Orientador: Clóvis Augusto Ribeiro / Coorientador: Hernane da Silva Barud / Banca: Jorge Manuel Vieira Capela / Banca: Fernando Luis Fertonani / Banca: Pedro Paulo Corbi / Banca: Éder Tadeu Gomes Cavalheiro / Resumo: Supra-anfifílicos são moléculas com capacidade de auto-organização em variadas estruturas mantidas por interações não-covalentes e, por isso, muitas vezes são desenvolvidas mimetizando sistemas biológicos. Inicialmente, este trabalho descreve o estudo comparativo de dois ácidos graxos homólogos, ácido esteárico e ácido oleico interagindo com o carboidrato meglumina (AOMEG e AEMEG), formando supra-anfifílicos mantidos por interações eletrostáticas, preparados em diferentes razões molares, 1:1, 1:1,5 e 1:2 do ácido graxo em relação a meglumina, com diferentes proporções de solventes e com adição de 60% de água a diferentes temperaturas, 65, 72 e 80°C. Um delineamento experimental foi realizado para otimizar a síntese, usando como respostas a bioadesão in vitro, anisotropia em microscópio de luz polarizada e temperatura de fusão da água por DSC. Pelas superfícies de resposta, sistemas de AOMEG são influenciados pela quantidade de solvente e pela razão molar, enquanto apenas este último gera respostas diferentes para sistemas de AEMEG. Em seguida, nove sistemas de cada ácido graxo nas proporções molares 1:1 e 1:2 foram sintetizados em ausência de solvente, contendo de 10 a 90% de água adicionada à 65°C e estudados quanto aos tipos de água, bioadesividade e organização estrutural, cujos resultados indicaram que em baixas concentrações de supra-anfifílicos (inferior a 30%) não é possível a organização dos sistemas, visto que estes são mantidos por ligações de hidrogênio. Acima de 4... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Supra - amphiphiles are molecules capable of self - a ssembling in various structures maintained by non - covalent intera ctions and often are developed by mimicking biological systems. This work describes the comparative study of two homologous fatty acids, stearic acid and oleic acid interacting with the carbohydrate meglumine (AOMEG and AEMEG), forming supra - amphiphiles ma intained by electrostatic interactions, prepare d in different molar ratios, 1:1, 1 :1.5 and 1:2 of the fatty acid to meglumine, with different proportions of solvents followed by the addition of 60% of water at different temperatures, 65, 72 and 80 °C. An e xperimental design was performed to optimize the synthesis, using in vitro bioadhesion study, anisotropy under a polarized light microscope and water melting temperature obtained by DSC. By the response surfaces, the amount of solvent and the molar ratio i nfluenced AOMEG systems, whereas only the molar ratio generates different responses to AEMEG systems. Then, nine syste ms of each fatty acid prepared in 1:1 and 1: 2 molar ratios (fat acid - meglumine) were synthesized in the absence of solvent, containing fro m 10 to 90% of water added at 65 ° C and studied according to water types, bioadhesiveness and structural organization . The results indicate d that in low concentrations of supra - amphiphiles (less than 30%) the systems did not show organization, since these are maintained by hydrogen bonds. Above 40% of supra - amphiphiles, all system... (Complete abstract click electronic access below) / Doutor

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeröy / A set of multifunctional molecules [isomeric forms of 1-(pyridylmethyl)-2,2'-biimidazole] was synthesized and subjected to systematic co-crystallizations with selected hydrogen- and halogen-bond donors in order to explore the impact of interaction type, geometry and electrostatics on the resulting supramolecular architectures. The structural outcome with hydrogen-bond donors (carboxylic acids) is somewhat unpredictable because of the presence of the acid···biimidazole heterosynthon that can compete with biimidazole···biimidazole homosynthon. In contrast, the solid-state supramolecular behavior of those probe molecules is largely unchanged in halogen-bonded co-crystals. Only two types of primary interactions, the two-point hydrogen bonds responsible for pairing biimidazole moieties, and the single-point halogen bonds responsible for the co-crystal formation and structure extension, are present in these systems. The results highlight that, by incorporating geometric biases along with orthogonal interactions, one can effectively prevent synthon crossover which is of paramount importance in complex crystal engineering endeavors. Heterobifunctional ligands pave the way for elaborate metallo-supramolecular systems, and are also useful for combining metal-ligand bonding with other types of non-covalent interactions. Nine new acetylacetonate ligands featuring either pyridyl- or thiophenyl-heterocycles were successfully prepared, and their metal binding abilities were studied with selected di- and tri-valent transition metal ions. As expected, the acetylacetonate ligation to metal dications remains consistent. In each case, the metal is four-coordinate and