A Multiscale Approach to Organic Chemistry Laboratory Introduction of Kilo-scale Experiments Howard D. Perlmutter New Jersey Institute of Technology, Newark, NJ 07102 Rudolph K. Kapichak, Chief Implementation Section, U.S. Environmental Protection Agency, New York, NY 10278 The past 20 years has seen a n increasing awareness of the importance of industrial chemistry and chemical technology in the chemistry curriculum (1-10). Amajor portion of this interest has been in industrial organic chemistry, a s evinced by the large amount of literature in this area (7). A recent survey of undergraduate organic chemistry courses does reveal a small, but discernible change in the direction of putting more industrial chemistry into the leeture (11). (Our organic chemistry lecture a t N. J. I. T., taken mainly by chemical engineering and applied chemistry majors, has had an industrial component for a number of years). However, similar changes in the orgamc chemistry laboratory have not occurred. In fad, the most prominent change in laboratory instruction has been in the opposite direction, namely, the scaling down of experiments from semimicro to microscale. The merits of microscale procedure have been enumerated (121, and a column on the subject appears regularly in
this J o u r a l . Nevertheless, responses to a recent survey suggested that students he exposed to a variety of scales (11). Scaleup of reactions is not o d y a n important part of industrial research that should be experienced, but also it exposes students to concepts, such a s heat transfer, that usually are not encountered in smaller scale work. Industry-oriented undergraduate laboratory programs have been described, but emphasis was placed on type, rather than scale, of experiment (13, 14). We wish to report on a truly multiscale undergraduate organic chemistry laboratory at N, J, I, T,, featuring a KILO scale, In this course, reactions are run on volumes ranging from 0.5 md
L.
The Multiscale Laboratory Syllabus Our multiscale lab, first run in the Spring of 1990, was developed by converting our one-semester lab course from one cnmposed of one microscale experiment and the rest semimicro scale to one with two microscale syntheses (0.52 mL), one classical semimicro Syllabus of Inaugural Semester of Multiscale Organic Chemistry Laborato~y preparation (50-250 mL), and six Spring 1990 experiments performed on both semimicro and KILO scales (the Techniques l a t t e r being from 3-5 L). Since Experiment Scale wt. stall Max. Vol. Product (mL) State safety, cost, space, and waste dismat. (g) posal considerations precluded the 1 Dehydration of t-Amyl SM 30 90 L Distillation, entire class working on a KILO 1800 L Extraction K 600 Alcohol scale a t once, groups of two o r . 25 350 S Extraction, 2 Isolation of Caffeine from SM three students working together K 100 1400 S Distillation, Tea ran a particular experiment on the Sublimation, TLC KILO scale while the rest of the 3 Preparation of SM 5.3 50 S Reflux, Extraction. class worked individually on the Phenylmagnesium Recrystallization. semimicro scale version of t h e Bromide and its Reaction m.p. same experiment. By rotating the with Benzophenone students from experiment to ex4 Cannizzaro Reactiopn of M 0.15 2.8 S Extraction, periment, each student was expchlorobenzaldehyde Recrystallization posed to the KILO scale a t least once. Reflux,Filtration, 5 Saponification of Methyl SM 5 200 S Salicylate K 100 4000 Recrystallization, The multiscale lab syllabus used m.p. in the inaugural semester is shown in the table. The follow-up lab, run 6 Synthesis of Aspirin SM 2.5 45 S Filtration, K 50 900 S Recrystallization i n the Spring of 1991, used the same syllabus, but was improved 7 Haloform Reaction of SM 1 40 S Reflux, Filtration, by making changes in the proceK 50 2050 S Recrystallization Acetophenone d u r e s u s e d t h e previous year. 8 Fischer Esterificationof SM 10 25 L Reflux, Filtration. These modifications will be disBenzoic K 300 750 L Recrystallization cussed below. 