Thesis (Ph. D.)--University of Queensland, 2002. / Includes bibliographical references.

Matériaux à base de graphène et d’oxyde de graphène ont attiré une grande attention depuis sa découverte. Cependant, comme la feuille de graphène a une surface spécifique élevée, il tend à former un agglomérat irréversible ou même empiler pour former le graphite par π-π empilage et Van-der Waals interactions. Les modifications doivent être faites pour séparer les feuilles de graphène sans apporter trop de dégâts dans sa structure aromatique. Dans cette thèse, nous avons lancé deux méthodes pour faire la modification du graphène, réaction de substitution nucléophile pour l’oxyde de graphène avec un C/O ~ 2 (FGS2), tandis que la demande électronique inverse réaction de Diels-Alder pour l’oxyde de graphène avec un très faible teneur en oxygène C/O ~ 20 (FGS20). Comme dans le second cas, FGS20 fonctionnalisés par tetrazine possède une excellente conductivité, il a été en outre combiné avec un polypyrrole pour fabriquer un matériau de supercondensateur.Dans le chapitre 2, nous avons greffé de manière covalente des dérivés de tétrazine à l'oxyde de graphène par substitution nucléophile. Comme l'unité de tétrazine est électroactif et riche en azote, avec un potentiel de réduction sensible du type de substituant et degré de substitution, nous avons utilisé l'électrochimie et la spectroscopie de photoélectrons X pour démontrer des preuves claires pour le greffage par liaison covalente. La modification chimique a été soutenue par spectroscopie infrarouge à transformée de Fourier et analyse thermique. Tétrazines greffé sur l'oxyde de graphène affichent différentes pertes de masse par rapport à graphène non modifiée et sont plus stables que les précurseurs moléculaires. Enfin, un dérivé de pontage tétrazine a été greffée entre des feuilles d'oxyde de graphène pour démontrer que la distance de séparation entre les feuilles peut être maintenue lors de la conception de nouveaux matériaux à base de graphène, y compris les structures d'oxydo-réduction chimiquement liés, les structures d'oxydoréduction.Dans le chapitre 3, des molécules modèles de graphène ont été sélectionnés afin de déterminer les conditions optimales de réaction entre graphène et tétrazine dérivés. Toutes les molécules de tétrazine ont d'abord été étudiés par électrochimie et ensuite mis à réagir avec le graphène par la demande électronique inverse Diels-Alder (DAinv) réaction dans un réacteur à micro-ondes, la XPS a été réalisée pour étudier sa composition chimique et de prouver la modification avec succès du graphène. Ensuite, le matériau de graphène tétrazine fonctionnalisé a été appliqué sur une électrode en acier inoxydable et ses performances électrochimiques ont été évaluées par voltamétrie cyclique et les tests de charge-décharge. La plupart des tétrazine modifié matériaux de graphène a montré de très bonnes performances électrochimiques et une faible résistance due à une bonne accessibilité des ions, ce qui en fait l'un des matériaux d'électrodes les plus prometteuses pour les supercondensateurs jusqu'à présent. Dans le chapitre 4, polypyrrole (PPy)-graphène nanocomposites ont été synthétisés par polymérisation de PPy sur les feuilles de graphène fonctionnalisés par tétrazine. Le matériau de graphène modifié contient des unités pyridazine tel que démontré par XPS. Puis PPy a été déposé sur ce matériau de graphène fonctionnalisé soit par polymérisation chimique ou électrochimique. Cellules de pièces symétriques ont été faites pour mesurer la capacité dans une configuration à deux électrodes. Les nanocomposites de polypyrrole-graphène avec 40% PPy présentent les meilleures performances électrochimiques et une faible résistance en raison d'une bonne accessibilité des ions, ce qui en fait l'un des meilleurs matériaux d'électrodes pour supercapacitor jusqu'à présent. / Graphene and graphene oxide based materials have attracted great attention since its discovery. However, as graphene sheet has a high specific surface area, it tends to form an irreversible agglomerates or even restack to form graphite through π–π stacking and van-der Waals interactions. Modifications need to be done to separate graphene sheets without bringing too much damage in its aromatic structure.In this thesis, two methods have been introduced to do the modification of graphene, nucleophilic substitution reaction for graphene oxide with a C/O~2 (FGS2), while inverse electron demand Diels-Alder reaction for graphene oxide with a very low oxygen content C/O~20 (FGS20). As in the latter case, tetrazine functionalized FGS20 has excellent conductivity, it has been further combined with polypyrrole to fabricate supercapacitor material.In chapter 2, we have covalently grafted tetrazine derivatives to graphene oxide through nucleophilic substitution. Since the tetrazine unit is electroactive and nitrogen-rich, with a reduction potential sensitive to the type of substituent and degree of substitution, we used electrochemistry and X-ray photoelectron spectroscopy to demonstrate clear evidence for grafting through covalent bonding. Chemical modification was supported by Fourier transform infrared spectroscopy and thermal analysis. Tetrazines grafted onto graphene oxide displayed different mass losses compared to unmodified graphene and were more stable than the molecular precursors. Finally, a bridging tetrazine derivative was grafted between sheets of graphene oxide to demonstrate that the separation distance between sheets can be maintained while designing new graphene-based materials, including chemically bound, redox structures.In chapter 3, model molecules of graphene were selected to determine the optimal reaction conditions between graphene and tetrazine derivatives. All tetrazine molecules were firstly studied by electrochemistry and then reacted with graphene through inverse electron demand Diels-Alder (DAinv) reaction in microwave reactor, X-ray photoelectron spectroscopy was carried out to study its chemical composition and prove the successfully modification of graphene. Then the tetrazine functionalized graphene material was coated on a Stainless Steel electrode and its electrochemical performances were assessed by cyclic voltammetry and charge-discharge experiments. Most of the tetrazine modified graphene materials showed very good electrochemical performance and a small resistance due to a good ion accessibility, which makes it one of the most promising electrode materials for supercapacitors so far.In chapter 4, polypyrrole (PPy)-graphene sheet nanocomposites have been synthesized by both chemical and in situ electrochemical polymerization of PPy on tetrazine derivatives functionalized graphene sheets. The modified graphene material contains pyridazine units as demonstrated by XPS. Then PPy was deposited on this functionalized graphene material either by chemical or electrochemical polymerization. Symmetrical coin cells were made to measure the capacitance in a two-electrode configuration. Polypyrrole-graphene nanocomposites with 40% PPy show the best electrochemical performances, with a very large capacitance per weight (326 F g-1 at 0.5 A g-1 and 250 F g-1 at 2 A g-1) and a small resistance due to a good ion accessibility, which makes it one of the best electrode materials for supercapacitors so far.

