Douglas C. Neckers Hope College Holland, Michigan 49423
Project Orientation in the Organic Laboratory
Though goals of organic chemists teaching the laboratory course for undergraduate students differ somewhat, a general goal for every teacher seems to require that the laboratory course be designed to both teach experimental technique and instill independence in the student. Experiments must be designed for independent study of the students taking the course while still serving to develop technical facility in the laboratory. There are many mays in which independent study can be introduced in lower level courses. The simplest way is to provide a series of unknown compounds for the student to identify. Thus, each unknown becomes a research problem for the student. Use of unknowns at the sophomore level instills independence but also supplements the student's limited knowledge of organic reactions. Nevertheless, it does very little to improve technique. Coupled with the approach using organic qualitative analysis to provide an independent basis for the laboratory is the independent synthesis. The students like independent synthetic activity, though it is sometimes hectic for the instructor. I t is useful as an adjunct to organic qualitative analysis in the sophomore level course. Reported herein is an independent synthesis sequence which allowed a great degree of flexibility in the organic laboratory. The work reported provided about a 4 week study period for a group of 38 sophomore students enrolled in the second semester of organic laboratory. These students were in their third quarter of study of theoretical organic chemistry. As a group project, we chose to synthesize dicyclopropyl ketone. This accomplished, the students were told to now "do something with the product". The synthesis of dicyclopropyl lietone proceeds essentially as Hart and Curtis describe it.' We repeat that preparation in the experimental section with the modifications necessary to conduct the experiment without expensive apparatus.
CURTIS,0. E., SANDRI,J. M., CR~CICER, R . E., A N U HART, H., "Organic Synthesis," John Wiley & Sons, Inc., New York, 1962, Vol. IV, p. 278. The only step which requires some precautio~lin the preparation is the first, making sodium methoxide. I n the event the instructor worries about this procedure, commercial sodium methoxide can be substituted with no change in the overall reaction. HART,H., AND CURTIS,J. E., J. Amer. Chem. Soc., 78, 112 (1956). Obviously any synthesis that requires hydrazine hydrate requires some special precautions. This experiment was no exception and the students that ran the Wolfe Kishner did so in our best hoods with immediate supervision-at all times.
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The synthesis as it stands is exceedingly useful from a pedagogical point of view. It provides an example of a base catalyzed condensation of a carbonyl derivative. I t couples well with work in the last chapters of R4orrison and Boyd. I t further provides a fine example of base catalyzed ring closure and an acid catalyzed decarboxylation reaction is thrown in for good measure.
-
11
ClCHzCH2CHzCCH2CHzCH,C1
NaOH
A-C-A
1
(1)
The synthesis takes about three 3-hr laboratory periods though some slower students tooli a bit longer. One may stop the synthesis at any of the three successive steps without hindering the total yield to any great degree. The preparation is safe, the product smells like camphor, and the procedure is without undue mess.2 Of 38 students performing the synthesis, about 35 of them got some yield the first time through. On the first attempt, the total average yield for these students was 357'. Those students that got no product, knew where they had gone astray and repeated the experiment to obtain a satisfactory yield of ketone. Every student obtained a gas chromatogram and infrared spectrum of his product. Independent Study
The ingenuity demonstrated by the group in designing something to do with their product was helped in large measure by the fact that the product was a ketone. Further that the lietone was a cyclopropane gave each student a plethora of potential reactions from which to choose. Hart,3 in his original description of the synthesis of dicyclopropyl ketone, provides a variety of interesting reactions for which dicyclopropyl ketone can be used. For the students, the easy way out in the activity at this point was simply to choose one of fIart's syntheses and carry out the reaction in question.
NOH A-C-A
11
0 H+
11
bC-NH-A
Certain students made the hydrocarbon by the Wolfe Kishner r e d ~ c t i o n other ,~ students reduced the ketone to the alcohol using sodium borohydride, some students made the azine, others the oxime and the Beckmann rearrangement amide. The ingenuity and perseverance demonstrated by other students was tlhe exciting feature of the entire independent work. Two students ran the Wittig reaction and made 1,l-dicyclopropylethylene.
II
A-C-A
+ +,P=CHz
+
+tPtO-,
+ A-C-AII
(2)
Another student tried to measure the relative rate of reduction of dicyclopropyl ketone with sodium borohydride in isopropyl alcohol and compare this rate with a known ketone. The procedure he used was brown'^.^ Still other students made countless Grignard addition products.
