Organic synthesis
This research theme brings together activities centered around the search for new synthesis methodologies. It exploits the department's know-how in organic synthesis, heterochemistry, organometallic catalysis (Fe, Cu, Mn, Au, …), organocatalysis or asymmetric synthesis. Applications range from the development of small bioactive molecules, the synthesis of molecular bricks for applications in organic materials, the total synthesis, development and development of new eco-responsible processes based on both methodological and technological foundations.
Methodology of organic synthesis assisted or not by metals:
This research activity is conceptually based on the discovery of new non-toxic and non-polluting economic methods and processes, to achieve the synthesis of molecules with high added value (in the field of pharmacy , agrochemistry and materials), from simple starting molecules that may eventually come from the plant world. It is divided into several axes: (i) Nucleophile arylation reactions (Nu) (formation of C-N, C-O, C-C, C-F, C-S, C-P bonds, …) catalyzed by inexpensive and low-toxic transition metals (iron, copper or manganese), in order to obtain ubiquitous Ar-Nu motifs in bioactive molecules (applications in human, animal and plant health). Regarding this axis, the same type of reaction will be considered by freeing itself from catalysts, using simple radical systems without metal photocatalysts. (ii) Hydrofunctionalization of unsaturated bonds (including hydroamination) by copper catalysis (formation of C-C and C-heteroatom bonds). (iii) C-F binding activation of aromatic or trifluoromethylated polyfluorinated molecules, by the use of lanthanides or other transition metals as well as the development of flux techniques. (iv) The preparation of small fluorinated molecules intended to be incorporated into vitrimer type materials: the greatest reactivity of these molecular bricks should be transmitted to the network whose adaptability is expected while avoiding the incorporation of additives. (v) The development of original organocatalytic methods (ion pair catalysis or NHC) for the preparation of fluorinated building blocks is also proposed. (vi) The synthesis of new polylude phosphorus species as well as their nitrogen counterparts (polyazaylides) which will be tested as ligands in coordination chemistry (with transition metals and lanthanides) and in homogeneous catalysis (coupling reactions) as well as in organic synthesis (azawittig reaction). (vii) The synthesis of pheromones (as an alternative to pesticides) to protect crops by trapping insect pests according to two very different strategies using respectively phosphorus chemistry ( phosphorus diylides) and homogeneous copper catalysis (formation of C-C bonds by arylation reaction).
Unconventional amide synthesis:
An unconventional synthesis strategy of the amide function has been developed in the laboratory in recent years. Several lines of development are proposed, including the transposition of this method developed in solution to a synthesis on solid support, the realization of couplings by fragments / cyclizations (which remains a major challenge in peptide synthesis) and the extension of this method to the synthesis of non-peptide amides (the amide function being present in more than 25% of marketed drugs).
Synthesis of chiral ligands for asymmetric catalysis:
The growing demand for enantiopide molecules is one of the major current challenges in organic synthesis. Recent environmental regulations are forcing the emergence of efficient, cost-effective and environmentally friendly processes for the manufacture of these new chemical entities. With this in mind, several ligand synthesis approaches for asymmetric catalysis will be developed: new highly modular phosphorus systems and chiral carbenic ligands. Regarding the latter, while N-heterocyclic carbenes (NHCs) have shown their effectiveness in recent years as neutral, stable, and electron-rich ligands, they still cannot compete with the structural diversity of more traditional chiral phosphine ligands. The synthesis of new chiral carbenic ligands other than NHCs, cyclic alkylaminocarbenes (CAAC), is therefore envisaged in order to complete the growing range of this type of ligand. For new phosphorus systems, the objective will be the preparation of C2 symmetry systems with a highly modular bisindolizine motif. The evaluation of catalytic properties will focus on reference or difficult enantioselective reactions.
Synthesis of small bioactive molecules:
Several approaches will be explored for the next contract:
  • A family of macrolactams called "macrotermycins" has shown antibacterial activities against multidrug-resistant strains of S. Aureus and antifungals against the fungal "garden" of termites. Due to the small amounts isolated and to satisfy structure/activity relationship studies, a total synthesis of macrolactam aglycone is considered. This study will include the fundamental study of Diels-Alder reactions (two macrolactams resulting from a cycloaddition [4+2] of the Diels-Alder type) and the synthesis of analogues.
Two families of sugar analogues will be developed:
  • A first family will consist of precursors of iminosugars. The originality will focus on the development of a synthesis methodology exploring electrochemical glycosylation by anodic CH activation of a donor glycoside and its trapping by a nucleophile. This electro-oxidation will be carried out in continuous flow to access multigram scales.
