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Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Orienterend onderzoek naar de integrale inpassing van aanzuren van varkensmengmest = Pre-investigation on the integrated implementation of pig slurry acidification
    Derikx, P.J.L. ; Vijn, T.K. ; Willers, H.C. - \ 1993
    Wageningen : IMAG-DLO (Rapport / Instituut voor Mechanisatie, Arbeid en Gebouwen 93-34) - 41
    luchtverontreiniging - ammoniak - chemische reacties - emissie - stikstof - vervluchtiging - air pollution - ammonia - chemical reactions - emission - nitrogen - volatilization
    Enzymatic synthesis of polyol seters in aqueous - organic two-phase systems
    Janssen, A. - \ 1993
    Agricultural University. Promotor(en): K. van 't Riet. - S.l. : Janssen - ISBN 9789054851271 - 181
    emulgeermiddelen - chemische reacties - synthese - carboxyl ester hydrolasen - tannase - choline esterase - triacylglycerol lipase - koolhydraten - vetzuren - carbonzuren - emulsifiers - chemical reactions - synthesis - carboxylic ester hydrolases - tannase - cholinesterase - triacylglycerol lipase - carbohydrates - fatty acids - carboxylic acids

    The last decade increasingly attention is paid to lipases as catalysts for synthesis of components, such as fatty acid-based surfactants, flavors, edible oil equivalents, monomers and polymers, and amides. In this thesis, the lipase-catalyzed esterification of polyols and fatty acids is described. These esters consist of a nonpolar part (fatty acid) and a polar part (polyol). Therefore, polyol esters have surface-active properties and are used as emulsifier in food, pharmaceutics; and cosmetics. One of the aims of this thesis is to develop a reaction system for the esterification of polyols (carbohydrates) and fatty acids, without any modification of the substrates. Also, high reaction rates are desired.

    Enzymatic esterification is often performed in the presence of organic solvents. Besides activity and stability of the enzymes, the solvents will affect the equilibrium position of reactions. In literature, models were described for the prediction of the equilibrium position in dilute two-phase systems. However, for industrial applications, high product concentrations are desired, which implicate the use of nondilute reaction systems. Another aim of this thesis is to gain a better insight in factors that affect the equilibrium position of a reaction and to predict the product concentrations at equilibrium in non-dilute two-phase systems.

    In chapter 2 and 3, the lipase-catalyzed esterification of sorbitol and fatty acid is studied in two different two-phase reaction systems. In chapter 2, 2-pyrrolidone is used as a cosolvent for sorbitol. In this study, the lipase from Chromobacterium viscosum is used and the initial esterification rate is high as compared to literature data. The water activity is found to be important for the ester concentrations at equilibrium. High concentrations of the cosolvent 2-pyrrolidone should be avoided, because these will inactivate the lipase. In the reaction system that is described in chapter 3, water is used to dissolve sorbitol. Candida rugosa lipase is used in this study and initial esterification rates are slightly higher than in chapter 2. The water activity is dependent on the sorbitol mole fraction in the aqueous phase and lowering of the water activity is limited by the solubility of sorbitol. A two-phase membrane reactor is a suitable type of reactor, since the water activity of the aqueous phase can be kept constant during the experiment and lipase possesses a good stability. In both reaction systems, besides sorbitol also glucose and fructose can be used as a substrate, while disaccharides, such as sucrose, are not reactive at all.

    In chapter 4, the lipase-catalyzed esterification of glycerol and decanoic acid has been studied in aqueous-organic two-phase systems. The addition of an organic solvent is found to influence the ester mole fractions at equilibrium. For the synthesis of polar products (monoesters), a polar solvent (low log P) is favorable, while for the synthesis of nonpolar products (triesters), it is better to choose a nonpolar solvent (high log P). The computer program 'Two-phase Reaction Equilibrium Prediction' (TREP) has been developed for the prediction of the ester concentrations in nondilute two-phase systems, in case both the reaction equilibrium as well as the phase equilibrium are achieved. This program is based on mass balances and the UNIFAC group contribution method. Deviations in the prediction with TREP are generally less then a factor of 2 and are due to inaccuracies of the UNIFAC group contribution method.

    The lipase-catalyzed acylglycerol synthesis with fatty acids of different chain length is studied in chapter 5. For predictions with TREP, one set of equilibrium constants is used for monoester, diester, and triester synthesis. It is shown that with this set the equilibrium position of the reaction between glycerol and all saturated fatty acids with a chain length from 6 to 18 and oleic acid can be calculated within some margins. For fatty acids with different chain length, the ester mole fractions at equilibrium are clearly different. With the short-chain hexanoic acid, the monoester mole fraction is highest, while for the long-chain oleic acid, the diester mole fraction is the highest one. Besides the equilibrium position, also the reaction rates are affected by the solvent that is added. In polar solvents, the monoester production rate is enhanced. This is caused by the shift in the equilibrium mole fractions.

    In chapter 6, the effect of solvents on the esterification of decanoic acid and several alcohols, such as 1-dodecanol, 1-butanol, 1,3-propanediol, and sorbitol is studied. In agreement with the previous results, the ester mole fractions at the reaction equilibrium are dependent on the solvability of the ester in the organic phase. This effect is most striking for the polar sorbitol esters. Almost no esters are present at equilibrium in systems with nonpolar solvents, while reasonable high ester mole fractions can be obtained in systems with polar solvents. In contrast with the results of chapter 5, the equilibrium constants are clearly affected by the type of alcohol that is chosen as a substrate. Calculations with TREP showed that the calculated ester mole fractions did not deviate more than a factor of 1.5 from the measured ones. However, it appears that the calculated water mole fractions deviate systematically in the downwards direction.

    Chapter 7 shows a comparison between models in literature for the prediction of the equilibrium position in dilute two-phase reaction systems and calculations with TREP. It is shown that the models from literature are limited to reaction systems in which partition coefficients are constant. The program TREP can be used for nondilute as well as dilute reaction systems.

    Furthermore, this chapter shows that the ester mole fractions at equilibrium can be increased with increasing temperature. This is due to the increase of the solubility of sorbitol with increasing temperature. Most pronounced is the effect of temperature on the reaction rate, which is increased enormously. However, for long-term processes at high temperatures it is important that heat-stable lipases will be used.

    Enzymatic acylglycerol synthesis in membrane reactor systems
    Padt, A. van der - \ 1993
    Agricultural University. Promotor(en): K. van 't Riet. - S.l. : Van der Padt - ISBN 9789054851264 - 151
    derivaten - alcoholen - glycerol - acylglycerolen - diacylglycerolen - triacylglycerolen - chemische reacties - membranen - omgekeerde osmose - ultrafiltratie - fermentatie - voedselbiotechnologie - vetzuren - carbonzuren - derivatives - alcohols - glycerol - acylglycerols - diacylglycerols - triacylglycerols - chemical reactions - membranes - reverse osmosis - ultrafiltration - fermentation - food biotechnology - fatty acids - carboxylic acids

    Up till twenty years ago, only chemical modifications of agricultural oils for novel uses were studied. Because of the instability of various fatty acids, enzymatic biomodifications can have advantages above the chemical route. Nowadays, enzymatic catalysis can be used for the modification of oils and fats. One way of biomodification is the enzymatic esterification of glycerol with fatty acid for the synthesis of mono- and triacylglycerols. Monoesters (monoacylglycerols) are used as emulsifiers in food and in cosmetics, tailor made triesters (triacylglycerols) are used to adjust the melting range of foods and cosmetics. This thesis describes a number of membrane reactor systems for the enzymatic esterification of glycerol with decanoic acid in hexadecane as solvent. Description and modelling of the kinetics and thermodynamic equilibrium have resulted in reactor concepts to reach the objective of mono- and triester synthesis.

    The basic reactor studied is a two-phase immobilized enzyme membrane reactor. In the membrane reactor, lipase from Candida ragosa is immobilized at the inner fibre side of a hydrophilic hollow fibre module. Decanoic acid in n-hexadecane is circulated at the same side, meanwhile a water-glycerol phase is circulated at the shell side. The glycerol diffuses through the membrane matrix allowing the synthesis to take place at the interface. The water produced diffuses backwards.

    Chapter 2 describes the enzymatic esterification of decanoic acid with glycerol for an emulsion system and for a hydrophilic membrane system. In a two-phase system, the enzyme activity is related to the oil-phase volume, the interface area and the enzyme load. The rate per unit interface area of the membrane system approximates the rate measured in an emulsion system. This implies that the cellulose membrane does not affect the esterification. Another consequence is that the activity per oil-phase volume is only specific surface area related, therefore a hollow fibre device is desirable. The optimum enzyme load in the membrane system is half of that in the emulsion system.

    The enzyme stability in glycerol-water mixtures is described in chapter 3. The activity of lipase from Candida rugosa with time can be described with a two-step model, assuming the native lipase reversibly altering its conformation to a form having no activity. The reversibility is experimentally verified. Both, the native and inactive form do inactivate irreversible at the same time to a completely inactive form. The inactivation is a function of the glycerol concentration. The activity of immobilized enzyme is reduced to the same level of activity as is found for free lipase.

    Not only activity and stability of the enzymatic system are of importance, also the equilibrium ester concentrations must be known in the non-ideal two-phase system. Chapter 4 presents the program TREP (Two-phase Reaction Equilibrium Prediction). With the use of measured thermodynamic activity based equilibrium constants, mass balances and the UNIFAC group contribution method, TREP predicts the equilibrium product and substrate concentrations for given initial amounts. Equilibrium predictions show that an excess of triesters can be obtained only at low water activity conditions, in this case an one-phase system is predicted. Predictions show that pure monoesters cannot be obtained in a two-phase system of decanoic acid-hexadecane phase and a glycerol-water phase, even with a high glycerol to fatty acid ratio. This is experimentally verified.

    From the knowledge gathered in these chapters, two membrane reactor systems are designed, one membrane reactor for the triester production and a second membrane reactor system equipped with an in-line adsorption column for the synthesis of monoesters.

    Chapter 5 describes a pervaporation system in which an excess of triesters can be synthesized at low water activity conditions. Lipase is immobilized onto the lumen side of a cellulose membrane where the organic phase is present. At the shell side, air circulates and the water activity is controlled with the use of a condenser. The lipase catalyzed esterification of decanoic acid with partial glycerides is studied in this reactor. In agreement with the predictions made in chapter 4, an excess of triacylglycerols, is obtained at low water activity conditions only.

