Nucleophilic addition of Nitrones to Electron deficient acetylenes and related studies

Nitrones or azomethine-N-oxides are important precursors for the synthesis of several heterocyclic systems. They belong to the allyl anion type 1,3-dipoles and possess unique structural features which make them extraordinarily useful synthons. They behave as 1,3-dipoles in 1,3-dipolar cycloaddition reactions and as electrophiles in reactions with organometallic reagents. These are the two basic reactions given by nitrones. Nitrones also act as ‘spin traps’ in which they react with short-lived radicals to furnish stable nitroxide radicals which can be detected and identified by electron paramagnetic resonance (EPR) spectroscopy. Recently SmI2 catalysed reductive cross-coupling reactions of nitrones have gained significant interest in which the reactions are initiated by single electron transfer (SET) to nitrones. Apart from these reactions, nitrones are also known to participate in reactions which are initiated by the nucleophilic attack of nitrone-oxygen. In our group, we have also explored the nucleophilic character of nitrones through various reactions. The results obtained enabled us to develop a novel two-step one-pot strategy for quinolines and indoles - the heterocycles renowned for their pharmacological applications, from nitrones and electron deficient acetylenes. Using dibenzoylacetylene and phenylbenzoylacetylene as dipolarophiles, we could introduce a desired functional group at a predetermined position of the quinolines or indoles to be synthesised. In this context, the thesis entitled “NUCLEOPHILIC ADDITION OF NITRONES TO ELECTRON DEFICIENT ACETYLENES AND RELATED STUDIES” portrays our attempt to expand the scope of our x novel synthetic protocol using ester functionalised acetylenes: dimethyl acetylenedicarboxylate (DMAD) and methyl propiolate. The thesis is organised in to five chapters. The first chapter briefly describes the different classes of reactions that nitrone functionality can tolerate. The research problem is defined at the end of this chapter. The second chapter describes the synthesis of different nitrones used for the present study. The optimisation and expansion of scope of the novel strategy towards quinoline synthesis is discussed in the third chapter. The fourth chapter portrays the synthesis of indole-3-carboxylates using the novel strategy. In the fifth chapter, the reaction of N-(2,6-dimethylphenyl) and N-(2,4,6-trimethylphenyl)nitrones are discussed. Here we also discuss the mechanistic reinvestigation of Baldwin’s proposal in the isoxazoline-oxazoline rearrangement. The major outcome of the work is given at the end of the thesis. The structural formulae, schemes, tables and figures are numbered chapter-wise since each chapter of the thesis is organized as an independent unit. All new compounds (except two compounds reported in fourth chapter) are fully characterised on the basis of spectral and analytical data and single crystal X-ray analysis on representative examples. Relevant references are included at the end of individual chapters.

Improving the stability of an oxime based electrochemical microsensor for organo-phosphate vapor detection

A micro gas sensor has been developed by our group for the detection of organo-phosphate vapors using an aqueous oxime solution. The analyte diffuses from the high flow rate gas stream through a porous membrane to the low flow rate aqueous phase. It reacts with the oxime PBO (1-Phenyl-1,2,3,-butanetrione 2-oxime) to produce cyanide ions, which are then detected electrochemically from the change in solution potential. Previous work on this oxime based electrochemistry indicated that the optimal buffer pH for the aqueous solution was approximately 10. A basic environment is needed for the oxime anion to form and the detection reaction to take place. At this specific pH, the potential response of the sensor to an analyte (such as acetic anhydride) is maximized. However, sensor response slowly decreases as the aqueous oxime solution ages, by as much as 80% in first 24 hours. The decrease in sensor response is due to cyanide which is produced during the oxime degradation process, as evidenced by the cyanide selective electrode. Solid phase micro-extraction carried out on the oxime solution found several other possible degradation products, including acetic acid, N-hydroxy benzamide, benzoic acid, benzoyl cyanide, 1-Phenyl 1,3-butadione, 2-isonitrosoacetophenone and an imine derived from the oxime. It was concluded that degradation occurred through nucleophilic attack by a hydroxide or oxime anion to produce cyanide, as well as a nitrogen atom rearrangement similar to Beckmann rearrangement. The stability of the oxime in organic solvents is most likely due to the lack of water, and specifically hydroxide ions. The reaction between oxime and organo-phosphate to produce cyanide ions requires hydroxide ions, and therefore pure organic solvents are not compatible with the current micro-sensor electrochemistry. By combining a concentrated organic oxime solution with the basic aqueous buffer just prior to being used in the detection process, oxime degradation can be avoided while preserving the original electrochemical detection scheme. Based on beaker cell experiments with selective cyanide sensitive electrodes, ethanol was chosen as the best organic solvent due to its stabilizing effect on the oxime, minimal interference with the aqueous electrochemistry, and compatibility with the current microsensor material (PMMA). Further studies showed that ethanol had a small effect on micro-sensor performance by reducing the rate of cyanide production and decreasing the overall response time. To avoid incomplete mixing of the aqueous and organic solutions, they were pre-mixed externally at a 10:1 ratio, respectively. To adapt the microsensor design to allow for mixing to take place within the device, a small serpentine channel component was fabricated with the same dimensions and material as the original sensor. This allowed for seamless integration of the microsensor with the serpentine mixing channel. Mixing in the serpentine microchannel takes place via diffusion. Both detector potential response and diffusional mixing improve with increased liquid residence time, and thus decreased liquid flowrate. Micromixer performance was studies at a 10:1 aqueous buffer to organic solution flow rate ratio, for a total rate of 5.5 μL/min. It was found that the sensor response utilizing the integrated micromixer was nearly identical to the response when the solutions were premixed and fed at the same rate.

