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Aqueous ring-opening metathesis polymerization (ROMP) is a powerful tool for polymer synthesis under environmentally friendly conditions, functionalization of biomacromolecules, and preparation of polymeric nanoparticles via ROMP-induced self-assembly (ROMPISA). Although new water-soluble Ru-based metathesis catalysts have been developed and evaluated for their efficiency in mediating cross metathesis (CM) and ring-closing metathesis (RCM) reactions, little is known with regards to their catalytic activity and stability during aqueous ROMP. Here, we investigate the influence of solution pH, the presence of salt additives, and catalyst loading on ROMP monomer conversion and catalyst lifetime. We find that ROMP in aqueous media is particularly sensitive to chloride ion concentration and propose that this sensitivity originates from chloride ligand displacement by hydroxide or H2O at the Ru center, which reversibly generates an unstable and metathesis inactive complex. The formation of this Ru-(OH)n complex not only reduces monomer conversion and catalyst lifetime but also influences polymer microstructure. However, we find that the addition of chloride salts dramatically improves ROMP conversion and control. By carrying out aqueous ROMP in the presence of various chloride sources such as NaCl, KCl, or tetrabutylammonium chloride, we show that diblock copolymers can be readily synthesized via ROMPISA in solutions with high concentrations of neutral H2O (i.e., 90 v/v%) and relatively low concentrations of catalyst (i.e., 1 mol %). The capability to conduct aqueous ROMP at neutral pH is anticipated to enable new research avenues, particularly for applications in biological media, where the unique characteristics of ROMP provide distinct advantages over other polymerization strategies.


Introduction


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Olefin metathesis has emerged as a powerful tool for the construction of C–C bonds, both in organic transformations of small molecules and the synthesis of polymers via ring-opening metathesis polymerization (ROMP).(1) As applications of this versatile technology continue to expand, the demand for increasingly active and robust metathesis catalysts has intensified, requiring a deeper understanding of the factors underlying catalyst performance and deactivation pathways under a variety of reaction conditions. Modern Ru-based catalysts containing N-heterocyclic carbene (NHC) ligands exhibit high functional group tolerance, and their robustness has recently been leveraged to carry out metathesis reactions in alcoholic or aqueous media.(2,3) Increasing interest in performing metathesis in H2O, a green alternative solvent, has led to the optimization of cross-metathesis (CM) and ring-closing metathesis (RCM) reactions under aqueous conditions using water-soluble catalysts. In addition to reducing the environmental impact of these processes, it has further broadened the applications of aqueous olefin metathesis in biochemical research.(4−9) More recently, aqueous metathesis has been exploited to graft polymers from proteins in biological media,(10,11) realize molecular transformations within living cells,(12) and prepare polymeric nanoparticles via self-assembly methods such as ring-opening metathesis polymerization-induced self-assembly (ROMPISA)(13−17) and others.(18−20)
Despite these accomplishments, aqueous olefin metathesis remains challenging. Metathesis catalysts must be rendered water-soluble through ligand modification to achieve homogeneous reactions. Water-soluble Ru-NHC catalysts have been developed by the groups of Grubbs,(21−25) Grela,(26,27) Emrick,(28,29) and others,(30−33) that display charged/PEGylated NHC, phosphine, pyridine (Py), or styryl ether (Hoveyda-type) ligands. Although these efforts have simplified aqueous-phase metathesis chemistry, the impact of H2O on the activity and stability of Ru-NHC catalysts remains largely unexplored. It is convenient to assume that the chemical structure of the metathesis-active species is consistent regardless of solvent; however, anomalous results reported in the literature and obtained in our lab,(13,22,29,34,35) including higher than expected polymer molecular weights, low monomer conversions, and slow polymerization kinetics compared with polymerizations in aprotic solvent, suggest that a different, less active, and less stable species could be present in alcoholic/aqueous solution.
Our lack of understanding of aqueous metathesis chemistry stems, in part, from the methodology typically employed to evaluate new water-soluble catalysts. Substrates used to probe the aqueous metathesis activity of these new catalysts are most often readily cyclized RCM targets or highly reactive CM substrates. In addition, high catalyst loadings (i.e., 5–10 mol %) are often employed in initial screenings, giving exaggeratedly high reaction conversions while masking issues of catalyst deactivation. Such artificial conditions do not reflect the complexity involved in RCM or CM of challenging substrates, reactions involving biomacromolecules, or the synthesis of high MW or multiblock polymers via ROMP.
Our group recently developed a two-step approach to carry out controlled ROMPISA in aqueous solution using Grubbs’ third-generation catalyst, G3, which is commercially available.(13,14,17) Initiation of G3 in a water-miscible solvent and polymerization of a few units of hydrophilic monomer was found to be sufficient to achieve catalyst solubilization in solvent mixtures containing high concentrations of H2O (e.g., ≥ 90 v/v %). However, acidification of the reaction mixtures with HCl to ca. pH 2 was required to attain quantitative monomer conversions during chain-extension, limiting our capability to carry out polymerizations in the presence of sensitive biomolecules such as enzymes. Thus, it became important to understand the dependence of catalyst activity on acid to enable polymerization under neutral conditions. In this contribution, we investigate the influences of solution pH, catalyst loading, salt concentration, and other factors on the activity and stability of common metathesis catalysts in aqueous media using monomer conversion as the principal parameter of comparison. Chloride concentration, in particular, was found to play a pivotal role in both enhancing the rate of propagation and slowing the rate of catalyst decomposition, resulting in increased catalyst turnover and lifetime. These effects were consistent for both G3 and the water-soluble catalyst AquaMet (AM), suggesting that chloride ion concentration is generally important for aqueous metathesis using Ru-based catalysts. In addition, we provide mechanistic insights into the nature of the active catalytic species in aqueous solution and demonstrate practical implications by preparing diblock copolymer nano-objects via ROMPISA.

