When speciality chemicals are manufactured within the pharmaceutical industry, they are often produced in stirred batch/semi-batch reactors. A ‘methodology’ was explored, to help with the development of continuous fixed-bed catalytic reactors for this sector. This was tested on two different types of model reactions: (a) In the first, the viability of producing tertiary amines via ‘borrowing hydrogen’ was explored, and the reaction of morpholine and benzyl alcohol was studied, on Ru and Pt catalysts. This provided an opportunity for an early involvement in small-scale batch testing of catalysts, and then experiments were performed with the catalyst supported on granules in a packed bed (i.d. = 7 mm, length = 300 mm). Although it was shown that continuous processing is viable, and that high conversions (e.g. 73 to 98%, at 150 ºC) could be achieved, unfortunately further work was necessary to identify a more robust catalyst system, before moving on to pilot-scale trials. (b) In the second, the partial oxidation of benzyl alcohol to benzaldehyde was studied, using a Pt catalyst on a carbon support. This proved to be successful, and the reaction was finally demonstrated at pilot-scale. Carbon monoliths were used as catalyst supports (monolith o.d. = 19 mm; length = 50 mm long; square 0.7 mm x 0.7 mm channels; catalyst loading 2.5 and 2.7 wt% Pt). With a liquid flow of 1 L h-1 and a reactant concentration of ~1 mol L-1, operating at 110 ºC, conversion ranged from 80 to 90% and selectivity from 65 to 99%. The catalyst system was tested for 160 h of operation, and retained its performance. While testing the 2nd reaction, a pilot-scale reactor was also developed, which could be used for a variety of novel reactions. The design was flexible and it was easy to insert and remove the catalytic monoliths.

The objective of this project is to improve productivity and efficiency for the inbound material handling operations in the warehouse of DC Älmhult. After three weeks pre-study in place of the distribution center, the authors have observed several problems existing in the current production, among which three types of wastes are found and analyzed by using VSM that are pick and drop, operator waiting time and inefficient transport. Two typical cases chosen from the inbound production are analyzed to reflect the current process and address problems. Fish-bone tool is used to identify wastes and roots. To eliminate or reduce the wastes, recommendations and solutions are developed by creating continuous flow combining with internal transport optimization. Future-state VSMs are drawn based on the suggested changes in line with continuous flow. Different productions models are simulated by elaborately developed excel sheets. A „distance table‟ is developed by using Microsoft Excel to help the loading or unloading leaders with the gate steering function so as to minimize internal transport distance. A new layout of the conveyor system is also suggested to lower the idle transport rate.

Ice crystals in clouds frequently form upon a subset of aerosol particles called ice nuclei (IN). IN influence cloud ice crystal concentrations, consequently affecting cloud lifetime and reflectivity. The present understanding of these effects on climate is hindered by limited data on the global distribution of IN. This thesis presents measurements of deposition-mode IN concentrations under conditions relevant to mid-level clouds, 238 K and 138% RHi. at two Canadian sites: Toronto, a major city, and Whistler, a pristine coniferous rainforest. In Toronto, chemically-resolved surface areas were estimated by single-particle mass spectrometry and regressed against IN concentrations to identify a significant relationship between IN concentrations and both carbonaceous aerosols (EC and/or OC) and dust. In Whistler, IN concentrations during a biogenic secondary organic aerosol (SOA) event did not increase from background levels (0.1 /L), suggesting that biogenic SOA particles do not nucleate ice under these conditions.

Ice crystals in clouds frequently form upon a subset of aerosol particles called ice nuclei (IN). IN influence cloud ice crystal concentrations, consequently affecting cloud lifetime and reflectivity. The present understanding of these effects on climate is hindered by limited data on the global distribution of IN. This thesis presents measurements of deposition-mode IN concentrations under conditions relevant to mid-level clouds, 238 K and 138% RHi. at two Canadian sites: Toronto, a major city, and Whistler, a pristine coniferous rainforest. In Toronto, chemically-resolved surface areas were estimated by single-particle mass spectrometry and regressed against IN concentrations to identify a significant relationship between IN concentrations and both carbonaceous aerosols (EC and/or OC) and dust. In Whistler, IN concentrations during a biogenic secondary organic aerosol (SOA) event did not increase from background levels (0.1 /L), suggesting that biogenic SOA particles do not nucleate ice under these conditions.

