Development of an Advanced Synthesis Laboratory Course in Nobel Prize Winning Chemistry Kenneth M. Doxsee University of Oregon. Eugene, OR 97403 Traditional laboratory instruction in chemical synthesis has often been descrihed as followine a "cookbook" approach, in which students follow time-worn and proven preparations and, if successful in following instructions, ohtain the results they knew they would or should. Though laboratory techniques may he reliably learned through such instruction, much of the excitement of chemical lahoratory work tends to be lost (by both the student and the instructor) under such a format. There has been an increasing awareness of this problem, and a growing number of innovative alternative approaches to the teaching of laboratory technique are being discussed (1). An additional Drohlem with the traditional teachine- of chemistry has been the loss of any sort of historical perspective. Verv few students are aware of even the most famous of chemisgor of their work. Indeed, it is a rare student (undermaduate or eraduate) who is ahle to name even a few, or the most r e c e n t r r e ~ i ~ i e n of t s the Nobel Prize in chemistry. I t has been my that knowledge of the people and . experience . the historical context, as well as the scientific concepts, behind a reaction type or mechanism, adds tremendously to one's interest in learnine about the subiect. However. formal .-~ instruction in the histoFy of cbemistriis provided at only a relativelv small ~ r o ~ o r t i oofncolleees and universities. while laboratory instruction with historical relevance is provided a t only a very small handful of institutions (2). When presented with the opportunity to teach an advanced undereraduate course in chemical synthesis a t the University o1'~outhernCalifornia, I chose totake ndvantage of the course ro attempt co accomplish two aims: (1) t u make laboratory chemistry seem exciting, not routine, and (2) to instill an appreciation in my students for the history of chemistry. T o achieve these goals, I chose a perhaps arbitrary but, in my mind, immediately compelling approach: we would study, through a combination of lectures and laboratory investigations, the work of those chemists who were ultimatelv awarded the Nohel Prize in Chemistry. Amone the lessons I felt could be transmitted through such a study, in addition to the development of advanced synthesis laboratory technique, were an appreciation of thechemical literature, an awareness of that chemistry deemed worthy of the world's highest honor, and an apprecintlon uf the peraonal and scient~ficinterrelationships of research. 111the process, I hoped students would learn several other important facts of life, including the facts that even great scientists can make mistakes and that chance discovery can play an important role in the advancement of science. Finally, along the wav I intended for the students to pain some exposure to a littlejust plain history, in thr formot', for elample, an understandineoiwhv it was that Nobel Prizesuerr not nwarded in 1916 0;1917,or again from 1940 through 1942, and why certain winners were "prevented from accepting the prize .. .owing to political conditions a t the time." In this article, I will provide a general overview of the course. ~.includine an outline of the material covered in both the lecture and the lahoratory. In succeeding submissions to rhisJourna1, I will present rhedetailsof the more successful &
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of the laboratory projects, as well as discussions of the more interesting pieces of chemical history that were presented through a combination of lecture and laboratory work. Thoueh this course as descrihed was taueht as a lecture/ lahoratory combination, the chemistry appears quite suitable for lecture resenta at ion alone (3).For effective exoloration of the most interesting ramifications of Nobel chemistrv. - of oreanic - chemistrv. .. as well ..a strone workine knowledee as good exposure to general and inorganic chemistry, should be nrereauisites for enrollment. This is ~articularlv . impor. tant from a safety perspective, as discussed below. The course was taueht with the assistance of one full-time and two half-time teaching assistants. If each lah class is kept fairly small (recommend 10-15 students), proper supervision and instruction may easily be provided by a single instructor, without TA's. Running this lab, in fact, was rather similar to running a functional research group.
