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We report the application of pure shift and J‐edited nuclear magnetic resonance spectroscopies to the structural analysis of a protected maltotrioside synthetic intermediate whose crowded 1H spectrum displays highly crowded regions. The analytical strategy is based on the implementation of J‐edited and TOCSY experiments whose resolution is optimized by the use of broadband homonuclear decoupling and selective refocusing techniques, to assign and measure chemical shifts and homonuclear scalar couplings with high accuracy. The resulting data show a high level of complementarity, providing a detailed insight into each subunit of this oligomeric saccharide, even for proton sites whose nuclear magnetic resonance signals strongly overlap. This approach allowed for fully assigning proton chemical shifts and extracting 80% of the 3JHH couplings that are in excellent agreement with those expected for D‐gluco‐pyranosyl units in 4C1 conformations. [ABSTRACT FROM AUTHOR]

The interaction between humic acid (HA) and engineered nanoparticles (NPs) is critical in environmental sciences, especially for understanding the behavior of NPs in natural waters. This study employs 1 H 2D Multi-Exponential Transverse Relaxation (METR) NMR spectroscopy to examine the molecular-level interactions between Pahokee Peat humic acid (HA) and carboxyl-functionalized iron oxide nanoparticles (NPCOs). First, 1 H 2D METR NMR spectroscopy allowed not only the identification of HA in terms of its chemical composition but also the separation of molecules with the same chemical shift values but different rates of molecular tumbling. Then, using solutions with varying NPCO concentrations (0, 10, 40, and 100 μM), we observed significant changes in the T 2 relaxation times of HA components, indicating interactions between HA and NPCO. Analysis showed the biggest effect on two chemical shift regions, corresponding to lipids and carbohydrates, revealing that smaller molecules within these regions exhibit the most significant changes in T 2 values upon the addition of NPCO. This suggests that these molecules are the initial sites of interaction, with the entire HA system being affected at higher NPCO concentrations. These findings highlight the utility of METR NMR spectroscopy in studying complex environmental mixtures and provide insights into the behavior of HA and NPs, essential for understanding the fate of NPs in the environment., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study investigates the potential and complementarity of high-throughput multipulse and multidimensional NMR methods for metabolomics. Through a chemical ecology case study, three methods are investigated, offering a continuum of methods with complementary features in terms of resolution, sensitivity and experiment time. Ultrafast 2D COSY, adiabatic INEPT and SYMAPS HSQC are shown to provide a very good classification ability, comparable to the reference 1D 1 H NMR method. Moreover, a detailed analysis of discriminant buckets upon supervised statistical analysis shows that all methods are highly complementary, since they are able to highlight discriminant signals that could not be detected by 1D 1 H NMR. In particular, fast 2D methods appear very efficient to discriminate signals located in highly crowded regions of the 1 H spectrum. Overall, the combination of these recent methods within a single NMR metabolomics workflow allows to maximize the accessible metabolic information, and also raises exciting challenges in terms of NMR data analysis for chemical ecology.

Efficient and robust analytical methods are needed to improve the identification and subsequent regulation of new psychoactive substances (NPS). NMR spectroscopy is a unique method able to determine the structure of small molecules such as NPS even in mixtures. However, high-field NMR analysis is associated with expensive purchase and maintenance costs. For more than a decade, compact NMR spectrometers have changed this paradigm. It was recently shown that a dedicated analytical workflow combining compact NMR and databases could identify the molecular structure of NPS, in spite of the lower spectral dispersion and sensitivity of compact spectrometers. This approach relies on 1 H- 13 C HSQC to both recognize NPS and elucidate the structure of unknown substances. Still, its performance is limited by the need to compromise between resolution and experiment time. Here, we show that this strategy can be significantly improved by implementing non-uniform sampling (NUS) to improve spectral resolution in the 13 C dimension of HSQC at no cost in terms of experiment time. Gains in the range of 3 to 4 in resolution are achieved for pure NPS and for a mixture. Finally, 2D HSQC with NUS was applied to improve the identification of NPS with the assistance of databases. The resulting method appears as a useful tool for the characterization of NPS in mixtures, which is essential for forensic laboratories., (© 2023 The Authors. Magnetic Resonance in Chemistry published by John Wiley & Sons Ltd.)

