This dissertation focuses on the assessment and development of heterogeneous catalysts for the deperoxidation of cyclohexyl hydroperoxide and oxidation of cyclohexane, which will be based in metal oxides and gold nanoparticles. For this endeavour a multidisciplinary approach will be used combining theoretical chemistry, kinetic studies and synthesis and characterisation of materials. The starting choice for the catalyst to carry out the process is supported gold nanoparticles. The approach of this dissertation is to first model the mecha- nism of cyclohexyl hydroperoxide decomposition and oxidation of cyclohexane on gold nanoparticles by theoretical calculations, and use these findings to synthesise efficient heterogeneous catalysts which will be subsequently tested and optimised experimentally. But as it will be seen, some metal oxides are active rather than acting as mere supports, which will also be studied both theoretical and experimentally. Each chapter has a specific focus and constitutes a strand of the overall goal: Chapter 1 provides an introductory background on the topics that this dissertation lies upon: oxidation of cyclohexane, heterogeneous catalysis and catalysis by gold and metal oxides. Chapter 2 outlines the objectives of the thesis, formulating the relevant hypotheses of this research and the subsequent validation tests. Chapter 3 exposes the methodology with a brief conceptual background that has been used to carry out this work. Chapter 4 is the first chapter dealing with results. It consists in a theoretical study using density functional theory of the reaction mechanism over different models of gold nanoparticles, in order to study the influence of several parameters on their catalytic activity: the particle size, atom coordination, and presence of additional species like oxygen atoms and water. Chapter 5 uses the findings found in chapter 4 to drive the synthesis of supported gold nanoparticles. It consists in a experimental study of gold-based catalysts, which is combined with a theoretical study which takes into account an additional variable: the support. Chapter 6 exploits one of the findings of chapter 5. One of the supports used for anchoring the gold nanoparticles is active by itself, namely cerium oxide. This chapter comprises an experimental work about its activity, studying parameters like particle size, morphology and the effect of doping. Chapter 7 continues with the catalytic activity of cerium oxide-based materials, but now from a theoretical point of view. It first presents a systematic study of the parameters relevant for the proper quantum mechanical description of cerium oxide, which is followed by a mechanistic study on different models. Chapter 8 outlines the conclusions obtained in this dissertation, present- ing them in a summarised way. Even though each chapter presents its corresponding conclusions at its end, this chapter groups them all in a structured way for the reader's convenience, so a global view of the project can be swiftly grasped. The results herein further the knowledge of heterogeneous catalysis for the oxidation of cyclohexane, one of the most important industrial reactions, and which continues to be a challenge. Although the ultimate goal is to develop an industrial catalyst, the dissertation also aims to show how computational chemistry can drive the design of novel materials, and how it can help to understand catalytic reactions at the atomic level. / El presente trabajo se centra en el estudio y desarrollo de catalizadores heterogéneos para la desperoxidación de ciclohexil hidroperóxido y la oxidación de ciclohexano, basados en óxidos metálicos y nanopartículas de Au. Para lograr tal objetivo se ha usado un enfoque multidisciplinar, que combina química teórica y estudios cinéticos, a la vez que síntesis y caracterización de materiales. El candidato inicial para llevar a cabo el proceso consiste en partículas de Au soportadas. El camino a seguir pasa primero por modelizar el mecanismo de descomposición de ciclohexil hidroperóxido y oxidación de ciclohexano mediante cálculos teóricos, y utilizar el conocimiento generado por este estudio para dictar la síntesis de catalizadores heterogéneos, comprobando y optimizando posteriormente su actividad de forma experimental. Sin embargo, como será visto a lo largo de este trabajo, algunos óxidos metálicos dejan de lado