    A second membrane reactor concept is described in chapter 6, the organic-phase is led over an adsorption column in order to adsorb the monoglycerides onto the adsorbate. When the column is saturated with monoesters, the column can be desorbed off-line in a continuous membrane/repeated batch column process. If a 5 % ethanol in hexane solution is used as desorption solvent, monoesters are desorbed selectively leading to a 90 % purity.

    Finally, in chapter 7, the potentials and limitations of the enzymatic esterification are discussed. To predict the steady-state concentration of a continuous reactor, the enzyme kinetics must be described. The membrane reactor is reaction limited, this could be overcome by placing a column packed with immobilized enzyme in the organic phase recirculation loop. Not only esterification can be performed in the pervaporation system, this system could also be suitable for interesterification or transesterification. Then the program TREP should be extended for reactions with different types of fatty acids.

    Engineering aspects of nitrification with immobilized cells
    Hunik, J.H. - \ 1993
    Agricultural University. Promotor(en): J. Tramper. - Wageningen : Hunik - 167
    chemische reacties - biotechnologie - chemische industrie - biochemie - cellen - immobilisatie - bradyrhizobiaceae - geïmmobiliseerde cellen - chemical reactions - biotechnology - chemical industry - biochemistry - cells - immobilization - bradyrhizobiaceae - immobilized cells

    Several aspects of a nitrification process with artificially immobilized cells in an airlift loop reactor have been investigated and are described in this thesis. In chapter 1 an overview of immobilization methods, suitable reactors, modelling, small-scale
    applications and scale-up strategy is given. The subjects of chapter 1 provide the starting point of the following chapters. Application of immobilized cells is beneficial for the nitrification process at high product and substrate concentrations and with a process temperature far below the optimal temperature of 30-35°C. In chapter 2 and 3 the kinetics of, respectively, Nitrosomonas europaea and Nitrobacter agilis cells at high product and substrate concentrations is presented. The results show a severe product inhibition of Nitrobacter agilis by nitrite, while Nitrosomonas europaea seems to be more sensitive
    for a high osmotic pressure. In chapter 4 a theoretical background of the immobilization method and further scale-up is presented. For the immobilization method the theory for the break-up of liquid jets, with Newtonian behaviour, is evaluated and a method to apply this theory for non-Newtonian liquids like a K-carrageenan solution is presented. In chapter 6 a dynamic model for the nitrification with immobilized Nitrosomonas europaea and Nitrobacter agilis cells is presented. The model includes mass-transfer rates, kinetic behaviour of the microorganisms, and reactor and gel bead properties. Predictions
    of reactor bulk concentrations of NH 4+, NO 2-and NO 3-(N-compounds) are given by the model together with concentration profiles of N-compounds, oxygen and biomass in the gel beads. A sensitivity analysis of the model parameters shows that the diffusion coefficient of oxygen in the gel beads and the radius of the gel beads are the most important parameters influencing the model output. The model is experimentally validated by means of reactor bulk concentrations and biomass profiles of Nitrosomonas europaea and Nitrobacter agilis in the gel beads. Predicted and measured values agree very well and the assumptions and equations used in the model seem to be valid. The biomass profiles of the two microorganisms co-immobilized in the gel beads are determined with immunofluorescence and a stereological method (chapter 5). The immunofluorescence technique was used to separate the Nitrosomonas europaea and Nitrobacter agilis colonies in the beads. From the position and diameter of the colonies it is possible to determine the spatial distribution of the two microorganisms in the gel beads. In chapter 7 the model is used as a tool to develop a strategy to scale-up the nitrification process with immobilized cells. A design for a large-scale application should be optimized with respect to the transport of oxygen to the immobilized cells in the gel beads. This is an advantage over the nitrification process with suspended cells, which is limited by the growth rate of the nitrifying bacteria. The growth of nitrifying bacteria is a slower process than the transport of oxygen to the cells. Some interesting aspects, which were not treated elsewhere in this thesis, are discussed in the general discussion in chapter 8.

    De beweeglijke balans tussen chemische bindingsprocessen en biologische opnameprocessen.
    Riemsdijk, W.H. van - \ 1993
    Bodem 3 (1993). - ISSN 0925-1650 - p. 173 - 175.
    chemische speciatie - chemische reacties - anorganische verbindingen - mineralen - voedingsstoffen - biologische beschikbaarheid - plantenvoeding - bodemchemie - bodemfumigatie - bodemeigenschappen - grondsterilisatie - binding (scheikundig) - chemical speciation - chemical reactions - inorganic compounds - minerals - nutrients - bioavailability - plant nutrition - soil chemistry - soil fumigation - soil properties - soil sterilization - bonding
    In het kader van bodembeschermingsbeleid wordt aandacht geschonken aan de problematiek van de biologische beschikbaarheid van (anorganische) stoffen in de bodem
    Physical aspects of liquid-impelled loop reactors
    Sonsbeek, H. van - \ 1992
    Agricultural University. Promotor(en): J. Tramper. - S.l. : [s.n.] - 135
    chemische reacties - uitrusting - massaoverdracht - vloeistofmechanica - vloeistoffen (liquids) - vloeistoffen (fluids) - vermenging - dichtheid - chemical reactions - equipment - mass transfer - fluid mechanics - liquids - fluids - mixing - density

    The liquid-impelled loop reactor (LLR) is a reactor that consists of two parts : the main tube and the circulation tube. Both parts are in open connection at the bottom and at the top. The reactor is filled with a liquid phase: the continuous phase. Another liquid phase is injected in the main tube by means of pumping. This liquid phase is immiscible with the continuous phase and its density is significantly different. If the density is higher than the density of the continuous phase, injection takes places at the top of the main tube. For a lower density injection takes place at the bottom. Due to the density difference the dispersed-phase droplets that are formed will fall or rise, respectively, and coalesce at the other end of the tube. The coalesced liquid is discharged from the reactor. Due to the presence of dispersed phase in the main tube a pressure difference exists which causes circulation of the continuous phase in the reactor. This results in good mixing without the use of an impeller. For biotechnological purposes it is most likely that the continuous phase is an aqueous phase that contains the biocatalyst, possibly immobilized. The work on the liquid-impelled loop reactor originates from two previous research studies. First, the physical characterisation and modelling of air-lift loop reactors for application in cultivating shear-sensitive biocatalysts. Second, the research focused on application of organic solvents in biological processes, which is a promising area for many years already.

    In a review the current state of the art is given with respect to biocatalysis in media consisting of two liquid phases that are not miscible. This research area has shown much progress in recent years, however, industrial applications seem still not very numerous. To carry out two-liquid-phase experiments on a scale bigger than shake flasks, in most cases existing bioreactors are used. Adjustments are made to the reactor and the processing to make them suitable for use with two liquid phases. The liquid-impelled loop reactor can be seen as a special case, where an air-lift loop reactor is adjusted for use with two liquid phases instead of a liquid and a gas phase.

    The research was started with characterisation of important physical aspects such as drop size, dispersed-phase concentration (holdup) and continuous-phase velocity as function of the dispersed-phase flow rate. Description of drop sizes that are formed in the liquid-impelled loop reactor at the liquid sparger, show good agreement with theoretical predictions. The hydrodynamic model that was used in the air-lift loop study is applied. It shows to be a good method to describe holdup and liquid velocity. The best results with this model are obtained when it is assumed that the continuous phase flows fastest in the centre of the tube and that the dispersed phase concentrates in the centre of the tube.

    On the topic of hydrodynamic models for air-lift loop reactors many articles are published. Because this still continues, this literature is analysed and the basic principles of the several models are described and compared. It appears that in all models the relative velocity between dispersed-phase bubbles and continuous phase plays an essential role. This quantity is difficult to determine and shows a wide spread due to the distribution in bubble size. Furthermore, velocity profiles or turbulence can have much influence but are not taken into account in the described models. Comparison of the models by means of using literature data did not yield a clear preference for one of the models nor for a particular basic principle.

    To describe mixing in the continuous phase, the one-dimensional axial dispersion model is used, which is in general suitable for flow in tubular devices. The mixing parameter is determined per reactor section. For the main tube a correlation between mixing parameter and energy dissipation is given. The mixing parameter can be used to describe the flow of the continuous phase as a plug flow with axial disturbances. Furthermore, dimensionless mixing times can be estimated. The dimensionless mixing time is the number of circulations that is necessary to achieve complete mixing of the continuous phase, where the criterium must be defined by the user.

    Mass transfer is investigated in an FC40 water system. For this purpose a new method is developed based on the principle of a steady-state measurement, in stead of the most widely used dynamic measurement. Compared to a gas/liquid system at equal dispersed-phase flow rates, the mass-transfer rate in the liquid/liquid system is favorable. This is due to the larger exchange area, because the drops are smaller than the bubbles and the drop velocity relative to the continuous phase is lower than the relative velocity of the bubbles. The mass-transfer coefficient for the liquid/liquid system, derived from experimental results, however, is lower than literature values for gas/liquid systems. This is probably caused by the lower diffusion coefficient of oxygen in liquid than of oxygen in gas. The transfer capacity can often be the highest for gas/liquid systems because the maximum dispersed-phase flow rate in liquid/liquid systems is limited with respect to drop formation and coalescence. Further physical reseach must be focussed on this limitation.

    Basic bioreactor design.
    Riet, K. van 't; Tramper, J. - \ 1991
    New York : CRC Press - ISBN 9780824784461 - 480
    biochemie - biotechnologie - chemische industrie - chemische reacties - uitrusting - fermentatie - voedselbiotechnologie - studieboeken - biochemistry - biotechnology - chemical industry - chemical reactions - equipment - fermentation - food biotechnology - textbooks
    Based on a graduate course in biochemical engineering, provides the basic knowledge needed for the efficient design of bioreactors and the relevant principles and data for practical process engineering, with an emphasis on enzyme reactors and aerated reactors for microorganisms. Includes exercises.
    Modelling and characterization of an airlift-loop bioreactor
    Verlaan, P. - \ 1987
    Agricultural University. Promotor(en): K. van 't Riet, co-promotor(en): K.C.A.M. Luyben. - S.l. : Verlaan - 129
    chemische reacties - uitrusting - biotechnologie - chemische industrie - biochemie - chemical reactions - equipment - biotechnology - chemical industry - biochemistry

    An airlift-loop reactor is a bioreactor for aerobic biotechnological processes. The special feature of the ALR is the recirculation of the liquid through a downcomer connecting the top and the bottom of the main bubbling section. Due to the high circulation-flow rate, efficient mixing and oxygen transfer is combined with a controlled liquid flow in the absence of mechanical agitators.

