A wolf in sheep’s clothing

Metallomonomers are copolymerized with organic cross-linking agents to form macroporous polymers and then activated with an external reagent to reveal an active catalyst, much like a wolf in sheep's clothing.

Brian P. Santora
Michel R. Gagné

Like the Wolf in Aesop’s fable, appearances can be deceiving and even beneficial, as is our case. This article describes a specific strategy wherein polymerizable metallomonomers (precatalysts) are incorporated into macroporous polymers. Subsequent activation with an external reagent reveals the active catalysts (the wolf). The removable ligands on the metallomonomer, which are the sheep’s clothing in our analogy, disguise and protect the reactive catalysts during the immobilization procedure. This methodology leads to new catalysts that combine the controllable reactivity and selectivity of homogeneous catalysts with the reusability and ease of separation from products of heterogeneous catalysts.

Homogeneous and heterogeneous catalysts
Homogeneous transition-metal catalysis is traditionally accomplished through metal choice, ligand design, and fine-tuning. On a small scale, homogeneous transition-metal catalysts are ideal for controlling reactivity and selectivity. However, on a large scale, these catalysts can be difficult to separate from the product. Heterogeneous catalysts, on the other hand, are more desirable for use in industrial processes because they can be readily separated and reused, and because they are amenable to continuous-flow operations. Despite the preferred use of heterogeneous catalysts, they can be difficult to synthesize, characterize, and optimize—making rational catalyst design challenging and thereby forcing the experimentalist to rely more on empiricism.

One approach is to “heterogenize” homogeneous catalysts, thus combining the attributes of both kinds of catalysts. This technique makes it possible to first optimize a catalyst’s reactivity and selectivity under more controllable conditions, and then support it on media suitable for the intended application.

Many heterogenization strategies have been examined (1), including attaching catalysts to Merrifield resins (2–4), oxide surfaces (e.g., SiO₂ [5, 6] and Al₂O₃ [7]), and dendrimers (8); using polymerizable ligands to form the backbone of the support (9); incorporating catalysts into a siloxane matrix or noncovalent porous network solids (10, 11); trapping catalysts inside the pores of a zeolite (12); encapsulating catalysts in an organic (13, 14) or inorganic (15) polymer; using catalyst–substrate solubility differences in biphasic catalysis (16–18); and using soluble polymeric supports (19). Each technique has attendant advantages and disadvantages, and so new approaches are needed.

The strategy
The “wolf in sheep’s clothing” strategy allows highly reactive, and perhaps nonisolable, catalysts to be incorporated into polymer supports because they are initially disguised (protected) as nonreactive sheep. In some instances the catalyst (wolf) that is revealed may have additional stability or reactivity because of its heterogenization or site isolation.

Moreover, by directly incorporating well-defined, premade metal complexes into the matrix, ambiguities associated with attaching a metal source to a supported ligand(s) can be avoided. Metal–ligand stoichiometry is often a critical variable in controlling reactivity and selectivity. Most heterogenization strategies add the metal to a preimmobilized ligand, a step that can be difficult to control. The primary advantage of using the metallomonomer system is that the catalyst coordination chemistry is predefined.

With suitable attention to the details of immobilization, the “wolf in sheep’s clothing” technique can produce novel heterogenized homogeneous catalysts that rival their solution homogeneous analogues in reactivity and selectivity.

Catalyst support
Macroporous polymers, with their permanent pore structures (and variable distributions of micro-, meso-, and macropores), offer several advantages for heterogenizing homogeneous catalysts (20). The permanent pores of a macroporous polymer allow unimpeded access to most of the polymer’s internal volume by polar protic solvents, that is, the matrix can be penetrated even by water and ethanol (20, 21). Consequently, reaction conditions (e.g., solvents) can be chosen to optimize the desired reactivity without needing to consider polymer swelling. In contrast, lightly cross-linked supports such as Merrifield resins require a swelling solvent for access to the interior volume, whereas protic solvents such as methanol collapse the polymer particle and block access to the resin interior. Another advantage to using macroporous polymers as catalyst supports is that they are amenable to molecular imprinting (22–26).

Because the support is not preformed (e.g., as in Merrifield polymers), the properties of the metal-containing polymer matrix can be optimized through choice of comonomer and polymerization conditions (27). In this way, the polarity and hydrophilicity of the matrix can be modified, as can the catalyst loading. Site isolation is normally maintained with catalyst loadings less than 5–10 wt% (4, 28). Moreover, a full range of catalyst shapes (e.g., beads, membranes, and monoliths) can be accessed.

