Letter Cite This: Org. Lett. 2018, 20, 736−739
pubs.acs.org/OrgLett
Removable Water-Soluble Olefin Metathesis Catalyst via Host−Guest Interaction Cheoljae Kim, Brian A. Ondrusek, and Hoyong Chung* Department of Chemical and Biomedical Engineering, Florida State University, 2525 Pottsdamer Street, Building A, Suite A131, Tallahassee, Florida 32310, United States S Supporting Information *
ABSTRACT: A highly removable N-heterocyclic carbene ligand for a transition-metal catalyst in aqueous media via host−guest interactions has been developed. Water-soluble adamantyl tethered ethylene glycol in the ligand leads a hydrophobic inclusion into the cavity of β-cyclodextrin. Ruthenium (Ru) olefin metathesis catalyst with this ligand demonstrated excellent performance in various metathesis reactions in water as well as in CH2Cl2, and removal of residual Ru was performed via filtration utilizing a host−guest interaction and extraction.
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catalysis,11 biomedical applications,8b,9c analytical chemistry,12 and many other areas due to its advantages in noncovalent interaction, reversibility, bio and environmental compatibility, and stimuli response. Adamantane (guest) and β-CD (host, 7membered cyclic polysaccharide) is known to demonstrate very high association constant, Ka (log Ka = 5.04)13 which will enable very efficient catalyst removal on a stationary solid according to the principle illustrated in Figure 1. Among many possible catalyst designs that can be used to introduce our principle of host−guest catalyst removal, Ru-based olefin metathesis catalysts are suitable catalyst systems due to their practical utility in wide areas and high stability of the resulting precatalysts toward air and moisture. Olefin metathesis itself represents a ubiquitous chemical transformation for the formation of carbon−carbon double bonds in the presence of a transition-metal catalyst.14,15 In particular, Ru-based olefin metathesis catalysts have garnered a strong following mainly due to the low oxophilicity of Ru and their tolerance toward polar functional groups, impurities, and solvents, including water. The most frequently used Ru-based olefin metathesis catalyst is the Hoveyda−Grubbs second-generation catalyst, which possesses metal alkylidene and N-heterocyclic carbene (NHC) ligands.15,16 In spite of the importance of Ru-based olefin metathesis catalysts, the complete removal of Ru residue from the resulting products still represents a major challenge for their practical application because the metal residue causes undesirable electronic properties, colorization, and toxicity of pharmaceutical products.4 Specifically, the maximum amount of Ru permissible in pharmaceutical products is less than 10 ppm.17,18 Herein, we
omplete removal of homogeneous organometallic catalysts is an important issue in modern chemistry.1−3 There are two major removal methods of well-defined organometallic catalysts: (1) solid-supported heterogeneous systems and (2) homogeneous methods utilizing modified catalyst ligands.4 Homogeneous catalysts typically display many advantages over heterogeneous catalysts such as rapid reaction rate, facile characterization, higher reactivity, and chemoselectivity.5 In spite of those general advantages, the homogeneous catalyst cannot be easily removed by the simple methods available for heterogeneous catalysts, such as filtration or decantation. Thus, the combination of the homogeneous reactivity and heterogeneous removal represent ideal design principles for highly reactive and removable organometallic catalysts as depicted in Figure 1. In addition, catalysts bearing thermomorphic character-
Figure 1. Working principle for heterogeneous catalyst removal of a homogeneous catalyst via host−guest interaction.