No description available.

Many cancer drugs are inherently cytotoxic, leading to severe toxicity towards healthy tissues and organs. One effective strategy to circumvent these side effects is to mask a cytotoxic drug with a “caging group” which, once at the target tissues, releases the masked drug upon an appropriate trigger. In this study, 1,2,4,5-tetrazines which undergo bioorthogonal inverse electron demand Diels-Alder cycloadditions, were used as “chemical triggers” to unmask a “caged cargo”. The vinyl carbamate bond was successfully used as a caging group to ‘cage coumarin’ and was decaged with trigger ‘dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate’. However the trigger underwent hydrolysis under physiological conditions. Various 1,2,4,5- tetrazines were synthesized and hydrolytic stable 1,2,4,5- tetrazines were evaluated for decaging of caged coumarin but with no success. In depth stability of 1,2,4,5-tetrazines under physiological conditions was investigated before exploration alternative caging groups. The results obtained showed basic and physiological conditions had a deteriorating impact on the stability of 1,2,4,5-tetrazine with rapid degradation (t1/2 5– 50 min) in culture medium. The half-lives were significantly increased in acidic pH compared to basic pH (with up to a 187-fold increase from pH 9 to pH 5). Exploration of ketene-N,S-acetals, enamides, thioether-norbornene, enolethernorbornene and vinyl ether as caging groups was conducted. Only vinyl ethers proved to be a success with caging of two fluorophores i.e. fluorescein and resorufin. Two 1,2,4,5-tetrazines were effective in the decaging of the vinyl ether caged fluorophores in water and PBS. Bis-vinyl fluorescein was successfully decaged in HeLa cells showing the potential of vinyl ethers as a caging groups. In future, the vinyl ether would be used to cage a cytotoxic drug and its activation by 1,2,4,5-tetrazine functionalised with tumor targeting peptide or antibodies would result in localised and selective drug release.

