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This study investigated the adsorption and dissociation of perchloroethene (PCE), trichloroethene (TCE), and cis-dichloroethene (cis-DCE) on zerovalent iron. The mechanisms by which iron decomposes chlorinated solvents by catalytic cleavage of the carbon-chlorine bond, are as not yet well understood. To develop process models for the optimal design of in situ and ex situ zerovalent iron treatment systems for the removal of chlorinated solvents from drinking water supplies, it is important to understand these mechanisms, and in particular how the degree of chlorination of the contaminant affects its reactivity on the iron surface. Periodic density functional theory (DFT) and the generalized gradient approximation (GGA) were used to determine the most thermodynamically favorable site on Fe(110) for the adsorption of all three chloroethenes. Climbing image nudged elastic band (CI-NEB) method with the periodic DFT and the GGA was employed to calculate activation energies of the chloroethene compounds according to the principal dechlorination mechanism of reductive β-elimination. The dechlorination rate constants of the chloroethenes were estimated using an Arrhenius equation with theoretically calculated vibrational frequencies of the compounds. Of the adsorption sites examined, an atop site, where the chloroethene C=C bond straddles a surface iron atom, was the most energetically favorable site for the adsorption of all three chloroethenes. Electronic structure and property analyses demonstrate the strong hybridization of the π-bonding orbital between the chloroethene C=C bond and the iron surface suggesting that adsorbed chloroethenes are strongly activated on Fe(110) and are likely precursors for subsequent chloroethene dissociation on the Fe surface. Taking into account the effect of solvation indirectly, the ordering of the adsorption energies of chloroethenes from the aqueous phase onto Fe(110) is in agreement with experimental observation (PCE > TCE > cis-DCE). Chloroethenes with a higher number of chlorine atoms have lower activation energies than those with fewer number of chlorine atoms. The activation energies of PCE, TCE, and cis-DCE at their rate-limiting steps are 9.9, 16.6, and 23.8 kJ/mol, respectively. At room temperature (300 K), for example, the dechlorination rate of PCE is 14 times and 338 times faster than those of TCE and cis-DCE, respectively.

Memory of chirality (MOC) is an emerging strategy for asymmetric synthesis which relies upon the intermediacy of transiently non-racemic reactive species. In these reactions the configuration of the sole stereogenic center of the enantiopure starting material is "memorized" by a chiral non-racemic conformation in the intermediate; trapping then captures the stereochemical information, and generates a new stereogenic center with high fidelity. We experimentally and computationally studied the highly retentive deprotonation/alkylations of 1,4-benzodiazepin-2-ones (BZDs) that rely upon this strategy. We captured a transiently non-racemic BZD enolate intermediate in enantiopure form, then released the enolate and observed its subsequent reaction. This approach allowed the first ever step-wise observation of the stereochemical course of such a MOC process. Approximately 2 million deaths are caused by malaria every year in the world. In total roughly 3.2 billion people are living under the risk of malaria transmission. Current use of anticholinesterase insecticides has been limited by their toxicity to human beings. A major African malaria insect vector, Anopheles gambiae (Ag), was targeted. Based on sequence alignment and homology models of AgAChE, a strategy of dual-site binding was adopted that targets Trp84 in the active site and Cys286 at the peripheral site. Selective AChE inhibitors have been designed and synthesized.

Density functional theory (DFT) calculations were performed to investigate the orbital interactions responsible for stereoactive lone pair distortions in ternary metal oxides. The calculations revealed that the stereoactivity of the lone pair is dependant upon the strength of interaction between the A-cation and the surrounding oxygen ligands. The resulting second order Jahn-Teller distortions are dependant upon the interactions and relative energies of the cation s, cation p, and oxygen p orbitals near the Fermi-level. The calculations also reveal fundamental differences in the orbital interactions responsible for the stereoactivity in Sn 2+, Pb 2+, and Bi 3+containing compounds. Ternary metal oxides involving Sr 2+, Pb 2+, and Ag +were also analyzed using DFT in order to evaluate the impact each cation plays on the band gap. Pb 2+and Ag +effectively reduce the band gap relative to Sr 2+by introducing electronically active states in close proximity to the valence band and conduction band edges. DFT calculations were performed on nine structural models of BaTaO 2N, SrTaO 2N, and CaTaO 2N revealing several similarities and differences in the local structure of each material. The calculations predict several trends: (i) a local cis configuration is more stable than a trans configuration, (ii) models involving a Ta 5+displacement are more stable than models in which the Ta 5+position is constrained to retain the inversion center of the undistorted octahedron, and (iii) the tendency for octahedral tilting increases from BaTaO 2N to SrTaO 2N to CaTaO 2N.

