From phosphinoboranes to mercaptopyridines : a journey into the reactivity of not so frustrated Lewis pairs

La catalyse est une des pierres d’assise de la chimie moderne. Elle permet de faire des transformations difficiles d’une manière efficace et sélective, rendant possible des voies de synthèse plus courtes qui permettent ainsi à l’industrie chimique des économies de temps et d’argent. Par conséquent, le développement de la catalyse est d’une grande importance. Dans les dernières décennies, la plupart des efforts ont été orientés vers l’utilisation de métaux de transition de la seconde et troisième rangée, une approche couronnée de succès. Cependant, la maturité de ce sous-domaine et les améliorations des méthodes de caractérisation et de modélisation ont encouragé les chercheurs académiques à explorer le potentiel d’autres éléments du tableau périodique pour la catalyse. Cette thèse explore la catalyse sans métal, ou comme nous aimons l’appeler, la chimie organométallique sans métal. Elle présente des avancées dans le domaine des paires de Lewis frustrées (PLFs), qui utilisent des molécules comportant des fonctions acide de Lewis et base de Lewis pour rendre possible des transformations qui ne le seraient pas en utilisant seulement l’une ou l’autre des fonctions. Le focus particulier du travail est de comprendre et d’exploiter la chimie des PLFs. Par conséquent, nous ne nous sommes pas limités à seulement une sous-classe de PLFs ni à une seule transformation chimique. Les sujets contenus dans la thèse sont diversifiés et incluent la réduction du CO2, la fonctionnalisation de liens C-H, la chimie des liens B-B, la chimie des liens B-S ainsi que des discussions plus fondamentales sur le futur de la catalyse utilisant les PLFs.Catalysis is one of the cornerstones of modern chemistry. It allows difficult transformations to take place in an efficient and selective manner, making possible the design of shorter synthetic pathways and saving the chemical industry time and money. Thus, the improvement of catalysis is of great importance. In the past decades, most efforts have been oriented toward the use of second and third row transition metals, an approach that has been very successful. However, the maturity of that subfield and the improvement of characterization and modelization techniques have been leading academic researchers in exploring catalysis with other elements of the periodic table. This thesis explores metal-free catalysis, or as we like to call it metal-free organometallic chemistry. It presents advances in frustrated Lewis pair (FLP) chemistry, which uses molecules containing Lewis basic and Lewis acidic functions to access transformations that would not be possible using only one or the other. The focus of the work is mostly on understanding and exploiting FLP chemistry. Thus, we did not limit ourselves to some sub-class of FLP nor to only one transformation. The subjects contained in the thesis are quite diverse and include CO2 reduction, C-H bond functionalization, B-B bond chemistry, B-S bond chemistry as well as more fundamental discussions on future FLP catalysis development

Ab initio design of efficient zeolite catalysts for methanol and hydrocarbons conversion

