Benchtop NMR spectroscopy

Putting NMR spectroscopy at theheart of the analytical chemistry lab
For many decades, access to Nuclear Magnetic Resonance(NMR) has been an intrinsic requirement for any analyticalchemistry lab. The technique, particularly due to its ability
to elucidate molecular structure and track reaction
dynamics, is recognised throughout industry and academia
as a powerful, non-destructive, non-invasive method andis taught in undergraduate chemistry curricula. But how isNMR now employed on the bench in almost any laboratoryenvironment?

X-Pulse is the world’s first broadband high-resolution
benchtop NMR spectrometer. It is designed to bemodular with an upgradeable user-removable probe
as standard and includes workflow enhancing
add-ons such as X-Auto, a 25 position autosampler,
and wide range variable temperature accessories.

Access to NMR has often been difficult, with the requirement
for substantial space, special facilities and expert users,
limiting the usability of the technique in synthetic chemistry
and industrial labs. However, the latest advances inbenchtop NMR instrumentation, brings this technique outof the basement or centrally managed facility and into
the heart of any laboratory. Benchtop NMR instruments
are a smaller, cryogen-free version of traditional high field
instruments that enable data collection even in the fume
hood. Recently, we have added broadband capability to thefield of benchtop NMR with X-Pulse. This new capability
significantly expands the range of challenges solved bybenchtop NMR across education, academia, and industry.

Industrial quality control
In industry, R&D scientists can utilise benchtop NMR at allstages of development. The flexibility and time efficiency ofNMR makes it an essential tool for routine analysis. Asthe X-Pulse is portable, it can be put to work wherever it
is needed. This can be as part of a reaction monitoring
set-up near line to provide feedback on a process; asconfirmational or corroborating analysis of product quality
in test labs; or as a discovery tool in development.
One of the most common applications of NMR in industry isQA/QC. The sample preparation, which can be as easy
as pipetting the sample into an NMR tube, and fast
data acquisition, make it ideal for this purpose. Thiswas demonstrated recently for fluorochemical reaction
feedstocks in an application note that can be viewed here.

The quality of the supplied starting material directly impacts
the quality of the final product. In the battery electrolyte
example shown in figure 1, it led to a vast deviationfrom the expected performance of the final product. The
remarkable nuclear and chemical specificity of NMR makes
it possible to detect different components of the desired
starting material and an impurity, which was found to bea breakdown product. This helps to understand how its
resulting performance impacts lithium battery charging
capacity, power output and lifespan.

The bottom (dark green) spectrumof the starting material the company
was expecting to use whereas
the top (light green) spectrum
was the chemical they received
from their supplier. Clearly, these
two are different. Not only is there
the desired starting material
in the light green spectrum,
but there is also a probablebreakdown product. The chemical
shifts (precise peak positions)fingerprinted the breakdown
product as difluorophosphoricacid and additional presence oflithium fluoride identified that theelectrolyte failure was caused by ahydrolysis reaction from traces of
unwanted water.
As well as QA/QC applications,Figure 1: A comparison of two electrolyte components.
industrial R&D scientists can benefit
from real-time feedback of theirreactions. As a benchtop NMR
instrument is small enough to fit
in a fume hood, it can be placed
right next to where the chemistry is
happening to acquire real-time dataon how the reaction is progressing.
Figure 2 shows the stacked
spectra of a reduction of
3-Nitrobenzaldehyde which is adrug precursor and used in thesynthesis of calcium channel
blockers. Spectra were taken every
20 seconds as the reaction mixture
was pumped continuously throughthe X-Pulse flow cell. The rapid
disappearance of the signal at 10ppm (aldehyde reactant) and theshifting signals in the aromatic
Figure 2: Time series NMR data of the reduction of 3-nitrobenzaldehyde.
region (7-9 ppm) indicate that thechemicals in the reaction have
By determining rate constants under different temperature conditions, thechanged, and that the reaction
enthalpy, entropy, Gibbs free energy changes and other kinetic reaction
proceeded rapidly to full completionparameters can be calculated. This supports optimizing reaction conditions,after 200 seconds. Tracking theimproving reaction efficiency, controlling the reaction process, and ultimately
concentration curves of reactants
designing reactors.
and products over time enables
the order and rate constant of theFurthermore, by tracking reaction reactants, intermediates and final products,
chemical reaction to be
it may be possible to incorporate NMR into a feedback loop to automate thedetermined.
addition of reagents to the chemical reaction.Figure 3: X-Pulse in a typicalanalysis laboratory, featuring
HPLC, UV-Vis, FT-IR anda high field NMR
Spectrometer.

Generating return on investment
For industry, the benefits of benchtop NMR are clear:shorter preparation times, automation capabilities,
fewer staff specialists, and a reduced space demand.
These mean that the time efficiencies and cost savings
versus a high field instrument can be made from day
one. High field instruments demand significant initial
capital investment and often require a dedicatedroom to operate in. This can be an inefficient use ofspace. Benchtop NMR solves this issue with its muchsmaller footprint enabling it to fit right beside existing
instruments in an analysis lab (see figure 3). As
benchtop NMR is cryogen-free, it is much cheaper torun than traditional high field instruments. Our analysis
showed that one can conservatively save over $9,000
per year in running cost just from the cryogens alone.

