In the Laboratory
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Synthesis and Use of Jacobsen’s Catalyst: Enantioselective Epoxidation in the Introductory Organic Laboratory John Hanson Department of Chemistry, University of Puget Sound, Tacoma, WA 98416-0320;
[email protected] Background Over the past 5 years we have refined the synthesis and use of Jacobsen’s enantioselective epoxidation catalyst into a unifying series of labs for the first semester of our sophomorelevel organic chemistry course. This series of labs accomplishes several important goals: it introduces students to an important modern synthetic method; it teaches them many common techniques used in running reactions, purifying products, and characterizing compounds; and it reinforces important concepts discussed in the lecture portion of the course (especially those dealing with chirality and stereochemistry). At the same time it is reliable, safe, and inexpensive enough to be successfully performed by large numbers of relatively inexperienced students. An important area of modern chemical research is the development of stereoselective methods for the preparation of chiral materials. In a recent article in the Journal of Chemical Education, Lipkowitz, Naylor, and Anliker persuasively argued that examples of such asymmetric syntheses should be incorporated into the undergraduate curriculum to reflect this importance (1). An important and extensively studied asymmetric method is conversion of achiral alkenes into optically active epoxides (2–4). Two articles describing undergraduate experiments that exemplify this method have appeared. The first demonstrates the high regioselectivity and stereoselectivity observed in the Sharpless epoxidation of geraniol (5); the second involves the synthesis and use of the fructosederived asymmetric epoxidation catalyst developed by Shi and coworkers (6 ). Both of these experiments are appropriate for advanced organic students. The procedures we describe can be successfully performed by beginning organic students and can also be used effectively with more advanced students. In 1994 N,N ′-bis(3,5-di-tert-butylsalicylidene)-1,2cyclohexanediaminomanganese(III) chloride (3, “Jacobsen’s Catalyst”) was awarded the Fluka Prize “Reagent of the Year” for its ability to produce enantiomerically highly enriched epoxides from unfunctionalized olefins (7). Numerous review articles demonstrating the usefulness and generality of this reagent have appeared (3, 8). Jacobsen’s catalyst produces good yields of epoxides in a wide variety of systems and is particularly effective on cis-disubstituted and trisubstituted olefins where enantiomeric excesses greater than 90% are common. Unlike many modern organometallic reagents, Jacobsen’s catalyst can be easily and safely used by beginning organic students. It is stable to air and water and is typically used in catalytic amounts (0.25–10 mol %) with sodium hypochlorite (bleach) as the ultimate oxidant (9). The catalyst is commercially available, but its preparation is straightforward (10) (Scheme I) and introduces students to many important laboratory techniques. During the five 4-hour laboratory periods devoted to the synthesis and use of Jacobsen’s catalyst, students learn to set up and run reactions, including those done at reflux. They learn several purification and isolation
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techniques: aqueous washing using a separatory funnel, use of drying agents, evaporation of solvents using a rotary evaporator, recrystallization, collection of solids by vacuum filtration, and flash chromatography. They also use a variety of analytical techniques to characterize their products: melting point, polarimetry, IR spectroscopy, H-NMR spectroscopy, thinlayer chromatography, and chiral gas chromatography. Procedures and Results Our synthesis of Jacobsen’s catalyst (Scheme I) is adapted from the Organic Syntheses preparation of Larrow and Jacobsen (10). It is carried out over three laboratory periods and is reliable and simple enough that nearly all of our firstsemester organic students obtain the desired catalyst. In the first step 1,2-diaminocyclohexane is purified and resolved by crystallization of the salt formed with L-tartaric acid. As the hot reaction mixture cools, product crystallizes from the reaction mixture. The crude product is collected and recrystallized from water. This experiment dovetails nicely with lecture discussions of acid–base chemistry and stereochemistry. For a thorough description of the resolution of 1,2-diaminocyclohexane and determination of its enantiopurity, readers are directed to an excellent article in this Journal (11). NH2
HO2C
OH H2O/AcOH
+ NH2
HO2C
OH
NH3 O2C
OH
NH3 O 2C
OH
1 2 eq K2CO3
O
OH C(CH3)3
H 2 eq
C(CH3)3
C(CH3)3
C(CH3)3
