Marginalia

In Praise of Synthesis

Roald Hoffmann

an is wonderful. We admire Nature's work 1. Elemental synthesis. You take substance A, perhaps as a Creationfirst?from simple things such the hoarfrost that set? element, perhaps compound, mix itwith substance B, beat on on an tled overnight the brown shingles of the house, to that itwith heat or light, zap itwith electrical discharge. In a a an most intricate creation, repeated thousands of times each puff of foul smoke, flash, explosion, out pop lovely a day, human infantbrought to term and born. Human cre? crystals of desired substance C. This is the comic-book ation second?Mozart and Lorenzo DaPonte, Elly Ameling stereotype of chemical synthesis. In general, an elemental an on a and English orchestra, 200 years apart, collaborating synthesis is not considered by the chemical community to a rendition of "V?i che sapete" that is so sweet and clear it al? be clever way ofmaking molecules. Unless, unless?the most hurts. Or David Hockney, assembling some 50 roughly product molecule has not been seen on earth before. This is a developed prints into photomontage inwhich the camera, how xenon tetrafluoride, XeF4, was made (4), with no py? Hockney, and we, like the eye, concentrate on a detail here, rotechnics, but still by an elemental synthesis. on a jump there, zoom in piece of the background. And Phil Eaton and Thomas Cole, who synthesized a Xe + -?2SU simple molecule, cubane, which has eight carbon atoms in 2F2 XeF4 a the shape of a cube, each carbon also bearing hydrogen: Behind its creation was some clever reasoning by Neil Bartlett (5), which allowed themakers of XeF4 to imagine that the compound might exist. Itwas the first simple com? pound of a noble gas and a halogen. The uniqueness of cre? ation can override stylistic reservations about how the prod? uct ismade. 2. Part by design, part by chance. In that limbo between serendipity and logic, there stirs the vast majority of chemi? a cal syntheses. One has rough idea of what one wants to do?cleave a bond there, form a new one here. One has read of similar reactions, on molecules that look vaguely like the It is themaking of such molecules?chemical synthesis? one at hand, and so one tries (ormore likely asks a graduate that Iwant to praise. Synthesis is a remarkable activity that student to try)one of those reactions. Itmight work, itmight is at the heart of , that puts chemistry close to not?perhaps the conditions must be juggled, the tempera? art, and yet has so much logic in it that people have tried ture changed, or perhaps one should follow a different to teach computers to design the strategy formaking regime of adding the reagents, giving them more or less molecules. time tomix. On the seventh run-through, something hap? make molecules. They do other things as well, pens. There ismostly insoluble brown gunk in the reaction to be sure?they study the properties of these molecules; vessel, but ifone separates the liquid, extracts itwith anoth? as they analyze, they form theories to what makes er solvent, allows the material to crystallize, out come molecules stable, why they have the shapes or colors that translucent lilac crystals of a product. they do; they study mechanisms, trying to find out how An example of such a synthesis is a reaction inwhich a molecules react. But at the heart of their science is the spectacular gold cluster formed. molecule that ismade, either by a natural process or by a human being (1). The ofmolecules chemists close to the synthesis puts very NqBH4 arts and We make the thatwe and engineering. objects study AuPR3I appreciate (2); in doing so we partake as much of the ethanol metaphor of creation as we do of discovery (3). There is not one way tomake molecules; there are many So letus look at some different kinds of chemical OAu ways. syn? OI .The methods are shaped by scientific needs, econom? AU|l(PR3)7l3 ic considerations, tradition and aesthetics. The chemists inMilan who did this work began with a Roald Hoffmann is professor of chemistry at . simple gold phosphine iodide. They subjected it to reaction

1991 January-February 11

This content downloaded from 128.253.229.89 on Thu, 25 Jun 2015 13:19:53 UTC All use subject to JSTOR Terms and Conditions S03H ONa 0^CH3 C02H /^wCOoH H2S04 NaOH C02 petroleum_ HoO acetic anhydrideo benzene aspirin

Figure 1. One industrial synthesis of aspirin from benzene.

