In the Laboratory
A Multistep Synthesis for an Advanced Undergraduate Organic Chemistry Laboratory
W
Chang Ji Department of Chemistry and Biochemistry, University of Guelph, Guelph, Ontario N1G 2W1, Canada Dennis G. Peters* Department of Chemistry, Indiana University, Bloomington, IN 47405; *
[email protected] Multistep syntheses are often important components of the undergraduate organic laboratory experience. Such projects require a higher level of skill from students than single-step reactions and come much closer to real-life syntheses encountered in graduate school or industry. Moreover, the synthesis of a product with novel applications can usually make the laboratory course more attractive to students. A number of articles offering multistep syntheses of compounds with biological significance have appeared (1–5). Wilen and co-workers (6) outlined a four-step procedure to prepare polystyrene from benzene. Student-designed multistep synthesis projects in organic chemistry were recently discussed by Graham and colleagues (7). However, there seem to be few synthesis procedures developed for the undergraduate laboratory that involve products with applications in other fields. step 1 OCH3
OH 47% HI
OH
I
1
Experimental Procedure
2
step 2 OH
OMgI
OH
O
1. (CH2O)n Et3N
CH3CH2MgI
H
2. HCl/H2O
I
I
2
I 4
3
step 3 OH
OH
O
Hazards
H 1. (H2N)2CS 2. KOH
SH 5
Scheme I. Synthesis of 5-(2-sulfhydrylethyl)salicylaldehyde, 5.
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All reagents were purchased from either Aldrich or Fisher. 4-(2-Iodoethyl) phenol, 2, (10) was synthesized by refluxing a mixture of 4-methoxyphenethyl alcohol, 1, and 47% hydriodic acid. Treatment of the aryloxymagnesium iodide, 3, freshly prepared from 2 and ethylmagnesium iodide, with paraformaldehyde and triethylamine gave 5-(2-iodoethyl)salicylaldehyde, 4 (11). The crude product was purified by silica gel column chromatography and recrystallized. Finally, 4 was converted to 5-(2-sulfhydrylethyl)salicylaldehyde, 5, in high yield through the use of thiourea (12). All key compounds were characterized by means of GC–MS and NMR spectrometry.
O
H
I 4
In this article we describe a three-step synthesis of 5-(2sulfhydrylethyl)salicylaldehyde. This experiment is suitable as a special project for an advanced undergraduate organic chemistry laboratory course and works well for either individual students or pairs of students. Under normal circumstances, this experiment takes four or five laboratory periods to complete. Shown in Scheme I is the recently reported route (8) to 5-(2-sulfhydrylethyl)salicylaldehyde that can be used to synthesize alkanethiol-substituted metal salens, which may have further application in the preparation of surface-modified gold electrodes (8, 9). First, 4-methoxyphenethyl alcohol, 1, is converted to 4-(2-iodoethyl)phenol, 2, by treatment with hydriodic acid (step 1). Next, 5-(2-iodoethyl)salicylaldehyde, 4, is formed via the use of a Grignard reagent, paraformaldehyde, and triethylamine (step 2). Finally, 5-(2-sulfhydrylethyl)salicylaldehyde, 5, is prepared by reaction of 4 with thiourea (step 3). With emphasis on TLC, column chromatography, and recrystallization, this experiment offers opportunities for students to master a number of essential bench techniques in the organic chemistry laboratory. In addition, students can learn or reinforce their knowledge about the use and handling of Grignard reagents, which are important organic reactants. Finally, GC–MS and NMR techniques give a real experience in spectrometric data interpretation.
