In the Laboratory
Nobel Chemistry in the Laboratory: Synthesis of a Ruthenium Catalyst for Ring-Closing Olefin Metathesis
W
An Experiment for the Advanced Inorganic or Organic Laboratory George E. Greco Department of Chemistry, Goucher College, Baltimore, MD 21204;
[email protected] The 2005 Nobel Prize in Chemistry was awarded to Yves Chauvin, Robert H. Grubbs, and Richard R. Schrock “for the development of the metathesis method in organic synthesis” (1). In its simplest form, olefin metathesis is a reaction in which two alkenes exchange their partners as indicated in eq 1:
R1
R3
R5
R7
R2
R4
R6
R8
R1
R7
R5
R3
R2
R8
R6
R4
(1)
A number of transition-metal complexes catalyze the reaction, but the common feature among all of them is the presence of a metal–carbon double bond, also known as a metal–alkylidene complex. The most successful metathesis catalysts are the molybdenum complex developed by Schrock and the ruthenium complexes developed by Grubbs (Figure 1). Following the Nobel Prize announcement, the metathesis catalysts were the Featured Molecules in the February 2006 issue of this Journal (2), and there are now several articles that provide an overview of the olefin metathesis reaction at a level accessible to undergraduate students including one in this Journal (3–5). Here we report an experiment designed for an advanced inorganic or organic laboratory course in which students synthesize complex 1 (Figure 2), one of the first-generation Grubbs ruthenium catalysts starting from ruthenium trichloride hydrate. After characterizing compound 1 by high-field 1H NMR spectroscopy, students use the catalyst they prepared in a ring-closing metathesis (RCM) reaction. This experiment brings Nobel Prize winning chemistry into the undergraduate laboratory. Two other excellent experiments involving the use of modern olefin metathesis catalysts have appeared in this Journal. One is directed towards the application of olefin metathesis to polymer synthesis (6), and the other is a cross-metathesis experiment designed for the second-year organic lab (7). Both of those experiments focus on the metathesis reaction and purchase the catalyst. This interdisciplinary experiment is designed for an advanced course, is more focused on the catalyst synthesis, and gives students the opportunity to use a catalyst that they made. In addition, students will learn Schlenk techniques for the manipulation of air-sensitive materials. We use this experiment in an advanced synthetic techniques course taken by third-year and fourth-year chemistry majors. This experiment combines the inorganic chemistry of the catalyst synthesis with the organic chemistry of the RCM reaction. Completing the entire experiment requires that students do some work on five days over the course of the semester; however, only two full lab periods are required. For more details on the logistics of scheduling this experiment see the Supplemental
Material.W This experiment is ideally suited for an integrated upper-level lab course; however, the experiment can be divided into sections for more specific courses. The synthesis of the catalyst can be carried out in a course that is exclusively inorganic as an opportunity to teach students about Schlenk techniques, while the RCM reaction and the purification of the product can be done in an organic lab course by using a similar commercially available ruthenium catalyst (Grubbs catalyst, 1st generation, Aldrich product #579726).
N
F3C O F3C F3C
Mo O
CF3 Schrock
N Cl Cl
P
Cl
Ru
Cl
N Ru P
P
classical Grubbs
second generation Grubbs
Figure 1. Schrock and Grubbs metathesis catalysts.
Cl Cl
P Ru P
1 Figure 2. Structure of ruthenium catalyst 1 synthesized in this experiment.
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In the Laboratory
Ring-closing metathesis (Scheme I) is a reaction in which an acyclic diene is cyclized with the extrusion of a small molecule such as ethylene. The importance of the RCM reaction in particular, cannot be overstated because unlike ring-opening metathesis polymerization (ROMP), the other extensively explored metathesis reaction, the chief application of RCM has been organic synthesis, rather than polymer chemistry. Since the RCM reaction will efficiently close rings of widely varying sizes, it has already been applied as a key step in the synthesis of numerous natural products by synthetic organic laboratories. One representative example is the closing of the 16-membered ring of the anticancer agent epothilone A by the labs of K. C. Nicolaou (8) and Samuel Danishefsky (9).
RCM: R
R
R
R catalyst
ROMP: catalyst
*
* n
Scheme I. Examples of RCM and ROMP reactions.
RuCl3
[(COD)RuCl2 ] x
EtOH ( CH3CHO)
Cl
H
Ru
Et 3N 2-butanol
H
PCy3 Cl
CH
H CH2Cl2
Cl
Ru
For the RCM reaction, diethyl diallylmalonate was chosen as the substrate because of its high reactivity since catalyst 1 is not as active as some of the more recent Grubbs catalysts (eq 2):
PCy3
PCy3
The Grubbs ruthenium catalysts are the most appropriate for synthesis and use in the undergraduate laboratory because, compared to the molybdenum catalysts, they are air stable over short periods of time and are also tolerant of more organic functional groups. While there are a number of active ruthenium metathesis catalysts, the synthetic routes to many of them are either tedious or require hazardous diazo compounds. Grubbs published a high-yielding route to catalyst 1 in which the alkylidene moiety is formed through insertion of a propargyl chloride into a ruthenium hydride, followed by expulsion of the leaving group (10). While Schlenk techniques are required owing to an air-sensitive intermediate, this catalyst synthesis is most conducive to the undergraduate lab environment. As indicated in Scheme II, students begin the catalyst synthesis by synthesizing [(COD)RuCl2]x (11) from RuCl3⋅H2O. The reaction takes place in ethanol, which also serves to reduce Ru(III) to Ru(II), and the product precipitates out after overnight reflux. Reaction of this complex with tricyclohexylphosphine under an atmosphere of hydrogen gas produces the key air-sensitive orange intermediate Ru(H)(H2)Cl(PCy3)2, which precipitates upon addition of methanol. The synthesis of this compound also gives instructors the opportunity to introduce dihydrogen complexes and sigma bonds in ligands as sources of electron density. The material is collected on a Schlenk filter, but is carried on to the next step immediately without characterization to avoid exposure to air. Addition of 3-chloro-3-methyl1-butyne to a dichloromethane solution of the dihydrogen complex gives magenta complex 1, which crystallizes upon addition of methanol and removal of dichloromethane. Complex 1 is air stable in the solid state; minimal decomposition was observed over a period of two years. Characterization of compound 1 by 1H NMR is instructive since it is diamagnetic, and its 1H NMR spectrum contains a low field resonance at δ 19.26 that is characteristic of metal alkylidenes. Ring-Closing Reaction
