Mountain Scholar :: Browsing by Author "Chen, Eugene, committee member"

Browsing by Author "Chen, Eugene, committee member"

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Open Access
Determining driving forces for small molecule aggregation using computational and theoretical methods
(Colorado State University. Libraries, 2022) Anderson, Jakob Edward, author; Rappé, Anthony, advisor; McCullagh, Martin, advisor; Kennan, Alan, committee member; Chen, Eugene, committee member; Shipman, Patrick, committee member
Molecular aggregation is largely dictated by noncovalent interactions and is a phenomenon found in a broad list of disciplines. Computational and theoretical methods, such as molecular dynamics simulations and Quantum Mechanical calculations, are well suited techniques to study the noncovalent association of various systems as they provide atomistic resolution and experimentally comparable results for the timescales on which association occurs. The studies found in this dissertation are introduced in the first chapter and are put in the context of using computational methods to study the noncovalent association and aggregation of small molecules. Chapters two, three, and four provide a foundation for the rational design of dipeptides for a given application. A wide range of potential applications for diphenylalanine (FF) have been proposed which would benefit from the development of design principles. Chapter two discusses the complexity of the noncovalent interactions at multiple stages in the FF self-assembly process. Specifically, we suggest the initial aggregation of FF is predominantly driven by electrostatics, and after a reorientation event, nanotube growth is suggested to be driven by solvent mediated forces. The results from this chapter use an array of generalized analyses enabling quantitative comparisons to future dipeptide studies. The impact of sidechain modification for either FF residue is studied in chapter three by considering valine-phenylalanine (VF) and phenylalanine-valine (FV). While the monomeric conformations are shown to sample the same states for these two dipeptides, the probabilities for state sampling as well as the water dynamics around the peptide bond are shown to differ. Chapter four connects chapters two and three by considering both the behavior of sequence dependence and dimerization of VF, FV, isoleucine-phenylalanine, and phenylalanine-isoleucine relative to that of FF. The modification of the C-terminus of FF to a smaller hydrophobic sidechain is hypothesized to enable tighter packing from this study. Additionally, N-terminus FF modification is hypothesized to increase the solvent mediated forces during dimerization in agreement with the results from chapter three. While not a completed study, chapter four provides a foundation for the continued development of design principles for FF-derivatives. A novel approach to computing the free energy of association from Quantum Mechanical calculations is then described in chapter five. Due to the treatment of low energy frequencies as harmonic and a lack of temperature dependence, calculations of the entropy of associating molecules is inaccurate. The rigid-rotor-Gaussian-oscillator approximation proposed addresses these issues by treating low lying modes with anharmonic Gaussian potentials and wave functions as well as adding a temperature dependence to the partitioning between vibrational and translational/rotational modes. This approximation significantly reduces the error in computing the entropy of associating molecules resulting in a more accurate calculation of the total free energy. The results from these studies as well as future studies based on the work in this dissertation are then summarized in the final chapter.
Open Access
Development of asymmetric N-heterocyclic carbene-catalyzed reactions
(Colorado State University. Libraries, 2017) Flanigan, Darrin Miles, author; Rovis, Tomislav, advisor; Chen, Eugene, committee member; Shi, Yian, committee member; Chatterjee, Delphi, committee member
N-Heterocyclic carbenes (NHCs) are ubiquitous organocatalysts in a variety of asymmetric transformations. The benzoin and Stetter reactions, which couple aldehydes to other aldehydes or Michael acceptors, respectively are the most commonly reported reactivity manifold employing NHC catalysts. However, other umpolung reactivity pathways exist, for example, when α,β-unsaturated aldehydes are reacted with NHCs, the Breslow intermediate can react through the double bond of the aldehyde to functionalize at the beta position of the carbonyl. A process that has come to be known has homoenolate reactivity. A range of reactivity manifolds were investigated, including the asymmetric intermolecular Stetter reaction and an enantioselective NHC-catalyzed nucleophilic dearomatization of pyridiniums. In the dearomatization chemistry, a homoenolate equivalent is first generated from an enal and an NHC, which then adds to the pyridinium to generate 1,4-dihydropyridines with high enantioselectivity. This is a rare example of catalytic, asymmetric addition of a nucleophile to the activated pyridinium that prefers C-4 functionalization leading to the 1,4-dihydropyridine product. The asymmetric intermolecular Stetter reaction was also investigated in an attempt to broaden the scope of the reaction to include less activated Michael acceptors, specifically, α,β-unsaturated ketones. The coupling of heteroaryl aldehydes to enones could be achieved with appreciable levels of enantioselectivity (up to 80% ee), but reactivity remains a major challenge with this methodology.
