Dissertations / Theses on the topic 'Nitroxide-Mediated Radical Polymerization'

De nos jours, la photopolymérisation est devenue un procédé important dans le domaine de la science des polymères. Cette méthode présente de nombreux avantages : la rapidité de la réaction, l‘aspect environnemental (formation limitée de composés organiques volatils et possibilité de réaction à température ambiante) ou encore un contrôle spatial et temporel. Ce mode d‘activation photochimique appliqué pendant les dernières décennies aux techniques de polymérisation radicalaire contrôlée telles que l‘ATRP, la RAFT ou la NMP permet de contrôler les propriétés des polymères mais aussi la préparation de polymères à blocs. Parmi ces techniques, la photopolymérisation contrôlée par les nitroxydes (NMP²) nécessite l‘utilisation d‘une alcoxyamine photosensible dont un groupement chromophore est porté par un nitroxyde. Dans ce manuscrit, nous présentons aussi bien la préparation d‘alcoxyamines photosensibles que les études de leurs propriétés photochimiques analysées par spectroscopie d‘absorption et par expériences de résonance paramagnétique électronique. Nous avons évalué les capacités de polymérisation des meilleurs candidats obtenus dans des conditions de NMP². Enfin, une autre méthode a été testée en effectuant une réaction de NMP² à partir d‘alcoxyamines produites par ESCP (Enhanced Spin Capturing Polymerization) ou par NMRC (Nitrone-Mediated Radical Coupling)
Nowadays, photopolymerization has become an important process in the field of polymer science. This method presents several advantages such as the speed of the reaction, the environmental-friendly side (limited formation of released volatile organic compound and possibility of a reaction at room temperature) but also a spatial and temporal control. This photochemical approach applied in the past decades to controlled radical polymerization techniques such as ATRP, RAFT or NMP enable the control of polymer properties but also the preparation of block polymers. Among these techniques, the Nitroxide-Mediated Photopolymerization (NMP²) requires the use of a photosensitive alkoxyamine which has a chromophore group on the nitroxide moiety. In this manuscript, we present both the synthesis of photosensitive alkoxyamines and the studies of their photochemical properties investigated by absorption spectroscopy and by electron spin resonance experiments. We evaluated the polymerization abilities of the best obtained candidates. Finally, another approach has been tested to perform a reaction of NMP² from alkoxyamines made by ESCP (Enhanced Spin Capturing Polymerization) or via NMRC (Nitrone-Mediated Radical Coupling)

The work presented in this thesis deals primarily with living free radical polymerization (LFRP). Two main specific areas of this process have been studied; thermal and photochemical reaction sequences. Stoichiometric unimolecular initiators were found to be ideal probes for studying the reactions involved in the LFRP process. The bond dissociation energy (BDE) of the labile C-O bond of the alkoxyamine initiators was found to be ca. 28 kcal/mol and is dependent on the resulting carbon centered radical produced upon thermal decomposition. Lower activation energies were measured for more stable carbon centered radicals. Complementary to the thermal studies, photoacoustic studies (PAC) involving photochemical decomposition of the initiators led to the homolytic N-O and C-O bond cleavages in addition to disproportionation product formation. The BDE for the N-O bond of these initiators is ca. 43 kcal/mol. These studies also provided insight into volume effects, where a strict homologous solvent series is not required for extrapolating true enthalpies of reactions and volume correction factors for PAC. The decomposition quantum yields of a series of ketone based actinometers used for PAC BDE studies were re-evaluated and found to be solvent independent. The specific kinetics of thermal LFRP were equally investigated through the use of probes which are normally used for thermal initiation. Fast time resolved techniques of laser flash photolysis (LFP) were used to measure the bi-molecular rate constant for the coupling reaction between a carbon centered radical and a nitroxide radical involved in LFRP. Typical values lay in the area of 108 M-1 s-1 and are influenced by the structure of the carbon centered radical and not that of the nitroxide. The rate constants were observed to be slower with more stable carbon centered radicals, similar to the BDE results where weaker dissociation energies were observed. The formation of minor disproportionation products upon thermal decomposition of the unimolecular initiators was assigned to a concerted four center elimination ultimately responsible for the lack of controlled polymerization with acrylates. The incorporation of steric effects into the monomer or the nitroxide suppressed the formation of these products by increasing the energy barrier necessary for correct orbital alignment required for the elimination reaction. Living polymerization of acrylate monomers was achieved with a nitroxide containing bulky substituents in its 2 and 6 positions. Moderate success of living polymerization was also achieved with acrylate type monomers through the use of an additional phase not miscible with the bulk phase. Chromophores producing triplet states upon excitation were found to undergo fast and efficient energy transfer to a covalently linked alkoxyamine subsequently promoting C-O bond homolysis. The orientation of the C-O bond relative to the chromophore in addition to the distance separating the two influences the efficiency of energy transfer and bond cleavage. Using a benzophenone type chromophore with a covalently linked alkoxyamine initiator promoted photoinduced living type polymerization of acrylate.

