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.

Simulation of structural stress history based on dynamic analysis

Modern machine structures are often fabricated by welding. From a fatigue point of view, the structural details and especially, the welded details are the most prone to fatigue damage and failure. Design against fatigue requires information on the fatigue resistance of a structure’s critical details and the stress loads that act on each detail. Even though, dynamic simulation of flexible bodies is already current method for analyzing structures, obtaining the stress history of a structural detail during dynamic simulation is a challenging task; especially when the detail has a complex geometry. In particular, analyzing the stress history of every structural detail within a single finite element model can be overwhelming since the amount of nodal degrees of freedom needed in the model may require an impractical amount of computational effort. The purpose of computer simulation is to reduce amount of prototypes and speed up the product development process. Also, to take operator influence into account, real time models, i.e. simplified and computationally efficient models are required. This in turn, requires stress computation to be efficient if it will be performed during dynamic simulation. The research looks back at the theoretical background of multibody dynamic simulation and finite element method to find suitable parts to form a new approach for efficient stress calculation. This study proposes that, the problem of stress calculation during dynamic simulation can be greatly simplified by using a combination of floating frame of reference formulation with modal superposition and a sub-modeling approach. In practice, the proposed approach can be used to efficiently generate the relevant fatigue assessment stress history for a structural detail during or after dynamic simulation. In this work numerical examples are presented to demonstrate the proposed approach in practice. The results show that approach is applicable and can be used as proposed.

On Dynamic Monitoring Methods for Networks-on-Chip

Rapid ongoing evolution of multiprocessors will lead to systems with hundreds of processing cores integrated in a single chip. An emerging challenge is the implementation of reliable and efficient interconnection between these cores as well as other components in the systems. Network-on-Chip is an interconnection approach which is intended to solve the performance bottleneck caused by traditional, poorly scalable communication structures such as buses. However, a large on-chip network involves issues related to congestion problems and system control, for instance. Additionally, faults can cause problems in multiprocessor systems. These faults can be transient faults, permanent manufacturing faults, or they can appear due to aging. To solve the emerging traffic management, controllability issues and to maintain system operation regardless of faults a monitoring system is needed. The monitoring system should be dynamically applicable to various purposes and it should fully cover the system under observation. In a large multiprocessor the distances between components can be relatively long. Therefore, the system should be designed so that the amount of energy-inefficient long-distance communication is minimized. This thesis presents a dynamically clustered distributed monitoring structure. The monitoring is distributed so that no centralized control is required for basic tasks such as traffic management and task mapping. To enable extensive analysis of different Network-on-Chip architectures, an in-house SystemC based simulation environment was implemented. It allows transaction level analysis without time consuming circuit level implementations during early design phases of novel architectures and features. The presented analysis shows that the dynamically clustered monitoring structure can be efficiently utilized for traffic management in faulty and congested Network-on-Chip-based multiprocessor systems. The monitoring structure can be also successfully applied for task mapping purposes. Furthermore, the analysis shows that the presented in-house simulation environment is flexible and practical tool for extensive Network-on-Chip architecture analysis.

Treatment of ununited anconeal process in 8 dogs by osteotomy and dynamic distraction of the proximal part of the ulna

A surgical technique for the treatment of ununited anconeal process in dogs treated by osteotomy and dynamic distraction of the proximal part of the ulna using a linear external skeletal fixator was evaluated. In all cases the osteotomy was distracted 1mm each day after the surgery until desired distraction had been achieved. Eight dogs and 9 joints diagnosed with ununited anconeal process were treated. The success of the procedure was determined by comparing clinical signs of lameness and degree of arthrosis at the time of diagnosis to 6 months after the surgical intervention. Radiographic union occurred in 88.9% of the affected joints between 21 and 42 days after the surgical procedure. Clinically, six elbows were classified as good, two as satisfactory and one as unsatisfactory. Six months after surgery two elbows had no arthrosis, one had Grade 1, two Grade 2 and one Grade 3. It is concluded the combination of ulnar osteotomy and dynamic distraction of the olecranon by a linear external skeletal fixator is a feasible procedure for the treatment of ununited anconeal process in dogs.

