only one ketone can and the 1.2-diketone is more electrophilic because each carbonyl group makes the othe= electrophilic. The fist reaction is unambiguous. tokChapter 27 Suggested solutions for Chapter 27 217 fe steps are needed ~ another aldal reaction and two dehydrations. The second aldol be faster than the frst as itis intramolecular and makes a stable five-membered ring. nations are by the EleB mechanism (Chapter 19) also via an enolate. + of the problem =sian of Mannich chemistry into the synthesis ofa new ring system. Its important that you © the relationship between reactions when they have similar mechanisms even if they look ferent. sted solution “-hyde and the amine combine in the usual way o form an imine. As the amine is secondary, ‘o-! actually be an iminium sal “ sleotrophilic iminium salt is perfectly positioned for an intramolecular aromatic substitution Ope £20 g-O- "= Se le of a Friedet-Crafis reaction (Chapter 22) except that the electrophile is & Mannich-style “=> salt rather than an acylium ion, The position of substitution has to be ortho asthe side “> an reach no farther.Organic Chemistry Solutions Manual Suggested solution ‘The structure of the product shows that no new atoms are added to the starting materi CO, and H,0 are lost. An intramolecular aldo! reaction between the enol of the acid (or » the enol of an anhydride formed between the acid and acetic anhydride, see box) and the: aldehyde must start things rolling. C1e oes hace Cketad~ (ay ‘The loss of CO; and HO may be concerted or else dehydration may be followed by loss a8 In either case one driving force forthe reaction isthe formation of an al-conjugated aromatic Ohm Oo —CO Problem 12° “Treatment ofthis keto aldehyde with KOH gives a compound CrHi00 with the st - deta shown. What eis structure and how is formed? You shoul, of ou'se, assign. NMR spectzum and give @ mechanism for the reaction, i e Ghee WOH parities i M9 wr30h a s55me Purpose of the problem Revision of compound identification, especially NMR, in the context ofthe aldol reaction, Suggested solution “The IR suggests a simple ketone, or possibly an aldehyde, but there is no aldehyde proton at 9-10 ppm, soit must be a ketone, The NMR shows an alkene with large chemical shifts (73: '8.8) suggesting that it is conjugated with the Ketone. The coupling constant (5.5 Hz) is very {far too small for a trans alkene and small even for a cis alkene so it must be in a ring. The ‘group is still there and the 2H singlet at 2.1 must be the CH next to the ketone, We can draw: ‘one structure ° ° Pe~a es 2a ame “re sisi SY Was For once, you could have worked out the structure from the mechanism, though this is generally a good idea. Only the ketone can enolize and it must react with the aldehyde = intramolecular aldol reaction followed by dehydration. a: AChapter 27 Suggested solutions for Chapter 27 m 43 i sai ee ‘i ence rod woe be foe mmole acs ° TwoH ay of the problem in considering all the enols from two carbonyl groups and making a reasoned choice the possibilities, Be. ted solution “ous enols are given below. The first three are straightforward, but the last may have “you: the proton removed to make this extended encl came from positon C4 in the enone ED FO SO o> enol can eycize atleast in theory, but we must not be left with a fans alkene in a six- ~sred ring. The most promising cyclization is perhaps from the last enol. eo lem 14 rata toe © sept ean pn ate pi auc Wi et of on stoning the solution depostscystas of a timer. Suggest mechanisms fc the fomation of the cer andthe timer. 2 they moe stable tan the menorer? _—orcing yourself that the aldol reaction can be applied quite simply to. complicated looking aeecules,220 Organic Chemisty Solutions Manual | i | Suggested solution “Biacety!’ (butan-2,3-dione) is unstable because the two carbonyl groups are both electra | ‘withdrawing and destabilize each other. One way in which they ca escape from this situations form an enol from one ofthe carbonyl groups ee gf stable DR Sle Finge ae = — ae 1 Bisel cme and inerwere so This enol can, of course, react with another molecule of bacetl in a simple aldol reaction. Tae | lari ueeter ene) immediate product once again has the unstable 1,2-diketone structure but it can escape = mate eee diferent way: it can form a hemiacctal and ths is ‘biacetl dimer’. You might have dscoverss structure of the intermediate ina different way i you had noticed that baceryl dimer isa her and unravelled it to discover the keto-alcoho Ty Ate tot ‘The trimer is also a heracetal and, if we take that functional group apart, we discover a ‘hemiacetal as intermediate. Taking that apart we find we have spit off a molecule of ace ax! ‘compound we are left with is the dimer with some stereochemisty drawn Evidently the dimer can react with another molecule of biaceyl and the product can eyliz= to form a new hemiacetal containing none of the unstable 1,2-diketone functional groups. VF: start the mechanism with the dimer as we have already made tht. phen 2 KM * of ‘We have not previously considered stereochemistry. Hemiacetl (and acetal) formation is thermodynamic control a all the reactions ate reversible, The dimer and trimer crystallize f= liquid so the stereochemistry may be governed by the formation of the most stable ps compound or by the fact that the crystallization of the least soluble diastereoisomer removes ® the equilibrium and so more is formed, We can see some reasons why the dastereoisomer ‘might be the most stable. The cis ing junction between the two five-membered rings is mu stable than the trans, the two acetyl groups may prefer to be trans to each other, and there ma: bond in the crystal, We cannot be sure ofthese reasons but they are explored more in Chap= psetie oops re nena ce tacina seested solutions for Chapter 28 28 1 Several prclems this chapter of simple enolate reaction (Chapter 21) and ao reactions (Chapter 27), Cla thinking 22208 Sete wn oie ‘es: happens when you put carbonyl compounds in basic solution is essential onda ld escto. age Scrovies conan on ents esse we want the aldehyde to form an enolate and we want the enolate toatack the ester. The bulyou sha eta te re See wl righ; the aldehyde wil orm an enolate more ready than the eter But under these") Poele rig anne fois conitons, ony asmall amount of enolate wil be formed and it wil reac faster withthe St avon. ake oy nave ban withthe les electrophilic eter. The aldehyde wil self-condene in an aldol reacion, Ss" wa oe otis ‘Sere tom ours, cc tn wba tat = Pe mke the product required we shall need to convert the aldehyde into a specific enol Heat. There are various alternatives, of which the best are either an enamine of a siyf enol zsters do not acyate either of these and an acyl chloride should be used. Don't forget the 1 if you use a silyl enol ether. ace, ee Ss = ‘ wo ee ‘Btn ~*~ say eat eer ono “enolate formation in the second example is a separate step and will work well because the onyl groups combine to form a stable enolate and NaOMe is quite strong enough to “the diketone entirely into the enolate. The problem is the acylation step. With a sodium ¢ and a reactive acylating agent, 2 charge-controlled (hard/hard interaction) reaction will 2t the oxygen atom to give an enol ether.222 Organic Chemistry Solutions Manual ‘The escape route from this difficulty suggested in the chapter was to use a magnesium « “Magnesium is chelated by the twa axygen atoms ofthe stable enolate and blocks reaction at ‘C-Acylation occurs even with acyl chlorides. “The starting materia is not symmetical and two possible yclzed peaduets can be for | Dray structures for these te products ana lain wy tis unmportant wns to Purpose of the problem ‘To make sure you understand how extra ester groups can solve apparentiy complex ac problems Suggested solution ‘The cjlization can occur in two ways to give two diferent products as either ester can form ar that attacks the other ester in an intramolecular acylation. We should draw the two product e103. Core roc 9 plete ened eee Though these compounds are diferent, cach gives the same ketone afer hydies decarboxylation ofthe ester group as the ketone carbonyl iso the ime position inthe ring = compounds.Chapter 28 Suggested solutions for Chapter 28. sei aicteie cuted athe japter but no mecha deals were ven, Suages echo) sms for the fst s. The ast sts a very unusual tp of reaction and you have not mat anything quite like it belo. However, organic Should be abe to draw mechani or new eatons and you might ihe to ty your ha a soe, Thr revision of mechanisms and a check that you realize what isthe exact product of the Claisen sation under the reaction conditions. solution step isan intramolecular condensation between two identical esters (Sometimes called the =n condensation). Under the reaction conditions the product isthe stable enolate of the . The base used is methoxide and this is strong enough (pK, about 16) to form the fof a fketo-ester (pK about 12). This enolate is alkylated in this sequence before the usual ination is a straightforward chlorination ofan enol (note enol not enolate as the catalyst ) 2s described in Chapter 21. The only unusual thing is that enough chlorine is used to get enolizing positions are blocked. = dee ante ee that the las step would be weird but at least the hydrolysis and decarboxylation are ‘vcard. We hope you remembered to use the cyclic mechanism forthe decarboxylation step. = &-& $e prodict will mainly exis in the more stable keto-form but the unusual hydrolysis of the fe to the ketone might be easier in the enol form. Loss of a chloride in an Si] reaction = 17) gives a stable allylic cation. The second chloride is lost more easly because the OH 1,224 15 The tue product ofthe actin |s the anon of the pheno: this helps the veaction since KOM vs mare asl than AH (Chapter 8), Organic Chemistry Solutions Manual z0up pushes it out. The final product is stable as the mono-enol with the most subst: bond (thermodynamic contra). ei) ot cy 1, Voit ° Lye Q on on xe Om Problem 4 i : Acylation of the phenolic ketone gives a compound A, which is converted into 2° = ‘compound B in base. Cyclization of B in acid gives the product shown. Suggest ‘for the reactions and structures for A and B, obsususoll Purpose of the problem Predicting, products of acylation reactions. This is always more difficult than jus: = ‘mechanisms but here you can work backwards from the final product as well as forwards. Suggested solution ‘The stating material is CyH,O; so A has an extra C;H,O. This looks like the additio and the loss of HCL The most obvious reaction is acylation at the phenolic oxyges enolate formation as OH is more acidic than CH. This isa very acidic phenol as the cs->o== helps to stabilize the oxyanion. Compound A is simply the benzoate ester of the phen. © swith KOH isomerizes A to B and this isthe heart ofthe problem. An intramolecular acsiz==— only possible enolate can be catalysed by KOH even though it produces only alittle = cyclization toa sixmembered ring i So easy. wate soba ret it an dey i atk sa Th nme din pts seemed ee fa one ee ey fe ica a tal pen io eas oe a al {Slaten mlChapter 28 Suggested solutions for Chapter 28. of the problem “using acylation at carbon to make compounds. ed solution _soblem has two possible solutions by direct acylation, labelled A and B in the di ‘soe to be controlled asthe straight-chain ester could selfcondense, but B needs no control ‘ketone can enolize, diethyl carbonate, CO(OFt}, is more electrophilic than a ketone, ‘ne wanted product can enolize again and form a stable enolate under the reaction However, route B adds only one carbon atom in the key step. A can be realized with either a lithium enolate or a i enol ether, a explained in the ‘sing an acyl chloride asthe electropile ee arc «requires the synthesis of the ketone starting material and this could be done by Grignard ¢ Chapter 9) or by acylation of a copper compound with an acy chloride. The final step, cof the enolate with diethyl carbonate, requires no special conteol. gc uta eco a ENB TE eka, of DSO, MeSOCH, as actualy ued) a for ating material has oth he ester groups on te outside of tne molecule Sonat eyzaton ible. What preiminat step must fst ocou or fo become possible? spose of the problem ‘vious thinking about the details of acylation reactions.Organic Chemistry Solutions Manual Problem 7 Suggest mechs other. ie ear com, Gf om — 5 0" this sequence leacing to bieyclic Compound wth four and sever-miembered rings cis fused to eo* Suggested solution ‘The strong base is necesary inthe cylization because no stuble enolate canbe formed fon: Se product. In other aclations of eters by eters the product has atleast one hydrogen atom o* Se carbon atom between the two carbonyl groups and forms a stable enolate under the re conditions. There are several examples in the chapter and the answer to Problem 3 makes a spe point of this The strong hase is needed to convert one of the esters completly int its enol The stereochemical point is that one of the esters becomes an enolate and 50 los = stereochemistry but the other most be pointing inwards for eyeization to occur. This an happs> te reversible formation of the enolate anion. oma Fa ye = 4 4 Purpose of the problem Practice at acylation reactions with groups other than carbonyl Suggested solution ‘The acylation of RLi or RMgBr by nities (cyanides) isan effective way to make ketones (Ch. and here we see the cyanide version of an intramolecular Claisen ester condensation, One ‘makes an ‘enolate’, which attacks the other. The resulting imine tautomerizes o the contas= cenamino nite Lon ‘The enamine is hydrolysed to the ketone and then the nitrile is hydrolysed under strong 22 conditions to the f-keto-acid, which decarboxyiates to give the final product. oe Oe ‘en aca agChapter 28 Suggested solutions fur Coapls’ BH Purpose of the problem Syhstion and related reactions in the synthesis of a natural product, Seggested solution First reaction is the acylation of a magnesium enolate of the kind we have seen before. The _szz:esium enolate is used to block the oxygen atoms of the delocalized enolate by chelation and to "genre C-acyation. The unusual acy! bromide is used as itis easy to prepare by direct bromination “=e acid. The product has an exceptionally stable enol with conjugation covering three carbonyl = (two ketones and the ester) Soe aw ane ‘©cclization oceuss by intramolecular Sy2 teaction, probably using the enolate as nucleophile 3s an amine can make this very stable enolate. Normally, tertiary halides do not react by the Sy2 “scion but this i intramolecular and next to a carbonyl group, which helps the $y2 reaction but ars the $1 reaction (Chapter 17) “DV | ' | Tz hydrolysis of the ester happens by the usual mechanism (Chapter 12), but the ‘oxylation is tricky. We need the Ketone carbonyl group for our cyclic mechanism ‘= can’t use it while the double bond is there. The solution is to protonate the enol ether hk reaction (Chapters 35 ena 3).228 Organic Chemistry Solutions Manual Purpose of the problem Making reactions work isan important part of organic chemistry Suggested solution ‘The first reaction isa standard acylation of an aldehyde creating a quaternary centre. You mig have used a silyl enol ether but an enamine, sch a the one made from a cyclic secondary amine = probably beter. Aen = DD A= OP BY ‘The second example might just go with simple base (MeO™) catalysis as the conjuset ‘ketone enolate is much more stable than that of the ester. However, it's probably safer to lithium enolate or a silyl enot ether (though then you'd have to use an acyl chloride a clectrophile)Chapter 28 Suggested solutions for Chapter 28 Purpose of the problem Peucice at drawing mechanisms for slightly unusual acylations on much more interesting “Srlcules. The mechanisms are the same, hovever complicated the setting. Suggested solution Be acid is converted into the mixed anhydride with acetic anhydride and the Lewis acid. The “séhride could enalize but no god intramolecular reaction can then happen. If the ketone enolzes “5c only side possible a sable five-membered rig can be formed, The stereochemistry sineviable “To tworatom bridge hasta be con the sb membered ring (and axial see Chaper 18) Sad example features an alkaloid —a typeof natural product to be discussed in Chapter 51. ‘ycrde sa strong base and could form an enelate from either ester. The product clearly results Sate formation from the ester on the side chain and an intramolecular acylation with the other As usual, this is because a stable enolate can be formed from the product under the reaction of the problem iS of « mechanistic problem concerning acylation. Revision of kinetic and thermodynamic230 Organic Chemistry Solutions Manual Suggested solution ‘The first pati what you should expect. A simple enolate anion has the largest charge density = ‘oxygen atom and aoyl chlorides are attracted by negative charge asthe carbon atom of thes group has a substantial charge itself The reaction isa charge-controlled combination of = rucleophile and a hard electropil \p 3 a * Ay, chew Ny, cae ate iS - ® ‘The second pris the interesting bit Now the enol eter te act as the acting open equilibrium is set up between the O- and C-acylated products. The C-acylated product stable enolate between the two carbonyl groups and this tips the equilibrium in its favour. oak ae ilo . oon 3 Re ms sa conse roe ® “in Problem 12 Tis @ Catylaton route to 3 simple ketone. Vy was NaH chosen as the hase? Nw ‘acylation not occur? Why were tbuty| esters used? What would have probably ha ‘he move obvious Fiedal-Craft (Chapter 22) oute had been ted instead? Longs “AL Nal TsO Es oe coyeay TOK ae Te eal son yale Purpose of the problem Anas ofa mechanistic problem concerning alton. Revision of kinetic and thermodyamic= Suggested solution “The expected result from acylation of a stable sodium enolate would be O-acyation 6 = previous problem. However, the two butyl esters are very large and inthe plane ofthe « ‘they will exert considerable steric hindrance at oxygen. The t-butyl groups are much fur-== the carbon atom, We show one possible arrangement of the enolate below. oan ‘The ebutyl esters were aso used to make ester ‘hydrolysis’ easier: the reaction with acid protonation of the carbonyl oxygen and loss ofthe butyl cation in an Sy1 reaction (Chare= or, more likely under these conditions with no good nucleophile, an El reaction (Chapte: Nises Tak SeerChapter 28 Suggested solutions for Chapter 28 “os Sv.adel-Crafts route would have required benzene to react with the acl chloride below. But volecular reaction to give a stable five-membered ring is much more likely. ° a ° ict, Nets “men 0 a = lem 13 catalysed reaction between these two esters allows the Isolation of one productin 82% Predict its stucture, 6 te i hem BOR Noe oe - SiR spectrum of the product shows that two species are present. Both show two 3H - at about by = 1 and two 2H quartets at about dy = 3 p.p.m. One has avery low feld ~ and an ABX system at 2.12.9 with Jag 16 He, Jax 8 Hz, and Jex 4 Hz. The other has. = singlet at 2.28 and two protons at 8.44 and 8.86 coupled with J 13 Hz. One of these ons exchanges with Dz0. Any attempt to separate the mixture (for example, by ation or chromatography) gives the same mixture. Both compounds, or the mixture, ‘vzatment with ethanol in acid solution gie the same product. What are these ounds? Ai role Cotes “EON Caste und B has IR 1740 om-*, by (p:p-m.) 1.15-2.25 (fourt, each 3H), 3.45 (2H, q), 3.62 “4.1 (two, each 2H}, 2.52 (2H, ABX system, Jap 16 Hz), 3.04 (1H, X of ABX split into “ror doublet by J Hz), and 4.6 (1H, d, J’5 H2). The couplings between A and X and 1B and X are not quoted In the paper. Nevertheless, you should be able to work out a se for compound B, : "Ssrose of the problem "ston of enol structure by NMR and a further exploration of what happens to aylation products. “eazested solution «diester can form an enolate and ethyl formate (HCOsEt~ itis half an aldehyde) is much rophilic than the diester. We should expect the diester to be acylated by ethyl formate ‘empound (A1) fits the formula for A (CHy,Os) and the NMR spectrum ofthe compound “low field signal (CHO) and an ABX system also fits this structure. But what isthe other # It obviously equilibrates easily with A2, which lacks both the aldehyde proton and theOrganic Chemistry Solutions Manual [ABX system, and it sounds like an enol. Compound Al is chiral so the CHs appears as == system but the enol is not chiral so the CH) is a singlet. Here ate the structures with tae assignments (in each case the OEt groups provide the 3H triplets and 2H quartets) ‘Treatment with acidic ethanol simply makes the diethyl acetal {rom the aldehyde group Since A1 and A2 are in equilibrium, all A2 is eventually converted into B via AL. Compozs= again chiral so the ABX system reappears with farther coupling of H* to the acetal proton. T= now four triplets and quartets for the four OEt groups. sao ye MOE oe Ko ‘oet = £0, 10,0. ‘coset 028 2 re CaattaeOe (8 pa of ABgested solutions for Chapter 29 29 blem 4. : {ull mechanisms for these reactions mentioned earlier in the chapter. |= Several problems inthis chapter | ‘i 23k you to suggest ways to make wa molecules by conugst addons of | pas : ~ i enol er enlates We give one 2 ual Pa possible ansver and sometimes j omment on alternatives, but you rr eee ‘shoud eaize thet there are mary sable ight answers to tis sor of ‘ueston. Make sie you have UY ape thee BAY | Sete “erent fous, eback th fomeone whe snows rzpose of the problem | _sxcrcse in writing out the full mechanisms of two standard conjugate addition reactions. ‘Se Lrst example LDA makes the lithium enolate on the only side possible. Evidently the lithium -» does conjugate adton rather than the expected direct addition, possibly because of tric } ars p= sy jus a =, pU., ‘te second example is «typical Lewis acid-catalysed conjugate addition ofa silyl enol ether. et exact details ofthe silyl transfer to the product need not bother you as long as you put the “acid on the carbonyl group of the enone and used the sist enol ether asthe nucleophile “sy enol ether produced by the conjugate ation is hydrolysed tothe product during the ssse200s work-up, Pt rR aR Tel | Problem 2 Hay i Perea ‘Suggest syntheses for these compounds. oe oa iOrganic Chemistry Solutions Manual oo a eGmetiees Purpose of the problem ‘An exercise in using standard conjugate addition reactions in making molecules. ‘Suggested solution ‘The nitro group and the tertiary centre next to it leave only one option for this synthesis. Tae {group is 50 anion-stabilizing that a tertiary amine is 2 strong enough base for this se 2G a + Arcome on oncom There are to allematives forthe nest compound but conjugate addition is so goed scrloniil that we should prefer that route expecially asthe anion can then be stabi and COstt, The reaction needs only catalyiebase as the initial formed adduct removes a from the next molecule of eyanoaccate. Purpose of the problem Exercising judgement in using standard conjugate addition reactions in making molecules. Suggested solution ‘There is little to choose between the two routes to the fist compound. Both unset ‘compounds are easy to make and enol(ate) formation is easy in both cases. Perhaps the uns ‘ster will be more reliable at conjugate addition. toe Tyg le SE ees ‘The second compound could also be done cither way, but both starting materials for route available while the unsaturated ketone needed for route B will have to be made. In both cases ‘enolizable ketone is being added to an enolizable unsaturated ketone, specific enol(ate)s migChapter 29 Suggested solutions for Chapter 29 235 2 very important reaction to make cyclic compounds. ted solution ‘=5 case we need first to unravel the aldol cyclization reaction and then the conjugate addition. If “ky we shall find no problems in putting the molecule back together again. Inthe first case the ‘es uteral was discussed in Chapter 28 (p. 727) and the eter group makes the conjugate addition ‘lization is unambiguous as no other stable cylic enone can be formed. aaa et ie Pt Ch ae | Sree errr ore Se at yeas aaa eae a eee Fe Saat sto noe Sa gy on product is stable and the conjugate addition can easily be managed with an enamine, a ‘so ether, or an extra CO;Et group added to cyclohexanone. =LD ee ‘the product that would be formed in these conjugate additions. rae ea aoe, andi 2 a AA = : : i se of the problem ny products: difficult but necessary! sted solution, “> one is relatively straightforward. The amine will make an enamine from the aldehyde, “vould give an efficient conjugate addition to a reliable Michael acceptor. A full mechanism somplete a better answer, 1. RaNH Scone mall a ey ae236 Organic Chemistry Solutions Manual ‘The second demands a bit of thought. The NH proton or else the proton between ‘x carbonyl groups might be removed. In the latter case, such a stable carbanion (actualy should be all right at conjugate addition even with an aldehyele. Ifyou sad the eazbanion wos direct addition or that the amide anion would either add director ina conjugate fashion, thy reasonable answers. Ta ae “Problem 6 : "Suggest mechanisms for this reaction, commenting on any selectivity. g ° Purpose of the problem ‘Tis is easier because you are given the product but, as the reactions get more complicate! «easier to overlook selectivity, Here isa reminder ofthe three main types (se p. 615 ofthe tex chemosclectvity (between separate functional groups); regioselectivty (between different asp the same functional group); and stereoselectivity (stereochemistry of the product). Suggested solution ‘The mechanism is a conjugate addition of the central enolate ofthe keto-ester to the enal fc bby an aldol cyclization of the Ketone enolate on to the aldehyde and dehydration. Base e S q = pie = 20" ¢ coy ee ne xe Sone on 2 2 In the first step there is chemosclectvity in that the enolate is formed at the centre ofthe ester and not on the aldehyde. You may not at frst think thatthe aldehyde can form an encis=/ think again. There i regioselectivity in thatthe koto-ester could have formed another enc: reason forall these selectivities isthe same: the conjugated enolate is much more stable thes of the alternatives Ase = Jno 7 Sok =I Sono, = ee In the cyclization step (the aldol reaction) there is chemoselectivity in the formation of an == feom the ketone and not from the aldehyde and repioselectivity in the formation from the enChapter 29 Suggested solutions for Chapter 29 237 soethyl group rather than between the ester and the Ketone. This last enolate would be most for the same reasons as above. tie dee end este ie, stir este ei fom tone ‘We cannot argue this time that the most stable enolate is formed because itis the less stable < at the methyl group of the ketone that leads to the observed reaction. This time we must ‘hat all the enolates are formed in equilibrium with each other and that the cyclization seines the selectivity, The other cyclizatons lead to less stable four-membered rings. mg camugte rte ite tom eye elt tom eserye aon es ysnton oon ctaon wes ‘otter sttmenert slocmmes tne . ‘There is a trivial kind of regioselectvity in the dehydration ~ the alternative would give @ “ese njugated enone and could not take place by the ElcB mechanism (Chapter 19). aly, steeosclectivity. One diatereoisomer is formed, the one with the two substituents (Me “2 £5,B trans This cannot be controlled in the conjugate addition, the reaction that forms both ==, because there would be no reason for such control in an open-chain compound, Far more “> «thatthe final product is formed asa mixture af cis and trans compounds that equlbrates to “ore stable tant compound by reversible enolate ion formation. ose of the problem ‘Wesion of the Mannich reaction.Organic Chemistry Solutions Manual Suggested solution at ‘The first step is the Mannich reaction itself. It requires an iminium salt asthe electrophile 5 reaction with an enol Meant co i _ Sa see Nes Ome 0 Con Me ‘The second step involves an elimination of the tertiary amine (E1¢B mechanism) and a conjcsse addition of the enolate anion of diethyl malonate to the resulting enone. This device prevents reactive enone from combining with itself by releasing it only in the presence of an excess 0 nucleophile. Purpose of the problem Looking at this complicated product, you might be forgiven for asuming that itis fic to Za This problem should coavince you otherwise and also show you how powerful s the combir of aol and conjugate addition. Suggested solution ‘The diketone can only furnish the central rib of the bicyclic compound so the two “wings come from the Keto-dester. One thing immediately obvious is that four ester groups must bes hydrolysis and decarboxylation and that must be what the second step (aqueous acid) is doirs product A of the first reaction must be the compound in the square box.Chapter 29 Suggested solutions for Chapter 29 239 ‘The first step must be an aldol reaction between the keto-diester (as enolate) and