Nitroxide mediated controlled radical polymerization (NMP) has been utilized since the early 1990s, as a simple and robust technique for the synthesis of various new polymeric architectures. Since the development of second generation initiators based on SG1 and TIPNO stable radicals, NMP is no longer restricted to the polymerization of just styrenics as it was initially and can now homopolymerize a plethoraof monomers such as acrylates and acrylamides. In this thesis, several advances in NMP due to these second generation initiators, were explored. The homopolymerization of methacrylates, by NMP, results inexcessive irreversible termination due to the elevated concentration of free radicals generated in the initial stages of the polymerization. However, the use of a small amount of a "controlling" comonomer can be used to control the copolymerization, as characterized by a linear increase in number average molecular weight (Mn), versus conversion (X) and a narrow molecular weight distribution (Mw/Mn < 1.5). The use of styrene ( 10 mol%) as a "controlling" comonomer for ethyl methacrylate, n-butyl methacrylate and tert-butyl methacrylate resulted in a controlled copolymerization of pseudo-"living" random copolymers characterized by a narrow molecular weight distributions (Mw/Mn = 1.2-1.5). In addition to styrene, 9-(4-vinylbenzyl)-9H-carbazole) (VBK) was used as a "controlling" comonomer for methyl methacrylate and 2-(dimethylamino)ethyl methacrylate, requiring as little as 1-2 mol% VBK relative to methacrylate, resulting in a controlled pseudo-"living" polymerization. In the second part of the thesis, NMP was utilized to control the copolymer microstructure. When using a non-equimolar feed of maleic anhydride (MA) and styrene (S), the synthesis of poly(MA-alt-S)-b-poly(S) block copolymers characterized by narrow molecular weight distributions (Mw/Mn = 1.3) where one block consisted of alternating MA and S monomers, was possible when the polymerization temperature was kept below 90 C. Finally a poly(ethylene-co-butylene)-SG12 initiator was synthesized and was used to successfully polymerize S and S/MA mixtures. The final poly(ethylene-co-butylene)-poly(MA-alt-S)2 block copolymers were tested as compatibilizers in blends with nylon-6.
L'utilisation de la polymèrisation radicale contrôlée en présence de radicaux nitroxyde (NMP) a débuté vers les annèes 1990s. Cette technique est simple et robuste, portant facilement à la synthèse de diverses nouvelles architectures de polymères. Grâce au développement d'initiateurs de deuxième génération basés sur radicaux stables de SG1 et de TIPNO, l'NMP n'est plus limité à la polymérisation des styrènes et peut maintenant homopolymériser une varietée de monoméres tels que des acrylates et des acrylamides. Dans cette thèse, plusieurs développements de l'NMP dus à ces initiateurs de deuxième génération, ont été explorés. L'homopolymérisation des methacrylates, par NMP, a pour consèquence un excés de terminaisons irréversibles en raison de à la concentration élevée de radicaux libres produits au début de la polymérisation. Cependant, une petite quantité de comonomère "contrôlant" peut être utilisée pour contrôler la copolymèrisation, donnant comme résultat une augmentation linéaire de la masse molaire moyenne en nombre (Mn) avec la conversion (X) ainsi que des copolymères qui possèdent une distribution moléculaire étroite (Mw/Mn < 1.5). Le styrène ( 10 mol%) a été utilisé comme comonomère "contrôlant" pour la synthèse du méthacrylate éthylique, le méthacrylate n-butylique et le méthacrylate de tert- butyl. Dans tous les cas la copolymèrisation était contrôlée, donnant comme résultat un copolymère qui est "vivant" et qui possède une distribution moléculaire étroite (Mw/Mn = 1.2-1.5). En ajout du styrène, 9-(4-vinylbenzyl)-9H-carbazole) (VBK) a été employé comme comonomère "contr^olant" pour le méthacrylate méthylique et le méthacrylate de 2-diméthylaminoéthyle, mais cette fois exigeant que 1-2 mol% de VBK par rapport aux méthacrylates, ayant comme résultat une copolymèrisationcontr^olée et des copolymères _naux qui sont "vivants". Dans la deuxième partie de la thèse, NMP a été utilisé pour contrôler la microstructure de divers copolymères. En employant une formulation non-équimolaire d'anhydride maléique (MA) et de styrène (s), la synthèse de blocs copolymères poly(MA-alt-S)-b-poly(S) ayant une distribution moléculaire étroite (Mw/Mn = 1.3) a été réalisée lorsque la température de polymérisation était maintenue en dessous de 90C. Finalement l'initiateur poly(éthyléne-co-butyléne)-SG12 a été synthètisé et employé pour la polymèrisation de S et de mélanges de S/MA. Finalement, des copolymères en bloc poly(éthyléne-co-butyléne)-poly(MA-alt-S)2 ont été examinés comme compatibilisateur de mélanges avec le nylon-6.

