3D Printed High‐Throughput Hydrothermal Reactionware for Discovery,Optimization, and Scale‐Up

3D printing techniques allow the laboratory‐scale design and production of reactionware tailored to specific experimental requirements. To increase the range and versatility of reactionware devices, sealed, monolithic reactors suitable for use in hydrothermal synthesis have been digitally designed and realized. The fabrication process allows the introduction of reaction mixtures directly into the reactors during the production, and also enables the manufacture of devices of varying scales and geometries unavailable in traditional equipment. The utility of these devices is shown by the use of 3D printed, high‐throughput array reactors to discover two new coordination polymers, optimize the synthesis of one of these, and scale‐up its synthesis using larger reactors produced on the same 3D printer. Reactors were also used to produce phase‐pure samples of coordination polymers MIL‐96 and HKUST‐1, in yields comparable to synthesis in traditional apparatus.     

3D Printed High‐Throughput Hydrothermal Reactionware for Discovery,Optimization, and Scale‐Up

3D printing techniques allow the laboratory‐scale design and production of reactionware tailored to specific experimental requirements. To increase the range and versatility of reactionware devices, sealed, monolithic reactors suitable for use in hydrothermal synthesis have been digitally designed and realized. The fabrication process allows the introduction of reaction mixtures directly into the reactors during the production, and also enables the manufacture of devices of varying scales and geometries unavailable in traditional equipment. The utility of these devices is shown by the use of 3D printed, high‐throughput array reactors to discover two new coordination polymers, optimize the synthesis of one of these, and scale‐up its synthesis using larger reactors produced on the same 3D printer. Reactors were also used to produce phase‐pure samples of coordination polymers MIL‐96 and HKUST‐1, in yields comparable to synthesis in traditional apparatus.     

3D‐Printing inside the Glovebox: A Versatile Tool for Inert‐Gas Chemistry Combined with Spectroscopy

3D‐Printing with the well‐established ‘Fused Deposition Modeling’ technology was used to print totally gas‐tight reaction vessels, combined with printed cuvettes, inside the inert‐gas atmosphere of a glovebox. During pauses of the print, the reaction flasks out of acrylonitrile butadiene styrene were filled with various reactants. After the basic test reactions to proof the oxygen tightness and investigations of the influence of printing within an inert‐gas atmosphere, scope and limitations of the method are presented by syntheses of new compounds with highly reactive reagents, such as trimethylaluminium, and reaction monitoring via UV/VIS, IR, and NMR spectroscopy. The applicable temperature range, the choice of solvents, the reaction times, and the analytical methods have been investigated in detail. A set of reaction flasks is presented, which allow routine inert‐gas syntheses and combined spectroscopy without modifications of the glovebox, the 3D‐printer, or the spectrometers. Overall, this demonstrates the potential of 3D‐printed reaction cuvettes to become a complementary standard method in inert‐gas chemistry.     

3D-Printed Phenacrylate Decarboxylase Flow Reactors for the Chemoenzymatic Synthesis of 4-Hydroxystilbene

Continuous flow systems for chemical synthesis are becoming a major focus in organic chemistry and there is a growing interest in the integration of biocatalysts due to their high regio- and stereoselectivity. Methods established for 3D bioprinting enable the fast and simple production of agarose-based modules for biocatalytic reactors if thermally stable enzymes are available. We report here on the characterization of four different cofactor-free phenacrylate decarboxylase enzymes suitable for the production of 4-vinylphenol and test their applicability for the encapsulation and direct 3D printing of disk-shaped agarose-based modules that can be used for compartmentalized flow microreactors. Using the most active and stable phenacrylate decarboxylase from Enterobacter spec. in a setup with four parallel reactors and a subsequent palladium(II) acetate-catalysed Heck reaction, 4-hydroxystilbene was synthesized from p-coumaric acid with a total yield of 14.7 % on a milligram scale. We believe that, due to the convenient direct immobilization of any thermostable enzyme and straightforward tuning of the reaction sequence by stacking of modules with different catalytic activities, this simple process will facilitate the establishment and use of cascade reactions and will therefore be of great advantage for many research approaches.     

Flow Asymmetric Propargylation: Development of Continuous Processes for the Preparation of a Chiral β‐Amino Alcohol

The development of a flow chemistry process for asymmetric propargylation using allene gas as a reagent is reported. The connected continuous process of allene dissolution, lithiation, Li‐Zn transmetallation, and asymmetric propargylation provides homopropargyl β‐amino alcohol 1 with high regio‐ and diastereoselectivity in high yield. This flow process enables practical use of an unstable allenyllithium intermediate. The process uses the commercially available and recyclable (1S ,2R )‐N ‐pyrrolidinyl norephedrine as a ligand to promote the highly diastereoselective (32:1) propargylation. Judicious selection of mixers based on the chemistry requirement and real‐time monitoring of the process using process analytical technology (PAT) enabled stable and scalable flow chemistry runs.     

