Olefin metathesis has had tremendous impact on synthetic approaches to the formation of new carbon-carbon bonds. Heterogeneous metathesis catalysts have been used in industry for decades, to effect redistribution of olefin chain lengths in petrochemicals processing. Only recently, however, has olefin metathesis emerged in pharmaceutical and specialty chemical manufacturing. The nearly 20-year gap between the discovery of easily-handled ruthenium catalysts and industrial implementation in these sectors is a result of many factors. One key contributor is the limited understanding of decomposition mechanisms that limit the reliability of olefin metathesis. Poor catalyst selectivities and yields remain a challenge for industrial uptake of olefin metathesis. Much academic effort focuses on designing methods and new catalysts for catalyst separation and reuse. Exploration of catalyst decomposition pathways has seen much less study in comparison. The limited recognition of decomposition as a problem in academia is undoubtedly due to the tendency to use high catalyst loadings, which mask catalyst decomposition problems. The catalyst loadings commonly reported in academia need to be decreased by a factor of 100–1000 for industrial viability in many processes. This thesis explores the decomposition of metathesis catalysts bearing a phosphine ligand. Such Grubbs-type catalysts, particularly second-generation versions containing an N-heterocyclic carbene ligand, are the most widely used metathesis catalysts in current use. This study follows up on an earlier discovery from the Fogg group, which showed that pyridine and amine donors drastically accelerate decomposition of the Grubbs catalysts. For the first-generation Grubbs catalyst, decomposition of the resting-state methylidene complex RuCl2(PCy3)2(=CH2) Ru-6 was shown to proceed via nucleophilic attack of PCy3 on the Ru=CH2 bond, forming a σ-alkyl complex that was intercepted and characterized crystallographically. Further reaction led to liberation of the methyl phosphonium salt [MePCy3]Cl 2. Under the same conditions, the second-generation methylidene complex Ru-4a decomposes rapidly without any detectable σ-alkyl intermediate. In this thesis, decomposition of the important second-generation catalysts is shown to proceed via the methylidene-abstraction pathway. These studies centered on the methylidene complex RuCl2(NHC)(PCy3)(=CH2), where the NHC ligand is H2IMes (Ru- 4a) or IMes (Ru-4b). The short lifetime of the σ-alkyl complex was tentatively attributed to the ease of activation of a C–H bond on the NHC ligand (specifically, those on the mesityl o-methyl group). This intermediate could not be observed for Ru-4a, but could be observed for the IMes system Ru-4b. This is suggested to reflect the slower rotation of the H2IMes ligand about the Ru–NHC bond, which promotes C–H activation. Also examined is the ability of other Lewis donors to trigger this methylidene abstraction pathway during catalysis. Lewis donors are shown to greatly accelerate decomposition of a wide range of phosphine-stabilized metathesis catalysts. Remarkably, even weak donors such as water, ethers, alcohols, and nitriles (i.e. functionalities that are widespread among contaminants, functional groups, and “green solvents”) are shown to promote this pathway. Phosphine-stabilized catalysts are generally regarded as more robust towards such donor functionalities, and the detrimental impact of such weak donors has gone widely unrecognized. These findings have profound implications for catalyst choice and use. Finally, a deuterium-labelling study was undertaken, in which the mesityl substituents on the NHC ligand were fully deuterated, to confirm that the proton in the phosphonium salt 2 indeed originates in the mesityl methyl group. Of note, the energies of the PCy3 dissociation and C–H activation steps were found to be closely similar. This was unexpected, given prior evidence that PCy3 loss is rate-determining in the Ru-2 precatalysts, and the much stronger Ru–PCy3 bonding known to be present in the methylidene complexes. This finding highlights the need to impede C-H activation for phosphine-stabilized metathesis catalysts. More broadly, it underscores the risks inherent in the use of phosphine-stabilized catalysts, or indeed of catalysts that are stabilized by a donor group that can function as both a Lewis base, and a nucleophile.

