GLUT1-mediated, facilitated sugar transport is proposed to be an example of transport by a carrier that alternately presents exofacial (e2) and endofacial (e1) substrate binding sites, commonly referred to as the alternating access carrier model. This hypothesis is incompatible with observations of co-existent exo- and endofacial ligand binding sites, transport allostery, and e1 ligand (e.g. cytochalasin B) induced GLUT1 sugar occlusion. The fixed-site carrier model proposes co-existent, interacting e2 and e1 ligand binding sites but involves sugar translocation by geminate exchange through internal cavities. Demonstrations of membrane-resident dimeric and tetrameric GLUT1 and of e2, e1 and occluded GLUT conformations in GLUT crystals of monodisperse, detergent-solubilized proteins suggest a third model. Here, GLUT1 is an alternating access carrier but the transporter complex is a dimer of GLUT1 dimers, in which subunit interactions produce two e2 and two e1 conformers at any instant. The crystallographic structures in different conformations can be utilized to further understand the transport cycle, ligand binding behavior and complex kinetics observed in GLUT1. Specifically, the GLUT1 crystal structure and homology models based upon related major facilitator superfamily proteins were used in this study, to understand inhibitor binding, ligand binding induced GLUT1 transport allostery and the existence of helix packing/oligomerization motifs and glycine induced flexibility. These studies suggest that GLUT1 functions as an oligomeric allosteric carrier where cis-allostery is an intramolecular behavior and trans-allostery is an intermolecular behavior. Additionally, mutations of a dynamic glycine affect the turnover of the transporter while mutations to helix packing motifs affect affinity.

Benzothiazole dibenzoic acid derivative (BTDB) is well-known organic linkers utilized for the syntheses of various metal organic frameworks, and demonstrates interesting photophysical properties upon concentration variations in solution. The presence of two carboxylic acid functional groups at each side of the rod-like molecule, facilitates dimerization and oligomerization equilibria. Interestingly, dimers and oligomers have completely different emission behaviors from the monomer of the same species. At a low range of concentration, 0.1 – 64 μM, dimerization process is dominant, and that the equilibrium constant of dimer formation found to be 18,000 M-1. On the other hand, in the 64 – 1000 μM concentration range, oligomerization takes over, and that it results in the formation of a small linear chain of 8 molecules, or 4 dimers, with a high equilibrium constant of 1.2 × 1013 M-3. Various experimental measurements and theoretical calculations have suggested hydrogen-bond formation is the main driving force for the dimerization and oligomerization in the nano- and micro- molar regime, and that structure rigidity of a species is a key factor in controlling its photophysical properties, such as emission quantum yield and excited state lifetime.

Several bacterial pathogens including Shigella (shigellosis), Escherichia coli (urinary tract infections), Pseudomonas (lung infections), Salmonella (food poisoning), and Yersinia (plague) critically rely on a complex type three secretion system (T3SS) for infection. With the rise in multi-antibiotic resistant strains of several of these pathogens, we turn to the T3SS as a promising target for the development of novel therapeutics. The Dickenson lab at Utah State University has been the first to identify and characterize the ATPase Spa47, the energy source of the Shigella infection system. We show that Spa47 is necessary for proper T3SS formation and function, being ultimately responsible for overall Shigella virulence. We find that proper ATPase function and in turn T3SS apparatus formation can be affected by something as simple as a single mutation to the removal of a non-catalytic domain. The insights gained from this work expands our understanding of the powerhouse that fuels these infection systems and brings us a step closer to developing novel therapeutics to combat infection.

付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム / 京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21790号 / 工博第4607号 / 新制||工||1718(附属図書館) / 京都大学大学院工学研究科分子工学専攻 / (主査)教授 白川 昌宏, 教授 梶 弘典, 教授 森 泰生 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