9 Synthesis of Methyl m M 0.3 1.0 S Filtration, Nitrobenzoate Recrystallization KILO Equipment 10 Preparation of Methyl SM 8 360 S Filtration Glassware and equipment for K 80 3600 S Orangea KILO-scale work that was not al14 Weeks, 4lnhrlwk. Text: Zubrick, J. W. The Organic Chem Lab Survival Manual: Wiley: New York; 2nd ed., ready on hand was purchased. We 1988. used safety shields, 5-L standardCode: M = Micro; SM = Semimicro;K=KILO:L = Liquid; S = Solid taper, three-necked, round-bot'Planned but not conducted 506
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Figure 1. "Semimicro"and KlLO suction filtrations - preparation of aspirin (Expt. #6) tomed flasks plus appropriate heating mantles, a oncoiecc standard taoer c~~ml)ination still head and condenser, &bore-type st&ers, stirrer motors, 4-L beakers, 4 L and 6-L Erlenmeyer flasks, a 24-cm Buchner funnel and 4-L suction flask, a 24-cm benchtop suction funnel, 24-cm filter paper, a standard taper 34-cm Vigreux fractionating column, West-type standard taper condensers, and 4-L separatory funnels. Selection of KlLO Scale Experiments Safety Considerations
Each student worked in a large, well-ventilated hood. The KILO students used a pair of side-by-side hoods equipped with safety shields. Excluded from wnsideration for KILO-scale modification were those experiments that used: readion solvents that are very flammable andlor otherwise noxious or hazardous (e.g., ethyl ether, Expt. 3). strong oxidizing agents (e.g., nitric acid, Expt. 9). Waste Disposal
Experiments 1, 5,6, 7, and 8 involved disposal of aqueous mineral acid solutions, some containing acetic acid and methanol. Organic water-immiscible solvents were recovered in experiments 2, 7, and 8. In experiments 2 and 8, the solvents, dichloromethane and ethyl ether, respectively, were reused. In experiment #7, the recovered chloroform was put into the halogenated organics disposal container. Experiments 5 and 6 entailed disposal of recrystallization filtrates. More product could be isolated from these aqueous or alcoholic solutions. Experiment 2 involved disposal of tea leaves and bags, as well as aqueous tea solutions. Disposal and neutralization of the wastes in these experiments were done according to appropriate regulations.
Most KILO experiments were run on a scale 20-50 times that of the corresoondina semimicro run. The techniaues required for manipulating solids and liquids on the K~LO scale were the same as those needed for semimicro scale work except for the use of the mechanical stirrer and benchtop funnel on the larger scale, as well as the adjustment to handling large glassware. Since the students also ran microscale syntheses with special microscale techniques, they gained, and appreciated, the experience of handling a wide variety of sizes and types of equipment. Figures 1 and 2 show comparisons of 'semimicro" and KILO filtration and final product yield in the aspirin synthesis (Expt. #6) during the inaugural semester.