Open Access
Development of tethered micelle hydrogel networks through sphere-forming AB/ABA block copolymer melts
(Colorado State University. Libraries, 2013) Guo, Chen, author; Bailey, Travis S., advisor; Kipper, Matt J., committee member; Chen, Eugene, committee member; Wickramasinghe, S. Ranil, committee member
The overriding theme of the work contained in this thesis is concerned with the preparation of tethered micelle hydrogel networks through the melt-state self-assembly of sphere-forming AB diblock and ABA triblock copolymer blends. The first chapter of this dissertation introduces the various projects pursued and provides background information for the reader. The second chapter of this thesis contains the initial demonstration of this novel strategy using polystyrene-poly(ethylene oxide) (PS-PEO, SO) diblock and PS-PEO-PS (SOS) triblock copolymers. Included in this chapter is a discussion of the synthetic polymerization techniques used to produce the SO and SOS block copolymers, the basic melt-state fabrication and characterization strategies used to pre-structure the tethered micelle networks, and the impact of changing both the SOS concentration and temperature on the resultant properties of the hydrogels produced. In these initial studies, the SOS triblock copolymer was constructed to be exactly double the SO diblock copolymer molecular weight, such that the preferred lattice dimensions during self-assembly were "matched". These "matched" hydrogels produced equilibrium swelling ratios (3.8-36.9 g water/g polymer) and dynamic elastic moduli (G' = 1.7-160 kPa) tunable across an impressive range of values using only temperature (10-50 °C) and SOS concentration (3.3-72.0 mol%). The third chapter of this thesis describes our efforts to influence the swelling and mechanical properties exhibited by simply modifying the PEO midblock molecular weight in the SOS tethering molecules. In doing so, we were able to show that the degree of coronal layer overlap between adjacent micelles was the primary contributing factor determining the dynamic mechanical response of the hydrogel. That is, the changes in mechanical properties produced due to altering tether concentration, tether length, or temperature, could all be understood in terms of their impact on the degree of coronal layer overlap in the system. In addition to these findings, we also discovered an interesting relationship between swelling and tether length. Increases in tether length by a factor of 1.6 compared to that of the matched system, resulted in higher swelling ratios and smaller elastic moduli (due to reduced coronal layer overlap). However, increases in tether length by a factor of 2.3 produced swelling behavior and mechanical properties nearly identical to that of the matched system. We concluded that the increase in tether length by a factor of 2.3 was sufficient to allow bridging into the second shell of the nearest neighbor micelles, negating the swelling advantage anticipated for the system. The fourth chapter of this thesis concerns our efforts to demonstrate the modification potential of the swollen hydrogel systems of Chapters 2 and 3. In this study, the terminal hydroxyl functionality present in the aforementioned SO diblock copolymers was substituted with either an azide or alkyne functionality. Cu(I) catalyzed coupling of the azide/alkyne functional diblock copolymer was then performed in the swollen state, producing a secondary network of tethers in the system. Installation of the secondary network produced dramatic improvements in the hydrogel tensile modulus, strain at break, stress at break, and toughness, while permitting swelling ratios, small strain rheological properties, and response in unconfined compression to remain largely unchanged. The fifth and final chapter of this thesis concerns a discussion of preliminary data supporting several promising directions for future work involving the further development of these tethered micelle networks.
Open Access
Dual nickel- and photoredox-catalyzed enantioselective desymmetrization of meso anhydrides and C-O bond activation via phosphines and photoredox catalysis
(Colorado State University. Libraries, 2018) Stache, Erin Elizabeth, author; Rovis, Tomislav, advisor; Doyle, Abigail G., advisor; Chen, Eugene, committee member; McNally, Andy, committee member; Reynolds, Melissa, committee member; Kipper, Matt, committee member
Described herein is the application of photoredox catalysis in the development of new synthetic methods. A dual nickel- and photoredox catalyzed desymmetrization of meso succinic anhydrides was developed to generate stereodefined cis keto-acids in high enantioselectivity and diastereoselectivity. The approach employed benzylic radicals as a coupling partner, generated from a photoredox catalyzed single-electron oxidation of benzylic trifluoroborates using an inexpensive organic dye. A unique epimerization event was discovered and the degree of epimerization was rendered tunable by changing catalyst loadings to ultimately form the trans diastereomer preferentially in high enantioeselectivity. A method for the C–O bond activation of aliphatic alcohols and carboxylic acids was developed using phosphines and photoredox catalysis. This novel reaction platform was used to generate aliphatic or acyl radicals directly from benzylic alcohols and aliphatic and aromatic acids, and with terminal hydrogen atom transfer, afforded the desired deoxygenated alkanes and aldehydes. Additionally, the intermediate acyl radicals could be intercepted in an intramolecular cyclization reaction to generate new lactones, amides and ketones.
Open Access
Elucidation of the biogenesis of the paraherquamides, malbrancheamides, citrinalins, and brevianamides
(Colorado State University. Libraries, 2019) Klas, Kimberly R., author; Williams, Robert M., advisor; Shi, Yian, committee member; Chen, Eugene, committee member; Crick, Dean, committee member
Various fungi of the genera Aspergillus, Penicillium and Malbranchea produce prenylated indole alkaloids that possess a bicyclo[2.2.2]diazaoctane ring system and a variety of biological activities such as insecticidal, cytotoxic, anthelmintic, and antibacterial properties. After the discovery of distinct enantiomers of the natural alkaloids Stephacidin A, Notoamide B and their corresponding diastereomers, from Aspergillus protuberus MF297-2, Aspergillus amoenus NRRL 35660 and Aspergillus taichungensis, the structurally diverse metabolites became of particular biosynthetic interest. The bicyclo[2.2.2]diazaoctane core of the divergent natural metabolites may be enzymatically derived via a putative intramolecular hetero-Diels-Alder cycloaddition. We completed the total synthesis of ZwtP and MeZwtP, unveiling the role of a newly discovered Diels-Alderase. We are also undergoing further synthetic efforts to access other novel natural products, as well as further understand additional unprecedented transformations in nature.
