Spinsolve is a powerful, fully featured NMR Spectrometer and is used by a number of the worlds top NMR research groups. Below is a selected list of journal articles where a Magritek Spinsolve Benchtop NMR spectrometer has been used in the published research. Spinsolve is being used for Research in topics such as online Reaction Monitoring, Hyperpolarisation, Ultrafast 2D NMR, Residual Dipolar Couplings and Process Control.
A short abstract for each paper is included below, along with a hyperlink to more detailed information about each the papers.
1. Towards dial-a-molecule by integrating continuous flow, analytics and self-optimisation
Victor Sans, Leroy Cronin, Chemical Society Reviews, (2016), 45, 2032-2043 DOI: 10.1039/C5CS00793C
The employment of continuous-flow platforms for synthetic chemistry is becoming increasingly popular in research and industrial environments. Integrating analytics in-line enables obtaining a large amount of information in real-time about the reaction progress, catalytic activity and stability, etc. Furthermore, it is possible to influence the reaction progress and selectivity via manual or automated feedback optimisation, thus constituting a dial-a-molecule approach employing digital synthesis. This contribution gives an overview of the most significant contributions in the field to date.
2. Process control with compact NMR
Klas Meyer, Simon Kern, Nicolai Zientek, Gisela Guthausen, Michael Maiwald, Trends in Analytical Chemistry, (2016) DOI: 10.1016/j.trac.2016.03.016
Compact nuclear magnetic resonance (NMR) instruments make NMR spectroscopy and relaxometry accessible in industrial and harsh environments for reaction and process control. An increasing number of applications are reported. To build an interdisciplinary bridge between “process control” and “compact NMR”, we give a short overview on current developments in the field of process engineering such as modern process design, integrated processes, intensified processes along with requirements to process control, model based control, or soft sensing. Finally, robust field integration of NMR systems into processes environments, facing explosion protection or integration into process control systems, are briefly discussed.
3. Paramagnetic fluorinated nanoemulsions for sensitive cellular fluorine-19 magnetic resonance imaging
Alexander A. Kislukhin, Hongyan Xu, Stephen R. Adams, Kazim H. Narsinh, Roger Y. Tsien, Eric T. Ahrens, Nature Materials, (2016),15, 662–668 DOI: 10.1038/NMAT4585
Fluorine-19 magnetic resonance imaging (19F MRI) probes enable quantitative in vivo detection of cell therapies and inflammatory cells. Here, we describe the formulation of perfluorocarbon-based nanoemulsions with improved sensitivity for cellular MRI. Reduction of the 19F spin–lattice relaxation time (T1) enables rapid imaging and an improved signal-to-noise ratio, thereby improving cell detection sensitivity. We synthesized metal-binding β-diketones conjugated to linear perfluoropolyether (PFPE), formulated these fluorinated ligands as aqueous nanoemulsions, and then metallated them with various transition and lanthanide ions in the fluorous phase. Iron(III) tris-β-diketonate (‘FETRIS’) nanoemulsions with PFPE have low cytotoxicity (<20%) and superior MRI properties. Moreover, the 19F T1 can readily be reduced by an order of magnitude and tuned by stoichiometric modulation of the iron concentration. The resulting 19F MRI detection sensitivity is enhanced by three- to fivefold over previously used tracers at 11.7 T, and is predicted to increase by at least eightfold at the clinical field strength of 3 T.
4. Ultrafast 2D NMR on a benchtop spectrometer: Applications and perspectives
Boris Gouilleux, Benoît Charrier, Serge Akoka, François-Xavier Felpin, Mireia Rodriguez-Zubiri, Patrick Giraudeau, Trends in Analytical Chemistry, (2016) DOI: 10.1016/j.trac.2016.01.014
Benchtop NMR spectrometers are associated with significant resolution losses, as peak overlaps become ubiquitous at low field. 2D spectroscopy offers an appealing solution to this issue. However 2D NMR is associated with long experimental times which are ill-suited for high-throughput applications such as real-time reaction monitoring or rapid screening. The first implementation of ultrafast (UF) 2D NMR on a benchtop spectrometer –including B0 gradients– was recently reported, making it possible to record 2D spectra in a single –or at most a few– scans. In the present review, we investigate the analytical performance of UF 2D NMR at low field (43 MHz) and its application potential in two complementary research fields: real-time reaction monitoring and rapid screening. UF 2D spectroscopy at low field appears to be a powerful complement to existing analytical methods, and paves the way towards a number of developments in the field of spatially-encoded NMR at low field.
5. Introduction to compact NMR: A review of methods
Bernhard Blümich, Trends in Analytical Chemistry, (2016) DOI: 10.1016/j.trac.2015.12.012
NMR spectroscopy with compact instruments opens new perspectives for the use of NMR. While the field strength of compact instruments is low, they potentially match today’s high-field instruments in methodical diversity, although by default they are operated in non-expert mode with a mouse click. Because size and price are low, they open new opportunities for the use of NMR spectroscopy. One is product and quality control and another is real-time reaction monitoring in the academic and industrial research laboratory on the workbench by observing nuclei such as 1H, 13C, 31P, 19F, 7Li and 11B. With compact NMR spectrometers, not only standard one-dimensional experiments can be executed to retrieve chemical information but also the two-dimensional experiments such as HSQC, HMBC, HETCOR and COSY. The state of the art and progress in compact NMR spectroscopy is reviewed concerning 1D and 2D spectroscopy along with their use in product control and reaction monitoring.
