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Oxidative Decomposition Pathways and Catalyst Protection Strategies in Olefin MetathesisTon, Stephanie Jean 13 July 2020 (has links)
Olefin metathesis is an outstandingly versatile methodology for the catalytic assembly of carbon-carbon bonds. Metathesis methodologies have been widely embraced since the advent of easily-handled ruthenium catalysts. However, industrial implementation has lagged. Problems of reliability and productivity arising from catalyst decomposition have impeded broad uptake of metathesis in process chemistry. Such challenges also hamper deployment of metathesis in forefront applications such as chemical biology. Better understanding of the mechanisms by which catalysts decompose can thus improve performance in demanding applications, as well as providing guidelines for informed process and catalyst design. Oxygen is often viewed as a relatively innocuous contaminant in reactions promoted by these late transition metal catalysts. Indeed, multiple reports comment on the desirability and operational simplicity of metathesis in air. We suspected, however, that deleterious impacts of O2 may be masked by the high catalyst loadings typically deployed in such reports. The first part of this thesis focuses on examining the robustness of leading metathesis catalysts toward oxygen. Systems examined include the classic, dominant N-heterocyclic carbene (NHC) derivatives, as well as recent breakthrough analogues containing cyclic alkyl amino carbene (CAAC) ligands. Both are shown to be decomposed by oxygen, but the CAAC catalysts are found to be not only more productive, but significantly more O2-tolerant. This is important as it overturns the widespread belief that high catalyst activity is invariably a trade-off against higher sensitivity. Studies of the initial oxidation event for the second-generation Grubbs catalyst RuCl2(H2IMes)(PCy3)(=CHPh) suggest that [2+2] cycloaddition of O2, as well as bimolecular decomposition of the four- coordinate species generated by PCy3 oxidation, account for ca. 90% of the observed decomposition. A previously-proposed pathway involving attack of O2 at the benzylidene ligand appears to be a minor contributor. In Chapter 3 of this thesis, a new strategy for inhibiting catalyst decomposition is examined. Specifically, cationic metathesis catalysts were encapsulated within a supramolecular resorcinarene capsule, which self-assembles around the catalysts in water-saturated toluene. Encapsulation nearly doubles RCM yields relative to the parent, neutral catalyst in water-saturated toluene. The increased catalyst productivity is enabled by site-isolation of the catalyst within the capsule, which prevents bimolecular decomposition, and by the hydrophobic nature of the capsule interior, which limits decomposition by water. A final study focuses on attempts to identify a more robust catalyst via ligand redesign. Examined for this purpose are recently reported, electron-rich pyridinylide aminophosphines (PyAPs; these take the general form R2P–N=Ar), which exhibit enhanced s-donor properties relative to NHCs. Strategies for incorporation of PyAP ligands into Ru metathesis catalysts are developed, and the catalytic activity of these species is described. PyAP catalysts are found be significantly less active than the corresponding NHC catalysts, despite their higher donicity. Poor performance results from facile catalyst decomposition. Where the N=Ar group lacks substituents at the ortho sites, o- metalation enables decomposition of the precatalyst. More problematically, the nitrogen atom appears to participate in nucleophilic attack on the key, metathesis-enabling [Ru]=CHR functionality, limiting the potential use of this class of phosphine in metathesis. Criteria for the development of more robust second-generation phosphine catalysts are proposed.
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Olefin Metathesis Catalysts: From Decomposition to Redesigndo Nascimento, Daniel Luis 13 August 2021 (has links)
Olefin metathesis is arguably the most versatile catalytic route yet developed for the assembly of carbon-carbon bonds. Metathesis methodologies are attractive from both synthetic and ecological standpoints, because they employ unactivated double bonds. This reduces the total number of synthetic steps, and the associated generation of chemical wastes. The drive to deploy olefin metathesis in highly demanding contexts, including pharmaceutical manufacturing and chemical biology, puts severe pressure on catalyst lifetime and productivity. Understanding the relevant decomposition pathways is critical to achieve essential performance goals, and to enable informed catalyst redesign. This thesis work expands on significant prior advances that identified and quantified critical decomposition pathways for ruthenium catalysts stabilized by N-heterocyclic carbene (NHC) ligands. Because pristine catalyst materials are essential for mechanistic study, it focuses first on methods aimed at improving efficiency and purity in catalyst synthesis. Merrifield iodide resins were shown to function as efficient, selective phosphine scavengers in the production of clean second-generation catalysts from PCy3- stabilized precursors.
The thesis then turns to mechanistic examination of decomposition pathways that underlie success and failure for leading NHC catalysts, for comparison with a new family of catalysts stabilized by cyclic (alkyl)(amino) carbene (CAAC) ligands. These represent the first in-depth mechanistic studies of the CAAC catalysts, which have attracted much attention for their breakthrough productivities in challenging metathesis reactions. The remarkable productivity of the CAAC catalysts is shown to originate in their resistance to decomposition of the key metallacyclobutane intermediate via b-elimination, and (to a lesser extent) in their resistance to attack by nucleophiles and Bronsted bases. Importantly, however, they are more susceptible to bimolecular decomposition. The latter behaviour, as well as their resistance to b-elimination, is traced to the strong trans influence of the CAACs relative to NHC ligands. This insight significantly advances our understanding of the fundamental properties governing both productivity and decomposition.