Enantioselective addition of diethylzinc to aldehydes catalyzed by β‐amino alcohols derived from (1R,2S)‐norephedrine

β‐Amino alcohols derived from (1R,2S)‐norephedrine were synthesized and used as ligands in the catalytic enantioselective diethylzinc addition to benzaldehydes. N‐alkylated (1R,2S)‐norephedrine‐based derivative 3a gave the highest enantioselectivity. The effects of different parameters on the enantioselectivity of the product were investigated. Copyright © 2009 John Wiley & Sons, Ltd.     

A Mechanistic Investigation of the Visible‐Light Photocatalytic Trifluoromethylation of Heterocycles Using CF3I in Flow

Photocatalytic radical trifluoromethylation strategies have impacted the synthesis of trifluoromethyl‐containing molecules. However, mechanistic aspects concerning such transformations remain poorly understood. Here, we describe in detail the mechanism of the visible‐light photocatalytic trifluoromethylation of N‐methylpyrrole with gaseous CF₃I in flow. The use of continuous‐flow microreactor technology allowed for the determination of different important parameters with high precision (e.g., photon flux, quantum yield, reaction rate constants) and for the handling of CF₃I in a convenient manner. Our data indicates that the reaction occurs through a reductive quenching mechanism and that there is no radical chain process present.     

Multistage Microfluidic Platform for the Continuous Synthesis of III–V Core/Shell Quantum Dots

We present a fully continuous chip microreactor‐based multistage platform for the synthesis of quantum dots with heterostructures. The use of custom‐designed chip reactors enables precise control of heating profiles and flow distribution across the microfluidic channels while conducting multistep reactions. The platform can be easily reconfigured by reconnecting the differently designed chip reactors allowing for screening of various reaction parameters during the synthesis of nanocrystals. III–V core/shell quantum dots are chosen as model reaction systems, including InP/ZnS, InP/ZnSe, InP/CdS and InAs/InP, which are prepared in flow using a maximum of six chip reactors in series.     

New 3,3′[2,2′‐oxy‐bis‐(oxazaborolidine)]‐ethylenes. Structural studies by NMR,X‐ray,and quantum chemistry methods

3,3′‐[2,2′‐Oxy‐bis‐(4S‐methyl, 5R‐phenyl‐1,3,2‐oxazaborolidine)]ethylene ( 4a ) and 3,3′‐[2, 2′‐oxy‐(4S‐methyl‐5R‐phenyl‐1,3,2‐oxazaborolidine)‐ (1,3,2‐benzoxazaborolidine)]ethylene ( 4b ) were synthesized by the reaction of N,N′‐bis‐[(1R,2S)‐norephedrine]oxalyl ( 3a ) or N,N′‐[((1R,2S)‐norephedrine, o‐hydroxyphenylamine]oxalyl ( 3b ) with BH₃‐THF. The molecular structure of these compounds was established by NMR and infrared spectroscopy. The molecular geometry for 4 was studied by means of theoretical methods, resulting in structures that were in total agreement with those obtained by spectroscopy data and X‐ray diffraction. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:513–519, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20151     

Continuous Consecutive Reactions with Inter‐Reaction Solvent Exchange by Membrane Separation

Pharmaceutical production typically involves multiple reaction steps with separations between successive reactions. Two processes which complicate the transition from batch to continuous operation in multistep synthesis are solvent exchange (especially high‐boiling‐ to low‐boiling‐point solvent), and catalyst separation. Demonstrated here is membrane separation as an enabling platform for undertaking these processes during continuous operation. Two consecutive reactions are performed in different solvents, with catalyst separation and inter‐reaction solvent exchange achieved by continuous flow membrane units. A Heck coupling reaction is performed in N,N‐dimethylformamide (DMF) in a continuous membrane reactor which retains the catalyst. The Heck reaction product undergoes solvent exchange in a counter‐current membrane system where DMF is continuously replaced by ethanol. After exchange the product dissolved in ethanol passes through a column packed with an iron catalyst, and undergoes reduction (>99 % yield).     

Continuous Synthesis of Aryl Amines from Phenols Utilizing Integrated Packed‐Bed Flow Systems

Aryl amines are important pharmaceutical intermediates among other numerous applications. Herein, an environmentally benign route and novel approach to aryl amine synthesis using dehydrative amination of phenols with amines and styrene under continuous‐flow conditions was developed. Inexpensive and readily available phenols were efficiently converted into the corresponding aryl amines, with small amounts of easily removable co‐products (i.e., H₂O and alkanes), in multistep continuous‐flow reactors in the presence of heterogeneous Pd catalysts. The high product selectivity and functional‐group tolerance of this method allowed aryl amines with diverse functional groups to be selectively obtained in high yields over a continuous operation time of one week.     

