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IChemE SYMPOSIUM SERIES NO. 153 # 2007 IChemE

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, 76318 Pfinztal, Germany; e-mail: [email protected]

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 reac-

tions 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 ther-

molability 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 concen-

trations or varied stoichiometries which are not possible to apply on a macroscopic scale. Such par-

ameter 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-flow-

through 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 20–30 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

INTRODUCTIONMicroreaction technology (MRT) is today one of the mostexciting innovations in chemical and pharmaceuticalsynthesis, chemical processing and process technology. Itis at the threshold of widespread application in industryand research.

In the last decade, worldwide research activities haveimpressively demonstrated that microstructured reactors,mixers, and other microprocess components whose internaldimensions fall within the sub-millimeter and/or sub-milliliter range offer a multitude of advantages in chemicalreaction technology. Today, microstructured reactors arewell known to provide far better heat exchange character-istics than attainable in macroscopic batch or flow-throughreactors due to their high surface-to-volume ratio – whichis by a factor of at least 100 higher than in conventionaldevices. A large number of studies have impressivelydemonstrated that the accumulation of strong reactionheats and hot spots, which result in unwanted side,subsequent and decomposition reactions, can be success-fully surpressed in microreactors; strong exothermic

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processes can be run isothermally. Consequently, the useof microreactors greatly reduces the hazardous potentialassociated with reactions that are highly exothermic orpotentially explosive. Greater safety is also attained withtoxic substances due to the small hold-up of microfluidicdevices.

In addition to better heat exchange, microstructuredreactors also intensify mixing and mass transport. Thisadvantage is particularly important in multi-phase reactionsystems (gas/liquid or liquid/liquid) and all other types ofmixing sensitive processes.

As microreactors permit greatly intensifying the heatand mass transport together with highly precise continuousprocess management, the resultant improvements in yield,selectivity, product quality, and safety are significantindeed compared to conventional synthesis processes. Inaddition, microreaction technology offers access to newsynthetic products and process methodologies. A remark-able number of successful applications of MRT have beendescribed in literature. Recently published reviews[Jaehnisch 2004, Pennemann 2004, Jensen 2001] and

Figure 1. Synthesis of trinitroglycerin (GTN)


books [Hessel 2004, Kockmann 2006] are recommended tointerested readers.

Nowadays, microreaction technology has success-fully lost its mark of a mere academic plaything and isnow broadly accepted as a tool for process screening andoptimization in the R&D labs of chemical companies andresearch institutions. An indication of a considerable pro-gress in this direction is the appearance of new companiesthat provide products for MRT applications such as micro-fluidic devices made of different materials and evencomplex microreaction systems, for example based ontoolkit concepts.

Here we report on the use of microreactors for the safeprocessing of strong exothermic reactions in the liquid andliquid/liquid regime. The hazardous potential of such reac-tions often arises from the huge reaction enthalpy and/or thethermolability of the reaction products or intermediates. Asa first example, the synthesis and subsequent work-up oftrinitroglycerine in a fully automated microreaction processis described. As a second example, we report on the syn-thesis and point-of-use conversion of diazomethane, ahighly toxic and explosible reactant.

In our studies microreactors have been particularlyused to systematically investigate hazardous reactionsunder unusual process conditions such as higher tempera-tures or higher concentrations which are not easy to applyon a macroscopic scale. Such parameter screenings offervaluable routes for process intensification in terms ofimproved yield and selectivity but also with respect toenergy savings and improved safety. Hence, microreactorshave been deliberately used as tools for safety analyses toinvestigate experimentally worst case scenarios at thethreshold of decomposition and runaway reactions.

Moreover, we use microreactors also as analyticaltools to quantify the heat release under strong exothermicprocess conditions. For this purpose, we have developed acontinuous mL-flow-through calorimeter which consists ofa microreactor embedded between thermoelectric modules.With its small hold-up and very short time constant themicrofluidic calorimeter is ideally suited to measure enthal-pies of fast and highly exothermic reactions under both iso-thermal and continuous process conditions.

EXAMPLE I: SYNTHESIS AND PURIFICATION

OF TRINITROGLYCERIN IN A MICROREACTION

PROCESSTrinitroglycerin (glyceroltrinitrate, GTN) is a colourlessliquid explosive, which is used in pharmaceutical industryas 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 nitratingacid (mixed HNO3/H2SO4 acid), a strong exothermic reac-tion that requires accurate temperature control (Figure 1).Since GTN is a highly shock and impact sensitive oil thattends to abrupt decomposition at temperatures above 458Csafety is a key issue in GTN production processes.

The hazardous potential of GTN synthesis arises fromboth the huge reaction enthalpy and the thermolability of thereaction product. Moreover, crude GTN that is obtainedafter the nitration step features a significant higher instabil-ity compared to pure GTN due to acid residues. As a conse-quence, crude GTN has to be washed by water and a weakbase (e.g. soda) until its pH becomes neutral.

