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Amphotericin B has been an essential drug in the fight against leishmaniasis and fungal pathogens for decades, and has more recently gained attention for the very limited microbial resistance displayed against it. However, its toxicity has restricted its use to only the most severe cases of disease, and attempts to reduce these ill effects via formulation have had only minor success. Genetic engineering has allowed the development of superior amphotericin analogues, notably 16-descarboxyl-16-methyl amphotericin B (MeAmB), which shows a ten-fold reduction in toxicity in addition to a slight improvement in therapeutic activity. However, MeAmB is difficult to extract from its bacterial source and purify. Presented here is an alternative method of MeAmB purification. A biomimetic polymer with a high affinity for MeAmB was designed via computational modelling and synthesised. Prepared as a separation column, the polymer was able to retain the target MeAmB whilst allowing the removal of cell debris from the bacterial extract. Starting with a simple bacterial extract, the relatively simple process allowed the purification of an MeAmB salt complex at approximately 70% MeAmB, and likely higher purification from further extraction. The mean MeAmB recovery between the pre-purification extract sample and the final product was 81%. This is the first successful demonstration of extraction or purification of any amphotericin molecule with any polymeric material. The biomimetic polymer was additionally reusable and simple to fabricate, giving this technique significant advantages over traditional methods of extraction and purification of valuable compounds.

Polydentate ligands are used for thermodynamic stabilization of tetrylenes—low-valent derivatives of Group 14 elements (E = Si, Ge, Sn, Pb). This work shows by DFT calculations how the structure (the presence or absence of substituents) and type (alcoholic, Alk, or phenolic, Ar) of tridentate ligands 2,6-pyridinobis(1,2-ethanols) [AlkONOR]H2 and 2,6-pyridinobis(1,2-phenols) [ArONOR]H2 (R = H, Me) may affect the reactivity or stabilization of tetrylene, indicating the unprecedented behavior of Main Group elements. This enables the unique control of the type of the occurring reaction. We found that unhindered [ONOH]H2 ligands predominantly led to hypercoordinated bis-liganded {[ONOH]}2Ge complexes, where an E(+2) intermediate was inserted into the ArO-H bond with subsequent H2 evolution. In contrast, substituted [ONOMe]H2 ligands gave [ONOMe]Ge: germylenes, which may be regarded as kinetic stabilized products; their transformation into E(+4) species is also thermodynamically favorable. The latter reaction is more probable for phenolic [ArONO]H2 ligands than for alcoholic [AlkONO]H2. The thermodynamics and possible intermediates of the reactions were also investigated.

One of the most effective synthetic pathways to produce unsaturated compounds and polymers, meant for both industrial and pharmaceutical applications, is olefin metathesis. These useful reactions are commonly promoted by ruthenium-based precatalysts, namely the second-generation Grubbs’ catalyst (GII) and complexes bearing a styrenyl ether ligand, referred to as the second-generation Hoveyda–Grubbs’ catalyst (HGII). By altering the steric and electronic characteristics of substituents on the backbone and/or on the nitrogen atoms of the NHC ligand, it is possible to increase the reactivity and stability of second-generation ruthenium catalysts. The synthesis of an HG type II complex bearing two anti-phenyl backbone substituents (anti-HGIIPh-Mes) with mesityl N-substituents is reported. The catalytic performances of the new complex were investigated in standard ring-closing metathesis (RCM) and ring-opening metathesis polymerization (ROMP) and compared to those of the analogue complex syn-HGIIPh-Mes and to the classic HGII complex. A thorough analysis of the temperature dependence of the performances, along with a detailed comparison with the commercially available HGII, is conducted. The HGIIPh-Mes complexes are more thermally stable than their parent HGII, as shown by the fact that their activity in the ROMP of 5-ethylidene-2-norbornene does not alter when the polymerization is carried out at room temperature after the complexes have been held at 180 °C for two hours, making them particularly interesting for materials applications.

This work focuses on the design, synthesis, characterization, and application projections of low-coordinated heavy pnictogen-containing (described by the generic letter E, hence E=C) phosphaalkenes (P=C) and arsaalkenes (As=C), with emphasis on the E=C group motifs. The work aims to understand their functional and modular character, reactivity, and potential applications by stabilizing, isolating, and characterizing these species in low-coordination environments. The thesis defines a set of elementary principles that allowed the author to better understand the materials from the perspective of "functional materials", with a subset of the compounds categorized as "smart materials" after exploring and elucidating their fascinating responses in a series of experiments using electrochemical and spectroscopic techniques. The thesis successfully explains the role of the As=C and P=C units and their innate role as "directors" of the molecular electronic structure of the compounds based on their relevant actions and interactions, which led to their naming as "group motifs". By focusing on fluorene-based and DBU-based phosphaalkene systems, the research projects extend these two families of compounds. It characterizes their responses to different functional groups, environmental conditions, and constraints as settings. The work illustrates the ability of hydrogen bonding to regulate or stabilize the reactivity of the P=C sites, showing the synthesis of hydrogen-bonded adducts that are more stabilized while maintaining the intrinsic compound identity with the P=C moieties. In addition, a fascinating copper(I)-phosphaalkene complex exhibiting photoluminescence and ambipolar properties is studied. The excited state lifetimes of the compound were measured to be in the nanosecond range, which is of interest for applications. Overall, this work represents a comprehensive study of the chemistry of heavy p-block elements and their potential as materials. This work sheds light on their modularity, reactivity, and potential use as "functional materials" and "smart materials" for a variety of future applications ranging from organic electronics and catalysis to artificial intelligence

Spatial control of reactivity is intrinsically difficult in gold catalysis due to the linear coordination mode of Au(I) and the commonly flat ligands employed for Au(III) complexes. Our recent report of a novel and sterically encumbered (NNN)diiPrAu−OH complex (Eur. J. Inorg. Chem. 2021, 3561–3564.) suggested that the (NNN) ligand framework is capable of sterically interacting with substrates through its conveniently oriented aryl groups. We have now examined these steric properties in more detail by varying the ortho-substituent of the aryl group in (NNN)xAu−Cl complexes. With just small modifications we were able to vary the buried volume around the Cl atom and correlate this to yields obtained in a Au-catalyzed Overman rearrangement. Computationally we further elucidate that the stark difference in yields obtained originates from a shift in binding mode of the substrate to the Au catalyst in the rate limiting step of the reaction. We thus conclude that delicate spatial control can be exercised in gold catalysis and propose the (NNN) ligand framework to be an attractive platform for the efficient design of Au(III) complexes for stereoselective catalysis.

Novel seven‐membered cyclic imine‐based 1,3‐P,N ligands were obtained by capturing a Beckmann nitrilium ion intermediate generated in situ from cyclohexanone with benzotriazole, and then displacing it by a secondary phosphane under triflic acid promotion. These “cycloiminophosphanes” possess flexible non‐isomerizable tetrahydroazepine rings with a high basicity; this sets them apart from previously reported iminophophanes. The donor strength of the ligands was investigated by using their P‐κ1‐ and P,N‐κ2‐tungsten(0) carbonyl complexes, by determining the IR frequency of the trans‐CO ligands. Complexes with [RhCp*Cl2]2 demonstrated the hemilability of the ligands, giving a dynamic equilibrium of κ1 and κ2 species; treatment with AgOTf gives full conversion to the κ2 complex. The potential for catalysis was shown in the RuII‐catalyzed, solvent‐free hydration of benzonitrile and the RuII‐ and IrI‐catalyzed transfer hydrogenation of cyclohexanone in isopropanol. Finally, to enable access to asymmetric catalysts, chiral cycloiminophosphanes were prepared from l‐menthone, as well as their P,N‐κ2‐RhIII and a P‐κ1‐RuII complexes., Complexes, chirality and catalysts: 1,3‐P,N hybrid ligands are broadly applied in cooperative catalysis, but show limited electronic variation. We report novel analogues with a high N‐basicity, based on 7‐membered cyclic imines. Their transition metal complexes demonstrated their donor strength (W), hemilabile coordination (Rh), and catalytic activity for nitrile hydration (Ru) and transfer hydrogenation (Ru, Ir). Chiral derivatives were also obtained, synthesized from l‐menthone.