[ES] Toda esta disertación ha utilizado la química computacional como herramienta fundamental para el análisis científico. Por ello, en el Capítulo 2 se explican los modelos y métodos teóricos sobre este tema. La primera parte del capítulo se centra en los fundamentos de la química cuántica y, en concreto, se explica con detalle la Teoría del Funcional de la Densidad la cual constituye la base de los métodos computacionales aplicados. En esta sección, las nociones básicas del método Hartree-Fock sirven de prólogo a la DFT. El Capítulo 3 presenta los primeros resultados de este trabajo correspondientes a la reacción de metanol a olefinas catalizada por diferentes zeolitas con cavidades de poro pequeño. Esta reacción es un proceso industrial relevante que produce olefinas de cadena corta como eteno (C2=), propeno (C3=) y buteno (C4=) a escala industrial a partir de la biomasa. El sistema catalítico comprende tanto la estructura inorgánica de la zeolita que contiene los sitios ácidos Brønsted como las especies orgánicas confinadas, que forman la "hydrocarbon pool" y producen olefinas ligeras mediante pasos sucesivos de metilación y craqueo. Hemos centrado nuestros esfuerzos en comprender la naturaleza de la "hydrocarbon pool", una molécula de benceno polimetilada, y sus mecanismos de reacción para poder discernir entre ellos e identificar los catalizadores adecuados para mejorar la producción de propeno o eteno en función de la topología de cada cavidad zeolitica. Hemos podido identificar el grado de metilación de la "hydrocarbon pool" como el factor clave para potenciar el mecanismo de la ruta "paring", donde el propeno es el producto mayoritario, o el mecanismo de la ruta "side-chain", siendo el eteno el producto predominante. Este hallazgo nos permite establecer una relación entre la estabilización de los dos intermedios clave y la selectividad experimental observada con un alto grado de correlación. En el Capitulo 4 presentamos una nueva herramienta para el estudio de reacciones competitivas catalizadas por zeolitas. Utilizando un cribado computacional rápido con "force fields" para los intermedios clave de la reacción y un detallado estudio mecanístico usando la teoría del funcional de la densidad somos capaces de reconocer y cuantificar sutiles diferencias en la estabilización de intermedios y estados de transición dentro de huecos microporosos similares, aproximándonos así al nivel de reconocimiento molecular de las enzimas. Con estas herramientas somos capaces de seleccionar como catalizador una zeolita que obstaculice el mecanismo "alkyl-transfer" reduciendo la producción de eteno no deseado y potenciando al mismo tiempo el mecanismo "diaryl-mediated pathway". También somos capaces de obstaculizar la desproporción de dietilbenceno, una ruta no deseada del mecanismo "diaryl-mediated pathway" que conduce a la producción de trietilbenceno, mientras que se favorece la transalquilación de dietilbenceno aumentando el rendimiento obtenido de etilbenceno. en la primera sección del Capítulo 5, estudiamos la afinidad energética de cationes alquilamonio comercialmente disponibles con ligeras diferencias en sus grupos alquilo, TEA, MTEA y DMDEA, para la síntesis de CHA y sus efectos sobre la calidad del material obtenido. Evaluamos las energías de interacción entre la zeolita y el catión de diferentes combinaciones de agentes directores y cationes Na+ con métodos DFT periódicos pudiendo distinguir pequeños efectos de estabilización causados por ligeras diferencias estructurales entre moléculas que repercuten en la estructura final sintetizada. Durante la segunda sección del Capítulo 5, identificamos las características estructurales de diferentes agentes directores de estructura para la síntesis de AEI que mejoran las probabilidades de dispersión del Al en posiciones tetraédricas distintas de T1 obteniendo un catalizador AEI diferente de los sintetizados clásicamente.[CA] Tota aquesta dissertació utilitza la química computacional com eina fonamental per a l'anàlisi científica. Per això, en el Capítol 2 s'expliquen els models i mètodes teòrics sobre aquest tema. La primera part del capítol es centra en els fonaments de la química quàntica i, en concret, s'explica amb detall la Teoria del Funcional de la Densitat la qual constitueix la base dels mètodes computacionals aplicats. En aquesta secció, les nocions bàsiques del mètode Hartree-Fock serveixen de pròleg a la DFT. El Capítol 3 presenta els primers resultats d'aquest treball corresponents a la reacció de metanol a olefines catalitzada per diferents zeolites amb cavitats de porus petit. Aquesta reacció és un procés industrial rellevant que produeix olefines de cadena curta com etè (C2=), propè (C3=) i butè (C4=) a escala industrial a partir de la biomassa. El sistema catalític comprèn tant l'estructura inorgànica de la zeolita que conté els llocs àcids Brønsted com les espècies orgàniques confinades, que formen la "hydrocarbon pool" i produeixen olefines lleugeres mitjançant passos successius de metilació i craqueig. Hem centrat els nostres esforços en comprendre la naturalesa de la "hydrocarbon pool", una molècula de benzè polimetilada, i els seus mecanismes de reacció per a poder discernir entre ells i identificar els catalitzadors adequats per millorar la producció de propè o etè en funció de la topologia de cada cavitat zeolitica. Hem pogut identificar el grau de metilació de la "hydrocarbon pool" com el factor clau per a potenciar el mecanisme de la ruta "paring", on el propè és el producte majoritari, o el mecanisme de la ruta "side-chain", sent l'etè el producte predominant. Al Capítol 4 presentem una nova eina per a l'estudi de reaccions competitives catalitzades per zeolites. Utilitzant un cribratge computacional ràpid amb "force fields" per als intermedis clau de la reacció i un detallat estudi