Novel technology for preparation of optically active chemicals

Asymmetric synthesis using modified heterogeneous catalysts has gained lots of interest in the production of optically pure chemicals, such as pharmaceuticals, nutraceuticals, fragrances and agrochemicals. Heterogeneous modified catalysts capable of inducing high enantioselectivities are preferred in industrial scale due to their superior separation and handling properties. The topic has been intensively investigated both in industry and academia. The enantioselective hydrogenation of ethyl benzoylformate (EBF) to (R)-ethyl mandelate over (-)-cinchonidine (CD)-modified Pt/Al2O3 catalyst in a laboratory-scale semi-batch reactor was studied as a function of modifier concentration, reaction temperature, stirring rate and catalyst particle size. The main product was always (R)-ethyl mandelate while small amounts of (S)-ethyl mandelate were obtained as by product. The kinetic results showed higher enantioselectivity and lower initial rates approaching asymptotically to a constant value as the amount of modifier was increased. Additionally, catalyst deactivation due to presence of impurities in the feed was prominent in some cases; therefore activated carbon was used as a cleaning agent of the raw material to remove impurities prior to catalyst addition. Detailed characterizations methods (SEM, EDX, TPR, BET, chemisorption, particle size distribution) of the catalysts were carried out. Solvent effects were also studied in the semi-batch reactor. Solvents with dielectric constant (e) between 2 and 25 were applied. The enantiomeric excess (ee) increased with an increase of the dielectric coefficient up to a maximum followed by a nonlinear decrease. A kinetic model was proposed for the enantioselectivity dependence on the dielectric constant based on the Kirkwood treatment. The non-linear dependence of ee on (e) successfully described the variation of ee in different solvents. Systematic kinetic experiments were carried out in the semi-batch reactor. Toluene was used as a solvent. Based on these results, a kinetic model based on the assumption of different number of sites was developed. Density functional theory calculations were applied to study the energetics of the EBF adsorption on pure Pt(1 1 1). The hydrogenation rate constants were determined along with the adsorption parameters by non-linear regression analysis. A comparison between the model and the experimental data revealed a very good correspondence. Transient experiments in a fixed-bed reactor were also carried out in this work. The results demonstrated that continuous enantioselective hydrogenation of EBF in hexane/2-propanol 90/10 (v/v) is possible and that continuous feeding of (-)-cinchonidine is needed to maintain a high steady-state enantioselectivity. The catalyst showed a good stability and high enantioselectivity was achieved in the fixed-bed reactor. Chromatographic separation of (R)- and (S)-ethyl mandelate originating from the continuous reactor was investigated. A commercial column filled with a chiral resin was chosen as a perspective preparative-scale adsorbent. Since the adsorption equilibrium isotherms were linear within the entire investigated range of concentrations, they were determined by pulse experiments for the isomers present in a post-reaction mixture. Breakthrough curves were measured and described successfully by the dispersive plug flow model with a linear driving force approximation. The focus of this research project was the development of a new integrated production concept of optically active chemicals by combining heterogeneous catalysis and chromatographic separation technology. The proposed work is fundamental research in advanced process technology aiming to improve efficiency and enable clean and environmentally benign production of enantiomeric pure chemicals.

SC HIOMON JA PAPERIKONEEN LÄMPÖTASAPAINON HALLINTA

Kivihiokkeen valmistus on energiaintensiivistä. Käytetystä energiasta muuttuu yli 90 prosenttia lämmöksi. Hiomolla käytetystä lämmöksi muuttuneesta tehosta voidaan paperikoneelle siirtää noin puolet. Mekaanisen massan valmistuksen ja paperikoneen vesikierrot erotetaan toisistaan häiriöaineiden kulkeutumisen estämiseksi. Vesikiertojen erottamisella katkaistaan myös lämmön siirtyminen hiomolta paperikoneelle massojen mukana. Käyttämällä lämmönsiirtimiä hiomon vesien jäähdytyksessä, voidaan hiomon hiomakoneiden suihkuvesivesilämpötilaa alentaa. Lämmönsiirto vaikuttaa paperikoneella annostelumassojen laimennusten kautta perälaatikkolämpötilaa kohottavasti. Työn tehtäväksi määritettiin kesäkuukausina esiintyvä hiomakoneiden suihkuveden raakavesijäähdytyksen tarpeen poistaminen ensisijaisesti niin, että ylimäärälämpö hyödynnetään tehtaalla. Työn muiksi tavoitteiksi muodostui annostelumassojen lämpötilan hallinta, etenkin muutokset, joilla voidaan nostaa hylkymassan annostelulämpötilaa. Työn kokeellinen osa tehtiin UPM Kymmene Oyj Kajaanin tehtailla syksyn 2004 aikana. Työssä tutkittiin WinGEMS simulointiohjelmalla tehtyjen mallien avulla lämmön siirtymistä hiomon ja paperikone 2:n välillä, sekä lämmönsiirtoa pois tasealueelta. Simulointimalli nykytilanteesta rakennettiin yksityiskohtaisesti nykyisen tuotantoprosessin kaltaiseksi ja siitä muokattiin eri vaihtoehtoja, joilla ratkaistiin tutkimukselle asetetut tehtävät. Kytkentämuutoksilla pystyttiin siirtämään hiomolta yli 85 % hiomakoneiden suihkuveden ylimäärälämmöstä ilman uusia laitehankintoja. Asentamalla lopuksi lämmönsiirrin hiomon puhdassuodoslinjaan, hiomakoneiden suihkuveden jäähdytystarve poistettiin kokonaan. Samalla alennettiin valkaisuun menevän massan lämpötilaa, jolloin peroksidivalkaisun kemikaalikulutus väheni yli 10 %. Lämmönsiirrinverkostosta tehtiin kesätilanteen pinch-analyysi, jolla selvitettiin prosessin lämmitys ja jäähdytystarpeet. Analyysin perusteella selvisi, että kytkennöissä ei rikota pinch sääntöjä ja, että prosessissa esiintyy kynnysongelma, jossa prosessi tarvitsee ainoastaan jäähdytystä.