Various reactions with implications for combustion chemistry were modeled. The enthalpies and energies of reaction for hydrogen-atom loss and alkyl-group fragmentations at various temperatures were calculated for the alkylated heterocycles that provide a model framework for understanding coal combustion, using density functional theory (B3LYP/6-311+G**//B3LYP/6-31G*) and CBS-QB3 calculations. The oxidation steps of the resulting radicals were modeled, and pathways of the resulting peroxy radicals explored. These species can undergo intramolecular reactions to form bicyclic structures. Several pathways are feasible and must be considered in rationalizing coal chemistry: formation of either a four-membered or five-membered ring occurs with similar kinetics and thermodynamics; cyclization at nitrogen to form a nitroso species has a high reaction barrier but is ultimately quite exoergic. An internal H-atom transfer can occur on the substituted side chain with a low barrier and favorable energy of reaction. Conformational possibilities for n-propylperoxy radical were explored via B3LYP/6-31G* and mPW1K/6-31+G** levels of theory to ensure that rotational barriers would not compete with energies of reaction. Building on these results, the unimolecular decomposition of propan-1-ol-1-peroxy radical was similarly modeled using DFT methods. The quantitative energetics of the relevant decompositions were similar to those of the hydrocarbon analogue, although a wider variety of functionalized products were formed; these small model compounds are of interest in understanding larger hydrocarbon and functionalized fuels. Complexes of ethanol with various solvents were modeled to better understand certain spectroscopic phenomena and potential atmospheric behaviors of oxygenated species. Experimental work on these complexes had noted a red shift due to complexation of ethanol with benzene that was not seen with any other solvents. Theoretical spectra were generated using HF/6-31G* and MP2/6-31G* optimizations and compared well to the experimental spectra. The red shift seen in benzene was attributed to an interaction of ethanol with the pi system of the benzene ring. Hydrogen has often been proposed as an alternative fuel that would improve engine performance and minimize harmful emissions. Its use as a fuel additive was explored with n-heptane and the primary reference fuels (a mixture of iso-octane and n-heptane), using the master equation program CHEMKIN 4.1.

Numerous enzymatic reactions are controlled by the chemistry of metallic ions. This dissertation investigates the electronic properties of three transition metal (copper, chromium, and nickel) complexes and describes modeling studies performed on glutathione synthetase. (1) Copper nitrene complexes were computationally characterized, as these complexes have yet to be experimentally isolated. (2) Multireference calculations were carried out on a symmetric C2v chromium dimer derived from the crystal structure of the [(tBu3SiO)Cr(µ-OSitBu3)]2 complex. (3) The T-shaped geometry of a three-coordinate β-diketiminate nickel(I) complex with a CO ligand was compared and contrasted with isoelectronic and isosteric copper(II) complexes. (4) Glutathione synthetase (GS), an enzyme that belongs to the ATP-grasp superfamily, catalyzes the (Mg, ATP)-dependent biosynthesis of glutathione (GSH) from γ-glutamylcysteine and glycine. The free and reactant forms of human GS (wild-type and glycine mutants) were modeled computationally by employing molecular dynamics simulations, as these currently have not been structurally characterized.

Different computational chemistry methods were applied to study a variety of problems at the molecular level. These problems are involved with protein-protein interactions, the mechanism of reaction for enzymatic purine biosynthesis, structural interconversion in non-natural oligomeric folding, and carbohydrate synthesis. Molecular dynamic simulations were applied to study the elements of molecular recognition in FKBP12 for binding to transient receptor potential-canonical 6 (TRPC6) calcium channels. A peptide model of the wild-type TRPC6 intracellular domain, a phosphorylated Ser768 analog of the wild-type peptide, and Ser768Asp and Ser768Glu mutants, were subject to FKBP12 binding simulation. The phosphorylated peptide demonstrated the greatest binding affinity, due to the strong interaction between the phosphate group and two lysine (Lys44 and Lys47) residues of FKBP12. The simulations also revealed transient, non-simultaneous interactions with the epsilon-NH3+ group of these lysine residues. Catalytic reaction mechanisms of the enzyme PurE Class I, which catalyzes the transformation from N5-carboxyaminoimidazole ribonucleotide (N5-CAIR) to 4-carboxyaminoimidazole ribonucleotide (CAIR) in the purine biosynthetic pathway, were investigated by density functional theory (DFT) methods. The potential energy surfaces (PES) of these enzymatic reactions have been explored. A cationic pathway is predicted as the most favorable mechanism in both the simplified and full reaction models. Four azobenzene oligomers which could fold into both right- and left-handed helices were studied computationally for their dynamical properties. Two helices were shown as the global minimum among the conformations generated by Monte Carlo simulation. Replica-exchange molecular dynamics (REMD) simulations were performed on these oligomers. Both right- and left-handed helices were successfully sampled in the simulation for all four oligomers. Careful investigation of REMD trajectories revealed twisted conformations as intermediate structures in the interconversion pathway between two helices. Computational studies have been done to understand the mechanism of the regioselective epoxide ring-opening process catalyzed by the presence of (-)-sparteine in the synthesis of beta-arabinofuranosides. MD simulations revealed interesting conformational changes of the (-)-sparteine unit, which could push Li+ toward the epoxide oxygen in a catalytically useful fashion. Quantum molecular dynamics methods were applied to simulate four systems for the epoxide ring-opening process.

