Le N-acétylcolchinol est un composé hémi-synthétique connu pour inhiber la polymérisation de la tubuline en microtubules. Il a montré une activité prometteuse en tant qu’agent ciblant la vascularisation tumorale, cependant, sa cardiotoxicité a conduit à l’arrêt des essais cliniques en phase I. Cette thèse porte sur la synthèse et l'évaluation biologique de nouveaux allocolchicinoïdes, composés analogues du N-acétylcolchinol. Dans un premier temps, une nouvelle voie de synthèse permettant l’accès, de façon racémique, au squelette dibenzoxépine de ces molécules a été mise au point. Elle comprend notamment trois étapes clés, un couplage de Suzuki-Miyaura, une addition de Grignard et une cyclodéshydratation effectuée en présence d’un acide de Brønsted. Par la suite, trois séries d’allocolchicinoïdes de structures variées, que ce soit au niveau du cycle médian oxépine ou des substituants présents sur les noyaux benzéniques, ont été synthétisées. L’activité sur tubuline de la plupart de ces molécules a été évaluée, ce qui a conduit à une rationalisation des relations structure-activité. / N-acetylcolchinol is a semi-synthetic inhibitor of the polymerization of tubulin into microtubules, that showed promising activity as vascular-disrupting agent. However, its toxicity evidenced in phase I clinical trials precluded its further development. This thesis describes the synthesis and biological evaluation of new allocolchicinoids, analogues of N-acetylcolchinol.A racemic synthesis of the dibenzoxepine framework of these compounds was first established. A Suzuki-Miyaura coupling, a Grignard addition and a Brønsted acid-mediated cyclodehydration constituted the key steps of the strategy. Then, three different series of dibenzoxepines have been synthesized, which differ by the nature of the substituent on the oxepine medium ring and on phenyl rings. These new dibenzoxepines were tested against the inhibition of microtubule assembly, leading to a structure-activity relationship study.

Les alcools sont des partenaires électrophiles attractifs pour des réactions de substitution nucléophile puisque l'eau est le seul sous-produit de la réaction en présence de nucléophiles protiques. Malgré le fait que la réaction soit fortement intéressante, la portée des transformations catalytique reste limitée à une combinaison spécifique alcool/nucléophile, ce qui rend l’emploi d’un ensemble général de conditions catalytiques fortement élusif. Cette thèse décrit le développement d'un système général de catalyse doux pour l'activation d'une large gamme d’alcools π-activés ainsi que d’alcools aliphatiques abordant ainsi les limitations clés dans le domaine. B(C6F6)3•H2O, un acide de Brønsted fort quand il est combiné avec le nitrométhane, a été découvert comme étant un système catalytique idéal pour la substitution chimiosélective d'alcools en présence de fonctionnalités et de groupements protecteurs sensibles aux conditions acides sans le compromis typique entre vitesse de réaction, réactivité substrat/nucléophile et quantité de catalyseur. Plus particulièrement, un effet co-catalytique de composés nitro est décrit pour la réaction d’azidation des alcools aliphatiques tertiaires en employant B(C6F6)3•H2O, permettant, pour la première fois, un turnover catalytique. Sur la base des investigations cinétiques, électroniques et spectroscopiques qui ont été menées, des agrégats de composés nitro et d’acides liés par des intéractions hydrogènes sont proposé comme étant l’espèce catalytiques responsables de la cinétique de la catalyse observée. L'utilité des nouvelles conditions catalytiques a été étendue au-delà de l'activation d'alcool et appliquée au clivage des liaisons fortes C-F dans les réactions de Friedel-Crafts défluorinatives de fluorures aliphatiques tertiaires. / Alcohols are attractive electrophilic partners for nucleophilic substitution reactions as water is the only by-product in a reaction with protic nucleophiles. Despite being a highly desirable reaction, the scope of useful catalytic transformations remains limited to specific alcohol-nucleophile pairs and a general set of catalytic conditions remains elusive. This thesis describes the development of