published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

Supercritical carbon-dioxide has long been considered an inexpensive, safe and environmentally benign alternative to organic solvents for use in industrial processing. However, at readily accessible conditions of temperature and pressure, it is by itself too poor a solvent for a large number of industrially important solutes and its use as solvent necessitates concomitant use of surfactants. Especially desirable are surfactants that stabilize dispersions of water droplets in carbon-dioxide. So far only molecules containing substantially fluorinated moieties e.g. fluoroalkanes and perfluorinated polyethers, as the CO₂-philes have proved effective in stabilizing dispersions in supercritical carbon-dioxide. These fluorocarbons are expensive, non-biodegradable and can degrade to form toxic and persistent environmental pollutants. Hence there is great interest in developing non-fluorous alternatives. Given the development of powerful computers, excellent molecular models and standardized molecular simulation packages we are in a position to augment the experiment-driven search for effective surfactants using the nanoscopic insights gleaned from analysis of the results of molecular simulations. We have developed protocols by which to use standard and freely available molecular simulation infrastructure to evaluate the effectiveness of surfactants that stabilize solid metal nanoparticles in supercritical fluids. From the results, which we validated against experimental observations, we were able to determine that the alkane-based surfactants, that are so effective in organic fluids, are ineffective or only partially effective in CO₂ because the weak C-H dipoles cannot make up for the energetic penalty incurred at the surfactant-fluid interface by CO₂ molecules due to loss of quadrupolar interactions with other CO₂ molecules. Though the effectiveness of purely alkane-based surfactants in carbon-dioxide can be improved by branching, they cannot approach the effectiveness of the fluoroalkanes. This is because the stronger C-F dipole can supply the required quadrupolar interactions and a unique geometry renders repulsive the fluorocarbons' electrostatic interactions with each other. We have also determined the source of the fluoroalkanes' hydrophobicity to be their size which offsets the effect of favourable electrostatic interactions with water. Hence we can provide guidelines for CO₂-philic yet hydrophobic surfactants. / text

The use of compressed CO2 processing to alter the pore size, structure and timescale of silica condensation in surfactant templated silica thin films and powders is investigated by systematically varying the template structure and CO2 processing conditions. Tailoring the mesoporous materials increases its potential applications, as demonstrated in catalysis, drug delivery, chromatographic and electrode applications. This work demonstrates for the first time the applicability of fluorinated surfactants as templates for the synthesis of mesoporous silica thin films by dip coating. Well-ordered films with 2D hexagonal close-packed pore structure are synthesized in an acid-catalyzed medium using three cationic fluorinated templates of varied tail length and branching (C6F13C2H4NC5H5Cl, C8F17C2H4NC5H5Cl and (CF3)2CFC5F9C2H4NC5H5Cl). CO2 processing of the fluorinated templated silica results in a significant and controlled increase in pore diameter relative to the unprocessed films. The pore expansion is significantly greater compared to the negligible expansion observed in hydrocarbon (C16H23NC5H5Br) templated silica. The greater swelling of the fluorinated templates is attributed to the favorable penetration of CO2 in the CO2-philic fluorinated tail and the relative solvation of each template is interpreted from their interfacial behavior at the CO2-water interface. The CO2 based pore expansion observed in fluorinated surfactant templated films is extended successfully to base-catalyzed silica powders templated with a fluorinated surfactant (C6F13C2H4NC5H5Cl). Pore expansion in silica powders is significantly less than in acid catalyzed films and demonstrates the effects of pH on surfactant selfassembly in CO2 and increased silica condensation at basic conditions, which inhibits pore expansion. Finally, the use of fluorescence probe molecules is demonstrated for in-situ monitoring of the of CO2 processing of surfactant templated silica films to provide time dependent data on the local environment and dynamics of CO2 penetration. CO2 uptake occurs in surfactant tails even for hydrocarbon templates (C16H23N(CH3)3Br and C16H23NC5H5Br), which display negligible CO2 based swelling of the resulting pores. The timescale of silica condensation increases significantly in the presence of CO2 suggesting opportunities for structure alteration through application of external forces, such as magnetic fields and change in substrate chemistry and system humidity