the very sophie 1,2-diketone, This reaction must give an enone as we are going to have to do a gate addition to add the second molecule of keto-diester. ° ox BO A 08 poe eo cd ring ought to be a better one. This gives a compound that can do a double conjugate or with the second molecule of keto-diester. Se neal gare ° ° 2 do not, of course, mean that all thes rextions happen at once and thee i infact a good # Te ccopetanora Be ot n (margin) way they do not happen exactly in the order given. The final stage is a normal #0"ate (ow delosatzeselsctrons) isis and decarboxylation, The stereochemistry simply comes from the preference for two five- 2” pcbably not ered, The fr soared ings oe cinfned (Chapter 33) cote wasten ser sare enieupeaommrnd oo 1 ae Lee ba. Siete os ae . ee expose of the problem exe innocen-looking compounds need a bit of thought as several stages are needed foreach “secound. _Suagested solution ‘T+ last conjugate addition in the synthesis of the first compound is fairly obvious as the “se~bination of ester and ketone provides a good enolate, Then we have acydoherenone rather ike “i compound in Problem 6. The compound needed for the intramolecular aldol reaction can be safe by a second conjugate addition using a sable enolate.Organic Chemistry Solutions Manual ‘The final stage inthe synthesis of the second compound must be an aldol reaction as the prode= isan enone. That eaves us wit adiketone (the aldol cyclization is shown with a dotted arrow) ad this could be made by two different conjugate additions or os lo a im. Ay Since the enones will be made from the parent ketones it doesn’t really matter which way we de & (Cyclohexanone is symmetrical but the other ketone is not and, whichever way we do the reaction. shall have to get selective enolization of 4-phenylbutan-2-one, We could carry out a Mannich reazine ‘on 4-phenyibutan-2-one and then use the enamine, the silyl enol ether, or the Keto-ster fers cyelohexanone in the conjugate addition. The final cyclization could be carried out in acid or base joe a aoe ees Seu ae Purpose of the problem NMR revision in the context of conjugate addition. Suggested solution ‘The IR suggests a dicarbonyl compound and the #C NMR suggests one aldehyde or ketone (32 and one acid derivative (178), The proton NMR confirms an aldehyde (10.1) and suggests tha: acid derivative isa meth! ester (3H singlet at 8 4.3). Both NMRs show that there is no double Wess any more. The proton NMR reveals a CMe; group on saturated carbon with no adjacent hydrox (GH singlet at 1.21. There are two CH, groups coupled to each other but to nothing else (the = triplets). All this adds up to this aldehyde-ester. ee vetoed ne, tn Se ae, Sn Heer eeChapter 29 Suggested solutions for Chapter 29 ‘Tae mechanism isthe usual Lewis acid-catalysed conjugate addition ofa silyl enol ether on to an Spe, rather like the one we saw in Problem 1. rrpose of the problem ination of sythess, mechanisms, and selectivity ~ the whole works. ested solution ‘S-ketoraldehyde combination suggests stale enolate adding to an enone. The enone is Sule and the eto-aldchyde can be made by an unambiguous acylation of yelohexanone with olzable but electrophilic thy formate, Ce ac “Te: mechanism for the cyclization is staightforward: the ketone forms an enolate at the methyl and attacks the aldehyde. ° ° Ho be Kou a: Kou ies ° ‘0 ce formation at the same site but attack on the Ketone in the ring. Presumably, the ation is kinetically controlled and the enolate prefers to attack the more electrophilic sydOrganic Chemistry Solutions Manual Purpose of the probler Rehearsal of the mechanism ofa conjugate addition with an extended enolate, Suggested solution ‘The enone could form an enolate on the methyl group (kinetic) oF more table extended enoat be removal of a proton from the far end (7) of the molecule, Evidently, this is what happens here ane e extended enolate attacks at the frst cazbon along te chain (2) to ade one cyanoethyl group. Repetio= adds the second cyanoethyl group and Blocks the postion aginst any further enolate formation een Purpose of the problem Extension of conjugate addition to a new functional group (nitro) and a remote electrophilic = ‘Suggested solution “The nitro-estr will form a very sable anon that could add to the for 8 potions on the dene Adaltion wo the 8 poston removes the very reactive ‘exo-methylene’ group from the rng and l= ‘only the much more stable conjugated alkene inside the ring. Addition to the position destroy the conjugation.Suggested solutions for Chapter 30 30 1 Several problems n is cast Suggest ways 10 make these two compounds. Show your ls recone ‘3 ee ‘molecules. We piv one possible ae ‘raver and omer coment on ‘tematves, bu you shoud realize that here ae mary posse gt ‘xswers tos sor of question. ‘Make sure you Rave understood the : ilo bein each aeatin : fn, you arawerls afer from ‘us, check twit soraone wha Purpose of the problem aia: st steps in designing a synthesis. Suggested solution Both compounds havea 1.-diX relationship Between the two oxygen atoms attached to the sare carbon atom. You might have seen this in another way by recognizing the acta! functional gros In any case, both compounds can be made from a diol (or two molecules of an alcohol) and == aléchyde or ketone. ie = TS el FS ae a pens Continuing with che first compound we must next count the relationship between the == functional groups. We have 2 1,3-dol so we need to think of various aldol or Claisen ester styles = 1 Fo) stores ortuctora geup _"#tions. These require a preliminary FGI and a few suggestions appear below. interconversion. ‘on ow is es anes Since we shall reduce all the carbonyl groups to alcohols, t doesn't really matter which route == follow. Compound A would require a crossed aldal reaction between two aldehydes so we'll a= that. Compound B is easier as we can use a specific enol equivalent (we have chosen the zinc eno2= as itis less basic than most; see p, 706) from an ester to add to the aldehyde. ‘@ TM stands for target molecule, . oe ‘or anc enciate remem ge Te ERE,Chapter 30 Suggested solutions for Chapter 30 245 Direct disconnection of compound C suggests a crossed Claisen ester condensation but, if we rove one methyl group fist, «great simplification results as we can use a self-condensation ce a ve geo we ee ‘he shes tage but thee i an ets asp rege ~ the lation ofthe conte der Thee ae of ous, many ther poblies and you have «diferent Your sys may ao work ; : E10" Leo hos. oto Le ‘e other compound has a 1,5-relationship between the two functionalized carbon atoms and =equire some sort of conjugate addition (Chapter 29). This time we want to reduce only one of 10 carbonyl groups s0 we must make sure they are different, We choose an ester to help with conjugate addition, seH0 a one SARS Se"? + PNcome Ty The aklehyde must be used a a specific enol equivalent in the conjugate addition. An enamine or We chose te ety exe to ‘enol ether would be fine. Now we must reduce the ester in the presence ofthe aldehyde, but_ 0H eH exchange int step, 4 Problem 2. Zronose smtheses ofthese to compounds, exnaning your choice of regents and how the steps in designing a synthesis with selectivity required. Saggested solution first compound is an a,pi-unsaturated carbonyl compound and this is one of the most ‘=rortant functional group combinations for you to recognize in planning syntheses, It is the‘eand Ibiove dienons rnd lease Chapter 29 Suggested solutions for Chapter 29 A Yeoette 028 come costes" 603M Completion of the synthesis requires epoxidation of the enone. This electrophilic alkene Chapter 231 is best epoxidized by alkaline bydrogen peroxide (p. 588}. Nucleophilie attack on he enone occurs from the opposite face 10 the large substituent already present. The nitro group must aso be reduced (oan amino group. I is best t0 do this after the cpoxidatin to ‘oid oxidation oF the amino group and because of tion of the alkene. 1 danger of yd ca co ¢ 5 oe Ye MM resin ee on caste oN conte on cone‘mtnesls a Cr a e ou Organic Chemistry Solutions Manual product of an aldol reaction ~ simply disconnect the alkene and write a new carbonyl group st far end from the old. Don’t lose any carbon atoms! OTe Or: ee We find that we need a crossed aldol condensation between two ketones so chemoselectivity. We also need to make one enolate) from an unsymmetrical ketone so = regioselectvity too. The obvious solutions are a lithium enolate, a silyl enol ether, or a conzes= with an extra ester group. on = Cre ‘The second compound contains another functional group you will often meet ~a lactone ster). Simply disconect the C-O bond and number the relationship between the two far groups, When we discover a 1,5-telationship we know at once that we must use conjugate ai and so we must have two carbonyl groups. There are alternative disconnection (a and b) of = Sntermediate, the keto-aci in the box ‘The synthesis will be easior if we use esters instead of acids. Syntheses based on disconnection a or b will be fine, We prefer a because the enone starting material is a dies acetone and very easly made (it can be bough). The bes specific enolate is probably malonz== ‘there is no problem with the chemoselective reduction as NaBH, reduces ketones but not < “The hydeoxy-ester will eyelize on work-up.Chapter 30 Suggested solutions for Chapter 30 247 pose of the problem out what goes wrong isan important part of planning a synthesis. ested solution ol reaction planned for the fist synthesis looks reasonable but the ketone is unsymmetrical <=avlensation has taken place on the wrong side. This not surprising in acid solution asthe sation. To avoid the problem, use a specific enol equivalent ofthe ketone such as an enamine sero-ester, the Darene reaction ©» the third case, eyelopentanone has sel-condensed and ignored the enone to which it was _ ose of the problem 2xercise in counting to show you that odd and even relationships realy are different.Organic Chemistry Solutions Manual ‘Suggested solution “The three diketones have 13, 14, and 1.5-dicarbony! relationships. In each cate the disconnection isthe bond joining the ring to te chain. For the 1.3-ketone, this means cys a Ketone. = Ghasde jae a = ‘The same disconnection on the 1,4-diketone leads to totally different chemistry and req different specific enolate) equivalent for cyclopentanone. ~ bp deny se Cee ate ‘The 1,5-diketone requires a conjugate addition approach and we use different specific ‘equivalent more for variety than necessity. sete eal) Saint nese Purpose of the problem Further exploration of the 1-4iCO relationship but disguised by further chemistry.Chapter 30 Suggested solutions for Chapter 30 Suggested solution a ene looks ike a Wittig product —the only easy way to get those exo-methylene groups, Wiig ~sonnection reveals a symmetrical 1,4-diketone and we really would prefer to disconnect the bond Seren the rings. ‘The second compound has an a,B-unsaturated ester so we are into aldol-style chemistry and here agin the Wittig looks good, mainly because of the chemoseleetvity needed in the aldol step. The -=oilate) equivalent must react with an aldehyde but not witha ketone and the phosphonium ylid “2 do just that. or i el t a OS ste SA aeaco ce Crt SS fo S08 ‘here is a problem with the aldehyde a? synthon. We don't want to use an unstable 2- ‘sidehyde so an ally halide is best. The alkene must be cleaved by ozonolysis with reductive =="-up (Mes5) to stop oxidation ofthe aldehyde. beedvede te = oe “S.agest a synthesis ofthis dikelo-ster from simple starting materials. “zrpose of the problem “> phrase ‘from simple starting materials in an exam warns you to go further back than you might Scszested solution “et disconnection of the 1,5-diCO relationship is fairly obvious as it trims off the side chain © the ring, The enolate is also a good one. = Scout conet ew, See Sh ok te28 Organic Chemistry Solutions Manual Now we have a choice between dealing with the 1.3-diCO relationship or disconnecting tse ‘unsaturated ketone naive 2 COE aot 1.31C0 Pe ae =>. . s > 0,8 Disconnection b solves no problems — we still have to make the o,f-unsaturated carbons! and now we have to make one particular geometcical isomer (ci). Disconnection a reveals» 1,5-4iC0 relationship. Disconnecting this 2 the branchpoint we get another simple availa: and a keto-ester (ethyl acetoacetate) that isthe product of a se-condensation of ethyl acer soa : ¢ e-em ssaco saeco wee de ~ 2 mon ° "This synthesis is indeed from very simple starting materials: two molecules of ethyl ace= ‘two of butenone (methyl vinyl ketone, MVK). Bite las Eran eae ig be ae he iss rete sete Hak ‘the oe” natal? By lal Purpose of the problem Revision of the Mannich reaction cooperating with conjugate addition and an aldol rea complete the Robinson annelation. Suggested solution “The base does two things: it makes the stable enolate from the P-keto-ster and it eliminate from the tetzaalkyl ammonium salt by the EleB mechanism, Each molecule of enone * released only in the presence ofa lange excess ofthe enolate anion with which itis to reac Yow’ ta-$ rae ane ale eneChapter 30 Suggested solutions for Chapter 30 ‘oo now react together in a conjugate addition and the rest of the Robinson annelation fllows. Re seme of retosymthetc ani ets these steps in summary. The dco to we the cb eatin forthe enone and adds COE group to alin the enclate woul be taken ef orthe slp “== varting material would be made by a Mannich reaction and the other by alkylation of ethyl sate, This is an added bonus of the extra CO:Et group. nse of the problem 1:0 see what happens when symtheses are not carefully planned. ed solution ‘Ssssving takes no account of chemoselectivty. The first Friedel-Crafs reaction will give a 0 three products, two of which can react again inthe second Friedel-Crafts reaction, The256 Organic Chemistry Solutions Manual dliketone faction ofthis product will be a miture of three compounds: two dimers and the mim product that is wanted, The alkylation could goat ether end ofthe molecule as there wil be ference inthe stability of the enolates. Even if dean monoalkylation occurs (unlikely) there wi be four final products, eer aie ae pT loon ae ‘ | mana Poeeson poe Ak Anke fe part) ed -dicarbonyl compound and can be specifically mz aoe a eu eed eg The mixed diketone required is a 15-dicarbonyl compound and can be specifically secon ue Seoac ane peop, cOnjugate addition. We can use the Mannich reaction for the enone as in Problem 11 and ws 4.Am. Chem, Soc, 1980, 102, you to choose the specific enolate. 720 ‘ucgost| reagents forthe "eacions marked 7 (goveral stops ane eet) sc ve mecneisms for those that are Purpose of the problem Now a complete synthesis that was carefully planned. There is variety of reactions typic complete synthesis,Chapter 30 Suggested solutions for Chapter 30 287 Scegested solution “est step givesa partly protected 1,5-dicazbony compound and so must be a conjugate addition “= = aldehyde fllowed by protection of the aldehyde as an acetal. The Second step isa Chasen ester -—~cnsation fllowed by hydrolysis and decarboxylation of the remaining ester group (sratexy ‘ned on pp. 727-8 ofthe textbook), and the third step isa reductive amination. mac. Ameo? moon Meo eee ee eee ee = E. Sah Soon last tw stages requite hydroljsis and decarboxylation of bth ester groups and a Wittig reaction = he deta are in Rv. Sevens za reduction ofthe alkene by ctaltic hydrogenation. The mechanism ofthe step that forms the 28 #040, 1 Am, hen. So “== amine looks complicated but sn. The conditions (pH. 55 in wate) will hydrolyse both acetals 197° chy, which wl immedatey start to form imines with the primary amine. The stable elo the “se lester adds to these imines. You mus just take it carefully stage by stage. gO CEB. GT Bo. ch reowst nso ae none (er 22) we Or stereochemistry comes from the intramolecular stage (ast mechanism shown). The enol “Ss tack the iminium ion from above or below, and ican reach only ithe chain is joined axially “+ ring alteady in existence (Chapter 18). The two ester groups are equatorial on the nev ring “223 they equilibrate by enolization to the most stable arrangement. all f~cosee oxat| Ceo.er to Boe “oO258 Omganis Chemisty Solutions Manu! Purpose of the problem A brief exploration ofthe 1,2-diCO relationship. Suggested solution tony i Cie ees “= = = sac : wiser ieontaN Tn ae AE ies CHO ae bal ar 7 A COM FS 18 Seo 0. W. Knight and EL panencen, rpea Soc, Penn 1h fact, it was made by a more interesting strategy using a dithiane as an acyl anion eq) Tans. 1979, 6, (4 reagent). O™O we Co exes 2.002 es Caco ‘The second compound is not a lactone as it might fist appear, but a Ketone, Disconnectic= ‘C-O bond reveals an a,B-unsaturated Ketone made by an aldol reaction from a hydroxy ‘= See J.£, dain nd geup, with a 1,2-diO relationship. Again, an acyl anion equivalent looks best. The published s:= 4. Chem. Soc, Chem. Commun, offers the two altematives shown. Reaction of the hydroxy-ketone with PhCHO and base 3976, 736, shown), followed by acid-caalysed cyclization, gives the target molecule, anatysis - CaS xe Ss aoe aCested solutions for Chapter 31 3 1 nce of the oduct oF is reaction fo the spectra and icin the Seva poems in tis tater sty Compound A nas dy 0.95 (GH, d, 17 Hz). 4.60 (3H, d J5 Ha), 2.65 (2H, KOU Ses ways to make Sse Aan We, 80H, JAD 8 end 595 (LH eG 20 ard SH) Toney crea ‘tematives but you should eaize ‘hat there ae mary possible rit nsias to tis sot of avestion. Mae size you nove undestacd the Pringles behind each question fn f your answer fleet rom urs, eneck it with someone wna none, of the problem Svs 0 a simple way to make Zalkenes with bit of NMR revision. “2 solution = susly a Wittig reaction and we should expect a Z-alkene product as the ylid is not “by further conjugation. The evidence is plain: the signals at 5.10 and 5.35 p.p.m. must be Ihydrogens and the coupling berween them is 10 Hz, Definitely a Z-alkene, 3098 91.60 LAM e208 ee SE ne. eas * a ea) 095m Ho535 insieolsorar of alse phoroione was prepped ihe folowing oy ‘Which isomers formed and vty? Outine sis of one other isomer. ‘your knowledge of the stereochemistry of the Wittig reaction, Seezsted solution Se Wittig, with a stabilized yli, gives the Eenal (A), The second, with an unstabilized yid, = Zalkene, and the final structure is an E.Z-diene. hia ge ee Ergon ng ete “ tne inect heroes260 Organic Chemistry Solutions Manual “There are many ways: make the othor isomers ZZ; EE: Z.E dienes! and you might have wied methods lionnatise stees of Withg zeactions oF tedustion of alkynes (pp. 815-79) or othe scribed in Chapter 3 Problem 3 How would you prepare samples of both geometrical isomers ofthis compound? cow wns Purpose of the problem A simple stereocontrolled alkene 8 ysis but Doth isomers are wanted. Suggested solution there.are many methods that can he wsed mn taekle this question. The onl a are protecting the 7 pct meee O41 Br0UP i neces’ and care in leasing the Z-compeund si sik wnmerie easily tothe F: IM San0S FE MOE rmpouind by reversible miguteadetion. Here iy one way ta the Zealkene using reduction af an alkyne to control the steenchemisty: The OF group iy protected as a bene ether removable by hydrogenation, perhaps ander the same conditions as Lae reduetion of the alkyne, sow newi nara Se go NO, zm rd SS zen, On So ee C0 alkene with alkali metal in ammonia but 3 ‘The Falkyne might be produced be reduction ot ‘Wig reaction is probably eases. Ether an fd or & phosphonate could be used, Protection of the QU as an acetate allows hycrolzsis of Doth esters in the same sep. neo eno = RHO Problom 4 Decomposition of this ciazocompound in methanol gies an unstable alkene A (CsH:40) vinose NMR spectrum contains these signals: (p.P.m.) 3.50 (3H, 8). 5.50 (2H, 34, 417.9 and 7.9 Hz}, 5.80 (3H, e0d, J 17.9, 9.2, and 4.3 H2), 4.20 (1M, m}, and 4.3-2.7 (BH, mh What Is its stucture and geometry? You are not exgected to work out @ mechanism for the reaction moot ig ea Purpose of the problem NMR revision aid & surprising structare ~ a test of your belief in physical methods, especialy RMR su Th val sip aks Sou Pu Rew Sug The thehoa wae nek seby 2M bara witbe em 0} 9 »). sally Chapter 34 Suggested solutions for Chapter 31 261, Suggested solution ‘he stating mater is CH 40 i has lost trogen (No and waned CH, ~ auethanol, We can se the MeO group at 45 apd the Four CHT: gtoups ithe ving ate stil here ‘8H a at 13-27), all hot ltr 2 mulrploe at 42, obsiouvv nest o MeO. and a pair of alkene sighls at 33 and 58, coupled with J = 17.9 Hy ~ obviously an Zalhene. One eu ofthe akere 5) ss eaupled fo ome peo, the ther (3.8) 0 2. We now have these fragments ie molecele al a Meo cote Cate Cake eo Cast ‘These add up t9 C.4Ts to0 much’ Cleats the CH attached (© OMe and! the CH attached to the alkene anast he the strne andthe CH; at che other end! of ie alkene must be ane end af the chain of four, We now have a structure, but it doesn’t join up. 2 4 ‘ ah is dove Ea oats ing, ast te diene aint nt gh 1080. 48 you were * Sige eastowsinonerton. hs NAN YN - oA ste aunt kon ehh ? MS ‘OMe La ome Cota a Problem 5 Why do these reactions give diferent alkene geometries? ° oom ° eosEt messich . ~~ owe - Purpose of the problem Revision of enol shemistrs from Chaptets 21 and 27 with the question of enol geometey ald Suggested solution the geometry of the enol product ofthe first reaction changes easly because of delocalization and tautomerism. It settles dossn in the more favourable geometry under thermodynamic contol and the Zealkene is favoured because of hydrogen bonding. at on -COH Oo262 Organic Chemistry Solutions Manual The sill enol eter does tot enfo the advantage of the hydrogen-bonded structure sa it petons the E-alkene for steric reasons. It might forea ony in equilibrate by silyl teaser. js shape trom the E-enviate hut it might also Problem 6 Here is a synthesis ofa prostaglandin analogue. Suggest reagents for the steps marked 7’. give mechaniems for those not so marked, and explain ary contol of alkene geometry. 7 lanl : by : oe an ieee" 7 ‘ closet eee AAO Teli, 7 Purpose of the problem ‘Making doable bonds or ins tings alin een chain Suggested solution ‘There iy oo dificult in allystng the B-keto-ester and removing the eter {yuestion of how ta intouduce the double bond into the five-membered! 1 Oh ate ‘The most obvious way is» halogenation in acid solution (Chapter 21) of the more substiqutee side of the Ketone and elimination of HX in base. The double bond will prefer to go inside the ri 2u tnd there is no argument about it stercochemistry, Typical bases would be tertiary’ amines 0! hindered alkoxides eg. Bu) ar mag tea? 2.08 m80, v0 “The mochaninen for this last sep rust involve conjugate aeiton of the nitromethane anion anc conversion of the nitr group to an aldehyde. The slersochemisty is et during the coniugan, dition when pronation of the enolate froma the les hindered side creates the iti relationship [Notice thatthe niteomethane anion iy regenerated in this sep, meno, >>Chapter 34. Suggested solutions for Chapter 31 263 ‘Conversion into the aldehyde involves hydrolysis ofthe ‘eno! form of the nitro compound. ‘his 1s rather ike the hydrolvsis of any innine and particularly like that of an oxime (Chapter 14) = OS a N NA nine “ Finally, the second alkene must be inserted stereospecifcally rans, Hove a Wittig reagent using stabilized yd is best as these react with sldhehydes anc ot with Ketores 8 Q ae NN one emi ° aa Ho 1 ° Problem 7 Isoeugenol, the flavouring crinciple of cloves, oceurs in the plant in both the E (solid) and 2 {liquid} forms. How would you arepare a pure sammie of each and how would you purity each fom any of tne other isomer? Yo~ Tot Purpose of the problem aking simple double bonds with fll sereochenseal conto Suggested solution There ure many posites. A Wittig approach is particularly atactve as the required aldehyde is soni, the common favouring. Since the yld would nor be stabilized, this approach would give mostly Z-isoeugenol, Two molecules of hise would be nett asthe fst would remave dhe proton From the phenol 2 Meo. cHo cr PhoP 7 2x Bul Esoengenol could be made from the same aldehyde by # Telia reaction (p. 810) o¢ by somerizing Z-isoeugenol with ight or iodine, or by a stereochemsiesly controled Peterson reaction S12] Pure Z-isocugenol cauld he separated fiom a small amount oF E-soeugenol by distillation +r chromatogtaphy and pure Fisocugenol could be sepacated from a small amount of Z-isoeugenol >» crystalliaation or shromatogeaphy.264 Organic Chemistry Solutions Manual Problem 8 ‘Thermal decomposition ofthis lactone gives mainly the Zalkene shown with minor amounts of the Ealkene and an unsaturated acid. Suggest a mecharusm for the reaction that explains these results, =e 7 " J ey le Ge of Nm ai a8 Purpose of the problem Ey Practice in analysing 2 mechanism where stereochem i. Suggested solution but my ae ray aoa a = mi Nroe be = Da te ftacarenyation 1 oer ac) I loss af CO: is faster than roration about the centeal band, the Z-acd is formed. If rotation ' be ind Tetraheoron Lett, 1980 occurs, then the Bu and Ph groups can adopt « favourable auc aligament and either CQ. or H can a s the lost depending on which happens to be in the right place. “ Problem 9 cars doe bom ene nes ean? seo nae oe hee teed re ° Pu soe pte we : 0 py NM Pa f ro 2. KHBOg, peat _ R Sug Purpose of the problem Practice in explaining or even predicting the stereochemistry of an. alkene Suggested solution ste ne costecty tae The fest simple, Addition af he Grignard te. tones more electronic Ban Y= dehydrates in acid. The dehycraton i reversible so the more sable este. sent to the ketane produces a terry alco, whieh alkene is formed selectivelyChapter 34. Suggested solutions for Chapter 31. \ poate ote \ pete Cv 1m eye 1 as Ea ene tenits ~ ome come are me “Te second case is more interesting. The initial ylid can form witha Z-or an E-double bond. The 4 cannot eyelize but the Z-yld can. The geometry ofthe second alkene is again determined “vy what is possible and what isnot. This trisubstituted bicyclic alkene will inevitably be cis in “rng and trans in the other. We can have either a cs- ora srans-alkene ina ten-membered ring “se are forced to have a civalkene in the six-membered ring ent of is epoxide wth base ges the same Ealene egaes ofthe stereochemistry ee i se of the problem, “sow that stereoselective reactions are sometimes better than stereospecific reactions in ing a single streoisomer ofa product, fed solution ‘5 an ElcB elimination. The intermediate isthe enolate ofthe ester s0 one of the stereogenic in the starting material is destroyed. No mater from which diastereoisomer it comes. the + can adopt a shape (C-O bond in the epoxide more-or-less parallel to the 7 orbitals ofthe "that allows elimination to the Ealkene (see margin). Dawe de 1 Tis wor snowed now 885 east make straned ales by the Wiig rection (W. 6, Dauben an JL palasei J. Am. Chem. Soc, 1973, 96, 5088). 