This work was supported by the Florida State University Energy and Materials Hiring initiative and the FSU Department of Chemical and Biomedical Engineering.

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, &#946;-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. Sy...

<ol>
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The authors declare no competing financial interest.

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...

The removal of the homogeneous organometallic catalysis from the product is an important issue in modern chemistry1,2. 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 chemistry4,5,6,7,8. Cyclodextrins (CDs), cyclic oligosaccharides, are representative host molecules9,10,11,12, and they have been applied in broad fields of science such as, polymer science13,14, catalysis15,16, biomedical applications6,10, and analytical chemistry17. A guest molecule, adamatane, binds strongly to the hydrophobic cavity of &#946;-CD (host, 7-membered cyclic saccharide) with high association constant, Ka (log Ka = 5.04)18. This supramolecular binding affinity is strong enough to remove residual catalyst complex from the aqueous reaction solution with solid supported &#946;-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 catalyst19,20,21,22. 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 solution28,29,30,31,32,33. 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 ligand35,36. 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 dichloromethane34,35,36,37. 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 &#946;-CD.
Herein, we described the protocols for catalyst synthesis, metathesis reactions, and catalyst removal in both water and dichloromethane.

<table border="0" cellpadding="0" cellspacing="0" style="width:767px;" width="767">
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Hoveyda-Grubbs Catalyst 1st Generation</td>
			<td style="width:160px;">Sigma-Aldrich</td>
			<td style="width:157px;">577944</td>
			<td style="width:167px;">Air sensitivie. Light sensitivie.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Diethyl diallylmalonate</td>
			<td style="width:160px;">Sigma-Aldrich</td>
			<td style="width:157px;">283479</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Ethyl vinyl ether</td>
			<td style="width:160px;">Sigma-Aldrich</td>
			<td style="width:157px;">422177</td>
			<td>Air sensitive.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Aluminum oxide</td>
			<td style="width:160px;">Sigma-Aldrich</td>
			<td style="width:157px;">06300</td>
			<td>Activated, neutral, Brockmann Activity I</td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:283px;">Potassium bis(trimethylsilyl)amide solution (0.5 M in toluene)</td>
			<td style="width:160px;">Sigma-Aldrich</td>
			<td style="width:157px;">277304</td>
			<td>Moisture sensitive.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Etyhl acetate</td>
			<td style="width:160px;">VWR</td>
			<td style="width:157px;">BDH1123</td>
			<td>Flammable liquid.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Methanol</td>
			<td style="width:160px;">VWR</td>
			<td style="width:157px;">BDH1135</td>
			<td>Flammable liquid. Toxic.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Deuterium Oxide 99.8%D</td>
			<td style="width:160px;">TCI</td>
			<td style="width:157px;">W0002</td>
			<td></td>
		</tr>
		<tr height="42">
			<td height="42" style="height:42px;width:283px;">Methylene Chloride-D2 (D, 99.8%)</td>
			<td style="width:160px;">Cambridge Isotope Laboratories, Inc.</td>
			<td style="width:157px;">DLM-23</td>
			<td>Flammable liquid. Toxic.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Activated carbon</td>
			<td style="width:160px;">Sigma-Aldrich</td>
			<td style="width:157px;">242276</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Magnesium sulfate</td>
			<td style="width:160px;">EMD Millipore</td>
			<td style="width:157px;">MX0075</td>
			<td></td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:283px;">Ethyl ether</td>
			<td style="width:160px;">EMD Millipore</td>
			<td style="width:157px;">EX0190</td>
			<td>Flammable liquid.</td>
		</tr>
	</tbody>
</table>

heterogeneous removal of water-soluble ruthenium olefin metathesis catalyst from aqueous media via host-guest interaction

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 &#946;-cyclodextrin (&#946;-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 &#946;-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.

Figure 2&#160;describes the ligand exchange reaction for our catalyst 1. The 1H NMR spectrum is shown in Figure 3.
Figure 4&#160;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...

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

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.

A highly efficient transition metal catalyst removal method is developed. The water-soluble catalyst contains a newly-designed NHC ligand for the catalyst ...

