京都大学 / 新制・課程博士 / 博士(理学) / 甲第23020号 / 理博第4697号 / 新制||理||1674(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 時任 宣博, 教授 若宮 淳志, 教授 依光 英樹 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Cost-effective purification and desalination of water is a global challenge. Reverse osmosis (RO), the current method of choice, requires high pressure drops across the membranes in order to achieve acceptably high flow rates. Conventional polymer membranes are limited in their performance by a trade-off between water permeability and water/salt selectivity. Biofilm fouling is another critical problem in RO applications. Recent simulations and experiments suggest that properly functionalized carbon nanotubes (CNTs) can be used to construct RO membranes that have high permeation flux as well as complete ion rejection, and that are resistant to biofilm formation. The objective of this research was to combine zwitterion-functionalized carbon nanotubes with traditional thin film polyamide (PA) to fabricate a novel desalination membrane which has both high permeability as well as selectivity. Zwitterion functional groups in CNTs act as molecular gatekeepers at the entrance of the nanotubes to enhance blockage for salt ions. Functionalized CNTs were oriented on a membrane support by high vacuum filtration. These oriented CNTs were sealed by a polyamide film via interfacial polymerization. Cross-sectional image of the nanocomposite membrane taken by scanning electron microscopy (SEM) showed semi-aligned zwitterion-CNTs on top of a porous support covered by a thin PA film with an overall thickness of approximately 250 nm. When the concentration of zwitterion-CNTs in the membrane increased, the nanocomposite membranes experienced significant improvement in permeation flux while the ion rejection increases slightly or remains unchanged. This indicated that the increased water flux is not due to an increase in nonspecific pores in the membrane, but rather due to an additional transport mechanism resulting from the presence of the functionalized CNTs. Significant increase of flux was also observed in separating cations other than sodium. The separation of the PA skin layer dominated the ion rejection mechanism by size exclusion even when the carbon nanotubes were introduced into the polyamide coating. The zwitterion functional groups exposed at the membrane surface also interacted with the feed water to form a strong hydration layer, which results in improved surface biofouling resistance. The adsorption rate of protein foulants on the nanocomposite membrane surface was significantly reduced compared to the control membrane without CNTs, and the adsorbed fouling layer could be easily removed by flushing with water. After washing, the nanocomposite membrane recovered 100% of the decreased water flux whereas the control membrane only recovered 10% of the decreased flux resulting in a permanent loss of 30% in water permeation. We have therefore demonstrated that advanced materials like CNTs can be synthesized with desired functional groups, and can be embedded into traditional RO membranes to simultaneously resolve the challenge of low flux and surface fouling in the current desalination process. / Ph. D.

Die vorliegende Arbeit beschäftigen sich mit Azobenzol-Photoschaltern zur Steuerung (makro)molekularer Prozesse. Aufgrund ihrer lichtinduzierten geometrischen Strukturänderung hat diese Substanzklasse als Steuereinheit Einzug in mehrere Bereiche der Lebens- und Materialwissenschaften gehalten. Vorteile wie die hohe Stabilität, gute Ansprechbarkeit und etablierte Synthesemethoden werden von einer großen Vielfalt an Derivaten vervollständigt. Als eines der populärsten photochromen Systeme bieten Azobenzole eine zuverlässige Grundlage für die Entwicklung neuer molekularer Maschinen. Der erste Teil dieser Arbeit hat die Vergrößerung der geometrischen Änderung des Schaltvorgangs zum Ziel. Dafür werden Azobenzole in starre Makromoleküle und makromolekulare Aggregate eingebaut, die der Bewegung der kleinen Wiederholungseinheiten aufgrund der gewählten Architektur folgen und somit idealerweise die Umwandlung der aufgenommenen Energie in mechanische Arbeit erhöhen. Dabei werden die Grundlagen der Photochromie, der Azobenzol-Photochemie sowie allgemeine Strategien