There is an increasing trend towards advancing the understanding and development of ethylene oligomerization catalysts, both in academia and industry. The metal of choice in this chemistry is invariably chromium, which has shown great versatility in selective trimerization/tetramerization, non-selective oligomerization and polymerization of ethylene. While much success has been achieved in ethylene trimerization, the same con not be said about tetramerization catalysis. Aminophosphine based ligands have demonstrated their ability towards selective 1-octene production, however, the popular PNP catalyst is able to achieve only 70% selectivity. In order to explore the possibility of developing and enhancing the selectivity of chromium based ethylene tetramerization catalyst, this thesis work was undertaken. The ligand systems we chose for our work were bidentate aminophosphine based (PN(CH2)nNP), which has yielded interesting selective oligomerization. Subtle modifications were found to result in drastic changes in selectivity, from tetramerization (PN(CH2)3NP) to trimerization (PN(CH2)2NP). We managed to successfully develop the first truly selective (over 90%) 1-octene catalyst with polymer-free behavior. Further modifications on the ligand framework, where one atom of Si was used to link the two NP units, resulted in non-selective oligomerization, in which case we determined that the oxidation-state of chromium is a key player. We explored other modifications on our selective ligands in which one of the arms on the bidentate ligand was replaced with a base-donor amine, phosphine or pyridine, and resulted in interesting selectivity changes. The final modification that we tested was a novel N(CH2)2P ligand and found it to be a highly active, non-selective oligomerization catalyst.

There is an increasing trend towards advancing the understanding and development of ethylene oligomerization catalysts, both in academia and industry. The metal of choice in this chemistry is invariably chromium, which has shown great versatility in selective trimerization/tetramerization, non-selective oligomerization and polymerization of ethylene. While much success has been achieved in ethylene trimerization, the same con not be said about tetramerization catalysis. Aminophosphine based ligands have demonstrated their ability towards selective 1-octene production, however, the popular PNP catalyst is able to achieve only 70% selectivity. In order to explore the possibility of developing and enhancing the selectivity of chromium based ethylene tetramerization catalyst, this thesis work was undertaken. The ligand systems we chose for our work were bidentate aminophosphine based (PN(CH2)nNP), which has yielded interesting selective oligomerization. Subtle modifications were found to result in drastic changes in selectivity, from tetramerization (PN(CH2)3NP) to trimerization (PN(CH2)2NP). We managed to successfully develop the first truly selective (over 90%) 1-octene catalyst with polymer-free behavior. Further modifications on the ligand framework, where one atom of Si was used to link the two NP units, resulted in non-selective oligomerization, in which case we determined that the oxidation-state of chromium is a key player. We explored other modifications on our selective ligands in which one of the arms on the bidentate ligand was replaced with a base-donor amine, phosphine or pyridine, and resulted in interesting selectivity changes. The final modification that we tested was a novel N(CH2)2P ligand and found it to be a highly active, non-selective oligomerization catalyst.

There is an increasing trend towards advancing the understanding and development of ethylene oligomerization catalysts, both in academia and industry. The metal of choice in this chemistry is invariably chromium, which has shown great versatility in selective trimerization/tetramerization, non-selective oligomerization and polymerization of ethylene. While much success has been achieved in ethylene trimerization, the same con not be said about tetramerization catalysis. Aminophosphine based ligands have demonstrated their ability towards selective 1-octene production, however, the popular PNP catalyst is able to achieve only 70% selectivity. In order to explore the possibility of developing and enhancing the selectivity of chromium based ethylene tetramerization catalyst, this thesis work was undertaken. The ligand systems we chose for our work were bidentate aminophosphine based (PN(CH2)nNP), which has yielded interesting selective oligomerization. Subtle modifications were found to result in drastic changes in selectivity, from tetramerization (PN(CH2)3NP) to trimerization (PN(CH2)2NP). We managed to successfully develop the first truly selective (over 90%) 1-octene catalyst with polymer-free behavior. Further modifications on the ligand framework, where one atom of Si was used to link the two NP units, resulted in non-selective oligomerization, in which case we determined that the oxidation-state of chromium is a key player. We explored other modifications on our selective ligands in which one of the arms on the bidentate ligand was replaced with a base-donor amine, phosphine or pyridine, and resulted in interesting selectivity changes. The final modification that we tested was a novel N(CH2)2P ligand and found it to be a highly active, non-selective oligomerization catalyst.

