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Two methods of C-H functionalisation of sp2 C-H bonds via ruthenium catalysis have been developed in this thesis. The first methodology is the preparation of meta-sulfonated heteroaromatics. Individual substrate optimisations were performed on various nitrogen containing heteroaromatics such as 2-phenylpyridine, 1-phenylpyrazole and benzo[h]quinoline. It was discovered that 2-phenylpyridine was the best substrate for C-H sulfonation with aryl sulfonyl chlorides and gave yields of 4 – 63% and provided functional handles allowing for further synthetic manipulations. The second methodology developed is a ruthenium(II) catalysed ortho-C-H acylation of heteroaromatics. Initial optimisation was performed on 2-phenylpyridine with ortho-toluoyl chloride for C-H acylation and it was found tricyclohexylphosphine was the best ligand for this reaction. Unfortunately, the scope of this reaction is limited, as only a couple of aryl acid chlorides were compatible for the acylation of 2-phenylpyridine. This methodology was then applied to 1-phenylpyrazole and demonstrated the first example of C-H acylation of 1-phenylpyrazole with acid chloride as the coupling partner. C-H acylation of 1-phenylpyrazole is more versatile than 2-phenylpyridine, as the reaction scope is much broader. Various aryl and alkyl acid chlorides were compatible for the acylation of 1-phenylpyrazole derivatives and gave yields of 4 – 91%. Sterically hindered acid chlorides provided the higher yields, which is indicative of a steric acceleration during the reductive elimination step. Ruthenium-substrate complexes were synthesised and employed in stoichiometric experiments under the meta-sulfonation and ortho-acylation conditions independently, to attempt to elucidate the mechanistic pathways of these two reactions. 1H NMR spectroscopy on the meta-sulfonations of 1-phenylpyrazole and benzo[h]quinoline complexes indicated the formation of sulfonated ruthenium-substrate complexes, where the sulfone is substituted para to the ruthenium-carbon bond. C-H activation of 1-phenylpyrazole with a ruthenium-phosphine complex was attempted, and found it was difficult to synthesise the C-H activated substrate-ruthenium complex in the presence of phosphine ligands.

1. C–H Functionalisation of 2 Aryl Cyclic 1,3-Dicarbonyl Compounds Two enolate-directed C–H functionalisation protocols have been developed using 2-aryl cyclic 1,3-dicarbonyl compounds as substrates. Reactions with activated alkenes, under ruthenium or palladium catalysis produced benzopyrans in most cases, in moderate to good yield. Alternatively, an oxidative annulation of 2-aryl cyclic 1.3-dicarbonyls with 1,3-enynes was facilitated under rhodium catalysis, forming functionalised spiroindene structures in most cases, in generally good yields and high regioselectivity. During the investigation, the serendipitous formation of spirodialin structures was also observed. 2. Enantioselective Rh(I)-Catalysed Cyclisation of Arylboron Compounds onto Ketones Chiral tertiary alcohols, bearing aza-, oxa- and carbocyclic core structures of varying ring size were successfully formed from arylboron substrates under rhodium catalysis. In general the reactions proceeded with good yield and with moderate to high enantioselectivity. A protocol for the formation of a bicyclic lactam system was also achieved in moderate yield and enantioselectivity.

During the COVID-19 outbreak, PCR tests were widely used for large-scale testing and screening. Yet, this technique requires bulky and time-consuming procedures to prepare the samples collected from the patients before their analysis by well-trained experts with expensive and specific equipment. PCR is therefore not competitive as a technique of detection for a widespread and rapid use in point-of-care sites. Thus, the COVID-19 pandemic highlighted the need for cheap and easy-to-implement biosensors. Surface plasmon resonance based sensors were suggested as a promising alternative in recent years. Indeed, they enable real-time and label-free detection of a wide range of analytes. That explains their widespread use in various fields of applications such as pharmacology, toxicology, food safety, and diagnosis. This thesis proposes and demonstrates a new plasmonic configuration of detection, which can address challenges posed by point-of-care settings. The gratings used as transducers in this configuration were fabricated based on laser interference lithography combined with a nanoimprinting process. The responses of these nanostructures interrogated by a p-polarized light beam result in a transfer of energy between two diffracted orders over an angular scan. This optical phenomenon termed as “optical switch”, was theoretically and experimentally investigated and optimized. The principle of detection based on this specific configuration was demonstrated for the detection of small variations in the bulk refractive index with solutions comprised of different ratios of de-ionized water and glycerol. A limit of detection in the range of 10−6 RIU was achieved. In addition, preliminary bio-assays obtained by combining this configuration with a functionalization are presented and demonstrate the selectivity and the potential of this new plasmonic configuration for biosensing applications. This thesis work paves the way for the use of the optical switch configuration as a biosensor aligned with low-cost manufacturing and relevant for diagnosing in point-of-care sites.

