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FT-ICR MS and NMR analysis of an isotopically labeled complex mixture of water disinfection byproducts formed by chloramine disinfection of model phenolic acids is described. A new molecular formula assignment procedure using the CoreMS Python library able to assign isotopically enriched formulas is proposed. Statistical analysis of the assigned formulas showed that the number of compounds, the diversity of the mixture, and the chlorine count increase during the chloramination reaction. The complex reaction mixture was investigated as a network of reactions using PageRank and Reverse PageRank algorithms. Independent of the MS signal intensities, the PageRank algorithm calculates the formulas with the highest probability at convergence of the reaction; these were chlorinated and nitrated derivatives of the starting materials. The Reverse PageRank revealed that the most probable chemical transformations in the complex mixture were chlorination and decarboxylation. These agree with the data obtained from INADEQUATE NMR spectra and literature data, indicating that this approach could be applied to gain insight into reactions pathways taking place in complex mixtures without any prior knowledge.

Proton-detected INADEQUATE NMR experiments are widely used for structure elucidation of small molecules, in particular the implementations that display 13 C single-quantum rather than double-quantum frequencies in the indirect dimension of 2D spectra. But unfortunately, such spectra in addition to the desired 1 H- 13 C two-bond correlations also contain HSQC artifacts of comparable magnitude. The redesigned versatile experiment presented in this paper requires no compromise based on different 13 C multiplicities and suppresses the HSQC artifacts that are a source of possible spectral misinterpretation. Demonstration of the new method is shown by applications to typical small molecules of different complexity., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Since its discovery in mid-20 th century, the sensitivity of Nuclear Magnetic Resonance (NMR) has increased steadily, in part due to the design of new, sophisticated NMR experiments. Here we report on a liquid-state NMR methodology that significantly increases the sensitivity of diffusion coefficient measurements of pure compounds, allowing to estimate their sizes using a much reduced amount of material. In this method, the diffusion coefficients are being measured by analysing narrow and intense singlets, which are invariant to magnetic field inhomogeneities. The singlets are obtained through signal acquisition embedded in short (<0.5 ms) spin-echo intervals separated by non-selective 180° or 90° pulses, suppressing the chemical shift evolution of resonances and their splitting due to J couplings. The achieved 10-100 sensitivity enhancement results in a 100-10000-fold time saving. Using high field cryoprobe NMR spectrometers, this makes it possible to measure a diffusion coefficient of a medium-size organic molecule in a matter of minutes with as little as a few hundred nanograms of material., (© 2023. The Author(s).)

We present modifications of the ADEQUATE experiment which more than double the sensitivity of carbon-carbon correlations of 13 CH- 13 CH moieties. Additionally, these improvements can be applied without a sensitivity penalty to obtain spectra with a 13 C chemical shift axis in the indirectly detected dimension, instead of a double-quantum frequency, allowing simpler interpretation of spectra. The modified experiments, which use refocussing of 1 J CH couplings and 1 H decoupling during J CC evolution intervals, were tested on several molecules, including a pentasaccharide (20 mg, 19 mM), where on average a 2.6-fold signal-to-noise improvement was achieved and the number of observable correlations increased. Doubling sensitivity results in a 4-fold reduction of the experimental time, allowing ADEQUATE spectra to be recorded overnight instead of over multiple days.

Benchtop NMR spectrometers provide a promising alternative to high-field NMR for applications that are limited by instrument size and/or cost. 19 F benchtop NMR is attractive due to the larger chemical shift range of 19 F relative to 1 H and the lack of background signal in most applications. However, practical applications of benchtop 19 F NMR are limited by its low sensitivity due to the relatively weak field strengths of benchtop NMR spectrometers. Here we present a sensitivity-enhancement strategy that combines SABRE (Signal Amplification By Reversible Exchange) hyperpolarization with the multiplet refocusing method SHARPER (Sensitive, Homogeneous, And Resolved PEaks in Real time). When applied to a range of fluoropyridines, SABRE-SHARPER achieves overall signal enhancements of up to 5700-fold through the combined effects of hyperpolarization and line-narrowing. This approach can be generalized to the analysis of mixtures through the use of a selective variant of the SHARPER sequence, sel SHARPER. The ability of SABRE- sel SHARPER to simultaneously boost sensitivity and discriminate between two components of a mixture is demonstrated, where selectivity is achieved through a combination of selective excitation and the choice of polarization transfer field during the SABRE step., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

We present a signal enhancement strategy for benchtop NMR that produces SNR increases on the order of 10 to 30 fold by collapsing the target resonance into an extremely narrow singlet. Importantly, the resultant signal is amenable to quantitative interpretation and therefore can be applied to analytical applications such as reaction monitoring.