Olefin metathesis is increasingly popular for the construction of carbon-carbon double bonds. In the past two decades, ruthenium metathesis catalysts have seen extensive development. Two marvelous early developments were the introduction of N-heterocyclic carbene (NHC) ligands, which greatly improved catalyst activity, and replacement of a nucleophilic stabilizing ligand (the alkylphosphine PCy3) by a chelated benzylidene-ether. A more recent breakthrough is the introduction of cyclic alkyl amino carbene (CAAC) ligands as alternatives to the NHCs. Over the past 5 years, the CAAC catalysts have drawn much attention for their breakthrough productivity in challenging reactions, including ethenolysis and RCM macrocyclization. Nevertheless, important challenges remain. As discussed in the first part of this thesis, these include the synthesis of key ligands (in particular, the styrenyl ether ligands H2C=13CH-C6H4-2-OiPr and H2C=13CH-C6H3-2-OiPr-5-NO2), which represent the source of the chelated benzylidene-ether noted above) and key catalysts (e.g., Hoveyda- and Grela-class catalysts bearing an H2IMes or CAAC carbene ligand). A further challenge lies in understanding the behaviour of the styrenyl ether ligands – for example, how they contribute to catalyst partitioning between active, resting-state, and decomposed species, and the impact of the carbene ligand on that partitioning. An initial objective was synthesis of labelled styrenyl ethers that would enable synthesis of Hoveyda and Grela catalysts with a 13C-label at the alkylidene carbon. While H2C=13CH-C6H4-2-OiPr could be accessed, its nitro analogue could not, probably owing to attack on the NO2 substituent. The remainder of Chapter 2 assessed reported routes to HII/nG and HII-C1/nG-C1, and reports on challenges and reproducibility issues. Difficulties in synthesis of the CAAC catalysts are attributed to the need for in situ-generated CAACs, and catalyst decomposition by the base required for deprotonation (i.e KHMDS or LiHMDS). The second part of this thesis explores the impact of the NHC or CAAC ligands on initiation and “boomerang” recapture of the styrenyl ether ligands for Hoveyda- and Grela-class catalysts. Examination of the kinetics of initiation with bulky t-butyl vinyl ether (tBuVE) revealed a linear dependence of kobs on [tBuVE], and faster reaction by the p-NO2-substituted Grela catalyst. These data suggest an associative or interchange-associative (IA) mechanism. A systematic comparison of initiation rate constants revealed the trend HII > nG-C1 > HII-C1 in chlorinated and aromatic solvents. Recapture of added styrenyl ether ligand was examined in macrocyclization (mRCM). Rate plots indicated inhibition by this ligand, even at the high dilutions required for mRCM, implying that boomerang re-uptake of the styrenyl ether is indeed operative for both Hoveyda- and Grela-class catalysts. However, inhibition was found to be more profound for HII than HII-C1 or nG-C1. That is, the NHC catalysts are much more susceptible to partitioning into the off-cycle (precatalyst) form than are the CAAC catalysts. This higher commitment to the active cycle may be an important contributor to the impressive productivity of the CAAC catalysts. In addition, the slow initiation of these catalysts indicated above may be an asset, rather than a limitation, as it inhibits their susceptibility to bimolecular decomposition.