Dynamic optimization for the trajectory planning of robot manipulators in the presence of obstacles

This paper presents an approach to the solution of moving a robot manipulator with minimum cost along a specified geometric path in the presence of obstacles. The main idea is to express obstacle avoidance in terms of the distances between potentially colliding parts. The optimal traveling time and the minimum mechanical energy of the actuators are considered together to build a multiobjective function. A simple numerical example involving a Cartesian manipulator arm with two-degree-of-freedom is described.

Curving simulation and stability of a creep-controlled wheelset for high speed rail-vehicles

Higher travel speeds of rail vehicles will be possible by developing sophisticated top performance bogies having creep-controlled wheelsets. In this case the torque transmission between the right and the left wheel is realized by an actively controlled creep coupling. To investigate hunting stability and curving capability the linear equations of motion are written in state space notation. Simulation results are obtained with realistic system parameters from industry and various controller gains. The advantage of the „creep-controlled wheelset" is discussed by comparison the simulation results with the dynamic behaviour of the special cases „solid-axle wheelset" and „loose wheelset" (independent rotation of the wheels). The stability is also investigated with a root-locus analysis.

Advances in modelling of mechatronic systems: the toolset FASIM_C++ for the simulation of vehicle dynamics

The increasing complexity of controller systems, applied in modern passenger cars, requires adequate simulation tools. The toolset FASIM_C++, described in the following, uses complex vehicle models in three-dimensional vehicle dynamics simulation. The structure of the implemented dynamic models and the generation of the equations of motion applying the method of kinematic differentials is explained briefly. After a short introduction in methods of event handling, several vehicle models and applications like controller development, roll-over simulation and real-time-simulation are explained. Finally some simulation results are presented.

Dynamics of coherent vortices in mixing layers using direct numerical and large-eddy simulations

Coherent vortices in turbulent mixing layers are investigated by means of Direct Numerical Simulation (DNS) and Large-Eddy Simulation (LES). Subgrid-scale models defined in spectral and physical spaces are reviewed. The new "spectral-dynamic viscosity model", that allows to account for non-developed turbulence in the subgrid-scales, is discussed. Pseudo-spectral methods, combined with sixth-order compact finite differences schemes (when periodic boundary conditions cannot be established), are used to solve the Navier- Stokes equations. Simulations in temporal and spatial mixing layers show two types of pairing of primary Kelvin-Helmholtz (KH) vortices depending on initial conditions (or upstream conditions): quasi-2D and helical pairings. In both cases, secondary streamwise vortices are stretched in between the KH vortices at an angle of 45° with the horizontal plane. These streamwise vortices are not only identified in the early transitional stage of the mixing layer but also in self-similar turbulence conditions. The Re dependence of the "diameter" of these vortices is analyzed. Results obtained in spatial growing mixing layers show some evidences of pairing of secondary vortices; after a pairing of the primary Kelvin-Helmholtz (KH) vortices, the streamwise vortices are less numerous and their diameter has increased than before the pairing of KH vortices.

Numerical study of Petrov-Galerkin formulations for the shallow water wave equations

The behavior of Petrov-Galerkin formulations for shallow water wave equations is evaluated numerically considering typical one-dimensional propagation problems. The formulations considered here use stabilizing operators to improve classical Galerkin approaches. Their advantages and disadvantages are pointed out according to the intrinsic time scale (free parameter) which has a particular importance in this kind of problem. The influence of the Courant number and the performance of the formulation in dealing with spurious oscillations are adressed.