mecanístic amb la teoria del funcional de la densitat som capaços de reconèixer i quantificar subtils diferències en l'estabilització d'intermedis i estats de transició dins de buits microporosos similars, aproximant-nos així al nivell de reconeixement molecular dels enzims. en la primera secció del Capítol 5, estudiem l'afinitat energètica de cations alquilamoni comercialment disponibles amb lleugeres diferències als seus grups alquil, TEA, MTEA i DMDEA, per a la síntesi de CHA i els seus efectes sobre la qualitat del material obtingut. Avaluem les energies d'interacció entre la zeolita i el catió entre diferents combinacions d'agents directors i cations Na+ amb mètodes DFT periòdics podent distingir petits efectes d'estabilització causats per lleugeres diferències estructurals entre molècules que repercuteixen en l'estructura final sintetitzada. Durant la segona secció del Capítol 5, identifiquem les característiques estructurals de diferents agents directors d'estructura per a la síntesi d'AEI que milloren les probabilitats de propagació de l'Al a través de posicions tetrahedriques diferents de T1 obtenint un catalitzador AEI diferent dels sintetitzats clàssicament.[EN] Computational chemistry has been used as the fundamental tool during the whole work. Therefore, the theoretical models and methods on this subject are explained in Chapter 2. The first part sketches the fundamentals of quantum chemistry and specifically explains the Density Functional Theory that constitutes the basis of the computational methods applied. In this section, basic notions of the Hartree-Fock method serve as prologue for DFT after which more practical aspects are elucidated. Chapter 3 presents the first results of this work corresponding to the methanol to olefins reaction catalysed by different small-pore cage-like zeolites. This reaction is a relevant process that produces short chain olefins such as ethene, propene and butene at industrial scale from biomass. The catalytic system comprises both the zeolite inorganic framework containing the Brønsted acid sites and the confined organic species, that form the hydrocarbon pool and produce light olefins by successive methylation and cracking steps. Our efforts are focused on understanding the nature of the hydrocarbon pool, a polymethylated benzene molecule, and its reaction mechanisms in order to be able to discern between them and identify the proper catalysts to enhance propene or ethene production based on each zeolite cavity topology. We have been able to identify the hydrocarbon pool methylation degree as the key factor to enhance paring route mechanism where propene is the predominant product, or side-chain mechanism, with ethene being the predominant product. This finding enables us to establish a relation between the stabilization of the two key intermediates and the experimental selectivity observed with a high degree of correlation. In Chapter 4 we present a new tool for the study of competing reactions catalyzed by zeolites. Using a fast computational screening with force fields for the key intermediates of the reaction and a detailed density functional theory mechanistic study we are able to recognize and quantify subtle differences in the stabilization of intermediates and transition states within similar microporous voids, thus approaching the level of molecular recognition of enzymes. With these tools we are able to select a zeolite catalyst that hinders alkyl-transfer mechanism reducing the production of non-desired ethene while enhancing the diaryl-mediated pathyways mechanism. Once we discard the non-desired mechanism, we are also able to hinder the diethylbenzene disproportionation, a non-desired route of the diaryl-mediated pathways that leads to triethylbenzene production, while favouring diethylbenzene transalkylation increasing the obtained yield of ethylbenzene. To close this chapter, the theoretical results are compared with experimental selectivities obtained for eight candidate zeolites obtaining a good correlation between theory and experiment. in the first section of Chapter 5, we study the energetic affinity of commercially available alkylammonium cations with slight differences on their alkyl chain groups, as TEA, MTEA and DMDEA, for CHA synthesis and its effects on the quality of the material obtained. We evaluate the host-guest interaction energies of different combinations of OSDAs and Na+ cations with periodic DFT methods being able to distinguish small stabilization effects caused by slight structural differences between molecules that have an impact on the final structure synthesized. On the other hand, we present a new theoretical methodology to address Al positioning prediction in SSZ-39 zeolite with the AEI framework. During the second section of Chapter 5, we identify the structural features of different OSDAs for AEI synthesis that improve the probabilities of spreading Al through different T-site positions other than T1 obtaining an AEI catalyst different from the classically synthesized.Vull agrair al Instituto de Tecnología Química per la concessió d’un contracte predoctoral, a la Red Española de Supercomputación (RES), al Centre de Càlcul de la Universitat de València, al Flemish Supercomputer Center (VSC) de la Ghent University pels recursos computacionals i el suport tècnic, a la Unió Europea i al Gobierno de España pel finançament d’aquest projecte a traves dels programes ERC-AdG-2014- 671093 (SynCatMatch) “Severo Ochoa” (SEV-2016-0683, MINECO) i dels projectes MAT2017-82288-C2-1-P i PID2020-112590GB-C21 (AEI/FEDER, UE), i al CSIC pel finançament de la estada al CMM a través del projecte i- Link (LINKA20381).Ferri Vicedo, P. (2023). Ab initio design of efficient zeolite catalysts for methanol and hydrocarbons conversion [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/19349

