Access all areas: How NMR made it to the benchtop

As nuclear magnetic resonance spectroscopy moves to the benchtop, John Paul Cerroti explores its uses in organic chemistry The latest analytical technology to move to the benchtop is Nuclear Magnetic Resonance Spectroscopy, NMR. High-end, high-cost instrumentation has dominated the NMR sector for many years, with both the initial purchase price and annual running costs putting the technique beyond the reach of almost all individual laboratories. Specialist is the word that would come to mind. A special room, with special supplies and, not least, a specialist to run and interpret the data produced. This might be compared to how mass spectrometry was 20 years ago, but today the situation is very different: buyers have a choice of many benchtop footprint instruments from multiple suppliers. The last 12 months has seen the world of NMR make similar strides, with the arrival of several new instruments and suppliers. The world of organic chemistry is the principal beneficiary from the advent of benchtop NMR spectrometers. Whether the user is in academia or in industry; in the chemical or pharmaceutical arenas, a key goal of any synthetic chemist is to be able to quickly and reliably identify exactly what has been made at each stage of the process. NMR is the ultimate technique for this. While mass spectrometry, IR and UV spectroscopies are widely used, organic chemists agree that NMR provides the most definitive information about the structure of an organic compound. [caption id="attachment_40694" align="alignright" width="200"] Figure 1: The simultaneous observation of 1H and 19F in an esterification reaction[/caption] An example of the use of bench top NMR spectroscopy to monitor reactions in a research context has been demonstrated by the BAM, the German Federal Institute for Materials Research and Testing, in Berlin. The focus of the Process Analytical Technology (PAT) Division is the development and application of PAT technologies. This includes develop­ment and validation of analytical online and at-line methods. Users, Dr Michael Maiwald and his colleague, Nicolai Zientek, use NMR in their daily research and development work. They use a high resolution 500 MHz online NMR spectrometer as their reference instrument to “hyphenate” NMR with conventional online analytical techniques such as NIR, Raman, UV/VIS spectroscopy and, in particular, medium resolution NMR spectroscopy. Dr Maiwald says: “Our aim is to develop techniques to bring the benchtop lab instruments “into the plant” and to show (in projects) how MR NMR could already be used for technical applications like online reaction monitoring.” Asked why his group selected to use the Spinsolve, Maiwald said “We were impressed with the spectra – the symmetrical line shape and narrow line width was achieved even in technical mixtures. This is due to the use of Halbach magnets. The stability we observed over a given period of time without preparing the instruments was extremely good. We have seen that the Spinsolve remains working in specification for as much as 48 hours in a technical environment. Pre-magnetisation below the active region of the magnet is important to us for online measurements. As far as we see, the instrument meets this requirement.” Describing the projects to date, Maiwald said he has used the Spinsolve for flow-through reaction monitoring experiments. These have included the simultaneous observation of ¹H and ¹⁹F in an esterification reaction (Figure 1). This was observed within 1/16” FEP tubing using a 5 mm outer diameter Dewar insert to keep the elevated reaction temperature. In recent experiments, equilibrium pre-magnetisation for quantitative measurements is still achieved applying flow rates up to 0.3 mL min^–1 using this design. Looking ahead, Maiwald and his group are planning to further improve online reaction monitoring with medium resolution NMR spectroscopy by developing chemometric and automated signal processing tools. [caption id="attachment_40697" align="alignleft" width="400"] Figure 2a: The acetalisation reaction of acetaldehyde[/caption] Users of benchtop systems have found them to be particularly convenient and robust to use. In laboratories where time-to-getting-results is [caption id="attachment_40698" align="alignleft" width="400"] Figure 2b: The acetalisation of acetaldehyde monitored by the Spinsolve benchtop NMR spectrometer using continuous flow measurements of the reaction in real time. The three sets of green rectangles (around 1.4 ppm, 2.2 ppm, and 9.8 ppm) show the integration regions displayed in the figure below.[/caption] imperative, ease of operation makes these instruments perfect for bench chemists and analysts who need immediate results. Getting answers in the lab in a couple of minutes beats sending samples away for analysis. This has led to the adoption by synthetic chemists and chemical engineers of the Spinsolve benchtop NMR instrument, which can be deployed to synthetic laboratories and pilot plants to [caption id="attachment_40699" align="alignleft" width="400"] Figure 2c: The three integration regions from the image above plotted against time showing the quantitative measurement of reactant and product concentrations obtained in real time using a benchtop NMR.[/caption] monitor reactions in real-time. Now it is possible to bring the NMR to the synthesis instead of having to bring the synthesis to the NMR. This reaction monitoring capability is illustrated here by a simple acetalisation reaction, using a flow cell passing through the spectrometer (Figure 2a-c). For this experiment the software has been configured to take a 1-D proton NMR spectrum every 30 seconds, and the reaction is followed for just over 1 hour. The application takes advantage of the inherently quantitative nature of NMR, enabling chemists to follow the reaction as it is occurring, without the need for chemometrics or other complex analysis methods, which are so often necessary when trying to monitor reactions using other analytical techniques. In conclusion, the key ability to monitor reactions, by tracking reactants, products, intermediates and by-products, determination of end-points is now available. Benchtop NMR is now becoming a well-established technique in teaching, in academic research, and in industrial environments. It will continue to grow as a technique creating new opportunities for timely and cost-effective analysis. Author John Paul Cerroti, Director of Sales, EMEA, Magritek GmbH. Contact +49 (241) 70 525 6000 www.magritek.com sales@magritek.com