Thesis (PhD)--Stellenbosch University, 2012. / ENGLISH ABSTRACT: The possibility of utilizing the chromium/bis(diphenylphosphino)amine (PNP) type of catalysts in ethylene polymerization processes was investigated. These processes include the production of linear low density polyethylene (LLDPE), the production of polyethylene waxes and the synthesis of special comonomers for ethylene copolymerization. The chromium/Ph2PN{CH(CH3)2}PPh2 tetramerization system was used in combination with a polymerization catalyst to yield ethylene copolymers with controlled branching. Copolymers with bimodal chemical composition distributions were obtained in these tandem reactions. This chromium/PNP-type tetramerization catalyst and metallocene polymerization catalysts are not completely compatible in tandem catalytic systems due to different optimum temperatures for their effective functioning. The oligomerization to polymerization catalyst ratios, the catalyst to cocatalyst ratios and the temperature profile are all factors influencing the amount of -olefins formed and therefore the type of copolymer produced. The activity of the polymerization catalyst decreases in the presence of the oligomerization catalyst, indicating that the two catalysts interfere chemically. The main difference between copolymers produced in conventional or tandem fashion is the presence of a small amount of low molecular weight material produced by the oligomerization catalyst and also the presence of a highly crystalline component. The latter component results from the initial low concentration of a-olefins in the first conversion, but such a component is also independently produced by the oligomerization catalyst. LLDPE with butyl branches is obtained when a selective trimerization catalyst is used in combination with a polymerization catalyst. The chromium/(o-OMeC6H4)2 PN(CH3)P(o-OMeC6H4)2 trimerization system is more suitable than the chromium/Ph2PN{CH(CH3)2}PPh2 tetramerization system for use in tandem reactions with a metallocene catalyst due to its high activity and selectivity at higher temperatures. The chemical composition distribution varies with an increase in reaction time due to the increasing amount of 1-hexene produced. Comparison of CRYSTAF traces of tandem copolymers with conventional copolymers show that the tandem copolymers have a broader chemical composition distribution. Addition of 1- hexene during the course of a conventional copolymerization reaction produces copolymers with similar chemical composition distributions to that of the tandem copolymers. Later addition of the polymerization catalyst to the oligomerization reaction mixture results in copolymers with higher comonomer content, similar to conventional copolymers. Chromium/(o-EtC6H4)2PN(CH3)P(o-EtC6H4)2 is not suitable for LLDPE production in tandem reactions, since it is selective to higher oligomers or polyethylene waxes at higher temperatures. Variation of the MAO cocatalyst and hydrogen concentrations significantly influences the yield, viscosity and crystallization behaviour of the waxlike products. Low MAO concentrations resulted in multiple melting peaks, while higher concentrations display single melting peaks and lower viscosity values. Ethylene co-oligomerization reactions with styrene or p-methylstyrene using the chromium/PNP-type oligomerization technology produce various phenyl-hexene and phenyl-octene isomers either through cotrimerization or cotetramerization. The known ethylene trimerization catalysts show cotrimerization behaviour, while the catalysts with known selectivity for ethylene tetramerization also yield cotetramerization products. Chromium complexes that contain the more bulky ligands display lower selectivity towards co-oligomerization and greater preference for ethylene homotrimerization. These co-oligomerization products can be incorporated into a polyethylene chain by copolymerization in a simultaneous or sequential tandem reaction. The combined co-oligomerization-polymerization reactions yield copolymers with lower crystallinity than obtained from the conventional ethylene-styrene copolymerization reaction due to higher comonomer incorporation. The polymer yields are higher in the cooligomerization- copolymerization reactions. The ability of the different cooligomerization products to incorporate into the polyethylene chain was established: unreacted styrene and the more bulky isomers, 3-phenyl-1-hexene and 3-phenyl-1- octene, are not incorporated readily, while branches resulting from 4-phenyl-1- hexene, 4-phenyl-1-octene, 5-phenyl-1-octene and 6-phenyl-1-octene are detected in the NMR spectrum. / AFRIKAANSE OPSOMMING: Die moontlikheid om die chroom/bis-(difenielfosfino)amien (PNP) tipe katalisatore in etileen-polimerisasie reaksies te gebruik is ondersoek. Hierdie prosesse sluit die produksie van lineêre lae digtheid poliëtileen (LLDPE), die produksie van poliëtileenwasse en die sintese van spesiale komonomere vir etileenkopolimerisasie in. Die chroom/Ph2PN{CH(CH3)2}PPh2 tetramerisasie-sisteem is gebruik in kombinasie met ¢n polimerisasiekatalisator om etileenkopolimere met gekontroleerde vertakkings te vorm. Kopolimere met ‘n bimodale chemiese samestellingsverspreiding word verkry in hierdie tandemreaksies. Hierdie chroom/PNP-tipe tetramerisasiekatalisator en die metalloseenkatalisators is nie heeltemal verenigbaar in die tandemsisteem nie weens verskille in hul optimum reaksietemperature vir effektiewe funksionering. Die oligomerisasie tot polimerisasiekatalisatorverhouding, die katalisator tot kokatalisatorverhouding en die temperatuurprofiel is almal faktore wat die gevormde hoeveelheid -olefiene beinvloed, en dus die tipe kopolimeer wat gevorm word. Die aktiwiteid van die polimerisasiekatalisator verminder in die teenwoordigheid van die oligomerisasiekatalisator, wat aandui dat die twee katalisatore chemies met mekaar inmeng. Die duidelikste verskil tussen die kopolimere wat geproduseer word op die konvensionele of die tandem manier is die teenwoordigheid van ‘n klein hoeveelheid lae molekulere massa materiaal wat gevorm word deur die oligomerisasiekatalisator, asook ‘n komponent met baie hoë kristalliniteit. Die laasgenoemde komponent ontstaan weens die aanvanklike lae konsentrasie van die a-olefiene in die eerste omsetting, maar so ‘n komponent word ook onafhanklik gevorm deur die oligomerisasiekatalisator. LLDPE met butiel-vertakkings word verkry wanneer ‘n selektiewe trimerisasiekatalisator in kombinasie met ‘n polimerisasiekatalisator gebruik word. Die chroom/(o-OMeC6H4)2PN(CH3)P(o-OMeC6H4)2 trimerisasiesisteem is meer geskik as die chroom/Ph2PN{CH(CH3)2}PPh2 tetramerisasiesisteem vir gebruik in tandem met ‘n metalloseenkatalisator weens die katalisator se hoë aktiwiteit en selektiwiteid vir 1-hekseen by hoër reaksietemperature. Die chemiese samestellingsverspreiding verander soos die reaksietyd toeneem weens die toenemende hoeveelheid 1-hekseen wat gevorm word. Vergelyking van die CRYSTAF-diagram van die tandemkopolimere met konvensionele kopolimere toon dat die tandemkopolimere ‘n wyer chemiese samestellingsverspreiding het. Geleidelike byvoeging van 1-hekseen gedurende die loop van ‘n konvensionele reaksie, vorm kopolimere met ‘n soortgelyke chemiese samestelingsverspreiding as die tandemkopolimere. Latere byvoeging van die polimerisasiekatalisator lei tot die vorming van kopolimere met ‘n hoër komonomeerinhoud, soortgelyk aan die konvensionele kopolimere. Chroom/(o-EtPC6H4)2PN(CH3)P(o-EtC6H4)2 is nie geskik om LLDPE in tandemreaksies te vorm nie, aangesien dit selektief is vir hoër oligomere of poliëtileenwasse by hoër reaksietemperature. Variasie van die MAO-kokatalisator en die waterstofkonsentrasies beinvloed die hoeveelheid produk wat gevorm word, asook die viskositeit en kristallisasiegedrag daarvan. Lae MAO konsentrasies lei tot meer as een smeltpiek, terwyl hoër konsentraises ‘n enkelpiek vertoon. Die viskositeit van die produkmengsel is ook laer. Die gebruik van die chroom/PNP-tipe oligomerisasietegnologie in etileenkooligomerisasiereaksies met stireen, lei tot die vorming van verskeie feniel-hekseenen fieniel-okteenisomere deur of kotrimeriasie, of kotetramerisasie. Katilisatore met bekende etileentrimerisasieligande vertoon kotrimerisasiegedrag terwyl die ligande wat bekend is vir selektiwiteit in etileentetramerisasie, kotetramerisasieprodukte vorm. Die chroomkomplekse met die meer bonkige ligande het laer selektiwiteit vir ko-oligomerisasie en vertoon ‘n groter voorkeur vir etileenhomo-trimerisasie. Die ko-oligomerisasieprodukte kan in ‘n poliëtileenketting ingebou word deur kopolimerisasie in ‘n gelyktydige of opeenvolgende tandemreaksie. Die gekombineerde ko-oligomerisasie-polimerisasiereaksie vorm kopolimere van ‘n laer kristalliniteit as wat gevind word met die konvensionele etileen-stireen kopolimerisasie reaksie weens hoer komonomeerinkorporasie. Meer polimeer word gevorm in die ko-oligomerisasie-kopolimerisasie reaksie. Die vermoë van die verskillende ko-oligomerisasieprodukte om in die poliëtileenketting ingesluit te word is bepaal. Ongereageerde stireen en die meer bonkige isomere, 3-feniel-1-hekseen en 3-feniel-1-okteen, word nie maklik ingevoeg nie. Vertakkings as gevolg van die inkorporasie van 4-feniel-1-hekseen, 4-feniel-1-okteen, 5-feniel-1-okteen and 6- feniel-1-okteen kan waargeneem word in die KMR spektrum.

