<p>Automated reaction prediction has the potential to elucidate complex reaction networks for many applications in chemical engineering, including materials degradation, drug design, combustion chemistry and biomass conversion. Unlike traditional reaction mechanism elucidation methods that rely on manual setup of quantum chemistry calculations, automated reaction prediction avoids tedious trial-and-error learning processes and greatly reduces the risk of leaving out important reactions. Despite these promising advantages, the potential of automated reaction prediction as a general-purpose tool is still largely unrealized, due to high computational cost and inconsistent reaction coverage. Therefore, this dissertation develops methods to simultaneously reduce the computational cost and increase the reaction coverage. Specifically, the computational cost is reduced by the development of more efficient transition state (TS) localization workflows and fast molecular and reaction property prediction packages, while the reaction coverage is increased by a comprehensive reaction space exploration based on mathematically defined elementary reaction steps. These components are implemented in two open-source packages, one is TAFFI (Topology Automated Force-Field Interactions) component increment theory (TCIT) and the other is Yet Another Reaction Program (YARP).</p> <p><br></p> <p>The first package, TCIT, is the first component increment theory based molecular property prediction package. TCIT is based on the locality assumption, which decomposes molecular thermochemistry properties into the summation of the contributions of each subgraph. In contrast to the traditional "group" increment theory, TCIT treats each subgraph as the central atom plus its nearest and next-nearest neighboring atoms, and consistently parameterizes the contribution of each component according to purely quantum chemistry calculations. Although all parameterizations are based on quantum chemical calculations, when benchmarked against experimental data, TCIT provides more accurate predictions compared to traditional methods using the same experimental dataset for parameterization. With TCIT, the molecular properties (e.g., enthalpy of formation) and reaction properties (e.g., enthalpy of reaction) can be accurately predicted in an on-the-fly manner. The second package, YARP, is developed for automated reaction space exploration and deep reaction network prediction. By optimizing the reaction enumeration, geometry initialization, and transition state convergence algorithms that are common to many prediction methodologies, YARP (re)discovers both established and unreported reaction pathways and products while simultaneously reducing the cost of reaction characterization nearly 100-fold and increasing convergence of transition states, comparing with recent benchmarks. In addition, an updated version of YARP, YARP v2.0, further reduces the cost of reaction characterization from 100-fold to 300-fold, while increasing the reaction coverage beyond the scope of elementary reaction steps. This combination of ultra-low cost and high reaction-coverage creates opportunities to explore the reactivity of larger systems and more complex reaction networks for applications like chemical degradation, where computational cost is a bottleneck.</p> <p><br></p> <p>The power of TCIT and YARP has been demonstrated by a broad range of applications. In the first application, YARP was used to explore the reactivity of unimolecular and bimolecular reactants, comprising a total of 581 reactions involving 51 distinct reactants. The algorithm discovered all established reaction pathways, where such comparisons are possible, while also revealing a much richer reactivity landscape, including lower barrier reaction pathways and a strong dependence of reaction conformation in the apparent barriers of the reported reactions. Secondly, YARP was applied to the search for prebiotic chemical pathways, which is a long-standing puzzle that has generated a menagerie of competing hypotheses with limited experimental prospects for falsification. With YARP, the space of organic molecules that can be formed within four polar or pericyclic reactions from water and hydrogen cyanide (HCN) was comprehensively explored. A surprisingly diverse reactivity landscape was revealed within just a few steps of these simple molecules and reaction pathways to several biologically relevant molecules were discovered involving lower activation energies and fewer reaction steps compared with recently proposed alternatives. In the third application, predicting the reaction network of glucose pyrolysis, YARP generated by far the largest and most complex reaction network in the domain of biomass pyrolysis and discovered many unexpected reaction mechanisms. Further, motivated by the fact that existing reaction transition state (TS) databases are comparatively small and lack chemical diversity, YARP, together