Open Access
Energy transfer interactions with single molecule phenomena in small clusters of quantum dots
(Colorado State University. Libraries, 2014) Whitcomb, Kevin James, author; Van Orden, Alan, advisor; Bernstein, Elliot, committee member; Levinger, Nancy, committee member; Chen, Eugene, committee member; Gelfand, Martin, committee member
This dissertation describes the observed interactions between energy transfer in small clusters of nominally monodisperse semiconductor nanocrystals (quantum dots, QDs) and single molecule phenomena such as fluorescence intermittency (blinking) and antibunching. The relevant literature on energy transfer between QDs has typically invoked the Förster energy transfer mechanism to explain the observations in ensemble measurements. The size dispersion in QDs results in a dispersion in the electronic and optical properties of QDs due to size dependent confinement effects on photogenerated carriers. This size dispersion is thought to be the reason for energy transfer among nominally monodisperse QDs as in the single molecule work in this dissertation. The single molecule measurements in this dissertation were done using confocal microscopy and correlated atomic force microscopy (AFM). The experimental setup is described in detail. Confocal microscopy is used to excite a small region on a surface of sparsely deposited QDs or QD clusters. This allows for observation of individual QDs or individual clusters at a time. The fluorescence from these samples is collected through the microscope objective and spatially filtered using confocal techniques, i.e. spatially filtering the fluorescence with a pinhole. The excitation region can be correlated with a nanoscale topographical image using the light that is backscattered through the microscope objective by an atomic force microscope tip. This provides an additional method for distinguishing individual QDs from QD clusters. Methods for setup, alignment, maintenance of the instruments used will be described with sample preparation and practical measurement considerations. The interaction of energy transfer and QD blinking will be discussed in detail. The major findings are that the mechanism of energy transfer does not affect the individual blinking properties of QDs in a cluster, nor does the close proximity of other quantum dots. The findings will also show evidence that an individual QD governs the fluorescence state of the cluster through energy transfer. The clusters in this work were primarily identified and analyzed using fluorescence properties. The threshold in clusters is not as obvious as in individual QDs so an intensity threshold is set using a model of energy transfer that sets a threshold based on the lifetime. The findings impact future studies of QD clusters and applications that utilize QDs in close proximity to each other. The interaction of energy transfer and photon antibunching will also be discussed in detail. A simple model of energy transfer will be used to model the degree of antibunching in small clusters of QDs. The degree of antibunching observed in QD clusters is more characteristic of an individual emitter than multiple emitters which is a surprising find because it indicates that all QDs interact through energy transfer even in small nominally monodisperse aggregates. This work was done with correlated AFM to be sure that one QD or QD cluster is observed at a time. It is extremely important that only one emitter is in the excitation region because multiple independent emitters confound the analysis of antibunching and the observation of antibunching from multiple emitters heavily impacts single molecule study of QDs. Antibunching is thought to be the single definitive evidence that a single emitter is being probed but this is not so in the case of close proximity QDs even if the QDs are nominally the same size.
Open Access
Investigations into magnetic relaxation for vanadium complexes
(Colorado State University. Libraries, 2022) Jackson, Cassidy Elizabeth, author; Zadrozny, Joseph M., advisor; Shores, Matthew P., committee member; Chen, Eugene, committee member; Ross, Katherine, committee member
Magnetic molecules represent an emerging class of complexes that can be used to understand quantum phenomena impactful for quantum computing, non-invasive magnetic resonance imaging, and information storage. These organometallic complexes have the electronic spin is centered on the metal ion. Magnetic molecules based on electronic spins are extremely sensitive to changes in their local environment, such as nuclear spins. Electronic spins on a metal ion were employed to understand how nuclear spins in the local environment modulate electron spin dynamics. In this work, vanadium(IV) was chosen to study with varying catechol ligands. Electron paramagnetic resonance (EPR) was used to study two properties of these metal complexes, spin-lattice relaxation (T1) and phase memory relaxation (Tm or T2). Investigation of these parameters and fitting of these parameters provided information of how the local environment played a role in shortening these lifetimes. The complexes developed in this work indicates that the local environment is an extremely important piece of relaxation due to drastic changes in relaxation times. Chapter 1 introduces provides motivation for the work conducted in this dissertation and gives a thesis structure overview. Chapter 2 gives a broad summary of the field of molecular magnetism and provides metaphors for the synthetic chemist to learn about electron spin relaxation. Chapters 3 gives the first report of nuclear spin patterning on a ligand shell impacting spin relaxation times Chapter 4 details high-field, high-frequency orientation dependence on spin relaxation times for the V(IV) ion. Chapter 5 explores proton nuclear spin dynamics as they relate to nuclear spin patterns on a ligand and ligand complexed to a diamagnetic metal ion. Chapter 6 explores counterion dynamics and how they impact spin relaxation times. Chapter 7 gives a summary and future directions.
Open Access
Investigations of the effective temperature of sheared colloids and dynamic behavior of glass-forming liquids
(Colorado State University. Libraries, 2013) Zhang, Min, author; Szamel, Grzegorz, advisor; Ladanyi, Branka, committee member; Bernstein, Elliot, committee member; Chen, Eugene, committee member; Bradley, R. Mark, committee member
There are three projects in my dissertation. In chapter 2, a simple colloidal suspension under shear is studied. Four different methods are used to define the so-called effective temperature. The effective temperature calculated from the extended fluctuation-dissipation theorem is independent of the choice of the observables, and it controls the density distribution profiles. All the effective temperatures are larger than the bath temperatures. The effective temperature along the velocity gradient direction is somewhat larger than that along the vorticity direction. In chapter 3, a binary Lennard-Jones mixture at different temperatures is investigated. Due to the presence of shear flow, the ergodicity is recovered when the temperature is below glass transition. The dynamic behavior of the system is investigated. Above the glass transition, the dynamics is primarily controlled by the temperature, while below the glass transition, shear flow plays a dominant role. The violation of the Stokes Einstein relation, as well as the exponential tails in the self-part of the van Hove function are observed. In chapter 4, a binary hard-sphere mixture is researched. Four-point correlation functions are calculated, which suggest the presence of dynamic heterogeneity. To calculate four-point correlation functions, we need to specify the 'measuring stick' (the parameter a in the overlap function Fo(a, t)). When a is large enough, the four-point susceptibility at the structural relaxation time is independent of the choice of a. The dynamic correlation length is estimated from the Ornstein-Zernike fits for the four-point structure factor. We speculate that the maximum value of the dynamic correlation length is also independent of the 'measuring stick'.