su papel como mero soporte físico para las partículas de Au y son activos por sí mismos. Tal hecho será estudiado tanto teórica como experimentalmente. Cada capítulo tiene un objetivo específico, y es a su vez una parte del objetivo global de esta investigación: El capítulo 1 provee al lector de una breve introducción a los temas sobre los que yace este trabajo: oxidación de ciclohexano, catálisis heterogénea y catálisis mediante Au y óxidos metálicos. El capítulo 2 expone de una forma breve y concisa los objetivos de esta investigación, formulando la hipótesis de partida y los correspondientes experimentos para su validación. El capítulo 3 describe la metodología utilizada junto a una explicación de los fundamentos en los que se basa cada técnica. El capítulo 4 es el primer capítulo que discute los resultados obtenidos en esta investigación. Se trata de un estudio usando la teoria del funcional de densidad para investigar el mecanismo de reacción del proceso sobre diferentes modelos teóricos de Au, con el objetivo de comprender la influencia de diversos factores en la actividad catalítica, tales como el tamaño de partícula, la coordinación de los á'tomos de Au y la presencia de especies adicionales como átomos de O y agua. El capítulo 5 hace uso de los resultados obtenidos en el estudio anterior, y los utiliza para dirigir la síntesis de nanopartículas soportadas de Au. Se trata de un estudio experimental en el que se investigan diversos factores que pueden afectar a su actividad catalítica. Este estudio se combina a su vez con uno de tipo teórico en el que se tiene en cuenta la influencia del soporte en la actividad catalítica de las particulas de Au. El capítulo 6 se basa en uno de los resultados obtenidos en el capítulo 5. Uno de los soportes utilizados para anclar las partículas de Au resulta de por sí activo: el CeO2. Su notable actividad para catalizar este proceso exige un estudio en mayor profundidad, el cual se lleva a cabo en este capítulo. Parámetros como el tamaño de particula, la morfología de superficie y el dopaje entre otros se investigan en este punto. El capítulo 7 sigue la estela del trabajo anterior sobre CeO2, pero ahora desde el punto de vista de la química teórica. Presenta primero un estudio sistemático de parámetros relacionados con la mecánica cuá'ntica que afectan al CeO2, con el objetivo de alcanzar una descripción satisfactoria de los modelos teóricos para este óxido. Tras esto, se lleva a cabo un estudio del mecanismo de reacción en dichos modelos de CeO2, a fin de comprender el origen de su actividad catalítica. El capítulo 8 presenta de forma estructurada y concisa todas las conclusiones que se han sacado a raíz de los resultados obtenidos. Aún a pesar de que cada capítulo presenta sus correspondientes conclusiones al final, aquí se presentan de una forma agrupada a comodidad del lector, para que pueda obtener de forma ágil una visión global de los resultados de esta investigación. / Aquest treball es centra en l'estudi i desenvolupament de catalitzadors hetero- genis per a la desperoxidació de ciclohexil hidroperòxid i la oxidació de ciclohexà, basats en òxids metàl·lics i nanopartícules de Au. Per aconseguir aquest objectiu s'ha utilitzat un enfocament multidisciplinari, en el qual es combinen química teòrica i estudis cinètics amb síntesi i caracterització de materials. El candidat inicial per dur a terme el procés consisteix en partícules de Au suportades. El camí a seguir passa primer per modelitzar el mecanisme de descomposició del ciclohexil hidroperòxid i la oxidació de ciclohexà mitjançant càlculs teòrics, i utilitzar el coneixement generat per aquest estudi per dirigir la síntesi de catalitzadors heterogenis, comprovant i optimitzant posteriorment la seua activitat de forma experimental. No obstant això, com es veurà al llarg d'aquest treball, alguns òxids metàl·lics deixen de costat el seu paper com a suport físic de les partícules de Au y són actius per si mateixos. Aquest fet s'ha estudiat tant teòrica com experimentalment. Cada capítol té un objectiu específic i és al mateix temps una part de l'objectiu global d'aquesta recerca: El capítol 1 proporciona al lector una breu introducció als temes tractats en aquest treball: oxidació de ciclohexà, catàlisi heterogènia i catàlisi mitjançant Au i òxids metàl·lics. El capítol 2 exposa d'una forma breu i concisa els objectius d'aquesta