with the concept of a graphically defined model reaction, were utilized to address the data gap by comprehensively characterizing a reaction space associated with C, H, O, and N containing molecules with up to 10 heavy (non-hydrogen) atoms. The resulting dataset, namely Reaction Graph Depth 1 (RGD1) dataset, is composed of 176,992 organic reactions possessing at least one validated TS, activation energy, enthalpy of reaction, reactant and product geometries, frequencies, and atom-mapping. The RGD1 dataset represents the largest and most chemically diverse TS dataset published to date and should find immediate use in developing novel machine learning models for predicting reaction properties. In addition to exploring the molecular reaction space, YARP was also extended to explore and characterize reaction networks in heterogeneous catalysis systems. With ethylene oligomerization on silica-supported single site Ga catalysts as a model system, YARP illustrates how a comprehensive reaction network can be generated by using only graph-based rules for exploring the network and elementary constraints based on activation energy and system size for identifying network terminations. The automated reaction exploration (re)discovered the Ga-alkyl-centered Cossee-Arlman mechanism that is hypothesized to drive major product formation while also predicting several new pathways for producing alkanes and coke precursors. The diverse scope of these applications and milestone quality of many of the reaction networks produced by YARP  illustrate that automated reaction prediction is approaching a general-purpose capability.</p>

Geometry optimization is a key step in the computational modeling of chemical reactions because one cannot model a chemical reaction without first accurately determining the molecular structure, and electronic energy, of the reactants and products, along with the transition state that connects them. These structures are stationary points— the reactant and product structures are local minima, and the transition state is a saddle point with one negative-curvature direction—on the molecular potential energy surface. Over the years, many methods for locating these stationary points have been developed. In general, the problem of finding reactant and product structures is relatively straightforward, and reliable methods exist. Converging to transition states is much more challenging. Because of the difficulty of transition-state optimization, researchers have designed optimization methods specifically for this problem. These methods try to make good choices for the initial geometry, the system of coordinates used to represent the molecule, the initial Hessian, the Hessian updating method, and the step-size. The transition-state optimization method developed in this thesis required considering all of these methods. Specifically, a new method for finding an initial guess geometry was developed in chapter 2; good choices for a coordinate system for representing the molecule were explored in chapters 2 and 6; different choices for the initial Hessian are considered in chapter 5; chapters 3 and 4 present, and test, a sophisticated new method for updating the Hessian and controlling the step-size during the optimization. iv The methods created in the process of this research led to the development of Saddle, a general-purpose geometry optimizer for transition states and stable structures, with and without constraints on the molecular coordinates. Saddle can be run in conjunction with the Gaussian program or almost any other quantum chemistry program, and it converges significantly more often than the other traditional methods we tested. / Thesis / Doctor of Science (PhD)

An important role of Pin1 is to catalyze the cis-trans isomerization of pSer/Thr-Pro bonds; as such, it plays an important role in many cellular events through the effects of conformational change on the function of its biological substrates, including Cdc25, c-Jun, and p53. The expression of Pin1 correlates with cyclin D1 levels, which contributes to cancer cell transformation. Overexpression of Pin1 promotes tumor growth, while its inhibition causes tumor cell apoptosis. Because Pin1 is overexpressed in many human cancer tissues, including breast, prostate, and lung cancer tissues, it plays an important role in oncogenesis, making its study vital for the development of anti-cancer agents. Many inhibitors have been discovered for Pin1, including 1) several classes of designed inhibitors such as alkene isosteres, non-peptidic, small molecular Pin1 inhibitors, and indanyl ketones, and 2) several natural products such as juglone, pepticinnamin E analogues, PiB and its derivatives obtained from a library screen. These Pin1 inhibitors show promise in the development of novel diagnostic and therapeutic anticancer drugs due to their ability to block cell cycle progression. In order to develop potent Pin1 inhibitors, the concept of