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Spinsolve is a powerful, fully featured NMR Spectrometer and is used by a number of the world’s 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, Oil Adulteration as well as Process and Quality Control.

A short abstract for each paper is included below, along with a hyperlink to more detailed information about each the papers.

The latest publications are at the top of this list. You can jump to the bottom by clicking on this link.

 

118. Reaction monitoring by Benchtop NMR spectroscopy using a novel stationary flow reactor setup

Anne Friebel, Erik von Harbou, Kerstin Münnemann, and Hans Hasse, Industrial & Engineering Chemistry Research, (2019) DOI: 10.1021/acs.iecr.9b03048

A flow reactor setup for non-invasive monitoring of reactions using a compact medium field nuclear magnetic resonance (NMR) spectrometer is presented, in which a tubular flow reactor is inserted into the bore of the NMR spectrometer and operated at stationary conditions. To monitor the composition change of reaction mixture in the flow reactor, the entire reactor is moved to different longitudinal positions in the bore. As the flow is stationary, the composition of the reaction mixture does not change with time at a fixed reactor position. Thus, also time-consuming 2D NMR techniques can be applied to elucidate unknown products. As quantitative information is obtained directly from the NMR spectrum without calibration, the method is also appropriate for quantifying substances that are unstable as pure components. As test cases, two esterification reactions, the formation of methyl formate (MF) and the formation of methyl acetate (MA) from the pure alcohols and acids, were investigated using this technique. In addition, three 2D NMR pulse sequences (H-H-COSY, HETCOR, and HMBC) were applied in flow. The comparison of the results of the present work to literature data shows that the new method gives reliable results.

 

117. SQUID-based ultralow-field MRI of a hyperpolarized material using signal amplification by reversible exchange

Seong-Joo Lee, Keunhong Jeong, Jeong Hyun Shim, Hyun Joon Lee, Sein Min, Heelim Chae, Sung Keon Namgoong & Kiwoong Kim, Scientific Reports, (2019) DOI: 10.1038/s41598-019-48827-5

The signal amplification by reversible exchange (SABRE) technique is a very promising method for increasing magnetic resonance (MR) signals. SABRE can play a particularly large role in studies with a low or ultralow magnetic field because they suffer from a low signal-to-noise ratio. In this work, we conducted real-time superconducting quantum interference device (SQUID)-based nuclear magnetic resonance (NMR)/magnetic resonance imaging (MRI) studies in a microtesla-range magnetic field using the SABRE technique after designing a bubble-separated phantom. A maximum enhancement of 2658 for 1H was obtained for pyridine in the SABRE-NMR experiment. A clear SABRE-enhanced MR image of the bubble-separated phantom, in which the para-hydrogen gas was bubbling at only the margin, was successfully obtained at 34.3 μT. The results show that SABRE can be successfully incorporated into an ultralow-field MRI system, which enables new SQUID-based MRI applications. SABRE can shorten the MRI operation time by more than 6 orders of magnitude and establish a firm basis for future low-field MRI applications.

 

116. Lignin analysis with benchtop NMR spectroscopy

Jerk Rönnols, Ernesto Danieli, Hélène Freichels and Fredrik Aldaeus, Holzforschung, (2019) DOI: 10.1515/hf-2018-0282

Benchtop nuclear magnetic resonance (NMR) spectroscopy is an emerging field with an appealing profile for industrial applications. The instrumentation offers the possibility to measure NMR spectra in situations where high-field NMR spectroscopy is considered too expensive or complicated. In this study, we investigated the scope and limitations of 1H NMR measurements on kraft lignins and black liquors at low magnetic field strengths (1.0 and 1.5 T). The ability to quantify different classes of compounds was investigated and found to be promising. NMR-based diffusion measurements were performed, with the aim of gaining insight into the molar mass of the lignins at hand. These measurements were fast, repeatable and in good agreement with established methods.

 

115. Optimization of Ultrasound Assisted Extraction of Pectin from Custard Apple Peel: Potential and New Source

C.S. Shivamathi, I. Ganesh Moorthy, R. Vinoth Kumar, Michael, Rahul Soosai, J. Prakash Maran, R. Shyam Kumar, P. Varalakshmi, Carbohydrate Polymers, (2019) DOI: 10.1016/j.carbpol.2019.115240

Pectin was extracted from the waste custard apple peel using ultrasound technique and optimized the extraction process by RSM. The various significant process parameters such as liquid-solid ratio, ultra-sonication time, temperature and pH of solution were studied in the range of 10 – 25 mL g-1, 10 – 30 min, 50 – 80 °C, and 1 – 3, respectively. The maximum yield of pectin (8.93%) was attained at the optimum condition of 23.52 mL g-1 of liquid-solid ratio, 18.04 min of ultra-sonication time, 63.22 °C of temperature and 2.3 pH of solution. The extracted and commercially available fresh pectin (for comparison purposes) were characterized by various analytical techniques namely, FTIR, DSC, XRD, SEM, and NMR to evaluate their functional groups, thermal properties, crystallinities, morphological and structural characteristics, respectively. The extracted pectin was a toxic free compound as determined by its anti nutritional property study and about 20 mg/mL of antioxidant presented in it.

 

114. Benchtop flow NMR spectroscopy as an online device for the in vivo monitoring of lipid accumulation in microalgae

Dylan Bouillaud, Vladimir Heredia, Thomas Castaing-Cordier, Delphine Drouin, Benoît Charrier, Olivier Gonçalves, Jonathan Farjon, Patrick Giraudeau, Algal Research, (2019) DOI: 10.1016/j.algal.2019.101624

The sustainable production of lipids by microalgae is widely developed among the bioprocess community targeting various applications such as feed, food, health or bioenergy. The cultivation of microalgae needs dedicated systems with the optimal illumination geometry. Performing non-invasive online analyses on these bioprocesses is limited to few analytical techniques, often based on optical properties and can however rarely be related to intracellular products. The real-time knowledge of the lipids accumulation in microalgae is –in this case– not possible. In this article, the proof-of-concept that the recent benchtop NMR spectroscopy device can be used for the non-invasive and selective detection of lipids inside microalgae cells is carried out. Three cultures of Nannochloropsis gaditana were analyzed in flow conditions. The relative quantitative feature is confirmed by the correlation with a reference technique classically used for lipid analysis, i.e. the FAME (Fatty Acid Methyl Ester) profiling by gas chromatography.

 

113. Benchtop Flow-NMR for Rapid Online Monitoring of RAFT and Free Radical Polymerisation in Batch and Continuous Reactors

Stephen T. Knox, Sam Parkinson , Raphael Stone and Nicholas J. Warren, Polymer Chemistry, (2019) DOI: 10.1039/C9PY00982E

A “Benchtop” NMR spectrometer is used for detailed monitoring of controlled and free radical polymerisations performed in batch and continuous reactors both offline and in real-time. This allows detailed kinetic analysis with unprecedented temporal resolution for reactions which reach near completion in under five minutes.

 

112. Change of C(2)-Hydrogen–Deuterium Exchange in Mixtures of EMIMAc

Caroline Marks, Alexander Mitsos, Jörn Viell, Journal of Solution Chemistry, (2019) DOI: 10.1007/s10953-019-00899-7

1-Ethyl-3-methylimidazolium acetate (EMIMAc) is an ionic liquid (IL) often investigated as a solvent, especially in the context of biopolymers and biomass pretreatment. A reduced solvent efficacy occurs upon the addition even of low amounts of water to EMIMAc. Molecular mechanisms have not yet been fully understood. It is expected that the functionality as hydrogen bond donor and acceptor is key for the solvent–solute interactions. In this work, we analyze the solvent efficacy of EMIMAc in terms of hydrogen–deuterium (H/D) exchange at the C(2)-position in mixtures with water or acetic acid added as proton donors. Low-field NMR spectroscopy and deuterated solvents are used for a time-resolved evaluation of H/D exchange reactions. The H/D exchange is also modeled to explore changes in the reaction kinetics as a function of the mixture composition. The significant difference in calculated rate constant values among the concentration regimes shows that the chosen model equations of a possible pseudo-first-order and second-order reaction mechanism including water dissociation do not cover all interaction phenomena that influence the exchange in the individual concentration ranges. However, the modeling also indicates that the investigated interaction of EMIM+ and Ac remains constant for concentrated IL mixtures containing 70 mol% of EMIMAc in water up to diluted mixtures as low as 30 mol% EMIMAc. This exemplifies the change between ions strongly associated in networks in concentrated mixtures suitable for biomass pretreatment and the much less associated anion–cation pairs in diluted mixtures which leads to the decreased efficiency of EMIMAc with increasing water content.

 

111. Influence of time-temperature cycles on potato starch retrogradation in tuber and starch digestion in vitro

Yu-Fan Chen, Jaspreet Singh, Jocelyn Midgley, Richard Archer, Food Hydrocolloids, (2019) DOI: 10.1016/j.foodhyd.2019.105240

A long storage time (>7 days) is generally required for starch retrogradation sufficient to resist enyzmatic breakdown. To accelerate retrogradation in tuber to 3 days, two sets of time-temperature cycle processes were studied: cooked potato tubers were stored between (i) −20 °C and 4 °C, TTC1; and between (ii) 4 °C and 65 °C, TTC2 for 3 days. Relaxation times measured by LF NMR indicated that freeze-chill cycles led to the redistribution of water pools signifying the creation of starch-rich and starch-depleted (once ice) regions in tuber. Consistent with this, the TTC1 samples had higher retrogradation enthalpies than both TTC2 samples and 3-day chill retrograded samples which were never frozen. TTC-processed tubers subsequently exposed to digestive enzymes in vitro showed 60–67% starch hydrolysis, significantly lower than tubers retrograded for 3-days at 4 °C (72%) or freshly cooked tubers (87%). The residual enthalpies of digesta of TTC-processed tubers suggest the formation of slowly digestible starch.

 

110. Microstructure evolution during nano-emulsification by NMR and microscopy

Carmine D’Agostino, Valentina Preziosi, Abdulaziz Khan, Mick Mantle, Einar Fridjonsson, Stefano Guido, Journal of Colloid and Interface Science, (2019) DOI: 10.1016/j.jcis.2019.04.098

Diffusion coefficients of emulsions made of water, mineral oil and surfactants (Span 20 and Tween 80) were measured as a function of water composition and compared with the morphological features of the emulsions obtained by CLSM. In the absence of water, two phases are visible from CLSM, and two diffusion components are observed with PFG NMR, a major fast component attributed to a continuous oil phase containing the more hydrophobic surfactant Span 20 with traces of Tween 80, and a minor slow component attributed to a dispersed phase of the more hydrophilic surfactant Tween 80 with traces of mineral oil and Span 20. At the inversion point (25 wt% water) the two-component diffusion behavior of the oil-rich phase is drastically reversed in terms of populations, with the slow diffusion process becoming dominant. This suggests a significant structuring of the oil-rich phase in the presence of surfactants enhanced by water, which can be explained by the formation of aggregates in the oil phase as reverse micelles or of a lamellar structure, and ties in well with the rheological measurements.

 

109. Benchtop NMR Spectroscopy and Spectral Analysis of the cis– and trans-Stilbene Products of the Wittig Reaction

Mark Edgar, Benita C. Percival, Miles Gibson, Jinit Masania, Ken Beresford, Philippe B. Wilson and Martin Grootveld, Journal of Chemical Education, (2019) DOI: 10.1021/acs.jchemed.8b00657

It is demonstrated that a combination of spectral analysis and simulation at low-fields (40–80 MHz) allows the fine structure of second-order effects and overlapping spectra to be deduced, enabling an improved understanding of the low-field benchtop NMR technique within undergraduate student cohorts. The evolution of well-resolved and distinct multiplets at 400 MHz to complex, overlapping multiplets at 40–80 MHz also serves as a useful guide for laboratory demonstrators and academic staff when explaining the advantages of such benchtop systems. The Wittig reaction has been a standard reaction practical session in many university teaching laboratories since the 1980s, the products of which are a mixture of cis- and trans-stilbenes. This reaction serves as an ideal example of how benchtop NMR spectrometers and analysis can support chemistry teaching laboratories.