resides in a square planar environment. Differences in the overall architectures arise from the role played by the terminal heterocycles and the solvent. In seven (out of nine) structures, the heterocyclic end is involved in a structure-directing interaction and it is more prevalent in ligands bearing 4-pyridinyl unit. Divergent molecules containing bulky substituents tend to produce porous materials via frustrated packing. Two rigid tetrahedral cores, tetraphenylmethane and 1,3,5,7-tetraphenyladamantane, grafted peripherally with four (trimethylsilyl)ethynyl moieties were found to have only isolated voids in their crystal structures. Hence, they were modified into tecton-like entities, tetrakis(4-(iodoethynyl)phenyl)methane [I₄TEPM] and 1,3,5,7-tetrakis(4-(iodoethynyl)phenyl)adamantane [I₄TEPA], and the effect of motif-forming characteristics of iodoethynyl units on molecular arrangement and crystal porosity was analyzed. I₄TEPM not only holds increased free volume compared to its precursor, but also forms one-dimensional channels. Furthermore, it readily co-crystallizes with Lewis basic solvents to afford two-component porous materials even though they suffer from stability issues. As the binding sites in I₄TEPM and I₄TEPA are tetrahedrally-predisposed, they can be further utilized for the modular assembly of highly symmetric, three-dimensional extended architectures. With that in mind, these two building blocks were subsequently allowed to react with various halide salts, and it was found that the reactions between I₄TEPM and tetraphenylphosphonium halides readily yield four-fold interpenetrated diamondoid networks sustained by C–I⋯X⁻ (X⁻ = chloride, bromide, iodide) halogen-bonding interactions. The halide anions exhibit mutual-induced fitting of their coordination and act as four-connecting tetrahedral nodes, while the tetraphenylphosphonium cations render essential templating information and structural support.

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeröy / Four different methods; molecular electrostatic potentials (MEPs), hydrogen-bond energies (HBE), hydrogen-bond propensities (HBP) and hydrogen-bond coordination (HBC) were used for mapping out the structural landscape of twelve pyrazole and twelve thiazole based molecules. In seven out of eight crystal structures obtained in pyrazoles, a combination of HBE and HBP predicted the experimentally observed synthons correctly. In all eight crystal structures obtained in thiazoles, the synthons were predicted correctly using all four methods. A series of co-crystallizations between twelve pyrazole with twenty carboxylic acids (240 experiments), and twelve thiazole with twenty carboxylic acids (240 experiments) were carried out to build an experimental library that could be used for evaluating the ability of electrostatics, energies, propensities and molecular complementarity methods to rationalize the observed intermolecular interactions. The results suggested that a combination of electrostatics and molecular complementarity are essential for identifying the predominant molecular recognition events in the pyrazole based study, and methods such as MEPs, HBE, and HBP all predicted the observed synthons in co-crystals of the thiazole-based molecules. In order to examine competition between hydrogen and halogen bonds, and to synthesize ternary co-crystals, four thiazole based molecules were co-crystallized with 15 hydrogen-bond donors and one halogen bond donor resulting in new co-crystals in 44 out of 60 experiments, and the crystal structures of two ternary co-crystals were obtained. A series of eight unactivated and activated amide functionalized molecules were synthesized to establish a supramolecular halogen-bond hierarchy. The positive electrostatic potential on the halogen atoms was enhanced through an sp-hybridized carbon and electron-withdrawing fluoro group(s) next to amide group. Tetraflourinated and iodoethynyl based molecules were identified as the most effective halogen-bond donors and were therefore least successful for co-crystal synthesis. In order to predict crystallizability of 83 drug-like molecules a molecule, logistic regression approach was employed using molecular descriptors such as molecular weight, rotatable bond, surface area, heteroatom, melting temperature, glass transition temperature, and molecular shape/volume. Four different models were developed, and the success rate was above 85% (using experimental DSC data for the crystallization classification). Finally, the solid-form landscape of urea was explored using full interaction maps (FIMs), and data from the CSD to develop optimum protocols for synthesizing co-crystals of this compound. As a result, 49 of 60 attempted reactions produced new co-crystals. Moreover, the goal of reducing solubility and lowering hygroscopicity of the parent compound was achieved, which, in turn, offers new opportunities for a slow-release fertilizer with limited hygroscopicity thereby reducing many current problems of transport, handling, and storage of urea.

