Top NMR From the Tabletop

Analysis in Real Time on the Chemical Workbench

  • Prof. Dr. Bernhard Blümich.Prof. Dr. Bernhard Blümich.
  • Prof. Dr. Bernhard Blümich.
  • Fig. 1: High-resolution NMR spectra from the table top. a) 60 MHz 1H NMR spectrum of CHCl3 magnified to show the 13C-satellites at 0.55% peak amplitude of the 1H resonance and the superior line-shape of the Spinsolve Ultra spectrometer. b) 1H NMR spectra of urine acquired at 60 MHz in 8 minutes at 2000-fold magnification. At narrow linewidth, the metabolite signals do not overlap with the foot of the water resonance.
  • Fig. 2: NMR spectroscopy for chemical analysis. a) 60 MHz 1H NMR spectra of a solution with a concentration difference of 100. With multi-frequency saturation and 13C decoupling the solute resonances can be identified without interference from the 13C satellites of the solvent. b) Heteronuclear multiple bond 1H-13C correlation (HMBC) spectrum of ibuprofen acquired at 80 MHz in 52 min.
  • Fig. 3: Monitoring the formation of a-fluoro-a,b-unsaturated esters at 40 MHz. a) The heterogeneous reaction batch is homogenized by stirring and passed through the spectrometer. b) The reaction involves three steps. c) The deprotonation of the educt (step 1) and the formation of the product (step 3) monitored at 293 K by acquiring 1H NMR spectra in 15-s and 10-min intervals. d) Decays of the -CHF (top) and benzaldehyde (bottom) resonances monitoring the deprotonation and product formation steps, respectively.

Among chemists, nuclear magnetic resonance (NMR) is an indispensable tool that provides spectra with unsurpassed detail on molecular structure and dynamics. Yet the instruments are huge, expensive and difficult to operate.

While a long time ago other analytical instruments like mass and infrared spectrometers have found their way to the laboratory benchtop for operation on demand, quality benchtop NMR spectrometers have become available only recently. They employ maintenance-free permanent magnets and are simple to operate without expert training. Using them shortens the time to wait for the NMR spectrum to a few minutes, but their field strengths are lower than those of today’s high-field spectrometers with superconducting magnets, compromising sensitivity and spectral dispersion. Nevertheless, thanks to superior electronics and advanced methodology they are better suited for chemical analysis than their bulky predecessors from the seventies and eighties of the last century, which operated at similar field strengths.

NMR finds many applications. Its most popular use is in diagnostic medical imaging to measure magnetic resonance images (MRI). The second most important one is for chemical analysis by measuring spectra. Moreover, NMR is employed to characterize foodstuffs, porous media and polymer materials in terms of relaxation times and their distributions. In the early days, the instruments for all three types of applications employed magnetic fields in the range of 0.5 to 2 T, which are considered low by today’s standards. These were generated with conventional electromagnets and with permanent magnets until higher fields could be produced with superconducting magnets. The newer high-field magnets need to be cooled with liquified gases and require regular maintenance. Essentially, the size of the magnet increased with field strength while the size of the spectrometer electronics decreased with time, so that chemists got used to a footprint of NMR spectrometers for chemical analysis which occupied a considerable fraction of the laboratory floor.

Tabletop NMR

The first commercial tabletop NMR instruments were developed in the early seventies of the last century.

But they could not measure NMR spectra, only NMR relaxation signals. These are important to characterize materials such as foodstuffs and polymer products. The permanent magnets of these relaxometers could be made small, because to measure relaxation signals, the magnetic field does not need to be as homogeneous as for resolving the chemical shift of hydrogen nuclei. The common approach to achieve the extreme field homogeneity of better than 10-8 across a standard 5 mm diameter sample tube for NMR spectroscopy is to make the magnet much bigger than the sample. But to produce a small spectroscopy magnet for a large sample is extremely challenging, because the field across the sample volume inside the magnet must be homogeneous and essentially zero outside the magnet, so that the field gradient from the outside to the inside is the higher the smaller the magnet is. This challenge could be solved about a decade ago [1]. Since then tabletop NMR spectrometers are commercially available, which thanks to superior electronics, show better performance than their predecessors from four decades ago which  they operated at the same field strengths between 1 and 2 T.

What Compact NMR Spectrometers Can Do

Sensitivity and resolution are the key parameters that define the quality of an NMR spectrometer. The resolution is proportional to the field strength and the sensitivity approximately proportional to its 3/2 power. Consequently, the common understanding is that the higher the field strength is, the better are both, sensitivity and resolution. But for high-resolution NMR spectroscopy the line-shape is also important. For small molecules in solution the line is the narrower the more homogeneous the magnetic field is. Reducing the linewidth by a factor of two not only increases the spectral resolution by a factor of two but also the peak amplitude, so that the signal-to-noise-ratio of the spectrum doubles. Doubling the resolution at constant linewidth would require twice the field strength and doubling the sensitivity would require raising the field strength by a factor of 22/3 ≈ 1.6. Therefore, a 60 MHz NMR spectrometer with twice the field homogeneity of a given 80 MHz spectrometer may show better performance than the 80 MHz spectrometer.

