A compact hydrogenation flow reactor for educational purposes H-Cube Mini: A compact hydrogenation flow reactor for educational purposes 1

What is Hydrogenation? Addition of hydrogen to a functional group Produces cis predominantly over trans (hydrogens attack same side of double bond) Utilizes a catalyst, which is either homogeneous (soluble) or heterogeneous (insoluble and solid supported) Key reaction in pharmaceutical, fine chemical, chemical, agrochemical, and petrochemical industries, as well as academia Hydrogenation accounts for 5-10% of all reactions in the chemistry industries!

Possible Applications Double bond saturation Triple bond reduction/saturation Aromatic ring saturation Nitro reduction Heterocycle saturation Nitrile reduction

Some Representative Applications Production of methanol (triple bond reduction) Partially saturating plant fats: solid butter produced from vegetable oil (double bond reduction) Production of aniline (nitro reduction) Refinement of gasoline (aromatic ring reduction) Bioremediation (aromatic ring reduction) Drug synthesis (deprotection/hydrogenolysis) Producing vitamin A from phenylacetylene (Lindlar’s catalyst)

Typical Protocols Hydrogenations usually takes place in a pressure vessel (batch processes) Parr reactor Autoclave Balloon The Parr Shaker 78 years old Industry standard Homo- and heterogeneous hydrogenations Pressures up to 2 atm. Temperatures up to 40oC Batch process

Disadvantages of Batch Processes Need hydrogen cylinder - tough safety regulations Separate laboratory needed Time consuming and difficult to set up Analytical samples difficult to obtain Different reaction scales require different reactors Mixing of 3 phases is inefficient, resulting in poor reaction rates and consequently, long reaction times Notoriously dangerous hydrogen gas is flammable most catalysts are pyrophoric Catalytic residue can dry out sitting in the waste container and eventually ignite Self explanatory

H-Cube Mini 7

H-Cube Mini Specifications Flow rate: 0,3-3 mL/min Temperature: 25°C to 100°C Pressure: 1-100 bar 30-70 mm CatCarts used 1 hydrogen cell Reusable drying CatCart applied Hydrogen production: 0 or 22 mL/min Foldable screen Small footprint, compact design Territory specific languages Updated graphical user interface Main screen Graph options Service screen

HPLC pumps continuous stream of solvent How does it work? Hydrogenation reactions: Nitro Reduction Nitrile reduction Heterocycle Saturation Double bond saturation Protecting Group hydrogenolysis Reductive Alkylation Hydrogenolysis of dehydropyrimidones Imine Reduction Desulfurization HPLC pumps continuous stream of solvent Hydrogen generated from water electrolysis Sample heated and passed through catalyst Up to 100°C and 100 bar. (1 bar=14.5 psi) Reactions go in one pass in 5 minutes. 9 9

No H2 cylinders They are a severe safety hazard H-Cube doesn’t use gas cylinders Only water Clean No transportation costs High pressure Low energy Safe Just 2 mL H2 @ 1bar

Catalyst System-CatCart® Benefits Safety No filtration necessary Enhanced phase mixing Over 100 heterogeneous and Immobilized homogeneous catalysts 10% Pd/C, PtO2, Rh, Ru on C, Al2O3 Raney Ni, Raney Co Pearlmans, Lindlars Catalyst Wilkinson's RhCl(TPP)3 Tetrakis(TPP)palladium Pd(II)EnCat BINAP 30 CatCarts have number of advantages. The CatCart has a filter at each end which means the catalyst stays in the CatCart so 1) no filtering 2) the catalyst can be reused 3) Easy Catalyst handling because No weighing out and easy disposal. The Catcart is disposed of in a „Deactivation Vial” (supplied with the CatCart). The deactivation vial contains 1ml of 1.0M sodium hydrogen sulfite. Once placed in the vial at the end of the experiment, the solution kills the catalyst and makes the dangerous catalysts, such as Raney Ni, safe. At 1ml/min the compound has 30 seconds residence time on the smallest CatCart. This means that reactions are less likely to react again with themselves and form side products. After 30 seconds 100% product should be formed, except in cases which are very difficult, such as aromatic heterocycle reduction, and hindered double bond saturation. The reason for the higher reaction rate over the standard batch reactors is becuase of catalyst ratios. In the case of the H-Cube, when you push the compound through the catalyst bed, the ratio of catalyst over the substrate and hydrogen is very much higher. Mass transfer rates are higher which leads to higher reaction rates with increases by orders of magnitude. In a standard batch reactor, everything is placed in a vessel and everything is reacting. In this case the ratio of the catalyst to everything els is much smaller and hence the reaction rates smaller. The catalyst should have a greater longevity in a Catcart because any product which may poison the catalyst is removed continuously from the catalyst and doesn’t hang around. In a batch reactor, the product remains with the catalyst and can lead to deactivation. For those people interested, work is under way to create enantioselective catalysts. The amounts reduced on each catalyst varies and depends on what compound is being put through the CatCart. On the smallest CatCart(CatCart30) you can react anywhere from 10mg to 10g. On average 1 g can usually be reduced, but, again, this depends on the quality and type of coumpound you put through the catalyst. The largest CatCart (CatCart70) has performed reductions up to 100g. However, this won’t be possible on all compounds. It is a best case scenario. 11

