MICROREACTORS FOR PROCESSING OF HAZARDOUS AND EXPLOSIBLE REACTIONS

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1 MICROREACTORS FOR PROCESSING OF HAZARDOUS AND EXPLOSIBLE REACTIONS S. Loebbecke, J. Antes, W. Ferstl, D. Boskovic, T. Tuercke, M. Schwarzer and H. Krause Fraunhofer Institute for Chemical Technology ICT, P.O. Box 12 40, Pfinztal, Germany; Microstructured reactors are well known to provide far better heat exchange characteristics than attainable in macroscopic batch or flow-through reactors due to their high surface-to-volume ratios. In the last decade, a large number of studies have impressively demonstrated that the accumulation of strong reaction heats and hot spots, which result in unwanted side, subsequent and decomposition reactions, can be successfully surpressed in microreactors. Consequently, the use of microreactors greatly reduces the hazardous potential associated with reactions that are highly exothermic or potentially explosive. Greater safety is also attained with toxic substances due to the small hold-up of microfluidic devices. Here we report on the use of microreactors for the safe processing of strong exothermic reactions in the liquid and liquid/liquid regime, such as nitrations, oxidations, esterifications, etc. The hazardous potential of such reactions often arises from the huge reaction enthalpy and/or the thermolability of the reaction products or intermediates. Microreactors have been particularly used in our studies to systematically investigate strong exothermic reactions under unusual process conditions such as higher temperatures, higher concentrations or varied stoichiometries which are not possible to apply on a macroscopic scale. Such parameter screenings provide valuable routes for process intensification in terms of yield and selectivity but also with respect to energy savings and improved safety. Hence, microreactors have been deliberately used as tools for safety analyses to investigate experimentally worst case scenarios at the threshold of decomposition and runaway reactions. Moreover, we use microreactors also as measurement tools to quantify the heat release under strong exothermic process conditions. For this purpose, we have developed a continuous ml-flowthrough calorimeter which consists of a microreactor embedded between thermoelectric modules (Seebeck and Peltier elements). This new ml-calorimeter has a very small time constant of about 2 s which is by a factor of smaller than that of conventional reaction calorimeters. Hence, it is ideally suited to measure enthalpies of fast and highly exothermic reactions under both isothermal and continuous process conditions. KEYWORDS: microreactor, safety, nitration, nitroglycerine, diazomethane, point-of-use synthesis, calorimeter INTRODUCTION Microreaction technology (MRT) is today one of the most exciting innovations in chemical and pharmaceutical synthesis, chemical processing and process technology. It is at the threshold of widespread application in industry and research. In the last decade, worldwide research activities have impressively demonstrated that microstructured reactors, mixers, and other microprocess components whose internal dimensions fall within the sub-millimeter and/or submilliliter range offer a multitude of advantages in chemical reaction technology. Today, microstructured reactors are well known to provide far better heat exchange characteristics than attainable in macroscopic batch or flow-through reactors due to their high surface-to-volume ratio which is by a factor of at least 100 higher than in conventional devices. A large number of studies have impressively demonstrated that the accumulation of strong reaction heats and hot spots, which result in unwanted side, subsequent and decomposition reactions, can be successfully surpressed in microreactors; strong exothermic processes can be run isothermally. Consequently, the use of microreactors greatly reduces the hazardous potential associated with reactions that are highly exothermic or potentially explosive. Greater safety is also attained with toxic substances due to the small hold-up of microfluidic devices. In addition to better heat exchange, microstructured reactors also intensify mixing and mass transport. This advantage is particularly important in multi-phase reaction systems (gas/liquid or liquid/liquid) and all other types of mixing sensitive processes. As microreactors permit greatly intensifying the heat and mass transport together with highly precise continuous process management, the resultant improvements in yield, selectivity, product quality, and safety are significant indeed compared to conventional synthesis processes. In addition, microreaction technology offers access to new synthetic products and process methodologies. A remarkable number of successful applications of MRT have been described in literature. Recently published reviews [Jaehnisch 2004, Pennemann 2004, Jensen 2001] and 1