Open Access
Molecular design of a fatigue-resistant and energy-dissipative hydrogel
(Colorado State University. Libraries, 2022) Klug, Allee Shiryce, author; Bailey, Travis, advisor; Reynolds, Melissa, committee member; Chen, Eugene, committee member; Weinberger, Chris, committee member
Hydrogels at the most basic iteration are cross-linked polymer networks swollen in water. They show promise in biomedical applications due to their high water content and flexibility. However, intentional design of new hydrogel networks by modification of the choice of polymer, the fabrication of the polymer network, and the choice of cross-link have resulted in hydrogels which have useful properties ranging from fatigue resistance to elasticity to bulk toughness. Of particular interest is a hydrogel which can dissipate energy as a way to resist failure of the polymer network. Unfortunately, many of the design strategies previously used to insert an mechanism for energy dissipation into the hydrogel result in hydrogels which are not elastic or their mechanical properties fatigue throughout multiple cycles of use. Therefore, our goal was to design a hydrogel network that is able to both dissipate energy and be resistant to fatigue of mechanical properties. This design strategy is based on the self-assembly of blends of ABC and ABCBA block polymers, specifically polystyrene-b-polyisoprene-b-poly(ethylene oxide) (PS-PI-PEO, SIO) and polystyrene-b-polyisoprene-b-poly(ethylene oxide)-b-polyisoprene-b-polystyrene (PS-PI-PEO-PI-PS, SIOIS) into a sphere morphology where the A block is spheres of glassy, hydrophobic polystyrene surrounded by the B block of rubbery, hydrophobic polyisoprene as the surface of the sphere. These AB spherical domains sit in a matrix of the C block, poly(ethylene oxide). The spherical domains are tethered together by the SIOIS polymer so that the glassy spheres are evenly-spaced physical crosslinks in the polymer network. The tethered spheres provide the network with elasticity and fatigue resistance while the hydrophobic PI block is accessible to forcibly mix with water as a way to dissipate energy when the hydrogel is strained. This dissertation describes the design, testing, and optimization of a hydrogel where an energy dissipation mechanism was placed directly onto every crosslink of a known elastic and fatigue-resistant network. The possibility of even designing such a network was tested by studying the self-assembly of the SIO polymers into the ABC block polymer sphere morphology. Once, the formation of the sphere morphology in the tethered micelle network was confirmed, the effectiveness of the design strategy of a fatigue-resistant network with an intrinsic energy dissipation mechanism was studied by comparison of the mechanical properties of the SIOIS hydrogel to a similar hydrogel that is fatigue-resistant but does not contain an energy dissipation mechanism. Finally, the design of the SIOIS hydrogel is optimized by studying the effect of changes to the hydrogel processing method and changes to the PS molecular weight on the self-assembly of the energy dissipation PI block and the formation of the tethered micelle network.
Open Access
N,N-Diaryl Dihydrophenazine photoredox catalysis for organocatalyzed atom transfer radical polymerization
(Colorado State University. Libraries, 2019) Ryan, Matthew David, author; Miyake, Garret, advisor; Chen, Eugene, committee member; Kota, Arun, committee member; Snow, Christopher, committee member
The synthesis, application, and mechanistic investigation of the 5,10-diaryldihydrophenazine catalyst family as applied to organocatalyzed atom transfer radical polymerization is presented in this dissertation. The N,N-Diaryl Dihydrophenazine catalyst family, which will be referred to in this dissertation as the phenazines, are an appealing class of molecules due to their strongly reducing excited states, accessed through modular syntheses enabling a wide range of photophysical and electrochemical properties. This class of molecules represented the first example of organic catalysts capable of operating a controlled, visible light driven, organocatalyzed atom transfer radical polymerization for the precision syntheses of (meth)acrylic polymers. Phenazine catalysts were shown to polymerize (meth)acrylic monomers to polymers of very low dispersities (< 1.10) in a process with quantitative initiator efficiency; both features crucial to produce precision polymeric materials poised for myriad applications. Supported by computational efforts, mechanistic understanding and structure-property-catalyst activity relationships were identified and harnessed to design optimal polymerization conditions, which have laid the groundwork for new research efforts into highly reducing, visible light absorbing, organic photocatalysts.
Open Access
N-heterocyclic carbene catalyzed α-redox reaction: catalytic synthesis of amides and carboxylic acids
(Colorado State University. Libraries, 2011) Vora, Harit, author; Rovis, Tomislav, advisor; Williams, Robert, committee member; Wood, John, committee member; Chen, Eugene, committee member; McNeil, Michael, committee member
N-heterocyclic carbene catalyzed α-redox reaction has been utilized towards the catalytic synthesis of amides utilizing amines and substoichiometric quantities of an acyl transfer reagent in a waste reduced acylation process. The reaction is amenable to a plethora of amines and amine hydrochloride salts as nucleophiles. The reaction is applicable towards a variety α-reducible aldehydes as α,α-dichloro aldehydes, enals, epoxy and aziridnyl aldehydes all provide the respective amides in moderate to excellent yields with the latter in high diastereoselectivity. The asymmetric amidation reaction provides chiral amides in moderate enantioselectivity. Additionally, the N-heterocyclic carbene catalyzed α-redox reaction was also utilized for the synthesis of enantioenriched α-chloro and α-fluoro carboxylic acids. The reaction also provide for a mild installation of a deuterium from D2O furnishing enantioenriched isotopically labeled compounds. Investigations in to the mechanism have revealed that the carbene displays behavior of a phase transfer reagent by shuttling hydroxide from the aqueous phase to the organic phase. Additionally, it has been found that the turnover limiting step in this acylation process in the hydrolysis of the acyl azolium.