 

108. Reaction Monitoring Using SABRE-Hyperpolarized Benchtop (1 T) NMR Spectroscopy

Olga Semenova, Peter M. Richardson, Andrew J. Parrott, Alison Nordon, Meghan E. Halse, and Simon B. Duckett, Analytical Chemistry, (2019) DOI: 10.1021/acs.analchem.9b00729

The conversion of [IrCl(COD)(IMes)] (COD = cis,cis-1,5-cyclooctadiene, IMes = 1,3-bis(2,4,6-trimethyl-phenyl)imidazole-2-ylidene) in the presence of an excess of para-hydrogen (p-H2) and a substrate (4-aminopyridine (4-AP) or 4-methylpyridine (4-MP)) into [Ir(H)2(IMes)(substrate)3]Cl is monitored by 1H NMR spectroscopy using a benchtop (1 T) spectrometer in conjunction with the p-H2-based hyperpolarization technique signal amplification by reversible exchange (SABRE). A series of single-shot 1H NMR measurements are used to monitor the chemical changes that take place in solution through the lifetime of the hyperpolarized response. Non-hyperpolarized high-field 1H NMR control measurements were also undertaken to confirm that the observed time-dependent changes relate directly to the underlying chemical evolution. The formation of [Ir(H)2(IMes)(substrate)3]Cl is further linked to the hydrogen isotope exchange (HIE) reaction, which leads to the incorporation of deuterium into the ortho positions of 4-AP, where the source of deuterium is the solvent, methanol-d4. Comparable reaction monitoring results are achieved at both high-field (9.4 T) and low-field (1 T). It is notable that the low sensitivity of the benchtop (1 T) NMR enables the use of protio solvents, which when used here allows the effects of catalyst formation and substrate deuteration to be separated. Collectively, these methods illustrate how low-cost low-field NMR measurements provide unique insight into a complex catalytic process through a combination of hyperpolarization and relaxation data.

 

107. Assessment of 213Bi-anti-EGFR MAb treatment efficacy in malignant cancer cells with [1-13C]pyruvate and [18F]FDG

Benedikt Feuerecker, Michael Michalik, Christian Hundshammer, Markus Schwaiger, Frank Bruchertseifer, Alfred Morgenstern and Christof Seidl, Scientific Reports, (2019) DOI: 10.1038/s41598-019-44484-w

Evaluation of response to therapy is among the key objectives of oncology. A new method to evaluate this response includes magnetic resonance spectroscopy (MRS) with hyperpolarized 13C-labelled metabolites, which holds promise to provide new insights in terms of both therapeutic efficacy and tumor cell metabolism. Human EJ28Luc urothelial carcinoma and LN18 glioma cells were treated with lethal activity concentrations of a 213Bi-anti-EGFR immunoconjugate. Treatment efficacy was controlled via analysis of DNA double-strand breaks (immunofluorescence γH2AX staining) and clonogenic survival of cells. To investigate changes in metabolism of treated cells vs controls we analyzed conversion of hyperpolarized [1-13C]pyruvate to [1-13C]lactate via MRS as well as viability of cells, lactate formation and lactate dehydrogenase activity in the cellular supernatants and [18F]FDG uptake in treated cells vs controls, respectively. Lactate/pyruvate ratios of hyperpolarized [1-13C]pyruvate proved to detect early treatment response effects, holding promise for future clinical applications in early therapy monitoring.

 

106. On-line SEC-MR-NMR hyphenation: optimization of sensitivity and selectivity on a 62 MHz benchtop NMR spectrometer

Carlo Botha, Johannes Höpfner, Britta Mayerhöfer and Manfred Wilhelm, Polymer Chemistry, (2019) DOI: 10.1039/C9PY00140A

The development of sophisticated synthetic routes for polymeric materials and more complex formulations used in current products require more advanced analytical techniques. As simple 1D experiments do not suffice to provide the necessary information. The development of coupled techniques, especially liquid chromatography (LC) in conjunction with molecular spectroscopy, is one promising approach to fit these requirements. The focus of this article is the optimization of a medium resolution (MR), benchtop 1H-NMR spectrometer coupled to a SEC instrument, where the NMR acts as an on-line chemical selective detector. The approach is to retain typical SEC selectivity while obtaining NMR on-line data with the highest possible sensitivity through full optimization of the entire set-up, pulse sequence and numerical data evaluation. A detailed description will be provided on how each part has been improved, including instrumental demands e.g. custom designed flow cells. Application examples of a PS/PMMA blend and PS-b-PMMA block copolymer are given to illustrate the potential of the hyphenated technique and the necessity of optimization. It is shown that the MR-NMR can be successfully hyphenated to SEC as an information rich chemical detector, providing the average chemical composition (CC) as a function of molar mass distribution (MMD), for polymers at isocratic mobile phase conditions.

 

105. Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactions

Peter Sagmeister, Jason Douglas Williams, Christopher Hone and C. Oliver Kappe, Reaction Chemistry & Engineering, (2019) DOI: 10.1039/C9RE00087A

Currently, the monitoring of multistep continuous flow processes by multiple analytical sources is still seen as a resource intensive and specialized activity. In this article, the coupling of a modular microreactor platform with real-time monitoring by inline IR and NMR, in addition to online UPLC, is described. Using this platform, we rapidly generated experimental data (17 iterations in under 2 hours) to access information on the different chemical species at multiple points within the reactor and to generate process understanding. We highlight the application of the platform in the optimization of a multistep organolithium transformation. The optimized continuous flow conditions were demonstrated in a scale-out experiment with in-process monitoring to afford the desired product in 70% isolated yield and provided a throughput of 4.2 g h−1.

 

104. Polarization Transfer via Field Sweeping in Parahydrogen-Enhanced Nuclear Magnetic Resonance

James Eills, John W. Blanchard, Teng Wu, Christian Bengs, Julia Hollenbach, Dmitry Budker, Malcolm H. Levitt, JCP, (2019) DOI: 10.26434/chemrxiv.7946807

We show that in a spin system of two magnetically inequivalent protons coupled to a heteronucleus such as 13C, an adiabatic magnetic field sweep, passing through zero field, transfers proton singlet order into magnetization of the coupled heteronucleus. This effect is potentially useful in parahydrogen-enhanced nuclear magnetic resonance, and is demonstrated on singlet-hyperpolarized [1-13C]maleic acid, which is prepared via the reaction between [1-13C]acetylene dicarboxylic acid and para-enriched hydrogen gas. The magnetic field sweeps are of microtesla amplitudes, and have durations on the order of seconds. We show a polarization enhancement by a factor of 104 in the 13C spectra of [1-13C]maleic acid in a 1.4 T magnetic field.

 

103. On the reactivity of anodically generated trifluoromethyl radicals toward aryl alkynes in organic/aqueous media

Wolfgang Jud, C. Oliver Kappe and David Cantillo, Organic and Biomolecular Chemistry, (2019) DOI: 10.1039/c9ob00456d

An in-depth study of the reaction of electrochemically generated trifluoromethyl radicals with aryl alkynes in the presence of water is presented. The radicals are readily generated by anodic oxidation of sodium triflinate, an inexpensive and readily available CF3 source, with concomitant reduction of water. Two competitive pathways, i.e. aryl trifluoromethylation vs. oxytrifluoromethylation of the alkyne, which ultimately lead to the generation of α-trifluoromethyl ketones, have been observed. The influence of several reaction parameters on the reaction selectivity, including solvent effects, electrode materials and substitution patterns on the aromatic ring of the substrate, has been investigated. A mechanistic rationale for the generation α-trifluoromethyl ketones based on cyclic voltammetry data and radical trapping experiments is also presented. DFT calculations carried out at the M06-2X/6-311+G(d,p) level on the two competing pathways account for the observed selectivity.

 

102. Flexible automation with compact NMR spectroscopy for continuous production of pharmaceuticals

Simon Kern, Lukas Wander, Klas Meyer, Svetlana Guhl, Anwesh Reddy Gottu Mukkula, Manuel Holtkamp, Malte Salge, Christoph Fleischer, Nils Weber, Rudibert King, Sebastian Engell, Andrea Paul, Manuel Pereira Remelhe, Michael Maiwald, Analytical and Bioanalytical Chemistry, (2019) DOI: 10.1007/s00216-019-01752-y

Modular plants using intensified continuous processes represent an appealing concept for the production of pharmaceuticals. It can improve quality, safety, sustainability, and profitability compared to batch processes; besides, it enables plug-and-produce reconfiguration for fast product changes. To facilitate this flexibility by real-time quality control, we developed a solution that can be adapted quickly to new processes and is based on a compact nuclear magnetic resonance (NMR) spectrometer. The NMR sensor is a benchtop device enhanced to the requirements of automated chemical production including robust evaluation of sensor data. Beyond monitoring the product quality, online NMR data was used in a new iterative optimization approach to maximize the plant profit and served as a reliable reference for the calibration of a near-infrared (NIR) spectrometer. The overall approach was demonstrated on a commercial-scale pilot plant using a metal-organic reaction with pharmaceutical relevance.

 

101. Hyperpolarised 1H-13C benchtop NMR spectroscopy

Alastair D. Robinson, Peter M. Richardson and Meghan E. Halse, Applied Sciences, (2019) Web: http://eprints.whiterose.ac.uk/143732/

Benchtop NMR spectrometers with sub-ppm spectral resolution have opened up new opportunities for performing NMR outside of the standard laboratory environment. However, the relatively weak magnetic fields of these devices (1 – 2 T) results in low sensitivity and significant peak overlap in 1H NMR spectra. Here we use hyperpolarised 13C{1H} NMR to overcome these challenges. Specifically, we demonstrate the use of the signal amplification by reversible exchange (SABRE) parahydrogen-based hyperpolarisation technique to enhance the sensitivity of natural abundance 1D and 2D 13C{1H} benchtop NMR spectra. We compare two detection methods for SABRE-enhanced 13C NMR and observe an optimal 13C{1H} signal-to-noise ratio (SNR) for a refocused INEPT approach, where hyperpolarisation is transferred from 1H to 13C. In addition, we exemplify SABRE-enhanced 2D 13C benchtop NMR through the acquisition of a 2D HETCOR spectrum of 260 mM of 4-methylpyridine at natural isotopic abundance in a total experiment time of 69 mins. In theory, signal averaging for over 300 days would be required to achieve a comparable SNR for a thermally polarised benchtop NMR spectrum acquired of a sample of the same concentration at natural abundance.

 

100. Monitoring Hydrogenation Reactions using Benchtop 2D NMR with Extraordinary Sensitivity and Spectral Resolution

Dariusz Gołowicz, Krzysztof Kazimierczuk, Mateusz Urbańczyk, Tomasz Ratajczyk, ChemistryOpen, (2019) DOI: 10.1002/open.201800294

Low‐field benchtop nuclear magnetic resonance (BT‐NMR) spectrometers with Halbach magnets are being increasingly used in science and industry as cost‐efficient tools for the monitoring of chemical reactions, including hydrogenation. However, their use of low‐field magnets limits both resolution and sensitivity. In this paper, we show that it is possible to alleviate these two problems through the combination of parahydrogen‐induced polarization (PHIP) and fast correlation spectroscopy with time‐resolved non‐uniform sampling (TR‐NUS). PHIP can enhance NMR signals so that substrates are easily detectable on BT‐NMR spectrometers. The interleaved acquisition of one‐ and two‐dimensional spectra with TR‐NUS provides unique insight into the consecutive moments of hydrogenation reactions, with a spectral resolution unachievable in a standard approach. We illustrate the potential of the technique with two examples: the hydrogenation of ethylphenyl propiolate and the hydrogenation of a mixture of two substrates – ethylphenyl propiolate and ethyl 2‐butynoate.

