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The GC–MS Observation of Intermediates in a Stepwise Grignard Addition Reaction Devin Latimer Department of Chemistry, University of Winnipeg, 515 Portage Ave., Winnipeg, MB R3B 2E9 Canada;
[email protected] A challenging lab in third-year organic synthesis is crucial in the undergraduate education of a chemist. The Grignard addition is one such procedure, requiring dry glassware and an inert atmosphere, providing a useful examination of a student’s ability to perform careful manipulations. While many such experiments are available in practical organic textbooks and journals, few offer an exercise that enables students to observe the reaction as it progresses. In fact, only two articles (1, 2) of this type are available and are interesting but relatively long (three to four lab sessions) and are complicated Grignard mechanistic investigations involving synthesis, thinlayer and column chromatography, 1H and 13C NMR, and FTIR. We have taken a relatively routine Grignard reaction— the preparation of phenylmagnesium bromide as described by Eckert (3) and the subsequent addition of three equivalents of this Grignard reagent to diethyl carbonate to form triphenylmethanol (4) (Figure 1)—and developed a series of GC–MS procedures (30 min) in which students observe the intermediates that are formed as the reaction proceeds. In the procedure, a small quantity (1 mL) of the reaction mixture is analyzed midway by GC–MS. The total ion chromatogram (TIC) shows several significant peaks. The experiment also becomes an interesting mass spectral exercise as students are first asked to predict the products of each of the Grignard additions as well as expected mass spectra of each compound. Mass spectral analysis of each of the peaks in the TIC yields the molecular ion and fragment weights that would be expected from the organic intermediates and final product seen in Figure 1. The Grignard preparation and subsequent addition uses inexpensive, commercially available reagents and fits easily into a three-hour lab period, while the GC–MS analysis provides an instructionally valuable instrumental exercise for the student while the reaction is refluxed to completion and cools. In our three-year experience of conducting this experiment in the presence of one instructor and one teaching assistant, 10 students out of the course maximum of 12 (divided into two lab sections) are normally successful in the entire experiment, with the others failing to achieve proper Grignard initiation. Each student is required to wash and oven-dry their own glassware ahead of lab time and only students who take care in this and the other preliminary steps of Grignard preparation are successful in the experiment. Once a successful Grignard preparation occurs, Grignard addition, workup, and analysis of intermediates and product are fairly routine since the optimal GC parameters are established prior to the experiment. Even though our students study Grignard reactions as well as mass spectrometry in second year, it is our experience that students must be strongly encouraged (with the prelab questions given in the Supplementary MaterialW) to review the important material in order to fully understand the experiment. In addition, we find the instructor, techni-
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cal, and student requirements for successful Grignard reactions cause it to be only suitable for our smaller, third-year organic synthesis lab sections. Students completing this experiment gain a deeper understanding of the Grignard addition reaction, the care necessary for many organic reactions to be successful as well as the power of GC–MS in providing immediate and detailed feedback on the progress of a reaction. Experiment The Grignard preparation flask is flame-dried containing the magnesium and one or two crystals of iodine under a flow of dried nitrogen. Once all flames are extinguished and the flask has cooled, diethyl ether solvent and halide are added via dropping funnel and Grignard preparation occurs. Half of the required quantity of diethyl carbonate is then added dropwise, the reaction mixture is then cooled, and a 1-mL aliquot removed by syringe. The 1-mL aliquot is immediately worked up and 1 µL is analyzed by GC–MS (HP5890 GC–MS), while the second half of the Grignard addition reaction is continued. At the completion of the re-
Figure 1. The formation of phenylmagnesium bromide and stepwise addition to diethyl carbonate to form triphenylmethanol.
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action, triphenylmethanol is isolated, purified by recrystallization, and then characterized by melting point, 1H NMR, and TLC.
A
Hazards Diethyl ether is flammable. Flame-drying should be done in a fumehood by all students without ether in the room. After all flames are extinguished and glassware has cooled, solvents and reagents can be handled. Standard safety precautions should also be exercised with respect to the pressurized gases used in the gas chromatography. Safety goggles should be worn when handling the chemicals. Benzene is produced by the hydrolysis of unreacted phenylmagnesium bromide.
B
Discussion C
D
Figure 2. Total ion chromatogram (A) and mass spectra of compounds eluting at 7.6 min (B), 13.9 min (C), and 17.3 min (D).
The GC–MS analysis of the 1-mL aliquot that is removed from the reaction flask after the addition of half of the required equivalents of diethyl carbonate contains significant quantities of each stable organic intermediate as well as the final product. Three or four large peaks are typically found in the total ion chromatogram (TIC) with mass spectra (Figure 2) matching the molecular ion and fragment weights expected from the organic compounds (5) (Figures 3, 4, and 5). For example, the TIC displays a peak at 7.6 min (Figure 2A), which exhibits significant mass spectral abundance at 150, 122, 105, 77, and 51 amu (Figure 2B). These weights are consistent with the molecular ion as well as the typical carbonyl and phenyl group fragments and the McLafferty rearrangement of ethyl benzoate as outlined in Figure 3. Ethyl benzoate is seen in Figure 1 as the product of the addition of one equivalent of phenylmagnesium bromide to the diethyl carbonate starting material. Likewise, the addition of a second equivalent of the Grignard reagent yields benzophenone (Figure 1), with corresponding mass spectrum observed at 13.9 min in the TIC (Figures 2 and 4). Finally, a compound elutes at 17.3 min displaying the mass spectrum of the product triphenylmethanol (Figures 1, 2, and 5),
Figure 3. Molecular ion and fragments observed at 7.6 min in GC–MS.
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Figure 4. Molecular ion and fragments observed at 13.9 min in GC–MS.
Figure 5. Molecular ion and fragments observed at 17.3 min in GC–MS.
formed by the addition of the third equivalent of phenylmagnesium bromide and acidification (from the reaction workup). It should be noted that, even though there is six times as much Grignard reagent as diethyl carbonate in the reaction flask at the time that the 1-mL aliquot is removed, the intermediates and final product are observed. Thus, for the observation of the intermediates, removal of the 1-mL aliquot early in the reaction is more important than relative quantities of reactants present. Conclusion The Grignard reagent preparation of three equivalents of phenylmagnesium bromide and the addition to one equivalent of diethyl carbonate is a challenging synthesis, requiring glassware and reagents free of water and careful handling techniques on the part of the student. With proper manipulations, this Grignard reaction occurs readily and allows for the removal of a 1-mL aliquot for mid-reaction GC–MS analysis. The analysis is consistent with a gas chromatogram and mass spectrum for each of the expected intermediates and
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final product of the reaction, demonstrating the stepwise addition of the Grignard reagent while also making for an interesting mass spectrometric exercise. WSupplemental
Material
Instructions for the students and notes for the instructors are available in this issue of JCE Online. Literature Cited 1. Anam, K. T.; Curtis, M. P.; Irfan, M. J.; Johnson, M. P.; Royer, A. P.; Shahmohammadi, K.; Thottumkara, K. V. J. Chem. Educ. 2002, 79, 629. 2. Ciaccio, J. A.; Volpi, S.; Clarke, R. J. Chem. Educ. 1996, 73, 1196. 3. Eckert, T. S. J. Chem. Educ. 1987, 64, 179. 4. Williamson, K. L. Macroscale and Microscale Organic Experiments; D.C. Heath and Company: Lexington, MA, 1989; pp 354–368. 5. Lambert, J. P.; Shurvell, H. F.; Lightner, D. A.; Cooks, R. G.; Organic Structural Spectroscopy; Prentice Hall: Upper Saddle River, NJ, 1998; pp 392–417.
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