1 Tis ester was used inthe sites of seid (Chapter $1) by the Diels Ale" reacton (Chaptr 35% Z. Varta ana group, Car, J Chem, 1979, 57, 3384. howd266 Organic Chemistry Solutions Manual Problem 14, : Which alkene would be formed in each ofthe following reactions? Explain your answer mechanistically. Pop? PrSO, Mest ‘MesSi ee ae ey ee eae be jn in Purpose of the problem Revision of three main methods for stereoselective (or specific) alkene bond formation. Suggested solution ‘The first is a Wittig reaction with an unstablizedylid, the second a Julia reaction, and the last two are Peterson reactions under different conditions. Each reaction is described in detail in the chaptes. ‘The Wittig reaction is under kinetic control and is a streospecifcally cs elimination, tn this case the product isthe Z-alkene. hsp? 1 PhP. Phs + PhsP=0 pews =n, Ses ae aya i k ki ome e ‘The Julia reaction is under thermodynamic control as the equilibration occurs under the reaction conditions. The product, formed storcosclectively, isthe alkene othe en Ree one one one ‘The Peterson reaction is a syn elimination under basic conditions, giving the Z-alkene, and az ‘ani elimination under acidic conditions, giving the E-alkene. e Problem 12 Comment on the difference between these two reactions: Purpose of the problem ‘To show that ring size combined with double bond geometry can affect the repioselectivty lf cyclization reactionsChapter 34. Suggested solutions for Chapter 31 267 “sezzested solution "ve should draw the mechanisms ofthe reactions and see what i different. Be lee lara Ry LAe% st example is conjugate ae and the second direct alkylation. We might expect stable Ths queson explored in etal sd enolate anions to do one othe other and not chop and change, The first product has anon sp. 604-13. Ss in a ten-membered ring. This is much more favourable than the Falkene in a eight- = This chemsty made the "srs ring that would be the product from the same reaction onthe second compound. Direct SEES af mesum sa a ing “= gives an alkene with no geometry. U. Tau and group 1 Am. Chem ‘Seo, 1978, 100, 7424), _ Problem 13 ‘+ sliminaton of tcanols 13A to glvecinnamie aids rans 138 in aqueous suc acid has been studled. optically ctve |< sused and the reaction stopped at 10% completion the statrg material i found to be completely racemized. What can "2 Seduce about the mechanism ofthe elimination step? Has, he tee ee Jot “oe aes a es i rain aim ae "9s © cinnamic acids cis:13B also Isomerize to the trans acids under the same conditions but more slowly. What is the “s=chanism of this reaction? _Sepose of the problem >» of Chapter 13 and a challenge to your ability to think through @ mechanistic problem in “sion with elimination reactions and the geometry of alkenes. "seested solution Shation ofthe secondary benzylic alcohol in acid solution mus bean El reaction since the table cation is formed easly. Racemization ofthe stating material suggests thatthe formation of 's rapidly reversible and the loss ofthe proton isthe slow step in the EL mechanism q 804 sf “ aa Se, are iat the cation is achiral, any alcohol formed fom it-must necessarily be racemic, The Beaton ofthe Zalkene must occur by protonation ofthe alkene to gre the same eatin, "5 the protonation of the alcohol had to be fast the protonation of the alkene canbe slow (it ‘ers ofthe sow step in the elimination ofthe alcohol). The isomerization of Z- to Elkene = than the dehydration ofthe alcohol because the protonation ofthe Z-alkene is even shower ‘he deprotonation ofthe cation ay a LO aa18 5.R son and R.A. Sauk, J. Org. Chom, 1979, 44, 287. Organic Chemistry Solutions Manual —— =. LORE aie Purpose of the problem ‘To show that double bond geometry can affct the stereochemistry of tetrahedral centres by stereospecific reactions. ‘Suggested solution First, we must draw mechanisms forthe reactions. The frst reaction clearly stars by brominatior =f the Z.lkene to form a bromonium ion (Chapter 20) tat is attacked by the amine. The amine = choose which end i attacks (and it prefers to form two five-membered rings rather than even 0a strained four-membered ring) but it has no choice about stereochemistry. We must have t= addition tothe alkene. dlscussed in fallin Chapter 35 (pp. 936-7). The starting material cannot form a lactone as the® = group is held away from the CO;H group by the alkene, Once the molecule is dihydroxy there is no Tonger any barrier to lactone formation andl a five-membered ring is again prefer ome West S - sop = ieSuggested solutions for Chapter 32 32 Purpose of the problem ‘A gentle introduction to the determination of stereochemistry with two dimensions only. Suggested solution ‘The IR suggests a conjugated carbonyl compound, confirmed by the two alkene and one carbonyl signals in the carbon NMR with the additional information that it is an aldehyde or ketone (8c about 200). The proton NMR shows that this isa ketone (no CHO proton) and thatthe alkene tha two protons (5.99 and 6.71) and that they are rans (J 16). We also see an ethy] group (2H q and. 3H t) attached to something with no Hs (looks like the carbonyl group). This suggests the unit in ‘the margin, which leaves only C,Hs. We know we have Me,CH- from the 6H d and that leaves only (CH, We have a structure. ayers ‘090 eas te Me 537 my se Mo ia, assis Fe ap 228 1.0, sc 5:5Me, A TH od? eet . 6,249 4,8.9 8,208 S042? Se2348 6847 A283 su nV sits are pm. at coupling constants are qucted in Hers. The usual arovatons Used: d= duit; tiple: and a= quanet. 1 stalls ere in. J, Fauliner ana .N- Raw, Tetrahedron Let, 1960, 2,23.270 Organic Chemistry Solutions Manual Purpose of the problem Slightly more dificult determination of stereochemistry moving from two dimensions to three Revision of the Karplus relationship and of conjugate addition. Suggested solution The structure of Ais easy. It has a trans (E-) double bond with two Hs (J 15) and two tertiary but roups. There isn’t much else it can be and we suspect an aldol reaction between the enolizable ketone and the unenolizable aldehyde oh = ope = otk B is more dificult The alkene has obviously gone (no signals beyond 4.48) and there is one extra "Jouve 015% ae unt, Telooks as though HBr has added. The coupling of 17.7 Hz cannot bea tranalkene as ther ist eee erie any kind of alkene soit must be geminal (7) coupling. This means the molecule is chiral so that a CH; geoup is distereotopic. In fact, the expected conjugate addition of HBr (Chapter 23) has occurred. arpa he ‘The three marked hydrogens form an ABX system: AB are the dastereotopic CH group (Jas = 8 Seo. Kennedy and roton = 19), leis not ne sible to say wl SES formas ond, 17.7) and His the CHB proton Uax = 10; Jax = 1.9). I's not normally posible to say which sera sartie: Proton is A and which B but here with such large groups we may guess that there is one favoured conformation with one dihedral angle about 180° and one about 60 120160" ene) Problem 3 (One of the sugar components in the antibiotic kjanimycin has the gross structure (margin) ‘and the NMR spectrum shown below, What is its stereochemisty? All couplings in Hz; ‘signals marked * exchange with D0. {4 1.33 (BH, d, J6), 1.61" (1H, broad s), 1.87 (1H, déc, 114, 3, 3:5), 2.24 (1H, ddd, 14, 3,45), 2.87 (2H, dd, J10, 3), 3.40 (3H, s), 3.47 (3H, s), 3.99 (AH, da, J 10, 6), 4.24 (LH, dd, 13, 3, 3.5), and 4.79 (1H, 64, 13.5, 1.5). Purpose of the problem ‘Your frst attempt ata serious assignment of three-dimensional stereochemistry from NMR,Chapter 32 Suggested solutions for Chapter 32 271. Suggested solution can make some preliminary assignments from a combination of shift and coupling. sent Comments Assignment as ‘3H d must be Gre we? iar ‘exchanges so must be OM on ast $14 looks tne geminal) coupling Hort aa 2.21 ane 187 ae CHa oun He ort 257 ‘must be ail proton (10 Ha) He ort a0 (ne Ohte ou OMe a7 ‘be othe OMe group Ole aso ‘qmeans H", must be aval (10H) Ke as ‘eal J, must be eqtoil HS or a fl smal J, must be equatorial " ‘We don’t mind which is H? or H? as they don't affect the stereochemistry, but we do mind which A. Mallams and group, Am. or H’, Since HY isa 10 Hz doublet with H°, we know that HP is at 2.87 and is axial. This gives PM Soe. 1981, 108, 2938, = che entre assignment and the stereochemistry: HP and HY are axa H and HY are equatorial. “sats why there are no large vicinal °) couplings to the dasteeotopic CH. group (Hand H?), ay138 287/220 H 879 Suara scutes eraeieer ° Problem 4 “wo dlastereolsomers ofthis occ ketotactam have been prepared. The NMR spectra have “many overlapping signals but the proton marked in green in the texthook and here ringed can A, clearly be seen. In isomer A itis §y 4.12 (1H, q, 13.6) and isomer Bhas 54 3.90(1H,at,J4, +43, 12). Which isomer has which stereochemisty’? Q Purpose of the problem +ssignment of three-dimensional stereochemistry from NMR when only one signal can be made -: cleary Suggested solution ze to isomers have isand trans ring junctions so we should first make conformational drawing. The trans compound is easy as it has a fxed conformation like @ transdecalin (p. 463). The es -mpound can have two conformations as both rings can flip. Sade 2b x272 Organic Chemistry Solutions Manual |= Tis compound was used in @ : = ‘The vital proton is clearly axial in isomer B as it has two couplings to other axial hydroger= al nen twit (19 Ha) and hia man b the rename lore Aha hee egal ral coupling (3.5 Hi) ad ee See | lipeet ee teem ee ae ee scsi Po bon 238hef" Purpose of the problem ‘Am approach from the other end: how would you do the job? Also to reinind you that we 2t determine relative stereochemistry (ie. which diastereoisomer do. we have?) but not abssia= stereachemisty (ie, which enantiomer do we have?) by NMR. ‘Suggested solution ‘a Rinaegee et ap pet By NMR, of course. Both compounds are six-membered rings so we should first me ator gos the 8 1 oormational drawings of all the possible. The frst compound can have the rut! Tr oe ease eset methyl groups cor trans and the butyl group wil go equatorial The second compound can >= te we ca easy pute catony oth methyl groups on the same side asthe t-butyl group, bth onthe ater side, oF one on each fo08 atte or side, Two ofthese are mao compounds, though this doesn't alec the asignent ee ye re ge a oe ‘The key H atoms in the NMR are those we can see! Inthe first compound they are marke. 1H tells us nothing ait is coupled to nothing. HP and H® are useful in that they tell us about = ‘is eaily identified by its quartet coupling to the methyl group. If t has a large axal-axal cow | (about 10 Hz) to H® then we have the cis compound, but if all its couplings are small (pope <4 He, as in Problem 4) then iti the tans compound, Meo ineChapter 32 Suggested solutions for Chapter 32 273 In the second compound a dificulty emerges: there is no coupling! We can tell by symmetry ‘nhether we have, on the one hand, the os, cs- or the trans rans-compound or, on the other hand, ‘Re cis, rans-compound. But how can we tell which of the symmetrical compounds we have? The sical shifs will be different but we won't know which is which. However, if we irradiate the znal for the methyl groups we should get a strong NOE effect (p. 844) at HY in the alles compound and nothing in the trans compound, Problem 6 “The structure and stereochemistry ofthe antifungal antibiotic ambruticin was in part deduced ‘rom the NMR spectrum of this simple cyclopropane. interpret the NMR spectrum and show how it gives definite evidence on the stereochemisty. Sy 4.24 (3H, d, 17 He), 1.29 (3H, t, 19), 4.47 (BH, 5), 1.60 (14, t, 16), 4.77 (2H, dq, 6, 43, 7), 2.46 (1H, dt, J6, 13), 4.48 (2H, q, 19}, 6.05 (4H, a, J20), and 6.62 (2H, 66, 113, 20. Purpose of the problem ‘signing a more complex NMR and making deductions about stereochemistry i small ings Suggested solution In gylopropanes the cs coupling is usually larger than the tras coupling because the dihedral angle ‘or cis Hs is O° but that of trans Hs is not 180°. Assigning the three ring hydrogens depends on (a) che quartet coupling to the methyl group and (b) the 13 Hz coupling to the proton on the alkene, This means thatthe third (6 Hz triplet) must be next to the carbonyl group. The two trans couplings ound the ring are the same (6 Hz) and smaller than the cis coupling (7 Hz). The geometry of the double bond is on more certain grounds (20 Hz can only be a trans coupling) ne > panes 0 2194 ON io Jone Problem 7 In Chapter 20 we set a problem asking you what the stereochemistry of a product was. Now we can give you the NMR spectrum of the product and ask: how do we know the stereochemisty ofthe product? You need only the partial NMR spectrum: 8, 3.9 (1H, del, 442, 4, 7) and 4.3 (4H, dd, 144, 3).74. Organic Chemistry Solutions Manual Purpose of the problem You can prove for yourself that this deduction made in earlier chapters is tue. Suggested solution {A saturated sixcmembered ring means conformational drawings again. The proton next to © mus be the ddg because it is next to the methyl group and the one at 43 mus therefore be the prote= next to Br. Both have one large coupling (12 or 11 Hz) and this must be axia-axal so both protozs smust be axial sa3h Purpose of the problem Exploration of the usfulnes of the NOE when coupling constants are of litle use. Suggested solution ‘The signal at 5.72 is obviously the proton on the alkene. The 2H triplet must be next to the N atom and the 2H doublet must be between the alkene and the ketone, The NOE fills off as the si power of the distance so the fist (E-) alkene is correct. The second (Z-) alkene would give the ‘opposite result. The NOF also suggests that the predominant conformation ofthe top chain must as shown wit the chain bent away from the alkene. oH cont ‘The product must he formed by a Wittig reaction ofthe usual sort (probably E-sclective a this stabilized yid) followed by base-catalysed isomerization of the alkene into conjugation with theChapter 32 Suggested solutions for Chapter 32 275 ———_— : athe 12 ner was done cams ig carbonyl group. This must be under thermodynamic contol as too must be the geometry of Th non dra by emi the fina alkene. ‘ed is coset by AG. Cale ‘group, J Chem. Soc. Pork 9 Tans. 1, 1980, 495 i wi y ° Problem 9 How would you determine the stereochemistry ofthis eylopropane? The NMR spectra ofthe PY. three protons on the ring are given: (5 3.64 (AM, dd, 6, 8}, 2.07 (2H, dé, 6, 10), and 2.89 moo PH (GH, da, 120, 8) 15 This work was done by chemists ‘tUnversty Cateye, Dublin and ls Purpose of the problem ‘Sescribes by J. 8. Dooney end Finding out how to determine stereochemistry when there isa quaternary chiral centre. oup, 1 Oem. Sa Pai Tans Suggested solution radiation ofthe MeO signal (2.07) should give an NOE and reveal which of H! and H? ison the same side ofthe ring and may show that His also on the same side. Irradiation of Hand H? in turn (you wee given the NMR shifts ofthis part ofthe molecule so you could see that, fortunately, H?, HE, and H? are well separated in the NMR spectrum) should give definite information on the relative stereochemistry. The original wrk shows cary thatthe compouin is one diastereaizomer ‘but which one was not determined. os eo Meo al Problem 410 ‘A chemical reaction produces two dlasterecisomers of the product. Isomer A has 5, 3.08 (AH, dt, 44, 9, 9) and 4.32 (4H, d, 49) while isomer B has 6, 4.27 (AH, d, 14). The other cote Protons overlap. Isomer B is converted into isomer A on treatment with base, What is the ‘stereochemistry of A and B? Purpose of the problem Determining stereochemistry on the minimum of information. Suggested solution There ae two diasteroisomers and the diference in coupling constants is striking, These are not true eyelohexanes but partly flattened by the benzene ring and best drawn as cyclohexenes (P. 469). You should imagine the benzene ring coming towards you where the double bond is drawn.276 Organic Chemistry Solutions Manual “The two protons we can seein isomer A must be H and HE as they have the largest shifts proton with only one coupling must be H! as it has only one neighbour (H?),Isomer A has a¥ = ‘coupling between Hand H? so both these protons must be ail. Isomer A is therefore the © isomer. The signal for H? is dt because it has two axial neighbours (H? and HP) and one equate neighbour (H'), Isomer B shows H only and itis clearly equatorial (Jig = 4). Though we can» HE it must be axial as B must be che cisisomer since itis different from A, e ow “Oy osm neo. come +e aa - Problem 44 “ ° ‘Muscatine, the poisonous principle of the death cap mushroom, has the following structur= hasan pteion NMR ssecirum. Assign the spectrum. Can you see dete evidence for tre oo stereachemist? Al couplings in He; signals marked exchange with 020. 44 1.16 (3H, d, 16.5), 1.86 (1H, ddd, J 12.5, 9.5, 5.5), 2.02 (2H, ddd, J12.5, 2.0, 6.0. 3.36 (OH, s), 3.54 (1H, od, 113, 9.0), 3.74 (1H, dé, J 13, 1.0), 3.92 (1H, da, J2.5, 6.5, 4.03 (AH, m), 4.30* (1H, d, 13.5), and 4.68 (4H, m). Purpose of the problem Demonstrating that it can be very dificult to determine stereochemistry even with all = information ‘Suggested solution 18 The detas ae in. Muteor ava Coupling constants around five-membered rings tend to be much the same whether they are ‘Youn, Uebigs A, Chem., 1967, 7. (geminal, "Fn OF Jnms (icinl). Even So, the two diasteeotopic CH groups are easy to find w= their large 2/ couplings of 13 and 12.5. The one with one extra coupling must be in the side che~ and the others in the ring, Here isthe full analysis. You will ee that itis in fact very difficult. & conclusive evidence on stereochemistry though you should see that, in general, cis couplings tené. be larger than. rans sees an 202(0H, ded, 1328, 20, on 6.0) fre A rN ae 14.03 (24, of 684. tm) or 468 Nites-=-—-6 3300, eaasisia asta te samunesasmccy Seat ssa mane, engin eesti Problem 12 ‘An antifeedont compound that deters insects from eating food crops has the gross structure shown below. Some ofthe NM signals that can clearly be made out are aso given. Since a NM coupling constants ae clearly useless in assigning he stereochemisty, how would you Nort? set bout it? 42.22 (1H, d, 14), 2.99 4M, dd, 14, 2.4), 4.96 1H, d, 1423), 4.70(2H, dd 147, 14.7), 4.88 (1H, 6, 123)Chapter 32 Suggested solutions for Chapter 32 Purpose of the problem Assigning stereochemistry when there are isoleted spin systems. .ggested solution se signals given are allo protons next to electronegative atoms. There are two AB systems for the -stereotopic CH» groups in the epoxide and the CHOAc group. The CH,OAc group is ‘normal’ th2J123 and a large shift (84.36 and 4.88). The epoxide is unusual with a much smaller J of sly 4 Hz (actualy normal for epoxides) and smaller shifts (84 222 and 298). Both appear isolated «one ofthe epoxide protons shows long-range coupling to some other proton. These are no help “the stereochemistry but the proton next to the other OAc group (Bx 4.70) is clearly axial with ical axiallaxal (11.7) and axil/equatoral (4.7) couplings. The answer came from NOE experiments There were large NOEs between the 64.70 axial =roton and one ofthe epoxide protons and between the axial methyl group and one of the protons 1. the CH,OAe group. The stereochemistry is like ths. &: Reig 43 neo \ 8" 4 fase an. 9. 1223340 Sosa, 123% Problem 43 ‘The seeds of the Costa Rican plant Ateleia herbert smithif ere avoided by all seed eaters (exept a weevil that adants them for its defence) because they contain two toxic amino {acids (IR spectra lke other amino acids). Neither compound ischial, What isthe structure of ‘hese compounds? They can easly be separated because one (A) Is soluble in aqueous base but the other (B) is not. Ais CeHaNO, (mass spectrum) and has 5; 24.0 (a), 40.0 (t), 56.2 (s), 184.8 (s), and 186.0 (3) Its proton NM has three exchanging protons on nitrogen end one on oxygen and ‘wo complex signals at 5y 2.68 (4H, AaB. part of AgBaX system) and 3.37 (X part of AgBaX system) with Jee 9.5. J 9-4, and Jax smal Bis CeHeNO- (mass spectrum) and has 8; 8.0 (a), 44.3 ft), 50.4 (t), 75.2(s), and 173.0 (s). ts proton NMR spectrum contains two exchanging protons on nitrogen and by 1.27 (2H, dd, J2.3, 6.2, 9.5), 2.34 (2H, broad m), 2.90 (1H, broad t, 43.2), and 3.40 (2H, broad s).. Because the coupling pattern did not show up clearly as many of the coupling constants fare small, decoupling experiments were used. irradiation at 8, 3.4 simplifies the 8, 2.3, signal to (2H, dad, 15.8, 3.2, 2.3), sharpens each line ofthe ddd at 4.47, and sharpens the inlet at 2.9. Irradiation at 2. sharpens the signals at 1.47 and 2.9 and makes the signal at 2.31 into a broad doublet, J about 6. radiation at 2.31 sharpens the signal at 3.4 slighty and reduces, the signals at 2.9 and 4.17 to broad singlets. radiation at 1.17 sharpens the signal at 3.4 ‘slightly so that itis a broad doublet, J about 4.0, sharpens the signal at 2.9 to triplet, and ‘sharpens up the signal at 2.91 but radiation here had the least effect, ‘This s quite a cifficult problem but the compounds are so small (Cs only), have no methy| {7 0uDs, and have some symmetry so you should ty drawing structures at an early stage. Purpose of the problem A difficult problem for those of you who like to try the real thing. WS. Ley and group, J. Chem. ‘See, Chem. Commun, 198, 001.278 Organic Chemistry Solutions Manual Suggested solution 1 Tenread ol aboutitin€. Bet The compound are unusual cyclobutane amino acids. The simplest thing ¢ 4p yu te arene fang group, J. Am. Chem. Soc. and let you se if your suggestions fit and if you can assign the spectra, uae ” . 8 SeSuggested solutions for Chapter 33 33 Problem 1. CCornment on the control over stereochemistry achieved in this sequence. Purpose of the problem ‘A gentle introduction to stereochemical control in rings. Suggested solution ‘The reducing agent could attack ether side ofthe rng inthe fest step but it react with the free OT troup to produce a new reducing agent and hydride delivery is intramolecular from the bottom face. The mesylation (mechanism on p. 484) does not affect the stereochemistry as no bonds are formed or broken to any of the chiral centres. A eae ‘ as Re Se ot a ra non er es De ¥ Re : rR rR? Re ) i) y Fa ve = ji et trees Peis SM apcyan anTE moiety 2Tecmer eee ee ae ee ee ee, Sane fortunately, the amine is already on the bottom face, “a Z moi, Problem 2 ah a Biplane seeachonsty of ths Sequence of reactions, Nong te sesond step In articular, i oe i sume tf ‘2.NA0e 3. LAs iyOrganic Chemistry Solutions Manual 18 H.W. Plane and Y. Chang, Tovaecron Lett, 1978, 857 res en ale Su dgmdgt ae Purpose of the problem ‘To show how even ‘non-redctons can influence stereochemistry. Suggested solution ‘There appears to be a mistake at fst since the hydrogenation will add a molecule of hydroge ‘one face ofthe alkene to give what appears to be the wrong product. ‘The second step is now rather important. Ethoxide will form the enclate ofthe ester reversi and tur it to the outside, the convex face, ofthe molecule. Though nitrogen is not normally a fixes ‘chiral centre because it undergoes rapid pyramidal inversion, hee itis fixed by the need of the five five fused ring system to have a cis ring junction. The last step is just the reduction of the ester ‘no change in the stereochemistry. insise G03Et (cone foe) Problem 3 ie i i Explain how the stereo- and restochemist of these compounds are controlled. Why isthe oxidation only moderately stereoselective, and why does the amine altack where it Purpose of the problem An exercise to remind you how important conformational analysis i in any stereoselective react ‘of saturated six-membered rings Suggested solution “The conformation of the cyclohexene will hve the CO;Me group in an equatorial poston, ales in the plane of the alkene so that it offers only slight steric hindrance. The opening of the epoxic: stereochemical coniel Finally, the double bond is introduced by selenium chemistry (p. 1271). Tae steps straightforward and the geometry ofthe alkene is dictated by the ring.7 ae Chapter 33 Suggested solutions for Chapter 33 285 Problem 9 ve f : A revision problem. Suggest mechorioms forthe reactions used o ake his starting meter sed in the chopt eo ee Purpose of the problem Revision of mechanisms in the context of Chapter 33 (p. 864), Suggested solution ‘The stable enolate ofthe keto-ester adds to the ntroalkene ina conjugate addition for which both pariuers are excellent (Chapter 28) Hydrolysis and decarboxylation gives the fist intermediate. You can discover how this starting material was made in Problem 40.4, p. 1076, sho = Cs - ee oe Congest af oe omasbemconds te tape bitin ead Uninet teoyed 8 1. nt Nagoven 2 by an extremely good intramolecular aldol reaction giving the fused five-membered ring. a he oy he ane SS, % im 1 Sie seth ° xo p> = 4 Problem 10 ‘And enother problem ‘tom the chapter. Here also craw a mechanism forthe fomation of the starting material. You hve never seen the cyclopropane reagent, but think how it mig reac a ike poe m2 L Pm Ml eo” eet Stuck? The fist step opens the ‘tinee membered fing and the second ‘step is a welhknown alkere-orming, actor :Organic Chemistry Solutions Manual Purpose of the problem Revision of mechanisms in the context of Chapter 33 (p. 865). Suggested solution ‘The las reaction is, of course, a Witig reaction so the first must be nucleophilic attack by the ano ‘of the imide on the cyclopropane with the phosphonium yd asthe leaving group. cal Cais - coset in the cnapter ws introduced the selective, redvetion ‘of the Wieland-Miescher ketone (0. 869}. Te problem is: con you suggest a reason for hs steenselectvty? Purpose of the problem Back to the main subject of the chapter: explaining stersoselectvity in reactions of yet: compounds. Suggested solution ‘This is an example of a small nucleophile adding to a ketone in a six-membered ring. The b> added (H) is smaller than the bit already there (O) and the reagent (NaBH) is also small so ax? artack is preferted so that the larger substituent OH) ends up equatorial. A larger reagent, <2 NaAIH(OBu-1)s, would add equatorially (see p. 852). pte poe 8Chapter 33 Suggested solutions for Chapter 33 Problem 12 ‘Suggest mechanisms for these reactions and explain the stereochemistry. ‘e03Me ‘00,Me Purpose of the problem ‘Though ultimately it disappears explaining the stereoselectvty ofthe reduction is interesting and applicable elsewhere. Suggested solution This looks complicated but it’s just _a question of working through each reaction. ‘The stereochemistry needs some thought. The fist reaction is a conjugate addition of sulfur nucleophile toa very electrophilic alkene. The base used piperidine, isan ordinary secondary amine ‘but that is basic enough (pK about 11) to produce reasonable amounts of anion from the thiol |pK; also about 10). There is no stereochemistry inthis step. oe tt, The next stage is an intramolecular Claisen ester condensation. We can easily discover which ‘enolate reacts with which este by drawing the starting material in the shape of the product. The alternatives are three-or six-membered rings: five-membered rings are more stable than three- and ‘more rapidly formed than six-membered. Under the reaction conditions ther i no stereochemistry a the product exists asa stable conjugated enolate ion (p. 724) comme ‘002Me ‘The reduction isthe stereoselective step and the hydrogen atom is added from the face of the ketone opposite the larger substituent. The oxyanion so formed reacts with the ester to give a five- membered lactone. The other ester group equiibrats va the stable enol or enolate until the ketone 's reduced. Then itis fixed in whatever configuration it happens to be. Meo0.Organic Chemistry Solutions Manual Finally, the second ring is opened again by an ElcB elimination via the enolate of the ester. This removes all the stereochemistry and gives the starting material for the chemistry described in the chapter (p. 876). ome eos. a 3 & 7 l d Se ae ) ‘C0:Me ° e Problem 13 Cyne i 4 y Hydioisis ofa bissilated ene-dol ves @ hydroxy ketone A whose stereochemity is supposed to be 3s shown. Reduction ofA gives a dio), The ‘$C NM spectrum of B has five signals: one ip the 100-150 p,p.m, range, one in the 50-200 p.p.m. range, and three below 60 p p.m, The proton NMR of tne three marked hyerogens in Ais ven below “with Some, irragiation data, Does this information lve you confidence inthe stereachemistyy assigned to A? You may wish to consider the tkely stereochemical result of the reduction of A. H siMes ~ sites © Alas dy 4.46 (4H, dd, 19.0, 381 Hz), 3.25 (2H, ie 7.5, 4.5 H2), and 3.48, (an. ‘dda, 47.8, 55, 38 be, kradiaton at 3.48 collapses the signal at 4.46 to (4, 19.0 Hz) and te Signal at 3.25 to (4, 19.0, 4.5 Hr: radiation at 4.46 collapses the signal at 3.48 to (6, JTS, 85) and the signal at 3.25 to (6, J7.5, 45), oe Purpose of the problem NMR revision, In determining stereochemistry, a5 in other parts of chemistry, the evidence does ‘matter, Suggested solution ‘The structure of B is obviously symmetrical and the two OH groups must be cs (both in or bot out). We should expect A to be reduced to the sans compound as the nucleophile would attacs from the convex face of the folded molecule. This suggests that Bs the cs inside) diol and A has its ‘one OH group inside too. ae sructi ofA? caiman orton ‘The NMR spectrum of A has two large couplings (7.5 and 9,0) between the marked Hs. These look more like cis than trans couplings (cis couplings are larger than trans couplings in four- ‘membered rings). The signal at 4.46 must be the proton next to OH and the other two must haveChapter 33 Suggested solutions for Chapter 33 289 «aditional couplings to protons H¥ and HY. All this data fits if protonation of the sly enol ether Doan 8. M. Tost ana gn, joceurs on the exo face to give A and reduction of A also accurs on the exo face. 4.0% Chom, 1978, 43,4858, H9348 W ere We: w ‘0 te: Pe meSuggested solutions for Chapter 34 34 Purpose of the problem A gentle introduction to stereochemical control in open-chain compounds Suggested solution ‘The compounds are acetals and can both be made from the corresponding diols with no change in stereochemistry. The question really i: how do you make cis and trans diols from the alkene! Yon ete he ht ‘The Gs diol is best made by dihydroxylation with OsO, as the reagent and a co-oxidant to regenerate it. The trans diol comes from the epoxide by aucleophilic attack with water Purpose of the problem Chelation-controlled reduction is an important method for stereochemical control in open-chait compoundsChapter 34 Suggested solutions for Chapter 34 294 Suggested solution {in both reductions the zinc atom is coordinated to the oxygen of the nearer functional group 1. Nakata and grou, Tetraheckon OnE! in the fst and OH inthe second) and the oxygen atom ofthe ketone being reduced. This Ut, 1983, 24,2557 325 the conformation ofthe molecule and the borohydride ion attacks from the les hindered side (> 893). Anti stereochemistry results in both cass. Purpose of the problem ‘Tals may seem trivial but the principle is important. Suggested solution he relationship between the two chiral centres i the product is 1.5 and this i too