In the Laboratory
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Using a Premade Grignard Reagent To Synthesize Tertiary Alcohols in a Convenient Investigative Organic Laboratory Experiment
Michael A. G. Berg* Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060-0212; *
[email protected] Roy D. Pointer† Department of Chemistry, Bloomsburg University, Bloomsburg, PA 17815
This Journal has published a number of interesting laboratory experiments utilizing Grignard reagents (1–7). The importance of utilizing the Grignard reagent is often overshadowed by the preparation of the Grignard reagent itself. Often, the preparation of the Grignard reagent fails (8–12). Anecdotally, most chemists remember making the Grignard reagent in second-year organic chemistry, but do not remember what they used it for. We have felt that while making the Grignard reagent leaves a lasting impression on our students’ minds, the application of the Grignard reagent is of more importance. To this aim, we wished to have a laboratory experience that focused on the carbon–carbon bond formation aspect of the Grignard reaction by using a commercially available, premade Grignard reagent. We further wished to make it an experiment that could easily be performed early in the second semester of organic chemistry, corresponding to when the Grignard reaction material is covered in the lecture portion of the course. Experimental Overview In our laboratory courses, we wished to foster a degree of ownership and independent thinking in the laboratory. In this lab we allow the students to choose which tertiary alcohols they wish to make, design the workup of the reaction, and to characterize their product. The students are given a packet of information on how to perform a Grignard reaction, including literature procedures for the synthesis of triphenylmethanol (see the Supplemental MaterialW). They are told to run the Grignard reaction on a scale of 10 millimoles in which the ketone is the limiting reagent with phenyl magnesium bromide used in 10% excess. The students set up their notebooks with the necessary calculations and physical-constant data. The students assemble the necessary glassware, and the calculated quantity of phenyl magnesium bromide solution is dispensed by the instructor. Next, the students slowly add an ether solution of their ketone and then proceed through the rest of the reaction, isolation, and purification steps. They characterize the compound using spectroscopy. This laboratory can be accomplished in two three- or fourhour laboratory periods. †
Retired as an Emeritus Professor from Bloomsburg University.
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Experimental Procedure The following is a representative procedure that is generally followed by the students based on the literature provided. The students may wish to develop and suggest a modified procedure for approval by the instructor. However, the instructor should well understand the Grignard reaction and handling of air-sensitive reagents and be able to provide helpful guidance when necessary. We have successfully performed this experiment using other ketones, aldehydes, and esters, based on student’s interest in trying alternative carbonyl-containing compounds. A predried three-neck 100-mL round-bottom flask is fitted with a rubber septum, condenser, and an addition funnel. The calculated quantity of the ketone (10 mmol) is dissolved in 30 mL of anhydrous ether and quickly added to the addition funnel. The top openings of the condenser and addition funnel are quickly fitted with plugs of cotton. The calculated quantity of phenyl magnesium bromide is dispensed from a syringe by the instructor through the rubber septum into the flask. The ketone solution is slowly added to the Grignard reagent with stirring. After the initial reaction is complete, the product alkoxide is protonated using an aqueous acid. The suspension is extracted with several portions of ether. Residual acid in the combined ether layers is neutralized by washing with saturated sodium bicarbonate solution. The combined ether layers are dried using an anhydrous drying agent and the ether is evaporated. The solid product is recrystallized and dried. The melting point and TLC of the crude and purified alcohol product are compared. Crude and purified percent yields are calculated and the IR, proton, and carbon NMR spectra are obtained to characterize the product. Hazards Ether is extremely flammable and should be kept away from ignition sources such as hotplates and drying ovens! Ether is also extremely volatile and should be used in a wellventilated area. The handling of phenylmagnesium bromide is discussed below. Care should be taken in preparing aqueous sulfuric acid and ammonium chloride solutions.
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Journal of Chemical Education
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In the Laboratory
Table 1. Ketones Used, Average Yields, and Physical Data of the Tertiar y Alcohol Products
a
Average Yield(%)
Melting Point/ ºC
CO Stretch/ cm᎑1c
Triphenylmethanol
54
160–163a
1156
Acetophenone
1,1-Diphenylethanol
65
a
77–81
1192
4-Chlorobenzophenone
(4-Chlorophenyl)diphenylmethanol
54
84–85b
1154
Ketone
Product
Benzophenone
Ref 13. bRef 14.
c
Experimentally derived.