a general and mild catalyst system for the activation of a broad range of π-activated and aliphatic alcohols to address key limitations in the field. B(C6F6)3•H2O, a strong Brønsted acid, when combined with nitromethane has been found as a widely useful catalyst system for chemoselective alcohol substitution in the presence of acid sensitive functionalities and protecting groups without the typical compromises in reaction rates, substrate/nucleophile scope and catalyst loading. In particular, a co-catalytic effect of nitro compounds is described for the B(C6F6)3•H2O catalyzed azidation of tertiary aliphatic alcohols, enabling catalyst turnover for the first time. On the basis of kinetic, electronic, and spectroscopic investigations, higher order hydrogen-bonded aggregates of nitro compounds and acids are proposed as kinetically competent Brønsted acid catalysts at the origin of the enhanced reactivity. The utility of the new catalytic conditions has been extended beyond alcohol activation and applied to the cleavage of strong C–F bonds in defluorinative Friedel-Crafts reactions of tertiary aliphatic fluorides.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-04T13:24:36Z No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T15:55:49Z (GMT) No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) / Made available in DSpace on 2016-01-25T15:55:49Z (GMT). No. of bitstreams: 1 daniellelobojustopinheiro.pdf: 4869021 bytes, checksum: b4acfc12a41a6f83bf195e5947ae47cc (MD5) Previous issue date: 2015-03-31 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Carboidratos têm sido utilizados como organocatalisadores em síntese orgânica devido a sua quiralidade intrínseca. Neste trabalho foi sintetizado um novo organocatalisador aproveitando a estrutura da D-galactose como indutor de quiralidade. A síntese ocorreu em cinco etapas, a saber: proteção seletiva das hidroxilas das posições 1, 2, 3 e 4, seguida pela iodação da posição 6, substituição nucleofílica pelo grupo azido, redução à amina e por fim uma reação com anidrido ftálico. O rendimento global foi de 60 %. O organocatalisador foi testado na reação de adição de Michael entre o dibenzilideno acetona e a azalactona derivada da alanina. 20 mol% do catalisador conduziu ao produto com 57 % de rendimento e com total controle da régio- e diasteroseletividade. No escopo, vários produtos com funcionalização no esqueleto de dbas foram preparados e devidamente caracterizados pelas técnicas convencionais de análise. A determinação da estereoquímica relativa foi realizada através do uso de HPLC com fase estacionária quiral e foi atribuída como 1,2-anti após a comparação do tempo de retenção com um padrão já descrito na literatura. De maneira geral, é reportada, pela primeira vez, uma metodologia mais geral para a dessimetrização diasterosseletiva entre dbas e azalactonas catalisadas por ácido de Brønsted. / Carbohydrates have been used as organocatalysts in organic synthesis due to its inherent chirality. In this work, D-galactose was choose as a chiral pool in the catalyst design and it was prepared in five steps: selective ketalyzation of hydroxyl groups, following by an iodination and nucleophilic substitution in the presence of azide. To complete, reduction of the azide to amine and a coupling reaction with phthalic anhydride leading to the catalyst. Overall yield was 60 % for five steps. Then, the catalyst was adopted in the Michael addition reaction between dibenzylidene acetone and azalactone derivative of alanine. The product was obtained in 57% yield and with fully control of both regio- and diastereoselectivity. Next, various funcionalizated dbas were evaluated under the optimized reaction condition and the corresponding final products were fully characterized through conventional elemental analysis. The relative stereochemistry was assigned as being 1,2-anti by using chiral HPLC method. To this end, an authentic sample already described in the literature was prepared in order the retention time. In general, for the first time, a method more general to perform a diastereoselective dessymetrization of dbas in presence of azlactones by using a Brønsted acid as catalyst was described.

