Communication pubs.acs.org/jchemeduc
Undesired Synthetic Outcomes During a Project-Based Organic Chemistry Laboratory Experience Adam M. Kiefer,* Kevin M. Bucholtz, David R. Goode, Jeffrey D. Hugdahl, and Bridget G. Trogden Department of Chemistry, Mercer University, Macon, Georgia 31207, United States ABSTRACT: While project-based chemistry laboratories are effective at providing second-year organic students with simulated research experience, there can be unexpected consequences when students carry out literature procedures. During an organic synthesis project, students accidentally added reagents for an aromatic iodination reaction in an incorrect order, resulting in the synthesis of nitrogen triiodide and the evacuation of the laboratory. A brief discussion of the events leading up to the reaction and steps taken to remediate the situation identify potential pitfalls in developing project-based chemistry laboratories. KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Safety/Hazards, Inquiry-Based/Discovery Learning, Misconceptions/Discrepant Events, Aromatic Compounds, Electrophilic Substitution, Synthesis
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Scheme 1. Synthesis of 4-Hydroxy-3-iodobenzonitrile
roject-based laboratories for introductory undergraduate chemistry courses provide students with a research-like experience early in their undergraduate career.1−3 In 1999, we contributed an article to this Journal outlining the development and implementation of a second-year-level organic synthesis project (OSP).4 Since 1993, the OSP has been pedagogically successful: students utilize chemical databases, read the primary literature, work in small groups to develop detailed research proposals, and undertake projects that involve reactions not commonly carried out in a second-year organic laboratory. Student results are disseminated through poster presentations to all students and faculty. These skills simulate research in a controlled environment and combat laboratory “cookbooking” by allowing students to actively design their own experience.1 Over the years, the OSP was modified to incorporate a central theme (specified name reaction) due to waste management issues and expense. As part of the ongoing assessment of the organic laboratory, the OSP is being reevaluated due to safety concerns resulting from an unanticipated side reaction that resulted in the need to evacuate the laboratory and necessitated outside assistance to render the laboratory safe for students. In a previous OSP, students were directed to develop a threestep reaction sequence incorporating the Ritter reaction, generating an amide from a nitrile and an incipient carbocation. Many student groups modified commercially available nitriles prior to the name reaction. Following a reference in the primary literature, one student group reacted 4-cyanophenol (1) with KI and I2 in concentrated aqueous NH4OH to produce 4hydroxy-3-iodobenzonitrile (2) (Scheme 1).5 The literature procedure clearly states that I2 and KI should be added to a solution of 1 in NH4OH. Workup after stirring overnight allowed 2 to be carried on without further purification. The reaction was successful on the small scale as judged by a crude 60 MHz 1H NMR, and students attempted to run the reaction on the same scale as the literature procedure.6 © 2012 American Chemical Society and Division of Chemical Education, Inc.
Although each student is required to maintain notebook entries for each reaction run during the laboratory, responsibility for measuring out reactants, reagents, volumes of solvent, and preparing laboratory equipment is delegated. This “synthesis by committee” occasionally leads to reagents not added in the appropriate order, or at all. In the present reaction, students apparently added KI and I2 to stirring ammonium hydroxide, and then added 1. Although out of context, this procedure may be recognizable to the reader as the synthesis of the contact explosive nitrogen triiodide (3) (Scheme 2).7−9 Scheme 2. Inadvertent Synthesis of Nitrogen Triiodide
While transferring the reaction mixture, a small amount of the material was spilled. The teaching assistant was surprised to find that the floor “crackled” and immediately called the professor to evaluate the situation. While examining the workspace and the student notebook, a small amount of 3 detonated on the bench top, releasing the telltale purple smoke (gaseous I2).8 The laboratory was immediately evacuated of students, and the container was sequestered behind a blast shield. On the basis of the quantities of material used, it was estimated that the theoretical yield of 3 was ∼11.5 g.10 The Director of the Environmental Health and Safety Office at Mercer University was immediately contacted. Following the Published: February 29, 2012 685
dx.doi.org/10.1021/ed200495w | J. Chem. Educ. 2012, 89, 685−686
Journal of Chemical Education
Communication
(8) The utilization of 3 in demonstrations, as well as the dangers associated with its synthesis and use have been well documented for over 80 years: (a) Jordy, L. C. J. Chem. Educ. 1930, 7, 653−659. (b) Bodner, G. M. J. Chem. Educ. 1985, 62, 1105−1107. (9) Tudela, D. J. Chem. Educ. 2002, 79, 558. (10) For obvious reasons, no attempt was made to quantify or recreate the results of this experiment. (11) (a) Cowart, M.; Pratt, J. K.; Stewart, A. O.; Bennani, Y. L.; Esbenshade, T. A.; Hancock, A. A. Bioorg. Med. Chem. Lett. 2004, 14, 689−693. (b) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727−4729. (c) Johnsson, R.; Meijer, A.; Ellervik, U. Tetrahedron. 2005, 61, 11657−11663. (12) (a) White, J. D.; Amedio, J. C. J. Org. Chem. 1989, 54, 736−738. (b) Zubia, E.; Luis, F. R.; Massanet, G. M.; Collado, I. G. Tetrahedron 1992, 48, 4239−4246.
