This thesis presents investigations into the interactions of ionic liquids (ILs). An investigation on the interaction of the ionic liquid 1-octyl-3-methylimidazolium tetrafluoroborate ([C8C1Im][BF4]) with three small molecules will focus on how the desorption kinetics are perturbed by interaction with the IL. A monolayer of 1-ethyl-3-methylimidazolium bis[(trifluoromethyl)sulfonyl]imide ([C2C1Im][NTf2]) interacting with a Au(110) crystal facet is investigated using normal incidence x-ray standing wave (NIXSW) to resolve positional information. Acetone, sulfur dioxide and water interacting with [C8C1Im][BF4] are investigated. The desorption of pure species has been characterised. Acetone multilayers desorb with an activation energy of Ea = 38(2) kJ mol^-1 and a pre-exponential of A = 4.3x10^14(1) s^-1. Sulfur dioxide desorbs with an activation energy of Ea = 32(2) kJ mol^-1 and a pre-exponential of A = 6x10^14(1) s^-1. Water is observed to have an amorphous to crystalline phase change over the desorption region. Amorphous water is calculated to have a desorption activation energy of Ea = 49(5) kJ mol^-1 compared to Ea = 43(2) kJ mol^-1 for crystalline water. The pre-exponential is calculated to be A = 10^17(2) s^-1 and A = 10^15(1) s^-1 for the amorphous and crystalline water respectively. [C8C1Im][BF4] is found to stabilise both acetone and sulfur dioxide to a fixed capacity. A mole fraction of 1.2 of acetone to [C8C1Im][BF4] was stabilised over a range of Ea = 45 – 61 kJ mol^-1. A mole fraction of 6 of sulfur dioxide to [C8C1Im][BF4] was stabilised over a range of Ea = 40 – 52 kJ mol^-1. No fixed capacity was found for water despite being in great excess of the [C8C1Im][BF4]. The full coverage of water was influenced by the presence of [C8C1Im][BF4] with an activation energy of Ea = 42 kJ mol^-1 at full water coverage which increased to Ea = 49 kJ mol^-1 as the water coverage tended to zero. Several possible positions of [C2C1Im][NTf2] on Au(110) are presented. Near edge absorption fine structure (NEXAFS) spectroscopy informed that the imidazolium ring is flat on the surface. The position of the cation and the anion on the surface is found through simulation of each ion separately. The NIXSW is used to propose two real space position which the cation could occupy. The position of the anion is reduced to five possible configurations on the surface through the use of NIXSW.

Several novel methodologies were explored with the general purpose of rapid access to molecular complexity and sp3-rich scaffolds. A number of novel scaffolds were successfully synthesised, utilising two-directional synthesis and tandem reactions. The chemistries applied have been demonstrated to be capable of readily fabricating many novel and interesting diverse molecular scaffolds. Indeed, the azaspirocyclic cores found in halichlorine and pinnaic acid were synthesised using this approach starting with ethyl formate. More diverse scaffolds were generated from simple symmetrical linear molecules derived from ethyl formate, utilising the nitrone produced in situ by the treatment of the central ketone with either hydroxylamine hydrochloride or amino acids. These afforded number novel skeletons [A-C], which are expected to have interesting biological activity. In addition, they are conceivably useful skeletons in the synthesis of natural products, or in drug synthesis due to its high saturation (high Fsp3) characters. Using the tandem reactions, we have also managed to develop a rapid synthetic route to an sp3 -rich chemical scaffold [F] derived from novel isoxazolidine scaffold [E]. This project has been published with a contribution of other group member. We were interested to synthesise of some natural products. We tried to explore the possibility of developing an enantioselective synthesis approach to the key intermediate in the synthesis of hippodamine [H], few attempts toward the synthesis of the marine alkaloids phakellin [I]. Several novel applications of chiral sulfinimines were explored. Initially some preliminary results toward the synthesis of piperidine dione [I] were recorded. Successful attempts of tert-butyl sulfinimines with dianion tert-butyl-acetoacetate afforded a range of cyclic compound piperdine dione [J] in a good yield.

