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.

Conventional techniques for the synthesis of deuterated compounds utilize D2 gas as a deuterium source. However, there are drawbacks to utilizing deuterium gas on a laboratory scale, such as the handling of the gas itself. Other methods have been employed to overcome this difficulty such as catalytic H–D exchange reactions between H2 and D2O. However, these methods are time consuming and do not produce high purity D2 and they also require high pressure, the use of a special catalyst, or an excess amount of a strong base or acid1.

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.


High purity deuterated compounds can be generated in high yield as long as a few guidelines are followed. The first step is to remove the H2O from the water tank. This is easier to perform if your system is made of stainless steel with the “Purge Water” function on the Service screen.

Step 1: Drain the water from the reservoir using a syringe.

Step 2: Remove the back of the water reservoir with the supplied Allen wrench. Clean and dry the insides with a paper towel.

Step 3: Go to the Service screen. Press the “Purge Water” function and press Stop after 10 seconds.

Step 4: Replace the back of the water reservoir. Add 30 mL of deuterated water. Press “Purge Water” for 10 seconds.

Step 5: Remove the back of the water reservoir, dry the inside again, and press “Purge Water” for 10 seconds again.

Step 6: Replace water reservoir back and fill with deuterated water. Press “Purge Water” to refill cell with D2O.

Step 7: Take a blank CatCart® (titanium) and pass the reaction solvent and run the system at Full H2 mode for 20 minutes. Remove blank cartridge.

Table 1: Deuteration of selected unsaturated compounds

EntrySubstrateProductDayield (%)Yieldb (%)
1Substrate 1Product 19999
2Substrate 2Product 29798
3Substrate 3Product 39397
4Substrate 4Product 49698
5Substrate 5Product 59699
6Substrate 6Product 69599
7Substrate 7Product 79795
8Substrate 8Product 89898

a: Deuterium content in %

b: Isolated yield.


  • Only use an aprotic solvent to avoid H–D exchange.
  • Do not use hydrogen saturated catalysts such as, Raney catalysts for the reaction.

There are two literature examples of where the H-Cube® has been utilized for the deuteration of compounds.
Fülöp et al. performed deuterations on a series of unsaturated compounds1. Optimum conditions were first explored using cinnamic acid as a standard.

Early reactions using methanol and 10% Pd/C led to only a 30% incorporation of deuterium into the molecule. Changing from methanol to an aprotic solvent, ethyl acetate, increased deuterium incorporation to 70%. The catalyst was then changed to a less active catalyst (5% Pd/BaSO4) to reduce the deuteration of the phenyl ring and selectively deuterate the double bond. This catalyst change increased deuterium content to 95%. The reaction was carried out at room temperature. Pressures in the 40-60 atm range and flow rates between 0.7-2 mL/min did not affect yield or deuterium levels.

Once the optimized conditions had been found, the same conditions were applied to a series of other unsaturated compounds. The results are displayed in Table 1.

As you can see from the results, the products were synthesized in near quantitative yield with a high deuterium incorporation. No purification was necessary. The structures included foldamer building blocks, so there is potential for structure elucidation via deuteration where bacteria labeling is not possible. The D2O consumption was very low (4.41 μL/min), which is a much higher deuterium efficiency when compared to other methods.

The other paper is from Kappe et al. and describes the deuteration of ethyl cinnamate2. Using a flow rate of 1 mL/min, 10% Pd/C, room temperature, and Full H2 mode, the product was successfully synthesized in 92% yield with a 95% degree of deuterization.


Utilizing D2O instead of H2O, the H-Cube® is able to deuterate compounds in high yield and with a deuteration incorporation of >95%. These results offer up the H-Cube® as a reliable alternative to other deuteration methods.


[1] Mándity, I.M.; Martinek T.A.; Darvas, F.; Fülöp, F.; Tet. Lett.; 2009; 50; 4372-4374.

[2] Irfan, M.; Petricci, E.; Glasnov, T.; Taddei, M.; Kappe, O.; Eur.J. Org. Chem.; 2009; 1327-1334