Ce travail de thèse s’inscrit dans l’étude des matériaux moléculaires photo-commutables. L’objectif est le contrôle réversible et persistant des propriétés physiques de la matière par application d’un stimulus externe, tel qu’une excitation optique. Le travail de thèse est constitué de deux parties principales. La première partie traite de la photo-isomérisation des ligands NO dans les complexes de ruthénium di-nitrosyle. Une démarche expérimentale systématique a été effectuée sur trois complexes. La spectroscopie infrarouge et la diffraction des rayons-X ont été utilisées conjointement à basse température. De multiples isomères de liaison photo-induits (PLI) ont été détectés. Il a été montré qu’il est possible de photo-commuter chacun des deux ligands nitrosyles indépendamment. De plus, une double photo-isomérisation a été caractérisée. La deuxième partie présente le développement et la mise en œuvre d’une expérience de diffraction des rayons-X résolue en temps en laboratoire. Le dispositif est un diffractomètre prototype avec un détecteur à pixel hybride XPAD, permettant des mesures à l’échelle de la milliseconde. Un système pompe-sonde est couplé au diffractomètre permettant une excitation périodique de l’échantillon et une caractérisation in-situ de la photo-commutation. Cette expérience a été validée par la mesure de l’état métastable MSII du complexe nitrosyle Na2[Fe(CN)5NO].2H2O, d’une durée de vie de 12 ms à 150 K / This work is part of the study of photo-switchable molecular materials. The objective is the reversible and persistent control of the physical properties of matter by the application of an external stimulus, such as optical excitation. The thesis work consists of two main parts. The first part deals with the photoisomerization of NO ligands in ruthenium di-nitrosyl complexes. A systematic experimental approach was performed on three complexes. Infrared spectroscopy and X-ray diffraction were used together at low temperature. Multiple photoinduced linkage isomers (PLI) were detected. It has been shown that it is possible to photo-switch each of the two nitrosyl ligands independently. In addition, a double photoisomerization was characterized. The second part presents the development and implementation of an in-house time-resolved X-ray diffraction experiment. The device is a prototype diffractometer with a XPAD hybrid pixel detector, allowing measurements on a millisecond time-scale. A pump-probe system is coupled to the diffractometer allowing periodic excitation of the sample and an in-situ characterization of the photo-switching. This experiment was validated by measuring the metastable state MSII of the nitrosyl complex Na2[Fe(CN)5NO].2H2O, with a lifetime of 12 ms at 150 K

Based on the success of diacyl-tert-butylhydrazines RH-5849 and RH-1266 in controlling agricultural crop pests, we endeavored to synthesize our own diacylbenzyl- and arylhydrazine derivatives for use against the malaria vector Anopheles gambiae. In the process of producing a library of compounds for assay against An. gambiae, it became clear that employing regioselective acylation techniques (in molecules that feature two nucleophilic, acyclic nitrogen atoms α to one another) would be imperative. Synthesis of the library derivatives proceeded rapidly and after topical assay, we found three compounds that were more toxic than the RH-series leads. One of the three displayed an LD50 value of half that of RH-1266, though patch clamp assay concluded that toxicity was not necessarily linked to inhibition of mosquito K+ channel Kv2.1. The acylation of monoarylhydrazines appears simple, but its regioselectivity is poorly understood when assumed as a function of basicity correlating to nucleophilic strength. We determined the ratio of the rate constants for distal to proximal N-acylation using 19F NMR spectroscopic analysis of reactions of 4-fluorophenylhydrazine with limiting (0.2 equiv) acylating agent in the presence of various bases. Acid anhydrides gave consistent preference for distal acylation. The selectivity of acylation by acyl chlorides when using pyridine gives strong distal preference, whereas use of triethylamine or aqueous base in conjunction with aroyl chlorides showed a moderate preference for proximal acylation. This observation yielded a convenient one-step method to synthesize proximal aroylarylhydrazines in yields comparable or superior to that provided by the standard three-step literature approach. Combined with NMR evidence of the distal nitrogen as the unambigiously stronger base of the two nitrogens, we propose a single electron transfer mechanism that predicts the regiochemistry of arylhydrazines toward acylating agents better than the nucleophilicity model based on pKa values. While synthesizing the acylhydrazine library for assay against An. gambiae, NMR spectroscopy revealed rotational isomerisms of two types: chiral helicity (M)/(P) and acyl (E)/(Z)-isomerism due to hindered rotation. Variable temperature NMR allowed the measurement of N-N bond rotational barriers, as well as estimate the barrier of (E)/(Z) interconversion. We obtained the X-ray crystal structures of four diacylhydrazines to test this hypothesis and revealed both the twist conformation around the N-N bond axis and (E)/(Z)-isomerism around the proximal acyl group. Computation (which agreed with the crystal structures) allowed us to estimate which (E)/(Z)-isomers were most likely being observed in solution at room temperature by NMR spectroscopy. In addition, we were able to calculate transition structures corresponding to N-N bond rotational barriers of (E,Z)- and (Z,Z)-isomers of model molecules and rationalize the difference in coalescence temperatures between (E,Z)- and (Z,Z)-isomers. / Ph. D.

