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<p>The controlled synthesis of functional low molecular weight polyethylene and polyethylene mimics is important in tuning polymer properties and is of great industrial interests. Living polymerization is a method that allows for precise control in polymer structure. Although high molecular weight polymers with controlled structures can be efficiently produced via living polymerization, the production of low molecular weight polymers faces the challenges of the use of large amounts of expensive catalyst and the broadening of polydispersity.</p> <p>The synthesis of well-defined functional low molecular weight polyethylene and polyethylene mimics is studied. Promising polymerization systems, including living ring opening metathesis polymerization (ROMP), living coordination polymerization, coordinative chain transfer polymerization (CCTP), and living C1 polymerization, are identified and are analyzed based on product properties, efficiency, cost, and safety.</p> <p>Within the identified systems, living ROMP is selected for study due to the industrial relevance of ROMP polymers, the availability of raw materials, and the ease of reaction setup. The efficiency of ROMP is challenged by polydispersity broadening resulting from slow initiation and poor reactor volume efficiency due to its implementation as a solution polymerization process. The challenges are addressed by the use of excess phosphine and the realization of ROMP as a bulk polymerization process.</p> <p>Experimental results demonstrate that bulk ROMP with and without phosphines yield product with similar or enhanced molecular weight distribution control as solution ROMP. Kinetic studies confirm living polymerization behaviour of bulk ROMP. A mathematical model is developed for the first time using method of moments to describe the kinetics and development of molecular weight distribution of ROMP. The model is a useful tool in preliminary research and commercialization of ROMP. The success of bulk ROMP and the development of a representative model yield ROMP as a promising method for the production of low molecular weight polymers with controlled architecture.</p> / Master of Applied Science (MASc)

Ring-opening metathesis polymerization (ROMP) is a robust synthetic technique for synthesizing complex polymer architectures (topologies). To achieve complex architectures, specifically bottlebrush polymers, using ROMP, attaining the highest degree of living character is essential. As the molecular weight of the side chain or backbone increases, the "livingness" of the polymerization suffers due to premature catalyst degradation. Attaining large, well-defined, bottlebrush polymers requires precision so it was our goal to determine how seemingly simple reaction variables could affect the rates of propagation and achievable conversion, as well as why these variables have these effects. We tested several reaction parameters to understand how they affect the rate of polymerization, the rate of catalyst degradation, and the conversion that can be reached. We performed a systematic study using six organic solvents to determine the propagation rate of three macromonomers (MMs), one polystyrene and two poly(n-butyl acrylate) MMs, in ROMP with varying side chain chemistries and end groups, as well as rate of catalyst degradation in each of the solvents. We determined that solvent affected that rate of propagation primarily by interacting with the catalyst, while there was some evidence of polymer sidechain chemistry affecting the rate. We found that ethyl acetate (EtOAc) and CH2Cl2 had the highest rates of propagation compared to the other solvents, while DMF and THF were the slowest. UV-Vis testing on the catalyst in each solvent revealed that DMF and THF had fast rates of catalyst decomposition, while toluene was much slower to decompose. From these experiments we learned that toluene, despite its slower propagation rate, has the most living character, due to its slower rate of decomposition. We also learned that purification greatly affects the propagation rate, with THF requiring purification to have any conversion to bottlebrush polymer, while purification of EtOAc slows the rate of propagation almost 2-fold. From the decrease in rate after purification, and the conclusion that it was due to an acetic acid impurity in the impure EtOAc, we decided to systematically test small molecule additives and found that acids can increase the propagation rate and the conversion of the polynorbornene backbone achievable in ROMP reactions. Notably, in reactions performed in DMF with added CF3COOH we were able to polymerize a norbornene-functionalized unprotected peptide, which was insoluble in most organic solvents, to a higher conversion than in DMF without the added acid. We learned from our research that changing reaction variables can lead to substantial changes in the rate of propagation as well as the achievable conversion in bottlebrush polymer synthesis. By understanding this we can further test other reaction variables and do systematic studies on atmosphere and temperature. We hope this research and future fundamental research can guide scientists toward synthesizing large, well-defined, complex polymer architectures using ROMP. / Doctor of Philosophy / Nature has shown that complex molecular architectures lead to unique material properties. This has inspired scientists to synthetically mimic nature to create these polymer architectures in an effort to obtain novel material properties. Ring-opening metathesis polymerization (ROMP) has become a powerful synthetic method for synthesizing complex polymer architectures. Specifically, ROMP has been used to synthesize bottlebrush polymers, so named due to the polymer backbone with long, densely grafted, polymer side chains attached. These materials exhibit very interesting properties compared to their linear polymer counterparts. Using ROMP to synthesize bottlebrush polymers is not uncommon; however, difficulties can arise if trying to use sidechains that are very long or bulky. We have worked to understand how manipulating some of the reaction parameters can allow us, and other researchers, to synthesize bottlebrush polymers that contain long and/or bulky polymer side chains. We tested the purity and type of solvent that the reaction was performed in on one polystyrene macromonomer and two poly(n-butyl acrylate) macromonomers, as well as adding small molecules, including acids, bases, and salts, to determine if these variables could improve the synthesis of bottlebrush polymers. What we found was that all of the tested variables, solvent, purity, additives, and combinations of all of these variables, did have an effect on the synthesis of these materials. This fundamental information will assist our lab, and many others, in efficiently synthesizing complex architectures, thus achieving unique material properties.