Experimental and theoretical methods were used to study the structure, and spectroscopic properties of carcinogenic nitrated polycyclic aromatic hydrocarbons Structure-function and structure-spectroscopy correlations were examined. Initial investigations focused on the relationships between the orientation of the nitro group relative to the plane of the aromatic ring, vis-à-vis known mutagenic effects. Synthesis of specific isomers of nitro-PAHs and elucidation of their crystal structure is required to establish the validity of the structure-function relationships. Such studies are scarce. Fortunately, electronic structure calculations can be readily done. We used density functional theory calculations to predict structures of 1-, 2-nitronaphthalenes, 1-, 2-, 9-nitroanthracenes, 1-, 2-, 3-, 4-, 9-nitrophenanthrenes, 1-, 2-, 4-nitropyrenes, 6-nitrochrysene, 1-, 3- and 6-nitrobenzo[a]pyrenes. In accord with other studies, we showed that the mutagenic ability of one nitro-PAH isomer over another in the same ring may be predicted from its dihedral angle. However, 1-, 2- and 4-nitropyrene with calculated C-C-N-O angles of ~23°, 0° and 26°, respectively, presented contradictory results. We suggest that the nitrated pyrenes undergo different enzymatic reduction routes when interlocking to enzymes. For further insights into structure-function and structure-spectroscopy correlations, 1-, 3-, and 6-nitrobenzo[a]pyrene were synthesized. Detailed infrared and Raman spectroscopic data of BaP, and its three mononitrated isomers are provided for the first time. By utilizing B3LYP/6-311+G**, the molecular geometries and the vibrational spectra was calculated. Good agreement between calculated and experimental geometry for BaP was noted, and predictions of the vibrational data for all compounds were within ~5 cm-1 of the experimental data. νsNO2/νasNO2 assignments are proposed. The geometrical distortions of the BaP structure upon nitro group substitution and correlations between structural parameters and vibrational data, and structure-function relationships related to the mutagenicity are discussed. The profound influence and electronic effects of the nitro group was shown to correlate to quantum yield (Φf) trends. Nitro-PAHs whose nitro group was non-planar to the aromatic plane exhibited higher quantum yields, and showed absorption bands similar to the parent PAH. UV-Vis absorption bands of the singlet excitation states were assigned via TDDFT, and the πPAH ring→π*PAH ring excitations mainly predominated in nitro-PAHs with a non-planar nitro group.

Coupled cluster (CC) and density functional theory (DFT) are highly regarded as robust quantum chemical methods for accurately predicting a wide variety of properties, such as molecular structures, thermochemical data, vibrational spectra, etc., but there has been little focus on the theoretical prediction of optical rotation. This property, also referred to as circular birefringence, is inherent to all chiral molecules and occurs because such samples exhibit different refractive indices for left- and right- circularly polarized light. This thesis focuses on the theoretical prediction of this chiroptic property using CC and DFT quantum chemical models. Several small chiral systems have been studied, including (S)-methyloxirane, (R)-epichlorohydrin, (R)-methylthiirane, and the conformationally flexible molecules, (R)-3-chloro-1-butene and (R)-2-chlorobutane. All predicted results have been compared to recently published gas-phase cavity ringdown polarimetry data. When applicable, well-converged Gibbs free energy differences among confomers were determined using complete-basis-set extrapolations of CC energies in order to obtain Boltzmann-averaged specific rotations. The overall results indicate that the theoretical rotation is highly dependent on the choice of optimized geometry and basis set (diffuse functions are shown to be extremely important), and that there is a large difference between the CC and DFT predicted values, with DFT usually predicting magnitudes that are larger than those of coupled cluster theory.

A variety of experimental spectroscopic techniques complemented by theoretical calculations when appropriate were used to investigate DNA adlayers on surfaces and proteins in solution. The formation and characterization of DNA adlayers on gold and indium tin oxide surfaces were characterized along with subsequent surface DNA hybridization. Prior to the modification of indium tin oxide surfaces with DNA, the optical and electronic properties of this metal oxide, fluorine doped tin oxide and iridium oxide were investigated. The detection of DNA hybridization on indium tin oxide surfaces utilized gold nanoparticle labeled target ssDNA. Further work on gold surfaces was performed using infrared spectroscopy to detect sugar binding to a phenylboronic acid terminated self-assembled monolayer. The binding properties and stability of gold nanoparticles were investigated by characterizing citrate and bovine serum albumin binding to gold surfaces and the stability of particles stabilized by these molecules. The stability and folding kinetics of the three helix bundle protein, villin headpiece subdomain was also investigated in addition to a theoretical investigation of the vibrational Stark effect. Finally, a time resolved step scan FTIR spectrometer was implemented with five microsecond time resolution.