Three molybdenum trihalogenido complexes supported by different PN3P pincer ligands were synthesized and investigated regarding their activity towards catalytic N2-to-NH3 conversion. The highest yields were obtained with the H-PN3PtBu ligand. The corresponding Mo(V)-nitrido complex also shows good catalytic activity. Experiments regarding the formation of the analogous Mo(IV)-nitrido complex lead to the conclusion that the mechanism of catalytic ammonia formation mediated by the title systems does not involve N-N cleavage of a dinuclear Mo-dinitrogen complex, but follows the classic Chatt cycle.

Funder: Knut and Alice Wallenberg Foundation; Id: http://dx.doi.org/10.13039/501100004063, Enzymes are effective biological catalysts that accelerate almost all metabolic reactions in living organisms. Synthetic modulators of enzymes are useful tools for the study of enzymatic reactions and can provide starting points for the design of new drugs. Here, we report on the discovery of a class of biologically active compounds that covalently modifies lysine residues in human liver pyruvate kinase (PKL), leading to allosteric activation of the enzyme (EC50 =0.29 μM). Surprisingly, the allosteric activation control point resides on the lysine residue K282 present in the catalytic site of PKL. These findings were confirmed by structural data, MS/MS experiments, and molecular modelling studies. Altogether, our study provides a molecular basis for the activation mechanism and establishes a framework for further development of human liver pyruvate kinase covalent activators.

This thesis attempts to elucidate the mechanistic understanding for metal complexes ligated with 1,5-R-3,7-Rʹ-1,5-diaza-3,7-diphosphacyclooctane (PR2NRʹ2) ligands, which were utilized for organic transformations. Alkyne hydrofunctionalization reactions, including hydroamination and hydroalkoxylation, were previously catalyzed with [Ru(Cp/Cp*)(PR2NRʹ2)(MeCN)]PF6 catalysts. However, validation of the proposed mechanistic pathway for these complexes has not yet been realized. Investigation of these catalysts through substrate studies, intermediate isolation, kinetic analysis, and isotopic labelling was performed in an attempt to better understand the mechanism. Ligand and substrate interactions were identified that stabilized the coordinatively unsaturated complexes. Ligand modification enabled mitigation of a previously observed deactivation species, which enabled investigations for previously problematic hydroalkoxylation reactions. Formation of a new deactivation species was observed, which completely arrested productive catalysis, but gave insight into organic product release steps of the mechanism. Isolation of two vinylidene complexes enabled stoichiometric investigations to assess intermolecular hydroamination. Stoichiometric reactions with the vinylidene complex and amine nucleophiles resulted in the formation of a ruthenium acetylide complex, confirmed via independent synthesis, via deprotonation of Cβ instead of the desired nucleophilic attack of Cα. Formation of the ruthenium acetylide complex was not observed with stoichiometric reactions with aniline which was then targeted for attempted intermolecular hydroamination. Finally, investigation of palladium PR2NRʹ2 complexes were assessed for the Heck coupling of phenyltriflate and styrene, which showed regioselective formation of linear or branched product formation based on the phosphorus R substituent. Investigations into the factors controlling the regioselective product formation were performed through attempted synthesis of reaction intermediates and kinetic studies.

International audience; We report a rh(I)-catalyzed C-H bond alkylation of PhenCarPhos [= N-(2-(diphenylphosphaneyl)phenyl)carbazole] and some congener phosphine ligands with alkenes. The C-H bond functionalization occurred exclusively at the C1 position of the carbazolyl unit because the trivalent phosphine acts as a directed group. This protocol provides straightforward access to a large library of C1-alkyl substituted PhenCarPhos, which outperformed common commercial or unfunctionalized phosphines and their precursors in the Pd-catalyzed carbon dioxide-fixation reactions with propargylic amines. Designing more active ligands is one of the most important fields of catalysis and organometallic chemistry. Despite numerous advances in transition metal-catalyzed reactions, developing efficient catalytic systems is still highly desirable for industrial application, significantly decreasing their environmental impact. Among the different classes of ligands, phosphines remain the most popular with several well-established industrial processes. 1 It is admitted that the associated phosphines can modulate the activity of metal centers of catalysts through fine-tuning of their steric and electronic properties or by weak interactions in the second coordination sphere. However, the synthesis of such multifunctional phosphines with different substituents often requires multistep synthesis and the use of organometallic reagents may limit the diversity of the functional group that can be introduced in the phosphine scaffold. Since the pioneer observation by Hartwig and co-workers on Pd-catalyzed direct polyarylation of 1-(di-tert-butylphosphino)ferrocene, 2 P(III)-chelation-assisted C-H bond functionalization has become a straightforward strategy to

The synthesis and characterization of a small series of cyclic triimidazole derivatives functionalized with methylated pyridine or guanidine moieties is reported. These compounds were tested for their ability to bind to G-quadruplexes from both telomeric and oncogene promoter sequences. Some of them exhibited high affinity and effective G-quadruplex-stabilizing properties. Overall, these compounds may represent useful leads for developing more potent and selective analogues.

International audience; One monometallic and three bimetallic ruthenium nitrosyl (RuNO) complexes are presented and fully characterized in reference to a parent monometallic complex of formula [FTRu(bpy)(NO)]3+, where FT is a fluorenyl-substituted terpyridine ligand, and bpy the 2,2’-bipyridine. These new complexes are built with the new ligands FFT, TFT, TFFT, and TF-CC-TF (where an alkyne C≡C group is inserted between two fluorenes). The crystal structures of the bis-RuNO2 and bis-RuNO complexes built from the TFT ligand are presented. The evolution of the spectroscopic features (intensities and energies) along the series, at one-photon absorption (OPA) correlates well with the TD-DFT computations. A spectacular effect is observed at two-photon absorption (TPA) with a large enhancement of the molecular cross-section (σTPA), in the bimetallic species. In the best case, σTPA is equal to 1523±98 GM at 700 nm, in the therapeutic window of transparency of biological tissues. All compounds are capable of releasing NO⋅ under irradiation, which leads to promising applications in TPA-based drug delivery.

