polymers

Review Supported Catalysts Useful in Ring-Closing Metathesis, Cross Metathesis, and Ring-Opening Metathesis Polymerization

Jakkrit Suriboot 1, Hassan S. Bazzi 2 and David E. Bergbreiter 1,*

1 Department of Chemistry, Texas A & M University, College Station, TX 77840, USA; [email protected] 2 Department of Chemistry, Texas A & M University at Qatar, P.O. Box 23874, Doha, Qatar; [email protected] * Correspondence: [email protected]; Tel.: +1-979-845-3437

Academic Editor: Changle Chen Received: 17 March 2016; Accepted: 7 April 2016; Published: 12 April 2016

Abstract: Ruthenium and molybdenum catalysts are widely used in synthesis of both small molecules and macromolecules. While major developments have led to new increasingly active catalysts that have high functional group compatibility and stereoselectivity, catalyst/product separation, catalyst recycling, and/or catalyst residue/product separation remain an issue in some applications of these catalysts. This review highlights some of the history of efforts to address these problems, first discussing the problem in the context of reactions like ring-closing metathesis and cross metathesis catalysis used in the synthesis of low molecular weight compounds. It then discusses in more detail progress in dealing with these issues in ring opening metathesis polymerization chemistry. Such approaches depend on a biphasic solid/liquid or liquid separation and can use either always biphasic or sometimes biphasic systems and approaches to this problem using insoluble inorganic supports, insoluble crosslinked polymeric organic supports, soluble polymeric supports, ionic liquids and fluorous phases are discussed.

Keywords: ROMP; supported catalysts; olefin metathesis; green chemistry

1. Introduction The use of metal complexes in catalysis has become a standard practice in organic synthesis. Olefin metathesis is among these various catalytic reactions. The carbon-carbon double bond rearrangements effected by olefin metathesis have developed into one of the most powerful tools in organic synthesis due to the facility with which this chemistry constructs carbon-carbon double bonds and the compatibility of this reaction with other functionalities [1,2]. The search for novel applications of olefin metathesis reactions and study of improvements of the catalysts’ reactivity, stability, and selectivity have been extremely active fields since the breakthrough introduction of the current two most recognized alkylidene-types of catalyst families of ruthenium and molybdenum based complexes introduced in the 1980s by the Grubbs and Schrock groups, respectively (Figure1)[ 3,4]. Examples of these catalysts are bis(tricyclohexylphosphine)benzylidine ruthenium(II) dichloride (a Grubbs 1st generation catalyst) 1 and 2,6-diisopropylphenylimidoneophylidene molybdenum(IV) bis(hexafluoro-t-butoxide) (a Schrock catalyst) 4. A critical aspect of the development of these families of catalysts is the fact that the properties of these olefin metathesis catalysts can be modified by alteration of the organic ligands in these ruthenium and molybdenum complexes. The success and impact of such modifications have been the subject of many studies that have led to a variety of organic ligands for both of the catalyst families (Figure1). For example, in the case of Ru metathesis catalysts, these studies led to a variety of N-heterocyclic carbene complexes including

Polymers 2016, 8, 140; doi:10.3390/polym8040140 www.mdpi.com/journal/polymers Polymers 2016, 8, 140 2 of 23 Polymers 2016, 8, 140 2 of 22

(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinylidene)-dichloro(ruthenium (an example of a Hoveyda-Grubbs 2nd generationo-isopropoxyphenylmethylene) catalyst) 2 and [1,3-bis(2,4,6- ruthenium (antrimethylphenyl)-2-imidazolidinylidene]dichloro-(phenylmethylene)bis(3-bromopyridine) example of a Hoveyda-Grubbs 2nd generation catalyst) 2 and [1,3-bis(2,4,6-trimethylphenyl)- ruthenium(II) (a2-imidazolidinylidene]dichloro-(phenylmethylene)bis(3-bromopyridine) Grubbs 3rd generation catalyst) 3. Similar studies that use ligands to influence ruthenium(II) catalyst utility (a Grubbs have been3rd generation carried out catalyst) with Mo3. Similar catalysts studies leading, that usefor ligandsexample, to influenceto more catalystuseful chiral utility catalysts have been like carried 2,6- diisopropylphenylimido-neophylidene-[(out with Mo catalysts leading, for example,S to)-( more−)-BIPHEN]-molybdenum(IV) useful chiral catalysts like 2,6-diisopropylphenylimido- catalysts (an (S)-Schrock- Hoveydaneophylidene-[( catalyst)S)-( 5´. )-BIPHEN]-molybdenum(IV) catalysts (an (S)-Schrock-Hoveyda catalyst) 5.

Figure 1. Examples of olefin olefin metathesis catalysts 1–5.

Although these studies have led to newer versions of olefin metathesis catalysts that have Although these studies have led to newer versions of olefin metathesis catalysts that have improved reactivity, air and moisture stability, functional groups tolerance, and stereoselectivity, improved reactivity, air and moisture stability, functional groups tolerance, and stereoselectivity, challenges still remain in using these transition metal complexes. Challenges that remain include: (i) challenges still remain in using these transition metal complexes. Challenges that remain include: the high cost of the transition metal complexes used as catalysts or precatalysts; (ii) the cost and/or (i) the high cost of the transition metal complexes used as catalysts or precatalysts; (ii) the cost and/or tediousness of the ligand syntheses; and (iii) the potential environmental toxicological or practical tediousness of the ligand syntheses; and (iii) the potential environmental toxicological or practical concerns that ensue when there is significant metal or ligand contamination in the product. This last concerns that ensue when there is significant metal or ligand contamination in the product. This last issue is a green chemistry issue in that additional process steps have to be used to sequester or remove issue is a green chemistry issue in that additional process steps have to be used to sequester or remove metals or ligands from products. Such steps increase overall process cost and can be an metals or ligands from products. Such steps increase overall process cost and can be an environmental environmental issue because of the waste that is typically generated in such catalyst/ligand/product issue because of the waste that is typically generated in such catalyst/ligand/product separation steps. separation steps. The last issue is especially critical in pharmaceutical industry and in materials The last issue is especially critical in pharmaceutical industry and in materials synthesis. In the case of synthesis. In the case of pharmaceuticals, the acceptable level of ruthenium content in products pharmaceuticals, the acceptable level of ruthenium content in products should be less than 10 ppm in should be less than 10 ppm in the final compound [5–7]. An efficient separation of ruthenium the final compound [5–7]. An efficient separation of ruthenium impurities is also important in the case impurities is also important in the case of polymeric materials used in electronic or device of polymeric materials used in electronic or device applications. In addition, other issues can arise. For applications. In addition, other issues can arise. For example, in some syntheses, an efficient example, in some syntheses, an efficient separation of ruthenium impurities is important as ruthenium separation of ruthenium impurities is important as ruthenium residues can lead to undesirable side- residues can lead to undesirable side-reactions like hydrogenation or alkene isomerization in reaction reactions like hydrogenation or alkene isomerization in reaction products [8,9]. products [8,9]. There are several ways to approach the three issues noted above. Perhaps the simplest approach There are several ways to approach the three issues noted above. Perhaps the simplest approach is is to simply reduce the amount of catalyst that is used in the reaction. Originally, ring-closing to simply reduce the amount of catalyst that is used in the reaction. Originally, ring-closing metathesis metathesis (RCM) reactions required catalyst loadings that were 1–5 mol % or greater depending on (RCM) reactions required catalyst loadings that were 1–5 mol % or greater depending on specific specific application. However, this level of catalyst loadings seems to be an overestimate. For application. However, this level of catalyst loadings seems to be an overestimate. For example, example, according to the studies by Mol and Dinger in 2002, they found that catalyst loadings could according to the studies by Mol and Dinger in 2002, they found that catalyst loadings could be much be much lower in some cases. Their work shows that in suitable cases Ru-catalyzed olefin metathesis lower in some cases. Their work shows that in suitable cases Ru-catalyzed olefin metathesis can be can be carried out effectively with catalyst loadings that are several orders of magnitude lower than carried out effectively with catalyst loadings that are several orders of magnitude lower than normally normally reported [10]. In suitable cases, the effective turnover number for the Ru catalysts can be as reported [10]. In suitable cases, the effective turnover number for the Ru catalysts can be as high as high as 600,000. While these studies focused on achieving the maximum turnover number, the reactions with very low catalyst loadings in some cases never reached 100% conversion. Nonetheless,

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600,000. While these studies focused on achieving the maximum turnover number, the reactions with very low catalyst loadings in some cases never reached 100% conversion. Nonetheless, their work demonstrated the potential of lower mol % loadings of Ru catalysts, a potential that has been realized by others such as the Grubbs group who reported success in reducing the catalyst loadings to be as low as 25 ppm in ring-closing metathesis of diethyl diallylmalonate, by employing more sterically demanding and reactive Ru-based catalysts [7]. An alternative strategy to address the issue of separation of transition metal complexes and products in metathesis that has been also used in other transition metal catalyzed chemistry is to design the catalyst and its ligands such that both can be efficiently separated, recovered, and recycled. If such separations recover an active catalyst, a reuse of this catalyst can in effect increase turnover numbers. In any case, a simpler way to separate catalyst residues from products can minimize the effects of catalyst or ligand contamination in products. Various methods to separate, recover and recycle the catalyst have been developed. The most classical approach is to design a catalyst such that it is coupled to an always insoluble support such as silica gel or a cross-linked and thus insoluble polymer. Such an approach leads to so-called heterogeneized catalysts on supports that are always insoluble before, during and after a reaction. A second approach is to design a catalyst such that it has some sort of phase selective solubility. Examples of this second approach have involved ligands that contain ionic liquid compatible functionality, or fluorocarbon groups that make metathesis catalysts soluble in fluorocarbon solvents, or soluble polymers that lead to catalysts whose solubility mirrors that of the polymer to which they are attached. Unlike cases where catalyst immobilization involves an insoluble support, these catalysts can typically be characterized by conventional spectroscopy. A further advantage of each of these approaches is that the catalysts that can be used as homogeneous catalysts avoiding potential problems of heterogeneous catalysts. However, in each of these three cases, some sort of biphasic separation is required after a reaction to separate the tagged catalyst and ligands from the products. Such separations can involve a simple filtration in the case of heterogeneous supports. Soluble supports usually require some sort of liquid/liquid separation or extraction to separate catalysts and products. The discussion below briefly summarizes some examples where heterogeneous and homogeneous supports are used in metathesis. It then describes in more comprehensive detail examples where phase separable metathesis catalysts are used in ring-opening metathesis polymerization (ROMP).

2. Heterogeneous Supported Olefin Metathesis Catalysts The use of a heterogeneous insoluble support is among the oldest and most widely used tool to effect separation and isolation of catalysts from the products. The first insoluble organic support explored by the scientific community that was later used for homogeneous catalysts was based on a paper that was published by Merrifield—work that subsequently earned Merrifield a Nobel Prize [11]. While Merrifield’s work was directed at using cross-linked polystyrene resins (Merrifield’s resin) in peptide and nucleotide synthesis [11], others recognized that the physical separation of a growing peptide bound to an insoluble organic support he described had potential applications in separation of homogeneous catalysts and products and that if catalysts had stable stationary states that such catalysts could be recycled. Thus, this discovery of Merrifield that focused on peptide synthesis led to many studies using similar insoluble polymeric materials as supports for homogeneous catalysts. As is true in peptide synthesis, catalysts immobilized on these divinylbenzene (DVB)-cross-linked polystyrene supports have the principle advantage of allowing for separation of catalysts and their ligands from a solution of the product in the solvent phase of a reaction mixture via simple filtration. In some cases, heterogeneous supports can also improve catalyst stability and prevent bimolecular decomposition pathways via a phenomenon known as site isolation [12–15]. However, in other cases, the heterogeneity of an otherwise homogeneous catalyst can change activity in undesirable ways. If the goal of immobilization is to replace a homogeneous catalyst with a separable catalyst with the same activity, this is undesirable. Polymers 2016, 8, 140 4 of 23

