Heterogeneous Removal of Water-Soluble Ruthenium Olefin Metathesis Catalyst from Aqueous Media Via Host-Guest Interaction

Summary

A removable water-soluble N-heterocyclic carbene (NHC) ligand in aqueous media via host-guest interaction has been developed. We demonstrated representative olefin metathesis reactions in water as well as in dichloromethane. Via either host-guest interaction or extraction, the residual ruthenium (Ru) catalyst was as low as 0.14 ppm after the reaction.

Abstract

A highly efficient transition metal catalyst removal method is developed. The water-soluble catalyst contains a newly-designed NHC ligand for the catalyst removal via host-guest interactions. The new NHC ligand possesses an adamantyl (guest) tethered linear ethylene glycol units for hydrophobic inclusion into the cavity of a β-cyclodextrin (β-CD) host compound. The new NHC ligand was applied to a Ru-based olefin metathesis catalyst. The Ru catalyst demonstrated excellent activity in representative ring-closing metathesis (RCM) and ring-opening metathesis polymerization (ROMP) reactions in aqueous media as well as organic solvent, CH₂Cl₂. After the reaction was complete, the lingering Ru residue was removed from the aqueous solution with the efficiency of more than 99% (53 ppm of Ru residue) by simple filtration utilizing a host-guest interaction between insoluble silica-grafted β-CD (host) and the adamantyl moiety (guest) on the catalyst. The new Ru catalyst also demonstrated high removal efficiency via extraction when the reaction is run in organic solvent by partitioning the crude reaction mixture between layers of diethyl ether and water. In this way, the catalyst stays in aqueous layer only. In organic layer, the residual Ru amount was only 0.14 ppm in the RCM reactions of diallyl compounds.

Introduction

The removal of the homogeneous organometallic catalysis from the product is an important issue in modern chemistry^1,2. Residual catalyst causes not only a toxicity problem from its heavy metal element, but also an undesired transformation of product from its potential reactivity. Homogeneous catalyst provides many advantages, such as high activity, rapid reaction rate, and chemoselectivity³, however, its removal from the product is much more difficult than heterogeneous catalyst which is simply removed by filtration or decantation. The combination of the advantages of homogeneous and heterogeneous catalyst, i.e., homogeneous reaction and heterogeneous removal, represents important concept for highly reactive and easily removable organometallic catalyst. Figure 1 illustrated the working principle for homogeneous reaction and heterogeneous removal of the catalyst via host-guest interaction.

Host-guest chemistry is noncovalent bonding molecular recognition between host molecules and guest molecules in supramolecular chemistry^4,5,6,7,8. Cyclodextrins (CDs), cyclic oligosaccharides, are representative host molecules^9,10,11,12, and they have been applied in broad fields of science such as, polymer science^13,14, catalysis^15,16, biomedical applications^6,10, and analytical chemistry¹⁷. A guest molecule, adamatane, binds strongly to the hydrophobic cavity of β-CD (host, 7-membered cyclic saccharide) with high association constant, K_a (log K_a = 5.04)¹⁸. This supramolecular binding affinity is strong enough to remove residual catalyst complex from the aqueous reaction solution with solid supported β-CD.

Among many catalysts that are eligible for the host-guest removal, Ru olefin metathesis catalyst was studied due to high practical utilities and high stability against air and moisture. The olefin metathesis reaction is an important tool in synthetic chemistry to form a carbon-carbon double bond in the presence of a transition metal catalyst^19,20,21,22. The development of stable Ru olefin metathesis catalyst trigged the metathesis as a major field in synthetic chemistry (e.g., RCM and cross metathesis (CM)) as well as polymer science (e.g., ROMP and acyclic diene metathesis (ADMET)). In particular, the RCM synthesizes macrocycles and medium-sized rings that have been hard to construct²³.

In spite of synthetic utilities of Ru catalyzed olefin metathesis, complete removal of used Ru catalyst from the desired product is a major challenge for many practical applications²⁴. For example, 1912 ppm of Ru residue was observed in ring-closing metathesis product after silica gel column chromatography²⁵. Residual Ru may cause problems such as olefin isomerization, decomposition, colorization, and toxicity of pharmaceutical products²⁶. International Conference on Harmonization (ICH) published a guideline of residual metal reagents in pharmaceuticals. The maximum allowed Ru level in pharmaceutical product is 10 ppm²⁷. For these reasons, various approaches were tried to remove Ru residue from the product solution^{28,29,30,31,32,33}. Also, the developments of removable Ru catalysts have been studied for purification without any special treatment after the reaction. Among various purification methods, catalyst ligand modifications were tried to improve efficiency of silica gel filtration and liquid extraction. For example, highly efficient silica gel filtration can be achieved by introduced ion tag on benzylidene³⁴ or backbone of NHC ligand^35,36. The catalyst bearing poly(ethylene glycol)³⁷ or ion tag³⁵ on a NHC ligand can improve the efficiency of aqueous extraction for Ru catalyst removal.