Brønsted and Lewis acid sites located within microporous solids catalyze a variety of chemical transformations of oxygenates and hydrocarbons. Such reactions occur in condensed phases in envisioned biomass and shale gas upgrading routes, motivating deeper fundamental understanding of the reactivity-determining interactions among active sites, reactants, and solvents. The crystalline structures of zeolites, which consist of SiO₄ tetrahedra with isomorphously-substituted M⁴⁺ (e.g., Sn⁴⁺, Ti⁴⁺) as Lewis acid sites, or Al³⁺ with charge-compensating extraframework H⁺ as Brønsted acid sites, provide a reasonably well-defined platform to study these interactions within confining voids of molecular dimension. In this work, gas-phase probe reactions that afford independent control of solvent coverages are developed and used to interpret measured rate data in terms of rate and equilibrium constants for elementary steps, which reflect the structure and stability of kinetically relevant transition states and reactive intermediates. The foundational role of quantitative kinetic information enables building molecular insights into the mechanistic and active site requirements of catalytic reactions, when combined with complementary tools including synthetic approaches to prepare active sites and surrounding environments of diverse and intended structure, quantitative methods to characterize and titrate active sites and functional groups in confining environments, and theoretical modeling of putative active site structures and plausible reaction coordinates.<br><div><br></div><div>Bimolecular ethanol dehydration to diethyl ether was developed as a gas-phase catalytic probe reaction for Lewis acid zeolites. A detailed mechanistic understanding of the identities of reactive intermediates and transition states on Sn-Beta zeolites was constructed by combining experimental kinetic measurements with density functional theory treatments. Microkinetic modeling demonstrated that Sn active site configurations undergo equilibrated interconversion during catalysis (404 K, 0.5–35 kPa C₂H₅OH, 0.1–50 kPa H₂O) from hydrolyzed-open configurations ((HO)-Sn-(OSi≡)₃---HO-Si) to predominantly closed configurations (Sn-(OSi≡)₄), and identified the most abundant productive (ethanol-ethanol dimer) and inhibitory (ethanol-water dimer) reactive intermediates and kinetically relevant transition state (S_N2 at closed sites). Mechanism-based interpretations of bimolecular ethanol dehydration turnover rates (per Lewis acidic Sn, quantified by CD₃CN IR) enabled measuring chemically significant differences between samples synthesized to contain high or low densities of residual Si-OH defects (quantified by CD₃CN IR) within microporous environments that confine Sn active sites. Hydrogen-bonding interactions with Si-OH groups located in the vicinity of Sn active sites in high-defect Sn-Beta zeolites stabilize both reactive and inhibitory intermediates, leading to differences in reactivity within polar and non-polar micropores that reflect solely the different coverages of intermediates at active sites. The ability of confining microporous voids to discriminate among reactive intermediates and transition states on the basis of polarity thus provides a strategy to mitigate inhibition by water and to influence turnover rates by designing secondary environments of different polarity via synthetic and post-synthetic techniques. </div><div><br></div><div>Despite the expectation from theory that Sn active sites adopt the same closed configurations after high-temperature (823 K) oxidation treatments, distinct Sn sites can be experimentally identified and quantified by the ν(C≡N) infrared peaks of coordinated CD₃CN molecules, and a subset of these sites are correlated with first-order rate constants of aqueous-phase glucose-fructose isomerization (373 K). In contrast, <i>in situ</i> titration of active sites by pyridine during gas-phase ethanol dehydration catalysis (404 K) on a suite of Sn-zeolites of different topology (Beta, MFI, BEC) quantified the dominant active site to correspond to a different subset of Sn sites than those dominant in glucose-fructose isomerization. An extensive series of synthetic and post-synthetic routes to prepare Sn-zeolites containing Sn sites hosted within diverse local coordination environments identified a subset of Sn sites located in defective environments such as grain boundaries, which are more pronounced in Beta crystallites comprised of intergrowths of two polymorphs than in zeolite frameworks with un-faulted crystal structures. Sn sites in such environments adopt defect-open configurations ((HO)-Sn-(OSi≡)₃) with proximal Si-OH groups