Thesis (PhD)--University of Stellenbosch, 2011. / In this thesis we describe the application of novel salicylaldimine and iminopyridyl nickel metallodendrimer complexes as catalysts in the transformation of á-olefins as well as in the polymerization of norbornene. New cyclic dendrimers based on cyclam as a core (L1-L8) were synthesized and characterized via FTIR and NMR spectroscopy, mass spectrometry and microanalysis. Subsequently the generation 1 cyclam-based dendrimers as well as the commercial generation 1 to generation 3 DAB-PPI dendrimers were functionalized with salicylaldimine and iminopyridyl moieties on the periphery to produce new ligands, DL1-DL10. These modified dendritic ligands were subsequently complexed to Ni salts to obtain the metallodendrimer complexes, C1-C8. The metallodendrimers were characterized by FTIR spectroscopy, mass spectrometry, microanalysis, magnetic susceptibility measurements, UV-Vis spectroscopy and thermal gravimetrical analysis (TGA). The DAB G1-G3 salicylaldimine ligands (DL1-DL3) were subjected to computational studies and the optimized structures were obtained by density functional theory (DFT) calculations. The effect of the increase in dendrimer generation on the structural arrangement of the dendrimer was also investigated. The following aspects were probed using molecular modeling: a) the possible coordination site for the Ni to the first generation dendrimer ligand, DL1, and b) the optimized structure of the first generation salicylaldimine nickel complex, C1. We subsequently evaluated catalysts, C1-C7, in the vinyl polymerization of norbornene, using methylaluminoxane (MAO) as a co-catalyst. All the catalysts were found to be active for norbornene polymerization with the weight of the polymers obtained ranging from 5.12 x 105 - 11.17 x 106 g/mol. The DAB-based iminopyridyl catalysts (C4-C6) exhibited higher activities than its analogous salicylaldimine catalysts (C1-C3) under the same reaction conditions. Also, the cyclam-based salicylaldimine nickel catalyst (C7) exhibited higher activities than the DAB-based salicylaldimine nickel catalyst, C1. A negative dendritic effect was observed for the G1-G3 DAB salicylaldimine catalysts since the optimum activity for the G3 catalyst, C3, was lower than that for the G2 catalyst, C2. These nickel complexes were also evaluated as ethylene oligomerization catalysts and were found to produce a range of ethylene oligomers (C4-C18) as well as some longer chained oligomers, when employing EtAlCl2 as a co-catalyst. We observed however that the free EtAlCl2 mediates the Friedel-Crafts alkylation of the solvent, toluene, in the presence of the obtained ethylene oligomers to give uneven carbon number products, which are mixtures of alkylated benzenes. Our metallodendrimer catalysts also isomerized and in some cases dimerized 1-pentene. In both ethylene oligomerization and 1-pentene isomerization processes, the salicylaldimine catalysts exhibited higher activity towards olefin transformation than the iminopyridyl catalysts. The cyclam-cored dendrimer catalyst again showed the highest activity. From the results obtained thus far it can be concluded that these nickel metallodendrimers exhibit great potential as catalysts in the transformation of unsaturated hydrocarbons.