6. NMR spectroscopy with compact instruments
Kawarpal Singh, Bernhard Blümich, Trends in Analytical Chemistry, (2016) DOI: 10.1016/j.trac.2016.02.014
Recent progress in magnet design has led to compact permanent magnets capable of resolving the chemical shift, so that small NMR spectrometers are now available, which can measure multi-nuclear and multi-dimensional NMR spectra on the workbench of the chemical laboratory. Although not as powerful as today’s high-field spectrometers, their performance by far exceeds that of spectrometers from former times when high-field instruments were not available. Moreover, they are compact and robust, enabling the use of NMR in studies currently constrained by the demands posed by operating large cryogenically cooled magnets. The current state-of-the-art of compact low-field NMR instruments is reviewed from a methodological point of view making reference to basic NMR theory where needed to characterize their performance.
7. Hyperpolarization of Nitrogen-15 Schiff Bases by Reversible Exchange Catalysis with para-Hydrogen
Angus W. J. Logan, Thomas Theis, Johannes F. P. Colell, Warren S. Warren, Steven J. Malcolmson, Chemistry A European Journal, (2016) DOI: 10.1002/chem.201602393
NMR with thermal polarization requires relatively concentrated samples, particularly for nuclei with low abundance and low gyromagnetic ratios, such as 15N. We expand the substrate scope of SABRE, a recently introduced hyperpolarization method, to allow access to 15N-enriched Schiff bases. These substrates show fractional 15N polarization levels of up to 2 % while having only minimal 1H enhancements.
8. Real-time reaction monitoring by ultrafast 2D NMR on a benchtop spectrometer
Boris Gouilleux, Benoît Charrier, Ernesto Danieli, Jean-Nicolas Dumez, Serge Akoka, François-Xavier Felpin, Mireia Rodriguez-Zubiria, Patrick Giraudeau, Analyst, (2015),140, 7854-7858 DOI: 10.1039/C5AN01998B
Reaction monitoring is widely used to follow chemical processes in a broad range of application fields. Recently, the development of robust benchtop NMR spectrometers has brought NMR under the fume hood, making it possible to monitor chemical reactions in a safe and accessible environment. However, these low-field NMR approaches suffer from limited resolution leading to strong peak overlaps, which can limit their application range. Here, we propose an approach capable of recording ultrafast 2D NMR spectra on a compact spectrometer and of following in real time reactions in the synthetic chemistry laboratory. This approach – whose potential is shown here on a Heck–Matsuda reaction – is highly versatile; the duration of the measurement can be optimized to follow reactions whose time scale ranges from between a few tens of seconds to a few hours. It makes it possible to monitor complex reactions in non-deuterated solvents, and to confirm in real time the molecular structure of the compounds involved in the reaction while giving access to relevant kinetic parameters.
9. On-Line Monitoring of Chemical Reactions by using Benchtop Nuclear Magnetic Resonance Spectroscopy
E. Danieli, J. Perlo, A. L. L. Duchateau, G. K. M. Verzijl, V. M. Litvinov, B. Blümich, F. Casanova, ChemPhysChem, (2014),14 (14), 3060–3066 DOI: 10.1002/cphc.201402049
Real-time nuclear magnetic resonance (NMR) spectroscopy measurements carried out with a bench-top system installed next to the reactor inside the fume hood of the chemistry laboratory are presented. To test the system for on-line monitoring, a transfer hydrogenation reaction was studied by continuously pumping the reaction mixture from the reactor to the magnet and back in a closed loop. In addition to improving the time resolution provided by standard sampling methods, the use of such a flow setup eliminates the need for sample preparation. Owing to the progress in terms of field homogeneity and sensitivity now available with compact NMR spectrometers, small molecules dissolved at concentrations on the order of 1 mmol L−1 can be characterized in single-scan measurements with 1 Hz resolution. Owing to the reduced field strength of compact low-field systems compared to that of conventional high-field magnets, the overlap in the spectrum of different NMR signals is a typical situation. The data processing required to obtain concentrations in the presence of signal overlap are discussed in detail, methods such as plain integration and line-fitting approaches are compared, and the accuracy of each method is determined. The kinetic rates measured for different catalytic concentrations show good agreement with those obtained with gas chromatography as a reference analytical method. Finally, as the measurements are performed under continuous flow conditions, the experimental setup and the flow parameters are optimized to maximize time resolution and signal-to-noise ratio.
10. Simultaneous 19F–1H medium resolution NMR spectroscopy for online reaction monitoring
Nicolai Zientek, Clément Laurain, Klas Meyer, Matthias Kraume, Gisela Guthausen, Michael Maiwald, Journal of Magnetic Resonance, (2014), 249, 53–62 DOI: 10.1016/j.jmr.2014.10.007
Medium resolution nuclear magnetic resonance (MR-NMR) spectroscopy is currently a fast developing field, which has an enormous potential to become an important analytical tool for reaction monitoring, in hyphenated techniques, and for systematic investigations of complex mixtures. The recent developments of innovative MR-NMR spectrometers are therefore remarkable due to their possible applications in quality control, education, and process monitoring. MR-NMR spectroscopy can beneficially be applied for fast, non-invasive, and volume integrating analyses under rough environmental conditions.