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Nobel Prize Wlnnlng Synthetic Chemistry A survey of Nobel Prize winners in chemistry reveals that a sizeable proportion of these prizes have been awarded for work in the synthesis of organic or inorganic molecules. (Nearly a third of all the chemistry prizes awarded, 31 out of 109, were for work that was largely synthetic in nature.) Tahle 1 lists those Prize winners whose work appeared of potential relevance to a synthesis lahoratory. A most useful reference for this analysis was provided by the complete puhlished transcripts of the Nohel lectures presented by recipients, as puhlished in book form (4)or, for the more recent lectures, as articles in Science or the Angewandte Chemie. Course Organlzatlon Students received three hours of lectures per week and spent a total of eight hours per week two four-hour sessions) in the lahoratory. Homework assignments were made intermittently, and a midterm examination and final were administered, though it was made clear from the start that evaluation would be based primarily upon the lahoratory work. Students were generally given the option of choosing hetween two or three sub-~roiects within the context of each project and were allowed i o proceed a t their own pace (withFollowin reason: final deadlines were set for each oroiect). . . ing completion of appropriate pre-lab preparations and readings, students carried out their laboratory work. Upon conclusion of each project, a detailed lab report, written in the format of a scientific paper, was required. Lecture Content Both the lahoratory and the attendant lectures for this course of instruction really need to be somewhat free-form, adapting to the needs and desires of the students from year to year. General topics which merit some discussion are listed in Tahle 2; this listing comprised the original syllabus outline for the course. The issue of laboratorv safetv was and must be raised early and strongly in thk lecture as well as periodically throughout the laboratory sessions. As largely unchecked Volume 67 Number 12 December 1990
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Table 1. Year
Winner Emil Fischer Adolf M n Baeyer on0 Waliach Victor Grignard Alfred Werner Richard Willst;lner Heinrich Wieiand Adolf Wlndaus Hans Fischer Walter Haworth Paul Karrer Richard Kuhn Adolf Butenandl Leopold Ruricka Robert Robinson Otto Dleis Kurt Alder Vincent Du Vigneaud Alexander TDM Guilio Natta Karl Ziegier Robert 8. Wwdward Ernst Fischer Geoffrey Wllkinson Herben C. Brawn Gewg Winig Bruce Merrifield Donald J. Cram Jean-Marie Lehn Char ss Pedersen
Also of potential relevance: 1981 Roald HoffmannIKanichi Fukui 1983
Henrv Taube
Synthesis of sugars and purines Organic dyes and hydmsromatics Chemisby of slicyciic compounds Olignard reagent discovery Coordination complexes Plant pigme* (chlorophyll) Bile acids Sterols and vitamins Structure and synthesis of hemin Carbohydrates and vitamin C Carotenoids, flavins, vitamlnsA B B Carotenoids and vitsmins Sex hormones Polymelhylenss and higher terpenes Alkaloids Did-Alder reaction Did-Alder reactlon Polypeptide hormone synthesis Nucleotides Polymerization catalysis Polymerization catalysis Synthesis of natural products Organometallic synthesis Organometallic synthesis Bomn in organic synthesis Phosphorus in organic synthesis Methods far polypeptide synthesis Molecular desian and recoonition Mo ecLlar design an0 recognltton Molec~iardesign and recognot on Orbital symmetry conbol of chem ical reactions EIe~lrm transfer reactions
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Journal of Chemical Education
Suggested Lecture Toplcs
l n r ~ ~on c to t me course lnrcam on 10 tne laooratory Safety The lab natebaak Laboratory technique me chemical literature and how to use it Synthetic chemisby-what and why? Synthesis and the Nobel Prize Early synthetic chemistry Spectral identificationof compounds Synlhetic strategies
Area of Research
procedures form the basis of the laboratory work, one must carefully consider any potential hazards in the proposed procedures. Proper instruction in laboratory safety and techniaue and discussions of routine and extraordinarv chemical hazards and disposal of chemical waste all must de provided. The instructor's common sense can and should of course play a key role, both in avoiding obviously hazardous procedures (e.g., reactions with HCN) and in identifying all hazards associated with reagents to be used. Such hazards (e.g., properties of POC13 and CS2) were clearly indicated in lab handouts describine the orocedures to be followed. Given the advanced stan&ng of the students enrolled, it is aonronriate t o exoect them to anticioate safetv issues as Ail; students were required to submit a discussion of the properties and potential hazards of all reagents, solvents, and products before they were permitted to begin laboratory work. This level of safety instruction seemed t o provide appropriate preparation for the graduate research-setting many of these students were anticipating. As both lectures and laboratory work proceeded, several obvious deficiencies in student backgrounds appeared, and the course content was chaneed accordinelv to address these. For example, during preparatory discussions for exdorations of the Diels-Alder reaction. it became aonarent that experiments directed toward an kderstanding'of the Alder endo selectivity rule (5) would be of limited utility, since no one in the class had ever heard of this effect. A spontaneous lecture and discussion of the endo effect ensued, following which students were eager to get into the laboratow t o check out this rather unusual phenomenon for themselves. The hirrtoriral context wan maintained, in that we discussed original work by Diels and Alder to drive these poinrs home. These same experiments were used as a foundation for a discussion of NMR spectnacopy as a tool for the 1058
Table 2.