The first chapter of this thesis introduces the fundamental concepts governing the design and synthesis of supramolecular complexes. By illustrating the synthesis of several coordination cages reported in the literature, the principles underlying the construction of coordination cages by subcomponent self-assembly are elucidated. Ionic liquids are then proposed as solvents for cage systems; general methods for the preparation and synthesis of these solvents are described. The second chapter explores the use of ionic liquids as solvents for existing coordination cages. Potential methods of characterising these cages in ionic liquids are discussed; cages are demonstrated to be stable and capable of encapsulating guests in these ionic environments; and systems in which cages have good solubility in ionic liquids are designed. Building upon these observations, a triphasic sorting system is presented such that each of three different host-guest complexes are soluble in only one of three immiscible liquid phases. In contrast to the static triphasic system described in the second chapter, the third chapter explores directed phase transfer of coordination cages and their cargos from water, across a phase interface, and into an ionic liquid phase. The host-guest complex can then be recycled from the ionic liquid layer back into water after several additional steps. Furthermore, phase transfer of cationic cages is used to separate a mixture of cationic and anionic host-guest complexes. In the fourth chapter, fully reversible phase transfer of coordination cages is developed. Using anion exchange to modulate the solubility of three different cationic cages, reversible transport between water and ethyl acetate is demonstrated. Sequential phase transfer can also be achieved such that, from a mixture of cubic (+16) and tetrahedral (+8) cages, the cubic cage transfers from water to ethyl acetate before the tetrahedral cage. This process is fully reversible; upon the addition of a hydrophilic anion, the tetrahedral cage returns from ethyl acetate to water before the cubic cage.

Making use of the non-covalent bond to make materials is of great interest in many fields of research. This PhD thesis describes a variety of highly interdisciplinary research undertaken at the interface between chemistry, materials science, physics and engineering. Chapter 1 is an introductory chapter into the core concepts underlying this thesis. Supramolecular chemistry as a broad research field is briefly reviewed, followed by a focus on host-guest chemistry. The macrocyclic cucurbit[n]urils (CB[n]s) in particular are highlighted with a discussion on their recent applications since their discovery. Emulsions and their controlled generation with microfluidic techniques are then reviewed, as they have been used as templates for self-assembly processes throughout this thesis. A study into the synthesis of extended polymer networks composed entirely from small molecules held together by non-covalent interactions is described in Chapter 2. These highly dynamic and responsive supramolecular polymer networks have not yet been constructed with CB[n] host-guest chemistry. The ability of the larger CB[8] macrocycle to encapsulate multiple guest molecules in a stepwise fashion was taken advantage on in designing the synthesis of branching monomers. The monomers had two (A$_2$) or three (B$_3$) terminal guest moieties for CB[8], which upon combination formed branching supramolecular polymers that were multi-stimuli responsive. However, the polymers precipitated from solution at high concentrations rather than form a cross-linked network, due to competing intra-chain cyclisation and the limited water solubility of CB[8]. By confining these polymers to microfluidic droplets, directed assembly to the liquid-liquid interface could drive polymerisation to form an interfacial cross-linked gel that was both elastic and self-healing. Chapter 3 follows on from these results, describing attempts into constructing hyperbranched supramolecular polymers from an AB$_2$ guest molecule and CB[8] that would form globular polymers. Intramolecular complexation dominated with the guest molecules synthesised (A and B complexing within the molecule), evidenced by a variety of characterisation. Compared to previous works that relied on linear molecules