Development of a Scalable Process for Lentiviral Vector Mass Production by Transient Transfection

Ansorge, Sven (2010) 

A COMBINED DIRECTED METALATION CROSS-COUPLING ROUTE TO A NEW SMECTIC LIQUID CRYSTAL WITH A PHENANTHRENE CORE

Authors:	GAN, WEI
Files in This Item: File Description Size Format Gan_Wei_200908_PhD.pdf 5.64 MB Adobe PDF
Keywords:	directed metalation liquid crystal
Issue Date:	2009
Series/Report no.:	Canadian theses
Abstract:	A series of phenanthrene and oxidized phenanthrene derivatives with typical substitution patterns, 1.31, 1.32, 2.30a-f, 3.1a,b and (-)-4.1 have been synthesized as liquid crystal cores by a combined Directed ortho Metalation (DoM), cross coupling and Directed Remote Metalation (DreM) strategy. The synthetic methodology employed allowed variation of the tail and core structures, for the preparation of a new smectic liquid crystal compound (1.32), a homologous series of 9,10-dihydrophenanthrene-9,10-diones (2.30a-f), a diastereomeric trans-9,10-dihydrophenanthrene-9,10-diol (1.31), two enantiomeric 9,10-dihydrophenanthrene-9,10-diones (R)-3.1a-b) and an enantiomeric 9,10-dihydro-9,10-dimethylphenanthrene-9,10-diol ((-)-4.1). Polarized microscopic and differential scanning calorimetric measurements suggest that 1.31 forms a large range of SmC phase, ca. 100 ºC, followed by a small range of nematic phase, ca. 10 ºC; the 2.30a-f series show similar mesogenic properties, but with the extension of the length of a side chain from six carbons to eleven carbons, the nematic phase has disappeared (in the cases of 2.30a-c). Although (R)-3.1a-b and (-)-4.1 are not liquid crystals, they show ferroelectric induction by doping, in the amount of ca. 5 mol%, into unchiral liquid crystal hosts PhB, DFT, PhP1, NCB76 and 2.30f. However, due to the detection limit of the instrument, i.e., ca. 0.5 nC/cm2, the spontaneous polarizations (Ps) induced could not be measured.

Metal ion promoted hydrolysis of the organophosphorus pesticide diazinon

Authors:	Wyer, Martin
Files in This Item: File Description Size Format wyer_martin_J_finalsubmission200801_degree.pdf 12.19 MB Adobe PDF
Keywords:	Organophosphorus pesticide Metal ion Hydrolysis Diazinon
Issue Date:	2008
Series/Report no.:	Canadian theses
Abstract:	The chemical fate of organophosphorus pesticides is influenced by several factors, one being the chemistry of their aquatic environment. Dissolved metal ions have been shown in several instances to promote the hydrolysis of organophosphorus pesticides, with various reasons forwarded as to the intimate mechanism of metal ion promoted hydrolysis. Several postulates have suggested metal ion co-ordination of Lewis sites to be an important factor in promoting the reaction. In view of this, the study herein reports on the promoted hydrolysis of diazinon at various pH’s in the presence of several metal ions including Hg2+, Cu2+, Cd2+ and Ag+. The observed 1H and 31P NMR data indicated complexation of Cu2+ and Ag+ with diazinon through the formation of a six-membered ring (chelate), via co-ordination at both nitrogen and sulfur Lewis base sites. In contrast, NMR results with Hg2+ indicated Hg2+ ion promoted hydrolysis of diazinon through co-ordination at sulfur alone, possibly through stronger binding to the altered transition state than the reactant state. Another possibility would entail lowering of the pKa of H2O on metal complexation, thus facilitating nucleophilic attack. Electrospray ionization mass spectrometry (ESI-MS) substantiated the proposed metal ion complexation. In the case of Cu2+ and Ag+, complexation between diazinon and metal ions was observed at given m/z ratios, while subsequent MS/MS analysis of the complexed ions revealed co-ordination at both S and N sites by Cu2+ and Ag+. No complexation between diazinon and Hg2+ was observed in ESI-MS; however Hg2+ was shown to complex the hydrolytic product O,O diethyl phosphorothioic acid, presumably through sulfur. Hydrolysis of diazinon was studied at several pH’s at 22oC in the presence of Hg2+, Cu2+, Cd2+ and Ag+, by following spectrophotometrically the appearance of 2-isopropyl-6-methylpyrimidin-4-ol. Kinetic data showed Hg2+, Cu2+ and Ag+ to be extremely effective in neutral-to-mildly acidic conditions, with a reduced effect in the presence of Cd2+. Smaller rate enhancements were also observed at slightly lower pH of 4.0. Possible factors include; 1) Competing acid hydrolysis involving protonation at one heterocyclic N of diazinon (N-3). 2) The dominant nature of the HgCl2 species at pH 4.0. 3) Metal speciation.