The discussion below first describes in a general way some examples where olefin metathesis catalysts have been immobilized on always phase separated supports (i.e., insoluble inorganic or cross-linked polymer supports). It then describes similar chemistry that uses sometimes phase-separated supports (i.e., biphasic catalysis or soluble polymers that can be phase separated after a catalytic reaction). Finally, it goes on to discuss in more detail issues associated with the specific example of immobilized ring-opening metathesis polymerization (ROMP) catalysis. Ru metathesis catalysts like those shown in Figure2 have been immobilized on divinylbenzene cross-linked polystyrene (DVB-PS). An early example of such catalyst was 6 which was first reported by Grubbs and Nguyen in 1995 [16]. In this example, they used an established type of supported ligand—a phosphine modified DVB-PS. This supported catalyst had extended lifetimes. This was ascribed to the reduced diffusivity of the catalyst molecules on the polystyrene support, which prevents a decomposition pathway that occurs via a bimolecular reaction. However, while 6 was recycled three times in a metathesis reaction of cis-2-pentene to form cross metathesis products of 3-hexene and 2-butene, the catalyst lost 20% of its activity after each cycle. This catalyst also had a modest activity that was ascribed to (i) incomplete substitution of phosphine; (ii) the diffusion limit of olefin into the cavities of cross-linked DVB-PS support; and (iii) the local high concentration of phosphine on the support. The amount of Ru leaching in the products was not analyzed. However, given that the Ru complex is immobilized by a labile phosphine ligand, given that the Ru and phosphine ligand dissociate in the reaction, and that the recovered polymer-bound catalyst loses significant activity cycle to cycle, it is likely that there is a significant amount of Ru leaching. Several years later, Barrett and co-workers described an alternative scheme that also used DVB-PS as a support. In this case, they immobilized a Ru pre-catalyst onto DVB-PS using a benzylidine group. In this second approach, Barrett introduced a new concept called the “boomerang” effect [17]. This was a quite different scheme for use of a heterogeneous-supported catalyst. In this case a pre-catalyst 7 was synthesized by a metathesis reaction, shaking Grubbs 1st generation catalyst and a vinyl-substituted DVB-PS derivative for 2 h in dichloromethane. The resulting benzylidene-immobilized pre-catalyst 7 is immobilized on the insoluble resin by a strong bond and the immobilized pre-catalyst was isolated by filtration. According to their report, 7 was indefinitely stable under normal atmospheric conditions with no loss of activity. In the application of 7, a so-called boomerang reaction was involved. In this scheme, the Ru initially undergoes a metathesis reaction with an alkene of a ring-closing metathesis (RCM) substrate like diethyl diallylmalonate. The resulting metallocycle then forms a new Ru alkylidene and the original vinyl-substituted DVB-PS. The alkylidene complex goes into solution, becoming a homogeneous catalyst effecting ring-closing metathesis (RCM) on the rest of the substrate. Then, when the substrate is consumed, the authors postulate that the remaining soluble alkylidene reacts with the vinyl-substituted DVB-PS. This leads to a recapture of the Ru complex by the resin by a strong bond after the completion of the reaction. This behavior of the ruthenium catalyst where it comes off the resin and returns later was likened to the action of a “boomerang”. In this work, the catalyst was recycled up to three times in an RCM reaction of diethyl diallylmalonate, with addition of 3,3-dimethyl-1-butene (9 mol % based on diethyl diallylmalonate), with Ru contamination in the product of 500 ppm. Catalyst recycling was accomplished by simple filtration of the solid-supported catalyst and the product was isolated from the filtrate by evaporation of the solvent. Following Grubbs’ and Barrett’s work on polymer-supported catalysts and the other studies of homogeneous Ru metathesis catalysts that had shown the utility of Ru-based alkylidene catalysts that contained N-heterocyclic carbene (NHC) ligands, Blechert and co-workers described the synthesis of Grubbs 2nd generation catalysts like 8 that were immobilized on DVB-PS via an N-heterocyclic carbene ligand [18]. An advantage of this approach using N-heterocyclic carbene (NHC) ligands to immobilize a Ru complex is that an NHC ligand is a stronger sigma donor than phosphine ligands. Unlike phosphine ligands like those in 7 that are thought to dissociate from the ruthenium center to initiate catalysis [19], the NHC ligand should remain bound to the ruthenium center before, during, and after the metathesis reaction. Thus, leaching of Ru from the resin was expected to be reduced [18]. Polymers 2016, 8, 140 5 of 23

In the first example of this chemistry, the solid-supported catalyst 8 was prepared by ligand exchange between a DVB-PS-supported N-heterocyclic carbene ligand and the phosphine ligand on Grubbs PolymersPolymers 2016 2016, 8, 140, 8, 140 5 of 522 of 22 1st generation catalyst 1. The resulting DVB-PS supported heterogeneous ruthenium catalyst was Polymers 2016, 8, 140 5 of 22 31 characterizedwaswas demonstrated demonstrated by Pby NMR bythe the use and use of IR 8of spectroscopy. in8 variousin various metathesis The metathesis general reactions reactivityreactions including ofincluding8 was RCM demonstrated RCM and and yne-ene yne-ene by was demonstrated by the use of 8 in various metathesis reactions including RCM themetathesisandmetathesis use yne-ene of 8 reactions.in reactions. various In metathesis theIn the case case of reactions ring-closingof ring-closing including me tathesisme RCMtathesis reaction and reaction yne-ene of diethylof metathesis diethyl diallylmalonate, diallylmalonate, reactions. Inup the upto to metathesis reactions. In the case of ring-closing metathesis reaction of diethyl diallylmalonate,casefourfour ofcyclesring-closing upcycles toof ofcyclization cyclization metathesis of ofdiethyl reaction diethyl diallylmalonate of diallylmalonate diethyl diallylmalonate, to 4,4-dicarboethoxycyclopenteneto 4,4-dicarboethoxycyclopentene up to four cycles of cyclization could could be of be four cycles of cyclization of diethyl diallylmalonate to 4,4-dicarboethoxycyclopentenediethyleffectedeffected could diallylmalonateusing beusing 8. These 8. These reports to reports 4,4-dicarboethoxycyclopentene stated stated that that the the products products were were couldobtained obtained be effectedas colorless as colorless using solids 8solids. These or oils. or oils. reports While While effected using 8. These reports stated that the products were obtained as colorless solidsstated thisor oils.this visual that visualWhile assay the assay products of Ru of Ruleaching wereleaching obtainedis promising, is promising, as colorless a mo a more quantitativere solids quantitative or oils. assay assay While of the of thisthe amount amount visual of assayRu of Ruleaching ofleaching Ru this visual assay of Ru leaching is promising, a more quantitative assay of the amount ofleachingwas Ruwas notleaching not isreported. promising, reported. This aThis morework work quantitative was was subsequently subsequently assay of ex the tendedex amounttended in of ain Ru reporta leachingreport where where was the not the Blechert reported. Blechert group This group was not reported. This work was subsequently extended in a report where the Blechertworkreportedreported was group solid-supported subsequently solid-supported extended Ru Rumetathesis metathesis in a report catalysts catalysts where like the like 9 Blechertand 9 and 10 that10 group that had reportedhad high high stability, solid-supported stability, activity, activity, and Ru and reported solid-supported Ru metathesis catalysts like 9 and 10 that had high stability,metathesisrecyclability activity,recyclability and catalysts [20]. [20]. In recycling likeIn recycling9 and experiments10 experimentsthat had highusing using stability, thes these twoe activity,two catalysts, catalysts, and both recyclability both catalysts catalysts were [20 ].were Inrecycled recycling recycled up up recyclability [20]. In recycling experiments using these two catalysts, both catalysts wereexperimentsto recycled fourto four times timesup using in RCM in theseRCM reaction two reaction catalysts, of diallyltosylamide.of diallyltosylamide. both catalysts However, were However, recycled the the upability toability four to catalyze to times catalyze in cross RCM cross metathesis reaction metathesis of to four times in RCM reaction of diallyltosylamide. However, the ability to catalyze crossdiallyltosylamide.(CM) metathesis(CM) reactions reactions of However,complexof complex 9 the was 9 abilitywas showed showed to catalyze to beto behigher cross higher metathesisthan than that that of (CM) complexof complex reactions 10 . 10 ofFor. complexFor example, example,9 was the the (CM) reactions of complex 9 was showed to be higher than that of complex 10. For showedconversionexample,conversion to the be of higher CMof CM between than between that acrylonitrile of acrylonitrile complex 10and. Forand 4-pentenyl example,4-pentenyl benzoate the benzoate conversion catalyzed catalyzed of CM by between by9 was 9 was 98% acrylonitrile 98% in 12in h12 h conversion of CM between acrylonitrile and 4-pentenyl benzoate catalyzed by 9 wasandwhile 98%while 4-pentenyl thein 12the conversion h conversion benzoate was was catalyzedonly only 15% 15% byin 129inwas h12 in h 98% thein the case in 12case of h 10 whileof. 10The. The the authors conversionauthors suggested suggested was onlythat that the 15% the superior in superior 12 h while the conversion was only 15% in 12 h in the case of 10. The authors suggested thatinactivity the theactivity superior case of ofofcomplex 10 complex. The authors9 owe9 owe suggestedto tothe the ability thatability theof ofthe superior the catalyst catalyst activity to todissociate of dissociate complex in9 oweinsolution, solution, to the becoming ability becoming of activity of complex 9 owe to the ability of the catalyst to dissociate in solution,thehomogeneous homogeneous catalystbecoming to dissociateactive active species, inspecies, solution, unlike unlike becoming complex complex homogeneous10 . 10The. The leaching leaching active of species, ofRu Ruin unlikeinthe the products complexproducts was10 was. Thenot not homogeneous active species, unlike complex 10. The leaching of Ru in the productsleachingdescribed.described. was of not Ru in the products was not described. described.

FigureFigure 2. Examples2.Examples Examples of ofDVB-PS-supportedof DVB-PS-supportedDVB-PS-supported ( ( (= divinylbenzene = divinylbenzene divinylbenzene cross- cross- cross-linkedlinkedlinked polystyrene polystyrene polystyrene or or or= = Figure 2. Examples of DVB-PS-supported ( = divinylbenzene cross-linked polystyrene or divinylbenzene ==divinylbenzene divinylbenzene cross-linked cross-linked cross-linked 4-vinylpyr 4-vinylpyr 4-vinylpyridine)idine)idine) olefin olefin olefin metathesis metathesis metathesis catalysts catalysts catalysts 6–11 6–116–11. .. divinylbenzene cross-linked 4-vinylpyridine) olefin metathesis catalysts 6–11. The invention of new highly active ruthenium olefin metathesis catalyst pyridine-ligated Grubbs TheThe invention invention of newof new highly highly active active ruthenium ruthenium olefin olefin metathesis metathesis catalyst catalyst pyridine-ligated pyridine-ligated Grubbs Grubbs 3rd generation catalysts has led to a new type of Ru catalyst which can catalyze cross metathesis The invention of new highly active ruthenium olefin metathesis catalyst pyridine-ligated3rd3rd generation Grubbs generation catalysts catalysts has has led led to ato new a new type type of Ruof Ru catalyst catalyst which which can can catalyze catalyze cross cross metathesis metathesis reactions of a broader range of substrates and afford polymers with narrow polydispersity (PDI) by 3rd generation catalysts has led to a new type of Ru catalyst which can catalyze crossreactions metathesisreactions of a of broader a broader range range of substrates of substrates and and afford afford polymers polymers with with narrow narrow polydispersity polydispersity (PDI) (PDI) by a by a ring-opening metathesis polymerization (ROMP). Grela and Kirschning reported the first example reactions of a broader range of substrates and afford polymers with narrow polydispersityring-openinga ring-opening(PDI) by metathesis metathesis polymerization polymerization (ROMP). (ROMP). Grela andGrela Kirschning and Kirschning reported reported the first the example first example of a of a solid-supported version of this catalyst in 2005 [21]. Their report noted the possibility of using a ring-opening metathesis polymerization (ROMP). Grela and Kirschning reported the solid-supportedfirstof example a solid-supported version version of this catalystof this catalyst in 2005 in [21 2005]. Their [21]. report Their notedreport the noted possibility the possibility of using of this using this supported catalyst in a continuous flow process due to the ability to reload the catalytic species of a solid-supported version of this catalyst in 2005 [21]. Their report noted the possibilitysupportedthis of supportedusing catalyst catalyst in a continuous in a continuous flow process flow process due to the due ability to the to ability reload to the reload catalytic the catalytic species ontospecies onto the same solid support. Thus, even if leaching were to occur, the catalyst could be easily be this supported catalyst in a continuous flow process due to the ability to reload the catalytictheonto same species the solid same support. solid Thus,support. even Thus, if leaching even wereif leaching to occur, were the catalystto occur, could the catalyst be easily could be regenerated. be easily be regenerated. The recyclability of 11 was tested in a ring-closing metathesis reaction of diethyl onto the same solid support. Thus, even if leaching were to occur, the catalyst couldThe beregenerated. recyclabilityeasily be The of 11 recyclabilitywas tested of in a11 ring-closing was tested metathesisin a ring-closing reaction metathesis of diethyl reaction diallylmalonate of diethyl diallylmalonate at 110 °C. This solid-supported catalyst showed activity up to 5 cycles but a decrease regenerated. The recyclability of 11 was tested in a ring-closing metathesis reactionat 110diallylmalonateof ˝diethylC. This solid-supported at 110 °C. This catalyst solid-supported showed activitycatalyst upshowed to 5 cyclesactivity but up ato decrease 5 cycles but in product a decrease in product yield was noted in each subsequent cycle. The authors ascribed this to the thermal diallylmalonate at 110 °C. This solid-supported catalyst showed activity up to 5 cycles butyield ina decrease wasproduct noted yield in each was subsequent noted in each cycle. subsequent The authors cy ascribedcle. The thisauthors to the ascribed thermal this instability to the ofthermal11 instability of 11 or leaching of Ru from the weakly bound pyridine ligands. However, the authors in product yield was noted in each subsequent cycle. The authors ascribed this toor the leachinginstability thermal of of Ru 11 from or leaching the weakly of Ru bound from pyridine the weakly ligands. bound However, pyridine the ligands. authors However, were able the to showauthors instability of 11 or leaching of Ru from the weakly bound pyridine ligands. However,were thewere ableauthors able to show to show that that 11 could11 could indeed indeed be reactivatedbe reactivated by washing/Ruby washing/Ru re-addition re-addition protocol protocol (1 M (1 HCl,M HCl, were able to show that 11 could indeed be reactivated by washing/Ru re-addition protocol1 M1 (1 NaOH,M M NaOH, HCl, H 2 O,H 2O,MeOH, MeOH, toluene, toluene, then then addition addition of 3of). 3Ru). Rucontamination contamination in thein the products products was was not not 1 M NaOH, H2O, MeOH, toluene, then addition of 3). Ru contamination in the productsmentioned.mentioned. was not mentioned. TheThe other other general general strategy strategy for forcatalyst catalyst immobilization immobilization on insolubleon insoluble supports supports commonly commonly is to is use to use The other general strategy for catalyst immobilization on insoluble supports commonlyinorganicinorganic is to usesupports. supports. Silica-based Silica-based materials materials are are the the most most common common examples examples of theseof these sorts sorts of solidof solid inorganic supports. Silica-based materials are the most common examples of these sorts of solid

