pH-Sensitive brush polymer-drug conjugates by ring-opening metathesis copolymerization

Representing a new category of polymer-drug conjugates, brush polymer-drug conjugates were prepared by ring-opening metathesis copolymerization. Following judicious structural design, these conjugates exhibited well-shielded drug moieties, significant water solubility, well-defined nanostructures, and acid-triggered drug release.

One-dimensional models for organic magnetic materials

In the preparation of small organic paramagnets, these structures may conceptually be divided into spin-containing units (SCs) and ferromagnetic coupling units (FCs). The synthesis and direct observation of a series of hydrocarbon tetraradicals designed to test the ferromagnetic coupling ability of m-phenylene, 1,3-cyclobutane, 1,3- cyclopentane, and 2,4-adamantane (a chair 1,3-cyclohexane) using Berson TMMs and cyclobutanediyls as SCs are described. While 1,3-cyclobutane and m-phenylene are good ferromagnetic coupling units under these conditions, the ferromagnetic coupling ability of 1,3-cyclopentane is poor, and 1,3-cyclohexane is apparently an antiferromagnetic coupling unit. In addition, this is the first report of ferromagnetic coupling between the spins of localized biradical SCs.

The poor coupling of 1,3-cyclopentane has enabled a study of the variable temperature behavior of a 1,3-cyclopentane FC-based tetraradical in its triplet state. Through fitting the observed data to the usual Boltzman statistics, we have been able to determine the separation of the ground quintet and excited triplet states. From this data, we have inferred the singlet-triplet gap in 1,3-cyclopentanediyl to be 900 cal/mol, in remarkable agreement with theoretical predictions of this number.

The ability to simulate EPR spectra has been crucial to the assignments made here. A powder EPR simulation package is described that uses the Zeeman and dipolar terms to calculate powder EPR spectra for triplet and quintet states.

Methods for characterizing paramagnetic samples by SQUID magnetometry have been developed, including robust routines for data fitting and analysis. A precursor to a potentially magnetic polymer was prepared by ring-opening metathesis polymerization (ROMP), and doped samples of this polymer were studied by magnetometry. While the present results are not positive, calculations have suggested modifications in this structure which should lead to the desired behavior.

Source listings for all computer programs are given in the appendix.

Synthesis and biological activity of anticoagulant heparan sulfate glycopolymers

Heparin has been used as an anticoagulant drug for more than 70 years. The global distribution of contaminated heparin in 2007, which resulted in adverse clinical effects and over 100 deaths, emphasizes the necessity for safer alternatives to animal-sourced heparin. The structural complexity and heterogeneity of animal-sourced heparin not only impedes safe access to these biologically active molecules, but also hinders investigations on the significance of structural constituents at a molecular level. Efficient methods for preparing new synthetic heparins with targeted biological activity are necessary not only to ensure clinical safety, but to optimize derivative design to minimize potential side effects. Low molecular weight heparins have become a reliable alternative to heparin, due to their predictable dosages, long half-lives, and reduced side effects. However, heparin oligosaccharide synthesis is a challenging endeavor due to the necessity for complex protecting group manipulation and stereoselective glycosidic linkage chemistry, which often result in lengthy synthetic routes and low yields. Recently, chemoenzymatic syntheses have produced targeted ultralow molecular weight heparins with high-efficiency, but continue to be restricted by the substrate specificities of enzymes.

To address the need for access to homogeneous, complex glycosaminoglycan structures, we have synthesized novel heparan sulfate glycopolymers with well-defined carbohydrate structures and tunable chain length through ring-opening metathesis polymerization chemistry. These polymers recapitulate the key features of anticoagulant heparan sulfate by displaying the sulfation pattern responsible for heparin’s anticoagulant activity. The use of polymerization chemistry greatly simplifies the synthesis of complex glycosaminoglycan structures, providing a facile method to generate homogeneous macromolecules with tunable biological and chemical properties. Through the use of in vitro chromogenic substrate assays and ex vivo clotting assays, we found that the HS glycopolymers exhibited anticoagulant activity in a sulfation pattern and length-dependent manner. Compared to heparin standards, our short polymers did not display any activity. However, our longer polymers were able to incorporate in vitro and ex vivo characteristics of both low-molecular-weight heparin derivatives and heparin, displaying hybrid anticoagulant properties. These studies emphasize the significance of sulfation pattern specificity in specific carbohydrate-protein interactions, and demonstrate the effectiveness of multivalent molecules in recapitulating the activity of natural polysaccharides.