Polymer functional groups have critical impacts upon physical, chemical and mechanical properties, and thus affect the specific applications of the polymer. Functionalization of cellulose esters and ethers has been under extensive investigation for applications including drug delivery, cosmetics, food ingredients, and automobile coating. In oral delivery of poorly water-soluble drugs, amorphous solid dispersion (ASD) formulations have been used, prepared by forming miscible blends of polymers and drugs to inhibit crystallization and enhance bioavailability of the drug. The Edgar and Taylor groups have revealed that some cellulose omega-carboxyalkanoates were highly effective as ASD polymers, with the pendant carboxylic acid groups providing both specific polymer-drug interactions and pH-triggered release through swelling of the ionized polymer matrix. While a variety of functional groups such as hydroxyl and amide groups are also of interest, cellulose functionalization has relied heavily on classical methods such as esterification and etherification for appending functional groups. These methods, although they have been very useful, are limited in two respects. First, they typically employ harsh reaction conditions. Secondly, each synthetic pathway is only applicable for one or a narrow group of functionalities due to restrictions imposed by the required reaction conditions. To this end, there is a great impetus to identify novel reactions in cellulose modification that are mild, efficient and ideally modular. In the initial effort to design and synthesize cellulose esters for oral drug delivery, we developed several new methods in cellulose functionalization, which can overcome drawbacks of conventional synthetic pathways, provide novel cellulose derivatives that are otherwise inaccessible, and present a platform for structure-property relationship study. Cellulose omega-hydroxyalkanoates were previously difficult to access as the hydroxyl groups, if not protected, react with carboxylic acid/carbonyl during a typical esterification reaction or ring opening of lactones, producing cellulose-g-polyester and homopolyester. We demonstrated the viability of chemoselective olefin hydroboration-oxidation in the synthesis of cellulose omega]-hydroxyesters in the presence of ester groups. Cellulose esters with terminally olefinic side chains were transformed to the target products by two-step, one-pot hydroboration-oxidation reactions, using 9-borabicyclo[3.3.1]nonane (9-BBN) as hydroboration agent, followed by oxidizing the organoborane intermediate to a primary alcohol using mildly alkaline H2O2. The use of 9-BBN as hydroboration agent and sodium acetate as base catalyst in oxidation successfully avoided cleavage of ester linkages by borane reduction and base catalyzed hydrolysis. With the impetus of modular and efficient synthesis, we introduced olefin cross-metathesis (CM) in polysaccharide functionalization. Using Grubbs type catalyst, cellulose esters with terminally olefinic side chains were reacted with various CM partners including acrylic acid, acrylates and acrylamides to afford families of functionalized cellulose esters. Molar excesses of CM partners were used in order to suppress potential crosslinking caused by self-metathesis between terminally olefinic side chains. Amide CM partners can chelate with the ruthenium catalyst and cause low conversions in conventional solvents such as THF. While the inherent reactivity toward CM and tendency of acrylamides to chelate Ru is influenced by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides. We observed that the CM products are prone to crosslinking during storage, and found that the crosslinking is likely caused by free radical abstraction of gamma-hydrogen of the alpha, beta-unsaturation and subsequent recombination. We further demonstrated successful hydrogenation of these alpha, beta-unsaturated acids, esters, and amides, thereby eliminating the potential for radical-induced crosslinking during storage. The alpha, beta-unsaturation on CM products can cause crosslinking due to gamma-H abstraction and recombination if not reduced immediately after reaction. Instead of eliminating the double bond by hydrogenation, we described a method to make use of these reactive conjugated olefins by post-CM thiol-Michael addition. Under amine catalysis, different CM products and thiols were combined and reacted. Using proper thiols and catalyst, complete conversion can be achieved under mild reaction conditions. The combination of the two modular reactions creates versatile access to multi-functionalized cellulose derivatives. Compared with conventional reactions, these reactions enable click or click-like conjugation of functional groups onto cellulose backbone. The modular profile of the reactions enables clean and informative structure-property relationship studies for ASD. These approaches also provide opportunities for the synthesis of chemically and architecturally diverse cellulosic polymers that are otherwise difficult to access, opening doors for many other applications such as antimicrobial, antifouling, in vivo drug delivery, and bioconjugation. We believe that the cellulose functionalization approaches we pioneered can be expanded to the modification of other polysaccharides and polymers, and that these reactions will become useful tools in the toolbox of polymer/polysaccharide chemists. / Ph. D.