investigació, formulant la hipòtesi inicial i els corresponents experiments per a la seua validació. El capítol 3 descriu la metodologia utilitzada conjuntament amb una explicació dels fonaments en els quals es basa cada tècnica. El capítol 4 és el primer capítol que discuteix els resultats obtinguts en aquesta investigació. Es tracta d'un estudi usant la teoria del funcional de densitat per investigar el mecanisme de reacció del procés en diferents models teòrics de Au, amb l'objectiu de comprendre la influència en l'activitat catalítica de diversos factors, com ara la grandària de partícula, la coordinació dels àtoms de Au i la presencia d'espècies addicionals, com àtoms de O i aigua. El capítol 5 fa ús dels resultats obtinguts en l'estudi anterior, i els utilitza per dirigir la síntesi de nanopartícules suportades de Au. Es tracta d'un estudi experimental en el qual s'investiguen diversos factors que poden afectar a la seua activitat catalítica. Aquest estudi es combina amb un altre de caràcter teòric en el qual es té en compte la influència del suport en la activitat catalítica de les partícules de Au. El capítol 6 es basa en un dels resultats obtinguts en el capítol 5. Un dels suports utilitzats per fixar les partícules de Au resulta de per si actiu: el CeO2. La seua notable activitat per catalitzar aquest procés demana un estudi de major profunditat, el qual es duu a terme en aquest capítol. Paràmetres com la grandària de partícula, la morfologia de superfície i el dopatge, entre altres, s'investiguen en aquest punt. El capítol 7 continua l'estudi anterior sobre el CeO2, però ara des del punt de vista de la química teòrica. Presenta en primer lloc un es- tudi sistemàtic de paràmetres relacionats amb la mecànica quàntica que afecten al CeO2, amb l'objectiu d'aconseguir una descripció satisfactòria pels models teòrics d'aquest òxid. Després, es duu a terme un estudi del mecanisme de reacció en aquests models de CeO2, a fi de com- prendre l'origen de la seua activitat catalítica. El capítol 8 presenta de forma estructurada i concisa totes les conclusions que s'han extret arran dels resultats obtinguts. Encara que cada capí- tol presenta les seues corresponents conclusions al final, ací es presenten d'una forma agrupada per a la comoditat del lector, per què puga obtindre de forma àgil una visió global dels result d'una forma agrupada per a la comoditat del lector, per què puga obtindre de forma à / López Auséns, JT. (2016). From Quantum Mechanics to Catalysis: Studies on the oxidation of alkanes by gold and metal oxides [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/76806

Kovalente Inhibition stellt einen effektiven Weg dar, die Verweildauer des Liganden innerhalb einer Bindetasche zu erhöhen. In dieser Arbeit wurden theoretische Methoden angewendet, um die Reaktivität und den nichtkovalenten Zustand vor der Reaktion zu modellieren. Im Rahmen einer Fallstudie zu Cathepsin K wurden nichtkovalente Modelle von kovalenten Inhibitoren generiert. Für verschiedene Komplexe aus Cathepsin K und einem kovalent gebundenem Liganden wurde der Zustand vor der Reaktion modelliert und dessen Stabilität im Rahmen einer klassischen MD-Simulation überprüft. Die Stabilität des Warheads in der Bindetasche hing hauptsächlich vom gewählten Protonierungszustand der katalytischen Aminosäuren ab. Für eine Reihe von Inhibitoren der ChlaDUB1 wurde ein Protokoll aus quantenmechanischen Rechnungen genutzt, um die Reaktivität verschiedener Warheads abzuschätzen. Die erhaltenen Aktivierungsenergien korrelierten mit experimentell bestimmten Raten zur Inaktivierung des Enzyms. Im Rahmen eines Wirkstoffdesign-Projektes zur Deubiquitinase USP28 wurden von unpublizierten Kristallstrukturen ausgehend erste Docking-Experimente durchgeführt. Es konnte gezeigt werden, dass ein literaturbekannter Inhibitor von USP28 mit einem Warhead so modifiziert werden kann, dass die reaktive Einheit in direkter Nachbarschaft zu einem Cystein positioniert wird. Für diese Warheads wurden ebenfalls quantenmechanische Rechnungen zur Bestimmung der Aktivierungsenergie durchgeführt. Um besser nachvollziehen zu können, warum bei einem Photoswitch-Inhibitor der Butyrylcholin-Esterase der cis-Zustand des Moleküls besser inhibiert als der trans-Zustand, wurde eine Docking-Studie des Zustandes vor der Reaktion durchgeführt. Es konnte ein qualitatives Modell aufgestellt werden, das