remote for any Mov and grup, Tetrahedron zealitic hope of control. The only way is to disconnect between the two centres and add a $989 39.2439 wvable anion-stabilzing group to the nucleophilic synthon and a leaving group to the trophilc synthon. Salone and iodide are good choices. The starting materials mut, of course, 7 singe enantiomers ~ then only one diastereoisomer can be produced. neh oe Problema # i Explain the stereochemical contol in this reaction, drawing al the intermeriates.292 Organic Chemistry Solutions Manual Purpose of the problem ‘The aldal isa versatile and important way of controling open-chain stereochemistry by way n= cyclic transition state. Suggested solution. ‘The geometry of the enolate is all important (p. 898) and here the large t-butyl group wil give == the Zlithium enolate. Then the mechanism has 2 saturated six-membered cyelic (Zimmerns= ‘Traxler) transition state with the R group ofthe aldehyde RCHO taking up an equatorial posits i ‘This gives the syn aldol. sresleske. [Notice that inthe transition state: (1) R chooses to go equatorial; (2) the methyl group is forsal axial because iti cis to OLis (3) the Hbutyl group forces the aldehyde to add to the back face of = enolate as drawn, "Problem 5 ‘When this hydrontester is treated wih a twofold excess of LDA and then alive, one Pe eninge eae Purpose of the problem Analysis of an apparently simple case where chelation has the last word. Suggested solution “The first LDA molecule removes the OH proton and only the second gives the enolate. The enol: fs held in a ring by chelation to the first lithium atom so that the allyl group adds to the less hindered face ~ opposite the methyl group.Chapter 34 Suggested solutions for Chapter 34 293 Purpose of the problem Aan example ofthe important iodolctonzation reaction Suggested solution The bicarbonate (NaHCOs) isa strong enough base to produce the anion of the carboxylic acid Iodine attacks the alkene reversibly to give a mixture of diastereoisomers of the iodonium ion, Ifthe TF and Me groups are on the same side ofthe chain, the COr group can attack the iogonium ion from the back and set up 2 runs fodolactone. The iodolactone is cleaved by methoxide and the oxyanion displaces iodide to give the epoxide a Mh at ot Paes Problem 7 Explain now hese Wo Teaco eve deren asterism of he product. Ae i ae Purpose of the problem Practice at the Felkin-Anh style of stereochemical control Suggested solution “each case we have nucleophilic attack ona carbonyl group witha neighbouring chiral centre, The kin analysis tells ws ist to put the largest group perpendicular to the carbony group and then to ring the nucleophile in alongside the smallest substituent. This is best shown with a Newman zrojecton (p. 888). In the first casei is better to rtate the front atom so that the two Ph groups are 21 180" and we can draw the structures in the same way. pdt. Be pe ote294 Organic Chemistry Solutions Manual Purpose of the problem Practice at an electronically controlled Felkin-Anh style of stereochemical conto. Suggested solution In this cae the chlorine dominates because it has an electronic interaction with te carbonyl group. T= ‘so ally chains come out opposite one another its easy to daw the product in a sensible fics. ¢ “To draw the stereochemistry ofthe epoxide formation itis sensible to put the reacting groups i= the plane of the paper and arranged so that the oxyanion can do an Sx? displacement Purpose of the problem Practice at relating the stereochemistry of cyclic and open-chain compounds, Suggested solution ‘We should first discover which atoms in the cyclic compound provide which atoms in the prod ‘Nambering the atoms is the easiest way and it shows litle change except that C9 has gone ané has become an aldehyde. os 4 + E t # whee =F yo? on Wwe: ani fiz Purpo A sore Segee Opn — = Dore a rdChapter 34 Suggested solutions for Chapter 34 295 ‘We need to hydrolyse the ester and the acetal and oxidize the 1,2-diol. The stereochemistry at C3 and C7 is unchanged and neither is threatened by any of the reaction conditions 4 Problem 10 How would you transform this alkene stereoseectively it ether ofthe dasterenisomers of _ the amino aieohor? Purpose of the problem [A more dificult extension of Problem Suggested solution Opening the epoxice with a nitrogen nucleophile makes one isomer. At least the alkene is symmetrical soit doesn't matter which end of the epoxide is attacked by the nucleophile, We have chosen aide ion (N) as the nucleophile, Ammonia wil also do as, although it can react repeatedly, it usually behaves itself with epoxides. You were not asked to make both distereoisomers, so we can stop there warae a Eiplan te foration ot scent ‘one stereoisomer inthis reaction. Purpose of the problem ‘A more dificult extension of Problem 4 with aldedFelkin complications ns296 Organic Chemistry Solutions Manual Suggested solution ‘The sym selectivity of the aldol reaction comes from the chair conformation of the cys (Zimmerman-Traxler} transition state. Ignoring the stereochemistry ofthe aldehyde we have ths simplified explanation, ae ae ol. ottd ‘We have inevitably drawn the sym aldol product as one enantiomer but so far there is no control ‘over absolute stereochemistry. The aldehyde is itself a single enantiomer and so the two faces oft carbonyl group are diasterotopic and which one the enolate will attack would normally & determined by the usual Felkin argument. 18 And to te surprise of Sators ‘To our surprise this isnot the prefered isomer. Infact the ‘anti-Felkin’somer predominates Masamune ae! ns comer about 3:1. The compound is entirely the sy aldol but attack has occurred on the aldehyde in fase. Chom. Int. Ed. Ere. 1980, aternative conformation. Of s-O ‘There is an important lesson to be learnt here. The principles we have been explaining ace generally true but in any individual case the result may not follow the principle, This is particulars true of Felkin control with aldehyles as H and O are not that different in size. You should first apps the principle (here Felkin control) and then check the result. You should not be ashamed if you gs this one wrong. How would you atampt to transform this alle alco! Ito bath elateeoisomers of he crt sterneletve¥y? You are rt expected io ent ie cng of suncens, Purpose of the problem ‘An exercise in true control ~ geting whichever isomer you want. Suggested solution ‘The OH group will direct a simple mCPBA epoxidation by hydrogen-bonding tothe reagent an delivering the oxygen atom to the same face in a Houk conformation (p. 877). To get the ars «epoxide we must block the OH group with a lage removable protecting group to get control297 Chapter 34 Suggested solutions for Chapter 34 ‘atic hindrance. You might have chosen a large sly] group, a benzyl group, or many others. In the ™ Fallowing on om the ast ook (p. 884) we suggested an acetate en 9 aan they ae nt oen very god Deperang on he syn salactvty itn mOPBA maybe only 60:40. The Prine wor, but nat wo Arco im hoy : els Taeeaer RE Ae, SIRs, PROM, ate, Problem 43 Revision. Here Is an outline of the AstraZeneca synthesis of a thromboxane analogue, Explain the reactions, giving mechanisms for each step, and explain how the stereochemistry is controlled. In what way could this be considered an ‘example ofthe contol of open-chain preaaea sin je We matic gied? ° ° 2. 800K, PMP coy ay ° 2. CFyCMOHs ed Purpose of the problem “sinly revision but there is some stereochemical contra both in two and three dimensions, Suggested solution 2 first reaction clearly involves the formation ofan enolate from the only enolzable compound “2 anyride) and its attack on the aromatic achyde. The ycization that follows may look a bit, -e~Socard but it forms a five-membered ring and the lewving group is a stable carboxylate anion. is no stereochemical control inthis step. = re) vy F ° Or 1b 264. “Treatment with acid allows the formation of the enol of the acid and the molecule adopts the ore table anti configuration under thermodynamic control. Borane reduces the acid (p. 618) and ‘SS°AL reduces the lactone to the lactol (pp. 620-1),Organic Chemistry Solutions Manual 121. M.Lawor ana M.B. Nacramee, Tevanearon Late, 1983, 24, 2711. The product 's a thvorborane antagonist eveloped by te then Il and ‘escrbed in S, se a8 66 Reainsan, Process development, (Orford University Press, Ore, 1998, pp. 27-37. BA--ot Now a Wittig reaction with an unstailized ylid selectively gives the Zalkene. Note that sw ‘molecules of base are needed: one to open the lactol, one to remove the proton from CO:H, an ‘one to make the yid. eel toon Me PH HHO PP oo { See on “The las reagent is the hydrate of teiuoroacetaldehyde with which it isin equilibrium. The vex reactive aldehyde forms an acetal with the diol we have just made and does so ui= thermodynamic control The product has two equatorial groups and the one ail group hes = 1,3-diaxil interactions as the relevant atoms inthe ring ae the oxygens of the acta. SH ll {In what way could this be considered an example of the control of open-chain stereocher== ‘when all the molecules are cyclict Well, they are all cyclic except the last intermediate and i === ‘ease the ring concerned isan ester (lactone) or an acetal that can be hydrolysed to an open-cham ‘compound without disrupting the stereochemistry. TFSuggested solutions for Chapter 35 35 Problem 1 {Give mechanisms for these reactions, explaining the stereochemisty. At be, ony! ooo as Purpose of the problem Not the expected Diels-Alder reaction, but (2 + 2] eylondditons of ketenes. Suggested solution “Treatment of acid chlorides with tertiary amines produces ketenes. In this case an intramolecular 1+ 2] eyelouddition is possible. The stereochemistry is trivial the cis ring junction is the only ee , & : i a oe: ee ay ‘sossible outcome, Ifa more reactive alkene (electron-donating O makes the HOMO energy higher) is provided, the “etene adds to that instead. Notice that the alkene must be present when the ketene is generated. The mechanisin and part of the stereochemistry is simple. Because the cyclic alkene has cis stereochemistry, the two hydrogens on the six-membered ring must be cit in the product. The regiochemistry arises because the alkene is an enol ether and the large coefficient in its HOMO interacts with the central atom of the ketene, that i, the largest coefficient in the LUMO. a] por} HOMO q “t 1 res a ore ni an ‘The stereochemistry at the remaining centre comes from the way in which the two molecules We can discuss here; seo approach each other The two components ae orthogonal and the date lines in the middle ™ M-DSeeis on 1, Cra Eiagram below show how the new bonds are formed. The carbonyl group of theketene wil prefer toe 1, fein the mide ofthe rngand the side cain onthe ketene wll bend down away fom he tp ring These (2 + 2] thermal cycloadditions normally give the all-cis product. eas QO ats, af bo of —300 Organic Chemistry Solutions Manual Purpose of the problem Now the expected Diels-Alder reaction. Suggested solution The diene is electron-rich and will se ts HOMO in the eyloadaition. Ie wil therefore pret alkene with the lowest LUMO and that must be the unsaturated ester. Both substituents o7 the dene dzect reaction tthe same end. We can predict this from eecton donation fom the o¥-e= on =) ap ean ef id oo pe ct ae dejo neces ie ‘bath substuents pt largest HOMO coerce hero count oe ‘nti fhe anttonou agent product. The stereochemistry ofthe OMe group comes from endo attack ~ we should tack the 2 venato y S Danse aed |Soup underneath he den 0 that it can oveap with he orbital ofthe mide two atoms. Fy== Soe, A PMS 3976.28, oo said that this product will eliminate methanol on work-up and that only the stereochemist = the ring junction really matters, you'd be quite right Purpose of the problem More details ofthe intramolecular Diels-Alder reation, ‘Supl etna owlChapter 35 Suggested solutions for Chapter 35, Suggested solution ‘The dienes are the same, the ring sizes are the same, and the only difference isthe presence of the benzene ring in the faster reacting compound. We should draw a mechanism for one of the reactions just to see what is happening. We are making two new rings. The sixcmembered ring containing « cisalkene presents no problem. The eight-membered ring with a ketone in it might present a problem, and the ten- membered ring with the trans-alkene is defintely a problem, It is much easier to make medium (8: to 14-membered) rings when there isa cis-alkene elsewhere in the ring and the benzene ring helps there, It increases the population of conformations with the ends of their chains close together. It probably also lowers the energy of the LUMO. Problem 4 5 Jus the stereoselctty inthis intramolecular Diels-Alder reaction. Purpose of the problem Investigating the stercoslectvty of the intramolecular Diel-Alder reaction ‘Suggested solution Intramolecular Diels-Alder reactions can give endo or exo products. We should first discover ‘hich this is. Drawing the transition state for the endo product, we find that the endo product is indeed formed. So electronic factors dominate, perhaps because the dienophile has such a low- ‘energy LUMO and has two carbonyl groups for secondary orbital overlap with the back of the diene, ora wo el 15 Ths reaction is part of @ ‘syncs ofthe tran haicton (KJ Sea and PD. Davi, angen: (hem, Int Ed. Eng, 1988, 22, 419). 12.0. whe and BG. Shen, 4 Org. cham, 1983, 46, 2273.302 Organic Chemistry Solutions Manual Problem 5 Explain the formation of single adducts in these reactions. Purpose of the problem Investigating the regio- and stereoseectivity of one inter-and one intramolecular Diels-Alder reaction. ‘Suggested solution ‘The stereoselectvity of the first reaction is straightforward. It gives the endo product. Sah Ep ‘ ‘The regiachemisty is not quite so simple. The diene has the larger HOMO coefficient at the tend, as drawn, so we must deduce thatthe largest LUMO coefficient inthe unsymmetrical quin. is atthe top let as drawn. This is probably because conjugation with the MeO group makes the tor ‘carbonyl and the right-hand alkene less electrophilic and the bottom carbonyl activates the top ene of the let om = BE Sens ftp roe (heme aca! ey aS ye ede ic ncaa gly Lela 800, 2031-6) ‘ster linkage between the diene and the dienophile is oo short for them to join up the other w= round. This same link (‘tether’) also forces the dienophile to approach the diene from the botto=: face, All that remains is the endo/exo question and the diagram shows thatthe answer is endo wit: the carbonyl group tucked under the back of the diene.Chapter 35 Suggested solutions for Chapter 35 | Zevision elements. Suggest two syntheses of this spiracycic ketone from ve staring atefls shown Neither stating material is vale oapeS= ose of the problem “+n of eymhesis (Chapters 25 and 30) with some cycloaddition. Helping you to resize that cos se alternative ways to make scmembered rings sted solution ost obvious disconnection is ofthe 2,8-unsaturated ketone with an aldol reaction (Chapter 27) | =r. This reveals a I4-diearbonyl compound, Direct disconnection to one ofthe starting materials "possible and suggests a Diels-Alder reaction. “Ts: Diels-Alder reaction has the right (par) cegoselectivity, especially if we use Lewis acid ‘=> © SnCly, and we shall need a nonbasic specific enol equivalent for the alkylation ~ an enamine fine. Fede ge Ti other route demands a different disconnection of the keto-aldehyde plus one further aldol "<= snection. The starting material is more easily made by Birch reduction than by a Diels-Alder Bao=525 “2 Birch reduction gives the enol ether of the ketone and demands careful hydrolysis to avoid = 5 bond moving into conjugation with the earbonyl group. The aldol reaction requires = \erd of contro; perhaps the silyl enol ether of acetone will do. Then we need a reagent forOrganic Chemistry Solutions Manual CHO’ that will do conjugate addition. The most obvious choices are eyanide ion or nitromethane. ‘The last step i the same as inthe fist synthesis, Purpose of the problem Revision of synthesis (Chapters 25 and 30) with some cyloaddition. Helping you to realize that ‘here are allerative ways to make six-membered rings. Suggested solution “The regioselectvty comes from the contribution of the EtO group to the HOMO of te diene sné the dominating influence of the conjugated CO,Me group on the LUMO of the dienophil. Neithe: the other COzMe group nor the sulfur atom is conjugated 10 the alkene ofthe dienophile and ‘either as much influence on the reaction. Aernatively, you could say thatthe OEt and CO:Me ‘groups are ‘par! in the product. eR “pa over facile ae the cis elationship between H and CO2Me in the dienophile, which i {faithfully reproduced atthe ring junction of the product,Chapter 35 Suggested solutions for Chapter 35 305 Purpose of the problem “Exploration of stereochemical control by 1,3-dipalarcjeloadditions, Revision ofthe importance of ‘oli compounds, ‘Suggested solution nitrile oxide adds in one step tothe civalkene to give a single diastereoizomer of 13-dipolar Joadduct. Tis is also a [4 + 2) cyeloaddition with the dipole supplying fou electrons. The two Sectyl groups on the alkene start i and remain so in the adduct. ont Cg fe L. a a Sot hem, 1960, 122, ‘The first reduction must be of the imine as it also is stereoselective with hydride being transferred ‘om the face of the five-membered ring opposite to the methyl groups. If reduction of the N-O ‘ond occurred first, we should expect litte control in the reduction of the imine. Revision. One of he nirones used as an Maem ieee roar nee ‘ Expl ce 1s happening and give etals of 36 Feactons. Purpose of the problem Revision of mechanisms from previous chapters. Suggested solution ‘The fist reaction is a base-catalysed conjugate addition of the kind described in Chapter 29 pp. 766-8) followed by the formation of an acetal by the mechanisms described in detal in Chapter 14 (pp. 342-5). OLS og lk Rone Nog clon vahy oss306 Organic Chemistry Solutions Manual Re roe as ad ng ‘The next step isthe reduction of the nitro group to the hydroxylamine by the very versatile Zin sytesis of vopane alien dhe cyclization ofthe hydr ‘on to the released aldehyde to give the nitrone. (9.1430) by. Tefal ad ei ria of te it ay adehrde wie he alone. foun 1, Am. Cron. Sox, 1978, ° oH 40,2435. oH as "ain ye Diels-Alder readin glen ta) resoasecy on storeospecity but no steraoseletvty, What he “inechanism ofthe secone step? What altematve route might you have considered if you wanted to make this al _ and why would you reject it? i) ies Purpose of the problem ‘More on selectivity in the Diels-Alder reaction and more comparison with Birch reduction. Suggested solution ‘The regioselectivity is dominated by the nitro and MeO groups ~ we can tell that by the way ther end up ‘orto’ in the product. The stereospecifcity is the faithful reproduction of the stereochemistry of the dienophile The stereosclecivity that might have been observed would hae: been exoendo steeochemistiy but there are two groups (NO; and CO;Me) that might have goce «endo and apparently no preference ne mu ‘The base-catalysed elimination must be an ElcB loss of nitrite (NOP) from the ester enolate aeChapter 35 Suggested solutions for Chapter 35 Alternative vatheses would include a direct Diels-Alder reaction with an alkyne, but that would M1198 6a general sythess of tthe wrong para) regioisomer, oF the Bitch zeduction at a m-methosybenzoate ester but that eRUERY Hed aroma empovnes by 8, Dan oo would have given the wrong resioslecivity: emmovnes tS Der one i” \ Me a, eou0H er) come come Problem 44 Give mecranisms for these reactions and explain the rego- and stereochemical convo or the lack of it i Oh. an A. zn, Hoke ° Nah Seater] betta Purpose of the problem Selectivity and application of 1.3 dipolar eytoaduitions, Suggested solution were AE UAN hond ee nh he HOM of he doe wr ge cece the seb) Ean rey fom te phe] gop. The s osetia thee conan group and Teme med et + no exoferide selection, - aa ‘ ms g ! = Reduction with rine deaves the N-O bond and Ma asidines the allie slo) to the enone. AL his point there is only one chiral centre so the misture of diastereoisonsers become one compound. Conjugate addition of the amine gives the new ring, 2.Mn02 the stereochemistey i more difficult to explain. The product bas a erans cing junction trons choice but has the Ph group axial ~ obviously nox from choice. This rmust be the Kisetie produc. It308 15 Ths i por of synthesis of various altsiods by C. Kayan and gow. J Chem. Soc, Chem. ‘Commun, 1983, 1343, 12 Tis soquerce was used by 0.5, Watt and EJ. Corey ina Ssyrtess of cedertail (Tevahedren Let, 1972, 4651). Organic Chemistry Solutions Manual ‘looks as though the ing must close with the best overlap between the nitrogen lone ‘orbital of the enone to give a csring junction, which equlibraes by pyramidal inve to the more stable trans ring junction. “Suggs a trechism for the tescon ad exan tho sere en redochemisty. How eas YOU Hae ra ketone ee material? Selectivity and application of forward and reverse Diels-Aldar cycloadditions. Suggested solution ‘The reaction is clearly a eyeloaddition but at fist sight the regoseectvty i all wrong, The answ comes from tion that this is a reverse electron demand Diels-Alder reaction. The dies very electron-deficent with two conjugated carbonyl groups so the dienophile needs to be electro=> rich. The enone isnot electron-rich enough but its enol is. The enone could be prepared by Bir reduction,Chapter 35 Suggested solutions for Chapter 35 ‘Purpose of the problem Ssvigy and application of photochemical [2 + 2] eyloadations. Suggested solution 1 of the wo starting materials could absorb the light to provide the SOMO for the -setaddition. This does not affect the stereochemistry of the reaction. There is no endo effect in { = 2] photocycloadditions so the molecules simply come together with the rings arranged in an ‘== ‘ashion to give the least steric hindrance (diagram in fame in margin). Moose Shain ra a ie mo OT “com mod h pu ‘The stereochemistry of the reduction is easy to explain as the molecule is folded in such a way ‘bar only the bottom face of the carbonyl group is open to nucleophilic attack. The oxyanion ‘reduced can immediately cylize to form the lactone. Cleary, this is possible ony ifthe O- group © 2p, but itis also possible only if the CO;Me groups are on this side of the molecule. The ormation of the lactone does prove the stereochemisiry ofthe cycloaddition. Purpose of the problem Exploration of anew structure, revision of aromaticity, and encounter with [8 + 2] cyeloadditions. Suggested solution ‘his particular thioketone i stable because the C=S bond is very polarized by delocalization making ‘Se seven-membered ring an aromatic cation with six eleettons in it. Though all the diagrams are sorrec, the one in the frame (margin) gives a better representation of the structure. Oe ee ee se oO310 Organic Chemistry Solutions Manual 15 T-Machiguchl et a, J. Chem. But we cant use diagrams like that for mechanisms The cycloaddition uses maleic anhydride as 2 ‘See Cham. Commun. 1973, 196. pwo-electron component with alow LUMO. We could use one of the dienes in the ring to provige four electrons but their ends are far apart and the electron-deficient ring is 8 poor HOMO. Ife include the sulfar atom we ean provide eight electrons and an atom (S) with a large HOMO ‘coefficient. The tricyclic product is clerly folded back on itself so thatthe tiene in the sever ‘membered ring and the carbonyl groups in the anhydride are close, There must bean endo effet i= [8 +2] eydloadditions. Purpose of the problem Discovery of a common effect in intramolecular cycloadditions. Suggested solution ‘= JA Gras and M.Servond, Ifthe starting material were heated it would no doubt undergo a Diels-Alder reaction but the diese Tetranewon Let, 1979, 4543, and dienophile are poorly matched. Both have high-energy HOMOs but there isn't a low-enes-7 LUMO in sight. Once the enone is formed, the energies match well and cycloaddition is fast. T= 37 stereochemistry comes from an endo arrangement (diagram in fiame in margin). Avide ve Mo. iene verge The Chapter 35 Suggested solutions for Chapter 35 Purpose of the problem Two tnasual things: 9 sterooseect 4 a subsequent reaction, Suggested solution There has obviously heon a cycloaddition between the furan as diene and maleic anhydride and an ‘esterication ofthe free OH geoup by the anhyeide. Whichever we do frst, the stereochemistry exo, This is because furans ae aromatic and the Diel-Aller ceaction is reversible and under hermadsnamie control, We'll do that frst Kd ° ‘The second step is obsiously some sort of elimination driven by che formation ofa benzene ring. Both the lactone and the COsH group are still there soit looks as though MeO acts asa ase and thatthe bridging oxygen atom is lost, presumably as water. The E1eB niechanise looks likely o © 0) 0 Seap cop “oy _ 5 coy ° = ‘o Moo? - = Ho” we , bp 8 7 com ® aaa. 18 4 Peter ana 8. Sagoo, J Gaem Soa. Pein Tans 4, 4983, 1360,‘A gentle introduction to an electrocyelic reaction without stereo- or regioslectivty. ‘Suggested solution Grignard reagents generally prefer direct to conjugate addition especially with unsatuate! aldehydes. MaOs specializes in oxidizing allylic alcohols nd isthe gene oxidizing agent we need produce the unstable dienone. ‘The perieyclic process comes next and it is a Nazarov reaction (p. 962), a conrotatox ectrocyelie closure of a pentadienyl cation to give a cyclopentenyl cation. There is > stereochemistry and the only regiochemistry isthe position of the double bond at the end of &: reaction, Here it prefers the mote substituted side of the ring ope ‘The final cuprate addition goes in conjugate fashion as we should expect as this isthe special ‘of Cult) compounds. The cis 5/5 ring junction is much preferred to trans and can equilibrate c= ‘work-up by enolization,Chapter 36 Suggested solutions for Chapter 36 343 Purpose of the problem A gentle introduction to an electrocycic reaction without stereo- or repioselectvity. Suggested solution This isa classic Clasen(3,3]-sigmatropic rearrangement sequence starting with an allylic alcohol This product was used ina 2nd forming a vinyl ether by acetal (or inthis case, orhoester) exchange. The reaction is very trans. Sythess of chnsantemic acs by sclective (p. 944). ‘acquelie Fn and Jean Angle, ee Tetrahedron Lett, 1976, 2441 ‘Parpose of the problem Als iroducon to an decry reaction without ero rpc | Seagested solution ‘Tis Grst stage isan aliphatic Fridel-Crafis reaction with an aclium ion attacking the alkene. 5 : a So: fh. OL ‘Next a Nazarov reaction catalysed by a different Lewis acid closes the five-membered ring and _™ W. Oppolzer and K. Bittg, Helv. "= she double bond inthe only place it can go. The electrocylic sep is conrotatory but ths has no Chim. Acta, 4981, 64, 2489, i ‘meaning with this achiral product. of oh = ah atc}aaa Organic Chemistry Solutions Manual Purpose of the problem ‘Two perieyclic reactions: a sigmatropic shift and a cycloaddition in one reaction scheme. Suggested solution ‘The aromatic anion of cyclopentadiene displaces tosylate from the alkyl group and then a [1,5] Inydeogen sift gives the first prodct. Such ashi is lloeed suprtacially on the ring (pp. 953-5) = —reig. aD) Now there is an intramolecular Diels-Alder reaction requiring a high temperature because the ‘= Tos sor of Diets-Alder reaction dienophile is not activated. The stereochemistry is not obvious but there is no endo effect so the as used ina sntnesis of cedoity molecule folds to give the new five-membered ring a cis ring junction with the old. EG. Brethole and A. Fale, a J 0g Chom, 1978, 43, 2968, | 4. eg0, pyridine cmuaarerChapter 36 Suggested solutions for Chapter 36 345 Purpose of the problem ‘elating the material of this chapter to that of previous chapters and a bit of revision of basic ‘sschanisms. Suggested solution “The fest sequence of reactions is simple, The Sy2 reaction goes with inversion and reduction occurs an the outside (convex, exo-fae) of the folded ketone ee Pets lo Sneiiote in, S2 Cy as na 04 4. tn ne 1 “The second reaction involves a reverse Diels-Alder reaction and an electrocyelic opening of the ‘svclabutene product. This is a four-electron conrotatory process, The two substituents may both rotate out to give the E.F-diene or both in to give the Z,Z-diene. oe oe Srey a ee a deeesenrer ‘The NMR spectrum shows clearly that the EE-diene is formed. The two coupling constants for ty ths methcd was vey Use in. the simple doublets must be forthe terminal hydrogens and 14.7 Hz.is definitely a tans coupling, ©¥osadtons (8. M. Wost ang might wonder about 12.1 Hizasit is on the ow side but the alkene hasan electronegative yen Og Gham, 2978, 43, Ac) substituent and couplings will be low (pp. 269-70). near SPM oy eee 22608 5Ph sig 782 0H, J3240 9.28 0N.4a, 110,247) Ph 0 p23 SosiimasJs03120H HOSLMasIAN Ph j/247 Problem6 a ie attempts to cany out a Clasen rearrangement, otis ay ether often jpoune shown instead ofthe expected procuct. Whats the expectee cree Ries lee alee aie sacl ste Ss feshoee: eh 05 tm HEE Purpose of the problem Exploration of what may follow a simple (33]-sigmatropie rearrangement. ==| 316 Organic Chemistry Solutions Manual Suggested solution ‘The expected Clasen rearrangement is straightforward and evidently happens. Ce Cpa Oee ‘The ring is formed by addition ofthe phenol to the alkene, The alkene is an ordinary alkene tha: ‘reacts with electrophiles, not nucleophiles, so this must be an acid-catalysed reaction and can be suppressed by a weak base. Purpose of the problem ‘Am unusual example of an electrocyelic reaction on an anion. Suggested solution ‘#19 nese feat angie of The proton from the mide ofthe molecule remoned to give an anion stabilized by two niteogers Sarectemal sg navere and two phenyl groups. A si-lectron eletrocyclic rection closes the five-membered ring and this feareaes rotons: see must be dirtatry moving both phenyl groups up (or down) Gorm Soe. 1969, 91. 