    Liquid velocities and gas hold-ups in an external-loop airlift reactor (ALR) on different scales were modelled on the basis of a simple pressure balance. The model is adapted for non-isobaric conditions and takes into account nonuniform flow profiles and gas hold-up distributions across the duct. The friction coefficient together with the reactor dimensions are input parameters. It has been shown that the friction coefficient can be obtained from simple one-phase flow calculations based on known data of the seperate reactor parts. The model predicts liquid velocities and local gas hold-ups in an ALR to within 10% and can be applied easily to an internal loop reactor.

    Mixing in the individual sections of the ALR is determined by a newly developed parameter estimation procedure which has proven to be reliable for the estimation of axial dispersion coefficients in the individual sections of the ALR. From the results it can be concluded, that in an ALR the liquid flow behaves like plug-flow with superimposed dispersion except for the topsection for which it is not reasonable to assume plug-flow. The mixing results simplified the modelling of oxygen transfer in the ALR as it appeared not to be necessary to incorporate the dispersion contribution Into the oxygen model.

    The non-isobaric plug-flow model, presented in this thesis, predicts dynamic and stationary dissolved oxygen concentration (DOC) profiles in large-scale ALRs and has been applied also to estimate the volumetric oxygen transfer coefficient, k 1 a, in the pertinent ALR. Comparison with the results on the basis of a simple isobaric stirred-tank-reactor model demonstrates, that such a model yields conservative values though for the present situation the underestimation did not exceed a value of 10% relative to the plug-flow model. Therefore, due to its simplicity, it is recommended to use the stirred tank model for a rapid characterization of the overall aeration capacity of laboratory scale and pilot-scale ALRs. Oxygen depletion of the gas phase, even during a fermentation, appeared to be very limited and was fairly well predicted by the plug-flow model. For this reason an ALR is a very suitable reactor for aerobic processes having a high oxygen demand. If necessary, the aeration capacity of the ALR can be enhanced by injection of a small amount of gas at the entrance of the downflow region. This phenomenom is also accurately predicted by the plug-flow model. In the present ALR the aeration capacity of the air-sparger region did not significantly differ from the main aeration process in the upflow region due to its special geometry.

    The intermediate flow region between the ALR and the bubble-column (BC) flow regime was investigated by gradually closing a butterfly valve at the bottom of the downcomer. When the valve is further shut and thus the friction is enhanced, the liquid velocity will be reduced thereby enlarging the gas hold-up. The maximum value for the gas hold-up is obtained when the ALR is operated as a BC. In the transition flow regime between ALR and BC flow, the liquid velocity was found to be a simple power law function of the gas flow rate. The coefficients of the power law depend on the flow characteristics in the reactor. In the transition flow regime the hydrodynamic calculations based on the plug-flow behaviour of an ALR are only valid up to a certain defined value of the total gas-liquid flow rate. For greater values, the ALR type of flow will change Into a BC type of flow. A simple criterium qualifies the distinction between both flow patterns, determined by the superficial liquid velocity and the liquid circulation velocity.

    The transition of ALR to BC flow coincides with the decrease of the Bodenstein number which also indicates a less established plug flow. As the dispersion coefficient at a constant gas-flow rate, remained constant for as well the ALR, the BC and the transition flow, the decreased Bodenstein number in the BC-type of flow is mainly attributed to the decreased convective transport as the liquid circulation is impeded. The number of circulations required to achieve complete mixing diminshes when the liquid circulation is impeded and appeared to be proportional to the Bodenstein number.

    In the transition flow regime, the volumetric oxygen transfer coefficient was estimated by both the stirred-tank model and the plug-flow model. The stirred-tank model yielded reliable results for the entire range of operation while the plug-flow model only appeared to be appropiate for the ALR operation mode. The volumetric oxygen transfer coefficient was found to increase for the BC operation mode and appeared to be a power law function of the ratio of the superficial liquid and gas velocity and the Bodenstein number.

    Addition of immobilized biocatalysts to the ALR, in our case simulated by neutral buoyant particles with diameters ranging from 2.4-2.7 am, significantly reduces the liquid velocity and the gas hold-up in an ALR. The decrease in liquid velocity is attributed to the decrease in gas hold-up and an increased friction in the ALR. The gas hold-up is reduced mainly because the presence of the particles increases the collision frequency of the air bubbles thereby increasing coalescence due to the diminished flowed area available for the air-water mixture. In comparison to a gas-liquid flow, axial dispersion in the three-phase flow is reduced as the presence of the particles damps the small eddies which are, apart from other mechanisms, responsible for the axial dispersion. Moreover. the increased coalescence also contributes to a decrease in axial dispersion. The presence of the particles negatively influences aeration due to a reduction in the gas-liquid interfacial area as a result of the increased coalescence. The effect of the increase in apparent viscosity in the ALR was not supposed to contribute to the decrease in the aeration process.

    Design of an organic-liquid-phase / immobilized-cell reactor for the microbial epoxidation of propene
    Brink, L.E.S. - \ 1986
    Landbouwhogeschool Wageningen. Promotor(en): K. van 't Riet; K.C.A.M. Luyben; J. Tramper. - Wageningen : Brink - 114
    biochemie - biotechnologie - chemische industrie - chemische reacties - constructie - ontwerp - ontwikkeling - uitrusting - biochemistry - biotechnology - chemical industry - chemical reactions - construction - design - development - equipment
    Replacement of a considerable part of the traditional, aqueous reaction medium in biotechnology by an organic medium is a promising technique to broaden the scope and range of biotechnological processes. This seems especially to be true for the conversion of non-polar substances. The high capacity of solvents for sparingly water-soluble substrates and products could reduce the required volume of the reaction mixture significantly, and may also lead to less substrate and/or product inhibition in the aqueous biocatalyst phase, when these mechanisms are involved. Furthermore, the use of an organic solvent could shift reaction equilibria favourably and facilitate down-stream processing. In chapter 1 a general review is presented of non-aqueous solvent systems in biocatalytic processes. Special attention is paid to two-liquid-phase systems, involving water-immiscible solvents. Several facets of these biphasic systems have been studied in this thesis using the epoxidation of propene by gel-entrapped Mycobacterium cells as a model.

    After the description of the throughout this work employed techniques of gas-analysis automatization and of substrate-level control (chapter 2), the far-reaching consequences of the solvent choice are treated in chapter 3. Many solvents cause rapid inactivation of the free, propene-epoxidizing cells. This appears also to be the case if the cells are immobilized in calcium alginate. However, the support material prevents direct cell-organic solvent contact and the associated aggregation and clotting of cells, mostly accompanied with loss of activity. High activity retentions of the immobilized cells relate to low polarities and high molecular weights of the used solvents. The polarity, as expressed by the Hildebrand solubility parameter, is also useful for describing the solvent capacity for one of the two substrates, oxygen, and for the product, propene oxide. The capacity for propene is less well described by the Hildebrand solubility parameter, but also less relevant, as the capacity of the solvents for propene is always about two orders of magnitude higher than that of water, and thus limitation of the rate by unsufficient supply of propene is less likely to occur. It is stressed that optimization of the solvent polarity is necessary, as the requirement of a high activity retention conflicts with the need for a high solvent capacity for the polar propene oxide. Optimization of the polarity will also be likely in case of other types of two-liquid-phase bioconversions.

    External and internal-diffusion limitations, which are to be expected when using cells entrapped in a hydrophilic: gel, are quantified in chapters 4 and 5. With negligible product inhibition, satisfactory predictions of the mass-transfer effects on the intrinsic Michaelis-Menten kinetics of the immobilized cells are obtained by using a simple pore-diffusion model (chapter 4). Internal diffusion is found to severely limit the epoxidation rate. A more complex model for the intrinsic epoxidation kinetics has been derived for modelling of mass-transfer rates in case of product inhibition (chapter 5).

    The microkinetic model defined in chapter 4 is integrated in a macrokinetic model to describe the behaviour of a packed-bed immobilized-cell reactor (chapter 6). Depletion of the limiting substrate, oxygen, along the length of the bioreactor can be prevented by using an organic solvent, n-hexadecane, as the transport medium. It is argued that this finding may eliminate the need for a separate gas phase in the fixed-bed reactor. Model predictions of the oxygen conversion in the bioreactor at various degrees of external and internal-diffusion limitation, at various liquid space times and with water or n-hexadecane as the continuous phase are in good agreement with experimentally obtained values. In chapter 7 some other, main limitations of the epoxide production in the packed-bed organic-liquid-phase/immobilized-cell reactor are quantified. Product inhibition is reduced by absorption of the inhibitory epoxide in a cold di-n-octyl phthalate phase. The stability of the immobilized cells is increased by supplying the cells alternately with propene and a co-substrate (ethene). About 50 g dry weight of cells in a 1.7 dm 3packed-bed reactor were used, which produced ~ 1.5 g chiral propene oxide; two third of the epoxide was absorbed in the octyl phthalate phase.

    Finally, in the last chapter of this thesis a general discussion is presented. The significance of optimization of the solvent polarity and of the interphase polarity, i.e. the polarity of the phase between biocatalyst and organic solvent is underlined. In case of entrapment in prepolymers, the hydrophobicity/hydrophilicity balance of the gel can be optimized with respect to polarities of substrates and products. Several features of hydrophilic and hydrophobic gels are compared. A quantitative illustration is given concerning the design on a technical scale of a fixed-bed organic-liquid-phase/immobilized-cell reactor. The advantages of using solvents with a high substrate capacity (often oxygen in case of aerobic processes) are demonstrated.

    Biocatalysts in organic syntheses : proceedings of an International symposium organized under auspices of the Working Party on Immobilized Biocatalysts of the European Federation of Biotechnology : Noordwijkerhout, The Netherlands, 14-17 April 1985
    Tramper, J. ; Plas, H.C. van der; Linko, P. - \ 1985
    Amsterdam : Elsevier (Studies in organic chemistry 22) - ISBN 9780444425416 - 259
    biochemie - biotechnologie - katalysatoren - katalytische activiteit - chemische industrie - chemische reacties - enzymen - fermentatie - organische verbindingen - synthese - biochemistry - biotechnology - catalysts - catalytic activity - chemical industry - chemical reactions - enzymes - fermentation - organic compounds - synthesis
    The Chichibabin amination of diazines geometrical isomerism in anions of aromatic amines
    Breuker, J. - \ 1982
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - Wageningen : Breuker - 101
    azinen - pyridazinen - pyrimidines - purinen - chemische reacties - aminen - reactiemechanisme - azines - pyridazines - pyrimidines - purines - chemical reactions - amines - reaction mechanism
    The first part of this thesis describes investigations into the mechanistic aspects of the Chichibabin amination of some diazines in liquid ammonia containing potassium amide.