some cases conditions (NaBH4, ethanol) that in other had the past, this led to research strategies such as "take the next an led to novel gold-gold bonding. The synthesizers had chemical off the shelf and try it." Today the progressive seg? idea that something interestingmight happen. But I think it ment of industry invests in basic studies of themechanisms is fair to say they did not anticipate exactly what did hap? of their reactions, the rational way to improve a process. pen, even though, and this is very important, theywere well The competitive pressure to reduce cost is also the source prepared to follow up and determine justwhat molecules of much creativity in industrial synthesis. The academic were created in their flask. In fact, a marvelous cluster, one can and will flit to the next exciting problem ifone gold atom in themiddle, with ten others (an icosahedron synthesis doesn't work out. The industrial chemist does not minus two) on the outside, assembled itself (6). have that choice. So he or she pushes on, often to ingenious 3. Industrial synthesis. Figure 1 shows one of theways in solutions (8). which aspirin ismade commercially. The number of pills 4. Planned synthesis.Actually, it is in the academic setting manufactured in theU.S. each year approaches the number thatmany of themasterpieces of synthesis are created. The a of dollars in the nation's defense budget. From petroleum constraints of cost are relaxed, though they are still there. fraction,benzene is separated out, then reacted sequentially Imagination is set free.Marvelous syntheses result. Here is wa? with sulfuric acid, sodium hydroxide (lye), dry ice and one, already mentioned, that of cubane. This carbon die is an ter,and acetic anhydride (vinegar hiding) to yield acetylsal unnatural product; itwas made not because itwas a icylic acid, which is aspirin. thought useful (9), but because it is beautiful, in simple Some years ago, Punch published an apt verse commentary Platonic-solid sense. Itwas also made because itwas there, on synthesis and what are called "chemical feedstocks": (7) like the proverbial mountain, waiting to be made. Others failed to synthesize itbefore two people at theUniversity of a There's hardly thing a man can name Chicago succeeded in 1964. or use a of beauty in life's small game, Figure 2 is diagram redrawn from the original paper by But you can extract in alembro or jar, Eaton and Cole, showing how they did it (10).We have be? From the physical basis of black coal tar: fore us tenmolecules, with nine arrows, representing reac? Oil and ointment, and wax and wine, tions, between them. Above each arrow is the briefest And the lovely colours called aniline: mnemonic description of the reaction conditions. Each reac? You can make anything, from salve to a star tion might be composed of from five to twenty distinct (If only you know how), from black coal tar. physical manipulations: weighing out reagents, dissolving them in a solvent, mixing, stirring and heating, filtration, The making of aspirin, likemost fine chemical manufac? desiccation, and so on. A stepmight take an hour or a week. ture,begins from a portion of refined petroleum. Right there And the scheme does not include the laborious and inge? a is a problem, and challenge?how tomake those complex nious analytical chemistry required to identify those inter? structures from sources less easily depleted. mediate molecules. An important factor in any industrial synthesis is safety. At the end of the synthesis is cubane. The chemist's sign The manufacturing process must not injure thehealth of the for it is just a simple polyhedron; the professional privy to workers, and the final product must be safe for the con? the code knows that each vertex stands forCH. At the be? sumer. In this context, people have speculated whether as? ginning of the synthesis ismolecule I. It doesn't look sim? pirin would be allowed on themarket as a nonprescription ple?one thinks that at the start of any construction there ma? medication if itwere newly introduced today. should be readily available materials. Actually, starting The overriding imperative in industrial synthesis is cost. terial I is easy tomake. The Chicago chemists had synthe? Starting products and reagents had better be as close as pos? sized it earlier, in three steps, from another molecule that sible to earth, air, fire and water (and fire is getting awfully costs pennies per gram. expensive). All of the reagents in the aspirin synthesis are on Below each arrow is a percentage. This is the yield, the the "top 50" list of the chemical production hits chart, being percent of the theoretically possible product that is actually among the highest in volume of production and among the obtained. Our synthesizers got 85 percent of that theoretical re? lowest in cost. Expense also drives producers to optimize yield for the firstreaction in the synthesis. In subsequent a a a the efficiency of synthesis. If step in synthesis gives actions, they got yields ranging from 30 percent to 98 per? yield of 90 percent (that is, 90 percent of the theoretically cent. You might think that themain reason theywrote down an possible amount?more on yields below), then improve? these yields is to demonstrate efficiency. Indeed, it is easy to ment to 95 percent, perhaps through a new catalyst, might calculate how many carloads of the starting material they provide a competitive advantage of millions of dollars. In would have to use to get one milligram of cubane, if each

12 American Scientist, Volume 79

This content downloaded from 128.253.229.89 on Thu, 25 Jun 2015 13:19:53 UTC All use subject to JSTOR Terms and Conditions ft (l)(CH2OH)2-H+ (2)oqueous. 10% C\ ^Br HCI_ KOHa 85% ^ 95% ?"c>SfBrBr III

9A (DSOCI2 cumene -p-0> 75% H2SO4 55% Br 90% HOOC (CH3)3C00C IV VI

(l)SOCI2 CT 25% KOH 0 xCOOH (2)(CH3)3C00H-pyridine^ II 55% 98% .COOC(CH3)3

VII IX diisopropy Ibenzene 150? ca. 30%

X, cubane

Figure 2. Synthesis of cubane, as originally performed by Philip Eaton and Thomas Cole.