Monitoring of centrifugal pump operation by a frequency converter

Centrifugal pumps are widely used in industrial and municipal applications, and they are an important end-use application of electric energy. However, in many cases centrifugal pumps operate with a significantly lower energy efficiency than they actually could, which typically has an increasing effect on the pump energy consumption and the resulting energy costs. Typical reasons for this are the incorrect dimensioning of the pumping system components and inefficiency of the applied pump control method. Besides the increase in energy costs, an inefficient operation may increase the risk of a pump failure and thereby the maintenance costs. In the worst case, a pump failure may lead to a process shutdown accruing additional costs. Nowadays, centrifugal pumps are often controlled by adjusting their rotational speed, which affects the resulting flow rate and output pressure of the pumped fluid. Typically, the speed control is realised with a frequency converter that allows the control of the rotational speed of an induction motor. Since a frequency converter can estimate the motor rotational speed and shaft torque without external measurement sensors on the motor shaft, it also allows the development and use of sensorless methods for the estimation of the pump operation. Still today, the monitoring of pump operation is based on additional measurements and visual check-ups, which may not be applicable to determine the energy efficiency of the pump operation. This doctoral thesis concentrates on the methods that allow the use of a frequency converter as a monitoring and analysis device for a centrifugal pump. Firstly, the determination of energy-efficiency- and reliability-based limits for the recommendable operating region of a variable-speed-driven centrifugal pump is discussed with a case study for the laboratory pumping system. Then, three model-based estimation methods for the pump operating location are studied, and their accuracy is determined by laboratory tests. In addition, a novel method to detect the occurrence of cavitation or flow recirculation in a centrifugal pump by a frequency converter is introduced. Its sensitivity compared with known cavitation detection methods is evaluated, and its applicability is verified by laboratory measurements for three different pumps and by using two different frequency converters. The main focus of this thesis is on the radial flow end-suction centrifugal pumps, but the studied methods can also be feasible with mixed and axial flow centrifugal pumps, if allowed by their characteristics.

Development of racemization catalysts for dynamic kinetic resolution

Preparation of optically active compounds is of high importance in modern medicinal chemistry. Despite recent advances in the field of asymmetric synthesis, resolution of racemates still remains the most utilized way for preparation of single enantiomers in industrial scale due to its cost-efficiency and simplicity. Enzymatic kinetic resolution (KR) of racemates is a classical method for separation of enantiomers. One of its drawbacks is the limitation of target enantiomer yield to 50%. Dynamic Kinetic Resolution (DKR) allows to reach yields up to 100% by in situ racemization of the less reactive enantiomer. In the first part of this thesis, a number of half-sandwich ruthenium complexes were prepared and evaluated as catalysts for racemization of optically active secondary alcohols. A leading catalyst, Bn5CpRu(CO)2Cl, was identified. The catalyst discovered was extensively characterized by its application for DKR of a broad range of secondary alcohols in a wide range of reaction loadings (1 mmol – 1 mol). Cost-efficient chromatography-free procedure for preparation of this catalyst was developed. Further, detailed kinetic and mechanistic studies of the racemization reactions were performed. Comparison of racemization rates in the presence of Bn5CpRu(CO)2Cl and Ph5CpRu(CO)2Cl catalysts reveals that the performance of the catalytic system can be adjusted by matching of the electronic properties of the catalysts and the substrates. Moreover, dependence of the rate-limiting step from the electronic properties of the reagents was observed. Important conclusions about reaction mechanism were made. Finally, an alternative approach to DKR of amines based on space separated vessels was addressed. This procedure allows the combination of thermolabile enzyme with racemization catalysts active only at high temperatures.

