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From an (R)-(+)-pulegone-derived building block that incorporates the stereo-defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four-step synthesis of (−)-4-epi-presilphiperfolan-8-α-ol was achieved. The key processes involved are a ring-closing metathesis leading to a bridged alkene-tethered ketone and its subsequent FeIII-mediated metal-hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon-centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans-fused hydrindanols structurally related to botrydial compounds. Financial support for this research was provided by the Grants PID2019-104188GB-I00 and PID2019-110008GB-I00 funded by MCIN/AEI/10.13039/501100011033. We also thank SGIker (UPV/EHU) for providing human and computational resources. B.B. acknowledges the Serra Hunter program (Generalitat de Catalunya).

The tandem gold(I)-catalyzed rearrangement/Nazarov reaction of enynyl acetates in which the double bond is embedded in a piperidine ring was computationally and experimentally studied. The theoretical calculations predict that the position of the propargylic acetate substituent has a great impact on the reactivity. In contrast to our previous successful cyclization of the 2-substituted substrates, where the nitrogen favors the formation of the cyclized final product, the substitution at position 3 was computed to have a deleterious effect on the electronic properties of the molecules, increasing the activation barriers of the Nazarov reaction. The sluggish reactivity of 3-substituted piperidines predicted by the calculations was further confirmed by the results obtained with some designed substrates.

Trabajo presentado a la XXXVII Reunión Bienal de la Real Sociedad Española de Química, celebrada del 26 al 30 de mayo de 2019 en Donostia-San Sebastián.

Resumen del trabajo presentado al 2nd Trans Pyrenean Meeting in Catalysis (TraPCat), celebrado en Tarragona (España) del 18 al 19 de octubre de 2018., In this communication we present the regio- and stereoselective synthesis of 1,3-diaminotruxillic and 1,2-diaminotruxinic acid derivatives from [2+2]-photodimerization of (Z)-4-aryliden-2-(alkyl,aryl)-5(4H)-oxazolones. Truxillic acids are of outstanding interest due to their pharmacological properties. Under direct irradiation conditions 1,3-diaminotruxillic acids are selectively obtained by 1,3-coupling (head-to-tail) of Z-oxazolones. However, when the irradiation is performed in the presence of a Ru-coordination complex, a complete change in the orientation of the reaction is observed, and 1,2-diaminotruxinic acids are obtained as single regio- and stereoisomers by head-to-head 1,2-coupling of E-oxazolones. In fact, from six possible diastereoisomers only one of them is finally isolated. The reaction is highly sensitive to the temperature, and additional isomers or rearrangement processes of high synthetic interest can be detected. The determination of the mechanism through DFT methods of this energy transfer-based photochemical processes provides a reasonable interpretation of the experimental facts. We have been able to fully determine the role of the ruthenium complex and the ultimate reason of the selectivity, which seems to reside in the different spin state (S1 vs T1) of the oxazolone in the excited state.

Resumen del trabajo presentado al European Colloquium on Inorganic Reaction Mechanisms (ECIRM), celebrado en Barcelona (España) del 8 al 11 de julio de 2018.

Chiral L-prolinamides 2 containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a 2-pyrimidinyl unit are synthesized and used as general organocatalysts for intermolecular and intramolecular aldol reactions with 1,6-hexanedioic acid as a co-catalyst under solvent-free conditions. The intermolecular reaction between ketone–aldehyde and aldehyde–aldehyde must be performed under wet conditions with catalyst (S,S)-2b at 10 °C, which affords anti-aldols with high regio-, diastereo-, and enantioselectivities. For the Hajos–Parrish–Eder–Sauer–Wiechert reaction, both diastereomers of catalyst 2 give similar results at room temperature in the absence of water to give the corresponding Wieland–Miescher ketone and derivatives. Both types of reactions were scaled up to 1 g, and the organocatalysts were recovered by extractive workup and reused without any appreciable loss in activity. DFT calculations support the stereochemical results of the intermolecular process and the bifunctional role played by the organocatalyst by providing a computational comparison of the H-bonding networks occurring with catalysts 2a and 2b. The Spanish Ministerio de Ciencia e Innovación (MICINN) (projects CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-00006), the Spanish Ministerio de Economia y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), Fondos Europeos para el Desarrollo Regional (FEDER), Generalitat Valenciana (PROMETEO 2009/039 and PROMETEOII/2014/017), the Basque Government (GV Grant IT-291-07), the European Commission, FP7 Marie Curie Actions through the ITN ECHONET network (MCITN-2012-316379), the University of Alicante, and the University of the Basque Country are gratefully acknowledged for financial support.