Polymers 2016, 8, 140 6 of 23

that 11 could indeed be reactivated by washing/Ru re-addition protocol (1 M HCl, 1 M NaOH, H2O, MeOH, toluene, then addition of 3). Ru contamination in the products was not mentioned. The other general strategy for catalyst immobilization on insoluble supports commonly is to use inorganic supports. Silica-based materials are the most common examples of these sorts of solid supports. Select examples of Ru metathesis catalysts immobilized on silica are shown in Figure3. Fürstner and co-workers reported the synthesis of an immobilized Grubbs 2nd generation ruthenium complex on silica gel using hydroxyalkyl groups on N-heterocyclic carbene ligand 12 [22]. This immobilized catalyst was successfully recycled in RCM reaction of diethyl diallylmalonate through three cycles. The catalyst 12 was separated from the RCM product by simple filtration. The crude product was isolated as colorless liquid. The authors did report a detailed analysis of Ru leaching noting that the products had ca. 250 ppm of Ru contamination based on ICP-MS analysis. Grubbs and co-workers have also described other versions of silica-supported olefin metathesis ruthenium catalysts 13 and 14 [23]. The silica-supported complexes 13 and 14 were competent catalysts in RCM and CM reactions with reactivity that was comparable to that of their homogeneous analogs. The catalytic activity toward an RCM reaction of diethyl diallylmalonate of catalyst 14 (31% conversion after 10 min) was shown to have slightly lower than the catalytic activity of 13 (67% conversion after 10 min). The authors also showed that immobilized ruthenium catalyst 13 can be recycled up to eight times in RCM reaction of allyl(2-methyl-2-propenyl)malonate with conversions of substrate to product in the 60%–80% range when reaction time was 2 h, conversions that could reach 100% with reaction times of 12 h. The authors suggested that these catalysts improve recyclability and eliminate issues associated with the decomposition of the ruthenium complex via bimolecular pathway. Such immobilized ruthenium catalysts on silica support have less intermolecular activity between the catalysts—the same phenomena reported earlier by Grubbs’ group for site isolated DVB-PS supported species [16]. The analysis of the Ru leaching in this case would seem to support this claim. In this example, the ruthenium leaching studied by ICP-MS revealed the contamination level in products to be less than 5 ppb for those prepared by both 13 and 14. This is especially notable since it is by several orders of magnitude the lowest Ru leaching ever reported. Ying group also described using click chemistry for the immobilization of Hoveyda-Grubbs type complexes on nanoporous silica 15 [24]. The catalyst they prepared exhibits good activity and stability as well as recyclability. In addition, these authors demonstrated that this catalyst can be used in a circulating flow reactor. The catalyst was reused in RCM reaction of diethyl diallylmalonate over 8 times with overall conversions of 90% with Ru leaching levels of 11.3 ppm at the first 60 min and 1.6 ppm at 180 min based on ICP-MS analysis of the isolated products. Yet another example of silica-bound Ru metathesis catalysts was reported by Balcar and co-workers who used commercially available molecular sieves as supports for the Ru catalyst 16 [25]. These SBA-15 molecular sieves possess several advantages including high surface area, narrow pore size distribution, and high thermal and mechanical stability. The solid-supported ruthenium complex 16 on such sieves was shown to be competent as an RCM catalyst using diethyl diallylmalonate as a substrate. The leaching of Ru into RCM product was found to be as low as 17 ppm. However, attempts to recycle this catalyst were unsuccessful, with the conversion reaching 90% for only two cycles. More recently, Monge-Marcet and co-workers also reported a synthesis of recyclable silica-supported Hoveyda-Grubbs type complex using an NHC ligand 17 [26]. This catalyst proved to be recyclable for RCM reaction of diethyl diallylmalonate with Ru contamination of 221 ppm found in the product based on ICP-MS of products from the first cycle. Ru leaching in subsequent cycles was not measured but would likely be less as Ru leaching in the first or second cycles of a catalytic reaction could reflect undetectable issues in the synthesis of a catalyst. If a catalyst were only 99% pure (pure by most analyses used in synthesis), the 1% impurity would represent most or all of the observed Ru leaching but would not be relevant in later cycles. Polymers 2016, 8, 140 7 of 23 Polymers 2016, 8, 140 7 of 22

Figure 3. Examples of silica-supported olefinolefin metathesis catalysts 12–17..

Schrock’s molybdenum olefin metathesis catalysts have also been supported on always insoluble Schrock’s molybdenum olefin metathesis catalysts have also been supported on always insoluble supports. Some examples of such silica-supported catalysts supports are shown in Figure 4. For supports. Some examples of such silica-supported catalysts supports are shown in Figure4. For example, Schrock and co-workers described the synthesis of well-defined surface immobilized example, Schrock and co-workers described the synthesis of well-defined surface immobilized catalysts catalysts 18 and 19 [27]. These two silica-supported catalysts showed very similar activities in cross 18 and 19 [27]. These two silica-supported catalysts showed very similar activities in cross metathesis metathesis reaction of ethyl oleate (EO) with TOF (turnover frequency measured after 5 min of reaction of ethyl oleate (EO) with TOF (turnover frequency measured after 5 min of reaction expressed reaction expressed in mol of substrate converted per mol of Mo per sec) of 0.04 and 0.03, respectively. in mol of substrate converted per mol of Mo per sec) of 0.04 and 0.03, respectively. However, the However, the silica-supported 18 was reportedly more stable than 19, a difference that was ascribed silica-supported 18 was reportedly more stable than 19, a difference that was ascribed to the site to the site isolation of metal complexes on the silica support [28]. The stability of 18 and 19 were isolation of metal complexes on the silica support [28]. The stability of 18 and 19 were determined by determined by the time needed to reach equilibrium in the CM reaction of ethyl oleate (i.e., around the time needed to reach equilibrium in the CM reaction of ethyl oleate (i.e., around 50% conversion), 50% conversion), which was 1 and 24 h, respectively (the longer the time was presumed to reflect a which was 1 and 24 h, respectively (the longer the time was presumed to reflect a faster decomposition faster decomposition rate for the catalyst). Shortly later, Schrock and co-workers developed more rate for the catalyst). Shortly later, Schrock and co-workers developed more active, stable, and selective active, stable, and selective silica supported molybdenum olefin metathesis catalyst 20 [29]. The silica supported molybdenum olefin metathesis catalyst 20 [29]. The increase in reactivity was achieved increase in reactivity was achieved by replacing one imido group with a siloxy group from the by replacing one imido group with a siloxy group from the surface. Keeping one remaining imido surface. Keeping one remaining imido ligand enhanced the stability of the molybdenum catalyst. ligand enhanced the stability of the molybdenum catalyst. This catalyst was also tested its activity This catalyst was also tested its activity in CM of ethyl oleate. The results showed that the TOF of 20 in CM of ethyl oleate. The results showed that the TOF of 20 was 0.15 and the time needed to reach was 0.15 and the time needed to reach reaction equilibrium was only 10 min. More recently, Schrock reaction equilibrium was only 10 min. More recently, Schrock group described the silica immobilized group described the silica immobilized molybdenum alkene metathesis catalyst 21 that showed molybdenum alkene metathesis catalyst 21 that showed enhancement in metathesis activity compared enhancement in metathesis activity compared to its low molecular weight analog in CM reactions of to its low molecular weight analog in CM reactions of ethyl oleate. The TOFs of 21 and its low ethyl oleate. The TOFs of 21 and its low molecular weight analog were 0.07 and 0.01, respectively molecular weight analog were 0.07 and 0.01, respectively [30]. None of these reports reported an [30]. None of these reports reported an analysis of Mo leaching. analysis of Mo leaching.

Polymers 2016, 8, 140 8 of 22

Polymers 2016, 8, 140 8 of 23 Polymers 2016, 8, 140 8 of 22

Figure 4. Examples of silica-supported olefin metathesis catalysts 18–21.

The first recyclable supported chiral olefin metathesis catalyst was reported by Hoveyda and Figure 4. Examples of silica-supported olefin metathesis catalysts 18–21. Schrock in 2002 [31].Figure Examples 4. Examples of these of silica-supported catalysts are olefinshown metathesis in Figure catalysts 5. The 18 polystyrene-supported–21. catalyst 22 showed similar activity to its homogeneous analog both in terms of yield and enantioselectivityTheThe first first recyclable recyclable in asymmetric supported supported chiral chiralring-o olefin olefinpening metathesisme tathesiscross catalystmetathesiscatalyst was was reported reactionreported by by Hoveydaof Hoveyda(1R,4 andS,7 Rand)-7- Schrock in 2002 [31]. Examples of these catalysts are shown in Figure5. The polystyrene-supported catalyst (benzyloxy)bicyclo[2.2.1]hept-2-eneSchrock in 2002 [31]. Examples of these 31 catalystsand styrene are shown to yield in Figure product 5. The 32 polystyrene-supported(92% yield and 98% 22 showed similar activity to its homogeneous analog both in terms of yield and enantioselectivity in enantiomericcatalyst 22 showedexcess (ee)) similar (Scheme activity 1). Theto itspolymer- homogeneoussupported analog complex both can in be terms recycled of threeyield timesand asymmetric ring-opening cross metathesis reaction of (1R,4S,7R)-7-(benzyloxy)bicyclo[2.2.1]hept-2-ene enantioselectivity in asymmetric ring-opening cross metathesis reaction of (1R,4S,7R)-7- but conversion31 and styrene significantly to yield product dropped32 (92% in yieldthe third and 98%cycle. enantiomeric However, excess there (ee))was (Scheme little difference1). The in (benzyloxy)bicyclo[2.2.1]hept-2-ene 31 and styrene to yield product 32 (92% yield and 98% enantioselectivitypolymer-supported in the complex product can in be the recycled three cycles three times. This but catalyst conversion also significantlyaffords good dropped recoverability in the of theenantiomeric catalyst.third cycle. The excess However, reported (ee)) there (Schemeleaching was little 1).of differenceThemolybdenum polymer- in enantioselectivitysupported in the product complex in was the productcan 3% beof recycledthe in the charged three three cycles. catalyst. times Threebut Thisconversion years catalyst later also Hoveydasignificantly affords and good dro Schrock recoverabilitypped describedin the of third the ne catalyst. wcycle. immobilized TheHowever, reported catalysts there leaching was using of little molybdenum both difference polystyrene- in in andenantioselectivity thepolynorbornene-based product was in 3% the of product the supports, charged in the catalyst. 23 three–26 and Threecycles 27 years.– This29, respectively latercatalyst Hoveyda also [32]. affords and These Schrock good polymer-supported described recoverability new of catalyststhe immobilizedcatalyst. can Thebe catalystsused reported in usingasymmetric leaching both polystyrene- of ring-opening molybdenum and polynorbornene-basedcross in the metathesis product was reaction supports,3% of of the the23 charged– 26sameand substrates27 catalyst.–29, mentionedThreerespectively years earlier later [32 Hoveyda and]. These the polymer-supportedcatalystsand Schrock can describedbe separated catalysts new canfrom immobilized be the used reaction in asymmetriccatalysts mixture using ring-opening by both simple polystyrene- filtration. cross Theand metathesis leachingpolynorbornene-based of reaction molybdenum of the samesupports, in substratesthe 23product–26 mentioned and was 27 –found29 earlier, respectively to and be the as catalysts low[32]. asThese can1%, be polymer-supportedwith separated reactivity from and the reaction mixture by simple filtration. The leaching of molybdenum in the product was found to enantioselectivitycatalysts can be used similar in asymmetric to their homogeneous ring-opening counterparts. cross metathesis The reactionsynthesis of ofthe a samepolynorbornene substrates be as low as 1%, with reactivity and enantioselectivity similar to their homogeneous counterparts. monolith-supportedmentioned earlier and Schrock-type the catalysts catalyst can be separated30 was also from reported the reaction by the mixture groups by of simple Buchmeiser filtration. and The synthesis of a polynorbornene monolith-supported Schrock-type catalyst 30 was also reported FürstnerThe leaching [33]. Theof molybdenum monolith-supported in the product chiral catalyst was found 30 was to usedbe as with low excellentas 1%, with product reactivity yields and and enantioselectivityby the groups ofsimilar Buchmeiser to their and homogeneous Fürstner [33]. counterparts. The monolith-supported The synthesis chiral of catalysta polynorbornene30 was withused excellent with excellentresults in product term of yields recovery and of with the excellent catalyst resultsin asymmetric in term of RCM recovery reactions of the of catalyst 3-(allyloxy)- in monolith-supported Schrock-type catalyst 30 was also reported by the groups of Buchmeiser and 2,4-dimethylpenta-1,4-dieneasymmetric RCM reactions and of 3-(allyloxy)-2,4-dimethylpenta-1,4-diene its derivatives. In most cases, the reaction and its derivatives.proceeded Inwith most yields Fürstner [33]. The monolith-supported chiral catalyst 30 was used with excellent product yields and that cases,exceeded thereaction 99% with proceeded the molybdenum with yields thatcontamination exceeded 99% in withthe products the molybdenum being less contamination than 2% in all with excellent results in term of recovery of the catalyst in asymmetric RCM reactions of 3-(allyloxy)- cases.in The the productsenantioselectivity being less thanwas 2%also in comparable all cases. The to enantioselectivity its homogeneous was analog also comparable with slightly to its lower 2,4-dimethylpenta-1,4-diene and its derivatives. In most cases, the reaction proceeded with yields enantiomerichomogeneous excesses. analog with slightly lower enantiomeric excesses. that exceeded 99% with the molybdenum contamination in the products being less than 2% in all cases. The enantioselectivity was also comparable to its homogeneous analog with slightly lower enantiomeric excesses.