Reactive distillation is a combination of a traditional multi-stage distillation column with a chemical reaction. The primary benefits of a reactive distillation process are reduced capital costs for equipment and energy in addition to enhanced conversion for equilibrium-limited reactions. One such equilibrium-limited reaction is an olefin metathesis. Olefin metathesis is a catalyzed reaction that breaks the double bond in olefins and rearranges the alkene fragments into new olefinic products. A comprehensive investigation of a reactive distillation based olefin metathesis and supporting experimentation is documented here. A small pilot plant study was performed for pilot scale performance comparison. Bench reactor experimentation was conducted for the purposes of learning detailed information on specific metathesis reactions. Lastly, a process simulation study was completed for comparison in performance with the small pilot plant process. The small pilot plant study involved the design, construction, testing, operation, and optimization of a reactive distillation column. Continuous operation campaigns at two different hydraulic capacities within the reactive zone were performed and their performances were compared. A higher hydraulic capacity proved to be more efficient and more selective for the conversion of medium molecular weight olefins into both lighter and heavier olefinic products. Bench reactor experiments were designed with the intent of investigating specific alpha olefin metathesis reactions and obtaining conversions, selectivities, and yield structures for future simulation work. However, under conditions similar to that within the small pilot plant process, there existed a high frequency of secondary double bond isomerization (possibly due to an isomerization activity for alumina). There was also an observed dependence on temperature for both the primary metathesis and secondary isomerization reactions. A process simulation representative of the small pilot plant process was constructed in AspenPlus. Using a simplified reaction network based on assumptions and analysis of the reactive zone, its performance was compared with that of the small pilot plant process. The simulation performance tended to underpredict overhead compositions, but accurately simulated the bottoms product composition. Because reactive distillation has not been used with a heavy olefin metathesis reaction, this dissertation demonstrates the uniqueness and effectiveness of a reactive distillation based heavy olefin metathesis. / text

The past two years have witnessed groundbreaking advances in the industrial deployment of olefin metathesis. While metathesis methodologies have been an integral part of the chemical manufacturing landscape for 60 years, implementation in pharmaceutical and specialty chemicals manufacturing represents a new frontier. The imperative to develop greener and more cost-effective manufacturing processes is anticipated to spur further improvements in sustainable synthesis. Advances in catalyst productivity, however, are critical to expansion of the uptake of metathesis methodologies in this and other manufacturing sectors. Key to increased catalyst productivity is elimination of side reactions that lower yield and errode selectivity. Among such reactions, double-bond isomerization is by far most common. Accumulating evidence suggests that unwanted isomerization during olefin metathesis is due to ruthenium species generated via catalyst decomposition. The identification of these species and how they are formed is thus of great importance. Two hydride complexes, RuHCl(CO)(H2IMes)(PCy3) and a dinuclear hydride, are known to form under some circumstances by decomposition of the second-generation Grubbs catalyst, RuCl2(H2IMes)(PCy3)(=CHPh), GII. These complexes have been widely viewed as responsible for unintended isomerization reactions. However, examination of their performance in olefin isomerization under conditions relevant to metathesis reveals that their activity is too feeble to account for the levels of isomerization observed during metathesis. Alternatively, kinetically competent culprits emerge from decomposition studies that reveal unexpected ruthenium products on decomposition of GII during metathesis; specifically, formation of ruthenium nanoparticles. The formation and catalytic non-innocence of RuNPs constitutes a new paradigm in this field, which opens the door to new approaches to prevent or to harness olefin isomerization. Key to prevention, clearly, is circumventing the decomposition pathways that enable ligand stripping from the active catalyst. New approaches to catalyst design that involve use of truncated NHC ligands are also examined. Finally, the power and utility of isomerization when coupled with metathesis is explored. The opportunities and limitations of orthogonal isomerization–metathesis catalysis are examined in the context of the two-step synthesis of cinnamates from 1-allylbenzenes abundant in essential oils. An efficient one-pot, two-catalyst protocol is developed for conversion of these biorenewable feedstocks to high-value-added chemicals.

Ruthenium-alkylidene catalysts are widely used in organic synthesis to generate new C=C bonds in a process known as olefin metathesis. Much research has been dedicated to examining the organometallic species responsible for this transformation, and understanding the benefits and limitations of current state-of-the-art catalysts allows for the design of new and more efficient alternatives. Over the past decade, a topic of much debate has been the so-called “boomerang” (or release-return) mechanism, and whether it operates in the Hoveyda catalysts. The ability of the styrenyl ether ligand, once released from the catalyst during initiation, to be recaptured by the vulnerable active species, has major implications in catalyst recyclability. Chapter 3 describes the use of a 13C-labeled styrenyl ether ligand, in conjunction with an unlabeled second-generation Hoveyda catalyst, to confirm the operation of this mechanism during catalysis. This study demonstrated that the labeled styrenyl ether ligand competes with the substrate for the four-coordinate active species: the labeled moiety rapidly incorporates into the Hoveyda catalyst during both ring-closing- and cross-metathesis examples. Chapter 4 focuses on addressing the selectivity challenges associated with olefin metathesis, particularly during RCM macrocyclization reactions where E/Z mixtures are typically obtained. Designing catalysts that can dictate and control the stereochemistry of a product mixture minimizes waste, and ultimately reduces cost by eliminating the need for separation techniques. A great deal of research has focused on constructing catalysts with ligands that can exert the appropriate steric pressure on a metallocyclobutane intermediate, in order to generate the desired Z-product. Chapter 4 of this thesis examined the ability of a Hoveyda- and Grubbs-type catalyst containing monothiolate ligands, to promote Z-selective RCM macrocyclization. Catalyst lifetimes were also examined, in addition to the impact of altering reaction conditions, specifically concentration, on product distribution. These experiments afford information that will aid in the design of improved catalysts for Z-selective RCM macrocyclization.