Hyperpolarized 13 C NMR at natural abundance, based on dissolution dynamic nuclear polarization (d-DNP), provides rich, sensitive and repeatable 13 C NMR fingerprints of complex mixtures. However, the sensitivity enhancement is associated with challenges such as peak overlap and the difficulty to assign hyperpolarized 13 C signals. Ultrafast (UF) 2D NMR spectroscopy makes it possible to record heteronuclear 2D maps of d-DNP hyperpolarized samples. Heteronuclear UF 2D NMR can provide correlation peaks that link quaternary carbons and protons through long-range scalar couplings. Here, we report the analytical assessment of an optimized UF long-range HETCOR pulse sequence, applied to the detection of metabolic mixtures at natural abundance and hyperpolarized by d-DNP, based on repeatability and sensitivity considerations. We show that metabolite-dependent limits of quantification in the range of 1-50 mM (in the sample before dissolution) can be achieved, with a repeatability close to 10% and a very good linearity. We provide a detailed comparison of such analytical performance in two different dissolution solvents, D 2 O and MeOD. The reported pulse sequence appears as an useful analytical tool to facilitate the assignment and integration of metabolite signals in hyperpolarized complex mixtures.

New psychoactive substances (NPS) have become a serious threat for public health due to their ability to be sold in the street or on internet. NPS are either derived from commercial drugs which are misused (recreational rather than medical use) or whose structure is slightly modified. To regulate NPS, it is essential to accurately characterize them, either to recognize molecules that were previously identified or to quickly elucidate the structure of unknown ones. Most approaches rely on the determination of the exact mass obtained by high-resolution mass spectrometry requiring expensive equipment. This motivated us to develop a workflow in which the elucidation is assisted with databases and does not need the exact mass. This workflow combines 1D and 2D NMR measurements performed on a benchtop spectrometer with IR spectroscopy, for creating a multi-technique database to characterize pure and mixed NPS. The experimental database was created with 57 entries mostly coming from seizures, mainly cathinones, cannabinoids, amphetamines, arylcyclohexylamines, and fentanyl. A blind validation of the workflow was carried out on a set of six unknown seizures. In the first three cases, AF, AB-FUBINACA, and a mixture of 2C-I and 2C-E could be straightforwardly identified with the help of their reference spectra in the database. The two next samples were elucidated for the first time with the help of the database to reveal NEK and MPHP substances. Finally, a precise quantification of each characterized NPS was obtained in order to track NPS trafficking networks., (© 2022 The Authors. Drug Testing and Analysis published by John Wiley & Sons Ltd.)

New psychoactive substances (NPS) have become a serious threat to public health in Europe due to their ability to be sold in the street or on the darknet. Regulating NPS is an urgent priority but comes with a number of analytical challenges since they are structurally similar to legal products. A number of analytical techniques can be used for identifying NPS, among which NMR spectroscopy is a gold standard. High field NMR is typically used for structural elucidation in combination with others techniques like GC-MS, Infrared spectroscopy, together with databases. In addition to their strong ability to elucidate molecular structures, high field NMR techniques are the gold standard for quantification without any physical isolation procedure and with a single internal standard. However, high field NMR remains expensive and emerging "benchtop" NMR apparatus which are cheaper and transportable can be considered as valuable alternatives to high field NMR. Indeed, benchtop NMR, which emerged about ten years ago, makes it possible to carry out structural elucidation and quantification of NPS despite the gap in resolution and sensitivity as compared to high field NMR. This review describes recent advances in the field of NMR applied to the characterization of NPS. High-field NMR methods are first described in view of their complementarity with other analytical methods, focusing on both structural and quantitative aspects. The second part of the review highlights how emerging benchtop NMR approaches could act as a game changer in the field of forensics., Competing Interests: Declarations of interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Across the evolutionary history of insects, the shift from nitrogen-rich carnivore/omnivore diets to nitrogen-poor herbivorous diets was made possible through symbiosis with microbes. The herbivorous turtle ants Cephalotes possess a conserved gut microbiome which enriches the nutrient composition by recycling nitrogen-rich metabolic waste to increase the production of amino acids. This enrichment is assumed to benefit the host, but we do not know to what extent. To gain insights into nitrogen assimilation in the ant cuticle we use gut bacterial manipulation, 15 N isotopic enrichment, isotope-ratio mass spectrometry, and 15 N nuclear magnetic resonance spectroscopy to demonstrate that gut bacteria contribute to the formation of proteins, catecholamine cross-linkers, and chitin in the cuticle. This study identifies the cuticular components which are nitrogen-enriched by gut bacteria, highlighting the role of symbionts in insect evolution, and provides a framework for understanding the nitrogen flow from nutrients through bacteria into the insect cuticle.