transition-state analogues was used for the design of three classes of compounds: ketoamide, ketone, and reduced amide analogues. Specifically, a convergent synthesis of α-ketoamide inhibitors of Pin1 was developed. An α-hydroxyorthothioester derivative of Ser was reacted directly with an aminyl synthon. The reaction was catalyzed by HgO and HgCl2 to form an α-hydroxyamide. Hydrolysis and coupling were combined in one step in 80% yield. Two diastereomers of a phospho-Ser-Pro α-ketoamide analogue were synthesized. The resulting IC50 values of 100 µM and 200 µM were surprisingly weak for the Pin1 peptidyl-prolyl isomerase. Diastereomeric ketones were synthesized by coupling cyclohexenyl lithium to the serine Weinreb amide, via the Michael addition of a carboxylate synthon. The IC50 values of the two ketone diastereomers were determined to be 260 μM and 61 μM, respectively. Five reduced amide inhibitors for Pin1 were synthesized through a selective reduction using borane. The most potent inhibitor was found to be Fmocâ pSerâ Ψ[CH2N]-Proâ tryptamine, which had an IC50 value of 6.3 µM. This represents a 4.5-fold better inhibition for Pin1 than a comparable cis-amide alkene isostere. The co-crystal structure of Acâ pSerâ Ψ[CH2N]-Proâ tryptamine bound to Pin1 was determined to 1.76 Ã resolution. Towards understanding the two proposed mechanisms of Pin1 catalysis, nucleophilic-additition mechanism and twisted-amide mechanism, three classes of Pin1 inhibitors (ketoamide, ketone, and reduced amide analogues) involving a total of nine compounds were synthesized and evaluated. The weak inhibitory activities of ketoamide and ketone analogues do not support the nucleophilic-addition mechanism, while the twisted-amide mechanism of Pin1 catalysis is promising based on the reduced amide inhibitors with good potencies. / Ph. D.

Oxidative processes are linked to a number of major disease states as well as the breakdown of many materials. Of particular importance are reactive oxygen species (ROS), as they are known to be endogenously produced in biological systems as well as exogenously produced through a variety of different means. In hopes of better understanding what controls the behavior of ROS, researchers have studied radical chemistry on a fundamental level. Fundamental knowledge of what contributes to oxidative processes can be extrapolated to more complex biological or macromolecular systems. Fundamental concepts and applied data (i.e. interaction of ROS with polymers, biomolecules, etc.) are critical to understanding the reactivity of ROS. A detailed review of the literature, focusing primarily on the hydroxyl radical (HO•) and hydrogen atom (H•) abstraction reactions, is presented in Chapter 1. Also reviewed herein is the literature concerning high density polyethylene (HDPE) degradation. Exposure to treated water systems is known to greatly reduce the lifetime of HDPE pipe. While there is no consensus on what leads to HDPE breakdown, evidence suggests oxidative processes are at play. The research which follows in Chapter 2 focuses on the reactivity of the hydroxyl radical and how it is controlled by its environment. The HO• has been thought to react instantaneously, approaching the diffusion controlled rate and showing little to no selectivity. Both experimental and calculational evidence suggest that some of the previous assumptions regarding hydroxyl radical reactivity are wrong and that it is decidedly less reactive in an aprotic polar solvent than in aqueous solution. These findings are explained on the basis of a polarized transition state that can be stabilized via the hydrogen bonding afforded by water. Experimental and calculational evidence also suggest that the degree of polarization in the transition state will determine the magnitude of this solvent effect. Chapter 3 discusses the results of HDPE degradation studies. While HDPE is an extremely stable polymer, exposure to chlorinated aqueous conditions severely reduces the lifetime of HDPE pipes. While much research exists detailing the mechanical breakdown and failure of these pipes under said conditions, a gap still exists in defining the species responsible or mechanism for this degradation. Experimental evidence put forth in this dissertation suggests that this is due to an auto-oxidative process initiated by free radicals in the chlorinated aqueous solution and propagated through singlet oxygen from the environment. A mechanism for HDPE degradation is proposed and discussed. Additionally two small molecules, 2,3-dichloro-2-methylbutane and 3-chloro-1,1-di-methylpropanol, have been suggested as HDPE byproducts. While the mechanism of formation for these products is still elusive, evidence concerning their identification and production in HDPE and PE oligomers is discussed. Finally, Chapter 4 deals with concluding remarks of the aforementioned work. Future work needed to enhance and further the results published herein is also addressed. / Ph. D.