Discussion
Summary
Solutions of phenylmagnesium bromide in ether are readily available from chemical supply companies. These solutions come in bottles fitted with septa-sealed caps. The solution must be transferred from the reagent bottle to the reaction flask using a clean, dry syringe. Also, all glassware and Teflon-coated stir bars were kept in a drying oven until ready for use. In our lab, we had a small, under-the-counter oven, but were able to easily accommodate twenty setups for the lab. Additionally, after the equipment was assembled, no extraordinary measures were taken to keep the glassware dry other than placing a ball of cotton in the top openings of the condenser and the addition funnel. For a 14兾20 size joint opening, approximately a 1-cm diameter ball of cotton was used. The students charged their addition funnel with the ketone of their choice dissolved in anhydrous ether. The instructor dispensed the phenyl magnesium bromide into each reaction vessel using a 10-mL glass syringe with an 18- or 20-gauge 6to 10-in. LuerLock needle. The syringe was purged with dry nitrogen using a simple manifold (see the Supplemental MaterialW) before the uptake of Grignard reagent solution. The syringe could be used multiple times before becoming contaminated with salt deposits. When this occurred, the syringe was opened and flushed with ethanol followed by water. (Caution: This syringe should be set aside and thoroughly dried in an oven before using again.) We routinely used two or three separate clean, dry syringes per group of 18 students. In our lab, students were allowed to select from a choice of ketones as shown in Table 1. All of the reactions produced solids. We have allowed students to use other ketones, most notably, 4-methylbenzophenone and 4-methylacetophenone, but were unable to isolate solid products from these reactions. We have also allowed students to use benzaldehyde and substituted benzaldehydes. However, since these aldehydes oxidize upon storage, the students got significantly lower yields for the Grignard reaction and a considerable quantity of byproduct when using old aldehydes. We are also aware that other premade Grignard reagents are available, such as 4chlorophenylmagnesium bromide in diethyl ether and are currently exploring this reagent as a simple modification for additional projects.
We have used this experiment to successfully introduce students to modern organic synthesis as well as methods involving air-sensitive reagents. The use of the premade Grignard reagent is relatively easy and involves a minimal quantity of expensive glassware and no inert atmosphere lines other than a purge for the transfer syringe. In all cases, students are able to obtain their product in good yields without any of the typical failures associated with making the Grignard reagent.
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Supplemental Material
Detailed student instructions for the experiment and instructor’s notes are available in this issue of JCE Online. Literature Cited 1. Ciaccio, J. A.; Bravo, R. P.; Drahus, A. L.; Biggins, J. B.; Concepcion, R. V.; Cabrera, D. J. Chem. Educ. 2001, 78, 531. 2. Everett, T. S. J. Chem. Educ. 1998, 75, 86. 3. Ciaccio, J. A.; Volpi, S.; Clarke, R. J. Chem. Educ. 1996, 73, 1196. 4. Taber, D. F.; Meagley, R. P.; Supplee, D. J. Chem. Educ. 1996, 73, 259. 5. Abhyankar, S. B.; Dust, J. M. J. Chem. Educ. 1992, 69, 76. 6. Silversmith, E. F. J. Chem. Educ. 1991, 68, 688. 7. Kulp, S. S.; DiConcetto, J. A. J. Chem. Educ. 1989, 66, 586. 8. Smith, D. H. J. Chem. Educ. 1999, 76, 1427. 9. Orchin, M. J. Chem. Educ. 1989, 66, 586. 10. Williamson, K. L. J. Chem. Educ. 1988, 65, 376. 11. Eckert, T. S. J. Chem. Educ. 1987, 64, 179. 12. Clough, S.; Goldman, E.; Williams, S.; George, B. J. Chem. Educ. 1986, 63, 176. 13. Aldrich Handbook of Fine Chemicals and Laboratory Equipment; Aldrich Chemical Company; Milwaukee, WI, 2003– 2004. 14. Alberola, A.; Pedrosa, R.; Perez Bragado, J. L.; Rodriguez Amo, J. F. Anales de Quimica, Serie C: Quimica Organica y Bioquimica 1982, 78, 159–165.
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