A simple change in the polarity of the solvent allows both enantiomers of substituted succinimides to be obtained in the enantioselective conjugate addition reaction of aldehydes, mainly α,α-disubstituted, to maleimides catalysed by chiral carbamate-monoprotected trans-cyclohexane-1,2-diamines. Using a single enantiomer of the organocatalyst, both enantiomers of the resulting Michael adducts are obtained in high yields by simply changing the reaction solvent from aqueous DMF (up to 84 % ee) to chloroform (up to 86 % ee). Theoretical calculations are used to explain this uncommon reversal of the enantioselectivity; two transition state orientations of different polarities are differently favoured in polar or nonpolar solvents. The authors are grateful for the financial support from the Spanish Ministerio de Economía y Competitividad (MEC) (project number CTQ2011-24151), Fondos Europeos para el Desarrollo Regional (FEDER), the COST Action CM0905 “Organocatalysis”, the FP7 Marie Curie Action of the European Commission via the ITN ECHONET Network (FP7-MCITN-2012-316379), the University of Alicante and the University of the Basque Country.

The monoguanylation of (1S,2S)- and (1R,2R)-cyclohexane-1,2-diamine affords chiral primary amine-guanidines that are used as chiral organocatalysts in the enantioselective Michael addition of aldehydes, particularly α,α-disubstituted aldehydes, to maleimides. The reaction is carried out in the presence of imidazole, as an additive, in aqueous N,N-dimethylformamide, as the solvent, and affords the corresponding enantioenriched succinimides in high or quantitative yields with enantioselectivities up to 96 % ee. Theoretical calculations (DFT and M06–2X) suggest a different hydrogen-bonding coordination pattern between the maleimide (C=O) and the catalyst (NH groups) is responsible for the enantioinduction switch that is observed when the reaction is carried out using primary amine-guanidines versus primary amine-thioureas as the organocatalysts. The authors thank the Spanish Ministerio de Economía y Competitividad (MEC) (projects CTQ2010-20387, CTQ2010-21263-C02, and Consolider Ingenio 2010, CSD2007-00006), the Fondos Europeos para el Desarrollo Regional (FEDER), the COST Action CM0905 “Organocatalysis”, the Generalitat Valenciana (Prometeo/2009/039), the Basque Government (GV grant IT-291-07), the University of Alicante, and the University of the Basque Country for the financial support.

A wide variety of chiral succinimides have been prepared in high yields and enantioselectivities by asymmetric conjugate addition of 1,3-dicarbonyl compounds to maleimides under very mild reaction conditions using a bifunctional benzimidazole-derived organocatalyst. Computational and NMR studies support the hydrogen-bonding activation role of the catalyst and the origin of the stereoselectivity of the process. Financial support from the Ministerio de Educación y Ciencia (MEC) (project numbers CTQ2007-62771/BQU, CTQ2010-20387), from Consolider INGENIO 2010 (grant number CSD2007-00006), from the Generalitat Valenciana (PROMETEO/2009/038), from Fondos Europeos para el Desarrollo Regional (FEDER), from the University of Alicante, and from the European Union (EU) (ORCA Action CM0905) is acknowledged.