This thesis investigates the underlying causes of friction and ine ciency within an internal combustion engine, focusing on the ring-liner conjunction in the vicinity of the power-stroke top dead centre reversal. In such lubricated contacts, friction is the result of the interplay between numerous kinetics, with those at micro- and nano-scale interactions being signi cantly di erent than the ones at larger scales. A modi ed Elrod's cavitation algorithm is developed to determine the microscopic tribological characteristics of the piston ring-liner contact. Predicting lubricant tran- sient behaviour is critical when the inlet reversal leads to thin lms and inherent metal-to-metal interaction. The model clearly shows that cavitation at the trailing edge of the ring-liner contact generated pre-reversal, persists after reversal and pro- motes starvation and depletion of the oil lm. Hence, this will lead to boundary friction. A fractal based boundary friction model is developed for lightly loaded asperity con- tacts, separated by diminishing small lms, usually wetted by a layer of molecules adsorbed to the tips of the asperities. In nano-scale conjunctions, a lubricant layering e ect often takes place due to the smoothness of surfaces, which is governed by the surface and lubricant properties. A molecularly thin layer of lubricant molecules can adhere to the asperities, being the last barrier against direct surface contact. As a result, boundary friction (prevailing in such diminishing gaps) is actually determined by a combination of shearing of a thin adsorbed lm, adhesion of approaching as- perities and their plastic deformation. A model for physio-chemical hydrodynamic mechanism is successfully established, describing the formation of thin adsorbed lms between asperities. This model is e ectively integrated with separately devel- oped models that predict the adhesive and plastic contact of asperities.

Atomic clusters are attractive candidates for building motifs for new nano-assembled materials with desirable properties. At this nano-regime of matter, the size, shape, and composition of clusters changes their electronic structure and hence their properties. Computational modeling must work hand in hand with experiment to provide robust descriptions of the geometries and energetics of atomic clusters and how they might behave in a nano-assembled material. To this end, we have investigated three distinct species as model systems: antimony oxides SbxOy (x = 1, 2; y = 0 - 3), metal ion-solvent complexes Mm(NH3)n (M = Bi, Pb; m = 1 - 2, n = 0 - 4), and quantum dots Z10H16 (Z = Si, Ge) and β-Sn12H24. Their geometries and electronic structures have been determined using gradient-corrected density functional theory. The relative stabilities for antimony oxides have been examined by the respective comparison of highest-occupied and lowest-unoccupied molecular orbital (HOMO-LUMO) gaps and atomization energies. The superior electronic stability of Sb2O3 is indicated by its closed shell structure, wide HOMO-LUMO gap calculated to be 3.11 eV, and high atomization energy of 4.21 eV. Spin-orbit corrections were necessary for accurate calculation of the metal-solvent energetics, closing the gap between experimental and theoretical values by 1.05 eV for the electron affinity of the Pb atom. Quantum dot modeling of the well-established Si and Ge as well as the less-investigated Sn illuminated the accuracy of the CEP basis sets and the B3LYP functional over other DFT computational routes for clusters containing elements beyond the third row. Throughout, the results correlate well with experiment and higher order ab initio methods where data is available. These comparisons validate the accuracy of the computational routes used. This document was prepared in the Linux Ubuntu Open Office Suite 2.4.1.

