It has become increasingly important to develop accurate and reliable techniques for the separation of chiral drugs. Separation of epinephrine and eight chiral structural analogues by Cyclodextrin Modified Electrokinetic Capillary Chromatography or CECC has been examined. Steady-state fluorescence measurements are used to categorize the complexing abilities o epinephrine with eleven native and derivatized cyclodextrins. Using the relative fluorescence intensity values, the drugs/cyclodextrin interactions are qualitatively categorized as strong, weak or moderate. This data is tabulated or each drug. CECC experiments using different combinations of these cyclodextrins were used to separate epinephrine as a model enantiomer. It is found that most of the cyclodextrin combinations that successfully separated the epinephrine enantiomers were cyclodextrins that either strongly and/or moderately interact with the drug as determined from steady state fluorescence measurements. This knowledge was used to predict apriori, the separation of the eight structural analogues of epinephrine. The results show good agreement between the predicted and the observed separation results.

The first portion of this dissertation entails the development of new transition-metal salen complexes, which are used to chelate lanthanides in their compartmental units (both cis and 3,3'-methoxy oxygens). The resulting complexes possess the ability to be used as sensitizers for near-infrared emission and MRI contrasting agents. The second part details the rapid synthesis of imidazo[1,5-ɑ]pyridine scaffold was further examined as a ligand chelated with RuII, FeIII, and VOIV salts.

Structure, substrate selectivity, and catalytic mechanism of the fosfomycin resistance enzyme, FosB, from Gram-positive pathogens By: Mary E. Keithly Fosfomycin, a broad spectrum antibiotic, is used clinically to treat lower urinary tract infections and gastrointestinal infections and has been suggested as part of a regimen for treatment of multi-drug resistant bacterial infections. However, bacterial fosfomycin resistance enzymes limit the efficacy of the antibiotic. A better understanding of the enzymatic mechanism of fosfomycin resistance can contribute to increasing the efficacy and use of fosfomycin. One resistance enzyme, FosB, is a Mn2+-dependent thiol-transferase found in Gram-positive bacteria. FosB modifies fosfomycin by catalyzing nucleophilic addition of a thiol, resulting in an inactive compound. In vitro time course kinetic analyses for FosB from four different bacterial strains using L-cysteine and bacillithiol (BSH) reveal a preference for BSH over L-cysteine. Probing metal dependent activation of FosB by Ni2+, Mg2+, Zn2+, and Mn2+ revealed the highest activation of FosB with Mn2+ as the metal cofactor, whereas Zn2+ inhibits FosB enzymes. I concluded that FosB is a Mn2+-dependent BSH-transferase. Fourteen high-resolution crystal structures of FosB from both Bacillus cereus and Staphylococcus aureus have been determined in complex with various substrates, divalent metals, and products. These structures confirm that FosB is a member of the Vicinal Oxygen Chelate (VOC) superfamily of enzymes. Additionally, a cage of conserved residues orients fosfomycin in the active site such that it is poised for nucleophilic attack by the thiol. The structures also reveal a BSH binding pocket and suggest a highly conserved loop region must change conformation for fosfomycin to enter the active site. Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) experiments were utilized to investigate the structural dynamics of FosB. HDX-MS data analysis for this enzyme incubated with various substrates and cofactors indicates that FosB is a highly stable globular protein. Moreover, low signal-to-noise for the conserved loop region made analysis of the dynamics of this area difficult to assess with HDX-MS. These observations suggest nuclear magnetic resonance (NMR) should be applied to investigate the critical loop movement of FosB.