zur Steigerung geometrischer Änderungen in molekularen Systemen vorgestellt. Des Weiteren wird das Design, die Synthese und die Charakterisierung eines durch Licht ansprechbaren Polymeraggregats beschrieben. Der zweite Teil dieser Arbeit beschäftigt sich mit der reversiblen Bildung von ionischen Substanzen. Geladene Spezies sind von großer Wichtigkeit für die Aufrechterhaltung verschiedener Körperfunktionen in Lebewesen, können jedoch auch Adsorptions- und bakterizide Eigenschaften auf Oberflächen regulieren. Basierend auf dem Modell des Spiropyrans wird der theoretische Hintergrund für die Herstellung eines Azobenzol-Äquivalents vorgestellt. Daten aus DFT-Rechnungen werden in Modellverbindungen umgewandelt, die mittels NMR-Analyse untersucht werden. Abschließend wird eine vielversprechende Zielstruktur eines durch Licht steuerbaren dynamisch kovalenten Zwitterions vorgestellt. / The present thesis employs azobenzene photoswitches to control (macro)molecular processes. As a light-responsive molecule undergoing a large geometrical change upon E/Z photoisomerization, azobenzenes have found their way into multiples areas of life and material sciences. Advantages such as high stability, good addressability, and well-established synthesis methods are accompanied by a large variety of derivatives. Being one of the most popular photochromic compounds, azobenzenes provide a reliable basis for the development of new responsive systems. The first part of this work is aimed at the amplification of the switching dimensions by incorporating azobenzene into rigid macromolecules and macromolecular aggregates. Based on the polymer architecture, the motion of the small responsive repeating units is transferred to the entire macromolecule, which ideally helps to increase the conversion of consumed energy into mechanical work. Following a small overview about the basics of photochromism and azobenzene photochemistry, general strategies to increase geometrical changes in molecular systems are presented. Furthermore, the design and synthesis as well as the characterization of a light-responsive polymer aggregate that exhibits a large geometrical change upon isomerization is described. The second part of this work deals with the reversible formation of ions. Besides their great importance for vital functions in living organisms, adsorption characteristics as well as bactericidal properties can be regulated by ionic modifications on surfaces. Based on the model of spiropyran, the theoretical background for the preparation of an azobenzene equivalent is presented. The computational data is converted into model compounds that were investigated by means of NMR analysis. Based on these combined theoretical and experimental data, a promising target structure for a light-responsive dynamic covalent zwitterion is described.

Die vorliegende Dissertation stellt einen Beitrag zur Chemie des höherkoordinierten Siliciums dar. Im Rahmen dieser Untersuchungen wurden neuartige zwitterionische spirocyclische lambda5Si,lambda5Si'-Disilicate, zwitterionische spirocyclische lambda5Si-Silicate und neutrale pentakoordinierte Silicium(IV)-Komplexe dargestellt. Weiterhin wurden neutrale hexakoordinierte Silicium(IV)-Komplexe sowie neutrale pentakoordinierte Germanium(IV)-Komplexe synthetisiert. Die Charakterisierung dieser Verbindungen erfolgte durch Elementaranalysen, Festkörper-NMR-Spektroskopie (13C-, 15N-, 29Si- und 77Se-VACP/MAS-NMR) und Kristallstrukturanalysen. Ergänzend wurden einige Verbindungen durch NMR-Spektroskopie in Lösung (1H, 13C, 19F, 29Si, 31P und 77Se) charakterisiert. / This dissertation deals with the chemistry of higher-coordinate silicon. In the course of these studies, novel zwitterionic spirocyclic lambda5Si,lambda5Si'-disilicates, zwitterionic spirocyclic lambda5Si-silicates, and neutral pentacoordinate silicon(IV) complexes were prepared. Furthermore, neutral hexacoordinate silicon(IV) complexes and neutral pentacoordinate germanium(IV) complexes were synthesized. These compounds were characterized by elemental analyses, solid-state NMR spectroscopy (13C, 15N, 29Si, and 77Se VACP/MAS NMR), and single-crystal X-ray diffraction. In addition, some of these compounds were characterized by NMR spectroscopy in solution (1H, 13C, 19F, 29Si, 31P, and 77Se).