Bivalent drug design is an efficient strategy for increasing potency and selectivity of many drugs. We devised a strategy to prepare agonist-benzodiazepine heterodimers that could simultaneously bind to agonist and BZD sites of the GABAAR. We synthesized a benzodiazepine-MPEG model compound that relied on physiological GABA to elicit flux. We established that a tether at the N1 position of the BZD would not prevent binding to the receptor. However, coupling of GABA amides with long chain PEG tethers studied by another group member resulted in complete loss of agonist activity. We therefore ceased research in this particular area. 1,4-Benzodiazepin-2,5-diones display a wide range of pharmacological activities. Compounds containing the tricyclic proline-derived subtype have received attention as potent anxiolytic agents and as starting materials for anthramycin-inspired anticancer agents. More recently enantiopure (S)-proline-derived 1,4-benzodiazepin-2,5-diones have been recognized as selective α5 GABAA receptor ligands. Despite the impressive diversity of 1,4-benzodiazepine-2,5-diones prepared to date, enantiopure examples possessing a quaternary stereogenic center have been largely unexplored. "Memory of chirality" (MOC) is an emerging strategy for asymmetric synthesis. This technique enables the memory of a sole chiral center in the substrate to be retained in a process that destroys that center. We have used this technique to prepare a library of quaternary proline-derived, thioproline-derived and hydroxyproline-derived 1,4-benzodiazepin-2,5-diones, in high ee. We have developed an efficient synthetic method for preparing oxaproline-derived 1,4-benzodiazepin-2,5-diones in high yields, and by applying the MOC strategy we have prepared quaternary derivatives in acceptable %ee. We envision oxaproline-derived 1,4-benzodiazepin-2,5-diones may exhibit similar or more potent pharmacological properties than proline-derived 1,4-benzodiazepin-2,5-diones. Using density functional theory (DFT) methods, we modeled the formation of an enantiopure, dynamically chiral enolate intermediate and the slow racemization of the enolate on the alkylation reaction time scale.

Metal-metal (M 2 ) quadruply bonded complexes have a rich, diverse chemistry. From providing insight into fundamental chemistry, to having applications in materials chemistry, they continue to fuel the imagination of many inorganic chemists. Perhaps the most interesting aspect of complexes containing M 2 (M = Mo, W) quadruple bonds are their physical and electronic structures. This thesis demonstrates an “aufbau” for understanding metal-metal quadruply bonded complexes. We begin by examining the spectral and electronic properties of simple paddlewheel complexes of the form M 2 (O 2 CR) 4 (M = Mo, W; R = t Bu—experimental; CH 3 , H—computational models). From there, we move to understanding the subtle electronic and thermodynamic features of more complex systems, i.e. [(HCO 2 ) 3 M 2 ] 2 (µ-O 2 CCO 2 ). We then move from understanding complexes of the form [(HCO 2 ) 2 M 2 ] 4 (µ-O 2 CCO 2 ) 4 to [M 2 (µ-O 2 CCO 2 )] ∞ , the “infinite limit” of an extended structure. Finally, we investigate the unique chemistry of systems linked by 4,4’-azodibenzoic acid, applying what we know from similar studies of related systems. Throughout this work, computational techniques utilizing density functional theory is emphasized, as it has proven quite successful in predicting and reproducing experimental results.

A novel nanolithography technique is developed for nanoscale patterning of polymers: atomic force microscope assisted electrostatic nanolithography (AFMEN). In AFMEN, nanostructures are generated by mass transport of polymeric material within an initially uniform, planar film. The combination of localized softening of attolitres of polymer, a strongly non-uniform electric field to polarize and manipulate the soften dielectric, and single-step process methodology using conventional atomic force microscopy (AFM), establishes a new paradigm for polymer nanolithography. We develop a basic theoretical understanding of the processes associated with AFMEN and present modeling of the relevant phenomena. The analysis of polymer heating indicates that the AFMEN resolution is not directly limited by the radius of the AFM tip, which is distinctly different from alternative AFM–based lithographic techniques. Instead, the feature size depends critically on the thermal characteristics of the polymer, such as its thermal conductivity. The dielectric properties of the polymer play a secondary role, affecting the magnitude of the electric field but do not directly impact the feature size. The nanostructure shape is determined by the competition between the ponderomotive forces acting on the dielectric material in non–uniform electric field, and the polymer surface tension. An exact analytical solution, as well as numerical solutions, are determined for the electric field distribution in the tip–sample junction, which allow prediction of the nanostructure geometry. The response of the AFM tip during the nanolithography process is investigated. An analysis of the free energy of the system, comprising AFM tip, sample surface and water meniscus, shows that the tip is spontaneously lifted away from the polymer surface. The mechanical work required to lift the tip is drawn from the energy of electric field. In addition, water condensation in the proximity of nanoscale asperities such as an AFM tip is studied. A general framework based on the density functional theory (DFT) is developed and applied to describe the liquid meniscus condensation, providing the first (to the best of our knowledge) molecular–level theory of water condensation on the nanoscale in the presence of external electric fields.