SchemeScheme 1. Asymmetric 1. Asymmetric Ring-Opening Ring-Opening Cr Crossoss Metathesis Reaction Reaction of of31 31catalyzed catalyzed by 22 by. 22.

Scheme 1. Asymmetric Ring-Opening Cross Metathesis Reaction of 31 catalyzed by 22.

Polymers 2016, 8, 140 9 of 23 Polymers 2016, 8, 140 9 of 22

iPr tBu tBu

N N Me O Me O Mo iPr Mo Me O Me O R Ph tBu tBu

22;R=Ph 24 23;R=Me

R R tBu tBu N N R O Mo R Me O Mo O Me O R' tBu tBu

27;R=iPr 25; R = iPr; R' = Ph 28;R=Cl 26; R = Cl; R' = Me

tBu n iPr tBu N O Me O Mo N Me O Me O Mo iPr Me O Ph tBu O tBu

30 29 n

Figure 5.5.Polystyrene-based-supported Polystyrene-based-supported Schrock Schrock catalysts catalysts22–26 and22– polynorbornene-based-supported26 and polynorbornene-based- supportedSchrock catalysts Schrock27 catalysts–30. 27–30.

3. Homogeneous Homogeneous Supported Supported Olefin Olefin Metathesis Metathesis Catalysts Catalysts Up to thisthis point,point, thisthis discussiondiscussion has has focused focused on on the the immobilization immobilization of of olefin olefin metathesis metathesis catalysts catalysts on onheterogeneous heterogeneous supports. supports. While While this hasthis been has abeen common a common technique technique to isolate to andisolate recycle and the recycle catalysts, the catalysts,it is not the it onlyis not possible the only scheme possible for catalystscheme productfor catalyst separation product and separation catalyst recycling. and catalyst Soluble recycling. phase Solubletag methods phase used tag inmethods combinatorial used in chemistrycombinatorial and inchemistry peptide synthesisand in peptide have also synthesis been developed have also asbeen an developedalternative as tool an for alternative separation tool process for separation between catalystsprocess between and the products.catalysts and In these the products. cases, the In strategy these cases,is to use the two strategy different is to phasesuse two to different recover phases catalysts. to recover The presence catalysts. of theThe two presence phases of canthe resulttwo phases from perturbationcan result from of aperturbation homogeneous of reactiona homogeneous mixture orreaction can involve mixture two or liquid can involve phases. two Thus, liquid the supports phases. Thus,for this the technique supports do for not this always technique have do to benot macromolecules—small always have to be macromol moleculesecules—small like fluorous molecules tags or likeionic fluorous tags can tags also or be usedionic totags effect can catalyst/product also be used to effect separation catalyst/product and catalyst separation recycling. Suchand catalyst soluble recycling.supports haveSuch potential soluble advantagessupports have in thatpotential they can advantages avoid some in ofthat the they problems can avoid of heterogeneized some of the problemscatalysts that of heterogeneized include more complicated catalysts that analyses include and more the observation complicated that analyses the reactivity and the and observation selectivity thatof an the immobilized reactivity catalystand selectivity differ from of whatan immobili is seen withzed catalyst an optimized differ homogeneousfrom what is catalyst seen with analog. an Theseoptimized problems homogeneous reflect the catalyst fact that an thealog. advantage These problems of heterogeneous reflect the catalysts, fact that which the isadvantage their ease of heterogeneousseparation from catalysts, the reaction which mixture, is their is ease an issue of sepa notration just at from the separationthe reaction step mixture, after the is an reaction issue butnot justalso at during the separation the reaction step and after during the reaction the catalyst but synthesis.also during The the strategy reaction in and which during phase the tag catalyst that is synthesis.soluble is usedThe strategy can avoid in this which issue phase in that tag catalyst that is solublesoluble supportsis used can or phaseavoid tagsthis allowissue in the that catalysts catalyst to soluble supports or phase tags allow the catalysts to be synthesized and characterized in homogeneous solution and allow them to carry out their reaction as homogenous catalysts. Such tags are only used to effect separation after the reaction is complete.

Polymers 2016, 8, 140 10 of 23

Polymers 2016, 8, 140 10 of 22 be synthesized and characterized in homogeneous solution and allow them to carry out their reaction as homogenousAn example catalysts. of this approach Such tags is the are use only of used ionic to liquid effect (IL) separation immobilized after thecatalysts reaction (Figure is complete. 6). Ionic liquidsAn are example alternative of this solvents approach that is are the useful use of because ionic liquid of their (IL) unique immobilized properties catalysts including (Figure non-6). volatility,Ionic liquids high are stability, alternative and solventsgood recyclability that are useful [34]. These because alternative of their solvents unique propertiesare immiscible including with mostnon-volatility, organic solvents. high stability, Thus, andthey goodcan be recyclability used in catalytic [34]. Thesereactions alternative as a recyclable solvents phase. are immiscible Buijsman andwith co-workers most organic reported solvents. the use Thus, of theyGrubbs can 1st be generation used in catalytic catalyst reactions 1 and Grubbs as a recyclable 2nd generation phase. catalystBuijsman in andan RCM co-workers reaction reported of 1,5-diallyl-3-benzyl-5-isobutylimidazolidine-2,4-dione the use of Grubbs 1st generation catalyst 1 and in Grubbs 1-butyl-3- 2nd methylimidazoliumgeneration catalyst hexafluorophosphate in an RCM reaction of(BMI 1,5-diallyl-3-benzyl-5-isobutylimidazolidine-2,4-dione PF6) as an ionic liquid solvent. These catalysts were recycledin 1-butyl-3-methylimidazolium up to three times with Ru hexafluorophosphate residues of ca. 5000 (BMIand 1600 PF6) ppm as an in ionic the liquidproduct, solvent. respectively These [35].catalysts One were year recycled later, Dixneuf up to three reported times withthe use Ru residuesof BMI PF of 6ca as. 5000 solvent and 1600in an ppm RCM in thereaction product, of diallyltosylamiderespectively [35]. Onecatalyzed year later, by a Dixneuf ruthenium reported benzylidine the use salt of BMI and PF was6 as able solvent to recycle in an RCM the catalyst reaction for of twodiallyltosylamide cycles [36]. Following catalyzed this by work, a ruthenium Guillemin benzylidine and co-workers salt and introduced was able to the recycle ionic the liquid-tagged catalyst for rutheniumtwo cycles [catalyst36]. Following 33 which this was work, synthesized Guillemin in andorder co-workers to minimize introduced the leaching the of ionic the liquid-taggedcatalyst from theruthenium ionic liquid catalyst phase33 which[37]. This was ionic synthesized liquid-bound in order catalyst to minimize 33 completed the leaching an RCM of thereaction catalyst of diallyltosylamidefrom the ionic liquid with phase BMI.PF6 [37 ].as Thisa solvent ionic at liquid-bound 60 °C in 45 min catalyst using 332.5completed mol % of 33 an. The RCM isolation reaction of ˝ theof diallyltosylamide product was achieved with BMI by .extractionPF6 as a solvent with toluene at 60 C and in 45 the min ionic using liquid 2.5 molphase % ofcontaining33. The isolation 33 was reusedof the product for an RCM was achieved reaction byof extractiondiallyltosylamide with toluene for 8 andcycles. the Importantly, ionic liquid phasethis catalyst containing was33 stablewas enoughreused forto ancatalyze RCM reactionthe ninth of cycle diallyltosylamide of this RCM forreaction 8 cycles. without Importantly, any loss this in activity catalyst after was stablethree months.enough toYao catalyze and Sheets the ninth reported cycle ofth thise synthesis RCM reaction of a similarly without stable any loss ionic in activityliquid-tagged after three catalyst months. 34 [38].Yao andThis Sheets catalyst reported too was the recycled synthesis very of a similarlyeffectively stable through ionic 17 liquid-tagged cycles in the catalyst RCM34 reaction[38]. This of diallyltosylamidecatalyst too was recycled without very any effectivelyloss in activity. through In 17contrast, cycles ina similar the RCM untagged reaction analog of diallyltosylamide of 34 lost its activitywithout in any the loss second in activity. and subsequent In contrast, runs. a similar In 200 untagged7, Dixneuf analog and co-workers of 34 lost its reported activity inthe the synthesis second ofand 35 subsequentand 36, an improved runs. In version 2007, Dixneuf of 34 [39]. and However, co-workers while reported the activities the synthesis of both catalysts, of 35 and toward36, an theimproved same substrate version of mentioned34 [39]. However, earlier, were while good the activities for the first of bothcycle, catalysts, the catalyst toward activities the same significantly substrate droppedmentioned in earlier,the second were cycle. good In for general, the first these cycle, stud theies catalyst relied activitieson measuring significantly catalystdropped reactivity in as the a basissecond for cycle. catalyst In general,recyclability. these The studies amount relied of on Ru measuring leaching was catalyst typically reactivity not mentioned as a basis forexcept catalyst in a fewrecyclability. cases. The amount of Ru leaching was typically not mentioned except in a few cases.

Figure 6. Ionic liquid-tagged ruthenium catalysts 33–36. Figure 6. Ionic liquid-tagged ruthenium catalysts 33–36.