11. Nanofluidity of Fatty Acid Hydrocarbon Chains As Monitored by Benchtop Time-Domain Nuclear Magnetic Resonance
Michelle D. Robinson, David P. Cistola, Biochemistry, (2014), 53, 48, DOI: 10.1021/bi5011859
The functional properties of lipid-rich assemblies such as serum lipoproteins, cell membranes, and intracellular lipid droplets are modulated by the fluidity of the hydrocarbon chain environment. Existing methods for monitoring hydrocarbon chain fluidity include fluorescence, electron spin resonance, and nuclear magnetic resonance (NMR) spectroscopy; each possesses advantages and limitations. Here we introduce a new approach based on benchtop time-domain 1H NMR relaxometry (TD-NMR). Unlike conventional NMR spectroscopy, TD-NMR does not rely on the chemical shift resolution made possible by homogeneous, high-field magnets and Fourier transforms. Rather, it focuses on a multiexponential analysis of the time decay signal. In this study, we investigated a series of single-phase fatty acid oils, which allowed us to correlate 1H spin–spin relaxation time constants (T2) with experimental measures of sample fluidity, as obtained using a viscometer. Remarkably, benchtop TD-NMR at 40 MHz was able to resolve two to four T2 components in biologically relevant fatty acids, assigned to nanometer-scale domains in different segments of the hydrocarbon chain.
12. Liquid-liquid equilibrium in binary and ternary mixtures containing formaldehyde, water, methanol, methylal, and poly(oxymethylene) dimethyl ethers
Niklas Schmitz, Anne Friebel, Erik von Harbou, Jakob Burger, Hans Hasse, Fluid Phase Equilibria, (2016), 425, 127-135, DOI: 10.1016/j.fluid.2016.05.017
Poly(oxymethylene) dimethyl ethers (OME) are an interesting class of oxygenated fuel components and solvents for the absorption of carbon dioxide. The chemical structure of OMEn is H3C–O–(CH2O)n–CH3 with n ≥ 2 and the IUPAC names are methoxy(methoxymethoxy)methane (n = 2), 2,4,6,8-tetraoxanonane (n = 3), and 2,4,6,8,10-pentaoxaundecane (n = 4). This work studies the liquid-liquid equilibrium (LLE) in the binary systems (water + methylal), (water + OME2), (water + OME3), and (water + OME4) and the ternary systems (water + methanol + OME2), (water + methanol + OME3), (formaldehyde + water + OME2), (formaldehyde + water + OME3), and (water + methylal + OME2) in the temperature range 280 K – 340 K. The systems were studied by gas chromatographic- and titrimetric analysis of samples that were drawn from the coexisting liquid phases, as well by in situ analysis with a medium-field NMR spectrometer. The LLE was modeled by extending a UNIFAC-based activity coefficient model of the system (formaldehyde + water + methanol + methylal) from the literature. One new structural group is introduced to represent the OME.
13. Automated data evaluation and modelling of simultaneous 19F–1H medium-resolution NMR spectra for online reaction monitoring
Nicolai Zientek, Clément Laurain, Klas Meyer, Andrea Paul, Dirk Engel, Gisela Guthausen, Matthias Kraumee, Michael Maiwald, Magnetic Resonance in Chemistry, (2016), 54 (6), 513–520, DOI: 10.1002/mrc.4216
Medium-resolution nuclear magnetic resonance spectroscopy (MR-NMR) currently develops to an important analytical tool for both quality control and process monitoring. In contrast to high-resolution online NMR (HR-NMR), MR-NMR can be operated under rough environmental conditions. A continuous re-circulating stream of reaction mixture from the reaction vessel to the NMR spectrometer enables a non-invasive, volume integrating online analysis of reactants and products. Here, we investigate the esterification of 2,2,2-trifluoroethanol with acetic acid to 2,2,2-trifluoroethyl acetate both by 1H HR-NMR (500 MHz) and 1H and 19F MR-NMR (43 MHz) as a model system.
14. Compact NMR spectroscopy for real-time monitoring of a biodiesel production
M.H.M. Killner, Y. Garro Linck, E. Danieli, J.J.R. Rohwedder, B. Blümich, Fuel, (2015), 139, 240-247, DOI: 10.1016/j.fuel.2014.08.050
The use of biodiesel shows innumerous advantages compared to fossil fuels, since biodiesel is a biodegradable and non-toxic fuel. Nowadays, most of the biodiesel commercialized in the world is produced by the transesterification reaction of vegetable oils with methanol and basic catalysis. Understanding the reaction kinetics and controlling its optimum progress for improving the quality of the final product and to reduce production costs is of paramount importance. The present work explores compact 1H NMR spectroscopy to follow the course of the transesterification reaction in real time. For this purpose the magnet is integrated into a flow setup which allows one to transport the neat solution from the reactor into the measurement zone and back again into the reactor. A multivariate calibration model applying Partial Least Squares regression was built to analyze the measured data and to obtain information about the biodiesel conversion ratio with errors on the order of 1%.