    The nucleophilic attack of the amide ion on 4-phenylpyrimidine readily takes place at C-2, due to its low electron density, and at C-6 because of the thermodynamic stability of the resulting σ-adduct. The former kinetically determined C-2 adduct isomerizes into the latter as shown by NMR spectros copy. Both adducts, but no analogous isomerization are observed in 4- t -butyl-pyrimidine. In 5-phenylpyrimidine an adduct on C-2 is not formed.

    Phenylpyrazine initially undergoes nucleophilic addition in KNH 2 /NH 3 at all three unsubstituted pyrazine carbon atoms. The C-5 adduct is thermodynamically. the most stable one.

    Amination of 4-phenylpyrimidine in 15N-labeled KNH 2 /NH 3 clearly shows that a ring opening-ring closure sequence (the S N (ANRORC) mechanism) must be in volved in the formation of the main product 2-amino-4- phenylpyrimidine. Quenching of the reaction with ammonium salt is an essential requirement for this mechanism. The conclusion is that the intermediate 6-amino-1,6-dihydro-4-phenylpyrimidine undergoes the ring opening. In the amination of 5-phenylpyrimidine the product 2-amino-5-phenylpyrimidine is also formed via an acyclic intermediate. In contrast, 4- t -butylpyrimidine, pyrazine and phenyl-pyrazine do not follow this S N (ANRORC) mechanism.

    The second part of this thesis deals with the occurrence of geometrical isomerism in the anions of aromatic amino compounds. NMR spectroscopy reveals the presence of two isomers of azaaromatic amines in liquid ammonia containing potassium amide, and even of anilines, in which the rotational barrier is lower. Coalescence is observed on increasing the temperature.

    The 1H and 13C NMR spectra are assigned to the syn - and anti -isomers. In all anions the ortho -hydrogen atom in the syn position relative to the lone pair of the exocyclic nitrogen atom resonates at lower field than in the anti position.

    In contrast, the ortho13C atoms do not show such a straightforward rela tionship in the anions of amino- as well as (methylamino)pyridines. In the former ions the signal of the ortho -carbon in the syn position relative to the nitrogen lone pair is found at higher field than in the anti position, whereas in the (methylamino)pyridine anions this signal is observed at lower field.

    With these data it is shown that the presence of a methyl substituent ortho to the amino group in aminopyridine anions causes a preference for the iso mer in which the amino hydrogen and the methyl group are directed towards each other. The conclusion is that the effective size of the lone pair is larger than that of an amino hydrogen, probably due to solvation. Stabilization of the preferred isomer by other effects, however, cannot be excluded.

    The reactivity of substituted purines in strongly basic medium : the occurrence of geometrical isomerism in the anions of aromatic amino compounds
    Kos, N.J. - \ 1981
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - Wageningen : Kos - 107
    aminen - azinen - chemische reacties - chemie - kinetica - purinen - pyridazinen - pyrimidines - stereochemie - isomeren - heterocyclische verbindingen - amines - azines - chemical reactions - chemistry - kinetics - purines - pyridazines - pyrimidines - stereochemistry - isomers - heterocyclic compounds
    In this thesis two subjects are described: a. the amination of substituted purines by potassium amide in liquid ammonia and b. the occurrence of geometri cal isomerism in the anions of aromatic amino compounds.

    It is shown that the first step in the amination of purines, being present as anions under these strongly basic conditions, is the formation of a σ-adduct as position 6 to give a 6-amino-1,6-dihydropurinide. If position 6 is occupied by a blocking group an attack at position 2 or 8 does not occur. The further reaction course depends on the nature of the substituents and their position in the purine ring. i. If a leaving group (Cl,SCH 3 ) is present at the same position where the amide ion has attacked, this substituent is expelled (S N (AE) mechanism). In case no leaving group is present a Chichibabin amination occurs due to expulsion of a hydride ion from position 6 (this reaction is described in Chapter 2).

    The Chichibabin amination can also occur at position 6 when a leaving group (Cl,SCH 3 ) is present at position 8. ii. In the last-mentioned system a tele substitution is possible besides the S N (AE) reaction. This reaction is exemplified in the conversion of 8-chloropurine into adenine (formed besides 8-chloro adenine). The σ-adduct at position 6 is protonated at position 8, after which dehydrohalogenation occurs (S N (AE) tele , see Chapter 3). iii. If a leaving group is present at position 2 (Cl,F,SCH 3 ) the σ-adduct at position 6 undergoes ring opening of the pyrimidine ring with expulsion of the leaving group. The resulting imidazole derivative undergoes ring closure to give a 2-aminopurine. This type of reaction is referred to as an S N (ANRORC) mechanism and is described in Chapter 4.

    It has been established that in an S N (AE) mechanism the second step, involving the expulsion of the leaving group, is fast; the intermediary a-adduct cannot be observed. However, in the Chichibabin amination, tele amination and reaction according to the S N (ANRORC) mechanism, the second step is slow and therefore the σ-adduct can be observed by low temperature NMR spectroscopy.

    In Chapter 5 a new method is presented for the reductive removal of amino and alkylamino groups from position 6 of 9-substituted purines with sodium in liquid ammonia. The reaction involves reduction of the N(1) - C(6) bond, followed by elimination. This reaction is of special interest since the alternative method for the removal of amino groups i.e. the diazotization cannot be used with alkylamino groups. Therefore this new method is especially useful for the deamination of 6-(alkylamino)-9-substituted purines.

    In the last part of this thesis the occurrence of geometrical isomerism in the anions of aromatic amino compounds in liquid ammonia containing potassium amide is described. It is shown that this phenomenon occurs even in anilines, where the rotational barrier will be lower than in azaaromatic systems. This is confirmed by the occurrence of coalescence with increasing temperature (Chapter 6). The 1H and 13C NMR spectra of the anions of aminopyridines, aminopyrimidines and N-methylaminopyridines are assigned to the syn - and anti isomers. It has been revealed that in all these anions the ortho hydrogen atom in the s yn position relative to the lone pair resonates at a lower field than the hydrogen atom in the anti position. For the 13C NMR shifts of the ortho carbon atoms it was found that in the anions of N-methylaminopyridines the ortho carbon atom in the syn position relative to the lone pair resonates at lower field than the ortho carbon atom in the anti position. In the anions of aminopyridines and aminopyrimidines this phenomenon is reversed. We have also shown that the presence of a methyl group ortho to the anionic amino group causes a preference for the isomer, in which the proton of the NH group is in a syn position relative to the methyl group. This is explained in terms of the electron pair being "larger" than a proton, but it is possible that the preferred isomer is also stabilized by a better solvation and by an electronical effect.

    Synthesis and amination of naphthyridines
    Haak, H.J.W. van den - \ 1981
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - S.l. : S.n. - 88
    pyridines - chemische reacties - aminen - synthese - organische verbindingen - pyridines - chemical reactions - amines - synthesis - organic compounds
    In the introduction of this thesis (chapter 1) the reactions of nephthyridines with potassium amide which were known at the start of our research are reviewed. It is shown in chapter 2, that in the amination of 1,X-naphthyridines with potassium amide in liquid ammonia at about -35° to -45°C the initial adduct formation is charge controlled. Thus, at these temperatures the site with the lowest electron density is most susceptible for amide attack (C-2 in 1,5 naphthyridine, C-2 in 1,6-naphthyridine, C-2 and C-8 in 1,7-naphthyridine, C-2 in 1,8-naphthyridine), as proved by NMR spectroscopy. On raising the temperature to about 10°C the site of addition has been found to change for 1,5- and 1,7-naphthyridine (NMR spectroscopy):from C-2 to C-4 in 1,5-naphthyridine and from C-2 and C-8 to C-8 only in 1,7-naphthyridine. Thus, at about 10°C the amination is thermodynamically controlled. The several factors which contribute to the stability of these addition products have been discussed. It has been found that the anionic a adducts (2(4,8)-aminodihydro-l,X-naphthyridinides) can easily be oxidized with potassium permanganate into their corresponding 2(4,8)-amino-1,X-naphthyridines.
    In chapter 3 a facile synthesis of 2,6-naphthyridine is described. Both 2,6 and 2,7-naphthyridine undergo with potassium amide under kinetically and thermodynamically controlled conditions a adduct formation at position 1. Chichibabin amination of 2,6-naphthyridine yields 1-amino-2,6-naphthyridine in 54% yield. The conversion of 1-halogeno-2,6-naphthyridines into 1-amino-2,6-naphthyridine is shown in chapter 4 to proceed via an even telesubstitution process [S N (AE) tele process]. The amination of 2-bromo-1,5-naphthyridine into 2-amino-1,5-naphthyridine is shown to proceed via an S N (AE) ipso substitution mechanism.
    Chapter 5 deals with the reaction of 1-halogeno-2,7-naphthyridines with KNH 2 /NH 3 yielding 1-amino-2,7-naphthyridine. Experiments with deuterated compounds show that these reactions proceed via an S N (AE) ipso process and not via an S N (AE) tele process, even though a adduct formation at C-8 takes place, as is shown by NMR spectroscopy.
    In chapter 6 the occurrence of an open-chain intermediate in the amination of 8-bromo-1,7-phenanthroline is shown by NMR spectroscopy. The reaction of 3-bromo-2-ethoxy-1,5-naphthyridine with KNH 2 /NH 3 is described in chapter 7. The procedure in the literature for its preparation does not lead to this compound but to the isomeric 3-bromo-1-ethyl-1,5-naphthyridin-2(1H)-one. Reaction of this compound with KNH 2 /NH 3 yields 3- and 4-amino-1-ethyl-1,b- naphthyridin-2(1H)one, the latter being the main product. 3-Bromo-2-ethoxy-1,5-naplithyridine was prepared on reacting 2,3-dibromo-1,5-naphthyridine with sodium ethoxide. A mixture of 3- and 4-amino-2-ethoxy- 1,5-naphthyridine was obtained on amination of 3-bromo-2-ethoxy-1,5-naphthyridine. In both cases the intermediacy of the respective 3,4,-dihydro compounds was proposed.