The choice of DFT exchange-correlation functional, basis set and scalar-relativistic method were examined by comparison to experimental gas-phase actinide hexafluoride data. A variety of GGA, MGGA and ACM functionals with DZ and TZ Slater or Gaussian basis sets are explored in combination with the quasi-relativistic Pauli Hamiltonian, ZORA and RECP scalar-relativistic methods. Excellent agreement between experimental and calculated values is observed for TZ or higher quality basis sets. MGGA functionals are found to be superior to GGA and ACM functionals for use because of their systematically predictable errors. Correlation-consistent valence basis sets improve computed results when using RECPs. The coordination and bonding of equatorial hydroxide, carbonyl, cyanide (CN - ), and isocyanide (NC - ) ligands with uranyl dication, [UO 2 ] 2+ , was studied using DFT with RECPs. Good agreement is seen between experimental and calculated geometries of [UO 2 (OH) 4 ] 2- . Newly predicted ground state structures of [UO 2 (OH) 5 ] 3- , [UO 2 (CO) 4 ] 2+ , [UO 2 (CO) 5 ] 2+ , [UO 2 (CN) 4 ] 2- , [UO 2 (CN) 5 ] 3- , [UO 2 (NC) 4 ] 2- , and [UO 2 (NC) 5 ] 3- are reported. Four-coordinate uranyl isocyanide complexes are the predicted gas-phase species while five-coordinate uranyl cyanide complexes are energetically favorable in aqueous solution. Small energy differences between cyanide and isocyanide complexes indicate the energetic feasibility of mixed cyanide and isocyanide complexes. A D 2d uranyl tetrahydroxide is the dominant gas-phase and aqueous species, but formation of uranyl carbonyl complexes is seen to be exothermic in the gas-phase and endothermic in aqueous solution. Oxygen atoms of the nine coordinated waters in both actinide(III) and lanthanide(III) nonaaqua triflate salts adopt a highly symmetric tricapped, trigonal-prismatic geometry about the metal center. The prismatic-water bond is consistently longer than capping-water bonds for known lanthanide and actinide complexes. Longer prismatic bond lengths are predicted by DFT for the entire actinide(III) nonaaqua complexes. The prismatic-water bond length elongation is shown to be a result of steric repulsion rather than f-electron covalency, symmetry constraints, or ligand choice. Ferrioxamine siderophores are low molecular weight chelating agents designed to bind Fe(III) and transport it into microbes. The first DFT calculations on H3DFOE, Fe(III)DFOE, and [PuDFOE(H 2 O) 3 ] + are reported for ground-state structures. Three negatively charged hydroxamate groups are shown to accurately model [DFOE] 3- . A QM subsection for use in future QM/MM calculations is proposed.

Density functional theory (DFT) is a tool of many-body physics whose popularity has grown over the years, primarily because it provides a useful balance between accuracy and computational cost, allowing large systems to be treated in a simple self-consistent manner. Effective field theory (EFT) is a framework which allows us to study the low-energy phenomena of a system in a systematic fashion. In this thesis, EFT methods are applied to DFT as part of a program to systematically go beyond mean-field approaches to medium and heavy nuclei. A system of fermions with short-range, natural interactions and an external confining potential (e.g., fermionic atoms in an optical trap) serves as a laboratory for studying DFT/EFT. An effective action formalism leads to a Kohn-Sham DFT by applying an inversion method order-by-order in the EFT expansion parameter. Results showing the convergence of Kohn-Sham calculations at zero temperature in the local density approximation (LDA) are compared to Thomas-Fermi calculations and to power-counting estimates. When conventional Kohn-Sham DFT for Coulomb systems is extended beyond the local density approximation, the kinetic energy density is sometimes included in energy functionals in addition to the fermion density. However, a local (semi-classical) expansion of the kinetic energy density is used to write the energy as a functional of the density alone, in contrast to the Skyrme approach. The difference is manifested in different single-particle equations, which in the Skyrme case include a spatially varying effective mass. The EFT framework for DFT is generalized to reconcile these approaches. An effective action approach is used to illustrate how the exact Green's function can be calculated in terms of the Kohn-Sham Green's function. An example based on Skyrme energy functionals shows that single-particle Kohn-Sham spectra can be improved by adding sources used to construct the energy functional. Finally, spin-orbit interactions are incorporated in the formalism leading to an energy functional having the same form as that of the Skyrme functional. Gradient expansions in terms of the local Fermi momentum are also worked out, which will be of use in the immediate future.

Density functional theory has been used to investigate the structure, bonding and spectroscopic properties of a variety of interesting and potentially useful inorganic complexes. The photoluminescent (CuN(SiX 3 ) 2 ) 4 complex has an unusual square geometry with no formal Cu-Cu bonding. TDDFT calculations were performed to investigate the origin of the photoluminescence. It was determined that the complex undergoes a significant change in geometry in the cluster-centered, weakly Cu-Cu bonding, excited state. Another unusual copper cluster, Cu 3 (O 2 C X ) 6 , was also examined. This complex is triangular, paramagnetic, and has no formal Cu-Cu bonding. The complex is spin-frustrated, resulting from the arrangement and interaction of the three unpaired electrons on the Cu centers. The EPR parameters were calculated and the possibility of Jahn-Teller stabilization of the doublet state was investigated. The majority of this work focuses on the structure, energetics and bonding of series of isomeric transition metal complexes. There are a surprising number of “missing” (as of yet unobserved) simple, linear, sandwich complexes that could be formulated with transition metals and C n H n rings from n=3 to n=8. The Group 6 MC 12 H 12 isomers [(η 6 -C 6 H 6 ) 2 M, (η 5 -C 5 H 5 )M(η 7 -C 7 H 7 ), (η 4 -C 4 H 4 )M(η 8 -C 8 H 8 )], Group 8 MC 10 H 10 isomers [(η 5 -C 5 H 5 ) 2 M, (η 4 -C 4 H 4 )M(η 6 -C 6 H 6 ), (η 3 -C 3 H 3 )M(η 7 -C 7 H 7 )] and NiC 8 H 8 isomers [(η 4 -C 4 H 4 ) 2 Ni, (η 3 -C 3 H 3 )Ni(η 5 -C 5 H 5 )] were studied. The NiC 8 H 8 study was extended to include (η 2 -C 2 H 2 )Ni(η 6 -C 6 H 6 ) and (η 8 -C 8 H 8 )Ni. The ground-state geometry was determined for all isomers, and bonding analysis was performed to determine the dominantly bound fragment in all the species. It was found that, in general, the distance between the metal and ring centroids was long for π-bound rings and significantly shorter in δ-bound rings. The out-of-plane bending of the C-H bonds in the ring ligands varied according to how mismatched the ring π orbitals were in relation to the M δ orbitals. The bonding analysis found that the dominantly bound rings were not necessarily those with π bonds, the most covalent character, or best size match. Each complex was analyzed individually to determine the dominantly bound ring, and to understand the interactions. Attention was paid to the changes seen as the metal was changed both moving across and down the transition metal block.