Thesis (Ph. D.)--University of Chicago, Dept. of Chemistry, December 1997. / Includes bibliographical references. Also available on the Internet.

This dissertation is composed of 5 chapters detailing advances in the synthesis and post-modification of polymers using tetrazines. The research described herein conveys three new discoveries each of which should forge new fields of research concerning tetrazines in polymer chemistry, that is the use of tetrazines as chemical blowing agents in generating polymer foams, as agents for incorporating large concentrations of antioxidants into polymers, and their attachment to polymers, adding a photodegradable functional unit which alters the refractive index of the materials after degradation. The first chapter is a review which highlights the use of tetrazines in polymer chemistry as repeat units incorporated into polymers, tools for post-modification, and cross-linkers for the formation of gels. Tetrazines are unique molecules which been utilized in many different types of materials. Their tetra-azo core has provided the basis for preparing high energetic explosive materials, and the high nitrogen content has also been exploited in metal chelating polymers. Being highly electron deficient, the tetrazine ring has found use in donor – acceptor (D – A) copolymers for use in polymer solar cells (PSCs). Its ability to undergo an irreversible cycloaddition reaction without the requirement of metal catalysis, has created an entire field of research in bioorthogonal ligation and has also found use in polymer chain extension, post-modification, and gel formation. The versatility of the tetrazine ring is demonstrated in this review with the shear variety of its applications in polymer chemistry. The second chapter reports on the discovery of 3,6-dichloro-1,2,4,5-tetrazine's (DCT) use as a chemical blowing agent in preparing polymer foams. This discovery demonstrates the first reported use of tetrazines as chemical blowing agents, and the production of a new class of polymers foams through exploitation of this chemistry. Nitrogen is released from a cycloaddition reaction between DCT and polybutadiene (PBD). As the reaction proceeds, the foam grows and increases in viscosity eventually setting up into a solid material. The product of the cycloaddition reaction, a dihydropyridazine ring, is demonstrated to provide the foams with a built-in antioxidant, and a change in fluorescence of the foams provides indication for extent of oxidation. Also in this chapter, a new method is proposed for comparing antioxidant properties of small molecules, and two dihydropyridazines are shown to outperform commercial antioxidant BHT with this method. Chapter 3 follows up on the results from the previous chapter, with the synthesis of four new polymers through solution-based cycloaddition reactions between dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (DMDT) and PBD. Near quantitative conversions results in the formation of two new classes of dihydropyridazine polymers, providing an entirely new class of polymer which contains its own built-in antioxidant on nearly every repeat unit along the polymer backbone. Oxidation of these materials results in an additional 2 new classes of heteroaromatic pyridazine polymers reported for the first time in this chapter. The properties of these new materials are reported and the antioxidant properties of the dihydropyridazine ring are further explored through cyclic voltammetry (CV). Quenching of fluorescence is observed upon oxidation of the materials, providing a visual indicator for extent of oxidation, and an explanation for the quenching is also provide through CV analysis. Chapter 4 diverges from tetrazine IEDDA modification of polybutadienes and instead focuses on the post-modification of poly(methyl methacrylate-co-2-hydroxyethyl methacrylate) with DCT to generate photobleachable materials. This chapter represents the first reported use of tetrazine photobleaching in modifying the optical properties of polymers, and the generation of a new copolymer containing pendant tetrazine repeat units. The modified copolymer is demonstrated to be solvent processable, but crosslinks upon heat treatment. Extended UV or ambient light excitation of the copolymer results in degradation of the tetrazine ring and bleaching of the polymer. A refractive index change for the polymer is observed after degradation, leading to the hypothesis that these polymers may find use in optical waveguide materials. Finally, chapter 5 provides a summation of the dissertation and discusses unfinished projects that can be pursued further by future Loy group graduate students.

