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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Org Lett. Author manuscript; available in PMC Sep 10, 2008.
Published in final edited form as:
PMCID: PMC2533312
NIHMSID: NIHMS62277
Efficient Removal of Ruthenium Byproducts from Olefin Metathesis Products by Simple Aqueous Extraction
Soon Hyeok Hong and Robert H. Grubbs*
The Arnold and Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA 91125
rhg/at/caltech.edu
Abstract
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Object name is nihms62277u1.jpg Object name is nihms62277u1.jpg
Simple aqueous extraction removed ruthenium byproducts efficiently from ring-closing metathesis (RCM) reactions catalyzed by a PEG-supported N-heterocyclic carbene-based ruthenium complex.
Olefin metathesis is a powerful carbon-carbon bond formation reaction in both polymer and small molecule synthesis.1,2 In particular, the recent development of ruthenium olefin metathesis catalysts such as 13 (Figure 1), which show high activity and functional group tolerance, has expanded the scope of this reaction.3 However, it has proved very difficult to remove the highly-colored ruthenium complexes completely from the desired product even after purification by silica gel column chromatography. The residual ruthenium complexes can cause problems such as olefin isomerization,46 decomposition over time,7,8 and increased toxicity of the final product which is critical especially in connection with the synthesis of biologically active materials.9
Figure 1
Figure 1
Ruthenium-based olefin metathesis catalysts.
Several protocols have been reported to remove the ruthenium byproducts. The use of tris(hydroxymethyl)phosphine (THMP),9 Pb(OAc)4,10 DMSO (or Ph3P=O),11 activated carbon,12 supported phosphines,13 supercritical fluid,14 modified catalyst,15 mesoporous silicates,16 and a polar isocyanide (CNCH2CO2K)17 have all been reported to reduce the ruthenium content from homogeneous olefin metathesis reactions. Although these purification methods afford low levels of residual ruthenium, they also have drawbacks, such as high loadings of expensive, toxic, and/or unstable ruthenium scavengers, long processing times, the requirement of silica gel column chromatography, or numerous washings and extractions, which are not practical and economical in many cases.14 Furthermore, most methods do not actually reduce the ruthenium contamination below 10 ppm level, which is necessary for pharmaceutical applications.18,19
Recently, we reported a poly(ethylene glycol) (PEG) supported catalyst 4 (Mn ~ 2639, Mn = number average molecular weight) which is active and stable in aqueous media (Figure 1).20 The unique solubility profile of PEG renders 4 soluble in some organic solvents such as dichloromethane and toluene, which are typical solvents for olefin metathesis, as well as aqueous media. The catalyst is not soluble in other organic solvents such as diethyl ether, isopropyl alcohol, and hexanes, following the solubility profile of PEG. This extraordinary solubility of 4 prompted us to develop a simple aqueous extraction method to remove the ruthenium byproducts after olefin metathesis reactions. The idea is simple – to extract PEG-bound ruthenium complexes with water from diethyl ether solution containing the desired organic products, after performing the olefin metathesis reaction homogeneously in CH2Cl2 or toluene (Scheme 1).
Scheme 1
Scheme 1
Removal of Ruthenium Byproducts by Simple Aqueous Extraction
The activity of catalyst 4 in CH2Cl2 was compared with catalysts 2 and 3 in the RCM reaction of diethyl diallylmalonate (5).21 As shown in Figure 2, the attachment of a PEG chain to the N-heterocyclic carbene (NHC) does not significantly affect the catalyst activity.
Figure 2
Figure 2
RCM of diethyl diallylmalonate (conditions: 1 mol % Ru catalyst, 0.1 M, CD2Cl2, 30 °C).21
The RCM of substrate 5 by catalyst 3 followed by purification using several reported methods was undertaken to collect reference data (Table 1). Silica gel chromatography, which is not practical and efficient on an industrial scale, was avoided in all cases. Simple extraction reduced the ruthenium content by approximately half (entry 1). DMSO treatment, without being followed by silica gel chromatography, is not as effective as THMP and activated carbon treatment.11 THMP9 and activated carbon12 treatment with an aqueous workup effectively reduced the ruthenium level below 100 ppm; however, this ruthenium level is still too high for practical use.
Table 1
Table 1
Ruthenium Level in 6 (ppm) After Purification.
In contrast, simple aqueous extraction reduced the ruthenium level to 41 ppm following RCM with catalyst 4, which is lower than both the THMP and activated carbon treatment from the reaction with 3 (entry 5).22 Clear diethyl ether and brown aqueous phases were observed during the extraction. Employing the aqueous extraction protocol in combination with THMP or activated carbon reduced the ruthenium level below 10 ppm, which is suitable for pharmaceutical applications (entries 6 and 7).14 The activated carbon treatment after aqueous extraction was extremely efficient reducing the ruthenium level below the detection limit of our analysis, <0.04 ppm.
