Selectivity, activity, and stability of ruthenium-carbene based olefin metathesis initiators

The olefin metathesis reaction has found many applications in polymer synthesis and more recently in organic synthesis. The use of single component late metal olefin metathesis catalysts has expanded the scope of the reaction to many new applications and has allowed for detailed study of the catalytic species.

The metathesis of terminal olefins of different steric bulk, different geometry as well as electronically different para-substituted styrenes was studied with the ruthenium based metathesis initiators, trans-(PCy₃)₂Cl₂Ru=CHR, of different carbene substituents. Increasing olefin bulk was found to slow the rate of reaction and trans internal olefins were found to be slower to react than cis internal olefins. The kinetic product of a11 reactions was found to be the alkylidene, rather than the methylidene, suggesting the intermediacy of a 2,4-metallacycle. The observed effects were used to explain the mechanism of ring opening cross metathesis and acyclic diene metathesis polymerization. No linear electronic effects were observed.

In studying the different carbene ligands, a series of ester-carbene complexes was synthesized. These complexes were found to be highly active for the metathesis of olefinic substrates, including acrylates and trisubstituted olefins. In addition, the estercarbene moiety is thermodynamically high in energy. As a result, these complexes react to ring-open cyclohexene by metathesis to alleviate the thermodynamic strain of the ester-carbene ligand. However, ester-carbene complexes were found to be thermolytically unstable in solution.

Thermolytic decomposition pathways were studied for several ruthenium-carbene based olefin metathesis catalysts. Substituted carbenes were found to decompose through bimolecular pathways while the unsubstituted carbene (the methylidene) was found to decompose unimolecularly. The stability of several derivatives of the bis-phosphine ruthenium based catalysts was studied for its implications to ring-closing metathesis. The reasons for the activity and stability of the different ruthenium-based catalysts is discussed.

The difference in catalyst activity and initiation is discussed for the bis-phosphine based and mixed N-heterocyclic carbene/phosphine based ruthenium olefin metathesis catalysts. The mixed ligand catalysts initiate far slower than the bis-phosphine catalysts but are far more metathesis active. A scheme is proposed to explain the difference in reactivity between the two types of catalysts.

Attempts to Synthesize Cyclic Group 8 Metallaesters

In studying a proposed carbon monoxide reduction scheme an attempt has been made to synthesize bifunctional group 8 transition metal carbonyl complexes containing intramolecular nucleophiles. The incorporation of alkoxide nucleophiles through cyclopentadienyl ligands was hoped to encourage attack on carbonyl ligands thereby forming cyclic metallaesters. The attempts to synthesize these substituted cyclopentadienyl group 8 transition metal complexes have thus far been unsuccessful.

Synthetic and structural studies of permethylscandocene and permethyltantalocene derivatives

Cp*_2Sc-H reacts with H_2 and CO at -78°C to yield Cp*_2ScOCH_3. A stepwise reduction of CO to an alkoxide is observed when CO reacts with Cp*_2ScC_6H_4CH_3-p to give the η^2-acyl Cp*_2Sc(CO)C_6H_4CH_3-p, which then reacts with H_2 to produce Cp*_2ScOCH_2C_6H_4CH_3-p. Cp*_2ScCH_3 and Cp*_2ScH(THF) react with CO to give unchar- uncharacterizable products. Cp*_2ScH and Cp*_2ScCH_3 react with Cp_2MCO (M = Mo, W) to give scandoxycarbenes, Cp_2M=C(CH_3)OScCp*_2, while a wide variety of Cp*_2ScX (X = H, CH_3, N(CH_3)_2, CH_2CH_2C_6H_5) reacts with CpM(CO)_2 (M = Co, Rh) to yield similar carbene complexes. An x-ray crystal structure determination of Cp(CO)Co=C(CH_3)- OScCp*_2 revealed a µ^2: η^1, η^1 carbonyl interaction between the Co-CO and Sc.

CO_2 inserts cleanly into Sc-phenyl bonds at -78°C to produce a carboxylate complex, Cp*_2Sc(O_2C)C_6H_4CH_3-p. The structure of this compound was determined by x-ray crystallographic techniques.