Finally, two new catalysts are developed, building on the principle that nucleophilic stabilizing ligands should be avoided in the precatalysts. In the first of these complexes, an o-dianiline ligand is employed to stabilize the precatalyst. This flexible, H-bonding chelate serves the further purpose of accelerating macrocyclization of flexible dienes that bear polar functionalities. As its H-bonding capacity also increases its sensitivity to trace water, however, an alternative catalyst architecture was pursued. The latter consists of a dimer bearing bulky Ru-indenylidene centers, in which a dative bond from a bridging chloride affords the fifth ligand essential to stabilize the precatalyst.
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Roles for Nucleophiles and Hydrogen-Bonding Agents in the Decomposition of Phosphine-Free Ruthenium Metathesis CatalystsGoudreault, Alexandre 09 January 2020 (has links)
With its unrivaled versatility and atom economy, olefin metathesis is arguably the most powerful catalyst methodology now known for the construction of carbon-carbon bonds. When compared to palladium-catalyzed cross-coupling methodologies, however, catalyst productivity lags far behind, even for the “robust” ruthenium metathesis catalysts. Unexpected limitations to the robustness of these catalysts were first widely publicized by reports describing the implementation of metathesis in pharmaceutical manufacturing. Recurring discussion centered on low catalyst productivity resulting from decomposition of the Ru catalysts by impurities, including ppm-level contaminants in the technical-grade solvent. Over the past 7 years, a series of mechanistic studies from the Fogg group has uncovered the pathways by which common contaminants (or indeed reagents) trigger catalyst decomposition. Two principal pathways were identified: abstraction of the alkylidene or methylidene ligand by nucleophiles, and deprotonation of the metallacyclobutane intermediate by Bronsted base. Emerging applications, however, notably in chemical biology, highlight new challenges to catalyst productivity.
The first part of this thesis emphasizes the need for informed mechanistic insight as a guide to catalyst redesign. The widespread observation of a cyclometallated N-heterocyclic carbene (NHC) motif in crystal structures of catalyst decomposition products led to the presumption that activation of a C-H bond in the NHC ligand initiates catalyst decomposition. Reducing NHC bulk has therefore been proposed as critical to catalyst redesign. In experiments designed to probe the viability of this solution, the small NHC ligand IMe4 (tetramethylimidazol-2-ylidene) was added to the resting-state methylidene complexes formed in metathesis by the first- and second-generation Grubbs catalysts (RuCl2(PCy3)2(=CH2) GIm or RuCl2(H2IMes)(PCy3)(=CH2) GIIm, respectively). The intended product, a resting-state methylidene species bearing a truncated NHC, was not formed, owing to immediate loss of the methylidene ligand. Methylidene loss is now shown to result from nucleophilic attack by the NHC – a small, highly potent nucleophile – on the methylidene. Density functional calculations indicate that IMe4 abstracts the methylidene, generating the N-heterocyclic olefin H2C=IMe4. The latter is an even more potent nucleophile, which attacks a second methylidene, resulting in liberation of [EtIMe4]Cl. These findings report indirectly on the original question concerning the impact of ligand truncation. The ease with which a small, potent nucleophile can abstract the key methylidene ligand from GIm and GIIm underscores the importance of increasing steric protection at the [Ru]=CH2 site. This chemistry also suggests intriguing possibilities for efficient, selective, controlled methylidene abstraction to terminate metathesis activity while leaving the “RuCl2(H2IMes)(PCy3)” core intact. This could prove an enabling strategy for tandem catalysis applications in which metathesis is the first step.
The second part of this thesis, inspired by the potential of olefin metathesis in chemical biology, focuses on the impact of hydroxide ion and water on the productivity of phosphine-free metathesis catalysts. In reactions with the important second-generation Hoveyda catalyst HII, hydroxide anion is found to engage in salt metathesis with the chloride ligands, rather than nucleophilic attack. The resulting Ru-hydroxide complex is unreactive toward any olefins larger than ethylene, while ethylene itself causes rapid decomposition. Proposed as the decomposition pathway is bimolecular coupling promoted by the strong H-bonding character of the hydroxide ligands.