[EUS] Gradu Amaierako Lan honetan, interes handiko konposatuak diren fluorenonen sintesia burutu egin da. Molekula hauek sintetizatzeko metodo aunitz egon arren, ikertu den metodoa, Pd bidez katalizatutako C-H azilazio intramolekular bat da, substratu bezala azido [1,1 ́-bifenil] karboxilioaren ester aktibatuak, Pd(OAc)2 aurrekatalizatzaile bezala eta PCy3·HBF4 ligando moduan erabiliz. Transformazio intramolekular hau burutu ahal izateko, lehenik eta behin, talde ateragarri ezberdinak dituzten ester aktibatu batzuk prestatu egin dira, aurretik aipatutako erreakzioarekiko beraien erreaktibitatea ikertu nahian. Horrela, fluorenonak sintetizatzeko substratu egokienak zeintzuk diren aztertu da. Behin talde ateragarri optimoa zein den ikusita, substratuaren eraztun aromatikoetan ordezkatzaile ezberdinak jartzeak ziklazio erreakzioan izan ditzakeen efektuak aztertu dira [ENG] In this Final Degree Project, the synthesis of fluorenones has been carried out. Although there are many methods to synthesize these interesting molecules, the method herein studied consists of a Pd-catalyzed intramolecular C-H acylation, using activated esters derivated from [1,1 ́-biphenyl] carboxyl acid as a substrate, Pd(OAc)2 as a precatalyst and PCy3·HBF4 as a ligand. In order to achieve this intramolecular transformation, firstly the synthesis of some activated esters has been acomplished, bearing different leaving groups, with the aim of studying their reactivity. Thus, the most suitable substrates for the synthesis of fluorenone have been tested. Once the optimal leaving group has been determined, the possible effects of placing different substitutes on the aromatic rings of the substrate in the cyclization reaction have been studied.

The present thesis describes computational and experimental studies used to drive the reactivity of allylic and enol substrates towards new transformations. These synthetic methods give access to a number of organic molecules that may serve as important moieties in synthetic organic chemistry. Additionally, this thesis describes the synthesis of Metal-Organic Frameworks (MOFs) and their use in catalytic organic reactions. The introductory chapter (Chapter 1) gives an overview of the concept of catalysis and its typologies, emphasizing those that have been used in the thesis. Moreover, synthetic procedures for the formation of MOFs and their use in catalysis are described. The importance and reactivity of allylic substrates are also presented. The chapter follows with a short introduction to hypervalent iodine and their reactivity. Finally, a brief description of computational studies and those used in this thesis are presented. In Chapter 2, an umpolung protocol for the cross-nucleophile coupling of silyl enol ethers with heteronucleophiles mediated by an hypervalent iodine reagent has been explored (Paper I). The mechanistic study of the reaction has been carried out employing DFT calculations and kinetic investigations. Together with deuterium labelling studies and kinetic simulations, DFT calculations have been used in Chapter 3 for the examination of the base-catalyzed [1,n]-proton shift in conjugated polyenyl ethers (Paper II). Chapter 4 describes the synthesis of the family MIL-101(Cr) and MIL-101(Cr)-NH2 employing microwave-assisted methods. The method has been compared to the common solvothermal synthetic pathways using common characterization techniques for heterogeneous materials (Paper III). Finally, Chapter 5 of this thesis describes the synthesis of a UiO-67 MOF containing a phosphazene superbase to study the effect of spatial confinement within a MOF on the stereospecific isomerization of allylic alcohols (Paper IV). Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry

[SPA] El objetivo de este trabajo es sintetizar cantidades considerablemente grandes de tres metabolitos derivados del insecticida spidoxamato para su posterior uso en estudios ecotoxicológicos y de evaluación de riesgos medioambiantales. Dichos estudios son necesarios en el proceso de desarrollo de este nuevo ingrediente activo. Para ello, se ha trabajado en el diseño de protocolos sintéticos para la preparación de estas moléculas de una manera rápida y efectiva. El primer metabolito sintetizado en este trabajo, spidoxamato-desciclohexilcetona, ha sido preparado mediante la condensación de una amida con oxalato de dietilo para la formación del anillo de maleimida presente en la molécula. Por otro lado, la cantidad requerida del segundo metabolito, spidoxamato-desclorohidroxi, también ha sido obtenida gracias a la optimización de las condiciones necesarias para la hidroxilación del insecticida spidoxamato catalizada por paladio. Finalmente, se ha abordado la síntesis del tercer metabolito, spidoxamato-ciclohidroxi-bencilalcohol (cis), para el cual se ha diseñado un procedimiento algo más largo debido a su complejidad estructural. Este incluye una condensación de Dieckmann para formar el anillo de ácido tetrámico que constituye la molécula y su posterior desmetilación para dar el producto. Este procedimiento ha resultado no ser lo suficientemente selectivo para sintetizar la cantidad deseada del metabolito. Sin embargo, se han propuesto rutas alternativas que podrían ser útiles en futuros intentos de sintetizar esta molécula. [ENG] The main goal of this work is to synthesize considerably big amounts of three metabolites derived from spidoxamat insecticide for their subsequent use in ecotoxicology studies and environmental risk evaluation. These studies are necessary in the development process of this new active ingredient. For that purpose, synthetic protocols have been designed for the fast and efficient preparation of the desired molecules. The first metabolite synthesized in this work, spidoxamat-decyclohexylketone, has been prepared through the condensation of an amide with diethyl oxalate which leads to the formation of the maleimide ring present in the molecule. On the other hand, the required amount of the second metabolite, spidoxamat-dechlorohydroxy, has also been obtained thanks to the optimization of the necessary conditions for the palladium-mediated hydroxylation reaction of spidoxamat insecticide to form the product. Finally, the synthesis of spidoxamat-cyclohydroxy-benzylalcohol (cis) metabolite has been tackled. A longer pathway has been designed in this case due to the structural complexity of the metabolite, which includes a Dieckmann cyclization to form the tetramic-acid core of the molecule followed by its demethylation to give the product. This procedure has not been selective enough to prepare the desired amount of the metabolite. Nevertheless, alternative pathways have been proposed that could be helpful in future attempts to synthesize the molecule.