The ability to control nanoscale morphology and molecular organization in organic semiconducting polymer thin films is an important prerequisite for enhancing the efficiency of organic thin-film devices, including organic light-emitting and photovoltaic devices. The current top-down paradigm for making such devices is based on utilizing solution-based processing (e.g. spin-casting) of soluble semiconducting polymers. This approach typically provides only modest control over nanoscale molecular organization and polymer chain alignment. A promising alternative to using solutions of pre-synthesized semiconducting polymers pursues instead a bottom-up approach to prepare surface-grafted semiconducting polymer thin films by surface-initiated polymerization of small-molecule monomers. This dissertation mainly focuses on development of an efficient method to prepare semiconducting polymer thin films utilizing surface-initiated Kumada catalyst transfer polymerization (SI-KCTP). In chapter 2, we describe SI-KCTP with a new Ni(II) external catalytic initiator to prepare polythiophene (PT) thin films. We provided evidence that the surface-initiated polymerization occurs by the highly robust controlled (quasi-living) chain-growth mechanism. Extensive structural studies of the resulting thin films revealed detailed information on molecular organization and the bulk morphology of the films, and enabled further optimization of the polymerization protocol. Achieving such a complex mesoscale organization is virtually impossible with traditional methods relying on solution processing of pre-synthesized polymers. In addition to controlled bulk morphology, uniform molecular organization and stability, unique feature of SI-KCTP is that it can be used for the preparation of large-area uniformly nanopatterned polymer thin films. This was demonstrated using combination of particle lithography and surface-initiated polymerization. We expanded scope of the surface-initiated polymerization towards all-conjugated diblock copolymer (polythiophene-b-poly(para-phenylene)) thin films, which is described in chapter 3. In addition to the preparation of such films, we carried out detailed structural studies and investigated optoelectronic characteristics of the films. In chapter 4, we studied using SI-KCTP to prepare poly(3,4-ethylenedioxithophene) (PEDOT) thin films. PEDOT is a practically important highly conductive conjugated polymer. Our investigation of the properties of a surface-confined PEDOT film revealed that, after doping with iodine, the film became highly conductive, with conductivity comparable to that of inorganic semiconductors. Therefore, surface-confined PEDOT films may find applications in replacing traditional inorganic electrode for the fabrication of flexible organic electronics.

Damage to DNA results from many endogenous and exogenous sources and plays a significant role in cancer etiology. 3-Nitrobenzathrone (3-NBA) is a component of diesel exhaust that is known to form DNA adducts. Aminobenzanthrone (ABA) DNA adducts result through the reaction of electrophilic nitrenium ions formed during 3-NBAâs metabolic reduction in vivo. Furthermore, 3-NBA has been reported as being carcinogenic in animal model systems and human exposure has been demonstrated. Here I examine structural impacts of the C8-guanine-aminobenzanthrone (C8-dG-ABA) adduct, a major DNA adduct of 3-NBA, which occurs at the C8 position of guanine. This adduct produced a base-displaced intercalated structure within a DNA duplex. The ABA moiety intercalated into the duplex displacing the cytosine opposite the lesion. The adducted guanine rotated about the glycosidic bond into the syn conformation. The overall stability of the DNA duplex was reduced as demonstrated by a decrease in melting temperature of 11º C compared to the undamaged duplex. Another structure was determined for C8-dG-ABA in complex with a trans-lesion synthesis polymerase, human polymerase eta (hPol η). The conformation of the C8-dG-ABA adduct within the active site of hPol η was markedly different from the structure observed in duplex DNA. The complex was captured in a non-mutagenic insertion state. The adducted guanine was in the anti conformation and was observed to form a Watson-Crick basepair with an incoming cytosine triphosphate (dCTP). The ABA moiety was rotated out of the active site of hPol η and resided in a hydrophobic pocket. The position of the ABA moiety did not allow for a clear path for the next template base to be translocated into the active site, and may reflect a means by which the adduct blocks replication.

This study documents an effort to design and construct an apparatus for the continuous generation hydrogen atoms to convert aliphatic and aromatic molecules to their respective dimers, by free radical mechanisms. The addition of hydrogen atoms to alkene and aromatic molecules, and hydrogen atom abstraction from alkanes by atomic hydrogen, followed by dimerization or disproportionation has been extensively studied. Emphasis here is placed on proving the efficacy of this device by production of known dimeric products. This prototype incorporates critical factors known to effect gas phase free radical dimerizations and attempts to address each. Close attention then, has been paid to the temperature of the reacting gases and the tendency of the intermediates to disproportionate. This device introduces pre-cooled substrate molecules, at atmospheric pressure, to a perpendicular stream of hydrogen atoms produced by electrical discharge. The argon purged reaction chamber is packed with glass wool to enhance three body collisions and promote dimerization. The conversion of isobutene, benzene and toluene to dimers in this device was studied. Products were separated via simple distillation and product determinations made by comparing GC-Mass Spec peaks with the literature.