 

99. Synthesis of α‐Fluoro‐α,β‐unsaturated esters monitored by 1D and 2D benchtop NMR Spectroscopy

Dennis Weidener, Kawarpal Singh and Bernhard Blümich, Magnetic Resonance in Chemistry, (2019) DOI: 10.1002/mrc.4843

This present study explores the use of a robust and compact NMR spectrometer to monitor the stereo‐selective formation of α‐fluoro‐α,β‐unsaturated esters from α‐fluoro‐β‐keto esters via deprotonation and deacylation in real‐time. These compounds are precursors of various pharmaceutically active substances. The real‐time study revealed the deprotonation and deacylation steps of the reaction. The reaction was studied at temperatures ranging from 293 to 333 K by interleaved 1D 1H, 19F and 2D 1H‐1H COSY experiments. The kinetic rate constants were evaluated using a pseudo‐first order kinetic model. The activation energies for the deprotonation and deacylation steps were determined to (‐28 ± 2) and (63.5 ± 8) kJ/mol, respectively. This showed that the deprotonation step is fast compared to the deacylation step and that the deacylation step determines the rate of the overall reaction. The reaction was repeated three times at 293 K to monitor the repeatability and stability of the system. The compact NMR spectrometer provided detailed information on the mechanism and kinetics of the reaction which is essential for optimizing the synthetic routes for stepwise syntheses of pharmaceutically active substances.

 

98. Benchtop NMR for the monitoring of bioprocesses

Dylan Bouillaud, Jonathan Farjon, Olivier Gonçalves, Patrick Giraudeau, Magnetic Resonance in Chemistry, (2019) DOI: 10.1002/mrc.4821

This minireview focuses on the usefulness of benchtop nuclear magnetic resonance (NMR) for the monitoring of bioprocesses, highlighting new perspectives opened by the reduced size of devices in relaxometry, magnetic resonance imaging, and NMR spectroscopy. Using benchtop NMR in bioprocesses is not exempt of limitations—especially the loss of sensitivity and resolution arising from the use of a low magnetic field—and which are even further exacerbated by the sample complexity. Still, several studies have shown the efficiency of benchtop NMR in being a noninvasive probe to monitor the evolution of biological samples. If benchtop relaxometry and imaging have been developed for decades and have shown their capacity in monitoring such processes, the more recent emergence of the benchtop NMR spectroscopy gives a breath of fresh air for many applications and benefits from recent research led by spectroscopy specialists, which are adapted on these new devices, from nonconventional pulse sequences to advanced data processing. There is no doubt that these recent devices are powerful tools that will open numerous perspectives for the real‐time study of bioprocesses in the coming years.

 

97. Highly resolved Pure-Shift spectra on a compact NMR Spectrometer

Thomas Castaing-Cordier, Dylan Bouillaud, Paul Bowyer, Olivier Gonçalves, Patrick Giraudeau, and Jonathan Farjon, ChemPhysChem, (2019) DOI: 10.1002/cphc.201801116

Benchtop NMR spectrometers experience a great success for a wide range of applications. However, their performance is highly limited by peak overlaps. Emerging “pure‐shift NMR” (PS NMR) methods have been intensively used at high‐field to enhance the resolution by homodecoupling strategies. Here, different PS methods have been implemented on a compact NMR spectrometer operating at 43 MHz. Among the PS methods, the recent PSYCHE scheme appears more sensitive than Zangger‐Sterk (ZS) experiments and offers a substantial resolution improvement as compared to 1D 1H. On the other hand, despite their slightly lower sensitivity, ZS methods are more efficient to reduce broad signals and are more immune to strong couplings. Finally, the classical J‐resolved pulse sequence is more efficient to reduce larger signals for bigger‐sized molecules. The three approaches appear relevant for benchtop NMR and their combination forms an efficient toolbox to analyze a great diversity of samples.

 

96. Analytical evaluation of low-field 31P NMR spectroscopy for lipid analysis

Boris Gouilleux, Nichlas Vous Christensen, Kirsten Gade Malmos, and Thomas Vosegaard, Analytical Chemistry, (2019) DOI: 10.1021/acs.analchem.8b05416

We investigate the potential of 31P NMR with simple, maintenance-free benchtop spectrometers to probe phospholipids in complex mixtures. 31P NMR-based lipidomics has become an important topic in a wide range of applications in food- and health-sciences, and the continuous improvements of compact, maintenance- and cryogen-free instruments opens news opportunities for NMR routine analyses. A prior milestone is the evaluation of the analytical performance provided by 31P NMR at low magnetic field. To address this, we assess the ability of state-of-the-art benchtop NMR spectrometers to detect, identify and quantify several types of phospholipids in mixtures. Relying on heteronuclear cross-polarization experiments, phospholipids can be detected in 2 h with a limit of detection of 0.5 mM at 1 T and 0.2 mM at 2 T, while the headgroups of PC, PE, PI, PS and PG can be unambiguously assigned based on 2D 1H-31P TOCSY spectra. Furthermore, two quantitative methods to obtain absolute concentrations are proposed and discussed, and the performance is evaluated regarding precision and accuracy.

 

95. Monitoring the mechanism and kinetics of a transesterification reaction for the biodiesel production with low field 1H NMR spectroscopy

Kawarpal Singh, Sharoff Pon Kumar, Bernhard Blümich, Fuel, (2019) DOI: 10.1016/j.fuel.2019.01.084

The present work reports the use of desktop NMR spectroscopy for a real-time study of the transesterification of triglycerides (vegetable oil) with methanol for formation of methyl esters (biodiesel) to detail catalytic activity, reaction mechanism and kinetics. The reaction was investigated for different catalyst concentrations, different molar ratios of reactants, and different temperatures. The changes in the chemical shift of the hydroxyl protons in the reaction mixture resulting from changing catalyst concentration and temperature provide information about the role of the catalyst in the aqueous and organic phases. The reaction was determined to be mass transfer controlled in the initial stage and kinetically controlled at later stage depending upon the reaction conditions. Analysis of the reaction for different molar ratios of oil and biodiesel and for increasing methanol concentration suggests the formation of dimers. The time variation of the methyl ester (bio-diesel) concentration was determined by partial least squares regression (PLS-R) using high-field NMR spectroscopy as reference. To obtain rate constants for each reaction the kinetics were modeled assuming fatty acid methyl esters as major product, and mono and diglycerides as intermediates. The 95% confidence intervals were derived by a Monte-Carlo analysis. The reaction kinetics are compared to those obtained by peak fitting of low-field spectra.

 

94. Differentiation of fentanyl analogues by low-field NMR spectroscopy

Jonathan Duffy, Aaron Urbas, Matthias Niemitz, Katrice Lippa, Ioan Marginean, Analytica Chimica Acta, (2019) DOI: 10.1016/j.aca.2018.12.014

Forensic laboratories commonly receive new psychoactive substances such as fentanyl analogues and other synthetic opioids that are difficult to identify. Slight changes to chemical structures, e.g. shifting the position of functional groups such as methyl groups or halogens on the aromatic ring, may not be distinguished using traditional methods. NMR is a powerful tool used to elucidate distinctive structural information needed to differentiate regioisomers. However, the cost, size, and cryogen maintenance of superconducting NMR spectrometers can be impractical for some forensic laboratories. Recent studies have shown potential applications of low-field NMR as an alternative in forensic drug analysis. These benchtop, semi-portable instruments are less costly, have a smaller footprint, do not use cryogens, and require little maintenance. In this study, we show that 65 fentanyl and related substances, including various types of positional isomers, were readily differentiated using low-field (62 MHz) 1H NMR spectroscopy. In addition, the use of quantum mechanical spin system analysis was investigated for the purposes of translating experimentally observed high-field 1H spectra to lower field strengths. Spin system analysis of 600 MHz NMR spectra was conducted on a subset (15) of the reference materials analyzed. The results were used to calculate 62 MHz spectra for comparison purposes with the experimental spectra. This was successfully demonstrated, showing that field-strength independent 1H NMR spectral libraries are feasible and can facilitate reference material data dissemination across forensic drug laboratories.

 

93. Carboxylic acids production via electrochemical depolymerization of lignin

Davide Di Marino, Tim Jestel, Caroline Marks, Jörn Viell, Malte Blindert, Stefanie M.A. Kriescher, Antje C. Spiess, Matthias Wessling, ChemElectroChem, (2018) DOI: 10.1002/celc.201801676

Facing the challenge of lignin valorization is one of the unsolved key‐steps for a sustainable and economically feasible biorefinery. Several processes were developed with the aim of producing value‐added compounds from lignin. Thermal, enzymatic and catalytic processes represent common techniques for lignin valorization. However, expensive catalysts or enzymes and harsh conditions hampered the implementation of these methodologies on an industrial scale. Here, we propose the utilization of a simple “swiss‐roll” electrochemical reactor for the production of valuable carboxylic acids. We showcase that production of phenolic compounds, such as vanillin, is hindered by the electrochemical mechanism. Additionally, electrochemical stability experiments of possible products showed high reactivity of vanillin against the low reactivity of mono‐ and dicarboxylic acids. Simultaneously, the electrochemical process leads to stable carboxylic acids with high yields of 6.4, 26.8 and 4.2% for oxalic, formic and acetic acids respectively, therefore representing a competitive alternative to catalytic and hydrothermal degradation process for the production of carboxylic acids.

 

92. Flow reactors integrated with in-line monitoring using benchtop NMR spectroscopy

Patrick Giraudeau and François-Xavier Felpin, Reaction Chemistry & Engineering, (2018) DOI: 10.1039/10.1039/c8re00083b

The monitoring of chemical reactions on the fly conducted in flow through the use of benchtop NMR spectroscopy is an emerging field of research allowing tremendous perspectives. In-line benchtop NMR enables diversified structural and quantitative data on the chemical composition to be obtained and determination of reaction conversions, kinetics and mechanisms. This review provides an overview of the state-of-the-art of flow reactors integrating in-line monitoring with benchtop NMR spectrometers. A brief discussion on the main characteristics of benchtop NMR and associated recent technological developments is provided in the section after the Introduction.

 

91. Solvent-free organocatalytic preparation of cyclic organic carbonates under scalable continuous flow conditions

Zhiguo Wang, Romaric Gérardy, Guillaume Gauron, Christian Damblon and Jean-Christophe M. Monbaliu, Reaction Chemistry & Engineering, (2018) DOI: 10.1039/C8RE00209F

A solvent-free organocatalyzed process for the transesterification of dimethyl carbonate (DMC) with 1,2-diols under scalable continuous flow conditions is presented. Process parameters, such as temperature, residence time, DMC/glycerol molar ratio and catalyst loading are optimized for the carbonation of bio-based glycerol using 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as a model organocatalyst. The catalytic performance of DBU is next compared with other homogeneous organic superbases including the proton sponge, Verkade’s base, guanidines and phosphazenes. 2-tert-Butyl-1,1,3,3-tetramethylguanidine (Barton’s base) stands as the most efficient organocatalyst, providing glycerol carbonate at 87% selectivity and 94% conversion within 2 minutes of residence time at 1 mol% loading. Representative examples of polystyrene-supported (PS) organic superbases of the amidine, guanidine and phosphazene-types are also considered as alternative heterogeneous catalysts. PS superbases typically enable up to 80 h of continuous operation with minor deactivation at elevated flow rates. The methodology is amenable to a library of other 1,2-diols, including biomass-derived substrates. Depending on the unique structural features of both substrates and products, either on-line IR or on-line NMR analytical procedures are implemented for real-time qualitative reaction monitoring. A final demonstrator showcases the transposition of the glycerol carbonation to a pilot-scale continuous flow reactor, affording the target cyclic carbonate with a 68.3 mol per day productivity (8 kg per day).

 

90. A Field-invariant Method for Quantitative Analysis with Benchtop NMR

Yevgen Matviychuk, Jet Yeo, Daniel J. Holland, Journal of Magnetic Resonance, (2018) DOI: 10.1016/j.jmr.2018.11.010

Recently developed benchtop instruments have the potential of bringing the benefits of NMR spectroscopy to the wide variety of industrial applications. Unfortunately, their low spectral resolution poses significant challenges for traditional quantification approach. Here we present a novel model-based method designed to overcome these challenges. By defining our models in terms of quantum mechanical properties of the underlying spin system, we make our approach invariant to the spectrometer field strength and especially suitable for analyzing benchtop data. Our experimental results on prepared samples and natural fruit juices confirm the applicability of our method for quantitative analysis of medium-field NMR spectra. The developed method succeeds in accurately separating the spectra of glucose anomers and even monitoring their interconversion in non-deuterated water. Furthermore, the compositions of unbuffered natural fruit juices estimated using data from 43 MHz and 400 MHz spectrometers are in good agreement with each other and with the reference values from nutrition databases.