En los proyectos de investigación dirigidos a la búsqueda de compuestos con actividad biológica, es una práctica habitual sintetizar análogos donde se mantiene siempre intacto el núcleo estructural (en este caso, un pirazol, heterociclo que ha sido empleados en campos de estudios farmacéuticos) y únicamente se modifican los grupos funcionales de las cadenas laterales de la estructura general. En este proyecto de grado, se ha trabajado la síntesis orientada a la diversificación. Se han creado, por tanto, múltiples compuestos análogos que posteriormente han sido estudiados en el campo de la actividad herbicida. Aunque todas las moléculas sean estructuralmente muy similares, al diferir en uno o varios grupos funcionales, sus propiedades biológicas son completamente diferentes e impredecibles. Todos estos análogos han sido recogidos en rutas sintéticas lineales formadas por reacciones de acoplamiento como Suzuki y Sonogashira y otras reacciones orgánicas como clorinaciones, saponificaciones, esterificaciones, etc.

211 p. [EN]This thesis describes the synthesis of a library of novel sp3-rich N-heterocycles containing orthogonal functionality via a palladium-catalysed allylation-condensation sequence. The employment of a readily available cyclic carbamate in the presence of a palladium catalyst generates a palladium-stabilised zwitterion, which reacts with a wide range of carbonyl substrates to provide the corresponding a-allylated compounds. These products can be further converted into six-membered N-heterocycles through a TFA-mediated deprotection-condensation step. The scope of this methodology to 1-aryl-2-indanones, 1-aryl-2-tetralones, a-fluoro-ß-ketoesters and a-trifluoromethylthio-ketones is discussed, and the potential of the final heterocyclic compounds to undergo further derivatisation is demonstrated. Furthermore, the application of this methodology towards the synthesis of lysergic acid is presented. [ES]Esta tesis describe la síntesis de una biblioteca de nuevos heterociclos nitrogenados ricos en carbonos sp3, que contienen funcionalidad ortogonal, introducida mediante una secuencia de alilación-condensación catalizada por paladio. El empleo de un carbamato cíclico fácilmente disponible, en presencia de un catalizador de paladio, genera un ion híbrido estabilizado por el metal, que reacciona con una amplia gama de sustratos de carbonilo para proporcionar los compuestos α-alilados correspondientes. Estos productos se pueden convertir adicionalmente en N-heterociclos de seis miembros, mediante una etapa de desprotección-condensación mediada por TFA.Se discute el alcance de esta metodología para 1-aril-2-indanonas, 1-aril-2-tetralonas, α-fluoro-β-cetoésteres y α trifluorometiltiocetonas, y se analiza el potencial de los compuestos heterocíclicos finales para experimentar una derivación adicional. Además, se presenta la aplicación de esta metodología a la síntesis de ácido lisérgico.