L
Figure 2. " Semimicro"and KlLO yields of pure aspirin (Expt. #6) The Unique Role of Multistep Synthesis in the Multiscale Lab
Our multiscale lab featured two multistep reaction sequences, namely, experiments 5 and 6, and experiments 7-9. Multistep syntheses such as these can help cut the cost of chemicals in large scale experiments. The large amount of intermediate prepared in the first reaction is not only used as the starting material in the next step, but future semimicro and microscale experiments can be designed to utilize the large amounts of chemicals available. We derived a n unanticipated benefit from the KILOscale syntheses when a few.semimicro students preparing salicylic acid actually fell behind the KILO group and wound up with wet product on the day they were scheduled to synthesize aspirin. They were able to borrow a small amount of dried salicylic acid from the KILO students and eventually paid them back with their own dried material. Other Aspects of the Multiscale Laboratory Text
Since we may be trying out new experiments, we decided to use an excellent "techuiques-only" text (Zubrick, J. W. The Organic Chem Lab Suruiual Manual, Wiley: New York, 2nd ed., 19881, and hand out experimental procedures to the students. Lab Reports
Students doing KILO-scale experiments included in their lab reports a comparison of their results with those of students doing the same experiment on a semimicro scale. Plant Trip
Near the end of the semester, the students were taken on a plant trip to a local pharmaceutical company. They were able to see the relevance of their multiscale lab, since they observed all phases of organic synthesis, from reactions in glass totalling a few milliliters to large scale runs using hundred gallon glass-lined metal reactors. Typical Step-by-step Comparison of KlLO and Semimicro Scale Procedures Dehydration of t-Amy1AlcoholSemimicro Scale
Slowly pour 18 mL of conc. sulfuric acid into 36 mL of ice-cooled water in a 250-mL round-bottomed flask. Continue to cool this mixture. While swirling by hand, slowly pour in 36 mL of t-amyl alcohol. Shake the resulting mixVolume 69
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ture by hand and mount the flask for fractional distillation with ice-cooling of the distillate. Add boiling chips and slowly heat the flask with a heating mantle until hydrocarbon distillation is comolete. Transfer the distillate to a 125-mL separatory &el and extract with 10 mL of 10% aqueous sodium hydroxide. Draw off the lower (aqueous) layer and dry the crude olefin mixture with anhydrous granular sodium sulfate. Carefully decant the dried liquid into a dry 50-mL round-bottomed flask and fractionally distill. Analyze the distillate by gas chromatography. Dehydration of t-Amy1Alcohol-KILO Procedure
Fit a 5-L, 3-necked round-bottomed flask with a Truboretype stirrer shaft and bushing and Teflon blade. Attach the shaft to a stirrer motor. Cool the empty flask by placing it on a cork ring in a large plastic Rubbermaid-type container filled with ice and water. Add 720 mL of distilled water to the flask. To the gently stirred, cooled water, slowly pour in 360 mL of conc. sulfuric acid. Increase the stirring rate and slowly pour in 720 mL of t-amyl alcohol. Stop the stirrer, revlace the coolinc bath with a 5 L heating mantle, and fit th;? flask with a a c mVigreux fractionating column. Resume the stirring and fractionally distill the crude product. The work-up and final purification of crude product follows the semimicro procedure, using larger glassware and larger amounts of aqueous sodium hydroxide. Evaluation of the KILO Scale-up of Semimicro Procedures changes were made in KILO procedures used in the follow-up semester as a result of shortcomings during the inaugural lab, when the scaled-up experiments often resulted in relatively poor yields and longer times, compared to semimicro runs. These modifications made the KILO-scale experiments as efficient as their smallerscale analogs. These changes were i Mechanical stirring of reactions (Expts. 1,5,7,and 8 )