An alternative scheme for liquid/liquid separation that has been used in metathesis and in other chemistryAn alternative is fluorous scheme phase technology. for liquid/liquid In this sc separationheme, catalysts that has are beenmodified used with in metathesisfluorinated and phase in tagsother to chemistry facilitateis separation, fluorous phase recovery technology. and recycling In this scheme, in perfluorinated catalysts are solvents modified [40]. with Examples fluorinated of fluorous-taggedphase tags to facilitate Ru catalysts separation, are shown recovery in andFigure recycling 7. Since in the perfluorinated first report by solvents Horváth [40 ].[41], Examples fluorous of biphasic catalysis has greatly expanded and developed into a general strategy for separations [42]. This chemistry typically uses a mixture of organic and fluorous solvents, relying on the fact that

Polymers 2016, 8, 140 11 of 23

fluorous-tagged Ru catalysts are shown in Figure7. Since the first report by Horváth [ 41], fluorous biphasic catalysis has greatly expanded and developed into a general strategy for separations [42]. Polymers 2016, 8, 140 11 of 22 This chemistry typically uses a mixture of organic and fluorous solvents, relying on the fact that fluorousfluorous solvents are often immiscible with most organic solvents at room temperature and such solvent mixtures are often biphasic. Such solvent mi mixturesxtures can be used in two ways. In one type of experiment, aa reaction reaction is carriedis carried out underout under biphasic biphasic conditions conditions with a biphasic with a liquid/liquid biphasic liquid/liquid separation afterseparation a reaction. after Alternatively, a reaction. Alternatively, in some cases fluorousin some and cases organic fluorous solvents and become organic miscible solvents at elevatedbecome temperature.miscible at elevated In those temperature. thermomorphic In those systems, thermo a reactionmorphic can systems, be effected a reaction under monophasic can be effected conditions under andmonophasic the catalyst conditions and the and fluorous the catalyst phase and can the be separatedfluorous phase from can an organicbe separated product from in anan organic phaseproduct at in room an organic temperature phase when at room the temperature biphasic mixture when reforms the biphasic and themixture phases reforms can be and separated the phases one fromcan be another separated by aone gravity-based from another liquid/liquid by a gravity-based biphasic liquid/liquid separation. Inbiphasic 2004, Yaoseparation. and Zhang In 2004, reported Yao theand immobilizationZhang reported of the a Grubbs-typeimmobilization catalyst of a Grubbs-type on poly(fluoroalkyl catalyst acrylate)on poly(fluoroalkyl37 [42]. The acrylate) catalyst 37 was[42]. usedThe catalyst in RCM 37 reactions was used of in diallyltosylamide RCM reactions of in diallyltosylamide a monophasic PhCF in a3/CH monophasic2Cl2 (1:19 PhCFv/v)3/CH solvent2Cl2 system.(1:19 v/v Extraction) solvent system. of the fluorousExtraction species of the using fluorous perfluorohexane species using (FC-72) perfluorohexane and EtOAc (FC-72) after each and reaction EtOAc allowedafter each the reaction catalyst allowed to be recovered the catalyst and to reused. be reco Thevered authors and reused. were able The to authors recycle thiswere fluorous-tagged able to recycle rutheniumthis fluorous-tagged catalyst for ruthenium 20 cycles. catalyst However, for leaching 20 cycles. was However, not described. leaching Inspired was not by described. this work, Inspired Curran groupby this reportedwork, Curran the study group of reported other recoverable the study of metathesis other recoverable catalysts metathesis using lighter catalysts fluorous using supports, lighter withfluorous only supports, 17 fluorine with atoms only per17 fluorine Ru in 38 atomsand 39 perversus Ru in170 38 fluorineand 39 versus atoms 170 per fluorine Ru in 37 atoms[43]. per These Ru catalystsin 37 [43].38 Theseand 39catalystsshowsimilar 38 and activity39 show to similar their non-fluorous-bound activity to their non-fluorous-bound analogs in RCM reactionanalogs ofin diallyltosylamide.RCM reaction of diallylt However,osylamide. the separations However, of the catalysts separations38 and of39 catalystsinvolved 38 theand use 39 ofinvolved fluorous the silica use gelof fluorous rather than silica a gel liquid/liquid rather than extraction.a liquid/liquid Thus, extraction. extra solvents Thus, extra including solvents acetonitrile including were acetonitrile needed towere obtain needed the to product obtain andthe product ether was and needed ether was to recover needed the to recover fluorous-tagged the fluorous-tagged catalyst. The catalyst. recovered The catalystrecovered can catalyst be reused can for be atreused least fivefor at cycles least withfive cycles the average with the product average yield product of 97%. yield Later of on, 97%. Matsugi Later andon, Matsugi co-workers and reported co-workers two otherreported light two fluorous-tagged other light fluorous-tagged catalysts 40 and catalysts41 [44]. Compared40 and 41 to[44].39, fluorous-taggedCompared to 39 catalyst, fluorous-tagged40 had an improvement catalyst 40 inhad activity an improvement with similar recyclability in activity (90%with recovery similar ofrecyclability catalyst), while(90% recove41 showedry of highercatalyst), activity while than41 showed both 39 higherand 40 activitybut was than not both recoverable 39 and 40 [ 44but]. was The fluorous-taggednot recoverable [44]. catalyst The40 fluorous-taggedwas recycled and catalyst reused 40 in was an RCMrecycled reaction and reused of diethyl in an diallylmalonate RCM reaction for of fivediethyl times. diallylmalonate The product yieldfor five was times. 95%–100% The product in each yield cycle. was 95%–100% in each cycle.

Figure 7. Fluorous-tagged ruthenium catalysts 37–41. Figure 7. Fluorous-tagged ruthenium catalysts 37–41. Soluble polymeric supports are an alternative to ionic or fluorous tags. Poly(ethylene glycol) (PEG)Soluble is one of polymeric the most widely supports used are such an alternativesupports for to reagents ionic or and fluorous organometallic tags. Poly(ethylene complexes [45–47]. glycol) (PEG)PEG has is one been of theused most both widely to bind used catalysts such supports and ha fors been reagents used andas a organometallic solvent [48]. Examples complexes of [45 PEG-–47]. PEGbound has Ru been metathesis used both catalysts to bind are catalysts shown and in hasFigu beenre 8. used Although as a solvent PEG and [48]. PEG-bound Examples of catalysts PEG-bound are Rusoluble metathesis in many catalysts organic are solvents shown including in Figure 8water,. Although they are PEG insoluble and PEG-bound in solvents catalysts like hexane, are soluble diethyl in ether, and cold ethanol. Thus, these PEG derivatives can be utilized to separate catalysts and products for catalyst recovery and recycling by either solvent precipitation or liquid/liquid extraction. An early example of the synthesis and application of a PEG5000-bound ruthenium metathesis catalyst 42 was reported by Yao in 2000 [49]. This soluble polymer-supported catalyst 42 was recycled 8 times in the RCM reaction of allyl(4-pentenyl)tosylamide with more than 92% conversion in each cycle. The

Polymers 2016, 8, 140 12 of 23 many organic solvents including water, they are insoluble in solvents like hexane, diethyl ether, and cold ethanol. Thus, these PEG derivatives can be utilized to separate catalysts and products for catalyst recovery and recycling by either solvent precipitation or liquid/liquid extraction. An early example of the synthesis and application of a PEG -bound ruthenium metathesis catalyst 42 was reported Polymers 2016, 8, 140 5000 12 of 22 by Yao in 2000 [49]. This soluble polymer-supported catalyst 42 was recycled 8 times in the RCM reactioncatalyst was of allyl(4-pentenyl)tosylamide recovered by precipitation with with more diethy thanl ether. 92% Although conversion the in auth eachor cycle. reported The catalyst the success was recoveredin catalyst byrecycling, precipitation the analysis with diethyl of Ru leaching ether. Although was not thereported. author It reported also should the successbe noted in that catalyst this recycling,type of process the analysis for catalyst of Ru recovery leaching wasrequires not reported. a large excess It also of should the ether be noted solvent—a that this possible type of issue process in forgreen catalyst chemistry recovery terms. requires In 2003, a large Lamaty excess and of theco-workers ether solvent—a described possible the study issue of in a green PEG3400 chemistry-bound terms.Hoveyda-Grubbs In 2003, Lamaty 2nd generation and co-workers catalyst described 43 [48]. the The study soluble of a PEG support3400-bound was Hoveyda-Grubbsattached to the 2ndbenzylidene generation ligand catalyst ortho43 [48to ].the The metal soluble carbene. support This was attachedcatalyst tocan the catalyze benzylidene RCM ligand reactionortho toof thediallyltosylamide metal carbene. for This 5 cycles catalyst at canroom catalyze temperature. RCM reaction The recovery of diallyltosylamide of this catalyst forfrom 5 cyclesRCM reaction at room temperature.was also carried The out recovery by precipitation of this catalyst in diethyl from ether RCM and reaction filtration. was alsoIn this carried work, out the by authors precipitation carried inout diethyl some additional ether and filtration.characterization In this work,of the thereco authorsvered PEG-bound carried out Ru some complex. additional The characterization precipitate was 1 ofanalyzed the recovered by 1H NMR PEG-bound spectroscopy, Ru complex. measuring The precipitate the intensity was of analyzed the vinyl by protonH NMR of the spectroscopy, alkylidene measuringgroup in the the catalyst intensity at 16.50 of the δ. vinylThe results proton showed of the alkylidenethat only 57% group of 43 in was the catalystrecovered at after 16.50 theδ. first The resultscycle of showed RCM reaction. that only 57% of 43 was recovered after the first cycle of RCM reaction.

Figure 8. PEG-supported Hoveyda-Grubbs catalyst 42 and 43..

The Bergbreiter and Bazzi groups have also described the use soluble polymer supports for The Bergbreiter and Bazzi groups have also described the use soluble polymer supports for ruthenium olefin metathesis catalysts. In their work, they focused on soluble polyolefin oligomers ruthenium olefin metathesis catalysts. In their work, they focused on soluble polyolefin oligomers that can be more efficiently separated as an alternative to PEG supports whose separation typically that can be more efficiently separated as an alternative to PEG supports whose separation typically generates large volumes of solvents waste during the polymer precipitation step. These alternative generates large volumes of solvents waste during the polymer precipitation step. These alternative polymers are polyethylene (PEOlig) and polyisobutylene oligomers (PIB). Several techniques for polymers are polyethylene (PE ) and polyisobutylene oligomers (PIB). Several techniques for separation of these types of polymer-supportedOlig species including liquid/liquid separation and separation of these types of polymer-supported species including liquid/liquid separation and solid/liquid separation shown in Figure 9 can be used. The first synthesis and application of PIB- solid/liquid separation shown in Figure9 can be used. The first synthesis and application of supported Hoveyda-Grubbs type catalyst using such polymers was described in 2007 [50]. In this PIB-supported Hoveyda-Grubbs type catalyst using such polymers was described in 2007 [50]. In this case, the PIB (Mn = 1000) was attached to the catalyst as a benzylidene ligand following a prior case, the PIB (M = 1000) was attached to the catalyst as a benzylidene ligand following a prior strategy strategy describedn by Barrett [17]. This pre-catalyst 44 was then used to catalyze RCM reactions in described by Barrett [17]. This pre-catalyst 44 was then used to catalyze RCM reactions in heptane. heptane. The products were then separated from the catalyst solution by an acetonitrile extraction. The products were then separated from the catalyst solution by an acetonitrile extraction. In some In some cases, the RCM product self-separated from the catalyst. In such cases where the product cases, the RCM product self-separated from the catalyst. In such cases where the product precipitated precipitated from the heptane solution, a filtration was only needed to isolate the product. This PIB- from the heptane solution, a filtration was only needed to isolate the product. This PIB-supported supported ruthenium complex 44 was reused for at least five cycles. The Ru leaching into the product ruthenium complex 44 was reused for at least five cycles. The Ru leaching into the product was was measured and varied from 20 to 1000 ppm, suggesting that the “boomerang” scheme for measured and varied from 20 to 1000 ppm, suggesting that the “boomerang” scheme for recycling the recycling the catalyst was not as effective as desired. In order to improve the recoverability of the catalyst was not as effective as desired. In order to improve the recoverability of the PIB-supported PIB-supported ruthenium catalyst, an alternative type of catalyst was prepared where the PIB (Mn = ruthenium catalyst, an alternative type of catalyst was prepared where the PIB (M = 1000) chains 1000) chains were attached to the non-dissociating N-heterocyclic carbene ligandsn of a Hoveyda- were attached to the non-dissociating N-heterocyclic carbene ligands of a Hoveyda-Grubbs catalyst as Grubbs catalyst as in complex 45 [51]. This catalyst design led to improvements in both the in complex 45 [51]. This catalyst design led to improvements in both the consistency and effectiveness consistency and effectiveness of Ru catalyst/product separation. Leaching levels dropped to values of Ru catalyst/product separation. Leaching levels dropped to values as low as 73 ppm (0.37% of as low as 73 ppm (0.37% of the charged Ru catalyst). Moreover, catalyst 45 could be reused for 20 the charged Ru catalyst). Moreover, catalyst 45 could be reused for 20 cycles. More recent work cycles. More recent work from our group on polymer-supported olefin metathesis catalyst explored from our group on polymer-supported olefin metathesis catalyst explored the use of Polyethylene the use of Polyethylene oligomer (PEOlig) (Mn = 550) as catalyst supports [52]. The unique property of PEOlig is that it is like higher molecular weight polyethylene and does not dissolve in any solvent at room temperature. However, like high molecular weight polyethylene, it does dissolve at elevated temperature. Moreover, polyethylene oligomers that are commercially available as 500–2000 Da materials are soluble in toluene or THF at relatively modest temperatures like 65 °C. A PEOlig- supported Hoveyda-Grubbs catalyst 46 formed from PEOlig with an Mn of 550 Da can be dissolved in a solvent with modest heating to form a monophasic solution. The complex 46 quantitatively precipitates on cooling. Thus, 46 can be added to substrate, the suspension that forms can be heated

