ED Sciences Chimiques
Design and study of chiral selenium- and tellurium-based organocatalysts
by Emilie VIAUD (Institut des Sciences Moléculaires)
The defense will take place at 10h00 - Salle de conférence 3ème Est Institut des Sciences Moléculaire Bâtiment A12 351 Cours de la Libération 33405 TALENCE Cedex
in front of the jury composed of
- Philippe PEIXOTO - Chargé de recherche - Université de Bordeaux - Directeur de these
- Claudia LALLI - Chargée de recherche - ISCR - Rapporteur
- Xavier BUGAUT - Professeur des universités - LIMA - Rapporteur
- Sébastien REDON - Maître de conférences - ICR - Examinateur
- Luc VELLUTINI - Professeur des universités - ISM - Examinateur
- Patrick TOULLEC - Professeur des universités - ISM - Examinateur
Since early 2000s, organocatalysis has experienced significant growth, providing an alternative to metal-based catalysts, which are often costly and unsustainable options. In particular, organochalcogen-based (S, Se and Te) organocatalysis has become a major area of research due to the remarkable versatility of these atoms. Indeed, they are capable of initiating a wide range of chemical transformations depending on their oxidation state, acting either as a Lewis base, a Lewis acid, or even as oxidants. In contrast to selenium or sulfur, tellurium remains relatively underexplored, although it exhibits fairly similar reactivities. In this context, this thesis focuses on the design, synthesis, and application of chiral chalcogen-based catalysts. Various compounds, including chiral and achiral diselenides, selenides, and tellurides, were synthesized and subsequently employed in different asymmetric catalytic transformations. These species were notably used as Lewis bases in halolactonization, Baylis-Hillman and Corey-Chaykovsky reactions, as well as oxidantstellu in lactonization and allenylation processes. Furthermore, this work also investigated the stability of the absolute configuration of their oxidized forms (selenoxides) in solution, revealing an efficient dynamic kinetic resolution phenomenon occurring at the selenium stereocenter; a feature controlled by chiral arms possessing hydrogen-bonding capable motifs.
ED Sciences Physiques et de l'Ingénieur
Study of two-step nucleation in supercritical CO2-assisted crystallisation processes
by Pierre GUILLOU (I2M - Institut de Mécanique et d'Ingénierie de Bordeaux)
The defense will take place at 10h30 - Amphithéâtre ICMCB, 87, avenue du Dr Albert Schweitzer, 33600 PESSAC
in front of the jury composed of
- Arnaud ERRIGUIBLE - Professeur - Université de Bordeaux - Directeur de these
- Samuel MARRE - Directeur de recherche - Université de Bordeaux - CoDirecteur de these
- Jean-Noël JAUBERT - Professeur - Université de Lorraine - Rapporteur
- François PUEL - Professeur des universités - Université Paris Saclay / CentraleSupélec - Rapporteur
- Elisabeth BADENS - Professeure - Université Aix-Marseille - Examinateur
- Kévin ROGER - Chargé de recherche - Université Paul Sabatier - Examinateur
- Cyril AYMONIER - Directeur de recherche - Université de Bordeaux - Examinateur
In recent decades, numerous experimental observations of crystallisation phenomena have revealed significant discrepancies with the predictions of classical nucleation theory (CNT), suggesting, in particular, two-step nucleation mechanisms. One such mechanism is the "oiling-out" phenomenon, which corresponds to liquid-liquid demixing preceding crystallisation. This process leads to the formation of a metastable liquid phase within the parent phase prior to crystallisation, profoundly altering the crystallisation kinetics and the properties of the resulting precipitates. Whilst the oiling-out phenomenon has already been the subject of a few studies at ambient pressure, it has never been explored in compressed fluids or under supercritical conditions, particularly in the context of SAS (Supercritical AntiSolvent) and RESS (Rapid Expansion of Supercritical Solutions) processes. However, these processes offer advantages, particularly during the precipitation of active pharmaceutical ingredients (APIs) assisted by supercritical CO2, by allowing the control of certain properties of the resulting products. A better understanding of the oiling-out phenomenon under these conditions would thus enable the optimisation of these processes, and even open up avenues for controlling the amorphisation of APIs. The aim of this thesis is to provide an in-depth understanding of the mechanisms involved in oiling-out under supercritical conditions, from both a thermodynamic and a kinetic perspective, specifically concerning the mixing operation in SAS processes. An approach combining modelling and experimentation is proposed. The experimental set-ups include a high-pressure solubility measurement system using Raman spectroscopy and a microfluidic system dedicated to the study of SAS mixing operations under controlled temperature and pressure conditions. Solubility measurements of a benzoxazole (BZX) derivative at 100 bar and 40°C in acetone and CO₂ were carried out. From a thermodynamic perspective, a model of solid-fluid equilibria was established based on solubility data for the systems {(S)-naproxen + CO2}, {(RS)-ibuprofen + CO2}, {(S)-naproxen + acetone + CO2} and {BZX + tetrahydrofuran + CO2}, supplemented by their metastable liquid-vapour equilibria and spinodal limits. The model is based on the Peng-Robinson equation of state and enables the generation of phase diagrams for these systems. In parallel, a kinetic description of mixing phenomena has been proposed specifically for SAS processes. Various flow regimes have been considered, ranging from purely diffusive mixing to situations involving convection and/or turbulence. The modelling is based on the Navier-Stokes equations to describe the flows, coupled with the Maxwell-Stefan equations to incorporate the effects of non-ideal multi-component diffusion. Direct numerical simulations (DNS) were carried out, enabling a detailed analysis of the supersaturation fields and the quality of the mixture, in conjunction with the phase diagrams. Finally, we proposed a general framework for identifying conditions conducive to the occurrence of oiling-out in supercritical CO2 depending on the compounds studied. This framework highlights the coupling between thermodynamic conditions (notably the properties of triple points in the case of binary {API + CO2} mixtures) and the dynamics of the mixing operation in SAS in the emergence of this phenomenon. It also opens up prospects for extending this work to the comparative study of polymorphs, as well as enantiomerically pure or racemic compounds under supercritical conditions in CO2, with a view to achieving greater control over the properties of precipitates obtained by SAS and RESS processes.