Select note:
Flash vacuum pyrolysis, the key step in the synthesis of a novel oxadiazolo-pyrimidinone library

While a number of avenues are available to organic chemists for the synthesis of novel structures, it has also been shown that chemists employ a relatively small chemical technology toolbox that is limiting the potentially attainable chemical space, in conventional laboratories  all around the world. It is especially true once extreme process conditions are applied in order to attain the desired, (in most cases novel) compounds.

In response to these limitations and needs we have developed and launched the Flash Reactor Plus System onto the market that reaches  beyond the already known capabilities of the usual vacuum flash pyrolysis instruments by enabling one to apply non volatile starting  materials as well, via our own interchangeable vaporizer system.

Check out our newest application note about Flash Vacuum Pyroliysis:

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Direct Alkylation of N-Heterocycle Under Heterogeneous Catalytic Conditions in Flow

Flow reactors are now being applied to conduct high temperature and high pressure chemistry towards extending the accessible chemical space to access new applications. Also, theability to precisely control the residence time and other reaction
parameters results in higher yields and tunable selectivity values for existing transformations. In addition, the utilization of extreme temperature and pressure environment eliminates the need for high boiling point solvents making the workup process faster, greener and economically more friendly. 

In this application note, we demonstrate the versatility of our Phoenix Flow Reactor by presenting results from the direct alkylation of N-heterocycle, which is described as an alternative route to the standard C-C cross coupling methods (one of the most frequently used synthetic reaction types in medicinal chemistry).

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Guideline Towards the Synthesis of 3D Shaped N-Heterocycles

This guide provides information on the optimized, general conditions for the hydrogenation of different N-heterocycles in order to easily generate novel compounds with a higher sp3/sp2 ratio.

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Phoenix Flow Reactor Application Note

The ability to explore wider chemistry space to discover new chemistry and compounds is becoming increasingly more critical as increased R&D costs go hand in hand with lower new registered molecules year on year. To achieve this, we, as chemists, must seek to expand the capabilities that we have in the lab in terms of temperature and pressure, but in a reliable and safe way. The Phoenix Flow Reactor™ is technology designed specifically for this process. With the ability to perform homogeneous and heterogeneous chemistry up to 450 ºC and 200 bar, the Phoenix Flow Reactor™ is versatile enough to create new or improve on existing chemistry.

In this application note, we demonstrate the flexibility of the Phoenix Flow Reactor™ by presenting various applications such as N-substitution, thermal Boc removal, scalable Claisen rearrangement, and synthesis of soluble polyphosphide anions.

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Radiochemical Synthesis of 18F-labelled Compounds Using the H-Cube Reactor

In this application note we demonstrate the first application on flow hydrogenation for the development of a PET radiotracer in a fast, efficient, and reproducible way.

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Safe and Fast Ozonolysis Using the IceCube Flow Reactor

Ozonolysis is a fundamentally important oxidation reaction, which has never been fully adopted due to the safety concerns with performing the process. Its main importance stems from the fact that you can selectively oxidize double or triple bonds to form hydroxyl groups, aldehydes, or carboxylic acids in the presence of other oxidizable groups. Other conventional oxidative methods are not so selective, are slower to react, require addition of water or need purification to eliminate side products leading to lower yields or need the use of metal catalysts. Compared to other methodologies, ozonolysis is considered as a greener way of oxidation. Ozonolysis has been used frequently in major drug syntheses such as (+)-Artemisinin, Indolizidine 251F, and D,L-Camptothecin and with finechemical syntheses such as L-Isoxazolylalanine and Prostaglandin endoperoxides.

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Synthesis of nanoparticles and their efficient use in the H-Cube® and H-Cube Pro™

Synthesis of nanoparticles and their efficient use in the H-Cube® and H-Cube Pro™ flow reactors for reductions and H-D exchange reactions.

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Curtius rearrangement reaction in the X-Cube Flash™

The Curtius rearrangement is the thermal decomposition of carboxylic azides to produce an isocyanate. These intermediates may be isolated or the resulting isocyanate can be trapped by a variety of nucleophiles, including water, which hydrolyze the isocyanate to an amine; amines result in ureas or alcohols leading to carbamates.

Various carbamates and ureas were prepared from an acyl azide and directly from an acid using the thermal Curtius rearrangement  reaction in the X-Cube Flash™ countinouos flow reactor under homogenous conditions. The high temperature and pressure capabilities of the reactor radically shortened the effective reaction time.