  • The second family will target fibrosis induced in non-alcoholic steatohepatitis (NASH). To do this, we will extend the only family of molecules known to date, inhibiting GnT-V, a key enzyme for regulating glycoprotein biosynthesis and which led to the creation of the start-up Phost'In. Preliminary in vivo results from the lead compound have already shown a very good efficacy that must be optimized.
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Coordination chemistry
Like organic synthesis, coordination chemistry is a transversal competence within the department and will be used in many projects belonging to other themes. The design and study of the reactivity of coordination complexes is a key element in synthesis methodology allowing the formation of C-C or C-heteroatom bonds (theme 1) or in the development of metal nanoparticles (theme 3). In this theme, some projects for which coordination complexes are at the heart of methodological development and/or innovation are presented.
Chiral molecular complexes of lanthanides:
Magnetoelectric (ME) materials combine magnetization (M) and polarization through M(E) and P(H) cross-couplings. Modifying the polarization/magnetization with magnetic/electric fields would reduce the energy required and increase the calculation speed in non-volatile memories. This axis of the project will aim to (i) synthesize paramagnetic molecular ferroelectrics with high chemical stability and based on the association between lanthanide ions and Schiff base chiral ligands , (ii) shape them (single crystals, thin films, molecular ceramics), (iii) understand ferroelectricity in such materials, and (iv) highlight the ME linkage.
Molecular materials:
Improving the performance of molecular materials for gas release, separation and sorption application remains a major challenge. Here, the molecular materials studied will fall under both Porous Coordination Polymers (PCPs) and Metal Organic Frameworks (MOFs). On the one hand, materials based on cyano-bridged PCPs will be developed to develop self-healing composites allowing the controlled delivery of nitric oxide (NO). The goal is that NO (which is involved in many bactericidal, wound healing or hypotensive processes) is then released via various external stimuli whether in the solid phase or suspended in water. Cyano-bridged PCPs will also be developed to present high stability and an optimal hydrophilic/hydrophobic balance in order to separate Volatile Organic Compounds (VOCs) such as saturated and unsaturated hydrocarbons under wet conditions. The synthesis of cyanocunded PCPs incorporating chiral ligands will also be declined for the separation of racemic mixtures. On the other hand, the MOFs developed will be developed with fluorinated or phosphonate bridging ligands. In the first case, the idea will be to develop chemically stable molecular materials integrating the functionalities required to capture toxic VOCs such as NOx and COx and degrade/transform them into a valuable resource. In the second case, CO2 capture will be the first application domain considered for MOFs built around bipyridine-bisphosphonates (for 2D-3D connectivity) or tris-imidazopyridylphosphonates derivatives (for 3D connectivity). Three families of polyphosphonate ligands combining modular rigidities, from rigid to flexible through "flexi-rigid" systems, will be targeted, and synthesized by solvent-free processes (mechanochemistry). These MOFs will also include basic sites for proton transport and will be assembled with Ni, Co or Fe cations. In addition to these syntheses, an approach by classical and quantum molecular modeling will determine the structure-properties relationship in order to optimize the adsorption properties of gases and vapours according to the nature of the ligands studied. The challenge is to rationalize the properties of the different molecular materials studied and therefore to propose the most efficient material for the targeted applications related to the adsorption of gases and vapors. 
NMR methodology for the characterization of coordination links:
The mode of binding of ligands involved in coordination polymers or grafted to the surface of NPs is not always easy to determine, especially in the absence of crystallographic structure. The objective will be to develop methods for the analysis of the binding mode and dynamics of ligands in molecular (nano)materials of interest, based on the use of solid-state multinuclear NMR techniques, in order to better rationalize their properties. In particular, in the case of oxygenated ligands, the use of oxygen-17 isotope enrichment processes through mechanochemistry will be considered, in order to study the mode of binding of ligands by solid 17O NMR.
Coordination complexes supported on nano-objects:
This research axis concerns the search for eco-compatible catalysts for organic synthesis by a complementary approach to that presented in theme 1. Indeed, in cases where precious metals cannot be substituted by cheap analogues, catalyst recycling strategies are an alternative. Thus, this project aims to graft active coordination complexes in homogeneous catalysis on various nano-objects including dendrimers, polyhedral oligomeric silsesquioxanes, nanostructured materials or magnetic NPs, and to evaluate their performance in hydrogen transfer and hydrogenation reactions. The nanometric size (or magnetic character) of the targeted catalytic systems should allow their recovery by selective precipitation (or magnetic settling). The support can also be exploited to improve performance compared to the corresponding molecular complex (limitation of metal leaching, concentration of substrates near catalytic sites).