2 books [Hessel 2004, Kockmann 2006] are recommended to interested readers. Nowadays, microreaction technology has successfully lost its mark of a mere academic plaything and is now broadly accepted as a tool for process screening and optimization in the R&D labs of chemical companies and research institutions. An indication of a considerable progress in this direction is the appearance of new companies that provide products for MRT applications such as microfluidic devices made of different materials and even complex microreaction systems, for example based on toolkit concepts. Here we report on the use of microreactors for the safe processing of strong exothermic reactions in the liquid and liquid/liquid regime. The hazardous potential of such reactions often arises from the huge reaction enthalpy and/or the thermolability of the reaction products or intermediates. As a first example, the synthesis and subsequent work-up of trinitroglycerine in a fully automated microreaction process is described. As a second example, we report on the synthesis and point-of-use conversion of diazomethane, a highly toxic and explosible reactant. In our studies microreactors have been particularly used to systematically investigate hazardous reactions under unusual process conditions such as higher temperatures or higher concentrations which are not easy to apply on a macroscopic scale. Such parameter screenings offer valuable routes for process intensification in terms of improved yield and selectivity but also with respect to energy savings and improved safety. Hence, microreactors have been deliberately used as tools for safety analyses to investigate experimentally worst case scenarios at the threshold of decomposition and runaway reactions. Moreover, we use microreactors also as analytical tools to quantify the heat release under strong exothermic process conditions. For this purpose, we have developed a continuous ml-flow-through calorimeter which consists of a microreactor embedded between thermoelectric modules. With its small hold-up and very short time constant the microfluidic calorimeter is ideally suited to measure enthalpies of fast and highly exothermic reactions under both isothermal and continuous process conditions. EXAMPLE I: SYNTHESIS AND PURIFICATION OF TRINITROGLYCERIN IN A MICROREACTION PROCESS Trinitroglycerin (glyceroltrinitrate, GTN) is a colourless liquid explosive, which is used in pharmaceutical industry as a heart medication agent (medicine for angina pectoris/ coronary heart disease). It is synthesized by the nitration (resp. esterification) of glycerin in the presence of nitrating acid (mixed HNO 3 /H 2 SO 4 acid), a strong exothermic reaction that requires accurate temperature control (Figure 1). Since GTN is a highly shock and impact sensitive oil that tends to abrupt decomposition at temperatures above 458C safety is a key issue in GTN production processes. Figure 1. Synthesis of trinitroglycerin (GTN) The hazardous potential of GTN synthesis arises from both the huge reaction enthalpy and the thermolability of the reaction product. Moreover, crude GTN that is obtained after the nitration step features a significant higher instability compared to pure GTN due to acid residues. As a consequence, crude GTN has to be washed by water and a weak base (e.g. soda) until its ph becomes neutral. To significantly reduce the hazardous potential of the entire GTN process a microreaction process was developed in co-operation with Dynamit Nobel GmbH Explosivstoffund Systemtechnik, Leverkusen, Germany (now part of the Novasep Group). The microfluidic process comprises both the nitration reaction and the subsequent washing steps of crude GTN. The continuous nitration step was conducted by mixing glycerin and HNO 3 /H 2 SO 4 in temperature controlled microreactors made of silicon and glass that were specially designed to provide high mixing efficiencies (Figure 2). Pumping of the viscous reactants was realized with reasonable care by using continuously operating syringe pumps to avoid any pulsation and thus to ensure constant stoichiometric conditions. The latter are also important for safety reasons since an excess of glycerin might result in uncontrolled runaway reactions. The nitration step was investigated under systematic variation of process conditions such as temperature, stoichiometry (within reasonable limits), residence time, and composition of the nitrating agent to identify process optima. The microreaction process allowed even to screen unusual process conditions such as temperatures up to 458C (in contrast to industrial batch processes at significantly lower temperature) in a safe way (Note: process temperatures.458c may result in spontaneous decomposition/ deflagration reactions due to the thermolability of GTN! Although the small hold-up of the microreactors prevent serious damages, deflagration of GTN in microchannels will definitively lead to the destruction of the microdevices). In comparison to industrial processes the GTN synthesis in microreactors provides significantly increased space-time yields (no dosing time) and an excellent phase separation of crude GTN and the mixed acid when leaving the microreactor. This is an additional key benefit compared to macroscopic processes since it allows a much more faster separation of crude GTN for further processing steps without any losses. Continuous washing of crude trinitroglycerin was conducted in micromixers made of silicon and glass by mixing crude GTN with excess of water or soda solution in only 3 to 4 successive washing steps at temperatures up 2