C(CH3)3 O
N
Mn Cl N
C(CH3)3
1. Mn(OAc)2•4H2O Air 2. LiCl
O C(CH3)3
3
N
OH
N
OH C(CH3)3
C(CH3)3
C(CH3)3 2
Scheme I
The diimine 2 (aka “Jacobsen’s ligand”) is formed by addition of 3,5-di-tert-butyl-2-hydroxybenzaldehyde (dis-
Journal of Chemical Education • Vol. 78 No. 9 September 2001 • JChemEd.chem.wisc.edu
In the Laboratory
solved in hot ethanol) to a refluxing solution of diaminocyclohexane salt 1 and potassium carbonate dissolved in a mixture of ethanol and water. After formation of the diimine, the reaction mixture is cooled in an ice bath. The crude solid product is then collected by vacuum filtration and dissolved in dichloromethane and washed with water and brine. Drying with sodium sulfate and evaporation of the solvent affords the diimine 2 as a yellow solid. The median student yield is 1.7 g (73%) and most students report a narrow melting point range that is within 5° of the 205–207 °C range cited in the Aldrich Chemical Company catalog (#40,441-1). Students also confirm the presence of the imine functionality by acquiring an infrared spectrum that clearly shows the imine absorption at 1631 cm᎑1. To demonstrate that the resolution of 1,2-diaminocyclohexane was successful, students measure the optical activity of the diimine 2. Since the diimine 2 has a relatively large specific rotation ([α]D20 = ᎑315° (c = 1, CH2Cl2)) even a relatively modest polarimeter can be used effectively. For example, students typically use a concentration of 0.5 g of the diimine per 10 mL, producing an observed rotation near ᎑16° in the 1-dm cell. Most students obtain specific rotations that are close to the literature value. In the final step of the synthesis of Jacobsen’s catalyst (3), manganese(II) acetate is added to a refluxing solution of the diimine 2 in ethanol. Air is then bubbled through the reaction mixture to oxidize the manganese, resulting in a dark brown solution. The reaction is monitored by thin-layer chromatography and after the ligand has disappeared the air is discontinued and lithium chloride is added. The solvent is removed by rotary evaporation and the residue is dissolved in dichloromethane and washed with water and brine. After the dichloromethane layer is dried (Na2SO4), heptane is added and the dichloromethane (but not the heptane) is removed by
rotary evaporation. The resulting dark brown solid is collected by vacuum filtration and allowed to air-dry. The median student yield is 0.6 g (52%) and most students report a narrow melting point range that lies within 10° of the 330–332 °C range reported in the Aldrich Chemical Company catalog (#40,444-6). For the epoxidation reaction (Scheme II) students select one of the following alkenes: styrene (4, R 1 = R2 = H), α methylstyrene (4, R 1 = CH 3, R 2 = H), or 1,2-dihydronaphthalene (4, R1 = H, R2 = –CH2CH2– connected to ortho position). These alkenes are all commercially available and the enantiomers of the resulting epoxides 5 are separable on the chiral GC column we use. The students dissolve 0.5 g of the alkene and 10 mol % (approximately 0.3 g) of the Jacobsen catalyst in dichloromethane. A pH 11.3 solution containing household bleach (purchased from a local grocery store) is then added and the resulting two-phase mixture is vigorously stirred. Students follow the reaction by TLC and after approximately 1–2 hours they work up the reaction by adding more organic solvent and washing with brine. The crude product is stored until the next lab period, when it is purified by flash chromatography. R1
R1
O
Jacobsen Catalyst (3) NaOCl
R2
R2 4
5
Scheme II
Typical yields range from 50 to 300 mg of product. The students characterize their products by both H NMR and IR spectroscopy. The enantioselectivities of the reactions are determined by chiral GC analysis (Fig. 1). (An alternative H NMR-based procedure using a chiral shift reagent is described in the supplemental material.W) As expected for Jacobsen’s catalyst, the styrene and α-methylstyrene oxides are produced with relatively modest enantiomeric excesses of approximately 48%, whereas the dihydronaphthalene is typically near 85%. Although most students obtain the desired epoxide, some find that their product is contaminated with an aldehyde or ketone resulting from acid-catalyzed rearrangement (Scheme III). The acid-catalyzed rearrangement of epoxides is well known (12) and has been the subject of two laboratory experiments described in this Journal (13). We find that the presence of an unexpected side-product provides an instructive, if originally unintended, dimension to the experiment. R1
R1
O
O
Acid-catalyzed Rearrangement
R2
R2 5
6
Scheme III
Figure 1. Chiral gas chromatogram of epoxides produced using the Jacobsen catalyst. A: styrene oxide. B: α-methylstyrene oxide. C: 1,2dihydronaphthalene oxide. Retention times are in minutes.