Emerging low cost, compact NMR spectrometers that can be connected in-line to a flow reactor are suited to study reaction mixtures. The main limitation of such spectrometers arises from their lower magnetic field inducing a reduced sensitivity and a weaker spectral resolution. For enhancing the spectral resolution, the merging of Pure-Shift methods recognized for line narrowing with solvent elimination schemes was implemented in the context of mixtures containing protonated solvents. One more step was achieved to further enhance the resolution power on compact systems, thanks to multiple elimination schemes prior to Pure-Shift pulse sequence elements. For the first time, we were able to remove up to 6 protonated solvent signals simultaneously by dividing their intensity by 500 to 1700 with a concomitant spectral resolution enhancement for signals of interest from 9 to 12 as compared to the standard 1D 1 H. Then, the potential of this new approach was shown on the flow synthesis of a complex benzoxanthenone structure., (© 2020 Wiley-VCH GmbH.)

Benchtop NMR spectroscopy has been on the rise for the last decade, by bringing high-resolution NMR in environments that are not easily compatible with high-field NMR. Benchtop spectrometers are accessible, low cost and show an impressive performance in terms of sensitivity with respect to the relatively low associated magnetic field (40-100 MHz). However, their application is limited by the strong and ubiquitous peak overlaps arising from the complex mixtures which are often targeted, often characterized by a great diversity of concentrations and by strong signals from non-deuterated solvents. Such limitations can be addressed by pulse sequences making clever use of magnetic field gradient pulses, capable of performing efficient coherence selection or encoding chemical shift or diffusion information. Gradients pulses are well-known ingredients of high-field pulse sequence recipes, but were only recently made available on benchtop spectrometers, thanks to the introduction of gradient coils in 2015. This article reviews the recent methodological advances making use of gradient pulses on benchtop spectrometers and the applications stemming from these developments. Particular focus is made on solvent suppression schemes, diffusion-encoded, and spatially-encoded experiments, while discussing both methodological advances and subsequent applications. We eventually discuss the exciting development and application perspectives that result from such advances., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

NMR spectroscopy of oriented samples makes accessible residual anisotropic intramolecular NMR interactions, such as chemical shift anisotropy (RCSA), dipolar coupling (RDC), and quadrupolar coupling (RQC), while preserving high spectral resolution. In addition, in a chiral aligned environment, enantiomers of chiral molecules or enantiopic elements of prochiral compounds adopt different average orientations on the NMR timescale, and hence produce distinct NMR spectra or signals. NMR spectroscopy in chiral aligned media is a powerful analytical tool, and notably provides unique information on (pro)chirality analysis, natural isotopic fractionation, stereochemistry, as well as molecular conformation and configuration. Significant progress has been made in this area over the three last decades, particularly using polypeptide-based chiral liquid crystals (CLCs) made of organic solutions of helically chiral polymers (as PBLG) in organic solvents. This review presents an overview of NMR in polymeric LCs. In particular, we describe the theoretical tools and the major NMR methods that have been developed and applied to study (pro)chiral molecules dissolved in such oriented solvents. We also discuss the representative applications illustrating the analytical potential of this original NMR tool. This overview article is dedicated to thirty years of original contributions to the development of NMR spectroscopy in polypeptide-based chiral liquid crystals., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The reactivity and selectivity of non-heme Fe II complexes as oxidation catalysts can be substantially modified by alteration of the ligand backbone or introduction of various substituents. In comparison with the hexadentate ligand N,N,N',N'-tetrakis(pyridin-2-ylmethyl)ethane-1,2-diamine (TPEN), N,N'-bis[1-(pyridin-2-yl)ethyl]-N,N'-bis(pyridin-2-ylmethyl)ethane-1,2-diamine ( 2Me L 6 2 ) has a methyl group on two of the four picolyl positions. Fe II complexation by 2Me L 6 2 yields two diastereomeric complexes with very similar structures, which only differ in the axial/equatorial positions occupied by the methylated pyridyl groups. In solution, these two isomers exhibit different magnetic behaviors. Whereas one isomer exhibits temperature-dependent spin-state conversion between the S=0 and S=2 states, the other is more reluctant towards this spin-state equilibrium and is essentially diamagnetic at room temperature. Their catalytic properties for the oxidation of anisole by H 2 O 2 are very different and correlate with their magnetic properties, which reflect their lability/inertness. These different properties most likely depend on the different steric constraints of the methylated pyridyl groups in the two complexes., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This mini-review highlights the potential of benchtop nuclear magnetic resonance (NMR) for the monitoring of bioprocesses. It describes recent perspectives opened by the reduced size of devices in relaxometry, magnetic resonance imaging and NMR spectroscopy. In particular, the recent emergence of the benchtop NMR spectroscopy gives access to many applications thanks to the implementation of advanced experiments., (© 2018 John Wiley & Sons, Ltd.)