Excess C_2H_2 reacts with Cp*_2ScR (R = H, alkyl, aryl, alkenyl, alkynyl, amide) at temperatures below -78°C to form the alkynyl species Cp*_2Sc-C≡C-H, which then reacts with the remaining acetylene to form polyacetylene. Cp*_2Sc-C≡C-H further reacts to yield Cp*_2sc-C≡C-ScCp*_2. This unusual C_2 bridged dimer was characterized by x-ray crystallography.

Attempts were made to model the C-N bond breaking step of hydrodenitrogenation by synthesizing Cp*_2TaH(η^2-H_2C=N(C_6H_4X)) and studying its rearrangement to Cp*_2Ta(=N(C_6H_4X))(CH_3). The 1,2 addition/elimination reactions of Cp*_2Ta(η^2- H_2C=N(CH_3)H and Cp*_2Ta(=X)H (X=O, S, NH, N(C_6H_5)) were investigated. Cp*_2Ta(=NH)H was found to react with D_2 to give Cp*_2Ta(=ND)H, implying a nonsymmetric amide-dihydride intermediate for the addition/elimination process. Cp*_2Ta(=S)H and H_2O equilibrate with Cp*_2Ta(=O)H and H_2S, which allowed determination of the difference in bond strengths for Ta=O and Ta=S. Ta=O was found to be approximately 41 kcals/mole stronger than Ta=S.

New materials for biological applications prepared by olefin metathesis reactions

With the advent of well-defined ruthenium olefin metathesis catalysts that are highly active and stable to a variety of functional groups, the synthesis of complex organic molecules and polymers is now possible; this is reviewed in Chapter 1. The majority of the rest of this thesis describes the application of these catalysts towards the synthesis of novel polymers that may be useful in biological applications and investigations into their efficacy.

A method was developed to produce polyethers by metathesis, and this is described in Chapters 2 and 3. An unsaturated 12-crown-4 analog was made by template- directed ring-closing metathesis (RCM) and utilized as a monomer for the synthesis of unsaturated polyethers by ring-opening metathesis polymerization (ROMP). The yields were high and a range of molecular weights was accessible. In a similar manner, substituted polyethers with various backbones were synthesized: polymers with benzo groups along the backbone and various concentrations of amino acids were prepared. The results from in vitro toxicity tests of the unsubstituted polyethers are considered.

The conditions necessary to synthesize polynorbornenes with pendent bioactive peptides were explored as illustrated in Chapter 4. First, the polymerization of various norbornenyl monomers substituted with glycine, alanine or penta(ethylene glycol) is described. Then, the syntheses of polymers substituted with peptides GRGD and SRN, components of a cell binding domain of fibronectin, using newly developed ruthenium initiators are discussed.

In Chapter 5, the syntheses of homopolymers and a copolymer containing GRGDS and PHSRN, the more active forms of the peptides, are described. The ability of the polymers to inhibit human dermal fibroblast cell adhesion to fibronectin was assayed using an in vitro competitive inhibition assay, and the results are discussed. It was discovered that the copoymer substituted with both GRGDS and PHSR peptides was more active than both the GRGDS-containing homopolymer and the GRGDS free peptide.

Historically, one of the drawbacks to using metathesis is the removal of the residual ruthenium at the completion of the reaction. Chapter 6 describes a method where the water soluble tris(hydroxymethyl)phosphine is utilized to facilitate the removal of residual ruthenium from RCM reaction products.

Transition metal clusters supported by multinucleating ligand frameworks as models of biological active sites

This dissertation describes efforts to model biological active sites with small molecule clusters. The approach used took advantage of a multinucleating ligand to control the structure and nuclearity of the product complexes, allowing the study of many different homo- and heterometallic clusters. Chapter 2 describes the synthesis of the multinucleating hexapyridyl trialkoxy ligand used throughout this thesis and the synthesis of trinuclear first row transition metal complexes supported by this framework, with an emphasis on tricopper systems as models of biological multicopper oxidases. The magnetic susceptibility of these complexes were studied, and a linear relation was found between the Cu-O(alkoxide)-Cu angles and the antiferromagnetic coupling between copper centers. The triiron(II) and trizinc(II) complexes of the ligand were also isolated and structurally characterized.