193 p. In this thesis, Density Functional Theory (DFT) methods have been applied to study the mechanisms of three different multicomponent organic reactions. Also, a new synthetic procedure for the preparation of quinolinium salts is presented, and its mechanism also studied by DFT calculations. The thesis summarizes the work realized in two universities, and is divided in the following way: The first part of the thesis concerns the development of an experimentally simple, but mechanistically complex, reaction for the formation of quaternary quinolinium salts catalyzed by palladium salts. This multicomponent process uses readily available propylamine and its derivatives as starting materials. Through DFT studies a mechanism through the activation of two aliphatic C¿H bonds is proposed. The second part focuses on the mechanistic investigation of a three-components reaction, namely terminal alkynes, CO2 and allylic chlorides, mediated by an N-heterocyclic carbene catalyst that yields propargylic esters. By DFT calculations, the rate-limiting step was identified to be the reaction between the carboxylated catalyst and the allylic chloride. Through DFT, we were also able to understand the limitations of this reaction. The mechanism of a multicomponent reaction in which allylic alcohols are transformed into ¿-functionalized carbonyls was also investigated. The reaction relies on an umpolung strategy that enables to react enol intermediates with different nucleophiles. By DFT studies, a mechanism via enolonium intermediates is proposed, which provides an understanding of the selectivity of the reaction. The final chapter of the thesis deals with another multicomponent solvent-free reaction for synthesizing propargylamines catalyzed by manganese via a KA2 coupling. DFT studies were undertaken and a mechanism via manganese phenylacetylide species is proposed. 193 p.

[EU]Lan honetan laborategian egin diren diamina kiralez organokatalizatutako enamina eta maleimida molekulen arteko Michael adizio erreakzioaren enantioselektibotasuna ikerketa konputazionalen bidez azaldu da. Azterketan katalizatazaileak erreakzioan duen mekanismoan sakondu da, diamina organokatalizatzailearen talde desberdinen eta disolbatzailearen efektua azalduz purutasun enantiomerikoan. [EN]In this work, Michael addition of enamine and maleimide organocatalyzed by diamine reactions have been explained by a computational study. In the research, the mechanism of the catalyst has been studied in depth, explaining the effect of different groups of the diamine organocatalyst and the solvent.

78 p.(parte I); 110 p.(parte II) La presente tesis consiste en una serie de estudios realizados en el marco de la química computacional. La teoría del funcional de la densidad ha sido aplicada para la simulación de diversas reacciones químicas. Mediante la optimización y el cálculo de las energías de sustratos, intermedios, productos y estados de transición, se han elucidado los mecanismos de reacciones pericíclicas y de reacciones catalizadas por metales. Concretamente, se ha examinado la estereoespecificidad de reacciones 6¿-electrocíclicas que utilizan oximas como producto de partida. El mecanismo ha estudiado y clasificado como pseudopericíclico mediante el analisis de la aromaticidad del estado de transición. En cuanto a las reacciones organometálicas, por un lado se ha estudiado una reacción intramolecular de Fujiwara-Moritani para la síntesis de 1,4-dihidroquinolinas, explorando el mecanismo con el objetivo de explicar los diferentes isómeros observados experimentalmente. Por otro lado, se han estudiado una serie de cicloisomerizaciones catalizadas por oro y platino, cuya compleja reactividad ha podido ser racionalizada. Los estudios computacionales han sido llevados a cabo en colaboración con diferentes grupos experimentales, y han dado como resultado tres publicaciones científicas.

275 p. The present thesis deals with three different topics that have in common the formation of carbo- and heterocycles. The whole work is organized as a synergy of experimental and computational studies to provide a deep understanding of the systems of interest.The first chapter contains an introduction about computational chemistry with a particular focus on DFT and its application. The second chapter regards asymmetric catalysis and includes two works made in collaboration with the group of Prof. Palomo at the Universidad del País Vasco. Bifunctional catalysts are employed to afford good levels of stereoselectivity in the alpha-functionalization of challenging substrates, as substituted dienolates and trienolates, with olefins. Computational studies were performed mainly to rationalize the role of the catalyst. The third chapter in collaboration with the group of Prof. E. Occhiato at the Universitá degli Studi di Firenze presents two examples of gold catalysis applied to the [3,3]-rearrangement/Nazarov reaction of propargylic esters and the tandem Claisen Rearrangement/Hydroarylation reaction of propargyl vinyl ethers. The mechanism of the reactions were studied computationally, as well as the effect of particular features in the substrates or in the catalysts. The last two chapters concern the synthesis of fluorinated isoquinolines and computational studies on particular issues encountered experimentally. The strategy employed is a two step reaction that includes a Rh-catalyzed CH activation of oximes with difluoroalkenes and an electrocyclisation.