15. Differentiation of enantiomers by 2D NMR spectroscopy at 1T using residual dipolar couplings
Martin R. M. Koos, Ernesto Danieli, Federico Casanova, Bernhard Blümich, Burkhard Luy, Magnetic Resonance in Chemistry, (2016), 54 (6), 527-530, DOI: 10.1002/mrc.4222
Differentiating enantiomers using 2D bench-top NMR spectroscopy. Spectrometers working with permanent magnets at 1 T field strength allow the acquisition of 2D data sets. In conjunction with previously reported chiral alignment media, this setup allows the measurement of enantiomeric excess via residual dipolar couplings in stretched gelatine as a result of the reduced line width obtained by 2D J-resolved spectroscopy.
16. Online Monitoring of Fermentation Processes Via Non-Invasive Low-Field NMR
Dirk Kreyenschulte, Eva Paciok, Lars Regestein, Bernhard Blümich, Jochen Büchs, Biotechnology and Bioengineering, (2015), 112 (9), 1810-1821, DOI: 10.1002/bit.25599
For the development of biotechnological processes in academia as well as in industry new techniques are required which enable online monitoring for process characterization and control. Nuclear magnetic resonance (NMR) spectroscopy is a promising analytical tool, which has already found broad applications in offline process analysis. The use of online monitoring, however, is oftentimes constrained by high complexity of custom-made NMR bioreactors and considerable costs for high-field NMR instruments (>US$200,000). Therefore, low-field 1H NMR was investigated in this study in a bypass system for real-time observation of fermentation processes. The new technique was validated with two microbial systems. Both applications clearly demonstrate that the investigated technique is well suited for reaction monitoring in opaque media while at the same time it is highly robust and chemically specific. It can thus be concluded that low-field NMR spectroscopy has a great potential for non-invasive online monitoring of biotechnological processes at the research and practical industrial scales
17. A Self Optimizing Synthetic Organic Reactor System Using Real-time In-line NMR spectroscopy
Victor Sans, Luzian Porwol, Vincenza Dragone, Leroy Cronin, Chemical Science, (2015), 6, 1258-1264, DOI: 10.1039/C4SC03075C
A configurable platform for synthetic chemistry incorporating an in-line benchtop NMR that is capable of monitoring and controlling organic reactions in real-time is presented. The platform is controlled via a modular LabView software control system for the hardware, NMR, data analysis and feedback optimization. Using this platform we report the real-time advanced structural characterization of reaction mixtures, including 19F, 13C, DEPT, 2D NMR spectroscopy (COSY, HSQC and 19F-COSY) for the first time. Finally, the potential of this technique is demonstrated through the optimization of a catalytic organic reaction in real-time, showing its applicability to self-optimizing systems using criteria such as stereoselectivity, multi-nuclear measurements or 2D correlations.
18. Gradient-based solvent suppression methods on a benchtop spectrometer
Boris Gouilleux, Benoît Charrier, Serge Akoka and Patrick Giraudeau, Magnetic Resonance in Chemistry, (2016), 55, 91–98, DOI: 10.1002/mrc.4493
In this article, we highlight the need for efficient suppression methods compatible with flowing samples, which is not the case of the common pre-saturation approaches. Thanks to a gradient coil included in our benchtop spectrometer, we were able to implement modern and efficient solvent suppression blocks such as WET or excitation sculpting to deliver quantitative spectra in the conditions of the on-line monitoring. While these methods are commonly used at high field, this is the first time that they are investigated on a benchtop setting. Their analytical performance is evaluated and compared under static and on-flow conditions. The results demonstrate the superiority of gradient-based methods, thus highlighting the relevance of implementing this device on benchtop spectrometers. The comparison of major solvent suppression methods reveals an optimum performance for the WET-180-NOESY experiment, both under static and on-flow conditions.
19. Continuous Processing and Efficient In Situ Reaction Monitoring of a Hypervalent Iodine (III) Mediated Cyclopropanation using Benchtop NMR Spectroscopy
Batool Ahmed-Omer, Eric Sliwinski, John Paul Cerroti, and Steven V Ley, Organic Process Research & Development, (2016), 20 (9), 1603–1614, DOI: 10.1021/acs.oprd.6b00177
Real-time NMR spectroscopy has proven to be a rapid and an effective monitoring tool to study the hypervalent iodine (III) mediated cyclopropanation. With the ever increasing number of new synthetic methods for carbon-carbon bond formation, the NMR in situ monitoring of reactions is becoming a highly desirable enabling method. In this study, we have demonstrated the versatility of benchtop NMR using inline and online real-time monitoring methods to access mutually complementary information for process understanding, and developed new approaches for real-time monitoring addressing challenges associated with better integration into continuous processes
20. Utilizing on- and off-line monitoring tools to follow a kinetic resolution step during flow synthesis
Kathleen A. Farley, Usa Reilly, Dennis P. Anderson, Brian P. Boscoe, Mark W. Bundesmann, David A. Foley, Manjinder S. Lall, Chao Li, Matthew R. Reese and Jiangli Yan, Magnetic Resonance in Chemistry, (2016), DOI: 10.1002/mrc.4494
Real-time NMR spectroscopy has proven to be a rapid and an effective monitoring tool to study the hypervalent iodine (III) mediated cyclopropanation. With the ever increasing number of new synthetic methods for carbon-carbon bond formation, the NMR in situ monitoring of reactions is becoming a highly desirable enabling method. In this study, we have demonstrated the versatility of benchtop NMR using inline and online real-time monitoring methods to access mutually complementary information for process understanding, and developed new approaches for real-time monitoring addressing challenges associated with better integration into continuous processes.