Polyimides were synthesized from bicylic dianhydrides and diamines. The bicyclic monomers used were bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride, 1,4,7,8-tetrabromobicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride and 1,4,7,8-tetrachlorobicyclo [2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride. The diamines used were benzidine, 4,4’-diaminodiphenyl ether, 4,4’-(hexafluoroisopropylidene)dianiline and 4,4’-(1,4-phenylenedioxy)dianiline. Each dianhydride was polycondensed with each of the diamines in N-methyl pyrrolidinone (NMP) at elevated temperatures. The polymers were characterized by means of IR and 13C NMR spectroscopy, elemental analysis, solubility and thermal analysis such as differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). TGA studies indicate that the polymers were all stable to above 320°C. Most of the polymers were found to be soluble in highly polar, high boiling point solvents such as dimethyl sulfoxide (DMSO), N-methyl pyrrolidinone (NMP), dimethyl acetamide (DMAc) as well as concentrated sulfuric acid. Selected comparative solubility studies with wholly aromatic analogues of the bicyclic polyimide indicate that the bicyclic polymers show better solubility. Thermal studies of the behavior of the bicyclic components of the polyimides were carried out by the use of low molecular weight imide dimers. The results obtained indicate that the bicyclic ring system undergoes a thermal retro Diels-Alder reaction thus separating into two fragments.

The proton is the smallest Lewis acid and has been utilized in nature by enzymes for catalysis and stereocontrol of a variety of reactions long before chemistry was pursued as the discipline it is today. This precedent notwithstanding, there are very few examples of asymmetric catalysis which utilize a polar ionic hydrogen bond (essentially, a chiral proton complex). We have developed bifunctional Bis(AMidine) (BAM) catalysts that are efficient chiral proton catalysts for several mechanistically distinct transformations. <p> This dissertation explores a rationally designed extension of BAM catalysis to an aza-Henry reaction employing α-nitro esters as pronucleophiles. This allows for the enantio- and diastereoselective synthesis of α,β-diamino acid derivatives. A reagent-controlled diastereodivergence is observed from the selectivity typically observed in BAM catalysis and is further explored with preliminary computational analysis. This methodology was applied to the synthesis of a potent heterocyclic proteasome inhibitor. Additionally, a chiral proton chaperoned biomimetic hetero-Diels-Alder reaction was effected with moderate enantioselectivity, and preliminary results towards the synthesis of fluorinated tetrahydroisoquinoline alkaloids are reported.

This work is a comprehensive summary of research projects the author conducted when attending the PhD program at the University of Arizona. Research topics cover the structural chemistry of lanthanide-amino-acid clusters, optical up-conversion properties of lanthanide based nanomaterials, magnetic and luminescent properties of lanthanide metal-organic frameworks (MOFs), as well as two research projects focusing on transition metal MOFs, which were derived from lanthanide metal-organic framework projects. In chapter 2, the discovery of halide anion templated lanthanide-histidine hydroxide cluster and a comprehensive study of the influence of anionic size on cluster nuclearity are discussed. Both Cl⁻ and Br⁻ were able to serve as template anions assisting the formation of pentadeca-nuclear lanthanide hydroxide clusters for Nd, Gd and Er. When I⁻ was used as the template anion, pentadeca-nuclear hydroxide cluster only formed in neodymium case. In erbium case a dodeca-nuclear hydroxide cluster formed when I⁻ was used as template ion. However I⁻ was not effective in assisting the formation of high nuclearity gadolinium hydroxide cluster. In chapter 3, doping Er³⁺ ion into CuₓSe nanoparticles for the purpose of making efficient optical up-conversion materials is discussed. Er³⁺ ion was successfully doped into CuₓSe nanoparticles. However no up-conversion luminescence was detected, possibly due to the in-direct bandgap nature of CuₓSe. Chapter 4 discuses attaching CuxSe nanoparticles on the surface of NaYF₄:Gd, Er,Yb nanorod. The purpose is to increase up-conversion efficiency of NaYF₄:Gd, Er,Yb nanorod through surface plasmon resonance enhancement property of CuₓSe nanoparticle. The CuₓSe nanoparticles were successfully attached onto NaYF₄:Gd, Er,Yb nanorod surface through exposing the suspension containing CuₓSe nanoparticles and NaYF₄:Gd, Er,Yb nanorods to UV irradiation. The up-conversion efficiency of NaYF₄:Gd, Er,Yb nanorods was increased after CuₓSe nanoparticle attachment. Chapter 5 discussed the synthesis and characterization of functional Ln(BDC)(1.5)∙DMF (Ln = Eu, Tb, Gd) metal-organic frameworks (MOFs). The absence of OH group containing species within this MOF rendered them ideal substrates as luminescent material because luminescence quenching caused by OH groups could be avoided. A series of MOF with luminescent color ranging from red, orange, yellow and green were obtained by adjusting the relative Eu and Tb content in the MOF lattice. The magnetocaloric effect of Gd(BDC)1.5∙DMF was also studied. Chapter 6 discussed doping Co²⁺ ion into pyrochlore-like Zn(INA)₂ (INA = isonicotinate) MOF lattice for the purpose of making magnetically active pyrochlore-like MOF structures. The highest Co²⁺ doping concentration of 57% was successfully achieved. However, no significant magnetic frustration was observed, possibly due to the far separation between doped Co²⁺ ions. Chapter 7 discussed the etching of Zn(INA)₂ MOF crystal to increase microporous exposure. When Zn(INA)₂ MOF crystals were immersed in Co(NO₃)₂∙6H₂O acetonitrile solution, defined effective etching, which could effectively increase microporous exposure, took place. When Zn(INA)₂ MOF crystals were immersed in Co(NO₃)₂∙6H₂O N,N-dimethylformamide solution, defined ineffective etching, which could not increase microporous exposure, took place dominantly. Increasing etching temperature resulted in similar but more severe etching. However, new cobalt dominant MOF phases formed when etching was performed under elevated temperature.