6202 ss heatsChapter 36 Suggested solutions for Chapter 36 Purpose of the problem Revision of aromaticity and two alternative electrocyclic reactions. Suggested solution “The amine as eight electrons in double bonds and a lone pair on the nitrogen atom making ten ‘a all It could be aromatic with 4n + 2 electrons (n = 2). The two reactions are clearly siectroeyelic and must be disrotatory to get cs ring junctions (the only possible arrangement for Pinging two flat rings). Therszlly this means a six-electron proczss, but photochemically an ight-elecron process is all right. The nitrogen does not appear to be involved in either reaction, CEN couse doe ee Purpose of the problem nother electrocylclycoadditon combination fo you to work out Suggested solution ‘he three-membered ring opens usin the lone par on nitrogen in a four-letron conrotatory -2ctrocyeie process. One phenyl group must rotate inwards and the other outwards. Then & loaddition of the four-election dipole on to the two-electron dienophile goes without ange of stereochemistry. The ester groups remain cis and the phenyls must be one up and one eal 347 12 Ts was an iewestigation no We ‘omatcy ofthe staring material Dy AG. Anastassiou ano LH, Getvian, Tevanewan Let, ‘1969, 5238 1 Tis extensive tusy of the ‘opening of tree membered beterosyel rings came fom ‘isgen’s group in Munch Chom, ‘Soe, hem. Commun, 1973. 487, 186, 1190, 2d 1192)Oss 15 K Bepiesen ond. Satta ‘Acta Chem. Scar, 1978, B32, 553. Organic Chemistry Solutions Manual Problem 10 Cie a Lira abi Nm cites ‘Treatment of jlonexe. Sone wih tis acetylene emine ees a stable enamine in gooe Yie. Reflaing this enamine in irobenzene eves a pytcine after & remarkable series of reactions. Fill in the details: give mechanisms for the reactions. structures for any Intermediates, and suitable explenations for each a Step. A mechanism is not benaene acts a8 an oxidant). Purpose of the problem Practice in unraveling complicated reaction sequences involving pricycic steps Suggested solution ‘The formation of the enamine requires only a patient adding and subtracting of protons J=QJ*Q)-Gg-O ‘The cascade of reactions in hot nitrobenzene starts with a [3,3]-sigmatropic rearrangement k= ‘unusual in that it forms an allene but is otherwise straightforward. To get to the next interme === the stable conjugated primary enamine, we must enolize and go back tothe ketone again but = the double bond into conjugation, dg-ds-eg-u> [Now we can transfer a proton from nitrogen to the middle ofthe allene. This is formally [| shift and i, of cours, allowed but it may be the movement of a proton as nitrogen is involved sgives a diene that can twist round fora sixelectron electrocyclic reaction. This would no dos! isrotatory but we can't tell as there is no stereochemistry. bem dyadpot gat = rot Chapter 36 Suggested solutions for Chapter 36 319 Problem in Chapter 32 was concerned with two dasteoisomers ofthis vere fomned in what we then eal erigraticaly ‘a chemical reaction’ mo Purpose of the problem | lectrocylic and cycloaddition reactions again with some stereochemical interest. Suggested solution The yelobutene opens in a four-lectron conrotatoryclestocyclic reaction. The cyanide can go citer way and it will prefer to go out. The dene so prodiced i unstable and is extremely reactive in sxeloadalitons asi regenerates the benzene rng that way. The repochemisey is predictably ‘rho! sad we should probably use the HOMO of the diene and the LUMO ofthe unsaturated este. on “oy Sta 2 “ €03Me The stereochemistry shows that a 1:1 mixture of eso and endo products is formed. Presumably the “Eine is so reactive that tha ile neo of secondary otal interactions and steric hindrance plays an “pal part The omerzaton in base mus be by enolation (of ether group) so tat both substituents = be equatorial, The digas omit the benzene rng for cary. The cs compound i Band the as. pes! os an AK320 18 Tis study was onal aimed at ‘the aromaticty ofthe staring matoral (A 6. Anastassou and fgoup, 4. Chem. Soc, Chem {Commin, 1981, 647), Problem 13 Organic Chemistry Solutions Manual Purpose of the problem ‘An unesual electrocylic reaction on an anion with stereochemistry and NMR revision, Suggested solution “The fist anion A is formed by removal ofthe only possible protons - those on the one CH gro in the molecule. This anion might be considered aromatic (six electrons from the three dou bonds, two from the nitrogen, and two from the anion) but it is clearly unstable as it closes ir = electrocyelic reaction at > ~35°C. Ths is snceectron process and must therefore be disrotate= ‘The rotating hydrogens are marked on the diagram of A. Both anions, A and B, are extensv= delocalized and it s a matter of choice where you draw the negative charge 2-28 creo Me Anion B is protonated by water with preservation of the right-hand aromatic ring. The # product is achiral molecule having no plane of symmetry so the ringed CH group i diastereotr ‘ith Jus 15.4 Hz. This i larger than usual because of the 7 contribution ~ a neighbouring = bom increases "J by about 2 Hz. How would you make the starting material for these reactions? Treatment ofthe anhycride with butanol gives an ester the: {ives two inseparable compounds on heating. On treatment with an amine, an easily separable mixture of an acicie ane = neutral compound is formed. What are the components of the frst mixture and how are they formed? ost Se Os Purpose of the problem Exploration of alternative conrotatory openings of a cyclobutene. Suggested solution “The starting material can be made by a photochemical [2+ 2] eyloadtion of acetylene and a= anhydride, Treatment with butanol and base lads tothe monoester because, afer the butans! = "attacked once, the product isthe anion ofthe carboxylic acid and cannot be attacked again b= nucleophile. DMAP isa base whose structure appears in the margin. 3 i tl PP ode ie omar oo I 1» - | aot eosseChapter 36 Suggested solutions for Chapter 36 etn “hon te de ‘Heat opens the cyclobutene in a conrotatory four-electron electrocyclic reaction. As the two groups are ci on the cyclobutene, one must rotate outwards and one inwards. The two groups ae similar but not the same so there is little selection in the rotation and both produets are formed. Treatment with the tertiary amine forms the anions of the carboxylic acids, That of B can do a conjugate addition to the unsaturated ester and form the lactone but the carboxylate of A cannot seact Purpose of the problem oration of a less well defined pericycic sequence. Suggested solution DQ oxidizes the position between the two carbonyl groups to insert a double bond conjugated ‘with both. We can now put in some stereochemistry asthe three-membered ring has to be cis fased 0 both six-membered rings. This diene undergoes electrocyclic ring opening to form a seven- ‘membered ring. This isa sixelectron and therefore disrotatory reaction and the two bonds to the ‘old three-membered ring are therefore both allowed to rotate inwards the only rotation that can sive the product, 15 Ts obsenation was tl in developing a syethesis of ‘varocarin A, a natura product with atturmour acti (8. M. Tost and PG. McDougal JO. Chem., 11984, 49,458), 1 Tis reaction i pa of sthesis ofthe skieton of the atu reduetspnfern by JOA. Mahal and. €, Com, 5h Am. Cham, Soe. 1980, 102, A278,Organic Chemistry Solutions Manual 1 This reseton was cared out as, Dan of mecnanste sty by EN. Manvel and 8.1 Amond, Tovahecton tet, 1979, 2777. Problem 15 _ i : Explain the following observations. Heating this phenol brings it into rapid equilibrium wit = eee ae een treated with acta. i: Purpose of the problem Another electrocyclc reaction involving a three-membered ring. The o bonds in three-membs== rings are strained and more reactive than normal bonds and take part readily in perisss ‘Suggested solution ‘The fist step is very ikea Cleisen rearrangement but, as there is no oxygen atom, it is strc) = ‘Cope rearrangement, but in any case it isa favourabe [3,3|-sigmatropic rearrangement becaus: «bond involved is in a three-membered ring. This product cannot go directly to an arom= ‘compound a that would requite a [1.3] (ora [1,7] depending on how you count) hydrogen $= “These would have to be antarafacial on the 7 system and cannot happen in this rigid structir= ‘The aromatization can happen by an ionic mechanism. If the extended enol is protonated 2: = remote end it can then lose a proton from the ring junction and form the phenol =Suggested solutions for Chapter 37 37 Rrra fio Ts proBlocr teeta saad teak or wxkane ule sncomvents by nuicosrg: ‘There are io comlicated new reactions here, Just daw a mechanism. : ee ae Purpose of the problem 48s the problem says, to help you learn about simple rearrangements ~ those where the carbon Skeleton doesn't change. Suggested solution The frst reaction isthe preparation of Corey's protecting group for carboxylic acids The Lewis LE oe ay acid complexes one of the oxygens and all the atoms in the starting material end up in the ™ aay oduct. Atoms 3 and 5 are easy to identify inthe product and it doesn't much mate which of ‘he CH: groups you label 1,2, and 4. The dated lines show the new bonds made or old bonds aroken. ‘The mechanism can be drawn in various ways; here are two possibilities, the second being peter The second reaction is even easier to work out. Atoms 2 and 3 are easy to find and they identify 1 and 4. Just one C-O bond has been made, and one broken. As the compounds are acetals, we must324 Organic Chemistry Solutions Manual ‘use oxonjum ion intermediates and not do Sy? reactions (Chapter 14). Loss of BF; and rotation « the last intermediate though 180° gives the product. = ee ODE 8 EJ. Cory and M. 6. Back, Fotateson ono. 0008, The third eacin inves cyztion Atos nd 7 ary make the new bond andthe res cP atoms int place eho change except thatthe Bs gone andthe alkene has meoved from 78 to S= oo cei is ee ce Nee tte one oft soete ons ce Reteeer carer Seas ‘compounds IM. F. Senmethack, Gnd C.5:Mh, Am Chom Soc, Zine will insert oxidatively into the C-Br bond and the mechanism follows from the nucleop = Seon Latumaaainet - = sa". Bs ogh : ce b= ” ial if "Problem 2 Explain this series of reactions. i Purpose of the problem ‘Working out the stereochemistry and mechanism ofthe Beckmann rearrangement. ‘= rns example comes trom a Stiggested solution ener! imestgtion ito tne The first reaction forms the axime by the usual mechanism (Chapter 14). This reaction is === Sechrann andthe welt Schmit ehermodynamic control x0 the OH group will bend avay fromm the aryl substituent. Then we b= earner. Pre Backman Fearengment (pp 987-5). The oop ano the OH Boup mig frm © oes. and that gives the product after rehydration and adjustment of protons ; ~ wi, on ana rie HT ET Aa} VeChapter 37 Suggested solutions for Chapter 37 Problem 3 y z i Draw mechanisms for the reactions and structures for the Intermediates. Explain the stereochemisty, especially of the reactions involving boron Why was BEN chosen asthe hyeroborating ogent? he a e0r= Oca sec or Purpose of the problem ®earrangements involving boron and a ring closing rearrangement of sorts pls stereochemistry. Suggested solution ‘The starting material is symmetrical soit doesn't matter which face of which alkene you attack. The ‘aly important thing is thatthe boron binds to the more nucleophilic end of the alkene and that 3,B and H are edded cis. Alkaline HO, makes the hydroperoxide anion (HO-O~) and that attacks ‘oron, The important migration follows: the whole ring moves from boron to oxygen with -xention of configuration. Hydrolysis and mesylation (p. 484) give the first intermediate (Po—on es ne ae Gt ‘This mesylate cylizes an aqueous base. The more nucleophilic end of the other alkene displaces ‘>e mesylate with inversion to make the cis ring junction much preferred by a 5/5 fused system. “ater then attacks the tertiary cation to give the next intermediate Eimination of the alcohol (El, of course, its tertiary) gives the alkene and a repeat ofthe ‘ydcoboration from the outside (ex, convex) face ofthe folded molecule gives the ial aloha “sth ve new stereogenic centres. 2 Tis protic was wed a8 @ founsaien for te syttess of “ii terpenes by. 5. Mathews andi. KWnitasel, Og. Chem, 40.3315Organic Chemistry Solutions Manual i 18 JA, Chem, Soe. 1970, 92. (5057; see also 1K Crande and S.A. Soha, Tevahodio Lett {9-BBN was chosen because itis very large and reinforces the natural electronic preference of =~ borane to bind to the less substituted end of the alkene with 2 steric preference. It also *= bridgehead atoms bound to the boron and they make poor migrating groups (p. 1283) preven competitive migrations, The structure of 9-BBN isin the margin. Problem 4 ‘tis very dificult to prepare threemembered ring lactones. One sttemoted preperation by the epoxidation of d+-tbuty ketene gave an unstable compound with an IR stretch 2: __ 1900 om that decomposed ral tothe fourmembered lactone shown. Oo you thine ‘they made the threemembered ing? econ, ee Purpose of the problem Rearrangements as proof of structure? Surely not! Wait and se. Suggested solution. ‘The expected three-membered lactone would have a very high carbonyl stretching freque== because of ring strain (pp. 365-6). A three-membered cyclic Ketone has a carbonyl stretch of ab 1815 cm” and lactones have higher-frequency absorptions, So it might be the lactone, If tis. = rust find a mechanism for the ring expansion to the four-membered ring and that will have involve rearrangement because one of the butyl groups has gone. The general conclusion from = and other evidence is that R. Wheland and P. D. Bartlett did indeed make the first a-lactone ERROR Problem 5 ‘Suggest a mechanism for this rearrangement. Mee Purpose of the problem “Working out the mechaniim of @ new rearrangement, ‘Suggested solution ‘The starting material isan enamine and wil react with bromine in the manner ofan enol. Additi-= ‘of hydroxide to the first product gives the starting material for the rearrangement, Notice that ==Chapter 37 Suggested solutions for Chapter 37 327 nitrogen atom migrates rather than the carbon atom in the other ring and that suggests This raxton was sscovored by bartpatin in the loss ofthe bromide. Ubuntu noe 1 OB. CS ee oui Chem., 1979, 44, 3576, Problem 6 fe S a A single enantiomer ofthe epotde below rearranes with Lewis acid cataysis a ee 9 single enantiomer of product. Suggest a mechanism and comment on the stereoctiemisty. Purpose of the problem ‘unusual group migrates and stereochemistry gives a clue to mechanism, Suggested solution | The mechanism for the reaction must involve Lewis acid complexation of the epoxide oxygen stom, ction formation, and migration of CO:Et. This lst point may suprise you but inspection ofthe structure ofthe product shows thatthe COsEt group is indeed bonded tothe other carbon r i ee pon Me ke awe OL Aang sciething i sme appey Gr rechinen raes a5 manque t Je Wy a i ed ge pe ar nate yeaa ee ae ed ia oe Ce eae Wy does the CO; 81 poup migrate rer than the Hao Answer Forth sume eon! fhe Has ag peer ell ga (a Lae eto spose aj non ml COME pa te Se eekeet eeiienle ner lapel eabiealghad bere’ Tiee = Monet mctentgset ‘was the purpose of the investigation. One chiral centre is lost in the reaction so only absolute R: D. Bach and coworkers; J. Am, Sereochemissy relevant One explanation tthe eon is chore ved and that bond vo S27 2578, 3078 tation is fast in the direction shown (the CO;Et group is already down and has to rotate through so aly 30° get in the igh poston for migration), The thers tht te migation sconce Ths locks unl atthe ena algnment re por,328 Organic Chemistry Solutions Manual 15 The pinao!eimertationsooaars on p 1029. Purpose of the problem For you to discover that four-membered rings rearrange easly to form five-membered rings Suggested solution The first reaction is a simple pinacol rearrangement (p. 984). The molecule is symmeta = protonation of either alcohol and migration of either C-C bond give the produc. acts CoH wo, a b-Bp-tpate Reduction ofthe ketone to the alcobol is trivial and then acid treatment allows the los of wise and a ring expansion of the second fout- membered ring. You may have drawn thi asa concerted = stepwise process. The elimination gives the most highly substituted alkene. Both rearrangeme== happen very easily because of the relief of strain in going from four- to five-membered rings. Purpose of the problem Prediction in rearrangements is a important as elsewhere and the Baeyer-Viliger is one of th: tmore predictable rearrangements, Suggested solution ne There are afew minor traps here that we're sure you avoided. The first compound has two carbon soups, bu eters don't do Baeyer-Wiliger rearrangements so only the Ketone reacts. The moreChapter 37 Suggested solutions for Chapter 37 329 substituted carbon ator migrates with retention of configuration (pp. 992-7). he aldehyde rearranges with migration of the benzene ring in preference to the hydzogen atom. The last compound is C; symmetric s0 it doesn’t matter which group migrates as long as you ensure retention of configuration (and take care when re-draving as the migrating group is drawn the other way up). The products ate Eh OT sh Problem 9 ‘Suggest mechenisms for these rearrangements explaining the stereochemistry in the second example. Kee OT PEO Purpose of the problem Unravelling one rearrangement after another involving ring expansion and ring contraction wit some stereochemistry. Suggested solution The first reaction is a simple ring expansion. The amine is not involved as it is completely protonated. The final loss ofthe proton may be concerted with the migration as this would explain the position ofthe alkene in the product. tee BBR The cond eon srt with ominton of the len nd interception of the bromonium ‘on by the amine. Only when the bromine adds to the opposite face ofthe alkene can the amine slize s@ this reaction resembles iodolactonization. Probably the initial bromination is *eversible330 Organic Chemistry Solutions Manuat mney stoves sees ily the weak bas bicarbonate HCO5) is enough to remove a peoton fom the cation frm weiitacinebicctietce BY aitogen parcciation in the displacement of bromide. The five-membered heterocycle expen’: ‘fCanata( Manco eae am 10 sicmembered. This alkene is formed because the C-N* bond tothe eran cazbon is broker Orem. Soe 1973, 96,7510, preferentially Purpose of the problem Sling te emia e formation igement with some revision of stereochemistry and scet2 Suggested solution ‘The formation ofthe acetal is by the usual mechanism (p. 342) with one twist. The double bond + in conjugation with the ketone in the starting material but has moved in the acetal. There is me longer any conjugation possible bt how and why does it move? How is easy. At several stages in acetal mechanism, intermediates are formed that can enolize ~ we show one possibility. The ‘conjugated and the unconjugated intermediate are in equilibrium and either can cyelize to the acetal, So the ‘unconjugated’ acetal must be more stable. This is partly because one of the C-O bonds must be axial and itis better for the acetal centre to be on a true chair than on a twist-chaie ‘conformation. ‘The next stage isa standard dihydroxylation with 050g. The two OH groups must be added ins cis fashion but why do they add to the top face of the alkene? This is easier to see in = conformational drawing. The top face of the alkene is virtually unhindered whereas the botiom face ahs satelChapter 37 Suggested solutions for Chapter 37 334. has most of the other ring ~ indeed all of the rest of the molecule except (ust) the methyl group. This sequence was pat of he ‘The product is a cis-decalin (Chapter 18, p. 463). Srbaret tn ae ‘oun, 4m. Chem. Soc, 1982, % Ton ‘ey 104, 1907. 19 2) . pooh fom wo: I! ‘The rearrangement starts with chemoselective tosylation of the secondary alcohol. Base then initiates the rearrangement itself by removing the proton from the tertiary alcohol, The stereochemistry follows the usual path ~ the migrating group goes with retention and the tosylate carbon is inverted. In an ordinary pinacol rearrangement ether ofthe alcohols could be protonated Dut in ths ‘semi-pinacol’ rearrangement only the secondary alcohol tosylate and so it must leave. ‘The migrating group is selected by whichever bond is anti-periplanar to the C-OTs bond. In this «ase itis the ring junction bond as the OTs group is equatorial (see diagram in the margin). ee scnseie ‘me oshara mo Pee ; Rt 2.x qo es = he Problem 11 Suggest mechanisms for nese eactons tat expan ary selectivity in he migaton tae! on on cae 100% ee g an “a mM i: ‘o Purpose of the problem ‘To show that ring expansion from three- to four-membered rings and ring contraction the other way are about as easy Suggested solution ‘The frst mechanism is & pinacol rearrangement and the compound is symmetrical soit doesn't J+M. Conia and J.P. Bamir, matter which alcohol is protonated. Both three and four-membered rings are strained and the Tevanewon Let, 1973, 4963, ‘-bonds are more reactive (higher HOMO energy) than normal. This makes ring contraction an «easy reaction even though the strain isnot relieved. Eon 0m ‘The second example looks at fist to be a similar pinacol restrangement. But the resulting ketone «cannot easily be transformed into the product Fy git332 12M. Danis and Conia, Tevahedon Let, 1972, 4583. 15 Tis suprising reaction is one way to make the impotan [actams present peiciine ang oer andbives J. Deyrup ant 8.6. Cough, Am. Chem. Soc, 11909, 91.4550 Organic Chemistry Solutions Manual Breaking one of the cyclopropane rings gets us off to a better start. Ths gives a hydroxy-ker=e that can rearrange in a pinacol fashion to the product with ring expansion of the remaizme cyelopropane. due he ci chloride rom this unusual amin ee ie Purpose of the problem ‘To show that ring expansion from three- to four-membered rings is even easier in hetero ‘because of participation. Suggested solution ‘The formation ofthe acid ebloride might go to completion ori might be some intermediate on the ‘way to the acid chloride that rearranges. We shal use an intermediate, Whichever you use, participation by nitcogen that stats the ring expansion going, though the next intermediate is vert ‘unstable. When chloride attacks the bicyclic cation, it cleaves the most strained bond, the one = both three-membered tings. Purpose of the problem To show that heteroatoms can migrate too given the chance and revision of Chapters 14 and 2! Suggested solution “The firs step is a standard acd-catalysedhalogenation of a ketone via the enol (p. 533) and tke second looks at fist like a standard imine formation (p. 349) until you ntice that the Br has beesChapter 37 Suggested solutions for Chapter 37 333 seplaced by OH. Imine formation starts in the usual way but, before the carbonyl oxygen leaves its “deally placed to displace the bromine and form an epoxide. Opening the epoxide with the nitrogen atom completes the migration of oxygen from one atom to another. wi) Me Me o. Hm 9° Cin 9 y ae Z he iv ‘Protonation of the imine provides the perfect platform for a ing expansion as the OH group can ©. L. Stevens et a, J. Or. sha ring bond across to the imine carbon, In this sequence we see participation by heteroatom ¥"' 1965, 30, 2907. ‘a the frst rearrangement and then heteroatoms at electron sources and electron sinks in the Problem 14 Suggest a mechanism fortis rearrangement, comparing it with a restion lscussed in the chapter. What controls the stereochemisty? ax = ch Purpose of the problem &clping you to recognize the Favorskil reaction (p. 990) Suggested solution "most acti proton inthe molecule isthe NH ofthe amie. Los ofthe chloride ion from thew Ts work wos cari ot ing aon gives a sort of cally cation and ths can cose in a disoatryeecroycic w+ Hosea n Fantom tan by von proces. The resulting cation is just a strange way of drawing a three-memberedcyic HeMng eH Ua side and attack of hydroxide on this strained molecule releases the best anion (nitrogen) and gives *”™*"*d0” Let» 1983, “product We know that the CO:H group i the product is down and so the conrtation mast scsi with the hydrogen (and the lone pair om nitrogen) rotating up. This pus the new thee nbered ring on the outside (em- or conver fice) ofthe fold rng ester.Suggested solutions for Chapter 38 38 ‘ogentoos y mbes, tom amano te iragrenttions = __basl solution SNe, Purpose of the problem As the problem says, to help you learn about simple fragmentations. Suggested solution ‘We can identify the six-membered ring in both compounds ~ the sequence 1-6 is larly the =e in both with aside chain at C3. The fragmentation is easy enough too ~ the OH proton is rece and the mesylate must be the leaving group so we have our ‘push and pull clear from the sta ‘The two CO:H groups in the second product might cause a moment's concern but one is 0 = -CH¥s-CH,- side chain and one is at a branchpoint and we can soon fil in the rest of the numbers Clearly also, the OH proton is removed and one of the carboxyl is the leaving group. T= stereochemistry disappeats in the fragmentation but itis important as the conformational dravins shows. One lone pair on the O-, the bond being fragmented, and the bond to the leaving group =. all parallel (shove in thick lines).Chapter 38 Suggested solutions for Chapter 38 335 Problem 2 ‘Treatment ofthis hydroxy-ketone with base followed i bos pres the enone shown. What is be suc fe emedate pow is ome, an wa te means ot he ‘oman offal ic? d ae Purpose of the problem ragmentation may be followed by another reaction. Revision of Chapter 27. Suggested solution emoral ofthe hydroxyl proton by the base promotes a fragmentation that is really @ reverse aldal reaction. I works because the bond being fragmented is in afour-membered rng. Then an acid- “atalysed aldol reaction in the normal direction allows the formation of much more stable six- bib sti = ct y, Purpose of the problem Revision of the mechanism of acetal hydrolysis plus an acid-catalysed fragmentation. Suggested solution Hydrolysis ofthe acetal gives a ketone whose enol can fragment. You would not expect such a “agmentation o occur unless as here, the C-C bond being broken isin a strained ring. tis not336 Organic Chemistry Solutions Manual ‘even necessary to complete the hydrolysis of the acetal. Several intermediates in this reactiam (p. 344) have the required lone pair of electrons on oxygen and can initiate fragmentation. = LEH LOO, Problem 4 Eaplan why both hese trecliketones fragment othe same dlastereoisomar of th sam= eencctasone sl i i tate ii . ie i Ore ote Purpose of the problem Fragmentations linked 10 ester hydrolysis (contrast acetal hydrolysis in Problem 3) plas stereochemistry. Suggested solution Its obvious from the reactions that two features have disappeared from the starting materials: == ester group (OAc) and a four-membered ring. The ester can be hydrolysed with KOH and the fos ‘membered ring disappears in the fragmentation, As usual, drave the mechanisms first and wor= about the stereochemistry later. For the frst compound, this sequence gives the enolate of 1 dliketone and hence the diketone itself, prlentotp ‘The second compound follows the same sequence and a different enolate emerges, but i is simp another enolate of the same diketone. Both compounds give the same basi structure ° 9 hs Ly 1m > t ? ‘But what about stereochemistry? We are not told the stereochemistry ofthe stating materials Dut we do know thatthe 5/4 fused rings must have cs ring junctions. Ths junction survives inChapter 38 Suggested solutions for Chapter 38, ~-cmentation product is an enolate atthe ring junction. When it tautomerizes to the ketone it wll ‘fc the more stable trans 8/5 ring junction. Inthe same way, the enolate from the first sequence is “qilbrium under the reaction conditions with all the other enolates of the same diketone “Sciuding those at the ring junction, This is «stereoselective reaction, Purpose of the problem + splelooking mechanistic problem but itis not obvious