Chemical surface modification of cellulose nanocrystals has had a fast development and increased interest from the scientific community as cellulose is the most abundantly available renewable polymer with many advantages such as nanoscale dimensions, high specific strength and modulus, high surface area, unique optical properties and the extraordinary modification potential to increase the application field. This thesis is aimed at expanding and improving upon the current knowledge in order to unlock new applications. Four esterification techniques were applied to the formation of cellulose nanocrystal esters of acrylic acid and methacrylic acid. The degree of surface substitution reached two to three surface hydroxyl groups (the maximum number) available for functionalization and this degree of substitution is very much dependent on the chosen esterification methodology. Two new fluorescently modified cellulose esters based on carbazole-9-yl-acetic acid and coumarin-3-carboxylic acid were synthesised using p-toluenesulfonyl chloride/pyridine and carbodiimide esterifications methods. Absorption and fluorescent properties were also measured and showed fluorescence proportional to the extent of surface functionalization. The maximum theoretically attainable degree of substitution could be reached while still maintaining the crystal structure of cellulose. Cationic cellulose nanocrystals were produced with a high positive surface charge when compared with the literature. The synthesis procedure was attempted in two steps and in a single step. The degree of modification for pyridinium acetate cellulose and methyl imidazolium acetate cellulose was found to depend significantly on the selected pathway. The cationic nature of the modifications was verified using zeta potential measurements and through adsorption of an anion dye. Synthesised cellulose acrylates and methacrylates were used in Thiol-Ene click reactions in which very mild and environmentally friendly reaction conditions proved to work from 10 min reaction times. Four different thiols were added, with and without hexylamine catalyst. In addition, an amidine functionalised cellulose nanocrystal was synthesised based on previously click-modified cellulose in a 2-hour reaction. Furthermore, the switchable behaviour of the synthesised nanoparticles was demonstrated by reverse bubbling with CO2 and Ar.

Amorphous solid dispersions over the last decade or so have been widely investigated by the pharmaceutical industry as a formulation method to increase the effective solubility of poorly water soluble drugs and subsequently their bioavailability. Cryomilling is attractive technique to render crystalline materials amorphous without using heat or solvent as are typically used in current processes. The possibility of amorphous formation via cryomilling was studied for three different types of drugs with different glass forming ability (GFA); Felodipine (class III) an easy glass former, paracetamol (class II) a moderate glass former and aspirin (class I) a poor glass former. These drugs were cryomilled alone, cryomilled then mixed with cryomilled hydroxypropyl methylcellulose (HPMC) physically (i.e. cryomilled separately) or co-cryomilled with HPMC together. The subsequent formulations were characterised by DSC, XRPD and FTIR. It was found that when felodipine is cryomilled alone, it can be transformed into the amorphous form, however no amorphous formation was achieved when cryomilling paracetamol or aspirin alone. It is thought that the relatively higher Tg of felodipine compared to paracetamol,and aspirin enables this transformation, however, this transformation was difficult to achieve for paracetamol or aspirin due to their rapid recrystallisation directly after cryomilling due to their low Tg and their resistance to mechanical disorder. Although felodipine was rendered amorphous when milled alone it then recrystallised within a day. It was thought that the conversion of these three drugs into amorphous form or not depends on the glass forming ability of each drug. The amount of polymer required to stabilise the amorphous form of each drug varied according to their glass forming ability with more polymer required for poor glass formers. Felodipine was selected as a model drug for further study with different polymers. This is because felodipine is widely used for the production of amorphous solid dispersion by hot melt extrusion and spray drying. Secondly this drug is practically insoluble but it is an important drug in the emergency treatment of hypertension due its high selectivity and its lack of a negative inotropic effect. Felodipine was co-cryomilled with different polymers and polymer blends that varied in water solubility namely HPMC, HPMCAS, Soluplus R, PMMA, HPMC-HPMCAS, HPMC:PMMA and Soluplus R:HPMCAS at 5, 25, 50 and 75% (w/w) drug loadings. For each mixture the miscibility was predicted using the Gordon-Taylor equation and solubility parameter value. All these mixtures at 50% drug loading were further investigated in dissolution studies for 6 hours under sink condition. All co-cryomilled samples except PMMA showed a high level of drug release (> 90%) after 6 hours dissolution. Only PMMA, which is water insoluble, retarded the release of felodipine from the co-cryomilled mixtures but in ternary mixture felodipine-HPMC/PMMA it showed more than 95% drug release after 6 hours dissolution. As felodipine with Soluplus R showed a good miscibility and stability at 0% humidity and high drug release this co-cryomilled mixture with 50% drug loading was used in the formulation of an orodispersible tablets (ODTs). Six different formulations were manufactured using different superdisintegrants such as F-melt and Glycolate. All the co-cryomilled formulas showed a higher release of felodipine compared to the physical mixtures. Obtaining miscible and stable amorphous solid dispersions without heat or solvent through co-cryomilling is promising as a manufacturing method. Use of heat or solvents can lead to instability in the dispersions and degrade certain drugs. Following this work, amorphous solid dispersions formed via cocryomilling with a high drug loading can be considered for future development for the formulation of fast release dosage form and for drugs liable to thermal or solvent mediated degradation.