Physical organic studies of substituted norbornyl systems: aspects of mechanisms and chirality

Fenchone and camphor are essential natural products that are available optically pure and contribute to the chiral pool in asymmetric synthesis. Further, they are both derivatives of norbornane, a structure that undergoes a remarkable diversity of rearrangements in acidic conditions. This work explores two aspects of the camphor/fenchone derived systems. Firstly an attempt to clarify rearrangement mechanisms on a camphor system successfully via deuterium labelling and unsuccessfully via derivatization of fenchone (with rearrangement) to produce other 13C-labelled camphor substitutions, has resulted in confirmation of a theoretically proposed, highly concerted Wagner-Meerwein, 6,2 - hydride shift, Wagner-Meerwein rearrangement in competition with an associated 2,3-methide shift. Kinetics and activation parameters for many steps have been resolved in this rearrangement of the deuterium labelled camphor-derived tosylate system to two pairs of isotopomers. Further, the kinetics and formation of an unexpected pair of dimers encountered during the scheme for 13C labelling are investigated in detail. These dimers (forming during the initial stages of the synthetic scheme) are unusual in that they are not expected rotamers of each other, but diastereomers resulting from chirality of a sulfur atom in a sulfite moiety. A feasible mechanism of formation that matches the kinetics has been proposed in this unexpectedly complex system, and thermodynamic parameters have been determined. The second aspect of substituted norbornyl systems pertains to their chirality, and the influence of this chirality on reaction mixtures, with an aim to identify novel chiral micellar catalysts for use in heterogeneous reaction mixtures. Headway has been made towards the synthesis of the appropriate surfactants to be used in the construction of these micelles, but extensive molecular dynamics simulations have illustrated the feasibility of forming the stable chiral micelles in a dual-solvent system, and detail precisely the influence of chirality on surrounding media. These studies add important physical organic data as well as show the immense possibilities pertaining to substituted norbornane systems

Studying protein-ligand interactions using a Monte Carlo procedure

[eng] Biomolecular simulations have been widely used in the study of protein-ligand interactions; comprehending the mechanisms involved in the prediction of binding affinities would have a significant repercussion in the pharmaceutical industry. Notwithstanding the intrinsic difficulty of sampling the phase space, hardware and methodological developments make computer simulations a promising candidate in the resolution of biophysically relevant problems. In this context, the objective of the thesis is the development of a protocol that permits studying protein-ligand interactions, in view to be applied in drug discovery pipelines. The author contributed to the rewriting PELE, our Monte Carlo sampling procedure, using good practices of software development. These involved testing, improving the readability, modularity, encapsulation, maintenance and version control, just to name a few. Importantly, the recoding resulted in a competitive cutting-edge software that is able to integrate new algorithms and platforms, such as new force fields or a graphical user interface, while being reliable and efficient. The rest of the thesis is built upon this development. At this point, we established a protocol of unbiased all-atom simulations using PELE, often combined with Markov (state) Models (MSM) to characterize the energy landscape exploration. In the thesis, we have shown that PELE is a suitable tool to map complex mechanisms in an accurate and efficient manner. For example, we successfully conducted studies of ligand migration in prolyl oligopeptidases and nuclear hormone receptors (NHRs). Using PELE, we could map the ligand migration and binding pathway in such complex systems in less than 48 hours. On the other hand, with this technique we often run batches of 100s of simulations to reduce the wall-clock time. MSM is a useful technique to join these independent simulations in a unique statistical model, as individual trajectories only need to characterize the energy landscape locally, and the global characterization can be extracted from the model. We successfully applied the combination of these two methodologies to quantify binding mechanisms and estimate the binding free energy in systems involving NHRs and tyorsinases. However, this technique represents a significant computational effort. To reduce the computational load, we developed a new methodology to overcome the sampling limitations caused by the ruggedness of the energy landscape. In particular, we used a procedure of iterative simulations with adaptive spawning points based on reinforcement learning ideas. This permits sampling binding mechanisms at a fraction of the cost, and represents a speedup of an order of magnitude in complex systems. Importantly, we show in a proof-of-concept that it can be used to estimate absolute binding free energies. Overall, we hope that the methodologies presented herein help streamline the drug design process.[spa] Las simulaciones biomoleculares se han usado ampliamente en el estudio de interacciones proteína-ligando. Comprender los mecanismos involucrados en la predicción de afinidades de unión tiene una gran repercusión en la industria farmacéutica. A pesar de las dificultades intrínsecas en el muestreo del espacio de fases, mejoras de hardware y metodológicas hacen de las simulaciones por ordenador un candidato prometedor en la resolución de problemas biofísicos con alta relevancia. En este contexto, el objetivo de la tesis es el desarrollo de un protocolo que introduce un estudio más eficiente de las interacciones proteína-ligando, con vistas a diseminar PELE, un procedimiento de muestreo de Monte Carlo, en el diseño de fármacos. Nuestro principal foco ha sido sobrepasar las limitaciones de muestreo causadas por la rugosidad del paisaje de energías, aplicando nuestro protocolo para hacer analsis detallados a nivel atomístico en receptores nucleares de hormonas, receptores acoplados a proteínas G, tirosinasas y prolil oligopeptidasas, en colaboración con una compañía farmacéutica y de varios laboratorios experimentales. Con todo ello, esperamos que las metodologías presentadas en esta tesis ayuden a mejorar el diseño de fármacos