Enhancing the physicochemical properties of solid-state materials through crystal engineering enables optimization of these materials without covalent modification. Cocrystals have become a reliable means to generate novel crystalline forms with multiple components and they exhibit different physicochemical properties compared to the individual components. This dissertation exemplifies methodologies to generate cocrystals of active pharmaceutical ingredients (API's) based upon knowledge of supramolecular interactions (supramolecular synthons), while focusing on enhanced delivery through in vitro and in vivo processes with both salts and cocrystals respectively. The utility of mechanochemistry involving small amounts of an appropriate solvent, or solvent drop grinding (SDG), has been shown to reliably reproduce cocrystals with the anti-convulsant carbamazepine that were originally obtained by solution crystallization. This technique has been confirmed as a reliable screening method using solvents in which both components exhibit some solubility. The benefits of this technique lie in the time and cost efficiency associated with it as well as its inherently small environmental impact making it a "Green" method. SDG was also used as an efficient way to discover cocrystals of the anti-inflammatory meloxicam with carboxylic acids after analysis of existing reports and the analysis of structural data from the Cambridge Structural Database (CSD) to guide the choice of coformer. It has been shown that SDG can be used to screen for cocrystalline forms that are also obtainable by solution crystallization which is important in later stage development and manufacturing including but not limited to large scale up processes. Single crystals suitable for single crystal X-ray diffraction were obtained with meloxicam and two of the coformers, fumaric and succinic acid. Some of the meloxicam cocrystals exhibited enhanced pharmacokinetic (PK) profiles in rats exemplifying significantly higher serum concentrations after only fifteen minutes and consistently higher exposure over the time studied while others maintained lower exposure. This reveals that cocrystals can fine tune the PK profile of meloxicam in order to reduce or enhance exposure. Two different sulfonate salts, 4-hydroxybenzenesulfonate (p-phenolsulfonate) and 4-chlorobenzenesulfonate, of the anti-spastic agent (R,S) baclofen were developed by strategically interrupting the intramolecularly stabilized zwitterionic structure of baclofen. This zwitterionic structure results in low solubility associated with physiological pH required for intrathecal administration. Structural data for both salts in the form of single crystal X-ray diffraction data was successfully obtained. Solubility based on baclofen was assessed and shown to increase in pure water and at pH's 1 and 7. Only the 4-chlorobenzenesulonate salt maintained an increased solubility over two days at pH 7 making it a viable candidate for further study in terms of intrathecal administration. During crystallization experiments with (R,S) baclofen two polymorphic forms of the baclofen lactam were generated, Forms II and III. Both forms are conformational polymorphs confirmed by single crystal X-ray diffraction and Form II has a Z' of 4 with an unusual arrangement of enantiomers.