CH3 CH3 C
PCy3 Cl
H2 2 PCy3
Catalyst Synthesis
O EtO
1 Scheme II. Synthesis of catalyst 1.
OEt
catalyst 1
O
O
EtO
OEt
(2)
2
Table 1. Student Yields for Compounds Prepared in This Experiment Compound
O
Student Yields (%) Average
Range
[(COD)RuCl2]x
83
70–98
Catalyst 1
65
60–69
Ring-closed product 2
80
57–98
The metathesis reaction takes place rapidly under an atmosphere of air. The product is purified using column chromatography, and then characterized by 1H NMR spectroscopy. Results Student yields for the synthesis of the compounds in this experiment can be found in Table 1. All students have successfully carried out all aspects of the experiment and, in the process, were exposed to important cutting-edge chemistry and a variety
1996 Journal of Chemical Education • Vol. 84 No. 12 December 2007 • www.JCE.DivCHED.org
In the Laboratory
of important experimental techniques that students will need if they take a job or begin graduate school in synthetic chemistry. Furthermore, by working in pairs on the complicated catalyst synthesis step, they have the opportunity to collaborate to avoid procedural errors.
Acknowledgments
Equipment and Chemicals
WSupplemental
A detailed list of all of the equipment and chemicals needed for this experiment can be found in the Supplemental Material.W A double Schlenk manifold supplying vacuum or gas and a vacuum pump capable of delivering pressures of less than 1 torr are the biggest pieces of equipment needed for this experiment. Several Schlenk flasks and a Schlenk filter are also needed; they are all available from Chemglass and the relevant part numbers are in the Supplemental Material.W Compressed gas cylinders of hydrogen and nitrogen are required; they are readily available from all gas suppliers. All other chemicals can be purchased from Aldrich.
Student handout, detailed notes for the instructors including details on the logistics of scheduling this experiment, list of all of the equipment and chemicals needed for this experiment, and NMR spectra are available in this issue of JCE Online.
Hazards RuCl3 triethylamine, and iodine are corrosive. 1,5-Cyclooctadiene, ethanol, diethyl ether, 2-butanol, triethylamine, methanol, acetone, hydrogen, 3-chloro-3-methyl-1-butyne, and petroleum ether are flammable. 1,5-Cyclooctadiene and triethylamine have bad odors. Ethanol, tricyclohexylphosphine, 2-butanol, dichloromethane, acetone, diethyl diallylmalonate, and silica gel are irritants. 3-Chloro-3-methyl-1-butyne is a lachrymator. Methanol, dichloromethane, petroleum ether, diethyl ether, and iodine are toxic. Standard precautions should be employed when working with compressed gases; cylinders should be chained to a wall or lab bench, and should not be opened without the proper regulator securely attached. While Ru(H)(H2)Cl(PCy3)2 will decompose if accidentally exposed to air, it does not do so in a violent or hazardous manner.
GEG thanks the students at Goucher College who pioneered this experiment: Anne Saunders, Rajan Pragani, Tiffany Lowery, Erin Wright, Jennie Towner, Kristina Hadlich, Matthew Kier, Kevin Kerr, and Kate Sosinsky. Material
Literature Cited 1. Chemistry 2005. http://nobelprize.org/nobel_prizes/chemistry/ laureates/2005 (accessed Sep 2007). 2. Coleman, William F. J. Chem. Educ. 2006, 83, 236. 3. Casey, Charles P. J. Chem. Educ. 2006, 83, 192–195. 4. Rouhi, A. Maureen. Chem. Eng. News 2002, 80 (51), 29–33. 5. Rouhi, A. Maureen. Chem. Eng. News 2002, 80 (51), 34–38. 6. France, Marcia B.; Uffelman, Erich S. J. Chem. Educ. 1999, 76, 661–665. 7. Taber, Douglass F.; Frankowski, Kevin J. J. Chem. Educ. 2006, 83, 283–284. 8. Nicolaou, K. C.; He, Y.; Vourloumis, D.; Vallberg, H.; Roschangar, F.; Sarabia, F., Ninkovic, S.; Yang, Z.; Trujillo, J. I. J. Am. Chem. Soc. 1997, 119, 7960–7973. 9. Meng, Dongfang; Su, Dai-Shi; Balog, Aaron; Bertinato, Peter; Sorensen, Erik J.; Danishefsky, Samuel J.; Zheng, Yu-Huang; Chou, Ting-Chao; He, Lifeng; Horwitz, Susan B. J. Am. Chem. Soc. 1997, 119, 2733–2734. 10. Wilhelm, Thomas E.; Belderrain, Tomás R.; Brown, Seth N.; Grubbs, Robert H. Organometallics 1997, 16, 3867–3869. 11. Albers, M. O.; Ashworth, T. V.; Oosthuizen, H. E.; Singleton, E. Inorg. Synth. 1989, 26, 69.
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