Thesis (DSc)--Stellenbosch University, 2012.
ENGLISH ABSTRACT: Examples of the use of NMR spectroscopy in the study of radical polymerization processes have been described. The studies presented have made a significant contribution to the understanding of the fundamental mechanistic processes in these polymerization systems. It is pointed out that NMR in conventional radical polymerization is of limited use due to the concurrent occurrence of all elementary reactions (initiation, propagation and termination). Conversely, for living radical polymerization, NMR has great value. In that case, the elementary reactions are somewhat more restricted to specific times of the polymerization process. This allows for example the detailed study of the early stages of chain growth in Reversible Addition-­‐Fragmentation Chain Transfer (RAFT) mediated polymerization. Two different studies are described. The first is related to the early stages of RAFT-­‐mediated polymerization. A process for which we coined the name initialization was studied via in situ 1H NMR spectroscopy. It is shown that in many cases, there is a selective reaction that converts the original RAFT agent into its single monomer adduct. A few different examples and their mechanistic interpretation are discussed. It is also shown that NMR spectroscopy can be a valuable tool for the assessment of a RAFT agent in conjunction with a specific monomer and polymerization conditions. In the second study, 15N NMR, 31P NMR and 1H NMR are used for two different types of experiments. The first is a conventional radical copolymerization in which the growing chains are trapped by a 15N labeled nitroxide to yield a stable product. In the second experiment, a similar copolymerization is conducted under nitroxide-­‐mediated conditions. The nitroxide of choice contains phosphorous, which enables the quantification of the terminal monomer in the dormant chains. Each of the experiments individually provides interesting information on conventional radical copolymerization and nitroxide-­‐mediated copolymerization, respectively. Combination of the experimental data reveals an interesting discrepancy in the ratio of terminal monomer units in active chains and dormant chains. Although not unexpected, this result is interesting and useful from a mechanistic as well as a synthetic point of view. In terms of future perspectives, it is expected that the advanced analytical techniques as described here will remain crucial in polymer science. Present developments in radical polymerization, such as investigations into monomer sequence control, rely on accurate knowledge of kinetic and mechanistic details of elementary reactions. It is expected that such detailed studies will be a main challenge for the next decade of polymer research.
AFRIKAANSE OPSOMMING: Voorbeelde van die gebruik van KMR-­‐spektroskopie in die studie van radikaalpolimerisasies word beskryf. Hierdie studies het ʼn beduidende bydrae gelewer tot die verstaan van die fundamentele meganistiese prosesse in hierdie polimerisasiesisteme. Dit het daarop gewys dat KMR beperkte gebruike het in konvensionele radikaalpolimerisasies as gevolg van die gelyktydige voorkoms van alle basiese reaksies (afsetting, voortsetting en beëindiging). Aan die anderkant het KMR groot waarde vir lewende radikaalpolimerisasie. In hierdie geval is die elementêre reaksies ietwat meer beperk tot spesifieke tye van die polimerisasieproses. Gedetailleerde studies kan byvoorbeeld van die vroeë stadiums van die kettinggroei in Omkeerbare Addisie-­‐Fragmentasie-­‐ KettingOordrag (OAFO)-­‐bemiddelde polimerisasie gedoen word. Twee verskillende studies is beskryf. Die eerste het betrekking op die vroeë stadiums van die OAFO-­‐bemiddelde polimerisasie. 'n Proses wat “inisialisering” genoem is, is bestudeer deur middel van in situ 1H KMR-­‐spektroskopie. Dit is bewys dat daar in baie gevalle 'n selektiewe reaksie is wat die oorspronklike OAFO-­‐agent in sy enkelmonomeeradduk verander voor polimerisasie. 'n Paar ander voorbeelde en hul meganistiese interpretasie is bespreek. Dit is ook bewys dat KMR-­‐spektroskopie 'n waardevolle hulpmiddel kan wees vir die assessering van 'n OAFO-­‐agent in samewerking met 'n spesifieke monomeer en polimerisasie toestande. In die tweede studie is 15N KMR, 31P KMR en 1H KMR gebruik vir twee verskillende tipes van die eksperiment. Die eerste is 'n konvensionele radikaalkopolimerisasie waarin die groeiende kettings vasgevang word deur 'n 15N-­‐gemerkte nitroksied om 'n stabiele produk te lewer. In die tweede eksperiment is 'n soortgelyke kopolimerisasie gedoen onder nitroksied-­‐ bemiddelde toestande. Die gekose nitroksied bevat fosfor wat die kwantifisering van die terminale monomeer in die dormante kettings moontlik maak. Elkeen van die individuele eksperimente lewer interessante inligting oor konvensionele radikale kopolimerisasie en nitroksied-­‐bemiddelde kopolimerisasie, onderskeidelik. ʼn Kombinasie van die eksperimentele data toon 'n interessante verskil aan in die verhouding van die terminale monomeereenhede in die aktiewe en sluimerende kettings. Alhoewel dit nie onverwags is nie, is die resultate interessant en van waarde vanuit 'n meganistiese-­‐ sowel as 'n sintetiese oogpunt. In terme van toekomstige perspektiewe word daar verwag dat gevorderde analitiese tegnieke soos hier beskryf, belangrik sal bly in polimeerwetenskap. Huidige ontwikkelinge in radikaalpolimerisasie, soos ondersoeke na die beheer van monomeervolgorde, maak staat op akkurate kennis van kinetiese en meganistiese besonderhede van die basiese reaksies. Daar word verwag dat sulke gedetailleerde studies ʼn uitdaging sal bied vir die volgende dekade van polimeernavorsing.

High molecular weight star-shaped polystyrenes were prepared via the coupling of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) terminated polystyrene oligomers with divinylbenzene (DVB) in m-xylene at 138 °C. Linear polystyrene oligomers (Mn = 19,300 g/mol, Mw/Mn = 1.10) were synthesized in bulk styrene using benzoyl peroxide in the presence of TEMPO at approximately 130 °C. In situ mid-infrared spectroscopy was successfully utilized to follow initiation, monomer conversion, and polymer formation. Real-time data allowed for the determination of apparent rate constants of 2.1E-5 s-1 at 132 °C and 1.2E-5 s-1 at 126 °C from the profile of the decaying styrene vinyl carbon-hydrogen (=CH2) absorbance at 907 cm-1. Coupling of the TEMPO terminated oligomers under optimum conditions resulted in a compact and dense product with a number average molecular weight exceeding 300,000 g/mol (Mw/Mn = 3.03) after 24 h, suggesting the formation of relatively well-defined star-shaped polymers. Synthetic factors that affected the molecular weight, yield, and composition of maleic anhydride (MAH), norbornene (Nb), and tert-butyl 5-norbornene-2-carboxylate (NbTBE) terpolymers were investigated. Pseudo first order kinetic analysis using in situ FTIR indicated that the observed rate of reaction was a strong function of the Nb/NbTBE ratio with a maximum of 6.7E-5 s-1 for a 50/0/50 Nb/NbTBE/MAH monomer ratio and a minimum of 1.1E-5 s-1 for a 0/50/50 Nb/NbTBE/MAH ratio. Polymer yields were also observed to be a function of the Nb/NbTBE ratio and also decreased with increasing NbTBE. Calculated work of adhesion values (Wadh) values were observed to increase as the content of NbTBE was increased. 193 nm photoresist formulations incorporating polymers with high NbTBE content showed increased imaging performance using 193 nm light and successfully produced sharp and defined features as small as 110 nm, which was demonstrated via scanning electron microscopy (SEM). Additional functionality was introduced via the copolymerization of MAH with several norbornene (Nb) derivatives that were synthesized from facile Diels-Alder cycloaddition reactions of cyclopentadiene with a-olefins containing electron withdrawing groups. Subsequent hydrolysis of the anhydride offered further versatility and provided an avenue to introduce aqueous base solubility into Nb/MAH copolymers.
Ph. D.