In this dissertation, various dinuclear organometallic carbonyls (DOCs) – that is, compounds containing two metal atom centers, each bonded to one or more CO ligands – are used to evaluate, both qualitatively and quantitatively, the strengths, weaknesses, possibilities, and limitations of density functional theory (DFT). This evaluation largely concerns itself with the ability of DFT to provide insight and data of relevance to inorganic chemists. The accuracy of DFT as applied to both ground-state and electronically excited-state systems is explored. The first chapter primarily concerns the ability of DFT to distinguish between different isomers of a given molecule, based on both relative stabilities as calculated by DFT and through comparisons between experimentally observed and computationally simulated vibrational absorption spectra. It is shown that calculations of this sort can aid experimental inorganic chemists in a number of ways, including verification of proposed structures, discernment between likely possible structures, and even identification of previously undetermined structures. The accuracy is such that it is even possible to assign the individual infrared peaks of multicomponent systems to their sources. In the second chapter, the precision of DFT is rigorously quantified, using these DOC compounds, and a procedure ideally suited for computational inorganic chemistry is recommended. The following chapter provides similar recommendations for investigations into excited-state chemistry, using the recent methodology of time-dependent density functional theory (TD-DFT). Finally, the procedures are applied to another common DOC, known colloquially as Fp dimer. For this compound, as well as for certain analogues, insight into the complicated solution-phase behavior and photochemistry is afforded through the use of the accurate DFT and TD-DFT approaches explored in the previous chapters. It is expected that the results and recommendations presented herein will be of great use to any inorganic chemist who would seek to address problems that are not easily amenable to experimental study, that show contradictory experimental results, or that are merely in need of verification. The accuracy demonstrated for DFT in this work shows that this computational technique is more than adequate for the task of addressing these concerns.

Density functional theory calculations are used to unravel the mysterious third step of aromatase catalysis. The feasibility of mechanisms in which the reduced ferrous dioxygen intermediate mediates androgen aromatization are explored and determined to be unlikely. Mechanisms for the aromatization/deformylation sequence which are initiated by 1beta-hydrogen atom abstraction by P450 Compound I are considered. 1beta-Hydrogen atom abstraction from substrates in the presence of the 2,3-enol encounters strikingly low barriers,whereas barriers for this same process are higher in the keto tautomer. Transition states for 1beta-hydrogen atom abstraction from enolized substrates in the presence of the 19-gem-diol decayed directly to the experimentally observed products. If the C19 aldehyde remains unhydrated, aromatization occurs with concomitant decarbonylation, and therefore does not support dehydration of the C19 aldehyde prior to the final catalytic step. Ab initio molecular dynamics on the confirmed that the 1beta-hydrogen atom abstraction and deformylation or decarbonylation occur in a non-synchronous, coordinated manner. These calculations support a dehydrogenase behavior of aromatase in the final catalytic step, which can be summarized by 1beta-hydrogen atom abstraction followed by gem-diol deprotonation. Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormone-dependent breast cancer. There are several classes of natural products that exert potent activities in aromatase inhibition, with the flavonoids being most prominent. Previous studies have exploited flavone and flavanone scaffolds for the development of new aromatase inhibitors. In this dissertation, we describe design, synthesis, and biological evaluation of a novel series of 2-(4-pyridylmethyl)thioisoflavones as the first example of synthetic isoflavone-based aromatase inhibitors. The biological evaluation of a series of 2-azole and 2-thioazole isoflavones as potential aromatase inhibitors are described. Differences in inhibitory activity of triazole and imidazole inhibitors are rationalized with density functional theory to expose a key difference in the electronic structure of these molecules. In addition, difference binding spectra of inhibitors to immunoaffinity-purified aromatase produces classical Type II spectra consistent with coordination of the nitrogen lone pair electrons to the P450 heme.