istics are well-established for their ability to be separated from reaction solution. This can be achieved by utilizing a fluorous biphasic system, thermoregulated phase-transfer catalyst, or soluble polymer-based catalyst.6 Host−guest chemistry is a widely studied topic in supramolecular chemistry describing noncovalent molecular recognition events between host molecules and guest molecules.7−9 Host−guest chemistry, in particular using cyclodextrin (CD) hosts, has been extensively studied in polymer science,10 © 2018 American Chemical Society
Received: December 12, 2017 Published: January 19, 2018 736
DOI: 10.1021/acs.orglett.7b03871 Org. Lett. 2018, 20, 736−739
Letter
Organic Letters
fluoroborate yielded imidazolium salt 8. In situ generation of the carbene of 8 with potassium bis(trimethylsilyl)amide, followed by the addition of Hoveyda−Grubbs first-generation catalyst 9, generated the desired precatalyst 3. Figure 3 describes a Ru-catalyzed metathesis and catalyst removal in aqueous media via host−guest interactions. After
report a new NHC ligand and the resulting Ru-based olefin metathesis catalyst designed for the removal of Ru catalyst residues via host−guest interactions and phase selective solubilities of the new catalyst. One defining trait of the designed catalyst is its complete solubility in water, allowing for high performance in both aqueous and organic conditions. To the best of our knowledge, the present report is the first example of an almost complete removal of Ru-based olefin metathesis catalyst in aqueous media after olefin metathesis and ring-opening metathesis polymerization (ROMP). Figure 2 displays three catalyst structures that utilize host− guest interactions for the removal of organometallic catalysts.
Figure 3. Illustration of a typical olefin metathesis and host−guest removal process in aqueous media.
Figure 2. Examples of catalysts which engage in host−guest interactions with β-cyclodextrin, including our catalyst 3.
completion of the homogeneous metathesis reaction in water, as soon as a host compound was added to the reaction mixture, the heterogeneous host−guest complex was generated spontaneously between β-CD grafted silica and the adamantyl moiety on the catalyst. Finally, the resulting heterogeneous solution was filtered through a cotton plug to isolate the host−guest complex containing the catalyst. The efficiency of removal was analyzed by inductively coupled plasma mass spectrometry (ICP-MS) of the filtered product. Herein, β-CD grafted silica was prepared separately prior to the host−guest removal process by previously reported methods.20 With the water-soluble catalyst 3, we explored a scope of ringclosing metathesis (RCM) reactions of commonly used substrates in aqueous media (Table 1). Overall, 3 demonstrated high-efficiency on par with previously reported water-soluble Rubased olefin metathesis catalysts.21,22 Residual Ru levels were measured by ICP-MS with fully converted examples. In entry 1, quaternary ammonium salt 10 was fully converted into 17 with only 53 ppm of residual Ru (calculated Ru level in the crude product without any purification ∼5600 ppm). In order to examine the affinity of catalyst 3 to unmodified silica without βCD, the product treated with unmodified silica showed significant 1H NMR signals corresponding to the ethylene glycol moiety of the NHC ligand. This result implies that the removal of Ru from solution occurs effectively via host−guest interactions. In addition, the Grubbs first-generation catalyst demonstrated 1912 ppm residual Ru after careful silica gel column chromatography in CH2Cl2 according to previous studies.17,23 RCM of primary ammonium salt 12 showed 90% conversion with 1 mol % catalyst after 48 h. Then 3 mol % catalyst loading yielded full conversion (entry 2). The residual Ru level in this