21. Sampling Hyperpolarized Molecules Utilizing a 1 Tesla Permanent Magnetic Field
Sui Seng Tee, Valentina DiGialleonardo, Roozbeh Eskandari, Sangmoo Jeong, Kristin L. Granlund, Vesselin Miloushev, Alex J. Poot, Steven Truong, Julio A. Alvarez, Hannah N. Aldeborgh and Kayvan R. Keshari, Scientific Reports, (2016), 6, DOI: 10.1038/srep32846
Hyperpolarized magnetic resonance spectroscopy (HP MRS) using dynamic nuclear polarization (DNP) is a technique that has greatly enhanced the sensitivity of detecting 13C nuclei. However, the HP MRS polarization decays in the liquid state according to the spin-lattice relaxation time (T1) of the nucleus. Sampling of the signal also destroys polarization, resulting in a limited temporal ability to observe biologically interesting reactions. In this study, we demonstrate that sampling hyperpolarized signals using a permanent magnet at 1 Tesla (1T) is a simple and cost-effective method to increase T1s without sacrificing signal-to-noise. Biologically-relevant information may be obtained with a permanent magnet using enzyme solutions and in whole cells. Of significance, our findings indicate that changes in pyruvate metabolism can also be quantified in a xenograft model at this field strength.
22. Size-dependent MR relaxivities of magnetic nanoparticles
Alexander Joos, Norbert Löw, Frank Wiekhorst, Bernhard Gleich, Axel Haase, Journal of Magnetism and Magnetic Materials, (2017), 427, 122-126, DOI: 10.1016/j.jmmm.2016.11.021
Magnetic nanoparticles (MNPs) can be used as carriers for magnetic drug targeting and for stem cell tracking by magnetic resonance imaging (MRI). For these applications, it is crucial to quantitatively determine the spatial distribution of the MNP concentration, which can be approached by MRI relaxometry. Theoretical considerations and experiments have shown that R2 relaxation rates are sensitive to the aggregation state of the particles, whereas R*2 is independent of aggregation state and therefore suited for MNP quantification if the condition of static dephasing is met. We present a new experimental approach to characterize an MNP system with respect to quantitative MRI based on hydrodynamic fractionation. The first results qualitatively confirm the outer sphere relaxation theory for small MNPs and show that the two commercial MRI contrast agents Resovist® and Endorem® should not be used for quantitative MRI because they do not fulfill the condition for static dephasing. Our approach could facilitate the choice of MNPs for quantitative MRI and help clarifying the relationship between size, magnetism and relaxivity of MNPs in the future.
23. Introducing Students to NMR Methods Using Low-Field 1H NMR Spectroscopy to Determine the Structure and the Identity of Natural Amino Acids
Aleksandra Zivkovic, Jan Josef Bandolik, Alexander Jan Skerhut, Christina Coesfeld, Nenad Zivkovic, Miomir Raos, Holger Stark, Journal of Chemical Education, (2017), 94 (1), 115–120, DOI: 10.1021/acs.jchemed.6b00168
Nuclear magnetic resonance (NMR) spectroscopy is a widely used analytical technique for molecular structure determination, and is highly valued in the fields of chemistry, biochemistry, and medicinal chemistry. The importance of NMR methods in the European (PhEur) and United States Pharmacopeia (USP) is steadily growing. However, undergraduates often have problems becoming familiar with handling the complex data. We have developed a simple experiment in which undergraduates, who are learning 1H NMR spectroscopy for the first time, investigate natural amino acids, and determine their structure and identity using low-field 1H NMR measurements and simple COSY experiments. These students see and learn the connection between the chemical shift of the αC-proton and the isoelectric point of the amino acid. They engage with the spectroscopic topic by acquiring their own spectra, and processing and interpreting the data. Understanding important natural amino acids and their physicochemical character is highly relevant to all students studying life sciences.
24. Quantitative Analysis of Multicomponent Mixtures of Over-the-Counter Pain Killer Drugs by Low-Field NMR Spectroscopy
Aleksandra Zivkovic, Jan Josef Bandolik, Alexander Jan Skerhut, Christina Coesfeld, Momir Prascevic, Ljiljana Zivkovic, Holger Stark, Journal of Chemical Education, (2017), 94 (1), 121–125, DOI: 10.1021/acs.jchemed.6b00105
Marketed pain relief drugs with one to three biologically active components, as well as mixtures of these ingredients, were qualitatively and quantitatively analyzed in an undergraduate student lab using a compact, low-field 1H NMR spectrometer. The students successfully analyzed more than 50 self-made sample mixtures with two or three components as well as the two marketed tablet formulations containing acetylsalicylic acid/l-ascorbic acid, or acetylsalicylic acid/paracetamol (acetaminophen)/caffeine. The NMR-based quantification is an attractive application of the technique, as well as a helpful introduction to NMR spectroscopic applications in life sciences. Problem-based learning on NMR techniques on commonly known drugs provided students the opportunity to develop and improve their skills in solving 1H NMR problems.