 

89. Variable magnet arrays to passively shim compact permanent-yoke magnets

Till Überrück and Bernhard Blümich, Journal of Magnetic Resonance, (2018) DOI: 10.1016/j.jmr.2018.11.011

C-shaped permanent magnets offer a compromise between sample accessability and field strength as well as homogeneity compared to single-sided devices or Halbach arrays. A new approach to passively shim C-shaped dipole magnets is presented. It relies on the magnet poles being constructed from a set of adjustable magnet elements. Two pole concepts are introduced, which allow the correction of the field profile and passively shim the magnet without the need of additonal pole shoes or shim pieces.

 

88. Scalability of Visible Light Induced Nickel Negishi Reactions: A Combination of Flow Photochemistry, use of Solid Reagents and in-line NMR Monitoring

Irini Abdiaj, Clemens R. Horn, and Jesus Alcazar, The Journal of Organic Chemistry, (2018) DOI: 10.1021/acs.joc.8b02358

The scale up of light induced nickel catalyzed Negishi reactions is reported herein, with output rates reaching multigram quantities per hour. This level of throughput is suitable to support preclinical medicinal chemistry programs in late lead optimization, where tens of grams to hundreds of grams of final product is needed. Adjusting reaction times and concentrations was critical in achieving this robust output. This example demonstrates how visible photochemistry and use of solid metal reagent can be used, and how the progress of the reaction can be followed by in-line NMR monitoring.

 

87. Low Field, Benchtop NMR Spectroscopy as a Potential Tool for Point-of-Care Diagnostics of Metabolic Conditions: Validation and Protocols

Benita Percival, Yasan Osman, Martin Grootveld, Miles Gibson, Marco Molinari, Fereshteh Jafari, Mark Martin, Federico Casanova, Melissa Mather, Mark Edgar, Philippe Wilson, Preprints, (2018) DOI: 10.20944/preprints201810.0089.v1

Novel sensing technologies for liquid biopsies offer a promising prospect for the early detection of metabolic conditions through -omics techniques. Indeed, high-field NMR facilities are routinely used for metabolomics investigations on a range of biofluids in order to rapidly recognize unusual metabolic patterns in patients suffering from a range of diseases. However, these techniques are restricted by the prohibitively large size and cost of such facilities, suggesting a possible role for smaller, low-field NMR instruments in biofluid analysis. Herein we describe selected biomolecule validation on a low-field benchtop NMR spectrometer (60 MHz), and present an associated protocol for the analysis of biofluids on compact NMR instruments. We successfully detect common markers of diabetic control at low-to-medium concentrations through optimized experiments, including glucose (≤ 2.6 mmol./L) and acetone (25 μmol./L), and additionally in readily-accessible biofluids. We present a combined protocol for the analysis of these biofluids with low-field NMR spectrometers for metabolomics, and offer a perspective on the future of this technique appealing to point-of-care applications.

 

86. Dynamics of ionic liquids in poly(vinyl alcohol) porous scaffold. Low field NMR study

Carlos Mattea, Bulat Gizatullin, Siegfried Stapf, Magnetic Resonance Imaging, (2018) DOI: 10.1016/j.mri.2018.09.032

In this study molecular dynamics of ionic liquids in poly(vinyl alcohol) scaffolds were investigated. The binary poly(vinyl alcohol) – ionic liquid (PVA-IL) compound was prepared from initial solutions of water, ionic liquid (IL) and poly(vinyl alcohol) (PVA) at different concentrations. Subsequently water was evaporated under open conditions, leaving the scaffold/IL system of interest. Low field nuclear magnetic resonance (NMR) relaxation and diffusion measurements, as well as 2D T1T2 correlated NMR experiments were performed to determine specific local and translational dynamics properties at different time scales. Data suggest that during water evaporation, partial demixing of IL from the polymeric matrix leaves the remaining solvent confined in the porous structure formed by the PVA polymer. The results show that the translational diffusion, as well as the local rotational molecular dynamics is comparable to the bulk liquid state. Moreover, in partial saturation conditions, diffusion shows enhancements relative to the bulk.

 

85. Evaluation of benchtop NMR Diffusion Ordered Spectroscopy for small molecule mixture analysis

Evan R. McCarney, Robin Dykstra, Petrik Galvosas, Magnetic Resonance Imaging, (2018) DOI: 10.1016/j.mri.2018.09.033

Diffusion Ordered Spectroscopy (DOSY) is an attractive method for analyzing chemical mixtures in the liquid state because it separates spectra by the molecular weight of the associated molecule. It has been compared with hyphenated chromatographic and analytical methods such LC-MS and has broad potential in servicing those same applications including forensics, reaction analysis, quality control, and fraud detection. Benchtop NMR can collect quality spectra on small molecules, however, lacks the chemical shift dispersion of high field instruments, can suffer from spectral overlap common in mixtures, and the diminished sensitivity of the lower field compounds these problems. In this work, we show that existing high field pulse sequences and processing methods perform well at 43 MHz. Spectra from molecular mixtures where the constituents had 20% differences in diffusion coefficients and significant overlap were able to be matched to a bespoke spectral library and identified correctly. In addition, spectra from mixtures with constituents that have severe overlap in the spectrum and differ by 50% in diffusion coefficients were also able to be match and identified correctly. The combination of benchtop NMR and easy implementation of modern pulse sequences and processing show promise of bringing these useful methods to chemistry laboratories in research and industrial environments.

 

84. Non-destructive analysis of polymers and polymer-based materials by compact NMR

Alina Adams, Magnetic Resonance Imaging, (2018) DOI: 10.1016/j.mri.2018.09.015

Low-field nuclear magnetic resonance (NMR) based on permanent magnet technologies is currently experiencing a considerable growth of popularity in studying polymer materials. Various bulk properties can be probed with compact NMR tabletop instruments by placing the sample of interest inside the magnet. Contrary to this, compact NMR sensors with open geometries give access to depth-dependent properties of polymer samples and objects of different sizes and shapes truly non-destructively by performing measurements in the inhomogeneous stray-field outside the magnet system. Some of the sensors are also portable being thus well suited for onsite measurements. The gain of both bulk and depth-dependent microscopic properties are important for establishing improved structure-property relationships needed for the rational design of new polymer formulations. Selected recent applications will be presented to illustrate this potential of compact NMR.

 

83. Overhauser DNP FFC study of block copolymer diluted solution

Bulat Gizatullin, Carlos Mattea, Siegfried Stapf, Magnetic Resonance Imaging, (2018) DOI: 10.1016/j.mri.2018.09.005

Overhauser dynamic nuclear polarization (DNP) is the dominating hyperpolarization technique to increasing the nuclear magnetic resonance signal in liquids and diluted systems. The enhancement obtained depends on the overall mobility of the radical-carrying molecule but also on its specific interaction with the host molecules. Information about the nature of molecular and radical dynamics can be identified from determining the nuclear T1 as a function of Larmor frequency by Fast Field Cycling (FFC) relaxometry. In this work, DNP and FFC methods were combined for a detailed study of 1H Overhauser DNP enhancements at 340 mT (X-band) and 73 mT (S-band) for diluted solutions of a block-copolymer with and without the addition of TEMPO radicals. NMR relaxation dispersions of these solutions are measured at thermal polarization and DNP conditions in the X-band, and the obtained DNP data were analyzed by a model of electron-nucleus interactions modulated by translational diffusion. The coupling factors for the two different blocks of the copolymer are obtained independently from DNP and NMRD experiments. An additional contribution from scalar interactions was found for polystyrene blocks.

 

82. An Autonomous Self-Optimizing Flow Reactor for the Synthesis of Natural Product Carpanone

Daniel Cortés-Borda, Eric Wimmer, Boris Gouilleux, Elvina Barré, Nicolas Oger, Lubna Goulamaly, Louis Peault, Benoît Charrier, Charlotte Truchet, Patrick Giraudeau, Mireia Rodriguez-Zubiri, Erwan Le Grognec, and François-Xavier Felpin, The Journal of Organic Chemistry, (2018) DOI: 10.1021/acs.joc.8b01821

A modular autonomous flow reactor combining monitoring technologies with a feedback algorithm is presented for the synthesis of natural product carpanone. The autonomous self-optimizing system, controlled via MATLAB®, was designed as a flexible platform enabling an adaptation of the experimental setup to the specificity of the chemical transformation to be optimized. The reaction monitoring uses either on-line high pressure liquid chromatography (HPLC) or in-line benchtop nuclear magnetic resonance (NMR) spectroscopy. The custom-made optimization algorithm derived from the Nelder-Mead and golden section search methods performs constrained optimizations of black-box functions in a multi-dimensional search domain, thereby, assuming no a priori knowledge of the chemical reactions. This autonomous self-optimizing system allowed fast and efficient optimizations of the chemical steps leading to carpanone. This contribution is the first example of a multi-step synthesis optimized with an autonomous flow reactor.

 

81. Ion Transport Properties and Ionicity of 1,3-Dimethyl-1,2,3-Triazolium Salts with Fluorinated Anions

Pulst M, Golitsyn Y, Reichert D, Kressler J, Materials, (2018) DOI: 10.3390/ma11091723

1,2,3-Triazolium salts are an important class of materials with a plethora of sophisticated applications. A series of three novel 1,3-dimethyl-1,2,3-triazolium salts with fluorine, containing anions of various size, is synthesized by methylation of 1,2,3-triazole. Their ion conductivity is measured by impedance spectroscopy, and the corresponding ionicities are determined by diffusion coefficients obtained from 400 MHz 1H and 19F pulsed field gradient nuclear magnetic resonance (PFG NMR) spectroscopy data, revealing that the anion strongly influences their ion conductive properties. Since the molar ion conductivities and ionicities of the 1,3-dimethyl-1,2,3-triazolium salts are enhanced in comparison to other 1,2,3-triazolium salts with longer alkyl substituents, they are promising candidates for applications as electrolytes in electrochemical devices. A Magritek Spinsolve 43 MHz benchtop NMR spectrometer was used to confirm the structure and purity of the newly synthesized triazolium salts.

 

80. Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized 13C-MRSI

Hundshammer C, Braeuer M, Müller CA, Hansen AE, Schillmaier M, Düwel S, Feuerecker B, Glaser SJ, Haase A, Weichert W, Steiger K, Cabello J, Schilling F, Hövener JB, Kjær A, Nekolla SG, Schwaiger M, Theranostics, (2018) DOI: 10.7150/thno.25162

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information.

 

79. Quantification of Ammonium Phosphatide Emulsifiers in Chocolate Using 31P NMR Spectroscopy

Kirsten Gade Malmos, Boris Gouilleux, Patrick Sønderskov, Tommy Andersen, Jens Viggo Frambøl, and Thomas Vosegaard, Journal of Agricultural and Food Chemistry, (2018) DOI: 10.1021/acs.jafc.8b04379

31P NMR is a valuable tool to study phosphorus-containing biomolecules from complex mixtures. One important group of such molecules are phosphorus-containing emulsifiers including lecithins and ammonium phosphatides (AMPs), which are used in chocolate production. By developing extraction protocols and applying high resolution 31P nuclear magnetic resonance (NMR), we enable identification of the type of emulsifier used in chocolate. We furthermore demonstrate that this method allows quantification of AMPs in chocolate. To our knowledge, this is the first method that allows verification of the type and amount of emulsifier present in chocolate samples.