Catalyst 1 contains an adamantyl tether for the recovery of Pd catalyst following Suzuki−Miyaura coupling.19 Catalyst 2 is the first example from our group of showing high removal of Rubased olefin metathesis catalyst in organic solvent using host− guest interactions.20 The present work is concerned with catalyst 3, which is highly reactive in aqueous solution with excellent removal rates of catalysts (0.14 ppm Ru residue in CH2Cl2 and 53 ppm in water). In order to prepare water-soluble catalyst 3, we began with readily available tetraethylene glycol (Scheme 1). Tetraethylene glycol was converted into the adamantyl-tethered extended ethylene glycol 4 via multiple iterative steps (see the Supporting Information (SI) for details). The number of ethylene glycol repeating units was increased sequentially through iterative substitution reactions between tosylated ethylene glycol and alcohols of another ethylene glycol compound. We were concerned that a large number of oxygens from extended ethylene glycols would increase the likelihood of coordination to the central metal, thereby decreasing the catalytic activity. To avoid this deactivation, we sought to find the minimum length of ethylene glycol units to satisfy water solubility of the catalyst with 8, 16, 24, and 32 repeating units. Finally, 32 repeating units were determined to be the minimal number. The 32 ethylene glycol repeating unit containing methanesulfonate 5 was generated from compound 4 with methanesulfonyl chloride and triethylamine. Diamine compound 7 was synthesized using a substitution reaction between compound 5 and N,N′-dimesityl-2,3-diamino-1-propanol 6. The reaction of the resulting diamine 7 with triethyl orthoformate and ammonium tetraScheme 1. Preparation of Catalyst 3
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DOI: 10.1021/acs.orglett.7b03871 Org. Lett. 2018, 20, 736−739
Letter
Organic Letters Table 1. RCM in Aqueous Media and Catalyst Removal via Host−Guest Interactiona
Scheme 2. ROMP in Aqueous Media with Use of Catalyst 3
water, and polymer 22 was obtained in quantitative yield. For the removal of Ru catalyst with using the developed host−guest interaction, we quenched the reaction with 0.1 mL of ethyl vinyl ether. After removal of Ru catalyst by host−guest interaction from polymer 22, the final Ru content was 269 ppm which represents a 97.7% removal of Ru from solution (calculated Ru level in crude polymer product ∼11500 ppm). In addition, because the catalyst 3 is also homogeneously soluble in organic solvents, we studied the scope of several olefin metathesis substrates in CH2Cl2 (Table 3).24 The evaluated Table 3. RCM in CH2Cl2 Solvent and Catalyst Removal via Phase Selectivitya
Reactions were carried out at 45 °C in D2O for 24 h. Conversions were determined by 1H NMR spectroscopy. bAnalyzed by ICP-MS. Fully converted products 11 and 13 were characterized to measure the residual ruthenium levels. cIsolated yield. dReactions were carried out for 48 h. a
case was 284 ppm, which means that 98.7% of the total Ru was removed by the host−guest interaction (theoretical Ru level in crude product ∼22000 ppm). Presumably, the reason is that while the nitrogen of the tetraalkyl ammonium salt was highly shielded having no association to Ru metal due to alkyls, nitrogen of the primary ammonium may coordinate to the metal center after ionization in water. RCM of hydrochloric acid salts (14, 16) were tested (entries 3 and 4). Although they were moderately active compared to carbocyclic substrates, the six-membered Nheterocycle 15 was more favorably formed by RCM than fivemembered product 17 due to the low reactivity of catalyst as a result of the formation of Ru hydride decomposition products according to previous literature reports.21,22b Isomerization and cross-metathesis (CM) of two different olefins were successfully performed in aqueous media with catalyst 3 as shown in Table 2. The first substrate cis-2-buteneTable 2. Isomerization and Cross-Metathesis Reactions in Aqueous Mediaa Reactions were carried out at 40 °C with 1 mol % of catalyst 3 in CH2Cl2 for 1 h. Conversions were determined by 1H NMR spectroscopy. The detailed catalyst removal procedure is described in the SI. bAnalyzed by ICP-MS. cReactions were carried out at room temperature. dIsolated yield. eThe diluted crude product was washed with water 5 times. fThe extracted crude product was filtered through a silica plugged column. a
a
Reactions were carried out at room temperature with 5 mol % of catalyst 3 in D2O for 24 h. Conversions were determined by 1H NMR spectroscopy. b6% of cis isomer remains due to thermodynamic equilibrium. cE/Z ∼ 8.5:1.