<div>The present work seeks to use high throughput experimentation (HTE) to guide chemical synthesis. We demonstrate the use of an HTE system utilizing a robotic liquid handler to prepare arrays of reactions and print them onto a surface to be analyzed by desorption electrospray ionization mass spectrometry (DESI-MS) as a tool to guide reaction optimization, synthetic route selection, and reaction discovery. DESI-MS was employed as a high throughput experimentation tool to provide qualitative predictions of the outcome of a reaction, so that vast regions of chemical reactivity space may be more rapidly explored and areas of optimal efficiency identified. This work is part of a larger effort to accelerate reaction optimization to enable the rapid development of continuous-flow syntheses of small molecules in high yield. In the present iteration of this system, reactions are scaled up from these nanogram surface printed reactions to milligram scale microfluidic reactions, where more detailed analysis and further optimization may be performed. In the earliest iterations of this screening system prior to the use of DESI, the initial screening reactions were performed in electrospray (ESI) droplets and leidenfrost droplets before scaling up to microfluidic reactions which were analyzed by ESI-MS. The insights from this combined droplet and microfluidic screening/rapid ESI-MS analysis approach, helped guide the synthesis of diazepam. The system was further refined to by the use of liquid handling robots and DESI-MS analysis, greatly accelerating the overall pace of screening. In order to build confidence in this approach, however, it is necessary to establish a robust predictive connection between reactions performed under analogous DESI-MS, batch, and microfluidic reaction conditions. To achieve this goal, we first explored the potential of high throughput DESI-MS experiments to identify trends in reactivity based on chemical structure, solvent, temperature, and stoichiometry that are consistent across these platforms. While DESI-MS narrowed the scope of possibilities for reaction</div><div>13</div><div>selection with some parameters such as solvent, others like stoichiometry and temperature still required further optimization under continuous synthesis conditions. With our increased confidence in DESI-MS HTE, we proceeded to explore it’s application to rapidly evaluate large sets of aldol reactions of triacetic acid lactone (TAL), a compound well studied for use as a bio-based platform molecule that may be converted to a range of useful commodity chemicals, agrochemicals, and advanced pharmaceutical intermediates. Our DESI-MS HTE screening technique was used to rapidly evaluate known reactions of triacetic acid lactone, in an effort to accelerate reaction discovery with platform chemicals. Our rapid experimentation system, when applied to reaction discovery in this manner, may help to shorten the time scale of platform chemical development.</div>

The Technicon AutoAnalyzer II was evaluated for automatic quantitation of non-casein protein (NCP) in milk. The Lowry method f or colorimetric measurement of proteins was adapted to the automated method and found to be accurate in the determination of non-casein protein in milk. The automated Lowry method obeyed Beer's law. Casein content was calculated by difference between total protein determined by infrared milk analysis (IRMA) and non-casein protein. In the analysis of twenty-five replicate milk samples, the standard deviation was 0.32 and the coefficient of variability was 0.90. The casein content as a percentage of total protein in the milk of cows in the Utah State University dairy herd was found to vary from 41.0 to 81.3%. The automated or continuous flow method was affected by as little as 0.05% (w/w) mercuric chloride, a chemical preservative used in milk, whereas potassium dichromate and formaldehyde had insignificant effects upon the assay.