Electroactive ion exchange membranes based on conducting polymers

Ion exchange membranes are indispensable for the separation of ionic species. They can discriminate between anions and cations depending on the type of fixed ionic group present in the membrane. These conventional ion exchange membranes (CIX) have exceptional ionic conductivity, which is advantageous in various electromembrane separation processes such as electrodialysis, electrodeionisation and electrochemical ion exchange. The main disadvantage of CIX membranes is their high electrical resistance owing to the fact that the membranes are electronically non conductive. An alternative can be electroactive ion exchange membranes, which are ionically and electronically conducting. Polypyrrole (PPy) is a type of electroactive ion exchange material as well as a commonly known conducting polymer. When PPy membranes are repeatedly reduced and oxidised, ions are pumped through the membrane. The main aim of this thesis was to develop electroactive cation transport membranes based on PPy for the selective transport of divalent cations. Membranes developed composed of PPy films deposited on commercially available support materials. To carry out this study, cation exchange membranes based on PPy doped with immobile anions were prepared. Two types of dopant anions known to interact with divalent metal ions were considered, namely 4-sulphonic calix[6]arene (C6S) and carboxylated multiwalled carbon nanotubes (CNT). The transport of ions across membranes containing PPy doped with polystyrene sulphonate (PSS) and PPy doped with para-toluene sulphonate (pTS) was also studied in order to understand the nature of ion transport and permeability across PPy(CNT) and PPy(C6S) membranes. In the course of these studies, membrane characterisation was performed using electrochemical quartz crystal microbalance (EQCM) and scanning electron microscopy (SEM). Permeability of the membranes towards divalent cations was explored using a two compartment transport cell. EQCM results demonstrated that the ion exchange behaviour of polypyrrole is dependent on a number of factors including the type of dopant anion present, the type of ions present in the surrounding medium, the scan rate used during the experiment and the previous history of the polymer film. The morphology of PPy films was found to change when the dopant anion was varied and even when the thickness of the film was altered in some cases. In nearly all cases the permeability of the membranes towards metal ions followed the order K+ > Ca2+ > Mn2+. The one exception was PPy(C6S), for which the permeability followed the order Ca2+ ≥ K+ > Mn2+ > Co2+ > Cr3+. The above permeability sequences show a strong dependence on the size of the metal ions with metal ions having the smallest hydrated radii exhibiting the highest flux. Another factor that affected the permeability towards metal ions was the thickness of the PPy films. Films with the least thickness showed higher metal ion fluxes. Electrochemical control over ion transport across PPy(CNT) membrane was obtained when films composed of the latter were deposited on track-etched Nucleopore® membranes as support material. In contrast, the flux of ions across the same film was concentration gradient dependent when the polymer was deposited on polyvinylidene difluoride membranes as support material. However, electrochemical control over metal ion transport was achieved with a bilayer type of PPy film consisting of PPy(pTS)/PPy(CNT), irrespective of the type of support material. In the course of studying macroscopic charge balance during transport experiments performed using a two compartment transport cell, it was observed that PPy films were non-permselective. A clear correlation between the change in pH in the receiving solution and the ions transported across the membrane was observed. A decrease in solution pH was detected when the polymer membrane acted primarily as an anion exchanger, while an increase in pH occurred when it functioned as a cation exchanger. When there was an approximately equal flux of anions and cations across the polymer membrane, the pH in the receiving solution was in the range 6 - 8. These observations suggest that macroscopic charge balance during the transport of cations and anions across polypyrrole membranes was maintained by introduction of anions (OH-) and cations (H+) produced via electrolysis of water.

Slurry flows in progressive cavity and in hose pumps

The aim of this thesis was to research how slurry’s viscosity and rheology affect to pumping in peristaltic hose pump and in eccentric progressive cavity pump. In addition, it was researched the formed pressure pulsation in hose pump. Pressure pulsation was studied by pumping different slurries and by using different pipe materials. Pressure and power curves were determined for both used pumps. It was also determined NPSHR curve for the progressive cavity pump. Literature part of the thesis considered to distribute fluids to different rheology types, as well as theories and models to identify different rheology types. Special attention was paid to non-Newtonian fluids, which were also used in experimental part of this thesis. In addition, the literature part discusses about pumps, parameters for pump sizing, and pressure pulsation in hose pump. Starch, bentonite, and carboxymethyl cellulose slurries were used in the experimental part of this thesis. The slurries were pumped with Flowrox peristaltic hose pump (LPP-T32) and eccentric progressive cavity pump (C10/10). From the each slurry was taken a sample, and the samples were analyzed for concentration, viscosity and rheology type. The used pipe materials in pressure pulsation experiments were steel and elastic, and it was also used a prototype of pulsation dampener. The pulsation experiments indicated that the elastic pipe and the prototype of pulsation dampener attenuated pressure pulsation better than the steel pipe at low pressure levels. The differences between different materials disappeared when pressure level and pump rotation speed increased. In slurry experiments, pulsation was different depending on rheology and viscosity of the slurry. According to experiments, the rheology did not significantly affect to pump power consumption or efficiency.