As well as the on-going, and ever rising, cost of cryogens
there is also the peripheral logistics of buying and installinga high field system to consider:•	Can one establish a reliable and continuous
supply of liquid helium and liquid nitrogen?
• How will they be stored safely on site?
•	Is there someone on site that is qualified to handle themin a safe manner?
Any business looking to invest in high field NMR needs
to answer these questions. As benchtop NMR utilises acryogen-free permanent magnet, these questions andassociated costs simply do not exist. This enables one toextract a return from that initial investment much morequickly.

Flexibility of benchtop NMR
As benchtop NMR is mobile, the instrument can bephysically placed inside any lab and transported
between labs, paving the way for equipment sharing
between groups in a department to make NMR analysis
cheaper. As X-Pulse is a broadband spectrometer, theflexibility to rapidly tune between the nuclei of interest ineach individual sample further enables sharing acrossa wide range of applications whilst also future-proofing
research or development capabilities.

Figure 4: Comparative running costs for a typical highfield vs. a benchtop NMR instrument.

Figure 5 below shows a selection of the 31 nuclei that
it is possible to monitor using X-Pulse. Hence, complex
mixtures can be investigated in a non-invasive andnon-destructive way. This allows for future changes
in research focus whilst simultaneously providing
the potential for X-Pulse to be based in a multiuser facility. This critical functionality has facilitatedspecific applications in battery development research.
Quantifying the many different chemical species inelectrolytes with multiple nuclei of interest accelerate
new formulation development, elucidates degradation
mechanisms and improves quality control.

Figure 5: A selection of the many nuclei X-Pulse is capable of detecting.

Figure 6: A 31P spectrum ofdimethylphenylphosphonate and1,2-Bis(diphenylphosphino)ethane (dppe)in deuterated chloroform.

Phosphorus NMR is used in coordination chemistry,
catalysis, and for qualifying pharmaceuticals anddietary supplements. In figure 6 a spectrum of a
mixture containing dimethylphenylphosphonate and1,2-Bis(diphenylphosphino)ethane is shown. Bothmolecules contain aromatic rings, and would therefore bedifficult to separate using proton NMR. Both phosphorousnuclei are in similar environments, so one might expect
them to have similar chemical shift, however, even at
low field the spectral dispersion is good enough to easily
distinguish them. This shows how NMR can be used to
distinguish between structurally similar molecules.

Education: from teaching to novel research
Synthetic chemistry education benefits from early handson NMR exposure to deepen understanding of theanalytical technique. Having benchtop NMR in the lab
speeds up acquisition, so students can be analysing what
they have synthesised minutes after having made it. To
prepare students for a future in chemistry it is essential thatthey are well versed in NMR, which is employed widely
throughout the chemical research world and industry.
For education, NMR can now be a much more hands-onexperience. To learn structural elucidation, often students
are handed paper copies of spectra which have beenat least partially processed for them, sometimes withchallenging-to-read axes.

They perform the analysis with the knowledge that all theinformation they require to determine the structure has
been provided to them. This process is not a reality in a
research environment where researchers interact with thedata electronically, and where they may need to identify
and run more complex spectra to complete their analysis.
Using benchtop NMR, even these more complex spectra
are readily available in the lab. Two-dimensional (2D)
experiments are now commonplace in most instruments
and the most used ones come as standard on the X-Pulse.
The extra dimension of data provided by these experiments
accelerates structure determination of small molecules.
You can read more about structure elucidation using
X-Pulse here.
In the example of variable temperature as shown in figure
7, students can watch the progression of dynamic changes
in molecular structure using NMR to reinforce learning
concepts from both molecular structure and NMR. Here,the NMR spectra show that as the sample temperature
increases, the two methyl group signals coalesce intoa single signal. At the molecular level, increasing thesample temperature increases the rotational energy ofthe molecule which speeds up the rotation of the methylgroups until they are spinning so fast that they become
equivalent. With a benchtop instrument, NMR experiments
can now follow a more similar pattern with prediction,experiment, and result happening in the same session.

The benefits within a higher
education environment also extend
beyond the teaching lab into theresearch lab. With benchtop NMR,
analysis can be run in minutes todetermine the success of a reaction– no more running down to the user
facility or even sending samples
to external companies for routine
analysis. If your samples do require
higher fields, then benchtop NMR
can become an invaluable prescreening tool to determine if theproduct or sample you are looking
at really does warrant the timeand money required for high fieldevaluation.

Figure 7: Stacked spectra of 3-Dimethylaminoacroleinat various temperatures.

This pre-screening functionality can be useful to NMR
facility managers too. As well as taking up much lessspace than a traditional high field set-up, benchtop NMR
can also free up the more expensive-to-run magnets to be
used in a more efficient way.

Conclusion
In summary, cryogen-free benchtop NMR has become
an essential tool in any analytical chemistry laboratory.
It removes the high upfront, and ever-increasing runningcosts of traditional high field NMR providing a simple to use
portable solution. With the arrival of the true broadband
X-Pulse NMR system, incorporating comprehensive
flow and temperature control, a single instrument now
addresses needs from student teaching, right through tohigh end R&D and industrial quality control.

For more information about X-Pulse, please contact us: magres@oxinst.com or visit: nmr.oxinst.com
visit nmr.oxinst.com/illicit-drugs-testing for more information or email magres@oxinst.com© Oxford Instruments Industrial Products Ltd trading as Oxford Instruments Magnetic Resonance,2023. All rights reserved. Do not reproduce without permission. Part no: MR/251/0223