This thesis describes studies directed to the ring opening metathesis polymerisation (ROMP) of some fluorinated compounds using a range of well-defined initiators. Chapter 1 reviews some general aspects of olefin metathesis and ring opening metathesis polymerisation of relevance to the work described in this thesis. Topics such as piezo- and pyro-electricity and optical and electrical properties of conjugated polymers are introduced and these receive more detailed attention later in the thesis. Chapter 2 describes the synthesis, characterisation and properties of . poly(bis(trifluororaethyl)norbomadiene) in detail. The use of various initiating systems that have been used previously and the effect they have on the tacticity of the resulting polymer raicrostructure are discussed. The latter part of this chapter reviews some of the current thinking concerning the detailed mechanistic aspects of this polymerisation. Chapter 3 reviews attempts directed to an improvement in tacticity control in the synthesis of poly(bis(trifluoromethyl)norbomadiene). The synthesis and activity of the new well-defined initiators used in these studies are reported. It is shown that varying the nature of the ancillary Ligands surrounding the metal centre can have a dramatic influence on the tacticity of the resulting polymer. Chapter 4 reports studies directed to an examination of the limits of the well controlled synthesis of poly(bis(trifluoromethyl)norbornadiene). The syntheses of high trans and high cis, highly tactic poly(bis(trifluoromethyl)norbornadiene samples using well-defined initiating systems are described. It is shown that by varying the monomerinitiator ratio, samples with a wide range of molecular weights can be achieved and these are reported. Chapter 5 describes experiments concerning the ROMP of fluorinated monomers containing six membered rings. In particular ROMP studies of the monomers, 2,3-bis(trifluoromethyl)bicyclo[2.2.2]octa-2,5-diene . and 2,3- (tetrafluorobenzo)bicyclo[2.2.2]octatriene are described finally, Chapter 6 provides a summary of the work reported and outlines some ideas for future studies.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Through the use of quantum theory of atoms in molecules (QTAIM) the similarities and differences between transition metal complexes ligated by phosphines and N-heterocyclic carbenes (NHC) were elucidated. Among the key findings, the phosphines were identified as stronger charge donors than NHCs; however, the latter class of ligands exhibits a weaker p-accepting character than the former. Furthermore, Tolman electronic parameter (TEP) was determined to be an inadequate gauge for the total electron donating ability of phosphines and NHCs; rather TEP can serve as a measurement of population of dp set of orbitals of a metal center in question. Computational and experimental studies of the mechanism of NHC-catalyzed boron and silicon addition to a,ß-unsaturated carbonyls reactions were carried out. Through the use of radical traps the mechanisms involving homolytic cleavage of B-B or B-Si bonds were ruled out. Computational (DFT) studies of the mechanism identified two pathways: (1) direct activation of diboron or borosilyl reagents through coordination of NHC to the B atom, (2) net oxidative addition of the diboron or borosilyl reagents to the carbon (II) of the NHC. The insights gained from the aforementioned studies were employed to rationalize the observed lack of reactivity of NHC-activated diboron complexes in the presence of aldehydes. Chapter 2. New C(1)-symmetric chiral monodentate N-heterocyclic carbenes were prepared, and corresponding chiral Ru-carbene complexes were synthesized. These complexes were employed to gain empirical understanding of factors that govern stereoselectivity in Ru-catalyzed enantioselective olefin ring-closing metathesis. The data thus obtained was employed to infer that syn-to-NHC reaction pathways are competitive and non-selective. One plausible mechanism, through which syn-to-NHC pathways can be accessed, involves Berry pseudorotations. Through the use of stereogenic-at-Ru complexes diastereomeric Ru-carbenes were isolated (silica gel chromatography) and spectroscopically characterized in solution phase. The