Cette thèse étudie la conception de différentes ligands pour les complexes de Ru(II) et leur activité comme photosensibilisateur (PS) dans l'évolution photocatalytique de l'hydrogène. Le système catalytique contient généralement un catalyseur, un donneur d'électron sacrificiel (SED) et un PS, qui doit présenter une forte absorption et luminescence et un comportement redox réversible. Les substituants pyridine attracteurs d'électrons sur le récepteur d'ions métalliques terpyridine entraînent une augmentation de la durée de vie de l'état excité et du rendement quantique (Φ = 74*10-5; τ = 3.8 ns) et permettent au complexe III-C1 de présenter une activité en tant que PS. Bien que la fréquence (TOFmax) et le nombre de cycle catalytique (TON) soient relativement faibles (TOFmax = 57 mmolH2 molPS-1 min 1; TON(44 h) = 134 mmolH2 molPS-1), le système catalytique a une longue durée de vie, ne perdant que 20% de son activité au cours de 12 jours. De manière intéressante, la conception hétérolytique dans III-C1 s'avère être bénéfique pour la performance en tant que PS, malgré des propriétés photophysiques et électrochimiques comparables à celles du complexe homoleptique IV-C2 (TOFmax = 35 mmolH2 molPS-1 min-1; TON(24 h) = 14 mmolH2 molPS-1). L'extinction réductive de la PS excitée par le SED est identifiée comme l'étape limitant la vitesse dans les deux cas. Par conséquent, les ligands sont modifiés pour être plus accepteurs d'électrons, soit par N-méthylation des substituants pyridine périphériques, soit par introduction d'un cycle pyrimidine dans le récepteur d'ion métallique, ce qui conduit à une augmentation des durées de vie des états excités (τ = 9–40 ns) et des rendements quantiques de luminescence (Φ = 40–400*10-5). Cependant, le caractère plus accepteur d'électrons des ligands entraîne également des potentiels de réduction décalés anodiquement, ce qui conduit à un manque de force motrice pour le transfert d'électrons du PS réduit au catalyseur. Ainsi, cette étape de transfert d'électrons s'avère être un facteur limitant de la performance globale du PS. Alors que des TOFmax plus élevés dans les expériences d'évolution de l'hydrogène sont observés pour les PS contenant le motif pyrimidine (TOFmax = 300–715 mmolH2 molPS-1 min-1), la longévité de ces systèmes est réduite avec des temps de demi-vie de 2–6 h. L'expansion des ligands contenant le motif pyrimidine en complexes dinucléaires conduit à une absorptivité plus forte (ε = 100–135*103 L mol-1 cm-1), une luminescence accrue (τ = 90–125 ns, Φ = 210–350*10-5) et peut également entraîner un TOFmax plus élevé si la force motrice est suffisante pour le transfert d'électrons vers le catalyseur (1500 mmolH2 molPS-1 min-1). En comparant des complexes avec des forces motrices similaires, une luminescence plus forte se traduit par un TOFmax plus élevé. Outre les considérations thermodynamiques, les effets cinétiques et l'efficacité du transfert d'électrons sont supposés avoir un impact sur l'activité observée dans l'évolution de l'hydrogène. En résumé, ce travail montre que la conception ciblée de ligands peut faire du groupe précédemment négligé des complexes de Ru(II) avec des ligands tridentés des candidats attrayants pour une utilisation comme PS dans l'évolution photocatalytique de l'hydrogène., This thesis investigates different ligand designs for Ru(II) complexes and the activity of the complexes as photosensitizer (PS) in photocatalytic hydrogen evolution. The catalytic system typically contains a catalyst, a sacrificial electron donor (SED) and a PS, which needs to exhibit strong absorption and luminescence, as well as reversible redox behavior. Electron-withdrawing pyridine substituents on the terpyridine metal ion receptor result in an increase of excited-state lifetime and quantum yield (Φ = 74*10-5; τ = 3.8 ns) and lead to complex III-C1 exhibiting activity as PS. While the turn-over frequency (TOFmax) and turn-over number (TON) are relatively low (TOFmax = 57 mmolH2 molPS-1 min-1; TON(44 h) = 134 mmolH2 molPS-1), the catalytic system is long-lived, losing only 20% of its activity over the course of 12 days. Interestingly, the heteroleptic design in III-C1 proves to be beneficial for the performance as PS, despite III-C1 having comparable photophysical and electrochemical properties as the homoleptic complex IV-C2 (TOFmax = 35 mmolH2 molPS-1 min-1; TON(24 h) = 14 mmolH2 molPS-1). Reductive quenching of the excited PS by the SED is identified as rate-limiting step in both cases. Hence, the ligands are designed to be more electron-accepting either via N-methylation of the peripheral pyridine substituents or introduction of a pyrimidine ring in the metal ion receptor, leading to increased excited-state lifetimes (τ = 9–40 ns) and luminescence quantum yields (Φ = 40–400*10-5). However, the more electron-accepting character of the ligands also results in anodically shifted reduction potentials, leading to a lack of driving force for the electron transfer from the reduced PS to the catalyst. Hence, this electron transfer step is found to be a limiting factor to the overall performance of the PS. While higher TOFmax in hydrogen evolution experiments are observed for pyrimidine-containing PS (TOFmax = 300–715 mmolH2 molPS-1 min-1), the longevity for these systems is reduced with half-life times of 2–6 h. Expansion of the pyrimidine-containing ligands to dinuclear complexes yields a stronger absorptivity (ε = 100–135*103 L mol-1 cm-1), increased luminescence (τ = 90–125 ns, Φ = 210–350*10-5) and can also result in higher TOFmax given sufficient driving force for electron transfer to the catalyst (TOFmax = 1500 mmolH2 molPS-1 min-1). When comparing complexes with similar driving forces, stronger luminescence is reflected in a higher TOFmax. Besides thermodynamic considerations, kinetic effects and electron transfer efficiency are assumed to impact the observed activity in hydrogen evolution. In summary, this work shows that targeted ligand design can make the previously disregarded group of Ru(II) complexes with tridentate ligands attractive candidates for use as PS in photocatalytic hydrogen evolution., In dieser Arbeit werden verschiedene Liganden für Ru(II)-Komplexe und die Aktivität der Komplexe als Photosensibilisatoren (PS) in der photokatalytischen Wasserstoffentwicklung untersucht. Das katalytische System besteht typischerweise aus einem Katalysator, einem Opferelektronendonator (SED) und einem PS, welcher eine starke Absorption und Lumineszenz sowie ein reversibles Redoxverhalten aufweisen sollte. Elektronenziehende Pyridin-Substituenten am Terpyridin-Metallionenrezeptor resultieren in einer Erhöhung der Lebensdauer des angeregten Zustands sowie der Quantenausbeute (Φ = 74*10-5; τ = 3.8 ns), was dazu führt, dass Komplex III-C1 als PS aktiv ist. Während die Wechselzahl (TOFmax) und der Umsatz (TON) relativ niedrig sind (TOFmax = 57 mmolH2 molPS-1 min-1; TON(44 h) = 134 mmolH2 molPS 1), ist das katalytische System langlebig und verliert im Laufe von 12 Tagen nur 20% seiner Aktivität. Das heteroleptische Design in III-C1 erweist sich als vorteilhaft für die Leistung als PS, obwohl III-C1 vergleichbare photophysikalische und elektrochemische Eigenschaften besitzt wie der homoleptische Komplex IV-C2 (TOFmax = 35 mmolH2 molPS-1 min-1; TON(24 h) = 14 mmolH2 molPS-1). In beiden Fällen erweist sich das reduktive Lumineszenzlöschen des angeregten PS durch den SED als geschwindigkeitsbestimmender Schritt. Daher werden die Liganden entweder durch N-Methylierung der peripheren Pyridin-Substituenten oder durch Einführung eines Pyrimidinrings in den Metallionenrezeptor elektronenziehender gestaltet, was zu erhöhten Lebensdauern des angeregten Zustands (τ = 9–40 ns) und Lumineszenzquantenausbeuten (Φ = 40–400*10-5) führt. Der stärker elektronenziehende Charakter der Liganden führt allerdings auch zu anodisch verschobenen Reduktionspotentialen, wodurch die treibende Kraft für den Elektronentransfer vom reduzierten PS zum Katalysator reduziert wird. Daher erweist sich dieser Elektronentransferschritt als ein limitierender Faktor für die Gesamtleistung des PS. Während höhere TOFmax in Wasserstoffproduktionsexperimenten für Pyrimidin-haltige PS beobachtet werden (TOFmax = 300–715 mmolH2 molPS-1 min-1), ist die Langlebigkeit für diese Systeme mit Halbwertszeiten von 2–6 h deutlich reduziert. Die Erweiterung der Pyrimidin-haltigen Liganden zu zweikernigen Komplexen führt zu einem stärkeren Absorptionsvermögen (ε = 100–135*103 L mol-1 cm-1), erhöhter Lumineszenz (τ = 90–125 ns, Φ = 210–350*10-5) und kann bei ausreichender treibender Kraft für den Elektronentransfer zum Katalysator auch zu einer höheren TOFmax führen (TOFmax = 1500 mmolH2 molPS-1 min-1). Beim Vergleich von Komplexen mit ähnlichen treibenden Kräften spiegelt sich die stärkere Lumineszenz in einem höheren TOFmax wider. Es wird angenommen, dass neben thermodynamischen Faktoren auch kinetische Effekte und die Effizienz des Elektronentransfers die beobachtete Aktivität bei der Wasserstoffentwicklung beeinflussen. Zusammenfassend zeigt diese Arbeit, dass gezieltes Ligandendesign die bisher vernachlässigte Gruppe der Ru(II)-Komplexe mit tridentaten Liganden zu attraktiven Kandidaten für den Einsatz als PS in der photokatalytischen Wasserstoffentwicklung machen kann., This thesis was conducted as cotutelle-de-thèse between the Université de Montréal and the Universität Würzburg (Germany). Cette thèse a été réalisée en cotutelle de thèse entre l'Université de Montréal et l'Universität Würzburg (Allemagne).