25. Fast Sampling, Analyses and Chemometrics for Plant Breeding: Bitter Acids, Xanthohumol and Terpenes in Lupulin Glands of Hops (Humulus lupulus)
Daniel P. Killeen, Oliver C. Watkins, Catherine E. Sansom, David H. Andersen, Keith C. Gordon and Nigel B. Perry, Phytochemical Analysis, (2016), 28, 50–57, DOI: 10.1002/pca.2642
Lupulin glands from 139 plants (39 cultivars/advanced selections) were analysed by Raman and 1H NMR spectroscopy, and head-space solid-phase microextraction (HS-SPME) GC-FID. The digital X,Y-data were subjected to principal component analysis (PCA) and the results compared with conventional analyses of extracts of whole hops from the same plants. Quantitative 1H NMR analyses were also done for the bitter acids.
Raman spectroscopy rapidly identified hops cultivars with high xanthohumol concentrations and high α:β bitter acid ratios. 1H NMR spectroscopy was slower, requiring a solvent extraction, but distinguished cultivars by cohumulone content as well as α:β acid ratios. HS-SPME-GC rapidly distinguished aroma hops with high myrcene and farnesene contents, and pinpointed a novel selection with unusual sesquiterpenes. The quantitative NMR analyses showed correlations between bitter acid concentrations related to biosynthetic pathways.
26. Hyperpolarized 13C Metabolic Magnetic Resonance Spectroscopy and Imaging
Eugen Kubala, Kim A. Muñoz-Álvarez, Geoffrey Topping, Christian Hundshammer, Benedikt Feuerecker, Pedro A. Gómez, Giorgio Pariani, Franz Schilling, Steffen J. Glaser, Rolf F. Schulte, Marion I. Menzel, Markus Schwaiger, Journal of Visualized Experiments, (2016), DOI: 10.3791/54751
In the past decades, new methods for tumor staging, restaging, treatment response monitoring, and recurrence detection of a variety of cancers have emerged in conjunction with the state-of-the-art positron emission tomography with 18F-fluorodeoxyglucose ([18F]-FDG PET). 13C magnetic resonance spectroscopic imaging (13CMRSI) is a minimally invasive imaging method that enables the monitoring of metabolism in vivo and in real time. As with any other method based on 13C nuclear magnetic resonance (NMR), it faces the challenge of low thermal polarization and a subsequent low signal-to-noise ratio due to the relatively low gyromagnetic ratio of 13C and its low natural abundance in biological samples. By overcoming these limitations, dynamic nuclear polarization (DNP) with subsequent sample dissolution has recently enabled commonly used NMR and magnetic resonance imaging (MRI) systems to measure, study, and image key metabolic pathways in various biological systems. A particularly interesting and promising molecule used in 13CMRSI is [1-13C]pyruvate, which, in the last ten years, has been widely used for in vitro, preclinical, and, more recently, clinical studies to investigate the cellular energy metabolism in cancer and other diseases. In this article, we outline the technique of dissolution DNP using a 3.35 T preclinical DNP hyperpolarizer and demonstrate its usage in in vitro studies. A similar protocol for hyperpolarization may be applied for the most part in in vivo studies as well. To do so, we used lactate dehydrogenase (LDH) and catalyzed the metabolic reaction of [1-13C]pyruvate to [1-13C]lactate in a prostate carcinoma cell line, PC3, in vitro using 13CMRSI.
27. Process spectroscopy in microemulsions—setup and multi-spectral approach for reaction monitoring of a homogeneous hydroformylation process
K Meyer, J-P Ruiken, M Illner, A Paul, D Müller, E Esche, G Wozny and M Maiwald, Measurement Science and Technology, (2017), 28 (3), DOI: 10.1088/1361-6501/aa54f3
Reaction monitoring in disperse systems, such as emulsions, is of significant technical importance in various disciplines like biotechnological engineering, chemical industry, food science, and a growing number other technical fields. These systems pose several challenges when it comes to process analytics, such as heterogeneity of mixtures, changes in optical behavior, and low optical activity. Concerning this, online nuclear magnetic resonance (NMR) spectroscopy is a powerful technique for process monitoring in complex reaction mixtures due to its unique direct comparison abilities, while at the same time being non-invasive and independent of optical properties of the sample. In this study the applicability of online-spectroscopic methods on the homogeneously catalyzed hydroformylation system of 1-dodecene to tridecanal is investigated, which is operated in a mini-plant scale at Technische Universität Berlin. The design of a laboratory setup for process-like calibration experiments is presented, including a 500 MHz online NMR spectrometer, a benchtop NMR device with 43 MHz proton frequency as well as two Raman probes and a flow cell assembly for an ultraviolet and visible light (UV/VIS) spectrometer. Results of high-resolution online NMR spectroscopy are shown and technical as well as process-specific problems observed during the measurements are discussed.