Carbonylative cross coupling reactions are of high interest in many organic chemistry syntheses, because they cover numerous organic transformations. A huge number of publications have been done in the last years with regard to C-C cross coupling reactions, but not many of them are related to one- pot late stage functionalization. In this thesis a novel methodology for one-pot carbonylative Sonogashira coupling reaction has been established. In this process aryl iodides are used as starting materials and N-formyl saccharin is employed as CO source, in order to avoid CO gas directly. Carbon isotope exchange has also been studied. For that labeled CO source is used; 13C N-Formyl saccharin. The introduction of 14C in this procedure could in one future be used for different analysis of regulative administrations as part of drug discovery and development processes. Akoplamendu gurutzatu karbonilatiboko erreakzioak oso interesgarriak dira kimika organikoaren sintesi askotan, eraldaketa organiko ugari hartzen dituztelako. Azken urteotan, C-C akoplamendu gurutzatuaren erreakzioei buruzko argitalpen ugari egin dira, baina ez dira asko pote batean eta fase berantiar baten funtzionalizazioari buruzkoak. Tesi honetan Sonogashira karbonilazio akoplamenduerreakziorako metodologia berritzaile bat ezarri da, erreakzioa pote batean eginez. Prozesu honetan, ioduro ariloak erabiltzen dira abiapuntuko material bezala, eta N-formilsakarina erabiltzen da karbono monoxidoaren iturri bezala, zuzenean CO gasa erabili beharrean. Karbono-isotopo trukea ere aztertu da. Horretarako 13C N-formilsakarina etiketa-iturria erabili da. 14C etorkizunean prozedura honetan ere erabil liteke administrazio arautzaileen analisi desberdinetarako, sendagaiak aurkitzeko eta garatzeko prozesuen zati gisa.