Three-dimensional self-assembly of brush block copolymers to photonic crystals

The development of Ring Opening Metathesis Polymerization has allowed the world of block copolymers to expand into brush block copolymers. Brush block copolymers consist of a polymer backbone with polymeric side chains, forcing the backbone to hold a stretched conformation and giving it a worm-like shape. These brush block copolymers have a number of advantages over tradition block copolymers, including faster self-assembly behavior, larger domain sizes, and much less entanglement. This makes them an ideal candidate in the development of a bottom-up approach to forming photonic crystals. Photonic crystals are periodic nanostructures that transmit and reflect only certain wavelengths of light, forming a band gap. These are used in a number of coatings and other optical uses. One and two dimensional photonic crystals are commercially available, though are often expensive and difficult to manufacture. Previous work has focused on the creation of one dimensional photonic crystals from brush block copolymers. In this thesis, I will focus on the synthesis and characterization of asymmetric brush block copolymers for self-assembly into two and three dimensional photonic crystals. Three series of brush block copolymers were made and characterized by Gel Permeation Chromatography and Nuclear Magnetic Resonance spectroscopy. They were then made into films through compressive thermal annealing and characterized by UV-Vis Spectroscopy and Scanning Electron Microscopy. Evidence of non-lamellar structures were seen, indicating the first reported creation of two or three dimensional photonic crystals from brush block copolymers.

Facile Synthesis and Visualization of Janus Double-Brush Copolymers

Well-defined double-brush copolymers with each graft site carrying a polystyrene (PSt) graft and a polylactide (PLA) graft were synthesized by simultaneous reversible addition fragmentation chain transfer (RAFT) and ring-opening polymerization (ROP) processes, followed by ring-opening metathesis polymerization (ROMP) "grafting through" of the resulting diblock macromonomer (MM). Their Janus-type 1 morphologies were detected by transmission electron microscopy (TEM) imaging after thermal annealing to facilitate the intramolecular self-assembly of PSt and PLA grafts. This finding provides critical evidence to verify double-brush copolymers as Janus nanomaterials.

Synthesis and characterization of main-chain bile acid-based degradable polymers

Les acides biliaires sont des composés naturels existants dans le corps humain. Leur biocompatibilité, leur caractère amphiphile et la rigidité de leur noyau stéroïdien, ainsi que l’excellent contrôle de leurs modifications chimiques, en font de remarquables candidats pour la préparation de matériaux biodégradables pour le relargage de médicaments et l'ingénierie tissulaire. Nous avons préparé une variété de polymères à base d’acides biliaires ayant de hautes masses molaires. Des monomères macrocycliques ont été synthétisés à partir de diènes composés de chaînes alkyles flexibles attachées à un noyau d'acide biliaire via des liens esters ou amides. Ces synthèses ont été réalisées par la fermeture de cycle par métathèse, utilisant le catalyseur de Grubbs de première génération. Les macrocycles obtenus ont ensuite été polymérisés par ouverture de cycle, entropiquement induite le catalyseur de Grubbs de seconde génération. Des copolymères ont également été préparés à partir de monolactones d'acide ricinoléique et de monomères cycliques de triester d’acide cholique via la même méthode. Les propriétés thermiques et mécaniques et la dégradabilité de ces polymères ont été étudiées. Elles peuvent être modulées en modifiant les différents groupes fonctionnels décorant l’acide biliaire et en ayant recours à la copolymérisation. La variation des caractéristiques physiques de ces polymères biocompatibles permet de moduler d’autres propriétés utiles, tel que l’effet de mémoire de forme qui est important pour des applications biomédicales.

Electronic synergism in [RuCl(2)(PPh(3))(2)(amine)] complexes differing the reactivity for ROMP of norbornene and norbornadiene

