the microscale laboratory Selectivity versus Reactivity: The Safe, Efficient Metal Hydride Reduction of a Bifunctional Organic Katrina Smith, Robert Beauvais, and R. W. Holman Western Kentucky University Bowling Green, KY 42101
The advantages of performing organic reactions a t the microscale are well documented (l4),and include reduced cost, reduced generation of waste, shorter reaction time and enhanced safety. The development of microscale techniques has facilitated the inclusion of a vastly greater number of important organic reactions into the typical sophomore-level organic laboratory sequence. Since the development of microscale techniques, experiments such a s heterocyclic s y n t h e s i s (51, t h e u s e of l i t h i u m diisopropylamide (LDA) (6), hydroboration-iodination (71, have bcome common. Organic chemistry lecture textbooks possess extensive treatments on the chemistry of the metal hydrides; lithium aluminum hydride (LiAIHJ a n d sodium borohydride (NaBH,). However, LiAIH4 a n d NaBH4 reductions are rarely performed in the undergraduate lab, owing to the dangers - involved with u s i w- large - amounts of such reactive species. The experiments proposed in this communication incorporate microscale quantities of LiAIH, a n d NaBH,, a& represent yet another type of reaction that is both safe and simple when performed a t the microscale. Experiment Overview Lithium aluminum hydride and sodium borohydride are auite different in their reactivities. Lithium aluminum hviride is a powerful reducing agent which reduces aldehydes, ketones, carboxylic acids, esters, amides, and nitriles. I n contrast, sodium borohydride is less reactive. I t is a more selective reducing agent reducing only aldehydes and ketones. The proposed experiments are designed to illustrate the principles of selectivity and reactivity in the metal hydride reagents, NaBH4 and LiAIH4.Abifunctional compound, levulinic acid, has been chosen a s the substrate to illustrate these concepts. Levulinic acid is commercially available, relatively inexpensive, and safe to use. Levulinic acid i s a bifunctional compound which possesses a carboxylic acid and a ketone functional group. When levulinic acid is reacted with NaBH,, the ketone functionality is selectively reduced to a n alcohol while the carboxylic acid functionality is left unreacted. However,
edited by Cortland, AROEN SUNY-Cartland NY P. 13045 Z l
when levulinic acidis reacted with LiAlH,, both the ketone and the carboxylic acid fuuctionalities are reduced to alcohols Experimental This experiment is to be performed by a pair of students. The first student r e a d s levulinic acid with LiAIH,,. while the second student r e a d s levulinic acid with N ~ B & .The startine material and both reaction ~ r o d u c t are s analvzed by infrared spectroscopy.
Equipment
RVO 10-mL round-bottomed flasks, micro air condenser (packed with glass wool and anhydrous calcium chloride), micro Claisen adapter, magnetic stirrer, stir bar, cap with septum, 1-mL syringe, 50-mL Erlenmeyer flask are required. All glassware must be flame dried. Reaction Times and Yields
.Ihe . reaction times, including setup, reaction, malyiiis,
and takedown is 3 h for wch reaction. Thus. a tuwitudent team can conduct both reactions in a singlelaboratory period. The yield for both reactions are typically in the 75 to 85% range. Experimental Procedure for NaBH4 Reductions The preparationof the NaBH, solution should be done by the instructor andlor stockroom personnel. For every four students performing the reaction, add 166 mg of sodium methoxide and 340 mg of NaBH, to 7.5 mL of dried methanol in a n appropriately sized Erlenmeyer flask. 1. Place 200 pL of levulinic acid, and 750 pL of methanol into
the 10-mLround-bottomed flask. 2. Add 2.0 mL of NaBH, solution to the flask via a syringe. 3. Allow the solution to stir for 30 min, and then add 3 mL of
cold 10%HC1 and 1.5 mL of methylene chloride. 4. Extract the mixture three times using 1.5-mL portions of methylene chloride,placing each of the organic layers into
a common flask. 5. Dry the combined organic layen with anhydmus Na2S0,. 6. Remove the dried organic phase from the drying agent via
filter Pasteur pipet. 7. Distill the organic phase to remove the methylene chlor-
ide from the product. 8. Analyze product via infrared spectroscopy.
Experimental Procedure for LiAIH4 Reductions Caution: Lithium aluminum hydride reads violently with water and has been deemed too dangerous for inclusion in sophomore-level undergraduate laboratories. However, it can be used at the microscale without any cause for fear. Prior to the below described experiment, the faculty member andlor stockroom assistant transfers 300-mg portions of LiAlH, from the large stock bottle to small 1-mL vials that are handed to the students a t the beginning of the lab period. In this manner, the students never have to deal with the stock bottle or weigh their metal hydride. After three years of conducting this experiment in our sophomore-l&l labs rover 150 student ex&ments, there has not been a jingle safety problem. In fact, ench stu&nts amount 01'/.iAIH., is so smnll ,300mg, thnt wen ff added
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Journal of Chemical Education
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directly to water the reaction is absolutely harmless. Hence, the use of LiAlH4in this experiment is as safe as virtually any other microscale experiment. 1. Place 5 mL of THF and 300 mg of LiAlH, into the 10- mL stir bar. round-bottomed flask. Insert a mametic 2. Place a condrnaer onto the ruund-bottomed flask, and place
heentire apparatus into an ice bath sirunred a h v t
a magnetic stirrer.