Many chemical reactions can be described as the crossing of an energetic barrier. This process is mediated by an invariant object in phase space. One can construct a normally hyperbolic invariant manifold (NHIM) of the reactive dynamical system which is an invariant sphere that can be considered as the geometric representation of the transition state itself. The NHIM has invariant cylinders (reaction channels) attached to it. This invariant geometric structure survives as long as the invariant sphere is normally hyperbolic. We applied this theory to the hydrogen exchange reaction in three degrees of freedom in order to figure out the reason of the transition state theory (TST) failure. Energies high above the reaction threshold, the dynamics within the transition state becomes partially chaotic. We have found that the invariant sphere first ceases to be normally hyperbolic at fairly low energies. Surprisingly normal hyperbolicity is then restored and the invariant sphere remains normally hyperbolic even at very high energies. This observation shows two different energy values for the breakdown of the TST and the breakdown of the NHIM. This leads to seek another phase space object that is related to the breakdown of the TST. Using theory of the dividing surface including reactive islands (RIs), we can investigate such an object. We found out that the first nonreactive trajectory has been found at the same energy values for both collinear and full systems, and coincides with the first bifurcation of periodic orbit dividing surface (PODS) at the collinear configuration. The bifurcation creates the unstable periodic orbit (UPO). Indeed, the new PODS (UPO) is the reason for the TST failure. The manifolds (stable and centre-stable) of the UPO clarify these expectations by intersecting the dividing surface at the boundary of the reactive island (on the collinear and the three (full) systems, respectively).

La simulation moléculaire est un outil indispensable pour comprendre le comportement de systèmes complexes pour lesquels les expériences s'avèrent coûteuses ou irréalisables à l'heure actuelle. Cette thèse est dédiée aux aspects méthodologiques de la simulation moléculaire et comprend deux volets. Le premier volet porte sur la recherche de chemins de réaction et de points col d'une surface d'énergie potentielle. Nous proposons, dans le chaptire 3, une amélioration d'une des méthodes de cette classe, appelée '"Activation Relaxation Technique"(ART). Nous donnons également une preuve de convergence pour un algorithme prototype. Le deuxieme volet porte sur le calcul d'énergie libre pour les transitions caractérisées par une coordonnée de réaction. Nous nous plaçons dans le cadre d'une méthode d'échantillonnage d'importance adaptative, appelée 'Adaptive Biasing Force' (ABF). Ce volet comprend en soi deux sous-parties. La première partie (chapitre 5) s'attache à montrer l'applicabilité à un système biomoléculaire, d'une nouvelle mise en oeuvre parallèle d'ABF, nommée 'multiple-walker ABF' (MW-ABF), consistant à utiliser plusieurs répliques. Cette mise en oeuvre s'est avérée utile pour surmonter des problèmes liés à un mauvais choix de coordonnée de réaction. Nous confirmons ensuite ces résultats numériques en étudiant la convergence théorique d'un algorithme d'ABF adapté. Le chapitre 6 comprend une étude de convergence en temps long utilisant les méthodes d'entropie relative et les inégalités de Sobolev logarithmiques / Molecular simulation is an essential tool in understanding complex chemical and biochemical processes as real-life experiments prove increasingly costly or infeasible in practice . This thesis is devoted to methodological aspects of molecular simulation, with a particular focus on computing transition paths and their associated free energy profiles. The first part is dedicated to computational methods for reaction path and transition state searches on a potential energy surface. In Chapter 3 we propose an improvement to a widely-used transition state search method, the Activation Relaxation Technique (ART). We also present a local convergence study of a prototypical