Ammonia oxidation catalyzed by molecular compounds is of current interest as a carbon-free source of dihydrogen. Activation of N-H bonds through coordination to transition metal centers is a key reaction in this process. We report the substantial activation of ammonia via reaction with low-valent molybdenum complexes of a diborate pentadentate ligand system. Spontaneous loss of dihydrogen from (B

Herein, we report the synthesis of a series of heteroleptic magnesium complexes stabilized with the scorpionate ligand tris(2-pyridylthio)methanide (Tptm). The compounds of the general formula [Mg(Tptm)(X)] (1-X; X = Cl, Br, I) were obtained via protonolysis reaction between the proligand and selected Grignard reagents. Attempts to isolate the potassium derivative K(Tptm) lead to decomposition of Tptm and formation of the alkene (C5H4N-S)2C=C(C5H4N-S)2, and this degradation was also modelled using DFT methods. Compound 1-I was treated with K(CH2Ph), affording the degradation product [Mg(Bptm)2] (2; Bptm = {CH(S-C5NH3)2}−). We analyzed and quantified the steric properties of the Tptm ligand using the structural information of the compounds obtained in this study paired with buried volume calculations, also adding the structural data of HTptm and its CF3-substituted congener (HTptmCF3). These studies highlight the highly flexible nature of this ligand scaffold and its ability to stabilize various coordination motifs and geometries, which is a highly desirable feature in the design of novel organometallic reagents and catalysts.

Metal sites in biology catalyse some of the most challenging and consequential reactions on Earth, ranging from oxygen transport in animals to photosynthesis in plants and nitrogen-fixation in bacteria. This astounding breadth of reactivity includes attractive features such as small molecule activation and late-stage functionalisation, all of which are achieved under physiological conditions and with exquisite stereo- and regioselectivity. For bioinorganic chemists, the direct deployment, engineering or mimicry of metalloenzymes and metal-containing biomolecules in research and commercial applications holds great potential for improving the green credentials of today’s chemical industry. The present thesis describes the synthesis, structure and reactivity of bioinspired iron complexes that model O2-activating non-heme iron enzymes such as isopenicillin N synthase (IPNS), which contains the 2-His-1-Carboxylate facial triad (2H1C) at its active site. A family of bioinspired N,N,O phenolate ligands was developed to structurally model the 2H1C and their coordination chemistry to iron and zinc was explored. These efforts resulted in the creation of an interesting series of N,N,O-bound iron and zinc thiolate complexes that model important structural aspects of the substrate-bound active site of IPNS. This research also showed that mononuclear N,N,O-bound iron(II) alpha-ketoacid complexes could be synthesised, opening up a new field of exploration related to alpha-ketoglutarate-dependent enzymes, the largest sub-family of 2H1C-containing non-heme iron enzymes.

Metal sites in biology catalyse some of the most challenging and consequential reactions on Earth, ranging from oxygen transport in animals to photosynthesis in plants and nitrogen-fixation in bacteria. This astounding breadth of reactivity includes attractive features such as small molecule activation and late-stage functionalisation, all of which are achieved under physiological conditions and with exquisite stereo- and regioselectivity. For bioinorganic chemists, the direct deployment, engineering or mimicry of metalloenzymes and metal-containing biomolecules in research and commercial applications holds great potential for improving the green credentials of today’s chemical industry. The present thesis describes the synthesis, structure and reactivity of bioinspired iron complexes that model O2-activating non-heme iron enzymes such as isopenicillin N synthase (IPNS), which contains the 2-His-1-Carboxylate facial triad (2H1C) at its active site. A family of bioinspired N,N,O phenolate ligands was developed to structurally model the 2H1C and their coordination chemistry to iron and zinc was explored. These efforts resulted in the creation of an interesting series of N,N,O-bound iron and zinc thiolate complexes that model important structural aspects of the substrate-bound active site of IPNS. This research also showed that mononuclear N,N,O-bound iron(II) alpha-ketoacid complexes could be synthesised, opening up a new field of exploration related to alpha-ketoglutarate-dependent enzymes, the largest sub-family of 2H1C-containing non-heme iron enzymes.

Metal sites in biology catalyse some of the most challenging and consequential reactions on Earth, ranging from oxygen transport in animals to photosynthesis in plants and nitrogen-fixation in bacteria. This astounding breadth of reactivity includes attractive features such as small molecule activation and late-stage functionalisation, all of which are achieved under physiological conditions and with exquisite stereo- and regioselectivity. For bioinorganic chemists, the direct deployment, engineering or mimicry of metalloenzymes and metal-containing biomolecules in research and commercial applications holds great potential for improving the green credentials of today’s chemical industry. The present thesis describes the synthesis, structure and reactivity of bioinspired iron complexes that model O2-activating non-heme iron enzymes such as isopenicillin N synthase (IPNS), which contains the 2-His-1-Carboxylate facial triad (2H1C) at its active site. A family of bioinspired N,N,O phenolate ligands was developed to structurally model the 2H1C and their coordination chemistry to iron and zinc was explored. These efforts resulted in the creation of an interesting series of N,N,O-bound iron and zinc thiolate complexes that model important structural aspects of the substrate-bound active site of IPNS. This research also showed that mononuclear N,N,O-bound iron(II) alpha-ketoacid complexes could be synthesised, opening up a new field of exploration related to alpha-ketoglutarate-dependent enzymes, the largest sub-family of 2H1C-containing non-heme iron enzymes.

The synthesis of the new bulky vinyllithium reagent (MeIPr=CH)Li, (MeIPr=[(MeCNDipp)2C]; Dipp=2,6‐iPr2C6H3) is reported. This vinyllithium precursor was found to act as a general source of the anionic 2σ, 2π‐electron donor ligand [MeIPr=CH]−. Furthermore, a high‐yielding route to the degradation‐resistant SiII precursor MeIPr⋅SiBr2 is presented. The efficacy of (MeIPr=CH)Li in synthesis was demonstrated by the generation of a complete inorganic divinyltetrelene series (MeIPrCH)2E: (E=Si to Pb). (MeIPrCH)2Si: represents the first two‐coordinate acyclic silylene not bound by heteroatom donors, with dual electrophilic and nucleophilic character at the SiII center noted. Cyclic voltammetry shows this electron‐rich silylene to be a potent reducing agent, rivalling the reducing power of the 19‐electron complex cobaltocene (Cp2Co)., Silylene? NHO Problem! Access to a new lithiated anionic N‐heterocyclic olefin (NHO) yields a complete acyclic divinyltetrelene series.

A novel sterically demanding bis(4‐benzhydryl‐benzoxazol‐2‐yl)methane ligand 6 (4−BzhH2BoxCH2) was gained in a straightforward six‐step synthesis. Starting from this ligand monomeric [M(4‐BzhH2BoxCH)] (M=Na (7), K (81 )) and dimeric [{M(4‐BzhH2BoxCH)}2] (M=K (82 ), Rb (9), Cs (10)) alkali metal complexes were synthesised by deprotonation. Abstraction of the potassium ion of 8 by reaction with 18‐crown‐6 resulted in the solvent separated ion pair [{(THF)2K@(18‐crown‐6)}{bis(4‐benzhydryl‐benzoxazol‐2‐yl)methanide}] (11), including the energetically favoured monoanionic (E,E)‐(4‐BzhH2BoxCH) ligand. Further reaction of 4−BzhH2BoxCH2 with three equivalents KH and two equivalents 18‐crown‐6 yielded polymeric [{(THF)2K@(18‐crown‐6)}{K@(18‐crown‐6)K(4‐BzhBoxCH)}]n (n→∞) (12) containing a trianionic ligand. The neutral ligand and herein reported alkali complexes were characterised by single X‐ray analyses identifying the latter as a promising precursor for low‐valent main group complexes., Bis(4‐benzhydryl‐benzoxazol‐2‐yl)methane (4−BzhH2BoxCH2) provides a versatile platform for monomeric ligands in [M(4‐BzhH2BoxCH)] (M=Na, K) and dimeric [{M(4‐BzhH2BoxCH)}2] (M=K, Rb, Cs) alkali metal complexes. Even more remarkable the reaction of 4−BzhH2BoxCH2 with three equivalents KH and two equivalents 18‐crown‐6 yields polymeric [{(THF)2K@(18‐crown‐6)}{K@(18‐crown‐6)K(4‐BzhH2BoxCH)}]n (n→∞), containing a trianionic ligand. While the monoanions only provide N,N‐chelation like NacNac the latter trianion potentially provides C,N,N,C‐chelation and should be another promising ligand platform.