Les poly (3-hydroxyalcanoate)s (PHAs) constituent une solution alternative aux plastiques issus des ressources pétrolières en raison de leur biodégradabilité et leur biocompatibilité. Cependant, les coûts de production élevés et les difficultés de mise en œuvre des PHAs ont limité leur développement à plus grande échelle. Il convient donc de modifier les PHAs afin d’accroître leurs propriétés et de développer des stratégies permettant de réduire leurs coûts de production pour permettre leur utilisation en remplacement des plastiques conventionnels. Parmi les matières premières issues des ressources renouvelables, les huiles métropolitaines de colza ou de tournesol sont des candidats intéressants pour la synthèse et la modification chimique des PHAs de par leur coût compétitif, leur biodisponibilité et leurs fonctionnalités intrinsèques. Ainsi, notre travail a porté sur réduction des coûts de production des PHAs en utilisant des substrats tels que l’huile de colza ou le glycérol. La souche sélectionnée, Haloferax mediterranei, a démontré sa capacité à biosynthétiser du PHB92HV8. Par ailleurs, nous avons développé deux approches permettant d’améliorer les performances des PHAs : la plastification par des molécules terpéniques issues des plantes et la synthèse de réseaux semi-interpénétrés (semi-IPNs) par réaction de thiolène entre l’huile de tournesol et un thiol trifonctionnel au sein d’une matrice de PHAs linéaire. L’utilisation de terpènes pour la formulation des PHAs a permis de réduire la température de mise en œuvre du polymère de 7 °C et d’augmenter sa souplesse. La synthèse d’un réseau semi-interpénétré biosourcé a permis d’améliorer la stabilité thermique des PHAs et d’augmenter leur allongement à la rupture de 2400 %. Enfin, de nouveaux matériaux biosourcés ont également été produits à partir de terpènes et d’huiles végétales, en faisant appel à un procédé simple et vert. Les matériaux obtenus, aux propriétés intéressantes en termes de flexibilité et d’élasticité ont la capacité de piéger et de libérer des molécules hydrophobes telle que la molécule d’eugénol aux propriétés antibactériennes et antifongiques. Ainsi, une large gamme de bioplastiques a été synthétisée en valorisant les huiles végétales et les PHAs, dont les propriétés variées pourraient concurrencer les plastiques actuels issus des ressources fossiles / Poly (3-hydroxyalkanoate)s (PHAs) are an alternative to petroleum-based plastics because of their biodegradability and their biocompatibility. However, the high production costs, the limited mechanical performance and the narrow processing window of PHAs have limited their development on a larger scale. It is therefore necessary to modify the PHAs in order to increase their properties and develop strategies to reduce their production costs to allow their use as replacement for conventional plastics. Among the raw materials derived from renewable resources, metropolitan rapeseed or sunflower oils are interesting candidates for the synthesis and chemical modification of PHAs because of their competitive cost, their bioavailability and their built-in functionalities. Thus, we aimed to reduce the cost productions of PHAs by using rapeseed oil and glycerol as cheap substrates. The strain, Haloferax mediterranei, has demonstrated its ability to biosynthesize a PHB92HV8. In addition, we have developed two approaches to improve the performance of PHAs: plasticization of PHAs by terpene molecules from plants and synthesis of semi-interpenetrating networks (semi-IPNs). The use of terpenes for the formulation of PHAs reduced the processing temperature of the polymer and increased its flexibility. The synthesis of a biobased semi-IPN is obtained by crosslinking sunflower oil and a trifunctional thiol, using the thiolene reaction, within a matrix of linear PHAs. The network improved the thermal stability of PHAs and increased their elongation at break of 2400%. Finally, new biobased materials were also produced from terpenes and vegetable oil, using a simple and "green" process. The resulting materials exhibited flexibility and elasticity with the ability to absorb and to release antibacterial and antifungal hydrophobic molecules such as the eugenol. Therefore, a wide range of bioplastics have been synthesized using vegetable oils, PHAs or a combination of both, with wide range of properties to compete with plastics derived from fossil resources