diastereomeric Ru-carbenes were found to undergo non-metathesis stereomutations at Ru center, thereby providing additional support for the above hypothesis regarding accessibility of syn-to-NHC olefin metathesis pathways. Non-metathesis stereomutation at Ru was found to be accelerated in the presence of protic additives, suggesting the plausibility of hydrogen bonding between the acidic proton and the X-type ligands on Ru. Occurrence of hydrogen bonding was corroborated through the use of chiral allylic alcohols in Ru-catalyzed diastereoselective ring-opening/cross metathesis, which was developed into a versatile method for highly diastereoselective functionalization of terminal olefins. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1. Exploring Ligand Effects in Ruthenium Dithiolate Carbene Complexes. Ruthenium dithiolate metathesis catalysts discovered in the Hoveyda group have been a valuable addition to the field of olefin metathesis. While the catalyst shows unique selectivity and reactivity, quantifying and mapping key interactions in the catalyst framework to elucidate and explain causes is difficult. We, therefore, decided to use the neutral chelating or monodentate ligand, controlling initiation, as a structural probe. By altering its properties and observing changes in the catalyst, we sought to deepen our understanding of these complexes. We established a trans influence series with over 20 catalysts and correlated the impact on catalyst initiation. Further, we show that in the case of strongly σ-donating and π-accepting ligands such as phosphites and isonitriles, the complex exhibits fluxional behavior. The catalysts ground state is elevated to such a degree that thiolate Ruthenium bonds become labile and rapidly exchange. While Ruthenium dithiolate catalysts were readily applied to metathesis polymerization, their use in the synthesis of small molecules was initially less forthcoming. Specifically, reactions involving terminal olefins lead to rapid catalyst deactivation and only low conversion. We were able to determine that the potential energy stored in the trans-influence between the thiolate ligand and the NHC can be released in a sulfur shift to reactive Ruthenium methylidene species. Since methylidenes are formed by reaction with terminal olefins, use of an excess of internal olefins can prevent their formation. Chapter 2. Harnessing Catalyst Fluxionality in Olefin Metathesis. Depending on its use, material requirements can vary significantly. Materials that can easily be adapted to a given application, for example by varying tensile strength, melting point or solubility, are desirable. Controlling the polymers tacticity (the adjacent stereocenters in a polymer chain) is a straight forward way to achieve just that. Ru dithiolate catalysts should give highly syndiotactic polymers due to their single stereocenter undergoing inversion during every metathesis step. The fluxional nature of the catalyst allows for control of polymer tacticity from 50% (atactic) to ≥95% syndiotacticity by changing monomer concentration. We determined the factors which are responsible for fluxionality and synthesized complexes that give either high or low levels of tacticity over a broader range of monomer concentration. Chapter 3. Harnessing Catalyst Fluxionality in Olefin Metathesis. The importance of fluorine-containing molecules is hard to understate, keeping in mind the surge of new methodologies for their synthesis and the medical breakthroughs they enable. However, efficient and practical syntheses of stereodefined alkenyl fluorides are rare. In this context, we have developed enantioselective boryl allylic substitution of allylic fluorides, which yield enantioenriched γ-alkenyl fluoride substituted allyl boronate esters. The reaction is catalyzed by Cu-based catalysts that are prepared in-situ and delivered as products with high yield and enantioselectivity. Mechanistic inquiry shows the reaction is not a concerted allylic substitution. An intermediate Cu alkyl complex is formed after the Cu boron addition is made to the double bond, which only slowly undergoes β-fluorine elimination in the presence of a Lewis acid. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

No description available.