Hemilabile ligands that undergo reversible changes in denticity have long been exploited to enable catalyst activation and to increase lifetime. However, this common description does not fully reflect reality with respect to the diversity of known ligand types, modes of action, and impacts on catalysis. The term structurally responsive ligand (SRL) is employed here to encompass ligands that exhibit selftuning denticity, hapticity, or versatile coordination. This Perspective covers case study examples of SRLs in catalysis and their influence on catalyst lifetime, rate, and selectivity. The examples include leading and emerging catalysts for enabling transformations, which emphasizes both the breadth and significance of this class of ligands.

Hexaarylbenzenes (HABs) are valuable precursors for the bottom-up synthesis of (nano-)graphene structures. In this work the synthesis of several bis-pyrimidine substituted HABs furnished with tert-butyl groups at different sites of the four pendant phenyl rings is reported. The synthetic procedure is based on modular [4 + 2]-Diels–Alder cycloaddition reactions followed by decarbonylation. Analysis of the solid-state structures revealed that the newly synthesized HABs feature a propeller-like arrangement of the six arylic substituents around the benzene core. Here, the tilt of the aryl rings with respect to the central ring strongly depends on the intermolecular interactions between the HABs and co-crystallized solvent molecules. Interestingly, by evading the closest proximity of the central ring using an alkyne spacer, the distant pyrimidine ring is oriented in the coplanar geometry with regard to the benzene core, giving rise to a completely different UV-absorption profile.

An enantioselective sulfimidation of 3‐thiosubstituted 2‐quinolones and 2‐pyridones was achieved with a stoichiometric nitrene source (PhI=NNs) and a silver‐based catalyst system. Key to the success of the reaction is the use of a chiral phenanthroline ligand with a hydrogen bonding site. The enantioselectivity does not depend on the size of the two substituents at the sulfur atom but only on the binding properties of the heterocyclic lactams. A total of 21 chiral sulfimides were obtained in high yields (44–99 %) and with significant enantiomeric excess (70–99 % ee). The sulfimidation proceeds with high site‐selectivity and can also be employed for the kinetic resolution of chiral sulfoxides. Mechanistic evidence suggests the intermediacy of a heteroleptic silver complex, in which the silver atom is bound to one molecule of the chiral ligand and one molecule of an achiral 1,10‐phenanthroline. Support for the suggested reaction course was obtained by ESI mass spectrometry, DFT calculations, and a Hammett analysis., A picky ligand: A chiral phenanthroline ligand allows for the site‐ and enantioselective imidation (Ns=para‐nitrosulfonyl) of a variety of sulfides. Silver acts in concert with an achiral 1,10‐phenanthroline (1,10‐phen) ligand as the catalytically active center.

Computers have become closely involved with most aspects of modern life, and these developments are tracked in the chemical sciences. Recent years have seen the integration of computing across chemical research, made possible by investment in equipment, software development, improved networking between researchers, and rapid growth in the application of predictive approaches to chemistry, but also a change of attitude rooted in the successes of computational chemistry—it is now entirely possible to complete research projects where computation and synthesis are cooperative and integrated, and work in synergy to achieve better insights and improved results. It remains our ambition to put computational prediction before experiment, and we have been working toward developing the key ingredients and workflows to achieve this.The ability to precisely tune selectivity along with high catalyst activity make organometallic catalysts using transition metal (TM) centers ideal for high-value-added transformations, and this can make them appealing for industrial applications. However, mechanistic variations of TM-catalyzed reactions across the vast chemical space of different catalysts and substrates are not fully explored, and such an exploration is not feasible with current resources. This can lead to complete synthetic failures when new substrates are used, but more commonly we see outcomes that require further optimization, such as incomplete conversion, insufficient selectivity, or the appearance of unwanted side products. These processes consume time and resources, but the insights and data generated are usually not tied to a broader predictive workflow where experiments test hypotheses quantitatively, reducing their impact.These failures suggest at least a partial deviation of the reaction pathway from that hypothesized, hinting at quite complex mechanistic manifolds for organometallic catalysts that are affected by the combination of input variables. Mechanistic deviation is most likely when challenging multifunctional substrates are being used, and the quest for so-called privileged catalysts is quickly replaced by a need to screen catalyst libraries until a new “best” match between the catalyst and substrate can be identified and the reaction conditions can be optimized. As a community we remain confined to broad interpretations of the substrate scope of new catalysts and focus on small changes based on idealized catalytic cycles rather than working toward a “big data” view of organometallic homogeneous catalysis with routine use of predictive models and transparent data sharing.Databases of DFT-calculated steric and electronic descriptors can be built for such catalysts, and we summarize here how these can be used in the mapping, interpretation, and prediction of catalyst properties and reactivities. Our motivation is to make these databases useful as tools for synthetic chemists so that they challenge and validate quantitative computational approaches. In this Account, we demonstrate their application to different aspects of catalyst design and discovery and their integration with computational mechanistic studies and thus describe the progress of our journey toward truly predictive models in homogeneous organometallic catalysis.

Boron reluctantly forms B=X (X=O, S, Se, Te) moieties, which has stimulated the quest for such species in the past few years. Based on the N,N′‐chelating β‐diketiminato ligand (HNacNac), a new amido imidazoline‐2‐imine ligand system (HAmIm) is presented, giving rise to the isolation of an exhaustive series of Lewis acid free, monomeric chalcogen B=X boranes with documented π‐bond character between boron and the chalcogen. The chalcogenoboranes are isoelectronic and isolobal to the respective ketones. The chemical behavior of the oxoborane (B=O) strongly resembles the classical carbonyl reactivity in C=O bonds. The improved stability provided by HAmIm arises from the formation of more‐stable five‐membered boron chelates versus the six‐membered NacNac analogues and from the imidazoline‐2‐imine moiety providing enhanced σ‐ and π‐donation. The HAmIm ligand class may supersede the widely employed NacNac system in certain applications., The new N,N′‐chelating amido imidazoline‐2‐imine ligand (HAmIm) was designed to supersede the widely employed β‐diketiminato ligand (HNacNac). The superior stability of the HAmIm system is exemplified for a series of chalcogenoboranes with confirmed B=X double bonds (X=O, S, Se, Te), which are isoelectronic and isolobal to ketones, including their heavier analogues.

The valence isoelectronic imido analog H2S(NtBu)4 (1) of sulfuric acid H2SO4 was synthesized, isolated, and characterized by NMR spectroscopy and high‐resolution X‐ray charge density analysis. The latter reveals strongly polarized Sδ+−Nδ− bonds with virtually no double bond character. The easy‐to‐polarize S−N bonds are an advantageous and versatile feature of sulfur nitrogen ligands, which enables them to adapt to different electron requirements of various metal cations., H2S(NtBu)4 was synthesized, isolated and characterized by NMR spectroscopy and high‐resolution X‐ray charge density analysis. The topological parameters ρ(r), ∇2 ρ(r), and ϵ characterize the two different amido S−N(H)tBu and imido S−NtBu bonds as strongly polarized single bonds. The entire SN4 unit can easily adapt to different electronic requirements.

Transition metal‐catalyzed reactions in aqueous media are experiencing a constant increase in interest. In homogenous catalysis the use of water as a solvent offers advantages in cost, safety, the possibility of two‐phase catalysis and simplified separation strategies. In the life sciences, transition metal catalysis in aqueous systems enables the ligation or modification of biopolymers in buffer systems or even in their cellular environment. In biocatalysis, aqueous systems allow the simultaneous use of enzymes and transition metal catalysts in cascade reactions. The use of water‐soluble phosphine ligands still represents the most reliable and popular strategy for transferring metal catalysts into the aqueous phase. This review summarizes the recent advancements in this field since 2009 and describes current synthetic strategies for the preparation of hydrophilic phosphines and phosphites. In addition, recent applications of transition metal catalysis in aqueous solvents using these hydrophilic ligands are presented.