Integrated Micro Flow Synthesis Based on Sequential Br–Li Exchange Reactions of p‐, m‐, and o‐Dibromobenzenes

A micro flow system consisting of micromixers and microtube reactors provides an effective method for the introduction of two electrophiles onto p‐, m‐, and o‐dibromobenzenes. The Br–Li exchange reaction of p‐dibromobenzene with nBuLi can be conducted by using the micro flow system at 20 °C, although much lower temperatures (p‐bromophenyllithium was allowed to react with an electrophile in the micro flow system at 20 °C. The p‐substituted bromobenzene thus obtained was subjected to a second Br–Li exchange reaction followed by reaction with a second electrophile at 20 °C in one flow. A similar transformation can be carried out with m‐dibromobenzene by using the micro flow system. However, the Br–Li exchange reaction of o‐dibromobenzene followed by reaction with an electrophile should be conducted at ?78 °C to avoid benzyne formation. The second Br–Li exchange reaction followed by reaction with an electrophile can be carried out at 0 °C. By using the present method, a variety of p‐, m‐, and o‐disubstituted benzenes were synthesized in one flow at much higher temperatures than are required for conventional batch reactions.     

Highly Efficient Photocatalysts and Continuous‐Flow Photocatalytic Reactors for Degradation of Organic Pollutants in Wastewater

One of the most important applications for photocatalysis is engineered water treatment that photodegrades organic pollutants in wastewater at low cost. To overcome the low efficiency of batch degradation methods, continuous‐flow photocatalytic reactors have been proposed and have become the most promising method for mass water treatment. However, most commercial semiconductor photocatalysts are granular nanoparticles with low activity and a narrow active light wavelength band; this creates difficulties for direct use in continuous‐flow photocatalytic reactors. Therefore, a high‐performance photodegradation photocatalyst with proper morphology or structure is key for continuous photocatalytic degradation. Moreover, a well‐designed photocatalytic device is another important component for continuous‐flow photocatalysis and determines the efficiency of photocatalysis in practical water treatment. This review describes the basic design principles and synthesis of photocatalysts with excellent performance and special morphologies suitable for a filtering photocatalysis process. Certain promising continuous photodegradation reactors are also categorized and summarized. Additionally, selected scientific and technical problems that must be urgently solved are suggested.     

Large‐Scale Synthesis of Enantiopure Molecular Cages: Chiroptical and Recognition Properties

A convenient and efficient gram‐scale synthesis for enantiopure hemicryptophane–tren (tren=tris(2‐aminoethyl)amine) derivatives has been developed. The four‐step synthesis is based on the optical resolution of a key intermediate, cyclotriveratrylene, for which the energy barrier for racemization has been measured to ensure that no racemization occurs during the two last steps of the synthetic pathway. The assignments of the absolute configurations have been performed by electronic circular dichroism and the enantiopurity was determined by NMR spectroscopy in the presence of enantiopure camphor sulfonic acid. To highlight the interest of such compounds, the recognition of norephedrine neurotransmitter was investigated and showed a remarkable enantioselectivity towards the C₃ symmetrical hosts. Finally, this highly modular synthetic pathway was used to provide eight enantiopure hemicryptophanes with different sizes, shapes, and functionalities. These results underline the high potential of this approach, which could lead to many applications in chiral recognition or asymmetric supramolecular catalysis.     

Decarboxylative Palladium(II)‐Catalyzed Synthesis of Aryl Amidines from Aryl Carboxylic Acids: Development and Mechanistic Investigation

A fast and convenient synthesis of aryl amidines starting from carboxylic acids and cyanamides is reported. The reaction was achieved by palladium(II)‐catalysis in a one‐step microwave protocol using [Pd(O₂CCF₃)₂], 6‐methyl‐2,2′‐bipyridyl and trifluoroacetic acid (TFA) in N‐methylpyrrolidinone (NMP), providing the corresponding aryl amidines in moderate to excellent yields. The protocol is very robust with regards to the cyanamide coupling partner but requires electron‐rich ortho‐substituted aryl carboxylic acids. Mechanistic insight was provided by a DFT investigation and direct ESI‐MS studies of the reaction. The results of the DFT study correlated well with the experimental findings and, together with the ESI‐MS study, support the suggested mechanism. Furthermore, a scale‐out (scale‐up) was performed with a non‐resonant microwave continuous‐flow system, achieving a maximum throughput of 11 mmol h^?1 by using a glass reactor with an inner diameter of 3 mm at a flow rate of 1 mL min^?1.     