We demonstrate an extension to the SHARPER (Sensitive Homogenous and Refocussed Peaks in Real Time) NMR experiment which allows more than one signal to be monitored simultaneously, while still giving ultra-sharp, homo- and hetero-decoupled NMR signals. This is especially valuable in situations where magnetic field inhomogeneity would normally make NMR a problematic tool, for example when gas evolution is occurring during reaction monitoring. The originally reported SHARPER experiment only works for a single, on-resonance NMR signal, but here we demonstrate the Multiple Resonance SHARPER approach can be developed, which in principle can acquire multiple on-/off-resonance signals simultaneously while retaining the desirable properties of the parent sequence. In practice, the case of two resonances, e.g. those of a reactant and a product, will most of the time be considered for MR-SHARPER, as illustrated here.

Addressing limitations of the existing NMR techniques for the structure determination of mono-fluorinated compounds, we have developed methodology that uses 19 F as the focal point of this process. The proposed 19 F-centred NMR analysis consists of a complementary set of broadband, phase-sensitive NMR experiments that utilise the substantial sensitivity of 19 F and its far reaching couplings with 1 H and 13 C to obtain a large number of NMR parameters. The assembled 1 H, 13 C and 19 F chemical shifts, values of J HF , J HH , and J F isotopic shifts constitute a rich source of information that enables structure elucidation of fluorinated moieties and even complete structures of molecules. Here we introduce the methodology, provide a detailed description of each NMR experiment and illustrate their interpretation using 3-fluoro-3-deoxy-d-glucose. This novel approach performs particularly well in the structure elucidation of fluorinated compounds embedded in complex mixtures, eliminating the need for compound separation or use of standards to confirm the structures. It represents a major contribution towards the analysis of fluorinated agrochemicals and (radio)pharmaceuticals at any point during their lifetime, including preparation, use, biotransformation and biodegradation in the environment. The developed methodology can also assist with the investigations of the stability of fluoroorganics and their pharmacokinetics. Studies of reaction mechanisms using fluorinated molecules as convenient reporters of these processes, will also benefit.FC coupling constants and the size of 13 C induced 19 F isotopic shifts constitute a rich source of information that enables structure elucidation of fluorinated moieties and even complete structures of molecules. Here we introduce the methodology, provide a detailed description of each NMR experiment and illustrate their interpretation using 3-fluoro-3-deoxy-d-glucose. This novel approach performs particularly well in the structure elucidation of fluorinated compounds embedded in complex mixtures, eliminating the need for compound separation or use of standards to confirm the structures. It represents a major contribution towards the analysis of fluorinated agrochemicals and (radio)pharmaceuticals at any point during their lifetime, including preparation, use, biotransformation and biodegradation in the environment. The developed methodology can also assist with the investigations of the stability of fluoroorganics and their pharmacokinetics. Studies of reaction mechanisms using fluorinated molecules as convenient reporters of these processes, will also benefit., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Although the number of natural fluorinated compounds is very small, fluorinated pharmaceuticals and agrochemicals are numerous. 19 F NMR spectroscopy has a great potential for the structure elucidation of fluorinated organic molecules, starting with their production by chemical or chemoenzymatic reactions, through monitoring their structural integrity, to their biotic and abiotic transformation and ultimate degradation in the environment. Additionally, choosing to incorporate 19 F into any organic molecule opens a convenient route to study reaction mechanisms and kinetics. Addressing limitations of the existing 19 F NMR techniques, we have developed methodology that uses 19 F as a powerful spectroscopic spy to study mixtures of fluorinated molecules. The proposed 19 F-centred NMR analysis utilises the substantial resolution and sensitivity of 19 F to obtain a large number of NMR parameters, which enable structure determination of fluorinated compounds without the need for their separation or the use of standards. Here we illustrate the 19 F-centred structure determination process and demonstrate its power by successfully elucidating the structures of chloramination disinfectant by-products of a single mono-fluorinated phenolic compound, which would have been impossible otherwise. This novel NMR approach for the structure elucidation of molecules in complex mixtures represents a major contribution towards the analysis of chemical and biological processes involving fluorinated compounds., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)