Self-assembled monolayers and surface-initiated polymer, or polymer brushes, have attracted attention as they form dense layers with much higher structural order than bulk or solution polymers. Another field of research which has emerged over the last two decades is the field of organic and polymer electronics. In this field molecular order and surface modification are of major influence on the device performance, hence that both self-assembled monolayers as polymer brushes have been investigated to find applications in organic electronic devices. After an introduction into the field self-assembled monolayers, polymer brushes and organic electronics, the first part of this thesis focusses on three applications of surface modification techniques for applications in devices. Alignment of the active material is crucial for high mobilities in organic electronics. Chapter 2 discusses the synthesis of a liquid crystalline surface-initiated polymer and its application to induce strong homeotropic alignment. The alignment is homogeneous over large areas and can be patterned by combining the polymerization with soft lithographic techniques. Mobilities of organic electronic materials can also be strongly influenced by dopants in the material. In field-effect transistors the positioning of the dopant is thought to be crucial, as the conductance predominantly takes place in only a small channel near the dielectric interface. In chapter 3 dopant functionalized monolayers and polymer brushes are presented which enable the localized deposition of dopants in the channel of organic transistors. It is shown that the mobility of charges and hence the device performance is affected by the introduction of this dopant layer. Polymer brushes have been suggested for the fabrication of highly ordered semiconducting polymers. In chapter 4 the use of a thiophene functionalized polymer brush is shown, that can be used as a template for the subsequent growth of highly conjugated surface grafted polythiophene layers. Thick polythiophene layers are obtained, that are low in roughness and show photoluminescence and polychromism upon doping. The second part (chapter 5 and 6) of this thesis presents new techniques for surface polymerizations. It is attractive to investigate reduction of reactor volume for polymer brush growth. Chapter 5 discusses a method to achieve volume reduction by back-filling the superfluous volume with beads. It is found that this influences the polymerization kinetics significantly. The combined advantages of less volume and enhanced reaction speeds enable reduction of the total amount of monomer needed by up to 90%. Chapter 6 presents a controlled way to convert initiators for atom transfer radical polymerization into initiators for nitroxide mediated polymerization. In this way mixed polymer brushes and block co-polymer brushes become accessible. This combination makes it an attractive tool to fabricate complex polymer architectures. The technologies used in this thesis show that the synthesis of polymer brushes enable the fabrication of complex architectures without the wastes normally associated with surface-initiated polymers. Combined with several functionalized polymer brushes with properties that enhance order, influence mobility or serve as template for the growth of surface attached conjugated polymers this shows the high potential for the application of surface-initiated polymers in organic electronics.