Thesis advisor: Amir Hoveyda / Chapter 1: E- and Z-, Di- and Trisubstituted Alkenyl Nitriles through Catalytic Cross MetathesisWe have described the development of several catalytic cross-metathesis strategies, which can deliver a considerable range of Z- or E-disubstituted alkenyl nitriles and their corresponding trisubstituted variants. Through careful examination of the steric and electronic attributes of the starting materials, a Mo-based monoaryloxide pyrrolide or chloride complex may be the optimal choice depending on the reaction type. In the event, equimolar amounts of the two substrates are necessary to maximize reaction efficiency; a pyridine ligand is more desirable than a phosphine ligand, as a stabilizing ligand for a Mo-based complex, for improving reaction stereoselectivity. We also highlighted the utility of this approach with the synthesis of several biologically active compounds, such as LR5182 (Cocaine abuse treatment), alliarinoside (anti-feedant), perhydrohistrionicotoxin (natural product), CC-5079 (anti-cancer) and indatraline (anti-depressant). Chapter 2: Traceless Protection for More Broadly Applicable Olefin Metathesis We have devised an operationally simple in-situ protection/deprotection strategy that significantly expands the scope of kinetically controlled catalytic olefin metathesis. Pretreatment of an olefin containing a protic group with commercially available HB(pin) or HB(trip)2 is sufficient for generating the desired product efficiently through the catalytic cross-metathesis reaction. A wide range of stereochemically defined Z- and E-alkenyl halides and boronates as well as Z-trifluoromethyl-substituted alkenes with a hydroxy or carboxylic acid group were prepared. We also discovered that a small amount of HB(pin) may be used for the removal of residual water and impurities, significantly enhancing the efficiency of a multigram-scale olefin metathesis transformation. Chapter 3: E- and Z-Macrocyclic Trisubstituted Alkenes for Natural Product Synthesis and Skeletal Editing We have introduced a reliable catalytic strategy for the synthesis of a variety of macrocyclic trisubstituted olefins in either stereoisomeric form. This was achieved by overcoming the unexpected difficulties through careful mechanistic studies, including addressing complications arising from pre-metathesis alkene isomerization. Macrocyclic ring-closing metathesis can be performed with a commercially available Mo-based complex and an easily accessible linear diene precursor. Accordingly, we can synthesize a skeletally diverse array of otherwise difficult-to-access macrocyclic alkenes, a critical set of compounds in drug discovery, in either isomeric form. The utility of the method is highlighted in two instances. The first is the near complete reversal of substrate-controlled selectivity in the generation of the macrolactam intermediate, in the total synthesis of the anti-fungal agent Fluvirucin B1. The second is an exceptionally stereoselective late-stage formation of a 24-membered macrocyclic E-trisubstituted alkene, enabling the completion of the total synthesis of a cytotoxic natural product dolabelide C, which is seven times more efficient than that reported previously. Chapter 4: Stereodefined Alkenes with a Fluoro-Chloro Terminus as a Uniquely Enabling Compound Class We have offered a practical solution for the synthesis of trisubstituted alkenyl fluorides by unveiling a widely applicable strategy for stereodivergent synthesis of olefins bearing a fluoro and chloro terminus. The core transformation is unprecedented: cross-metathesis between two trisubstituted olefins, one of which is a commercially available but scarcely utilized trihalo alkene. Alkenes bearing a fluoro,chloro-terminus are versatile substrates for the generation of otherwise difficult-to-access trisubstituted alkenyl fluorides, through stereospecific catalytic cross-coupling reactions. We also highlighted the utility of the method throguh synthesis of, among others, a fluoro-nematic liquid crystal component, peptide analogs bearing an E- or a Z-amide bond mimic, and all four stereoisomers of difluoro-rumenic ester (anti-cancer). / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Chemical modification of naturally occurring cellulose into ester and ether derivatives has been of growing interest due to inexhaustible cellulose resources, and to excellent properties and extremely broad applications of these derivatives. However, traditional esterification and etherification involve relatively harsh conditions (strongly acidic or strongly alkaline), greatly limiting the content and range of functional groups that may be installed onto the cellulose backbone. Amorphous solid dispersion (ASD) is an effective method to promote oral delivery of poorly-soluble