 

78. Online monitoring of the kinetic isotope effect in chemical reactions with 1H and 19F low-field NMR spectroscopy

Kawarpal Singh, Bernhard Blümich, Analyst, (2018) DOI: 10.1039/C8AN01028E

The kinetic isotope effect (KIE) describes the change in the rate of a chemical reaction by substituting one of the atoms in the reactants with one of its isotopes. Investigating the KIE and its temperature dependency in reactions renders information for reconstructing chemical processes and confirming the rate-determining step. However, conventional methods to study the KIE, e.g. by calorimetry, conductivity, titration, Raman spectroscopy etc., require calibration and sophisticated handling of the reaction calorimeter, and the data are obtained at irregular and sparse intervals. This current study employs a compact NMR system as an alternative means to determine the temperature dependency of the reaction rate and, thus, the KIE, as well as the activation energy, enthalpy, and entropy of each reaction. Here the neutral hydrolysis of acetic anhydride and ethyl trifluoroacetate was studied in H2O, D2O and H2O-D2O mixtures with 1H and 1H-19F NMR spectroscopy. The activation energies for the hydrolysis of acetic anhydride with D2O and H2O were found to be 45 ± 2 kJ/mol and 40 ± 2 kJ/mol, respectively. The activation energies of ethyl trifluoroacetate hydrolysis via 19F NMR spectroscopy were determined to 46.7 ± 1 kJ/mol and 54.9 ± 1 kJ/mol for the reaction with H2O and D2O, respectively, and via 1H NMR spectroscopy to 48 ± 3 kJ/mol and 55.8 ± 1 kJ/mol. The differences in rate constants and activation energies for both reactions in H2O and D2O are due to the kinetic isotope effect, involving the breakage and formation of O-H and O-D bond during the rate-determining step. The proton inventory studies were performed for both the reactions for determining the isotopic fractionation factors for the given transition states of the reactions which help to predict the reaction mechanisms of other similar reactions. The compact NMR system is a relevant and practical tool to unmask precise reaction pathways, by tracing the KIE in real time with densely sampled data, which are essential for obtaining accurate rate constants.

 

77. Monitoring of Hydrogenation by Benchtop NMR with Parahydrogen‐Induced Polarization

Keunhong Jeong, Sein Min, Heelim Chae, Sung Keon Namgoong, Magnetic Resonance in Chemistry, (2018) DOI: 10.1002/mrc.4791

Reaction monitoring using nuclear magnetic resonance (NMR) spectroscopy is a powerful tool that provides detailed information on the characteristics and mechanism of the reaction. Although high‐field NMR provides more accurate and abundant data, which can be explained in terms of Boltzmann factors, benchtop NMR is commonly used because of its low cost and simple maintenance. Therefore, hyperpolarization of the sample in benchtop NMR is a suitable protocol for real‐time reaction monitoring. Herein, the principle‐based experimental setup, integrating the reaction monitoring system in a 60‐MHz benchtop NMR instrument with a parahydrogen‐induced polarization (PHIP) system, is used. Enhanced signals by the ALTADENA mechanism were obtained after PHIP on styrene, and reasonable kinetic data were collected, supporting the known reactivity of Wilkinson’s catalyst. These results should provide a foundation for future applications of NMR‐based reaction monitoring systems utilizing hyperpolarization.

 

76. Quantitative in-situ monitoring of parahydrogen fraction using Raman spectroscopy

Parrott, AJ, Dallin, P, Andrews, J, Richardson, PM, Semenova, O, Halse, ME, Duckett, SB and Nordon, A, Applied Spectroscopy, (2018) Link: http://eprints.whiterose.ac.uk/134335/

Raman spectroscopy has been used to provide a rapid, non-invasive and non-destructive quantification method for determining the parahydrogen fraction of hydrogen gas. The basis of the method is the measurement of the ratio of the first two rotational bands of hydrogen at 355 cm−1 and 586 cm−1 corresponding to parahydrogen and orthohydrogen, respectively. The method has been used to determine the parahydrogen content during a production process and a reaction. In the first example, the performance of an in-house liquid nitrogen cooled parahydrogen generator was monitored both at-line and on-line. The Raman measurements showed that it took several hours for the generator to reach steady state and hence, for maximum parahydrogen production (50 %) to be reached. The results obtained using Raman spectroscopy were compared to those obtained by at-line low-field NMR spectroscopy. While the results were in good agreement, Raman analysis has several advantages over NMR for this application. The Raman method does not require a reference sample, as both spin isomers (ortho and para) of hydrogen can be directly detected, which simplifies the procedure and eliminates some sources of error. In the second example, the method was used to monitor the fast conversion of parahydrogen to orthohydrogen in-situ. Here the ability to acquire Raman spectra every 30 s enabled a conversion process with a rate constant of 27.4 × 10−1 s−1 to be monitored. The Raman method described here represents an improvement on previously reported work, in that it can be easily applied on-line and is approximately 500 times faster. This offers the potential of an industrially compatible method for determining parahydrogen content in applications that require the storage and usage of hydrogen.

 

75. Diffusion-ordered spectroscopy on a benchtop spectrometer for drug analysis

Gaëtan Assemat, Boris Gouilleux, Dylan Bouillaud, Jonathan Farjon, Véronique Gilard, Patrick Giraudeau, Myriam Malet-Martino, Journal of Pharmaceutical and Biomedical Analysis, (2018) DOI: 10.1016/j.jpba.2018.08.011

The first reported two-dimensional diffusion-ordered spectroscopy (DOSY) experiments were recorded at low field (LF) on a benchtop NMR spectrometer using the BPP-STE-LED (bipolar pulse pair-stimulated echo sequence with a longitudinal eddy current delay) pulse sequence which limits phase anomalies and baseline discrepancies. A LF DOSY map was first obtained from a solution of a model pharmaceutical formulation containing a macromolecule and an active pharmaceutical ingredient. It revealed a clear separation between the components of the mixture and gave apparent diffusion coefficients (ADC) values consistent with those measured from the reference high field experiment. LF DOSY was then applied to a real esomeprazole medicine and several gradient sampling schemes (linear, exponential and semi-gaussian (SG)) were compared. With a pulsed field gradient range of 4–70%, the most reliable results were given by the SG ramp. The resulting LF DOSY map obtained after 2.84 h of acquisition confirmed that the diffusion dimension is of prime interest to facilitate the assignment of overcrowded LF spectra although relevant ADC values could not be obtained in part of the spectrum with highly overlapped signals.

 

74. A non-synthetic approach to extending the lifetime of hyperpolarized molecules using D2O solvation

Andrew Cho, Roozbeh Eskandari, Vesselin Z. Miloushev, Kayvan R. Keshari, Journal of Magnetic Resonance, (2018) DOI: 10.1016/10.1016/j.jmr.2018.08.001

Although dissolution dynamic nuclear polarization is a robust technique to significantly increase magnetic resonance signal, the short T1 relaxation time of most 13C-nuclei limits the timescale of hyperpolarized experiments. To address this issue, we have characterized a non-synthetic approach to extend the hyperpolarized lifetime of 13C-nuclei in close proximity to solvent-exchangeable protons. Protons exhibit stronger dipolar relaxation than deuterium, so dissolving these compounds in D2O to exchange labile protons with solvating deuterons results in longer-lived hyperpolarization of the 13C-nucleus 2-bonds away. 13C T1 and T2 times were longer in D2O versus H2O for all molecules in this study. This phenomenon can be utilized to improve hyperpolarized signal-to-noise ratio as a function of longer T1, and enhanced spectral and imaging resolution via longer T2.

 

73. Statistical optimisation of enzymatic detoxification with laccase from Trametes versicolor for spent sulphite liquors using a novel in-situ NMR method

Laura Sparlinek, Viktoria Leitner, Kamm Birgit, Journal of Biotechnology, (2018) DOI: 10.1016/j.jbiotec.2018.07.026

Within this study the mediated detoxification of spent sulphite liquor via laccase from Trametes versicolor was analysed and optimised using an in-situ NMR-spectroscopy method. The enzymatic degradation kinetic was optimised using the degradation rate of aromatic compounds as indirect parameter. Via response surface methodology the impact of the temperature, the pH and the enzyme concentration was analysed and the conditions were optimised focusing on optimal detoxification. The results of the statistical calculation revealed a valid statistical model for the optimal impact on the aromatic degradation with a temperature of 31 °C, a pH of 6 and a laccase concentrations of 179 U g-1 dry matter of spent sulphite liquor. By using these conditions 88.73 % of aromatic compounds could be degraded.

 

72. Controlling an organic synthesis robot with machine learning to search for new reactivity

Jarosław M. Granda, Liva Donina, Vincenza Dragone, De-Liang Long and Leroy Cronin, Nature, (2018) DOI: 10.1038/s41586-018-0307-8

The discovery of chemical reactions is an inherently unpredictable and time-consuming process. An attractive alternative is to predict reactivity, although relevant approaches, such as computer-aided reaction design, are still in their infancy. Reaction prediction based on high-level quantum chemical methods is complex, even for simple molecules. Although machine learning is powerful for data analysis, its applications in chemistry are still being developed. Inspired by strategies based on chemists’ intuition, we propose that a reaction system controlled by a machine learning algorithm may be able to explore the space of chemical reactions quickly, especially if trained by an expert. Here we present an organic synthesis robot that can perform chemical reactions and analysis faster than they can be performed manually, as well as predict the reactivity of possible reagent combinations after conducting a small number of experiments, thus effectively navigating chemical reaction space. By using machine learning for decision making, enabled by binary encoding of the chemical inputs, the reactions can be assessed in real time using nuclear magnetic resonance and infrared spectroscopy. The machine learning system was able to predict the reactivity of about 1,000 reaction combinations with accuracy greater than 80 per cent after considering the outcomes of slightly over 10 per cent of the dataset. This approach was also used to calculate the reactivity of published datasets. Further, by using real-time data from our robot, these predictions were followed up manually by a chemist, leading to the discovery of four reactions.

 

71. Analysis and Isolation of Potential Artemisinin Precursors from Waste Streams of Artemisia Annua Extraction

Rodger W. Stringham, Gary L. Moore, David S. Teager, and Tai-Yuen Yue, ACS Omega, (2018) DOI: 10.1021/acsomega.8b00974

High-performance liquid chromatography, liquid chromatography–mass spectrometry, and gas chromatography–mass spectrometry methods were developed to analyze the process waste streams of Artemisia Annua extraction. 13C NMR spectra were obtained at the field strength of 15 MHz using a Magritek Spinsolve 60 NMR spectrometer. Results from these methods suggested that the final waste from the extraction process could serve as a source of dihydroartemisinic acid (DHAA) that could be converted to additional artemisinin. Two additional impurities were isolated and identified in the waste material as well as in A. annua leaf samples. That these impurities also appear as side-products in chemical transformations of DHAA to artemisinin supports the conclusion that the in vivo transformation proceeds as nonspecific oxidations. These impurities do not appear in isolated artemisinin. A simple, high-yielding procedure for recovery of DHAA from the primary waste stream was developed.

 

70. A Convergent Continuous Multistep Process for the Preparation of C4-Oxime-Substituted Thiazoles

Edouard Godineau, Claudio Battilocchio, Matthias Lehmann, Steven V Ley, Ricardo Labes, Letitia Birnoschi, Srinivas Subramanian, C. S Prasanna, Amol Gorde, Mahesh Kalbagh, Vivek Khade, Anton Scherrer, and Anthony Cornelius Cornelius O’Sullivan, Organic Process Research & Development, (2018) DOI: 10.1021/acs.oprd.8b00095

We report a strategy designed for the rapid and convergent assembly of C4-oxime substituted thiazoles. Our approach relied on 3-bromo-2-oxopropanal O-methyl oxime 7 as a key building block. A three-step sequence to 7 was designed, which for safety concerns, could only be operated in batch mode on limited scales (<< 100g). We describe herein how we addressed such a limitation, by designing a multistep continuous synthesis of this intermediate and further demonstrate the advantages of flow reactor configuration upon scaling up.

 

69. Analytical Methods for the Determination of Mineral Oil Saturated Hydrocarbons (MOSH) and Mineral Oil Aromatic Hydrocarbons (MOAH)—A Short Review

Sandra Weber, Karola Schrag, Gerd Mildau, Thomas Kuballa, Stephan G Walch and Dirk W Lachenmeier, Analytical Chemistry Insights, (2018) DOI: 10.1177/1177390118777757

Mineral oils (such as paraffinum liquidum or white oil), which consist of mineral oil saturated hydrocarbons (MOSH) and mineral oil aromatic hydrocarbons (MOAH), are widely applied in various consumer products such as medicines and cosmetics. Contamination of food with mineral oil may occur by migration of mineral oil containing products from packaging materials, or during the food production process, as well as by environmental contamination during agricultural production. Considerable analytical interest was initiated by the potential adverse health effects, especially carcinogenic effects of some aromatic hydrocarbons. This article reviews the history of mineral oil analysis, starting with gravimetric and photometric methods, followed by on-line-coupled liquid chromatography with gas chromatography and flame ionization detection (LC-GC-FID), which still is considered as gold standard for MOSH-MOAH analysis. As alternative to chromatography, nuclear magnetic resonance (NMR) spectroscopy has recently been suggested for MOSH-MOAH analysis, especially with the possibility of detecting only the toxicologically relevant aromatic rings. Furthermore, NMR may offer potential as rapid screening especially with low-field instruments usable for raw material control.

