Deuterated Solvents
If you’ve ever prepared an NMR sample, you’re familiar with the fact that we almost always use deuterated solvents to dissolve our samples of interest. These special solvents, in which the majority (>99%) of hydrogen atoms have been replaced by deuterium, include lab staples such as: water (D2O), chloroform (CDCl3), dichloromethane (CD2Cl2), dimethyl sulfoxide (DMSO-d6), acetonitrile (CD3CN), methanol (CD3OD), acetone (acetone-d6), benzene (C6D6), toluene (toluene-d8), tetrahydrofuran (THF-d8), and trifluoroacetic acid (TFA-d). By using deuterated solvents, we can retain their respective solubilizing properties, while also ensuring that the solvent signal does not overwhelm the 1H spectrum we are acquiring. Conveniently, since no solvent is ever truly 100% deuterated, the residual solvent peak from each solvent (i.e., the small amount of regular proteo solvent that remains non-deuterated) is often used as an internal chemical shift reference. Finally, deuterated solvents are also commonly used as a field lock in NMR instruments! Now that we’ve confirmed their usefulness, it’s time to ask: how are deuterated solvents made!?
Historically, the most widely used approach for making one of the most popular deuterated solvents, D2O, involved the use of the Girdler sulfide process,1 sometimes referred to as the Geib-Spevack process. This approach takes advantage of the following equilibrium:
Figure 1. Equilibrium between water and partially deuterated hydrogen sulfide.
The equilibrium constants for this exchange are K ≈ 2.3 @ 30 °C and K ≈ 1.9 @ 130 °C, indicating that while the equilibrium always favors formation of HDO, this is even more favored at lower temperatures.2 By using a cold column (30 °C) and a hot column (130 °C), between which hydrogen sulfide is circulated in a closed loop, an iterative enrichment process allows for the formation of partially deuterated water (15-20%). For most applications, further enrichment to >99% is required and this is commonly done using a variety of distillation techniques.3 Once sufficiently pure D2O has been isolated, it can then be used for the preparation of other deuterated solvents!
Certainly, the most popular deuterated solvent used by chemists for NMR spectroscopy is deuterated chloroform, or CDCl3. This can be prepared as follows4:
Figure 2. Reaction scheme for the preparation of chloroform-d from hexachloroacetone and deuterium oxide in the presence of pyridine.
Similarly, deuterated acetone, or acetone-d6, can be prepared as follows4:
Figure 3. Reaction scheme for the preparation of acetone-d6 from acetone and excess deuterium oxide in the presence of deuterated lithium hydroxide.
These types of transformations typically require multiple steps, wherein the same reaction is repeated with further enrichment occurring over time. While using D2O to prepare other deuterated solvents is a very useful method, many solvents are prepared using transition metals catalysts. These reactions often proceed via C-H bond activation by the metal, often coupled with either activation of C-D bonds or D2 gas, and terminating in C-D bond formation, leading to the desired products. Unfortunately, most industrial processes currently in-use to produce most common deuterated solvents used in NMR today are proprietary and the full details of these techniques are not public knowledge. Nonetheless, it’s important to realize that the deuterated solvents we often take for granted in NMR are not always straightforwardly prepared, and this perhaps helps to explain why they can often be so prohibitively expensive!
Figure 4. Proton lock (as opposed to deuterium lock) can easily be selected on the Nanalysis benchtop NMR instrument by selecting the highlighted box and choosing the appropriate solvent from the box beside it.
Thankfully, deuterated solvents are not required to acquire spectra on our benchtop NMR instruments (Figure 4). Liquid samples can be run neat (i.e., not diluted), or protonated solvents can be used as an alternative to deuterated solvents. Expensive deuterated solvents are undoubtedly very useful, but they aren’t always necessary!
If you have any questions about the benchtop NMR, or about how you could incorporate our instruments into your workflow, please don’t hesitate to reach out to us.
References
(1) Neuburg, H. J.; Atherley, J. F.; Walker, L. G. in Girdler-Sulfide Process Physical Properties, International Nuclear Information System, 1977.
(2) Rae, H. K. ACS Symp. Ser. 1978, 68, 1–26.
(3) Andreev, B. M. Sep. Sci. and Technol. 2001, 8-9, 1949–1989.
(4) Paulsen, P. J.; Cooke, W. D. Anal. Chem.1963, 35, 1560.