Proteins play an important role in the function of biological systems. Developing a thorough understanding of the dynamics, structure and function is a goal of many biological spectroscopists. One commonly used tool for probing different features and properties of proteins and polypeptides is infrared (IR) spectroscopy. The spectra obtained however lacks resolution due to broad, featureless peaks that are hard to interpret. Overlapping of the bands is also an issue, especially from the amide I region; an important region that is sensitive to secondary structure elements of proteins. Isotope labelling of residues of interest is a solution to disentangle the band profiles, however the technique lacks any meaningful insight regarding coupling between different local sites. For the past few decades, 2D IR (an analogue of its NMR counterpart) has been used in various experiments to improve the quality of 1D IR by spreading the signal to a second frequency domain, thus revealing coupling interactions. The technique has helped reveal different relationships between the secondary structural elements of proteins or between protein-ligand complexes. The main challenge so far has been the computational requirement needed to compute the 2D IR signals of large proteins. This is due to the nonlinear response function scaling with the fourth power of the number of residues involved in the calculations. Moreover, convolution of the bands is still an issue as the number of residues grows, albeit not so much compared with 1D IR. In this thesis, we utilize the exciton approach and molecular dynamics (MD) simulations to compute the 1D and 2D IR signals of small peptides, globular proteins and [Leu]-Enkephalin in the presence of three opioid receptors of interest. The work presented in this thesis complements previous experiments on globular proteins and the behaviour of [Leu]-enkephalin and aims to provide more insight into the behaviour of such systems under the conditions outlined.

Orientador: Aguinaldo Robinson de Souza / Banca: Nelson Henrique Morgon / Banca: Renato Carlos Tonin Ghiotto / O Programa de Pós-Graduação em Ciência e Tecnologia de Materiais, PosMat, tem caráter institucional e integra as atividades de pesquisa em materiais de diversos campi da Unesp / Resumo: Grande parte dos fenômenos químicos e físicos, em especial a química dos elementos mais pesados da tabela periódica, somente pode ser compreendida à luz da teoria quântica relativística. As propriedades catalíticas da platina, por exemplo, são em grande parte devidas aos efeitos relativísticos. Esses efeitos relativísticos, por sua vez, são mais pronunciados nos elementos de número atômico superior a 103, elementos conhecidos como transactinídeos ou super-pesados. Neste trabalho, investigamos a ligação química com carbonilas entre o elemento químico de maior número atômico (z=118) já sintetizado, o Uuo. Nossos resultados em relação a este novo elemento, que supostamente está localizado na família dos gases "nobres" (grupo 18), sugerem que a química do Uuo deve ser distinta da química dos demais elementos do grupo, indicando novas propriedades para este grupo. / Abstract: Great part of chemical and physical phenomena can only be understood under the relativistic quantum mechanics framework, mainly the chemistry of the heavier elements. For example, the catalytic propertiers of platinum are in the most part due to relativistic effects. These relativistic effects are more intense in elements beyond atomic number 103, elements known as super heavy elements or transactinides. In this work, we investigated the chemical bound between the chemical element of highest atomic number that has been sintetized, the Uuo with z=118, and carbonyls. Our results, despite the fact that the new element Uuo is located at noble gas family, suggest that its chemical properties are probably different from the other elements of the same group and a possible break of periodic properties. / Mestre

