Monitoring H -> D exchange

Question

I was wondering how the exchange of hydrogen by deuterium, like on arenes like benzene

could be monitored for a reaction on a scale larger than say 10 g of product. While I know that C6D6 is commercially available, used for NMR spectroscopy, I recognize

• the observable signal of the protons bound to carbon is attenuated by the advancement of the reaction, and

• the very deuterium installed equally serves as lock signal for the 1H-NMR spectrometer (similar to the deuterium in CDCl3). So there might be an experimental problem, from the spectrometer, too.

But what is a typical standard compound may serve as an added inner standard in such a reaction, provided protocols accessed so far mention extended heating / autoclave or/and presence some hydrogen gas to initiate the reaction as reaction conditions? Do commercial suppliers carry out the exchange hydrogen by deuterium, and (perhaps by virtue of even larger batches) obtain the 99%+ isotopically enriched product by sophisticated distillation / zone melting, recycling the partially deuterated product?

Answer 1

You've managed to squeeze a few questions into one here, but all nice questions, so let's have a go at answering them.

1. What standard could be used for monitoring this type of reaction? As you indicate, any internal standard needs to be inert to any reaction process, and many industrial processes for deuteration are fairly extreme, so it is unlikely that a reliable standard could be found. Instead, what is commonly done is to add an internal standard post-reaction. That is, take an accurately measured aliquot of the reaction mixture and add a known amount of standard. This is commonly done for quantitative analysis, and is easy and accurate to do. Take 0.5mL of your reaction mixture and add 0.1ml of a stock solution of your standard. Common standards include TMS, TSP, acetonitrile, methylsulfone, benzene, 1,4-dioxane and dichloromethane and of course the one to use wil depend on the expected peak ranges of your material. Wise spectroscopists use a stock solution containing two standards.

   Many modern spectrometers can use an electronic form of providing an internal integration standard. The ERETIC method (search NMR ERETIC) introduces a highly accurate and reproducible concentration measurements by applying a synthesised electronic reference, and can be postioned anywhere in the spectrum out of the way of other peaks. This method is used extensively in qNMR methodology. A precaution that you need to take care with to ensure accurate results is in ensuring no loss of solvent volume (ie changes to concentration) over time of your reaction mixture.

2. Interference of 2H signal in experiment. It is entirely possible to run an experiment without an internal lock. You can use an external lock, or simply turn of field sweep for short durations (up to a few hours). Alternatively, it is possible to use 19F as a spectrometer lock on spectrometers where the hardware allows. In the event of requiring an internal lock, this too would be no problem, providing the signal was well away from your peaks of interest. Similarly, large amounts of 1H signal from other reactants could easily be eliminated by solvent suppression methods.

3. Commercial deuteration of common solvents for NMR typically use processes involving D2O. D2O is manufactured by a number of means, such as the Girdler sulfide process, and is pretty cheap to manufacture. Other solvents will use multi step processes to drive the exchange. DMSO, for example, is heated over CaO to induce partial exchange, and the process repeated several times before (almost) complete conversion.