Open Access
New strategies to synthesize complex pyridines and tetrahydropyridines using main group chemistry
(Colorado State University. Libraries, 2021) Fricke, Patrick J., author; McNally, Andrew, advisor; Crans, Debbie, committee member; Chen, Eugene, committee member; Kipper, Matthew, committee member
Pyridine and piperidine are important molecular scaffolds in small molecule drug development in medicinal chemistry research. Because of their importance, methods to synthesize complex pyridines and piperidines are highly desirable. Chapter one discusses the importance of these scaffolds in the pharmaceutical industry along with the history of pyridine and piperidine synthesis and the challenges that still remain. Chapter two discusses the switching strategies for selective installation of phosphonium salts on polyazines. The methods include an acylation, base-mediate, phosphine mediate, and order-of-reagent addition strategies. Additionally, we demonstrate how these methods can be applied to medicinal chemistry research during structure-activity relationship studies by derivatizing the phosphonium salts. Chapter three presents a new strategy for selective pyridine alkylation at the 4-position of the pyridine ring. Using a triazine chloride activating group allows for 4-selective phosphonium ylide formation inside the pyridine ring. A Wittig olefination-rearomatization sequence with an aldehyde then furnishes the alkylated pyridine. This method offers an alternative strategy to conventionally used metal-catalyzed cross coupling and Minisci-type reactions. Chapter four describes a stepwise reduction method for the synthesis of dihydropyridine and tetrahydropyridine. Using N-Tf activation allows for a selective hydride reduction to the dihydropyridine, which can subsequently undergo hydrogenation to the tetrahydropyridine.
Open Access
Nitric oxide generation from S-nitrosothiols via interactivity with polymer-supported metal-organic frameworks
(Colorado State University. Libraries, 2018) Neufeld, Megan J., author; Reynolds, Melissa, advisor; Chen, Eugene, committee member; Finke, Richard, committee member; Kipper, Matthew, committee member; Ravishankara, A. R., committee member
Catheters, extracorporeal systems, stents, and artificial heart valves are all common blood-contacting medical devices. Due to the differences in the chemical and physical properties of the polymeric materials used to construct medical devices and biological tissues in the cardiovascular system, complications such as thrombus formation arise from the resulting incompatibilities. Introduction of foreign materials that lack critical biological cues can result in disruption of the delicate balance maintained within the circulatory system. This disruption of homeostasis initiates a complex cascade of events such as platelet adhesion and protein deposition that ultimately result in thrombus formation. As such, the propensity of blood to clot upon contact with a foreign surface represents a challenge unique to devices intended for vascular applications. The current clinical use of devices such as vascular catheters includes the administration of anticoagulants, however their associated complications such as internal hemorrhaging renders this practice undesirable as a long-lasting solution. A general limitation of existing devices made from synthetic polymers is their inability to integrate with their environment through biological cues (natural regulators). Materials that lack this behavior are often described as passive towards their environment. In comparison, active materials that can simulate natural molecules used to maintain biological responses may result in enhanced integration of medical devices. In the natural, healthy endothelium, the prevention of thrombus formation occurs through the release of anticoagulants and platelet inhibitors such as gaseous nitric oxide (NO). While the use of NO for medicinal purposes began indirectly in the late 1800s, the significance of its endogenous production was not known until the 1970s. In particular, NO is a key factor in the prevention of thrombus formation. While its remedial potential has led to its use as an exogenous therapeutic agent, its high reactivity limits its applicability as a localized therapeutic. This limitation is addressed by mimicking the natural endothelium and using small molecules in the bloodstream known as S-nitrosothiols (RSNOs) to produce NO directly from this physiological source. Biological RSNOs are theorized to aid in the stabilization and transport of NO and undergo an NO-forming decomposition in the presence of heat, light, and certain metals such as copper. Prior strategies have evaluated exploiting the physiological supply of RSNOs through the incorporation of copper complexes into polymeric materials. While these copper-based materials demonstrate the production of NO from RSNO decomposition, limitations arise due to the gradual loss of the catalytic material and toxicity from copper leaching. In order for this type of approach to be feasible, the active metal species must remain immobilized within the structural framework. Metal–organic frameworks (MOFs) are a class of crystalline materials that consist of organic ligands coordinated to metal centers. Certain copper-based MOFs have demonstrated the ability to enhance the generation of NO from RSNOs without the gradual loss of the active species. Through integration of certain copper-based MOFs with medically relevant polymers, materials can be prepared that promote the localized generation of NO at their surfaces. However, the feasibility of utilizing copper-based MOFs for such applications depends on effective incorporation within a supporting polymeric matrix and the retention of useful activity thereafter. As such, it is necessary to assess different MOF/polymer composites for their ability to promote NO generation from RSNOs prior to use in medical applications. This dissertation investigates the incorporation of two distinct copper-based MOFs into a selection of medically-relevant polymeric materials including cotton, poly(vinyl chloride), chitosan, and poly(vinyl alcohol). These MOF/polymer materials were subsequently tested for their ability to promote NO generation from RSNOs in an effort to assess the impact of incorporation within a polymer matrix. Overall, this work demonstrates the potential for blood-contacting MOF-containing materials in biomedical settings by identifying ideal characteristics that MOF/polymer composites should exhibit for optimization and translation to a clinical setting.
