Effects of large anphiphilic ligands upon the spectra and kinetics of cytochrome C oxidase

Cytoch ro me c oxidase (ferrocytochrome c : 02 oxidoreductase ; EC 1.9. 3.1) is the terminal enzyme in the mitochondrial electron transport chain, catalyzing the transfer of electrons from ferrocytochrome c to molecular oxygen. The effects of two large amphiphilic molecules - valinomycin and dibucaine upon the spectra of the isolated enzyme and upon the activity of both isolated enzyme and enzyme in membrane systems are investigated by using spectrophotometric and oxygen electrode techniques. The results show that both valinomycin and dibucaine change the Soret region of the speetrum and cause a partial inhibition in a concentration range higher than that in which they act as ionophores. It is concluded that both valinomycin and dibucaine binding induce a conformational change of the protein structure which modifies the spectrum of the a3 CUB centre and diminishes the rate of electron transfer between cytochrome a and the binuclear centre.

Asymmetric hydrogenation of alkenes with cationic iridium(I) complexes of 2-phosphino-1-aminoferrocene ligands

Iridium complexes with bidentate P,N ligands represent a class of catalysts that significantly expand the application range of asymmetric hydrogenation. New substrate classes, for which there have previously been no suitable catalysts, can now be efficiently hydrogenated in high conversion and enantioselectivity. These substrates are often of synthetic importance, thus iridium catalysis represents a significant advance in the field of asymmetric catalysis. Planar chiral ferrocenyl aminophosphine ligands in which both heteroatoms were directly bound to the cyclopentadienyl ring were prepared by BF3-activated lithiationsubstitution in the presence of a chiral diamine in 49-59% yield and 75-85% enantiomeric excess. Some of these ligands were recrystallized to enantiomeric purity via ammonium fluoroborate salt formation of the phosphine sulfide. A crystal structure of one of these compounds was obtained and features an intramolecular hydrogen bond between the nitrogen, hydrogen, and sulfur atoms. Neutralization, followed by desulfurization, provided the free ligands in enantiomeric purity. Iridium complexes with these ligands were formed via reaction with [Ir(COD)Clh followed by anion exchange with NaBArF. These complexes were successfully applied in homogeneous hydrogenation of several prochiral substrates, providing products in up to 92% enantiomeric excess. Variation of the dimethyl amino group to a pyrrolidine group had a negative effect on the selectivity of hydrogenation. Variation of the substituents on phosphorus to bulkier ortho-tolyl groups had a positive effect, while variation to the more electron rich dicyclohexyl phosphine had a negative effect on selectivity.

Understanding the Origin of Selectivity in the Asymmetric Lithiation Reaction of N-Heterocycles: A Theoretical Study

The natural abundance of the N-heterocycle containing compounds has pushed the synthetic community toward the invention of new synthetic methods that result in the structural diversity of N-heterocycles. Among this, is the efficient and highly selective diamine mediated asymmetric lithiation process. Amongst the diamine chiral ligands, (-)-sparterine, which is a naturally occurring alkaloid proved to be an efficient one. Many successful, good yielding and highly selective lithiation reactions have been accomplished with the mediation by this chiral diamine base. Although, there are some examples of experimental and theoretical mechanistic studies in the literature, there is a lack of detailed understanding as to how it exactly induces the chirality. In this thesis is described a systematic investigation of how (-)-sparteine influences the stereoselectivity in the course of asymmetric lithiation reaction. This led us to the establishment of the function of A-ring’s β-CH2 effect and D-ring effect. Consequently, the importance of the A-ring and D-ring portions of (-)-sparteine in the stereoselectivity is unraveled. Another part of this thesis deals with the asymmetric lithiation of BF3-activated N,N- dimethylaminoferrocene in the presence of (1R, 2R)-N1,N2-bis(3,3-dimethylbutyl)-N1,N2-dimethylcyclohexane-1,2-diamine ( a (R,R)-TMCDA surrogate) with i-PrLi. Computational findings were in full accord with the experimental observations. Subsequently, the theoretically provided insights into the mechanism of the reaction were exploited in computational design of a new ligand. Unfortunately, the outcome of this design was not experimentally robust and an updated approach towards a successful design was explained.