Results and Discussion


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To better understand the relationship between solution pH and aqueous ROMP activity, we carried out screening studies at 1 mol % catalyst in mixed solutions (9:1 v/v H2O/THF, 100 mM phosphate) with different pH values (pH 2–7). HCl was employed to adjust solution pH. Common metathesis catalysts G3, AM, and G2 were selected for screening and MPEG, a water-soluble exo-norbornene derivative, was used as the monomer (Figure 1). After 2 h, the polymerizations were analyzed by 1H NMR spectroscopy to determine monomer conversion and size-exclusion chromatography (SEC) to calculate polymer number-average molecular weight (Mn) and dispersity (ĐM), respectively. For comparison, an additional polymerization was conducted in pure organic solvent (THF) at the same monomer and catalyst concentrations. The results of this initial screening are shown in Figure 1 (additional results can be found in Table S1 and Figure S4).

Figure 1

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Figure 1. (A) Chemical structures of Ru-based metathesis catalysts used in initial ROMP screening. (B) Polymerization conditions employed for ROMP screening. (C) Monomer conversion under various conditions, as determined by 1H NMR spectroscopy in methanol-d4. (D) Conversion-normalized SEC RI traces (eluent: THF + 2 v/v% NEt3) of polymers obtained via ROMP using G3 at different pH values, or in THF (green, dotted trace).