To significantly reduce the hazardous potential of theentire GTN process a microreaction process was developedin co-operation with Dynamit Nobel GmbH Explosivstoff-und Systemtechnik, Leverkusen, Germany (now part ofthe Novasep Group). The microfluidic process comprisesboth the nitration reaction and the subsequent washingsteps of crude GTN.

The continuous nitration step was conducted bymixing glycerin and HNO3/H2SO4 in temperature con-trolled microreactors made of silicon and glass that werespecially designed to provide high mixing efficiencies(Figure 2). Pumping of the viscous reactants was realizedwith reasonable care by using continuously operatingsyringe pumps to avoid any pulsation and thus to ensureconstant stoichiometric conditions. The latter are alsoimportant for safety reasons since an excess of glycerinmight result in uncontrolled runaway reactions.

The nitration step was investigated under systematicvariation of process conditions such as temperature, stoichi-ometry (within reasonable limits), residence time, andcomposition of the nitrating agent to identify processoptima. The microreaction process allowed even to screenunusual process conditions such as temperatures up to 458C(in contrast to industrial batch processes at significantlylower temperature) in a safe way (Note: process tempera-tures .458C may result in spontaneous decomposition/deflagration reactions due to the thermolability of GTN!Although the small hold-up of the microreactors preventserious damages, deflagration of GTN in microchannelswill definitively lead to the destruction of the microdevices).

In comparison to industrial processes the GTNsynthesis in microreactors provides significantly increasedspace-time yields (no dosing time) and an excellent phaseseparation of crude GTN and the mixed acid when leavingthe microreactor. This is an additional key benefit comparedto macroscopic processes since it allows a much more fasterseparation of crude GTN for further processing stepswithout any losses.

Continuous washing of crude trinitroglycerin wasconducted in micromixers made of silicon and glass bymixing crude GTN with excess of water or soda solutionin only 3 to 4 successive washing steps at temperatures up

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Figure 2. Exemplary microreactors made of glass (left) and silicon (right) with internal passive mixing microfluidic channels

(channel diameters: 50–350 mm)


to 408C. It turned out that specially designed micromixersare indispensable to provide sufficiently high mixing qual-ities which are required to completely remove acid residuesfrom GTN and fulfil pharma grade specifications. Again, anexcellent phase separation can be achieved which acceler-ates the entire continuous washing procedure drasticallyand leads also to significantly reduced waste water contami-nations. Moreover, the amount of washing water was alsosignificantly reduced by more than 50%.

In summary, a continuous microreaction process wasrealized that allows a safe, remarkably intensified synthesisand subsequent purification of trinitroglycerin.

EXAMPLE II: SYNTHESIS AND “POINT-OF-USE”

CONVERSION OF DIAZOMETHAN

IN MICROREACTORSDiazomethane, CH2N2, is a highly reactive gas, useful in awide range of chemical reactions. It reacts readily withcarboxylic acids, yielding the corresponding methyl estersin excellent yields. The only side product following transferof a methyl group is gaseous nitrogen. Further common andextremely useful reactions employing diazomethane arereactions with alcohols to form methyl ethers, cyclopropa-nations of olefins, methylations of aldehydes to methylke-tones, and diazoketone formations starting from acidhalides.

Figure 3. Continuous synthesis of diazomethane in a micro

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In contrast to its very useful chemical properties,diazomethane is physiologically hazardous. It is known tobe a powerful carcinogen, allergen, and it is also highlytoxic. However, the major drawback of diazomethane isits extreme explosive nature.

To overcome these safety problems a continuousmicroreaction process was developed that allows thesynthesis and subsequent conversion of diazomethane atthe “point-of-use”. Owing to the precise control of heatand residence time in microreactors highly toxic and explo-sible diazomethane can be continuously synthesised andinstantaneously converted to the target product in a safe way.

In the microreaction process, diazomethane is syn-thesised under isothermal conditions by intensively mixingN-methyl-N-nitroso urea (dissolved in diethyl ether/THF)with a 5% aqueous potassium hydroxide solution (Figure 3).Following standard protocols described in literature [Archi-bald 1998] a maximum yield of 82 + 2% diazomethanewas obtained within 6 seconds. However, by using methy-tert.-butyl ether (MTBE) instead of diethyl ether/THF thediazomethane yield could be increased to 95 + 2%.

The size and internal microfluidic structure of themicroreactor depend highly on the nature of the intendedsubsequent reaction. For example, the kinetics of the reac-tion define the hold-up and residence time that must be pro-vided by the microreactor, the viscosity of the reactantsmight have an impact on the microchannel dimensions toprovide a certain pressure drop.

reaction process by conversion of N-methyl-N-nitroso urea

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 withstyrene in presence of a Pd catalyst was conducted in amicroreaction process (Figure 4). Styrene is completely con-verted at room temperature within 60 seconds formingcyclopropylbenzene quantitatively. For this mixing sensi-tive reaction a passive mixing microreactor made of glasscontaining internal chaotic mixing elements was used(Figure 5). To ensure that the microreaction process pro-vides sufficient residence time a microstructured residencetime unit comprising additional passive mixing microchan-nels was connected to the microreactor.