Síntese, caracterização e reatividade de complexos organoestânicos contendo bases de Schiff derivadas de aminoácidos com carbonilas de Mo. W e Re

Tese (doutorado)–Universidade de Brasília, Instituto de Química, Programa de Pós-Graduação em Química, 2015.

Exploring coordination-driven self-assembly with autonomous chemical robots

The work presented herein focused on the automation of coordination-driven self assembly, exploring methods that allow syntheses to be followed more closely while forming new ligands, as part of the fundamental study of the digitization of chemical synthesis and discovery. Whilst the control and understanding of the principle of pre-organization and self-sorting under non-equilibrium conditions remains a key goal, a clear gap has been identified in the absence of approaches that can permit fast screening and real-time observation of the reaction process under different conditions. A firm emphasis was thus placed on the realization of an autonomous chemical robot, which can not only monitor and manipulate coordination chemistry in real-time, but can also allow the exploration of a large chemical parameter space defined by the ligand building blocks and the metal to coordinate. The self-assembly of imine ligands with copper and nickel cations has been studied in a multi-step approach using a self-built flow system capable of automatically controlling the liquid-handling and collecting data in real-time using a benchtop MS and NMR spectrometer. This study led to the identification of a transient Cu(I) species in situ which allows for the formation of dimeric and trimeric carbonato bridged Cu(II) assemblies. Furthermore, new Ni(II) complexes and more remarkably also a new binuclear Cu(I) complex, which usually requires long and laborious inert conditions, could be isolated. The study was then expanded to the autonomous optimization of the ligand synthesis by enabling feedback control on the chemical system via benchtop NMR. The synthesis of new polydentate ligands has emerged as a result of the study aiming to enhance the complexity of the chemical system to accelerate the discovery of new complexes. This type of ligand consists of 1-pyridinyl-4-imino-1,2,3-triazole units, which can coordinate with different metal salts. The studies to test for the CuAAC synthesis via microwave lead to the discovery of four new Cu complexes, one of them being a coordination polymer obtained from a solvent dependent crystallization technique. With the goal of easier integration into an automated system, copper tubing has been exploited as the chemical reactor for the synthesis of this ligand, as it efficiently enhances the rate of the triazole formation and consequently promotes the formation of the full ligand in high yields within two hours. Lastly, the digitization of coordination-driven self-assembly has been realized for the first time using an in-house autonomous chemical robot, herein named the ‘Finder’. The chemical parameter space to explore was defined by the selection of six variables, which consist of the ligand precursors necessary to form complex ligands (aldehydes, alkineamines and azides), of the metal salt solutions and of other reaction parameters – duration, temperature and reagent volumes. The platform was assembled using rounded bottom flasks, flow syringe pumps, copper tubing, as an active reactor, and in-line analytics – a pH meter probe, a UV-vis flow cell and a benchtop MS. The control over the system was then obtained with an algorithm capable of autonomously focusing the experiments on the most reactive region (by avoiding areas of low interest) of the chemical parameter space to explore. This study led to interesting observations, such as metal exchange phenomena, and also to the autonomous discovery of self assembled structures in solution and solid state – such as 1-pyridinyl-4-imino-1,2,3-triazole based Fe complexes and two helicates based on the same ligand coordination motif.