    Homoaromatics as intermediates in the substitution reactions of 1,2,4,5-tetrazines with ammonia and hydrazine
    Counotte-Potman, A. - \ 1981
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - S.l. : - 113
    chemische reacties - hydrogenering - oxidatie - reductie - substitutie - heterocyclische verbindingen - chemical reactions - hydrogenation - oxidation - reduction - substitution - heterocyclic compounds
    This thesis describes some nucleophilic substitution reactions between the red 1,2,4,5-tetrazines and hydrazine-hydrate or ammonia. Special attention was paid to the occurrence of the S N (ANRORC) mechanism in these substitution reactions. This mechanism comprises a sequence of reactions, involving the A ddition of a N ucleophile to a heteroaromatic species, followed by a R ing- O pening and R ing C losure reaction to the substitution product.

    σ-Adducts, namely 6-hydrazino- and 6-amino-3-aryl(alkyl)-1,6-dihydro-1,2,4,5-tetrazines, are formed upon addition of hydrazine or ammonia to 3-aryl(alkyl)-1,2,4,5-tetrazines. This is accompanied by a change in colour from red to yellow. These adducts can be observed by NMR spectroscopy. ln heteroaromatics in liquid ammonia, an upfield shift (Δδ) of 4-5 ppm is usually measured for the hydrogen atom, attached to the carbon atom to which addition takes place. An extra ordinary large upfield shift is observed however upon addition to 1,2,4,5-tetrazines; Δδ= ~ 8.5 ppm in hydrazine and Δδ= ~ 8.7 ppm in liquid ammonia (at 230 K, chapters 4 and 6).

    The fact that 3-aryl(alkyl)-1,2,4,5-tetrazines are converted into the 6-amino compounds by oxidation of the intermediate in liquid ammonia (chapter 2), indicates that an intermediary 1,6-dihydro-6-amino structure must exist. 1H NMR measurements at various temperatures of 1,6-dihydro-1,2,4,5-tetrazines as model compounds for these σ-adducts gave an explanation for the large up field shift (Δδ). 1,6-Dihydro-1,2,4,5-tetrazines and their conjugate acids and bases were found to be homoaromatic and they are present in the monohomotetrazole conformation. The hydrogens at the sp 3carbon atom have a different orientation towards the tetrazole ring. One (H A) is oriented above the aromatic ring, in the shielding regio; H Bis in the exo position, in the deshielding regio; thus resulting in a large difference in chemical shift. The homoaromatic species show a ring inversion. The kinetic parameters (ΔH, ΔS and ΔG) were determined by dynamic NMR measurements (chapter 3). Since a large substituent at C 6 of the homotetrazole (e.g. methyl or ethyl) is found exclusively in the exo position, the hydrogen of the above mentioned a-adducts is oriented above the ring current of the tetrazole ring, resulting in a chemical shift at high field.

    The charge of the tetrazole ring exerts an influence through space on H A, H Bis hardly influenced. This became obvious from δH Ain 1H NMR and JCH Ain 13C NMR (chapters 3 and 4).

    The homoaromatic σ-adducts in liquid ammonia and even in hydrazine- hydrate/ methanol are anionic species, as was primarily proven by a 13C NMR study (chapters 4 and 6). The driving force for the deprotonation is probably the larger resonance stabilization of the homoaromatic anion with respect to the neutral homoaromatic species.
    3-Alkyl(aryl)-1,2,4,5-tetrazines were found to undergo a Chichibabin hydrazination into 6-hydrazino-3-alkyl(aryl)-1,2,4,5-tetrazines on treatment with hydrazine-hydrate. The first step in this reaction sequence was the formation of a homoaromatic σ-adduct. Subsequently an open-chain intermediate was observed by NMR, on raising the temperature. Finally the hydrazino compound is formed by ring closure. This reaction sequence can be considered as an S N (ANRORC) process. With 15N-labelled hydrazine, only part of the label was found to be built in the 1,2,4,5-tetrazine ring of the 6-hydrazino compounds. This is the first example of a reaction in which both the hydrazino compound with the 15N-label in the ring and with the 15N-label in the exocyclic hydrazino group are formed according to the S N (ANRORC) mechanism (chapter 6).

    During the hydrazino-deamination and hydrazino-dehalogenation of 6-amino- and 6-halogeno-1,2,4,5-tetrazines only a part of the molecules was found to react according to the S N (ANRORC) process. The other part followed the alternative S N (AE), A ddition- E limination, pathway (chapters 5 and 6).

    The crystal structure of 6-ethyl-3-phenyl-1,6-dihydro-1,2,4,5-tetrazine was elucidated by X-ray structural analysis very recently. This analysis revealed that the molecule is in a boat-conformation. C 6 points upwards with a dihedral angle of 49.3° and C 3 with an angle of 26.7°. N 1 was found to be sp 2hybridized and the N(1)-N(2), N(2)-N(3), C(3)-N(4) and N(4)-N(5) bond distances were found to be between single- en double bond length, in agreement with the expected electron delocalization. Therefore we came to the conclusion that the crystal structure agrees with the homoaromatic character of the compound (chapter 7).

    Thermal and photochemical reactions of dihydrodiazines
    Stoel, R.E. van der - \ 1979
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - Wageningen : van der Stoel - 103
    azinen - derivaten - chemische reacties - fotochemie - azines - derivatives - chemical reactions - photochemistry
    This thesis describes the results of an investigation into the thermal and photochemical reactivity of dihydrodiazines.

    In order to prepare the title compounds the diazines and some phenyldiazines are treated with phenyllithium in ether, yielding adducts resulting from attack of phenyllithium on the various positions of the heteroaromatic ring. With pyrimidine addition takes place mainly at C(4), with pyridazine at C(3). By using TMEDA, addition at C(2) in 4-phenylpyrimidine and at C(4) in pyridazine is strongly promoted. The structure of the adducts is studied by n.m.r. spectroscopy. The charge distribution pattern in the C(4)-adduct of pyrimidine and in both the C(3)-adduct and the C(4)-adduct of pyridazine is determined by comparing the carbon chemical shifts of these compounds with those of the corresponding dihydrodiazines obtained by hydrolysis of the adducts. C(5) in the phenyllithium-pyrimidine adduct carries little negative charge, C(4) in the phenyllithium-pyridazine adduct has a considerable amount of charge while the charge density at C(6) in the 3-adduct and both C(3) and C(5) in the 4-adduct of pyridazine is moderate.

    Some organolithium-diazine adducts and some dihydropyrimidines are treated with electrophilic reagents. Both 4,6-diphenyl-1(3)-lithio-1,4(3,4)-dihydropyrimidine and 4,6-diphenyl-1,4(3.4)-dihydropyrimidine are attacked by the electrophilic reagent (methyliodide, methyl chloroformate) at N(3), yielding 4,6-dipheny]-3-methyl(methoxycarbonyl)-3,4-dihydropyrimidine. 4,4,6-Triphenyl-1,4(3,4)-dihydropyrimidine gives upon treatment with methyliodide mainly 3-methyl-4,4,6-triphenyl-3,4-dihydropyrimidine. The 3,4-dihydro structure of the products is established both spectroscopically and chemically. Reaction of 2-lithio-3-methyl-2,3-dihydropyridazine with methyliodide (methyl chloroformate, tosylchloride) gives the corresponding 2,3-dimethyl-(2-methoxycarbonyl-3-methyl-, 2-tosyl-3-methyl-)2,3-dihydropyridazine. 1-Lithio-2-phenyl-1,2-dihydropyrazine yields upon treatment with methyliodide 5-methyl-2-phenylpyrazine. Reaction with carbonyl compounds only yields high molecular material.

    Photolysis of 4-R-1,4(3,4)-dihydropyrimidines causes rearrangement to 5-R-1,2(2,3)-dihydropyrimidines, provided that the substituent R contains a π-bond in αposition to the heterocyclic ring (R=phenyl,isobutenyl,phenylethynyl). 4-Methyl-1,4(3,4)-dihydropyrimidine does not show this rearrangement. Chemical evidence is presented that the rearrangement occurs via the di-π-methane mechanism leading to 6-R-2,4-diazabicyclo [3.1.0] hex-2(3)-ene. This latter intermediate undergoes a thermal homo [1,5] hydrogen shift into 5-R-2,5-dihydropyrimidine which on tautomerization gives the final product. The reaction can be sensitized by acetone. 4,5-Diphenyl-, 5-methyl-4-phenyl and 5-bromo-4-phenyl-1,4(3,4)-dihydropyrimidine do not rearrange under photochemical conditions.

    Several 4-R-1,4(3,4)-dihydropyrimidines (R=2- or 3-thienyl,2-furyl, 1-methyl-2-pyrrolyl and 3-pyridyl) containing heteroaryl vinyl methane moieties undergo photochemical rearrangement into 5-R-1,2(2,3)-dihydropyrimidines. Oxidation of these compounds yield 5-heteroarylpyrimidines. The chemical yields are strongly dependent of the nature of the heteroaryl group.

    The existence of a 6-R-2,4-diazabicyclo [3.1.0] hex-2(3)-ene as an intermediate in the photoisomerization of 4-R-1,4(3,4)- dihydropyrimidines into 5-R-1,2(2,3)-dihydropyrimidines is confirmed spectroscopically in case R= p -trifluoromethylphenyl. It is established that the p -trifluoromethylphenyl group is in exo position in the bicyclic compound. 6- Exo -( p -trifluoromethylphenyl)-2,4-diazabicyclo [3.1.0] hex- 2(3)-ene immediately gives 5-( p -trifluoromethylphenyl)-1,2(2,3)- dihydropyrimidine upon addition of potassium hydroxide in methanol.

    Photolysis of 4-R-1,4(3,4)-dihydropyrimidines causes ring contraction into imidazoles, provided that the substituent R is sufficiently capable of stabilizing an anionic centre (R=2-thiazolyl and 2- or 4-pyridyl). Chemical evidence is presented that the ring contraction of 6-phenyl-4-(2-pyridyl)-1,4(3,4)-dihydropyrimidine occurs via heterolytic fission of the C(1)-C(6) bond of intermediate 1-phenyl-6-(2-pyridyl)-2,4-diazabicyclo [3.1.0] hex-2(3)-ene. The anion stabilizing effect of R is correlated with the acid strength (pKa) of R-CH 3 . A pKa value around 30 determines the border-line between ring contraction into an imidazole and formation of an isomeric 5-R-1,2(2,3)-dihydropyrimidine.

