Patrick Löb

Flow chemistry using milli- and microstructured reactors - From conventional to novel process windows

The terminology Novel Process Window unites different methods to improve existing processes by applying unconventional and harsh process conditions like: process routes at much elevated pressure, much elevated temperature, or processing in a thermal runaway regime to achieve a significant impact on process performance. This paper is a review of parts of IMMs works in particular the applicability of above mentioned Novel Process Windows on selected chemical reactions. First, general characteristics of microreactors are discussed like excellent mass and heat transfer and improved mixing quality. Different types of reactions are presented in which the use of microstructured devices led to an increased process performance by applying Novel Process Windows. These examples were chosen to demonstrate how chemical reactions can benefit from the use of milli- and microstructured devices and how existing protocols can be changed toward process conditions hitherto not applicable in standard laboratory equipment. The used milli- and microstructured reactors can also offer advantages in other areas, for example, high-throughput screening of catalysts and better control of size distribution in a particle synthesis process by improved mixing, etc. The chemical industry is under continuous improvement. So, a lot of research is being done to synthesize high value chemicals, to optimize existing processes in view of process safety and energy consumption and to search for new routes to produce such chemicals. Leitmotifs of such undertakings are often sustainable development(1) and Green Chemistry(2).

Continuous Synthesis of tert‐Butyl Peroxypivalate using a Single‐Channel Microreactor Equipped with Orifices as Emulsification Units

The two-step synthesis of tert-butyl peroxypivalate is performed in a single-channel microreactor. The first step, the deprotonation of tert-butyl hydroperoxide, is done in a simple mixer tube setup. The residence time section for the second reaction step is equipped with orifices for interfacial area renewal, needed for ensuring mass transfer between the two immiscible phases. The strong dependence of the reaction performance on the size of the interfacial area is demonstrated by using a setup with 4 orifices (distance of 52 cm), giving a HPLC yield of 71% at a residence time of 8 s and a reaction temperature of 23 °C. A further shortening of orifice distances helped to shorten the residence time down to 1.5 s and 0.5 s (using 9 orifices and 3 orifices with a distance of 5 cm). When using these setups, the produced heat could not be removed from the system sufficiently quickly (ΔT=38 K). The achieved yields (ca. 70% by HPLC) are close to the state of the art (cascaded batch processing) and provide an indication that the tert-butyl peroxypivalate synthesis can be performed at higher temperatures or at least, a more flexible process control can be allowed compared to high-volume batch reactors. Processing at higher reaction temperatures up to 70 °C shows a slight optimum at reaction temperatures between 40 °C to 50 °C, depending on the setup used. Knowing this novel process window as well as the optimum orifice geometry and distance will allow for tailored design of the microreactor. For the processing in the single-channel microreactor setup using 9 orifices (distance of 5 cm) and a reaction temperature of 40 °C a space-time-yield of 420,000 g  L(-1)  h(-1) was reached which is higher than the space-time-yield for the industrial 3 cascaded batch reactor process (190 g  L(-1)  h(-1)).

Orifice microreactor for the production of an organic peroxide – non-reactive and reactive characterization

In this article, the transfer of a two-step, biphasic, and exothermic peroxide synthesis into a microreactor assisted process is discussed as well as the non-reactive and reactive characterization of the developed orifice microreactor. Residence time distribution measurements showed nearly ideal plug-flow behaviour. The Bodenstein number at a flow rate of 21 mL min−1 is 180 and the corresponding cell number is 90, indicating a narrow residence time distribution. The determined residence times at two different flow rates are in good agreement with the theoretical values of 3.2 s and 1.5 s. The influence of flow rate on droplet size distribution is discussed as well as the influence of orifice geometry on the resulting energy density. These measurements showed a very small droplet size distribution over a wide range of flow rates applied. The smallest mean droplet size of 7 μm was obtained for a flow rate of 75 mL min−1. It is shown that a change from baffle type to conical orifices allows increasing of the throughput by keeping the homogenizing pressure similar to the baffle type system at a lower throughput. The measurement of the temperature profile on top of the thin reaction plate, covering the reaction channel is possible due to a special design of the orifice microreactor and enables monitoring the heat production under reactive conditions. A benchmark based on the product output of an industrial semi-continuous process points out the potential of micro process technology to intensify existing processes. On the examples of four fictive production scale microreactor assisted processes, it is shown that the footprint as well as the reaction volume can significantly be reduced. Using an orifice microreactor of the size of a shoebox the calculated space–time-yield for a product output of ca. 196 kg L−1 h−1 is 905 kg L−1 h−1. This is orders of magnitude higher than for the industrial semi-continuous process.

