Application Notes

The following application notes show the wide range of chemical reactions and synthetic methods which can be implemented in our continuous flow reactor systems. Take look into the list below to draw inspiration for your own research!

A continuous flow process for the green and sustainable production of N-alkyl imidazoles

Ionic liquids have gained great interest during the last three decades due to their green and sustainable behavior along with their added versatility as solvents in inorganic and organic reactions as well. N-Alkylimidazole derivatives are key intermediates for the synthesis of quaternary ionic liquid salts.

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.

Application note for ScavCarts™ – using H-Cube®

Metal contamination is a major problem for the pharmaceutical and fine chemical industries. A large amount of time and
resource is spent purifying compounds after catalytic steps, so that the metal concentration is within the acceptable limit. Generally, the acceptable limit is 0.05-10 ppm, for those metals that are utilized in hydrogenation. Scavenger resins are often used for metal contamination purification. In this application note, we will demonstrate how the H-Cube® and a scavenger cartridge (ScavCart™) may be combined to perform a reaction and purification in 1 step.

Aromatic nucleophilic substitutions using X-Cube Flash™ continuous flow reactor

ThalesNano has developed a high pressure/high temperature continuous flow reactor, called X-Cube Flash™, as a viable alternative to MW-chemistry. Several reactions previously reported under MW conditions were realized in the X-Cube Flash™ with improved yield and radically shortened reaction time under safe operation. 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.

Asymmetric hydrogenation using 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.

Automated hydrogenation using the H-Cube® continuous flow reactor

The pharmaceutical industry is 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.

Carbon-carbon coupling reactions using the X-Cube™ continuous flow reactor

The X-Cube™ is a continuous flow reactor, capable of performing chemical reaction under inert conditions, temperatures up to 200°C and pressures up to 150 bar. This paper shows that carbon-carbon bond forming reactions are far more efficient on the X-Cube™ in comparison to batch mode.

Catalyst screening and profiling

ThalesNano is already well-known for its novel solutions in revolutionizing heterogeneous catalytic hydrogenations with its H-Cube® hydrogenator, while the expanded H-Cube series of fixed bed reactors offers a broad range of chemistry applications. With a wide portfolio of different catalysts available in our proprietary CatCart® catalyst cartridges ThalesNano is also heavily involved in the development, of novel catalysts, screening and profiling of catalysts.
In this application note we share the results of the optimization of the flow rate and temperature during the stereoselective hydrogenation of diphenyl acetyle. Furthermore, the longevity of the catalyst is also described, showing a slight increase in conversion and selective over 20 reactions.

Chemistry at high temperature and pressure – using the X-Cube Flash™ continuous flow reactor

The X-Cube Flash™ is a continuous-flow system that can heat and pressurize solutions up to 350°C and 200 bar respectively. The high temperature and pressure significantly decrease reaction times and allows solvents to be reacted under supercritical
conditions. This application note demonstrates the results of important chemical reactions carried out in the X-Cube Flash™ reactor with comparison to literature results based on conventional batch or microwave-assisted reactions.

Chemoselective hydrogenation of fragrance precursor using H-Cube® continous flow reactor

The following application note demonstrates how ThalesNano’s H-Cube® flow reactor proved to be a paradigm change for safe, fast and easy to use hydrogen catalyst screening for Givaudan.

Continuous Ozonolysis as a Key Step of the Darunavir Synthesis Using the IceCube™ Flow Reactor

AIDS is one of the most threatening diseases spread across the planet, affecting about 35 million people worldwide. To improve the quality of life of those affected by HIV, a number of antivirals were developed, such as Darunavir. This molecule has a complex bicyclic core, the synthesis of which is well documented in the literature.

State of the art: An approach described by Ghosh and his co-workers includes an ozonolysis step, which is performed under batch conditions resulting in the desired ketone with 98% yield after 3 hours.[6,7] However, handling the gaseous ozone and working at a very low temperature (78°C) is inconvenient. Adapting the synthesis to a continuous flow system
provides a safe and rapid alternative solution by using in-situ generated ozone, a closed system, and higher temperatures. In this application note, we demonstrate that continuous flow ozonolysis can easily be carried out utilizing the IceCube™ Flow Reactor, developed by ThalesNano, in a safe and efficient way.