Photon Upconverting Nanophosphors: Unique Reporters for Optical Biosensing

Upconversion photoluminescence is a unique property of mostly certain inorganic materials, which are capable of converting low-energy infrared radiation into a higher-energy emission at visible wavelengths. This anti-Stokes shift enables luminescence detection without autofluorescence, which makes the upconverting materials a highly suitable reporter technology for optical biosensing applications. Furthermore, they exhibit long luminescence lifetime with narrow bandwidths also at the optical window of biomaterials enabling luminescence measurements in challenging sample matrices, such as whole blood. The aim of this thesis was to study the unique properties and the applicability of nano-sized upconverting phosphors (UCNPs) as reporters in biosensing applications. To render the inorganic nanophosphors water-dispersible and biocompatible, they were subjected to a series of surface modifications starting with silica-encapsulation and ending with a bioconjugation step with an analyte-recognizing biomolecule. The paramagnetism of the lanthanide dopants in the nanophosphors was exploited to develop a highly selective separation method for the UCNP-bioconjugates based on the magnetic selectivity of the high gradient magnetic separation (HGMS) system. The applicability of the nano-sized UCNPs as reporters in challenging sample matrices was demonstrated in two homogeneous sensing applications based on upconversion resonance energy transfer (UC-RET). A chemosensor for intracellular pH was developed exploiting UC-RET between the UCNP and a fluorogenic pH-sensitive dye with strongly increasing fluorescence intensity in decreasing pH. The pH-independent emission of the UCNPs at 550 nm was used for referencing. The applicability of the pH-nanosensor for intracellular pH measurement was tested in HeLa cells, and the acidic pH of endosomes could be detected with a confocal fluorescence microscope. Furthermore, a competitive UC-RET-based assay for red blood cell folic acid was developed for the measurement of folate directly from a whole blood sample. The optically transparent window of biomaterials was used in both the excitation and the measurement of the UC-RET sensitized emission of a near-infrared acceptor dye to minimize sample absorption, and the anti-Stokes detection completely eliminated the Stokes-shifted autofluorescence. The upconversion photoluminescence efficiency is known to be dependent on crystallite size, because the increasing surface-to-volume ratio of nano-sized UCNPs renders them more susceptible to quenching effects of the environment than their bulk counterpart. Water is known to efficiently quench the luminescence of lanthanide dopants. In this thesis, the quenching mechanism of water was studied using luminescence decay measurements. Water was found to quench the luminescence of UCNPs by increasing the non-radiative relaxation of the excited state of Yb3+ sensitizer ion, which had a very strong quenching effect on upconversion luminescence intensity.

Development of 3D super-resolution tomographic STED microscopy and its application to studies on bone resorption

In this doctoral thesis, a tomographic STED microscopy technique for 3D super-resolution imaging was developed and utilized to observebone remodeling processes. To improve upon existing methods, wehave used a tomographic approach using a commercially available stimulated emission depletion (STED) microscope. A certain region of interest (ROI) was observed at two oblique angles: one at a standard inverted configuration from below (bottom view) and another from the side (side view) via a micro-mirror positioned close to the ROI. The two viewing angles were reconstructed into a final tomogram. The technique, named as tomographic STED microscopy, was able to achieve an axial resolution of approximately 70 nm on microtubule structures in a fixed biological specimen. High resolution imaging of osteoclasts (OCs) that are actively resorbing bone was achieved by creating an optically transparent coating on a microscope coverglass that imitates a fractured bone surface. 2D super-resolution STED microscopy on the bone layer showed approximately 60 nm of lateral resolution on a resorption associated organelle allowing these structures to be imaged with super-resolution microscopy for the first time. The developed tomographic STED microscopy technique was further applied to study resorption mechanisms of OCs cultured on the bone coating. The technique revealed actin cytoskeleton with specific structures, comet-tails, some of which were facing upwards and some others were facing downwards. This, in our opinion, indicated that during bone resorption, an involvement of the actin cytoskeleton in vesicular exocytosis and endocytosis is present. The application of tomographic STED microscopy in bone biology demonstrated that 3D super-resolution techniques can provide new insights into biological 3D nano-structures that are beyond the diffraction-limit when the optical constraints of super-resolution imaging are carefully taken into account.