Directed ortho metalation-boronation Suzuki-Miyaura cross coupling leading to synthesis of azafluorenol core liquid crystals

Authors:	Lai, Ping-Shan
Files in This Item: File Description Size Format Lai_Ping-Shan_200708_MSc.pdf 3.22 MB Adobe PDF
Keywords:	Azafluorenol synthesis Chemistry
Issue Date:	2007
Series/Report no.:	Canadian theses
Abstract:	The synthesis of chiral fluorenol crystal materials employing directed ortho metalation (DoM) combined with directed remote metalation (DreM) and Suzuki-Miyauara Coupling was previously reported by McCubbin, Snieckus and Lemieux.ref? This study reported that certain fluorenol derivatives form a chiral smectic C phase (SmC*) with a spontaneous polarization (Ps) that is amplified by intermolecular hydrogen bonding. Dilution and deuterium exchange experiments suggest that antiparallel hydrogen bonded dimer formation increases the rotational bias about the director that is thought to induce the Ps.needs definition The research reported in this thesis is concernded with an investigation on the effects of hydrogen bonds on the Ps of the liquid crystal by the variation of core structure, particularly the substitution of one aryl ring to pyridinyl ring. An efficient synthesis of liquid crystals (LC) 1.14 and 2.22 by Directed ortho Metalation-boronation, Suzuki-Miyaura Cross Coupling reaction accompanied with Directed remote metalation was achieved. Compound 1.14 was found to be not useful as a LC material because it was unstable in the air and underwent rapid oxidation to give 2.22 upon heating. Thus, this project was focused on the preliminary study on mesophase characterization of 1.14 and 2.22. The results (Table 2.3) show both 1.14 and 2.22 formed SmC phases, but only 1.14 showed smectic A (SmA) mesophase and only 2.22 showed nematic (N) mesophase cooling from isotropic liquid phase. The increase in temperature range of smectic phases for the azafluorenol 1.14 is expected because intermolecular hydrogen bonding between the hydroxyl group and aza group as shown by Figure 1.21 may play a role to stabilize the formation of smectic (Sm) phase.

Investigating the chirality transfer feedback model in ferroelectric liquid crystals using deuterium NMR spectroscopy