It was evident from these data that pH (and thus acid concentration) had a dramatic impact on monomer conversion. In all cases, increasing the pH of the polymerization solutions resulted in decreased conversions. These data appear to oppose previous reports on aqueous ROMPISA using AM, where quantitative conversions and narrow molecular weight distributions were obtained at neutral pH.(16,36) However, these studies employed relatively higher initial catalyst concentrations than those used herein.(37) Increasing the solution pH from 2 to 4 also resulted in broader ĐM despite both polymerizations achieving quantitative conversion, indicating slower catalyst initiation and/or catalyst decomposition at pH 4. It was also surprising that monomer conversions when using G2 were generally low regardless of pH. Fogg and co-workers showed that PCy3 catalyzes Ru carbene decomposition in the presence of basic or donor compounds;(38,39) thus, we supposed that G2 might decompose more rapidly in aqueous media relative to G3 or AM.
We also evaluated different acid sources. HCl has been used almost exclusively as the Brønsted acid additive in previous studies on aqueous ROMP. We wondered if, in addition to H+ concentration, the identity of the acid counterion was also important. Thus, additional screening polymerizations were carried out in pH 2 solution acidified with H2SO4 or H3PO4 using G3 as the catalyst under otherwise identical experimental conditions (Figure 2A and Figure S6A and Table S3).

Figure 2

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Figure 2. Monomer conversions obtained from additional screening polymerizations of MPEG using G3 to evaluate different (A) acids or (B) salt additives, as determined by 1H NMR spectroscopy in methanol-d4.


In contrast to the polymerizations conducted with HCl, the use of H2SO4 or H3PO4 as the source of acid did not enable quantitative monomer conversions. Therefore, it was concluded that additional mechanistic complexity, related to the identity of the acid counterion (Cl– in initial screening), was underlying the activity of the catalyst in aqueous conditions. The role of H+ has been widely implicated as the primary determinant in aqueous metathetical activity, promoting ligand dissociation,(40−42) and protecting the catalysts from decomposition via nucleophilic addition,(38,43) or β-elimination,(39,44) pathways.(23,34) However, added salt has also been shown to increase RCM conversions in H2O and has been suggested to improve control in aqueous dispersion ROMP.(45,46) Thus, the importance of the chloride ion was further considered by employing various salts as neutral sources of chloride ions instead of HCl. It was found that the addition of both organic (TBAC) or inorganic (NaCl or KCl) chloride salts at 100 mM to polymerizations of MPEG under neutral conditions in 9:1 v/v H2O/THF had a profound effect, enabling quantitative monomer conversions (Figure 2B). Moreover, ROMP with TBAC yielded a polymer with Mn and ĐM values similar to those of the sample obtained via ROMP at pH 2 (Figure S6B).

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The dependence of monomer conversion on the presence of chloride ions indicated that chloride ligand displacement, perhaps by water or hydroxide ions, was occurring at the Ru center in aqueous media, resulting in low catalyst turnover. The exchange of halide ligands with anionic compounds has been well documented in the literature.(47−51) Indeed, DFT calculations indicate that Cl– dissociation from Ru-based complexes in polar solvents can compete with dissociation of so-called “labile” ligands such as PCy3 and Py.(52) Moreover, Grubbs and co-workers identified that Cl– dissociation and subsequent coordination of H2O to Ru was a key step in the formation of high energy, unstable carbene intermediates, and the formation of such species could introduce alternative catalyst decomposition pathways in aqueous media.(53) In the case of chloride exchange in aqueous media, the formation of inactive and unstable Ru-(OH)n species could account for the observed decreases in monomer conversion. Ru-(OH)n complexes are ubiquitous,(54,55) but hydroxide-containing Ru carbene catalysts have only very recently been demonstrated to exist. Fogg and co-workers synthesized a Ru-(OH)n carbene complex, HG2-(OH)2, by treating Hoveyda-Grubbs second-generation catalyst (HG2) with an excess of tetrabutylammonium hydroxide in mixed media containing THF and H2O.(51) The resulting complex was shown to be completely inert to metathetical activity, attributed to reduced electron density on the Ru center via inductive withdrawal by the hydroxide ligands. It was also shown that HG2-(OH)2 was more susceptible to degradation than the native chloride complex. Thus, we supposed that chloride ligand displacement would be equally probable for other Ru carbene catalysts, such as G3, and that ligand exchange equilibria, involving both H+ and Cl–, explained the observed effects of the various acids and salts that were screened (Scheme 1).