Pressure effects on regioselectivity and yield of cycloaddition reactions have been shown to exist. Nevertheless, high pressure synthetic applications with subsequent benefits in the production of natural products are limited by the general availability of the equipment. In addition, the virtues and limitations of microflow equipment under standard conditions are well established. Herein, we apply novel-process-window (NPWs) principles, such as intensification of intrinsic kinetics of a reaction using high temperature, pressure, and concentration, on azide–alkyne cycloaddition towards synthesis of Rufinamide precursor. We applied three main activation methods (i.e., uncatalyzed batch, uncatalyzed flow, and catalyzed flow) on uncatalyzed and catalyzed azide–alkyne cycloaddition. We compare the performance of two reactors, a specialized autoclave batch reactor for high-pressure operation up to 1800 bar and a capillary flow reactor (up to 400 bar). A differentiated and comprehensive picture is given for the two reactors and the three methods of activation. Reaction speedup and consequent increases in space–time yields is achieved, while the process window for favorable operation to selectively produce Rufinamide precursor in good yields is widened. The best conditions thus determined are applied to several azide–alkyne cycloadditions to widen the scope of the presented methodology.

Die Claisen-Umlagerung wurde in über 100 Jahren durch zahlreiche Forscher äußerst eingehend im Rührbetrieb untersucht. Insbesondere der Reaktionsmechanismus wurde in allen Details erforscht. Quantenmechanische Modellierung und moderne Kurzzeit-Spektroskopie haben hier ganz neue Impulse gegeben. Auch wurden schon erste Erfahrungen im Durchflussbetrieb in Mikroreaktoren gesammelt. Wie für viele andere Reaktionen so konnte eine massive Beschleunigung in neuen Prozessfenstern erreicht werden. Dieser Übersichtsartikel zeigt, dass das wahre Potenzial dennoch darauf wartet, für den Mikroreaktorbetrieb entdeckt zu werden.

The Claisen rearrangement has been extensively studied over the past 100 years in batch mode. Especially the reaction mechanism has been determined in all details. Quantum-mechanical modelling and ultrashort pulse spectroscopy have recently provided entirely new insight. First experiments were carried out in microreactors using flow chemistry. An enhancement of the yield and selctivity in the new processing windows has been observed. This review shows, that the true and full potential has still not been fully explored for the microreactor processing.

In Part 2, the factors impacting the Claisen rearrangement both in batch and flow processing are analyzed, including the choice of substituent, catalyst, temperature, pressure, concentration, flow rates, and solvent. Part 1 of this review series discussed the potential of using short-time spectroscopy and quantum mechanical calculations to elucidate the mechanism and transition state of the Claisen rearrangement. Flow processing offers profound opportunities for studying these factors known to impact the Claisen rearrangement done in batch. It is shown that the same impact factors also rule flow processing, yet now superposed by the very different residence and reaction time settings and by novel process windows which go beyond conventional processing. As a result, massive intensification can be reached and a mechanistic analysis can be done in entirely unpaved processing fields. This links to the analysis given in part 1: it is likely that flow processing can further promote the understanding of the mechanism and transition state of the Claisen rearrangement and, thereby, promote the achievement of better reaction performance.

The synthesis of adipic acid by means of a direct oxidation of cyclohexene by hydrogen peroxide was carried out in a continuous-flow packed-bed microreactor. The reaction uses Na₂WO₄·2H₂O as a catalyst and [CH₃(n-C₈H₁₇)₃N]HSO₄ as a phase transfer catalyst without additional solvent. A parametric process optimization, such as glass beads size, residence time, concentration of hydrogen peroxide, addition of acid, reaction temperature, and molar ratios of reactants and catalysts, was performed. It is demonstrated that smaller glass beads result in a better yield of adipic acid and that the addition of acid plays an important role in the oxidation of cyclohexene to adipic acid. Based on the concept of Novel Process Windows, the influence of elevated temperatures is investigated.