that do not permit condensation to closed configurations, which resolves debated spectroscopic assignments to hydrolyzed-open site configurations. Defect-open Sn sites are dominant in glucose-fructose isomerization because their proximal Si-OH groups stabilize kinetically relevant hydride shift transition states, while closed framework Sn sites are dominant in alcohol dehydration because they stabilize S_N2 transition states via Sn site opening in the kinetically relevant step and re-closing as part of the catalytic cycle. The structural diversity of real zeolite materials, whose defects distinguish them from idealized crystal structures and allows hosting Lewis acid sites with distinct local configurations, endows them with the ability to effectively catalyze a broad range of oxygenate reactions.</div><div><br></div><div>During aqueous-phase catalysis, high extra-crystalline water chemical potentials lead to intra-pore stabilization of H₂O molecules, clusters, and extended hydrogen-bonded networks that interact with adsorbed intermediates and transition states at Lewis acid sites. Glucose-fructose isomerization turnover rates (373 K, per defect-open Sn, quantified by CD₃CN IR) are higher when Sn sites are confined within low-defect, non-polar zeolite frameworks that effectively prevent extended water networks from forming; however, increasing exposure to hot (373 K) liquid water generates Si-OH groups via hydrolysis of siloxane bridges and leads to lower turnover rates commensurate with those of high-defect, polar frameworks. Detailed kinetic, spectroscopic, and theoretical studies of polar and non-polar titanosilicate zeolite analogs indicate that extended water networks entropically destabilize glucose-fructose isomerization transition states relative to their bound precursors, rather than influence the competitive adsorption of water and glucose at active sites. Infrared spectra support the stabilization of extended hydrogen-bonded water networks by Si-OH defects located within Si- and Ti-Beta zeolites, consistent with ab initio molecular dynamics simulations that predict formation of distinct thermodynamically stable clustered and extended water phases within Beta zeolites depending on the external water chemical potential and the nature of their chemical functionality (closed vs. hydrolyzed-open Lewis acid site, or silanol nest defect). The structure of water confined within microporous solids is determined by the type and density of intracrystalline polar binding sites, leading to higher reactivity in aqueous media when hydrogen-bonded networks are excluded from hydrophobic micropores.</div><div><br></div><div>Aluminosilicate zeolites adsorb water to form (H₃O⁺)(H₂O)_n clusters that mediate liquid-phase Brønsted acid catalysis, but their relative contributions to the solvation of reactive intermediates and transition states remain unclear. Bimolecular ethanol dehydration turnover rates (per H⁺, quantified by NH₃ temperature-programmed desorption and <i>in situ</i> titrations with 2,6-di-<i>tert</i>-butylpyridine) and transmission infrared spectra measured on Brønsted acid zeolites under conditions approaching intrapore H₂O condensation (373 K, 0.02–75 kPa H₂O) reveal the formation of clustered, solvated (C₂H₅OH)(H⁺)(H₂O)_n intermediates, which are stabilized to greater extents than bimolecular dehydration transition states by extended hydrogen-bonded water networks. Turnover rates deviate sharply below those predicted by kinetic regimes in the absence of extended condensed water networks because non-ideal thermodynamic formalisms are required to account for the different solvation of transition states and MARI. The condensation of liquid-like phases within micropores that stabilize reaction intermediates and transition states to different extents is a general phenomenon for Brønsted acid-catalyzed alcohol dehydration within zeolites of different topology (CHA, AEI, TON, FAU), which governs the initial formation and structure of clustered hydronium-reactant and water-protonated transition state complexes. Systematic control of liquid-phase structures within confined spaces by gas-phase measurements around the point of intrapore condensation enables more detailed mechanistic and structural insights than those afforded by either kinetic measurements in the liquid phase, or structural characterizations of aqueous systems in the absence of reactants.</div>