A continuous flow, passive separation device was designed using an equivalent circuit to create variable flow rates for hydrodynamic focusing to drain channels and collection outlets. By varying the diameter of the sample inlet connection into the reservoir, the particle position was influenced significantly, which enabled desired separations. Additionally it was noted that the relative, horizontal position of the inlet also had a significant influence on particle position within the device. A dimensionless number, the Characteristic Sample Inlet, was developed to relate geometric properties of the inlet reservoir to downstream particle distribution. It was found that a 2:1 ratio between inlet reservoir and sample inlet diameter, and placed at the top of the reservoir yielded the best separation results. Fluid velocity profiles in the reservoir were explored using Comsol Multyphysics. The experimentally observed particle trajectories and COMSOL predictions were in good agreement. Based on Comsol models a dimensionless parameter to relate the unique velocity profiles within the inlet reservoir to downstream separation of particles was also developed. A mixture of 10, 5.5, and 3.0 µm particles were separated to three distinct collection outlets at 73.4%, 64.7%, and 52.8% respectively. Therefore this project shows that passive separations of particles can be achieved simply by alerting the ratio of inlet hole relative to inlet reservoir diameter, and by placing the inlet hole at the top of the reservoir.

No description available.

Palladium-catalyzed reactions have become one of the most important tools in modern organic chemistry due to its ability to catalyze the formation of new carbon-carbon bonds. The aim of the work presented in this thesis was to develop new palladium(II)-catalyzed addition reactions. In this work, cyanamides were investigated as a new substrate to give aryl amidines as products. The first protocol developed employed aryltrifluoroborates as the aryl partner, and the insertion of the aryl group into un-, mono-, and di-substituted cyanamides was successful for a wide variety of aryltrifluoroborates. An alternative method of generating the necessary intermediate for insertion into the cyanamide is the decarboxylative formation of aryl-palladium from aryl carboxylic acids. A protocol was developed for this reaction, but was unfortunately limited to a small number of ortho-substituted electron-rich aryl carboxylic acids. The mechanism was investigated by the means of DFT calculations and ESI-MS studies, and the rate-determining step was suggested to be the 1,2-carbopalladation based upon those results. A translation of the batch protocol to continuous-flow conditions was also demonstrated. The ideal method of generating the aryl-palladium species is by C-H bond activation, and this approach was demonstrated with indoles, giving a variety of 3-amidinoindoles as products. The mechanism was investigated by DFT calculations and a plausible catalytic cycle was proposed. A continuous-flow application of a desulfitative palladium(II)-catalyzed addition to nitriles to give ketones was developed. In addition, different reactor materials were evaluated in the microwave heated reactor cavity. Thus the reaction was shown to proceed with microwave heating in a borosilicate glass and an aluminum oxide reactor, and also in conditions mimicking conventional heating in a silicon carbide reactor. Finally, a protocol was developed for the convenient synthesis of sodium aryl sulfinates from Grignard and lithium reagents using a solid sulfur dioxide source as a safe alternative to the gas. The products of this protocol can be used as aryl-palladium precursors by a desulfitative process.

Over the past decades, functional group manipulation of aromatic precursors has been a common strategy to access new aromatic compounds. However, these classical methods, such as Friedel-Crafts alkylations and electrophilic/nucleophilic aromatic substitutions, have shown lack of regioselectivity besides the use of activators in excess amounts. To this end, numerous benzannulations to form benzo-fused substrates via Diels-Alder (DA), ring-closing metathesis (RCM), cycloaddition, and transition-metal-promoted processes have been reported. Appending a benzene ring directly onto a pre-existing ring is preferable to many classical methods due to the likely reduction of reaction steps and superior regiocontrol. However, many of these benzannulation reactions require air- and/or moisture- sensitive reaction conditions, a last oxidation step, or the use of highly functionalized precursors. Here we disclose three ‘complementary’ intramolecular ring-opening benzannulations to access a large array of functionalized (hetero)aromatic scaffolds utilizing cyclopropenes-3,3-dicarbonyls, alkylidene cyclopropanes-1,1-diesters, and 2,3-dihydrofuran O,O- and N,O- acetals as building blocks. More than 70 benzo-fused aromatic compounds were synthesized using this complementary approach with yields up to 98% and low catalyst loadings. With these benzannulation reactions in hand, we aim to open the synthetic door to a handful of bioactive natural products.