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General laboratory safety procedures, including the wearing of safety goggles and gloves, must be followed at all times. All organic chemicals involved in this experiment are considered hazardous, and direct physical contact with them or inhalation should be avoided. Acetone, ethanol, ether, ethyl acetate, and hexanes are highly flammable liquids. 4-Methoxyphenethyl alcohol is an irritating solid at room tempera-
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In the Laboratory
ture. Iodoethane, tetrahydrofuran, and triethylamine are flammable, corrosive, or irritating. Benzene and paraformaldehyde are carcinogenic and flammable. Chloroform is a cancer suspect agent and mutagen. Both hydrochloric acid and hydroiodic acid are corrosive liquids. Magnesium sulfate is hygroscopic and potassium hydroxide can cause burns to the skin. Silica gel is harmful to the respiratory system and irritating to the eyes and skin. Thiourea is carcinogenic and toxic. All experiments must be performed in a fume hood, and wearing a laboratory coat or apron is strongly recommended. Unfortunately, the final product, which is a thiol, does have an unpleasant smell and is toxic. It is suggested that all glassware used for the third step of the synthesis be cleaned in a fume hood. Results and Discussion As a special project, this experiment was incorporated into an advanced organic chemistry laboratory course, and the student response was highly positive. Students found the synthesis attractive because the final product has its own application in electrochemistry (8) and the overall yield was satisfactory. Each step of the synthesis requires no more than an intermediate knowledge of organic laboratory skills, and students can readily complete the experiment with moderate effort. Each of the three products has a unique form or color and can be differentiated by simple inspection, which provides an opportunity for students to recognize that the change of a functional group of a molecule can result in dramatic differences in spectroscopic and physical properties. During the refluxing time involved with each step, students can do other experiments or collect the GC–MS and NMR data for the products. Most students are able to finish the synthesis within four laboratory sessions. For a shortened project, step 3 can be omitted, at the discretion of the course instructor. This synthesis offers numerous learning opportunities to students by introducing or reinforcing recrystallization, vacuum filtration, melting-point measurement, handling of a Grignard reagent, TLC, GC–MS, and NMR analysis, and chemical calculations. GC–MS is employed to assess the purity of each product as well as to confirm the identity of each species. Students gain knowledge concerning the interpretation of MS and NMR data since each compound displays different fragmentation patterns in mass spectra and various proton-splitting patterns in NMR spectra. Although optional, IR spectroscopy could be introduced into the experiment as a supplemental analytical tool. Students can acquire more experience in making KBr plates for IR measurements of solid organic compounds. Because 4 possesses a carbonyl moiety, whereas 2 does not, the former can be easily distinguished from the latter with the aid of IR spectroscopy. Column chromatography, which is critical for the success of this experiment, is emphasized. Such training enables
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students to build proficiency in purifying crude compounds. With the proper eluting solvent, adequate separation between compounds 2 and 4 is achieved within reasonable time. For step 1, 48% hydrobromic acid can be used instead of hydroiodic acid. Consequently, the corresponding product is 4-(2-bromoethyl)phenol, the mass spectrum of which provides an excellent example for students to learn how to use isotopic abundances to characterize organic halides. Students are encouraged to search the literature and, if possible, to propose their own synthetic route to make the final product. It is also recommended that students read some of the references to understand the reaction mechanisms, especially with regard to the role of the Grignard reagent. Overall, this three-step synthesis is ideal as an end-of-semester or special project for an advanced organic chemistry laboratory course. Acknowledgments The authors thank all the undergraduate students who participated in this special project. Abdelaziz Houmam at the University of Guelph is also gratefully acknowledged for his suggestions in the preparation of this manuscript. W
Supplemental Material
Instructions for the students and notes for the instructor are available in this issue of JCE Online. Literature Cited 1. Rose, N. C.; Rome, S. J. Chem. Educ. 1970, 47, 649–650. 2. Schatz, P. F. J. Chem. Educ. 1978, 55, 468–470. 3. Bartlett, P. A.; Marlowe, C. K.; Connolly, P. J.; Banks, K. M.; Chui, D. W.-H.; Dahlberg, P. S.; Haberman, A. M.; Kim, J. S.; Klassen, K. J.; Lee, R. W.; Lum, R. T.; Mebane, E. W.; Ng, J. A.; Ong, J.-C.; Sagheb, N.; Smith, B.; Yu, P. J. Chem. Educ. 1984, 61, 816–817. 4. Howell, J.; deLannoy, P. J. Chem. Educ. 1997, 74, 990–991. 5. Williams, B. D.; Williams, B.; Rodino, L. J. Chem. Educ. 2000, 77, 357–359. 6. Wilen, S. H.; Kremer, C. B.; Waltcher, I. J. Chem. Educ. 1961, 38, 304–305. 7. Graham, K. J.; Schaller, C. P.; Johnson, B. J.; Klassen, J. B. Chem. Educator 2002, 7, 376–378. 8. Ji, C.; Peters, D. G. Tetrahedron Lett. 2001, 42, 6065–6067. 9. Creager, S. E.; Rowe, G. K. J. Electroanal. Chem. 1994, 370, 203–211. 10. Cheng, C.-S.; Ferber, C.; Bashford, R. I., Jr.; Grillot, G. F. J. Am. Chem. Soc. 1951, 73, 4081–4084. 11. Wang, R. X.; You, X. Z.; Meng, Q. J.; Mintz, E. A.; Bu, X. R. Synth. Commun. 1994, 24, 1757–1760. 12. Cossar, B. C.; Fournier, J. O.; Fields, D. L.; Reynolds, D. D. J. Org. Chem. 1962, 27, 93–95.
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