The synthesis of unprecedented BINOL‐derived cationic phosphonites is described. Through the use of these phosphanes as ancillary ligands in AuI catalysis, a highly regio‐ and enantioselective assembly of appropriately designed alkynes into 1‐(aryl)benzo[5]carbohelicenes is achieved. The modular synthesis of these ligands and the enhanced reactivity that they impart to AuI‐centers after coordination have been found to be the key features that allow an optimization of the reaction conditions until the desired benzo[5]helicenes are obtained with high yield and enantioselectivity., A new family of α‐cationic phosphonites derived from BINOL has been synthesized. Their use as ancillary ligands in AuI catalysis allows the enantioselective assembly of 1‐aryl [5]helicenes with excellent yields and in up to 98 % ee.

In recognition of the key role played by integrins in several life-threatening dysfunctions, the search for novel small-molecule probes that selectively recognize these surface receptors is still open and widely pursued. Inspired by previously established aminoproline (Amp)-RGD based cyclopeptidomimetics with attracting αVβ3 integrin affinity and selectivity, the design and straightforward synthesis of 18 new AmpRGD chemotypes bearing additional structural variants were herein implemented, to shift toward peptide-like αVβ6 integrin targeted binders. The ligand competence of the synthesized products toward αVβ6 was evaluated in competitive binding assays on isolated receptors, and αVβ6/αVβ3 selectivity was determined for a subgroup of compounds, resulting in the identification of four very promising candidates. SAR considerations and docking simulations allowed us to appreciate the key structural features responsible for the observed activity.

A one‐dimensional nanotubular metal–organic framework (MOF) [Ni(Cu‐H4TPPA)]⋅2 (CH3)2NH2 + (H8TPPA=5,10,15,20‐tetrakis[p‐phenylphosphonic acid] porphyrin) constructed by using the arylphosphonic acid H8TPPA is reported. The structure of this MOF, known as GTUB‐4, was solved by using single‐crystal X‐ray diffraction and its geometric accessible surface area was calculated to be 1102 m2 g−1, making it the phosphonate MOF with the highest reported surface area. Due to the extended conjugation of its porphyrin core, GTUB‐4 possesses narrow indirect and direct bandgaps (1.9 eV and 2.16 eV, respectively) in the semiconductor regime. Thermogravimetric analysis suggests that GTUB‐4 is thermally stable up to 400 °C. Owing to its high surface area, low bandgap, and high thermal stability, GTUB‐4 could find applications as electrodes in supercapacitors., A 1D nanotubular MOF, GTUB‐4, was constructed by using the highly conjugated arylphosphonic acid H8‐TPPA. The structure of this metal–organic framework (MOF) was solved by using single‐crystal X‐ray. GTUB‐4 is characterized by high surface area and, due to the extended conjugation of its porphyrin core, possesses narrow indirect and direct bandgaps in the semiconductor regime. Owing to its high surface area, low band gap, and high thermal stability, GTUB‐4 could find applications as electrode material in supercapacitors.

Triarylsilanolates are privileged ancillary ligands for molybdenum alkylidyne catalysts for alkyne metathesis but lead to disappointing results and poor stability in the tungsten series. 1H,183W heteronuclear multiple bond correlation spectroscopy, exploiting a favorable 5J‐coupling between the 183W center and the peripheral protons on the alkylidyne cap, revealed that these ligands upregulate the Lewis acidity to an extent that the tungstenacyclobutadiene formed in the initial [2+2] cycloaddition step is over‐stabilized and the catalytic turnover brought to a halt. Guided by the 183W NMR shifts as a proxy for the Lewis acidity of the central atom and by an accompanying chemical shift tensor analysis of the alkylidyne unit, the ligand design was revisited and a more strongly π‐donating all‐alkoxide ligand prepared. The new expanded chelate complex has a tempered Lewis acidity and outperforms the classical Schrock catalyst, carrying monodentate tert‐butoxy ligands, in terms of rate and functional‐group compatibility., Angewandte Chemie. International Edition, 59 (48), ISSN:1433-7851, ISSN:1521-3773, ISSN:0570-0833

The cerium(IV) pyrazolate complexes [Ce(Me2pz)4]2 and [Ce(Me2pz)4(thf)] initiate β‐hydride abstraction of the bis(dimethylsilyl)amido moiety, to afford a heteroleptic cerium(IV) species containing a dimethylpyrazolyl‐substituted silylamido ligand, namely [Ce(Me2pz)3(bpsa)] (bpsa=bis((3,5‐dimethylpyrazol‐1‐yl)dimethylsilyl)amido; Me2pz =3,5‐dimethylpyrazolato), along with some cerium(III) species. Remarkably, the nucleophilic attack of the pyrazolyl at the silicon atom and concomitant Si−H‐bond cleavage is restricted to the tetravalent cerium oxidation state and appears to proceed via the formation of a transient cerium(IV) hydride, which engages in immediate redox chemistry. When [Ce(Me2pz)4]2 is treated with [Li{N(SiMe3)2}], that is, in the absence of the SiH functionality, any redox chemistry did not occur. Instead, the ceric ate complex [LiCe2(Me2pz)9] and the stable mixed‐ligand ceric species [Ce(Me2pz)2{N(SiMe3)2}2] were obtained., Putative heteroleptic ceric species [Ce(Me2pz)x{N(SiHMe2)2}4−x] promote the formation of a new monoanionic dipyrazolylamido pincer ligand, while both tetravalent [Ce(Me2pz)2{N(SiMe3)2}2] and trivalent [Li2(thf)2Ce(Me2pz)2{N(SiHMe2)2}3] are isolable and stable.

Palladium allyl, cinnamyl, and indenyl complexes with the ylide‐substituted phosphines Cy3P+−C−(R)PCy2 (with R=Me (L1) or Ph (L2)) and Cy3P+−C−(Me)PtBu2 (L3) were prepared and applied as defined precatalysts in C−N coupling reactions. The complexes are highly active in the amination of 4‐chlorotoluene with a series of different amines. Higher yields were observed with the precatalysts in comparison to the in situ generated catalysts. Changes in the ligand structures allowed for improved selectivities by shutting down β‐hydride elimination or diarylation reactions. Particularly, the complexes based on L2 (joYPhos) revealed to be universal precatalysts for various amines and aryl halides. Full conversions to the desired products are reached mostly within 1 h reaction time at room temperature, thus making L2 to one of the most efficient ligands in C−N coupling reactions. The applicability of the catalysts was demonstrated for aryl chlorides, bromides and iodides together with primary and secondary aryl and alkyl amines, including gram‐scale applications also with low catalyst loadings of down to 0.05 mol %. Kinetic studies further demonstrated the outstanding activity of the precatalysts with TOF over 10.000 h−1., User‐friendly and easily accessible Pd complexes of three ylide‐substituted phosphines (YPhos) were prepared and applied in C−N coupling reactions giving way to extremely active catalysts that allow for high yields and selectivities at room temperature for a wide variety of substrates. Aryl chlorides, bromides, and iodides were successfully coupled also in gram‐scale and with low catalyst loadings including difficult substrates, such as alkyl amines.

A highly enantioselective synthesis of 1,12‐disubstituted [4]carbohelicenes is reported. The key step for the developed synthetic route is a Au‐catalyzed intramolecular alkyne hydroarylation, which is achieved with good to excellent regio‐ and enantioselectivity by employing TADDOL‐derived (TADDOL=α,α,α,α‐tetraaryl‐1,3‐dioxolane‐4,5‐dimethanol) α‐cationic phosphonites as ancillary ligands. Moreover, an appropriate design of the substrate makes the assembly of [4]helicenes of different substitution patterns possible, thus demonstrating the synthetic utility of the method. The absolute stereochemistry of the newly prepared structures was determined by X‐ray crystallography and characterization of their photophysical properties is also reported., Minimalistic helicenes: The use of a chiral gold catalyst bearing an α‐cationic TADDOL‐derived phosphonite as an ancillary ligand allows the enantioselective assembly of 1,12‐disubstituted [4]helicenes—one of the smallest helical polyarene architectures.

