October 25, 2007
by Ryan Sasaki, NMR Product Manager, ACD/Labs
Several months ago, I asked, “How Accurate Should NMR Predictions Be?”
Today, I ask how accurate and consistent are actual experimental chemical shifts?
In many ways, this post probably should have preceded the one I linked above because in reality, before a discussion about prediction accuracy can begin, the topic of experimental accuracy needs to be addressed.
The issue of experimental accuracy can be important from two perspectives. For example, accuracy is important for a chemical shift database that is used for producing the predictions (Hence ACD/Labs’ Purgatory Database). In addition, it is also important in identifying the accuracy of a predicted chemical shift when comparing it to an experimental one. How can we determine where the inaccuracy occurred?
In the process of producing an experimental NMR spectra, there are many variables that can affect a chemical shift that are not always carefully controlled. They include, but are certainly not limited to:
- Concentration of the sample
- Temperature of the probe
- Equilibration time in the probe
- Solvent type
- Residual water content of the solvent
- pH of the sample (if aqueous media)
- Digitization of the spectrum
- Shimming and phasing inaccuracies
- Choice of reference standard
Of course many of these factors, can significantly affect the chemical shift of the peaks in the spectrum. How much they are affected is sometimes hard to measure, but as an example, we can consider the range of database entries in our database for the shift of the methyl group protons in toluene. All of the following have been published in peer-reviewed journals.
Of course the deviations in these shifts are primarily based on the fact that each chemical shift was recorded in a different solvent. The reason for adding 8 sources of toluene in our database is so we can attempt to take the solvent into account when solvent-specific prediction is performed.
But as mentioned, solvent is not the only variable that can affect how an experimental chemical shift is recorded.
References:
1. Prog. Nucl. Magn. Reson. Spectrosc.,1996,v.28,p.161 (Toluene-d8)
2. Zh. Org. Khim.,v.12,p.275 (Tetrahydrofuran-d8)
3. J. Org. Chem.,1997,v.62,p.7512 (Chloroform-d; 300 MHz; 24 C)
4. J. Org. Chem.,1997,v.62,p.7512 (Acetone-d6; 300 MHz; 24 C)
5. J. Org. Chem.,1997,v.62,p.7512 (Dimethylsulfoxide-d6; 300 MHz; 24 C)
6. J. Org. Chem.,1997,v.62,p.7512 (Benzene-d6; 300 MHz; 24 C)
7. J. Org. Chem.,1997,v.62,p.7512 (Acetonitrile-d3; 300 MHz; 24 C)
8. J. Org. Chem.,1997,v.62,p.7512 (Methanol-d4; 300 MHz; 24 C)
I found the question of accuracy of chemical shifts relative to automated collection of data quite relevant with respect to our own automated verification project. In fact, one of the early confounding problems was a simple induced error of about 0.12 ppm in proton NMR that was the result of low level impurities in medchem spectra that were presumed to be at 0 ppm by the default action of the SREF command on a Bruker spectrometer. These were possibly silica grease related etc. This occasional induced error would affect the dark regioning of the compounds residual lock solvent and also shift the actual peaks of the spectrum enough to siginificantly reduce the automated scoring. So not only does reported chemical shift errors create prediction verification problems, so do the automated referencing induced errors on the experimental spectra that are to be compared to the predictions. In order to reduce this induced shift error, we have opted to remove the SREF command from our proc_1d AU programs and instead rely purely on the lock solvent for referencing and of course appropriate adjustment and configuration of our edlock table.
Thanks for sharing your thoughts Phil, as well as the tip
For those interested, my colleague Kirill has pointed me to an article written by Michael Grzonka and Antony Davies entitled,
“Emperical Investigation on the Reproducibility of 13C NMR Shift Values”
It’s an interesting read where the authors investigate how the polarity of solvents, referencing of samples, as well as faulty spectrometer and software configurations effect the reproducibility of experimental 13C NMR spectra.
Here’s a link to the abstract:
http://dx.doi.org/10.1021/ci980320q
The ability to handle solvent specific NMR prediction is a key element of realistic scoring. Currently, automation server version 10.05+, with specific and selective DB training, can handle only training DB selective solvent specific training (with scripting)… however, it certainly seems, that at some point in the future, universal solvent selective training will be a reality. Its been discussed for quite a few versions now but it seems close to coming to fruition. This should improve the quality of the verification scoring, as well as the the utility of predictions. Down the road , the next most important thing would be taking into account concentration and pH, but I think that would be quite a way off. It is still incumbent on the instrument managers to properly set up their own instrumentation to properly reference compounds. Two choices exist. Either mandatory reference compound (TMS) in lock solvents which can be bought that way … or lock referencing on deuterium. For the convenience of our own chemists workflow, we choose the later since it aids in their own recovery of the sample… if they need to.