Recently, we reported a highly water soluble Ru olefin metathesis catalyst, which demonstrated not only high reactivity, but also high catalyst removal rate. Moreover, the metathesis and catalyst removal occurred in both water and dichloromethane^34,35,36,37. The key feature of new catalyst is that the new NHC bears adamantyl tethered oligo(ethylene glycol). Oligo(ethylene glycol) provides high water solubility of the entire catalyst complex. In addition, the oligo(ethylene glycol) possesses adamantyl end group that can be used in host-guest interaction with external β-CD.

Herein, we described the protocols for catalyst synthesis, metathesis reactions, and catalyst removal in both water and dichloromethane.

Protocol

Note: We presented the synthesis of 4-(97-(adamantan-1-yloxy)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95-dotriacontaoxaheptanonacontyl)-1,3-dimesityl-4,5-dihydro-1H-imidazol-3-ium tetrafluoroborate (imidazolium salt A) and host complex, β-CD grafted silica, in our previous paper³⁸. In the protocol, we describe a synthesis of our water-soluble Ru olefin metathesis catalyst and metathesis reactions (RCM and ROMP).

1. Synthesis of (4-(97-((adamantan-1-yl)oxy)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71,74,77,80,83,86,89,92,95-dotriacontaoxaheptanonacontyl)-1,3-dimesitylimidazolidinylidene)dichloro( o -isopropoxyphenylmethylene)ruthenium (Catalyst 1)

1. Dry a 25 mL round-bottomed flask with a stirring bar, a 20 mL vial, and a spatula in oven.
2. Put 118 mg of imidazolium salt A (0.060 mmol) in a 4 mL vial.
3. Place the prepared imidazolium salt A in dried glassware, a septum and the spatula in a glove box chamber and vacuum for 2 h.
4. After completely removing the air in glove box chamber, purge the inert gas into the chamber, then move them into the glove box.
5. In the glove box, put 54 mg of Hoveyda-Grubbs (H-G) 1^st generation (0.090 mmol, 1.5 equiv.) in a 20 mL vial.
6. Dissolve the prepared imidazolium salt in 2.0 mL of toluene, then transfer it into the 50 mL round-bottomed flask with the stirring bar.
7. Add 0.18 mL of potassium bis(trimethylsilyl)amide (KHMDS) solution (0.5 M toluene solution, 0.090 mmol, 1.5 equiv.) into the imidazolium salt solution.
8. Swirl the flask to mix the reagents.
9. Dissolve the H-G 1^st generation in 3.0 mL of toluene, then add this solution into the reaction flask.
10. Seal the flask with septum, then remove this from the glove box.
11. Stir the reaction mixture for 3 h at 80 °C.
12. After 3 h, purify the catalyst by chromatography on neutral alumina, eluted with EtOAc/MeOH = 15/1. Collect the dark green solution.
    Note: Evaporation of the solvent is not required before chromatography. R_f value is 0.46 on neutral alumina, eluted with EtOAc/MeOH = 15/1.
13. Remove the solvent under reduced pressure.
14. Vacuum the final residue to obtain dark green waxy solid.

2. Metathesis Reaction and Removal of Catalyst Residue in Aqueous Media

1. Prepare degassed deuterium oxide (D₂O) or deionized water by bubbling D₂O or deionized water with nitrogen gas over 2 h.
2. Put 4.4 mg of the catalyst 1 (0.0020 mmol) and 41 mg of 2-allyl-N,N,N-trimethylpent-4-en-1-aminium chloride (tetraalkyl ammonium substrate) (0.20 mmol) in each 4.0 mL vial.
3. Dissolve the tetraalkyl ammonium substrate in 0.5 mL of degassed D₂O (or H₂O), then add the solution into catalyst 1.
4. Seal the reaction vial, then heat the reaction mixture for 24 h at 45 °C. Monitor the reaction conversion by ¹H NMR.
   NOTE: Monitor the ¹H NMR peak conversion from 3.25 ppm (doublet, -NCH₂CH- in substrate) to 3.52 ppm (doublet, -NCH₂CH- in product).
5. After the completion of the reaction, cool down the reaction vial at room temperature.
6. Add 150 mg of β-CD grafted silica into the reaction mixture.
   Note: Grafted β-CD unit onto the silica gel was calculated in 1.57 10^-4 mmol/mg by thermogravimetric analysis (TGA).
7. Stir the reaction mixture for 10 h at room temperature.
8. Filter the reaction mixture through cotton plug.
9. Remove the solvent in a freeze dryer.