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Ruthenium-catalyzed Metathesis Reaction Using Fixed-bed Continuous Flow Reactor

Olefin metathesis is an excellent method for the preparation of new rings and valuable intermediates in organic synthesis and polymer chemistry. Out of all the various catalysts that have been reported, the ruthenium type catalysts, have the widest application due to their easy handling and substrate variability. The most undesirable feature of these complexes is that they decompose to form ruthenium byproducts, which are difficult to remove.

In this paper we demonstrate a metathesis reaction using an immobilized catalyst on mesoporous silica MCM-417, which retaines high levels of activity, thus the obtained catalysts could potentially be applied in a fixed-bed flow reactors (like the X-Cube™ or the H-Cube Pro™). The supported catalyst was evaluated in metathesis reactions, both in batch and in the X-Cube™ flow reactor. This flow system provides fast optimization of the reaction conditions (flow rate, temperature, pressure, solvent, substrate concentration) in a short period of time with only a few mg of substrate needed.

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Lipase-catalyzed Kinetic Resolution Using the X-Cube™ Continuous Flow Reactor

Enzyme catalyzed biotransformation reactions are now widely used in the chemical industry, most commonly in the synthesis of fine chemicals, but also in the production of drugs, agrochemicals and plastics. One of these enzymes is the lipase which can catalyze hydrolysis and also the esterification of ester chemical bonds in lipid substrates. The main reason for using these enzymes is that they provide enantiomerically pure products during a reaction, often with higher purity than what can be achieved by non-enzyme enantiomer catalysts. Enzymes can be utilized in kinetic resolution, based on the different activity of enantiomers in certain reactions. These reactions can be successfully performed under flow conditions with high conversion, enantiomeric excess (ee %), and enantiomer selectivity (E).

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Rapid Catalyst Screening for Sonogashira Coupling Using the H-Cube® Continuous Flow Reactor

ThalesNano’s H-Cube® can be used to perform reactions other than hydrogenation by utilizing “No H2” mode. In “No H2” mode, the H-Cube® reactor can perform reactions at temperatures and pressures up to 100 °C and 100 bar, respectively in the absence of a reagent gas.In this application note we will be focusing on Sonogashira chemistry.

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Reductive Amination of Ketones: Novel One-Step Transfer Hydrogenations in the X-Cube™

Amines are indispensable building blocks in numerous drugs, pesticides, and colour pigments. One of the most convenient methods to synthesize amines is the reductive amination of carbonyl compounds. Nowadays, reductive transformations of ketones into amines are performed in the presence of catalysts.

This paper investigates the application of these methods for the reductive amination of ketones in continuous-flow systems using the X-Cube™ flow reactor. Retention of the homogeneous phase for the 10% Pd/C-catalyzed transfer hydrogenations of aliphatic and cycloaliphatic ketones allowed the recyclable, efficient, and reproducible use of this catalyst in a continuous flow reactor.

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Carbon-Carbon Coupling Reactions Using the X-Cube™ continuous-flow reactor

The Heck and Suzuki reactions are widely used in synthetic laboratories these days. However, high temperatures and long reaction times lead to the formation of undesired side products. The following paper outlines the optimised experimental protocol used on the X-CubeTM to perform Suzuki and Heck C-C coupling reactions in comparison with batch references.


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Saturation of Functionalized Pyridines using the H-Cube Continuous Flow Reactor

The saturation of aromatic ring systems is one of the hardest reactions in hydrogenation. Reactions are typically performed at high  temperature and pressure (above 80 bar and 80 °C). Typical laboratory batch reactors are not capable of reaching these conditions and so either the reactions do not work or they take days. In this application note we demonstrate the successfull  hydrogenation of  a number of ring saturation reactions using the H-Cube® continuous flow reactor.

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H-Cube Pro Flow Hydrogenation Quick Start Reaction Guide

In this paper you can find recommended conditions for various types of hydrogenation reactions.

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Asymmetric Hydrogenation Using the H-Cube® Continuous Flow Reactor

Catalytic asymmetric hydrogenation is one of the most efficient and convenient methods for synthesizing optically active compounds, e.g. amino acids, chiral amines, and itaconic acids, which are widely used in the pharmaceutical and fine chemical industries.