The development of a palladium-catalysed C–H carbonylation of hindered secondary amines is described. Central to this strategy is the temporary conversion of simple ketones into hindered secondary amines that facilitates a sterically promoted palladium-catalysed C–H activation. A range of functional groups are shown to be compatible with this catalytic process, and with exclusive regioselectivity for the terminal ethyl sp 3 C–H in most cases. This method allows an overall incorporation of a carboxyl group to the b-position of terminal ketones, generating 1,4- dicarbonyl moieties which are important synthetic building blocks. The sterically promoted C–H functionalisation strategy has been employed as the key step in the synthesis of a functionalised analogue of astemizole, a pharmaceutical agent which suffers from undesired hERG activity. The increased steric bulk around the tertiary amine, coupled with introduction of a polar hydroxyl group via the C–H acetoxylation reaction, is proposed to reduce binding to the hERG channel. The hERG profile of this analogue is not yet established.

In this work, the modification of conducting substrates with thin (nanometer thick) aryl films via reaction with aryldiazonium salts was investigated. Two methods were used: modification by electro-reduction of the aryldiazonium salts and modification by spontaneous reaction of aryldiazonium the salts with the surface at open circuit potential. The majority of the studies were undertaken using p-nitrobenenze diazonium salt, which gives electro-active nitrophenyl (NP) films at the surface that can be detected and characterized by cyclic voltammetry. Films prepared spontaneously on carbon and gold electrodes at open circuit potential were characterized by electrochemistry, atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS) and water contact angle measurements. At both carbon and gold, spontaneous modification proceeds via electron transfer from the surface to the diazonium salt.Furthermore, on both types of surface, spontaneously prepared NP films were found to be loosely packed multilayers of less than 5 nm in thickness. The spontaneous reaction was utilized for the patterning of carbon, gold, silicon and copper surfaces by microcontact printing (μCP) with diazonium salts. The presence of spontaneously formed films upon printing was confirmed by cyclic voltammetry and AFM. The films were demonstrated to be useful for the tethering of further molecules to the surface. Patterns prepared by μCP were imaged using scanning electron microscopy (SEM) and condensation figures. The preparation of two-component systems, with different chemical functionalities attached to different, well-defined, regions of the surface, was demonstrated. The optimization of the long term activity of glucose oxidase hydrogels by covalent attachment of the hydrogels to modified carbon electrodes was investigated. Covalent attachment was demonstrated, but the resulting electrode-hydrogel surfaces did not show long-term activities superior to those for physisorbed hydrogels. It is suggested that the limiting factor for long-term hydrogel activity is not adhesion of the hydrogel to the surface, but degradation of enzymatic activity by H2O2.

Nerve injury is a very common trauma affecting 300,000 people in Europe every year. Although autografts are currently the gold standard in surgery, they can cause loss of sensation and scar tissue formation. Artificial nerve conduits are a valid alternative for peripheral nerve repair. They can provide a confined environment during the regeneration process, enabling axons sprouting from the proximal to the distal nerve segments as well as reducing scar tissue formation. Poly-e-caprolactone (PCL) is a biocompatible and biodegradable polymer suitable for the fabrication of nerve guidances. In particular, previous works demonstrated that neural cells are able to adhere and proliferate on micropitted PCL films obtained through solvent casting. Also, short term studies showed that axons were able to bridge 1cm injury gap. In this work a 18 weeks long term in vivo experiment using a rat model was performed to investigate the reinnervation of end organ skin and muscle. PCL conduits were compared to autografts, with no significant differences in terms of regeneration and reinnervation. However, Schwann cells (SCs), the most important glial cells in the peripheral nervous system, showed poor attachment in vitro on PCL scaffolds; hence, surface modification was carried out in order to improve the material biocompatibility. The effect of both hydrophilicity and functional groups on SCs was first investigated. PCL films were then hydrolysed and aminolysed to modify the surface with carboxylic and amino groups respectively. Hydrolysed films increased remarkably the surface hydrophilicity, although topography and mechanical properties were not affected. Conversely, the tensile modulus and strength were significantly reduced by aminolysis, but still suitable for the desired application. The two treatments influenced also the morphology of SCs. It was demonstrated that cell elongation was induced by hydrophilic surfaces, whilst cells preferred cell-cell interaction when cultured on aminolysed films. However, cell proliferation was remarkably increased on the latter surfaces, confirming previous results obtained on substrates characterised by amino groups. These results confirmed that a good balance between hydophilicity and surface chemistry is necessary to guarantee the best cell response. In order to enhance both proliferation and morphology of SCs, arg-gly-asp (RGD) sequences were immobilised on the PCL film surface using two different reaction mechanisms. Carbodiimide chemistry was compared to a new mechanism developed in the present study based on the Thiol chemistry. Biological tests performed on these modified films demonstrated the improvement of SC response after the peptide immobilisation using the novel approach. Cell attachment and proliferation were three times higher compared to untreated PCL films. It was also observed that the presence of peptides on the film surface induced the formation of focal adhesion plaques by SCs, important for the perception of cellular signals when in contact with a particular substrate. Hence, a good balance between focal adhesion and adhesion forces was achieved after peptide immobilisation. Overall the results of this study showed that material functionalisation is very important for SC response and it will be fundamental for the production of artificial nerve conduits.