The reactivity of the new complex [RuCl(2)(PPh(3))(2)(3,5-Me(2)piperidine)], complex 1, was investigated for ring opening metathesis polymerization (ROMP) of norbornene (NBE) and norbornadiene (NBD) in the presence of ethyl diazoacetate (EDA) in CHCl(3). The aim is to observe the combination of PPh(3) and an amine as ancillary ligands concerning the steric hindrance and the electronic perturbation in the properties of the N-bound site when replacing the amines. Thus, the results with 1 were compared to the results obtained when the amine is piperidine (complex 2). Reaction with 1 provides 70% yield of isolated polyNBE (M(n) =8.3 x 10(4) g/mol; PDI = 2.03), whereas 2 provides quantitative reaction (M(n) = 1.2 x 10(5) g/mol; PDI = 1.90) with [NBE]/[Ru] = 5000, [EDA]/[Ru] = 48 and 1.1 mu mol of Ru for 5 min at 25 degrees C. The resulting polymers showed c.a. 62% of trans-polyNBE, determined by (1)H NMR, and T(g) = 32 degrees C, determined by DSC and DMTA. For ROMP of NBD, 1 showed quantitative yield with PDI =2.62 when [NBD]/[Ru] = 5000 for 20 min at 25 degrees C, whereas the reaction with 2 reached 55% with PDI = 2.16 in the same conditions. It is concluded that the presence of the two methyl groups in the piperidine ring provides an increase in the induction period to produce the Ru-carbene species justifying better polyNBE results with 2, and a greater amine(sigma)-> Ru(pi)-> monomer synergism which contributed to the best activation of less tensioned olefin as NBD. (C) 2010 Elsevier B.V. All rights reserved.

The influence of perhydroazepine and piperidine as further ancillary ligands on Ru-PPh(3)-based catalysts for ROMP of norbornene and norbornadiene

Polynorbornadiene and polynorbornene were synthesized via ring opening metathesis polymerization (ROMP) with [RuCl(2)(PPh(3))(2)(amine)] as catalyst precursors, amine = piperidine (1) or perhydroazepine (2) in the presence of 5 mu L of ethyl diazoacetate (EDA) ([monomer]/[Ru] = 5000; 40 degrees C with 1; 25 degrees C with 2). The effects of the solvent volume (2-8 mL of CHCl(3)) reaction time (5-120 min) and atmosphere type (argon and air) on the yields were investigated to observe the behavior of the two different precursors. Quantitative yields were obtained for 60 or 120 min regardless of the starting volumes, either in argon or air, with both Ru species. However, low yields were obtained for short times (5-30 min) when the reactions are performed with large volumes (6-8 mL). In argon, the yields were larger with 2, associated to a faster propagation reaction controlled by the Ru active species. In air, the yields were larger with 1, associated to a higher resistance to O(2) of the starting and propagating Ru species. The different activities between 1 and 2 are discussed considering the steric hindrance and electronic characteristics of the amines such as ancillary ligands and their arrangements with PPh(3) and Cl(-) ions in the metal centers. (c) 2009 Elsevier B.V. All rights reserved.

Ability of Ru complexes for ROMP tuned through a combination of phosphines and amines

Polynorbonerne with high molecular weight was obtained via ring opening metathesis polymerization using catalysts derived from [RuCl(2)(PPh(2)Bz)(2) L] (1 for L = PPh(2) Bz; 2 for L = piperidine) type of complexes when in the presence of ethyl diazoacetate in CHCl(3). The polymer precipitated within a few minutes at 50 degrees C when using 1 with ca. 50% yield ([NBE]/[Ru] = 5000). Regarding 2, for either 30 min at 25 C or 5 min at 50 degrees C, more than 90% of yields are obtained; and at 50 C for 30 min a quantitative yield is obtained. The yield and PDI values are sensitive to the [NBE]/[Ru] ratio. The reaction of 1 with either isonicotinamide or nicotinamide produces six-coordinated complexes of [RuCl(2)(PPh(2)Bz)(2)(L)(2)] type, which are almost inactive and produce only small amounts of polymers at 50 C for 30 min. Thus, we Concluded that the novel complexes show very distinct reactivities for ROMP of NBE. This has been rationalized on account of a combination of synergistic effects of the phosphine-amine ancillary ligands. (C) 2009 Elsevier B.V. All rights reserved.

Dimetilsulfóxidos como ligantes ancilares em complexos de rutênio: catalisadores duais para a combinação da ROMP de norborneno e ATRP de metacrilato de metila

Pós-graduação em Química - IBILCE

Tailored norbornene-based copolymer with systematic variation of norbornadiene as a crosslinker obtained via ROMP with alternative amine Ru catalysts

Copolymers of norbornene (NBE) with norbomadiene (NBD) were obtained via ROMP with [RuCl2(PPh3)(2)(L)] type complexes as initiators (1 for L = piperidine and 2 for L = 3,5-Me(2)piperidine). The reactions were performed using a fixed quantity of NBE (5000 equivalents/[Ru]) for different concentrations of NBD (500, 1000, 1500 and 2000 equivalents/ [Ru]) in CHCl3, initiated with ethyl diazoacetate at room temperature. The presence of NBD in the NBE chains was characterized by H-1 and C-13 NMR. Whereas the copolymer microstructure was influenced neither by the NBD quantity nor by the initiator type, the N-n and PDI values were improved when increasing the NBD quantity in the medium. When raising the NBD amount, DMA results indicated increased cross-linking with increasing T-g and E ' storage modulus, as well as the fact that SEM micrographs indicated decreased pore sizes in the porous isolated copolymers. (C) 2011 Elsevier Ltd. All rights reserved.