algorithm. The second part is dedicated to free energy computations. We focus in particular on an adaptive importance sampling technique, the Adaptive Biasing Force (ABF) method. The first contribution to this field, presented in Chapter 5, consists in showing the applicability to a large molecular system of a new parallel implementation, named multiple-walker ABF (MW-ABF). Numerical experiments demonstrated the robustness of MW-ABF against artefacts arising due to poorly chosen or oversimplified reaction coordinates. These numerical findings inspired a new study of the longtime convergence of the ABF method, as presented in Chapter 6. By studying a slightly modified model, we back our numerical results by showing a faster theoretical rate of convergence of ABF than was previously shown

Les travaux présentés dans ce mémoire se concentrent sur la compréhension, la description et enfin la modélisation de la décomposition des matériaux d’aménagement ou d’ameublement d’usage courant (principalement des polymères naturels et de synthèse) sous l’effet de la chaleur. Ce champ de la recherche n’est pas nouveau, et de nombreux modèles existent à ce jour (le plus souvent des modèles d’Arrhénius associés à diverses fonctions cinétiques). Toutefois, contrairement aux développements liés à la description de la cinétique chimique en phase gazeuse, la plupart des modèles exploités à ce jour pour la phase solide souffrent généralement d’une justification théorique insuffisante. De plus, des essais, en particulier à petite échelle, laissent apparaître des comportements qui, au-delà de ne pas être prédits par les modèles existant, viennent de surcroît invalider certaines de leurs hypothèses sous-jacentes. Le contexte des travaux est plus précisément celui de la décomposition anaérobie des solides, à petite échelle, pour des masses de l’ordre du milligramme, pour se concentrer à la fois sur la cinétique de perte de masse et, dans une moindre mesure, sur les transferts thermiques dans la phase condensée. Le travail est articulé autour de trois volets principaux qui forment chacun un chapitre du présent ouvrage. Le premier concerne la réalisation de nombreux essais à l’analyseur thermogravimétrique (ATG), sur la base de plans d’expérience. Le but est d’une part de déterminer les variables d’influence de la décomposition thermique et, d’autre part, d’identifier les écarts de comportement par rapport aux prédictions de certains modèles existant dans la littérature. Le résultat majeur de cette campagne est l’absence de convergence en masse des essais, même pour des masses expérimentales très faibles. De même, les effets de la vitesse de chauffage et de la dilution en phase solide ont été explorés, mettant ainsi en avant des comportements très éloignés des prédictions théoriques. Le second concerne la modélisation de la décomposition thermique d’un matériau soumis un essai à l’analyseur thermogravimétrique et la mise en évidence des problématiques liées aux transferts thermiques au sein du matériau. Il a été démontré que les conditions aux limites de Dirichlet, usuellement utilisées pour décrire ce dispositif, ne sont pas adaptées pour reproduire les spécificités liées au dispositif expérimental. Le troisième volet a consisté à construire un modèle cinétique issu d’hypothèses liées à la phase solide. Ce modèle est basé dans un premier temps sur les travaux d’Eyring concernant la théorie du complexe activé. Par la suite, l’exploitation du formalisme thermodynamique lié au complexe activé a permis de proposer une formulation nouvelle, dite « hors approximation d’Ellingham », pour décrire la décomposition des matériaux sous l’effet de la température. Ce modèle a été comparé à deux modèles usuels, dits (A, E, 1) et (A,E,n), et conduit à de meilleures modélisations pour les mécanismes mono-réactionnels. Enfin, les perspectives de ce travail concernent, en premier lieu, une meilleure caractérisation des conditions aux limites thermiques au sein d’un analyseur thermogravimétrique, afin de reproduire numériquement les essais réalisés. En second lieu, il apparaît comme pertinent d’étendre le modèle