At ThalesNano we have performed asymmetric hydrogenation on the H-Cube® flow hydrogenation system using solid-supported Rh catalysts bearing chiral phophorus ligands. The catalyst PTA/Al2O3/[Rh(COD)(chiral ligand)] was tested in the chiral hydrogenation of (Z)-α- acetamidocinnamic acid methyl ester.

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Scaling up Hydrogenation Reactions Using the H-Cube Midi™ Continuous Flow Reactor

The difficulties involved in scaling up reactions from laboratory to process scale are well known, especially when dangerous materials are involved. This paper will demonstrate the capability of the H-Cube Midi™ to successfully scale-up hydrogenation reactions.

The advent of flow technology has offered a methodology that can overcome these restrictions and allow rapid preparation of compounds with minimum workup. Reactions are carried out on a small scale but the amount of product can be increased by allowing a larger volume to fl ow through the system. This has a number of advantages. The thermo-chemistry of the reaction doesn’t change, so the reaction result will be constant. The heat production is highly controllable meaning many hazardous reagents that were prohibited previously may now be used in a safe controlled manner. Furthermore, reagents or compounds only undergo short reaction times and are then eluted into a collection vial, so further reaction with starting materials or thermal decomposition is unlikely. This paper will demonstrate the capability of the H-Cube Midi™ to successfully scale-up hydrogenation reactions.

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Fast Hydrogenation Reaction Examples Using the H-Cube® continuous flow reactor

In this application note we present the hydrogenation of a series of functional groups, performed using the H-Cube® continuous flow reactor. These experiments demonstrate that the H-Cube® can perform a diverse range of heterogeneous hydrogenation reactions with high yields and conversion rates and with reaction times of minutes. For example, 162 mg of  5-nitroindole was reduced in less than 10 minutes in quantitative yield.

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Fast Optimization Of Continuous Flow Hydrogenation Reactions Using the CatCart ChangerTM

To demonstrate the benefits of the CatCart Changer system two different hydrogenation reactions were optimized in terms of catalyst screening and reaction temperature. The two selected reactions were the deprotection of Cbz-tryptamine and the selective nitro- reduction of 3-chloro-7-nitroindole.

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Optimization of N-alkylation in the Phoenix Flow Reactor using 45 MHz picoSpin™ bench-top NMR for monitoring

Flow chemistry is a widely accepted technique in the synthesis field and makes optimization fast and convenient. Benchtop NMR instruments allow chemists to measure 1H NMR spectra directly in the fume hood and monitor pseudo real-time behavior of reaction chemistries. Here we give details on both the flow synthesis at extremely high temperature as well as the following analysis.

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Catalyst Screening and Profiling - Optimization of parameters during the stereoslective hydrogenation of diphenylacetylene

In this application note we share the results of the optimization of the flow rate and temperature during the stereoselective hydrogenation of diphenylacetyle. Furthermore the longitivity of the catalyst is also described, showing a slight increase in conversion and selective over 20 reactions.


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A High Temperature Green Method for Direct N-Alkylation with the Phoenix Flow Reactor

N-alkylation reaction is frequently used in various industrial, pharmaceutical, and agrochemical processes, such as the production of Piribedil; a drug used in the treatment of Parkinson’s disease. The most common way of performing N-alkylation to produce secondary amines is the reaction between a primary amine and an alkyl halide. However, this methodology often results in byproducts (overalkylation) and the produced halide acid needs to be removed from the product mixture. The use of halide derivatives should be avoided due to their toxic nature, therefore other environmentally friendly processes have been sought. N-alkylation reactions, where alkyl alcohols are used instead, may provide possible green procedures.

In this application note we demonstrate successful N-alkylation reactions using precise temperature control which has a major influence on the outcome of the reaction (150-180°C).

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Phoenix Flow Reactor: Your Solution To Dead End Chemistry

Today’s chemistry reaction space is severely restricted by conventional laboratory equipment; do not have too many options when it comes to temperature and pressure accessibility. ThalesNano’s Phoenix Flow Reactor is designed to overcome this problem by offering chemists a versatile solution that can extend their chemistry capability significantly. The continuous-flow reactor can fit either a fix bed reactor for heterogeneous catalyst/reagent chemistry or a coil for homogeneous reactions up to 450 °C and 100 bar safely.

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The Modeling of Industrial Scale Desulfurization Using the P-Cube™ Flow Reactor

In this application note we demonstrate the how the P-Cube can be used in petrochemistry to mimic a 100 mL and a kiloton plant reactor. The P-Cube™ showed that it could reproducibly replicate the reaction results of these larger reactors to within 2 ppm for sulfur content and 0.06% for diaromatic content. Only 5 cm3 of catalyst was needed and the reaction time was a period of hours instead of typical reaction times of days.