ROMP como um método versátil para a obtenção de materiais poliméricos diferenciados

Ring Opening Metathesis Polymerization (ROMP) of cyclic olefins is a powerful transition metal-catalyzed reaction for syntheses of polymers and copolymers. The key feature of this reaction is the [2+2]-cycloaddition mechanism, with retention of the olefinic unsaturation in the polymer chain and occurrence of living polymerization. With the development of metal-carbene type catalysts for this process, many addressed polymeric materials have been successfully prepared to be employed in several fields of the science and technology. This review summarizes recent examples of syntheses of polymers with amphiphilic features such as block, graft, brush or star copolymers; as well syntheses of biomaterials, dendronized architectures, photoactive polymers, cross-linked or self-healing materials, and polymers from renewed supplies.

Nanocapsules for self-healing materials

Im Rahmen dieser Arbeit wurden neue Ansätze für das Konzept der kapselbasierten Selbstheilungsmaterialien untersucht. Die Verkapselung von Selbstheilungsreagenzien in funktionellen Nanokapseln wurde dabei mittels drei verschiedener Herstellungsmethoden in Miniemulsion durchgeführt. Zunächst wurde die Synthese von Kern-Schale-Partikeln mit verkapselten Monomeren für die Ringöffnungs-Metathese-Polymerisation über freie radikalische Polymerisation in Miniemulsionstropfen beschrieben. Durch orthogonale Reaktionen wurden dabei verschiedene chemische Funktionalisierungen in die Schale eingebracht. Die Rolle des Tensides, das Verhältnis von Kernmaterial zu Monomer sowie die Variation der Lösungsmittelqualität hatte dabei einen Einfluss auf die Struktur der Kolloide. Die Heilungsreagenzien blieben auch nach der Verkapselung aktiv, was durch erfolgreich durchgeführte Selbstheilungsexperimente gezeigt werden konnte. Im zweiten Abschnitt wurde die Synthese von Silica-Nanocontainern für Selbstheilungsmaterialien über Hydrolyse und Polykondensation von Alkoxysilanen an der Grenzfläche der Miniemulsionstropfen beschrieben. Dieser Ansatz ermöglichte die effiziente Verkapselung sowohl von Monomeren als auch von Lösungen der Katalysatoren für die Metathese-Polymerisation in einem Einstufenprozess. Die Größe der Kapseln, die Dicke der Schale und der Feststoffgehalt der Dispersionen konnte dabei in einem weiten Bereich variiert werden. Anhand von erfolgreich durchgeführten Selbstheilungsreaktionen, die über Thermogravimetrie und 13C-NMR-Spektroskopie verfolgt wurden, konnte gezeigt werden, dass die Selbstheilungsreagenzien nach der Verkapselung aktiv blieben. Das dritte Konzept behandelte die Herstellung von polymeren Nanokapseln mittels Emulsions-Lösungsmittelverdampfungstechnik, welche eine milde Methode zur Verkapselung darstellt. Es wurde eine allgemeine und einfache Vorgehensweise beschrieben, in der Selbstheilungsreagenzien in polymeren Nanokapseln unter Verwendung von kommerziell erhältlichen Polymeren als Schalenmaterial verkapselt wurden. Zudem wurden Copolymere aus Styrol und verschiedenen hydrophilen Monomeren über freie radikalische Polymerisation sowie über polymeranaloge Reaktionen hergestellt. Diese statistischen Copolymere waren ebenso wie Blockcopolymere zur Herstellung von wohldefinierten Kern-Schale-Nanopartikeln mittels Emulsions-Lösungsmittelverdampfungsprozess geeignet. rnrnDes Weiteren wurde ein neues Konzept für die Synthese von pH-responsiven Nanokapseln aus tensidfreien Emulsionen unter Verwendung von Copolymeren aus Styrol und Trimethylsilylmethacrylat beschrieben. Der vorgeschlagene synthetische Ansatz ermöglicht dabei die erste Synthese von Nanokapseln über den Emulsions-Lösungsmittelverdampfungsprozess in Abwesenheit eines Tensides. Eine vollständig reversible Aggregation ermöglichte eine leichte Trennung der Nanokapseln von der kontinuierlichen Phase sowie eine Erhöhung der Konzentration der Nanokapseldispersionen auf das bis zu fünffache. Darüber hinaus war es möglich, Selbstheilungsreagenzien in stabilem Zustand zu verkapseln. Abschließend wurde die elektrochemische Abscheidung von mit Monomer gefüllten Nanokapseln in eine Zinkschicht zur Anwendung im Korrosionsschutz behandelt.