La nanomédecine, appliquée en particulier au traitement du cancer, suscite depuis une quinzaine d’années un intérêt grandissant, développant des stratégies innovantes pour le ciblage spécifique de tissues malades. De nouveaux progrès en la matière sont encore à venir, mais nécessitent de nouveaux matériaux offrant une grande flexibilité en termes de synthèse, ainsi que la possibilité de fonctionnalités et de propriétés physicochimiques variées ; avantages tous présentés par l’utilisation des techniques de polymérisation radicalaire contrôlée (CRP). Ces techniques de polymérisation ont déjà démontré leur fort potentiel à travers différents systèmes nanoparticulaires à base de prodrogues de polymère, mais aucun d’entre eux ne s’avère dégradable ce qui pourrait empêcher à l’avenir leur utilisation et leur développement.Anticipant les besoins, ce projet a eu pour but la synthèse de polymères PEGylés dégradables par la technique de polymérisation contrôlée par les nitroxydes (NMP), travail très en amont de l’habituel procédé d’élaboration d’un nouveau nanomédicament. Pour ce faire, la NMP du méthacrylate de méthyl éther oligo(éthylène glycol) (MeOEGMA) a été combinée à la polymérisation radicalaire par ouverte de cycle (rROP) des acétals de cétène cyclique (CKAs), connus comme précurseurs de fonctions esters.Parmi trois CKAs étudiés, le 2-méthylène-4-phényl-1,3-dioxolane (MPDL) a montré une capacité unique à copolymériser avec les dérivés de méthacrylates, grâce à sa structure ouverte de type « styrènique » permettant son utilisation en NMP. A travers une étude approfondie des propriétés de contrôle et de caractère vivant de ces copolymères, le MPDL s’est également révélé être le premier comonomère de contrôle des méthacrylates à être dégradable. Un lien direct entre dégradabilité et quantité de MPDL insérée a été démontré, permettant jusqu’à l’hydrolyse complète des matériaux. Ces copolymères n’ont montré aucune cytotoxicité, et ce sur trois types de cellules différents (fibroblastes, cellules endothéliales et macrophages), et une étude similaire sur la toxicité de leurs produits de dégradation a permis d’aboutir à la même conclusion, soulignant la possible biocompatibilité de ces nouveaux matériaux qui, si confirmée, permettrait leur utilisation pour des applications biomédicales.Parallèlement, un second projet portant sur la mise au point d’une nouvelle alcoxyamine à base du nitroxide SG1 et présentant une fonction azlactone, baptisée AzSG1, a été développé pour la synthèse de polymères fonctionnalisables par NMP. Utilisant l’alcoxyamine AzSG1 comme amorceur, les NMPs du styrène, de l’acrylate de n-butyle et du méthacrylate de méthyle ont été réalisées avec succès, ainsi que le couplage quantitatif de la benzylamine comme preuve de concept de la possible fonctionnalisation. Dans un avenir proche, utiliser cet amorceur fonctionnalisable pour la synthèse de copolymères à base de MeOEGMA et de MPDL pourrait ainsi permettre l’élaboration de copolymères PEGylés, dégradables et fonctionnalisables par NMP, pour des applications dans le domaine de la bioconjugaison et du drug delivery
Nanomedicine, especially for cancer treatment, has attracted much interest over the last fifteen years, developing innovative strategies for targeting diseased tissues. Further improvements of these approaches will require advanced new materials affording versatility, functionalities and specific physico-chemical properties, all advantages offered by the controlled radical polymerization (CRP) techniques. These radical polymerizations already showed their great potential through various efficient anticancer polymer nanocarriers but all lacking of degradability, which may hinder any actual developments.Anticipating the needs, this project focused on the synthesis of degradable PEG-based polymers by nitroxide-mediated polymerization (NMP), as an early stage in the usual process of nanocarrier design. To do so, NMP of oligo(ethylene glycol) methyl ether methacrylate (MeOEGMA) has been for the first time combined to the radical ring-opening polymerization (rROP) of various cyclic ketene acetals (CKAs), known as ester precursors.Among three CKAs tested, 2-methylene-4-phenyl-1,3-dioxolane (MPDL) has shown a unique ability to copolymerize with methacrylate derivatives, likely due to a styrene-like open structure allowing for its use in NMP. Through a careful study of the control and livingness properties of these copolymers, MPDL was also demonstrated to be the first degradable controlling comonomer for polymethacrylate synthesis. The degradability of the resulting PEG-based copolymers was proven to be proportional to the adjustable amount of MPDL inserted, up to complete degradation. These copolymers showed no cytotoxic effect on various cell types (fibroblasts, endothelial cells and macrophages), and an additional study of the innocuousness of their degradation products led to similar results, underlining their potential biocompatibility which, if confirmed, would allow these materials to be used for biomedical applications.A second project about a new azlactone-functionalized SG1-based alkoxyamine (AzSG1) was also set up, as initiator for the synthesis of functionalizable polymers by NMP. Using the AzSG1 alkoxyamine, the NMP of styrene, n-butyl acrylate and methyl methacrylate were successfully performed, as well as a quantitative coupling of benzylamine as proof of concept. In the near future, making use of this functionalizable initiator for copolymerizing MeOEGMA with MPDL may allow the easy synthesis of functionalized degradable copolymers by NMP, for bioconjugation and drug delivery applications

La copolymérisation radicalaire par ouverture de cycle contrôlée par les nitroxydes entre les esters méthacryliques et les acétals de cétène cycliques a permis de synthétiser des copolymères vinyliques bien contrôlés et dégradables contenant des fonctions esters le long de la chaine polymère. Plus précisément, des copolymérisations entre le 2-méthylène-4-phenyl-1,3-dioxolane (MPDL) et l’oligo(éthylène glycol) méthyl éther méthacrylate (OEGMA) ou le méthacrylate de méthyle (MMA) ont été amorcées par une alkoxyamine basée sur le nitroxyde SG1. Des copolymères de type P(OEGMA-co-MPDL) et P(MMA-co-MPDL) ont été obtenus et dégradés hydrolytiquement en conditions accélérées ou physiologiques. Leurs cinétiques de dégradation furent également comparées à celles de polyesters traditionnels (e.g., PLGA, PLA and PCL) où il a été montré que la dégradation des copolymères de P(OEGMA-co-MPDL) pouvait être ajustée par la stœchiométrie initiale en monomères et qu’elle se situait entre celles du PLA et du PCL. En revanche, les copolymères de P(MMA-co-MPDL), plus hydrophobes, ont présenté une hydrolyse très lente, bien inférieure à celle du PCL. Dans un deuxième temps, une nouvelle famille de prodrogues polymères dégradable a été synthétisé par copolymérisation radicalaire par ouverture de cycle contrôlée par les nitroxydes entre le MPDL et l’OEGMA ou le MMA, à partir d’un amorceur couplé à un principe actif (méthode du principe actif amorceur). Pour ce faire, la Gemcitabine, un principe actif anticancéreux, a été couplé à une alcoxyamine à base SG1 qui fut ensuite utilisée pour amorcer la réaction de copolymérisation. Les copolymères ainsi obtenus ont montré des propriétés de libération de la Gem et des activités cytotoxiques sur différentes lignées cellulaires en relation avec la nature de l’ester méthacrylique utilisé, la nature de la liaison entre la Gem et le copolymère ainsi que le taux de MPDL dans le copolymère. Cette étude nous a permis d’extraire des relations de type structure-activité importantes pour des développements futurs
Nitroxide-mediated radical ring-opening copolymerization of methacrylic esters and cyclic ketene acetals was investigated and enabled the synthesis of well-defined degradable vinyl copolymers containing ester groups along the main chain, whose amount was readily adjusted by changing the initial comonomer feed. More specifically, the copolymerizations of 2-methylene-4-phenyl-1,3-dioxolane (MPDL) and either oligo(ethylene glycol) methyl ether methacrylate (OEGMA) or methyl methacrylate (MMA) were initiated by an alkoxyamine initiator based on the SG1 nitroxide. It led to a library of P(OEGMA-co-MPDL) and P(MMA-co-MPDL) materials that were hydrolytically degraded under both accelerated and physiological conditions. Their hydrolytic degradation kinetics were also benchmarked against traditional polyesters (e.g., PLGA, PLA and PCL) where P(OEGMA-co-MPDL) copolymers showed tunable degradation rates as function of the MPDL content, being in between those of PLA and PCL. Conversely, the more hydrophobic P(MMA-co-MPDL) copolymers exhibited much slower hydrolysis than that of PCL. In a second step, a new class of degradable polymer prodrugs was developed by nitroxide-mediated radical ring-opening copolymerization of MPDL with OEGMA or MMA, from a drug-bearing initiator (‘drug-initiated’ method). To do so, Gemcitabine, an anticancer drug, was derivatized with a SG1-based alkoxyamine to initiate the copolymerization reaction. The resulting degradable polymer prodrugs exhibited interesting characteristics in terms of drug release and in vitro cytotoxicity, depending on the nature of the methacrylic ester used, the nature of the linker between the drug and the polymer and the MPDL content. This study enabled us to extract important structure-activity relationships of great importance for further development