    [Sigma]-Adducts of pteridines and 3-deazapteridines, structure and reactivity
    Nagel, A. - \ 1978
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - Wageningen : [s.n.] - 92
    azinen - purinen - pyridazinen - pyrimidines - chemische structuur - chemische reacties - structuuractiviteitsrelaties - azines - purines - pyridazines - pyrimidines - chemical structure - chemical reactions - structure activity relationships
    In the introduction of this thesis the reactions of pteridines and pyrido[2,3- b ]-pyrazines with nucleophiles are reviewed. In the following chapters the results of an NMR investigation on the formation of σ-adducts between these azaaromatic ring systems and nitrogen nucleophiles, especially KNH 2 /NH 3 , are described. In order to establish the structures of these - not isolable - σ-adducts, the 1H and 13C NMR spectra of pteridine, pyrido[2,3- b ]pyrazine and a number of derivatives of both these heterocyclic systems, containing one or more OCH 3 , SCH 3 , CH 3 , t-C 4 H 9 , OH, NH 2 , NHNH 2 , F, Cl, Br and C 6 H 5 substituents, were extensively analyzed. All resonance signals in the NMR spectra were unequivocally assigned.

    By means of 1H and 13C NMR, pteridines are shown to form in principle two different σ-adducts with NH 3 : at -60°C one molecule of NH 3 adds to C-4, yielding 4-amino-3,4-dihydro-2-R-pteridines (R=H, Cl), or alternatively, at temperatures up to +25°C, the addition of two molecules of NH 3 to C-7 and C-6 takes place, causing the formation of 6,7-diamino-4-R-2-X-5,6,7,8-tetrahydropteridines (R=X=H, R=H, X=Cl, OCH 3 , SCH 3 , C 6 H 5 , R=CH 3 , X=Cl. R=C 6 H 5 , X=Cl,H). This detailed NMR spectral information allowed straightforward interpretation of the 13C NMR spectra of the covalent hydrates 3,4-dihydro-4-hydroxypteridine, 6,7-dihydroxy-5,6,7,8-tetrahydroxypteridine and their cationic species.

    Due to the rapid decomposition of pteridine in KNH 2 /NH 3 , no σ-adduct could ever be detected. In sharp contrast, three σ-adducts between KNH 2 and pyrido[2,3- b ]-pyrazines are described i.e. the 3-amino-3,4-dihydropyrido[2,3- b ]pyrazinide ion, the 3-amino-2-t-butyl-3,4-dihydro-6-chloropyrido[2,3- b ]pyrazinide ion and the 2-amino-1,2-dihydro-3-phenylpyrido[2,3- b ]pyrazinide ion.

    The results are subsequently presented concerning the investigation of the reaction of KNH 2 /NH 3 with 2-X-4,6,7-triphenylpteridines (X=SCH 3 , Cl, F, H). Two reactions are found to take place : aminolysis at C-2, yielding 2-amino-4,6,7-triphenylpteridine (X=SCH 3 , Cl, F) and ring contraction, giving rise to the formation of 2-X-6,8-diphenylpurines (X=SCH 3 , H). By studying the aminolysis with both 15N labelled pteridines and with K 15NH 2 / 15NH 3 it is proved that the displacement at C-2 in the case of X=SCH 3 , occurs via a ring-opening and ring closing sequence [S N (ANRORC)]mechanism to the extent of 50-85% (depending on [KNH 2 ]); in the case of X=F this amounts to 40% and in the case of X=Cl to 100%.

    It is further proved that in the ring contraction of 2-methylthio-4,6,7-triphenylpteridine 85% of C-7 is expelled and 10% of C-6, both processes being preceded by addition of amide ion to C-7 and C-6 respectively.

    The possible elimination of C-7 and C-6 is clearly demonstrated by the fact that both 4,6- and 4,7-diphenyl-2-methylthiopteridines undergo ring contraction to the same product i.e. 6,8-diphenyl-2-methylthiopurine. As a consequence in the former isomer only C-7 is eliminated, while in the latter exclusively C-6 is expelled.

    In the next chapter the reactions of 6-chloro-2-R 1 , 3-R 2 -pyrido[2,3- b ]pyrazines [R 1 =H, R 2 =C 6 H 5 , t -C 4 H 9 , R= t -C 4 H 9 , R 2 =H, R 1 =R 2 =H, CH 3 , C 6 H 5 , phenanthro(9,10)] with KNH 2 /NH 3 are described.

    These compounds undergo ring contraction into 2-R-1H-imidazo[4,5- b ]pyridines (R=H, C 6 H 5 , t -C 4 H 9 ), besides reductive dechlorination. It is found that ring contraction of 2,3-diphenyl-6-X-pyrido[2,3- b ]pyrazines takes place exclusively if X=Cl; in the case of X=F only aminolysis is found, and in the case of X=Br reductive debromination occurs exclusively.

    The investigation on the mechanism of the ring contraction of 6-chloropyrido-[2,3- b ]pyrazine into 1H-imidazo[4,5- b ]pyridine is performed by using both is 15N-4 and 13C-2 labelled compounds and K 15NH 2 / 15NH 3 . The results can be explained by the initial formation of a σ-adduct of amide ion at C-2 - unfortunately not detectable by spectroscopic methods - in which σ-adduct, by an intramolecular rearrangement, the chlorine atom and C-2 are expelled simultaneously.

    Ring transformations in reactions of pyrimidine and N-alkylpyrimidinium salts with nucleophile
    Oostveen, E.A. - \ 1977
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - Wageningen : Pudoc - 58
    pyrimidines - chemische reacties - pyrimidines - chemical reactions

    Paper I

    On treatment with liquid ammonia at -33°C, the quaternary pyrimidinium salts, i.e. 1-methylpyrimidinium methyl sulfate, 1,2-dimethylpyrimidinium iodide, 1,4,6-trimethyl-pyrimidinium iodide and 1,2,4,6-tetramethylpyrimidinium iodide demethylate yielding pyrimidine. 2-methyl-, 4,6-dimethyl- and 2,4.6-trimethylpyrimidine, respectively. It was observed that under these conditions 1-methyl-[1,3- 15N]-pyriniidiniuni methyl sulfate yields [1- 15N]-pyrimidine. By measuring the PMR spectra of above- mentioned pyrimidinium salts in liquid ammonia it is shown that these salts undergo covalent amination on the 1,6-azomethin bond. These results indicate that the demethylation reaction occurs via an Addition-NucleophileRing-Opening-Ring Closure mechanism.

    Paper II

    On treatment with active methylene compounds in basic media the quaternary pyrimidinium salts, i.e. methyl 1-methylpyrimidinium sulfate, 1-methyl-4-phenylpyrimidinium iodide and 1-methyl-5- phenylpyrimidinium iodide are converted into pyridine derivatives. The mechanism of the reaction is discussed.

    Paper III

    On treatment of the quaternary pyrimidinium salts i.e. 1-methyl-4-phenylpyrimidinium iodide and 1-methyl-5-phenylpyrimidinium iodide with cyanamide, O -methylisouronium chloride or bis[S-methylisothiouronium] sulfate in basic media, 2-amino-4-phenylpyrimidine and 2-amino-5-phenylpyrimidine are formed respectively. A ring transformation is involved in which the two-atom fragment N(1)-C(2) of the pyrimidine ring is replaced by an N-C fragment of the reagent. On reacting 1-methylpyrimidinium iodide with benzamidinium chloride or pivalamidinium chloride in a solution of sodium ethoxide in ethanol, 2-phenylpyrimidine and 2- tert -butylpyrimidine are formed respectively.

    It is proved by 15N-labelling that this nucleophilic substitution occurs via a ring transformation in which the N(1)- C(2)-N(3) fragment of the pyrimidine is replaced by the N-C-N fragment of the amidine. These reactions are new examples of a nucleophilic substitution occurring according to an S N (ANRORC) mechanism.

    Paper IV

    Reaction of 4-alkoxy- or 4,6-dialkoxypyrimidines with 1 equivalent of triethyloxonium tetrafluoroborate yields 4-alkoxy-N-ethyl or 4,6-dialkoxy-N-ethylpyrimidinium salts, respectively. With two or more equivalents of this reagent, rearrangement of N-ethyl-alkoxypyrimidinium salts into 1-ethyl-3-alkyl-1,4(3,4)-dihydro-4-oxopyrimidinium salts takes place. These rearrangements can also be performed by heating. The mechanism of these rearrangement reactions is discussed.

    Paper V

    The crystal and molecular structures of two isomeric compounds, 1-ethyl-4,6-diethoxypyrimidinium tetrafluoroborate and 1,3-diethyl-1,4(3,4)-dihydro-6-ethoxy-4-oxopyrimidinium tetrafluoroborate, reaction products of 4,6-diethoxypyrimidine with Meerwein reagent [O(C 2 H 5 )3+BF4-] , have been determined by means of X-ray diffraction.
    1-Ethyl-4,6-diethoxypyrimidinium tetrafluoroborate is monoclinic a=10.794, b=13.361,c=10.892 Å, β =112.6°, space group P2 1 /n, four molecules per unit cell.
    1,3-Diethyl-1,4(3,4)-dihydro-6-ethoxy-4-oxopyrimidinium tetrafluoroborate is monoclinic, a=17.637, b=14.054, c=11.501 Å, β =101.7°, space group C2/c, eight molecules per unit cell.
    In both structures the fluoroborate ions are disordered. The bond distances in the π-electron systems are reasonably well described in terms of a small number of resonance structures.

    Paper VI

    Treatment of 1,3-diethyl-1,4(3,4)-dihydro-4-oxopyrimidinium tetrafluoroborate and its 2-phenyl, 6-phenyl, 6-methyl and 6-ethoxy derivatives with aqueous ammonia resulted in the formation of a mixture of open-chain compounds i.e. N -formyl(acetyl,benzoyl)- N -ethyl-3-(ethylamino)acrylamides and N -ethyl-3-[formyl(acetyl,benzoyl)ethylamino]-acrylamides. They are formed by cleavage of the pyrimidine ring between the N(1)-C(2) and N(3)-C(2) bond, respectively. In liquid ammonia the same ring cleavage generally occurs; however, in the case where a 6-ethoxy group is present, recyclisation can take place, leading to 6-(ethylamino)pyrimidine derivatives. This degenerate ring transformation has been observed also with the 2-methyl and 2-phenyl derivative of 1,3-diethyl-1,4(3,4)-dihydro-6-ethoxy-4-oxopyrimidinium tetrafluoroborate. Evidence is presented by means of 1H-NMR and 13C-NMR spectroscopy that all these reactions are iniated by attack of NH 3 at the C(2)-position. Some of the above-mentioned open-chain compounds underwent a ring closure to the initially used 1,3-diethyl-1,4(3,4)-dihydro-4-oxopyrimidinium tetrafluoroborates on treating them with hydrofluoroboric acid in absolute ethanol.