In various nickel(II) salicylaldiminato ethylene polymerization catalysts, which are a versatile mechanistic probe for substituent effects, longer perfluoroalkyl groups exert a strong effect on catalytic activities and polymer microstructures compared to the trifluoromethyl group. This effect is accounted for by a reduced electron density on the active sites, and is also supported by electrochemical studies. Thus, β‐hydride elimination, the key step of chain transfer and branching pathways, is disfavored while chain‐growth rates are enhanced. This enhancement occurs to an extent that enables living polymerizations in aqueous systems to afford ultra‐high‐molecular‐weight polyethylene for various chelating salicylaldimine motifs. These findings are mechanistically instructive as well as practically useful for illustrating the potential of perfluoroalkyl groups in catalyst design., A good influence: Long perfluoroalkyl substituents at remote positions of the ligand can influence the active center of nickel(II) salicylaldiminato catalysts to operate with higher activities and deliver linear polyethylene of higher molecular weights.

This PhD work relates to the study of cooperative effects in catalysis with group 10 metals pincer complexes, with a particular focus on palladium. In the first chapter of this manuscript, an extensive bibliographic survey on group 10 metals pincer complexes bearing a chemically non-innocent ligand is presented. Common ground and differences between the presented systems are highlighted and discussed. They have been divided in 3 big families, depending on the reactivity exhibited by the ligand backbone (electron-rich, Lewis-acid, functional group reservoir). The second chapter presents the development and application in catalysis of a new system based not only on MLC but its use in synergy with an external Lewis acid. Thanks to this new multi-cooperative system, the formation of carbocycles (and heterocycles) was efficiently promoted through a cycloisomerization reaction involving a C-C bond formation. A wide scope of substrates could be cyclized and a complementary stereoselectivity compared to that reported in the literature was displayed by our system. The third chapter is focused on the design and the synthesis of a new non-innocent pincer ligand along with its coordination to palladium. A new dearomatized species could be generated and characterized. The non-innocent behavior of the dearomatized ligand was demonstrated through stoichiometric reactions. During this work, a rare example of a palladium-hydride complex bearing an acidic hydrogen center at a non-innocent ligand was isolated and characterized. Thanks to our ligand design, a second cooperativity mode based on a palladium-sulfide interaction could be explored and is presented in the fourth chapter of this manuscript. The stoichiometric E-H bond activation (E = Si, Ge) with this complex results in the formation of a E-sulfide bond and a palladium hydride. This cooperativity was then applied to catalysis with the hydroelementation of alkynes. In this reactivity, our ligand design brings mechanistic diversity and a complementary reaction profile compared to known systems.; Ce travail de thèse porte sur l'étude des effets coopératifs en catalyse avec des complexes pince des métaux du groupe 10, et en particulier le palladium. Dans le premier chapitre de ce manuscrit, une étude bibliographique approfondie sur les complexes pince des métaux du groupe 10 comportant un ligand chimiquement non-innocent est présentée. Les points communs et les différences entre les différents systèmes sont discutés. Ils ont été divisés en 3 grandes familles, en fonction de la réactivité du site non-innocent sur le ligand (riche en électrons, acide de Lewis, réservoir de groupes fonctionnels). Le second chapitre présente le développement et l'application en catalyse d'un nouveau système multi-catalytique basé non-seulement sur la coopérativité métal-ligand mais sur sa synergie avec un acide de Lewis externe. Grâce à ce nouveau système multi-coopératif, la formation de cycles carbonés (et d'hétérocycles) a été réalisée efficacement à travers une réaction de cycloisomérization impliquant la création d'une liaison C-C. Une large librairie de substrats a pu être cyclisée et une stéréochimie complémentaire par rapport à la littérature a été montrée par notre système multi-coopératif. Ensuite, le troisième chapitre porte sur le design et la synthèse d'un nouveau ligand pince non-innocent ainsi que sa coordination sur le palladium. Une nouvelle espèce désaromatisée a pu être générée et caractérisée. Le caractère non-innocent du ligand désaromatisée a été mis en évidence au travers de réactions stoechiométriques. Au cours de ces travaux, un rare exemple de complexes palladium-hydrure portant un atome d'hydrogène acide au sein d'un ligand non-innocent a été isolé et caractérisé. Grâce à notre design de ligand, un second mode de coopérativité basé sur une liaison palladium-soufre a pu aussi être exploré, et il est présenté dans le quatrième chapitre de ce manuscrit. L'activation stoechiométrique de liaisons E-H (E = Si, Ge) par ce complexe se traduit par la formation d'une liaison E-soufre et palladium-hydrure. Cette coopérativité a pu être ensuite appliquée en catalyse à travers l'hydroélémentation d'alcynes. Dans cette réactivité, notre design de ligand apporte une diversité mécanistique et offre un profil réactionnel complémentaire par rapport aux systèmes déjà connus.

Enantioselective reactions that install functional groups at the positions of unactivated C-H bonds can be envisioned to produce intermediates for the synthesis of the active ingredients in pharmaceuticals and agrochemicals directly from simple feedstocks. Among these C-H bond functionalization reactions, those that form carbon-silicon (C-Si) and carbon-boron (C-B) bonds have been pursued because the products of these reactions can be converted to those containing a wide range of functional groups and because compounds containing silicon and boron possess unique properties that can be valuable for medicinal and materials chemistry. Although the silylation and borylation of C-H bonds have undergone extensive development during the past two decades, enantioselective versions of these reactions were not known until a few years ago. In this Minireview, we present the rapid development of enantioselective silylation and borylation of C-H bonds, with an emphasis on the design and development of the types of chiral ligands needed to achieve these reactions and an intention to inspire an expansion of these types of transformations.

International audience; The present review describes the homogenous catalytic methodologies for the synthesis of 2,2'-bipyridines involving C-C bond formation from C-H bond. There are three main approaches to build well-decorated 2,2'-bipyridines from C-H bond cleavage: i) the formation of C2-C2 ' bond by the dimerization of (activated) pyridines, ii) the C-H bond heteroarylation of activated pyridine, or iii) the late-stage functionalization of (activated) 2,2'-bipyridines including photoredox processes. Besides the scope and limitation of each methodologies, the relevant mechanisms of reaction are also discussed.

Alkaline earth metal iodides were used as templates for the synthesis of novel silicon‐based ligands. Siloxane moieties were (cross‐)coupled and ion‐specific, silicon‐rich crown ether analogues were obtained. The reaction of 1,2,7,8‐tetrasila[12]crown‐4 (I) and 1,2‐disila[9]crown‐3 (II) with MgI2 yielded exclusively [Mg(1,2,7,8‐tetrasila[12]crown‐4)I2] (1). The larger Ca2+ ion was then employed for cross‐coupling of I and II and yielded the complex [Ca(1,2,7,8‐tetrasila[15]crown‐5)I2] (2). Cross‐coupling of I and 1,2,4,5‐tetrasila[9]crown‐3 (III) with SrI2 enables the synthesis of the silicon‐dominant 1,2,4,5,10,11‐hexasila[15]crown‐5 ether complex of SrI2 (3). Further, the compounds [Sr(1,2,10,11‐tetrasila[18]crown‐6)I2] (4), [Sr(1,2,13,14‐tetrasila[24]crown‐8)I2] (5), and [Sr(1,2,13,14‐tetrasila‐dibenzo[24]crown‐8)I2] (6) were obtained by coupling I, 1,2‐disila[12]crown‐4 (IV) or 1,2‐disila‐benzo[12]crown‐4 (V), respectively. Using various anions, the (cross‐)coupled ligands were also observed in an X‐ray structure within the mentioned complexes. These template‐assisted (cross‐)couplings of various ligands are the first of their kind and a novel method to obtain macrocycles and/or their metal complexes to be established. Further, the Si−O bond activations presented herein might be of importance for silane or even organic functionalization., Templated synthesis: Alkaline earth metal iodides were used as templates for the synthesis of novel silicon‐based ligands. Siloxane moieties were (cross‐)coupled and ion specific, silicon‐rich crown ether analogues were obtained. The coupling of various ligands gives an outlook on Group 2 ion‐catalyzed macrocycle and/or silane syntheses.