zeigt, dass der trans-Zustand aufgrund seiner längeren Form mit wichtigen Aminosäuren am Eingang der Bindungstasche kollidiert. / Covalent inhibition is an effective way to increase the residence time of a ligand within the active site. In this work theoretical methods were used to model the reactivity and the noncovalent pre-reaction state. Noncovalent models of covalent inhibitors were generated as part of a case study of Cathepsin K. Several complexes of Cathepsin K and a covalently bound ligand were modeled in their state before the reaction, and their stability was assessed by classical molecular dynamics simulations. In most cases the warhead was positioned in close proximity to the catalytic unit, remaining there for up to several hundred nanoseconds. This stable positioning was largely dependent on the protonation state of the catalytic amino acids. To estimate the reactivity of a series of ChlaDUB1 inhibitors, a protocol of quantum mechanical calculations was adapted. The obtained activation energies correlated with experimentally obtained rate constants of enzyme inactivation. Using unpublished crystal structures, first design steps for the inhibition of the deubiquitinase USP28 were performed. Docking studies showed that modification of a literature-known inhibitor of USP28 with a warhead allowed to place this reactive unit close to a cysteine. Activation energies were also obtained for these structures via quantum mechanical calculations. To better rationalize the differences in inhibition between the cis- and trans-state of a photoswitch inhibitor of butyrylcholine esterase, a docking study of the noncovalent state was performed. The different ring conformers and stereochemical properties of the photoswitch were critical for a sensible model of the ligand. A qualitative model could be obtained which explains that the cis-isomer is more active than the trans-isomer due to a steric clash of the latter with amino acids at the entrance of the pocket.

This dissertation focuses on the computational investigation of gold(I) acyclic diaminocarbene (ADC) complexes and their application in homogeneous gold(I) catalysis. Chapter 2 is an in-depth computational investigation of the σ- and π-bonding interactions that make up the gold-carbene bond. Due to the inherent conformation flexibility of ADC ligands, distortions of the carbene plane can arise that disrupt orbital overlap between the lone pairs on the adjacent nitrogen atoms and the empty p-orbital of the carbene. This study investigated the affect these distortions have on the strength of the σ- and π-bonding interactions. This investigation demonstrated that while these distortions can affect the σ- and π-bonding interactions, the ADC ligand have to become highly distorted before any significant change in energy of either the σ- or π-bonding interactions occurs. Chapter 3 is a collaborative investigation between experimental and computational methods, DFT calculations were employed to support the experimental catalytic results and determine the role that steric effects have in controlling the regioselectivity of a long-standing electronically controlled gold(I)-catalyzed tandem 1,6-enyne cyclization/hydroarylation reaction with indole. This study demonstrated that by sterically hindering nucleophilic attack of indole at the favored position, nucleophilic attack would occur at a secondary position leading to the selective formation of the electronically unfavored product. Chapter 4 is a collaborative investigation between experimental and computational methods. DFT calculations were employed to investigate and rationalize the importance of secondary non-covalent interactions and their influence on the enantioselectivity of a gold(I)-catalyzed intramolecular hydroamination of allene reaction. Through computational investigation of the enantiodetermining step, and the non-covalent interactions present between 2′-aryl substituent and the rest of the catalyst, it was determined that the presence of CF3 group on the 3,5-position of the 2′-aryl ring is crucial to maintaining a more rigid chiral pocket leading to higher enantiomeric excesses in this dynamic system. This increased rigidity is believed to be attributable to the several weak non-covalent interactions that arise between the allene substrate or diisopropyl N-substituent and the fluorine atoms of the CF3 groups.