(Nano)materials & nanosystems
This research theme focuses on the development of new methodologies for the synthesis of nanoobjects, their surface chemical functionalization and the experimental development of measurements of the properties of unique nano-objects. This activity will enable the development of hybrid nanoplatforms, therapeutic nanoformulations, as well as the development of biosensors, and organic polymeric nanocomposite implants for healthcare applications (targeted therapies and imaging, miniaturized diagnostic tools, implants and tissue reconstruction). In addition, this activity will also enable the development of nanostructured materials for selective separation for environmental applications.
Methodological developments (synthesis, functionalization and measurement)
Part of the projects on nanomaterials focuses on the experimental development of original methodologies of synthesis, functionalization and measurement on single object, such as: (i) the study of mechanisms of synthesis and nucleation of metallic NPs (Cu, Ag, Au) by reductive way of inorganic precursors or by the development of new pathways of access to these same NPs by an innovative organometallic strategy. The NPs obtained will be used in particular for their plasmonic properties in imaging and/or in hybrid nanoplatforms for health, developed in this project. (ii) The chemical functionalization of porous silicon membranes for the design of integrated optical sensors (photonic circuit type), or for their monolithic integration into planar microfluidic systems for the development of lab-on-chip. Localized functionalization strategies will be studied by photo-induced hydrosilylation of porous silicon surfaces with hydride terminations, or by masking. This approach will be developed for the development of miniaturized, portable and low-cost diagnostic tools. (iii) The confinement of original Dysprosium-based chromophores in single-sheet semiconductor carbon nanotubes (CNTs). These nano-objects represent a unique model system for studying fundamental optical and optoelectronic phenomena . The interactions at the interface between confined molecules and CNTs, as well as the supramolecular organization of chromophores along the 1D structure of CNTs will be studied at the scale of an individual nano-object. The targeted devices will allow the development of nano photo absorbers and light-emitting emitters. (iv) Original experimental methodological developments will focus on the study on single cancer cell of the pancreas of magneto-induced effects (hyperthermia or mechanical) by magnetic nanoparticles and (v) on the development of biosensors via the reconstitution of a signaling cascade of cyclic adenosine monophosphate (cAMP) functional in a supported lipid bilayer (tBLM); this in order to develop extremely sensitive sensors (a few molecules) of adenylcyclase toxin, CyaA of Bordetella pertussis.
Hybrid nanoplatforms for health
The hybrid nanoplatforms developed within the department will be extremely varied both in their composition and in their application in health in oncology, osteoarthritic diseases, antibacterial devices, and bone pathologies, each of these axes being today a major challenge in public health. In oncology, the project focuses on the use of porous silicon nanostructures or NPs, or gold NPs. In the first case, we will consider the preparation of persistent luminescence nanosystems based on porous silicon NPs and ZGO-type NPs for applications in bioimaging and guided therapy. The porous silicon NPs will also be functionalized by grafting photosensitizers (porphyrins), targeting agents and nucleic acids for focused anti-cancer therapy (two-photon photodynamic therapy) and targeted rhabdomyosarcomas (pediatric cancers). For gold NPs, these, vectored by carbohydrates, will be used to demonstrate the synergistic effect of chemotherapy with NHCmetallodrugs and photodynamic therapy (PDT) with pyropheophorbide a. Another proposed approach will be the vectorization of gold NPs by gem-bisphosphonates associated with cytotoxic molecules for imaging and therapy of bone cancers. Regarding the treatment of osteo-artritic diseases, two types of nano-objects will be considered for the treatment of osteoarthritis: Prussian blue NPs and magnetic metallic NPs (FePt). The objective of the first approach is to develop manganese-doped Prussian blue NPs for their imaging (MRI) and therapy (photothermy) properties (ANR NANOBLUE). The second approach envisaged is to develop gels localized in the diseased joint containing vectorized FePt nanoparticles for an original immuno-senotherapy by magnetoinduced hyperthermia. Regarding antibacterial treatments, a first approach will concern the use of Prussian blue NPs active in photothermy functionalized by heat-sensitive alkoxyamines generating radicals. A second approach will involve the use of porous silica NPs or periodic mesoporous organosilica NPs combining the functionalities of two-photon imaging and photodynamic therapy for the control of infections during wound healing. Molecular simulations will be conducted to determine the co-encapsulation properties of active ingredients in these hybrid materials, as well as to predict the impact of the nature of the solvent on the stability of the material and the encapsulation and release performance of the active ingredients. A Monte Carlo-DFT coupling will be used to better understand the reactivity of materials vis-à-vis solvents and a Monte Carlo-Molecular Dynamics coupling to estimate the properties of the active ingredients in the porosity of materials in order to give the predominant parameters to consider for this health application.