The role of the solvent in ionic and ion-molecule interactions is of fundamental importance in kinetics and thermodynamics of solution chemistry. However, the study of the ionic interactions in the presence of a large number of solvent molecules is very challenging. Therefore, the gas-phase is the appropriate medium to study such reactions on a molecular level where the ion-solvent interaction can be examined by studying ions surrounded with a cluster of solvent molecules in the complete absence of the any interference caused by the bulk of the solvent. In nature, organic ions can form hydrogen bonds with solvents. An insight into basic molecular interactions is required to be extracted from the gas phase energies and structures of the solvated organic ions. Therefore, the stepwise hydration experiments of benzene.+, C3H3+, acetylene.+, pyridine.+, 2-fluoropyridine.+, phenyl acetylene.+ and acetylene dimer.+ have been investigated using quadrupole mass-selected ion mobility mass spectrometer. Thus, these systems can be considered as prototypical models for understanding the molecular aspects leading to hydrophobic hydration in the condensed phase. Two routes of the investigation of ion-molecule interactions are considered in this dissertation. The first route is concerned with injecting the same ion into various solvents to study the nature and strength of the ion-solvent interactions when protonated pyrimidine cation interacts with water, methanol and acetonitrile molecules. Association and proton transfer reactions were observed. On the other hand, the second route involves the injection of various ions into the same solvent where the interactions of hydrogen cyanide (HCN) molecules with different ions. Benzene, phenyl acetylene, pyridine, protonated pyridine, and pyrimidine ions were investigated. All the investigated ions exhibited hydrogen bonding with the hydrogen cyanide molecules with variable strength depending on the charge distribution on the specified ion as well as the nature of interaction. Additionally, ion mobility structural methods were utilized to investigate structures of binary clusters formed by supersonic expansion of mixed vapors. The structures can be identified by comparing the experimentally measured collision cross section values with those predicted from DFT computations.

Water and methanol are common solvents used in liquid chromatographic (LC) separations. It is highly desirable to model .the interactions of these solvents in order to better understand the nature of analyte solvation and its effect on retention. Therefore, structure and frequencies of complexes of these solvent molecules have been studied from a theoretical perspective as a first step in this direction. Specifically, cluster structures have been optimized at the RHF and MP2 levels in various flexible basis sets and with the counterpoise correction for basis set superposition error, and trends in the structure and binding energies of several clusters are described. Good agreement wasobtained for the water dimer with the experimental value for the binding energy of D20 using MP2 energies from 6-3 11G**/6-3 l+G** basis sets in conjunction with counterpoise optimizations and full counterpoise corrections. In this investigation harmonic frequencies have been calculated and corrected for the effects of anharmonicity by several methods, two of which are original. The first new method fits a Morse potential function to the energy computed along each normal mode. A second new method is based on fitting a quartic polynomial to energies computed along each normal mode. In cases where the quartic potential function is not very different from the harmonic well, a second order perturbation formula provides a reasonable approximation to the anharmonic vibrational frequencies. When the quartic potential is very far from the harmonic potential, a variational treatment of the vibrations is required. We find that the Morse method delivers reasonable estimates of frequencies of anharmonic motions at lower cost than multi-point potential mapping/multiple geometry optimization/Taylor series methods, and is more successful at predicting intermolecular frequencies than the anharmonic VSCF methods found in GAMESS software. Variational calculations using the quartic polynomials produce estimates of frequencies comparable to the more costly VSCF method. Both the Morse method and polynomial method are very fast computationally relative to these and other methods found in the literature.

A modelagem das interações entre macromoléculas e ligantes ainda se depara com diversos desafios na área de desenho de fármacos assistidos por computador. Apesar do crescimento da área, temas como a flexibilidade do receptor, funções de pontuação e solvatação ainda têm sido alvo de intensa investigação na comunidade científica. Com o objetivo de analisar a interação em milhares ou milhões de complexos, é imprescindível uma boa harmonização entre o custo computacional e a acurácia dos métodos computacionais que permitem a classificação de ligantes de acordo com a energia de interação. O LiBELa (Ligand Binding Energy Landscape) é um programa de docagem molecular com abordagem híbrida, ou seja, utiliza informações do ligante e do receptor durante o processo de docagem. Inicialmente, as características estéricas e eletrostáticas de um ligante de