 

68. Simultaneous quantification of aliphatic and aromatic hydrocarbons in produced water analysis using mobile 1H NMR

L Wagner, C Kalli, E O Fridjonsson, E F May, J Zhen and M L Johns, Measurement Science and Technology, (2018) DOI: 10.1088/1361-6501/aac98a

Legislated environmental limits regarding the hydrocarbon content of discharge water from offshore oil and gas are becoming rogressively more stringent. This is helping stimulate the development of analytical methods that are both robust and reliable whilst being able to quantify oil in water content at the ppm level of detection. Previously, we showed how such a measurement requirement of total oil content could be met by the application of mobile benchtop NMR. Here, we extend this non-optical measurement platform to enable separate quantification of the aromatic and aliphatic oil content of the discharge water; the aromatic content is of increasing interest on account of its much greater toxicity. Our revised method deploys a two solvent measurement protocol whilst retaining the self-calibration characteristic of the original approach. This new methodology was successfully validated using water contaminated with a variety of aromatic and aliphatic hydrocarbons. The uncertainty related to the NMR measurements was shown to be comparable to that of sample preparation; results were also successfully validated against gas chromatography and infrared measurements.

 

67. Quantitative produced water analysis using mobile 1H NMR

L Wagner, C Kalli, E O Fridjonsson, E F May, P L Stanwix, B F Graham, M R J Carroll and M L Johns, Measurement Science and Technology, (2016) DOI: 10.1088/0957-0233/27/10/105501

Measurement of oil contamination of produced water is required in the oil and gas industry to the (ppm) level prior to discharge in order to meet typical environmental legislative requirements. Here we present the use of compact, mobile 1H nuclear magnetic resonance (NMR) spectroscopy, in combination with solid phase extraction (SPE), to meet this metrology need. The NMR hardware employed featured a sufficiently homogeneous magnetic field, such that chemical shift differences could be used to unambiguously differentiate, and hence quantitatively detect, the required oil and solvent NMR signals. A solvent system consisting of 1% v/v chloroform in tetrachloroethylene was deployed, this provided a comparable 1H NMR signal intensity for the oil and the solvent (chloroform) and hence an internal reference 1H signal from the chloroform resulting in the measurement being effectively self-calibrating. The measurement process was applied to water contaminated with hexane or crude oil over the range 1–30?ppm. The results were validated against known solubility limits as well as infrared analysis and gas chromatography.

 

66. Detecting Low Concentrations of Unsaturated C-C Bonds by Parahydrogen-Induced Polarization using an Efficient Home-Built Parahydrogen Generator

Keunhong Jeong, Sein Min, Heelim Chae, Sung Keon Namgoong, Magnetic Resonance in Chemistry, (2018) DOI: 10.1002/mrc.4756

Parahydrogen is a potentially significant source of hyperpolarization. However, a heat exchanger at an ultra-low temperature, which is normally sustained wastefully using liquid nitrogen, is essential for the generation of hyperpolarized parahydrogen. In order to cut down on the use of liquid nitrogen, we employed a cryogenic storage dewar as the key component of our home-built parahydrogen generator, which lasted over 20 d with a single filling. Small concentrations of an unsaturated compound in a mixture were identified by hydrogenation in a principle-based experiment involving the use of hyperpolarization and phase difference. Less than 1 µL of styrene in 1 mL of chloroform was identified in a single scan with a 43 MHz benchtop nuclear magnetic resonance (NMR) spectrometer following hydrogenation with 50% parahydrogen. This method can potentially undergo a significant development through the use of high-field NMR techniques, higher parahydrogen concentrations, and increased scan times for data collection, among others. Since hydrogenation with parahydrogen induces a phase reversal during attachment to unsaturated C-C bonds, it may be possible to detect many other unsaturated bonds in organic molecules. All in all, this study not only broadens the research on parahydrogen-based unsaturated-bond detection, but also facilitates the use of hyperpolarization by a broader range of researchers through the introduction of a long-lasting home-built parahydrogen generator.

 

65. Potato starch retrogradation in tuber: Structural changes and gastro-small intestinal digestion in vitro

Yu-Fan Chen, Jaspreet Singh, Richard Archer, Food Hydrocolloids, (2018) DOI: 10.1016/j.foodhyd.2018.05.044

Structural changes of potato starch during retrogradation in tuber and its resulting digestibility were studied. Freshly cooked (FC) tubers were stored at 4?°C for 1,3 and 7 days (FCR) and then reheated at 50, 70, and 90?°C (FCR-r). The starch retrogradation enthalpy (?Hr) and crystallinity were both higher for retrograded tubers than for freshly cooked or for retrograded + reheated tubers. Different water populations in tuber were detected by a low-field NMR (LF-NMR), having relaxation times T21 (400?ms). The relaxation time of each water population decreased during refrigerated storage. The relaxation time T22 of 1, 3 and 7-day retrograded tuber increased during reheating but not to the level of the freshly cooked tuber. Ease of starch hydrolysis of the samples was studied by using an in vitro gastro-small intestinal digestion model. The 7-day retrograded + reheated sample showed a significantly lower starch hydrolysis (%), similar to those of the 1-day retrograded sample without reheating. The relaxation time of a water population indicates mobility – the water with low relaxation time is more mobile and less restricted which could facilitate enzyme diffusion leading to greater starch hydrolysis (%): in this study low relaxation time T22 was positively correlated to greater starch hydrolysis of the treated tubers (p?<?0.05).

 

64. Is Low-field NMR a Complementary Tool to GC-MS in Quality Control of Essential Oils? A Case Study: Patchouli Essential Oil

Andre Krause, Yu Wu, Runtao Tian, Teris A. van Beek, Planta Medica, (2018) DOI: 10.1055/a-0605-3967

In this study, 60 MHz 1H-NMR was compared with GC-MS and refractometry for the detection of adulteration of essential oils, taking patchouli essential oil as a test case. Patchouli essential oil is frequently adulterated, even today. In total, 75 genuine patchouli essential oils, 10 commercial patchouli essential oils, 10 other essential oils, 17 adulterants, and 1 patchouli essential oil, spiked at 20% with those adulterants, were measured. Visual inspection of the NMR spectra allowed for easy detection of 14 adulterants, while gurjun and copaiba balsams proved difficult and one adulterant could not be detected. NMR spectra of 10 random essential oils differed not only strongly from patchouli essential oil but also from one another, suggesting that fingerprinting by low-field NMR is not limited to patchouli essential oil. Due to advantages such as simplicity, rapidity, reproducibility, and ability to detect nonvolatile adulterants, 60 MHz 1H-NMR is complimentary to GC-MS for quality control of essential oils.

 

63. Impact of Exposure Conditions on the Morphology of Polyethylene by Compact NMR

Yadollah Teymouri, Alina Adams, Bernhard Blümich, Macromolecular Symposia, (2018) DOI: 10.1002/masy.201600156

This current work reviews the potential of compact NMR for monitoring and quantifying morphological changes in PE exposed to elevated temperatures and/or contact with different solvents. To prove the reliability of compact proton NMR relaxation measurements, the results are compared with data from conventional high-field proton wide-line NMR spectroscopy, DSC, and FTIR spectroscopy. It could be shown that simple, static proton relaxation measurements garner detailed information about the exposure-induced morphological changes through the quantification of phase composition and chain dynamics. Moreover, the NMR method has a key advantage over other methods, because the chain mobility of the soft amorphous phase is a very sensitive microscopic parameter under exposure conditions. The various presented examples and the good agreement of the NMR results with those of other analytical methods show that low-field NMR is a promising option for in-situ aging studies.

 

62. Non-Leachable Hydrophilic Additives for Amphiphilic Coatings

Guillaume Gillet, Fabrice Azemar, Fabienne Faÿ, Karine Réhel and Isabelle Linossier, Polymers, (2018) DOI: 10.3390/polym10040445

Amphiphilic surfaces are particularly effective at inhibiting the adhesion of microorganisms (bacteria, cells, microalgae, etc.) in liquid media. The aim of this study is to determine the best hydrophilic linker to promote bonding between poly(ethylene glycol) (PEG) as a hydrophilic additive and poly(dimethyl siloxane) (PDMS) as the hydrophobic matrix. Various parameters have been studied (molecular weight, linker type, and polymer end-group), as well as the efficiency of the linking, the capacity of PEG to access to the surface of the film, and overall film homogeneity. According to the results, a PDMS linker paired with a PEG moiety allows for compatibilization of the compounds during cross-linking. This compatibilization seems to provide a good bonding with the matrix and a good surface access to the hydrophilic moiety. Therefore, this structure comprising a linking function attached to the PDMS–PEG copolymer has high potential as a non-releasable additive for amphiphilic coating applications.

 

61. A 43 MHz Low-Field Benchtop 1H Nuclear Magnetic Resonance Method to Discriminate Perilla Oil Authenticity

Ju Hyun Kim, Hyeon Jeong Lee, Kisung Kwon, Hyang Sook Chun, Sangdoo Ahn, Byung Hee Kim, Journal of Oleo Science, (2018) DOI: 10.5650/jos.ess17243

The aim of this study was to discriminate the authenticity of perilla oils distributed in Korea using their 1H nuclear magnetic resonance (NMR) spectra acquired by a 43 MHz low-field benchtop NMR spectrometer. Significant differences existed in the integration values of all 6 peaks found in the spectrum between authentic and adulterated perilla oil samples. The integration values of 4 peaks that signify the methylene protons present in all fatty acids (FA) and allylic or olefinic protons present in all unsaturated FA were the best variables for establishing perilla oil authenticity. The procedure for applying the range of variables found in authentic perilla oil samples correctly discriminated between the samples of perilla oils with soybean oils added at concentrations of = 6 vol%. The results demonstrated that this NMR procedure is a possible cost-effective alternative to the high-field 1H NMR method for discriminating the authenticity of perilla oils.

 

60. Continuous hyperpolarization with parahydrogen in a membrane reactor

Sören Lehmkuhl, Martin Wiese, Lukas Schubert, Mathias Held, Markus Küppers, Matthias Wessling, Bernhard Blümich, Journal of Magnetic Resonance, (2018) DOI: 10.1016/j.jmr.2018.03.012

Hyperpolarization methods entail a high potential to boost the sensitivity of NMR. Even though the “Signal Amplification by Reversible Exchange” (SABRE) approach uses para-enriched hydrogen, p-H2, to repeatedly achieve high polarization levels on target molecules without altering their chemical structure, such studies are often limited to batch experiments in NMR tubes. Alternatively, this work introduces a continuous flow setup including a membrane reactor for the p-H2, supply and consecutive detection in a 1?T NMR spectrometer. Two SABRE substrates pyridine and nicotinamide were hyperpolarized, and more than 1000-fold signal enhancement was found. Our strategy combines low-field NMR spectrometry and a membrane flow reactor. This enables precise control of the experimental conditions such as liquid and gas pressures, and volume flow for ensuring repeatable maximum polarization.

 

59. Online low-field NMR spectroscopy for process control of an industrial lithiation reaction—automated data analysis

Simon Kern, Klas Meyer, Svetlana Guhl, Patrick Gräßer, Andrea Paul, Rudibert King, Michael Maiwald, Analytical and Bioanalytical Chemistry, (2018) DOI: 10.1007/s00216-018-1020-z

Monitoring specific chemical properties is the key to chemical process control. Today, mainly optical online methods are applied, which require time- and cost-intensive calibration effort. NMR spectroscopy, with its advantage being a direct comparison method without need for calibration, has a high potential for enabling closed-loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and rough environments for process monitoring and advanced process control strategies. We present a fully automated data analysis approach which is completely based on physically motivated spectral models as first principles information (indirect hard modeling—IHM) and applied it to a given pharmaceutical lithiation reaction in the framework of the European Union’s Horizon 2020 project CONSENS. Online low-field NMR (LF NMR) data was analyzed by IHM with low calibration effort, compared to a multivariate PLS-R (partial least squares regression) approach, and both validated using online high-field NMR (HF NMR) spectroscopy.