Open Access
Photo-induced electron transfer in cu(i) bis-phenanthroline based assemblies. Part I: Chromophore-acceptor diads. Part II: Donor-chromophore-acceptor triads
(Colorado State University. Libraries, 2013) Lazorski, Megan, author; Elliott, C. Michael, advisor; Shores, Matthew P., committee member; Chen, Eugene, committee member; Bailey, Travis S., committee member; Sites, James R., committee member
The photophysical behavior of [Cu(I)P2] (P=2,9-disubstituted-1,10-phenanthroline ligands) in donor-chromophore-acceptor (D-C-A) triads and chromophore-acceptor (C-A) diads is a complex and fascinating area of under developed, yet fundamental, electron transfer chemistry. In metal polypyridyl D-C-A and C-A triads/diads, metal polypyridyl chromophores (C) in which the polypyridyl ligands are covalently linked to acceptor (A) and/or donor (D) moieties, photo-excitation of the chromophore initiates a series of electron transfer events that result in the formation of a charge separated (CS)/charge transfer (CT) state, respectively. The majority of high-performing metal polypyridyl D-C-A/C-A complexes, on which [Cu(I)P2] D-C-A/C-A research is based, incorporate ruthenium (as [Ru(II)L3] where L=polypyridyl ligand) or other rare, expensive, and sometimes toxic metals such as osmium, rhenium and platinum. Although [Ru(II)L3] D-C-A/C-A's have historically set the benchmark for metal polypyridyl D-C-A/C-A performance, it is clear that these complexes are not a practical choice if D-C-A's or C-A's were incorporated into a device for large scale production. However, bisphenanthroline complexes of copper, a much more earth abundant, cheaper and less toxic metal, exhibit very similar photophysical properties to [Ru(II)L3] and have thus gained recognition as promising new materials for D-C-A/C-A triad/diad construction. In order to understand the electron transfer (ET) events occurring in [Cu(I)P2] D-C-A/C-A triads/diads, a complex must be synthesized that is capable of forming a CS with high quantum efficiency (Φcs/ct) and a long CS/CT lifetime (τcs/ct). Therefore, the intent of the research reported herein is to synthesize novel, yet functional heteroleptic [Cu(I)P2] D-C-A/C-A triads/diads and study their fundamental, photo-initiated electron transfer chemistry, specifically the formation of a CS/CT state. Many challenges, which are not present for [Ru(II)L3], make the design and synthesis of [Cu(I)P2] D-C-A/C-A assemblies an art in itself. Therefore, a significant amount of effort was spent on fabricating ligand architectures that (1) are appended with acceptor and/or donor moieties capable of being reduced/oxidized resulting in the formation of a CS/CT, (2) are able to be easily modified so the amount of energy stored in the CS/CT can be tuned, (3) favor the self-assembly of [Cu(I)P2] complexes, (4) are able to facilitate processes that maximize the Φcs/ct. Once the ligands were obtained, the complexation equilibria behavior of these [Cu(I)P2] triads and diads were studied. Despite efforts to design ligand architectures that favor heteroleptic formation, the thermodynamic driving force for heteroleptic D-C-A triad formation is less favor-able than expected. Thus, mixing stoichiometric quantities of D, C and A results in a statistical mixture of C-A, C-D and D-C-A products. Furthermore, since the ligands are labile and will re-arrange to the most thermodynamically stable configuration of products when these complexes are dissolved, isolation of the D-C-A product is impossible. However, recent advances in ligand design have shown promise for resolving this on-going issue. Despite having a mixture of products with the D-C-A, the electron transfer processes of the [Cu(I)P2] D-C-A triads and C-A diads were investigated. Using Transient Absorption (TA) laser spectroscopy, the CT state in the constructed C-A diads and the CS state in the D-C-A triads were detected and the lifetimes were determined. However, it was found that those lifetimes could be modulated to a small degree by solvent in the C-A diads (c.a. 6x longer in polar solvents), and drastically via the application of a magnetic field in D-C-A triads (c.a. 60x longer). The ability to modulate the lifetimes enabled the deconvolution of the effects due to the C-A diad vs D-C-A triad in the statistical product mixtures. Although the response in a magnetic field was a somewhat expected result, as similar effects occur in the [Ru(II)L3 D-C-A/C-A's, the magnitude of change in the lifetime and the quantum efficiency offers new insight into the electron transfer events that occur in the CS/CT formation process for [Cu(I)P2] D-C-A/C-A complexes.
Open Access
Preparation, regioselective chemistry, and electronic properties of perfluoroalkylfullerenes
(Colorado State University. Libraries, 2013) Whitaker, James B., author; Strauss, Steven H., advisor; Chen, Eugene, committee member; Finke, Rick, committee member; Williams, Bob, committee member; Ridley, John, committee member
A systematic study of how various reaction parameters affect the product distribution of gas-solid reactions was carried out in a new reactor of local design. These reactions involve the trifluoromethylation of C60, C70, and the endohedral metallofullerenes Sc3N@C80 and Y3N@C80; and in particular, the reactions were optimized to favor C60(CF3)2 and C60(CF3)4. A new solution phase homogeneous perfluoroalkylation method was used to prepare a series of 1,7-C60(RF)2 compounds with different RF chain lengths and branching patterns. A range of analytical methods including 19F NMR and UV-vis spectroscopy, APCI mass spectrometry, and X-ray crystallography were used to structurally characterize the compounds. Cyclic voltammetry, DFT E(LUMO) calculations, and gas phase electron affinity (EA) measurements were used to determine the substituent effect of the RF groups. The results conclusively showed that the solution phase E1/2, calculated E(LUMO), and EA values-- that are typically assumed to be correlated for a series of electron acceptors-- are not always correlated. Several highly efficient and selective methods were developed for the further functionalization of selected trifluoromethyl fullerenes (TMFs). These new functionalized TMFs were structurally characterized using the aforementioned analytical techniques and the X-ray crystal structures of five new derivatized TMFs were determined. Analysis of the how these newly derivatized TMFs pack in a crystalline solid revealed fullerene density values that were in general twice that of reported fullerenes that pack in the same motifs. These derivatized TMFs also exhibited extended networks of short C···C distances between fullerene cages of adjacent molecules that has been correlated to increased free charge carrier motilities in organic photovoltaic device active layers. The solution phase E1/2 values of the most commonly used fullerene derivatives in OPV devices were measured under carefully controlled conditions and revealed that poor reporting of electrochemical conditions, mistakes interpreting electrochemical data, and fullerene impurities have combined to cause significant confusion about the reported electrochemical values in the literature. A preliminary study of 32 OPV devices fabricated with active layers containing perfluoroalkylfullerenes (PFAFs) indicated that (i) PFAFs can function as suitable electron acceptors in OPVs, and (ii) that a more detailed study examining the complex electronic interplay between the fullerene electron acceptor and polymer donor is warranted.