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Safe and Fast Ozonolysis Using the O-Cube™ Continuous Flow Reactor

Ozonolysis is a fundamentally important oxidation reaction, which has never been fully adopted due to the safety concerns with performing the process. Its main importance stems from the fact that you can selectively oxidize double or triple bonds to form hydroxyl groups, aldehydes, or carboxylic acids in the presence of other oxidizable groups.  

In order to overcome the difficulties associated with ozonolysis, such as dangerous workup of the potentially explosive ozonide, use of low temperature, and complicated setting up of ozonizer equipment, ThalesNano has developed the O-Cube™ ozonolysis flow reactor. The O-Cube™ system is a compact instrument dedicated for performing ozonolysis and low temperature reactions. The O-Cube™ reactor is safer and more efficient than standard batch equipment due to the small reactor volume and precise temperature control. The compact manner of the O-Cube™ reactor allows chemists to carry out the formation and reductive or oxidative cleavage of the secondary ozonide in one instrument. Ozonolysis has been used frequently in major drug syntheses such as (+)-Artemisinin, Indolizidine 251F, and D,L-Camptothecin and with finechemical syntheses such as L-Isoxazolylalanine and Prostaglandin endoperoxides.

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Ozonolysis Combined with Hydrogenation for the Simple Synthesis of Aldehydes in Tandem Continuous Flow

While ozonolysis itself is a useful reaction in organic chemistry it is not performed regularly because of its hazardous nature. The O-Cube™ ozonolysis reactor is designed to increase the adoption of this useful technique and to make ozonolysis safer by quenching the potentially explosive ozonides continuously on a small scale. In order to enhance the performance of the O-Cube™ reactor further and simplify the workup procedure after ozonolysis, we have developed the combination of two flow systems where the intermediate of the ozonolysis reaction is converted to final product via hydrogenation in the H-Cube® continuous flow system. The setup also contains a ReactIR™ flow cell, so the reactions can be monitored in real-time and optimized rapidly in order to reach a high selectivity through precise residence time control.

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Hydrogenation of 2,4-dinitroanisole: A Comparative Study H-Cube® and the H-Cube Pro™

The H-Cube Pro™ improves upon the original H-Cube® by offering greater hydrogen production (up to 60 mL/min) for higher throughput, wider temperature range (from 10 - 150 °C) including - for the first time - active cooling for more selective reactions. In this application note, we compare the H-Cube® with the new H-Cube Pro™ in terms of throughput. The aim is to see how much more concentrated we can run a reaction on the H Cube Pro™ by taking advantage of the greater hydrogen production capability.

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Hydrogenation of D-Glucose to D-Sorbitol Using the H-Cube Pro™

This application note demonstrates the H-Cube Pro™’s increased productivity in the hydrogenation of D-glucose to D-sorbitol, which is believed to be a key intermediate in biofuel production. Both the use of elevated temperatures and increased concentration were proven to be advantageous for the outcome of the reaction, resulting in higher selectivity of the desired compound and higher throughput over the H-Cube® continuous flow system.

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Rapid Library Synthesis of Biologically Active Compounds using the H-Cube® Continuous Flow Reactor

All medicinal chemistry programs require elegant, and rapid synthetic techniques that can deliver novel building blocks from milligrams to several grams. Judicious choice of catalyst selection allowed the selective reduction of either the olefin double bond to the corresponding propanenitrile derivative (10% Pd/C) or the reduction of unsaturated nitriles to the corresponding propaneamine derivatives (Ra-Ni) in a flow manner. The involvement of the H-Cube® flow reactor in the synthesis steps allowed rapid condition screening and parameter optimization. The prepared scaffolds were then collected long enough to gather compounds for either subsequent building block syntheses or for biological screening.

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Gaseous reagent organic chemistry made easy

The Gas Module works seamlessly with the H-Cube Pro™ allowing a further 13 gases to be used at up to 100 bar using the same touch screen intuitive controls. Reactions such as carbonylation or oxidation can now be performed on the H-Cube Pro™ at the same high pressure and ease of use, extending the reactor’s chemistry capacity significantly, as it is presented in this applicaiton note.