210 p., Organometallic chemistry is one of the main research topics in chemical science.Nowadays, organometallic reactions are the subject of intensive theoretical investigations.However, in many cases, only joint experimental and theoretical effortscould reveal the answers what we are looking for.The fruits of such experimental and theoretical co-operations will be presentedhere. In this work, we are going to deal with homogeneous organometallic catalysisusing computational chemical tools. Particularly, DFT study of palladium andgold-catalyzed reactions and special carbometalations will be described.Chapter 1 gives an introductory overview of organometallic chemistry andcatalysis in general using a historical perspective. It covers the 9 thousand yearshistory of catalysis from 7000 BC (the earliest concrete evidence of man-made fermentation/biocatalysis) through several milestones (Libavius, Berzelius etc.) upto the present days of organometallic chemistry.Chapter 2 is a short methodological summary and intended to shed some lighton the theoretical foundations of the applied quantum chemical tools, but it is neithercomplete, nor deep, just enough to scratch the surface and give insight into thecomplexity of the theory.The results of our calculations presented in three separate chapters,(Chapter 3, 4 and 5) in each of which the calculations discussed along with theviiiSupervisor: Prof. Enrique Gómez Bengoa Author: Béla Fisercorresponding experimental findings of our collaborators and/or other scientists.Chapter 3 describe specific issues of palladium-catalyzed reactions. In this partof the work, palladium(II)-catalyzed dynamic kinetic asymmetric C¿P couplingfor the asymmetric synthesis of QUINAP and other atropos P,N-ligands is discussedand the reaction investigated at the M06/6-31+G(d,p)/SDD//B3LYP/6-31G(d)/LANL2DZ level of theory. The computational results along with xperimentalevidences collected by our collaborators allowed to propose a mechanismbased on the formation of cationic oxidative addition intermediates which underthe reaction conditions, undergo a fast interconversion (Figure 0.0.1). Coordinationof the isoquinoline N atom to Pd is essential to facilitate this process.Figure 0.0.1: Proposed Mechanism for the Epimerization of DiastereomericOxidative Addition Intermediates (OAI and OAI¿).The calculations also show that the energy requirements for a dynamic kineticprocess are met, since the fast equilibrating palladacyclic intermediates evolve throughixSupervisor: Prof. Enrique Gómez Bengoa Author: Béla Fiserdiastereomeric transmetalation steps of very large energy difference. The easinessof the final reductive elimination ensures the irreversibility of the process.Chapter 4 can be divided into two parts in which gold(I)-catalyzed reactionsare studied.In the first section, the tandem gold(I)-catalyzed rearrangement/Nazarov reactionof propargylic ester derivatives studied in deeply computationally and thecalculations revealed the details of the reaction mechanism (Figure 0.0.2) whichallowed us to evaluate energetically the influence of the substrate structures on thereaction rate and on the regio- and stereoselectivity.Figure 0.0.2: Reaction Mechanism. Top: Acetate Rearrangement in the InitialSteps of the Mechanism. Bottom: Cyclization Step from the pre-Nazarovcyclization complex III and Protodeauration. Gibbs Free Energy Changes(¿G) and Barrier Heights (¿Gz) are Given in kcal/mol.xSupervisor: Prof. Enrique Gómez Bengoa Author: Béla FiserIn the second section, gold(I)-catalyzed cycloisomerizations calculated (Figure0.0.3). The calculations showed that with both types of substrates, the oxyaurationstep has a low barrier or almost no barrier at all when it involves the internalposition of a terminal triple bond, resulting in a 5-exo-dig process. In contrast,the 6-endo-dig mechanism is always favoured with substituted alkynes. The preferencebeing purely geometrical and irrespective of the type of substitution, thusproviding either ß-enaminones or their reduced equivalents, ß-amino ketones, ina robust, reliable, and convenient way.Figure 0.0.3: Transition State Structures and the Corresponding BarrierHeights (¿Gz, in kcal/mol) for Terminal and Internal Alkynes.xiSupervisor: Prof. Enrique Gómez Bengoa Author: Béla FiserChapter 5 is a systematical study of intramolecular metal catalyzed cyclizations.Group 10 alkyl metalations are studied systematically by means of DFT calculationsand based on the results the extension of the Baldwin¿s rules for metal catalyzedring closure reactions is proposed (Figure 0.0.4).Figure 0.0.4: Studied Group 10 Alkyl Metalations.An intuitive summary of the qualitative results created and the results couldserve as a guide to explore not yet described cyclization processes based on the accessiblecomputed activation energies and the qualitative comparison of the preferences.Our manuscripts published in connection with the topics discussed in the thesiscan be found in the Appendix.xiiSupervisor: Prof. Enrique Gómez Bengoa Author: Béla FiserA Computational Glance at Organometallic Cyclizationsand Coupling ReactionsAbstractLa química organometálica es uno de los campos más activos