referência (cristalográfico, por exemplo) são utilizadas nos cálculos de similaridade e sobreposição, obtendo assim uma conformação inicial pré-otimizada do ligante testado. Em seguida, a energia de interação é minimizada no sítio ativo de receptor a partir de potenciais energéticos. Quatro funções de pontuação baseadas em campo de força foram testadas e otimizadas, compostas por potenciais de van der Waals, de Coulomb, e uma função empírica de solvatação denominada função de Stouten-Verkhivker (SV). A flexibilidade do sistema foi tratada através da geração de confôrmeros que amostram os graus de liberdade dos ligantes descritos como semi-rígidos e através de potenciais atenuados que suavizam a superfície de energia de interação, permitindo interações em distâncias interatômicas antes repulsivas. Como ponto de partida, os métodos implementados no programa LiBELa demonstraram resultados satisfatórios nos testes de cross- e self-docking, mostrando ser uma ferramenta eficiente em encontrar os modos de ligação cristalográficos de forma equivalente ou até melhor às dos programas comparados. Através de testes de enriquecimento nos conjuntos de dados DUD, DUDE e CM-DUD, foram otimizadas de forma sistemática as constantes dielétrica, do termo de solvatação, e dos termos de atenuação. Também foi realizado um paralelo entre as funções de pontuação, incluindo a atenuação e o termo de solvatação. Estes mesmos testes mostraram resultados superiores do LiBELa de 39% e 15% em comparação com um programa baseado puramente no receptor (DOCK 6.6), relativo à média da área sob a curva em escala semi-logarítmica nas bases de dados DUDE e DUD respectivamente. Apesar da função de solvatação SV implementada no LiBELa apresentar boa correlação com dados experimentais (r=0,72) e com o modelo Zou GB de solvatação (r=0,88), não apresentou correlação significativa com os métodos GB e PB implementados no pacote de programas disponível no AmberTools. Comparadas às funções de pontuação do LiBELa, as funções com correção para solvatação apresentaram pior enriquecimento, salvo alguns alvos específicos. Por fim, foram realizados ensaios de docagem molecular utilizando como alvo uma enzima β-galactosidase da família GH42, cuja estrutura fora resolvida em nosso grupo. Os resultados permitiram conclusões acerca de como o modo de ligação interfere na preferência de ligação entre dissacarídeos de ligações glicosídicas distintas, consistentes com dados experimentais de ensaios cinéticos de ligação. / Modeling the interactions between macromolecules and ligands still faces several challenges in the computer-aided drug design area. Despite the growth in the area, subjects such as receptor flexibility, scoring functions and solvation still have been widely explored in the scientific community. In order to analyze the interaction for thousands or millions of complexes, a good harmonization between the computational cost and the accuracy of the calculation methods in molecular docking programs is essential. LiBELa (Ligand Binding Energy Landscape) is a hybrid approach program that uses both ligand and receptor information for ligand docking. Initially, the steric and electrostatic characteristics from a reference binder (crystallographic, for example) are used to similarity and overlay calculations, thus obtaining an initial conformation of the ligand tested. Then, within the receptor´s active site, the interaction energy is minimized using energetic potentials. Four force field-based scoring functions were tested and optimized, composed of van der Waals and Coulomb potentials and an empirical solvation function called Stouten-Verkhivker (SV). Concerning the system flexibility, besides the confomers generation that sample the degrees of freedom for semi-rigid ligands, attenuated potentials smooth the energy surface allowing interactions between previously repulsive interatomic distances. As a starting point, LiBELa performed satisfactorily in the cross- and self-docking tests, showing that is an eficient tool to reproduce crystallographic binding modes equivalently to or even better than reference programs. Through enrichment of DUD, DUDE and CM-DUD datasets, the dielectric constant, solvation and softening terms were systematically optimized. It also allowed a parallel between scoring functions, including attenuation and solvation term. Finally, it revealed the LiBELa showed an enhancement of 39% and 15% as compared to the purely receptor-based program DOCK 6.6, relative to the mean of the area under the curve on a semi-logarithmic scale in the DUDE and DUD databases respectively. Although the SV solvation function implemented in LiBELa showed good correlations with experimental data (r = 0.72) and with the Zou GB / SA solvation method implemented in DOCK6 (r = 0.88), it did not show significant correlation with the GB/SA and PB/SA methods implemented in AmberTools. Comparing all the LiBELa tested scoring functions, those including solvation correction showed worse enrichments, except for some specific targets. Finally, molecular docking experiments using LiBELa were conducted with a β-galactosidase from GH42 family, whose structure was solved in our group. The results allowed conclusions concerning how the binding mode interferes the preference for some disaccharides of distinct glycosidic bonds, consistent with experimental data from kinetic assays.

