J. M. Bobbin ond Samuel J. Huang University of Connecticut Storrs. 06268
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A Simulated Research Project in Synthetic Organic Chemistry An undergraduate laboratory
The search for a meaningful, relevant, and interesting undergraduate organic laboratory continues ((1-6) and references cited therein). We find that we agree with most of the criticisms of the traditional course and that we also favor a more onen and less structured situation. We concluded several years ago that the traditional organic qualitative analvsis course with its three to five unknowns and its one or t k o mixtures was somewhat out of date in light of modem spectroscopic methods and the extensive files of spectra available in most libraries. However, this same traditional qualitative analysis course has almost surely been the most fascinating and challenging of all of the undergraduate laboratory courses. In it, students have been able to show their knowledge, imagination, and initiative to solve small prohlems in organic chemistry which do, however, have answers. We believe that it is quite necessaw that there should be answers in an undergraduate ~adoratory,a fact which distinguishes i t from senior undermaduate thesis work. The difficulties arise when one tries to tamper with the traditional qualitative analysis course and still maintain its interest and challenge. We have attempted to resolve these prohlems by substituting, for our qualitative analysis course, an advanced organic laboratory course taken primarily by chemistry majors. Course Structure The course is a three-credit lecture-laboratory course. In general, the students in the course have completed one semester of organic laboratory (6 hr/wk), and about half of them have completed two semesters of lecture. The other half are honors students who have had one semester of lecture a t a rather higher level than usual. The course is taken in the second half of the sophomore year by the honors students and in the first half of the junior year by the rest. I t is given in both semesters and usually contains I s 2 0 students. We have had graduate students from fields other than chemistry (pharmacy, biology, and agriculture). The laboratory part of the course involves three experiments: Experiment 1. Determination of one unknown substance in the traditional manner usinn the Shiner-Fuson-Curtin procedure (7). This takes u p ahout 3 w&. Experiment 2. Separation of a two-component mixture by preparative thin layer chromatography [and/or column chromatography] and characterization of the components by spectroscopic methods. This takes up about 3-4 wk. Experiment 3. Conversion of a given compound in reasonable yield (60% or better) to two known derivatives; if possible, one liquid and one solid containing different functional groups. In addition to the two known derivatives, the given compound is to be converted into two previously unknown derivatives (defined as not being in Beilstein or Chemical Abstracts). Finally, the results of the experiment are to be written up in the f o m of a manuPublished forms of this experiment are available from the Willard Grant Press, Inc., Boston, Massachusetts. 58
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script suitable for publication in the Joumal of Organic Chemistry. This takes u p the remaining 7-8 wk of the 14 wk semester. In all three experiments each student is given different compounds or mixtures. In addition to the laboratory work, the course involves 1 hr/wk spent in lecture and problem solving. The topics covered in lecture are qualitative analysis and the solubilities of organic compounds, chromatography of all types, and several types of spectroscopy (infrared, ultraviolet, nuclear magnetic resonance, and mass). The problems are traditional ones taken from Shiner, Fuson, and Curtin (7); spectroscopic problems are taken from Dyer (8). The first two experiments together with the lecture serve as preparation for the t h u d experiment. This third project on organic synthesis is the major point of this paper and is discussed in more detail in the following sections. Philosophy of the Experiment One of the basic philosophies inherent in the experimept is that students should he given an overall assignment and then allowed to decide what they need to know to carry it out. As an aid in the project they are given a set of general ground rules and suggestions and are introduced to the chemical literature. We consider this experiment to be a simulated research project in that there are answers to the experiment but the ways and means of obtaining the desired answers are up to the knowledge, imagination, and initiative of the students. In a way the experiment is similar to those of Fife (2) and Hiegel and Belloli ( 5 ) ,but i t goes a hit beyond both. Compound Choice and Literature Search The compounds for study are generally chosen hy the student with our help (and veto power). Once a compound has been chosen and approved, i t cannot be changed. We have learned several things about the choice of compounds: (1) Aromatic compounds are easier to work with than aliphatic; (2) Solids are easier t o handle than liquids; and (3) The functional groups ranging from easiest to hardest are: aldehvdes. " . acids. ketones. alcohols, arnines, aromatic nitro compounds, 'and aromatic hydro: carbons. Difunctional comnounds are frequentlv used. Alkyl halides and aliphatic hydrocarbon; have been avoided. The students are urged to approach their literature survev in the followina more or less systematic manner. Fit, tbLy should collectand write out all of the reactions found in standard textbooks involving the functional group or groups of their assigned compound. Secondly, they should search Beilstein and Chemical Abstracts for its specific known chemistry. A brief introduction to the chemical literature (9) and a discussion of the general organization of Beilstein and Chemical Abstracts are given at this time with a visit to the library for demonstrations. The abstracts in English given in the older copies of the Journal of the Chemical Society have been most useful to the students.
