Etudes Théoriques de Nouvelles Réactions Organométalliques : de la Catalyse à l'Or à la Chimie des Lanthanides Divalents

This dissertation comprises a series of theoretical studies of organometallic and organolanthanidiques complexes.Mon travail de thèse est constitué d’un ensemble d’études théoriques portant sur des complexes organométalliques et organolanthanidiques. Ces études ont toutes été réalisées en étroite collaboration avec des expérimentateurs au sein du laboratoire. Une de ces études concerne la réaction de silylation déshydrogénante des alcools catalysée par des complexes cationiques d’or (I) possédant un ligand bidente dérivé du Xantphos, le XDPP. Les résultats de cette étude nous ont conduits à proposer un cycle catalytique passant par une première étape de transfert d’hydrure du silane vers l’or et faisant intervenir le contre anion de façon explicite. Une telle participation du contre anion n’est pas courante dans la littérature et permet de rationaliser l’influence de celui-ci sur la cinétique de la réaction observée expérimentalement. Un autre pan important de ma thèse porte sur la réactivité de complexes divalents de lanthanides. La question centrale de ces travaux est celle de l’influence des propriétés électroniques des ligands sur les propriétés redox de ces complexes. En effet, il est généralement admis que les lanthanides conduisent à des complexes de coordination dans lesquels la liaison métal-ligand peut être considérée comme ionique (conséquence de la contraction spatiale des orbitales 4f). Or, des expériences récentes font soupçonner l’existence d’une influence non seulement stérique mais également électronique des ligands sur la réactivité des complexes résultants. Nos résultats viennent étayer cette hypothèse et apportent de nouveaux éléments de discussion quant à la nature exacte de l’interaction métal-ligand dans ces complexes organolanthanidiques

Enantiospecific sp(2)-sp(3) coupling of secondary and tertiary boronic esters

The cross-coupling of boronic acids and related derivatives with sp(2) electrophiles (the Suzuki-Miyaura reaction) is one of the most powerful C-C bond formation reactions in synthesis, with applications that span pharmaceuticals, agrochemicals and high-tech materials. Despite the breadth of its utility, the scope of this Nobel prize-winning reaction is rather limited when applied to aliphatic boronic esters. Primary organoboron reagents work well, but secondary and tertiary boronic esters do not (apart from a few specific and isolated examples). Through an alternative strategy, which does not involve using transition metals, we have discovered that enantioenriched secondary and tertiary boronic esters can be coupled to electron-rich aromatics with essentially complete enantiospecificity. As the enantioenriched boronic esters are easily accessible, this reaction should find considerable application, particularly in the pharmaceutical industry where there is growing awareness of the importance of, and greater clinical success in, creating biomolecules with three-dimensional architectures.</p

Stereospecific conversion of alcohols into pinacol boronic esters using lithiation-borylation methodology with pinacolborane

The synthesis of primary and secondary pinacol boronic esters via lithiation–borylation of carbamates and benzoates with pinacolborane is described. This new protocol enables the highly selective synthesis of enantioenriched and geometrically defined boronic esters that cannot otherwise be accessed by alternative methodologies

Homologation of Boronic Esters with Organolithium Compounds: A Computational Assessment of Mechanism

Ab initio calculations are reported for the reaction of methyl boronic ester with organolithium reagents with α-leaving groups. The best calculations rely on density functional theory prediction of structures and coupled-cluster theory calculation of accurate potential energies. The results provide strong confirmation of the feasibility of a two-step mechanism with rapid initial formation of a boron−ate complex followed by slower migration of methyl from boron to carbon with loss of the leaving group. The calculated free energy of activation is consistent with observed kinetic behavior, and the calculations provide a framework for exploring substituent and other effects on reactivity. Obtaining reasonable agreement with experiment in this way is not trivial and requires careful treatment of level of theory (density functional theory calculations tend to yield inaccurate results), of conformational complexity, especially for the ate complexes, and of the nature of the microscopic model of reactants and solvent. The methodological challenges and possible pitfalls, many of which are relevant more broadly to computational modeling of organic reaction mechanisms, are discussed in detail.status: publishe

Theoretical treatment of one electron redox transformation of a small molecule using f-element complexes

The theoretical treatment of single electron transfer (SET) of the redox chemistry mediated by f-element complexes is reviewed and summarized. The different computational strategies to account for the SET energy are presented and commented on the basis of the subsequent mechanistic investigation. Moreover, the mechanistic investigation of the subsequent reactivity, mainly in the field of heteroallene activation, using DFT-based approaches is also summarized. All reported reactivities are found to involve formation of bimetallic species and share in common the formation of the same key intermediate in which the substrate is doubly reduced and stabilized by two oxidized metal centers. Modern computational methods are found to efficiently account for such reactivity.</p

Development of Enantiospecific Coupling of Secondary and Tertiary Boronic Esters with Aromatic Compounds

The stereospecific cross-coupling of secondary boronic esters with sp² electrophiles (Suzuki–Miyaura reaction) is a long-standing problem in synthesis, but progress has been achieved in specific cases using palladium catalysis. However, related couplings with tertiary boronic esters are not currently achievable. To address this general problem, we have focused on an alternative method exploiting the reactivity of a boronate complex formed between an aryl lithium and a boronic ester. We reasoned that subsequent addition of an oxidant or an electrophile would remove an electron from the aromatic ring or react in a Friedel–Crafts-type manner, respectively, generating a cationic species, which would trigger 1,2-migration of the boron substituent, creating the new C–C bond. Elimination (preceded by further oxidation in the former case) would result in rearomatization giving the coupled product stereospecifically. Initial work was examined with 2-furyllithium. Although the oxidants tested were unsuccessful, electrophiles, particularly NBS, enabled the coupling reaction to occur in good yield with a broad range of secondary and tertiary boronic esters, bearing different steric demands and functional groups (esters, azides, nitriles, alcohols, and ethers). The reaction also worked well with other electron-rich heteroaromatics and 6-membered ring aromatics provided they had donor groups in the meta position. Conditions were also found under which the B­(pin)- moiety could be retained in the product, ortho to the boron substituent. This protocol, which created a new C­(sp²)–C­(sp³) and an adjacent C–B bond, was again applicable to a range of secondary and tertiary boronic esters. In all cases, the coupling reaction occurred with complete stereospecificity. Computational studies verified the competing processes involved and were in close agreement with the experimental observations

Construction of Multiple, Contiguous Quaternary Stereocenters in Acyclic Molecules by Lithiation-Borylation

Lithiation of carbamates followed by borylation provides a powerful method for the homologation of boron reagents. However, when applied to hindered systems (secondary carbamates with tBu-boronic esters) for the construction of two quaternary centers, this methodology fails. Instead, using mixed boranes (tBuBMe2) in place of boronic esters the synthesis of adjacent quaternary stereogenic centers with full stereocontrol is successful. The process can be repeated 2 or 3 times in one pot leading to carbon chains bearing multiple contiguous quaternary stereogenic centers. The boranes were converted into tertiary alcohols or C-tertiary amines using chloramine. The origin of the high selectivity for alkyl over Me group migration was determined computationally.status: publishe