to form a folded conformation for intramolecular complexes, these molecules were pre-organised with a unique cooperative complexation pathway. The stimuli-responsiveness of the complexes was probed, and the formation of self-sorting mixtures was demonstrated with multiple CB[n] and additional guest molecules. Controlling the self-assembly of semi-conducting nanocrystals with CB[7] is detailed in Chapter 4, a process that typically requires harsh conditions or extensive time-scales. Semi-conducting nanocrystals could be assembled instantaneously from water into extended networks that were highly porous with excess CB[7], retaining their nanoscale properties. Limiting quantities of CB[7] could then form nanoscale aggregates that remained in solution. Confinement of these assemblies within microfluidic droplets allowed the synthesis of dense microparticles, that retained their shape after re-dispersal in water. By simply including metallic nanocrystals as a minor component, mixed aggregates could be synthesised analogously. Finally, Chapter 5 draws overall conclusions from the results of this thesis, looking broadly at the potential for future prospects in these areas of research.

Tous les travaux effectués dans le cadre de cette thèse peuvent être placés sous la bannière de la chimie supramoléculaire. Différentes thématiques ont été abordées au cours de ces projets, qui s’inscrivent dans la continuité de ceux effectués précédemment au laboratoire.Les polymères, qu’ils soient supramoléculaires ou dynamiques (dynamères), ont constitué le squelette de cette thèse en étant étudiés en solution et à l’interface surface-solution. Le développement de certains autres axes de recherche s’est imposé à nous. Certains monomères utilisés dans la formation de nouveaux polymères ayant présenté un comportement inattendu aussi bien à l’interface surface-solution qu’en solution ; une étude approfondie a été menée pour en comprendre les raisons.Les résultats présentés dans ce manuscrit de thèse permettent d’affiner la compréhension de certains concepts en chimie supramoléculaire et dynamique. La première partie s’attache à montrer que la multiplication (ou la diversification) des fonctions dynamiques dans la chaîne principale d’un dynamère est une stratégie exploitable pour augmenter la complexité d’un système polymérique. La seconde partie de ce manuscrit présente différents auto-assemblages à l’interface surface-solution ainsi que l’étude approfondie d’un système auto-assemblé particulier et inattendu. Ces travaux tendent donc à améliorer la compréhension de la matière (par l’augmentation de la complexité dans des polymères dynamiques) et de ses interactions (par l’étude et la caractérisation de nouveaux auto-assemblages). / All the work described in this thesis falls within the domain of supramolecular chemistry. All the themes developed represent significant extensions of those previously developed in the laboratory. The focus has been on polymers, both supramolecular and dynamic covalent (dynamer) types, and their behaviour in solution and at the solid-solution interface.It has been essential to study also various other underlying aspects of this chemistry. Some of the monomers used as a source of new polymers have proven to exhibit unanticipated properties in solution and at interfaces, and a detailed investigation has been devoted to attempting to rationalise their behaviour.The results presented in this thesis provide a deeper understanding of several concepts central to supramolecular and dynamic chemistry. In the first section, it is shown that the multiplication or diversification of the dynamic links within the main chain of a dynamer is an effective strategy for enhancing the sophistication of a polymer system. The second section of the thesis concerns self-assembly processes at solid-solution interfaces and includes a detailed study of one completely unexpected self-assembled entity. The results obtained for this novel species have enabled its detailed characterisation and an analysis of its sensitivity to its environment and chemical stimuli.This work in total advances both an understanding of the nature of complex matter (through embellishment of the variety in dynamic polymers) and of the interactions which lead to its assembly (through the detailed characterisation of new materials).