3D printing for healthcare, pediatric formulations and organic polymeric nanocomposite implants
Drug research in paediatrics is still underdeveloped. The use of 3D printing technology is one of the solutions, developed to meet this challenge. Studies to use molten deposition technology will be conducted to design materials that meet the requirements of an immediate-release form, not currently available in the pharmaceutical industry. In addition, this research axis also aims at the development of organic polymeric-based nanocomposites including porous silicon, iron oxide or hydroxyapatite NPs, for implant applications. A first study will aim to develop a polymer composite material consisting of porous silicon NPs dispersed in an amphiphilic copolymer resin for the 3D fabrication by stereolithography of a cellular platform for bone regeneration. Porous silicon NPs allow the trapping of active molecules and their release during their hydrolytic degradation into osteoinductive orthosilicic acid. Another study aims to develop hybrid biomaterials combining a biodegradable polymer (PLA) with gadolinium-doped iron oxide or hydroxyapatite NPs to generate clinically transposable products that address the issue of post-implantation diagnosis of biomaterials.
Antioxidant nanoformulations
Drug research in paediatrics is still underdeveloped. The use of 3D printing technology is one of the solutions, developed to meet this challenge. Studies to use molten deposition technology will be conducted to design materials that meet the requirements of an immediate-release form, not currently available in the pharmaceutical industry. In addition, this research axis also aims at the development of organic polymeric-based nanocomposites including porous silicon, iron oxide or hydroxyapatite NPs, for implant applications. A first study will aim to develop a polymer composite material consisting of porous silicon NPs dispersed in an amphiphilic copolymer resin for the 3D fabrication by stereolithography of a cellular platform for bone regeneration. Porous silicon NPs allow the trapping of active molecules and their release during their hydrolytic degradation into osteoinductive orthosilicic acid. Another study aims to develop hybrid biomaterials combining a biodegradable polymer (PLA) with gadolinium-doped iron oxide or hydroxyapatite NPs to generate clinically transposable products that address the issue of post-implantation diagnosis of biomaterials.
Nanostructured materials for selective separation
While most of the research carried out in the (nano)materials and nanosystems theme is related to health, an activity based on the use of nanostructured silica is also oriented towards environmental issues. The first axis concerns the selective and efficient recycling of rare earths and in particular heavy rare earths (Eu, Gd, Terbium, Dy, Er, Y) via the use of mesostructured silica NPs. In addition, a research axis concerns the separation and self-conditioning of radionuclides (U, Pu, Cu) on mesostructured silica in powder or film form functionalized by appropriate organic grafts; the objective being their sorption, and their encapsulation within said material after closing the porosity according to a "soft" way (ANR AUTOMACT).
Pi-conjugated systems
The research theme dedicated to pi-conjugated systems uses not only a molecular engineering approach for the design and synthesis of new pi-conjugated systems but also supramolecular engineering to control their self-assembly, their assembly with nano-objects or their interactions with biomolecules. Thus, the molecular engineering of several original families of chromophores (fluorophores AIE (emission induced by aggregation), porphyrins, dibenzothienothiophen …) are developed to respond to current scientific and technological issues in the field of organic and bioorganic optoelectronics, health and catalysis. Some of the synthetic approaches envisaged are part of the development of plant chemistry and green chemistry by relying in particular on the use of biosourced molecules for the development of these chromophores. In this case, the targeted sequences may contain up to 70% bio-based atoms. In terms of supramolecular engineering, the engineering of side chains (ionic groups, hydroxyls) or terminal groups of pi-conjugated molecular and macromolecular systems will be exploited to modulate the self-organization of these nanostructures in solution and in the solid state or their interactions with nano-objects or biomolecules. The projects associated with this theme are as follows.