L’incorporation de particules inorganiques dans une matrice polymère confère de nouvelles propriétés au matériau ou améliore de manière significative les propriétés déjà existantes. Cependant, l’apparence visuelle perçue, telle que la transparence, peut être altérée par des phénomènes de diffusion de la lumière par les particules. Cette diffusion de la lumière est principalement conditionnée par la dimension des particules –ou agrégats de particules- et la différence d’indice de réfraction entre la matrice et les charges. Afin de traiter ces deux problèmes, l’objectif de nos travaux était de contrôler simultanément l’état de dispersion des nanoparticules inorganiques dans la matrice polymère et l’indice de réfraction des nanoparticules de façon à l’ajuster à celui de la matrice. Pour élaborer ce nouveau composite, nous avons synthétisé des nanoparticules hybrides cœur@écorce avec un cœur inorganique qui apporte les nouvelles propriétés et une écorce polymère d’épaisseur contrôlée, obtenue par polymérisation radicalaire contrôlée par voie nitroxyde amorcée à la surface des nanoparticules inorganiques. L’écorce polymère limite l’agrégation des particules et permet de modifier l’indice de réfraction moyen des nanoparticules cœur@écorce. En contrôlant l’épaisseur et la nature chimique de l’écorce polymère, nous cherchons à ajuster l’indice de réfraction des nanoparticules cœur@écorce à celui de la matrice. Les nanoparticules ont ensuite été dispersées dans une matrice de poly(méthacrylate de méthyle). Les propriétés optiques des composites ont été caractérisées par spectrogoniophotométrie, afin d’obtenir des informations sur l’intensité et la distribution angulaire de la lumière transmise par le composite. La transparence des nanocomposites a été fortement améliorée en ajustant l’indice de réfraction des nanoparticules cœur@écorce à celui de la matrice
The incorporation of inorganic particles into a polymer matrix confers new properties to the material or enhances significantly existing properties. However, the perceived visual appearance, such as loss of transparency, might be modified by the scattering of light by the particles. This light scattering is mainly due to the particle –or aggregates of particles- dimensions and the refractive index difference between matrix and fillers. In order to address both issues, the objective of the present work was to control simultaneously the dispersion state of the inorganic nanoparticles into the polymeric matrix and the refractive index of the nanoparticles to match the one of the matrix. To achieve this new composite, we designed hybrid core@shell nanoparticles with an inorganic core that brings new properties and a polymer shell of controlled thickness, obtained by surface-initiated nitroxide mediated controlled radical polymerization. The polymer shell limits the aggregation of the particles and enables us to tune the average refractive index of the hybrid core@shell particle. By controlling the thickness and the chemical nature of the polymeric shell, we targeted to match the refractive index of the hybrid core@shell particle to the one of the polymeric matrix. The nanoparticles were further dispersed into a poly(methyl methacrylate) matrix. Optical properties of composites were characterized by spectrogoniophotometry which gave us informations about the intensity and the angular distribution of the transmitted light by the nanocomposites. The transparency of the nanocomposites was strongly enhanced for core@shell particles fulfilling the refractive index matching conditions