L'activation catalytique d'alcools vers la formation déshydrative de liaisons chimiques sans pré-activation est devenue un intérêt de recherche majeur au cours des deux dernières décennies. Dans cette thèse, l’effet synergique particulier des acides forts en tant que catalyseurs dans l’hexafluoroisopropanol (HFIP) comme solvant de diverses classes de carbocations instables dans la chimie de Friedel-Crafts a été étudié. Il a été constaté que pour la première fois, les réactions de Friedel-Crafts d'alcools benzyliques primaires fortement désactivés, catalysées par un acide, se déroulaient facilement, en raison des phénomènes d'agrégation induits par l'acide dans HFIP. Une stratégie similaire a été utilisée pour l'activation d'alcools propargyliques, comme nouvelle voie d'accès sélectif aux allènes et indènes portant la fonction CF3, à partir des mêmes composés de départ. De plus, ce système catalytique a été appliqué avec succès pour les réactions de Friedel-Crafts de cyclopropanes de type non activés et donneur-accepteur. Enfin, il a été découvert que le HFIP pouvait atténuer le réarrangement de carbocation classique dans les alkylations de Friedel-Crafts, permettant l’accès aux produits avec chaînes alkyle linéaires en une seule étape à partir d’alcools aliphatiques linéaires. / The catalytic activation of alcohols towards dehydrative bond formation in the absence of pre-activation has become a major research interest over the past two decades. In this thesis, the peculiar synergistic effect of strong acids as catalysts in hexafluoroisopropanol (HFIP) as solvent on various classes of unstable carbocations in Friedel-Crafts chemistry was investigated. It was found that for the first time, Brønsted acid catalyzed Friedel-Crafts reactions of highly electronically deactivated primary benzylic alcohols proceeded smoothly due to the acid-induced aggregation phenomena in HFIP. A similar strategy was used for the activation of propargylic alcohols as a new route to selectively access CF3-substituted allenes and indenes from the same starting compounds. Furthermore, this catalytic system was succesfully applied for Friedel-Crafts reactions of unactivated and donor-acceptor cyclopropanes. Finally, it was discovered that HFIP can mitigate against classical carbocation rearrangement in Friedel-Crafts alkylations, allowing access to linear alkyl chain products in a single step from linear alkyl alcohols.

<p dir="ltr">Zeolites are microporous crystalline aluminosilicates that are widely used as catalysts for upgrading hydrocarbons and oxygenates to higher value chemicals and fuels. The substitution of tetrahedral Si⁴⁺ with Al³⁺ in a charge-neutral silica framework ([SiO_4/2]) generates anionic centers ([AlO_4/2]^-), which charge-compensate Brønsted acid protons (H⁺) that serve as active sites for catalysis. Brønsted acid sites in aluminosilicates of diverse topologies have similar acid strength, but can be located within varying intracrystalline (or internal) microporous environments (0.4‒2 nm diameter) or at extracrystalline (or external) surfaces and mesoporous environments (>2 nm diameter); yet, catalytic diversity exists, <i>even</i> for a fixed zeolite framework topology, because micropores impose constraints on molecular access to and from intracrystalline active sites and provide van der Waals contacts that influence the stabilities of reactive intermediates and transition states. Tailoring the material properties of a given zeolite framework for targeted catalytic applications requires strategies to design both the bulk crystallite properties (e.g., morphology, active site density) that influence intracrystalline diffusion and the secondary environments that surround active sites and influence intrinsic kinetics, and further necessitates molecular-level insights to elucidate the influences of bulk and active site properties on catalysis. In this work, we provide synthetic and post-synthetic strategies to respectively tune active site environments within varying micropore voids and at external surfaces of zeolites, and develop gas-phase toluene methylation and liquid-phase mesitylene benzylation as probe reactions to quantify the catalytic consequences of active site environments on aromatic alkylation catalysis.