Numerical Simulation of Stochastic Di erential Equations

Stochastic differential equation (SDE) is a differential equation in which some of the terms and its solution are stochastic processes. SDEs play a central role in modeling physical systems like finance, Biology, Engineering, to mention some. In modeling process, the computation of the trajectories (sample paths) of solutions to SDEs is very important. However, the exact solution to a SDE is generally difficult to obtain due to non-differentiability character of realizations of the Brownian motion. There exist approximation methods of solutions of SDE. The solutions will be continuous stochastic processes that represent diffusive dynamics, a common modeling assumption for financial, Biology, physical, environmental systems. This Masters' thesis is an introduction and survey of numerical solution methods for stochastic differential equations. Standard numerical methods, local linearization methods and filtering methods are well described. We compute the root mean square errors for each method from which we propose a better numerical scheme. Stochastic differential equations can be formulated from a given ordinary differential equations. In this thesis, we describe two kind of formulations: parametric and non-parametric techniques. The formulation is based on epidemiological SEIR model. This methods have a tendency of increasing parameters in the constructed SDEs, hence, it requires more data. We compare the two techniques numerically.

Differentiation of Metabolically Distinct Areas within Head and Neck Region using Dynamic 18F-FDG Positron Emission Tomography Imaging

Positron Emission Tomography (PET) using ¹⁸F-FDG is playing a vital role in the diagnosis and treatment planning of cancer. However, the most widely used radiotracer, ¹⁸F-FDG, is not specific for tumours and can also accumulate in inflammatory lesions as well as normal physiologically active tissues making diagnosis and treatment planning complicated for the physicians. Malignant, inflammatory and normal tissues are known to have different pathways for glucose metabolism which could possibly be evident from different characteristics of the time activity curves from a dynamic PET acquisition protocol. Therefore, we aimed to develop new image analysis methods, for PET scans of the head and neck region, which could differentiate between inflammation, tumour and normal tissues using this functional information within these radiotracer uptake areas. We developed different dynamic features from the time activity curves of voxels in these areas and compared them with the widely used static parameter, SUV, using Gaussian Mixture Model algorithm as well as K-means algorithm in order to assess their effectiveness in discriminating metabolically different areas. Moreover, we also correlated dynamic features with other clinical metrics obtained independently of PET imaging. The results show that some of the developed features can prove to be useful in differentiating tumour tissues from inflammatory regions and some dynamic features also provide positive correlations with clinical metrics. If these proposed methods are further explored then they can prove to be useful in reducing false positive tumour detections and developing real world applications for tumour diagnosis and contouring.

Combinatorics on Words. New Aspects on Avoidability, Defect Effect, Equations and Palindromes

In this thesis we examine four well-known and traditional concepts of combinatorics on words. However the contexts in which these topics are treated are not the traditional ones. More precisely, the question of avoidability is asked, for example, in terms of k-abelian squares. Two words are said to be k-abelian equivalent if they have the same number of occurrences of each factor up to length k. Consequently, k-abelian equivalence can be seen as a sharpening of abelian equivalence. This fairly new concept is discussed broader than the other topics of this thesis. The second main subject concerns the defect property. The defect theorem is a well-known result for words. We will analyze the property, for example, among the sets of 2-dimensional words, i.e., polyominoes composed of labelled unit squares. From the defect effect we move to equations. We will use a special way to define a product operation for words and then solve a few basic equations over constructed partial semigroup. We will also consider the satisfiability question and the compactness property with respect to this kind of equations. The final topic of the thesis deals with palindromes. Some finite words, including all binary words, are uniquely determined up to word isomorphism by the position and length of some of its palindromic factors. The famous Thue-Morse word has the property that for each positive integer n, there exists a factor which cannot be generated by fewer than n palindromes. We prove that in general, every non ultimately periodic word contains a factor which cannot be generated by fewer than 3 palindromes, and we obtain a classification of those binary words each of whose factors are generated by at most 3 palindromes. Surprisingly these words are related to another much studied set of words, Sturmian words.