Doctor of Philosophy

dissertationLinear free energy relationships have been a staple of reaction mechanistic studies for nearly 100 years, enabling the quantification of subtle steric and electronic interactions between ligand, catalyst, and substrate. Recent work has offered an integrated approach to both interrogate reaction selectivity origins and to predict more optimal conditions. Classic and modern approaches to analyze ligand effects are presented in Chapter 1. Chapter 2 focuses on the development of novel descriptors for monodentate phosphine ligands. The application of these parameters to a Suzuki reaction was complicated by multiple ligation states of the catalyst. Experimental outcomes indicated that two catalyst regimes are present in the reaction; thus, separation of the results into subclasses was necessary. Doing so simplified the selectivity models, revealing nuanced ligand effects that were quantified with the new parameters. Further applications of these phosphine descriptors are detailed in Chapter 3. First, two gold-phosphine catalyzed cycloisomerization reactions are investigated using physical organic techniques along with reaction selectivity correlations. Overall, these data are used to identify the origin of ligand induced chemoselectivity, and to predict a novel ligand to increase the desired product ratio. Second, studies of an alkyl-aryl Suzuki reaction are described. In this instance, the phosphine ligand is shown to affect the enantiospecificity and chemoselectivity in two different fundamental steps. Evidence of the role ligand size and electronics play in directing the reaction pathways are presented. Chapter 4 details our team's efforts to identify a catalyst system that favors the atypical oxidative addition pathway within a Buchwald-Hartwig coupling reaction of differentially halogenated hetero-aromatics. Bidentate phosphine ligands were found to induce moderate selectivity; thus, ligand parameterization was utilized. Guided by univariate correlations, an exceedingly selective diaminophosphine ligand was successfully predicted, the origins of which were additionally analyzed with density functional theory (DFT) calculations. Using similar multivariate techniques, Chapter 5 presents the parameterization of acyclic diaminocarbene ligands developed in the context of a gold-catalyzed rearrangement-cyclization reaction. Enantioselectivity in this case was found to be highly sensitive to two substituents on the ligand, and quantification of these effects enabled the identification of a reaction system that produces highly enantioenriched products

Solid State \u3csup\u3e13\u3c/sup\u3eC NMR and Thermal Analysis of Conformational Motion and Disorder in Small and Large Molecules

In this work it is attempted to explore the conformational motion and disorder through a large number of examples of molecular systems differing in shape, rigidity, and molecular weight: a series of tetra-n-alkylammonium bromides and iodides, a liquid-crystal-forming molecule, N,N\u27-bis(4-n-octyloxybenzal)-1,4-phenylenediamine (OOBPD), and polymers, poly[oxy-1,4-(3-methylphenylene)ethylene-1,4-phenyleneoxynonamethylene] (MBPE-9) and poly[oxy-1,4-(3-methylphenylene)ethylene-1,4-phenyleneoxypentamethylene] (MPBE-5). The techniques used to study the conformational motion and disorder are mainly solid state 13C nuclear magnetic resonance (NMR) spectroscopy and thermal analysis. The results of this work show that conformational disordered states (condis crystals) exist indeed in these molecules containing flexible chemical bonds (single bonds) or more than one accessible conformer. The unique characteristics of the condis crystal and the phase transitions to a condis crystal and to isotropic state have been studied in detail. It could be show that motifs in condis crystals show only conformational disorder but maintaining orientational and positional order, while liquid and plastic crystals show conformational motion in addition to their characteristic positional and orientational disorder and motion, respectively. The molecular motion in the condis state is slow compared to well-known plastic and liquid crystals. Besides the large-amplitude motion in a first-order transition, it is documented that gradual start of motion is possible increasing the conformational entropy over a broad temperature range