A presente tese tem por objetivo inicial estudar a reatividade de ésteres de Si, N, S e seus análogos em fase gasosa para obter informações detalhadas do mecanismo destas espécies quando submetidas a ataque nucleofílico, sobretudo no que tange a competição entre as vias de substituição nesses centros e no carbono. Esses estudos são realizados experimentalmente através da técnica de espectrometria de massas por transformada de Fourier e ressonância ciclotrônica de íons (FT-ICR) e amparados por cálculos de estrutura eletrônica. Os resultados obtidos indicam que, para o Si, as alcoxissilanas reagem com os nucleófilos através de um aduto pentacoordenado que desloca, preferencialmente, um alcóxido. De forma minoritária, pode ocorrer o deslocamento de outro ligante gerando silóxidos ou carbânions. Neste estudo, foi caracterizada uma reação inédita de troca de Me por F nos silóxidos mediada por NF3. Os estudos dos ésteres de nitrogênio indicam que as reações de eliminação são mais favoráveis que as de substituição e que a substituição no nitrogênio, apesar de ser considerada mais favorável pelos cálculos, não é observada. Esse comportamento foi elucidado através do uso de dinâmica molecular e indica que o complexo de entrada para a via de reação no nitrogênio não é formado devido à repulsão sofrida pelo nucleófilo pelos oxigênios que rodeiam o centro de N. Resultados teóricos semelhantes foram encontrados para os ésteres de enxofre e, em adição aos resultados experimentais disponíveis, indicam que não só a dinâmica de reação exerce um papel importante nesses sistemas, como também sugerem uma compensação entre o caráter dinâmico e a termoquímica destes sistemas. Para nucleófilos fracos que não são favoráveis do ponto de vista termoquímico, a formação do complexo de entrada não é impedida pela repulsão, dado que esses nucleófilos não costumam ter centros nucleofílicos com carga muito localizada. O oposto ocorre com nucleófilos fortes, que procederiam pelo caminho de substituição no S por uma via praticamente sem barreira, mas não o fazem já que a repulsão do nucleófilo é muito intensa. Em uma segunda etapa a solvatação dos íons F-, Br- e I- foram estudadas na fase gasosa a partir da espectroscopia dissociação no infravermelho. A partir da formação por uma fonte de eletrospray de agregados altamente solvatados, foi possível determinar o efeito dos íons na organização das moléculas de solvente, determinar a mudança da solvatação interna para solvatação de superfície e determinar o número de hidratação em fase gasosa para os íons Br- e F-. Além disso, tanto os resultados experimentais quanto teóricos mostram que a natureza do íon influencia a primeira camada de solvatação e que a carga formal tem um efeito predominante em longo alcance, podendo organizar até centenas de moléculas de solventes. Por fim, realizamos a adaptação do sistema de aquisição do FT-ICR do laboratório. Isso não só confere um sistema atualizado ao nosso instrumento, como possibilita que novos experimentos, como a espectroscopia de íons, possam ser realizados no nosso grupo de pesquisa. / This thesis comprises the study of the reactivity of gas-phase ions in the gas-phase and the structural modifications observed for gas-phase ions as a function of progressive solvation by spectroscopic techniques. In the first part, we describe the gas-phase reactivity of Si, N, and S esters and their analogs towards simple nucleophiles and a detailed analysis of the competition between different reaction channels namely substitution vs. elimination. These studies were carried out by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR) and supported by theoretical calculations. Our results suggest that alkoxysilanes react with nucleophiles via a pentacoordinated adduct that results in alkoxide displacement as the major reaction channel. The displacement of other ligands can also occur to yield siloxides or carbanions. As part of these studies, we also report a Me/F exchange reaction in siloxide ions mediated by NF3. Results obtained for the nitrogen esters show elimination-type reactions to be the most favorable pathway followed by nucleophilic displacement. No displacement was observed at the nitrogen center in spite of the fact that calculations predict this channel to be the most favorable pathway. This behavior was further explored by ab initio molecular dynamics calculations that show that the entrance complex for the nitrogen pathway is avoided because of the strong electrostatic repulsion exerted by the oxygen atoms as the nucleophile approaches the N center. Similar theoretical results were obtained for the sulfur esters. Comparison of these calculations with the experimental results also suggests that the reaction dynamics play an important role in these systems. Furthermore, we propose that a combination of thermochemical and dynamic balance hinders substitution at the heteroatom. For strong nucleophiles that could undergo substitution at the S center via a barrierless pathway, the reaction is hindered by the strong repulsion experienced by these nucleophiles. In the second part, we study the structure of gas-phase solvated F-, Br- and I- by infrared dissociation spectroscopy. The highly solvated clusters were generated by electrospray ionization and their structures probed to gather information regarding the short and long-range effect of these ions on the solvation network. Solvation parameters such as the number of water molecules needed for a switch from internal to surface solvation and the hydration numbers for F- and Br- were determined. Theoretical and experimental results show that the solvation pattern of the first solvation shell for these ions depends on the nature of the ion while the ion charge prevails in determining the long-range pattern. This pattern effect is shown to prevail up to hundreds of solvent molecules. Finally, a new data acquisition and control system is described for our FT-ICR spectrometer. This system not only updates the original instrument but it also brings in new capabilities to the spectrometer such as the ability to carry out gas-phase ion dissociation spectroscopy.