drugs by dispersing crystalline drugs in a polymer matrix, creating drug supersaturation upon release. Cellulose 𝜔-carboxyesters have been proven to be effective ASD matrices for many different drugs; however, synthesis of such polymers involves protecting-deprotecting chemistry and one synthetic route only leads to one structure. Developing a new generation of cellulosic polymers for oral drug delivery such as ASD matrices requires new synthetic techniques and powerful tools. Olefin cross-metathesis (CM) is a mild, efficient and modular chemistry with extensive applications in organic, polymer, and polysaccharide chemistry. Successful CM can be achieved by appending olefin “handles” from cellulose esters and reacting with electron-deficient olefins like acrylic acid. Cellulose ethers have much better hydrolytic stability compared to esters and are also commercially very important. The overarching theme of this dissertation is to investigate modification of cellulose ether derivatives, and to design and synthesize effective ASD polymers by olefin CM. We first validated the strategy of performing CM by appending metathesis “handles” through etherification and then subjected these terminal olefins to various partners (acrylic acid and different acrylates). After demonstration of the concept, we applied different starting materials (e.g. ethyl cellulose, methyl cellulose, microcrystalline cellulose, and hydroxypropyl cellulose) with distinctive hydrophobicity/hydrophilicity balance. Furthermore, α,β-unsaturated CM products tended to undergo radical crosslinking through abstraction of 𝛾-protons and recombination of polymer radicals. In order to resolve this issue, we first applied post-CM hydrogenation and then explored a thiol-Michael addition to the α,β-unsaturation, which also incorporates an extra functional group through the thioether. We have successfully prepared a collection of cellulose 𝜔-carboxyether derivatives through the above-mentioned method and preliminary drug induction experiments also revealed that these derivatives hold high promise for ASD application. We also explored the possibility of conducting CM in a reverse order: i.e. appending electron-deficient acrylate groups to the polymer, then subjecting it to electron-rich small molecule terminal olefins. The failure of this metathesis approach was speculated to be due mainly to low acrylate reactivity on an already crowded polymer backbone and the high reactivity of rapidly diffusing, small molecule terminal olefins. Last but not least, we further utilized olefin CM to conjugate bile salt derivatives (e.g. lithocholic acid and deoxycholic acid) to a cellulose backbone by converting bile salts into acrylate substrates. Successful CM of bile salt acrylates to cellulose olefin “handles” further demonstrated the great versatility, excellent tolerance, and very broad applicability of this strategy. Overall, we have founded the strategy for performing successful olefin CM in many cellulose ether derivatives with acrylic acid and a variety of different acrylates. Post-CM hydrogenation efficiently removes the α,β-unsaturation and provides stable and effective cellulose 𝜔-carboxyether derivatives for ASD application. Tandem CM/thiol-Michael addition not only eliminates the crosslinking tendency but also enables an even broader library of polymer structures and architectures for structure-property investigations. We anticipate these methods can be readily adapted by polysaccharide chemists and applied with numerous complex structures, which would greatly broaden the range of cellulose and other polysaccharide derivatives for applications including ASDs, P-glycoprotein inhibition, antimicrobial, coating, and other biomedical applications. / Ph. D. / When it comes to drug administration, oral delivery is often preferred over other methods like intravenous injection since it is cheap, convenient, painless and easily conducted without requiring professional training or clinical environment. However, one of the most common issues for oral drugs to be absorbed by human body is that a large portion of drugs do not dissolve in water. An effective method to conquer this problem is to blend a properly designed polymer with the poorly dissolving drug, making the drug dissolve in water more effectively and thus be able to enter the bloodstream. Such polymers have to be safe, stable, non-toxic, and biodegradable. Cellulose is one of the most abundant polysaccharides on earth and it has inexhaustible source from wood, cotton and many other plants. Natural cellulose is a linear polymer and is highly crystalline and therefore does not tend to dissolve in water or any other simple organic solvents. Chemical modifications of cellulose to make derivatives (e.g. cellulose esters and ethers) will