Les propriétés des quantum dots (QDs) en font des sondes adaptées à la reconnaissance moléculaire. Leur pic d’émission en fluorescence est très étroit et ajustable, tandis que la section efficace de leur spectre d’absorption est très large. En outre, ils sont très brillants et résistent mieux au photoblanchiment que les colorants organiques conventionnels.Notre objectif a été de concevoir un nouveau type de sondes fluorescentes pour une détection rapide à l’échelle de la molécule unique. L’utilisation d’agrégats contenant plusieurs milliers de QDs, plutôt que celle de QDs individuels, permet d’accroître le signal de fluorescence et de simplifier les modalités de détection. La morphologie et la chimie de surface des premiers agrégats préparés n’ont pas pu être contrôlées en les recouvrant avec des molécules de surfactants courts ou une couche de polymère en solution aqueuse. La stratégie centrale de ce manuscrit a permis d’assembler les QDs en nanobilles (NBs) monodisperses de quelques centaines de nanomètres de diamètre, encapsulées dans une couche de silice Stöber. Leur stabilité colloïdale et leur photostabilité ont ainsi été conservées. Un nouveau type d’hybride polymère-silane a été greffé sur la silice. Il présente des chaînes zwittérioniques, garantissant la solubilité en milieu aqueux et une adsorption non spécifique minimale, ainsi que des fonctions réactives pour la bioconjugaison. La réactivité de NBs fonctionnalisées par de la streptavidine avec des billes commerciales biotinylées a été démontrée. Nos résultats préliminaires ont également montré que les NBs peuvent être intégrées dans un dispositif microfluidique pour être comptées individuellement. / Using nanotechnology for molecular diagnostics holds many advantages e.g. an improvement in the simplicity and the sensitivity of analysis. Semi-conductor nanocrystals or quantum dots (QDs) demonstrate several unique properties that make them suitable probes for biomolecular recognition. These QDs present narrow size-tunable emission spectra and a broad excitation spectrum; in addition, they offer higher photostability and brightness than conventional organic dyes. Our aim was to design a new diagnostic probe based on fluorescent nanobeads containing QDs, envi-sioned as a tool for fast and single-molecule detection. An even brighter fluorescence and easily detectable analytical signals could indeed be achieved by aggregating several thousand of QDs together, as compared to single QDs. Coating QD clusters with small surfactants or a polymer layer didn’t provide morphological control or a suitable surface chemistry for bioconjugation. The strategy that we developed consists in self-assembling QDs into monodisperse nanobeads of a few hundreds of nanometers in diameter, on top of which a silica shell was grown by a Stöber-inspired process. This allowed us to protect their colloidal and photo-stability. A new type of multidentate polymer-silane hybrid was subsequently grafted onto the silica shell, presenting a zwitterionic chain for water solubility and antifouling, as well as reactive functions for conjugation with biomolecules. We succeeded in reacting streptavidin-conjugated nanobeads with commercial biotinylated beads. Preliminary results have also shown that we can integrate the nanobeads into a microfluidic system for an efficient single-particle counting.

Use of a mixed triisobutylaluminum/1,1-diphenylhexyllithium intiator enabled the anionic polymerization of methyl methacrylate at room temperature, resulting in narrow molecular weight distributions and syndiorich structures. Polymerizations were controlled above Al:Li = 2, and control significantly decreased at elevated temperatures above 25 °C. A significant increase in Tg with increasing control of syndiotacticity demonstrated the ability to tailor polymer properties using this technique. Analysis with MALDI-TOF/TOF spectroscopy revealed the dominance of a back-biting side reaction at elevated temperatures. Hydroxy-functional random and block copolymers of n-butyl acrylate (nBA) and 2-hydroxyethyl acrylate were synthesized using nitroxide mediated polymerization. Controlled polymerization was demonstrated, resulting in narrow polydispersities and linear molecular weight vs. conversion plots. In situ FTIR spectroscopy monitored the polymerizations and revealed pseudo first order rate kinetics for random copolymerizations. Protection of the hydroxyl using trimethylsilyl chloride alleviated isolation issues of amphiphilic polymer products. For the first time zwitterion-containing copolymers were electrospun to form nanoscale fibers with diameters as low as 100 nm. Free radical copolymerization of nBA and sulfobetaine methacrylamide produced zwitterionic copolymers with 6-13 mol % betaine. Dynamic mechanical analysis revealed a rubbery plateau and biphasic morphology similar to ionomers. Electrospinning from chloroform/ethanol solutions (80/20 v/v) at 2-7 wt % afforded polymeric fibers at viscosities below 0.02 Pa™s, which is the lowest viscosity observed for fiber formation in our laboratories. We hypothesized that intermolecular interactions rather than chain entanglements dominated the electrospinning process. Solution rheology of zwitterionic copolymers containing 6 and 9 mol % sulfobetaine methacrylate functionality revealed two concentration regimes with a boundary at ~1.5 – 2.0 wt %, regardless of molecular weight. This transition occurred at an order of magnitude lower specific viscosity than the entanglement concentration (Ce) for poly(nBA), and correlated to the onset of fiber formation in electrospinning. Comparison to existing models for polymer solution dynamics showed closest agreement to Rubinstein's theory for associating polymers, in support of our hypothesis that zwitterionic interactions dominate solution dynamics. The effect of ionic liquid (IL) uptake on mechanical properties and morphology of zwitterionic copolymers was explored using 1-ethyl-3-methylimidazolium ethylsulfate (EMIm ES). Dynamic mechanical analysis and impedance spectroscopy revealed a significant change in properties above a critical uptake of ~10 wt % IL. X-ray scattering revealed a significant swelling of the ionic domains at 15 wt % IL, with a 0.3 nm-1 shift in the ionomer peak to lower scattering vector. Results indicated the water-miscible IL preferentially swelled ionic domains of zwitterionic copolymers. / Ph. D.