Simple to use software

Monitor your reactions

The DryCart For water sensitive reactions Filled with molecular sieves to completely dry hydrogen gas production. Resealable CatCarts with specific, PTFE coated elements Works up to 24 hours reaction time Easy to regenerate: heat up to 120°C for 1 hour using nitrogen gas flow

HC-Pro and HC-Mini comparison H-Cube Mini H-Cube Pro Temperature 100°C 150°C Hydrogen amount 22 ml/min 60 ml/min Liquid Flow Rate Range 0,3 – 3,0ml/min Throughput 20mg-10g 20mg-50g Operation Manual Automated through valves. Hydrogen drying Cartridge Automated Reaction Modes No H2 and Full H2 (at all pressures) Hydrogen amount may be changed by the user. Module control Standalone operation Automated through touch screen

Chemistry examples All reactions go to completion in one pass

Solvent: EtOH 1ml/min, 100 bar, 30o C, 0.5 M 100% conversion 17

Reactor Product (%) (110 g/mol) Starting material (%) 1. 99 Reactor Product (%) (133 g/mol) Starting material (%) 1. 100

Non-hydrogenation: Sonogashira reaction Reaction parameters: H-Cube Mini, No gas mode Concentration: 0.05M Solvent: methanol Flow rate: 0.1 ml/min Temperature: 100oC Pressure: 100 bar Conversions Alkyne Halide Catalyst PdCl2(PPh3)2 Fibercat 1001 Fibercat 1007 10% Pd/C 2-methyl-3-butyn-2-ol 4-iodoanisole 95% 84% 92% 51% Phenyl-acetylene ~100% 93% 19% 1-ethinyl-cyclohexene 97% 53% 4-bromoanisole 89% 50% 8% 1% 42% 36% 14% 2% 44% 31% 0% 19

89,5% 2-methyl-4’-methoxybiphenyl 10,5% 4,4’-dimethoxybiphenyl Non-hydrogenation: Suzuki reaction Reaction parameters: 1 equivalent of 4-bromoanisole 1.2 equivalent of o-Tolylboronic acid Solvent: Methanol Analytics: GC-MS Flow rate [ml/min] Pressure [bar] Temperature [°C] Catalyst Result 0.5 20 100 Fibrecat 1001 Conversion: 100% 13% 2-methyl-4’-methoxybiphenyl 87% 4,4’-dimethoxybiphenyl Tetrakis (TPP)Pd 11,5% 2-methyl-4’-methoxybiphenyl 88,5% 4,4’-dimethoxybiphenyl Fibrecat 1007 (70mm) 89,5% 2-methyl-4’-methoxybiphenyl 10,5% 4,4’-dimethoxybiphenyl 20 20

Good For Research Too

Synthesis of Gabapentin Using H-Cube® Gabapentin: GABA anologue used for neuropathic pain relief and originally as an epilepsy treatment

Synthesis of Ritalin Using H-Cube® Ritalin (d-threo methylphenidate): common psychotropic medication for children; note, this enantiomer is thirteen times stronger than its racemate, so chiral synthetic strategies are crucial

Flow Publications

How to apply to practical lab session?

Practical lab material to help you Hydrogenation Powerpoint presentation Practical lab manual with different sessions Developed in conjunction With University Texas Arlington Video

Example

Academic Interest Over 250 Publications! Over 100 Universities: Oxford, Cambridge, Imperial MIT, Scripps, Boston Marie Curie, Paris Max Planck, Technical University Vienna Budapest Technical University Technical University Prague Yaroslavl University Russia Over 250 Publications!

THANK YOU FOR YOUR ATTENTION!! ANY QUESTIONS? 29 29