Authors:	Huntley, Christa Margaret
Files in This Item: File Description Size Format Huntley_Christa_M_200807_MSc.pdf 4.83 MB Adobe PDF
Keywords:	Liquid crystals Materials chemistry
Issue Date:	2008
Series/Report no.:	Canadian theses
Abstract:	Ferroelectric liquid crystals (FLCs) are being investigated as alternatives to nematic liquid crystals in display applications due to their low power requirements and fast switching times. Commercial FLCs consist of a chiral dopant in an achiral smectic C (SmC) liquid crystal host. A bulk property that arises from the chiral nature of this mixture is a spontaneous polarization (PS), which depends on the polarization power of the chiral dopant (δp). The magnitude of δp reflects the ability of a dopant to induce a polarization in an achiral host. It has been proposed that the magnitude of δp can be enhanced by matching dopant and host structures, which may enhance the propagation of chiral perturbations from the dopant to the host. This is known as the chirality transfer feedback (CTF) model. Previous studies in the Lemieux lab featured 2H NMR to detect chiral perturbations exerted by a dopant on the liquid crystal host based on the observation of pairs of quadrupolar doublets in the 2H NMR spectra. In the work described herein, the contribution of chirality transfer feedback to the difference in quadrupolar splitting between pairs of quadrupolar doublets (ΔΔνQ) was assessed by 2H NMR spectroscopy. These experiments confirmed the results reported by Finden and Yuh by demonstrating the presence of chiral perturbations exerted by a diester substituted 6,6’-spirobiindandione dopant ((RS)-2.6-d4) on the achiral SmC host NCB76, and the absence of those perturbations using the diester substituted 5,5’-spirobiindandione analogue ((RS)-2.3-d4). Subsequent studies explored the effect of modifying the chiral topography of the 2,2’-spirobiindan-1,1’-dione core on the magnitude of δp. Both the 5,5’- and 6,6’-disubstituted cores were reduced to give the corresponding mono-carbonyl derivatives ((R)-3.4-d4 and (R)-3.8-d4), substituted with ether side-chains. Finally, ester side-chains were added to the 6,6’- mono-carbonyl derivative ((R)-3.9-d4) for comparison with previous experiments. The ferroelectric induction properties of these dopants were investigated in NCB76 at mole fractions ranging from xd = 0.03 – 0.10. The mono-carbonyl 5,5’- and 6,6’-diether dopants gave absolute polarization powers of 120 nC/cm2 and 123 nC/cm2 respectively, which are not significantly different. This suggests that a reduction in the chiral topography of the spirobiindandione core greatly affects the polarization power of the dopant and may reduce the contribution from chirality transfer to δp. This was confirmed by a measurement of the polarization power of the 6,6’-diester mono-carbonyl dopant (R)-3.9-d4 in NCB76, which gave a δp value of 117 nC/cm2.

REACTIVITY AND LUMINESCENCE STUDY OF PLATINUM AND COPPER COMPLEXES OF 7-AZAINDOLE DERIVATIVES

Authors:	Zhao, Shu-Bin
Files in This Item: File Description Size Format ZHAO_SHUBIN_200805_PhD.pdf 8.54 MB Adobe PDF
Keywords:	C-H ACTIVATION LUMINESCENCE 7-AZAINDOLE Pt(II) COMPLEX Cu(I) COMPLEX PHOSPHORSCENCE
Issue Date:	2008
Series/Report no.:	Canadian theses
Abstract:	The objective of this thesis is to explore new reactivities and to improve luminescent properties of 7-azaindole-containing metal complexes. Selectivity for the activation of toluene and ethyl benzene has been investigated with two cationic Pt(II)(N,N-L) complexes, where N,N-L = 1,2-bis(1-N-7-azaindolyl)benzene (BAB) or bis(1-N-7-azaindolyl)methane (BAM). A high regioselectivity toward toluene and ethyl benzene benzylic C-H activation and a distinct diastereoselectivity for ethyl benzene benzylic C-H activation are demonstrated. Detailed mechanistic studies have been performed, leading to the establishment of both the intermediacy of the η3-benzylic Pt(II) complexes in the reactions and the ligand steric impacts as origins for the distinct diastereoselectivity. A PtMe2 complex of 1-N-(pyridin-2-yl)-7-azaindole (NPA) has been synthesized and found to undergo facile transformation at ambient temperature, resulting in the quantitive formation of a neutral Pt4 molecular square. The mechanism of the transformation process has been examined, establishing a distinct intramolecular C-H driven self-assembly process. The geometrical impacts of the BAB and BAM ligands on the structure and stability of their fac-Pt(IV)Me3 complexes has been investigated. The BAB ligand is more effective than the BAM ligand in stabilizing the five-coordinate Pt(IV)Me3 complexes. With the BAB ligand, a five-coordinate fac-Pt(IV)Me3 complex is obtained; with the BAM ligand, two six-coordinate fac-Pt(IV)Me3 complexes are obtained. In solution, the methyl groups in the BAB complex exchange slowly, but those in the BAM complexes exchange rapidly. Several new 7-azaindolyl derivative ligands via either modifying or altering the BAM and BAB bridging groups have been developed. The syntheses, structures and reactivities of their Pt(II) complexes have been examined, leading to the finding of an unconventional C-Sn oxidative addition reaction. The modification of the NPA ligand via the incorporation of a triarylboron group has been carried out. Several novel Pt(II) and Cu(I) complexes have been synthesized and studied. A Cu(I) complex is found to display exceptionally bright ambient temperature phosphorescence. A series of dinuclear Cu(I) compounds of the 1,2,3,4-tetra(1-N-7-azaindolyl)benzene (TTAB) ligand have been synthesized and examined. The close contacts between the TTAB bridging phenyl ring and the Cu(I) centers are present in the complexes.

