The ability to perform metathesis in aqueous media is desirable, but as yet largely unrealized, for the modification of water-soluble, biologically-relevant substrates.
The impact of water on catalyst productivity was assessed for both the second-generation Grubbs catalyst GII, and the phosphine-free Hoveyda catalyst HII, in ring-closing and cross-metathesis reactions.
The effectiveness of 4 for RCM and CM in aqueous–organic solution is comparable to that of complex 6b, which is among the best catalysts for metathesis in pure water. Two conclusions can be drawn: homogeneous aqueous–organic mixtures could be advantageous for some olefin metathesis reactions, and the principle advantage of current aqueous metathesis catalysts is merely water solubility. Conventional catalysts such as 4 are active in aqueous solvents, and hence can be used for metathesis of polar molecules if the substrate is amenable to aqueous DME, PEG, or acetone. For instance, some enzymes and polysaccharides are compatible with aqueous DME, suggesting that these biomolecules might be suitable for a metathesis strategy that avoids the synthesis of specialized complexes. Moreover, we have found that ribonuclease A is >90% soluble in 3:2 DME/phosphate-buffered saline (PBS). In this solution, complex 4 is not only soluble, but also catalyzes the quantitative RCM of N-tosyldiallylamine (8), even in the presence of ribonuclease A. Thus, apart from its insolubility in pure water, 4 is nearly as effective in the presence of water as are specialized complexes like 6b. Hence, additional advances in aqueous metathesis will require enhanced ligands that not only provide water solubility but also improve upon the NHC and isopropoxy chelate in protecting the complex from water.
Quantitative yields of metathesis product can be achieved under mild aerobic conditions in/on water by (micro)solubilization of both the catalyst and starting materials by the macrocycles.">
With optimized reaction conditions established, we probed the RCM of a variety of dienes using complex 4 in aqueous DME and acetone solutions. Under these homogeneous conditions, substrates with a variety of substituents were metathesized to form five-, six-, and seven-membered cyclic products (). High conversion was consistently achieved with traditional non-polar substrates, except for diallyldiphenylsilane (14). Water-soluble substrates such as 11 and 16—a putative model for peptide substrates—were more challenging, requiring increased catalyst loading and organic cosolvent concentrations for high conversion. As it has with many other metathesis systems, diallyldimethylammonium chloride (12) resisted RCM., Complex 4 is also capable of homodimerization of allyl alcohol (18) in acetone–water, achieving good conversion over several hours (). Nevertheless, CM of other substrates in aqueous solvents has proven elusive for us as well as others.,
The catMETium IMesPCy catalyst was developed and first patented by chemistry professor Wolfgang A. Herrmann at Technical University Munich, in Germany, and later licensed to Aventis Research & Technology, which Degussa acquired in 2001. Grubbs and Nolan also hold patents on catalysts with similar ligands. Owning IP is beneficial, because commercializing metathesis catalysts entails navigating through a forest of composition-of-matter, method-of-synthesis, and field-of-use claims.
The vast majority of olefin metathesis reactions are catalyzed by complexes of either molybdenum (Schrock type) or ruthenium (Grubbs type). Molybdenum catalyst 1 was developed before the Grubbs-type catalysts and is highly active, but sensitivity of this catalyst to air and water limits its applicability. Ruthenium catalysts 2 and 3 are less active and cannot be recycled, but exhibit better functional-group tolerance than the rather indiscriminate catalyst 1.
Quantitative yields of metathesis product can be achieved under mild aerobic conditions in/on water by (micro)solubilization of both the catalyst and starting materials by the macrocycles.
Meanwhile, more competitors are finding IP gaps in which they can offer alternative catalysts. These new catalysts differ structurally, sometimes subtly, but generally stray little from a basic ruthenium carbene complex developed by Grubbs. Although the molybdenum catalysts are more reactive, they are not as tolerant of air, water, or functional groups, and therefore, industrial use may be more limited. By exchanging or varying ligand structures, developers are altering catalyst sterics and electronics, and consequently the activity, stability, selectivity, and even patentability of new catalysts.
Next, we studied the performance of different commercially available catalysts in the DME–water solvent system with substrate 8 (). Phosphine-free complex 4 displayed the highest turnover, with both N-heterocyclic carbene (NHC) complexes outperforming the 1st-generation catalysts. The more σ-donating NHC ligand could aid olefin coordination over attack by water, favoring metathesis with the 2nd-generation catalysts as opposed to decomposition. The advantage of 4 over 2 is more difficult to rationalize because both complexes produce the same propagating species. The improved performance of 4 could be due to the presence of the chelating isoproxy moiety, which could potentially protect the catalyst from decomposition in water prior to entry into the catalytic cycle, as suggested by Blechert and coworkers for metathesis in organic solvents. Although the ether ligand binds more loosely than does the phosphine of 2 (4 initiates >800-fold faster at 25 °C), its rebinding to ruthenium prior to metathesis is unimolecular. As a result, the ether ligand is more likely to rebind the coordinatively unsaturated intermediate, protecting it from water to preserve the complex in solution. In addition to helping select known catalysts for use in water–organic systems, these results can inform the design of water-soluble catalysts. The combination of a chelate and an NHC produces a more effective catalyst for aqueous metathesis, as borne out by complexes 6a, 6b, and 7. Future catalyst designs should incorporate these features.
Grubbs's first-generation catalyst, a ruthenium benzylidene complex bearing two tricyclohexylphosphine (PCy3) ligands, was the first metathesis catalyst to be widely used in organic synthesis. It was followed by a more active second-generation analog, in which an N-heterocyclic carbene (NHC) replaces a PCy3. Then came the more active and more stable Hoveyda-Grubbs catalysts containing an alkoxybenzylidene ligand and either a PCy3 (first generation) or NHC (second generation); the latter was also reported by Blechert in 2000.
Metathesis in homogeneous aqueous systems would likely be faster and more versatile than in these heterogeneous systems. An effective system for metathesis with commercially available catalysts in homogeneous aqueous media would not only make this chemistry more accessible, but also highlight the limitations of the standard catalysts in water, informing catalyst-design efforts. Yet, reports of the use of common metathesis catalysts in an aqueous context are limited. For these reasons, we chose to test the capabilities of catalysts 1–4 in homogeneous aqueous media, and we report the results of our exploration herein. First, we screened various organic solvents as co-solvents for RCM of 8 in a homogeneous aqueous solution (). The solvents typically used for olefin metathesis reactions, such as CH2Cl2, 1,2-dichloroethane, and toluene, are immiscible with water, so we resorted to water-miscible solvents. Tetrahydrofuran (THF), used previously as a solvent for ROMP and acyclic diene metathesis with varying success, failed as a cosolvent for RCM. On the other hand, the ethylene glycol ether-based solvents dimethoxyethane (DME or glyme) and poly(ethylene glycol) (PEG) were excellent co-solvents. Their improved results with respect to THF and dioxane could relate to their better coordinating ability. Able to coordinate the tetracoordinate ruthenium complexes of the metathesis catalytic cycle, these ethers could more ably protect them from detrimental coordination by water. Grubbs and coworkers suggest that decomposition of metathesis intermediates in water results from water coordination at ruthenium in the methylidene-propagating species. Interestingly, these results show that the protective environment of the PEG-bearing ligand in 6a can also be provided by ethylene glycol ethers in the bulk solvent.