Pi-conjugated polyelectolytes and pi-conjugated nanocomposites
The first approach is to prepare trace – or pi-conjugated polyelectrolytes having a pi-delocalized electronic structure and dangling chains bearing ionic groups. These systems make it possible to combine the properties of organic semiconductors with the physico-chemical behavior of polyelectrolytes. In addition, unlike the majority of pi-conjugated molecules or polymers, pi-conjugated trace or polyelectrolytes can be dissolved in polar solvents. All these physical attributes allow them to cover a wide field of applications ranging from biology (bioimaging, biosensors, etc.). where their antenna and optical amplification capacities are exploited with organic electronics (PLEDs, OPVs…) where their semiconductor and self-assembly properties are used. In the framework of this project, their use as interface modifiers in optoelectronic devices such as organic or hybrid solar cells will be further developed, with the aim of establishing a relationship between their structure and the observed properties. Their solubility in polar environments will be used to develop hybrid nanomaterials with carbon nanotubes or gold nano-objects with the same solubility properties and thus meet one of the major challenges in molecular electronics, which is to study the electronic conductivity of the single molecule. The classical approach to obtain information on the properties of intramolecular transport which consists on the one hand in the synthesis of one-dimensional molecular wires of the order of 10 nm and on the other hand to manufacture nanogaps of controlled morphology and of the order of 10 nm also between two electrodes between which the molecular wires will be inserted. Although solutions have been found to this approach, the development of nano-gaps remains a challenge for physicists. To overcome this difficulty, researchers in the department have developed the bottom-up synthesis of gold nano-objects (nanoparticles and nano-rods of precise dimensions). These nano-objects will play the role of electrodes in the evaluation of the intramolecular mobility properties of one-dimensional oligo- or poly-electrolytes of controlled and functionalized sizes to interconnect them. On the other hand, the development of composites associating more generally inorganic nano-objects with a semiconductor pi-conjugated polymer via a coupling agent will also be studied, with a view to their use in branch n of thermoelectric devices.
Supramolecular engineering, Pi-conjugates-biomolecules interactions
The integration of functional materials and electronic devices into our bodies is attracting more and more attention, driven by the ambition to create intelligent and versatile interfaces capable of converting ionic biological currents into electronic currents and vice versa. An approach also based on the modification of the side chains will be considered using main chain patterns commonly used in the field of field-effect transistors and combining them with a functionalization of their side chains by a terminal hydroxyl group. This structuring function by hydrogen bond and extremely polar will make it possible to achieve new flexible materials consisting of a conjugated main chain to ensure good transport of electronic charge and polar flexible side chains to promote ion diffusion. These functional materials will open the door to the design of implanted electronic devices. In the same way, this functionalization by a hydroxyl function applied to small molecules has led to the emergence of a new case study, BTBT-C6OH, a molecular organic semiconductor that exhibits not only a colossal negative thermal expansion (NTE), but also good charge mobility in organic transistors. While conventionally, a compound contracts when the temperature decreases, in the case of an NTE, it expands in one direction while the temperature decreases, while contracting in the other two. This results in thermomechanical properties. Thus, for the first time, the study of the effect of NTE on the electronic properties of an organic semiconductor will be accessible, paving the way for new devices of organic electronics. The objective will be to understand the origin of exceptional electronic and thermomechanical properties, design semiconductors with superior performance (NTE and mobility) and demonstrate prototypes of new optoelectronic components (sensors ) exploiting this NTE. In addition to the incorporation of hydroxyl chains, the presence of cationic groups will also be exploited for pi-conjugated polyelectrolytes to promote interactions with nucleic acids (DNA, RNA). The polyelectrolyte DNA polyplexes will then be exploited in the detection of exogenous DNA in food matrices; the pi-conjugated skeleton acting as an optical sensor. Cationic pi-conjugated polyelectrolytes will also serve as vectors for gene delivery and visualization. In particular, dynamic covalent polymers (PDCs) incorporating fluorophores that will enable both the visualization of nucleic acid delivery at each step, the dynamics of compactiondecompaction throughout the delivery process, and the generation of reactive oxygen species (ROS) for dynamic therapy will also be studied. This approach should lead to new perspectives in the development of multifunctional therapeutic platforms by exploiting supramolecular polymers.
Photocatalysis and electrocatalysis
The development of novel pi-conjugated systems for catalysis is based on the combination of porphyrins and N-heterocyclic carbenes (NHCs) within unimolecular transition metal complexes. For applications in photocatalysis, porphyrins will play the role of photon collecting antennas in the visible range, capable of then performing energy and/or electron transfer reactions to nearby catalytic sites, i.e. peripheral NHC metal complexes. Synergistic effects, or even new reactivities, may eventually be observed depending on the modes of binding between porphyrins and NHC metal complexes. With these two-in-one compounds, photoinduced C-C coupling reactions, or the photochemical activation of small molecules (CO2 reduction, H2 evolution, H2O activation) will be studied. Finally, the electrocatalytic properties of recently developed bis-porphyrinic systems where porphyrin units are assembled face-to-face via the formation of carbene-metal bonds will be studied, particularly with regard to the reduction of O2 to 4 electrons.