For example, the benchtop spectrometer (Magritek) presented on page 31 provides a 1H NMR line-shape without spinning the 5-mm sample tube, which is as good as that measured with sample spinning on a high field spectrometer. (Fig. 1a). While the linewidths at half height is 0.11 Hz, it is less than 8 Hz at 0.11% of the peak amplitude so that solvent peaks can well be suppressed, and small peaks be identified next to large ones as, for example, the metabolites in urine next to the more than 2000-times higher water peak (Fig. 1b). This example nicely demonstrates the remarkable analytical power that compact low-field NMR spectrometers can provide. Due to their small size they can be placed inside the fume hood or the glove box ready to analyze hazardous compounds and other reaction products on demand without queuing delays. Given that they cost about the same as or less than a probe of a high-field spectrometer, one compact spectrometer typically serves one or two nuclei, for example 1H (along with 19F) and 13C or 1H/19F and 31P [2].

NMR Spectroscopy for Chemical Analysis

Low-field NMR spectrometers fitted with an external field-frequency lock do not need deuterated solvents as radiation damping at low field is less an issue than at high field. Nevertheless, modern tabletop spectrometers permit solvent signal saturation at multiple frequencies. But that leaves their solvent 13C satellite signals which can be mistaken for the resonances of low-concentration solutes at 50 to 100 times magnification (Fig. 2a). These satellites are suppressed by 13C decoupling so that the weak solute signals can unambiguously be identified in the 1H NMR spectrum.

While 1H NMR spectra at typical 50 to 100 mM solute concentrations can be measured by default with four scans in one minute, 13C spectra take more time due to the lower frequency and natural abundance of the 13C nuclei. Typical measurements times for 13C spectra of 400 mM solutions at 2 T (80 MHz 1H NMR frequency) are a few hours. Standard pulse sequences like Distortionless Enhancement of Polarization Transfer (DEPT) and various homo- and heteronuclear 2D experiments can be run with a click of the mouse button. For example, a 13C-1H Heteronuclear Multiple Bond Correlation (HMBC) spectrum of ibuprofen can be acquired at 80 MHz 1H NMR frequency in less than one hour (Fig. 2b).

Reaction Monitoring

Benchtop spectrometers are ideally suited for process control applications and reaction monitoring, because they can be operated in amultitude of environments, and the feedlines from the reactor to the detection region inside the magnet are short. Heterogeneous reaction batches can be homogenized by stirring in the reactor outside the spectrometer, and spectra can be acquired in real time every 15 s, much faster than by many other methods. For example, the formation of a-fluoro-a,b-unsaturated esters has been monitored at 40 kHz over 17 hours (Fig. 3), whereby the kinetics of the deprotonation and product-formation steps could be resolved on vastly different time scales for detailed analysis by modelling [4].

The Future of Compact NMR

Compact NMR has evolved from benchtop relaxometers to small spectrometers with analytical power superior the routine NMR spectrometers from 40 years ago which operated at similar field strengths but had a much larger footprint [3]. They can be employed on the chemical workbench, in the glove box and as process-control sensors monitoring chemical transformations [2]. One may speculate that someday even smaller, personalized spectrometers may become available at the cost of a premium smart phone with which the metabolites in urine can tracked at home, monitoring the performance of the human body as a chemical reactor which converts food to energy. They could detect a developing disease at an early stage and become a technology which enables the transition of medicine from curative to preventive [1,3].

Contact

Prof. Dr. Bernhard Blümich
RWTH Aachen University, Aachen, Germany
bluemich@itmc.rwth-aachen.de

CV

Bernhard Blümich has the chair of Macromolecular Chemistry at RWTH Aachen University. He is also president of the Ampere Society, associate editor of the Journal of Magnetic Resonance and director on the board of Magritek. His research activities aim at understanding the macroscopic properties of polymer and functional porous materials by NMR on a microscopic and molecular basis. He has pioneered several methodical innovations concerning multidimensional NMR spectroscopy with noise excitation, 1D and 2D methods of studying molecular motion in solids, solid-state imaging, and flow NMR. A growing focus in his recent work is the development of magnets for compact NMR. His scientific work is published in over 500 papers and three monographs. For his innovations in NMR, Bernhard Blümich has received several awards, among them the EAS award 2017 for outstanding achievements in NMR.

References:

[1] B. Blümich, K. Singh, Desktop NMR and Its Applications From Materials Science To Organic Chemistry, Angew. Chem. Int. Ed. 56 (2017) 2–17; DOI: 10.1002/anie.201707084.

[2] E. Pretsch, B. Blümich, eds., Special issue on Compact NMR, Trends Anal. Chem. 88 (2016) 1-198.

[3] B. Blümich, S. Haber-Pohlmeier, W. Zia, Compact NMR, de Gruyter, Berlin, 2000.

[4] D. Weidener, K. Singh, B. Blümich, Synthesis of α-Fluoro-α,β-unsaturated esters monitored by 1D and 2D benchtop NMR Spectroscopy, Magn. Reson. Chem. (2019), DOI: 10:1002/mrc.4843.

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