Proof of Concept: Magnetic Fixation of Dendron-Functionalized Iron Oxide Nanoparticles Containing Palladium Nanoparticles for Continuous-Flow Suzuki Coupling Reactions

A new concept for the magnetic immobilization of catalytically active material has been developed for continuous-flow Suzuki cross-coupling reactions. The reversible immobilization of the magnetic catalyst material inside a novel capillary microreactor has been achieved by utilizing a newly designed reactor housing with 208 small permanent magnets. As a catalyst material, magnetic Fe3O4 nanoparticles decorated with polyphenylenepyridyl dendrons and loaded with Pd nanoparticles have been employed. Both batch and continuous-flow experiments prove the activity of the catalyst and the applicability of this new microreactor concept.

A Falling-Film Microreactor for Enzymatic Oxidation of Glucose

Many oxidation processes require the presence of molecular oxygen in the reaction media. Reactors are needed that provide favorable conditions for the mass transfer between the gas and the liquid phase. In this study, two recent key technologies, microreactor technology and biotechnology, were combined to present an interesting alternative to conventional methods and open up excellent possibilities to intensify chemical processes in the field of fine chemicals. An enzyme‐catalyzed gas/liquid phase reaction in a falling‐film microreactor (FFMR) was examined for the first time. The test reaction was the oxidation of β‐D‐glucose to gluconic acid catalyzed by glucose oxidase (GOx). Various factors influencing the biotransformation, such as oxygen supply, temperature, enzyme concentration, and reaction time were investigated and compared to those in conventional batch systems. The most critical factor, the volumetric mass‐transfer coefficient for the efficient use of oxygen‐dependent enzymes, was determined by using the integrated online detection of dissolved oxygen in all systems. The extremely large surface‐to‐volume ratio of the FFMR facilitated the contact between the enzyme solution and the gaseous substrate. Hence, in a continuous bubble‐free FFMR system with a residence time of 25 seconds, a final conversion of up to 50 % in enzymatic oxidation was reached, whereas conversion in a conventional bubble column resulted in only 27 %. Finally, an option for scale‐up was shown through an enlarged version of the FFMR.

Applying a continuous capillary-based process to the synthesis of 3-chloro-2-hydroxypropyl pivaloate

Nowadays, continuous chemical processes (‘flow chemistry’) using micro process technology are becoming highly competitive, both for cost (better selectivity, higher productivity) and sustainability (low environmental impact) reasons. The first needs true process intensification and the second, among others, new eco-efficient starting and product materials. In this context, a new application for glycerol is reported with increasing industrial interest and tested here under highly intensified conditions. Starting from prior batch processing experience, it is reported about the transfer to a continuous process to transform dichloropropyl pivaloate, prepared from glycerol, into 3-chloro-2-hydroxypropyl ester. The continuous microreactor based process has up to three orders-of-magnitude reduced reaction times (5760×) by virtue of exploiting unusual experimental conditions in organic chemistry (Novel Process Windows), i.e. superheated pressurised processing much above the boiling point. The yields are fully comparable with the ones obtained under batch conditions, but with (expected) loss in selectivity through enhanced diproduct formation. This principally enables the new continuous process to target much higher productivities; however this also results in a more complex reaction mixture therefore the ease of separation and commercial value of the second product will decide its exploitation. Beyond such benefits for the individual reaction under investigation, this is among the very first reports about a superheated reaction with a distinct selectivity issue with two known byproduct pathways, and thus provides the first respective generic information after an upheavalled reporting on capillary- or microreactor-based superheated processing, so far mostly done for less complex reactions.