28. Optimized Droplet Sizing of Water-in-Crude Oil Emulsions Using Nuclear Magnetic Resonance
Einar O. Fridjonsson, Brendan F. Graham, Masoumeh Akhfash, Eric F. May, and Michael L. Johns, Energy & Fuels, (2014), 28 (3), 1756–1764, DOI: 10.1021/ef402117k
Water-in-crude oil emulsions are an increasing problem during production. Essential to any emulsion breaking method is an ability to accurately measure droplet size distributions; this is rendered extremely difficult given that the samples are both concentrated and opaque. Here, we systematically consider the use of a standard, low-field benchtop nuclear magnetic resonance (NMR) apparatus to accurately measure the droplet size distributions. Such measurements are challenging because the NMR signal from the oil phase erroneously contributes to the measured water droplet size distribution. Conventionally, the oil-phase signal is nulled-out based on differences in the NMR T1 relaxation parameter between water and oil. However, in the case of crude oil, the oil presents a broad T1 distribution, rendering this approach infeasible. On the basis of this oil T1 distribution, we present an optimization routine that adjusts various NMR measurement timing parameters [observation time (Δ) and inversion time (Tinv)] to effectively eliminate this erroneous crude oil contribution. An implementation of this optimization routine was validated against measurements performed using unambiguous chemical-shift selection of the water (droplet) signal, as would conventionally be provided by high-field superconducting NMR spectrometers. We finally demonstrate successful droplet sizing of a range of water-in-crude oil emulsions.
29. Hyperpolarized 13C pyruvate mouse brain metabolism with absorptivemode EPSI at 1 T
Vesselin Z. Miloushev, Valentina Di Gialleonardo, Lucia Salamanca-Cardona, Fabian Correa, Kristin L. Granlund, Kayvan R. Keshari, Journal of Magnetic Resonance, (2017), 275, 120-126, DOI: 10.1016/j.jmr.2016.12.009
The expected signal in echo-planar spectroscopic imaging experiments was explicitly modeled jointly in spatial and spectral dimensions. Using this as a basis, absorptive-mode type detection can be achieved by appropriate choice of spectral delays and post-processing techniques. We discuss the effects of gradient imperfections and demonstrate the implementation of this sequence at low field (1.05 T), with application to hyperpolarized [1-13C] pyruvate imaging of the mouse brain. The sequence achieves sufficient signal-to-noise to monitor the conversion of hyperpolarized [1-13C] pyruvate to lactate in the mouse brain. Hyperpolarized pyruvate imaging of mouse brain metabolism using an absorptive-mode EPSI sequence can be applied to more sophisticated murine disease and treatment models. The simple modifications presented in this work, which permit absorptive-mode detection, are directly translatable to human clinical imaging and generate improved absorptive-mode spectra without the need for refocusing pulses.
30. Molecular dynamics-based selectivity for Fast-Field-Cycling relaxometry by Overhauser and Solid Effect Dynamic Nuclear Polarization
Neudert, C. Mattea, S. Stapf, Journal of Magnetic Resonance, (2017), DOI: 10.1016/j.jmr.2017.01.013
In the last decade nuclear spin hyperpolarization methods, especially Dynamic Nuclear Polarization (DNP), have provided unprecedented possibilities for various NMR techniques by increasing the sensitivity by several orders of magnitude. Recently, in-situ DNP-enhanced Fast Field Cycling (FFC) relaxometry was shown to provide appreciable NMR signal enhancements in liquids and viscous systems. In this work, a measurement protocol for DNP-enhanced NMR studies is introduced which enables the selective detection of nuclear spin hyperpolarized by either Overhauser effect or solid effect DNP. Based on field-cycled DNP and relaxation studies it is shown that these methods allow for the independent measurement of polymer and solvent nuclear spins in a concentrated solution of high molecular weight polybutadiene in benzene doped with α,γ-bisdiphenylene-β-phenylallyl radical. Appreciable NMR signal enhancements of about 10-fold were obtained for both constituents. Moreover, qualitative information about the dynamics of the radical and solvent was obtained. Selective DNP-enhanced FFC relaxometry is applied for the measurement of the 1H nuclear magnetic relaxation dispersion of both constituents with improved precision. The introduced method is expected to greatly facilitate NMR studies of complex systems with multiple overlapping signal contributions that cannot be distinguished by standard methods.
31. By-line NMR emulsion droplet sizing
Nicholas N.A. Ling, Agnes Haber, Eric F. May, Einar O. Fridjonsson, Michael L. Johns, Chemical Engineering Science, (2017), 160, 362-369, DOI: 10.1016/j.ces.2016.11.045
By-line Nuclear Magnetic Resonance (NMR) measurements of emulsion droplet size distributions are presented based on pulsed field gradient (PFG) measurements. These are performed on temporarily immobilised samples extracted from a main process stream with corrections applied for any temporal variations in sample composition. The overall methodology is initially applied to pure fluids and then a range of water-in-oil emulsions. It is then demonstrated on an emulsification flow loop in which three commercial demulsifiers are separately applied; significant variation in their performance with respect to increasing emulsion droplet size (and thus emulsion destabilisation) is observed. Finally, a more rapid PFG method, Difftrain, is successfully demonstrated with the measured mean emulsion droplet size being used as the input into standard PID control of applied shear and hence the extent of emulsification.