Doctor of Philosophy / Department of Chemistry / Christer B. Aakeroy / A methodology for estimating hydrogen-bond preferences and binding affinities in solution, based on molecular electrostatic potential surfaces (MEPS), is presented using tritopic hydrogen bond acceptor and a series of aromatic carboxylic acids. The plot of calculated MEPS values against experimentally determined binding constants produces a goodness-of-fit of over 0.93 and a similar positive correlation is obtained between MEPS values and binding enthalpies. A series of tritopic N-heterocyclic compounds were synthesized and subjected to systematic co-crystallizations with selected multi-topic aliphatic and aromatic carboxylic acids to determine if ditopic and tritopic donors formulate assemblies with desired stoichiometries. The co-crystals formed contained the COOHᐧᐧᐧBzim synthon, and we observe vacant sites on the acceptor molecules. A series of co-crystallizations between tritopic N-heterocyclic compounds and perfluoroiodoarenes were carried to map out structural landscapes. At least one potential binding site on the acceptor is left vacant on all the four structures obtained. The absence of halogen bonds to all sites can be ascribed primarily due to deactivation of the σ-hole on the iodo-arene donors and partially due to steric hindrance. Four nonsteroidal anti-inflammatory (NSAID) drugs were chosen due to the presence of the COOH moiety, to establish if aqueous solubility can be modulated by systematic solubility measurements of the complex. Two different solids were obtained with a 1:1 and 1:3 stoichiometry. The solubility of the 1:1 co-crystal decreased by 12-fold compared to pure aspirin (3mg/mL at 20 °C) indicating that co-crystals can offer promising new solid forms of pharmaceutically relevant compounds. A series of hydrogen- and halogen bonding Tröger’s base derivatives were synthesized using aromatic N-heterocycles and the iodoethynyl functionality, followed by a series of co-crystallization between aliphatic dicarboxylic acids and symmetric ditopic acceptors. The results suggest that reducing the number of binding sites from three to two facilitates the formation of co-crystals with the desired stoichiometry. The results indicate that directed assembly can be achieved more easily when the molecular building blocks are conformationally rigid.

Afin d'obtenir une meilleure compréhension de l'étape clé du système photosynthétique (la formation d’un état à charges séparées), une nouvelle famille de systèmes donneur-accepteur supramoléculaires a été préparée.Nous avons notamment acquis une meilleure compréhension de la nature des interactions π-π entre le C60 et les porphyrines (résultant d'un processus régi principalement par des forces de van der Waals) et de l'affinité des éthers couronnes vis-à-vis des fullerènes (résultant d'une combinaison entre interactions π-π, n-π et CH-π). Les propriétés supramoléculaires des dimères de porphyrines ont été aussi explorées, prouvant leur communication électronique à travers leurs sous-unités. Finalement, la coopérativité chélate d'un de nos systèmes a été évaluée par la molarité efficace. / In order to gain a better understanding of the key step of the photosynthetic system (formation of a charged separated stated), a series of new supramolecular crown ether containing donnor-aceptor ensembles have been obtained.Notably we have gained further insight in the nature of π-π stacking between C60 and porphyrins (arising from a process mainly governed by van der Waals forces) and the affinity of crown ethers towards fullerenes(arising from an interplay of π-π, n-π and CH-π interactions). The properties of porphyrin arrays have been explored, evidencing the electronic communication through subunits. Finally, the chelate cooperativity of one our systems has also been assessed through the effective molarity.

El diseño molecular fundamentado en la imitación de las complejas estructuras y procesos que se encuentran en la naturaleza se conoce como Química bioinspirada o Química biomimética. Una de las aproximaciones utilizadas en esta disciplina es la preparación de compuestos seudopeptídicos macrocíclicos a partir de aminoácidos naturales y componentes abióticos. En la naturaleza existen proteínas con propiedades muy específicas y diversas. El uso de la información codificada en las cadenas laterales de los aminoácidos es un factor clave que, a su vez, puede utilizarse con ventaja para el diseño de seudopéptidos con propiedades específicas bien definidas. Por tanto, una selección apropiada de los componentes estructurales, naturales y no naturales, permite el diseño estructural adecuado para obtener la funcionalidad deseada. / The molecular design based on the imitation of the complex structures and processes found in nature is known as bioinspired Chemistry or biomimetic Chemistry. An approach used in this discipline is the preparation of macrocyclic pseudopeptidic compounds from natural amino acids and abiotic components. Proteins exist in nature with very specific properties encoded by the diverse structural and conformational information of the amino acids side chains. The use of this information is a key factor in the design of pseudopeptides with well-defined properties. Therefore, a suitable structural design to obtain the desired functionality relies on the appropriate choice of structural components, natural and abiotic.