olefins 23, 25, 29, 31, and 33 demonstrated full conversion under the optimized conditions, 1 mol % of 3 at 40 °C for 1 h. Unsubstituted cyclopentenes (24, 30) were obtained at room temperature. Hindered olefin substrate 27 showed very low conversion due to steric congestion. The results in Table 3 suggest that the new catalyst 3 can be universally used in both aqueous media and organic solvent with high catalytic efficiency over a broad range of olefin substrates. The catalyst 3 is easily soluble in water as well as in common organic solvents for olefin metathesis such as CH2Cl2 and toluene. However, 3 is not soluble in diethyl ether due to the presence of ethylene glycol
1,4-diol 18 was converted to its corresponding trans isomer 19 in 94%, while the remaining 6% resulting from thermodynamic E/Z equilibrium (Table 2, entry 1). A cross-metathesis reaction of allyl alcohol 20 yielded 94% of the desired metathesis product with 8.5:1 E/Z ratio (Table 2, entry 2). As shown in Scheme 2, the catalyst 3 was also utilized to perform ROMP of water-soluble norbornene monomer 21 in 738
DOI: 10.1021/acs.orglett.7b03871 Org. Lett. 2018, 20, 736−739
Letter
Organic Letters segment.24c By leveraging this observed phase-selective solubility of catalyst 3, the catalyst was extracted into the aqueous phase from the diethyl ether layer (see SI for detailed removal procedure). This phase-selective method yielded excellent removal efficiency, displaying 0.14−5.9 ppm of Ru residues according to ICP-MS results. Although phase-selective removal is not the key motivation of the present work, this removal method presents an alternative option for catalyst removal when organic solvents are preferred. We have developed a highly removable NHC ligand which relies upon host−guest interactions in aqueous media. The described NHC-containing Ru-based olefin metathesis catalyst demonstrated excellent catalytic efficiency for RCM, CM, and ROMP in both aqueous and organic solvents. After reaction, the Ru catalyst was successfully removed (53 ppm Ru residue 99.1% removalfrom RCM in water via host−guest interaction, 269 ppm Ru residue97.7% removalfrom ROMP in water via host−guest interaction, 0.14 ppm from RCM in CH2Cl2 via extraction). The new NHC ligand possessing ethylene glycol segment-tethered adamantyl moieties demonstrates a crucial role for high-yield catalyst removal via host−guest interactions and catalyst reactivity. The described NHC ligand and resulting catalyst demonstrates potential for application in many areas of organic synthesis, materials science, and green chemistry, not just those related to olefin metathesis. Further detailed studies of host−guest interactions of NHCs and organometallic catalysts are underway in our group.
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(b) Szczepaniak, G.; Kosinski, K.; Grela, K. Green Chem. 2014, 16, 4474. (c) Suriboot, J.; Bazzi, H.; Bergbreiter, D. Polymers 2016, 8, 140. (4) Skowerski, K.; Gułajski, Ł. In Olefin Metathesis: Theory and Practice; John Wiley & Sons, Inc.: Hoboken, 2014; pp 559−571. (5) Hartwig, J. F. In Organotransition Metal Chemistry: From Bonding to Catalysis; University Science Books: Sausalito, 2010; Chapter 14, pp 539−573. (6) For selected reviews of thermomorphic catalyst, see: (a) Behr, A.; Henze, G.; Schomäcker, R. Adv. Synth. Catal. 2006, 348, 1485−1495. (b) Bergbreiter, D. E. In Recoverable and Recyclable Catalysts; John Wiley & Sons, Ltd.: Chichester, 2009; pp 117−153. (7) Lehn, J.-M. Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 4763. (8) For recent reviews of host−guest chemistry, see: (a) Chen, G.; Jiang, M. Chem. Soc. Rev. 2011, 40, 2254. (b) Ma, X.; Zhao, Y. Chem. Rev. 2015, 115, 7794. (c) Shetty, D.; Khedkar, J. K.; Park, K. M.; Kim, K. Chem. Soc. Rev. 2015, 44, 8747. (d) Schmidt, B. V. K. J.; BarnerKowollik, C. Angew. Chem., Int. Ed. 2017, 56, 8350. (9) For selected reviews of cyclodextrins, see: (a) Szejtli, J. Chem. Rev. 1998, 98, 1743. (b) Khan, A. R.; Forgo, P.; Stine, K. J.; D’Souza, V. T. Chem. Rev. 1998, 98, 1977. (c) Li, J.; Loh, X. J. Adv. Drug Delivery Rev. 2008, 60, 1000. (d) Crini, G. Chem. Rev. 2014, 114, 10940. (10) (a) Zhang, Z.