Since the total hold-up of the entire microreactionprocess is in the sub-milliliter range a significant reductingof the hazardous potential of diazomethan chemistry canbe achieved. This offers new opportunities for a widerange of safe single-step chemical reactions.

REACTION CALORIMETRY IN

MICROREACTORS: FAST SCREENING

OF REACTION AND SAFETY PARAMETERSChemical reactions are often accompanied by a significantheat release and must therefore be thoroughly understoodto allow a profitable and safe processing on a plant scale.

Figure 5. Microreactor made of glass with internal structures

for chaotic mixing

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To identify optimal operating conditions of a chemicalprocess, knowledge on kinetic and thermodynamic par-ameters of the most important main and side reactions isrequired. Furthermore, for a detailed risk scenario analysisexperimental studies have to be carried out to investigatehow the process behaves under unsual process conditions.Hence, the limits of safe operation have to be determinedto avoid any hazardous incidents.

Such safety parameters of chemical reactions areusually measured with reaction calorimeters, such as theRC1 from Mettler Toledo or comparable instruments fromother suppliers. Most of the existing reaction calorimetersconsist of a reaction vessel and a surrounding jacket witha circulating fluid that transports the heat away from thereactor. Such calorimeters require an unfavourable largetest volume of about 0.3 – 2.0 l and thus a relatively hugeamount of test substance. Hence, the safety analysis offast exothermic reactions raises several problems. Forexample, the control of the reaction temperature and a suffi-ciently rapid mixing are difficult to achieve which maycause significant selectivity and safety problems. Moreover,critical process conditions have to be strictly avoided. Forunderstanding the behaviour of the reaction mass at criticalprocess conditions other analytical techniques have to beused, e.g. Differential Scanning Calorimetry (DSC) orAccelerated Rate Calorimetry (ARC).

Here we report on the development of a continuously-operating reaction calorimeter based on microreactiontechnology, that permit fast screening of reaction and safetyparameters as well as determining the thermokinetic charac-teristics of chemical reactions. The microreactors used inthis calorimeter are distinguished by high surface-to-volumeratios, small internal volumes (approx. 80 ml) short residencetimes, and high-precision continuous process control. Asthese microstructured reactors are capable of resisting highpressures and temperatures, even secondary reactions suchas decomposition reactions may be experimentally analysed.The microreactors themselves may be made of glass orsilicon and may be exchanged to adapt the microstructureddevice to the reaction being analysed, for example in termsof residence time or mixing performance.

Figure 6 shows the set-up of the microstructured reac-tion calorimeter. The microreactor is embedded betweenSeebeck elements. This sandwich set-up is placed into a

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 chosenreaction temperature. The power of the Seebeck elementsis recorded by a LabView program. The calorimetricmeasurement is performed by measuring continuouslythe heat flow (caused by the chemical reaction) from themicroreactor through the Seebeck element to an additionalPeltier element. The latter is regulated by a PID controllerto generate a constant temperature difference between themicroreactor and the lower Seebeck element by varyingthe power of the Peltier element. The heat pumped by thePeltier element is removed by the cryostat. Since a heating

Figure 7. Calorimetric monitoring of the stro

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foil (as a part of the sandwich set-up) is used to calibratethe measuring system, there is no need for time-consumingheat transfer calibrations as they are required for con-ventional reaction calorimeters. Even spatially-resolvedmeasurements of reaction heat are possible by usingseveral miniaturised high-performance Seebeck elementsmounted above and below the microreactor. Such spatiallyresolved calorimetric analysis provides kinetic data of theinvestigated chemical reaction.

The huge surface-to-volume ratio of the micro-channels ensures an instantaneous transfer of the reaction

ng exothermic nitration of toluene at 508C


heat towards the thermoelectric modules. Hence, the ml-calorimeter has a very small time constant of,3 secondsand is thus by a factor of 20 faster than conventional(macroscopic) reaction calorimeters. Therefore, this deviceis ideally suited for measuring fast and highly exothermicreactions at isothermal conditions under almost realtimeconditions. The microreaction calorimeter allows alsorunning chemical reactions at critical process conditions,for example at the threshold of decomposition andrunaway reactions.

Figure 7 shows as an example the calorimetric moni-toring of the strong exothermic nitration of toluene at 508C.The heat of reaction can be determined from the slope of themeasured heat flow (here: 110 kJ/mol).

The performance and the accuracy of the microreac-tion calorimeter have been demonstrated for several otherstrong exothermic reactions in the liquid and liquid/liquidregime [Antes 2005]. The kinetic and thermodynamic par-ameters obtained from the calorimetric measurementsagree well with literature values in cases where they areavailable.

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REFERENCESAntes, J., Schifferdecker, D., Krause, H., Loebbecke, S., 2005,

A New Concept for the Measurement of Strong Exo-

thermicities 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 Prep-

aration 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, Chem-

istry 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: Funda-

mentals, 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

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