Polymers 2016, 8, 140 13 of 23

oligomer (PEOlig) (Mn = 550) as catalyst supports [52]. The unique property of PEOlig is that it is like higher molecular weight polyethylene and does not dissolve in any solvent at room temperature. However, like high molecular weight polyethylene, it does dissolve at elevated temperature. Moreover, polyethylene oligomers that are commercially available as 500–2000 Da materials are soluble in toluene ˝ or THF at relatively modest temperatures like 65 C. A PEOlig-supported Hoveyda-Grubbs catalyst 46 formed from PEOlig with an Mn of 550 Da can be dissolved in a solvent with modest heating to formPolymers a monophasic 2016, 8, 140 solution. The complex 46 quantitatively precipitates on cooling. Thus, 46 can13 of be 22 added to substrate, the suspension that forms can be heated to form a monophasic reaction solution, andto form the catalysta monophasic can be separatedreaction solution, from asolution and the ofca thetalyst product can be by separated simply cooling from ait solution back to roomof the temperature.product by simply Filtration cooling then effects it back phase to room separation temper betweenature. theFiltration solid catalyst then effects species phase and the separation product solution.between Inthe reports solid catalyst describing species this catalyst,and the theproduct PEOlig so-supportedlution. In reports catalyst describing46 was used this in catalyst, a variety the of RCMPEOlig reactions-supported for catalyst at least 46 eight was cycles used in with a variety the Ru of leaching RCM reactions based on for ICP-MS at least analysis eight cycles that waswith less the thanRu leaching 0.3% based based on theon ICP-MS amount analysis of charged that Ru. was Examples less than of 0.3% these based polyolefin-supported on the amount of Ru charged metathesis Ru. catalystsExamples are of shown these in polyolefin-supported Figure 10. The effectiveness Ru meta of thethesis catalyst/product catalysts are separation shown in in Figure these processes 10. The waseffectiveness further tested of the in catalyst/product sequential reactions separation where thein these same processes sample of was46 wasfurther used tested to carry in sequential out three successivereactions where RCM reactions.the same sample This experiment of 46 was notused only to carry showed out that three Ru successive leaching wasRCM low reactions. but that This the productexperiment of one not reaction only showed was not that detectable Ru leaching in a subsequentwas low but cycle that that the usedproduct the of same one catalyst reaction used was in not a priordetectable different in a reaction. subsequent cycle that used the same catalyst used in a prior different reaction.

a)

catalyst heat catalyst cool catalyst product substrate product

1. separate 2. fresh polar solvent, substrate

b) catalyst rxn catalyst perturb substrate product catalyst solvents solvents product

1. separate 2. fresh polar solvent, substrate

c) catalyst substrateheat cool product product

1. filter 2. fresh solvent, substrate = polymer-bound catalyst Figure 9. Schematic representation of (a) thermomorphic liquid/liquid separation where a biphasic Figure 9. Schematic representation of (a) thermomorphic liquid/liquid separation where a biphasic mixture of polar and nonpolar solvent is heated to form a miscible solvent mixture; (b) a latent mixture of polar and nonpolar solvent is heated to form a miscible solvent mixture;(b) a latent biphasic liquid/liquid separation where a room temperature mixture of miscible solvents is used to biphasic liquid/liquid separation where a room temperature mixture of miscible solvents is used effect a reaction and the solvent mixture is perturbed (e.g., by addition of another solvent (e.g., water) to effect a reaction and the solvent mixture is perturbed (e.g., by addition of another solvent or some salt) to form a separable biphasic mixture of polar and nonpolar solvents; and (c) a (e.g., water) or some salt) to form a separable biphasic mixture of polar and nonpolar solvents; and (cthermomorphic) a thermomorphic solid/liquid solid/liquid separation separation system system where a where mixture a mixtureof substrate of substrate and insoluble and insoluble polymer- polymer-boundbound catalyst is catalyst heatedis to heatedform a tomonophasic form a monophasic solution that solution is in turnthat cooled is in turnto form cooled a precipitate to form aofprecipitate the polymer of bound the polymer catalyst boundthat is then catalyst separatedthat is from then the separated product solution from the byproduct filtration. solution by filtration.

Figure 10. Polyolefin-supported Hoveyda-Grubbs catalysts 44–46.

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to form a monophasic reaction solution, and the catalyst can be separated from a solution of the product by simply cooling it back to room temperature. Filtration then effects phase separation between the solid catalyst species and the product solution. In reports describing this catalyst, the PEOlig-supported catalyst 46 was used in a variety of RCM reactions for at least eight cycles with the Ru leaching based on ICP-MS analysis that was less than 0.3% based on the amount of charged Ru. Examples of these polyolefin-supported Ru metathesis catalysts are shown in Figure 10. The effectiveness of the catalyst/product separation in these processes was further tested in sequential reactions where the same sample of 46 was used to carry out three successive RCM reactions. This experiment not only showed that Ru leaching was low but that the product of one reaction was not detectable in a subsequent cycle that used the same catalyst used in a prior different reaction.

a)

catalyst heat catalyst cool catalyst product substrate product

1. separate 2. fresh polar solvent, substrate

b) catalyst rxn catalyst perturb substrate product catalyst solvents solvents product

1. separate 2. fresh polar solvent, substrate

c) catalyst substrateheat cool product product

1. filter 2. fresh solvent, substrate = polymer-bound catalyst Figure 9. Schematic representation of (a) thermomorphic liquid/liquid separation where a biphasic mixture of polar and nonpolar solvent is heated to form a miscible solvent mixture; (b) a latent biphasic liquid/liquid separation where a room temperature mixture of miscible solvents is used to effect a reaction and the solvent mixture is perturbed (e.g., by addition of another solvent (e.g., water) or some salt) to form a separable biphasic mixture of polar and nonpolar solvents; and (c) a thermomorphic solid/liquid separation system where a mixture of substrate and insoluble polymer- bound catalyst is heated to form a monophasic solution that is in turn cooled to form a precipitate Polymers 2016, 8, 140 14 of 23 of the polymer bound catalyst that is then separated from the product solution by filtration.

Figure 10. Polyolefin-supported Hoveyda-Grubbs catalysts 44–46. Figure 10. Polyolefin-supported Hoveyda-Grubbs catalysts 44–46.

Up to this point, this review has focused on background examples of ring closing and cross metathesis reactions where metathesis catalysts are separated either by liquid/solid or liquid/liquid separations. In these applications, the need for a separation strategy depends on the reactivity of the Ru catalyst. Catalysts with TONs that approach 105 or 106 may not even need a support and a separation strategy. This however is not true in polymerization reactions where no chain transfer occurs. In such cases, the living character of a ring-opening metathesis polymerization in a polymerization leads to one metal center being used for each polymer molecule synthesized. In these cases metal or metal-ligand separations are more critical. The balance of this review will discuss metathesis catalysts and ligand separation from products in this more demanding context.

4. Supported Catalysts in Ring-opening Metathesis Polymerization (ROMP) The first example of supported catalyst used in ROMP is also the first well-defined polymer-supported olefin metathesis catalyst [16]. In this study by Grubbs and Nguyen, a series of polystyrene-divinylbenzene (DVB-PS)-supported Cl2(PR3)2Ru=CH-CH=CPh2 olefin metathesis catalysts 6, 47, and 48 were synthesized as shown in Scheme2. These solid-supported catalysts showed activities that were similar to that seen for their homogeneous analogs where the catalyst reactivity varied depending on the nature of PS-supported phosphine ligands. For example, while catalyst 48 can only catalyze ROMP reaction of highly strained cyclic olefins such as norbornene, 6 and 47 can catalyze ROMP of the less strained cyclic olefins such as cyclooctene. Although 6, 47, and 48 were competent catalysts for ROMP of norbornene, the PDIs of the resulting polymer products were significantly higher than those prepared by the homogeneous analogs. For example, polynorbornene prepared from 6 had PDI values of 5.5, while 1 could be used to prepare similar polymers with PDI values ranging from 1.1 to 1.3. The broader molecular weight range for the polynorbornene prepared by the immobilized catalyst was postulated to be a result of the slow initiation rate of immobilized catalyst that could reflect its inhomogeneity or perhaps the fact that the actual catalyst is a complex that dissociates from the support. The amount of Ru contamination in the ROMP products was not reported. Alternative insoluble organic supports that have been used as catalyst supports for Ru ROMP catalysts include monolithic materials. While such materials have been known since the 1970s [53] but have received more attention [54,55] after studies by Fréchet and Svec highlighted their utility as high-performance separation media, scavengers, and reagent supports [56,57]. Such media have been used too as metathesis catalyst supports as noted above. That work includes studies by Buchmeiser whose group described a synthetic route to a monolith-supported ruthenium olefin metathesis catalyst 50 (Scheme3)[ 58]. The monolith was generated through ring-opening metathesis copolymerization of norbornene (NBE) and 1,4,4a,5,8,8a-hexahydro-1,4,5,8-exo-endo-dimethanonaphthalene (DMN.H6) in the presence of dichloromethane and 2-propanol within a borosilicate column. The functionalization of the catalyst onto the monolith was achieved by grafting a mixture of compound 49 and norbornene onto this solid support. After the grafting process was complete, it was terminated by addition of ethyl vinyl ether. The resulting grafts contained imidazolium salts that were then deprotonated with dimethylaminopyridine (DMAP) to generate an NHC ligand. The immobilization of a ruthenium Polymers 2016, 8, 140 15 of 23 catalyst onto the monolith support using these NHC ligands was then achieved by treating this monolith-immobilized NHC ligand with 1. As noted above, the monolith-supported ruthenium complex 50 showed high activity toward RCM. This RCM catalyst was also used in ROMP reactions, where the cis and trans ratio of ROMP products of norbornene and cis-cyclococtene were the same as those obtained using the analogous homogeneous catalyst. In the ROMP chemistry, the PDI of polymer products ranged from 1.2 to 2.6. However, while the extent of Ru leaching in RCM products was reported as 70 ppm, Ru leaching in the ROMP products was not reported. Schrock’s molybdenum catalysts that are used in ROMP have been also immobilized on heterogeneous supports. However, perhaps because of their sensitivity toward air and moisture, Polymersthere are 2016 relatively, 8, 140 few reports discussed about immobilizing these Mo-based ROMP catalysts15 onto of 22 solid supports. One example was reported by Basset group in 1996 [59]. The molybdenum complex 51 was immobilized onto silica at 70 °C.˝C. The loss of neopentane in 52 was postulated to be involved in the generation of an active silica-supported catalyst 53. While While the the structure structure of of 53 was inferred, the presence of of a a complex complex like like 5353 waswas confirmed confirmed by byelemental elemental analyses analyses that that yield yield a Mo/N/C a Mo/N/C ratio of ratio 1/1/10 of 1/1/10(Scheme (Scheme 4). This4 ).immobilized This immobilized complex complex 53 can53 preparecan prepare ROMP ROMP products products of norbornene of norbornene and andcis- ˝ cyclooctenecis-cyclooctene at 25 at °C 25 inC high in highyield yield (74% (74%and 85%, and 85%,respectively). respectively). These TheseROMP ROMP products products had Mn had valuesMn ofvalues ca. 310,000 of ca. 310,000 Da with Da a PDI with of a ca PDI. 1.8. of Theca. 1.8.metal The analysis metal analysisof molybdenum of molybdenum in ROMP in products ROMP products was not wasdescribed. not described.

Scheme 2. DVB-PS-SupportedDVB-PS-Supported Olefin Olefin Metathesis Catalysts 6, 47, and 48.

Scheme 3. Synthesis of Monolith-Supported Ruthenium Olefin Metathesis Catalyst 50.

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51 was immobilized onto silica at 70 °C. The loss of neopentane in 52 was postulated to be involved in the generation of an active silica-supported catalyst 53. While the structure of 53 was inferred, the presence of a complex like 53 was confirmed by elemental analyses that yield a Mo/N/C ratio of 1/1/10 (Scheme 4). This immobilized complex 53 can prepare ROMP products of norbornene and cis- cyclooctene at 25 °C in high yield (74% and 85%, respectively). These ROMP products had Mn values of ca. 310,000 Da with a PDI of ca. 1.8. The metal analysis of molybdenum in ROMP products was not described.

Polymers 2016, 8, 140Scheme 2. DVB-PS-Supported Olefin Metathesis Catalysts 6, 47, and 48. 16 of 23

SchemeScheme 3. 3.SynthesisSynthesis of of Monolith-Supported Monolith-Supported Ru Rutheniumthenium OlefinOlefin Metathesis Metathesis Catalyst Catalyst50 .50. Polymers 2016, 8, 140 16 of 22

SchemeScheme 4. 4. SynthesisSynthesis of of Silica-Su Silica-Supportedpported SchrockSchrock Catalyst Catalyst53 53. .