Open Access
Probing folding/unfolding kinetics, reaction mechanism and thermodynamic stability of nucleic acid hairpins
(Colorado State University. Libraries, 2013) Nayak, Rajesh Kumar, author; Van Orden, Alan, advisor; Barisas, George B., committee member; Chen, Eugene, committee member; McNaughton, Brian, committee member; Yalin, Azer, committee member
Nucleic acid hairpins play pivotal roles in biological and cellular processes. The functions of the DNA and RNA hairpins depend upon the conformational changes they adopt during the biological process. Therefore, a clear understanding of their conformational dynamics such as folding and unfolding kinetics, reaction mechanism as well as thermodynamic stability is essential to understand their biological functions. This dissertation describes folding kinetics, reaction mechanism and thermodynamic stability of stem-loop nucleic acid hairpins by using rapid-mixing stopped-flow kinetics and other spectroscopic techniques. Firstly, the folding kinetics and reaction mechanism of a five base-paired stem and twenty one polythymidine loop DNA hairpin as a function of varying monovalent counter ion concentrations have been discussed. The important observation of this investigation is that the DNA hairpin folding is not simply a two-state process, and based on our experiments and kinetic modeling, we proposed a three-state reaction mechanism, wherein, the intermediate formation occurs on microsecond time scale and the complete hairpin formation occurs on millisecond time scale. Secondly, the loop length and counter ion dependent thermodynamic stability and folding of DNA hairpins have been described. This investigation provides a detailed understanding of how the stability and folding changes as a function of loop length and counter ion concentrations. The most important conclusion of this part of the investigation is that the thermodynamic stability of tetraloop hairpins depend upon counter ion concentration regimes and we explained the exceptional stability of a tetraloop hairpin in the higher concentration regime, compared to longer loop length hairpins on the basis of base-stacking effect. Finally, the folding and unfolding kinetics of RNA hairpins with identical four base-paired stem but different nucleotide loop sequence is discussed. Here we observed that the RNA hairpin folding and unfolding can be much more complex than previously thought and also RNA hairpin folding process can be different than DNA hairpin folding process.
Open Access
Progress toward the total synthesis of stemocurtisine and asymmetric synthesis of endoperoxide anticancer agents via Brønsted acid cascade catalysis
(Colorado State University. Libraries, 2012) Rubush, David Michael, author; Rovis, Tomislav, advisor; Kennan, Alan, committee member; Crans, Debbie, committee member; Chen, Eugene, committee member; Kanatous, Shane, committee member
A viable route toward the pyrido-azepine core of stemocurtisine involving an N-heterocyclic carbene catalyzed Stetter reaction has been realized. The key steps involve a formal [3+2] cycloaddition of enones with isocyanoacetates and a catalytic asymmetric intramolecular Stetter reaction. Additionally, a diastereoselective intramolecular Stetter reaction was achieved to access highly substituted pyrrolidines. Asymmetric Brønsted acid catalyzed cascade reactions were also investigated. A diastereoselective acetalization/oxa-Micahel cascade has been developed to provide dioxolanes and oxazolidines using diphenylphosphinic acid as a catalyst. The enantioselective variant of this reaction was explored with minor success. The desymmetrization of p-peroxyquinols using a Brønsted acid catalyzed acetalization/oxa-Michael cascade was achieved in high yields and selectivities for a variety of aliphatic and aryl aldehydes. Mechanistic studies suggest that the reaction proceeds through a dynamic kinetic resolution of the peroxy-hemiacetal intermediate. The resulting 1,2,4-trioxane products were derivatized and show potent cytotoxicity toward specific cancer cells.
Open Access
Regioselective functionalization of pyridines and other azines
(Colorado State University. Libraries, 2021) Boyle, Benjamin T., author; McNally, Andrew, advisor; Chen, Eugene, committee member; Ackerson, Chris, committee member; Montgomery, Tai, committee member
Pyridines and diazines serve as cores in pharmaceuticals and are common motifs in organomaterials and ligands. Selective functionalization of these motifs is of importance for discovery and optimization of new bioactive molecules. Pyridine functionalization is of interest for synthetic chemists, and despite modern advances in derivatization challenges and limitations remain. Chapter one focuses on the impact of pyridines and diazines in the pharmaceutical industry. Classical and modern methods for C-H functionalization are discussed. Chapter two describes work on phosphorus ligand-coupling for bisazine synthesis using a three-stage protocol. This method provides an alternative to traditional metal-catalysis for bisazine synthesis and can be applied to drug-like fragments. This work is expanded on in chapter three by using a tandem SNAr-ligand-coupling strategy for bisazine synthesis, in particular 2,2'-bipyridines. Chapter four describes a facile SNAr reaction by phosphines on iodopyridines. A bis-salt N-phopsphonium pyridinium is the key intermediate and provides a broad scope of reactivity. Chapter five shifts towards functionalization of the 3-position of pyridine through a Zincke-type intermediate. By exploiting a ring-opening-functionlization-rearomatization strategy a selective halogenation of pyridines was achieved. The Zincke imine intermediate is also viable for other functionalizations and provides products directly from the C-H bond on the initial pyridine.