Experimental and Computational Studies on Copper and Hydrobenzoin Derivatives in Catalytic Asymmetric Reactions

The use of theory to understand and facilitate catalytic enantioselective organic transformations involving copper and hydrobenzoin derivatives is reported. Section A details the use of theory to predict, facilitate, and understand a copper promoted amino oxygenation reaction reported by Chemler et al. Using Density Functional Theory (DFT), employing the hybrid B3LYP functional and a LanL2DZ/6-31G(d) basis set, the mechanistic details were studied on a N-tosyl-o-allylaniline and a [alpha]-methyl-[gamma]-alkenyl sulfonamide substrate. The results suggest the N-C bond formation proceeds via a cisaminocupration, and not through a radical-type mechanism. Additionally, the origin of diastereoselection observed with [alpha]-methyl-[gamma]-alkenyl sulfonamide arises from avoidance of unfavourable steric interactions between the methyl substituent and the N -protecting group. Section B details the computationally guided, experimental investigation of two hydrobenzoin derivatives as ligands/ catalysts, as well as the attempted synthesis of a third hydrobenzoin derivative. The bis-boronic acid derived from hydrobenzoin was successful as a Lewis acid catalyst in the Bignielli reaction and the Conia ene reaction, but provided only racemic products. The chiral diol derived from hydrobenzoin successfully increased the rate of the addition of diethyl zinc to benzaldehyde in the presence of titanium tetraisopropoxide, however poor enantioinduction was obseverved. Notably, the observed reactivity was successfully predicted by theoretical calculations.

Heuristics for the Critical Node Detection Problem in Large Complex Networks

Complex networks have recently attracted a significant amount of research attention due to their ability to model real world phenomena. One important problem often encountered is to limit diffusive processes spread over the network, for example mitigating pandemic disease or computer virus spread. A number of problem formulations have been proposed that aim to solve such problems based on desired network characteristics, such as maintaining the largest network component after node removal. The recently formulated critical node detection problem aims to remove a small subset of vertices from the network such that the residual network has minimum pairwise connectivity. Unfortunately, the problem is NP-hard and also the number of constraints is cubic in number of vertices, making very large scale problems impossible to solve with traditional mathematical programming techniques. Even many approximation algorithm strategies such as dynamic programming, evolutionary algorithms, etc. all are unusable for networks that contain thousands to millions of vertices. A computationally efficient and simple approach is required in such circumstances, but none currently exist. In this thesis, such an algorithm is proposed. The methodology is based on a depth-first search traversal of the network, and a specially designed ranking function that considers information local to each vertex. Due to the variety of network structures, a number of characteristics must be taken into consideration and combined into a single rank that measures the utility of removing each vertex. Since removing a vertex in sequential fashion impacts the network structure, an efficient post-processing algorithm is also proposed to quickly re-rank vertices. Experiments on a range of common complex network models with varying number of vertices are considered, in addition to real world networks. The proposed algorithm, DFSH, is shown to be highly competitive and often outperforms existing strategies such as Google PageRank for minimizing pairwise connectivity.

Canadian Niagara Power Glass Slide - Large Group in Tunnel

A large group of men in hard hats in the tunnel. The names of the men are unknown.

Canadian Niagara Power Company - Large group photo in tunnel

Large group of men standing in the tunnel wearing boots and hard hats.

A DFT Guided/Experimental Approach to Asymmetric Allylation and Phase-Transfer Catalysis