A new, improved precatalyst for Suzuki-Miyaura cross-coupling reactions

Authors:	NORTON, DANIELLE
Files in This Item: File Description Size Format Norton_Danielle_M_200907_MSc.pdf 2.42 MB Adobe PDF
Keywords:	palladium precatalysts cross-coupling
Issue Date:	2009
Series/Report no.:	Canadian theses
Abstract:	Carbon-carbon bond formation is one of the most important reactions in organic chemistry, and the Suzuki-Miyaura cross-coupling reaction has become a forerunner in this area. Considerable research has been directed at the mechanistic aspects and synthetic utility of the reaction; however, little attention has been given to the formation of the putative PdL2 catalysts. Due to their high reactivities, these catalysts are typically difficult to store and therefore are often generated in situ in unknown yields and at unknown rates via any number of available palladium precursors. This thesis describes research directed towards determining the optimum conditions to quantitatively generate compounds of the type Pd(0)Ln (L = PMePh2, PPh3, PCy3, PMeBut2, PBut3, dppe, dppp, dppf) from Pd(h5-C5H5)(h3-1-Ph-C3H4). Pd(h5-C5H5)(h3-1-Ph-C3H4) has been found to be a superior precursor for synthesizing catalytically active PdL2 compounds due to its ease in handling and reactivity with tertiary phosphines. Furthermore, investigations into the role of water in the transmetallation step of the Suzuki-Miyaura reaction are presented. The research indicates that water is necessary to effect the transmetallation step when coupling [NBu4][PhBF3] with 4-bromotoluene in toluene; however, the amount of water above one equivalent has no significant effect on the rate or yield of the reaction.

Investigating the Effect of Smectic A Temperature Range Variation on De Vries Properties

Authors:	Song, Qingxiang
Files in This Item: File Description Size Format Song_Qingxiang_200911_MSc.pdf 8.02 MB Adobe PDF
Keywords:	Liquid Crystals de Vries Character
Issue Date:	2009
Series/Report no.:	Canadian theses
Abstract:	Ferroelectric liquid crystals (FLCs) have been investigated as the basis for a new type of liquid crystal display because of their fast switching times. Commercial FLC materials are mixtures consisting of a small amount of chiral dopant in an achiral liquid crystal host with an isotropic-nematic-smectic A-smectic C (INAC) phase sequence, which is required to achieve proper alignment between glass slides with rubbed polyimide alignment layers. However, the layer contraction occurring at the SmA-SmC phase transition on cooling from isotropic liquid is a severe problem that leads to a buckling of the smectic layers and results in zigzag defects that drastically degrade the optical quality of FLC films. To solve this problem, we are focusing on a new class of liquid crystal molecules with minimal or no smectic layer shrinkage at the SmA-SmC transition which is referred to as ‘de Vries-like.’ Previous work in the Lemieux group has shown that combining structural elements promoting SmA and SmC phases in a single molecule increases de Vries-like behavior. Giesselmann et. al. suggest that a correlation exists between the temperature range of the SmA phase and de Vries-like behavior. In the study described herein, two homologous series of molecules with 2-phenylpyrimidine cores with siloxane-terminated side-chain (SmC promoting element) and a chloro-terminated side-chain (SmA promoting element)are synthesized and characterized by polarized optical microscopy, differential scanning calorimetry and small-angle X-ray diffraction (SAXS). The reduction factor R for series 1.13 from 0.36 to 0.46 and for series 1.14 from 0.47 to 0.54. Results show that, although there is some correlation between % layer contraction and SmA temperature range, it can be explained primarily by differences in tilt angle θ. When θ is taken into account in the R values, there is no correlation. Another aspect of the study described herein, two siloxane-terminated 2-phenylpyrimidine chiral dopants are synthesized and characterized by polarized optical microscopy, differential scanning calorimetry and small-angle X-ray diffraction (SAXS).