The development of new catalytic enantioselective methods is routinely carried out using easily accessible and prototypical substrates. This approach to reaction development often yields asymmetric methods that perform poorly using substrates sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include new substrates is decidedly non-trivial. Here we address this challenge through the development of a systematic workflow to broaden the applicability and reliability of asymmetric conjugate additions to substrates conventionally regarded as sterically and electronically challenging. The copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles to form tertiary centers, although successful for linear alkyl chains, fails for more sterically demanding linear α,β-unsaturated ketones. Key to adapting this method to obtain high enantioselectivity was the discovery of new phosphoramidite ligands, designed using quantitative structure-selectivity relationships (QSSR). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of twenty chiral ligands. The copper-catalyzed asymmetric addition is now more broadly applicable, even tolerating linear enones bearing tert-butyl β-substituents. The presence of common functional groups is tolerated in both nucleophiles and electrophiles, giving up to 99% yield and 95% ee across twenty examples.

New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S‐methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.

The chemistry of the heavy alkaline-earth elements calcium, strontium and barium is open for new discoveries, especially in their stabilisation processes and ligand designs. This PhD presents new alkaline-earth complexes, based on the charge-neutral homoleptic and heteroleptic species, in addition to cationic compounds, where diverse coordination spheres were examined. First, low coordinated homoleptic compounds of the form of [Ae(OR)₂]ₙ (OR = fluorinated alkoxides) were generated devoid of coordinated Lewis bases. Furthermore, these latter were employed as starting materials for the synthesis of the fluorinated monocationic parents [{L}[Ae(OR)]⁺.[WCA]⁻ (WCA = weakly coordinating anion) with increased electrophilicity. Furthermore, the relative Lewis acidity of both families of compounds, in addition to their application as Lewis acid catalysts in the aza-Piancatelli reaction are described. The aza-Piancatelli reaction is an important catalytic procedure that produces heterocyclic products with cosmetic and therapeutic values. Next, molecular alkalineearth species [Ae(LX₂)] based on dianionic ligands were prepared. Tuning the ligands between fluorinated alkoxides and phenolates along with the metal centre, manage to display a variety of compounds with different electrophilicity and coordination spheres. Finally, the heteroleptic forms of low coordinated alkaline-earth complexes were generated based on the electron-poor boryloxides and borylamide ligands. These lasts proved their ability to stabilise the alkaline-earth metals by their steric hindrance., La chimie des larges métaux alcalinoterreux, calcium, strontium et baryum, reste ouverte à de nouvelles découvertes, notamment dans leurs processus de stabilisation et la conception de ligands. Cette thèse de doctorat présente des nouveaux complexes alcalinoterreux, basant sur les espèces homoleptiques et hétéroleptiques de charge neutre, en plus des complexes cationiques, où différents sphères de coordination ont été examinés. Premièrement, les complexes homoleptiques de basse coordinance de forme [Ae(OR)₂]ₙ (OR =alcoolate fluorés) ont été générés sans coordinence de bases de Lewis. De plus, ces derniers ont été utilisés étant des produits de départ pour la synthèse de leurs parents monocationic fluorés [{L}[Ae(OR)]⁺.[WCA]⁻(WCA = anion faiblement coordonné) avec une électrophile augmenté. L’acidité de Lewis de ces deux familles de composés, en plus de leurs applications étant des catalyseurs d’acide de Lewis dans la réaction d’aza-Piancatelli sont décrits. La reaction d’aza-Piancatelli est une procédure catalytique importante produisant des hétérocycles avec des valeurs cosmétiques et thérapeutiques. Ensuite, des espèces moléculaires d’alcalino-terreux [Ae(LX₂)] basant sur des ligands dianioniques ont été préparés. En variant les ligands entre alcoolates fluorés et phénolates de même que le centre métallique, ont abouti à avoir une variété de composés avec différents éléctrophilie et sphères de coordination. Finalement, des formes hétéroleptiques de basse coordinence des complexes alcalinoterreux ont été générés basant sur des ligands borylates et borylamides relativement pauvres en électrons. Ces derniers ont montré leur capacité à stabiliser les métaux alcalino-terreux par leur encombrement stérique.

The transition-metal-catalyzed α-arylation of carbonyl compounds was first reported by Buchwald and Hartwig in 1997. This transformation has been used and studied extensively over the last two decades. Enantioselective variants were also developed that allow for controlling the product stereochemistry. However, these suffer several limitations in the context of formation of tertiary stereocenters. Presented here is our group’s contribution to this research area. The chiral Cu-bis(phosphine) dioxides catalytic system that we reported allowed accessing the enantioselective α-arylation of ketones that were not suitable for this transformation before in good yields and er up to 97.5:2.5. Preliminary insight and speculation concerning the reaction mechanism involving the unusual pairing of bis(phosphine) dioxides with transition-metal catalysts is also given.1 Introduction2 State of the Art3 Enantioselective α-Arylation of Acyclic Ketones4 Summary and Conclusions

A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic N-cyanosuccinimide has been developed. High-throughput experimentation facilitated the screen of 90 different ligands and the resultant statistical data analysis identified that ligand sigma-donation, pi-acidity and sterics are key drivers that govern yield. Categorization into three ligand groups - monophosphines, bisphosphines and miscellaneous - was performed before the analysis. For the monophosphines, the yield of the reaction increases for strong sigma-donating, weak pi-accepting ligands, with flexible pendant substituents. For the bisphosphines, the yield predominantly correlates with ligand lability. The applicability of the designed reaction to a wider substrate scope was investigated, showing good functional group tolerance in particular with boronic acids bearing electron-withdrawing substituents. This work outlines the development of a novel reaction, coupled with a fast and efficient workflow to gain understanding of the optimal ligand properties for the design of improved palladium cross-coupling catalysts., Helvetica Chimica Acta, 104 (12), ISSN:0018-019X, ISSN:1522-2675

International audience; Pseudo-benzylic substitution is an important reaction in the ferrocene series, especially to obtain ligands for catalysis. Herein, we described new reactions conditions, using fluorinated alcohols as both solvent and promoter, able to deliver iodoferrocene derivatives faster than using classical solvents. Various N, O, P and C-nucleophiles were found compatible with this transformation which occurs with full retention of stereochemistry. Original P,N-ligands were prepared by using iodine/lithium exchange-chlorophoshine trapping sequences, and their properties were evaluated in Suzuki-Miyaura and Buchwald-Hartwig coupling as well as in ketone alpha-arylation reaction.

International audience; A dimeric Cu(II) complex [Cu(II)2L2(μ2-Cl)Cl] (1) built from an asymmetric tridentate ligand (2-(((2-aminocyclohexyl)imino)methyl)-4,6-di-tert-butylphenol) and weakly coordinating anions has been synthesized and structurally characterized. In dichloromethane solution, 1 exists in a monomeric [Cu(II)LCl] (1′) (85%)–dimeric (1) (15%) equilibrium, and cyclic voltammetry (CV) and electron paramagnetic resonance (EPR) studies indicate structural stability and redox retention. Addition of phenylacetylene to the CH2Cl2 solution populates 1′ and leads to the formation of a transient radical species. Theoretical studies support this notion and show that the radical initiates an alkyne C–H bond activation process via a four-membered ring (Cu(II)–O···H–Calkyne) intermediate. This unusual C–H activation method is applicable for the efficient synthesis of propargylamines, without additives, within 16 h, at low loadings and in noncoordinating solvents including late-stage functionalization of important bioactive molecules. Single-crystal X-ray diffraction studies, postcatalysis, confirmed the framework’s stability and showed that the metal center preserves its oxidation state. The scope and limitations of this unconventional protocol are discussed.