The Dudding group is interested in the application of Density Functional Theory (DFT) in developing asymmetric methodologies, and thus the focus of this dissertation will be on the integration of these approaches. Several interrelated subsets of computer aided design and implementation in catalysis have been addressed during the course of these studies. The first of the aims rested upon the advancement of methodologies for the synthesis of biological active C(1)-chiral 3-methylene-indan-1-ols, which in practice lead to the use of a sequential asymmetric Yamamoto-Sakurai-Hosomi allylation/Mizoroki Heck reaction sequence. An important aspect of this work was the utilization of ortho-substituted arylaldehyde reagents which are known to be a problematic class of substrates for existing asymmetric allylation approaches. The second phase of my research program lead to the further development of asymmetric allylation methods using o-arylaldehyde substrates for synthesis of chiral C(3)-substituted phthalides. Apart from the de novo design of these chemistries in silico, which notably utilized water-tolerant, inexpensive, and relatively environmental benign indium metal, this work represented the first computational study of a stereoselective indium-mediated process. Following from these discoveries was the advent of a related, yet catalytic, Ag(I)-catalyzed approach for preparing C(3)-substituted phthalides that from a practical standpoint was complementary in many ways. Not only did this new methodology build upon my earlier work with the integrated (experimental/computational) use of the Ag(I)-catalyzed asymmetric methods in synthesis, it provided fundamental insight arrived at through DFT calculations, regarding the Yamamoto-Sakurai-Hosomi allylation. The development of ligands for unprecedented asymmetric Lewis base catalysis, especially asymmetric allylations using silver and indium metals, followed as a natural extension from these earlier discoveries. To this end, forthcoming as well was the advancement of a family of disubstituted (N-cyclopropenium guanidine/N-imidazoliumyl substituted cyclopropenylimine) nitrogen adducts that has provided fundamental insight into chemical bonding and offered an unprecedented class of phase transfer catalysts (PTC) having far-reaching potential. Salient features of these disubstituted nitrogen species is unprecedented finding of a cyclopropenium based C-H•••πaryl interaction, as well, the presence of a highly dissociated anion projected them to serve as a catalyst promoting fluorination reactions. Attracted by the timely development of these disubstituted nitrogen adducts my last studies as a PhD scholar has addressed the utility of one of the synthesized disubstituted nitrogen adducts as a valuable catalyst for benzylation of the Schiff base N-diphenyl methylene glycine ethyl ester. Additionally, the catalyst was applied for benzylic fluorination, emerging from this exploration was successful fluorination of benzyl bromide and its derivatives in high yields. A notable feature of this protocol is column-free purification of the product and recovery of the catalyst to use in a further reaction sequence.

Diastereoselective Synthesis of Planar Chiral N-Substituted Ferrocenes Derived from Epimeric Imidazolones and their Application to Asymmetric Hydrogenation of Quinolines

This thesis describes the synthesis and use of an N-substituted ferrocene bearing a proline-derived chiral directing group and diastereoselective lithiation-electrophile quench of the pro-Sp hydrogen of the ferrocene to give planar chiral products in >95:5 dr. The auxiliary group is found to be stable to lithium bases of types RLi and R2NLi giving the same diastereoselectivity. The anti- epimer of the previously mentioned syn auxiliary induces lithiation of pro Rp rather than pro Sp hydrogen in >95:5 dr. Upon electrophile quench and elimination, the enantiomer of the syn-derived planar chiral imidazolone is obtained. Hence, this method provides a practical way to prepare planar chiral enantiomers in this series without the use of a more expensive D-proline derived starting material. The syn and anti epimers have β, γ-stereogenic centers and the origin of stereoselectivity in lithiation appears to be driven by the conformational bias exerted by the β-silyloxy moiety in each chiral auxiliary. In the thesis, this conclusion is supported using insensitivity of lithiation selectivity to the bulkiness of the base, comparison of enantiomers, deuteration experiments, nOe difference studies and computational modeling of the ground states and lithiation transition states for both substrates. The products are then converted to ligand precursors to make iridium and rhodium complexes. Among them, one of the cationic iridium complex is found to be effective in the asymmetric hydrogenation of 2-substituted quinolines with enantioselectivities up to 80% at pressures as low as 5 atm.

STRUCTURAL ANALYSIS, LAYER THICKNESS MEASUREMENTS AND MINERALOGICAL INVESTIGATION OF THE LARGE INTERIOR LAYERED DEPOSIT WITHIN GANGES CHASMA, VALLES MARINERIS, MARS

The interior layered deposit (ILD) in Ganges Chasma, Valles Marineris, is a 4.25 km high mound that extends approximately 110 km from west to east. The deposition, deformation, and erosion history of the Ganges ILD records aids in identifying the processes that formed and shaped the Chasma. To interpret structural and geomorphic processes acting on the ILD, multiple layer attitudes and layer thickness transects were conducted on the Ganges ILD. Mineralogical data was analyzed to determine correlations between materials and landforms. Layer thickness measurements indicate that the majority of layers are between 0.5 m and 4 m throughout the ILD. Three major benches dominate the Ganges ILD. Layer thicknesses increase at the ILD benches, suggesting that the benches are formed from the gradual thickening of layers. This indicates that the benches are depositional features draping over basement topography. Layer attitudes indicate overall shallow dips generally confined to a North-South direction that locally appear to follow bench topography. Layering is disrupted on a scale of 40 m to 150 m in 12 separate locations throughout the ILD. In all locations, underlying layering is disturbed by overlying folded layers in a trough-like geometry. These features are interpreted to have formed as submarine channels in a lacustrine setting, subsequently infilled by sediments. Subsequently, the channels were eroded to the present topography, resulting in the thin, curved layering observed. Data cannot conclusively support one ILD formation hypothesis, but does indicate that the Ganges ILD postdates Chasma formation. The presence of water altered minerals, consistently thin layering, and layer orientations provide strong evidence that the ILD formed in a lacustrine setting.