what happens. ‘Suggested solution Sortering is the best idea. Thre is no change necessary in the carbon skeleton other than the mnentation of the C=C bond at the ring junction. The OH proton is obviously removed, the ‘miionate group is lost, and the exo-methylene group becomes # methyl group. Evidently, other actions than fragmentation must occur. . Ss — a cam eg net et PN bond "sles = ages Boge ane) The C-C bond to be broken is not strained so a good reason for the fragmentation must be “sed. The base KH is easily strong enough to remove the OH proton entirely and sulfone isa good a-sabilizing group. Pros ‘That gives us the carbon skeleton of the product. Now the sulfone-stabilized carbanion can "rove a proton from either position next to the ketone to make an enolate. The Hs between the “ne and the double bond are the more acidic. Replacing this proton on the end of the double “= puts the methyl group in place. Finally, we repeat this process, removing a second hydrogen to338 Organic Chemistry Solutions Manual ‘make an extended enolate and eliminating the sulfone group a a sulfinate anion (PASO) in == ElcB process. These proton transfers need not be intramolecular. P-B-B-S ‘Suggest » mechanism fortis fragmentation and expian the stereochemistry of the dou: bonds in the product. This Is @ vicky problem but find the mechanism end = stereochemistry wil follow, ae Sttiriogv ey Purpose of the problem Probably the most beautiful application of fragmentation yet by a true Eschenmoser, Argon: Chem, Int. Ed Big, 1979, 18 634, 636 Suggested solution ‘The tosylate is obviously the leaving group, the two oxygen atoms in the rings must become the ester group, and the CO must leave as COs. All that remains is to trace an electram pathway from CO; to OTs via one of the cing oxygens using parallel bonds. Though ye <= ‘To do this we must draw the ‘sll’ as a covalent compound or tansfer one electron ftw = chloride ion to the diazonium ion. The other product would be a chlorine radical. Addition = alkene gives the more stable radical, which abstracts chlorine from the diazocompound ang == the chain going, Ges ORG ens =a Dee = Lain ~< So ore Problem 3 4 Sinatra fortis crt cern a i era Wh el ‘minor product likely to be? at a Purpose of the problem ‘A commonly used radical eylization: to help you to realize that activated alkenes ae unnecessi= Suggested solution The peroxide ie a source of henzoylory radicals (PCOS) and these capture hydrogen atoms ‘the most stable radical. The best radical is the tertiary one stabilized by both CN and COS. Cyetzation om tothe alkene gives a secondary radical on a six-membered ring and this abstrax hydrogen atom from the starting material to complete the cycle. nak nv See ee poem ana FHChapter 39 Suggested solutions for Chapter 39 The alernativeis to ao the more substituted end ofthe alkene. Tis ives ales abe primary" TS tp evened pe radical bat (p. 1050) this type of oization is often prefered because the orbital alignment is 2a ‘ater, The minor product has a five-membered ring oa eon Purpose of the problem important radical reaction: bromination at benzsic and allylic positions by NBS plus an *=plicaton, buat Suggested solution so preliminary reactions need to take place: NBS isa source ofa low concentration of bromine ‘25 AIBN initiates the radical chain by forming a ntrlestabiized tertiary radical oe = aoc na = NG ve new radical abstracts hydrogen atoms from the benzylic positions to make stable delocalized als. These react with bromine to give the benzylic bromide and release a bromine ator. OCG MO 2 OO. “il subsequent hyeogen abstractions are cari ot by the bromine atoms, either of the kind we “just een orto remove a hydrogen atom fom the other methyl group, This reaction provides “HBr that generates bromine fam NBS. Coe eer eoc:348 Organic Chemistry Solutions Manual 1 This product was used! to make Finally the dibromide reacts with NaOH to give the heterocycle. Both Sy2 displacements are vr» ove constrained amino aids by easy at a benzylic centre, the second particularly so because itis intramolecular and forms a Fs ‘membered ring. ‘5. Kotha and coworers, Totraneton Let, 1997, 38, 031, ie oe Purpose of the problem Another important radical reaction: cyclization of alkyl bromides on to alkenes with BusSnié = reagent Suggested solution ‘This time AIBN abstracts a hydrogen atom from the reagent and the BusSn* radicals carre ®t ‘chain along, First, they remove the bromine atom from the starting material to make a vow radical that eyclizes on to the unsaturated ester to give a radical stabilized by conjugation = the Ketone group. The chain is completed by hydrogen atom abstraction from another mol of BusSnH, a a ee be) FN. Marini and ‘The stereochemistry of the product comes from the requirement ofa 1,3-bridge to be diay H, Ramanathan Tetenecrn Lett, this is the only way the bridge can reach across the ring. At the moment of cyclization, the 1982, 24. 1871) developed this radical side chain must also be in an axial position. ahem itmChapter 39 Suggested solutions for Chapter 39 “earning how to avoid a trap in writing radical mechanisms and to show you that radical reactions can be useful. Suggested solution The most likely initiation at 500°C isthe cleavage of the C-CI bond to release allyl and chloride ‘adials The chloride radicals then attack the alkene and abstract a proton to give an allylic radical. che PA peor le os Ie ‘The trap is to form the product by dimerizng these allylic radicals. Dimerizing of radicals is Snown (in the acyloin reaction, for example, p. 1032), and these radicals will sometimes dimerize tit isa rare process. Anak ai, Ay ‘Much more efficient isa chain reaction. If we add the allylic radical to the alkene of the allylic chloride, we can create a chain. The chloride radical released is used to abstract a hydrogen atom fiom the next molecule of alkene and the chain continues. 1 The orgial workers at, ', Holland and DJ Miner, (Chem, and ind. (London 1878, ‘on.350 Organic Chemistry Solutions Manual Purpose of the problem Revision of structure determination anda radical reaction with a diference. Suggested solution Compound A contains chlorine (M 138/140 3:1) and that fits CyHyCl, it sill has the 1 disubstteted benzene ring (four aromatic Hs) and it is an alkene (IR 1640 cm!) with tne Inydrogen atoms on the double bond (By 6.5, 55, and 5.1). We can wate the structure immedi as there is no choice. Cy =p ‘Compound B has M_140/142 (3:1) and a carbonyl group (IR 1700 em™) and looks Ge CcHyCIO. It isan aldehyde (6 99) and again stl has the disubstituted benzene. The stuctut? = ‘ven easier this time! We have included the fragmentation in the mass spectrum jus to rezind ine that this stars with a radical reaction too. Occasionally in the mass spectrum (ges Phase, ‘vacuum you get the very rare loss of HY, a reaction that never occurs insolation. Here it doss = because ofthe grea stability ofthe acylium ion (139/140) (p. 558. 778 eH Wass a SO er et ya 1442 (3) ry s98/2e 8) yeas 9a) So how are these products formed? At such a high temperature, ¢-bonds break and the weiss Dbonds in the molecule are the C-C and C-O bonds in the four-membered ring next to the ber=ss= ring. Breaking these bonds releases strain and allows one ofthe radical products tobe secondary 2 Works oxy The =? Be pla Drow bat con lan oseChapter 39 Suggested solutions for Chapter 39 35 If methyleyclopropane is treated with 2Bu0Cl, various products are obtained, but the two. mejor products are C and D, At lower temperatures more of C is formed and at higher ‘temperatures more of D. m0 Sy cal eee Cumyne athe Treatment of the more highly substituted cyclopropane with PhSH and AIBN gives a single product in quantitative yield. Account for all of these reactions, identifying A and 8 and explaining the differences between the various experiments. Lue re a seem on ie a Purpose of the problem ‘Working ont the consequence of an important substituent fect om radical reactions: the sclopropyl group Suggested solution “The peroxide is source of BuO" radicals and these abstract « hydrogen atom from the methyl soup of the hydrocarbon. ‘The first spectrum is tha ofthe cyclopropyimethyl radical. The o€d dectron isin ap orbital represented by the circle andthe plane of the CH group is orthogonal to the plane of the ring but the two H's are the same because of rapid rotation The ad electron has a large coupling to the two hydrogens (H) on the same carbon, a smaller doublet coupling to H?, and. small couplings 1o the two H's and two Hs. The coupling to is small because the po containing the odd electron is orthogonal to the C-H® bond ” " ay i, 18 Tse data. come fem i from id Warming t -50°C eae decomposition wan open-No Lb —- De «echt Becca352 Organic Chemistry Solutions Manual 1 ring opeing of eclopoomnes is The last example also produces a radial next to a cyclopropane ring but this ime it = no a and wy of deste” decompose vey eal to ie 2 sable secondary hemi radical This apres hydrogen ak gens from PhSH releasing PhS* and maintaining an eficient radical cain, Rowen wn 73 nbn Mo SPs 0. 333-50 Pa cel = Ph Problem 9 ‘The last few stages of Corey's epibatcine synthesis are shown here. Give mechanisms for Eo te ines eee ener eres £8406 TH 78 cs Purpose of the problem Application of radical reactions in an important sequence plus revision of conformation a= stereochemisey. rT nl bew ee Suggested solution ‘The first step involves deprotonation of the rather acidic amide (the CFs group helps) and “> displacement of the only possible bromide ~ the one on the opposite face ofthe six-membered rz as the Sy2 must take place with inversion. cf, 2 er, i ee ae ‘The second step is a standaed dehalogenation by BusSnil. AIBN generates BusSn* by hydroge> abstraction from the reagent and this removes the bromine, The only tricky thing isto make sir= ‘you complete the chain and don’t use H? at any point, ee Fe oe, “ ™ t ® I \ f an Finally, we need to hydrolyse the amide. This normally requires strong acid or alkali but the ‘rifluoroacetyl group is significantly more electrophilic than most acyl groups and milder conditionsChapter 39 Suggested solutions for Chapter 39 353 an be usod, In this final step of his epibatidine synthesis, E. J. Corey actually used sodium mJ. Corey ana grou, JO. ethoxide (NaOMe) in methanol at 13°C for two houts and the yield was 9696. Any reasonable her, 1993, 88, 5600, up with water. You might then simply produce the product in one step by mechanism (a) but an -zzcttocyclic process via the cyclopropyl cation (b) might be better. This is allowed since the _rositably ci ring junction requires H and OH to rotate outwards. Finally, a double conjugate addition of MeNH, to the dienone forms the bicyclic amine. “Geajugate addition probably occurs first on the more electrophilic chloroenone, though it doesn't ‘s=ch matter. Ther is some steeoselectvity in that the remaining Cl prefers the equatorial positon (= The protuct has the stloton of the trope shales (pp. 2416-18) and this chamisty aioned T.-L. Macdonald ane R Onin 0g. Ohem, 1979, 44, 4973) t0‘© 4.0. Fton and RK. Sma Practeatnereroyee chemist, ‘easemic Press, London, 1988, pa. Organic Chemistry Solutions Manual powerful method. Suggested solution ‘Metathess is usually E-slective and these are both E-alkenes so prospects are good. We must siz cach alkene down the midale of the double bond and add something to the end of each, probs just CHs as the other product will then be volatile ethylene, Each starting material must now be made. The stereochemistry of the first tells us that we sho add an allyl metal compound to an epoxide. The metathesis catalyst can be any of those mentios ery 3 OKs (et in the chapter (pp. 1074-5). ‘The second molecule is not symmetrical but this is allright as it is an intramolecular (riaz closing) metathesis so we can expect few cross-produets, There are many ways to make the requ py a Cr aOCer:: starting material: alkylation of a simple ketone is probably the simplest though conjugate ad would have its advantages. Ifyou are not sure about your method, check with someone who kane ‘he same catalyst can be used and only about 2% would be needed, Purpose of the problem Problem 12 Heating this acyl azide in dry toluene under refx for 3 hours gives a 90% yield of = heterocyclic product. Suggest 2 mechanism, emahasizng the involvement of any reactive Our Op Demonstrating the practical nature of nitrene chemistry in the context of heterocyclic synthesis Suggested solution eating an azide liberates nitrogen gas and forms a nitrene In this ease rearrangement 0 = isocyanate is followed by intramolecular nucleophilic attack by the ortho amino group.Chapter 40 Suggested solutions for Chapter 40 365 Purpose of the problem ‘isthe turn of carbene chemistry to show its usefulness in that most practical ofall subjects ~ Seterooycic synthesis. Suggested solution Decomposition of trichloroacetate ion releases the CyC- carbanion. Loss of chloride gives 4ichlorocarbene and addition to one of the double bonds in the pyrrole gives bicyclic Fotermediate, pas tt (eae Ring expansion can be drawn in various ways, There isa direct route from the neutral amine, or w & o.Ftan ané R.K Smalley, ‘anion, that doesn’t look very convincing, or you can ionize one ofthe chlorides frst and open the Pracvealnetercete chemist, lopeopyl cation in an clcvocytic proces. This is «good method to make Substituted Moen Pes, enn, 308, vines,Suggested solutions for Chapter 41 4 1 © Propose 1 thie fundamentally “Airerent ‘mechanisms (other than vesitons of the ‘sont _ mechanism wth ferent ins cra} or this eacton, How wo) labeling ” “(b) "80 labelling help to distinguish the mechanisms? What otrier experiments, oni 308 Fou einate some of these mechani? Purpose of the problem Investigating «reaction where there ate serious doubts about the mechanism. Suggested solution ‘The reaction is an ester hydrolysis so the obvious mechanism isto attack the cazbonyl group. hydroxide (p. 291). Notice that we draw out each stage and do not use any summary or short mechanisms. ‘mechanism 2: normal ester hydrolysis “Cos Cs 0G". OS But the ester group is attached to an aromatic ring with a para nitro group. NucleoptSe substitution on the aromatic ring (p. 591) would give the same product, Finally, the CH. group between the carbonyl group and the benzene ring is acidic and can r= with hydroxide as base to form an enolate Elimination gives a ketene that can be attacked & hydroxide acting as a nucleophile to give the product. Purp Soon Sages eed Thep a cull 18 olsChapter 44. Suggested solutions for Chapter 44 367 Mechanism 8 requires the exchange of atleast one hydrogen atom with the solvent so, if D:O. were used as the solvent of, better, deuterated starting material were used, the exchange of one ‘whole deuterium atom would indicate mechanism 3 while no exchange or minor amounts from the inevitable enolization would show mechanisms 1 or 2. In mechanisms 1 and 3, the added OH ends up inthe acid group but in mechanism 2 it ends up as the phenol. Using labelled H}40 or, bette, labelling the ester oxygen as "*O would separate mechanisms 1 and 3 from 2, 8 ON. 7 vo nN. ce meen a oe esnieies een on , ox “oe sont oe stems OGu amas oe " Other experiments we might do could include tying to wap the ketene in a [2 + 2] re On > on bx 1 Fostin comparison with tack on But this is no ordinary ester. The leaving group is thiol (PK, about 8) not the usual alcohol (pK, G60, al the sow step. about 16) and so the thiolate anion is a much better leaving group than E1O~. Also. the CFs group is ‘ery eleetron-withdrawing so nucleophilic tack on the carbonyl group will be unusually fst. This is why there is a region of pH-independent hydrolysis not found with EtOAc (p. 1104). You could hhave suggested that accate was a nucleophilic ora general base catalyst but the solvent deuterium Ts 8 a.mueh sino eccapton fa sens of isotope effect suggests that itis @ general base. pacar (Fewer ana. €. Bruce Am. oe (Ghem. Soc, 1968, 87, 4138, enema anes; a eB! refs ——~ nye“ on + aes® bP one wn Problem 5 In acid solution, the hydrolysis of this carbodiimide has a Hammett p value of -0.8. What ‘mechanism might account for this? N uo a = ne370 Organic Chemistry Solutions Manual 1 Themyoresis of carbons in {eid and base soko was suc 8 Hing ota, Leis’ Anat, 3953, 679,87 Purpose of the problem Interpretation of a small Hammett p value Suggested solution ‘The most obvious explanation for a small Hammett p value, thatthe aromatic ring is too far a= from the reaction site, will not wash here asthe aromatic rings are joined directly to the reac nitrogen atoms ofthe carbodiimide, The reaction must surely start with the protonation of one." these nitrogen atoms. This cannot be the slow step and it would in any case have a large negat value. The small observed p value suggests thatthe rate-determining step must have a posit P value that nearly cancels out the lage negative p value for the first step. Attack by water on t= protonated carbodiimide looks right. ‘The expected equilibrium Hammett p value forthe protonation would be about -2.5 0-3 kinetic Hammett p value forthe attack of water would have to be about +2 to give anet Hammet: value of -0.8. Ths looks fine. The rest of the mechanism involves proton transfers, hydrolysis of = imide, and decarboxylation. Problem 6 Explain the diference between these Hammett p values by mechanisms for the ‘wo reactions. In both cases the ring marked with the substituent "is veried. When 0.3 but, when R= Ph, p = 5.2. oS esi . Purpose of the problem Inverpretation of a variation in Hammett p value with another structural variation. Suggested solution The reaction i obviously @ nucleophilic substitution at the benzylic centre so we are immediat! expecting ether the Sy1 or the Sy2 mechanism, When R = H, the reaction oceurs a a primary troup and Sy2 is expected. When R = Ph, the reaction occurs at a secondary benzvlic centre a Sxl is expected, com yr ane a e—_ ye cf Pro pene PreChapter 41, Suggested solutions for Chapter 41. 37a. Since Sy1 produces a carbocation delocalized around the benzene ring in the slow step, a large negative Hamaettp value is reasonable, It is not obvious what sign the Hammett p value would Ihave in the $42 mechanism as there is no build-up of charge near the benzene ring in the transition state so a small value is reasonable, The actual valve ~0.3 is very small indeed but, if we can eead anything into ita all it does suggests slightly Toose transition state with a very small (5 ~? ) charge: ‘on the catbon atom, os OP Oe Problem 7 eS kent : : = oO S 7 ON" (aoc Onn" Purpose of the problem [An extreme example of surprising catalysis, ‘Suggested solution AALrst you might ask how chloride can catalyse anything at all It isa weak base and nota very good rnudeophile forthe carbonyl group. However, in polar aprotic solvents like acetonitrile (MeCN), chloride is not solvated and is both more basic and more nucleophilic. In this reaction it cannot be a nucleophilic catalyst a6 attack on the carbonyl group simply regencrates the starting material It cannot be a specific base a its too weak, even in MeCN, to deprotonate methanol. Wut it can act as 1 general base. Notice how swe have arrived at general species catalysis as a last resort after eliminating the other possibilities. 7 ae LI Problem 8 ‘The hyccobsis of this oxazirdine in O.1M sulfuric acid has K(H:0)/k(D;0) = 0.7 and an eniropy of activation of aS* = =76 J mol-*K"*, Suggest a mechanism for the reaction. e PRcHO + eBUNHOH Suggested solutions for Chapter 42 42? Problem 4. Preciet the most favourable conformations of these insect dheromones. eee Purpose of the problem Jast to check that you can draw the conformations of spirocyclic acetals Suggested solution There are many good ways to daw these conformation and yet more not itso good. Make sre You et ere cre fou rend vou have each acetal oxygen atom axial on the other ring to enjoy the full anomeric effect Te Oe 2p. 11261), We show three ways to dra each compound, The natural products rn fact the us Wo estes ‘ompound in the frames according to R. Baker etal, J. Chem. Soc, Chem. Commu, 1982, 601. erences 9) Er Problem 2 : : : Rettuxing cyclohexanone with ethanolamine in toluene with a Dean Stark Separator to remove the water gives an excelent eld ofthis sprocyle. Whats the mechanism, and why is cid eaalsis or anyother Kind) unnezessany? ae o- Eas Purpose of the problem Revision of the mechanism ofa reaction related to acetal and imine formation (Chapter 14). Suggested solution ‘The nitrogen atom is more nucleophilic than the oxygen atom so we should stat with the amine w Athough tne clasue ote ong ie attacking the carbonyl group. The first product willbe an imine and addition ofthe alcohol to that formal aSendovigecizaon, is gives the product, Imine formation is acid-catalysed but occurs quite rapidly at neutral pHs and the Y6ite Oe fami and shone intramolecular second step is fast. The whole system is under equilibrium but the other product, rmavon Gammean 9.2342) water, is driven off as an azeotrope with benzene so the equilibrium is driven over to give the382 Organic Chemistry Solutions Manual heterocyclic product in 77-949 yield according to A. C. Cope and E. M, Hancock, J. Am. Cher. Soc, 1942, 64, 1503 Problem 3 2 - ‘What is Ain the folowing reaction scheme and how does it react to give the final product? es Cm Purpose of the problem Revision of reverse eycloudditions (Chapter 3) and an exercise in lithiation of heterocycles Suggested solution ‘The only sensible place to lithiate the starting material (which is of course, the popular sol ‘THE is next o the oxygen atom. A reverse cycloaddition then eliminates ethylene (ethene) ane ives the lithium enolate of acetaldehyte. Iti easier to see the reverse cycloaddition if we write the lithium derivative as an anion. ‘ mes Ce OS. Gs TREE wy * Cae i us i cero wor vettorots "| Thess A i Iba esl) asi ye Torre it abs al Srmwproecng oie Oublen accu (ep. 707 forthe importance ofthis) acylates on oxygen with the ai chloride SRF E Robots, Teahedon Lat. ass evdemly a charge conralleditracton between a bard nucleophile (the ongen atom 6 theenlae) and shard eecophie (ihe aid chloride). 4 nd ge wd u y Problem 4 {Give mechanisms for the formation ofthis spiro heterocycle. Why is the product not formed ‘simply on reacting the starting materials in acid solution without MesAI? maritalChapter 42 Suggested solutions for Chapter 42 Purpose of the problem alysis of the advantages of heterocycle formation. Suggested solution Srganosluminium compounds, like those of magnesium or lithium, react rapidly with acidic szotons like those in SH groups so the first thing that happens is evolotion of two molecules of “ethane as S-Al bonds are formed = we 3 ost we Nswhdha Me Cy The AIS bond is rather ike, say, the O-Li bond and provides a nclophic slr atom. robably the lactone fist adds to the aluminium to give a tetrahedral aluminium anion but, if you sew a direct attack releasing MezAl*, that is good enough. PRO GRO 6% Mesh me Mea * a samt wot ty This fist product isa kind of tetrahedral intermediate and eliminates the alkoxide leaving group. oss may object that S~ i more stable than O~ but the AI-O bond is stronger than the AI-S bond zd that decides which group leaves. < = ye Cp umm {2 Gd . ie Mophl’ —‘eumes—_MosAl ‘Now the second sulfar atom repeats the process and the loss of the second oxygen atom requires ‘= elimination into the earbon skeleton as this time a carbonyl group cannot be formed. fP-@-G Finally, on work-up, the AI-O bond is hydrolysed and cyclization to the final product occurs, robably by protonation of the very nucleophilic alkene Mesa¥0— fe = Be -co ‘The Lolum alkaloids havea stiking skeleton of saturated heterceeles. One way to make 1 Tis crete funesorl ‘wou was wtasuced by Corey fara. Bears, JA. Chem. 50, 1975, 95, 5829, 9 «now petecg _oup or etre and lactones.384 Organic Chemistry Solutions Manual Purpose of the problem Analysis ofa reaction to make a double heterocyelestreospecfclly Suggested solution f= This paricular reaction was uses Bromine, of course, attacks the alkene to form the bromonium ion, I it has the ‘B/S. R. wilson ota. JO Chem, stereochemistry it cyclizes but, if it doesn’t, it reverts to starting material. This reaction mis= os 3887-1020 e180 ersind you af halclactonization (p. 872) Problem 6 Fe Explain the stereochemical control inthis synthesis ofa fuse biyeic saturated heterocyele the trail pheromone of an ant 4 Purpose of the problem Analysis of a reaction to make a double heterocycle stereoselective Suggested solution “The fst stage involves reduction ofthe nitro group to an amine, condensation wit the ketone = ive an imine, and then the interesting step, reduction of the imine to the secondary amine, T= line binds tothe catalyst on the side away fom the butyl group the only group notin the plas The product is shown as one enantiomer but i is, of course, racemic ifthe starting materials Sale ae ‘T 0 Noy Noah Oty 4 oo Ma Pa/e_ tf “oH L/ won Co be 1 Tis monmosne gritos sb) The act is hydrolysed tpl to gve a second ketone: condensation with the secondary am R Steer and AWM. Les) "gies an iminium sult ati reduced by the eyanoborohydrde. The reagent approaches frm ts ape les hindered sie, that ix opporite the two groupe already there. The reel i that all three Iydeogen atoms end up on the sme side ofthe ring sherk -ch=Chapter 42 Suggested solutions for Chapter 42 385 Problem 7 In Chapter 31, one of the questions asked you to comment onthe diference between these two reactions. Now would you lke ‘0 comment again and add comments on the way we drew the starting materials. Cy te Purpose of the problem Sereoelectronis comes to the fore in the synthesis of medium-sized heterocyclic rings. ‘Suggested solution Themen ae enh dew — holy using why eth etn ifeent mae . Ad Jism cy As you now know (p. 1134 all exes and lactones prefer to be in the conformation shown fr the fst ompound so that they can enjoy sabiization by the anomeric efit. The second ester would alo prefer srg gan atapod version of 2» e ike this too (first diagram below) but inthis conformation it cannot cylize a al, Even inthe less facie eyntos' roporta Avourable conformation it uses for reaction, it prefers conjugate to direct substation asthe attr woul J Tsu ena group, J. Am. Chem ive a strained franseycloheptene. The fist compound can enjoy both the anomeric effect and $0» 1978.00, 7424 onjugate addition as a ransalkene in a tensmembered ring is fine. It is beter than fine in the heterocyclic product as the lactone also enjoys the anomeric effect. Problem 8 In Chapter 32, Problem 3, we asked you to work out the stereochemistry of a sugar. One of Me the sugar components in the antibiotic Kjanimycin has the gross structure (shown in the 0 margin) and NMR spectrum (shown below). What is its stereochemisty? Meo: —ome {54 (p:p:m.) 4.33 (3H, d, 46 He), 4.64" (2H, broad s), 1.87 (2H, dad, 124, 3, 3.5 He), 2.24 (aH, ddd, 124, 3, 1.5 He), 2.87 (4H, od, 110, 3Hz). 3.40 (3H, 5}, 3.47 (3H, s), 3.99 (4K, da, 0 10, 6 Ha}, 2.33 (GH, d, J6 Hz), 4.24 (2H, ddd, J3, 3, 3.5 Ha), and 4.79 (1H, dd, J 3.5, 4.5 Ho), The signal marked * exchanges with 020. When you did ths problem, you probably thougnt about the conformation but now draw it ‘and say why you think the molecule prefers that. conformation.Organic Chemistry Solutions Manual AK Matams ot al, JA. ‘hem. Soe, 3988, 203, 3938, Purpose of the problem Stereoclectronics decides the choice of conformation in acyclic acetal, Suggested solution ‘The deduction of the stereochemistry (and the conformation) is given in fallin the solution = Problem 32.3. The molecule has the configuration shown here and there ate two cho= conformations, A oF B, it could adopt ‘There seems at first sight to be little to choose between A and B: each has two axial and os ‘equatorial substituents. In fact, the NMR shows clearly that the molecule exists as A. The aceot prefers the OMe group axial because of the anomeric effect so that in A three groups have t= preferred conformation, Geet oe pi Meo: 1 ore C0 srg none A OH OMe. Purpose of the problem {An example ofthe formation and rearrangement of a four-membered heterocyle Suggested solution ‘The first reaction is a photochemically allowed [2 + 2] cycloaddition (pp. 927-8). The alterna== product would come from the alkene in the quinone being used instead ofthe carbonyl group. T= regiochemisty is not obvious but the light is absorbed by the quinone and the coefficient in == SOMO must be larger in the carbonyl groups. The stereochemistry simply results from ‘concerted reaction: those hydrogens were cs in eyelooctene and remain cs in the product,Chapter 42 Suggested solutions for Chapter 42 387 ‘The second step is the dienone-phenol rearrangement (pp. 988-9). The oxygen atoms in the ‘Sedu still have a para relationship soit must be the carbon atom in the ring that migrates. Notice ‘Aus the carbon atom migrates with retention of configuration, as expected from other migrations, ‘the cis ring junction is preserved in the product. 