A computational glance at organometallic cyclizations and coupling reactions

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.xvii

Ortho-Methoxy Group as a Mild Inhibitor of the Reactions Between Carboxylic Acid and Phenols

According to the current database of natural products, over 25,000 compounds contain a vanillyl ring in their structure. The reasoning behind the high occurrence of the vanillyl ring structure seemed to be poorly understood, specifically the preference for a methoxy-substituted phenol structure as opposed to its dihydroxy analogue. To better understand this, we investigated the reaction mechanisms of two methoxyphenol structures, in syn and anti conformations, two hydroxyphenol structures, also in syn and anti conformations, and phenol as a reference structure, with acetic acid. Of the starting structures, the syn hydroxyphenol was found to be kinetically the most reactive, and formed the most stable product, while both hydroxyl-substituted phenols reacted more favorably with acetic acid than the methoxyphenols. A preference for the methoxyphenol molecule may exist as a way to hinder the formation of stable covalent bonds between natural products and cellular components. This work is licensed under a Creative Commons Attribution 4.0 International License

Glutathione as a Prebiotic Answer to alpha-Peptide Based Life.

The energetics of peptide bond formation is an important factor not only in the design of chemical peptide synthesis, but it also has a role in protein biosynthesis. In this work, quantum chemical calculations at 10 different levels of theory including G3MP2B3 were performed on the energetics of glutathione formation. The strength of the peptide bond is found to be closely related to the acid strength of the to-be N-terminal and the basicity of the to-be C-terminal amino acid. It is shown that the formation of the first peptide activates the amino acid for the next condensation step, manifested in bacterial protein synthesis where the first step is the formation of an N-formylmethionine dipeptide. The possible role of glutathione in prebiotic molecular evolution is also analyzed. The implications of the thermodynamics of peptide bond formation in prebiotic peptide formation as well as in the preference of alpha- instead of beta- or gamma-amino acids are discussed. An empirical correction is proposed for the compensation of the error due to the incapability of continuum solvation models in describing the change of the first solvation shell when a peptide bond is formed from two zwitterions accompanied by the disappearance of one ion pair

Molecular Design of Sugar-Based Polyurethanes

Polyurethane (PUs) are present in many aspects of everyday lives such as the rigid foam insulation panel in construction, seat cushion in automotive and elastomeric materials in medical industries. Conventional PUs are made from petrochemical based starting materials which raised severe health and environmental concerns. The substitution of petro-based polyols with carbohydrate polyols have shown to improve biodegradability and mechanical properties of PUs. Reaction pathways were examined with density functional theory to design novel environmental friendly polyurethanes. Based on the calculated thermodynamic properties, the reactivity of sugars towards isocyanates was compared. Fructose was found to be the most reactive as the corresponding fructose-isocyanate reaction has the lowest energy barrier of 135.6 kJ/mol. Therefore, the results obtained have encouraged the synthesis of fructose-based polyurethane foam. The synthesis was successful, and the produced fully fructose-based foam was stable with minimal sign of shrinkage. This work is licensed under a Creative Commons Attribution 4.0 International License

Enantioselective Michael addition of isobutyraldehyde to nitroalkenes organocatalyzed by chiral primary amine-guanidines

Primary amine-guanidines derived from trans-cyclohexane-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of isobutyraldehyde to arylated and heteroarylated nitroalkenes. The reaction was performed in the presence of imidazole as the additive in aqueous DMF as the solvent at 0 °C. The corresponding Michael adducts bearing a new stereocenter were obtained in high yields and with enantioselectivities of up to 80%. Theoretical calculations are used to justify the observed sense of the stereoinduction.Spanish Ministerio de Economía y Competitividad (projects CTQ2010-20387, CTQ2010-21263-C02 and Consolider Ingenio 2010, CSD2007-00006), FEDER, the COST Action CM0905 ‘Organocatalysis’, the Generalitat Valenciana (Prometeo/2009/039), the Basque Government (GV Grant IT-291-07), the FP7 Marie Curie Actions of the European Commission via the ITN ECHONET Network (MCITN-2012-316379) and the universities of Alicante and the Basque Country

Pyrimidine-Derived Prolinamides as Recoverable Bifunctional Organocatalysts for Enantioselective Inter- and Intramolecular Aldol Reactions under Solvent-Free Conditions

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

Impairment of a model peptide by oxidative stress: Thermodynamic stabilities of asparagine diamide C(alpha)-radical foldamers

Electron structure calculations on N-acetyl asparagine N-methylamide were performed to identify the global minimum from which radicals were formed after H-abstraction by the OH radical. It was found that the radical generated by breaking the C–H bond of the alpha-carbon was thermodynamically the most stable one in the gas- and aqueous phases. The extended ((beta)L and (beta)D) backbone conformations are the most stable, but syn–syn or inverse gamma-turn ((gamma)L) and gamma-turn ((gamma)D) have substantial stability too. The highest energy conformers are the degenerate eL and eD foldamers. Clearly, the most stable beta foldamer is the most likely intermediate for racemization