"The accurate, fast and low cost computational tools are indispensable for studying the structure and dynamics of biological macromolecules in aqueous solution. The goal of this thesis is development and validation of continuum Fuzzy-Border (FB) solvation model to work with the Polarizable Simulations Second-order Interaction Model (POSSIM) force field for proteins developed by Professor G A Kaminski. The implicit FB model has advantages over the popularly used Poisson Boltzmann (PB) solvation model. The FB continuum model attenuates the noise and convergence issues commonly present in numerical treatments of the PB model by employing fixed position cubic grid to compute interactions. It also uses either second or first-order approximation for the solvent polarization which is similar to the second-order explicit polarization applied in POSSIM force field. The FB model was first developed and parameterized with nonpolarizable OPLS-AA force field for small molecules which are not only important in themselves but also building blocks of proteins and peptide side chains. The hydration parameters are fitted to reproduce the experimental or quantum mechanical hydration energies of the molecules with the overall average unsigned error of ca. 0.076kcal/mol. It was further validated by computing the absolute pKa values of 11 substituted phenols with the average unsigned error of 0.41pH units in comparison with the quantum mechanical error of 0.38pH units for this set of molecules. There was a good transferability of hydration parameters and the results were produced only with fitting of the specific atoms to the hydration energy and pKa targets. This clearly demonstrates the numerical and physical basis of the model is good enough and with proper fitting can reproduce the acidity constants for other systems as well. After the successful development of FB model with the fixed charges OPLS-AA force field, it was expanded to permit simulations with Polarizable Simulations Second-order Interaction Model (POSSIM) force field. The hydration parameters of the small molecules representing analogues of protein side chains were fitted to their solvation energies at 298.15K with an average error of ca.0.136kcal/mol. Second, the resulting parameters were used to reproduce the pKa values of the reference systems and the carboxylic (Asp7, Glu10, Glu19, Asp27 and Glu43) and basic residues (Lys13, Lys29, Lys34, His52 and Lys55) of the turkey ovomucoid third domain (OMTKY3) protein. The overall average unsigned error in the pKa values of the acid residues was found to be 0.37pH units and the basic residues was 0.38 pH units compared to 0.58pH units and 0.72 pH units calculated previously using polarizable force field (PFF) and Poisson Boltzmann formalism (PBF) continuum solvation model. These results are produced with fitting of specific atoms of the reference systems and carboxylic and basic residues of the OMTKY3 protein. Since FB model has produced improved pKa shifts of carboxylic residues and basic protein residues in OMTKY3 protein compared to PBF/PFF, it suggests the methodology of first-order FB continuum solvation model works well in such calculations. In this study the importance of explicit treatment of the electrostatic polarization in calculating pKa of both acid and basic protein residues is also emphasized. Moreover, the presented results demonstrate not only the consistently good degree of accuracy of protein pKa calculations with the second-degree POSSIM approximation of the polarizable calculations and the first-order approximation used in the Fuzzy-Border model for the continuum solvation energy, but also a high degree of transferability of both the POSSIM and continuum solvent Fuzzy Border parameters. Therefore, the FB model of solvation combined with the POSSIM force field can be successfully applied to study the protein and protein-ligand systems in water. "