Some general guidelines are issued to help the students choose snecific nrenarations. These are: (1) Ex~erimental ease of ;he r e a k i n itself (anhydrous syitem,high pressure reaction, long reflux times, etc. are avoided when possible); (2) Method of purification required (crystallization is easier than distillation and both are preferable to chromatography); and (3) Properties of the products (hygroscopic, easily oxidized, etc.). Preparation and Characterization of the Products The students must fill out a proposal form for each experiment they have chosen. In the form, they must report the references they are following, generally with a photocopy of the source. In addition, they must give the precise experimental procedure which they will carry out, and the form must he approved before the experiment is started. This represents-an attempt on our & to avoid unsafe and unauthorized experiments and to force the students to think through t h e entire experiment before they start mixing chemicals. Actually, the range of experiments suggested is so wide that we frequently have little notion of how they will go. The safety hazard is partially reduced by working with small amounts, and the overall air of uncertainty lends interest to the experiment. The known derivatives offer relatively little difficulty. The only problems really encountered are overamhition by the students, the 60% yield requirement, and the lack of precise experimental procedures for reactions which "are in all the textbooks." Sometimes, the students wish t o make quite exotic substances (especially from the German literature prior to 1900). These often work beautifully, hut more frequently, the final products are more prosaic. The 60% yield requirement can he waived when no such preparations can he found, hut a note is made not to issue the compound again. In the final grading, a bonus is given for yields higher than 60% in an attempt to help the students become more auantitative in their thinkine and work (10). There are approximately three w a y s t o approach 'the svnthesis of the known derivatives. First. the student mav prepare derivatives traditional to a qualitative analysis course (and similar to his first experiment). The general texts used in such a course (7, 11) can serve as references, but there are sometimes problems with low yields. The stipulation that one compound he a liquid (which can be waived) cannot be overcome by this approach. Secondly, the student may wish to follow a literature preparation turned up in his search. Finally, he may want to prepare a known compound by a new method, for example, NaBHl reduction of a ketone which has previously been reduced by other means. The most useful bwks for this aspect of the problem have been Vogel (129, Wagner and Zook (13), the Fiesers' books on reagents in organic chemistry (141, and the new Buehler and Pearson (15). The stipulation that the known compounds have different functional groups requires some comment. The intent is to prevent the preparation of a homologous series of compounds using the same reaction, hut the interpretation has been fairly generous. We have not normally allowed the students to prepare more than one of the traditional amine derivatives of aldehydes and ketones (oximes, semicarhazones, phenylhydrazones, etc.). A sequence of reactions can he carried out as long as each compound to he "counted" is isolated and characterized. After the literature survey is finished and the known derivatives have been prepared, the difficulties originally associated with unknown compounds have been considerably diminished. It is quite permissible and, in fact, a good idea to carry out p&allelsynthesis to make a known c o m ~ o u n dand an unknown compound. Most of the unknowns that have been preparedhave been Schiff bases, esters, amides, or salts. It is desired, but not mandatory, that the two unknowns have different functional groups.
The students are urged to use thin layer chromatography (16) to follow all of their reactions, known and unknown. In cases where an unknown spot appears in one of the known preparations, they have the option of :solating the material and using i t as an unknown. We suggest that the students hand in 1-2 g of solids and 3 4 g of liquids except when the compounds are part of a reaction sequence. We have found it difficult to be too demanding ahout the ahsolute structures of the unknowns since we do not have them analyzed. The compounds are characterized spectroscopically as well as possible (ir, uv, and nmr in our case) hut we have surely given credit in several cases for effort rather than results. Final Report The final report of the experiment is a manuscript suitable in form for suhmission to the J o u m l of Organic Chemistry. The students are given a sample paper entitled "The Chemistry of Benzoic A c i d to follow in the preparation of their own manuscript. In the paper, a series of experiments similar to the one they have carried out is described. In addition, they are given a copy of the "Notice to Authors" from a recent issue of the Journal and a mimeographed sheet describing some of the pitfalls frequently encountered. The first draft of the paper is due during the latter part of the last week t class and is vigorously edited in conference with the student. The final corrected manuscript is due on the day of the scheduled final examination and, in our case, is the examination. Laboratory Facilities and Texts We have been fortunate in that we can devote one lahoratory to this course alone. Thus, each student has his own lockers and bench space for the semester. The students are issued "kits" of standard taper equipment based upon the 19/22 joint size and some extra round-bottom flasks of vsrious sizes. The laboratory is equipped with rotary vacuum evaporators (one to about six students), vacuum distillation equipment, hot plates, magnetic stirrers. and a Paar low-pressure hydrogenation apparatus. We have our own ir and uv