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第14639号 / 工博第3107号 / 新制||工||1462(附属図書館) / 26991 / UT51-2009-D351 / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 榊 茂好, 教授 田中 庸裕, 教授 村上 正浩 / 学位規則第4条第1項該当

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第15396号 / 工博第3275号 / 新制||工||1493(附属図書館) / 27874 / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 榊 茂好, 教授 白川 昌宏, 教授 北川 進 / 学位規則第4条第1項該当

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第17525号 / 工博第3684号 / 新制||工||1560(附属図書館) / 30291 / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 佐藤 啓文, 教授 今堀 博, 教授 山本 量一 / 学位規則第4条第1項該当

In the first chapter of this thesis the aluminium promoted zinc Schlenk equilibrium of FG-ArZnX/AlMe3 is shown to provide good access for the synthesis of chiral secondary alcohols. This practical asymmetric 1,2-addition to aliphatic and aromatic aldehydes uses only commercially available reagents and ligands. Enantioselectivity is provided by the use of (1R,2S)-dibutylnorephedrine (1,2-amino alcohol ligand) giving selectivity, in most cases, between 80-96% ee. Yields are moderate to good, typically alcohols are prepared in 50-97% yield. Uniquely the FG-ArZnBr species can be prepared in situ directly from Ar-Br or Ar-I, via the cobalt catalysed zinc insertion. Optimisation of the zinc insertion allowed for rate acceleration and a subsequent slight reduction in enantiocontrol. Furthermore, enantioselectivity of the reaction can be enhanced via the simple addition of LiBr to the FG-ArZnBr species. A LiBr promoter can dramatically enhance the enantioselectivity of such ‘home made’ reagents (from 30 to ca. 90% ee in one case), however studies to explain this effect have not been investigated. Further investigation into zinc source optimisation via electron microscopy and energy dispersive X-ray (EDX) spectroscopy, has highlighted the necessity to use small particulate zinc in the range of 2-10 muM and having little surface oxide. Stereo correlations of the secondary alcohol products highlight a reverse in stereochemistry compared to the ‘classic Noyori’ transition state for the addition of ZnEt2 to PhCHO using chiral 1,2-aminoalcohol ligands. Analysis and investigation of our system showed there was no non-linear effect associated with the process, suggesting the catalyst to be monomeric in solution. A second thesis chapter describes facile DABAL-Me3 mediated preparation of aromatic and aliphatic amides. This procedure allows the coupling of a wide range of functionalised primary and secondary amines and esters, secondary amines and allows formation of versatile Weinreb amides. Microwave irradiation provides an improved rate of reaction allowing excellent yields (51-99%) in short reaction times (8-16 min). Wide applicability is shown in the variation and tolerance of a wide range of functional groups in both coupling partners. Functional groups tolerated include: acetal, alcohol, alkene, alkyne, Ar-X, cyano and ethers. Furthermore the stereochemical integrity of the coupling partners is retained in two representative examples with an epimerisable carbon centre. This procedure enables the coupling of less nucleophillic amines such as anilines. However, the reaction yields are diminished when highly electron poor anilines are used, or when highly sterically hindered esters or amines are used.