Why is tetramethylsilane (TMS) used as an internal standard in NMR spectroscopy?

Question

I understand that TMS has a large proton number, giving a strong peak in the NMR spectrum. But apart from that is there any other reason why just TMS is used and not any other molecule?

Answer 1

TMS was first proposed as a reliable internal chemical shift reference in 1958 by Tiers. Back in them good ol' days, 1H NMR was called proton nuclear spin resonance, or nsr, and the tau scale was used for reporting chemical shifts (10ppm in the delta scale was set to 0 and positive values were read to the right. So TMS came at t10.0), and CCl4 was the one of the most common solvents used for running dilute solution samples.

TMS was proposed as a reference at the time becasue it offered the following advantages:

• the chemical shifts are largely temperature and concentration independent
• it offered a single phase method for referencing (That is, it was an internal standard. Most common methods at the time used an external reference, such as a coaxial insert; a method which is still acceptably used today)
• The TMS peak lies outside the 'usual spectral region and is readily identifiable'
• It is largely inert, and is not likely to react with most samples
• It can be used for almost amy solvent (except H2O, D2O)

Today, TMS is still accepted as the single universal reference standard for NMR. For over a decade, the IUPAC recommendations have stated that, other than for 13C, all nuclei are referenced to the frequency of the 1H signal of 1% TMS solution in CDCl3. Yes, your 31P and 77Se peaks should actually be referenced to 1H of TMS. This unified reference scale is very easy to implement on modern instruments that incorporate a digital 2H lock (ask your friendly NMR custodian if they use it!). It is in fact arguably more accurate that referencing to internal solvent residues which are much more likely susceptible to concentration and temperature factors. Internal solvent residues are called secondary references, and are less accurate than the primary reference. However, they are accurate enough for the very vast majority of work done in the laboratory.

It has long been shown that the chemical shift of TMS is, in fact, both temperature and concentration dependent. But not much. There are actual corrections that should be applied to measured chemical shifts at extreme temperatures, but these are very small and rarely seen in the literature.

TMS is not water soluble, and in aqueous samples DSS is the recommended reference standard. It contains signals in the 1H spectrum at 3.1, 1.9 and 0.8ppm, all at a fraction of the intensity of the main reference signal, and these can interfere with analysis of other spectral regions. A deuterated version is widely used in the literature. An alternative, TSP, is sometimes used, although is more pH dependent. Other reference standards can also be used, however, and as long as the reference method and sample conditions are reported and verified, then all is good. For 1H NMR, compounds such as acetonitrile, methylsulfone, benzene, 1,4-dioxane and dichloromethane are all examples of internal standards that are sometimes used, both for chemical shift referencing and concentration measurements, as they all largely satisfy that important list of reference characteristics above. They all have very simple 1H spectra, soluble in common deuterated solvents and fairly unreactive. Plenty of other compounds with multiple peaks can be used as well, such as toluene and dmf.

So, to specifically answer your question, TMS is the adopted primary standard for 1H chemical shift referencing for the reasons stated above. Any other material can be used as a secondary reference, either internal or external, provided its chemical shift can be accurately determined against the chemical shift for TMS. Results reported should include a clear description of how chemical shifts were determined. For example, 1H chemical shifts of all reported compounds were measured relative to the methyl peak of n-dodecane, determined as 0.88ppm. The disadvantages of using other materials is that it needs to be shown that the chemical shift of these signals is independent of sample conditions (concentration, temperature etc), and that they will often have peaks overlapping regions of interest.

Answer 2

TMS has 12 protons which are all equivalent and four carbons, which are also all equivalent. This means that it gives a single, strong signal in the spectrum, which turns out to be outside the range of most other signals, especially from organic compounds.

Although the chemical shift scales are still zeroed at the TMS peak, most spectra are now calibrated against the residual solvent peak. Typically, deuterated solvents such as $\ce{CDCl3}$ and $\ce{DMSO}$-$\ce{d6}$ are used and these contain a very small amount of undeuterated, or partially deuterated, solvent which produces a peak in hydrogen NMR. In carbon NMR the solvent peak is recognised by its splitting pattern, which is a triplet for $\ce{CDCl3}$ and a heptet for $\ce{DMSO}$-$\ce{d6}$ and the fact that it always comes at exactly the same place.