<p> Addition of terminal or internal alkynes to a base free titanocene oxide results in synthesis of the corresponding oxometallocyclobutene. With appropriate cyclopentadienyl substitution, these compounds undergo reversible C-C reductive elimination offering a unique approach to cyclopentadienyl modification. Subsequent reactivity demonstrates the complete scission of the Ti=O multiple bond.</p><p> Cycloaddition of monosubstituted allenes with a monomeric, base free titanocene oxide resulted in isolation and crystallographic characterization of the corresponding oxatitanacyclobutanes. In solution these compounds are a mixture of <i>(E)</i> and <i>(Z)</i> isomers and interconvert by mechanisms that are dependent on the specific substitution of the allene. Facile carbonylation of the oxatitanacyclobutanes was also observed to yield rare examples of structurally characterized oxatitanacyclopentanones. These studies highlight the new chemistry available from synthesis of base free titanocene oxide compounds enabled by appropriate cyclopentadienyl substitution. </p><p> The hydrogenolysis of titanium nitrogen bonds in a family of bis(cyclopentadienyl) titanium amides, hydrazides, and imides via proton coupled electron transfer (PCET) is demonstrated. (&eta;⁵-C₅Me₅)(py-Ph)Rh-H (py-Ph = 2-pyridylphenyl, <b>[Rh]-H</b>) and (&eta;⁵- C₅R₅)(CO)₃CrH (<b>[Cr]^R-H, </b> R= H, Me) were used as catalysts for homolytic H₂ activation followed by PCET to the nitrogen-containing fragment. Detailed mechanistic studies and an analysis of the underlying thermochemistry are employed to explain the decreased catalytic efficiency of <b>[Cr]^R-H </b> compared to <b>[Rh]-H.</b> The N-H bond dissociation free energies (BDFEs) in 12 structurally similar compounds were determined through a combination of experimental and computational methods, providing a foundation for the use of N-H BDFEs as a metric to enable NH₃ synthesis from H₂ and N₂ at a well-defined metal center.</p><p> Combination of the readily available a-diimine ligand, ((<i>Ar</i>N=C(Me))₂ Ar = 2,6-ⁱPr₂-C₆H₃), (^iPrDI) with air-stable nickel(II) bis(carboxylates) generated a highly active catalyst exhibiting anti-Markovnikov selectivity for the hydrosilylation of alkenes with (EtO)₃SiH. The exclusive selectivity for formation of terminal alkyl silanes was also observed with internal alkenes via a tandem isomerization-hydrosilylation pathway. The hydrosilylation of 1-octene with triethoxysilane, a reaction performed commercially in the silicones industry on a scale of > 12,000,000 lbs/year, was performed on a 10 g scale with 96 % yield and >98 % selectivity for the desired product.</p>