Chapter 3 describes the synthesis of a series of heterometallic tetranuclear manganese dioxido complexes with various incorporated apical redox-inactive metal cations (M = Na⁺, Ca²⁺, Sr²⁺, Zn²⁺, Y³⁺). Chapter 4 presents the synthesis of heterometallic trimanganese(IV) tetraoxido complexes structurally related to the CaMn₃ subsite of the oxygen-evolving complex (OEC) of Photosystem II. The reduction potentials of these complexes were studied, and it was found that each isostructural series displays a linear correlation between the reduction potentials and the Lewis acidities of the incorporated redox-inactive metals. The slopes of the plotted lines for both the dioxido and tetraoxido clusters are the same, suggesting a more general relationship between the electrochemical potentials of heterometallic manganese oxido clusters and their “spectator” cations. Additionally, these studies suggest that Ca²⁺ plays a role in modulating the redox potential of the OEC for water oxidation.

Chapter 5 presents studies of the effects of the redox-inactive metals on the reactivities of the heterometallic manganese complexes discussed in Chapters 3 and 4. Oxygen atom transfer from the clusters to phosphines is studied; although the reactivity is kinetically controlled in the tetraoxido clusters, the dioxido clusters with more Lewis acidic metal ions (Y³⁺ vs. Ca²⁺) appear to be more reactive. Investigations of hydrogen atom transfer and electron transfer rates are also discussed.

Appendix A describes the synthesis, and metallation reactions of a new dinucleating bis(N-heterocyclic carbene)ligand framework. Dicopper(I) and dicobalt(II) complexes of this ligand were prepared and structurally characterized. A dinickel(I) dichloride complex was synthesized, reduced, and found to activate carbon dioxide. Appendix B describes preliminary efforts to desymmetrize the manganese oxido clusters via functionalization of the basal multinucleating ligand used in the preceding sections of this dissertation. Finally, Appendix C presents some partially characterized side products and unexpected structures that were isolated throughout the course of these studies.

Chelation-enforced metal-arene interactions : insights into substrate binding and catalysis by late transition metal complexes

Understanding and catalyzing chemical reactions requiring multiple electron transfers is an endeavor relevant to many outstanding challenges in the field of chemistry. To study multi-electron reactions, a terphenyl diphosphine framework was designed to support one or more metals in multiple redox states via stabilizing interactions with the central arene of the terphenyl backbone. A variety of unusual compounds and reactions and their relevance toward prominent research efforts in chemistry are the subject of this dissertation.

Chapter 2 introduces the para-terphenyl diphosphine framework and its coordination chemistry with group 10 transition metal centers. Both mononuclear and dinuclear compounds are characterized. In many cases, the metal center(s) are stabilized by the terphenyl central arene. These metal–arene interactions are characterized both statically, in the solid state, and fluxionally, in solution. As a proof-of-principle, a dinickel framework is shown to span multiple redox states, showing that multielectron chemistry can be supported by the coordinatively flexible terphenyl diphosphine.

Chapter 3 presents reactivity of the terphenyl diphosphine when bound to a metal center. Because of the dearomatizing effect of the metal center, the central arene of the ligand is susceptible to reactions that do not normally affect arenes. In particular, Ni-to-arene H-transfer and arene dihydrogenation reactions are presented. Additionally, evidence for reversibility of the Ni-to-arene H-transfer is discussed.

Chapter 4 expands beyond the chelated metal-arene interactions of the previous chapters. A dipalladium(I) terphenyl diphosphine framework is used to bind a variety of exogenous organic ligands including arenes, dienes, heteroarenes, thioethers, and anionic ligands. The compounds are structurally characterized, and many ligands exhibit unprecedented bindng modes across two metal centers. The relative binding affinities are evaluated spectroscopically, and equilibrium binding constants for the examined ligands are determined to span over 13 orders of magnitude. As an application of this framework, mild hydrogenation conditions of bound thiophene are presented.