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Scale up of a Reductive Amination Reaction Using the H-Cube Midi™ Reactor

Reductive amination is widely used as a form of amination between an aldehyde or ketone and a primary amine or ammonia. The reaction can be done either in two steps, via indirect reductive amination and performing the reduction after isolation of the imine compound, or simultaneously by choosing a way of reduction which prefers the reduction of the protonated imine over the reduction of starting material. Catalytic hydrogenation matches these criteria, e.g. Raney Nickel and can be used at low pressure as well as Pd(OH)2/C, and avoids the difficult purification processes when utilizing borohydrides.

In this application note an optimization of a reduction amination reaction is detailed resulting in 130.9 g of the final product with a 99.4% purity.

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How to Scale up Hydrogenation Reactions Using the H-Cube Midi™ Continuous Flow Reactor

The difficulties involved with scaling up reactions from laboratory to process scale are well known. The H-Cube Midi is designed so that the scale up of reactions from the milligram scale on H-Cube® to 100 s of grams is easy and non-problematic. Using several industrial examples, this application note will describe how reactions were scaled up.

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Chemoselective Hydrogenation of Fragrance Precursors Using H-Cube® Continous Flow Reactor

Chemoselective hydrogenation of fragrance precursors opens up the way to a vast variety of new candidates for olfactory screening. Their chemical syntheses are not only making them cheaper but they are also saving the natural resources of such compounds. Using flow method, novel, unique odor characteristics can be made that are not synthesized in nature.

In this application note the chemeoselective hydrogenation of alkenols; unsaturated and cyclopropanated carbonyls (e.g. derivatives and precursors of Pashminol™, cis-Javanol, Melonal™ etc) were investigated.

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Selective hydrogenation of cinnamaldehyde on a Pt nanoparticle based catalyst using the H-Cube® Flow Reactor

Selective catalytic hydrogenation of α-β-unsaturated aldehydes is an important step in the industrial preparation of fine chemicals.The hydrogenation of the C=C bond in α-β-unsaturated aldehydes is both kinetically and thermodynamically more favorable than that of the C=O group. The most significant factors determining the selectivity are: the type and the structure of the active metal, the type of the substrate, and the conditions of the reaction, namely, the hydrogen pressure and the reaction temperature. The influence of the latter factors can be easily investigated by using the H-Cube® continuous flow reactor, which is a standalone hydrogenation reactor combining continuous-flow microchemistry with on-demand hydrogen generation and a disposable catalyst cartridge (CatCart®) system.

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Deprotection Reactions Using the H-Cube® Continuous Flow Reactor

Protecting groups play a central role in modern organic synthesis. The benzyl groups and benzyl carbamate or Cbz groups are some of the most commonly used protecting groups and play a central role in the protection of alcohols, carboxylic acids, and amines. The benzyl and benzyl carbamate groups are removed using catalytic hydrogenation using elevated temperature. The H-Cube® continuous flow reactor is proven to be an ideal tool for performing deprotection catalytic hydrogenation. The H-Cube® is able to remove benzyl groups from amines, acids, or alcohols very efficiently in one pass through a 10% Pd/C CatCart®. The excellent yields in all cases and the easy handling of catalysts suggest this method to be a fast, efficient, and safe way to perform benzyl deprotection compared to batch and microwave methods.

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Swern Oxidation using the IceCube™ Flow Reactor

Swern oxidation is well known for the oxidation of alcohols to their corresponding carbonyls and it demonstrates good functional group selectivity. However, their regular application has been limited so far due to their low reaction temperature requirement, which is inevitable for maintaining a stable reactive intermediate.

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Automated Hydrogenation Using the H-Cube® Continuous Flow Reactor

All industries are continually searching to automate techniques for rapid optimization or library production. The automation of hydrogenation is one of those processes that is drawing high interest due to its frequency in drug synthesis.

Automated H-Cube® was used for hydrogenolysis and deprotection reactions.

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Deuteration Reactions Using the H-Cube® Continuous Flow Reactor

Deuterium-labeled compounds are widely used as research tools in chemistry. Their importance lies in a number of applications, such as: proving reaction mechanisms,  investigation of a compound’s pharmacokinetic properties, internal standards in mass spectrometry, compound structure determination in NMR spectroscopy.

The H-Cube® continuous flow system is capable of generating deuterium gas from the electrolysis of D2O, which is readily available in 99.98% purity and is easy to handle. These results offer up the H-Cube® as a reliable alternative to other deuteration methods.