Cryogenic applications in flow chemistry enabled by the IceCube Flow Reactor – Swern oxidation

In this application note we are about to demonstrate a classical Swern oxidation, conducted in ThalesNano’s novel IceCube Flow Reactor, as an example of performing high energy reactions safely and selectively.

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® is able to remove benzyl groups from amines, acids or alcohols very efficiently in one pass through a 10% Pd/C CatCart®. This application note gives examples of deprotection reactions performed on the H-Cube®.

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.

Diastereoselective hydrogenation of dihydropyrimidones using H-Cube®

The following application note will give details on how the H-Cube was used in the reduction of dihydropyrimidones to the corresponding tetrahydropyrimidones in high diastereoselectivity. Reactions were performed at Boston University.

Difficult hydrogenations – saturation of functionalized pyridines

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, 80 °C). Typical laboratory batch reactors are not capable of reaching these conditions and so, either the reaction does not work or the reactions take days. The H-Cube® flow hydrogenation reactor is capable of performing reactions at 100 °C and 100 bar safely. The H-Cube®’s improved mixing efficiency coupled with high temperature and pressure abilities means difficult reactions can be performed in minutes. Here are a few examples.

Direct alkylation of N-heterocycle under heterogeneous catalytic conditions in flow

Flow reactors are applied to conduct high temperature and high pressure chemistry towards extending the accessible chemical space to access new applications.

Efficient Curtius-rearrangement using X-Cube Flash™ continuous flow reactor

ThalesNano has developed a high pressure/high temperature continuous flow reactor, called X-Cube Flash™, to allow chemists to reach chemistry reaction extremities easier and safer compared to batch. In this application note we will focus on the study of the Curtius-reaction from an acyl azide as well ans from acids through in situ formation of the acyl azide using the X-Cube Flash™ reactor.

Ethanol oxidation with heterogeneous catalysis in flow: a batch to flow conversion

Acetic acid is considered to be an important chemical commodity as both a solvent and Bronsted acid. Being one of the first organic molecules that was synthesized in history (Kolbe, 1845), there are a wide range of procedures for its manufacturing. Despite this fact, industrial scale production now requires more environmentally friendly solutions for its sustainable production.

Heterogeneous catalysis has been found to be a useful alternative method to the current Monsanto process industry currently utilizes. With the combination of ThalesNano’s Phoenix Flow Reactor™ and Gas Module™ a reactor system has been built, which is capable to control high temperature–high pressure triphasic gas-liquid-solid reactions providing a safe and efficient environment for organic chemists.

Fast and continuous transfer hydrogenation of aromatic nitriles to amines

The reduction of nitriles is one of the most common route to synthesize primary amines, which are key intermediates in fine-chemical, pharmaceutical, and agricultural industries. Both direct (employing H2 gas) and transfer hydrogenation can be used for this purpose. The latter is a rapidly growing field taking into account green chemistry and economic considerations, avoiding the handle of hazardous hydrogen gas. By considering the last restriction, smart systems with in situ H2 gas production could be also an alternative solution.

Fast hydrogenation reaction examples using the H-Cube® flow reactor

The hydrogenation of a series of functional groups has been performed using H-Cube®, a novel continuous-flow microfluidic hydrogenation 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.

Fast optimization of continuous flow hydrogenation reactions using CatCart Changer

The optimization of reactions is a time-consuming process. Particularly when there are many different parameters to optimize. When hydrogenation is performed in batch reactors, if different temperatures, catalysts or pressures need to be validated, a separate reaction must be performed for each set of conditions. With the H-Cube and the CatCart Changer system, injections can be made at different temperatures and pressures on different catalysts, without having to perform separate reactions.

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.

Gaseous reagent organic chemistry makes 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 application note.

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.


If you are looking for broad reaction examples with H-Cube® Mini Plus, download our application overview.

How to scale-up hydrogenation reactions using the H-Cube Midi

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 100s of grams is easy and non-problematic. Using several industrial examples, this application note will describe how reactions were scaled up.

Hydrogenation of D-glucose to D-sorbitol using continuous flow hydrogenation apparatus

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 Pro continuous flow system.

Increased throughput delivered by the new 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.

Lipase-catalyzed kinetic resolution using 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.

Medicinal chemistry application of chemoselective hydrogenation of multiple functional groups

Flow hydrogenation can be applied in many different reaction pathways complementing traditional batch chemistry efforts, however articles describing chemoselective hydrogenations in a single flow process are scarce.