</p><p dir="ltr">The MFI framework (orthorhombic phase) consists of 12 crystallographic distinct tetrahedral-sites and 26 unique framework oxygen atoms located around channels (~0.55 nm diameter) or channel intersections (~0.70 nm diameter). The synthesis of MFI zeolites using the conventional tetra-<i>n</i>-propylammonium (TPA⁺) organic structure directing agent (OSDA) is known to place framework Al and their attendant H⁺ sites within the larger intersection environments, because electrostatic interactions are favorable between such locations of [AlO_4/2]^- and the quaternary N⁺ center in TPA⁺ that becomes positioned rigidly within channel intersections during crystallization. The methylation of toluene by dimethyl ether (DME; 403 K) on MFI-TPA zeolites of fixed active site densities (~2 Al per unit cell) result in <i>ortho</i>-xylene (<i>o</i>-X; ~65%) as the major product over <i>para</i>-xylene (<i>p</i>-X; ~27%) and <i>meta</i>-xylene (<i>m</i>-X; ~8%). In contrast, toluene methylation on MFI zeolites (~2 Al per unit cell) synthesized using non-conventional OSDAs, such as ethylenediamine (EDA) or 1,4-diazabicyclo[2.2.2]octane (DABCO), predominantly forms <i>p</i>-X (~75%) over <i>o</i>-X (~23%) and <i>m</i>-X (~2%). Within the subsets of MFI-TPA and MFI-EDA/DABCO zeolites, measured xylene formation rates and isomer selectivities are independent of crystallite sizes (0.1‒13 µm), toluene conversions (0.02‒2.0%) and external H⁺ content (up to 9% external H⁺ per total Al), indicating negligible effects of diffusion-enhanced secondary xylene isomerization reactions at intracrystalline or extracrystalline domains. The invariance of xylene isomer selectivity with reactant pressures (0.2‒9 kPa toluene, 25‒66 kPa DME) or methylating agent (1‒4 kPa methanol) indicate that differences in reactivity of toluene to form each xylene isomer reflects differences in the stabilities of their respective kinetically relevant transition states that share the same reactive intermediate. Measured xylene isomer formation rate constants and rate constant ratios, obtained from mechanism-derived rate expressions and interpreted using transition state theory formalisms, are used alongside density functional theory (DFT) calculations to reveal that intersection void environments (~0.70 nm diameter) similarly stabilize all three xylene transition states over unconfined surfaces (>2 nm diameter) without altering the established aromatic substitution patterns, while channel void environments (~0.55 nm diameter) preferentially destabilize bulkier <i>o</i>-X and <i>m</i>-X transition states thereby resulting in high intrinsic <i>p</i>-X selectivity. DFT calculations reveal that the ability of protonated DABCO complexes to reorient within MFI intersections and participate in additional hydrogen-bonding interactions with anionic Al centers during synthesis, facilitates the placement of Al in smaller channel environments that are less favored by TPA⁺. These molecular-level details, enabled by combining synthesis, characterization, kinetics and DFT, establish a mechanistic link between OSDA structure, active site placement and transition state stability, and provide active site design strategies orthogonal to crystallite design approaches that rely on complex reaction-diffusion phenomena.</p><p dir="ltr">For various reactions including toluene methylation at higher reaction temperatures (573‒773 K) and toluene conversions (>10%), extracrystalline H⁺ sites in MFI zeolites are reported to influence reactivity, selectivity, and deactivation behavior during catalysis in undesired ways. Post-synthetic chemical treatments to passivate external H⁺ sites on MFI zeolites result in unintended (but not always undesirable) changes to bulk structural properties and Al and H⁺ contents. The number of extracrystalline H⁺ sites is difficult to quantify using conventional spectroscopic or titrimetric methods, especially when present in dilute amounts on samples whose surfaces have been passivated. The systematic treatment of MFI zeolites (2.4, 5.7 and 7.1 Al per unit cell) using ammonium hexafluorosilicate (AHFS) at varying treatment duration times, AHFS concentrations and number of successive treatments resulted in MFI zeolites that retain their bulk structural properties and total Al and H⁺ contents, except for one parent MFI sample containing a significant amount of non-framework Al species. The benzylation of mesitylene by dibenzyl ether (363 K) occurs exclusively at external H⁺ sites because the bulky 1,3,5-trimethyl-2-benzylbenzene product is sterically prevented from forming at intracrystalline H⁺ sites. The intrinsic zero-order rate constant (per external H⁺) for mesitylene benzylation is extracted from rate measurements (per total Al) on a suite of untreated MFI samples with known amounts of external H⁺ sites (1‒15% external H⁺ per total Al) quantified using bulky 2,6-di-<i>tert</i>-butylpyridine base titrants. Measured zero-order rate constants on AHFS-treated MFI zeolites are used to quantify the extent to which AHFS treatments passivate external H⁺ sites, revealing efficacies that depend on the specific treatment conditions and the parent sample used. The developed kinetic methods demonstrate the utility of catalytic probes, when compared to stoichiometric probes based on spectroscopic or titration methods, in amplifying and quantifying dilute concentrations of external H⁺ sites on zeolites. The methods enable comparisons of the efficacy of various post-synthetic passivation strategies and permit rigorous assessments of the influence of external H⁺ during acid catalysis.