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Multi Step Azo Dye Formation in the IceCube Continuous Flow Reactor

Diazotization and azo-coupling reactions are chemical processes that lead to industrially important azo-dyes and other intermediary molecules. The formed intermediate diazonium salts are unstable above 5°C and might explode when they are left to dry. Both  diazotization and azo coupling reactions are always carried out with high precautions in the lab on any scale. The need for a safe  and high capacity process for diazotization and azo-coupling made us develop these reactions in a flow manner. The outcome is  reported in this application note using the IceCube™ continuous flow reactor.

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Using Flow Chemistry in Agrochemical Applications

The need for easy and fast high throughput screening tools to find target compounds which can be patented and produced in commercial scale is ever growing. Such a tool is flow chemistry, which is being employed in several chemical industries due to its benefits.

In this application note we provide information from patents from major agrochemical companies, Syngenta and Dow Agrosciences, where flow chemistry was used for the synthesis of active compounds.

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H-Cube Mini™ Application Overview

A list of possible applications for the H-Cube Mini™. Includes reductions, ring-closure, deuteration, oxidation, and carbonylation reactions.

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Reaction Optimization and Real-time Analysis

In this application note we report on the optimization of hydrogenation, oxidation and ring-closing reactions and their real time analysis. Homogeneous and heterogeneous reactions were performed in ThalesNano’s H-Cube Pro™ , Gas Module, and Phoenix  Flow Reactor™ systems, while these reactions were monitored by Mettler Toledo’s FlowIR™ device.


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Simple, Fast, and Safe Continuous Flow Nitrations with the IceCube Flow Reactor

Nitration of aromatics is one of the oldest and industrially most important reactions. A reaction between an organic compound and a nitrating agent leads to the introduction of a nitro group onto a carbon, nitrogen or oxygen atom of that organic compound.

Nitro derivatives of aromatic compounds are used in a variety of basic and specialty chemicals that are employed in dyes, perfumes, pharmaceuticals, explosives, intermediates, colorants, and pesticides.

Almost 65% of APIs require at least one nitration


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Performing Highly Exothermic Reactions Safely in Minutes

Exothermic reactions, by their very nature, often progress rapidly through unstable intermediates. Maintaining a firm control over parameters such as temperature and pressure is problematic, so their utilization is limited in synthetic practice. However, flow techniques have the potential of
keeping such reactions under control via their improved heat and mass transfer capabilities, allowing one to exploit untapped or avoided chemistries such organomettalic chemistry, nitration, and ozonolysis. In this application note we share details of the Grignard reaction, using EtMrBr and lithiation, which demonstrate the versatility of the IceCube™ flow reactor, dedicated to the safe running of exothermic reactions.

The Grignard reaction was performed using various aldehydes and ketones as starting materials, applying only one reaction zone, while the bromo-lithium exchange and the subsequent nucleophilic addition reaction required the use of both reaction zones in the IceCube™ flow reactor.


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Aromatic Nucleophilic Substitutions Using X-Cube Flash™ Continuous Flow Reactor

Fluorine aromatic ring substitution using N-based nucleophiles normally requires either harsh conditions and/or transition metal catalysis In the presence of electron-withdrawing groups (EWGs), non-catalyzed aromatic substitution takes place in ortho and para-position in good yields. In the case of metasubstituted compounds, long reaction times (about 50 - 100 h) at 100 °C are required. Our objective was to study the nucleophilic aromatic substitution reaction (F-amine exchange) in metapositions, since the substituted mono- and diaminobenzonitriles are important biological active molecules.

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Thermal Cyclisation Leading to Important Heterocyclic Carbonyl Intermediates Using X-Cube Flash™ Reactor

Heterocyclic carbonyl compounds e.g. quinolones, pyridopyrimidinones, naphthyridinones are important structural motifs in various biological active compounds (e.g. norfloxacin, nalidixic acid). One of the most practical approaches for their synthesis is the thermal cyclisation of the appropriate open chain intermediates containing a suitably substituted 3 carbon extension on the nitrogen.
We successfully carried out high temperature related thermal ringclosing reactions in excellent conversion and good to high yield in a continuous flow system with a very short residence time (1.33 min) and successfully replaced the high boiling solvents with a low boiling point solvent (THF). Additional advantages of performing this procedure in flow with a common low boiling point solvent are that it allows easy work-up, supports automation, and is suitable for process development and scale-up.

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