3 Figure 2. Exemplary microreactors made of glass (left) and silicon (right) with internal passive mixing microfluidic channels (channel diameters: mm) to 408C. It turned out that specially designed micromixers are indispensable to provide sufficiently high mixing qualities which are required to completely remove acid residues from GTN and fulfil pharma grade specifications. Again, an excellent phase separation can be achieved which accelerates the entire continuous washing procedure drastically and leads also to significantly reduced waste water contaminations. Moreover, the amount of washing water was also significantly reduced by more than 50%. In summary, a continuous microreaction process was realized that allows a safe, remarkably intensified synthesis and subsequent purification of trinitroglycerin. EXAMPLE II: SYNTHESIS AND POINT-OF-USE CONVERSION OF DIAZOMETHAN IN MICROREACTORS Diazomethane, CH 2 N 2, is a highly reactive gas, useful in a wide range of chemical reactions. It reacts readily with carboxylic acids, yielding the corresponding methyl esters in excellent yields. The only side product following transfer of a methyl group is gaseous nitrogen. Further common and extremely useful reactions employing diazomethane are reactions with alcohols to form methyl ethers, cyclopropanations of olefins, methylations of aldehydes to methylketones, and diazoketone formations starting from acid halides. In contrast to its very useful chemical properties, diazomethane is physiologically hazardous. It is known to be a powerful carcinogen, allergen, and it is also highly toxic. However, the major drawback of diazomethane is its extreme explosive nature. To overcome these safety problems a continuous microreaction process was developed that allows the synthesis and subsequent conversion of diazomethane at the point-of-use. Owing to the precise control of heat and residence time in microreactors highly toxic and explosible diazomethane can be continuously synthesised and instantaneously converted to the target product in a safe way. In the microreaction process, diazomethane is synthesised under isothermal conditions by intensively mixing N-methyl-N-nitroso urea (dissolved in diethyl ether/thf) with a 5% aqueous potassium hydroxide solution (Figure 3). Following standard protocols described in literature [Archibald 1998] a maximum yield of % diazomethane was obtained within 6 seconds. However, by using methytert.-butyl ether (MTBE) instead of diethyl ether/thf the diazomethane yield could be increased to %. The size and internal microfluidic structure of the microreactor depend highly on the nature of the intended subsequent reaction. For example, the kinetics of the reaction define the hold-up and residence time that must be provided by the microreactor, the viscosity of the reactants might have an impact on the microchannel dimensions to provide a certain pressure drop. Figure 3. Continuous synthesis of diazomethane in a microreaction process by conversion of N-methyl-N-nitroso urea 3

4 Figure 4. Synthesis of cyclopropylbenzene by point-of-use reaction of diazomethane with styrene in a microreaction process As an example, the reaction of diazomethane with styrene in presence of a Pd catalyst was conducted in a microreaction process (Figure 4). Styrene is completely converted at room temperature within 60 seconds forming cyclopropylbenzene quantitatively. For this mixing sensitive reaction a passive mixing microreactor made of glass containing internal chaotic mixing elements was used (Figure 5). To ensure that the microreaction process provides sufficient residence time a microstructured residence time unit comprising additional passive mixing microchannels was connected to the microreactor. Since the total hold-up of the entire microreaction process is in the sub-milliliter range a significant reducting of the hazardous potential of diazomethan chemistry can be achieved. This offers new opportunities for a wide range of safe single-step chemical reactions. REACTION CALORIMETRY IN MICROREACTORS: FAST SCREENING OF REACTION AND SAFETY PARAMETERS Chemical reactions are often accompanied by a significant heat release and must therefore be thoroughly understood to allow a profitable and safe processing on a plant scale. Figure 5. Microreactor made of glass with internal structures for chaotic mixing To identify optimal operating conditions of a chemical process, knowledge on kinetic and thermodynamic parameters of the most important main and side reactions is required. Furthermore, for a detailed risk scenario analysis experimental studies have to be carried out to investigate how the process behaves under unsual process conditions. Hence, the limits of safe operation have to be determined to avoid any hazardous incidents. Such safety parameters of chemical reactions are usually measured with reaction calorimeters, such as the RC1 from Mettler Toledo or comparable instruments from other suppliers. Most of the existing reaction calorimeters consist of a reaction vessel and a surrounding jacket with a circulating fluid that transports the heat