There are a very small number of structurally-characterized sandwich compounds of the type M2L2 where M = Mo, W and L = a (CH2)n carbocyclic ring. This is in contrast to the large number of mononuclear compounds of the same type. This interesting disparity may be a result of insufficient synthetic attempts to make such compounds rather than some inherent instability of the M2(carbocycle)2 species. A new family of half-sandwich complexes of ditungsten alkoxides is defined as structures having the formula W2(carbocycle)(OR)4. Attempts to make such compounds via the alcoholysis of 1,2-W2Cp2(NMe2)4 were unsuccessful. 1,2-W2Cp2(NMe2)4 shows a unique resistance among dimethylamide compounds of tungsten towards alcoholysis with the typical aliphatic alcohols used in such reactions. Strongly acidic alcohols, such as CF3CH2OH, are required to react with this dimethylamide. These reactions lead to over-alcoholysis products such as 1,1 W2Cp(η3-C5H7)(OCH2CF3)6. Unlike W2Cp2(NMe2)4, W2COT(NMe2)4 undergoes facile alcoholysis to form [W2COT(OR)4]n species where n = 1 for R = tert butyl, isopropyl, and neopentyl and n = 2 for R = Me, Et, and Pr. The dinuclear alkoxides exhibit a fluxional COT ligand which rotates about the W-W bond via a 1,2-alkyl exchange mechanism. Two strong and symmetrical W-OR-W alkoxide bridges between two W2COT(OR)3 fragments are found within the tetranuclear compounds. Several attempts to make sandwich compounds of ditungsten of stoichiometry W2COT2 were unsuccessful. Reactions of K2COT with quadruply-bonded W2Cl4(PR3)4 species lead to ill-defined species. Reactions of the Mo2(O2CCH3)4 paddlewheel compound with two equivalents of K2COT″ where COT″ = 1,4-bis-trimethylsilyl-1,3,5,7-cyclooctatetraene resulted in the formation of M2COT″3 compounds, despite the use of a bulky cyclooctatetraene ligand. Attempts to react the W4(OPr)16 cluster with two equivalents of Li2COT lead to reduction of the cluster and formation of two equivalents of Li2W2(OPr)8. DFT computational studies are used to explain the instability of W2COT2 sandwich compounds having both D8h and D2h symmetry. The same studies predict that (M2COT2)2+ species might be quite stable. DFT computational studies of W2(benzene)2 sandwich compounds indicate that the W-W bridging, antifacial D2h structure is more stable than the D8h nonbridged and D2h synfacial structures. W2(benzene)2 compounds are expected to be stable. A suitable synthetic route to these compounds might be the reaction of metal atoms with immobilized arenes or M(arene)2 compounds.

Cationâ Ï interaction is an important determinant in protein structure and function. Among the three proteinogenic aromatic amino acids, tryptophan (Trp) is the strongest cationâ Ï donor. We reported the asymmetric syntheses of tryptophan regioisomers in which the amino acid side chain is attached at different position of the indole moiety. These new tryptophan regioisomers can effect a different mode of cationâ Ï interaction. In nature, dramatic increases in binding affinity can be achieved through multivalent binding. Following a fragmentation-dimerization approach, we synthesized Taxol-based dimer in which the baccatin III core of Taxol is coupled with flexible PEG linker. However, microtubule assembly assay suggested that these new dimers are not capable of effecting bivalent binding to the Taxol binding sites in microtubules. Memory of chirality (MOC) is an emerging theme in asymmetric synthesis in which the dynamic chirality of the reactive intermediate "memorizes" the static chirality of the reactant. Using dynamic 1D and 2D NMR and density functional theory (DFT) methods, we studied the MOC effect of 1,4-benzodiazepin-2-ones. Reconstruction of the reaction pathway using DFT calculations supported our proposed contra steric, retention of configuration mechanism.

The lithiation reactions of mid-sized cyclic vinyl ethers were studied using density functional theory calculations at the level of B3LYP/6-31++G(d,p). Gas phase and several major solvation models were incorporated in the calculations in an attempt to reproduce and explain experimental results – the regioselectivity of these lithiation reactions. The solvation models employed here include the microsolvation model with one dimethylether solvent molecule, the continuum models such as the Onsager model, the Polarized Continuum model – PCM (including the polarizable conductor calculation model – CPCM, and the integral equation formalism model – IEFPCM), the isodensity PCM approach – IPCM, and the mixed continuum-microsolvation model (which is the combination of a continuum model and the microsolvation model). Transition structures of the reactions were located and optimized at the same theory level. The calculations with the continuum solvation model alone usually give inconsistent results with experiment. The short-range solvation effect, expressed by the microsolvation model, must be included along with the long-range solvation effect of continuum models. The relative electronic energies of the transition structures using this mixed continuum-microsolvation model are in better agreement with the experimentally observed regiochemistry than either model alone. Vinyl angle compression and allyl angle expansion were observed in optimized anions. The natural population analysis shows that all of the transition structures are of multi-center processes. The continuum solvation model calculations indicate that all three PCM approaches (PCM, CPCM, IEFPCM) tend to give very similar energies. The microsolvation model indicates that more than one solvent molecule might be needed in the “first shell of solvation” for large and flexible rings such as 2,3,4,5-tetrahydrooxepin.The 1-D and 2-D NMR characterizations of the trienolate product of 2,3-dihydrooxepin lithiation with 6-lithio-dihydropyran in THF are also reported. The NMR data support a direct ring-opening upon allylic lithiation via an E2 type mechanism rather than vinylic lithiation or stepwise allylic lithiation. We also found the structure of the trienolate product of this reaction to be the Z, Z configuration. These experimental observations are in agreement with our density functional theory calculation results.