3. Mix 300 pL of Levulinic acid with 1.4 mL of dried THF in a 10-mLbeaker. I Add rhr levul~nwac~dTllF.wlutwn t o the ruund-bottomed nark through the candenser drupuise, vra syrmgr, over a 5-min period. 5. Add 200 pL of 10%HzS04very slowly to the round-bottomed flask. 6. Add 200 pL of H20 slowly to the round-battamed flask. I . Add 1.5 mL of anhydrous ether to the raund-hottomed
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Figure 1. The infrared spectra of levulinic acid (dashed line),and the product form the NaBH, reduction of levulinic acid (solid line).
flask. 8. Remove the ethereal solution and place it into a 10-mL
reaction vial. 9. Extract the residue three times with 1.5-mL portions of
anhydrous ether. 10. Dry the combined organic layers with anhydrous Na2S04. 11. Remove the dried oreanie - ohase . from the drvine . aeent via the use of a fdter Pasteur pipet. Remove the solvent by distillation. 12. Analyze product with infrared spectroscopy.
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Results In the reduction of levnlinic acid by NaBH4, the ketone functional group is reduced to a n alcohol while the carboxylic acid is not affected. The ketone and carboxylic acid carbony1 groups (C=O), are distinguishable via IR spectroscopy. The IR spectra of levnlinic acid and the product from the NaBH4rednction of lewlinic acid are presented in Figure 1(the IR spectra of levnlinic acid is represented by a dashed line, while that for the NaBH, rednction product is a solid line). In general, a ketone carbonyl stretching frequency will be -1700-1710 em-', while the carboxylic acid carbonyl stretch will be a t 1730an-'. In the IR spectra of levulinic acid (Fig. 1, dashed line), the ketone and carboxylic acid carbonyl stretches overlap with the center of the composite peak a t -1717 cm-'. The IR spectra of the product from the NaBH* reduction of levnlinic acid (Fie. 1.solid line) shows a single C= 0 peak a t i730 cm-', representing the carboxylic acid carbonyl gronp. Therefore, the majority of the ketone was reduced, while the carboxylic acid functionalitv was unreacted. thus illustratine the selectivity of N ~ B & In the rednction of lewlinic acid bv LiAIHk.both the ketone and the carboxylic acid functio&lities i r e reduced to alcohols. The IR soectra of'levulinic acid and the oroduct from the L i m reduction of lewlinic acid is represented in Figure 2. The IR spectra of the L W 4 rednction product (Fig. 2, solid line) nossesses no C=O neaks a t 1700 cm-I or 1730 cm-I. he Hajor absorption i's an alcohol(0H) streteh a t 3300 cm-I. Thus, both of the carbonyl groups were reduced to alcohols, thus illustrating the reactivity (and corresponding lack of selectivity) of L A & as a reducing agent.
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F ~ g ~2r eThe infrareospecrra of e v ~nlc l ac d (dashed me),ana me prodLC1 from tne L AIH, reducson of evLllnlc acd (sol.0I ne) Conclusion Metal hydrides can be used safely and effectively in the sophomore organic laboratory when used on the microscale. When two parallel reactions are performed, one in which the bifunctional organic levnlinic acid is reduced by LiAlH,, and the other in which levnlinic acid is reduced by NaB&, two different products are formed. When functional gronp information is attained from each product (via IR spectroscopy), it is possible to determine which functional groups were reduced and which were left unreacted. In so doing, the concepts of selectivity and reacu are tivity in the metal hydride reagents NaBH4 and L illustrated clearly. Because the chemistryis followed by infrared spectroscopy, the students performing the experiments are provided with spectroscopic experience as well as the aforementioned s s t h e t i c and mechanistic experience. Literature Cited 1. Butcher, S. S.; Mayo. D.M.;Pike, R.M.;Foote,C.M.:Hotham,
J.R.:Page,D. S J.
Chom Educ. 1985,62,147.
M.;Butcher,S.S.;Pike,R.M.;Fmte,C.M.:Hothsm,J.R.:Psge,D. S. J. Chem Edue. 1985.62.149. . . 3. Mayo. D. M.: Pike, R.M.; Butcher, S. 5.; Meredith, M. L.J Chom. Educ. 19%. 62. 2. May0.D.
1114. 4. Mayo, D.M.;Pike,R.M.;B"Wler
S. S.;Buteher,D. J.:Hinkie,R. J . ; J chem. Edue. 1988.63.911. 5. Al-awar. R.; Wahl, G. Chem. E d w . 1690.67.265. 6. Si1wira.A.:Orlando, S. C. J. Chom. Educ. 1888,65,630 7. Gmch,E. E. J. Chom. Educ. 1690,67,A232.
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