Selectivity, activity, and stability of ruthenium-carbene based olefin metathesis initiators

The olefin metathesis reaction has found many applications in polymer synthesis and more recently in organic synthesis. The use of single component late metal olefin metathesis catalysts has expanded the scope of the reaction to many new applications and has allowed for detailed study of the catalytic species.

The metathesis of terminal olefins of different steric bulk, different geometry as well as electronically different para-substituted styrenes was studied with the ruthenium based metathesis initiators, trans-(PCy₃)₂Cl₂Ru=CHR, of different carbene substituents. Increasing olefin bulk was found to slow the rate of reaction and trans internal olefins were found to be slower to react than cis internal olefins. The kinetic product of a11 reactions was found to be the alkylidene, rather than the methylidene, suggesting the intermediacy of a 2,4-metallacycle. The observed effects were used to explain the mechanism of ring opening cross metathesis and acyclic diene metathesis polymerization. No linear electronic effects were observed.

In studying the different carbene ligands, a series of ester-carbene complexes was synthesized. These complexes were found to be highly active for the metathesis of olefinic substrates, including acrylates and trisubstituted olefins. In addition, the estercarbene moiety is thermodynamically high in energy. As a result, these complexes react to ring-open cyclohexene by metathesis to alleviate the thermodynamic strain of the ester-carbene ligand. However, ester-carbene complexes were found to be thermolytically unstable in solution.

Thermolytic decomposition pathways were studied for several ruthenium-carbene based olefin metathesis catalysts. Substituted carbenes were found to decompose through bimolecular pathways while the unsubstituted carbene (the methylidene) was found to decompose unimolecularly. The stability of several derivatives of the bis-phosphine ruthenium based catalysts was studied for its implications to ring-closing metathesis. The reasons for the activity and stability of the different ruthenium-based catalysts is discussed.

The difference in catalyst activity and initiation is discussed for the bis-phosphine based and mixed N-heterocyclic carbene/phosphine based ruthenium olefin metathesis catalysts. The mixed ligand catalysts initiate far slower than the bis-phosphine catalysts but are far more metathesis active. A scheme is proposed to explain the difference in reactivity between the two types of catalysts.

Block co-polymerization by transformation reactions

The aim of this study was to use the transformation of anionic to metathesis polymerization to produce block co-polymers of styrene-b-pentenylene using WC16 /PStLi and WC16/PStLi/ AlEtC12 catalyst systems. Analysis of the products using SEC and 1H and 13C NMR spectroscopy enabled mechanisms for metathesis initiation reactions to be proposed. The initial work involved preparation of the constituent homo-polymers. Solutions of polystyryllithium in cyclohexane were prepared and diluted so that the [PStLi]o<2x10-3M. The dilution produced initial rapid decay of the active species, followed by slower spontaneous decay within a period of days. This was investigated using UV / visible spectrophotometry and the wavelength of maximum absorbance of the PStLi was found to change with the decay from an initial value of 328mn. to λmax of approximately 340nm. after 4-7 days. SEC analysis of solutions of polystyrene, using RI and UV / visible (set at 254nm.) detectors; showed the UV:RI peak area was constant for a range of polystyrene samples of different moleculor weight. Samples of polypentenylene were prepared and analysed using SEC. Unexpectedly the solutions showed an absorbance at 254nm. which had to be considered when this technique was used subsequently to analyse polymer samples to determine their styrene/ pentenylene co-polymer composition. Cyclohexane was found to be a poor solvent for these ring-opening metathesis polymerizations of cyclopentene. Attempts to produce styrene-b-pentenylene block co-polymers, using a range of co-catalyst systems, were generally unsuccessful as the products were shown to be mainly homopolymers. The character of the polymers did suggest that several catalytic species are present in these systems and mechanisms have been suggested for the formation of initiating carbenes. Evidence of some low molecular weight product with co-polymer character has been obtained. Further investigation indicated that this is most likely to be ABA block copolymer, which led to a mechanism being proposed for the termination of the polymerization.