Catalyst activation
Because the metallomonomers are immobilized in a protected form, they must be activated prior to their usage in catalysis by either ligand removal or ligand substitution. In situ activation under the reaction conditions is occasionally possible, as described in the following examples: epoxidation, hydroformylation, hydrogenation, and hydroboration. Alternatively, ligand substitution may be necessary, as demonstrated by the titanium Lewis acids and the ruthenium transfer hydrogenation catalyst systems. Regardless of the activation protocol, selective, clean, and irreversible chemistry is critical to generating the expected reactivity and selectivity.

Olefin epoxidation. The immobilization of manganese(III) salen metallomonomers was originally shown by Salvadori and Dhal to yield catalytically active olefin epoxidation catalysts (29–31) [salen = bis(salicylidene)ethylenediamine]. Several variants on the original methods have since been reported and reviewed (Figure 1) (32). In all instances, ~5 wt% of a Mn(III) metallomonomer is copolymerized with the cross-linking acrylate monomer ethylene glycol dimethacrylate (EGDMA) using toluene as the porogenic agent. Under the oxidizing reaction conditions, the active Mn(V) oxo complex is presumably formed (the “wolf”, Figure 1), which serves to epoxidize the alkene.

Highlights of these systems include high yields of epoxide and high turnover numbers. In particular, the example in Figure 1 can be recycled several times without appreciably losing activity, a significant improvement over solution variants that typically give low turnover numbers before deactivation. Unfortunately, asymmetric variants of these systems tend to give poor-to-moderate enantioselectivities, although this could be partially controlled by modifying the point of polymer attachment (32).

Olefin hydroformylation. Nozaki and co-workers recently reported a striking example of an immobilized metallomonomer that maintains high enantioselectivities for the catalytic asymmetric hydroformylation of olefins (Figure 2) (33, 34). Free-radical polymerization of rhodium(I) phosphine–phosphite acetyl acetonate (acac) complexes (3 mol%) with 55% technical-grade divinylbenzene (DVB) (97 mol%), using toluene as porogen, yielded yellow, insoluble macroporous polymers. Under hydroformylation conditions, the Rh(I) precatalyst becomes activated (the wolf) for the hydroformylation of styrene and vinyl acetate. Enantioselectivities rival the homogeneous analogues in nearly all cases. Filtration yielded pure product and catalyst that could be reused without appreciable loss of reactivity or enantioselectivity.

In one case, the metallomonomer technique was superior to first polymerizing the ligand and then adding the rhodium. Nozaki speculated that the preformed complex enforces the polymerization of a ligand conformation that is optimal to metal chelation. Reaction rates depend on the rate of stirring, which suggests that mass transport of gases into the porous polymer phase may be more problematic than in liquids.

Olefin hydrogenation and hydroboration. We investigated the utility of polymer-immobilized cationic rhodium diphosphine complexes as heterogenized hydrogenation catalysts (Figure 3) (35). Copolymerization of template 1 (2 mol%) with EGDMA (98 mol%) in DMF under free-radical bulk polymerization conditions yields bright orange, insoluble polymer monoliths, 2. After crushing, treating with hydrogen reveals the wolf, presumably as the disolvate. Polymer 2 is an active catalyst for the hydrogenation of several olefin classes, including those containing functionality; amides, esters, and alcohols were all hydrogenated with isolated yields >93%. Turnover numbers of up to 8800 were obtained. Filtration and solvent removal yielded analytically pure products and catalyst that could be reused. Polymer removal midway through the reaction halts conversion, indicating that minimal catalyst leaching occurs.

Another advantage of a heterogenized cationic rhodium catalyst is that it is amenable to substrate-directable reactions (36, 37). This is highlighted in the chemoselective hydrogenation of geraniol (Figure 3). The olefin containing a proximal secondary coordination site is preferentially hydrogenated over the isolated olefin.

Polymer 2 (1 mol%) was also an efficient catalyst for the hydroboration of alkenes. For example, secondary alcohol was obtained in 85% yield (the secondary/primary ratio was 20:1) following oxidative workup.

Lewis acid-catalyzed Diels–Alder reaction. Our laboratory has also developed methods for incorporating Ti(IV) aryl oxide complexes into highly cross-linked DVB–styrene macroporous polymers (Figure 4) (38, 39). Copolymerization of an 80% tech-grade DVB (73 mol%), styrene (25 mol%), and metallomonomer 3 (2 mol%) under free radical bulk polymerization conditions gave the yellow-orange insoluble polymer 4. Treating a toluene suspension of 4 with SiX₄ (X = Cl, Br, or I; 20 equiv) results in a rapid color change to a dark red characteristic of the dihalide polymers 5. Even with large lumps (~0.5 cm³), the color change occurs throughout the polymer, demonstrating good mobility of reactants within the porous matrix (BET surface areas ~500–600 m²/g). Washing removes the excess SiX₄ and SiX₃NR₂ and generates a “pack” of polymer-immobilized Ti(IV) Lewis acid catalysts.