Inkjet additive manufacturing is the next step toward ubiquitous manufacturing by enabling multi-material printing that can exhibit various mechanical, electronic, and thermal properties. These characteristics are realized in the careful formulation of the inks and their functional materials, but there are many constraints that need to be satisfied to allow optimal jetting performance and build quality when used in an inkjet 3-D printer. Previous research has addressed the desirable rheology characteristics to enable stable drop formation and how the metallic nanoparticles affect the viscosity of inks. The contending goals of increasing nanoparticle-loading to improve material deposition rates while trying to maintain optimal flow dynamics is the closely held trade secret in formulating these inkjet compositions. We use data from previous experiments and the CRC Handbook of Chemistry and Physics to train machine learning regression models to predict the relevant factors of inkjet printability at a standardized temperature of 25ºC: viscosity, surface tension, and density. These models were used to predict the rheological factors of the main components of a UV-curable inkjet ink formulation: UV-curable monomers and oligomers, photoinitiators, dispersants, and humectants. This paper compares the relative performance of five machine learning algorithms to assess the effectiveness of each approach for chemoinformatics regression tasks.

Electrolytic solutions contain mobile ions that can pass current, and are essential components of any solution-phase electrochemical system. The Nernst–Planck–Poisson equations describe the electrodynamics and transport dynamics of electrolytic solutions. This thesis applies modern numerical and mathematical techniques in order to solve these equations, and hence determine the behaviour of electrochemical systems involving charge transport. The following systems are studied: a liquid junction where a concentration gradient causes charge transport; an ideally polarisable electrode where an applied potential difference causes charge transport; and an electrochemical cell where electrolysis causes charge transport. The nanometre Debye length and nanosecond Debye time scales are shown to control charge separation in electrolytic solutions. At equilibrium, charge separation is confined to within a Debye length scale of a charged electrode surface. Non-equilibrium charge separation is compensated in solution on a Debye time scale following a perturbation, whereafter electroneutrality dictates charge transport. The mechanism for the recovery of electroneutrality involves both migration and diffusion, and is non-linear for larger electrical potentials. Charge separation is an extremely important consideration on length scales comparable to the Debye length. The predicted features of capacitive charging and electrolysis at nanoelectrodes are shown to differ qualitatively from the behaviour of larger electrodes. Nanoscale charge separation can influence the behaviour of a larger system if it limits the overall rate of mass transport or electron transfer. This thesis advocates the use of numerical methods to solve the Nernst–Planck–Poisson equations, in order to avoid the simplifying approximations required by traditional analytical methods. As this thesis demonstrates, this methodology can reveal the behaviour of increasingly elaborate electrochemical systems, while illustrating the self-consistency and generality of fundamental theories concerning charge transport.

For the first time, successful synthesis and characterisation of the missing (Z)-isomer of thallium(I) methanediazotate has been accomplished, utilising low-temperature NMR monitoring analysis. The title compound was synthesised from N-methyl-N-nitrosourea and thallium(I) propoxide, under sub-ambient temperature conditions, as a highly moisture sensitive entity. Quantum chemical calculations, performed at the CCSD(T) level, depict excellent conformity to experimental results. Indeed, compared to its (E) counterpart, the formation of the title compound is thermodynamically less favoured, but preferred by means of kinetic control owing to a hindered isomerisation.

For the first time, successful synthesis and characterisation of the missing (Z)-isomer of thallium(I) methanediazotate has been accomplished, utilising low-temperature NMR monitoring analysis. The title compound was synthesised from N-methyl-N-nitrosourea and thallium(I) propoxide, under sub-ambient temperature conditions, as a highly moisture sensitive entity. Quantum chemical calculations, performed at the CCSD(T) level, depict excellent conformity to experimental results. Indeed, compared to its (E) counterpart, the formation of the title compound is thermodynamically less favoured, but preferred by means of kinetic control owing to a hindered isomerisation.