Nobel Prlzes for Sydhellc Chemlrtry
Table 3. Laboratow Proleds
project
Laureate
Year of award
Reference
Svnthesisof AnaIooues of Canlhmidln " Synlhesis of Crown Ethers Mixed Valence Complexes-lntramolecular Charge Transfer Synthesis of Testosterone Synthesis of Flower Pigments
Diels a d Alder PBderren Taube
1950 1987 1983
16 17 18
Butenandl Robimon
1939 1947
19 20
structural characterization of molecules. which aeain anpeared as adeficiency in the students' backgrounds.%imila~lv, deficiencies in recrvstallization techniques were addressed through a background discussion, followed by experimental work based on Robert Robinson's literature accounts of his flower pigment syntheses, which required a multitude of recrystallization steps. A numher of books orovided informative and interestine background reading for interested students. Available biog: raohies and autobioeraohies of Nohel Prize winnine chemisis, including ~ t a u & ~ e r(61, Todd (7),Werner i8), and Willstitter (9),proved especially fascinating. These books, as well as several more generally directed volumes on Alfred Nobel (10) and the Nohel Prize ( l l ) , were kept on reserve, though formal reading assignments were not made. Essence of the Laboratory
Extensive literature searches for the work of eachsynthetic -~ Nobel Prize winnine chemist turned uo literallv hundreds of procedures that s e h e d appropriate for advanced uudergraduates. Those projects which were ultimately chosen for the first presentation of this course are summarized in Table 3. These particular projects were chosen to provide as wide an exposure as possible to a number of techniques in both organic and inorganic synthesis and characterization, as well as a broad overview of a number of the most frequently cited bodies of synthetic chemical research. Introductory projects were either simple single-step or two-step sequences, while more advanced projects called for as many as five sequential transformations. In most cases, students were given the opportunity to choose among several alternative sub-projects kithin the context of the overall project. Much of the earlier literature detailing these investigations was in the German laneuaee. As one mav no loneer assume a working knowledge of German in our chemistry students. initial ~renarationincluded the translation of aopropriati e x p e r i m e k l sections from these articles. DLpending on both the age of the report and on the time during the semester in which the work was to be attempted, these experimentals were either embellished with helpful additional instructions or left unaltered, allowing students to experience the very true-to-life situation of attempting to reproduce a literature result. In order not to dilute the effect of this exposure, none of the procedures followed by students in this laboratory were checked beforehand. This ultimately provided the largest measure of excitement for ~~~
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the students, as was made clear through repeated comments both durine and after the course. Students felt thev were learning hdk chemistry reollj worked and especially seemed to eniov the realization that I did no! have vat answers for all thei;experimental problems. This was the first time these students were faced with the unknown, rather than the "cookbook", and the unknown appeared from the first day, when the "hard white crystals" that were supposed to precipitate did no such thing! A few lab periods later, another literature procedure afforded not the reported white crystalline precipitate, but rather a beautiful, though unfortunately completely intractable, purple syrup. These eventualities resulted in much lost sleen for the instructor before the term started, as one could envision a variety of student responses to such results. In retrospect, student response was so strongly favorable to these situations that i t is hard to imagine how else the course could have been presented. The requirement for unchecked experimental procedures, however, does present the major difficulty in teaching this course year after year. Once a group of stidents has worked through a literature report, virtually all of the previously unknown pitfalls will have been discovered; solvents for recrystallization will be known, etc. Thus,to retainthe sense of true chemical research, new experiments should be attempted each time the course is taught. Though this exacts a certain orice in terms of both laboratorv chemicals and the instructbr's preparation time, it would appear that the payoff in terms of student enthusiasm is high. Fortunatelv, Nobel winners were for the most part quiteprolific in thejr svntheses: there are enough interesting and realistically apgroachable projects to l& for decades of instruction. 1n follow-up papers t o this general introduction to the course concept;l~iilpresent a number of possible laboratory proiects and lecture discussions, including bibliographies, historical comments, and other relevant items, for a series of Nobel winners in synthetic chemistry. This course was directed toward students who had already been through a year of introdurtory organic chemistry and attendant iaboratories. Some exposuie to routine techniques such as UV/visible and infrared spectroscopy, crystallization, and thin-layer chromatography was sssumed. As the course developed, it became apparent that assumption of proficiency in a technique based upon one exposure in a more traditional lab setting was not appropriate. Fortunately, i t proved possible t o introduce these concepts easily within the historical setting of Nobel Prize winning chemistry. Students responded particularly well to this setting. For example, a student's first exposure to recrystallization