-X.; Liu, K. L.; Li, J. Angew. Chem., Int. Ed. 2013, 52, 6180. (b) Harada, A.; Takashima, Y.; Nakahata, M. Acc. Chem. Res. 2014, 47, 2128. (11) (a) Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Adv. Catal. 2011, 54, 63. (b) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Chem. Soc. Rev. 2014, 43, 1660. (12) Szente, L.; Szemán, J. Anal. Chem. 2013, 85, 8024. (13) Rekharsky, M. V.; Inoue, Y. Chem. Rev. 1998, 98, 1875. (14) Astruc, D. In Olefin Metathesis: Theory and Practice; John Wiley & Sons, Inc.: Hoboken, 2014; pp 1−36. (15) For selected reviews, see: (a) Samojłowicz, C.; Bieniek, M.; Grela, K. Chem. Rev. 2009, 109, 3708. (b) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746. (c) Herbert, M. B.; Grubbs, R. H. Angew. Chem., Int. Ed. 2015, 54, 5018. (16) Nelson, D. J.; Manzini, S.; Urbina-Blanco, C. A.; Nolan, S. P. Chem. Commun. 2014, 50, 10355. (17) Clavier, H.; Grela, K.; Kirschning, A.; Mauduit, M.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 6786. (18) Committee for medicinal products for human use (CHMP). Guidelines on the specification limits for residues of metal catalysts or metal reagents; Doc. Ref. EMEA/CHMP/SWP/4446/2000; European Medicines Agency: London, Feb 2008; pp 1−34. (19) Qi, M.; Chew, B. K. J.; Yee, K. G.; Zhang, Z.-X.; Young, D. J.; Hor, T. S. A. RSC Adv. 2016, 6, 23686. (20) Ondrusek, B. A.; Chung, H. ACS Omega 2017, 2, 3951. (21) Tomasek, J.; Schatz, J. Green Chem. 2013, 15, 2317. (22) For selected examples of olefin metathesis in aqueous media, see: (a) Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics 1996, 15, 4317−4325. (b) Gallivan, J. P.; Jordan, J. P.; Grubbs, R. H. Tetrahedron Lett. 2005, 46, 2577−2580. (c) Hong, S. H.; Grubbs, R. H. J. Am. Chem. Soc. 2006, 128, 3508. (d) Skowerski, K.; Szczepaniak, G.; Wierzbicka, C.; Gulajski, L.; Bieniek, M.; Grela, K. Catal. Sci. Technol. 2012, 2, 2424. (e) Skowerski, K.; Wierzbicka, C.; Szczepaniak, G.; Gulajski, L.; Bieniek, M.; Grela, K. Green Chem. 2012, 14, 3264. (23) Cho, J. H.; Kim, B. M. Org. Lett. 2003, 5, 531. (24) For selected examples of recoverable olefin metathesis catalyst in organic solvent, see: (a) Kingsbury, J. S.; Garber, S. B.; Giftos, J. M.; Gray, B. L.; Okamoto, M. M.; Farrer, R. A.; Fourkas, J. T.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2001, 40, 4251. (b) Michrowska, A.; Gulajski, L.; Kaczmarska, Z.; Mennecke, K.; Kirschning, A.; Grela, K. Green Chem. 2006, 8, 685. (c) Hong, S. H.; Grubbs, R. H. Org. Lett. 2007, 9, 1955. (d) Allen, D. P.; Van Wingerden, M. M.; Grubbs, R. H. Org. Lett. 2009, 11, 1261. (e) Al-Hashimi, M.; Hongfa, C.; George, B.; Bazzi, H. S.; Bergbreiter, D. E. J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 3954. (f) Kosnik, W.; Grela, K. Dalton Trans. 2013, 42, 7463.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03871. Experimental procedures, characterization data, and 1H, 13 C NMR spectra for catalysts and new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Cheoljae Kim: 0000-0002-4771-8656 Hoyong Chung: 0000-0003-0370-230X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the Florida State University Energy and Materials Hiring initiative and the FSU Department of Chemical and Biomedical Engineering. We acknowledge Dr. Banghao Chen for support of the NMR facilities and Dr. Umesh Goli for the mass spectroscopy at Florida State University. We also thank Evandro Barbosa da Silva at University of Florida for the ICP-MS analysis.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03871 Org. Lett. 2018, 20, 736−739