A Continuous Flow Process Using a Sequence of Microreactors with In‐line IR Analysis for the Preparation of N,N‐Diethyl‐4‐(3‐fluorophenylpiperidin‐4‐ylidenemethyl)benzamide as a Potent and Highly Selective δ‐Opioid Receptor Agonist

This article describes the design, optimisation and development of a continuous flow synthesis of N,N‐diethyl‐4‐(3‐fluorophenylpiperidin‐4‐ylidenemethyl)benzamide, a potent δ‐opioid receptor agonist developed by AstraZeneca. The process employs a sequence of flow‐based microreactors, with integrated purification employing solid‐supported reagents and in‐line IR analytical protocols using a newly developed ReactIR flow cell. With this monitoring device, initiation of the fourth input flow stream can be precisely controlled during the synthesis.     

Multi-Step Synthesis of Miltefosine: Integration of Flow Chemistry with Continuous Mechanochemistry

Herein we report for the first time, an advanced continuous flow synthesis of the blockbuster Leishmaniasis drug miltefosine from simple starting materials by a sequence involving four steps of chemical transformation including a continuous mechanochemical step. First three reaction steps were performed in simple tubular reactors in a telescopic mode, while in the last step the product precipitated from the 3^rd step was used for a continuous mechanochemical synthesis of miltefosine. When compared to a typical batch protocol that takes 15 h, miltefosine was obtained in 58 % overall yield in flow synthesis mode at the laboratory scale in a total residence time 34 min at synthesis rate of 10 g/hr, which is sufficient to treat 4800 patients per day.     

Dynamic postpolymerization of 3D‐printed photopolymer nanocomposites: Effect of cellulose nanocrystal and postcure temperature

Cellulose nanocrystal (CNC) reinforced methacrylate (MA) resin nanocomposite was prepared by 3D stereolithography printing. A postcure process, where the printed nanocomposite was heat‐treated under different temperatures, was applied to improve the property of the printed nanocomposites. To investigate the effect of CNC and postcure temperature on the kinetic behavior of the postpolymerization of printed nanocomposites, Fourier‐transform infrared spectroscopy and differential scanning calorimetry measurement of the printed nanocomposites before and after postcure were analyzed. The postpolymerization of MA nanocomposites was promoted at a postcure temperature of 140 °C for the printed 0.5% CNC/MA nanocomposites compared to the printed MA resin. The addition of CNC retarded the polymerization of MA resin during 3D printing, resulting in poorer mechanical properties of the printed nanocomposites compared to the printed MA resin. However, after postcure, the mechanical properties of the printed nanocomposites were improved by the postpolymerization of the MA nanocomposites. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2018 , 56, 935–946     

Continuous‐Flow Synthesis and Derivatization of Aziridines through Palladium‐Catalyzed C(sp3)−H Activation

A continuous‐flow synthesis of aziridines by palladium‐catalyzed C(sp³)?H activation is described. The new flow reaction could be combined with an aziridine‐ring‐opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C?H activation flow process and illustrates an approach towards first‐principles design based on novel catalytic reactions.     

Continuous‐Flow Synthesis of CdSe Quantum Dots: A Size‐Tunable and Scalable Approach

In recent years, continuous‐flow/microreactor processing for the preparation of colloidal nanocrystals has received considerable attention. The intrinsic advantages of microfluidic reactors have opened new opportunities for the size‐controlled synthesis of nanocrystals either in the laboratory or on a large scale. Herein, an experimentally simple protocol for the size‐tunable continuous‐flow synthesis of rather monodisperse CdSe quantum dots (QDs) is presented. CdSe QDs are manufactured by using cadmium oleate as cadmium source, selenium dioxide as selenium precursor, and 1‐octadecene as solvent. Exploiting selenium dioxide as selenium source and 1‐octadecene as solvent allows execution of the complete process in open air without any requirement for air‐free manipulations using a glove box or Schlenk line. Continuous‐flow processing is performed with a stainless steel coil of 1.0 mm inner diameter pumping the combined precursor solution through the reactor by applying a standard HPLC pump. The effect of different reaction parameters, such as temperature, residence time, and flow rate, on the properties of the resulting CdSe QDs was investigated. A temperature increase from 240 to 260 °C or an extension of the residence time from 2 to 20 min affords larger nanocrystals (range 3–6 nm) whereas the size distribution does not change significantly. Longer reaction times and higher temperatures result in QDs with lower quantum yields (range 11–28 %). The quality of the synthesized CdSe QDs was confirmed by UV/Vis and photoluminescence spectroscopy, small‐angle X‐ray scattering, and high‐resolution transmission electron microscopy. Finally, the potential of this protocol for large‐scale manufacturing was evaluated and by operating the continuous‐flow process for 87 min it was possible to produce 167 mg of CdSe QDs (with a mean diameter of 4 nm) with a quantum yield of 28 %.