An experimental and modeling investigation of nitroxide-mediated radical polymerization (NMRP) of styrene using 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as controller is presented. The objective was to examine the effect of temperature, controller to initiator molar ratio, and initiation mode on conversion, molecular weight and polydispersity development, and also to generate a source of reliable experimental data for parameter estimation and further model validation purposes. Polymerizations with a bimolecular initiator (Benzoyl Peroxide; BPO) were carried out at 120 and 130°C, with TEMPO/BPO molar ratios of 0.9 to 1.5. The effects of temperature and TEMPO/BPO ratio on polydispersity, molecular weight averages and conversion (rate) were studied. Results indicate that increasing temperature increases the rate of polymerization while the decrease in molecular weights is only slight. It was also observed that increasing the ratio of TEMPO/BPO decreased both the rate of polymerization and molecular weights. To investigate the contribution of thermal self-initiation in NMRP of styrene, thermal NMRP of styrene with TEMPO in the absence of initiator was carried out at 120 and 130°C. The results were compared with regular thermal polymerization of styrene and NMRP of styrene in the presence of BPO. It was observed that although the thermal polymerization of styrene can be controlled to some extent in the presence of TEMPO to provide lower polydispersity polystyrene, the polymerization was never as controlled as that obtained by a BPO initiated NMRP. Additional experiments were conducted with a unimolecular initiator and compared to the corresponding bimolecular system with the same level of nitroxide at 120°C, to gain additional insight on the advantages and disadvantages of each system. In addition, the importance of diffusion-controlled (DC) effects on the bimolecular NMRP of styrene was assessed experimentally by creating conditions where DC effects may be present from the outset. The results were corroborated by mathematical modeling and it was concluded that DC-effects are weak in the NMRP of styrene, even in the presence of “worst case scenario” conditions created. Finally, a mathematical (mechanistic) model based on a detailed reaction mechanism for bimolecular NMRP of styrene was presented and the predicted profiles of monomer conversion, molecular weight averages and polydispersity were compared with experimental data. Comparisons suggest that the present understanding of the reaction system is still inconclusive, either because of inaccuracy in values of kinetic rate constants used or because of some possible side reactions taking place in the polymerization system that are not included in the model. This was somewhat surprising, given that papers on controlled radical polymerization, and NMRP in particular, have clearly dominated the scientific polymer literature in the last fifteen years or so.

Living radical polymerization has proved to be a powerful tool for the synthesis of polymers as it allows for a high degree of control over the polymer microstructure and the synthesis of tailored molecular architectures. Although it has great potential, its use on an industrial scale is limited due to environmental and economical aspects. Nitroxide mediated polymerization is explored to bring this technology closer to adoption in commercial applications. One of the obstacles encountered using nitroxide mediated polymerization in microemulsion systems is the difficulty in controlling both the particle size and target molecular weight. Due to the nature of the formulation, a decrease in the target molecular weight is coupled to an increase in the particle size. For many applications, it is important to be able to design polymer particles with both specifications independently. Strategies to decouple these two properties and processing conditions required for targeting a range of particle sizes and molecular weights for n butyl acrylate latexes are presented. Furthermore, in an attempt to reduce the large amounts of surfactant typically used in microemulsions, these methods were explored at low surfactant to monomer ratios (0.2 to 0.5 by wt.) in order to reduce the costs associated with excess surfactant and post processing steps for surfactant removal (high surfactant levels also give poor water-resistance in coatings). Stable nanolatexes with particle sizes <40 nm have been obtained by other groups using NMP in microemulsions with SG1 but have done so by using much higher surfactant to monomer ratios (~2.5 by wt.) and at much lower solids content (6 10 wt. %). In this work, molecular weights of 20,000 to 80,000 g∙mol-1 were targeted and stable, n-butyl acrylate microemulsions with particle sizes ranging from 20 120 nm were prepared at a solids content of 20 wt. % using much lower surfactant concentrations. Although numerous studies have shown the effects of process parameters on particle sizes and methods to control the molecular weight, the decoupling of the molecular weight and particle size effect in NMP microemulsions under these conditions has not been done to this extent. In copolymer systems, nitroxide mediated polymerization also provides an efficient method to synthesize well defined block copolymers. Random copolymers are widely used as protective colloids, but the use of block copolymers for these applications has not been well studied. It is unclear what effects do the importance of a narrow molecular weight distribution and purity of block copolymers have on their performance as protective colloids. In order to investigate this, a range of block copolymers with different properties would need to be synthesized for systematic analysis. The direct synthesis of polystyrene b poly(acrylic acid) copolymers of varying lengths and compositions was successful by use of nitroxide mediated polymerization in bulk and solution polymerization. The characterization of these amphiphilic block copolymers was explored by titration and nuclear magnetic resonance spectroscopy.
Thesis (Master, Chemical Engineering) -- Queen's University, 2012-09-28 15:43:00.513

Significant advances have been made in the understanding of living/controlled radical polymerization processes since their discovery in the early 1990’s. These processes enable an unprecedented degree of control over polymer architecture that was previously not possible using conventional radical polymerization processes, and this has made possible the synthesis of many new and interesting materials. However, there has been only limited success in commercializing these new methods. Recently there has been increased focus on the development of more industrially viable processes. Dispersed aqueous phase reactions have received much attention because these water-based processes have several technical, economic, and environmental benefits over the more common solution and bulk reactions that were originally developed. Likewise, there has been some investigation of using continuous reactors that have potential technical and economic benefits over the more commonly employed batch reactors. This thesis presents an in-depth study that combines the three aforementioned technologies: living/controlled radical polymerization, dispersed phase aqueous reactions, and continuous reactors. Specifically, the system of interest is a nitroxide-mediated miniemulsion polymerization reaction in a continuous tubular reactor to produce polymer latex. Design of the continuous tubular reactor is discussed in some detail with a focus on specific technical challenges that were faced in building a functional apparatus for this system. Scoping experiments are described which identified a significant effect of temperature ramping rate that is critical to understand when moving to larger scale reactors for this system. The unexpected phenomenon of room temperature polymerization initiated by ascorbic acid is also described. There is demonstration for the first time that bulk and miniemulsion polymers can be produced in a tubular reactor under controlled nitroxide-mediated polymerization conditions, and copolymers can be produced. A detailed residence time distribution study for the tubular reactor is also shown, and several interesting phenomena are discussed that have implications on the practical operating conditions of the tubular reactor. This particular study makes it clear that one should experimentally verify the residence time distribution within a continuous system with the reactants of interest, and that model systems may not give an accurate picture of the real system.
Thesis (Ph.D, Chemical Engineering) -- Queen's University, 2010-12-20 12:00:37.974