The 5 polymers are good catalysts for the Diels–Alder reaction (Figure 4). Reaction rates for the insoluble polymer catalysts are typically only 2–3 times slower than soluble analogues, which points to good diffusion of substrates and products within the matrix. Control experiments indicate that polymer removal midway through catalysis halts the conversion to product, consistent with minimal leaching of catalyst. All catalysts gave a product endo/exo diastereoselectivity of 98:2, and the polymers could be recycled by filtration.

Transfer hydrogenation of olefins. Highly cross-linked, macroporous polymers are also amenable to molecular imprinting (22–26). Polborn and Severin have recently shown a molecular-imprinting effect in the transition-metal–catalyzed transfer hydrogenation of ketones (Figure 5) (40). A Ru(II) transition-state mimic for reducing a ketone (6, 1%) was incorporated into an EGDMA polymer matrix (99%) under free-radical polymerization conditions using chloroform as a porogen. Removing the phosphonate portion of the template with BnNEt₃Cl activates the metal for catalysis in what is presumably a benzophenone-shaped pocket 7. Compared with the nonimprinted ruthenium polymer catalyst, 8, benzophenone is reduced 3 times faster with 7. More importantly, though, 7 is better able to reduce benzophenone selectively in the presence of competing ketones than is the nonimprinted 8 polymer. These exciting results suggest a true molecular-imprinting effect at the metal center. Although mechanistically less interpretable, other imprinting effects on catalysis have been reported (41–44).

Future prospects
The use of the “wolf in sheep’s clothing” strategy to incorporate transition metal catalysts into macroporous polymers is a largely unexplored methodology. This is perhaps because the determining factor in the success of this approach is often the availability of metallomonomers and the selective activation protocol, although both are clearly solvable problems.

An exciting aspect of activating the catalyst after immobilization is that it provides the opportunity to use molecular imprinting to generate immobilized catalysts with unique coordination environments, much like Severin’s preliminary work.

Our lab is investigating the use of associated chiral cavities to generate selective catalysts. Our data indicate that chiral cavities can indeed control the enantioselectivity of reactions at a metal center. For example, enantiomerically pure diphosphine platinum–(R)-1,1´-bi-2-naphthol [P₂Pt–(R)-BINOL] metallomonomers lead to imprinted polymers that, after (R)-BINOL removal, contain platinum sites with associated (R)-BINOL-shaped cavities. Stoichiometric rebinding of the BINOL isomer mixture proceeds with aggregate selectivities of up to ~85:15 in favor of the R-isomer (Figure 6). Poisoning of the least selective sites indicates that some sites can provide enantioselectivities of up to 97:3 (45). Although only mimicking single turnover processes, these data suggest that molecular imprinting of transition-state analogues and metal-based catalysis are complementary and promise to yield a new area of catalysis research, one in which selectivity can be influenced by the shape of associated cavities.

The degree of control that is realized by immobilizing catalyst precursors into macroporous polymers bodes well for the future of this field. As Sherrington, one of the researchers in the field of polymer-supported catalysis, has aptly written, “for those of us committed to this area, a further period of patience and dedication may be required, but there is no doubt that the future for polymer-supported synthesis has never been so optimistic” (20). We are only limited by our imaginations.

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Brian P. Santora is a postdoctoral fellow working with Mark Davis at the California Institute of Technology (Chemical Engineering, 210-41, Pasadena, CA 91125). He recently obtained his Ph.D. from the University of North Carolina, Chapel Hill, under Michel Gagné. His research focused on polymer-immobilized transition-metal catalysis. During his graduate studies, he spent six months at DuPont as a visiting research scientist. He received his B.S. degree in chemistry from Canisius College (Buffalo, NY).

Michel R. Gagné is an assistant professor of chemistry at the University of North Carolina, Chapel Hill (Department of Chemistry, Chapel Hill, NC 27599-3290; 919-962-6341; mgagne@unc.edu). His research interests include a multidisciplinary approach to transition-metal–based catalysis spanning the fields of inorganic, organic, and polymer chemistries. He obtained his B.S. degree from the University of Alberta and his Ph.D. from Northwestern University, both in chemistry. He also conducted research at Caltech and Harvard University under postdoctoral fellowships from the Natural Sciences and Engineering Research Council of Canada.

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