Lastly, the impact of the water on Ru-catalyzed olefin metathesis is examined. In a survey of normally facile metathesis reactions using state-of-the-art catalysts, even trace water (0.1% v/v) is found to be highly detrimental. The impact of water is shown to be greater at room temperature than previously established at 60 °C. Preliminary evidence strongly suggests that the mechanism by which water induces decomposition is temperature-dependent. Thus, at high temperature, decomposition of the metallacyclobutane intermediate appears to dominate, but this pathway is ruled out at ambient temperatures. Instead, water is proposed to promote bimolecular decomposition. Polyphenol resin, which can sequester water by H-bonding, is shown to offer an interim solution to the presence of trace water in organic media. These findings suggest that major avenues of investigation aimed at reducing intrinsic catalyst decomposition may likewise be relevant to the development of water-tolerant catalysts.
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Inside the Cycle: Understanding and Overcoming Decomposition of Key Intermediates in Olefin MetathesisBailey, Gwendolyn Anne 19 April 2018 (has links)
Ru-catalyzed olefin metathesis is an exceptionally powerful, versatile methodology for the assembly of carbon–carbon bonds. The N-heterocyclic carbene (NHC)-stabilized, “second-generation” Ru catalysts have enabled groundbreaking recent advances, ranging from the RCM assembly of cyclic peptides as hepatitis C virus therapeutics, to the elaboration of renewable seed oils and phenylpropanoids into value-added products and chemicals. However, key limitations arise from facile catalyst decomposition. Despite a plethora of studies on the synthesis of new catalysts, and on the decomposition processes accessible to the precatalyst and resting-state species, the underlying principles that govern decomposition of the active intermediates have been surprisingly little examined. One important reason for this is their incredible reactivity: the four-coordinate methylidene intermediate RuCl2(H2IMes)(=CH2) is too short-lived to be observed, while the metallacyclobutane (MCB) intermediate RuCl2(H2IMes)(2-C3H6) can only be observed below –40 °C. This makes them extremely challenging, but also fascinating targets for study. Understanding the underlying chemistry that dictates their reactivity and decomposition is essential for informed catalyst and process redesign, and is thus of fundamental interest, but also considerable practical importance.
This thesis work thus aims at understanding the decomposition of active intermediates relevant to the highly-active, second-generation class of catalysts. Emphasis is placed on examining a variety of metathesis contexts, as well as providing solutions. Treated first are the decomposition pathways that arise during metathesis of electron-deficient olefins, a frontier area in organic synthesis, and in the utilization of renewable resources. An unexpected correlation is revealed between rapid catalyst decomposition, and the presence of a stabilizing PCy3 ligand in the standard catalyst for this reaction. The nucleophilic phosphine ligand is shown to attack an acrylate olefin, forming enolates that function as potent Brønsted bases. Literature evidence suggests that such strong bases are innocuous towards the precatalyst, pointing towards a key role for the active intermediates in Brønsted base-induced catalyst decomposition.
Precisely which intermediate is involved, as well as the site of deprotonation, is elucidated next. Prior to this work, the NHC ligand was widely believed to be the target for attack. However, through labelling experiments, analysis of the Ru and organic byproducts, and computational studies, deprotonation is shown to occur at the MCB ring. Moreover, MCB deprotonation is revealed to be unexpectedly general, and not contingent on the presence of either an exceptionally strong base, or an electron-deficient substrate. This understanding is key, given recent reports from pharma highlighting the adverse impact of base contaminants, as well as current interest in metathesis of amine-containing substrates.
Next examined are the intrinsic decomposition pathways operative for the MCB and four-coordinate methylidene. Prior to this work, the only reported pathway for decomposition of these two species involved beta-elimination of the MCB ring as propene. However, beta-elimination is shown to play an unexpectedly minor role in catalyst decomposition: less than 40% propenes are observed, even under conditions expected to favour MCB elimination. Bimolecular coupling of the methylidene, with loss of the methylidene moiety as ethylene, is proposed to account for the difference. Thus, transiently-stabilized adducts RuCl2(H2IMes)(=CH2)(L)n (L = o-dianiline or pyridine) are synthesized at temperatures down to –120 °C. On warming, these adducts lose Ln and rapidly decompose via bimolecular coupling, with loss of the methylidene moiety as ethylene. These experiments provide the first unambiguous evidence for bimolecular coupling in the important "second-generation" Ru systems, nearly two decades after which this pathway was dismissed in leading papers and reviews.
The last two sections focus on solutions. First, a powerful, straightforward solution to the “enolate problem” is developed, whereby the acrylate enolates are quenched and sequestered via reaction with a polyphenol resin. Then, methods for preventing catalyst decomposition during matrix-assisted laser desorption / ionization mass spectrometry (MALDI-MS) are developed, via elucidation of the instrumental and experimental factors that promote successful analysis. As one of the only MS methods capable of affording insight into neutral metal complexes and catalysts, MALDI has unique potential to enable routine analysis of catalyst speciation and decomposition in situ, under real catalytic conditions, for a wide range of catalytic reactions.
Collectively, the findings in this thesis offer a much more complete understanding of the fundamental pathways accessible to the important, highly-active metathesis intermediates, and offer strategies likely to inform practice in both academic and industrial settings. This understanding is key to harnessing the full potential of metathesis methodologies.
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