 

58. Compact low-field NMR spectroscopy and chemometrics: A tool box for quality control of raw rubber

Kawarpal Singh, Bernhard Blümich, Polymer, (2018) DOI: 10.1016/j.polymer.2018.02.057

This study reports experimental results from the analysis of 108 SBR samples by low-field 1H and 13C NMR spectroscopy at 1?T in combination with partial least square regression to develop methodology for quality control of raw rubber. The partial least square regression (PLS-R) models were developed for quantifying the individual monomer units present in the SBR which are impossible to quantify because of peak overlap in the SBR 1H NMR spectrum obtained at 1?T. The spectra revealed differences between samples from the same and different manufacturing batches of same and different manufacturers from different countries in a qualitative and quantitative fashion.

 

57. Application of Ultra-Centrifugation and Bench-Top 19F NMR for Measuring Drug Phase Partitioning for the Ophthalmic Oil-in-Water Emulsion Products

Xinyi Wang, Sharadrao M. Patil, David A. Keire, Xiaoming Xu, Kang Chen, AAPS PharmSciTech, (2018) DOI: 10.1208/s12249-018-0973-8

In complex oil-in-water emulsion drugs, the hydrophobic API is mainly formulated in oil droplets stabilized by surfactant and micelles composed of extra surfactant molecules. The API phase partition in oil and water (mainly micelle) is a critical quality attribute (CQA) of emulsion product in demonstrating physicochemical equivalence using difluprednate (DFPN) emulsion product Durezol® as a model, we developed a novel low-field benchtop NMR method to demonstrate its applicability in measuring DFPN phase partition for ophthalmic oil-in-water emulsion products. Low-field 19F spectra were collected for DFPN in formulation, in water phase and oil phase after separation from ultra-centrifugation. The NMR data showed the mass balance of DFPN before and after phase separation.

 

56. A subband Steiglitz-McBride algorithm for automatic analysis of FID data

M. A. R. Anjum, Pawel A. Dmochowski and Paul D. Teal, Magnetic Resonance in Chemistry, (2018) DOI: 10.1002/mrc.4723

Fast, accurate and automatic extraction of parameters of nuclear magnetic resonance Free Induction Decay (FID) signal for chemical spectroscopy is a challenging problem. Recently, the Steiglitz-McBride Algorithm (SMA) has been shown to exhibit superior performance in terms of speed, accuracy and automation when applied to the extraction of T2 relaxation parameters for myelin water imaging of brain. Applying it to FID data reveals that it falls short of the second objective, the accuracy. Especially, it struggles with the issue of missed spectral peaks when applied to chemical samples with relatively dense frequency spectra. To overcome this issue, a preprocessing stage of subband decomposition is proposed before the application of SMA to the FID signal. It is demonstrated that by doing so, a considerable improvement in accuracy is achieved. But this is not gained at the cost of the first objective, the speed. An Adaptive Subband Decomposition (ASD) is employed in conjunction with the Bayesian Information Criteria (BIC) to carry out an efficient decomposition according to spectral content of the signal under investigation. Furthermore, the ASD and BIC also serve to make the resulting algorithm independent of user-input which also fulfills the third objective, the automation. This makes the proposed algorithm favorable for fast, accurate and automatic extraction of FID signal parameters.

 

55. Multi-objective optimization for an automated and simultaneous phase and baseline correction of NMR spectral data

Mathias Sawall, Erik von Harbou, Annekathrin Moog, Richard Behrens, Henning Schröder, Joël Simoneau, Ellen Steimers, Klaus Neymeyr, Journal of Magnetic Resonance, (2018) DOI: 10.1016/j.jmr.2018.02.012

A new method is suggested that applies the phase and the baseline corrections simultaneously in an automated form without manual input, which distinguishes this work from other approaches. The underlying multi-objective optimization or Pareto optimization provides improved results compared to consecutively applied correction steps. The optimization process uses an objective function which applies strong penalty constraints and weaker regularization conditions. The new method includes an approach for the detection of zero baseline regions. The baseline correction uses a modified Whittaker smoother. The functionality of the new method is demonstrated for experimental NMR spectra. The results are verified against gravimetric data. The method is compared to alternative preprocessing tools. Additionally, the simultaneous correction method is compared to a consecutive application of the two correction steps.

 

54. Hyperpolarized Amino Acid Derivatives as Multivalent Magnetic Resonance pH Sensor Molecules

Christian Hundshammer, Stephan Düwel, David Ruseckas, Geoffrey Topping, Piotr Dzien, Christoph Müller, Benedikt Feuerecker, Jan B. Hövener, Axel Haase, Markus Schwaiger, Steffen J. Glaser and Franz Schilling, Sensors, (2018) DOI: 10.3390/s18020600

pH is a tightly regulated physiological parameter that is often altered in diseased states like cancer. The development of biosensors that can be used to non-invasively image pH with hyperpolarized (HP) magnetic resonance spectroscopic imaging has therefore recently gained tremendous interest. Here, we developed a systematic approach to tailor the pKa of molecules using modifications of carbon chain length and derivatization rendering these molecules interesting for pH biosensing. Notably, amino acid derivatives bear different spin-1/2 nuclei that exhibit a pH-dependent chemical shift in the physiological range and that can be polarized using DNP. 13C T1 measurements of hyperpolarized substances were performed on a Spinsolve Carbon.

 

53. A Catalyst-Free Flow Amination of Functional Organolithium Reagents

Heejin Kim, Yuya Yonekura, and Jun-ichi Yoshida, Angewandte Chemie International Edition, (2018) DOI: 10.1002/anie.201713031

We report an electrophilic amination of functional organolithium intermediates with well-designed aminating reagents under mild conditions using flow microreactors. The aminating reagents were explored and optimized to achieve an efficient C–N bond formation without using any catalyst. The electrophilic amination reactions of functionalized aryllithiums were successfully conducted under mild conditions within 1 min using flow microreactors. The aminating reagent was also prepared by the flow method. Based on stopped-flow NMR analysis, the reaction time for the preparation of the aminating reagent was quickly optimized without any necessity of work-up. Integrated one-flow synthesis consisting of generation of an aryllithium, the preparation of an aminating reagent, and their reaction was successfully achieved to give desired amine product within 5 min of total reaction time.

 

52. Medium Resolution 1H-NMR at 62 MHz as a New Chemically Sensitive Online Detector for Size-Exclusion Chromatography (SEC–NMR)

Johannes Höpfner, Karl-Friedrich Ratzsch, Carlo Botha and Manfred Wilhelm, Macromolecular Rapid Communications, (2018) DOI: 10.1002/marc.201700766

A state-of-the-art, medium-resolution 1H-NMR spectrometer (62 MHz) is used as a chemically sensitive online detector for size-exclusion chromatography of polymers such as polymethylmethacrylate (PMMA) and polystyrene (PS). The method uses protonated eluents and works at typical chromatographic conditions with trace amounts of analytes (<0.5 g L-1 after separation). Strong solvent suppression, e.g., by a factor of 500, is achieved by means of T1-filtering and mathematical subtraction methods. Substantial improvements are made with respect to previous work in terms of the sensitivity (signal-to-noise ratio up to 130:1, PMMA O CH3) and selectivity (peak width, full width half maximum (FWHM) 4 Hz on-flow). Typical homopolymers and a blend are investigated to deformulate their composition along the dimensions of molecular weight and NMR chemical shift. These results validate this new hyphenated chromatography method, which can greatly facilitate analysis and is much more effective than previously published results.

 

51. Scalable Photocatalytic Oxidation of Methionine under Continuous-Flow Conditions

Noémie Emmanuel, Carlos Mendoza, Marc Winter, Clemens R. Horn, Alessandra Vizza, Laurent Dreesen, Benoît Heinrichs, and Jean-Christophe M. Monbaliu, Organic Process Research & Development, (2017) DOI: 10.1021/acs.oprd.7b00212

Highly efficient and chemoselective singlet oxygen oxidation of unprotected methionine was performed in water using a continuous mesofluidic reactor. Sustainable process engineering and conditions were combined to maximize process efficiency and atom economy, with virtually no waste generation and safe operating conditions. Three water-soluble metal-free photosensitizers [Rose Bengal, Methylene Blue, and tetrakis(4-carboxyphenyl)porphyrin] were assessed. The best results were obtained with Rose Bengal (0.1 mol %) at room temperature under white light irradiation and a slight excess of oxygen. Process and reaction parameters were monitored in real-time with in-line NMR. Other classical organic substrates (a-terpinene and citronellol) were oxidized under similar conditions with excellent performances. In-line NMR analysis was carried out with a 43 MHz Spinsolve Carbon NMR spectrometer from Magritek® equipped with the flow-through module.

 

50. Volatile Changes in Hawaiian Noni Fruit, Morinda citrifolia L., During Ripening and Fermentation

Wall, M. M., Miller, S. and Siderhurst, M. S., Journal of the Science of Food and Agriculture, (2017) DOI: 10.1002/jsfa.8850

Noni fruit (Morinda citrifolia L., Rubiaceae) has been used in traditional medicine throughout the tropics and subtropics, and are now attracting interest in western medicine. Fermented noni juice is of particular interest for its promising antitumor activity. The current study collected and analyzed volatiles released at nine time intervals by noni fruit during ripening and fermentation using headspace autosampling coupled to gas chromatography-mass spectrometry. 1H NMR spectra were recorded using a SpinSolve Benchtop NMR Spectrometer operating at 42.5 MHz.

 

49. Desktop NMR and Its Applications From Materials Science To Organic Chemistry

Bernhard Blümich and Kawarpal Singh, Angewandte Chemie International Edition, (2017) DOI: 10.1002/anie.201707084

NMR spectroscopy is an indispensable method of analysis in chemistry, which until recently suffered from high demands for space, high costs for acquisition and maintenance, and operational complexity. This has changed with the introduction of compact NMR spectrometers suitable for small-molecule analysis on the chemical workbench. These spectrometers contain permanent magnets giving rise to proton NMR frequencies between 40 and 80 MHz. The enabling technology is to make small permanent magnets with homogeneous fields. Tabletop instruments with inhomogeneous fields have been in use for over 40 years for characterizing food and hydrogen-containing materials by relaxation and diffusion measurements. Related NMR instruments measure these parameters in the stray field outside the magnet. They are used to inspect the borehole walls of oil wells and to test objects nondestructively. The state-of-the-art of NMR spectroscopy, imaging and relaxometry with compact instruments is reviewed.

 

48. Real-time spectroscopic analysis enabling quantitative and safe consumption of fluoroform during nucleophilic trifluoromethylation in flow

Biagia Musio, Elena Gala, and Steven V Ley, AACS Sustainable Chemistry & Engineering, (2017) DOI: 10.1021/acssuschemeng.7b04012

The productive use of toxic waste materials derived from industrial processes is one of the main goals of modern chemical research to increase the sustainability of large scale production. Here we devise a simple and robust strategy for the utilization of trifluoromethane, obtained in large quantities from polytetrafluoroethylene (PTFE) manufacture, and the conversion of this greenhouse gas into valuable fluorinated compounds. The generation of the trifluoromethyl carbanion and its direct and complete consumption through trapping with a number of electrophiles were achieved by a fully contained flow reactor setup. The adoption of modern in-line analytical tools, such as portable FT-IR and NMR devices, allowed the accurate reagent dosage with considerable benefits in terms of controlling the environmental impact during this continuous process. The advantages of the method, with respect to the batch procedure, will be discussed and demonstrated experimentally.

 

47. An Experimental Validation of a Bayesian Model for Quantification in NMR Spectroscopy

Y. Matviychuk, E.v. Harbou, D.J. Holland, Journal of Magnetic Resonance, (2017) DOI: 10.1016/j.jmr.2017.10.009

In this paper, we present a general model for an NMR signal that, in a principled way, takes into account the effects of chemical shifts, relaxation, lineshape imperfections, phasing, and baseline distortions. We test the model using both simulations and experiments, concentrating on simple spectra with well-resolved peaks where we expect conventional analysis to be effective. Our results of quantifying mixture compositions compare favourably with the established methods.