Multistep 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.

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.

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 organometallic chemistry, nitration and ozonolysis.

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.

Polymerization and grafting onto particle surfaces via continuous flow chemistry

Polymer grafted inorganic particles are attractive building blocks for numerous chemical and material applications. Surface initiated controlled radical polymerization (SI-RAFT) is one of the most feasible methods to fabricate these materials. However, conventional in-batch approaches still suffer from several disadvantages, such as time-consuming purification processes, inefficient grafting, and possible gelation problems. A facile method was demonstrated to synthesize homopolymers and block copolymer grafted inorganic particles using continuous flow chemistry in an environmentally friendly aqueous media using the Phoenix Flow Reactor.

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.

Rapid catalyst screening for Sonogashira coupling using 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.

Rapid library synthesis of biologically active compounds using the H-Cube® flow reactor

All medicinal chemistry programs require elegant and rapid synthetic techniques that can deliver novel building blocks from milligrams to several grams. The following application note demonstrates a number of alleviated library synthesis techniques, where the H-Cube® flow reactor afforded several high yield and selective building block syntheses for biological screening.

Reaction optimization and real-time analysis using ThalesNano’s platform and Mettler Toledo’s FlowIR™ spectrometer

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.

Reductive amination of ketones: novel one-step transfer hydrogenations

Amines are indispensable building blocks in numerous drugs, pesticides and colour pigments. Development of general and efficient methods to prepare amino-compounds is still of high interest to the chemical industry. One of the most convenient methods to synthesize amines is the reductive amination of carbonyl compounds.

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. The development of metathesis catalysts that combine high activity with a tolerance towards different functional groups has been important for the widespread utilization of this application. 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.

Safe and efficient Diels-Alder cycloaddition reactions under continuous flow

Modern flow chemistry methods offer new chemical space for drug discovery programs: novel compounds can be synthesized in dedicated high temperature/high pressure (high T/p) reactors, while reaction times can be shortened dramatically.

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.

Scale-up of a reductive amination reaction using 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 and avoids the difficult purification processes when utilizing borohydrides.

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.

Selective hydrogenation of cinnamaldehyde to cinnamyl alcohol on a Pt nanoparticle based catalyst using the H-Cube® flow reactor

Selective catalytic hydrogenation of αβ-unsaturated aldehydes is an important step in the industrial preparation of fine chemicals and attracts much interest for fundamental research in catalysis. Cinnamyl alcohol plays an important role in the perfume and flavouring industries.

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 step in the whole process.

Simple flow deuterodehalogenation using polymer-based activated carbon (PBSAC) supported palladium catalysts in CatCart®

Deuterium-labelling is a widely used method in the fields of biomedical, chemical and pharmaceutical industry.

The FDA recently approved the first deuterated API, and nowadays several molecules with deuterated moieties are under clinical testing in order to treat Alzheimer’s, cystic fibrosis, Freidreich’s ataxia, and psoriasis. The kinetic isotope effect enhances pharmacokinetic properties of deuterium-labelled molecules, which might lead to high therapeutic values.

Continuous-flow deuteration has been demonstrated in the H-Cube® before, however the possibility to use it in a green chemical solvent is practically unexplored.



Sonogashira and Suzuki reactions using H-Cube® continuous flow reactor

ThalesNano’s H-Cube® is mainly used to perform hydrogenation reactions, however it can also perform reactions in the absence of hydrogen. When utilizing the “No H2” mode, the H-Cube® acts like a general flow reactor capable of performing other heterogeneous reactions at temperatures and pressures up to 100°C and 100 bar respectively.

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

In this application note we demonstrate the results of newly developed Pd, Ni nanocomposites and immobilized Ir complex catalysts for a wide range of chemical applications.

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.

Ullmann-type reductive homo-coupling reactions at room temperature

The implementation of sustainable and environmentally friendly protocols is an emerging field of the chemical industry. The need for safe and reliable processes as the alternative of demanding, wasteful, toxic or hazardous methods is pointing towards a new paradigm in organic synthesis. Enabling technologies, like flow chemistry, especially continuous flow heterogeneous catalysis makes green and sustainable chemical procedures available.

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.

Versatile chemistry examples performed on the Phoenix high temperature, high pressure flow reactor

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 °C 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.