Conventional free radical polymerization of n-butyl acrylate with 3-[[2-(methacryloyloxy)ethyl](dimethyl)-ammonio]-1-propanesulfonate (SBMA) and 2-[butyl(dimethyl)amino]ethyl methacrylate methanesulfonate (BDMAEMA MS), respectively, yielded zwitterionomers and cationomers of comparable chemical structures. Differential scanning calorimetry (DSC), small-angle X-ray scattering (SAXS), and atomic force microscopy (AFM) revealed that zwitterionomers promoted more well-defined microphase-separation than cationic analogs. Dynamic mechanical analyses (DMA) of the copolymers showed a rubbery plateau region due to physical crosslinks between charges for zwitterionomers only. We attributed improved microphase-separation and superior elastomeric performance of the zwitterionomers to stronger association between covalently tethered charged pairs. Zwitterionomer / ionic liquid binary compositions of poly(nBA-co-SBMA) and 1-ethyl-3-methylimidazolium ethylsulfate (EMIm ES) were prepared using both the 'swelling– and the –cast with– methods. Dynamic mechanical analysis revealed that the 'swollen– membranes maintained their thermomechanical performance with up to 18 wt% EMIm ES incorporation, while that of the –cast with– membranes decreased gradually as the ionic liquid concentration in the composite membranes increased. Small-angle X-ray scattering results indicated that the 'swollen– and the –cast with– membranes have different morphologies, with the ionic liquid distributed more evenly inside the –cast with– membranes. Impedance spectroscopy results showed that the –cast with– membranes had better ionic conductivity than the 'swollen– membrane at high ionic liquid concentration, in agreement with our proposed model. The results indicated that the different processing methods had a significant impact on thermomechanical properties, ionic conductivities, as well as morphologies of the zwitterionomer / ionic liquid binary compositions. Reversible addition-fragmentation chain transfer polymerization (RAFT) strategy afforded the synthesis of well-defined poly(sty-b-nBA-b-sty). 2-(Dimethylamino)ethyl acrylate (DMAEA), a tertiary amine-containing acrylic monomer, exhibited radical chain transfer tendency toward itself, which is undesirable in controlled radical polymerization processes. We employed a higher [RAFT] : [Initiator] ratio of 20 : 1 to minimize the impact of the chain transfer reactions and yielded high molecular weight poly[sty-b-(nBA-co-DMAEA)-b-sty] with relatively narrow PDIs. The presence of the tertiary amine functionality, as well as their quaternized derivatives, in the central blocks of the triblock copolymers afforded them tunable polarity toward polar guest molecules, such as ionic liquids. Gravimetric measurements determined the swelling capacity of the triblock copolymers for EMIm TfO, an ionic liquid. DSC and DMA results revealed the impact of the ionic liquid on the thermal and thermomechanical properties of the triblock copolymers, respectively. Composite membranes of DMAEA-derived triblock copolymers and EMIm TfO exhibited desirable plateau moduli of ~ 100 MPa, and were hence fabricated into electromechanical transducers. RAFT synthesized poly(sty-b-nBA-b-sty) triblock copolymer phase separates into long-range ordered morphologies in the solid state due to the incompatibility between the poly(nBA) phases and the poly(sty) phases. The incorporation of DMAEA into the central acrylic blocks enabled subsequent quaternization of the tertiary amines into sulfobetaine functionalities. Both DSC and DMA results suggested that the electrostatic interactions in the low Tg central blocks of poly(sty-b-nBA-b-sty) enhanced block copolymer phase separation. SAXS results indicated that the presence of the sulfobetaine functionalities in acrylate phases increased electron density differences between the phases, and led to better defined scattering profiles. TEM results confirmed that the block copolymers of designed molecular weights exhibited lamellar morphologies, and the lamellar spacing increased with the amount of electrostatic interactions for the zwitterionic triblock copolymers. Acrylic radicals are more susceptible to radical