not infrequently involves following a recipe: "add 1 g of compound X to 50 mL water, heat to boiling, and allow to cool slowly, then isolate the crystalline product by filtration." Not only does such an approach stifle any chance a student may have really to learn how to choose an appropriate solvent system for recrystallization, but i t rates extremely low on the interest scale as well. After all, every student in the class eets the same results. I contrast this situation with that of mistudents in the Nobel lab, who obtained an intractahle, odoriferous zoo after the first step of a five-step synthesis. These students, faced with t h e possibility that they would be unable to complete the synthetic sequence, which they had chosen for its interest to them (in thecase at point, the synthesis of aglycones of flower pigments), spent many huurs a t t e m ~ t i n eto find nurification conditions for their crude produ& fitimately they succeeded, obtaining nicely crystalline white material; this result, of course, was secondary to the fact that they were now quite expert in the technique of recrystallization. (As Hinshelwood paraphrased Lessing in his 1956 Nobel lecture, "To travel hopefully is a better thing than to arrive.") One additional important lesson resulted from this format of instruction. As students must discover sooner or later, ~~
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everything reported in the literature does not necessarily proceed as expected. Perhaps they may simpIy set up an experiment incorrectly, or perhaps the authors omitted some key . step - or explanation, or the authors were incorrect in their assignmeniof structure to either their product or their starting materials. Any of a myriad of explanations may be possible; the bottom line is, "Just because i t says so in print doesn't mean it's true." Perhaps a simple lesson, but not one that all students immediately appreciate. The Chemlcal Llterature Throughout the course, students were strongly encouraced t o utilize the chemical literature. Several lectures were divoted to a "how-to" approach to the library, with special emphasis on the indices to the primary literature, including the Chemical Abstracts and the Beilstein index, with the latter requiring a brief survey of useful German words and abbreviations (12).Thoueh students were nrovided with experimental sedtiom deriGed from the primary literature, I did not provide copies of the orieinal articles. Manv students spont&eously sought out the appropriate prima&literature in their effort to learn more about the laboratorv chemistrv: others were coerced to doso, either through for&literatu& assignmentsorout of necessitv, trving to find reported melting points or other physical p;oierGes of inteimediates in synthetic sequences. Further instruction in the use of the literature could very naturally follow in the context of this course. Rarely does a single paper suffice to provide all the details of a synthesis; frequently, for example, reported "starting materials" are not commercially available, but must be prepared according to an earlier report, which must in turn he sought out. The literature searchiue associated with uncoverina such exnerimental details is & important part of any synthetic chemist's backmound. (This exercise also not infrecluentlv convinces &dents of the importance of a well-written; complete experimental section!) Personal and Sclentltlc lnterrelatlonshlps ot Nobel Research As one peruses the Nobel lectures and the primary literature of the winners, one is immediately struck with the iutertwinine nature of much of the chemistrv discussed. No fewer than Gx Nobelwinners in chemi&y devoted considerable effort to the study of the structures and syntheses of steroids. Similmly, three approached the synthesis and characterization of flower pigments (the anthocyanins and anthocyanidins) (5),and three were actively involved in the synthesis of vitamins, especially the flavins (5). Intrieuina - personal relationships also appdar upon closer examination of the literature. One particularly interesting, though complex, example comes in a ~ e n ~ t h y ~ d i s pover u t e the siructure of the dimer of cyclopentadiene (5). At one point in this rather heated debate, which also hrought Kurt Alder and Otto Diels (Nobel Prize 19.50) and Heinrich Wieland (Nobel Prize 19271 into the frav. a former co-worker ~ F r a n sBereell of Wieland published bkk.to-hack papersdetai~in~ hislater studies with Hermann Staudineer (Nobel Prize 19531 refuting his own earlier work! (As ?ati would have it, Bergel's earlier work with Wieland proved correct.) I felt. and response to my lectures confirmed, that this provided a fascinating and heretofore unseen (at least by students and most if not all of my colleagues) view of chemical research in action. Several important points were clearly demonstrated by this study, including the importance of &I awareness of past work in carrying out research and the interactive, collaborative (as well as competitive) nature of chemical research. Mlstakes in Sclence Students often forget that even the famous are human. What better way to regain this appreciation than to see, to
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Number 12 December 1990
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use the above example, that Staudinger, considered the father of the field of macromolecular chemistry, was just plain wrong on a number of accounts, including in his impassioned series of publications belittling the structural suggestions of Dielsand Alder (131. How encouraeine. in a wav. toastudent who has been struggling with all t& s&cture&d reactions of oreanic chemistrv to see that two Nobel Prizes were awaried (Wieland,