Open Access
Selective functionalization of azines via phosphonium salts
(Colorado State University. Libraries, 2020) Koniarczyk, J. Luke, author; McNally, Andrew, advisor; Chen, Eugene, committee member; Barisas, George, committee member; Chatterjee, Delphi, committee member
Pyridines and diazines are ubiquitous in pharmaceuticals, agrochemicals, and materials. Therefore, methods to functionalize these structural motifs are increasingly valuable. We have shown that phosphonium salts can be formed on a range of azines, including complex biologicallyactive compounds. Additionally, these azinyl phosphonium salts serve as a general functional handle to facilitate a variety of bond formations. Chapter 2 focuses on a method to incorporate deuterium and tritium atoms onto azines and pharmaceuticals using azinyl phosphonium salts. Deuteration is commonly used as a means to deter unwanted oxidative metabolism on drugs, and tritium is installed as a radiolabel for metabolic studies in the pharmaceutical industry. The protocol of the reaction is simple, and it functions on a wide range of building blocks and complex molecules. Additionally, the tritiation protocol was effectively applied on a selection of drug molecules through a collaborative effort with Merck. In chapter 3, a pyridine-pyridine coupling reaction is discussed using azinyl phosphonium salts as radical precursors. The reaction functions through a radical-radical coupling mechanism using B2pin2 and 4-cyanopyridine as an electron-transfer reagent for reduction of the phosphonium salt. Azinyl phosphonium salts were found to be the only radical precursor amenable to the reaction, and the process functions as an alternative to the Minisci reaction to form bipyridine products.
Open Access
Static and dynamic study of metal salt hydrates of weakly-coordinating fluoroanions by vibrational spectroscopy, gravimetry, and an analysis of previously published x-ray structures
(Colorado State University. Libraries, 2021) Lacroix, Matthew R., author; Strauss, Steven H., advisor; Chen, Eugene, committee member; Bandar, Jeff, committee member; Ridley, John, committee member
Eighteen metal salt hydrates (Li(H2O)4(Al(OC(CF3)3)4), Li(H2O)(B(3,5-C6H3(CF3)2)4), Li(H2O)n(Ga(C2F5)4), Li(H2O)(PF6), Na(H2O)(PF6), Li2(H2O)4(B12F12), Na2(H2O)2(B12F12), K2(H2O)2(B12F12), Rb2(H2O)2(B12F12), Cs2(H2O)(B12F12), Mg(H2O)6(B12F12), Ca(H2O)n(B12F12), Sr(H2O)n(B12F12), Ba(H2O)n(B12F12), Co(H2O)6(B12F12), Ni(H2O)6(B12F12), Zn(H2O)6(B12F12), and Li2(H2O)2(TiF6)) containing weakly coordinating anions were analyzed using room temperature ATR-FTIR spectroscopy. The goal was to investigate the relative strengths of water–anion hydrogen bonds in the solid-state. In all but one case, these hydrogen bonds take the form of O–H···F hydrogen bonds. The one exception is in the salt Li2(H2O)4(B12F12) where there are both O–H···F and O–H···O hydrogen bonds present. Based on the magnitude of the redshift of the ν(OH) band(s) a qualitative scale for the comparison of the relative hydrogen bond strength is constructed. Included in this scale are additional metal salt hydrates taken from the literature. This spectroscopic study has produced some of the only room temperature spectra for water participating in hydrogen bonding in the solid-state where the νasym(OH) and νsym(OH) bands are individually resolvable. The weak nature of the O–H···F hydrogen bonds allows for resolution of ν(OH) bands only 5 cm−1 apart in some cases. The two metal salt hydrates (Li(H2O)4(Al(OC(CF3)3)4) and Li(H2O)(B(3,5-C6H3(CF3)2)4) are shown to possess the weakest O–H···F hydrogen bonds observed in the solid state at room temperature. The salt Li2(H2O)4(B12F12) contains a cyclic (H2O)4 water cluster, also known as the R4 cluster, is presented, and discussed in the context of the FTIR spectrum of water clusters. Due to the nature of the weak O–H···F hydrogen bonding between the cluster and the surrounding anions the E and B fundamental vibrations for the cluster were able to be determined. The peak-to-peak separation, and relative intensities of these two bands are consistent with computational results from the literature. This is the first time that the R4 water cluster has been successfully studied via FTIR spectroscopy without the presence of other clusters leading to ambiguity in the results. Finally, direct observation of the effect of cation acidity on the relative strength of water–anion hydrogen bonding has been directly observed for the first time in the metal hexahydrate salts M(H2O)6(B12F12) (M = Mg, Co, Ni, Zn). These results, along with the correlation curves constructed in this work, show that it is not possible to assign relative hydrogen bond strength based on O–H···X bond length, nor is it possible to accurately approximate O–H···X bond length based on degree of ν(OH) redshift. Instead, it is shown that the relative basicity of the anion is the primary factor governing the relative hydrogen bond strength, and thus the degree of redshifting experienced by the ν(OH) band(s). The cation acidity also is shown to have a lesser, but observable, effect on the relative strength of O–H···X hydrogen bond. In addition to broadening our fundamental understanding of hydrogen bonding in the solid state, this work also shows that FTIR spectroscopy can be a useful tool for rapidly assigning relative basicity of new weakly coordinating anions without need the for complex protonation experiments.