Olefin metathesis is an exceptionally versatile and general methodology for the catalytic assembly of carbon-carbon bonds. Ruthenium metathesis catalysts have been widely embraced in academia, and are starting to see industrial uptake. However, the challenges of reliability, catalyst productivity, and catalyst cost have limited implementation even in value-added technology areas such as pharmaceutical manufacturing. Key to the broader adoption of metathesis methodologies is improved understanding of catalyst decomposition. Many studies have focused on phenomenological relationships that relate catalyst activity to substrate structure, and on the synthesis of new catalysts that offer improved activity. Until recently, however, relatively little attention was paid to catalyst decomposition. The first part of this thesis explores a largely overlooked decomposition pathway for “second-generation” olefin metathesis catalysts bearing an N-heterocyclic carbenes (NHC) ligand, with a particular focus on identifying the Ru decomposition products. Efforts directed at the deliberate synthesis of these products led to the discovery of a succinct, high-yielding route to the second-generation catalysts. Multiple reports, including a series of detailed mechanistic studies from our group, have documented the negative impact of phosphine ligands in Ru-catalyzed olefin metathesis. Phosphine-free derivatives are now becoming widely adopted, particularly in pharma, as recognition of these limitations has grown. Decomposition of the phosphine-free catalysts, however, was little explored at the outset of this work. The only documented pathway for intrinsic decomposition (i.e. in the absence of an external agent) was -hydride elimination of the metallacyclobutane (MCB) ring as propene. An alternative mechanism, well established for group 3-7 and first-generation ruthenium metathesis catalysts, is bimolecular coupling (BMC) of the four-coordinate methylidene intermediate. However, this pathway was widely viewed as irrelevant to decomposition of second-generation Ru catalysts. This thesis work complements parallel studies from the Fogg group, which set out to examine the relevance and extent of BMC for this important class of catalysts. First, -hydride elimination was quantified, to assess the importance of the accepted pathway. Even at low catalyst concentrations (2 mM Ru), less than 50% decomposition was shown to arise from -hydride elimination. Parallel studies by Gwen Bailey demonstrated ca. 80% BMC for the fast-initiating catalyst RuCl2H2IMes(=CHPh)(py)2 GIII. Second, the ruthenium products of decomposition were isolated and characterized. Importantly, and in contrast to inferences drawn from the serendipitous isolation of crystalline byproducts (which commonly show a cyclometallated NHC ligand), these complexes show an intact H2IMes group. This rules out NHC activation as central to catalyst decomposition, suggesting that catalyst redesign should not focus on NHC cyclometallation as a core problem. Building on historical observations, precautions against bimolecular coupling are proposed to guide catalyst choice, redesign, and experimental setup. The second part of this thesis work focused on the need for more efficient routes to second-generation Ru metathesis catalysts, and indeed a general lack of convenient, well-behaved precursors to RuCl2(H2IMes). This challenge was met by building on early studies in which metathesis catalysts were generated in situ by thermal or photochemical activation of RuCl2(p-cymene)(PCy3) in the presence of diazoesters. Such piano-stool complexes (including the IMes analogue) have also been applied more broadly as catalysts, inorganic drugs, sensors, and supramolecular building blocks. However, RuCl2(p-cymene)(H2IMes), which should in principle offer access to the RuCl2(H2IMes) building block, has been described as too unstable for practical use. The basis of the instability of RuCl2(p-cymene)(H2IMes) toward loss of the p-cymene ring was examined. Key factors included control over reaction stoichiometry (i.e. limiting the proportion of the free NHC), limiting exposure to light, and maintaining low concentrations to inhibit bimolecular displacement of the p-cymene ring. A near-quantitative route to RuCl2(p-cymene)(H2IMes) was achieved using appropriate dilutions and rates of reagent addition, and taking precautions against photodecomposition. This approach was used to develop atom-economical syntheses of the Hoveyda catalyst, RuCl2(H2IMes)(=CHAr) (Ar = 2-isopropoxybenzylidene) and RuCl2(H2IMes)(PPh3)(=CHPh), a fast-initiating analogue of GII. Related p-cymene complexes bearing bulky, inflexible imidazolidene or other donors may likewise be accessible.