Indiana University-Purdue University Indianapolis (IUPUI) / Nanoparticles (NPs) are an emerging technology in biomedical engineering with opportunities in diagnostics, imaging, and drug delivery. NPs can be prepared from a wide range of organic and/or inorganic materials. They can be fabricated to exhibit different characteristics for biomedical applications. The goal of this thesis was to develop NPs with tunable surface properties for selective cell targeting. Specifically, polyelectrolyte complexes composed of heparin (Hep, a growth factor binding glycosaminoglycan) and poly-L-lysine (PLL, a homopolymeric lysine) were prepared via a pulse sonication method. The Hep/PLL core NPs were further layered with additional Hep, tetrazine (Tz) modified Hep, or dextran sulfate (DS). The addition of Tz handle on Hep backbone permitted easy modification of NP surface with norbornene (NB) modified motifs/ligands, including inert poly(ethylene glycol) (PEG), cell adhesive peptides (e.g., RGD), and/or fluorescent marker. Both Hep and DS coated NPs could be readily internalized by J774A.1 monocytes/macrophages, whereas PEGylated NPs effectively reduced cellular uptake/recognition. The versatility of this NP system was further demonstrated by laying DS on the Hep/PLL NP surface. DS-coated NPs were recognized by J774A.1 cells more effectively. Furthermore, DS-layered NPs seemed to reduce IL-10 production on a per cell basis, suggesting that these NPs could be used to alter polarization of macrophages.

Conjugated tetrazine-containing polymers that undergo Inverse Electron Demand Diels-Alder (IEDDA) reactions with trans-cyclooctenes are interesting not only for their intrinsic optoelectronic properties, but also their interactions with π-conjugated surfaces. Here, we prepared a series of poly(fluorene-co-tetrazine) polymers and carried out IEDDA reactions to decorate them with hydroxyl, hexadecyl, or triethylene glycol side chains. The polymers were investigated pre- and post-IEDDA coupling in terms of their ability to disperse single-walled carbon nanotubes (SWNTs) in organic solvent. It was found that polymer molecular weight, side chain structure, and degree of conjugation all impacted the quality of SWNT dispersions. While the starting poly(fluorene-co-tetrazine) polymer produced concentrated dispersions, the post-IEDDA polymer containing dihydropyridazine groups did not produce dispersions of equal concentration. However, upon oxidation to the fully aromatic pyridazines, the polymers regained their ability to form concentrated dispersions. Furthermore, the post-IEDDA polymers exhibited increased selectivity toward metallic SWNTs relative to the starting polymer. In addition, due to the efficiency of the IEDDA reaction, it was possible to perform modification of the polymer-SWNT dispersion formed with poly(fluorene-co-tetrazine) to modify the polymer structure while on the SWNT surface. Overall, this work demonstrates the first use of reactive polytetrazines to disperse SWNTs and to rapidly modify the solubility of polymer-nanotube complexes. / Thesis / Master of Science (MSc)