32. NMR reaction monitoring in flow synthesis
Victoria Gomez and Antonio de la Hoz, Beilstein Journal of Organic Chemistry, (2017), 13, 285–300, DOI: 10.3762/bjoc.13.31
Recent advances in the use of flow chemistry with in-line and on-line analysis by NMR are presented. The use of macro- and microreactors, coupled with standard and custom made NMR probes involving microcoils, incorporated into high resolution and benchtop NMR instruments is reviewed. Some recent selected applications have been collected, including synthetic applications, the determination of the kinetic and thermodynamic parameters and reaction optimization, even in single experiments and on the μL scale. Finally, software that allows automatic reaction monitoring and optimization is discussed.
33. In situ measurement of liquid-liquid equilibria by medium field nuclear magnetic resonance
Anne Friebel, Agnes Fröscher, Kerstin Münnemann, Erik von Harbou, Hans Hasse, Fluid Phase Equilibria, (2017), 438, 44–52, DOI: 10.1016/j.fluid.2017.01.027
A new method for non-invasive measurement of liquid-liquid equilibria (LLE) using a compact medium field nuclear magnetic resonance (NMR) spectrometer is presented. Mixing of all components, phase separation, and analysis of the composition of the coexisting phases is performed in situ in an NMR glass tube. Thus, the experimental effort is reduced and errors caused by sampling are eliminated. Furthermore, calibration of the analysis method is not necessary as quantitative information is obtained directly from the NMR spectra. The proposed method for studying LLE in situ can be swiftly conducted in standard chemical laboratories as medium field NMR spectrometer do not require dedicated laboratory infrastructure but enable convenient handling and fast analysis of the samples. In the present work, four non-reactive ternary solvent systems with closed miscibility gap (toluene + acetone + water, diethyl ether + acetone + water, diethyl ether + methanol + water, and acetonitrile + ethanol + cyclohexane) and one reactive ternary system (water + acetic acid + acetic anhydride) were investigated at a temperature of 22.0 °C using 1H medium field NMR spectroscopic measurements. For comparison, the composition of the coexisting phases is also examined for one non-reactive system (acetonitrile + ethanol + cyclohexane) using 13C medium field NMR spectroscopy as well as spatially resolved spectroscopy in a conventional high field NMR spectrometer. The comparison of the results of the present work to literature data shows that the new proposed method enables swift and reliable investigations of LLE.
34. Generalizing, Extending, and Maximizing Nitrogen-15 Hyperpolarization Induced by Parahydrogen in Reversible Exchange
Johannes F. P. Colell, Angus W. J. Loga, Zijian Zhou, Roman V. Shchepin, Danila A. Barskiy, Gerardo X. Ortiz Jr, Qiu Wang, Steven J. Malcolmson, Eduard Y. Chekmenev, Warren S. Warren, and Thomas Theis, Journal of Physical Chemistry, (2017) DOI: 10.1021/acs.jpcc.6b12097
Signal Amplification by Reversible Exchange (SABRE) is a fast and convenient NMR hyperpolarization method that uses cheap and readily available para-hydrogen as a hyperpolarization source. SABRE can hyperpolarize protons and heteronuclei. Here we focus on the heteronuclear variant introduced as SABRE-SHEATH (SABRE in SHield Enables Alignment Transfer to Heteronuclei) and nitrogen-15 targets in particular. We show that 15N-SABRE works more efficiently and on a wider range of substrates than 1H-SABRE, greatly generalizing the SABRE approach. In addition, we show that nitrogen-15 offers significantly extended T1 times of up to 12 minutes. Long T1 times enable higher hyperpolarization levels but also hold the promise of hyperpolarized molecular imaging for several tens of minutes. Detailed characterization and optimization are presented, leading to nitrogen-15 polarization levels in excess of 10% on several compounds.
35. Desktop NMR for structure elucidation and identification of strychnine adulteration
Kawarpal Singh, Bernhard Blümich, Analyst, (2017) DOI: 10.1039/C7AN00020K
This paper demonstrates the use of low-field NMR spectroscopy in chemical forensics for identifying strychnine and its counterions by exploring the chemical shift as a signature in different 1D 1H and 13C experiments. Hereby the applied methodologies combine various 1D and 2D experiments such as 1D 1H, 13C, DEPT, and 2D COSY, HETCOR, HSQC, HMBC and J-resolved spectroscopy to elucidate the molecular structure and skeleton of strychnine at 1 Tesla. Strychnine was exemplified here, because it is a basic precursor in the chemistry of natural products and is employed as a chemical weapon and as a doping agent in sports including the Olympics. In our study, the molecular structure of the compound could be identified either with a 1D experiment at high magnetic field or with HMBC and HSQC experiments at 1 T. In conclusion, low-field NMR spectroscopy enables the chemical elucidation of the strychnine structure through a simple click with a computer mouse. In situations where a high-field NMR spectrometer is unavailable, compact NMR spectrometers can nevertheless generate knowledge of the structure, important for identifying the different chemical reaction mechanisms associated with the molecule.