instruments and access to the departmental nmr machine. The laboratory is open from about 9-5 each day and supervised by one of us or by graduate students in an adjacent room. Although the scheduled lahoratory time is 6 hr/wk, a somewhat more realistic value would be twice that. In partial defense of the time spent, i t should he noted that the students chat (or interact?) with one another some and surely teach themselves a fair amount of chemistry in the process. The students have used the text by Monahan (17) in their previous laboratory course. For this course they normally buy copies of Shriner, Fusou, and Curtin (7) and Dyer (8)and several have bought Vogel's book (12). All of the hooks listed as references in this paper are kept in the laboratory for ready use. Beilstein and Chemlcal Abstracts are in a chemistry reading room. Discussion and Evaluation When the students emerge from the course, they have leamed (or have been forced to teach themselves) a number of different things. F i s t , they have leamed the general outlines of the chemical literature and how to seek information on specific compounds, synthetic procedures, and reagents. Second, they have leamed how to plan and organize their time and their laboratory work. Third, they have had the experience of trying to isolate an unknown substance by extrapolating its properties in trying to establish the structure of a new material. Fifth, the experience of writing a manuscript has taught them what type of data must be collected in an experiment and how to present this data in a standard and logical manner. Finally, we have found that a considerable esprit de corps has Volume 51, Number
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been generated among o w majors by the experience of working long hours with one another in a rather stimulating atmosphere. A numher of variations have been introduced in the course over the last six vears. Initiallv. we wanted four known derivatives and two unknown c£s. Now we ask for two and two and eive bonus ~ o i n t sfor additional preparations (to a maximum of two known and two unknown). At one time we had no yield restrictions for any of the derivatives. Initially, i t was hoped that the students could carry their compounds, both known and unknown, into the physical chemistry lahoratory and make some measurements on them, hut this was impractical. These and other variables can be juggled almost infinitely depending upon what importance is attached to the experiment, what laboratory facilities are available at what times, and the equipment a t hand. The grading of the course is extremely difficult. Because of the numerous aspects of the work which are heyond our control and the high level of initiative required, grades tend to be divided about equally between A's and B's with C's being reserved for those who do not make a reasonable attempt. There are two major disadvantages of the course: the staff time required and the money needed for equipment, solvents, and chemicals. The senior staff involved spend about 8-12 hr/wk in the laboratory and are on call for many more. The teaching assistants spend 15-20 hr/wk and are also on call. Although we have not dared to calculate the cost per semester, it is high. The course, however, seems to he well worth the effort on our part. Several new bits of chemistry have evolved from observations made in the laboratory. We have found, as have the others cited nreviouslv. " . that the students respond enthusiastically to the opportunities for original thoueht and initiative. More than one student has asked to be allowed to repeat the course for fun (denied so far). There have been no accidents as yet which would not be encountered in a more traditional course. It could well be argued that the students are not ex-
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posed to advanced laboratory techniques in a manner suitable to an "advanced organic laboratory." This is ~ r o b a b l vtrue. but we believe that the literature exueriknce, the initiative and original thought required, and the adventure of writing a manuscript largely make up for it. Acknowledgment The equipment used to set up this course was partically paid for from an Instructional Scientific Equipment Grant (no. GY-1238) from the National Science Foundation to Prnfessor Audrey Monahan of this Department. We would a h like to express o w appreciation to the graduate students who have served as teaching assistants in the course and who, by their interest and attitudes, have really made itpossihle. Literature Cited
17) Shrine.. R. L.. Fuaon. R. C.. and Curtin. D. Y., "The Systematic Identifieation of Organic Compounds.'. 5thEd..Wiley-lnteraeience. New York, N.Y.. I%5. (8) Dyer, J. R.. "Ap~licatiomof Absomtion Speetroacopy of Organic Compounda.'. Pmnlee-Hall, he.. E n q l o d ClrMs, N.J., 1965. (9) ~ ~j.E.H., ~J. CHEM. ~ EDUC., ~ 45,193, k ZM).336(1968). , (10) Newman. M. S.. "An Advanced Organic Laboratmy Course," The MaeMillan Co.. New Yolk. 1972. (11) Paste, D. J., and Johnson, C. R., "Organic Structure Detorminafion: RonfieeHell. loo., Englcwmd Cliff% N. J.. 1969. (12) Vacel, A. I.. "Practical Organic Chemintry.'.3rdEd., Longman, Landon, 1956. (13) Wagner, R B., and Zmk, H. D., "Synthetic Organic Chemistry," Wilcy-herscience. New York, 1953. (14) Fieser. L. F., and Fieser. M.. "Reagents for Organic Synthesis: Wiley-In*scienes,NevYork, V o l 1, l967:Vol. 2, 136J:Vol. 3, 1972. (15) Buohler. C. A,, and Pearson. D. E.. "Survey of Organic Syntheses: Wilsy-InteroUenco, New York. 1870. (16) Babbitt, J. M., Sehwmting, A. E., and Gdtter. R.J., "lntmduetian to Chromatography." VsnNaetrand Reinhold, New York, 1963. (17) Monahan, A. M., "Exprimmfs in Organic Chemistry," Bogden & Quigley. Inc., Tanytown-on-Hudson, NIW York. 1971. (13) Stocher. P. G., (Editor), "The Merck Index." 8th Ed.. Morek and Co., Ine., Rahway. N. J.. 1968. (19) "Dictionw of Organic Compounds," 4th Ed.. M o l d Unh. Press, &fold, England, 1965.