were step 10 percent efficient. But that is not themain rea? pie towrite computer programs to emulate the irtind of a son workers listed the a these percent yield. synthetic chemist. The design of such programs is high The in a chemical reaction is an yield aesthetic criterion. challenge toworkers in "artificial intelligence" and "expert To think one a as as appreciate this, about how might get only 10 systems," well to chemists. The prograrriming is an ed? a percent yield. A reaction is sequence of physical manipula? ucational act of great value; chemists who have worked on a tions performed by fallible human being using imperfect these programs have learned much about their own science to a as tools. One way get 10 percent yield is to spill 90 percent they analyzed their own thought processes. Use of these of the solution in the course of a transfer from a flask to a fil? programs is now common in some industrial laboratories; ter will not or can funnel. Sloppiness impress people, in science they be of help in routine syntheses. in art. Can the synthesis programs suggest interesting synthe? Suppose every transfer ismeticulously done. The crafts? ses, the kind that if turned to practice could be published one a manship is high. Still gets 10 percent yield. Now it is in a good chemical journal? I think this remains an open not human hands that are at it fault, is themind. Nature question. The papers ofworkers in computer-assisted syn? no to our has paid attention design, but has decided to do thesis typically illustrate the capability of their programs with our something else 90 percent of material. That does by demonstrating that the programs suggest routes to dif? not control ofmind over it not show matter, and does draw ficult targets identical to paths conceived earlier by other a re? admiration. Maybe there's better way to carry out that good (noncomputerized) chemists. But I'm still waiting action step. A sequence of high-yield reactions, such as the for the paper that begins: "There is great interest in a new sequence in the cubane synthesis, defines elegance in antiviral agent, Bussacomycin-F17, isolated from the slime chemistry. mold Castela manuelensis. We attempted a total synthesis of a There is high logic in synthetic strategy. The design of thismolecule with 15 asymmetric centers, but were unsuc? multistep synthesis resembles themaking of a chess prob? cessful. We then turned to the program MAGNASYN-3, end is In lem.At the cubane?the mating situation. between which suggested the eventually successful synthesis are with for are shown in 1...." moves, rules making them. The rules much Figure more interesting and free than those of chess. The synthetic The psychology of human beings leaves us ill-prepared to a chemist's problem is to design situation on the chessboard, admit thatwe could be replaced by a computer program, al? moves 10 back, which has themost ordinary appearance. though we may be ready to concede that other people can be. one a But from that position, player (or team of chemists), A chemical synthesis is obviously a building process. One by a clever sequence ofmoves, reaches themating position therefore sees architectonic considerations, and the aesthet? no matter what the recalcitrant opponent?the most ics of architecture figure prominently. Note, for instance, formidable opponent of all, Nature?does. that intermediates in the synthesis of cubane are more com? content or The obvious logical of synthesis has inspired peo plicated than the starting material product. Why is this

1991 January-February 13

This content downloaded from 128.253.229.89 on Thu, 25 Jun 2015 13:19:53 UTC All use subject to JSTOR Terms and Conditions so? Well, scaffolding has to be built to hold pieces of the "hands-off" kind of building! This is not the nailing together are structure in place while other parts assembled. A specif? of a wood box shaped like a cube, or even a Palladian villa. some ic detail gives further insight. In substance I there are In the reaction flask there is not one molecule, but 1023.They or car? are two ketone groups, CO groups bonded to two other tiny. They are all bouncing around, chaotically doing one own bon atoms. The reaction from I to II transforms of the their thing.And yet on the average they are being made ketone groups into a five-membered ring but leaves the oth? to do what we want them to do, driven only by the exter? er group alone. Then Cole and Eaton get towork on that nal macroscopic conditions we impose on the flask and other ketone, changing it from CO to COOH (III->IV), the the strong dictates of thermodynamics. We create local an COOH to (CH3)3COOCO (IV->V), and that toH (V->VI). In order, to order, through increase of disorder in the uncover VI->VII, they the second ketone group and then surroundings. proceed to do to it the same violence they did to the firstone Chemical synthesis not only shares some of the aesthetic a (VII-*VIII->IX->X). What waste of effort!Why not do criteria of art; I think it is art.At the same time, it is logic. To a both groups at once? quote modern master of synthesis, E. J.Corey: see a a What you here is the basic and simple idea of "pro? "The synthetic chemist ismore than logician and strate? or one a an tecting group," the padding concealment of piece of gist; he is explorer strongly influenced to speculate, to a on molecule while transformation is done another piece. imagine, and even to create. These added elements provide was Then the protecting group is removed. When cubane the touch of artistrywhich can hardly be included in a cata? were first being made, Eaton and Cole fearful that this loguing of the basic principles of Synthesis, but they are molecular skeleton might be unstable. So they proceeded in very real and extremely important.... small, cautious steps, using this strategy of protection. "The proposition can be advanced thatmany of themost They need not have worried. We know today that both distinguished synthetic studies have entailed a balance be? can one tween ketone groups be converted to COOH in step (11). two different research philosophies, one embodying was That this not attempted the first time themolecule was the ideal of a deductive analysis based on known methodol? no made in way detracts from the synthetic achievement. It ogy and current theory, and the other emphasizing innova? as points out the "historicity" of this human activity, of all tion and even speculation. The appeal of a problem in syn? was as others: something done, perhaps not well as it could thesis and its attractiveness can be expected to reach a level be done today, in tentative steps, but still created, for the out of all proportion to practical considerations whenever it first time, by human intelligence, human hands. presents a clear challenge to the creativity, originality and a a Synthesis is building process, but what marvelous imagination of the expert in synthesis." (12)