In Inattempting attempting to to develop a a greener greener metathesis metathesis reaction reaction process, process, the Grubbs the Grubbs group reported group severalreported severalsyntheses syntheses of highly of highly active PEG-boundactive PEG-bound ruthenium ruthenium complexes complexes that can be that used can in be aqueous used mediain aqueous to N mediacatalyze to catalyze ROMP reactions.ROMP reactions. One example One isexample the PEG 5000is theconjugated PEG5000 conjugated-heterocyclic N-heterocyclic carbene-containing carbene- containingruthenium ruthenium benzylidene benzylidene catalyst 54 catalyst[60] (Scheme 54 [60]5 ).(Scheme This catalyst 5). This initiated catalyst the initiated ROMP the of 55ROMPto give of 55 56 1 to polynorbornenegive polynorbornenein 73% 56 in conversion 73% conversion after 24 h,after as measured 24 h, as measured by H NMR by spectroscopy 1H NMR spectroscopy in D2O. The in rate of ROMP reaction with a catalyst like 55 depends on the rate of phosphine dissociation. In this case D2O. The rate of ROMP reaction with a catalyst like 55 depends on the rate of phosphine dissociation. the dissociation of phosphine from catalyst 54 may be disfavored in water. However, the protonation In this case the dissociation of phosphine from catalyst 54 may be disfavored in water. However, the of free phosphine by HCl could in principle inhibit re-association of the phosphine ligand. In this case, protonation of free phosphine by HCl could in principle inhibit re-association of the phosphine the rate of polymerization was dramatically increased to 95% conversion in 15 min when 1 equiv of ligand. In this case, the rate of polymerization was dramatically increased to 95% conversion in 15 min HCl, relative to catalyst 54, was present in the reaction. This chemistry is similar to the Phase Transfer whenActivation 1 equiv (PTA) of HCl, principle relative used to catalyst by the Gladysz54, was andpresent Bazzi in groupsthe reaction. where This a phosphine chemistry that is issimilar more to thesoluble Phase inTransfer a fluorous Activation or aqueous (PTA) phase isprinciple used with used a Grubbs by the catalyst Gladysz under and biphasic Bazzi conditions groups where a phosphinethe phosphine that is separationmore soluble into in a fluorousa fluorous or or aqueous aqueous phase phase precludes is used re-associationwith a Grubbs [61 catalyst,62]. In under the biphasicGrubbs’ conditions work, the where PEG-bound the phosphine ruthenium separation catalyst 54 intowas showna fluorous to catalyze or aqueous a ROMP phase reaction precludes of the re- associationmonomer [61,62].endo- 57 Inwith the 86%Grubbs’ conversion work, tothe polymer PEG-bound58 within ruthenium 14 h. It iscatalyst known 54 that was this shownendo-monomer to catalyze a ROMPis a more reaction challenging of the ROMPmonomer substrate endo- 57 than with the 86%exo-monomer conversion55 to[60 polymer]. The extent 58 within to which 14 h. the It ROMPis known thatproducts this endo were-monomer contaminated is a more by residues challenging of the ROMP PEG-bound substrate ruthenium than complexthe exo-monomer54 was not 55 reported. [60]. The extent to which the ROMP products were contaminated by residues of the PEG-bound ruthenium complex 54 was not reported.

Scheme 5. ROMP Reactions of 55 and 57 Catalyzed by 54.

The complex 59 prepared with a PEG2000 support that was used in RCM and CM reactions of substrates like 2-allyl-N,N,N-trimethylpent-4-en-1-aminium chloride and allyl alcohol in water has

Polymers 2016, 8, 140 16 of 22

Scheme 4. Synthesis of Silica-Supported Schrock Catalyst 53.

In attempting to develop a greener metathesis reaction process, the Grubbs group reported several syntheses of highly active PEG-bound ruthenium complexes that can be used in aqueous media to catalyze ROMP reactions. One example is the PEG5000 conjugated N-heterocyclic carbene- containing ruthenium benzylidene catalyst 54 [60] (Scheme 5). This catalyst initiated the ROMP of 55 to give polynorbornene 56 in 73% conversion after 24 h, as measured by 1H NMR spectroscopy in D2O. The rate of ROMP reaction with a catalyst like 55 depends on the rate of phosphine dissociation. In this case the dissociation of phosphine from catalyst 54 may be disfavored in water. However, the protonation of free phosphine by HCl could in principle inhibit re-association of the phosphine ligand. In this case, the rate of polymerization was dramatically increased to 95% conversion in 15 min when 1 equiv of HCl, relative to catalyst 54, was present in the reaction. This chemistry is similar to the Phase Transfer Activation (PTA) principle used by the Gladysz and Bazzi groups where a phosphine that is more soluble in a fluorous or aqueous phase is used with a Grubbs catalyst under biphasic conditions where the phosphine separation into a fluorous or aqueous phase precludes re- association [61,62]. In the Grubbs’ work, the PEG-bound ruthenium catalyst 54 was shown to catalyze a ROMP reaction of the monomer endo- 57 with 86% conversion to polymer 58 within 14 h. It is known that this endo-monomer is a more challenging ROMP substrate than the exo-monomer 55 [60]. The

Polymersextent to2016 which, 8, 140 the ROMP products were contaminated by residues of the PEG-bound ruthenium17 of 23 complex 54 was not reported.

Scheme 5. ROMP Reactions of 55 and 57 Catalyzed by 54.

The complex 59 prepared with a PEG2000 support that was used in RCM and CM reactions of PolymersThe 2016 complex, 8, 140 prepared with a PEG2000 support that was used in RCM and CM reactions17 of of22 substrates like 2-allyl-N,N,N-trimethylpent-4-en-1-aminium-trimethylpent-4-en-1-aminium chloride chloride and and allyl allyl alcohol alcohol in in water has also been used in the ROMP reaction of 57 (Scheme6)[ 63]. The polymerization of 57 occurred in 100% also been used in the ROMP reaction of 57 (Scheme 6) [63]. The polymerization of 57 occurred in 100%conversion conversion in 5 h. in The 5 removalh. The removal process ofprocess the PEG-bound of the PEG-bound ruthenium ruthenium complex 59 complexfrom the 59 products from the58 productswas not discussed 58 was not at discussed least in terms at least of the in terms catalyst of andthe catalyst products and in aproducts ROMP reaction. in a ROMP reaction.

SchemeScheme 6. ROMPROMP Reaction Reaction of of 5757 CatalyzedCatalyzed by PEG-Supported Hoveyda-Grubbs Catalyst 59.

The immobilization of a highly active Grubbs 3rd generation catalyst using a PEG350 support has The immobilization of a highly active Grubbs 3rd generation catalyst using a PEG support has also been reported [64]. Emrick and co-workers synthesized a PEG-supported Grubbs 3503rd generation also been reported [64]. Emrick and co-workers synthesized a PEG-supported Grubbs 3rd generation by ligand exchange between pyridine ligands and PEG-bound pyridine ligands. This PEG-supported by ligand exchange between pyridine ligands and PEG-bound pyridine ligands. This PEG-supported catalyst 60 was used to catalyze ROMP reactions in water (Scheme 7). The results showed that this catalyst 60 was used to catalyze ROMP reactions in water (Scheme7). The results showed that this catalyst works well at pH 1.5 with quantitative conversion of monomer 61 to polymer 62 in 2 h at catalyst works well at pH 1.5 with quantitative conversion of monomer 61 to polymer 62 in 2 h at room temperature. It was noted that the activity of 60 decreased with an increasing in pH, e.g., 23% room temperature. It was noted that the activity of 60 decreased with an increasing in pH, e.g., 23% conversion at pH 7 in 2 h at room temperature. However, with an addition of a Brønsted acid, i.e., conversion at pH 7 in 2 h at room temperature. However, with an addition of a Brønsted acid, i.e., CuSO4 and CuBr2, the conversion of monomer 61 was improved from 23% to 70%. The PDI of the CuSO and CuBr , the conversion of monomer 61 was improved from 23% to 70%. The PDI of the polymer4 products2 prepared from 60 ranged from 1.3 to 1.5. The amounts of Ru content in the products polymer products prepared from 60 ranged from 1.3 to 1.5. The amounts of Ru content in the products were not reported. were not reported.

Scheme 7. ROMP Reaction of 61 Catalyzed by PEG-Supported Hoveyda-Grubbs Catalyst 60.

An early report of the use of a PIB-supported catalyst was part of a study of a polyisobutylbenzylidene-supported Ru catalyst that was used in ring closing metathesis. That work showed that this “boomerang” catalyst could be used in ROMP with ca. 3% leaching of the charged Ru [50]. Subsequently in 2012, a more effective Ru separation was achieved by the use of PIB- supported catalyst 45 in ROMP of norbornene derivatives as described in a report by Bazzi and Bergbreiter [65]. The catalyst 45 can be separated from the polymer product at the end of the reaction by dissolving the dry crude mixture of polymer and PIB-supported catalyst in an equi-volume

Polymers 2016, 8, 140 17 of 22

also been used in the ROMP reaction of 57 (Scheme 6) [63]. The polymerization of 57 occurred in 100% conversion in 5 h. The removal process of the PEG-bound ruthenium complex 59 from the products 58 was not discussed at least in terms of the catalyst and products in a ROMP reaction.

Scheme 6. ROMP Reaction of 57 Catalyzed by PEG-Supported Hoveyda-Grubbs Catalyst 59.

The immobilization of a highly active Grubbs 3rd generation catalyst using a PEG350 support has also been reported [64]. Emrick and co-workers synthesized a PEG-supported Grubbs 3rd generation by ligand exchange between pyridine ligands and PEG-bound pyridine ligands. This PEG-supported catalyst 60 was used to catalyze ROMP reactions in water (Scheme 7). The results showed that this catalyst works well at pH 1.5 with quantitative conversion of monomer 61 to polymer 62 in 2 h at room temperature. It was noted that the activity of 60 decreased with an increasing in pH, e.g., 23% conversion at pH 7 in 2 h at room temperature. However, with an addition of a Brønsted acid, i.e., CuSO4 and CuBr2, the conversion of monomer 61 was improved from 23% to 70%. The PDI of the Polymers 2016polymer, 8, 140 products prepared from 60 ranged from 1.3 to 1.5. The amounts of Ru content in the products 18 of 23 were not reported.

SchemeScheme 7. ROMP 7. ROMP Reaction Reaction of 61of 61Catalyzed Catalyzed byby PEG-Supported Hoveyda-Grubbs Hoveyda-Grubbs Catalyst Catalyst 60. 60.

An early report of the use of a PIB-supported catalyst was part of a study of a Anpolyisobutylbenzylidene-supported early report of the use of Ru acatalyst PIB-supported that was used catalystin ring closing was metathesis. part of That a studywork of a polyisobutylbenzylidene-supportedshowed that this “boomerang” catalyst Ru catalyst could be that used was in ROMP used with in ring ca. 3% closing leaching metathesis. of the charged That work showedRu that [50]. this Subsequently “boomerang” in 2012, catalyst a more could effective be used Ru separation in ROMP was with achievedca. 3% by leaching the use ofof thePIB- charged Ru [50].supported Subsequently catalyst in 2012,45 in ROMP a more of effective norbornene Ru separationderivatives as was described achieved in bya report the use by ofBazzi PIB-supported and Bergbreiter [65]. The catalyst 45 can be separated from the polymer product at the end of the reaction catalyst 45 in ROMP of norbornene derivatives as described in a report by Bazzi and Bergbreiter [65]. by dissolving the dry crude mixture of polymer and PIB-supported catalyst in an equi-volume The catalyst 45 can be separated from the polymer product at the end of the reaction by dissolving the dry crude mixture of polymer and PIB-supported catalyst in an equi-volume mixture of DMF and heptane. The catalyst-containing heptane layer was then removed and the DMF layer was then evaporated to dryness to afford the crude polymer as an off-white solid. The crude polymer was Polymers 2016, 8, 140 18 of 22 dissolved in dichloromethane (DCM) and precipitated into an excess amount of hexane to afford the polymermixture product of DMF readyand heptane. for analysis The catalyst-contain for propertiesing heptane and ruthenium layer was then contamination removed and level.the DMF Polymers preparedlayer from was catalyst then evaporated45 have to a nearlydryness identicalto afford thEe/ crudeZ ratio polymer to those as an prepared off-white by solid. their The low crude molecular weight counterpartspolymer was dissolved with PDI in dichloromethane values ranging (DCM) from 1.39and precipitated to 1.78. The into amounts an excess of amount ruthenium of hexane content in the resultingto afford polymers the polymer were product 111–228 ready ppm. for analysis In subsequent for properties work and by ruthenium Bazzi and contamination Bergbreiter, thelevel. activities Polymers prepared from catalyst 45 have a nearly identical E/Z ratio to those prepared by their low 63 and recoverabilitymolecular weight of a counterparts PIB-supported with GrubbsPDI values second ranging generation from 1.39 to catalyst 1.78. The amountsformed of fromruthenium PIB with an Mn of 1000content Da in (Figure the resulting 11) in polymers ROMP were was studied111–228 ppm [66]. In in subsequent a polymerization work by Bazzi of norbornene and Bergbreiter, (Scheme 8). The polymerizationthe activities and rate recoverability of norbornene of a usingPIB-supported63 was 93%Grubbs which second is similargeneration to thatcatalyst of its63 lowformed molecular weight counterpartfrom PIB with64 an(99% Mn of conversion, 1000 Da (Figure after 11) 60 min).in ROMP However, was studied complex [66] in63 aexhibited polymerization a faster of ROMP initiationnorbornene with 70% (Scheme conversion 8). The in polymeri 10 minzation than rate that of of norbornene64 with 30% using conversion 63 was 93% atwhich the is same similar time to period. that of its low molecular weight counterpart 64 (99% conversion, after 60 min). However, complex 63 The PDI values of the polymer products 70–74 analyzed by GPC ranged from 1.11 to 2.34. The removal exhibited a faster ROMP initiation with 70% conversion in 10 min than that of 64 with 30% conversion of catalystat the63 samewas examinedtime period. in The the PDI ROMP values reactions of the polymer of monomer products65 70–69–74. Theanalyzed process by GPC used ranged in separation of residuesfrom from1.11 to catalyst 2.34. The63 removaland the of catalyst polymer 63 productwas examined involved in the dissolvingROMP reactions the of dry monomer crude mixture65– of polymer69 product. The process and Ruused catalyst in separation residue of residues in a minimum from catalyst amount 63 and of DCM the polymer and precipitating product involved themixture in hexanedissolving affording the thedry homopolymercrude mixture of aspolymer a white produc solid.t and The Ru Ru catalyst contamination residue in a levelminimum of polymers amount 70–74 preparedof byDCM63 andvaried precipitating from 71 the to mixture 252 ppm. in hexane affording the homopolymer as a white solid. The Ru contamination level of polymers 70–74 prepared by 63 varied from 71 to 252 ppm.