3. Ring-opening Metathesis Polymerization and Removal of Catalyst Residue in Aqueous Media

1. Prepare degassed D₂O or deionized water by bubbling D₂O or deionized water with nitrogen gas over 2 h.
2. Put 4.4 mg of the catalyst 1 (0.0020 mmol) and 17.1 mg of 2-((3aR^*,4S^*,7R^*,7aS^*)-1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl)-N,N,N-trimethylethan-1-aminium chloride (monomer, Figure 5) (0.060 mmol) in each 4.0 mL vial.
3. Dissolve the monomer in 0.5 mL of degassed D₂O (or H₂O), then add the solution into catalyst 1.
4. Seal the reaction vial, then heat the reaction mixture for 2 h at 45 °C. Monitor the reaction conversion by ¹H NMR.
   NOTE: Monitor the ¹H NMR peak disappearance at 6.14 ppm (-CH=CH- in monomer).
5. After the completion of the reaction, cool down the reaction vial at room temperature.
6. Quench the reaction with 0.1 mL of ethyl vinyl ether.
   Note: Quenching is necessary to dissociate Ru catalyst from polymer chain terminal.
7. Add 150 mg of β-CD grafted silica into the reaction mixture.
8. Stir the reaction mixture for 10 h at room temperature.
9. Filter the reaction mixture through cotton plug.
10. Remove the solvent in a freeze dryer.

4. Metathesis Reaction and Removal of Catalyst Residue from CH₂Cl₂

1. Put 4.4 mg of the catalyst 1 (0.0020 mmol) and 48 mg of diethyl diallylmalonate (0.20 mmol) in each 4.0 mL vial.
2. Dissolve the diethyl diallylmalonate in 0.5 mL of CH₂Cl₂, then add the solution into catalyst 1.
3. Seal the reaction vial, then keep the reaction mixture at room temperature for 1 h. Monitor the reaction conversion by ¹H NMR.
   Note: Monitor the ¹H NMR peak conversion from 2.63 ppm (doublet, -CCH₂CH=CH₂ in substrate) to 3.01 ppm (singlet, -CCH₂CH=CHCH₂C- in product).
4. After the completion of the reaction, transfer the resulting reaction mixture into a 30 mL vial.
5. Dilute the reaction solution with 15 mL of diethyl ether.
6. Wash the organic solution with 15 mL of water for five times.
7. Dry the organic layer with MgSO₄, then filter the solution through cotton plug to remove MgSO₄ particles.
8. Add 60 mg of activated carbon into the resulting solution, then stir the mixture for 24 h at room temperature.
9. Filter the solution through cotton plug to remove activated carbon, then remove the solvent under reduced pressure.

Results

Figure 2 describes the ligand exchange reaction for our catalyst 1. The ¹H NMR spectrum is shown in Figure 3.

Figure 4 shows the RCM in aqueous solution and subsequent removal of used catalyst from the reaction mixture via host-guest interaction, and Table 1 summarizes RCM in aqueous me...

Discussion

We described the synthesis of removable homogeneous Ru olefin metathesis catalyst and its removal from both aqueous and organic solutions. Homogeneous catalysis provides many benefits compared to heterogeneous catalysts, such as high reactivity and rapid reaction rate; however, the removal of the used catalyst from the product is more difficult than heterogeneous catalyst³. The key feature of synthesized catalyst is the NHC ligand, which bears adamantyl tethered water soluble oligo(ethylene glycol...

Materials

Name	Company	Catalog Number	Comments
Hoveyda-Grubbs Catalyst 1st Generation	Sigma-Aldrich	577944	Air sensitivie. Light sensitivie.
Diethyl diallylmalonate	Sigma-Aldrich	283479
Ethyl vinyl ether	Sigma-Aldrich	422177	Air sensitive.
Aluminum oxide	Sigma-Aldrich	06300	Activated, neutral, Brockmann Activity I
Potassium bis(trimethylsilyl)amide solution (0.5 M in toluene)	Sigma-Aldrich	277304	Moisture sensitive.
Etyhl acetate	VWR	BDH1123	Flammable liquid.
Methanol	VWR	BDH1135	Flammable liquid. Toxic.
Deuterium Oxide 99.8%D	TCI	W0002
Methylene Chloride-D2 (D, 99.8%)	Cambridge Isotope Laboratories, Inc.	DLM-23	Flammable liquid. Toxic.
Activated carbon	Sigma-Aldrich	242276
Magnesium sulfate	EMD Millipore	MX0075
Ethyl ether	EMD Millipore	EX0190	Flammable liquid.