At the end of this series of experiments students write a report in the form of a journal article describing their results and comparing them to those of students who used different alkenes or different reaction conditions. Students have a very positive reaction to this series of experiments. They feel a sense of accomplishment from successfully using a modern
JChemEd.chem.wisc.edu • Vol. 78 No. 9 September 2001 • Journal of Chemical Education
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In the Laboratory
synthetic method and see the obvious connection with many of the topics discussed in the first-semester organic course. Hazards We have occasionally observed fumes coming from the top of the condenser when air is bubbled through the refluxing reaction mixture during production of Jacobsen’s catalyst. Consequently we run this reaction in a hood. Deuterochloroform and aromatic epoxides are cancer-suspect agents that should be handled with appropriate care. Special Equipment, Chemicals, and Instruments L-(+)-Tartaric
acid
1,2-Diaminocyclohexane (mixture of stereoisomers) 3,5-Di-tert-butyl-2-hydroxybenzaldehyde Manganese(II) acetate tetrahydrate Lithium chloride Heptane Styrene α-Methylstyrene
1,2-Dihydronaphthalene Flash chromatography columns (22 mm × 400 mm) Silica gel for flash chromatography (35–70 µm particle size) Chiral GC column (30 m β-DEX 110 column, Supelco # 2-4301)
Acknowledgments I wish to thank my organic colleagues Bill Dasher, Tim Hoyt, and Eric Scharrer for their help and encouragement in implementing this lab. I also want to thank the many organic chemistry students at UPS whose enthusiasm and hard work have helped make this lab a success. W
Supplemental Material
Detailed experimental procedures and extensive suggestions for instructors are available in this issue of JCE Online.
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Literature Cited 1. Lipkowitz, K. B.; Naylor, T.; Anliker, K. S. J. Chem. Educ. 2000, 77, 305. 2. Katsuki, T. In Comprehensive Asymmetric Synthesis, Vol. II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York, 1999; pp 621–648. Johnson, R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthesis; Ohima, I., Ed.; VCH: Weinheim, 1993; pp 227–272. 3. Jacobsen, E. N.; Wu, M. H. In Comprehensive Asymmetric Synthesis, Vol. II; Jacobsen, E. N.; Pfaltz, A.; Yamamoto, H., Eds.; Springer: New York, 1999; pp 649–677. Jacobsen, E. N. In Comprehensive Organometallic Chemistry II, Vol. 12; Wilkinson, G.; Stone, R. G. A.; Abel, E. W.; Hegedus, L. S., Eds.; Pergamon: New York, 1995; Chapter 11.1. Jacobsen, E. N. In Catalytic Asymmetric Synthesis; Ohima, I., Ed.; VCH: Weinheim, 1993; pp 159–202. 4. Dakin; L. A.; Panek, J. S. Chemtracts—Org. Chem. 1998, 11, 531. 5. Bradley, L. M.; Springer, J. W.; Delate, G. M.; Goodman, A. J. Chem. Educ. 1997, 74, 1336. 6. Burke, A.; Dillon, P.; Martin, K.; Hanks, T. W. J. Chem. Educ. 2000, 77, 271. 7. Reagent of the Year 1994; Sigma-Aldrich Chemical Co.: Milwaukee, WI; http://www.sigma-aldrich.com/saws.nsf/pages/ flpr_reag94?opendocument (accessed May 2001). 8. Flessner, T.; Doye, S. J. Prakt. Chem. (Weinheim) 1999, 341, 436. Katsuki, T. Coord. Chem. Rev. 1995, 140, 189. Katsuki, T. J. Mol. Catal. 1996, 113, 87. 9. Typical epoxidation procedures: Zhang, W.; Jacobsen, E. N. J. Org. Chem. 1991, 56, 2296. Jacobsen, E. N.; Zhang, W.; Muci, A.R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113, 7063. Larrow, J. F.; Roberts, E.; Verhoeven, T. R.; Ryan, K. M.; Senanayake, C. H.; Reider, P. J.; Jacobsen, E. N. Org. Synth. 1999, 76, 46–56. Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378. 10. Larrow, J. F.; Jacobsen, E. N. Org. Synth. 1999, 75, 1–11. 11. Walsh, P. J.; Smith, D. K.; Castello, C. J. Chem. Educ. 1998, 75, 1459. 12. Two recent references: Anderson, A. M.; Blazek, J. M.; Garg, P.; Payne, B.; Mohan, R. S. Tetrahedron Lett. 2000, 41, 1527. Ranu, B. C.; Jana, U. J. Org. Chem. 1998, 63, 8212. 13. Garin, D. L.; Gamber, M.; Rowe, B. J. J. Chem. Educ. 1996, 73, 555. Sgariglia, E. A.; Schopp, R.; Gavardinas, K.; Mohan, R. S. J. Chem. Educ. 2000, 77, 79.
Journal of Chemical Education • Vol. 78 No. 9 September 2001 • JChemEd.chem.wisc.edu