The vibrational analysis of the exocyclic amino group of adenine using both experimental and computational methods is presented. The Fourier Transform infrared (FT-IR) spectra, of adenine, 2'-Deoxyadenosine and five isotopomers of them are reported. FT-IR attenuated total internal reflection (ATR) spectra of H216O, H218O and D216O in the liquid state were obtained. Molecular modeling of water was conducted and a 9-water PBC model was found to give an exceptionally good fit to the experimental line shapes and isotopic frequency shifts. Both harmonic and anharmonic approximations to the vibrational frequencies are used to analyze the matrix isolation adenine spectra. DFT calculations were made using the B3‑LYP/6‑31G* and GGA/DNP computational methods. The NH2 puckering mode is an out-of plane mode that is poorly modeled by both computational methods. Harmonic shift analysis is presented as a method for estimating mode anharmonicity and for determining mode-mode coupling in DFT calculation. The DFT analysis of the adenine spectra in a hydrogen-bonding environment is reported. The theoretical vibrational spectra of 26 model systems in which water has been hydrogen bonded to adenine is compared with the experimental frequencies of the solid state infrared spectra of polycrystalline adenine and the experimental frequencies observed in matrix isolation spectra of adenine. Density functional theory calculations of the vibrational spectra and potential energy surfaces of guanine and cytosine and adenine and thymine base pairs are reported and compared to the experimental FT-IR spectra of double-stranded dodecamer DNA (dsDNA) of adenine-thymine d(AT) composition and its isotopic 15N(10)-d(AT) dodecamer. The experimental isotopic shift was modeled using the adenine-thymine nucleotide DFT calculation. The isotopic shift pattern was found to be similar but the magnitude of the shift is too small.

Cadmium-113 NMR spectroscopy has been utilized as a metallobioprobe for studying metalloproteins such as concanavalin-A, calmodulin and TroponinC since 1976. NMR experiments on cadmium nuclei not only provide information on the number and type of coordinating groups but also help understand conformational changes and nature of protein interactions with inhibitors and substrates. Unlike 13C, 15N and 1H nuclei, 113Cd chemical shift spans about 900 ppm making it a valuable tool to differentiate various coordination numbers. Simple isotropic chemical shifts obtained from NMR of solution and solid samples can be used for the above purpose. At the same time, there were many instances when isotropic 113Cd chemical shift value was insufficient to understand the geometry around the central cadmium atom. To overcome this difficulty, chemical shift anisotropy tensor parameters of 113Cd are determined using slow spinning and static solid-state NMR experiments. These experimentally determined values can be even more informative with the help of calculated 113Cd chemical shielding values using ab initio methods. In this thesis, a protocol using density functional theory available in Gaussian-98 for determining chemical shielding values in cadmium and zinc complexes is presented. Additionally, both theoretical and experimental NMR studies on biologically important molecules have been performed to understand the importance of 113Cd chemical shifts in elucidating the structure. Our studies showed that increasing the size of the basis set will surely improve the performance of the ab initio calculations in estimating cadmium chemical shifts. Moreover, there is a better agreement between experimental and theoretical values when sadlej basis sets and hybrid functionals are used on molecules having limited intermolecular interactions such as hydrogen bonding or coordinate bonding. This thesis will also show the ability of solid-state NMR experiments in differentiating minor differences in the structure of cadmium molecules (such as anhydrous and hydrous cadmium formates).

A study of the freezing properties of simple liquids composed of hard and soft spheres is performed using classical density functional theory (DFT). The systems studied are composed of single component and binary mixtures. The behavior of binary mixtures as a function of the size ratio is analyzed. DFT equations are solved using an enhanced numerical method, which is based on a real-space mesh that does not constrain the shape of the density. Fast Fourier transforms are used to produce solutions efficiently. The reliability of the method is studied as a function of the mesh size in order to find an optimal implementation. A comparison with the exact known molecular dynamics result for single component systems shows excellent agreement. The solutions for binary mixtures of hard spheres reveal a qualitatively different behavior from previous results obtained using plane waves and gaussian parametrization. An fcc structure is found for almost identical particles, size ratio ~ 1:1. As the size ratio is reduced, a "sublattice-melt" phase is found with the small particles having a nonlocalized density and a multiple peak structure. Finally, the system reaches a NaCl structure at a size ratio of (0.45:1), with well-localized peaks in the density for small and large particles. For the same range of size ratios, the study of soft spheres mixtures reveals a similar behavior with the existence of non-stable solutions for size ratios of (0.80:1). Calculations on ternary systems were performed and the existence of the critical polydispersivity was found, which suggest similarities to real polydisperse systems.