Preheating of solvents used for digestion (Expt. 2) and recrystallization (Expts. 5 and 61,so that valuable time was not lost heating up large amounts of solvent. Replacement ofthe cumbersome 24-cm Buchner funnel atop a 4-L filter flask with a 24-em benchtop suction funnel (Expts. 5 , 6 , and 7). Two changes worthy of more detailed mention were those made in experiments 7 and 8. The KILO procedures used in the inaugural semester for both reactions called for simply refluxing the reaction mixtures using boiling chips. I n the case of experiment 7, the haloform reaction of acetophenone with dilute aqueous sodium hypochlorite, violent boiling occurred during the reflux, accnmpanied by evolution of a large amount of vapor (mainly chloroform) through the condenser. This mishap, probably caused by the escape of the denser, lower boiling chloroform through the upper aqueous layer, was eliminated in the follow-up semester, when mechanical stirring was used during the reflux. The initial attempt at KILO-scale Fischer esterification Wxpt. 8 )was unsuccessful,yielding95"c starting material. However, cxccllcnt product yields were obtained the filllowing semester' stirring was duced. Suggestions for Future Multiscale Laboratories Student Exposure to the KlLO Technique
KILO-scale experiments should, if possible, be done by students working in pairs, not in groups of three as was
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done most of the time in our class. Groups larger than two do not provide enough responsibility for each student. The frequency of exposure of each student to the KILO technique can be increased iE More than one KILO run is performed for each experiment. The KILO scale is used in a two-semester lab course, rather than a onesemester course that exists at N. J. I. T. The number of students in the lab is small. Organornetallic Reactions on the KILO Scale
Although the Grignard experiment (Expt. 3 ),run by the entire class on a semimicro scale only, gave very good results, we hope to be able to scale up Grignard and other organometallic reactions, perhaps by: Replacing ethyl ether as a Grignard solvent with the safer MTBE (methyl t-butyl ether). Using some of the recently reported aqueous reactions, such as that shown in eq l(15). CH3= CHCH2Cl+PhCHO
NH4CL Zn
>
H20,GI8 silica
CH3CH=CHCH2CH(OH,Ph) (1) Conclusion We have completed two years of what has proven to be a very exciting laboratory experience. With the introduction of multiscale experiments, the students have shown a n increased interest in the lab and feel more challenged than they had in previous years. We will be constantly striving to improve the multiscale laboratory, which we believe is a $gnificant contribution to the organic chemistry curricumm. Acknowledgment We thank the Department of Higher Education of the State of New Jersey for a n Excellence Initiation grant which enabled us to purchase KILO-scale glassware and equipment and to upgrade our microscale glassware. We also wish to thank David L. Coffen, Department Director, Synthesis Research and Sewices, Hoffmann-LaRoche, Inc., Nutley, NJ 07110, for his help in arranging for and personally escorting our students on the plant trip. Note Added in Proof During the spring 1992 semester, the KILO synthesis of metyhyl benzoate (Expt. #8) was run on twice the scale indicated in this paper. Literature Cited
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Z.: ~ e r m a n , 'A.~ ,J. Chom. Educ i11-:4.11
1988.61,329-
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n -'I> n,l.nllu.' ~ ~ of the ~ T-Lr FCRY r f~ the S ~ W I V~f ~ h . ~ , , cErI ~U C ~ ~ L O ~ A m m n n Chemunl .%r#-t), i ~ r d hr. 1514 p i 5 9 ' T ) r Cmrs-fcm.n*tr~nif Chrml.ln. rno Chennml Enqnrcnng C m c u l a . ' Fmal ~ ~ ~ 1 9 ~6 0 1~ ~ ~ ~lidlll.rl ~ r ,f ~."\II ~i ~rk.hllp9wnlorcdby lh ~ rhcExpcnmrn. w! ~ . l t ~ . x uC, ~m m ~ w ofihr m ~ m c n r a nChcmrr. i c i ~ y lrrl , I0 T h ~ l n d ~ ~ m ~ l C h ~ m ~ r ~ n ~ I r h ~ . A ~ n , r ~ ~ a ~ ~ AH-runmtncPrr.. Cl~rn.~c,~lSooclu
identid conference on ~ ~ d chemist8 ~ ~ and t the ~ An&ean d chemical society, St. l a c s , 1979 (publ. 1980). 11. Johnson,A.W J Chem.Educ. 1890,67.299303. 12. Rawls, R. Chem. Ens News Feb. 6, 1984, pp 2KZT. Maemff, 0. L.Nou, York limes, March 6,1984, pp C-l: Mayo, 0. W.; Pbe, R. M.; Butcher, S. D.Micmgeolp Orgonle hbomfory, 2nd ed.; Wiley: New Yor*,1989. 13. Beichl, G.J.; Kriner, W A. J. Chem. Edue. 1988,61,699- 7W. ~R.M.;~sig**~S . A - ~F ~ C ~ ~~, ~ 1913,5m b 10.17. ~ ~ 14. B 15. Wilson, S. R.: Guazzaroni. M. E. J. OW c h m 1989,54,3087.
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