7" 2 ; 8 y “ ! , Seo coca cars ice he enone eee ae og oa ea ay amma Oe ee d : F sce ath sreocetonie fa oie fst od od wep ae not good but heme" Te sin rae Sessons are probably thatthe intermediate is very strained with fused thre- and fouremembered nr io peucariny us and that oxygen i aso very good at staying behind and encouraging other groups to migrate, Sean oD yee ea, 5 should redraw our fst mechanism sgl 9 thatthe oxygen tom cam sil se alone pair, Cb. Se. 1987, 388. Purpose of the problem. e-suraging you to think rather than jus aply res. Suggested solution ‘should frst draw a mechanism for what does happen and then consider the reasons. However, 1s we draw the mechanism we see the reason: the anion formed from ths dithioacetal san enolate. Se a > ° & ° BGO eye388 Organic Chemistry Solutions Manual 1 This tection was snd in a thes ofthe nar pot Isecomane by WG. Oaubon and D.M, Walker, J. Om. Chem, 1983, 6, 1103. 18 Tis reseton wae cSsovered by P. Bravo and C. Tessa Nila, 4 Chem. Socy Chem Commune, 1079, 436, ‘The decomposition of the dithiolane anion is a reverse cycloaddition and occurs because ** stabilization given to the anion by two sulfur atoms isnot very great. This anion is an enolate as w so it is much more stable. Conjugate addition is preferred (p. 751) with more stable enolates ani this anion isan enolate additionally stabilized by two sulfur atoms. The three groups (ester and "=: S atoms) combine to make a stable anion good at conjugate additions LOOT Re 1 Propose a mechanism fr this reaction, Itdoes oot occur the absence of an ‘ortho or para. OH grou, Se Purpose of the problem |A mechanistic exercise in the transformation of a three-membered heterocycle into. a fs=~ membered one. Suggested solution ‘The most acidic proton is that of the phenol so we should remove that fist. Now we can pe electrons through the molecule to break open the reactive epoxide ring, The released oxyarin= returns in a conjugate addition to give the more stable five-membered ring ain why this ejclzation ges a preponderance (2 A) of the ‘oxetane: though the -terohyerofuren is much more stable. Purpose of the problem ‘A reminder that Baldwin’s rules may apply in any cyclization. Suggested solution (Clearly, iodine attacks an alkene and the OH group adds to the intermediate iodonium ion. Lets draw this frst without any stereochemistry and see what happens. satu Sex thew atthe ve Nes sereoch znd or al Purpo ing Son Sage oh cChapter 42 Suggested solutions for Chapter 42 ‘whether the oxetane or the THF is formed depends on which end of the iodonium ion is sacked by the OH group. In terms of Baldwin's rules (pp. 1140-4), oxetane formation is simple -0-tt action and is favoured. THF formation is slightly more complicate. Ie is S-exo-tet as far “2e new sing ix concerned bul itis 6-endo-tet as far as the Sy2 reaction is concerned. In the sition state the nucleophile, the carbon atom under attack, and the leaving group are part of the = sicmembered ring. Ii very difficult to get the two dotted lines in the transition state diagram “© Se required 180° to each other. Shon? Oey Now, what about the stereochemistry. Did you notice that each product has all-trans sscrzochemistry? And what about that second alkene? The two alkenes are, in fact, diastereotopic ich one is attacked by iodine as well as on which face determines the stereochemistry of the ‘Serduct. Ths is rather like iodolactonization. Iodine adds randomly and reversibly to both faces of ‘ou alkenes. Only when cyelzation gives the all-trans product does it continue. Lea Purpose of the problem it chemo, regio-, or stereosclectvity at work here? Suggested solution Secuction of both ester and Ketone i straightforward and a low-temperature tosyaton favours the bos hindered primary alcohol. We shall start with the two tosylate. The oxetane had 10 have a cs fg junction so isomer A must be the ds isomer. That leaves isomer B as trans and its fate is Segmentation (Chapter 38). Notice in the fragmentation that one lone pair on the oxyanion, the -€ bond being fragmented, and the C-O bond tothe leaving group are all atépanar. W= ‘ty wy _ 15 This important reaction was uses tomake antral compounds by M.Eng a ©. J. Neto, Tevahecro Lett. 1996, 37, 7687. 12 Tis remaraabie aterence Detween to dasterelsomers Was scored by 6. Knast and 1 Tieue, Chem. Bor, 1976, 108, 328.Organic Chemistry Solutions Manual 12 Ths now stasis of a ble amine was ported by F.D. King. Teapedon et, 1963, 24, 5282. Purpose of the problem ‘Baldwin's rules at work in the syess of a bicyclic heterocyle with one niogen atom in both ri Suggested solution Hydrolysis ofthe acetal releases an aldehyde and Mannich-style condensation leads to the produ ‘The cyelizatioa step in which the enol attacks the iminium ion is endo in both components {6-em= trig for both the electrophile and the nucleophile) and thus difficult to do. However, by folding = ‘molecule in a chair (frame in margin) a reasonable overlap between the required p orbitals = 121.4. Tuer and R.€. Gavone, Tevahecon Lett, 1978, 2753 Purpose of the problem Developing judgement in using Baldwin's rules in the symthesis of heterocycle compounds. ‘Suggested solution ‘The first ring system is the same as the one we have just been considering but the route to it = dlferent and is more demanding in terms of Baldwin's rules, though we should stil describe i 5 endo-trig, Manganese dioxide isa specific oxidant for ali alcohols and conjugate addition of f= amine to the enone gives the bieylic amine. This works because endo reactions ate just about ight in a six-membered ring and because conjugate addition is under thermodynamic control: = long as some of the reaction occurs, the product is the most stable compound in the mixture. CireChapter 42 Suggested solutions for Chapter 42 ‘The second example is again 6-endo-rigbut it i acid-atalysed and this makes a big difference as ‘5e protonation incteases the reactivity of the enone system and reduces the rity of the enone Setem. Both these G-endo-trig reactions go through charlie transition states rather like the -zample in Problem 14 but these are not endo as far a the nucleophile is concerned, only forthe Zectophile. arleclas PyeSuggested solutions for Chapter 43 43 3 Problem. is For each ofthe fling reactions: (Stale what kindof substations suggestee ()suagest what prod mite omea rmonesubstuion peu. E i ee m m0, eos me ov reste Se E eee oe 7 M804 ‘sect, Aa) Purpose of the problem. ‘A simple exercise in aromatic substitution with heterocycles. Suggested solution “The firs thee reaction are all ecrophilic substitution: 2 brominaton of a pyreole the nitration ‘quinoline, and a Friedel-Crafts acylation of thiophene, Bromination occurs on the prtale até: ‘only remaining st, Nitation of quinoline occurs on the benzene rather than the quinoline xy (actually giving a mixture of 5- and 8-nitroguinoines, but don't worry if you didn’t sce a E P. 1174), andthe acylation would occur next o sul chastise reer Oso PoG ‘The lst reaction isan aromatic nucleophilic substitution: here the pyridine is more reactive the benzene as the negative charge in the intermediate can be delocalized on to the pyriS=e ‘ 5 (com _* ; esa Soo. ae Sis epeleiany elastin ei dea ane he pee Masia, a " (€10);00 peChapter 43 Suggested solutions for Chapter 43 393 Purpose of the problem se crecise on side-chain extension with aromatic heterocycles. Suggested solution strong bate (LHMDS or Lithium HexaMthyl DiSilaie) removes proton fom the methyl w Ta sr of canis was ps that the charge i delocalized on both nitrogen atoms and acylation follows Ifyou drew —edvea yO. on iam atom covalently bound to one of the nirogen atoms, your answers beter than ours, FH: Movers 1 chem. So " ny aja ofthe ear be tercbanoues Perkin 1, 1972, 2506 ard used by 1S nend -. bamah Terede et, 190,24. 715i0 men of te anes fecburne fovea a Pern 6, Groner Problem 3 Give a mechanism for this reaction, commenting onthe position on the furan rng that reacts. Purpose of the problem ‘unusual electrophilic substitotion of «fran with interesting regioelectvty. Suggested solution Te allylic alcohol evidently gets protonated and forms an allylic cation. We can work out the echanism just fom the structure of the product. Furans normally prefer substitution at the a positions (2 and 5) but one a position is already 1 Ths new way to moke splat “cked and the other i too faraway to ceach the allylic cation. Attack atthe other end ofthe allylic COBeUNES MeSimertsd by ation would give an eight-membered ring with a trans alkene in it. That would theoretically be $oB."Su8 0621 Teranedon Let, »>ssible but closure of six-membered rings is much faster We could summarize both those reasons + saying that electrophile and nucleophile are tethered. Problem 4 ‘Suggest which product might be formed in each of these reactions and justity your choices. y=: ow i q POCy: Hs805CE re ah eral al LE ged hat aR eh 394 Organle Chemistry Solutions Manual Purpose of the problem Regiosclectivty test with contrasted electrophilic aromatic substitution. Suggested solution 1m each case we have a choice between an aromatic heterocycle and a benzene ring. The pyre = ‘more reactive than benzene and the pysidine less. The pyrrole does a Vilsmeier reaction (p. "158 = the remaining free position while the pyridine acts as a deactivating and meta-directng Subita_ fom the benzene ring (Chapter 22). fect oPao9 Purpose of the problem Can you explain this unasual rgioselectivi clectrophilic substitution on a pyrrole? Suggested solution ‘This is dearly some sort of Friedel-Crafts reaction with an alkyl halide and AICIs as the reags== “The alkyl halide forms a cation very easly because of the MeO group. Now we ean draw Se mechanism and we won't worry about the rgioselectivity until we have. @ " oh Me Meo’ tae” moo” h Pare. oy Hot yates one er dnay —aak me P roar Mani, 4 eos yen woo. Four at jon Bu Soc. him « w : France, 1972, 289 ard used in & ‘But why does the reaction happen at one of the B positions and not at the remaining 2 posiuat ‘yes of the coerayne a eae ‘The ester group deactivates the remaining 2 position but that is not enough. It must be Ter Henorcvson and 4.6. devies, additional effect of a complex formed with the ester group and the Lewis acid that deactivates tie cece See Some eee Oye Or, OO Ecsisn Purpose = Senet The Lew we il mhee Chapter 43 Suggested solutions for Chapter 43 398 Purpose of the problem ‘Checking up on your understanding of indole chemistry. Suggested solution ‘Tae Lewis acid combines with aly bromide to give either the allyl cation or, maybe the complex we saw here. In ether case, electrophilic atack occurs on the 3-postion, as is almost always the case (pp. 1170-1), and the benz group migrates to the 2-postion where there isa hykrogen, stom that canbe lost to restore the aromatic. 1 This reaction was escoverad at Purpose of the problem « clever use of seletve lithiation in furan chemistry. Suggested solution ‘rac ally group evidently goes into the 2-position so lthiston mast occur there fst fal helped by The outa edt 8 ar the Br atom andthe oxygen inthe ing (pp. 161-2). The second elecropile (Mel goes in Sete He porn ones Slice ofthe bromine so the avon lihiation occur there: Tes ‘notsurpeing that IDA acts sta (ugwem D008 DN: D. bya 157700, 2085,396 Orgaric Chemisty Sol-aicrs anus cot i. san Se ae ight ee ony Purpose of the problem Can you see why substitution atthe nitrogen atom of pyridine affects the extent of reductox? Suggested solution “The reducing agent isthe same in both reactions (NaBH,): the ony difference isthe acylation a: ie pyridine nitrogen atom. The reaction to the right looks straightforward so we'll tat with Gam ‘Acylation at nitrogen gives an electrophilic pyridinium ion that accepts hydride from BH to axe the product. Steric hindrance is not an issue with this small reagent and the ethyl group aie rene We orrass Ng ‘The second compound is a thiazole and we want to wie a tioamige to make i (pp. 1199-200). We should disconnect C-N and C-S bonds to give the thoamide and another 2-bromoketone, remembering oe the nucleophiles exercise ther natural preferences sulfur displaces the halide and nitrogen stacks the carbonyl group. PM sR N eees eee age ete{8 Tis avery ot eation ‘lscovered y von Pectann snd ©. Duiserg er, 1883, 48,2119. Organic Chemistry Solutions Manual ‘The third has the two heteroatoms joined together and we do best to keep them that war's! disconnect the C-N bonds outside the hidden molecule of hyéazine (NH;NH). We necd = diketone 50 we are into Claisen ester chemistry (pp. 791-4 and 1188), analyse: eee aie 22d A Purpose of the problem ‘An oxygen heterocycle and the question of selectivity in its synthesis. Suggested solution ‘The left-hand ing is obviously aromatic as itis a benzene ring. The right-hand ring has Se «lectrons from the double bonds and can have alone par from the oxygen in the ring, making sis = all, Alternatively, the whole system can be considered as a 4n + 2 system with 10 electrons. Fi ‘way, it is aromatic. This is more obvious in a delocalized form, Ze Seeceae 2 love pi lctons “The frst step in the reaction is trnssterfation and the cylnaton then occurs in an o-e poston. The slectivity is regoslctiviy for one ortho postion and i looks as though st hindrance is important. The other OF group is also ert, paa-netng nd the position choses = para J IS Sg Porpose capeer. Suggest Theres show the peeves I<Chapter 44 Suggested solutions for Chapter 44 eat ab Welpie ‘ combination of a Fischer indole synthesis with revision of abit of indole chemistry from the ast, chapter. Suggested solution The first step stars off a a normal Fischer indole; you just have to draw the molecules carefully to show the spiro ring system, and you have to stop before an indole is formed as the quaternary centre ‘Treatment with a Lewis acid initiates a rearrangement very like those occurring when 3- _m The new sovenmembered substituted indoles are attacked by clectrophiles (pp. 1170-1). The aromatic ring is a better Msteroeyete (an zepne) Is fend in ‘migrating group than the primary alkyl alternative and an indole can finally be formed. Soe er cee y : ;Organic Chemistry Solutions Manual _ Explain the reactions in this patio synthesis of | contain mo crore bet vee “tooes HO] Purpose of the problem ‘A-combination ofa Fischer indole synthesis with revision of abit of indole chemistry from the ss chapter. Suggested solution 1 Thismethoxsin smtesis | There is ceatly a Fischer indole synthesis in the second step but the frst step makes the usd escrbed by EJ, Corey ard 1X Trmontaro, Am: Chem. 198, 103, 5599, e030. Es ee, hhydrazone in a most unusual way. The fist reaction is diazotization so we have to combine ©: diazonium salt with the enolate of the keto-ester. That creates a quaternary centre and the KO= eacyates it to give the aryl hydrazone needed for the Fischer reaction. See., et ee ee OMe 1 [Now that we have got the hydrazone, the Fischer indole reaction is straightforward and gives = indole-2-carboxylic acid derivative. There is only one ste for the enamine, and the indole i for==2 away from the substituents already on the ring. ‘The next stage obviously involves the primary amine as nucleophile and the conjugated ke=> diester as electrophile, You may well have done direct addition to the ketone as that gives “==Chapter 44 Suggested solutions for Chapter 44 407 we _-roduct by a very reasonable mechanism. In fact, itis known that conjugate addition occurs as ‘Se tertiary alcohol A can be isolated. The dehydration ofthis alcohol is obviously acid-catalysed 1 A canbe ovded tothe root and the oxidation by air to the aromatic heterocycle is also acid-catalysed. an moe ‘os $e F wet may 2a a mego-0.029 a comme inyorolses NHCHO| a oe ome moos moos, 10, coum Je 19, osme 1) ite » ‘Her A ain NS come Wome gai comme fe et = . Problem 7. Sages a syrhess of feriazac, a nonsteroidal eninimmatary dr. The ens in the chapter but you need to explan why you need these particular starting materia 2s well 5 how you would make them, i Purpose of the problem Sarther exploration of concepts and chemistry from the chapter. Suggested solution The analysis in the chapter (p. 1200 reproduced below) shows that we need the thioamide of enzoic acid (thiobenzamide available from Aldrich) and an acbromoketone. We need these zanicular starting materials because the soft sulfur atom wil displace the bromide in a fronter- ovbta-controlled Sy2 reaction whilst the hard arsino group will atack the ketone in @ charge- controlled nucleopkilic attack on a carbonyl group. comes yf We still need to make the bromoketone and that will come from the bromination of the parent keto-acid, This in turn, being a 1,4-dicarbonyl compound, comes from chemistry Sscussed in Chapter 30 (pp. 800-1) and in Problem 3 above, A selection of possible isconnections is given here. There is no problem about the bromination as the ketone is moreOrganic Chemistry Solutions Manual 1 this seecive route to gunoines bythe Fedinder syehasis was | soe by ER Feel, Oe (hem, 1986, 3, 2809. ‘easily enolized than the acid and it can be brominated only on one side. The aromatic ring = deactivated by the carbonyl group. ot vw tr Me ses 14909 om iisaci, en - Sepain wy ese to autre syineses om oe same serra ne er inany Purpose of the problem An exercise in regiotlectvity of heterocylic sythesis controlled by pH, Suggested solution You have a choice here’ ether you first form an enolfate) from butanone and do an aldol reactié= with the aromatic Ketone or you first make an imine and then form enamines from that. In either case you would expect enol or enamine formation on the more substituted side in acid but on the less substituted side in base. Pirbbivr ryChapter 44 Suggested solutions for Chapter 44 Problem 9 Give mechanisms for these reactions used to prepare a fused pyridine. Why is it necessary 10 use a protecting group? Purpose of the problem Saturated and aromatic heterocycles combined with stereochemistry make a neat synthesis, Suggested solution ‘Thefist stating materia sa sable cyclic enamine and conjugate additions what we shouldexpect with an none. OF cours, ifthe aldehyde were unprotected, direct adition might occur there as well as carbonyt ondensations The productisinequilbium withbothitsenols, oneof whichcan qlizeto form thenew sx- _emberedring, The enol must attack the five-membered ringina cfsshionasthe theristooshorttoreach “othe Tereooconolnronesergeniete buat nimporanaonto diye Now the reaction with hydroxylamine in acid solution. Formation of the oxime of the Ketone . 348) produces one molecule of water ~ just enough to hydrolyse the acetal ~ and the pyridine sthess canbe completed by ylation anda double dehydration (p. 1194). 409 1 Th fest restion i catty by ‘Hot utter eno water present £0 yo ofthe acta es rat 1m Ths chemist was usedto make the akaoids fom Sceetim species (CP Ferbes ota Tovahecron, 2978, 34, 487)410 Organic Chemistry Solutions Manual Problem 10 lceniy se itemesates and gve mechanisms er the steps i is synthesis of tazoe OY *- LNNO HCL g 2. mane, ans CHO No Purpose of the problem Revision of aromatic ncleopilc substitution and a chance to unravel an interesting mechario= Suggested solution ‘The first reaction forms A, just the enamine from the ketone and the secondary ari (morpholine). Below we have diazotization of an aromatic amine and replacement by azide. 7 nucleophilic aromatic substitution (Chapter 23) could occur by the addition-eliminat== ‘mechanism, activated by the nitro group, or by the 1 mechanism, bor dadad cut cates |= An ternative mechanism isa Now comes the interesting bit. The two reagents A and B combine without losing anything — > = 4. Sdipelaroloation fe ase evident hat the enamine must be the nucleophile and so the azide must be the electrophile, We = Oe see from the final product thatthe enamine attacks one end or the other ofthe azide, Trial and «=== takes over! Here is one possible solution with the side chains of the intermediate abbreviateg = dlarty. This product C can be isolated but its stereochemistry is not known, 18 R Fusco a a, Gane. Ci. tt ‘8, ss Finally, the new aromatic system (a triazole) can be formed by elimination of the a Protonation of the most basic nitrogen is followed by expulsion of morpholine and aromatia% by deprotonation. This synthesis of 1,2,3-trazoles was discovered in Milan during a mechan’ study of the reactions of azides and enamines,Chapter 44 Suggested solutions for Chapter 44 a tailed mechanisms for this pyridine synthesis. The frst part revises Chapters 27 and 29. ee ee ‘Perpose of the problem Getssion of aldol and conjugate addition reactions of enol(ate}s and a synthesis involving one “oieciine and two furans. -Svegested solution “=> jist reactions are aldol condensation and conjugate ation, summarized below. Make sure Ths chemise was actualy used ‘©: san draw the full mechanism for both. The last step isa standard pyridine synthesis already 04s sone spre caroauies | iin Problems 1 and 9 .R.tuslen, Tereedon Let, 1984, 2,438. hed Problem 12 ‘TMs question reves a rue of prevous chapters, especialy Chapters 24-26 and 20 Give mechanisms forthe reactions inthis synthesis of furan and comment on the chee of reagents fr the various steps. df a at Purpose of the problem Revision, drawing mechanisms, discussing selectivity, and foran synthesis,412 Organic Chemistry Solutions Manual Suggested solution This question is longso a quick answers bes, Addition of two electrons and one proton in a Bins reduction (pp. 628-9) gives a unique structure with the dianion on oxygen and the two alkeses conjated with the OMe groups. Methylation ofthis enolate ives the fst intermediate. Bich reduton + a 5 See ‘The next few steps need no comment but the double hydrolysis ofthe enol ethers may. ‘This w= ‘considered in Chapter 21 (pp. 540-1) and is summarized here. we eS x = Le ome he q L se om ys oa ™ om sot o “ Mo io Some ee ‘ome Nee: ° 15 This seauonce was usedto make Finally, the furan synthesis, which takes place in the ame reaction as the alkylation of the enolas> lnderictore (A Gapalan and The only surprise is that the aldol reaction occurs first and O-alkylation afterwards, Maybe = Pe Mags Am. Cham. Soe ies 13080, 402, 1758, ae aoeeton: Thi ew Ps compat the The het Secsrbn such én sasine |Chapter 44 Suggested solutions for Chapter 44 Problem 13 Suegest shes fortis compoun,ewianng why you choose this patel: approach, Purpose of the problem he synthesis ofan indole with a slight twist Suggested solution “ais looks very much like a perfect subject for the Fischer indole synthesis. Let us see. Ph aR Pear eer na "come ‘This looks fine, though we may wonder how we are going to have an amino group in that tion on the keto-ster. Surely it wll cyclize on tothe ester to form a lactam? One solution would, = 10 protect it with something like « Boc group but the solution found by the Sterling Drug ‘mpany was partly motivated by a desite to make a variety of compounds with diferent amines on se side chain. They chose an OH group as a generally replaceable group and accepted that the Purpose of the problem. Teaching you to avoid a tap in asymmetric synthesis Suggested solution The two compounds look much the same in stereochemical terms and these are the very similar :cslts ofa simple hydrogenation. rote od ‘The difference is that there was already a chiral centre in the enone, but there wasn’t in the amide because the nitrogen atom is flat. All the stereochemistry in the amide product is induced in the hydrogenation. For the enone, ifthe starting material was racemic, the product will be racemic too, i, on the other hand, the enone starting material was a single enantiomer, then we don't need asymmetric reduction. In either case, asymmetric reduction is too late, pe te ot 1 The bakers yeast method Is ‘eviowed 87.1. Sh and C. Chen ‘agen. Chem, It ES Erg, 198, 2, 870, andthe practealties of ho BAP reduction ao dscusced by Novo ana ous, Or. St, 1995, 74,1 1 The enone was tnsogensted by 4. Froberg and. Magnusson, J Am ‘hem. Soe. 1978, 100, 6728, and te amie by W. Fitsen sna .. Wornsmann, Teranedron Let, 2981, 22, 739. No asymmettc reducton was attempted,Organic Chemistry Solutions Manual Le ea, EE Purpose of the problem ‘A combination of conformational analysis, stereoselective reactions, and resolution to get a side ‘enantiomer. ‘Suggested solution ‘The first reaction is @ conjugate addition that evidently goes without any worthwi stereoselectvity. The stereochemistry is not fixed in the addition but in the protonation of dae ‘enolate in the work-up. Equlibration ofthe mixture by reversible enolate formation gives mes ‘the all-equatorial compound. & Reduction by that smallest reagent, electron, gives the albequatorial product, Since the rato prot the same asthe ratio f starting material (87:13), the reduction i totally seeoselect ‘The all-equatorial ketone gives 100% all-equatorial alcohol and the other isomer must give s-= ‘other distercoisomer (we cannot say which). matic Od “The mixture sil has to be separated and, as itis misture of diastereoisomers it ean be separate’ by physical means. The chloroactae is just a convenient crystalline compound. Two fractions! caystalizatons actually give about 50% ofthe required compound according othe details giver b 0. Or, Org. Sth, Coll, 1993, VI, 352. 2 P AChapter 45 Suggested solutions for Chapter 45 423 Problem 12 Describe the stereochemical happenings in these processes. You should use terms lke diastereoselectve and diastereotopic. ‘here needed. Ifyou wanted to make single enantiomers of the products by these routes, at what stage would you introduce the asymmetry? You ate not expected to say how you would induce asymmetiy?) 4 Cote Purpose of the problem Making sute you understand some ofthese stereochemical terms and concepts. Suggested solution First we should see what is happening at each stage of the reaction, tO Naat "wap sd mera wa ‘The faces ofthe ketone are enantiotopic (the carbonyl group les ina plane of symmetry) so the ‘eduction mu give a 50:50 mixture of enantiomer, tat is the alcoho is racemic. Now the faces of the alkene are diastereotopic (ther is no longer plane of symmetry) and the epoxidation takes place stereoselectively on one face because the OH group hydrogen bonds tothe reagent (p 897). “Asymmetry must be introduced atthe Sst stage to create single enantiomer of the alcohol. Then ‘the epoxidation will automatically create a single enantiomer of the epoxide “The second eatin is a simple Witig proces. I stereosletively gives the ds (Z-) alkene as itis a ‘non stabilzed yi (pp. 814-18) The thre-dimensional stereochemisty is ently conrlled by the starting material. fwe want a single enantiomer ofthe product, we mist start with single enantiomer ofthe aldehyde-ster, Asymmetry must be introduced before this reaction sequence. Problem 13 ‘The unsaturated amine A, a useful intermediate in the synthesis of the amanilideceae {daffodil alkaloids, can be made from the tree starting materials shown below. Wht kind of ‘chemistry is required in each case? Which is best adapted tor asymmetrio synthesis? Outline your chosen syrthesis. as ome ome > ° ee pais xe ome . ue424 12 We eve the published solitons but tere are many others ~ yous, Wesferent, may be 98 goo |= Compound As en seagesic ‘made bythe mets eutined here though in race fr) 29 Bruderer and K Bemauer, Hel ‘Chim Ata, 1983, 68, 570. Organic Chemistry Solutions Manual Purpose of the problem Devising syntheses when asymmetry isan issue Suggested solution ‘The more stable enolate conjugated with the aromatic ring, can be made by a variety of met and alkylated by various lectrophies with groups suitable for transformation ino the requiced~ cain. It is easiest to go straight there. Reduction of the ketone gives an alcohol that can elimi only in the direction we want bes ome eS a Oe ‘or NaH/OMF ‘The allylic alcohol is designed for use in a[3,3)-sigmatropic rearrangement (pp. 945-6). Agai= variety of acid derivatives could be used but itis easiest to use the one we want. Tis route is shor== and more direct on ‘The last route depends on the stereochemistry of the starting material. If there is a ais roe junction, the conformation can be just right for an elimination (pp. 484-5) in base to give directly. IF it has a rans ring junction, this conformation is much les favourable. ome ran 4 vo Had Wud Me 1m all three cases the starting materials are already chiral. IF the allylic alcohol or the cy ammonium salt were prepared, by resolution or by asymmetric synthesis, asa single enantiomer then A too would be a single enantiomer. However, the ketone used inthe frst route, though als chiral, has an achiral enolate so asymmetry could be introduced at that point. It isn't possible to use the chiral enolates described in the chapter (p. 1230). Probably the easiest approach is to make the allylic alcoho! by asymmetric reduction, say by the CBS reducing ageat (p. 1234). Problem 14 deena en ’ py sO 8 Gk oo aes suber Prob BLE Purpos DesigChapter 45 Suggested solutions for Chapter 45 425 Purpose of the problem “sing your own asymmetic syntheses. Suggested solution ‘D> first compound isan ester derived from a cyclic secondary alcohol that should be made from “=: coresponding enone by asymmetric reduction. hese aoa Reduction with Corey's CBS reducing agent (margin and p. 1234) gave the alcohol in 93% ee and Ss compound was used to make a compound from the gingko tree by EJ. Corey and A. V. Gaval, trahedron Lett, 1988, 29, 3201, pce faethe dee Sra bu gk The second compound could be made by & Witig reaction with stabilized yh and the required diol fidehyde derived from an epoxy-alcohol and hence from an allylic alcohol by Sharpless epoxidation, ey A eno S sa nw SN ‘The first part of the synthesis was a demonstration that the Sharpless epoxidation was useful KB. Sharples and group, Am. Chom, Soc, 1981, 103, 464 a gave an iterate that had already been used (S, Masamune et al, J. Amn. Chem. Soc, 1975, 97, 3512) in the synthesis of the Lntibiotc methymyein, Problem 15 é ‘Suggest a synthesis of any stereoisomer {for example, RZ) of this compound. oo Purpose of the problem Devising your own asymmetric synthesis with no strings attached426 Organic Chemistry Solutions Manual ' Fol stands for tnctons! gow Suggested solution sreromersin. ‘This time there are so many possibilities that we don't want to push any one solution. We S24 = ‘ smind the asymmetric reduction ofan acetylenic ketone by CBS or some other asymmetric fez ‘ agent and then using the alkyne to make the transalkene. You also have to consider at what stay. Introduce the ester group. This open-ended problem cannot have a more defined solution, 20 oO So Problem 1600 i Revision. Give mechanisms fr the steps inte synthesis of tazadotne in Problem 2 Purpose of the problem Revision of Chapters 28, 4,24, 19, and 17. 