For the first time, successful synthesis and characterisation of the missing (Z)-isomer of thallium(I) methanediazotate has been accomplished, utilising low-temperature NMR monitoring analysis. The title compound was synthesised from N-methyl-N-nitrosourea and thallium(I) propoxide, under sub-ambient temperature conditions, as a highly moisture sensitive entity. Quantum chemical calculations, performed at the CCSD(T) level, depict excellent conformity to experimental results. Indeed, compared to its (E) counterpart, the formation of the title compound is thermodynamically less favoured, but preferred by means of kinetic control owing to a hindered isomerisation.

Notre travail de thèse a été dédié à la synthèse et à la caractérisation bio-physicochimique de complexes osmium nitrosyle, qui pourraient relarguer l’oxyde nitrique (NO) au sein des cellules tumorales pour conjuguer les propriétés anticancéreuses souvent associés aux complexes du groupe du platine avec la toxicité de l’oxyde nitrique. Le premier chapitre de notre mémoire de thèse présente l’état de l’art dans le domaine des composés anticancéreux et le rôle de l’oxyde nitrique dans l’apoptose cellulaire. Le deuxième chapitre concerne la synthèse et la caractérisation de complexes d’azole (C)[Os(NO)Cl4(A)] (C = Bu4N+, Na+, HA+; A = indazole, pyrazole, benzimidazole, imidazole), où le plus cytotoxique est H2ind[cis-Os(NO)Cl4(indazole)]. Le troisième chapitre est consacré à l’étude cinétique et thermodynamique par RMN de l’isomérisation trans ↔ cis du complexe (Bu4N)[Os(NO)Cl4(indazole)] qui met en évidence un processus d’isomérisation de type dissociatif. Le quatrième chapitre concerne la synthèse et la caractérisation de complexes d’aminoacides (Bu4N)[Os(NO)Cl4(L)] (L = gly, picolinate, L-, D-pro) qui ont une très faible activité antiproliférative. Le dernier chapitre est consacré à la synthèse et à la caractérisation de clusters hétérométalliques [{Os(NO)Cl3(Ox)}4Ln] (Ln = Gd, Tb, Dy, Y ; Ox=oxalate) dans lesquels la coordinance 8 ou 9 du lanthanide dépend de son rayon ionique. Le précurseur {Os(NO)Cl3(Ox)} a l’activité antiproliférative la plus élevée de tous les complexes osmium nitrosyle connus / The PhD thesis was dedicated to the synthesis and bio-physic-chemical characterization of osmium nitrosyl complexes which could release nitric oxide (NO) in tumor cells to combine the anticancer properties of the platinum group complexes and the nitric oxide cytotoxicity. The first chapter presents the state of the art in the field of anticancer compounds and the role of nitric oxide in the apoptosis. The second chapter concerns the synthesis and characterization of azole complexes with the general formulae (C)[Os(NO)Cl4(A)] (C = Bu4N+, Na+, HA+; A = indazole, pyrazole, benzimidazole, imidazole), where the most cytotoxic is H2ind[cis-Os(NO)Cl4(indazole)]. The third chapter focuses on the kinetic and thermodynamic study of the trans ↔ cis isomerisation of (Bu4N)[Os(NO)Cl4(indazole)] complex by NMR, which highlights a dissociative isomerisation process. The fourth chapter concerns the synthesis and the characterization of amino acids complexes with the general formulae (Bu4N)[Os(NO)Cl4(L)] (L = gly, picolinate, L-, D-pro) of whose antiproliferative activity is very low. The last chapter is dedicated to the synthesis and characterization of heterometallic clusters with the general formulae [{Os(NO)Cl3(Ox)}4Ln] (Ln = Gd, Tb, Dy, Y ; Ox = oxalate), where the coordination number 8 or 9 depends on its ionic radius. The precursor {Os(NO)Cl3(Ox)} has the highest antiproliferative activity among of all osmium nitrosyl known so far