References 1. a see For discussion of the natural/unnatural dichotomy R. Hoff? PERSONALBIBLIOGRAPHIC DATABASES mann, 1990, New England Review and Bread Loaf Quarterly XII (No. 4):323. THEFIRST GENERATION: was 2. This thought expressed by Marcellin Berthelot, I860, Chimie Or ? ? sur am SCI-MATE DMS 4 CITE PRO-CITE ganique Fondee la Synthese, Tome 2, Paris: Mallet-Bachelier. I REFERENCEMANAGER ? REF-11 grateful to Jean-Marie Lehn for this reference. The special role of chemistry, its contrast to parts of physics and resemblance to art and an THESECOND GENERATION: engineering, is taken up in article by J.-P.Malrieu, 1987, L'Actual iteChimique No. 3, p. ix.He coins the apt descriptor of technopoiese to characterize chemistry. 3. See R. Hoffmann, 1990, American Scientist 78:14.

4. H. H. Ciaassen, H. Selig, H. G. Malm, 1964, Journal of theAmerican Chemical Society 84:3593. PAPYRUS 5. N. D. Bartlett, 1962, Proceedings of the Chemistry Society: 218. VERSION 6.0 6. L. Malatesta, L. Naldini, G. Simonetta and F. Cariati, 1966, Coordina? tion Chemistry Reviews 1:255; V. G. Albano, P. L. Bellon, M. Man Manages up to 2 million 100% compatible with assero and M. Sansoni, 1970, Chemical Communications 1210; F. reference citations. Stores up to WordPerfect, Microsoft Word, Cariati and L. Naldini, 1971, Inorganic Chimica Acta 5:172. The crucial 16,000characters and 100 PC-Write,WordStar 2000, structure was an crystal that revealed the Auu cluster for SCN reference. WordStar keywords per Pro, XyWrite. derivative: M. McPartlin, R. Mason and L. Malatesta, 1969, Chemical Fast, powerful search Can also be used with virtually Communications 334. capabilities. all other word processors. 7. in Quoted by J.Read, 1958, Perkin Centenary London; 100 Years of Syn? Dozens of predefined output Able to import references from thetic London: Press, 23. formats,plus the ability to easily national databases, other bib? Dyestuffs, Pergammon p. some on design your own additional liography programs, or almost 8. For astute observations the contrast of creative chemistry in formats. other database or text file. see any industry and the universities G. S. Hammond, 1987, Chemtech: 140. IBM PC and compatibles Full Registered 9. There is now, 25 after its some interest in derivatives 00 VAX-VMS years synthesis, of cubane as and fuels. System $99 (Macintoshversion planned formid-1991) pharmaceuticals, explosives Pilot-plant pro? Fullmoney-back guarantee on in is of duction, kilogram quantities, proceeding. purchase RegisteredSystem. Research Software 10. P. E. Eaton and T. W. Cole, Jr., 1964, Journal of theAmerican Chemical ,00 Demo System $25' Society 86:3157. Demo price credited toward sub? 2718 SW Suite 181 11. P. E. Eaton, communication. sequent RegisteredSystem purchase. Kelly Street, private Portland, OR 97201 12. E. Pure and OutsideNorth America, add $10shipping J.Corey, 1967, Applied Chemistry 14:30. - U.S. ona U.S.bank. (503) 796-1368 FAX:503-241 -4260 charge funds, was a 13. This essay published in slightly different form inNegative Ca? Circle 60 on Reader Service Card pability(1990) X (No. 2,3):162.

14 American Scientist, Volume 79

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