Catalytic ethylene oligomerization is a well understood industrially viable process. The large majority of scientific literature and patents concerning this process has been developed with the use of chromium catalysts. Commercial systems producing selective tri/tetramerization, non-selective oligomerization and polymerization are all based on this metal with the exception of a few systems based on other transition metals (Zr, Ti, Ni etc.). This versatility raises interesting questions about chromium’s unique behaviour. Essentially, selective or non-selective oligomerization and polymerization processes could be regarded as belonging to the same category of C-C bond forming reactions, though different mechanisms are involved. The first part of this thesis explores a variety of chromium complexes for ethylene oligomerization purposes. In order to gather further information about the unique behaviour of chromium, we have explored a variety of nitrogen and phosphorus containing ligands. We started with a simple bi-dentate anionic amidophosphine (NP) ligand and assessed the role of the ligand’s negative charge and number of donor atoms in determining the type of catalytic behaviour in relation to the metal oxidation state. This ligand proved capable of generating a series of chromium dimeric, tetrameric or polymeric and even heterobimetallic chromium-aluminate complexes in different valence states. This allowed us to isolate a “single component” self activating Cr(II) complex as well as a rare example of mixed valence Cr(I)/Cr(II) species. Additionally, each of these species acted as switchable catalyst depending on the type of co-catalyst