4 ‘Suggested solution E “The frst step is a Lewis acid-catalysed Ce of an enol (Chapter 28). Gat = ees = [Next we have a reductive amination: the imine is formed (Chapter 14) from the more r= aliphatic ketone rather than from the conjugated aryl ketone and the hydrogenation reduc: = ‘the imine and the remaining ketone. This is unuswal (Chapter 24) but there are catalysts that = the job. emg SRS ‘Now comes an acid-catalysed dlimination (Chapter 19), probably by the El mechanism s+ = alcohel is secondary and benzylic. Each step is reversible so thermodynamic control ensures (= = E-enone is formed. The Z-cnone would have a sterie ash between the carbonyl oxygen sis = eee on 2 HP x i t 1 i ‘Coma and isin only the patent bet ier en earnoler 3 amine mi membered fire ry and en the pte Jeving group so that an intramolecular Sy2 reaction by th akes the four-membered ting est. 0,9 Bee) Neer iE ; OT Or aested solutions for Chapter 46 46 blema : : structures for intermediates A and B and mechanisms for the reactions. 2 Re ms] mes ym ; moot ee bt ose of the problem ‘cpl exercise in sulfur chemistry with some remarkable results, ested solution ible as it may seem, this ylid with an extra three-membered ring, still does the epoxide This method was called sation mentioned in the chapter (pp. 1258-60). The very strained intermediate rearranges in _‘s#:0ahlaton bits ivertors 2 and finally fragments in a way quite like the Eschenmoser fragmentation (p. 1008). SSM TTS eM Baer 4 re % ae Problem 2 i i Suggest a. mechanism for this reaction, commenting on the selectivity andthe stereochemistry. Purpose of the problem +2 intramolecular version ofan important reaction ~ what does it mean?428 Organic Chemistry Solutions Manual Suggested solution p 18 R.S.Mstnews and. £-Meter, The yd forms in the usual way but cant reach across the ring to attack the carbonyl group diese : 42.chern, Soe» Chem. Corman, soit has to do conjugate addition instead, It also has to attack from the top face a tis tte * | s971, 1896. there. Completion of the cyclopropane-forming reaction leaves the sulfur stl attached to 4 angular methyl group, from which itis feed by Raney nickel. This reaction shows thats ' | sulfonium ylds can do conjugate addition ~ they just prefer not co. Bmp iD 2.45 (6H, §), 4.22 (1H, 8), 5.41 (1H, d, J18 Hz), and 5.63 (1H, da, J25, 4.5 Hz). Sugges: a J + pears Pe x A Purpose of the problem Revision of NMR, structural identification, and sigmatropic rearrangements Suggested solution ‘The produet still has the CMe group, though no longer on double bonds ithas a tans alkene a methyl group atone end, two SMe groups (6H singlet at245), and hydrogen at 4.22 that mish be ‘ext to two sulfa atoms, All that adds up tothe stuetute shown and [23]-sigmatrpie shit = sulfonium yl 163 8,568 fe rg = et a te ot 5 ae me dora Problem 4 i = aA fot teed Lao cba Ni etieaa uns need Cae ar cially aloha eo one |s accelerated if Ris a carbonyl group {that is, R = COR’. The reaction is (slightly faster ane Se Fi wo Oe Explain the stereochemistry ofthe frst reaction in the following scheme and the postion c* the couble bond inthe nal preduct. e WA 2. MelChapter 46 Suggested solutions for Chapter 46 429 Purpose of the problem king that you understand the mechanism and stereochemistry of sulfoxide eliminations and ion of Chapter 41. ‘Suggested solution = mechanism given in the chapter (pp. 1269-70) is a reverse cycloaddition of a sulfenic acid and ‘> slkene, This can be drawn in to ways (they are really the same) depending on whether you draw ‘=: sulfoxide with S=O or as an yid. Ths its the evidence quite well. The substituent on sulfur is “4 involved but that on carbon (R) will accelerate the reaction if it makes the proton that is ‘ssuoved more acidic, We might expect a positive entropy of activation as two molecules are being ‘Smned from one, but pericylic reactions are notorious for large negative entropies of activation ‘e-ause ofthe high order of the transition state. A modest negative value scems fir. The sulfoxide is ‘ee bat the products are not so the transition state is presumably slightly less polar than the ung materials; hence the solvent effect. = Seale at yew m| ‘The first reaction is the alkylation of an enolate. The molecule is folded so the planar enolate will “=: the electrophile from the outside (exo- or convex) face. wa Sulfide elimination is a cs reaction so the oxygen atom cannot reach the hydrogen at the ring P.A. Geto and. Reap, ‘section and has to eliminate into the side chain methyl to give the unstable exo-methylene T@tahedon Let, 1974, 1097, Senpound. We know that the elimination into the ring is preferred because the other “Ssstereoisomer, which has a free choice, prefers to-do just that pro) Coton Problem5 ce ae Ha : i “vision content. Explain the reactions and the stereochemistry in these tt steps in a synthesis ofthe B vitamin bein Purpose of the problem ®-minding you of radical bromination (p. 1039), how to make a thio, that thiol are good at njugate aditon, and revision of 1,3-dipolarcylouddtions and ther stereochemistry (pp. 932-6) sen sulfur acts asa teer. This chemistry is described in outline on those pages.430 1 This sythosis of biota is ‘desorbed by FN. Conflone eta Jain. Chem. S20, 1980, 102, 41954 Organic Chemistry Solutions Manual Suggested solution ‘The first step i typical allylic bromination with NBS, fully described on p- 1039. The second >= an excellent Sy2 reaction with thiolacetate as a nucleophile displacing bromide fom an ais position. Ob O_O A, ven sy ss ° ‘The reagents for the next step are both disguised and are both unmasked by NaOH. The thiolester is hydrolysed to the free thiolate and the nitrocompound eliminates acetate in an 215 reaction. An excellent conjugate addition follows: both nucleophile (thiolae) and Michael acess (nitroalkene) are ideal OS Osis eae “Et [Now we have the 1,3-dipolar cycloaddition, A nitrile oxide is formed from the nitro compos by dehydration with PhNCO (the full mechanism is on p. 934) and cycloaddition can occur vei withthe regio- and stereoselectvity shown because of the short tether. We have shown the ni== ‘oxide approaching from the bottom face ofthe alkene so that all three hydrogens are up. Reduc"2= of the C=N bond then occurs from the top (outer, exo-, convex face) of the bowl-shaped molecs= Purpose of the problem Exploration of sulfur yd chemistry Suggel Terie esr sontral. he eal serage at Sesleri er Purpos seriemChapter 46 Suggested solutions for Chapter 46 434. ‘Suggested solution They stabie by conjugation ofthe anon with the exer group ~it alo anenalat.Wecan Thiet et apna expet reel alton tothe cabonyl group and ence conjugate alton by thermodynamic tho ees of at ‘oniol The stereochemistry ofthe ring junction is inevitable ony rng junction can be made. FOMEDY PA Wend The onl intereting cen the ett on the tree membered ring. oo iin the more sable mangement on the ouside of the folded molecule. The intermediate i probably mintre of siereisomert woe he cong alton reversible and ony tha astereoomer cycles that can give the more sible prodit oles Hie, the prod epimerizes by eoliation, ° 9 ° Be er 5 ‘The intermediate may. ‘altematively be reacted with @ selenium ‘compound in his sequence of reacions. Bleh wat 8 rappenng sammening one rages. Wry 1S We Nat Purpose of the problem Some sulfonium ylid chemistry, revision on rearrangements (Chapter 37), and some simple selenium reactions Suggested solution The first step has already been discussed in Problem 1 so we just give the mechanism, registering again our surprise that such a strained ‘oxaspiropentane’ can be made. BE; is chosen as the counterion since it is non-nucleophilic and will not open the epoxide or attack the carbonyl POS BE oe beh432 Organic Chemistry Solutions Manual ‘The epoxide rearrangement is triggered by acid. It opens to give the tertiary cation on the sis ‘membered ring as the cation on the three-membered ring would be very strained (60° ring angle 2 accommodate 2 120° angle between bonds). The OH group pushes one of the C-C bonds in the three-membered ring across in a ring expansion. con | |= This chemisty was deveiopes a= No other derivatives of the tertiary cation, such as the allylic alcohol in the last part, can be Dat ofa synthesis of spnicsooin, formed this way because the rearrangement is too fas. The reaction with PhSe-SePh and NaBH. = an antral natural product by trick to get this allylic alcohol, ‘The true reagent is PhSe~, formed by reduction of the Se-Se boos: BcTotetel Am Gan Se> 1 ery mdeopilic and wil tack even tetera epoide to give a sled: Oxidation toa selenoxide leads to a fast concerted cis elimination. The intermediate selenide is unstable as wel se very smelly and must be oxidized immediately before it decomposes. tLeeaw Purpose of the problem Sulfur acetals come into their own as d reagents (acyl anion equivalents). Suggested solution “The frst reaction isan acetal exchange controlled by entropy: three molecules go in and four co (the product, two molecules of methanol, and one of water). We show just art of the mechanChapter 46 Suggested solutions for Chapter 46 the two dithioacetals work asd reagents (acyl anion equivalents, p. 1256) by deprotonation -Spvlation, Hydrolysis needs mercury, Hg(Il) as described on p. 1255, of the problem ‘icky sulfonium yld rearrangement. solution = base can do nothing to our sulfur compound so it must do something by itself ~ a sulfur i the answer. Sulfur is good soft nucleophile and allylic iodides are excellent “les. Now the weak base can remove a proton because the result is an enolate and a lid as well See ee lid is perfectly arranged for a [2,3]-sigmatropic rearrangement forming a nine-membered with a trans (E>) alkene inside it LRQ-Y 1 Tis chomisty was used to make the perume cisasmone by R.A Eligon and WD. Woossoer, J. Orem. 806, Cher. Commun, era, 59, the sulfur were removes by Rarey nickel we should he a ‘rer memberes rng and ths was ‘te idea of E.Vedes eta, J OB ‘Chem, 1981, 46, 5452,434 Organic Chemistry Solutions Manual | | | BOR OR Purpose of the problem So you can se for yourself the versatility of sulfur Suggested solution | “The Grignard reagent from the starting material adds to CS, and the resulting anion is rapped 6 | Mel to givea dithioester. This tacked by second Grignard reagent and the anion agin rapes | $0 that we have built up a dithioucetal by making two new C-C bonds. ‘? ‘The dithioacetal is hydrolysed (mechanism like that on p. 1255) silver and cadmium being >t instead of mercury (not much gain in environmental friendliness there!), and the double b=? ; ‘moves into conjugtion with he resaking ketone to complet the synthesis of ar-urmerone car fut at Caen by A. Thilier and group, J. Org. Chem, 1979, 44,2807. Purpose of the problem } ‘Your first innocent encounter with the Pummerer rearrangement!Chapter 46 Suggested solutions for Chapter 46 435 Suggested solution ‘serthing i setup for a Pummerer rearrangement = the sulfoxide, the acidic hydrogens on one ‘de, the anhydride ~ so we must st react the oxygen ofthe sulfoxide withthe anhydride and make Pummerer cation, 4 4 eA Nn ome = i ra ys 4 ° Se 86. Now what will the cation do? It could capture the external nucleophile, trluoroacetate, but that _ % Io Bslivin's es terms, the < very weak and there is another nucleophile close at hand: the alkene, We know the reioselectivity ‘Saco s Senor cot ne ym the structure ofthe product, but it looks as though the alkene prefers to actin an exo manner, =robably because of better overlap of the orbitals. The stereochemistry of the side chain comes from Ths chemist was par ofan = transition state already having the side chain on the outside ofthe molecule ast folds and the lack yee alkaloid symesis (he sf conteol in the SMe group is unimportant as it can be removed with Raney nickel anyway. Sarg mato! was made form Toner. Soc, Chem. Commun. Problem 412 1986, 684, Problem 9 in Chapter 32 asked you to interpret the NMR spectrum ofa cyclopropane (A). This, ‘compound was formed using a sulfur yl. What is the mechanism of the reaction? Die kage ly ‘Attempts to repeat this synthesis on the bromo compound below led to a different product. ‘What is diferent this time? fw rnbet i ° ashe} Purpose of the problem “an you disentangle curious variation ina simple mechanism? Suggested solution The first reaction is @ straightforward cyclopropane formation with a sufoxonium yiid and a = reductive sin the second case with NaBH, the alcohol. The second case also shows repioseleca in that only the terminal alkene is attacked. Ifthe other alkene were to react, a proton nex ‘oxygen would have to he removed and this is unfavourable, aeieeasiggested solutions for Chapter 47 blem 4 = Hammett p value for the following reaction Is 4.8. Exolain this in terms of a anism. f the reaction were carried out in deuterated solvent, would the rate change mc would there be any deuterium incorporation into the product? What js the silicon: ining product? ‘ se of the problem “sion of electrophilic aromatic substitution (Chapter 22), the Hammett relationship fom 1 (pp, 1080-100), and establishing the importance of the Psy cation, ested solution « »‘proto-desilylation’ and the large negative Hammett p value shows that electrons are being Sad out ofthe ring in a big way inthe rate-determining step. Protonation at the ‘ipo’ position “sere the silicon is) is the only way to get a silyl cation (pp. 1291-3) and attack of a nucleophile “sa as water removes the silicon. F, ga eo Co vexatmacg tr he Ne * “y x Tis eon ws sod by ‘= a deuterated solvent, rate-determining proton transfer to carbon would be slower and the Hl TMS 2 On ‘rsed in the product would instead be deuterium. The slcon-containing producti initially the Soe" sosia62n ‘sral Me,Si-OH bat this quickly gives the ether MesSi-O-SiMe, Problem 2 enti the intermediates inthis reaction sequence and draw mechanisms fr the reactions, explaining the special role of the MesSi group. Pee mi A. ceemia Purpose of the problem ‘e:roducing the stabilization of anions by silicon, the Peterson reaction, and the chemistry of silyl oxides.440 Organic Chemistry Solutions Manual Suggested solution [Addition of R'Li to the double bond gives an anion stabilized by two silicon atoms. Petesin reaction gives a vinyl silane and epoxidation and hydrolysis (p. 1302) gives the carbonyl comy ‘There is no need to concern ourselves with stereochemistry asi all disappears in the final prod “The slicon atom i esential in every step except the final tautomerism. ose le ek Temwrnee oe eee ie i Problem 3 = i ‘The synthesis of @ compound used in a rcben n Chater 38 (ragmentain) is ven below. Give mechanisms forthe reactions explaining the role of slico, Purpose of the problem Reminder of the anion-stabilizing ability of sulfones and the excellence of the mesylate Jeavie group (Chapter 46) plus the special role of fluoride as a nucleophile for silicon, Suggested solution sa Tis product wes the stating Sodium hydride removes a proton from the sulfone to give an anion you can represent as = ‘natealorFrobiom & inChapter 38 enolate. Displacement of mesylate gives an alli silane converted into an allyl anion with fluorse and nas used ina treccarbonré_ Addition to the Ketone gives the 5/5 fused system, necessarily with cis stereochemistry. ‘rpansien devises by 8M. Tost (04. £.Vncort, JA Chm. Soe, 4980, 302, 5060. Give mechanisms for the following reactions, soning svickies ale including steeochemisty How would the reaction with BusSnH have 16 be done fr cChapter 47 Suggested solutions for Chapter 47 aaa. Purpose of the problem Introdaction to tin compounds as (4) reagents fr radial additions, especially to allynes, and (b) sources of steeochemically controlled vinl anion reagents by tin-lihium exchange Suggested solution ‘The reaction of the alkyne with BusSoH is a radial addition initially giving the cs (Z-) vinyl stannane but this equilibrates to the trans (E-) i (slight) excess of Bu,SnH is used 80 this is how the reaction must be done, gi Ba ohoye ~ Base ae nan Exchange with lithium via an ‘ate’ complex gives a vinyl-lithium with retention of configuration and this is alkylated again with retention. These reactions go with retention because they are ‘electrophilic substitution ~ the eletrophile attacks the filled o orbital of the C-Sn or C-Li bond. use Explain te following reactions. In particular, explain the role of tin and wy it is necessary and discuss the stereachemisty a moose“ coe 7 Purpose of the problem More tin chemistry with revision of stereochemical control in cylic compounds (Chapter 33), cycloaddition reactions (Chapter 38) and fragmentation (Chapter 38) Suggested solution ‘The action of the teriary amine on the acid chloride produces « ketene that does a [2 + 21 cycloaddition to eyclopentadiene (pp. 929-92). The ring junction in the adduct must be cis but the other centre need not be controlled as itis lost during the dehalogenation by the tin hydride. fe ais oy te 30 En BeheOrganic Chemistry Solutions Manual 2 is chomisoy was usea by 1 Ghosee arc group na syrthesis of postage U. An. Che, ‘Sec, 1981, 103, 4616), ‘er ‘The tn hydride reaction is «standard dehalogenation using the radical to sustain a chain reason (pp. 1040-1). The stereochemistry is that of the mos stable product with the COsMe group ax the ‘outside of the folded molecule. In fact, this stereochemistry is also unimportant as it disappeats = the next reaction, ier eet eee de CaN es CEO Reduction of the ketone gives an alcohol that fragments in a reverse aldol reaction to rely the strain in the four-membered ring. The product intially retains the cis stereochems: but equilibrates through the enolate (or enol) of the aldehyde to the more stable c= arrangement. Problem6 ik 4 stereochemisty and mechanism of this hydroborstion-carbonylation sequence, Purpose of the problem Checking that you understand regio- and stereoselectivity in hydroboration. Suggested solution Hydroboration occurs on the top face, away from the gem-dimethy] group on the lower bridge. ‘Carbon monoxide is one of those carbon nucleophiles that atacks boron and insets with retention (p. 1283) into the C-B bond. "nm, rer aon ee Se ee XG Ok a.Chapter 47 Suggested solutions for Chapter 47 443. ‘The ay borane is unstable and easly reduce to the sleohol and that gives the aldehyde when them This sown ws sed) MP. Caton and gout " aoxmal boron o oxygen migration sina with laine hydrogen peroxide. This reaction does MP Cn go = ot act any ofthe hil cenees Taare tote 1979 447. ene ae uaiot 5 Bh Mo, She om i Problem 7 Revision content. Give mechanisms for these reactions, commenting on the role of silicon and the stereochemistry ofthe. : ‘yetization. The Liat simply reduces the ketone to the corresponding alcohol. I you have trouble withthe Hgll}catalysed step, there is help in Chapter 36, AO Le Tee Purpose of the problem Revision of Chapter 36 (sigmatropic rearrangements), some tn-lithium exchange chemistry, and an exercise in vinyl silane mechanisns Suggested solution ‘The drawing of the frst two molecules gives you the clue that, after stereospecific fi exchange (pp. 1306-8), the vinyslthium attacks the carbonyl group direct. The ketone in the fst product is formed by hydrolysis ofthe enol ether (pp. 540-1} in the work-up. Jitu ‘The next step isa Claisen rearrangement, a [3.3]-sigmateopic rearrangement of a vinyl allyl ether pp. 944-6). The first two steps are just to set up that vital intermediate, using Hel) asa soft Lewis acid, ideal for carbon,aaa Organic Chemistry Solutions Manual A Lh Be kue 1 This chemist fom ne base Now the aldehyde is oxidized to an acid and the acid chloride does an intramolecular Leitch shaseer soposnte sero catalysed, aliphatic Friedel-Crafts reaction on the ving silane. Notice attack atthe ipo carbor = Sonnac by SD. Bute eft sive a stable esp cation intermediate and that ths vinl silane ha to rect with inversion as & tranalkene is impossible inthe ring. Purpose of the problem Another check on your understanding of the important regio- and stereoslectivity = hydroboration Suggested solution ‘= Ts was also ingorent in tte The most important interaction in hydroboration is between the HOMO of the alkene (here £ jet-Ader reaction, 5p. 919-21}, diene) and the empty orbital (LUMO) on boron (p. 1279). Here the ends of the diene have larger coflcients. The reaction occurs on the opposite face of the diene to the one occupied by f= substituent, especially asic must occur nex to that substituent. In the oxidation, the lss substituted sroup migrates with retention. = coe ‘= This chemisny was used ian _The closure ofthe lactone must be done with inversion of configuration atthe alcohol centre. W: asmmavie smthesis of should normally use a Mitsunobu reaction for this but mesyation isa good alternative. Mesylatio= ostaganans at Hotimants Rech occurs via the sulfene with retention and then displacement ofthis excelent leaving group require Lee the sulfene with retention and then displacement of this excellent leaving group req ‘Soe, 3973, 98, 7173), inversion and the cis lactone is formed x eatChapter 47 Suggested solutions for Chapter 47 Purpose of the problem Basic silicon chemistry: the Peterson reaction and allyl silanes as nucleophiles. Suggested solution The acylation ofthe Grignard regent is followed by an second attack on the ketone as expected but the tertiary alcohol isa Peterson intermediate and eliminates to give the alkene (pp. 812-14 and mec Liane. Sines ok ge i et020 1 5 gt0z0" mye ne Et," veal Now a Lewis-acidcatalysed reaction of the ally silane via @ silyl cation, gives the lactone. The a This silcon christy was double bond in these ‘exo-methylene' lactones easly moves into the ring in acid or base so the mild devised by A. Hacer, Sntesis, «conditions for ally silane reactions are ideal 4985, 271, hes oe Fe ee Bae446 Organic Chemistry Solutions Manual Purpose of the problem ‘More basic silicon chemistry: the Peterson reaction again with sulfur around and Posy catiom doing something new. Revision of the Beckmann fragmentation, Suggested solution ‘The frst reaction isa straightforward Peterson reaction (pp. 812-14 and 1296-7), without eve « ‘worry over stereochemistry. OO ele) sn a ls J Wtynenet cepa "The second step is « Hlt)- a oy “i ract a 7 Xe a 4 sis fererlsromateomeiaion Finally, che pyridine symthess is simply a double enaminefimine formation between ammors Seaumcs cara fom Moral” and the two carbonyl groups Probably the aldehyde reacts fs, (WA. Ts, Tevstecton Lett, 1962, mae ¥ ae 28 Z it ui a (Cr ‘ematon * J Problem 8 * Give a mechanism for this carbonylation reaction. Comment on the stereochemistry and explain why the yield Is higher if the reaction Is carted out under a carbon monoxide atmosohere, " ne 2 Purpose of the problem Revision of Chapter 47 with practice et Stille coupling and ca:bonyiaton. Suggested solution rs ‘The tin-palladium exchange (transmetallation) occurs (pp. 1326-7) with retention of configuratio: 4s at the double bond. The exchange of the benzyl group forthe benzoyl group is necessary just to ge the reaction started Pra Chapter 48 Suggested solutions for Chapter 48 487 "Now the coupling can take place on the palladium atom producing the product and Pd(), which can insert oxidatively in the C-Cl bond. Transmetallation now sets up a sustainable ole of reactions. It is better to have an atmosphere of carbon monoxide because the acyl palladium complex can ive off CO and leave a PdPh a-complex. The atmosphere of CO reverses this wy ~~poa mm mos pele Chee Neri bse coseien pn = comm TB coe = ag ME aay aie ou sis cnemiy was deveoped by Now the coupling reaction with the acid chloride takes place as before though this time we have Ty qaeaa amd 8 Se ‘an aliphatic carbonyl complex. There is no problem with B-elimination as that would give a ketene. Again, the stereochemistry ofthe vinyl stannane is retained in the product. nae Noir | — seth exces. aaa Osirrstou Problem 9. , Expain the mechanism and stereochefnsty ofthese reactions, The fst is revision and the second is ee sae =o Purpose of the problem Revision of sigmatropi rearrangements from Chapter 36 and just one example of Collman’s fe reagent. Suggested solution The first step is @ (3.3]-sigmatropic Claisen rearrangement with supralacial transfer of the vinyl troup across the aly part of the molecule. Then there isa simple reduction and tosylation ae : rt 3 ay458 Organic Chemistry Solutions Manual ‘= Ts par of a ayia of the Now for the organometallic bit. As described in the chapter (p. 1318) the ferrate anion is ve antral compound agicaln by IVE, MeMusry et a, J. Am. Chem ‘See, 1979, 104, 1330 usirg eremisvy developed by 4.P. Colman, Acc. Chem. Res, 4975, 8.342, nucleophilic and displaces the tosylate from the primary carbon. Catbonyl insertion gives an acyl complex and the neutral iron atom forms a x-complex with the alkene. The carbon! transferred tothe far end of the alkene as six-membered ings ae prefered o five-membered or and protonation of the C-Fe bond completes the reaction. ae 4 (om dracon s ieee aaa ‘of an antifungal drug was completed by this paliacium-catalysed reaction. Give @ mechanism and explain the rego- and stereoselectivity Purpose of the problem [AN nice simple example for once! The ides is to give you confidence Suggested solution ‘The palladium forms the usual ally cation complex and the nitrogen nucleophile attacks the le hindered end also retaining the conjugation. Attack at the triple bond would give an allene rte ae TL moa dis vine Problem 14. ‘Some revision content. Work out the structures of the compounds in this sequence and ‘suggest mechanisms for the reactions, explaining any selectiviy. plas ase arin Moe ra, 686402 KOK AO TH eatin clay | Bhas IR: 1730, 1740 em-*; y (p.pim.} 9.4 (3H, s), 2.6 (2H, 5), 2.0 (3H, 8), and 3.0 (6H, 5). Chas IR: 1710 om; 5, (p.p.m.) 7.3 (AH, o, 15.5 He), 6.8 (4H, d, J5.5Mz), 2.4 (2H. 8), and 1.15 (6H, 8). I L 5 uSeha it Chapter 48 Suggested solutions for Chapter 48 459 } Purpose of the problem A nice simple example again: a Wacker oxidation and an intramolecular aldol reaction (Chapter 27). Suggested solution Bis clearly an aldehyde anda ketone with nothing but singlets in the NMR. On the other hand has a cisdisubsttuted alkene with a small J value and is @ cyclopentenone. Here are theit structures. Kou, H20, THF OG Pat), Cue, 0 ‘Ho Purpose of the problem Looking at organometallic chemistry from the other sie: how isi used? Suggested solution ‘The simplest dsconnectons fo the two reactions are remarkably sini. Both make one bond next to the ketone and the bond on the far side ofthe ring, In addition, the Pauson-Khand reaction requires disconnection on the other side af the ketone a8 CO is one ofthe reagents. The position of the final alkene inthe Nazarov products not determined bythe position of the double bond in the starting material (pp. 962-3). 8 ° a ga AY = ft ascent wt. oT See Re = o im) i . =~ | 2 2 i x! (Our preferred solution for the frst compound is a Nazarov reaction asthe starting material is symmetrical and it is not necessary to use a vinyl silane, though this would work well too. The starting alkene is easly made from cs-butenediol. The double bond in the product will much prefer to go inside the ring where i is more highly substituted, C0 EA pl- bo )