The synthesis of phosphonium indenylides and an investigation of their coordination to group 4 metals

Authors:	Littlefield, Shalyn
Files in This Item: File Description Size Format Littlefield Shalyn L 201005 MSc.pdf 3.27 MB Adobe PDF
Keywords:	indenylide cyclopentadienylide
Issue Date:	2010
Series/Report no.:	Canadian theses
Abstract:	A class of phosphonium cyclopentadienylide ligands was first reported in 1956 by Ramirez and Levy, who synthesized triphenylphosphonium cyclopentadienylide. They discovered that this ylide was unusually inert, for instance being unreactive with ketones; they attributed this unusual stability to its ability to undergo charge delocalization. It was subsequently found that the ylide coordinates to metals in η5 fashion, and thus one might anticipate a rich chemistry involved with these ligands, although surprisingly little research on this fascinating ligand has been reported over the past 50 years. More recently, the coordination chemistry of its analogous compound, methyldiphenylphosphonium cyclopentadienylide, has been investigated, specifically using group six transition metals. As an extension of the latter work, we have now successfully developed a general synthetic route to similar phosphonium 1-indenylide compounds, IndPL3 (L3 = Ph3, PMePh2, PMe2Ph). The coordination of these compounds is of particular interest given that the compounds that form exhibit planar chirality and, as a result, enantioselective catalytic properties are anticipated. Furthermore, reactions involving two molar equivalents of phosphonium 1-indenylide, where two ligands coordinate, would produce diastereomers.It was our attempt to extend this work to group 4 metal halides, specifically to form coordination compounds of the type [TiCl3(IndPL3)]Cl and [TiCl2(IndPL3)2]Cl2. These compounds could be of great importance as enantioselective polymerization catalysts, or alternatively anti-cancer agents.

FOLDAMERS AND MACROCYCLES BASED ON FORMAMIDOXIME SUBUNITS

Authors:	ZHAO, WEIWEN
Files in This Item: File Description Size Format weiwen zhao-MSc Thesis-5th, August.pdf 7.8 MB Adobe PDF
Keywords:	Foldamer Formamidoxime Macrocycle
Issue Date:	10-Aug-2011
Series/Report no.:	Canadian theses
Abstract:	The objective of this thesis is the study of the control of the shape of formamidine motifs and application to folding open-ended structures and more elaborate macrocycles. The multi-step synthesis of macrocycles M1 and M2, which are analogs of 18-crown ether-6, have been successfully achieved. Macrocycles M1 and M2 have been fully characterized. The study of the crystal structures of M1 and M2 gave interesting information about their packing and molecular recognition properties. Moreover, analysis of some by-products formed in macrocyclizations gave intriguing results. The existence of a four-pyridine-unit interlocked catenane which was isolated from the synthesis of M1 has been confirmed by MS-MS. A surprisingly large 54-membered macrocycle “Maxi-M2” was isolated from the synthetic crude product of M2 and confirmed by X-ray crystallography. Driven by the desire to understand the formation of catenane and “Maxi-M2”, a systematic study of the corresponding condensation reaction was performed. The E isomers derived from N-acyl-N’-substituted formamidoximes were, for the first time, reported and isolated. The protons can facilitate E to Z isomerization. The best conditions to selectively generate either the E or Z isomers have been fully studied and applied to the synthesis. The unexpected formation of the E isomers may promote polymerization and limit the yield improvement of macrocyclization. Therefore, a new synthetic method for the target macrocycle M2 was investigated, trying to avoid the formation of E isomers and thus cyclize more efficiently.