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 1 H. 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., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Authentication of natural products is of major relevance in the context of manufactured drugs or herbal supplements since such active products generate a lucrative market. The analytical method to identify and quantify valuable natural products is critical for quality control and product assignment of herbal supplements. In this framework, we propose to apply a recently developed quantitative 2D NMR approach called Q QUIPU (Quick QUantItative Perfected and pUre shifted) in combination with 1D 1 H NMR capable to access the concentration of three major alkaloids, berberine, β-hydrastine and canadine, in the root extract of goldenseal (Hydrastis canadensis), one of the 20 most popular herbal supplements used worldwide. We highlight the complementarity of 1D and 2D quantitative NMR to accurately assess the amount of alkaloids with different range of concentrations and stability within extracts. In particular, unstable natural products having non-overlapped signals like berberine could only be quantified by sensitive and fast 1D 1 H, while overlapped signals of β-hydrastine and low intense ones of canadine could only be quantified with the recent 2D Q QUIPU HSQC. Results obtained from this combined approach have led to a good accuracy (<10%) as compared with coupled UHPLC-MS/UV techniques. This quantitative NMR approach paves the way to numerous applications where the accurate quantification of targeted compounds in complex mixtures is required, for instance in agricultural, food and pharmaceuticals products., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Quantitative NMR is intrinsically dependent on precise, accurate, and robust peak area calculation. In this work, we demonstrate how the use of complex-valued peak descriptions can improve peak fitting in the frequency domain - incorporating phase and baseline correction as well as apodization while working with commonly used Fourier-transformed data. The method has been implemented in an open source R package called rnmrfit that is available for download on GitHub (https://github.com/ssokolen/rnmrfit). Application to real data suggests that this approach can also result in dramatically higher precision than can be achieved with existing software. Simulation data indicates that coefficients of variation below 0.1% can be readily achieved at signal to noise (SNR) ratios of approximately 100. The use of complex-valued data in the frequency domain is demonstrated as a relatively simple and effective means of improving peak fitting for quantitative NMR analysis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Six-membered ring fused furans containing a tetrasubstituted tertiary carbon were prepared in an unprecedented one-pot BODIPY-catalyzed domino photooxygenation/reduction process. A series of functionalized furans was synthesized from readily available 2-alkenylphenols and mechanistic studies were performed to account for the domino photosensitized oxygenation., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The targeted analysis of metabolites in complex mixtures is a challenging issue. NMR is one of the major tools in this field, but there is a strong need for more sensitive, better-resolved, and faster quantitative methods. In this framework, we introduce the concept of FAst, QUantitative, hIghly Resolved and sEnsitivity enhanced (FAQUIRE) NMR to push forward the limits of metabolite NMR analysis. 2D 1 H, 13 C 2D quantitative maps are promising alternatives for enhancing the spectral resolution but are highly time-consuming because of (i) the intrinsic nature of 2D, (ii) the longer recycling times required for quantitative conditions, and (iii) the higher number of scans needed to reduce the level of detection/quantification to access low concentrated metabolites. To reach this aim, speeding up the recently developed QUantItative Perfected and pUre shifted HSQC (QUIPU HSQC) is an interesting attempt to develop the FAQUIRE concept. Thanks to the combination of spectral aliasing, nonuniform sampling, and variable repetition time, the acquisition time of 2D quantitative maps is reduced by a factor 6 to 9, while conserving a high spectral resolution thanks to a pure shift approach. The analytical potential of the new Quick QUIPU HSQC (Q QUIPU HSQC) is evaluated on a model metabolite sample, and its potential is shown on breast-cell extracts embedding metabolites at millimolar to submillimolar concentrations.