This thesis covers a range of methodologies to provide an account of the current (2010-2014) state of the art and to develop new methods for solubility prediction. We focus on predictions of intrinsic aqueous solubility, as this is a measure commonly used in many important industries including the pharmaceutical and agrochemical industries. These industries require fast and accurate methods, two objectives which are rarely complementary. We apply machine learning in chapters 4 and 5 suggesting methodologies to meet these objectives. In chapter 4 we look to combine machine learning, cheminformatics and chemical theory. Whilst in chapter 5 we look to predict related properties to solubility and apply them to a previously derived empirical equation. We also look at ab initio (from first principles) methods of solubility prediction. This is shown in chapter 3. In this chapter we present a proof of concept work that shows intrinsic aqueous solubility predictions, of sufficient accuracy to be used in industry, are now possible from theoretical chemistry using a small but diverse dataset. Chapter 6 provides a summary of our most recent research. We have begun to investigate predictions of sublimation thermodynamics. We apply quantum chemical, lattice minimisation and machine learning techniques in this chapter. In summary, this body of work concludes that currently, QSPR/QSAR methods remain the current state of the art for solubility prediction, although it is becoming possible for purely theoretical methods to achieve useful predictions of solubility. Theoretical chemistry can offer little useful additional input to informatics models for solubility predictions. However, theoretical chemistry will be crucial for enriching our understanding of the solvation process, and can have a beneficial impact when applied to informatics predictions of properties related to solubility.

The knowledge of the packing behaviour of small organic compounds in crystal lattices is of great importance for industries dealing with solid state materials. The properties of materials depend on how the molecules arrange themselves in a crystalline environment. Crystal structure prediction provides a theoretical approach through the application of computational strategies to seek possible crystal packing arrangements (or polymorphs) a compound may adopt. Based on the chemical diagrams, this thesis investigates polymorphism of several small organic compounds. Plausible crystal packings of those compounds are generated, and their lattice energies are minimised using molecular mechanics and/or quantum mechanics methods. Most of the work presented here is conducted using two software packages commercially available in this field, Polymorph Predictor of Materials Studio 4.0 and GRACE 1.0. In general, the computational techniques implemented in GRACE are very good at reproducing the geometries of the crystal structures corresponding to the experimental observations of the compounds, in addition to describing their solid state energetics correctly. Complementing the CSP results obtained using GRACE with isostructurality offers a route by which new potential polymorphs of the targeted compounds might be crystallised using the existing experimental data. Based on all calculations in this thesis, four new potential polymorphs for four different compounds, which have not yet been determined experimentally, are predicted to exist and may be obtained under the right crystallisation conditions. One polymorph is expected to crystallise under pressure. The remaining three polymorphs might be obtained by using a seeding technique or the utilisation of suitable tailor made additives.

A summary of research conducted since September 2007 at the University of Toronto in the laboratory of Professor Robert A. Batey is presented in this thesis, which is divided into four chapters. The first chapter contains a two-part introduction, where aryl- and aliphatic-Claisen rearrangements are discussed in part 1, and the nucleophilic addition of organoboron reagents to unsaturated C–N functionalities is described in part 2. Chapter 2 contains research involving synthetic and theoretical studies of aryl-Claisen rearrangements and other sigmatropic reactions. The work towards developing the lanthanide-catalyzed domino aryl-Claisen rearrangement for the synthesis of contiguous aryl–C(sp³) moieties is presented first. This is followed by computational studies involving E/Z-selectivity differences for the aryl-Claisen rearrangement, which was an issue noted for the domino aryl-Claisen reaction of a linear substrate. The mechanistic origins of E/Z-selectivity differences for the mono aryl-Claisen rearrangement, which was experimentally ambiguous for over 40 years, is resolved through computational methods. A theoretical analysis of selectivity differences for the allylic azide rearrangement is also described. The third section contains a discussion of Eu(fod)3-catalyzed aryl-Claisen rearrangements on vinyl bromide systems and preliminary studies involving application of the substrates in cross-coupling reactions, and other attempted mono- and domino sigmatropic rearrangements are presented in the fourth section. In chapter 3, the search for computational methods that can accurately predict experimental free energy of activation barriers for the aliphatic-Claisen rearrangement through benchmarking studies with a priori kinetic barrier and kinetic isotope effect data is described. Methods were found to predict new valid transition states and predict ΔG‡ values with a mean unsigned error of 0.3 kcal/mol relative to experimental values. In chapter 4, the development of new allylboration reaction is outlined, involving the double allylboration of nitriles and anhydrides, and initial studies towards the first aminoallylboration reactions of N-aluminoaldimines to form 1,2-diamines.