développé à des mécanismes multi-réactionnels, afin d’augmenter ses capacités prédictives pour les applications visées / The work presented in this thesis focuses on understanding, describing and finally modelling the degradation, under heat exposure, of commonly used furnishing materials (mainly natural or synthetic polymers). This is not a new research field, as many models exist nowadays (such as Arrhenius models associated with varied kinetics functions). However, unlike for development related to gas phase chemical kinetics, most current solid phase chemical kinetics related models suffer from insufficient theoretical backgrounds. Moreover, laboratory experiments, more precisely small scale ones, reveal some behaviours, that are not only unpredicted by current model, but also invalidate some of the underlying assumptions these models are based on. This work context is more precisely related to solid anaerobic decomposition, at small scale, for mass in the range of one milligram, in order to focus on both mass loss kinetics and, to a lesser extent, on thermal transfer in solid phase. This work was structured into three main sections, each of them being a chapter of this thesis. First part concerns numerous experiments based on experimental plans and performed with a thermogravimetric analyzer (TGA). This aims at, on the one hand, determining most influent variables on thermal decomposition, and, on the other hand, identifying behaviour discrepancies between experimental data and predictions of current models available in the literature. Test campaign main result is that there is no mass convergence with TGA, even for very low masses. In addition, the effect of both heating rate and solid phase dilution were explored. This led to some behaviours significantly different from theoretical predictions. Second part concerns the modelling of material thermal degradation in a TGA analysis. It also highlights problems related to heat transfer inside solid material. It is demonstrated in this work that Dirichlet boundary conditions, which are usually used to describe TGA device, are not adequate to reproduce such experimental specificities. Third and last part is dedicated to the elaboration of a kinetic model relying on assumptions specific to the solid phase. First and foremost this model is on based on Eyring’s work on transition state theory. Then exploring thermodynamic formalism related to transition state allowed the formulation of a new model of thermal degradation called “outside Ellingham assumption”. This model is compared to two commonly used ones, so-called (A, E, 1) and (A, E, n) and led to best prediction for single reaction mechanisms. Finally, the prospects inspired by this work concern, first, a better characterisation of thermal boundary condition in TGA, in order to be able to reproduce experiments by modelling. Secondly, it may be relevant to extend the develop model to multiple reaction mechanisms, in order to increase its predictive capabilities for the targeted applications

Submitted by Sandra Pereira (srpereira@ufrrj.br) on 2017-04-24T14:13:26Z No. of bitstreams: 1 2012 - Ana Carolina Bello de Souza.pdf: 1911170 bytes, checksum: 62c70571aeb2100b8313dc1ef44eac2b (MD5) / Made available in DSpace on 2017-04-24T14:13:26Z (GMT). No. of bitstreams: 1 2012 - Ana Carolina Bello de Souza.pdf: 1911170 bytes, checksum: 62c70571aeb2100b8313dc1ef44eac2b (MD5) Previous issue date: 2012-10-03 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior - CAPES / In this work, the theoretical study of the gas-phase bimolecular nucleophilic substitution reaction, CH3Cl + OH- CH3OH + Cl-, is introduced, aiming the description of the potential energy surface, the calculation of rate constants and the investigation of the effect of increasing the side chain (changing the CH3 radical in the reaction cited above by the radicals ethyl, n-propyl, i-propyl, n-butyl, s-butyl e t-butyl). The theoretical calculations have been first performed at the MP2/6-31+G(d) level for the geometry optimizations and vibrational frequencies calculations. Single point calculations at the