established chemical hygiene plan, the Macon−Bibb County Hazardous Material Team and the Macon Police Department Bomb Squad were summoned to destroy the reaction mixture. The students and faculty were lucky to avoid an explosion due to the extreme sensitivity of NI3. How could this situation have been avoided? The students are mostly blameless. It is expected that mistakes will be made during the OSP, often contributing to a better understanding of organic synthesis. Although there are alternative synthetic methods to eliminate the use of ammonium hydroxide as a solvent,11 students selected a viable procedure from the literature that did not require anhydrous conditions or flash chromatography for 2. The faculty member who vetted the proposal was unfamiliar with the synthesis and physical properties of 3. In discussions with the corresponding author of the original procedure,5 no issues arose during previous syntheses of 2 or similar structures. Similarly, the citations in the original article lead to papers without safety warnings.12 The harsh reality is that attempting real-world laboratory experiences with undergraduates can be hazardous. It is important for the department to have a plan in place to deal with incidences that can occur even with careful planning, organization, and forethought. Laboratory incidents such as the one presented here can be avoided by using highly structured and organized labs to reduce student exposure to unforeseen chemical reactions. Although these “cookbook” labs provide safety, cost-savings, and timesavings, they limit student exploration. The OSP was developed and adopted by the chemistry faculty as a means of reducing “cookbook” activities and to give our students experience with a simulated research environment. Immersive educational experiences are valuable but not risk free, and as such, they underscore the need for constant vigilance, careful review of student proposals for hidden hazards, and prudent safety oversight.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
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ACKNOWLEDGMENTS The authors wish to thank Marlon Cowart (Abbott Laboratories) for helpful discussions regarding lab safety and the synthesis of 2. An addition/correction has been published in J. Med. Chem. and is linked to the original article.5b
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REFERENCES
(1) For a comparison on current methods for teaching organic laboratory, see Horowitz, G. J. Chem. Educ. 2007, 84, 346−353. (2) For an example in the inorganic chemistry laboratory, see Vallarino, L. M.; Polo, D. L.; Esperdy, K. J. Chem. Educ. 2001, 78, 228−231. (3) (a) Dobrev, A. A. J. Chem. Educ. 1996, 73, 856. (b) Graham, K. J.; Schaller, C. P.; Johnson, B. J.; Klassen, J. B. Chem. Educator 2002, 7, 376−378. (c) Ruttledge, T. R. J. Chem. Educ. 1998, 75, 1575−1578. (4) Davis, D. S.; Hargrove, R. J.; Hugdahl, J. D. J. Chem. Educ. 1999, 76, 1127−1130. (5) (a) Sun, M.; Zhao, C.; Gfesser, G. A.; Thiffault, C.; Miller, T. R.; Marsh, K.; Wetter, J.; Curtis, M.; Faghih, R.; Esbenshade, T. A.; Hancock, A. A.; Cowart, M. J. Med. Chem. 2005, 48, 6482−6490. (b) Sun, M.; Zhao, C; Gfesser, G. A.; Thiffault, C.; Miller, T. R.; Marsh, K.; Wetter, J.; Curtis, M.; Faghih, R.; Esbenshade, T. A.; Hancock, A. A.; Cowart, M. J. Med. Chem. 2012, 55 (1), 563−563. (6) Theoretical yield of 2: 20.6 g, reported yield of 2: 14.2 g (69%). (7) Hambly, G. F.; Peters, R. J. Chem. Educ. 1993, 70, 943. 686
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