NMR Spectroscopic Investigations of Brønsted Acid Catalyzed Transfer Hydrogenations

In this thesis the interactions between different Brønsted acid catalysts and imines were investigated by NMR spectroscopy. First, the strong hydrogen bond between TRIP and various imines was investigated. In all cases the hydrogen geometry was not significantly affected by the substitution pattern of the imine. Therefore, the hydrogen bond seems to be a structural anchor of the pre-catalytic species. Since, the acidity of the catalysts is modulated by the variation of the 3,3’-substituents an internal acidity scale based on the 15N chemical shifts of the imine could be implemented. In this way it could be shown that the reactivity of the investigated transfer hydrogenation correlates inverse with the internal acidity. However, isomerization and ternary complex formation also play an important role. For example, a break down in reactivity was observed if the sterical bulk of the 3,3‘-substitents hinders the binding of the second substrate and thus the ternary complex formation is hampered. Additionally, the investigations of the more acidic disulfonimide catalyst showed, that the previously observed acidity/reactivity-correlation is not applicable between different classes of catalysts. This is most probably due to the extremely weakening of the hydrogen bond caused by the higher acidity of the disulfonimide catalyst, leading to an attenuated influence of the hydrogen bond strengths on the reactivity. Furthermore, by means of a detailed quantification of isomerization rates and barriers, it could be shown that the experimentally determined isomerization barriers are significantly higher than the calculated barriers for the hydride transfer. For this reason, the hydride transfer could be neglected as rate-determining step of the investigated transfer hydrogenation, if the ternary complex is formed sufficiently

Heavier Group 2 Metals: Application to Intermolecular Hydroamination, C-F Activation and Intramolecular Hydroalkoxylation

This thesis describes the reactivity of different heavier alkaline earth catalysts [M{X(SiMe3)2}2(THF)n]m (M = Ca, Sr, Ba; X = N, CH; n= 0, 2; m= 1, 2) in the intermolecular hydroamination of styrene derivatives. The scope of these reactions with respect to the substrate was determined and detailed kinetic studies to establish rate law and temperature dependence of the hydroamination reactions reported were conducted. Overall, it was found that [Ca{N(SiMe3)2}2]2 is favoured enthalpically (Ca: ΔH‡ = 51 kJ∙mol-1, Sr: ΔH‡ = 71 kJ∙mol-1) however the corresponding strontium bis(amide) proved a significantly better catalyst, likely due to a favourably high entropy of activation value (Ca: ΔS‡ = -168 J/mol-1 ·K-1, Sr: ΔS‡ = -92 J∙mol-1∙K-1). Large kinetic isotope effects of 4.1 and 7.9 at 55 °C for the intermolecular hydroamination of styrene with piperidine mediated by [Ca{N(SiMe3)2}2]2 and [Sr{N(SiMe3)2}2]2, respectively, suggest a rate-determining alkene insertion into the M-N bond with immediate or concerted protonolysis. The methodology used in these hydroamination reactions was extended to simple dienes, diphenylacetylene and an activated enyne. The catalyst initiation of the metal bis(amides) with piperidine was shown to be reversible and the equilibrium constant solvent dependent. Novel calcium and strontium dialkyl complexes [M{CH(SiMe3)2}2(THF)2] (M= Ca, Sr) were used to overcome the problem of catalyst initiation and showed a different solvent dependence. An enhanced reactivity was found for the dialkyl complexes compared to the metal bis(amides). This increased reactivity allowed the application in new reactions such as the C-F activation of fluorobenzenes. Furthermore, the use of these catalytic systems was successfully extended to intramolecular hydroalkoxylation reactions of alkynyl alcohols in the formation of five- and six-membered enol ethers. In this case, [Ba{N(SiMe3)2}2]2 displayed significant reactivity although the “catalyst of choice” for these reactions proved to be strongly dependent on substrate substitution pattern. Through detailed kinetic studies the catalyst, substrate and temperature dependence of the cyclisation reaction were established and an unusual rate law with inverse substrate dependence proposed