CCSD(T)/6-31+G(d) level have also been performed in order to improve the total energies for the stationary points. However, the relative energies of these stationary points at both MP2 and CCSD(T) level shown close results, so that the single point calculations at the CCSD(T) level have not been proved strictly necessary and have therefore not been performed for all the points along the potential energy surface. The minimum energy path has been described by the intrinsic reaction coordinate method, calculated at the MP2/6-31+G(d) by performing sequential geometry optimizations starting from the saddle point. The calculated enthalpy difference at 298K for the reaction has been determined as -49.5 kcal/mol, in good agreement with the literature value: -50.5 kcal/mol. The calculated rate constant has been obtained as 1.41 x 10-9 cm3.molecule-1.s-1, at 298,15K, in excellent agreement with the experimental data: 1.3 ? 1.6 x 10-9 cm3.molecule-1.s-1.Moreover, the rate constants show non-Arrhenius behavior, decreasing as the temperature increases, which is consistent with the experimental expectation. In this way, the performance of the variational transition state theory for this reaction can be considered satisfactory. By increasing the side chain of the reactant, other reaction channels have been observed: the bimolecular elimination E2 channel and the attack of the nucleophile from the same plane of the exit group (the front-SN2).For these reactions of the alkyl chlorides on n carbon atoms (1 < n ? 4), the B3LYP/6-31+G(d,p) level has been adopted for geometry optimizations and vibrational frequencies. Then, single point calculations at the CCSD(T)/6-31+G(d,p)//B3LYP/6- 31+G(d,p) level have been performed. A comparison of the reaction channels, back- SN2 and E2, shows that the E2 channel is kinetically favored, whereas the SN2 products are thermodynamically more stable. As expected, high values for the potential height have been observed for the front-SN2, being these channels disfavored in all cases. In general, the energy of the saddle points in respect to the isolated reactants slightly depend upon the size of the side chain. / Este trabalho trata do estudo te?rico das rea??es de substitui??o nucleof?lica de segunda ordem, CH3Cl + OH- CH3OH + Cl-, em fase gasosa, visando estudar a superf?cie de energia potencial, obter as constantes de velocidade e ainda verificando o efeito do aumento da cadeia lateral (trocando o radical CH3 na rea??o descrita acima por radicais etil, n-propil, i-propil, n-butil, s-butil e t-butil). Primeiramente, c?lculos te?ricos para otimiza??es de geometria e frequ?ncia foram realizados em n?vel MP2/6-31+G(d) para a rea??o CH3Cl + OH- CH3OH + Cl- e, em seguida, c?lculos single-point em n?vel CCSD(T)/6-31+G(d) foram realizados para corrigir os valores da energia eletr?nica dos pontos estacion?rios obtidos no caminho de rea??o. Entretanto, os valores obtidos para as energias relativas em n?veis MP2 e CCSD(T) foram muito pr?ximos, n?o sendo estritamente necess?rio refinar,atrav?s de c?lculos single-point em n?vel CCSD(T)/6- 31+G(d),os valores de energia de todos os pontos obtidos na superf?cie de energia potencial. O caminho de rea??o menor energia foi descrito pela coordenada de rea??o intr?nseca, calculada por otimiza??es de geometrias de uma sequ?ncia de configura??es ao redor do ponto de sela em n?vel MP2/6-31+G(d). A diferen?a de entalpia a 298K calculada para a rea??o foi de -49,5 kcal/mol, em bom acordo com o dado da literatura, -50,5 kcal/mol. A constante de velocidade da rea??o obtida foi de 1,41 x 10-9 cm3.mol?cula-1.s-1, a 298,15K, em excelente acordo com o dado experimental: 1,3 ? 1,6 x 10-9 cm3.mol?cula-1.s-1. Al?m disso, as constantes de velocidade globais apresentam comportamento n?o-Arrhenius, diminuindo conforme a temperatura aumenta, em um perfil consistente com a observa??o experimental. Dessa forma, a aplica??o da teoria de estado de transi??o se mostra satisfat?ria para essa rea??o. A partir do aumento da cadeia lateral, outros canais de rea??o foram observados, em prov?vel competi??o ? substitui??o nucleof?lica de ordem 2: a elimina??o de segunda ordem, E2. O ataque do nucle?filo pela frente da cadeia tamb?m foi obtido e investigado. Para as rea??es dos cloretos de alquila com cadeia lateral de n carbonos (1 < n ? 