Orientador: Anita Jocelyne Marsaioli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-05T16:28:19Z (GMT). No. of bitstreams: 1 Fernandes_SergioAntonio_D.pdf: 1655953 bytes, checksum: 3adfb8a50baef9f965f6836a338ce8c0 (MD5) Previous issue date: 2005 / Resumo: Esta tese teve como objetivo principal estudar interações intermoleculares empregando a espectroscopia de RMN de H como ferramenta principal. O primeiro capítulo visou "construir" um "hospedeiro quiral" através de interações não covalentes que foi aplicado na discriminação quiral e síntese assimétrica, ambos discutidos, no segundo e terceiro capítulo. Este hospedeiro quiral foi obtido via complexação de calixarenos com aminas quirais ((S)-feniletilamina, (S)naftiletilamina e (R)-2-aminobutanol). A topologia dos complexos foi determinada por RMN de H através de incremento de sinal devido ao acoplamento dipolar observado nas coordenadas girantes entre o hospedeiro (calixareno) e o hóspede (amina). Os experimentos de RMN de H a baixa temperatura foram usados para determinar a conformação preferencial e as mudanças na flexibilidade do calixareno livre e nos complexados. O segundo capítulo, descreve a aplicação dos complexos supramoleculares quirais no reconhecimento quiral e na determinação de excessos enantioméricos de sulfóxidos e ácidos. A importância do solvente, temperatura e topologia foram investigados. O terceiro capítulo focalizou a aplicação dos hospedeiros quirais na redução assimétrica de iminas e sais de metil isoquinolina com boroidreto de sódio. Os excessos enantioméricos são altamente dependentes dos substratos e variam de 0-90%. Finalmente o hospedeiro quiral foi obtido e a topologia totalmente descrita sendo o mesmo aplicado em reconhecimento quiral e síntese assimétrica, consolidando a importância deste tipo de hospedeiro quiral, que pode ser sintonizado para várias aplicações. A RMN de H mostrou ser uma ferramenta bastante eficaz quando aplicada aos estudos de complexos supramoleculares. / Abstract: This thesis concems intermolecular interactions using H NMR as major tooI. The first chapter will focus on the construction of a chiral host using non covalent bondings which will be used in chiral discrimination and asymmetric synthesis both discussed in the second and third chapters. This chiral host was obtained via calixarene complexation with chiral amines ((S)-phenylethylamine, (S)-naphthylethylamine and (R)-2-aminebutanol). The complexes topologies were determined via H NMR signal enhancements due to dipolar cross relaxation in the rotatory frame between the host (calixarene) and the guests (amines). H NMR experiments in variable temperatures were used to access preferential conformation and changes in calixarene flexibility under free and complexed conditions. The second chapter describes the application of chiral supramolecular complexes to chiral recognition and to the determination of enantiomeric excess of sulfoxides and acids. The importance of the solvent choice and topologies was aIso investigated. The third chapter focuses the application of the chiral host (calixarene/amine) to asymmetric reduction of imines and methyl isoquinolonium salts with sodium borohydride. The enantiomeric excesses were highly selective depending on the substrate and ranged between 0-90%. Finally a chiral host was obtained and its topology fully described and applications in chiral recognitions and asymmetric syntheses consolidated the importance of this type of chiral host that can be tuned to the desired application. H NMR techniques have once more proved to be unreplaceable in supramolecular investigations. / Doutorado / Quimica Organica / Doutor em Ciências