A μ²-process in the Ullmann-type CO coupling of potassium phenolate and 4-chloropyridine was successfully performed in a combined microwave (MW) and microflow process. Selective MW absorption in a micro-fixed-bed reactor (μ-FBR) by using a supported Cu nanocatalyst resulted in an increased activity compared to an oil-bath heated process. Yields of up to 80 % were attained by using a multisegmented μ-FBR without significant catalyst deactivation. The μ-FBR was packed with beads coated with Cu/TiO₂ and CuZn/TiO₂ catalysts. Temperature measurements along axial positions of the reactor were performed by using a fiber-optic probe in the catalyst bed. The simultaneous application of MW power and temperature sensors resulted in an isothermal reactor at 20 W. Initially, only solvent was used to adjust the MW field density in the cavity and optimize the power utility. Subsequently, the reaction mixture was added to ensure the maximum MW power transfer by adjusting the waveguide stub tuners to steady-state operations as a result of the changed reaction mixture composition and, therefore, the dielectric properties. Finally, the beneficial influence of the Cu/TiO₂- and CuZn/TiO₂-coated glass beads (200 μm) on the MW absorption as a result of the additional absorbing effect of the metallic Cu nanoparticles was optimized in a fine-tuning step. For the catalyst synthesis, various sol–gel, deposition, and impregnation methods provided Cu catalyst loadings of around 1 wt %. The addition of Zn to the Cu nanocatalyst revealed an increased catalyst activity owing to the presence of stable Cu⁰. Multilaminar mixing was necessary because of the large difference in fluid viscosities. To the best of our knowledge, this work is the first extended experimental survey of the decisive parameters to combine microprocess and single-mode MW technology following the concepts of “novel process windows” for organic syntheses.

Novel Process Windows make use of process conditions that are far from conventional practices. This involves the use of high temperatures, high pressures, high concentrations (solvent-free), new chemical transformations, explosive conditions, and process simplification and integration to boost synthetic chemistry on both the laboratory and production scale. Such harsh reaction conditions can be safely reached in microstructured reactors due to their excellent transport intensification properties. This Review discusses the different routes towards Novel Process Windows and provides several examples for each route grouped into different classes of chemical and process-design intensification.

The eluent droplet size defines the number of sampling compartments in a continuously operated annular electrochromatograph and therefore influences separation efficiency. In this work, an assembly of two capillaries, a feeding capillary on the top and a receiving capillary placed under it, has been investigated to control droplet size. The receiving capillary prevents the liquid droplet formation beyond a critical size, which reduces the volume of sampling compartment as compared with the case of the electrolyte flow driven solely by gravity. With a receiving capillary, the electrolyte droplet size was reduced from 1.5 to 0.46 mm. Further decrease of droplet size was not possible due to a so-called droplet jump upwards effect which has been observed on a hydrophilic glass surface with water. A typical electrolyte used in CAEC has high methanol content. In an attempt to improve the methanol-repellent properties of the glass surface, two approaches have been implemented: (i) self-assembled chemisorbed monolayers of an alkylsiloxane and (ii) fabrication of a nano-pin film. The methanol-repellent surface of the feeding capillary suppressed the droplet jump upwards effect. The surface remained methanol repellent in different solutions with lower polarity than that of water.

Flow processes with microstructured reactors allow paradigm changes in process development and thus can enable a faster development time to the final production plant. They do this by exploiting similarity effects along the development chain (modularity) and intensification. The final result can be a (significantly) reduced number of apparatus in the plant, a (significantly) reduced apparatus size, and a higher predictability in the scale-out of the apparatus. So far, this was mainly achieved via transport intensification given in microstructured reactors – improved mixing and heat transfer which increase productivity and possibly improve selectivity. A more new idea is chemical intensification through deliberate use of harsh chemistries at unusual (high) pressure, temperature, concentration, and reaction environment which again increases productivity. A very new idea is the process design intensification – the reaction-maximized flow processes need less separation expenditure and the small unit size together with the high degree in functionality gives large potential for system integration. Both means change and simplify the process scheme totally which can lead to a reduced number of apparatus and has impact on predictability. The modular nature of the small flow units allow an easy implementation to modern modular plant environments (Future Factories) which enables to perform all the testing cycles (lab, pilot, production) in one plant environment; an example are here container plants. All these measures have large potential for (much) decreased overall development time.