disrupt the crystallinity and make it more soluble and processible for many applications including coating, packaging, food and pharmaceuticals. The Edgar and Taylor groups have demonstrated that some cellulose derivatives with specific properties are very good polymer matrices to facilitate the delivery of poorly soluble drugs. These cellulose-based polymers can stabilize the active drugs, protect drug from the acidic stomach and make them more soluble in the digestive tract so they can be absorbed by human body. However, previous synthetic methods to prepare such cellulose derivatives are very timeand effort- consuming. Meanwhile, one polymer is usually not suitable for every drug since each drug will have different issues, for example different water solubility and/or stability in acidic stomach. Therefore, design and preparation of new polymers with enhanced performance is extremely desirable, which highly depends on development of new chemistry. This dissertation focuses on investigating novel chemistry to modify cellulose ethers and creating a broad range of polymer candidates for oral drug delivery. Unlike traditional methods, the new method is very mild and efficient with short reaction time, neutral pH, complete conversion and almost quantitative yield. It also allows incorporation with all kinds of functional groups to afford a variety of polymer structures. As a result, this method has enabled a library of polymers with diverse structures for drug delivery application and for structure-property relationship evaluations, which will further provide valuable information for designing nextgeneration polymers with optimized performance. The cellulose derivatives prepared in this way are also very promising for coating, food additive, and other biomedical applications.

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. / Bile acids are natural compounds in the body. Their biocompatibility, facial amphiphilicity, rigidity of steroid nucleus, and ease of chemical modification make them excellent candidates as building blocks for making biodegradable materials used in drug delivery and tissue engineering applications. We have prepared main-chain bile acid-based polymers having high molecular weights. Macrocyclic monomers were synthesized from dienes, which consist of flexible alkyl chains attached to a bile acid core through either ester or amide linkages, via ring closing metathesis using first-generation Grubbs catalyst. They were polymerized using entropy-driven ring-opening metathesis polymerization using second-generation Grubbs catalyst. Copolymers were also prepared from monolactone of ricinoleic acid and cholic acid-based cyclic triester monomer via the same method. The thermal and mechanical properties and degradation behaviours of these polymers have been investigated. The properties can be tuned by varying the chemical linking with the bile acid moiety and by varying the chemical composition of the polymers such as copolymerization with ricinoleic acid lactones. The tunability of the physical properties of these biocompatible polymers gives access to a range of interesting attributes. For example, shape memory properties have been observed in some samples. This may prove useful in the design of materials for biomedical applications.

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. / Bile acids are natural compounds in the body. Their biocompatibility, facial amphiphilicity, rigidity of steroid nucleus, and ease of chemical modification make them excellent candidates as building blocks for making biodegradable materials used in drug delivery and tissue engineering applications. We have prepared main-chain bile acid-based polymers having high molecular weights. Macrocyclic monomers were synthesized from dienes, which consist of flexible alkyl chains attached to a bile acid core through either ester or amide linkages, via ring closing metathesis using first-generation Grubbs catalyst. They were polymerized using entropy-driven ring-opening metathesis polymerization using second-generation Grubbs catalyst. Copolymers were also prepared from monolactone of ricinoleic acid and cholic acid-based cyclic triester monomer via the same method. The thermal and mechanical properties and degradation behaviours of these polymers have been investigated. The properties can be tuned by varying the chemical linking with the bile acid moiety and by varying the chemical composition of the polymers such as copolymerization with ricinoleic acid lactones. The tunability of the physical properties of these biocompatible polymers gives access to a range of interesting attributes. For example, shape memory properties have been observed in some samples. This may prove useful in the design of materials for biomedical applications.