Determination of the cytotoxic capacity of organotin compounds derivatives from salicylidene benzoylhidrazone

The successful application of metal complexes in the treatment of many diseases, including cancer, is a rapidly expanding area in biomedical chemistry and research. Organotin compounds studies show the versatility and the attractive features of these molecules. In the same manner, has been reported the development of new compounds derivative from bezoylhidrazones, which possess the azomethine fragment (-N = CH-), key pillar for designing new drugs with biological activity. Based on the above, we are interested in to synthesize four tin compounds derivatives from benzoylhidrazones, and the evaluation of their cytotoxic capacity. Conclusions and contribution: In this research work, we reported four new tin compounds derivatives from bezoylhidrazones, which were characterized by spectroscopic and spectrometric techniques and X-ray diffraction In the same manner, cytotoxic ability of each compound was studied and reported and compared with metaled base drugs like cisplatin and carboplatin. Also, in some cases it was possible to use their luminescent ability to study their intracellular behavior.

Remote Substituent Effects on the Stereoselectivity and Organocatalytic Activity of Densely Substituted Unnatural Proline Esters in Aldol Reactions

The organocatalytic activities of highly substituted proline esters obtained through asymmetric [3+2] cycloadditions of azomethine ylides derived from glycine iminoesters have been analyzed by 19F NMR and through kinetic isotope effects. Kinetic rate constants have been determined for unnatural proline esters incorporating different substituents. It has been found that exo-L and endo-L unnatural proline methyl esters yield opposite enantiomers in aldol reactions between cyclic ketones and aromatic aldehydes. The combined results reported in this study show subtle and remote effects that determine the organocatalytic behavior of these synthetic but readily available amino acid derivatives. These data can be used as design criteria for the development of new pyrrolidine-based organocatalysts.

Physicochemical complexity in complex chemical systems

Self-replication and compartmentalization are two central properties thought to be essential for minimal life, and understanding how such processes interact in the emergence of complex reaction networks is crucial to exploring the development of complexity in chemistry and biology. Autocatalysis can emerge from multiple different mechanisms such as formation of an initiator, template self-replication and physical autocatalysis (where micelles formed from the reaction product solubilize the reactants, leading to higher local concentrations and therefore higher rates). Amphiphiles are also used in artificial life studies to create protocell models such as micelles, vesicles and oil-in-water droplets, and can increase reaction rates by encapsulation of reactants. So far, no template self-replicator exists which is capable of compartmentalization, or transferring this molecular scale phenomenon to micro or macro-scale assemblies. Here a system is demonstrated where an amphiphilic imine catalyses its own formation by joining a non-polar alkyl tail group with a polar carboxylic acid head group to form a template, which was shown to form reverse micelles by Dynamic Light Scattering (DLS). The kinetics of this system were investigated by 1H NMR spectroscopy, showing clearly that a template self-replication mechanism operates, though there was no evidence that the reverse micelles participated in physical autocatalysis. Active oil droplets, composed from a mixture of insoluble organic compounds in an aqueous sub-phase, can undergo processes such as division, self-propulsion and chemotaxis, and are studied as models for minimal cells, or protocells. Although in most cases the Marangoni effect is responsible for the forces on the droplet, the behaviour of the droplet depends heavily on the exact composition. Though theoretical models are able to calculate the forces on a droplet, to model a mixture of oils on an aqueous surface where compounds from the oil phase are dissolving and diffusing through the aqueous phase is beyond current computational capability. The behaviour of a droplet in an aqueous phase can only be discovered through experiment, though it is determined by the droplet's composition. By using an evolutionary algorithm and a liquid handling robot to conduct droplet experiments and decide which compositions to test next, entirely autonomously, the composition of the droplet becomes a chemical genome capable of evolution. The selection is carried out according to a fitness function, which ranks the formulation based on how well it conforms to the chosen fitness criteria (e.g. movement or division). Over successive generations, significant increases in fitness are achieved, and this increase is higher with more components (i.e. greater complexity). Other chemical processes such as chemiluminescence and gelation were investigated in active oil droplets, demonstrating the possibility of controlling chemical reactions by selective droplet fusion. Potential future applications for this might include combinatorial chemistry, or additional fitness goals for the genetic algorithm. Combining the self-replication and the droplet protocells research, it was demonstrated that the presence of the amphiphilic replicator lowers the interfacial tension between droplets of a reaction mixture in organic solution and the alkaline aqueous phase, causing them to divide. Periodic sampling by a liquid handling robot revealed that the extent of droplet fission increased as the reaction progressed, producing more individual protocells with increased self-replication. This demonstrates coupling of the molecular scale phenomenon of template self-replication to a macroscale physicochemical effect.