Au cours de cette thèse, nous avons préparé différents classes de dérives de la s-tétrazine et étudies leurs propriétés de électrochimiques et de fluorescence. Dans la première partie, nous présentons une étude bibliographique de la tétrazine, principalement centre sur sa synthèse et ses propriétés. Dans le second chapitre, nous introduirons des nouveaux récepteurs de paires d’ions basés sur des bis-tétrazines. Ces récepteurs utilisent des interactions de type pi-anion, qui ont été rarement observées en solution, pour effectuer la reconnaissance. La complexation de ces récepteurs avec des sels d’halogénure d’ammonium (C8H17NH3Br et C8H17NH3I) a été démontrée par RMN et fluorescence. Il est démontré que le récepteur 82 forme des complexes plus stables avec les ammoniums que ces équivalents 80 et 81 à chaine plus courte. De plus, tous ces récepteurs présentent une sélectivité inattendue envers les halogènes suivant l’ordre : I->Br->Cl-. Enfin, une réaction secondaire a été mise en évidence par spectroscopie d’absorption qui conduit a la formation de Br2 ou I2. Un mécanisme probable pour cette réaction est propose au vu de tous les résultats spectroscopiques. Dans le troisième partie, de nombreux dérivés de la tétrazine portant des substituants de nature diverse ont été obtenus afin de mieux comprendre les propriétés physico-chimiques de cet aromatique. Il apparait clairement que les propriétés électrochimiques ne dépendent pas de la taille mais seulement de l’électronégativité du substituant. De plus, des groupes électrodonneurs conduisent à une inhibition de la fluorescence même s’ils ne sont pas directement liés. Une nouvelle classe de dérives de la s-tétrazine a été obtenue grâce à une nouvelle réaction des chlorotétrazines. Cette réaction conduit a l’obtention de dérivés non symétriques portant un hétéroatome et une chaine alkyle qui seront utiles pour de développements futurs. Dans la dernière partie, nous présentons de nouvelles dyades a base de tétrazine présentant une brillance améliorée. Ces dyades sont basées sur un transfert d’énergie entre un donneur (benzimidazole ou naphtalimide) et un accepteur (la tétrazine). Elles présentent des bons rendements quantiques de fluorescence, des durées de vie allongées et des brillances améliorées. L’un de ces dérivés a été utilisé pour fabriquer une cellule fluorescente à trois couleurs contrôlable par électrochimie. / In this thesis, we have prepared different types of s-tetrazine derivatives for electrochemical and fluorescence studies. In the first part, we present a blibliographic study of s-tetrazine focussing on theirs synthesis and properties. In the second chapter, we introduce s-tetrazine derivatives as the ion pair receptor. These receprtors uses pi-anion type of interactions between ion pairs and s-tetrazines whcih has been seldom been observed in solution. The formation of complex between the ammonium salt (C8H17NH3Br or C8H17NH3I) and bis-s-tetrazine receptors is demonstrated by NMR and fluorescence titration experiments. It is also proved that receptor 82 binds stronger to ammonium salt than the shorter equivalents 80 and 81. Furthermore, all of them give the same unexpected selectivity order toward anions namely: I- > Br- > Cl-. Finally, a side reaction has been uncovered by UV-vis absorption which leads to the formation of Br2 or I2. Taking fully into account all spectroscopic results, we proposed a mechanism for this transformation. In the third part, in order to better understand the physico-chemcal properties of s-tetrazine, various s-tetrazines with different types of substituents have been prepared. It is clear that the electrochemical properties of the tetrazine nucleus depend on the electron affinity of its substituent and not on the size. Furthermore, electron donor groups quench the fluorescence of s-tetrazine even if they are not directly linked. A new type of s-tetrazines has been obtained through an unexpected reactivity of chloro-s-tetrazine. This reaction could give unsymmetrical s-tetrazines bearing one heteroatom and one alkyl chain which is useful for future developmemt of their properties. In the last part, we talk about new s-tetrazine dyads with improved brightness. Based on energy transfer from a donor part (naphthalimide or benzimidazole) to an acceptor core (tetrazine), these compounds own good fluorescence quantum yields, longer lifetimes and higher brightness. One derivative has been used to prepare a three colors fluorescent and electrochemically switchable device.

The need for chemoselective bond formation within complex biological systems has driven much research in chemical biology and chemical medicine and has allowed control over the structure and biological properties of a range of chemical entities. Reactions that are highly biocompatible, selective and occur at low concentration are classified as being bioorthogonal. Although bioorthogonal reactions have been successfully applied to bioconjugation and imaging in living systems, only a few examples exist of bioorthogonal reactions being utilised for the activation of prodrugs. The tetrazine mediated inverse electron demand Diels-Alder reaction is characterized by excellent reaction rates and high biocompatibility in both in vitro and in vivo applications. To date, this chemistry has found only limited application in prodrug activation or drug release strategies. Herein, a series of tetrazine-trigger systems are reported in which an active drug is liberated from its inactive form upon triggering with tetrazine. It is shown that the release of encapsulated and conjugated drugs from polymeric nanoparticles can be triggered by tetrazines providing an on-demand release within biological systems. In a totally new approach that fully complies with the principle of bioorthogonality by avoiding the generation of any by-products, tetrazine was utilised as a prodrug scaffold leading to symbiotic and traceless dyadic prodrug activation. The simultaneous formation of two active drugs (here the anticancer drug camptothecin and a known micro RNA inhibitor) was confirmed and validated within a biological environment. The use of tetrazines as a trigger to activate or release an active drug will open new directions in the field of chemical biology/medicine.