One student compared the yield of Grignard obtained by treatment of dicyclopropyl ketone with an excess of Grignard reagent (phenyl magnesium bromide) and with a 1:1 ketone to Grignard mixture. Another student looked at the cation formed by the reaction of dicyclopropyl ketone with goy0 sulfuric acid.6 The nmr spectrum of the cation was taken after several tries a t obtaining the conditions described in the literature. Another student tried to add acetylene dicarboxylate to the excited state of dicyclopropyl ketone in a photochemical reaction. Altogether the group studied about as many different variations on the dicyclopropyl ketone theme as a group of 38 people could. Each student, to a greater or lesser degree, became his own expert in the reaction that he was trying to study or repeat. The students were tested on the experiments orally. Each student stood before a group of his peers and explained what he was doing. Discussion of the work took on the character of a research seminar in organic chemistry though some of the students were biology majors, others were pre-med, and the majority probably will not practice as organic chemists. Every student knew what he was doing-a far cry from the ordinary laboratory activity. The new bugaboo of academicians, relevance of their courses to the needs of society, is obviously left up to the individual student in this case. If a student's experiment was not relevant, he had only himiself to blame. I n that regard, a t least one student tried to see what effect the oxime of dicyclopropyl ketone had on rats-it was reported to be a muscle relaxant. Finally, the experimental procedures developed required, a t least in several cases, that the students reason by analogy. Using dicyclopropyl ketone as base reagent meant that some of the alcohols prepared by Grignard addition were unknown. These students then faced the typical situation of the laboratory chemist in that the products they obtained in the synthetic procedures had to be characterized and identified both spectroscopically and analytically after the procedures were completed.
Experimental The boiling points reported are the composite boiling points of several students. Neither the boiling points nor the melting points recorded are corrected. Preparation of Dicyclopropyl Ketone
A solution of sodium methoxide is prepared from 10 g (0.44 g atoms) of freshly cut sodium and 120 ml of absolute methanol (Note 1) in a 500-ml three-necked flask placed on a steam bath and equipped with a sealed stirrer (Note 2), dropping funnel, and a condenser set downward for distillation (Note 3). To the stirred solution is added in one portion 69 g (0.80 moles) of y-butyrolacetone (Note 4), and the flask is heated until methanol distills a t a rapid rate. After 95 ml of methanol is collected, a filter flask or other suitable device equipped with a side arm is connected to the condenser. This receiver is surrounded by an ice bath, and reduced pressure from an aspirator is applied cautiously (frothing) with continuous stirring. An additional 10-15 ml of methanol is collected in this way. The residue presumably is dibutyrolacetone (Note 5). The condenser is set for reflux, and the steam bath is replaced with a more potent source of heat (electric heating mantle, oil bath, or direct flame). Concentrated hydrochloric acid is added with stirring, cautiously a t first because a considerable amount of carbon dioxide is evolved. A total of 160 ml of acid is added in about 10 minutes (Note 6). The mixture is heated under reflux with stirring for 20 min, then cooled in an ice bath (Note 7). A solution of 96 g of sodium hydroxide in 120 ml of water is added to the stirred mixture as rapidly as possible, without allowing the temperature to go above 50°C (Note 8). The mixture is then heated under reflux for an additional 30 min. The condenser is arranged for downward distillation, and a total of 130 ml of ketone-water mixture is collected as distillate. Sufficient potassium carbonate is added to saturate the aqueous layer, and about 26 ml of ketone is separated. The aqueous layer is extracted with three 100-ml portions of ether, and the combined ether and ketone layers are dried over 5.0 g of anhydrous magnesium sulfate. The product remaining after removal of the ether is distilled through an efficient column. The yield of dicyclopropyl ketone boiling a t 72-74OC/33 mm, ng 1.4654, is 22-24 g (52-55%) (Note 9).
Note 1. Commercial sodium methoxide may be used instead of metallic sodium.
Note 2. The stirrer is not a necessity.