Improvement of The Driver Simulator Control and Comparison Between Driver-Road-Vehicle Interaction in Real and Simulated Environment

The present doctoral thesis discusses the ways to improve the performance of driving simulator, provide objective measures for the road safety evaluation methodology based on driver’s behavior and response and investigates the drivers' adaptation to the driving assistant systems. The activities are divided into two macro areas; the driving simulation studies and on-road experiments. During the driving simulation experimentation, the classical motion cueing algorithm with logarithmic scale was implemented in the 2DOF motion cueing simulator and the motion cues were found desirable by the participants. In addition, it found out that motion stimuli could change the behaviour of the drivers in terms of depth/distance perception. During the on-road experimentations, The driver gaze behaviour was investigated to find the objective measures on the visibility of the road signs and reaction time of the drivers. The sensor infusion and the vehicle monitoring instruments were found useful for an objective assessment of the pavement condition and the drivers’ performance. In the last chapter of the thesis, the safety assessment during the use of level 1 automated driving “ACC” is discussed with the simulator and on-road experiment. The drivers’ visual behaviour was investigated in both studies with innovative classification method to find the epochs of the distraction of the drivers. The behavioural adaptation to ACC showed that drivers may divert their attention away from the driving task to engage in secondary, non-driving-related tasks.

Motion Cueing Algorithm Development in a 2DOF Driving Simulator: a Driving Behaviour-Centered Approach

I simulatori di guida sono strumenti altamente tecnologici che permettono di svolgere attività di ricerca in vari ambiti quali la psicologia, la medicina e l’ingegneria. Tuttavia, affinché i dati ottenuti mediante le simulazioni siano rapportabili alla loro controparte reale, la fedeltà delle componenti del simulatore di guida deve essere elevata. Questo lavoro tratta del miglioramento del sistema di restituzione del movimento nel simulatore a due gradi di libertà (2DOF) SIMU-LACET Driving Simulator, costruito e sviluppato presso il laboratorio LEPSIS dell’IFSTTAR (Istituto Francese delle Scienze e Tecnologie dei Trasporti, dello Sviluppo e delle Reti), in particolare nella sua sede di Parigi – Marne-la-Vallée. Si è deciso di andare a riprogettare la parte software del sistema di restituzione del movimento (motion cueing), operando su due elementi principali: lo scale factor (fattore di scala) applicato agli impulsi dinamici provenienti dal modello veicolare e i Motion Cueing Algorihms (MCA, algoritmi di restituzione del movimento), questo per entrambi i gradi di libertà. Si è quindi intervenuti sul modello esistente implementato in MATLAB-Simulink nello specifico blocco del motion cueing sul surge (traslazione longitudinale) e sul yaw (imbardata). Riguardo lo scale factor, è stata introdotta una metodologia per creare uno scale factor non lineare in forma esponenziale, tale da migliorare la restituzione degli impulsi meno ampi, pur rispettando i limiti fisici della piattaforma di movimento. Per quanto concerne il MCA, si sono vagliate diverse transfer function dell’algoritmo classico. La scelta finale dei MCA e la validazione del motion cueig in genere è stata effettuata mediante due esperimenti ed il giudizio dei soggetti che vi hanno partecipato. Inoltre, in virtù dei risultati del primo esperimento, si è investigata l’influenza che la strategia in merito al cambio delle marce avesse sulla percezione del movimento da parte del guidatore.

Study of risky situations using experimental data coming from an instrumented bicycle

The aim of this master’s thesis is to study the risky situations of the cyclist when they interact with road infrastructure and other road users as well as the influence of speed on safety. This research activity is linked with the SAFERUP (Sustainable, Accessible, Resilient, and Smart Urban Pavement) European funded project where one of the doctoral candidate has performed experiments on the bicycle simulation at the Gustave Eiffel university in the PICS-L laboratory (Paris) and instrumented bicycle at the Stockholm (Sweden). The approach of the experiment was to hire a number of people who have participated in the riding of the Instrumented bicycle (Stockholm) and bicycle simulator (PICS-L) which were developed by attaching different sensors and devices to measure important parameters of the bicycle riding and their data was collected to analysis in order to understand the behavior of the cyclist to improve the safety. In addition, a mobile eye tracker wore by participants to record the real experiment scenario, and after the end of the trip, each participant shared their remarks regarding their experience of bicycle riding according to different portions of the road infrastructure. In this research main focus is to analyze the relevant data such as speed profiles, video recordings and questionnaire surveys from the instrumented bicycle experiment. In fact, critical situations, where there was a higher probability, were compared with the subjective evaluation of the participant to be conscious of the issues related to the safety and comfort of the cyclist in different road characteristics.