Photonic contacting of gas–liquid phases in a falling film microreactor for continuous-flow photochemical catalysis with visible light

A microstructured falling film reactor was applied to the dye-sensitized photochemical conversion of 1,5-dihydroxynaphthalene to juglone. This continuous-flow microreactor enables the efficient contacting of a gas and a liquid phase in combination with external irradiation by high-power LED arrays offering various wavelengths. Two sensitizers were used for the photochemical in situ generation of singlet oxygen as key step in the synthesis of the natural product juglone. The photochemical process was investigated according LED wavelength, LED power, oxygen partial pressure, reactor architecture, substrate concentration and flow rate, and optimized to a conversion of X = 97% with 99% selectivity. Based on the experimental results process parameters like quantum efficiency, productivity and space time yield were calculated and used for the evaluation of the photochemically catalyzed synthesis of juglone in continuous-flow mode.

Continuous-flow synthesis of fluorine-containing fine chemicals with integrated benchtop NMR analysis

A compact lab plant was designed for the continuous-flow synthesis of fluorine-containing compounds and was combined with an NMR analysis platform based on a benchtop NMR spectrometer. The approach of a unified synthesis and analysis strategy for fine chemicals was applied to three different reactions, all employing fluorine as a chemical probe for online-19F NMR analysis. A high temperature synthesis for the deprotection of a CF2H group was done as well as Ruppert–Prakash reactions for the perfluoroalkylation of benzaldehyde as a model substrate. The C–H arylation of furan with a trifluoromethylated aryldiazonium salt was performed as an example of a photochemically catalyzed reaction. All three reaction classes challenge the synthesis and analysis setup differently according to sample preparation (premagnetization of bubble-free sample) and spectrometer sensitivity (signal to noise ratio, spectral resolution, scan number, substrate concentration and flow rate), but nonetheless prove the successful application of the continuous-flow synthesis of fluorinated fine chemicals with integrated online NMR analysis.

Microstructured reactors for development and production in pharmaceutical and fine chemistry.

The true potential of microprocess technology for process intensification is not yet fully clear and needs to be actively explored, although more and more industrial case stories provide information. This paper uses a shortcut cost analysis to show the major cost portions for processes conducted by microstructured reactors. This leads to predicting novel chemical protocol conditions, which are tailored for microprocess technology and which are expected to highly intensify chemical processes. Some generic rules to approach this are termed new process windows, because they constitute a new approach to enabling chemistry. Using such process intensification together with scaled-out microstructured reactors, which is demonstrated by the example of gas-liquid microprocessing, paves the road to viable industrial microflow processes. Several such commercially oriented case studies are given. Without the use of new process windows conditions, microprocess technology will probably stick to niche applications.

Novel manufacturing techniques for microstructured reactors in industrial dimensions

Abstract The results of the development of novel manufacturing techniques for microstructured reactors in the framework of the European project CoPIRIDE are reported. The work was aimed at promoting the application of microstructured chemical reactors in the chemical industry. This can be achieved by completely new ways of production of microstructured plates, as manufactured by the roll embossing technique. This opens the door to mass manufacturing capability, which is a common enabler for cost reduction and resource efficiency. Roll embossing is especially suited for automated mass production, particularly on the larger scale. A modular reactor concept and a novel microreactor design for such microstructured plates were developed. The stacked plate reactors are joined either by laser welding or vacuum brazing. In this way, microstructured reactors can be manufactured for a wide range of throughputs, pressures, temperatures, for single and multi-phase reactions as well as for non-catalytic, homogeneously or heterogeneously catalyzed reactions. Within the project, the suitability of the novel techniques for the manufacture of microreactors with a reaction volume of up to 2 l, which is already the lower production scale of the fine chemical industry, was demonstrated. Three different reactor types could be successfully applied in pilot plants.