Figure 11. Polyisobutylene (PIB1000)-supported Grubbs second generation catalysts 63 and Grubbs Figure 11. Polyisobutylene (PIB )-supported Grubbs second generation catalysts 63 and Grubbs catalyst 64. 1000 catalyst 64.

Scheme 8. ROMP Reactions of 65–69 Catalyzed by 63.

The PEOlig-supported ruthenium catalyst 46 has also been used in ROMP reactions of norbornene derivatives [67]. Examples of polymer prepared using 46 are shown in Figure 12. This PEOlig- supported catalyst 60 was used to prepare polymers 74–78 using the same solid/liquid separation concept as was used previously in reactions where this catalyst was used to prepare RCM products. In this case, separation of the ROMP products from 46 was performed by filtration of reaction mixture through Celite and 0.2 μm filter to yield colorless solution containing polymer products. The resulting solution was concentrated and then precipitated in hexane to isolate polymers 74–78. In reactions with catalyst 46, it was found that the prior scheme where polyethylene oligomers were shown to be useful cosolvents facilitate Ru residue separations in ROMP chemistry [67]. Adding unfunctionalized polyethylene oligomers as a cosolvent further facilitated separations of the product polymer and catalyst residues. For example, when a commercially available unfunctionalized polyethylene

Polymers 2016, 8, 140 18 of 22 mixture of DMF and heptane. The catalyst-containing heptane layer was then removed and the DMF layer was then evaporated to dryness to afford the crude polymer as an off-white solid. The crude polymer was dissolved in dichloromethane (DCM) and precipitated into an excess amount of hexane to afford the polymer product ready for analysis for properties and ruthenium contamination level. Polymers prepared from catalyst 45 have a nearly identical E/Z ratio to those prepared by their low molecular weight counterparts with PDI values ranging from 1.39 to 1.78. The amounts of ruthenium content in the resulting polymers were 111–228 ppm. In subsequent work by Bazzi and Bergbreiter, the activities and recoverability of a PIB-supported Grubbs second generation catalyst 63 formed from PIB with an Mn of 1000 Da (Figure 11) in ROMP was studied [66] in a polymerization of norbornene (Scheme 8). The polymerization rate of norbornene using 63 was 93% which is similar to that of its low molecular weight counterpart 64 (99% conversion, after 60 min). However, complex 63 exhibited a faster ROMP initiation with 70% conversion in 10 min than that of 64 with 30% conversion at the same time period. The PDI values of the polymer products 70–74 analyzed by GPC ranged from 1.11 to 2.34. The removal of catalyst 63 was examined in the ROMP reactions of monomer 65– 69. The process used in separation of residues from catalyst 63 and the polymer product involved dissolving the dry crude mixture of polymer product and Ru catalyst residue in a minimum amount of DCM and precipitating the mixture in hexane affording the homopolymer as a white solid. The Ru contamination level of polymers 70–74 prepared by 63 varied from 71 to 252 ppm.

PolymersFigure2016 ,11.8, 140Polyisobutylene (PIB1000)-supported Grubbs second generation catalysts 63 and Grubbs19 of 23 catalyst 64.

SchemeScheme 8. ROMPROMP Reactions Reactions of of 6565––6969 CatalyzedCatalyzed by 63..

The PEOlig-supported ruthenium catalyst 46 has also been used in ROMP reactions of norbornene The PEOlig-supported ruthenium catalyst 46 has also been used in ROMP reactions of norbornene derivatives [67]. Examples of polymer prepared using 46 are shown in Figure 12. This PEOlig- derivatives [67]. Examples of polymer prepared using 46 are shown in Figure 12. This PE -supported supported catalyst 60 was used to prepare polymers 74–78 using the same solid/liquidOlig separation catalyst 60 was used to prepare polymers 74–78 using the same solid/liquid separation concept as concept as was used previously in reactions where this catalyst was used to prepare RCM products. was used previously in reactions where this catalyst was used to prepare RCM products. In this In this case, separation of the ROMP products from 46 was performed by filtration of reaction mixture case, separation of the ROMP products from 46 was performed by filtration of reaction mixture through Celite and 0.2 μm filter to yield colorless solution containing polymer products. The resulting through Celite and 0.2 µm filter to yield colorless solution containing polymer products. The resulting solution was concentrated and then precipitated in hexane to isolate polymers 74–78. In reactions solution was concentrated and then precipitated in hexane to isolate polymers 74–78. In reactions with catalyst 46, it was found that the prior scheme where polyethylene oligomers were shown to be with catalyst 46, it was found that the prior scheme where polyethylene oligomers were shown to be useful cosolvents facilitate Ru residue separations in ROMP chemistry [67]. Adding unfunctionalized useful cosolvents facilitate Ru residue separations in ROMP chemistry [67]. Adding unfunctionalized polyethylene oligomers as a cosolvent further facilitated separations of the product polymer and polyethylene oligomers as a cosolvent further facilitated separations of the product polymer and catalystPolymers 2016residues., 8, 140 For example, when a commercially available unfunctionalized polyethylene19 of 22 catalyst residues. For example, when a commercially available unfunctionalized polyethylene

(Polywax)(Polywax) ( (Mnn == 400) 400) [68] [68 was] was added added as asa co-solvent a co-solvent to PE toOlig PE-supportedOlig-supported catalyst, catalyst, the leaching the leaching of Ru ofresidues Ru residues from fromcatalyst catalyst 60 decreased60 decreased to 19–26 to 19–26 ppm ppm range range (ca (.ca 0.5%. 0.5% of of the the charged charged Ru Ru catalyst). catalyst). In addition, control experimentsexperiments showedshowed thatthat heatingheating aa suspensionsuspension ofof 4646 and Polywax to form a solution followed byby coolingcooling andand filtrationfiltration ledled toto only 0.04% leaching of Ru leaching, a value that increased to 0.42% (0.84 ppm, amount of Ru in the solution) if the heated solution of 46,, Polywax,Polywax, andand THFTHF waswas quenched withwith butylbutyl vinylvinyl ether. ether. This This suggests suggests that that most most of of the theca. ca.19–26 19–26 ppm ppm Ru Ru residues residues observed observed in thein the ROMP ROMP products products may may be due be due to some to some side reactionsside reactions that occurthat occur during during the quenching the quenching of the livingof the polymerliving polymer and not and from not the from polymerization the polymerization process process involving involving46. The 46 resulting. The resulting polymers polymers74–78 74have–78 thehave same the Esame/Z ratio E/Z as ratio those as to those those to prepared those prepared by its low by molecular its low weightmolecular counterpart weight counterpart2, comparable 2, Mcomparablen values, and Mn PDIsvalues, that and ranged PDIs fromthat ranged 1.23 to from 1.84. 1.23 to 1.84.

Figure 12. ROMP products 74–78..

5. Conclusions Conclusions Although manymany examples examples of newerof newer versions versions of olefin of metathesisolefin metathesis catalysts catalysts with improved with improved reactivity, airreactivity, and moisture air and stability, moisture functional stability, groups functional tolerance, groups and tolerance, stereoselectivity and stereoselectivity have been reported have sincebeen thereported discovery since of the the discovery first metathesis of the first catalysts, metathesis challenges catalysts, still challenges remain. These still challengesremain. These include: challenges(i) the highinclude: cost (i) of the the high transition cost of metalthe transition complexes metal used complexes as catalysts used or as precatalysts; catalysts or (ii)precatalysts; the cost and/or(ii) the tediousnesscost and/or oftediousness the ligand syntheses;of the ligand (iii) thesyntheses; potential (iii) environmental the potential toxicological environmental or practical toxicological concerns or practical concerns that ensue when there is significant metal or ligand contamination in the product; and (iv) the cost of and waste generated when metal or ligand contaminates have to be removed by post reaction processing steps. Several approaches have been proposed to address these issues. One approach is to reduce the amount of catalyst used in the reaction. Lowering the wt % of catalyst will necessarily reduce catalyst cost, ligand cost, and product contamination. However, examples of this strategy can be limited, especially in polymerizations where each polymer chain has one catalyst site. An alternative strategy that has proven to be more versatile is to immobilize the catalyst on either heterogeneous or homogeneous supports. Such scheme allow the supported catalysts to be recovered and subsequently reused or, in other cases, effect separation of inactive catalyst residues from products. Several examples of this chemistry have been reported in the past two decades showing the success in using this strategy to address the issues mentioned earlier, especially those focused on the removal of metal contamination in the final products. The benefit of using supported olefin metathesis catalysts to effectively minimize the level of metal contamination in the products is significantly increased in the case of ROMP reactions when reducing the amount of catalyst might not be an option. Although there is still room for further development (such as recoverability and application in asymmetric synthesis) before the strategy of catalyst immobilization can be widely used in both industry and academia, its potential to be recognized as a standard tool in synthetic applications is not to be underestimated.

Acknowledgments: Funding of this work by the National Science Foundation (CHE-1362735) (DEB), the Robert A. Welch Foundation (Grant A-0639) (DEB), the Qatar National Research Fund (project numbers NPRP-28-6-7-7 and NPRP-4-081-1-016) (HSB and DEB) are gratefully acknowledged.

Author Contributions: Jakkrit Suriboot, Hassan S. Bazzi, and David E. Bergbreiter wrote and edited the paper.

Conflicts of Interest: The authors declare no conflict of interest.

Polymers 2016, 8, 140 20 of 23 that ensue when there is significant metal or ligand contamination in the product; and (iv) the cost of and waste generated when metal or ligand contaminates have to be removed by post reaction processing steps. Several approaches have been proposed to address these issues. One approach is to reduce the amount of catalyst used in the reaction. Lowering the wt % of catalyst will necessarily reduce catalyst cost, ligand cost, and product contamination. However, examples of this strategy can be limited, especially in polymerizations where each polymer chain has one catalyst site. An alternative strategy that has proven to be more versatile is to immobilize the catalyst on either heterogeneous or homogeneous supports. Such scheme allow the supported catalysts to be recovered and subsequently reused or, in other cases, effect separation of inactive catalyst residues from products. Several examples of this chemistry have been reported in the past two decades showing the success in using this strategy to address the issues mentioned earlier, especially those focused on the removal of metal contamination in the final products. The benefit of using supported olefin metathesis catalysts to effectively minimize the level of metal contamination in the products is significantly increased in the case of ROMP reactions when reducing the amount of catalyst might not be an option. Although there is still room for further development (such as recoverability and application in asymmetric synthesis) before the strategy of catalyst immobilization can be widely used in both industry and academia, its potential to be recognized as a standard tool in synthetic applications is not to be underestimated.

Acknowledgments: Funding of this work by the National Science Foundation (CHE-1362735) (DEB), the Robert A. Welch Foundation (Grant A-0639) (DEB), the Qatar National Research Fund (project numbers NPRP-28-6-7-7 and NPRP-4-081-1-016) (HSB and DEB) are gratefully acknowledged. Author Contributions: Jakkrit Suriboot, Hassan S. Bazzi, and David E. Bergbreiter wrote and edited the paper. Conflicts of Interest: The authors declare no conflict of interest.

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