4), o n?vel B3LYP/6- 31+G(d,p) foi adotado para c?lculos de otimiza??es e frequ?ncias. Posteriormente, c?lculos em n?vel CCSD(T)/6-31+G(d,p)//B3LYP/6-31+G(d,p) foram realizados. Comparando os canais de rea??o de substitui??o nucleof?lica back e de elimina??o, o canal cineticamente favorecido foi o de elimina??o, por?m os produtos termodinamicamente mais est?veis s?o os de substitui??o nucleof?lica. Como esperado, observa-se uma barreira de potencial muito alta para as rea??es substitui??o pela frente, sendo esses canais desfavorecidos em todos os casos.Em geral, a diferen?a de energia dos pontos de sela em rela??o aos reagentes isolados mostra pequena depend?ncia com o aumento da cadeia lateral linear

<p>The overall aim of this thesis is to compare different methods for calculation of Core-Level shifts in metallic alloys. The methods compared are the Initial State model, the Complete screening and the Transition state model. Core-level shifts can give information of chemical bonding and about the electronic structure in solids.</p><p>The basic theory used is the so-called Density-Functional-Theory, in conjunction with the Local-Density Approximation and the Coherent-Potential- Approximation. The metallic alloys used are Silver-Palladium, Copper-Palladium, Copper-Gold and Copper-Platinum, all inface-centered-cubic configuration.</p><p>The complete screening- and the transition-state model are found to be in better agreement with experimental results than those calculated with the initial state model. This is mainly due to the fact that the two former models includes final-state effects, whereas the last one do not. The screening parameters within the Coherent-Potential approximation are also investigated. It is found that the Screened-Impurity Model can extend the validity of the Coherent-Potential-Approximation and increase it's accuracy.</p>

<p>HIV-1 protease inhibitors are important in the most frequently used regimen for the treatment of HIV/AIDS, the highly active antiretroviral therapy (HAART). For patients with access to this treatment, an HIV infection is no longer lethal, but rather a manageable, chronic infection. However, the HIV-1 protease inhibitors are generally associated with serious shortcomings such as adverse events, development of drug resistance and poor pharmacokinetic properties. Most of the approved inhibitors suffer from high protein binding, rapid metabolism and/or low membrane permeability. </p><p>In this project, novel HIV-1 protease inhibitors comprising a rarely used tertiary alcohol in the transition-state mimic were designed, synthesized and evaluated. The rationale behind the design was to achieve ‘masking’ of the tertiary alcohol by for example, intramolecular hydrogen bonding, which was believed could enhance transcellular transport. </p><p>A reliable synthetic protocol was developed and a series of highly potent inhibitors was obtained exhibiting excellent membrane permeation properties in a Caco-2 cell assay. However, the cellular antiviral potencies of these compounds were low. In an attempt to improve the anti-HIV activity, microwave-accelerated, palladium-catalyzed cross-coupling reactions and aminocarbonylation of aryl bromide precursors were employed to produce P1'-extended test compounds. Inhibitors demonstrating up to six times higher antiviral effect were obtained, the best derivatives having para 3- or 4-pyridyl elongations in P1'.</p><p>Fast metabolic degradation was observed in liver microsome homogenate, which is believed, at least partly, to be attributable to benzylic oxidation of the indanol P2 group of the inhibitors. To enable facile variation of the P2 side chain a new synthetic route was developed using an enantiomerically pure, benzyl-substituted epoxy carboxylic acid as the key intermediate. Cyclic and amino-acid-residue-derived P2 groups were evaluated, and inhibitors equipotent to the series containing an indanol moiety were produced.</p>