chain transfer than their styrenic and methacrylic counterparts. Controlled radical polymerization processes (e.g. RAFT, ATRP and NMP) mediate the reactivity of the acrylic radical and enable the synthesis of well-defined linear poly(alkyl acrylate)s. However, functional groups such as tertiary amine and imidazole on acrylic monomers interfere with the controlled radical polymerization of functional acrylates. Model CFR and RAFT polymerization of nBA in the presence of triethylamine and N-methyl imidazole revealed the interference of the functional group on the polymerization of acrylate. Various RAFT agents, RAFT agent to initiator ratios, degree of polymerization and monomer feed concentrations were screened with an imidazole-containing acrylate for optimized RAFT polymerization conditions. The results suggest that the controlled radical polymerization of functional acrylates, such as 2-(dimethylamino)ethyl acrylate and 4-((3-(1H-imidazole-1-yl)propanoyl)oxy)-butyl acrylate (ImPBA), remained challenging. / Ph. D.

L’objectif de ce travail a été d’introduire des groupements fonctionnels au sein de chaînes polymère silicone pour former des assemblages supramoléculaires, dans le but de former de nouveaux matériaux. Tout d’abord, une étude approfondie de la bibliographie a permis de cerner les avantages et limitations de la réaction d’aza-Michael appliquée aux silicones. Cette étude a aussi permis d’acquérir de solides connaissances générales sur la réaction d’aza-Michael appliquée à des composés organiques aminé et de soulever des points peu ou pas traités tels que la sélectivité et la réversibilité de la réaction. Afin de comprendre et contrôler cette réaction, une étude modèle impliquant un PDMS aminé simple et l’acrylate de butyle a été réalisée. Plusieurs paramètres tels que la présence de solvants polaires protiques, de catalyseurs, ou une température élevée permettent de promouvoir la réaction. Des données cinétiques ont également mis en relief la possibilité de contrôler la sélectivité de la réaction sur un groupement amine primaire (mono- ou di-addition). Un composé 100% mono-adduit et un composé 100% di-adduit ont ainsi été synthétisé en choisissant soigneusement les paramètres expérimentaux. La réaction d’aza-Michael a ensuité été appliquée à un accepteur de Michael moins réactif, l’acide acrylique. Ce composé a la particularité de réagir instantanément et exothermiquement avec les amines par réaction acido-basique. Un déplacement de l’équilibre chimique de la réaction acido-basique vers la formation d’adduits de Michael a été rendu possible, générant ainsi des groupements zwitterioniques. Une étude approfondie de la réaction avec des amines organiques et des oligomères/polymères siliciés et aminés a été réalisée afin de déterminer la structure exacte des groupements fonctionnels obtenus et d’évaluer les propriétés visco-élastiques de tels produits. La dernière partie de ce projet a été focalisée sur l’étude et la caractérisation de ces matériaux silicones supramoléculaires s’échelonnant du liquide visco-élastique à l’élastomère silicone thermoplastique. / This PhD thesis was focused on the incorporation of functional groups onto the siloxane polymer backbone such that supramolecular assemblies are formed, in order to prepare new supramolecular silicone materials. First, an in-depth review of the aza-Michael reaction applied to silicon-containing compounds was realized, highlighting the whole potential of this addition reaction. The aza-Michael reaction applied to organic amines was thoroughly analyzed in order to emphasize some open issues such as selectivity or retro-aza-Michael reaction. In order to understand and master the aza-Michael reaction, a model reaction involving a bis-(3-aminopropyl)-terminated PDMS and butylacrylate was then fully investigated. Operating parameters such as protic polar solvents, catalysts or temperature allow promoting the reaction rate. Kinetic data showed that the selectivity towards the main formation of mono- or di-adduct can be controlled by carefully selecting the solvent nature and content. The syntheses of 100% mono- and 100% di-adduct compounds was succesfully achieved. The