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

2. 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!

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

4. 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)

5. 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

6. 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

7. H-Cube Mini 7

8. H-Cube Mini Specifications
Flow rate: 0,3-3 mL/min
Temperature: 25°C to 100°C
Pressure: 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

9. 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

10. 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 1bar

11. 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

12. Simple to use software

13. Monitor your reactions

14. 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

15. 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

16. Chemistry examples
All reactions go to completion in one pass

17. Solvent: EtOH 1ml/min, 100 bar, 30o C, 0.5 M 100% conversion17

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

19. 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

20. 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

21. Good For Research Too

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

23. 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

24. Flow Publications

25. How to apply to practical lab session?

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

27. Example

28. 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!

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