In the Laboratory edited by
the microscale laboratory
Arden P. Zipp SUNY-Cortland Cortland, NY 13045
Synthesis of 4-Nitro-1-pentynylbenzene: An Example of Transitional Metal-Mediated Cross-Coupling Ronald G. Brisbois,* William G. Batterman, and Scott R. Kragerud Department of Chemistry, Hamline University, 1536 Hewitt Avenue, St. Paul, MN 55104-1284 While transition metal–mediated (i.e., catalyzed) reactions (1) are currently integral tools in the repertoires of synthetic organic chemists, the spectrum of introductory organic texts (both lecture and lab) does not reflect this contemporary state of affairs very well (2). This is unfortunate in view of the excellent opportunity afforded by even a limited introduction to such reactions. Learning the eighteen electron rule and how to use it for transition metal valence is a valuable skill for students to possess before taking biochemistry or advanced inorganic chemistry. Introductory organic students focus a major portion of their efforts on learning to think mechanistically, so they are ideally primed for an exposure to the key bond making–bond breaking processes general to most transition metal–mediated transformations. Additionally, consideration of catalytic reaction cycles complements the more linear mode of thinking students tend to develop with respect to reactions in which all critical materials are present in stoichiometric amounts. Although a number of interesting lab exercises have been reported in this Journal (3), these did not meet our specific requirements. We opted instead to modify a Pd-mediated cross-coupling method (4) to a microscale procedure to fit a 3.5-hour lab period (eq 1). Br
cat. (Ph3P)2PdCl2, cat. CuI O2N
O2N
(1)
THF-Et3N, 45 min, rt 1
2
3
Experimental Procedure To an oven-dried 10-mL round-bottomed flask, add a stir bar and 75 mg of 1-bromo-4-nitrobenzene, and cap with a rubber septum. Flush the reaction flask headspace with ca. 50 mL of dry N2 gas. Via separate 10-mL syringes, add 1 mL each of anhydrous Et3 N1 and THF2 to the reaction flask through the septum and stir at room temperature. Via a 1mL syringe, add 0.35 mL of 1-pentyne (d = 0.69 g/mL) to the reaction flask through the septum. Next, quickly weigh out 15–25 mg of bis(triphenylphosphine)palladium (II) chloride3 and 6–12 mg of copper(I) iodide,4 and add them to the reaction flask by temporarily removing the septum. Replace the septum and flush the reaction flask head space with ca. 50 mL of dry N2 gas. Allow the reaction mixture to stir for 45 minutes at room temperature.5,6 Transfer the reaction mixture to a 100-mL centrifuge tube with the aid of three 5-mL portions of hexane. Extract the organic layer with five 5-mL portions of 10% HCl solution and two 5-mL portions of saturated NaCl solution.7 Transfer the organic layer to a clean 25-mL Erlenmeyer flask and dry it over anhydrous Na2 SO4 (ca. 250 mg) for 10–15 minutes. Decant the organic layer into a clean 50-mL round-bottomed flask and strip off the solvent on a rotary evaporator. Purify the crude prod*Corresponding author.
832
uct via flash column chromatography8 (5), using a 0.5-cm (inner diameter) × 30 cm column9 with 8–10 g of SiO2 10 and eluting with 93:7 (v/v) hexane: ethyl acetate. Collect 2–3-mL fractions and check them for the presence of 3 using the same eluent system. Combine the clean fractions in an appropriately sized round-bottomed flask (usually 50 mL) and strip off the eluent on a rotary evaporator. The average student yield is 75%. 1H-NMR (250 MHz, CDCl3): δ 8.14 (d, 2H), 7.50 (d, 2H), 2.43 (t, 2H), 1.65 (m, 2H), 1.06 (t, 3H). 13C-NMR (100 MHz, CDCl3 ): δ 146.5, 132.2, 131.2, 123.4 96.5, 79.4, 21.8, 21.5, 13.5. IR (CCl4): 3106, 3075, 2964, 2237, 1596 cm{1. Discussion This lab was tested with excellent results in an introductory organic course with three lab sections of twelve to eighteen students each. Terminal alkyne/aryl (vinyl) halide cross-coupling very closely fit the concepts and mechanistic features being emphasized in the lecture. The reaction is catalytic in both Pd and Cu, forming a new Csp2 /C sp bond in one synthetic operation. In the course of transforming starting materials to products, oxidative addition, transmetallation, and reductive elimination are illustrated. Effectively, this sequence of mechanistic processes results in nucleophilic substitution at an sp2 carbon. Before lab, students are asked to think about how 3 might be synthesized using reactions they have learned to date. Almost all students readily invoke the dogma that such a thing could not happen via an SN2 pathway, while the more insightful students, recalling nucleophilic aromatic substitution, ask how it is known that that pathway is not operating. Comparing students’ multistep schemes to Pd-mediated cross-coupling impresses upon them the importance and value of convergence in synthesis. Also, this alternative synthetic application of a terminal alkyne allows for comparison to other aspects alkyne chemistry covered previously. Acknowledgment This work was supported by an NSF Presidential Faculty Fellowship (CHE 9350393) to R. G. B. Notes 1. The Et3N was distilled from CaH 2 before lab and stored over KOH pellets in an amber bottle. 2. We use THF freshly distilled over Na/benzophenone because a still is available in another lab. Anhydrous THF (Aldrich Chemical Company #40,175-7) works fine, but it should be degassed by bubbling with dry N2 gas. 3. Purchased from Aldrich Chemical Company (#20,867-1). 4. Purchased from Aldrich Chemical Company (#21,555-4). 5. The reaction can be maintained under the static blanket of N2 held only by the septum. 6. If desired, the progress of the reaction can be monitored
Journal of Chemical Education • Vol. 74 No. 7 July 1997
In the Laboratory by TLC. Elution with 93:7 (v/v) hexane: ethyl acetate and staining with phosphomolybdic acid solution (Aldrich Chemical Company #31,927-9) works well. 7. We do not cap and shake the centrifuge tube as some laboratory texts suggest for mixing aqueous and organic layers. Students use a 9-in. pipet to mix by repeatedly sucking the bottom aqueous layer into the pipet and vigorously squirting it through the organic layer. 8. Students use an atomizer bulb connected to glass tubing in a one-holed stopper (size 00) to provide pressure to the chromatography column. 9. We have found that packing the column with a SiO2/hexane slurry works just as well on this scale as the dry packing technique described by Still and coworkers. 10. SiO2 was purchased from Aldrich Chemical Company (#22,719-6; grade 9385; 230–400 mesh; 60 Å).
Literature Cited 1. Advances in Metal-Organic Chemistry Liebeskind, L. S., Ed.; JAI: Greenwich, CT; Vols. 1–5; Schlosser, M. Organometallics in Synthesis: A Manual; Wiley: New York, 1994; Tsuji, S. Palladium Reagents: Innovations in Synthesis; Wiley: New York, 1995. 2. For examples of texts that do include sections on transitional metal chemistry, see Solomons, T. W. G. Organic Chemistry, 5th ed.; Wiley: New York, 1992; pp 976–990; Streitwieser, A.; Heathcock, C. A.; Kosower, E. M. Introduction to Organic Chemistry, 4th ed.; Macmillan: New York, 1992; pp 1217–1224. 3. For examples we considered carefully as models, see Viswanathan, T.; Jethmalani, J. J. Chem. Educ. 1993, 70, 165; Lindley, J. J. Chem. Educ. 1980, 57, 671; Byers, J. H.; Ashfaq, A.; Morse, W. R. J. Chem. Educ. 1990, 67, 340. 4. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627. 5. Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
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