This thesis presents the results of a study on the kinetics of nitroxide-mediated radical polymerization of styrene with a unimolecular initiator. The primary objective was to obtain a more comprehensive understanding of how a unimolecular-initiating system controls the polymerization process and to clarify the effects of various reaction parameters. Previous work in this field has met with some difficulties in the initiator synthesis, such as low yield and inconsistency of molecular weight. These problems were overcome by adjusting reaction conditions and procedures. Better yields of initiator with consistent molecular weight were produced by the improved methods. Control of polymerization rate and polymer molecular weight in unimolecular nitroxide-mediated radical polymerization was studied by looking at the effects of the three main factors: initiator concentration, temperature, and the initiator molecular weight on polymerization rate, molecular weight and polydispersity. Results indicated that increasing the initiator concentration had no effect on polymerization rate at low conversion, but led to lower polymerization rate at high conversion; higher initiator concentration led to lower molecular weight of the resulting polymer. It was also found that temperature significantly increased the polymerization rate, yet had no effect on number-average molecular weight, Mn, at low conversion, while it caused a plateau at high conversion levels; there was no effect on weight-average molecular weight, Mw, through the whole conversion range. In addition, increasing initiator molecular weight was found to have no effect on either polymerization rate or molecular weight. The experimental molecular weights of the unimolecular system were compared to theoretical molecular weights based on ideal controlled radical polymerization (CRP). The results were found to be close to the theoretical values. This confirmed the advantages of the unimolecular system, namely, the degree of control over molecular weight was nearly ideal (for certain conditions); and molecular weights could thus be predicted by simply following general rules relating to CRP mechanisms.

Polystyrene (PS) is an important commodity polymer. In its most commonly used form, PS is a high molecular weight linear polymer, typically produced through free-radical polymerization, which is a well understood and robust process. This process produces a high molecular weight, clear thermoplastic that is hard, rigid and has good thermal and melt flow properties for use in moldings, extrusions and films. However, polystyrene produced through the free radical process has a very broad molecular weight distribution, which can lead to poor performance in some applications. To this end, nitroxide-mediated radical polymerization (NMRP) can synthesize materials with a much more consistently defined molecular architecture as well as relatively low polydispersity than other methods. NMRP involves radical polymerization in the presence of a nitroxide mediator. This mediator is usually of the form of a stable radical which can bind to and disable the growing polymer chain. This will “tie up” some of the free radicals forming a dynamic equilibrium between active and dormant species, through a reversible coupling process. NMRP can be conducted through one of two different processes: (1) The bimolecular process, which can be initiated with a conventional peroxide initiator (i.e. BPO) but in the presence of a stable nitroxide radical (i.e. TEMPO), which is a stable radical that can reversibly bind with the growing polymer radical chain, and (2) The unimolecular process, where nitroxyl ether is introduced to the system, which then degrades to create both the initiator and mediator radicals. Based on previous research in the group, which included experimental investigations with both unimolecular and bimolecular NMRP under various conditions, it was possible to build on an earlier model and come up with an improved detailed mechanistic model. Additionally, it was seen that certain parameters in the model had little impact on the overall model performance, which suggested that their removal would be appropriate, also serving to reduce the complexity of the model. Comparisons of model predictions with experimental data both from within the group and the general literature were performed and trends verified. Further work was done on the development of an additionally reduced model, and on the testing of these different levels of model complexity with data. The aim of this analysis was to develop a model to capture the key process responses in a simple and easy to implement manner with comparable accuracy to the complete models. Due to its lower complexity, this substantially reduced model would me a much likelier candidate for use in on-line applications. Application of these different model levels to the model-based D-optimal design of experiments was then pursued, with results compared to those generated by a parallel Bayesian design project conducted within the group. Additional work was done using a different optimality criterion, targeted at reducing the amount of parameter correlation that may be seen in D-optimal designs. Finally, conclusions and recommendations for future work were made, including a detailed explanation of how a model similar to the ones described in this paper could be used in the optimal selection of sensors and design of experiments.

This doctoral thesis is dedicated to the synthesis and characterization of novel functionalized hybrid structures for biomedical purposes. Systems reported in this work can be subdivided into the two main groups: natural-based materials and synthetic amphiphilic block copolymers. Both groups were studied as perspective theranostic agents for medical applications. In the first group, natural polysaccharides glycogen and mannan were selected as starting materials for preparation of novel nanoconjugates that possess ability for multimodal detection in vivo. Because grafting of natural macromolecules with synthetic polymers generally slows down the biodegradation rate, both polysaccharides were modified in two different ways to form nanoprobes with or without poly(2-methyl-2-oxazoline)s chains. The prepared nanoconjugates were functionalized with N-hydroxysuccinimide-activated fluorescence and magnetic resonance imaging labels. The resulting materials were tested both in vitro and in vivo and were shown to be completely biocompatible, biodegradable and exhibit some extra benefits in terms of their practical usage in biomedicine. Glycogen was functionalized with allyl and propargyl groups with following freeze-drying from aqueous solutions to form nano- and microfibrous materials. The presence of both...