away from the reactor. Such calorimeters require an unfavourable large test volume of about l and thus a relatively huge amount of test substance. Hence, the safety analysis of fast exothermic reactions raises several problems. For example, the control of the reaction temperature and a sufficiently rapid mixing are difficult to achieve which may cause significant selectivity and safety problems. Moreover, critical process conditions have to be strictly avoided. For understanding the behaviour of the reaction mass at critical process conditions other analytical techniques have to be used, e.g. Differential Scanning Calorimetry (DSC) or Accelerated Rate Calorimetry (ARC). Here we report on the development of a continuouslyoperating reaction calorimeter based on microreaction technology, that permit fast screening of reaction and safety parameters as well as determining the thermokinetic characteristics of chemical reactions. The microreactors used in this calorimeter are distinguished by high surface-to-volume ratios, small internal volumes (approx. 80 ml) short residence times, and high-precision continuous process control. As these microstructured reactors are capable of resisting high pressures and temperatures, even secondary reactions such as decomposition reactions may be experimentally analysed. The microreactors themselves may be made of glass or silicon and may be exchanged to adapt the microstructured device to the reaction being analysed, for example in terms of residence time or mixing performance. Figure 6 shows the set-up of the microstructured reaction calorimeter. The microreactor is embedded between Seebeck elements. This sandwich set-up is placed into a 4

5 Figure 6. Set-up of the microreactor-based continuous reaction calorimeter; total set-up (a), microreactor (b), calorimetric cell (c), and set-up of the calorimetric cell (d) thermostated heat reservoir (cryostat) to control the chosen reaction temperature. The power of the Seebeck elements is recorded by a LabView program. The calorimetric measurement is performed by measuring continuously the heat flow (caused by the chemical reaction) from the microreactor through the Seebeck element to an additional Peltier element. The latter is regulated by a PID controller to generate a constant temperature difference between the microreactor and the lower Seebeck element by varying the power of the Peltier element. The heat pumped by the Peltier element is removed by the cryostat. Since a heating foil (as a part of the sandwich set-up) is used to calibrate the measuring system, there is no need for time-consuming heat transfer calibrations as they are required for conventional reaction calorimeters. Even spatially-resolved measurements of reaction heat are possible by using several miniaturised high-performance Seebeck elements mounted above and below the microreactor. Such spatially resolved calorimetric analysis provides kinetic data of the investigated chemical reaction. The huge surface-to-volume ratio of the microchannels ensures an instantaneous transfer of the reaction Figure 7. Calorimetric monitoring of the strong exothermic nitration of toluene at 508C 5

6 heat towards the thermoelectric modules. Hence, the mlcalorimeter has a very small time constant of,3 seconds and is thus by a factor of 20 faster than conventional (macroscopic) reaction calorimeters. Therefore, this device is ideally suited for measuring fast and highly exothermic reactions at isothermal conditions under almost realtime conditions. The microreaction calorimeter allows also running chemical reactions at critical process conditions, for example at the threshold of decomposition and runaway reactions. Figure 7 shows as an example the calorimetric monitoring of the strong exothermic nitration of toluene at 508C. The heat of reaction can be determined from the slope of the measured heat flow (here: 110 kj/mol). The performance and the accuracy of the microreaction calorimeter have been demonstrated for several other strong exothermic reactions in the liquid and liquid/liquid regime [Antes 2005]. The kinetic and thermodynamic parameters obtained from the calorimetric measurements agree well with literature values in cases where they are available. REFERENCES Antes, J., Schifferdecker, D., Krause, H., Loebbecke, S., 2005, A New Concept for the Measurement of Strong Exothermicities in Microreactors, in: Proc. of 8th Int. Conf. on Microreaction Technology (IMRET 8), Atlanta, USA, 134b Archibald, T.G., Barnard, J., Reese, H., 1998, Continuous Preparation of Diazomethane, US Patent 5,854,405 Hessel, V., Hardt, S., Loewe, H., 2004, Chemical Micro Process Engineering: Fundamentals, Modelling and Reactions, WILEY-VCH, Weinheim Jaehnisch, K., Hessel, V., Loewe, H., Baerns, M., 2004, Chemistry in Microstructured Reactors, Angew. Chem. Int. Ed. 43: 406 Jensen, K.F., 2001, Microreaction engineering is small better?, Chem. Eng. Sci., 56: 293 Kockmann, N. (ed.), 2006, Micro Process Engineering: Fundamentals, Devices, Fabrication, and Applications, WILEY- VCH, Weinheim Pennemann, H., Watts, P., Haswell, S.J., Hessel, V., Loewe, H., 2004, Benchmarking of Microreactor Applications, Organic Process Research & Development, 8: 422 6