PEGs themselves were next tested for removing residual ruthenium from the RCM by 3. The tested PEGs (Mn ~ 10000 and Mn ~ 550) did not show effective removal of the ruthenium byproducts (entries 8 and 9). These results indicate that the PEG-supported NHC ligand binds to the ruthenium byproducts or scavenges them after olefin metathesis reactions. The NHC-bound decomposition products isolated from catalyst 2 have been reported in both organic solvents and aqueous media.7,23,24
In conclusion, we have demonstrated a convenient and efficient method for removing ruthenium-containing byproduct from olefin metathesis reactions by simple aqueous workup. This practical, economical and environmentally friendly method reduced the ruthenium contamination level down to the useful range for biologically active material applications.
Acknowledgments
We thank Prof. Shane Que Hee at UCLA and Dr. Nathan F. Dalleska at Caltech for ICP-MS analysis. Financial support was provided by the National Institutes of Health (5R01GM068647) and kind gift from Amgen.
1. Ivin KJ, Mol JC. Olefin Metathesis and Metathesis Polymerization. Academic Press; San Diego, CA: 1997.
2. Grubbs RH, editor. Handbook of Metathesis. Wiley-VCH; Weinheim, Germany: 2003. pp. 1–3.
3. Grubbs RH. Tetrahedron. 2004;60:7117–7140.
4. Courchay FC, Sworen JC, Ghiviriga I, Abboud KA, Wagener KB. Organometallics. 2006;25:6074–6086.
5. Hong SH, Sanders DP, Lee CW, Grubbs RH. J Am Chem Soc. 2005;127:17160–17161. [PubMed]
6. Schmidt B. Eur J Org Chem. 2004:1865–1880.
7. Hong SH, Day MW, Grubbs RH. J Am Chem Soc. 2004;126:7414–7415. [PubMed]
8. Ulman M, Grubbs RH. J Org Chem. 1999;64:7202–7207.
9. Maynard HD, Grubbs RH. Tetrahedron Lett. 1999;40:4137–4140.
10. Paquette LA, Schloss JD, Efremov I, Fabris F, Gallou F, Mendez-Andino J, Yang J. Org Lett. 2000;2:1259–1261. [PubMed]
11. Ahn YM, Yang K, Georg GI. Org Lett. 2001;3:1411–1413. [PubMed]
12. Cho JH, Kim BM. Org Lett. 2003;5:531–533. [PubMed]
13. Westhus M, Gonthier E, Brohm D, Breinbauer R. Tetrahedron Lett. 2004;45:3141–3142.
14. Gallou F, Saim S, Koenig KJ, Bochniak D, Horhota ST, Yee NK, Senanayake CH. Org Process Res Dev. 2006;10:937–940.
15. Michrowska A, Gulajski L, Kaczmarska Z, Mennecke K, Kirschning A, Grela K. Green Chemistry. 2006;8:685–688.
16. McEleney K, Allen DP, Holliday AE, Crudden CM. Org Lett. 2006;8:2663–2666. [PubMed]
17. Galan BR, Kalbarczyk KP, Szczepankiewicz S, Keister JB, Diver ST. Org Lett. 2007;9:1203–1206. [PubMed]
18. Welch CJ, Albaneze-Walker J, Leonard WR, Biba M, DaSilva J, Henderson D, Laing B, Mathre DJ, Spencer S, Bu XD, Wang TB. Org Process Res Dev. 2005;9:198–205.
19. Garrett CE, Prasad K. Adv Synth Catal. 2004;346:889–900.
20. Hong SH, Grubbs RH. J Am Chem Soc. 2006;128:3508–3509. [PubMed]
21. Ritter T, Hejl A, Wenzel AG, Funk TW, Grubbs RH. Organometallics. 2006;25:5740–5745.
22. A typical purification procedure is as follows: Crude 3,3-diethylester-pentene (6, 100 mg, 0.472 mmol) in diethyl ether (~30 mL) was transferred to a separatory funnel. The diethyl ether solution was washed 3 or 5 times by water (~30 mL), dried over MgSO4, and concentrated. Approximately 20 ~ 30 mg of the resulting clear oil was accurately weighed by a microbalance and digested with concentrated nitric acid overnight for ICP-MS analysis. For activated carbon purification, the activated carbon (1.3 weight equiv of the crude product 6) was added to the diethyl ether solution after the extraction and stirred for 24 hrs. After the carbon was filtered, the filtrate was concentrated in vacuo to provide 6 as clear oil. THMP and DMSO methods were carried out following the literature procedure except avoiding silica gel treatment or column chromatography.
23. Dinger MB, Mol JC. Eur J Inorg Chem. 2003:2827–2833.
24. Trnka TM, Morgan JP, Sanford MS, Wilhelm TE, Scholl M, Choi TL, Ding S, Day MW, Grubbs RH. J Am Chem Soc. 2003;125:2546–2558. [PubMed]