This method can help answer key questions in the practical application of transition metal catalyst field, such as polymer science and pharmaceutical industries. We can produce ultra pure product using this technology. The main advantage of this technique is that we can easily remove the homogeneous catalyst which is difficult to do by using Host-Guest Interaction.The implications of this technique extend toward recyclable homogeneous catalysis, because the catalyst removal method, Host-Guest Interaction is reversible. Though this method can provide insight into the same metastasis catalyst removal. It can also be applied to other metal containing catalyst such as palladium, platinum, copper, nickel and gold catalyst.Visual demonstration of this method is critical as the synthesis procedure and homogeneous catalyst removal are typical too long because Host-Guest Catalyst remover is new. First dry a 25 milliliter round bottom flask containing a magnetic stir bar, a 20 milliliter vial and a spatula in an oven. Place 118 milligrams of imidazolium salt in a 4 milliliter vial.Place the prepared imidazolium salt, the dried glassware, a septum, and the spatula in a glovebox chamber and vacuum for 2 hours. After completely removing the air in the glovebox can chamber, purge inert gas into the chamber. Then move the imidazolium salt, glassware, septum and spatula into the glovebox.In the glovebox, add 54 milligrams of first generation Hoveyda-Grubbs catalyst in the 20 milliliter vial. Dissolve the imidazolium salt in two milliliters of toluene, and transfer it into the 25 milliliter round bottom flask containing the magnetic stir bar. Next, add 0.18 milliliters of a 0.5 molar KH MDS solution to the imidazolium salt solution.Swirl the flask to mix the reagents. Now dissolve the catalyst in three milliliters of toluene and add the solution to the reaction flask. Seal the flask with the septum.Then remove the flask from the glovebox. Following this, stir the reaction mixture for three hours at 80 degrees Celsius. After cooling the reaction mixture to room temperature, purify the catalyst by chromatography on neutral alumina.Using a 15 to one mixture of ethyl acetate and methanol, collect the dark green solution. After combining the fractions containing product, removed the solvent under reduced pressure. When finished, dry the final residue under vacuum to obtain a dark green waxy solid.Prepare degassed deuterium oxide by bubbling with nitrogen gas for over two hours. Add 4.4 milligrams of the ruthenium catalysts and 41 milligrams of the tetra alkyl ammonium substrate in separate four milliliter vials. Dissolve the tetra alkyl ammonium substrate in 0.5 milliliters of degassed deuterium dioxide.Then add the solution to the catalyst. Seal the reaction vial and heat the reaction mixture for 24 hours at 45 degrees Celsius. Monitor the reaction conversion by proton NMR.After the reaction is complete, cool the reaction vial to room temperature. Then add 150 milligrams of beta CD grafted silica to the reaction mixture. Stir the reaction mixture for 10 hours at room temperature.After 10 hours, filter the reaction mixture through a cotton plug. Then remove the solvent in a freeze dryer. Prepare degassed deuterium oxide by bubbling with nitrogen gas for over two hours.At 4.4 milligrams of the ruthenium catalysts and 17.1 milligrams of monomer in separate four milliliter vials. Dissolve the monomer in 0.5 milliliters of degassed deuterium oxide. Then add the solution to the catalyst.Seal the reaction vial and heat the reaction mixture for two hours at 45 degrees Celsius. Monitor the reaction conversion by proton NMR. After the reaction is complete, cool the reaction vial to room temperature.Then quench the reaction mixture with 0.1 milliliters of ethyl vinyl ether. Next, add 150 milligrams of beta CD grafted silica to the reaction mixture. Stir the reaction mixture for 10 hours at room temperature.Filter the reaction mixture through a cotton plug. Then remove the solvent in a freeze dryer. Add 4.4 milligrams of the ruthenium catalysts and 48 milligrams of diethyl diallylmalonate in separate form in little vials.Dissolve the diethyl diallylmalonate in 0.5 milliliters of dichloromethane. Then add the solution to the catalyst. Seal the reaction vial and keep the reaction mixture at room temperature for one hour.Monitor the reaction conversion by proton NMR. After the reaction is complete, transfer the reaction mixture to a 30 milliliter vial. Dilute the mixture with 15 milliliters of diethyl ether.Then wash the organic solution five times with 15 milliliters of water. Dry the organic layer with magnesium sulfate. Then filter the solution through a cotton plug to remove the magnesium sulfate.Following this, add a magnetic stir bar and 60 milligrams of activated carbon to the filtered solution. Stir the mixture for 24 hours at room temperature. Filter the solution through a cotton plug to remove the activated carbon.Finally, remove the solvent under reduced pressure. The ligand exchange reaction for the ruthenium olefin metathesis catalysis is shown here. The proton NMR spectrum is displayed here.The ring closing metathesis reaction, an aqueous solution, and subsequent removal of used catalyst via Host-Guest Interaction is shown here. The dark reaction solution turned clear after the Host-Guest removal. The quaternary ammonium substrate was fully converted into the corresponding product with one mole percent of the catalyst and 53 parts per million of residual ruthenium was detected in the final product by inductively coupled plasma mass spectrometry or ICP-MS.Full conversion of the primary ammonium substrate was achieved with three mole percent of the catalyst, and the residual ruthenium level in the product was 284 parts per million. Ring-opening metathesis polymerisation and aqueous solution is displayed here. And the residual ruthenium content detected by ICP-MS was 269 parts per million.The ring closing metathesis reaction in dichloromethane and subsequent removal of used catalyst via extraction is shown here. With the exception of highly hindered substrates, the substrates achieved complete conversion in the ring closing metathesis reaction with one mole percent of the catalyst. ICP-MS detected 5.9 parts per million of ruthenium in the product.Without activated carbon treatment, the residual ruthenium level was 63 parts per million which is not acceptable for pharmaceutical purposes. This technique can be done in 12 hours if it is performed properly. My research group is currently doing research to shorten the time, and to increase the efficiency of catalyst removal.While attempting this procedure, it is important to remember to add sufficient guest bound solid to capture all available hosts containing catalyst molecules. Following this procedure, other catalysts like a palladium, platinum, copper, nickel and gold centered catalyst can be easily removed from the product by using the new guest containing NHC ligand and Host-Guest Interaction principle. After its development, this technique paved the way for researchers in the field of organometallic catalysis to explore the convenient and efficient removal methods of homogeneous catalysts to produce ultra pure polymers and pharmaceutical products.After watching this video, you should have a good understanding of how to remove a homogeneous organometallic catalysts from a reaction mixture by Host-Guest Interaction. Don't forget that working with ethyl acetate methanol, ethylene chloride and diethyl ether can be extremely hazardous. Precautions such as conducting the reaction in the fume hood should always be taken while performing this procedure.

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7.8K vistas.  Florida State University. This method can help answer key questions in the practical application of transition metal catalyst field, such as polymer science and pharmaceutical industries. We can produce ultra pure product using this technology. The main advantage of this technique is that we can easily remove the homogeneous catalyst which is difficult to do by using Host-Guest Interaction.The implications of this technique extend toward recyclable homogeneous catalysis, because the catalyst removal method, Hos...