Photograph - Woman Standing by a Large Tree Trunk

A woman wearing a hat and holding a small purse. She is standing next to a large tree trunk and there are benches behind her.

Safe Handling of Large Animals

The article discusses improving welfare by reducing fear by studying: Animal Sensory Perception, Animal Behavior Patterns, Animal Habituation and Temperament, Effects of Previous Handling, Training Animals, Training Time and Temperament, Genetic Effects on Handling, Handling of escaped Animals, Facilities, Aggression in Grazing Animals, Inherent Danger of Large Animals, Cattle and Car Accidents.

A Bicyclic L-Proline Derived Chiral Auxiliary for Asymmetric Synthesis

This thesis describes the use of an L−proline-derived chiral auxiliary for diastereoselective lithiation and ligand synthesis. Such compounds have been utilized in the Metallinos research group previously for the synthesis of N−substituted planar chiral ferrocenes. The first project describes the use of this chiral auxiliary as a directing group for N−benzyl substitution, providing products in up to 10:1 diastereomeric ratio (dr). These derivatives may serve as chiral ylidene precursors to serve as ligands in transition metal catalysis. In addition, an N−substituted planar chiral ferrocene ylidene ligand derived from the same chiral auxiliary was used to prepare rhodium complexes that were explored as potential catalysts for asymmetric hydroformylation.

Mirroring Enzymes: The Role of H-Bonding In HQuin-BAM Catalyzed Asymmetric Aza-Henry Reactions: A DFT Study into the Reactivity, Mechanism, and Origins of Selectivity

The exact mechanistic understanding of various organocatalytic systems in asymmetric reactions such as Henry and aza-Henry transformations is important for developing and designing new synthetic organocatalysts. The focus of this dissertation will be on the use of density functional theory (DFT) for studying the asymmetric aza-Henry reaction. The first part of the thesis is a detailed mechanistic investigation of a poorly understood chiral bis(amidine) (BAM) Brønsted acid catalyzed aza-Henry reaction between nitromethane and N-Boc phenylaldimine. The catalyst, in addition to acting as a Brønsted base, serves to simultaneously activate both the electrophile and the nucleophile through dual H-bonding during C-C bond formation and is thus essential for both reaction rate and selectivity. Analysis of the H-bonding interactions revealed that there was a strong preference for the formation of a homonuclear positive charge-assisted H-bond, which in turn governed the relative orientation of substrate binding. Attracted by this well-defined mechanistic investigation, the other important aspect of my PhD research addressed a detailed theoretical analysis accounting for the observed selectivity in diastereoselective versions of this reaction. A detailed inspection of the stereodetermining C-C bond forming transition states for monoalkylated nitronate addition to a range of electronically different aldimines, revealed that the origins of stereoselectivity were controlled by a delicate balance of different factors such as steric, orbital interactions, and the extent of distortion in the catalyst and substrates. The structural analysis of different substituted transition states established an interesting dependency on matching the shape and size of the catalyst (host molecule) and substrates (guest molecules) upon binding, both being key factors governing selectivity, in essence, offering an analogy to positive cooperative binding effect of catalytic enzymes and substrates in Nature. In addition, both intra-molecular (intra-host) and inter-molecular (host-guest, guest-guest) stabilizing interactions play a key role to the high π-facial selectivity. The application of dispersion-corrected functionals (i.e., ωB97X-D and B3LYP-D3) was essential for accurately modeling these stabilizing interactions, indicating the importance of dispersion effects in enantioselectivity. As a brief prelude to more extensive future studies, the influence of a triflate counterion on both reactivity and selectivity in this reaction was also addressed.