Flexible multibody dynamics and intelligent control of a hydraulically driven hybrid redundant robot machine

The assembly and maintenance of the International Thermonuclear Experimental Reactor (ITER) vacuum vessel (VV) is highly challenging since the tasks performed by the robot involve welding, material handling, and machine cutting from inside the VV. The VV is made of stainless steel, which has poor machinability and tends to work harden very rapidly, and all the machining operations need to be carried out from inside of the ITER VV. A general industrial robot cannot be used due to its poor stiffness in the heavy duty machining process, and this will cause many problems, such as poor surface quality, tool damage, low accuracy. Therefore, one of the most suitable options should be a light weight mobile robot which is able to move around inside of the VV and perform different machining tasks by replacing different cutting tools. Reducing the mass of the robot manipulators offers many advantages: reduced material costs, reduced power consumption, the possibility of using smaller actuators, and a higher payload-to-robot weight ratio. Offsetting these advantages, the lighter weight robot is more flexible, which makes it more difficult to control. To achieve good machining surface quality, the tracking of the end effector must be accurate, and an accurate model for a more flexible robot must be constructed. This thesis studies the dynamics and control of a 10 degree-of-freedom (DOF) redundant hybrid robot (4-DOF serial mechanism and 6-DOF 6-UPS hexapod parallel mechanisms) hydraulically driven with flexible rods under the influence of machining forces. Firstly, the flexibility of the bodies is described using the floating frame of reference method (FFRF). A finite element model (FEM) provided the Craig-Bampton (CB) modes needed for the FFRF. A dynamic model of the system of six closed loop mechanisms was assembled using the constrained Lagrange equations and the Lagrange multiplier method. Subsequently, the reaction forces between the parallel and serial parts were used to study the dynamics of the serial robot. A PID control based on position predictions was implemented independently to control the hydraulic cylinders of the robot. Secondly, in machining, to achieve greater end effector trajectory tracking accuracy for surface quality, a robust control of the actuators for the flexible link has to be deduced. This thesis investigates the intelligent control of a hydraulically driven parallel robot part based on the dynamic model and two schemes of intelligent control for a hydraulically driven parallel mechanism based on the dynamic model: (1) a fuzzy-PID self-tuning controller composed of the conventional PID control and with fuzzy logic, and (2) adaptive neuro-fuzzy inference system-PID (ANFIS-PID) self-tuning of the gains of the PID controller, which are implemented independently to control each hydraulic cylinder of the parallel mechanism based on rod length predictions. The serial component of the hybrid robot can be analyzed using the equilibrium of reaction forces at the universal joint connections of the hexa-element. To achieve precise positional control of the end effector for maximum precision machining, the hydraulic cylinder should be controlled to hold the hexa-element. Thirdly, a finite element approach of multibody systems using the Special Euclidean group SE(3) framework is presented for a parallel mechanism with flexible piston rods under the influence of machining forces. The flexibility of the bodies is described using the nonlinear interpolation method with an exponential map. The equations of motion take the form of a differential algebraic equation on a Lie group, which is solved using a Lie group time integration scheme. The method relies on the local description of motions, so that it provides a singularity-free formulation, and no parameterization of the nodal variables needs to be introduced. The flexible slider constraint is formulated using a Lie group and used for modeling a flexible rod sliding inside a cylinder. The dynamic model of the system of six closed loop mechanisms was assembled using Hamilton’s principle and the Lagrange multiplier method. A linearized hydraulic control system based on rod length predictions was implemented independently to control the hydraulic cylinders. Consequently, the results of the simulations demonstrating the behavior of the robot machine are presented for each case study. In conclusion, this thesis studies the dynamic analysis of a special hybrid (serialparallel) robot for the above-mentioned special task involving the ITER and investigates different control algorithms that can significantly improve machining performance. These analyses and results provide valuable insight into the design and control of the parallel robot with flexible rods.