Application Note 15

Chemical Reaction Feedstock
Troubleshooting with Benchtop NMR

Benchtop NMR has many advantages over similar
analytical techniques due to its high degree ofchemical specificity, especially when combining
information from multiple chemical nuclei. Minimal
or no sample preparation and quick data generation
allows the deployment of benchtop NMR in QA/
QC environments without the need for operation
by R&D scientists. This saves significant time andmoney. One example is in the quality control ofreaction feedstocks which are the raw chemicalmaterials required to supply large-scale chemical
manufacturing processes.
To confirm that lab technicians in a QA/QC
environment as well as organic, polymer andpharmaceutical chemists can identify good or bad
feedstock from a single, quick measurement, ourapplications team investigated a specific industrial
use case. A manufacturer of fluorochemical productssent us two samples from different suppliers. Bothsamples were reported to be the same reaction
feedstock compound. One of the samples worked
as a reaction feedstock but the second one didnot. Could the samples be efficiently screened toidentify the ineffective failed chemical? Importantly,
was this failure due to degradation of the material,
contamination, or was there another explanation?

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One advantage of multi-nuclei broadband
benchtop NMR is that a straightforward pass/failor fingerprinting method can be often developed
selecting a nucleus that gives very simple spectrum.
The compound in question was 2,3-Dichloro-1,1,1trifluoropropane, a relatively simple molecule thatgenerates a surprisingly complex 1H NMR spectrum
given that it has only three hydrogen atoms. Theproton spectra for both the known and unknown
samples are shown in figure 1, along with themolecular structure.

The complex splitting pattern makes very rapid
analysis potentially challenging to the untrained eye.
Although there are some clear similarities between
the samples, such as the two main groups of peaks,
there are also some obvious differences, such as thesplitting patterns and the chemical shifts. As there
are few minor peaks and the major peaks are quite
different, this initial result immediately suggested
that we had two different molecules rather thancontamination. To verify this result and to see ifother methods might quickly provide additional
information, we decided to further characterise
the molecules.

Figure 1: 1H 1D NMR spectra of 2,3-Dichloro-1,1,1-trifluoropropane (bottom, red) andthe unknown sample (top, blue).

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Next, we looked at the 13C spectrum of the moleculeso that we could better understand any potential
structural difference between the two samples.
As can be seen from figure 2, using 1H-decoupled
13C 1D NMR spectra allows easy identification of
structural differences. Without decoupling, a single
13C peak would be split into multiple peaks byneighbouring 1H nuclei, as well as by 19F nuclei. For
these nuclei, the general rule is that n equivalentneighbours will split a signal into n + 1 peaks. In
other words, if a 13C nucleus has 3 nearby 19F
neighbours, it will be split by them into a quartet.
This effect generally becomes less pronounced as
the nuclei become more distant from each otheron the molecular chain. This splitting can provide
useful information but can also make spectra
more complex and difficult to interpret. To obtain
the information we need without unnecessary
complexity, we can use decoupling, which removes
this connection. By decoupling on 1H, only splitting
due to 19F is seen in the 13C spectrum.

Comparing the unknown molecule with known
assignments from the 2,3-Dichloro-1,1,1trifluoropropane, we see that the CF3 quartet centred
near 125 ppm is essentially unchanged between
the two molecules, but there is a significant upfield(towards the right) shift of the other quartet fromthe sample, suggesting a change in the chemical
environment strongly affecting that carbon. Again,
there are significant differences but also similarities;
in this case both molecules have two quartets,indicating two carbon atoms coupled to three 19F
atoms each, one apparently a single-bond coupling(as in a CF3 group), and one more consistent with a
two-bond coupling (as would be seen on a carbon
neighbouring a CF3 group). They also each have
one singlet carbon peak, suggesting very similar
structures. The singlet shows some difference inchemical shift from that of 2,3-Dichloro-1,1,1trifluoropropane, but not as much as the upfieldshifted quartet. While the 13C spectrum is very useful
to gain information about the overall structure, it isimpractical for a rapid yes/no test due to the low
sensitivity of 13C, which requires relatively long dataacquisition times.

Figure 2: 13C 1D NMR spectra of 2,3-Dichloro-1,1,1-trifluoropropane (bottom, red)and the unknown sample (top, blue).
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Figure 3: 19F 1D NMR spectra of 2,3-Dichloro-1,1,1-trifluoropropane (bottom, red) and theunknown sample (top, blue), now assigned as 3-Chloro-1,1,1-trifluoropropane.
Since the molecule is fluorinated, we also acquired 19F
NMR data.
In figure 3, we see the fluorine spectra foreach molecule. Immediately the differences
are clear! We have significant chemical shift,
and we have a triplet instead of a doublet.
This suggests an obvious change in in themolecular structure; in the unknown sample,
the CF3 is now neighboured by a CH2 rather
than a CH.
Taken together, these spectra allow us
to complete the picture of the structuraldifferences between the molecules. The 1H
spectra are consistent with a similar overallstructure. From the 13C spectra, we know that
the CF3 group is still present and that theneighbouring carbon (-CHCl- group) has had
a much greater change in electronic environment
than the other two carbons. From this evidence, as wellas published NMR data of the respective molecules,
we concluded that instead of 2,3-Dichloro-1,1,1trifluoropropane, the unknown sample was actually
3-Chloro-1,1,1-trifluoropropane, a chemical also usedin reaction feedstocks, which had been mislabelled.

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More importantly, because the key question iswhether the compound could be screened by atechnician with a single measurement, the answer isclearly yes. Because the full structural determination
is not necessary to screen a compound, either
the 1H or the 19F spectra alone would provide theanswer. In particular, the differences in the 19F
spectrum were clear and extremely obvious, giving
us an effective yes/no test for a user with no NMR
background. More importantly, because both 1H and19
F are extremely sensitive in NMR, a measurement
time of less than a minute could be used, giving
us the perfect rapid analysis to ensure quality andconsistency of feedstocks. Using benchtop NMR at
the point where the feedstock is received, or where
the feedstock is added to the reactor will save hours
of reaction time and substantial cost of product.

If you have any questions about
this application note, pleasecontact our experts:
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