Chapter 5 studies nickel-mediated C–O bond cleavage of aryl alkyl ethers, a transformation with emerging applications in fields such as lignin biofuels and organic methodology. Other group members have shown the mechanism of C–O bond cleavage of an aryl methyl ether incorporated into a meta-terphenyl diphosphine framework to proceed through β-H elimination of an alkoxide. First, the electronic selectivity of the model system is examined computationally and compared with catalytic systems. The lessons learned from the model system are then applied to isotopic labeling studies for catalytic aryl alkyl ether cleavage under dihydrogen. Results from selective deuteration experiments and mass spectrometry draw a clear analogy between the mechanisms of the model and catalytic systems that does not require dihydrogen for C–O bond cleavage, although dihydrogen is proposed to play a role in catalyst activation and catalytic turnover.

Appendix A presents initial efforts toward heterodinuclear complexes as models for CO dehydrogenase and Fischer Tropsch chemistry. A catechol-incorporating terphenyl diphosphine is reported, and metal complexes thereof are discussed.

Appendix B highlights some structurally characterized terphenyl diphosphine complexes that either do not thematically belong in the research chapters or proved to be difficult to reproduce. These compounds show unusual coordination modes of the terphenyl diphosphine from which other researchers may glean insights.

Trimethylsilyl anions: stereospecific deoxygenation of epoxides and trimethylsilyldehalogenation of aryl halides

I. Trimethylsilylpotassium reacts with epoxides to give olefins with inversion of stereochemistry. The reaction appears to proceed via the potassium β-silyl alkoxide (2) formed from the S_N2 attack of the silyl anion on the epoxide. Subsequent stereospecific synelimination of 2 affords the olefin of inverted stereo-chemistry. The reaction is convenient and preparatively useful.

The byproduct of the reaction, potassium trimethylsilanolate (17), effectively cleaves hexamethyldisilane to yield trimethylsilylpotassium. Since the latter reagent is generated and reacted in situ with epoxides, the overall reaction can be carried out with less than one equivalent of potassium methoxide.

II. The reaction of aryl halides with trimethylsilyl anions in HMPT provides good yields of aryltrimethylsilanes, useful synthetic intermediates. The choice of metal cation is unimportant. Chlorides and bromides give high yields of silylated products, while iodides give lower yields, with correspondingly increased amounts of reduced products. Arylammonium and arylphosphonium salts also undergo the reaction.

We have permissive evidence for the reaction proceeding via both aryl radical and aryl anion intermediates.

III. Trimethylsilyl and trimethylstannyl methoxycarbene complexes of chromium and tungsten have been prepared. One of these, (CO)_5WC(OMe)SnMe_3, reacts with norbornene at 80° to afford a new olefin polymer. Efforts to effect the alpha-elimination of the nonmetallic carbene ligands have not yet been successful. Reactions of these carbene complexes with acetone have been investigated.

Oxy anion-accelerated rearrangements

The alkali metal salts of 1,5-hexadien-3-ols undergo accelerated Cope rearrangements to the enolates of δ, ε-unsaturated carbonyl compounds. The generality of the rearrangement was investigated in numerous systems, particularly acyclic cases, and the effect of changes in substituents, counterions, solvents, and geometrical structures were noted and discussed. Applications of this methodology in synthesis included the synthesis of the insect pheromone frontalin, the preparation of selectively monoprotected 1,6-dicarbonyl compounds from 4-methoxy- and 4-phenylthio-1,5-hexadien-3-ols, and the construction of complex ring structures such as a D-homo-estratetraenone derivative.

Thermochemical estimates of the energetics of anionpromoted alkoxide fragmentations were made, and in all cases heterolytic cleavage was favored over hemolytic cleavage by 8.5-53 kcal/mol. The implication of these and other thermochemical estimates is that the anionic oxy-Cope rearrangement occurs via a concerted mechanism rather than a dissociation-recombination process. The concepts of anion-induced bond weakening were successfully applied to an accelerated [1,3]-shift of a dithiane fragment in a cyclohexenyl system. Trapping experiments demonstrated that > 85% of the [1,3]-shift occurred within a solvent cage. Attempts at promoting an intramolecular ene reaction using the potassium salts of 2,7-octadien-1-o1 and 2,8-nonadien-1-o1 were unsuccessful. A general review of anion-promoted bond reorganizations and anion substituent effects is also presented.