H-Cube® Application Notes

The following application notes show the wide range of chemical reactions and synthetic methods which can be implemented in our H-Cube® continuous flow reactor systems.


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 resources are 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.


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.


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.


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.


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.


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.


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.



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


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.


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 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.


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.