aza-Michael reaction was then applied to a less reactive Michael acceptor, i.e. acrylic acid. This unsaturated organic acid reacts instantaneously with amines by acid-base reaction leading to the formation of ionic pairs. This acid-base equilibrium is then shifted in the forward direction allowing the synthesis of zwitterionic groups by aza-Michael. The aza-Michael reaction of this peculiar Michael acceptor was thoroughly investigated both with simple organic amines and aminosilicone oligomers and polymers in order to elucidate the structures and to evaluate the rheological properties. Finally, supramolecular silicone materials bearing zwitterionic-like groups were prepared leading to supramolecular materials with properties ranging from visco-elastic liquids to thermoplastic silicone elastomers.

Most of the biological systems in nature are sustained by molecular self-assemblies which are the finest examples of supramolecular architectures. Non-covalent interactions are key concepts which govern these molecular assemblies. Inspired by these examples crystal engineering emerged as an important tool in supramolecular chemistry which aids in the invention of new molecular structures with desired properties. Understanding of how the molecules interact at the molecular levels enables one to rationally design novel solid forms with modulated physicochemical properties. This feature of crystal engineering has heightened its position in materials chemistry and is currently one of the most well studied fields for generating novel compounds with pre-defined composition and supramolecular architectures. One such class of compounds that has immensely attracted the scientific community and is under continuous study for wider applications is cocrystals. The applications include various interdisciplinary fields such as pharmaceutics, catalysis, organic conductors, explosives etc. Distinctly on the other side, cocrystals also provide a means to discover new supramolecular synthons which is the ultimate key to molecular assembly. Many robust supramolecular synthons have been discovered and hierarchies are also being developed which can serves as a design tool for cocrystal synthesis. The Cambridge Structural Database (CSD) is an important accessory in determining the robustness of a supramolecular synthon but, this does not preclude us from discovering new synthons. The work presented here explores new persistent supramolecular synthons in polyphenols utilizing the basic concepts of crystal engineering and the CSD statistical analysis. This contribution also includes the implementation of cocrystallization for various categories of compounds which includes nutraceuticals, pharmaceuticals and ionic salts for the design and synthesis of molecular and ionic cocrystals. Chapter 1 highlights how supramolecular synthon approach can be used to design and synthesize multi-component crystals, namely, cocrystals. The role of the CSD and its importance in crystal engineering has also been discussed. Chapters 2 and 3 focus on new persistent supramolecular synthons in the context of nutraceuticals. The cocrystals isolated in the study are also compared with the existing cocrystals in the CSD supramolecularly in terms of synthon formation. These persistent supramolecular synthons are helpful in developing hierarchies which could be utilized and applied to similar and analogous compounds. The main feature of Chapter 4 is expanding the field of cocrystallization by studying the properties of cocrystals. Some of the properties which have been examined here include effects of cocrystallization on solubility and correlations between the solubility of cocrystal with cocrystal former (CCF) and melting point of the cocrystal. The extension of cocrystals to the active pharmaceutical ingredients (APIs) has been explored in the context of pharmaceutical cocrystals by selecting a BCS class IV drug, hydrochlorothiazide in Chapter 5. Chapter 6 highlights the hybridization of organic and inorganic components for the synthesis of ionic cocrystals and is exemplified by considering lithium salts with achiral and homochiral amino acids for the generation of 1:1 and 1:2 cocrystals.