Entre tous les techniques de l’imagerie, imagerie par résonance magnétique (IRM) offre plusieurs avantages en raison de sa faible invasivité, son innocuité et sa résolution spatiale en profondeur, mais souffre d'une mauvaise sensibilité. Pour résoudre ce problème, différentes stratégies ont été proposées, y compris l'utilisation de l’espèce hyperpolarisée comme ¹ ² ⁹ Xe.Le xénon est un gaz inerte avec un nuage d'électrons polarisable qui est très sensible à son environnement chimique. Sa capacité d'être hyperpolarisé permet d'obtenir un gain significatif de la sensibilité. Néanmoins, le xénon n'a aucune spécificité à une cible biologique, par conséquent, il a besoin d’être encapsulé et vectorisée. Des cages moléculaires différentes ont été proposées et nous sommes particulièrement intéressés à cryptophane qui est l'un des meilleurs candidats pour l’encapsulation du xénon.Dans ce contexte, l'objectif de cette thèse est de concevoir des nouveaux cryptophanes qui peuvent être utilisés comme les plates-formes moléculaires pour construire des nouvelles bio-sondes de ¹ ² ⁹ Xe IRM utilisables pour l'imagerie in vivo. Pour cette raison, ces cryptophanes devraient être hydrosoluble et mono-fonctionnalisable.Dans cette thèse, le polyéthylène glycol (PEG) est utilisé pour améliorer la faible solubilité de la cage moléculaire hydrophobe. Il y a également une discussion systématique des façons de casser la symétrie des cryptophanes et les stratégies différentes ont été tentées pour synthétiser cryptophanes mono-fonctionnalisé.En conséquence, plusieurs cryptophanes PEGylés et mono-fonctionnalisés ont été obtenus et leurs propriétés d'encapsulation du xénon ont été testées. / Among all the imaging techniques, magnetic resonance imaging (MRI) offers several advantages owing to its low invasiveness, its harmlessness and its spatial in-depth resolution but suffers from poor sensitivity. To address this issue, different strategies were proposed, including the utilization of hyperpolarizable species such as ¹ ² ⁹ Xe.Xenon is an inert gas with a polarizable electronic cloud which leads to an extreme sensitivity to its chemical environment. Its capacity of being hyperpolarized makes it possible to obtain a significant gain of sensitivity. Nevertheless, xenon has no specificity to any biological target therefore it needs to be encapsulated and vectorized. Different molecular cages were proposed and we are particularly interested in cryptophane which is one of the best candidates for xenon encapsulation.In this context, the objective of this thesis is to design new cryptophanes which can be used as molecular platforms to construct novel ¹ ² ⁹ Xe MRI biosensors usable for in vivo imaging. To meet this demand, these cryptophanes should be mono-functionalizable and enough soluble in water.In this thesis, the polyethylene glycol (PEG) group is used to improve the poor solubility of the hydrophobic molecular cage. And there is a systematic discussion of how to break the symmetry of cryptophanes and different strategies were attempted to synthesize mono-functionalized cryptophanes.As a result, several PEGylated mono-functionalized cryptophanes were obtained and their properties for encapsulating xenon were tested.