</p><p dir="ltr">Overall, this work provides (post-)synthetic strategies to tune active site environments within intracrystalline micropores or at extracrystalline surfaces and develops quantitative kinetic probes that enable a molecular-level understanding of catalytic consequences of active site environments on aromatic alkylation reactions. Taken together, the methodology and findings of this study have broader implications in zeolite catalyst design for selectively upgrading traditional fossil feedstocks (crude oil and shale gas) and emerging feedstocks (biomass and waste plastics).</p>

L'objectif de la thèse est d'étudier la transformation de la fraction cellulosique de la biomasse en acide lévulinique. Cet acide est une molécule plateforme permettant un accès à de multiples produits, tels que des solvants, des monomères ou encore des molécules à plus forte valeur ajoutée.Nous proposons d'étudier la transformation de la cellulose en acide lévulinique catalysée par des solutions aqueuses concentrées en acides de Brønsted. La forte acidité de ces milieux et leur capacité à rompre les liaisons hydrogène de la cellulose rendent possible des réactions à température modérée (80°C), ce qui laisse espérer la production sélective d'acide lévulinique.L'état de l'art concernant la production d'acide lévulinique à partir de glucose ou de cellulose est d’abord présenté, ainsi qu’une étude bibliographique sur les techniques permettant la mesure d’acidité de milieux concentrés.La caractérisation de l’acidité des milieux semblant être un point clé pour contrôler la réaction, la seconde partie concernera les mesures d’acidité des milieux concentrés utilisés. La méthodologie expérimentale pour identifier et quantifier les produits de réaction de la cellulose ainsi que les paramètres critiques qui la régissent sont ensuite détaillés.Enfin l’étude s’achèvera par deux chapitres traitant de la transformation du glucose ou la cellulose en acide lévulinique dans des milieux comportant une forte acidité de Brønsted combinée, ou non, avec des sels métalliques. La transformation du glucose conduit à des sélectivités en acide lévulinique de 50 mol% dans l’acide sulfurique 65 % et supérieures à 70 mol% dans l'acide sulfurique 48 % en présence de chlorure d'aluminium hydraté. La transformation de la cellulose conduit à des sélectivités en acide lévulinique d'environ 43 mol% dans les milieux acides de Brønsted concentrés et 60 mol% lorsque des sels métalliques sont ajoutés. De telles sélectivités en acide lévulinique n'ont jamais été décrites dans les milieux concentrés. / The thesis presented in this document aims at converting lignocellulosic biomass into levulinic acid. This target is a valuable building block which can lead to various products.This platform intermediate can be obtained by acid-catalyzed conversion of cellulose contained in raw biomass. However, the state of the art concerning this acid-catalyzed reaction revealed that the current conditions (diluted acids in harsh temperature conditions) result in numerous by-products formation. The selectivity issue often deals with process control, in particular with reaction time optimization.Our approach lies in using concentrated Brønsted acids as alternative media to catalyze cellulose conversion. Indeed, the high acidity level allow the interaction with hydrogen bonds in cellulose fibrils and favor cellulose decristallization. This property should promote the transformation of cellulose into levulinic acid at lower temperature thus limiting the formation of by-products. Therefore, acidity measurements in such media have been developed and performed. An extensive study on glucose and Avicel cellulose conversion in concentrated aqueous solutions of sulfuric acid was performed at 80°C. Levulinic acid yields, up to 50 mol%, were determined by HPLC analysis and a special attention was dedicated to the identification and quantification of soluble or insoluble by-products, allowing the characterization of new species never described in aqueous solutions. Referring to the acidity levels previously determined, a comparison between acidity and catalytic results will be setted.Finally, the effect of metallic chloride addition on the transformation of glucose and cellulose in sulphuric acid solutions has been investigated, revealing improvements yielding up to 70 mol% levulinic acid. This range of selectivity is unprecedented at such a low temperature.