    Paper VII

    On treatment with liquid ammonia at -33° the quaternary pyrimidinium salts i.e. 4-ethoxy-1-ethyl- and 4,6-diethoxy-1-ethylpyrimidinium tetrafluoroborate undergo amino-de-ethoxylation, yielding 1,4-dihydro-1-ethyl-4-iminopyrimidine hydrogen tetrafluoroborate and a mixture of 1,4-dihydro-6-ethoxy-1-ethyl-4-imino- and 1,6-dihydro-4-ethoxy-1-ethyl-6-iminopyrimidine hydrogen tetrafluoroberate, respectively. 1H-NMR and 13C-NMR spectroscopic evidence is presented for the fact that compounds 1 and 3 easily give σ-adducts at position 2. Using 15N-labelled ammonia it was shown that in these amino-de-ethoxylation reactions the substitution at C(4) or C(6) does not involve ring opening but probably occurs via an S N (AE n ) process. Reaction of 4-ethoxy-1-ethyl-2-phenyl-, 6-ethoxy-1-ethyl-4-phenyl-, 4,6-dimethoxy-1-ethyl-2-phenyl- and 4,6-dimethoxy-1-ethyl-2-methylpyrimidinium tetrafluoroborate with liquid ammonia gives besides the amino-de-ethoxylation product degenerate ring transformations leading to the N-deethylated products 14-16 and 4(6)-ethylaminopyrimidines 17-19. The salt 11 and 1,6-dihydro-1-ethyl-6-imino-4-phenylpyrimidine hydrogen tetrafluoroborate undergo, with potassium hydroxide, a Dimroth rearrangement to pyrimidines 20 and 17, respectively.

    Paper VIII

    The mechanism of the conversion of pyrimidine into 5-ethyl-2-methylpyridine has been investigated. It has been proved, using the labelled compounds [1,3- 15N]pyrimidine, [4,6- 14C]pyrimidine and [5- 14C]pyrimidine, that this reaction proceeds via a mechanism, in which the pyrimidine ring is fragmentated into two molecules of HCN and one molecule of N -methylacetaldimine. Four molecules of this imine undergo an aldol type condensation leading to 5-ethyl-2-methylpyridine.

    Reactions of pyridazines and pyridazine 1-oxides with nitrogen-containing nucleophiles
    Klinge, D.E. - \ 1976
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - Wageningen : [s.n.] - 40
    pyridazinen - chemische reacties - pyridazines - chemical reactions
    In dit proefschrift is een orienterend onderzoek beschreven naar het chemisch gedrag van halogeen-pyridazinen en halogeen-pyridazine-N-oxiden met kaliumamide in vloeibare ammoniak, met methanolische ammoniak en met vloeibare ammoniak. Dit onderzoek hangt nauw samen met uitvoerige studies over de reactiviteit van pyridinen, pyrimidinen en pyrazinen, die de afgelopen jaren in het laboratorium voor organische chemie te Wageningen zijn verricht. De resultaten van het door ons uitgevoerde onderzoek zijn in een vijftal publikaties verwerkt en laten zich als volgt samenvatten:

    Publikatie I:
    4-X-3-(methoxymethyl)-6-methylpyridazine (X=Cl, Br, I) geeft na aminering een mengsel van 4- and 5-amino-3-(methoxymethyl)6-methylpyridazine (verhouding 1 : 5); het is gebleken dat deze verhouding onafhankelijk is van de aard van het halogeen atoom. Daarom wordt als intermediair in deze reactie het 3-(methoxy-methyl)-6-methyl-4,5-didehydropyridazine aangenomen.

    Publikatie II:
    De reactie van 4-chloor-3,6-difenylpyridazine met kaliumamide in vloeibare ammoniak levert twee produkten op, namelijk 4-amino-3,6-difenylpyridazine en imino-4,4'-bis(3,6-difenylpyridazine). Uitgaande van 4-chloor-3,6-difenylpyridazine- [5- 13C] werd, door middel van quantitatieve 13C-NMR spectrometrie, van beide aminoverbindingen aangetoond dat zij gevormd zijn via het symmetrisch intermediair 3,6-difenyl-4,5-didehydropyridazine.

    De resultaten vermeld in I en II geven voor het eerst zeer gefundeerde aanwijzingen voor het bestaan van een intermediair 3,6-digesubstitueerd 4,5-didehydropyridazine in reacties van 3,6-digesubstitueerde 4-halogeenpyridazinen met kaliumamide in vloeibare ammoniak.

    Publikatie III:
    In de reactie van 6-chloor-3-methoxy-4-nitropyridazine 1-oxide met methanolische ammoniak en met vloeibare ammoniak treedt amino-demethoxylering op. Met behulp van 1H-NMR metingen kon worden aangetoond dat deze substitutie op een zeer ongewone wijze verloopt, n.l. in het op C(5) gevormde Meisenheimer complex.

    Publikatie IV:
    Van verschillende 3-mono- en 3,6-digesubstitueerde pyridazinen, 3-, 4- en 6-mono- en 3,6-digesubstitueerde pyridazine 1-oxiden en 4-nitro-3,6-digesubstitueerde pyridazine 1-oxiden zijn de 13C-absorpties bepaald. Hieruit werden de 13C-substituent effecten van substituenten in de 3-, 4- en 6-positie van de pyridazine ring en die van de N-oxide functie berekend. Door toepassing van deze substituent effecten konden de 13C-NMR spectra van de σ-adducten van 4-nitro-3,6-digesubstitueerde pyridazine 1-oxiden met vloeibare ammoniak worden geinterpreteerd.

    Uit de resultaten van de 1H-NMR en 13C-NMR metingen vermeld in III en IV kon zeer duidelijk worden vastgesteld dat 3-methoxy-4-nitropyridazine 1-oxiden een nucleofiele substitutie op CM kunnen ondergaan volgens een mechanisme, dat tot nu toe niet eerder in de literatuur is beschreven.

    Publikatie V:
    Bij de behandeling van 4-amino-3-X-pyridazine (X=Cl, Br) met kaliumamide in vloeibare ammoniak wordt 4-cyaanpyrazool gevormd. Onder dezelfde reactie omstandigheden ondergaat 4-amino-3,6-di-X-pyridazine (X=Cl, Br) een ringcontractie tot 3-(cyaanmethyl)-1,2,4-triazool.

    De in V beschreven ringcontractie tot 4-cyaanpyrazool kan worden beschouwd als een nieuw voorbeeld van een reactie, die reeds in andere ringsystemen beschreven is. De in V beschreven ringcontractie tot 3-(cyaanmethyl)-1,2,4-triazool is echter het eerste voorbeeld van een door kaliumamide gekatalyseerde ringcontractie, waarbij het gevormde vijfringsysteem meer stikstofatomen bevat dan het oorspronkelijke zesringsysteem.

    Inwerking van basen op N-oxiden van pyridine en pyrimidine
    Peereboom, R. - \ 1975
    Landbouwhogeschool Wageningen. Promotor(en): H.J. den Hertog, co-promotor(en): H.C. van der Plas. - Wageningen : [s.n.] - 70
    piperidinen - pyridines - pyrimidines - stikstofoxiden - chemische reacties - basen - alkaliteit - piperidines - pyridines - pyrimidines - nitrogen oxides - chemical reactions - bases - alkalinity
    A survey is given of investigations on reactions of halogeno- azahetarenes in basic media as described to date in the literature, chiefly of those on the behaviour of N-oxides of halogeno-azahetarenes and in some cases those of otherwise N-quaternised azahetarenes towards liquid ammonia and towards potassium amide in liquid ammonia. The reactions were found to proceed according to S N (AE)-, S N (EA)- and S N (AE a )-mechanisms and/or ring openings. The open-chain compounds formed in the latter process close either to the same (S N (ANRORC)- mechanism) or a new ring system (ring transformation) (Chapter

    In this connection we studied reactions of 3-bromopyridine 1-oxides with potassium amide in liquid ammonia and reactions of 4-X-6-methyl-(phenyl)pyrimidine 1-oxides with liquid ammonia and potassium amide in liquid ammonia.

    It was found that the reaction of 3-bromopyridine 1-oxide with potassium amide in liquid ammonia in the presence of isopropylamine affords 3-amino- and 3-(isopropylamino)pyridine 1-oxide whereas 3-bromopyridine 1-oxide remains unchanged in a mixture of liquid ammonia and isopro pylamine alone. These results affirm the previous hypothesis, that the amination of 3-bromopyridine 1-oxide with potassium amide in liquid ammonia proceeds by the S N (EA)-mechanism via 2,3-didehydropyridine 1-oxide (Chapter 2).

    3-Bromo-6-methylpyridine 1-oxide was converted into 4-amino- (main product), 3-amino- and 2-amino-6-methylpyridine 1-oxide by potassium amide in liquid ammonia, whereas 3-bromo-6-ethoxypyridine 1-oxide when treated with the same reagent only yielded 3-amino-6-ethoxypyridine 1-oxide Thus the methyl group occupying the 6-position changes the pathway of the amination of 3-bromopyridine 1-oxide, whereas the ethoxy group at the C(6)-atom does not. This difference can be explained by assuming that the methyl derivative is partly deprotonated yielding an anionic group which has a strong mesomeric interaction with the N-oxide group leading to a change of the charge distribution in the ring of the substrate. This causes the occurrence of a second reaction pathway, an S N (EA)-mechanism via 3,4-didehydro-6-methylpyridine 1-oxide (Chapter 2).

    The reaction of 3-bromoquinoline 1-oxide with potassium amide in liquid ammonia affords 3-hydroxy-4-[3-amino-2-quinolyl]quinoline 1-oxide together with 3- and 4-aminoquinoline 1-oxide. These products must be formed via 3,4-didehydroquinoline 1-oxide as an intermediate. That 3-bromoquinoline 1-oxide reacts differently from 3-bromopyridine 1-oxide is caused by the fused benzogroup which changes the charge distribution in the substrate considerably and enhances the stability of the intermediary 3,4-didehydroquinoline 1-oxide compared to that of 2,3-didehydroquinoline 1-oxide (Chapter 2).

    The oxidation of 4-X-6-methyl(phenyl)pyrimidines (X=Cl, Br and OC 6 H 5 can theoretically give two isomeric N-oxides (N(1)- and N(3)-oxide). The structure determination of the formed 4-X-6- methyl(phenyl)pyrimidine N-oxides was based on the structure of 4- chloro-6-methyl(phenyl)pyrimidine 1-oxide which was established by means of PMR spectroscopy on the dechlorinated compound (Chapter 3).