Konti-Prozesse mit mikrostrukturierten Reaktoren ermöglichen Paradigmenwechsel in der Prozessentwicklung und damit auch kürzere Entwicklungszeiten bis hin zur Produktionsanlage. Der Schlüssel liegt hier in analogen Prozesszuständen in der Entwicklungskette (Numbering-up), Standardisierung (Modularität) und Intensivierung. Das Resultat ist letztendlich eine reduzierte Apparateanzahl und -größe und eine höhere Voraussagekraft im Scale-out der Anlagen. Dies wird bislang meistens über die Transport-Intensivierung in mikrostrukturierten Reaktoren bewirkt. Ein neuer, mehr und mehr genutzter Ansatz ist die Chemie-Intensivierung durch Einsatz harscher Chemie bei ungewöhnlichen Reaktionsparametern und maßgeschneiderter Reaktionsumgebung. Eine ganz neuer Ansatz besteht zudem in der Prozessdesign-Intensivierung – zum einen brauchen selektivitätsoptimierte Durchflussprozesse weniger Reinigungsaufwand, zum anderen haben mikrostrukturierte Reaktoren aufgrund ihrer kleinen Baugröße und der Möglichkeit zur internen Funktionalisierung großes Potenzial für die Systemintegration. Beide Maßnahmen verändern und vereinfachen das gesamte Prozessschema grundlegend. Der modulare Aufbau der kleinen Konti-Einheiten erlaubt eine einfache Implementation in moderne modulare Anlagenumgebungen, in denen alle Testzyklen (Labor, Pilot, Produktion) in einer Anlagenumgebung durchgeführt werden sollen, wie z. B. Container-Anlagen.

Flow processes with microstructured reactors allow paradigm chances in process development and thus can enable a faster development time to the final production plant. They do this by exploiting similarity effects along the development chain (modularity) and intensification. The final result can be a reduction of the number and size of apparatus in the plant, and a higher predictability in the scale-out of the apparatus. So far, this was mainly achieved via transport intensification given in microstructured reactors. A new idea is chemical intensification through deliberate use of harsh chemistry at unusual reaction parameters and tailor-made reaction environment. A very new idea is the process design intensification – the reaction-maximized flow processes need less separation expenditure and the small unit size together with the high degree in functionality gives large potential for system integration. The modular nature of the small flow units allow an easy implementation to modern modular plant environments, that enable to perform all the testing cycles (lab, pilot, production) in one plant environment, e.g. container plants.

The miniaturization of continuous processes has been of increasing interest in the past decade, and microreaction technology and flow chemistry have moved from academic and industrial research to commercial applications. With industry taking up such innovations, this trend is also reflected in the patenting behavior of companies active in this area. This review is a continuation of the review paper on microreactor patents published by Hessel et al. and indicates major changes in patenting trends since 2006. Moreover, a different patent database search algorithm is presented, which complements the algorithm explained in the previous review. In addition, the preservation of intellectual property is analyzed for multiphase reactions and particularly solid-catalyzed gas–liquid reactions in microreactors, which play an important role in the chemical and pharmaceutical industries and are reactions that benefit largely from microprocessing. Among other results, we show that the number of patents has increased in this field, with solid-catalyst design and deposition, control of the flow pattern, and ensured stable flow as the main challenges.

Joule heat-induced hot-spot formation sets severe limits in the operation of continuous annular electrochromatography (CAEC), a new concept for preparative separation as an analog to analytical capillary electrochromatography (CEC). This may lead to eluent flow perturbance, even to boiling, which would massively weaken separation efficiency and may even hamper the stationary phase used for separation. For reasons of system integration and high-efficiency heat transfer, micro flow heat exchangers are considered with a separate coolant flow. A 3D numerical analysis of the heat transfer of water single-phase laminar flow in a square microchannel and different arrays of micro pin-fins was carried out using COMSOL Multiphysics. Several advanced materials with low electric conductivity and at the same time with high heat conductivity were put forward to be used in the CAEC system. As essential design point, it is proposed to constitute the micro heat exchanger from two different parts of the CAEC system, namely a microstructured pin-fins plate and a so-called conductive plate.