Novel group 6 complexes of cyclopentadienylidene ylides

Authors:	Brownie, John Hugh
Files in This Item: File Description Size Format Brownie_John_H_200709_PhD.pdf 2.73 MB Adobe PDF
Keywords:	Chemistry Coordination chemistry Phosphorus ylides Group 6
Issue Date:	2007
Series/Report no.:	Canadian theses
Abstract:	Abstract Methyldiphenylphosphonium cyclopentadienylide, C5H4PMePh2 (II), has been synthesized and characterized spectroscopically and crystallographically, and has been found to exhibit properties consistent with the zwitterionic structure IIb. New group 6 complexes, (η5-C5H4PMePh2)M(CO)3, have been synthesized and fully characterized. Comparisons of ν(CO) of these complexes with those of the isoelectronic (η6-C6H6)M(CO)3 and [(η5-C5H5)M(CO)3]- suggest that the electron donating ability of the ylide is between that of the cyclopentadienyl anion (Cp-) and benzene, but closer to Cp-. The electronic structures of II and of (η5- C5H4PMePh2)Cr(CO)3 have been investigated using ab initio methodologies. Thermal and photochemical substitutions of the CO ligands of (η5-C5H4PMePh2)M(CO)3 (M = Cr, Mo) by equimolar amounts of PMe3 and PPh3 were not observed, but the ylide is displaced photochemically from (η5-C5H4PMePh2)Mo(CO)3 by excess PMe3 to form fac- Mo(CO)3(PMe3)3 while (η5-C5H4PMePh2)Mo(CO)3 reacts with I2 to form [(η5- C5H4PMePh2)Mo(CO)3I]I. One electron oxidations of (η5-C5H4PMePh2)M(CO)3 (M = Cr, Mo, W) have been performed to give the cationic radicals [(η5-C5H4PMePh2)M(CO)3]+, which undergo dimerization to give dicationic metal-metal bonded dimers ((η5-C5H4PMePh2)M(CO)3)2 2+ in the solid state. These complexes have been fully characterized spectroscopically and crystallographically. It has been determined that the chromium dimer ((η5- C5H4PMePh2)Cr(CO)3)2 2+ undergoes dissociation extensively in solution to the persistent radical cation monomer (η5-C5H4PMePh2)Cr(CO)3 +, but that the heavier metal analogues iii ((η5-C5H4PMePh2)M(CO)3)2 2+ (M = Mo, W) dissociate very little, if at all. The Cr-Cr bond distance of the chromium complex is 3.3509(7) Å, which is the longest Cr-Cr bond distance known for a compound not containing some type of ligand bridging the metalmetal bond. The hitherto unknown indenyl-derived ylide, C9H6PMePh2, has been synthesized and characterized spectroscopically and crystallographically. The chromium tricarbonyl complex of this ligand, (η5-C9H6PMePh2)Cr(CO)3, has been synthesized and characterized spectroscopically and crystallographically. This complex is a mixture of two isomers exhibiting planar chirality generated upon coordination of the ligand. This complex represents the first structurally characterized phosphorus noncyclopentadienylide coordinated in an η5 manner. The spectroscopic and crystallographic behaviour of C9H6PMePh2 demonstrates that this ylide behaves much like the related cyclopentadienylides.