de investigación enciencias químicas. Hoy en día, las reacciones organometálicas son sujeto de numerosasinvestigaciones teóricas. Sin embargo, en muchos casos, sólo los esfuerzosconjuntos teóricos y experimentales son capaces de encontrar las respuestasque buscamos. En este trabajo se presentan los frutos de tales colaboracionesexperimentales/teóricas. Hemos empleado herramientas computacionales paraestudiar reacciones catalizadas en condiciones homogéneas, y más concretamentedescribimos a continuación estudios DFT de reacciones de ciclación catalizadaspor Paladio y Oro, así como algunos tipos de carbometalación.Capítulo 1. Se da un repaso introductorio de la catálisis organometálica ycatálisis en general usando una perspectiva histórica. Cubre los 9000 años de historiade la catálisis desde el 7000 a. C. (la más antigua evidencia de fermentación/ biocatálisis hecha por el hombre) a través de diversos hitos (Libavius, Berzelius,etc.) hasta la química organometálica de nuestros días.Capítulo 2. Es una breve descripción metodológica que intenta dar luz sobrelas formulaciones teóricas que se aplican en las herramientas químicas cuánticas,sin la intención de ser completa ni profusa, sino solamente arañando la superficiede esta parte tan compleja de la teoría.Los resultados de nuestros cálculos se presentan en tres capítulos separadosxiiiSupervisor: Prof. Enrique Gómez Bengoa Author: Béla Fiser(capítulos 3, 4 y 5), en cada uno de los cuales se entremezclan con los resultadosexperimentales de nuestros colaboradores y otros grupos de investigación.Capítulo 3. Describe algunas características especiales de la química del paladio.En esta parte de la Tesis, se han estudiado reacciones de síntesis asimétricade QUINAP, mediante un acoplamiento C-P dinámico cinético asimétrico catalizadopor complejos de paladio (II). Además de QUINAP, se han estudiado otrosatropo-ligandos P, N por métodos DFT al nivel de cálculoM06/6-31+G(d,p)/SDD//B3LYP/6-31G(d)/LANL2DZ.Figure 0.0.1: Mecanismo Propuesto para la Epimerización de los IntermediosDiastereoméricos de Adición Oxidante (OAI y OAI¿).xivSupervisor: Prof. Enrique Gómez Bengoa Author: Béla FiserLos resultados computacionales junto a las evidencias experimentales recopiladaspor nuestros colaboradores nos permiten proponer un mecanismo de reacciónbasado en la formación de intermedios catiónicos de adición oxidante, queen las condiciones de reacción sufren una interconversión rápida entre diferentesisómeros (Figura 0.0.1). La coordinación del nitrógeno de la isoquinolina al átomode Pd es esencial para facilitar el proceso.Los cálculos también muestran que se cumplen los requisitos energéticos parauna resolución cinética dinámica, ya que los intermedios de reacción equilibranrápidamente y evolucionan por estados de transición de transmetalación de barrerasde activación muy diferentes.xvSupervisor: Prof. Enrique Gómez Bengoa Author: Béla FiserCapítulo 4. Se divide en dos partes en las que se estudian dos reacciones catalizadaspor Au(I) diferentes. En la primera sección, se ha estudiado computacionalmenteal detalle la reacción tándem de transposición / ciclación Nazarov catalizadaspor Au(I) de ésteres propargílicos, y nuestros cálculos revelan el mecanismodetallado en la Figura 0.0.2, permitiéndonos evaluar energéticamente la influenciade las estructuras de los substratos en la velocidad de reacción y en la regio- yestereoselectividad.Figure 0.0.2: Mecanismo de Reacción. Arriba: Transposición de Acetato enlos Inicios de la Reacción. Abajo: Paso de Ciclación desde el Complejo pre-Nazarov III y Protodesauración. Los Cambios en la Energía Libre de Gibbs(¿G) y Barreras de Activación (¿Gz) se dan en kcal/mol.xviSupervisor: Prof. Enrique Gómez Bengoa Author: Béla FiserEn la segunda sección, se han calculado reacciones de cicloiosomerización catalizadaspor Au(I) (Figura 0.0.3). Los cálculos muestran que para ambos tipos desustratos mostrados, el paso de oxiauración ocurre con una barrera de activaciónmuy baja o inexistente cuando ocurre en la posición interna del triple enlace, resultandoen un proceso 5-exo-dig. La preferencia es puramente geométrica e independientedel tipo de sustitución, dando lugar tanto las ß-enaminonas como susequivalentes reducidos, ß-amino cetonas, de un modo robusto, apropiado y fiable.Figure 0.0.3: Estructuras de los Estados de Transición y sus CorrespondientesBarreras de Activación (¿Gz, se dan en kcal/mol) para los AlquinosTerminales e Internos.xviiSupervisor: Prof. Enrique Gómez Bengoa Author: Béla FiserCapítulo 5. Es un estudio sistemático de reacciones de ciclación catalizadaspor metales de transición. Se han estudiado sistemáticamente las ciclaciones conlos metales del grupo 10 por métodos computacionales, y basándonos en los resultados,se propone una extensión de las reglas clásicas de Baldwin para ciclacionesa la catálisis metálica (Figura 0.0.4)Figure 0.0.4: Metalaciones del Grupo 10 Estudiadas.Los resultados cualitativos han dado lugar a un resumen intuitivo de los resultadosque podría servir como guía para explorar nuevos procesos catalíticos decarbometalación.Los manuscritos publicados como resultado de estos capítulos se adjuntan enel Apéndice I.xviii