    The reactions of 4-chloro-6-methyl(phenyl)pyrimidine 1-oxide with liquid ammonia and with potassium amide in liquid ammonia yield a compound formed by amino-dechlorination, 4-amino-6-methyl(phenyl)pyrimidine 1-oxide and a ringtransformation product, 5-amino-3-methyl(phenyl)isoxazole.

    The results of the reactions of 4-chloro-6-methyl- and 4-chloro-6-phenyl-[l(3)- 15N]pyrimidine 1-oxide with liquid ammonia and with pot assium amide in liquid ammonia indicate that an S N (ANRORC)-mechanism is not operative in the conversion to the 4-amino-6-methyl- and 4-amino-6-phenylpyrimidine 1-oxide respectively. Furthermore it could be established that the dechlorination in liquid ammonia does not take place via a 4,5-didehydropyrimidine 1-oxide as intermediate, but according to an S N (AE)-process. This is based on the results of the reaction of 4-chloro-5-deutero-6-phenylpyrimidine 1-oxide The amino-dechlorination of the same substrate with potassium amide in liquid ammonia presumably takes place via the same pathway. This result is supported by studying the reactions of 4-chloro-5,6-diphenylpyrimidine 1-oxide in both media. 4-Amino-5,6-diphenylpyrimidine 1-oxide as well as 5-amino-3,4-diphenyl-isoxazole are formed. Since an S N (EA)-mechanism is prohibited because of the presence of a phenylgroup on position 5, this result is good evidence for the occurrence of an S N (AE)-mechanism in the nucleophilic displacement of the halogen atom in the 4-halogenopyrimidine 1-oxides (Chapter 4).

    The results of the reactions of 4-chloro-6-methyl-[l(3)- 15N]pyrimidine 1-oxide with liquid ammonia and with pot de in liquid ammonia have established two concurrent pathways for the formation of 5-amino-3-methylisoxazole. The first pathway involves addition of the nucleophile to the C(2)-atom, resulting in an isoxazole compound with the same 15N-enrichment as present in the substrate. In the second route addition to the C(4)-atom occurs leading to amino-dechlorination, as well as ring transformation to 5-amino-3-methylisoxazole with 15N enrichment at the ring nitrogen only . 6-Methyl-4-phenoxypyrimidine 1-oxide forms 5-amino-3-methylisoxazole but no 4-amino-6-methylpyrimidine 1-oxide in the reaction with potassium amide in liquid ammonia. In good accordance with these data it has been found that in this reaction the isoxazole formation only takes place via an addition of the amide ion to the C(2)-atom (Chapter 5).

    Variation of the substituent X of the 4-X-6-methyl(phenyl)pyrimidine 1-oxides influences the competition between the amination and the ring contraction. The substrates, in which X=Cl, Br and I, yield 4- aminopyrimidine 1-oxides, as well as 5-aminoisoxazoles, in both media. The addition of the amide ion or ammonia to the C(4)-atom is the principal reaction pathway. In the cases where X=OC 6 H 5 and X=SC 6 H 5 the activation by the substituent at the 4-position must be low, because these substrates only react with potassium amide in liquid ammonia at -33°C. The addition of the amide ion at the C(2)-atom is strongly favoured to the addition at the C(4)-atom. 6-Methyl-4-(trimethylammonio)pyrimidine 1-oxide affords 4-amino-6-methylpyrimidine 1-oxide as sole product in the reaction with liquid ammonia. The trimethylammonio group, a good leaving group, strongly activates the 4- position for the direct nucleophilic substitution and prohibits the addition of ammonia at the C(4)-atom (Chapter 6).

    Inwerking van stikstofhoudende nucleofielen op enige 15N-gemerkte pyrimidine- en chinazolinederivaten
    Kroon, A.P. - \ 1974
    Landbouwhogeschool Wageningen. Promotor(en): H.C. van der Plas. - S.l. : S.n. - 71
    chemische reacties - stikstof - pyrimidines - derivaten - chemical reactions - nitrogen - pyrimidines - derivatives
    In this thesis an investigation is described on the mechanism of aminations of pyrimidine- and quinazoline derivatives with nitrogen containing bases.

    In the introduction a survey is given of investigations, reported in the literature, concerning σ-complex formation on azahetarenes and their derivatives. The complex forming ability of different carbon atoms in these heterocyclic substrates with nucleophiles is very important for the explanation of the results of many reactions (Chapter I).

    On amination of 2-X-4-phenylpyrimidines (X=F, Cl, Br, J) with potassium amide in liquid ammonia at -75 °C, 2-amino-4-phenylpyrimidine is obtained in good yield. A second product, 3-amino-3-phenylacrylonitrile, is isolated in low yield.

    The formation of the 2-amino compound occurs to a large extent via a series of reactions, involving an initial Addition of the Nucleophile, to the C 6 atom, Ring-opening and Ring-Closure [S N (ANRORC)- mechanism] (X=F, Cl, Br, J; resp. 82, 88, 88, 73%). Proof for this mechanism is based on studies with 2-halogeno-4-phenyl-[1,3- 15N]-pyrimidines. In the case of the 2-chloro- and 2-bromo compound the open- chain intermediate postulated in the S N (ANRORC)-mechanism can be isolated. This intermediate cyclized slowly at room temperature to the 2- amino compound. Reaction with potassium amide or sodium hydroxide gave the same result. Surprisingly the 3-amino-3-phenylacrylonitrile obtained from the 15N-labelled compounds, contains no excess of 15N. Apparently both N- atoms present in this compound must come from the amide ion. It is proposed that the nitrile is formed by an initial attack of the amide ion on C 4 . Due to steric hindrance this addition is difficult and thus must be only a minor pathway. After ring opening of the C 4 adduct it is assumed that a second amide ion adds across the azomethine bond in this open-chain product. Loss of cyanamide and a subsequent reduction-oxidation process can then give rise to the formation of acrylonitrile. This second S N (ANRORC)- mechanism, via the C 4 adduct, cannot be ruled out but it is considered to be of less importance (Chapter II).

    Since there is very little information on the effect of leaving group mobility on the S N (ANRORC)-mechanism the influence of different groups on the occurrence of this mechanism was studied in the reaction of the 2-X- 4-phenylpyrimidines (X=SCH 3 , SO 2 CH 3 , SC 6 H 5 , SO 2 C 6 H 5 , SCN, CN and +N(CH 3 ) 3 ) with potassium amide. Using the [1,3- 15N]-labelled substrates, the corresponding 2-amino compounds are isolated and investigated by mass spectrometry. From the results the conclusion can be drawn that the methylthio-, the thiocyanato- and the methylsulfonyl group show a behaviour nearly identical to the 2-halogeno compounds [%-S N (ANRORC)mechanism resp. 91, 90 and 73] . The trimethylammonio- and the cyanogroup undergo almost exclusively a S N (AE) displacement process (90% and 95% resp.), while the phenylsulfonyl group has no special preference 34% S N (AE). It is very striking that the methylsulfonyl group - in contrast to the phenylsulfonyl group - mainly undergoes a S N (ANRORC)-amination. Deprotonation of the methyl group possibly is the cause of this difference; formation of the C 2 -NH 2 adduct, the first step in the addition-elimination, is then less favourable. 1H-NMR spectrometric measurements of the methylsulfonyl substrate in the amination medium showed the disappearance of the CH 3 signal. The C 6 -NH 2 adduct, postulated in the S N (ANRORC)-amination of the 2-substituted 4-phenylpyrimidines, is proven by measuring 5-deuterio-2-methylthio-4-phenylpyrimidine in its reaction medium with 1H-NMR (Chapter III).

    Investigations were carried out as to how the course of the reaction is influenced by the presence of a substituent in position 6, choosing for that purpose the phenyl group. This voluminous group can possibly prevent (or retard) the addition of the amide ion at position 6(4), making the competitive reaction pathway via an addition-elimination reaction more favourable. The results, obtained when aminating 2-X-4- phenyl- [1,3- 15N] -pyrimidine (X=F, Cl, Br) with potassium amide, give evidence that in the amination of the fluoro compound no ring opening occurs, but that 2-chloro- and 2-bromo-4-phenylpyrimidine react for a considerable part (~ 70%) via ring opening into the 2-amino compound. Since in the reaction of the 2-chloro- and 2-bromo-4-phenylpyrimidine about 90% reacts by a S N (ANRORC)-mechanism one has to conclude that the phenyl group in position 4 or 6 does actually influence the addition of the amide ion on that position. The reaction intermediate, postulated for the S N (ANRORC)-mechanism in the 2-halogeno-4,6- diphenylpyrimidines, is isolated for the 2-bromo- and 2-chloro compound in low yield, using short reaction times. (Chapter IV).

    In extension of the work on the amination of 2-halogeno-4,6-difenylpyrimidines, the possibility that a ring opening is also involved in the conversion of 2-chloro-4-phenylquinazoline into 2-amino-4- phenylquinazoline with potassium amide was investigated. Mass spectrometric determinations of this product indicate that about 70% of the substrate reacts via ring opening into the 2-amino compound. In this quinazoline substrate attack of amide ion at only one carbon atom can give rise to a S N (ANRORC)-mechanism, so we can conclude that this quinazoline is more vulnerable to the ring opening reaction than the 2-chloro-4,6-diphenyl-pyrimidine. This can be explained with the well-known high reactivity of the 3,4-bond in quinazoline. Experiments with other 2-substituted 4-phenyl-[3- 15N]-pyrimidines showed the same trend in occurrence of the S N (ANRORC)-mechanism as found for the 2-substituted 4- phenylpyrimidines: the 2-fluoro compound was aminated for 55% and the 2-cyano compound for 15% via a ring opening. investigation of (-chloro-4-phenylquinazoline in the amination reaction with ethanolic ammonia, using 15N labelled substrate showed as unexpected result that in the amination the S N (ANRORC)mechanism is operative for 34%. This percentage was found to be dependent on the concentration of the ammonia. The occurrence of the same ring opening reaction was shown in the amination of 2-chloro- and 4-chloroquinazoline with ethanolic ammonia (Chapter V).

    It is reported ill the literature that on heating 4-quinazolinone with phenyl phosphorodiamidate 4-aminoquinazoline is formed. It is now shown, using [3- 15N]-4-quinazolinon that the formed 4-amino compound contains a certain amount of 15N-label in the amino group. It is determined that in this reaction a ring opening is partly operative in the amination of the oxo compound. The amino compound however, also undergoes an exchange reaction with PPDA involving a ring opening (Chapter VI).

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