Continued agitation of the flask works just as well. Note 3. It is desirable to have the condenser arranged for reflux during preparation of the methanolic sodium methoxide, if it is made from sodium metal. Note 4. Commercial lactone (available from General Aniline and Film Corporation, 435 Hudson Street, New York 14, New York) should be redistilled, bp 88-90°C/12 mm, before use. Note 6 . Dibutyrolactone can be isolated as a crystalline solid, mp 86-87OC, from the residue. The preparation can be interrupted a t this point without jeopardizing the yield. Note 6. The color of the mixture changes from yellow through dark orange to dark reddish brown. Note 7. At this point, the following procedure may be used to prepare 1,7-dichloro-4-heptanone. To the cooled, stirred solution is added 200 ml of ether, which brings the dense dichloroketone to the upper layer. The latter is separated, and the acid layer is extracted with two 100-ml portions of ether. The combined ether layers are dried over 25 g of anhydrous calcium chloride. After removal of the solvent,
K., Tel., BROWN,H. C., WHEELER,0. H., and ICHIKAWA, 1,214 (1957). LYTTLE,D. A., JENSEN, E. H., A N D STRUEK,W. A., Anal. Chem. 24, 1843 (1952). S. P., J. Amer. Chem. PITTMAN, C. U. Jr., AND MCMANUS, SOC.,91, 5915 (1969). The procedure reported is an adaptation of that reported by Hart and Curtis (footnote 1). If the laboratory has stirrers and heating mantles available for general use, the Hart and Curtis procedure gives better yields. On the other hand, the procedure is sufficiently simple so that this reacton can be carried out without exotic apparatus. The scale reported is l / 4 that reported by the Michigan State workers. Volume 47, Number 7 0, October 1970
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the residue is distilled through an efficient column. The yield of 1,7-dichloro-4-heptanone,bp 106-110°C/4 mm, n g 1.4713, is 263-278 g (72-76%). The material takes on a purple cast rapidly and should be stored in a refrigerator. Note 8. Considerable salt separates a t this point but does not interfere with the subsequent steps. Note 9. According to the submitters,' a similar procedure can be applied to substituted lactones; di-(2-methylcyclopropyl) ketone, bp 65-67"C/7 mm, n g 1.4600, has been made from r-valerolactone in 50% yield. Preparation of Dicyclopropylethylene
A Wittig readion for the undergraduate laboratory. Triphenylphosphine 50 g (0.20 mol) and 45 ml of dry benzene were placed in a pressure bottle. When the phosphine was dissolved, 27.0 g (0.20 mole) of methyl iodide was added. The bottle was sealed with a rubber stopper and copper wire. The reaction started slowly, then it became quite exothermic as the benzene layer turned a deep yellow and a white precipitate, triphenylmethyl phosphonium iodide, precipitated in the b ~ t t l e . ~The bottle was left in the dark for two days. After two days, the solid was filtered from the bottle and dried in a vacuum oven a t 100°C for a period of 90 min over phosphorous pentoxide. Preparation of the Ylid
A 500-ml 3-necked round-bottom flask is equipped with a stirrer, a condenser and a nitrogen inlet. n-Butyl lithium (25.0 ml, 2.35 molar in hexane) is added to 200 ml of ether and placed in the flask. Triphenyl phosphonium iodide (37.5 g, (1.1 mole) is added slowly to the solution. A bright orange color ensues and the addition is completed after 5 min. The reaction mixture is stirred, under a constant pressure of nitrogen, for 4 hr after which time a bright yellow color has replaced the original orange. Dicyclopropyl ketone (13.5 g, 0.12 mol) is added over about 5 min and the reaction mixture is refluxed overnight. A white solid, triphenyl phosphine oxide, forms during this period. The product olefin is obtained by washing the white solid with ether (100 ml) and combining the ether wash with the solution obtained after filtration of the triphenyl phosphine oxide-lithium iodide mixture. The ether is removed by distillation of a steam bath and the product distilled; the fraction boiling from 120-134°C is collected as dicyclopropyl ethylene (bp 132-134OC), yield, 35%. The nmr spectrum of dicyclopropyl ethylene completely confirms its structure assignment as does its obvious octene odor. (nmr: 4.54 ppm 2 H singlet, 1.52-1.20 ppm. 2 H triplet, 1.100.60 ppm. 8 H multiplet.)
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Preparation of Dicyclopropyl Carbinol
A solution of the ketone (50 g, 0.45 mole) in methanol was cooled in an ice bath and 20 g (0.50 mole) of sodium borohydride solid was added in small portions. After the reaction was completed, the excess borohydride was decomposed by making the solution acidic. Evaporation of a bit of the methanol, followed by extraction with ether, produced 27.2 g of dicyclopropyl carbinol (54%).
Discussion
Independent activity in the laboratory with sophomore students required a great deal of perseverance and patience on the part of the assistants and the instructors in the course. It further requires that the instructor spend almost the entire laboratory session with the students in the laboratory. Experiments taken from the literature of chemistry sometimes require more experience and know-how than they require the ability to read and follow directions. A further prerequisite for an activity such as the one described above to procede with some semblence of success, as opposed to chaos, is that the instructor and the assistants be willing to spend extra time with those students that are a bit the slower as they are planning their experiments. This is the most frustrating of the activities for those students that have some trouble with the cowse anyway. Given a little extra effort on the part of the instructor and an increased amount of daring on the part of the students, the whole project can be emminently successful. Acknowledgment
The author would like to thank each student that participated in this experiment in teaching. The assistance of and discussion with Dr. 1\1.P. Doyle of the Hope staff is gratefully acknowledged. Extensive precaution must be exercised a t this point. The solution must be cooled during the addition of the methyl iodide and sealing of the pressure bottle. After the first hour, the bottle can be removed from the ice bath.