Nuclear magnetic resonance (NMR) is one of the most widely used analytical techniques in numerous domains where molecules are objects of investigation. However, major limitations of multidimensional NMR experiments come from their low sensitivity and from the long times needed for their acquisition. In order to overcome such limitations, fast repetition NMR techniques allowed for the reduction of 2D experimental time and for the conversion of the gained time into a higher number of scans leading to a better sensitivity. Thus, fast repetition 2D heteronuclear NMR techniques have allowed new advances in NMR, especially to access infomation on low abundant nuclei, to enhance the detection of low concentrated compounds and to probe weak interactions like hydrogen bonds at natural abundance. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

An efficient synthetic pathway leading to two carbonated analogues of ribavirin is described. The key-steps in the synthesis of these ribosyltriazoles bearing a quaternary carbon atom in the 2'-position are an indium-mediated alkynylation and a 1,3-dipolar cyclization.

Correction for 'Achieving high resolution and optimizing sensitivity in spatial frequency encoding NMR spectroscopy: from theory to practice' by Bertrand Plainchont et al., Phys. Chem. Chem. Phys., 2016, 18, 22827-22839.

A detailed analysis of NMR spectra acquired based on spatial frequency encoding is presented. A theoretical model to simulate gradient encoded pulses is developed in order to describe the spatial properties of the NMR signals that are locally created throughout the sample. The key features that affect the efficiency of the slice selection process during excitation as well as refocusing pulses are investigated on a model ABX spin system, both theoretically and experimentally. It is shown that the sensitivity and resolution of the pure shift and J-edited experiments based on a spatial frequency encoding can be optimized to a point where high-resolution techniques based on a spatial frequency encoding approach show optimal performance compared to other methods.

The quantification of metabolites is essential for understanding and improving biological systems. With the aim to quantify in one map a complex mixture composed of low concentrated metabolites, a new experiment called the (1)H-(13)C QUIPU HSQC allows improving of both resolution and sensitivity for investigation of vegetal extracts.

The presence of water has been shown to deeply impact the stability and geometry of Zn complexes in solution. Evidence for tetra- and penta-coordinated species in a pyridylmethylamine-Zn(II) model complex is presented. Novel (1) H NMR tools such as T1 -filtered selective exchange spectroscopy and pure shifted gradient-encoded selective refocusing as well as classical 2D ((1) H-(1) H) exchange spectroscopy, diffusion-ordered spectroscopy and T1 ((1) H) measurements, in combination with density functional theory methods allow the full conformational dynamics of a pyridylmethylamine-Zn(II) complex to be revealed. Four conformers and two families of complexes depending on the hydration states are elucidated., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Cyclic homologated amino acids are important building blocks for the construction of helical foldamers. N-aminoazetidine-2-carboxylic acid (AAzC), an aza analogue of trans-2-aminocyclobutanecarboxylic acid (tACBC), displays a strong hydrazino turn conformational feature, which is proposed to act as an 8-helix primer. tACBC oligomers bearing a single N-terminal AAzC residue were studied to evaluate the ability of AAzC to induce and support an 8-helix along the oligopeptide length. While tACBC homooligomers assume a dominant 12-helix conformation, the aza-primed oligomers preferentially adopt a stabilized 8-helix conformation for an oligomer length up to 6 residues. The (formal) single-atom exchange at the N terminus of a tACBC oligomer thus contributes to the sustainability of the 8-helix, which resists the switch to a 12-helix. This effect illustrates atomic-level programmable design for fine tuning of peptide foldamer architectures., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new correlation experiment cited as "push-G-SERF" is reported. In the resulting phased 2D spectrum, the chemical shift information is selected along the direct dimension, whereas scalar couplings involving a selected proton nucleus are edited in the indirect domain. The robustness of this pulse sequence is demonstrated on compounds with increasing structural and spectral complexity, using state-of-the-art spectrometers. It allows for full resolution of both dimensions of the spectrum, yielding a straightforward assignment and measurement of the coupling network around a given proton in the molecule. This experiment is intended for chemists who want to address efficiently the structural analysis of molecules with an overcrowded spectrum., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Probing scalar couplings are essential for structural elucidation in molecular (bio)chemistry. While the measurement of JHH couplings is facilitated by SERF experiments, overcrowded signals represent a significant limitation. Here, a new band selective pure shift SERF allows access to δ(1)H and JHH with an ultrahigh spectral resolution.