For the first time, successful synthesis and characterisation of the missing (Z)-isomer of thallium(I) methanediazotate has been accomplished, utilising low-temperature NMR monitoring analysis. The title compound was synthesised from N-methyl-N-nitrosourea and thallium(I) propoxide, under sub-ambient temperature conditions, as a highly moisture sensitive entity. Quantum chemical calculations, performed at the CCSD(T) level, depict excellent conformity to experimental results. Indeed, compared to its (E) counterpart, the formation of the title compound is thermodynamically less favoured, but preferred by means of kinetic control owing to a hindered isomerisation.

No description available.

Chimie dynamique: reconnaissance de nucléobases par des récepteurs synthétiques et isomérie cis-trans d'hydrazones acylées.Ce travail traite du développement des systèmes moléculaires qui peuvent s'adapter à l'addition de substances qui agissent comme un gabarit. Cette approche permet d'isoler une espèce majeure à partir d'un mélange de composés par le biais de la chimie combinatoire dynamique (CCD). La première partie de ma thèse de doctorat inclus l'utilisation d'un ADN simple brin (ADNsb) comme un gabarit pour le transfert d'information par auto-assemblage de récepteurs sans avoir besoin d'enzyme. De nouveaux récepteurs de l'adénine et de la guanine (pinces A et G) solubles dans l'eau ont été conçues dans ce but. Une approche utilisant la résonance magnétique nucléaire (RMN) a été utilisée pour déterminer l'affinité de liaison comme preuve d'une reconnaissance spécifique et efficace. Une évaluation dans l'eau par dichroïsme circulaire (CD) et mesure de la température de fusion par UV (Tm) a été réalisée. Cela a permis de tester respectivement la capacité d'auto-assemblage entre les pinces et un modèle ADNsb, et la force du processus de coopérativité. La deuxième partie de ce travail est axée sur le tri spontanné de motifs pyridine acylhydrazone et sur les configurations intéressantes qu'ils adoptent. Nous avons étudié la synthèse d'une série de motifs pyridine acylhydrazone: dimère, trimères et pentamères. Des études RMN ont permis d'évaluer les changements dans l'équilibre configurationnel cis / trans de ces systèmes dynamiques. Les études ont montré que l'équilibre attendu est biaise la cis acylhydrazone pyridine isomère a été observée par diffraction des rayons X. / Dynamic chemistry: nucleobase recognition by synthetic receptors and cis-trans acylhydrazone isomerism. This work deals with the development of molecular systems which can adapt upon the addition of substances that act as templates. This approach enables one major species to be identified from a mixture of compounds through the use of dynamic combinatorial chemistry (DCC). The first part of my PhD included the use of a single stranded DNA (ssDNA) as a template for information transfer via the self-assembly of receptors without the need for enzymes. New water soluble adenine and guanine receptors (A and G clamps) were designed and synthesised for this purpose. Nuclear magnetic resonance (NMR) titration studies were carried out to calculate the binding affinity and as a proof of specific and efficient recognition. An assessment in water via circular dichroism (CD) and UV temperature melting (Tm) studies was carried out. This tested the ability for self-assembly between the clamps and a ssDNA template and the strength of the cooperative process respectively. The second part of my PhD focused on the self-sorting of acylhydrazone pyridine motifs and the interesting configurations they adopt. The feasibility to synthesise these acylhydrazone pyridine motifs (dimer, trimers and pentamers) was investigated. X-ray and NMR studies showed that the equilibrium was found to be biased in an unusual way, and the cis acylhydrazone pyridine isomer was observed.