 

46. Desktop NMR spectroscopy for real-time monitoring of an acetalization reaction in comparison with gas chromatography and NMR at 9.4 T

Kawarpal Singh, Ernesto Danieli, Bernhard Blümich, Analytical and Bioanalytical Chemistry, (2017) DOI: 10.1007/s00216-017-0686-y

In the present study, an acetalization reaction was investigated with compact NMR spectroscopy in real-time. Acetalization is used for multistep synthesis of the variety of organic compounds to protect particular chemical groups. A compact 1 T NMR spectrometer with a permanent magnet was employed to monitor the acid catalyzed acetalization of the p-nitrobenzaldehyde with ethylene glycol. The concentrations of both reactant and product were followed by peak integrals in single-scan 1H NMR spectra as a function of time. The reaction conditions were varied in terms of temperature, agitation speed, catalyst loading, and feed concentrations in order to determine the activation energy with the help of a pseudo-homogeneous kinetic model. For low molar ratios of aldehyde and glycol, the equilibrium conversions were lower than for the stoichiometric ratio. Increasing catalyst concentration leads to faster conversion. The data obtained with low-field NMR spectroscopy were compared with data from GC and NMR spectroscopy at 9.4 T acquired in batch mode by extracting samples at regular time intervals. The reaction kinetics followed by either method agreed well.

 

45. High-throughput authentication of edible oils with benchtop ultrafast 2D NMR

Gouilleux, B., Marchand, J., Charrier, B., Remaud, G.S., Giraudeau, P., Food Chemistry, (2017) DOI: 10.1016/j.foodchem.2017.10.016

We report the use of an ultrafast 2D NMR approach applied on a benchtop NMR system (43MHz) for the authentication of edible oils. Our results demonstrate that a profiling strategy based on fast 2D NMR spectra recorded in 2.4 min is more efficient than the standard 1D experiments to classify oils from different botanical origins, since 1D spectra on the same samples suffer from strong peak overlaps. Six edible oils with different botanical origins (olive, hazelnut, sesame, rapeseed, corn and sunflower) have been clearly discriminated by PCA analysis. Furthermore, we show how this approach combined with a PLS model can detect adulteration processes such as the addition of hazelnut oil into olive oil, a common fraud in food industry.

 

44. Octanol-Water Partition Coefficient Measurement by a Simple 1H NMR Method

Hemi Cumming and Christoph Ru¨cker, ACS Omega, (2017) DOI: 10.1021/acsomega.7b01102

We describe a simple miniature shake-flask method to measure the octanol–water partition coefficient of an organic compound. Partition between water and octanol is performed in an NMR tube; the aqueous phase is analyzed by 1H NMR spectroscopy using a benchtop low-field NMR instrument. Neither pre-equilibration of solvents nor isolation of the two phases is required. The procedure is fast and easy enough to be used in a students’ laboratory. Scope and limitations as well as possible sources of error are discussed in detail.

 

43. Low Field NMR Determination of pKa Values for Hydrophilic Drugs for Students in Medicinal Chemistry

Aleksandra Zivkovic, Jan Josef Bandolik, Alexander Jan Skerhut, Christina Coesfeld, Miomir Raos, Nenad Zivkovic, Vlastimir Nikolic and Holger Stark, Magnetochemistry, (2017) DOI: 10.3390/magnetochemistry3030029

For an interdisciplinary approach on different topics of medicinal and analytical chemistry, we applied a known experimental pKa value determination method on the field of the bench top nuclear magnetic resonance (NMR) spectrometry of some known biologically active pyridine-based drugs, i.e., pyridoxine hydrochloride, isoniazid, and nicotine amide. The chemical shifts of the aromatic ring protons in the 1H NMR spectrum change depending on the protonation status. The data were analyzed on dependence of the chemical shifts by different pH (pD) environments and then the pKa values were calculated. The pKa values obtained were in agreement with the literature data for the compounds, searched by the students on web programs available at our university. The importance of the pKa values in protein-ligand interactions and distribution etc. of drugs was brought up to the students’ attention. In addition, by the use of a free web application for pKa values prediction, students calculated the predicted modeled pKa value. The experimental and in-silico approaches enhance the tool box for undergraduate students in medicinal chemistry.

 

42. High yield, solid exfoliation and liquid dispersion of graphite driven by a donor-acceptor interaction

Desi Hamed Gharib, Shaun Gietman, François Malherbe, Simon E. Moulton, Carbon, (2017) DOI: 10.1016/j.carbon.2017.08.025

Graphene derived from readily available graphite is viewed as the most effective route for large-scale production, due to the low cost of the raw material. However, the difficulty in achieving complete exfoliation, as well as the intrinsic insolubility of graphite, remains a key challenge. Herein, we describe a single-step approach to effectively disrupt and cleave the network of pep interactions, induce the exfoliation of graphite and disperse the resulting exfoliated material in organic solvents, all driven by electron rich (graphene) donor-acceptor interactions. 1H NMR measurements of the acceptors was recorded on Spinsolve carbon benchtop NMR.

 

41. Dynamic nuclear polarization fast field cycling method for selective study of molecular dynamics in block copolymers

B. Gizatullin, O. Neudert, S. Stapf, C. Mattea, ChemPhysChem, (2017) DOI: 10.1002/cphc.201700539

Dynamic nuclear polarization (DNP) is one of the most useful methods for increasing sensitivity in NMR. It is based on the transfer of magnetization from an electron to the nuclear spin system. Based on previous work demonstrating the feasibility of integrating DNP with Fast Field Cycling (FFC) relaxometry, and the possibility to distinguish between different mechanisms such as Overhauser Effect (OE) and Solid Effect (SE), the first FFC study of the differential relaxation properties of a copolymer is presented. For this purpose, concentrated solution of polystyrene-block-polybutadiene-block-polystyrene (SBS) triblock copolymer and their corresponding homopolymers were investigated. T1-T2 relaxation data are discussed in terms of molecular mobility and the presence of radicals. The DNP selective data indicate a dominant solid effect contribution to the enhancement of the NMR signal for both blocks of the triblock copolymer as well as for the homopolymer solutions. The enhancement factors are different for both polymer types and in the copolymer, which is explained by the individual 1H T1 relaxation times and different electron-nucleus coupling strength. T1 relaxation dispersion measurements of the SE enhanced signal were performed, leading to improved signal-to-noise ratios that allowed the site-specific separation of relaxation times and their dependence on Larmor frequency with a higher accuracy.

 

40. 1H and 31P benchtop NMR of liquids and solids used in and/or produced during the manufacture of methamphetamine by the HI reduction of pseudoephedrine/ephedrine

B. Bogan and S. Moore, Forensic Science International, (2017) DOI: 10.1016/j.forsciint.2017.06.026

In this study, the use of benchtop NMR spectroscopy in the analysis of solids and liquids used and/or produced during the HI reduction of pseudoephedrine was evaluated. The study focused on identifying organic precursors and phosphorus containing compounds used in and/or produced during the manufacturing process. Samples taken from clandestine laboratories, where this synthesis process was suspected of occurring, were also analysed and evaluated. Benchtop NMR was able to distinguish between ephedrine, pseudoephedrine and methamphetamine as the free base and hydrochloride salt. This technique was also effective at identifying and distinguishing between phosphorus containing compounds used and/or produced during the manufacture of methamphetamine. Benchtop NMR was also determined to be effective at analysing samples from suspected clandestine laboratories.

 

39. Hydrogen storage using a hot pressure swing reactor

H. Jorschick, P. Preuster, S. Dürr, A. Seidel, K. Müller, A. Bösmann and P. Wasserscheid, Energy & Environmental Science, (2017) DOI: 10.1039/c7ee00476a

Hydrogen storage in form of Liquid Organic Hydrogen Carrier (LOHC) systems offers the opportunity for infrastructure-compatible energy storage on a very large scale and over long periods of time without losses. Our contribution demonstrates that for stationary hydrogen storage the technology becomes much simpler and significantly more efficient if both, the LOHC hydrogenation and the LOHC dehydrogenation reaction are carried out in the same reactor using the same catalyst. It is shown that a Pt on alumina catalyst promotes the hydrogenation of dibenzyltoluene (H0-DBT) as well as the dehydrogenation of perhydro dibenzyltoluene (H18-DBT) in the temperature range of 290 to 310 oC with hydrogen pressure being the only variable for shifting the equilibrium between hydrogen loading and release. This way of operation safes investment for catalyst and reactor, drastically increases the hydrogen storage dynamics, and opens novel opportunities for heat integration and catalyst regeneration.

 

38. Oxidative Neutralization of Mustard-Gas Simulants in an On-Board Flow Device with In-Line NMR Monitoring

Picard, B., Gouilleux, B., Lebleu, T., Maddaluno, J., Chataigner, I., Penhoat, M., Felpin, F.-X., Giraudeau, P. and Legros, J., Angewandte Chemie Int. Ed., (2017) DOI: 10.1002/anie.201702744

The fast and effective neutralization of the mustard-gas simulant 2-chloroethyl ethyl sulfide (CEES) using a simple and portable continuous flow device is reported. Neutralization takes place through a fully selective sulfoxidation by a stable source of hydrogen peroxide (alcoholic solution of urea–H2O2 adduct/MeSO3H freshly prepared). The reaction progress can be monitored with an in-line benchtop NMR spectrometer, allowing a real-time adjustment of reaction conditions. Inherent features of millireactors, that is, perfect control of mixing, heat and reaction time, allowed the neutralization of 25 g of pure CEES within 46 minutes in a 21.5 mL millireactor (tR=3.9 minutes). This device, which relies on affordable and nontoxic reagents, fits into a suitcase, and can be deployed by police/military forces directly on the attack site.

 

37. Mobile compact 1H NMR spectrometer promises fast quality control of diesel fuel

M.H.M. Killner, E. Danieli, F. Casanova, J.J.R. Rohwedder, B. Blümich, Fuel, (2017) DOI: 10.1016/j.fuel.2017.04.081

To address the need for fast quality control of diesel fuel, this study introduces a compact 1H NMR spectrometer to develop Partial Least Squares (PLS) regression models for rapidly determining several quality parameters of diesel fuel such as specific gravity, cetane number, flash point, and distillation temperatures to 10% and 50% of recovery. For all these quality parameters, the developed models showed margins of error better or comparable than reference analytical techniques. The compact NMR spectrometer was also applied for determining biodiesel content (methyl- and ethyl esters) in diesel fuel by using a univariate calibration curve. For all tested commercial diesel fuel samples, this new tool generated comparable results, within the tolerable margin of error, to those obtained with Mid-IR as a reference technique. Operation of the compact low-field NMR spectrometer is simple and fast: no sample pre-treatment or dilution in deuterated solvents is required, and the single-scan measurements take only 15 s per spectrum.

 

36. A New Paramagnetically Shifted Imaging Probe for MRI

P. Kanthi Senanayake, Nicola J. Rogers, Katie-Louise N.A. Finney, Peter Harvey, Alexander M. Funk, J. Ian Wilson, Dara O’Hogain, Ross Maxwell, David Parker, Andrew M. Blamire, Magnetic Resonance in Medicine, (2017) DOI: 10.1002/mrm.26185

A contrast agent was developed for direct MRI detection through the paramagnetically shifted proton magnetic resonances of two chemically equivalent tert-butyl reporter groups within a dysprosium(III) complex. The complex was characterized in phantoms and imaged in physiologically intact mice at 7 Tesla (T) using three-dimensional (3D) gradient echo and spectroscopic imaging (MRSI) sequences to measure spatial distribution and signal frequency. Measurements at 1 T (42.5 MHz 1H) were made on a Magritek Spinsolve spectrometer.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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 a,?-bisdiphenylene-ß-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.

 

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.

 

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 (?) 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.

 

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.

 

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.

 

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 a:ß bitter acid ratios. 1H NMR spectroscopy was slower, requiring a solvent extraction, but distinguished cultivars by cohumulone content as well as a:ß 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.

 

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.

 

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 aC-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.

 

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.

 

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.

 

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.

 

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

 

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.

 

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.

 

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

 

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.

 

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%.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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.

 

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 ß-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-ß-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.

 

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.

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.

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