Efficient 19F signal amplification by reversible exchange (SABRE) remains difficult because enhancement depends on multiple substrate-specific structural and electronic factors. Here we report a machine-learning-assisted strategy for identifying and ranking high-performance 19F SABRE substrates. A chemical space of more than 180 000 fluorinated N-heterocycles was mapped using refined molecular descriptors, and 33 representative fluorinated pyridine substrates were selected for experimental SABRE screening. Random forest classification identified N_Sum_of_connectivity as a key descriptor separating high- and low-enhancement substrates. For substrates classified in the high-enhancement regime, forward stepwise multivariate linear regression with leave-one-out cross-validation produced an interpretable five-descriptor model for quantitative signal-enhancement-factor prediction. External validation with six additional substrates showed good agreement between predicted and experimental values for high-enhancement candidates. Notably, 3-amino-4-fluoropyridine gave an experimental enhancement of 7133-fold, close to the predicted value of 6637-fold, corresponding to approximately 3.2% polarization at 1.4 T without co-ligands. The selected substrates further enabled single-scan simultaneous hyperpolarization of 15 fluorinated pyridines. This workflow provides an interpretable framework for data-driven optimization of 19F SABRE substrates.

The unique multichannel capability of F-19 nuclear magnetic resonance (NMR) stands as a pivotal and rapidly advancing frontier in chemistry, biology, and medical imaging. However, its inherent low sensitivity limits its widespread applications. While hyperpolarization significantly enhances F-19 signals, simultaneously hyperpolarizing multiple F-19-containing substrates, which is essential for unlocking the multichannel potential of F-19 NMR, remains a key challenge. Here, we introduce an approach that achieves effective and simultaneous hyperpolarization of different F-19 nuclei from several molecular probes through parahydrogen-based signal amplification by reversible exchange (SABRE). Our strategy utilizes multiple F-19-labeled substrates for SABRE, acting as co-ligands for simultaneous enhancement of their F-19 NMR signal intensities. The synergistic effect among different F-19-labeled co-substrates is evidenced by the much higher signal enhancement, compared to the systems containing only one F-19-labeled substrate. The highest enhancement of the F-19 NMR signal reached over 9600-fold on a benchtop NMR (1.4 T), corresponding to a 4.3% polarization level. On this basis, we successfully implemented multichannel quantitative detection of enzymatic biomarkers at & micro;M levels. By utilizing three F-19-labeled pyridine-based substrates, each bearing a specific enzyme-responsive moiety, we demonstrate the capability of high-speed, cost-efficient, and highly sensitive SABRE-polarized F-19 NMR for applications in biomarker detection. Our work paves the way for future applications of highly sensitive multichannel F-19 NMR analysis.

Fluorine-19 nuclear magnetic resonance (19F NMR) is an attractive and widely studied heteronuclear platform due to its high gyromagnetic ratio, wide chemical-shift dispersion, and negligible endogenous background. However, if only the intrinsically low thermal nuclear polarization is available, then, as with any NMR nucleus, 19F still suffers from a high limit of detection. Hyperpolarization addresses this bottleneck and delivers orders-of-magnitude signal enhancements by creating non-Boltzmann nuclear spin populations. Here, we review recent progress in hyperpolarized 19F NMR in liquids, with a primary emphasis on parahydrogen-based techniques, including both hydrogenative PHIP and reversible binding approaches such as SABRE. We discuss how polarization is generated and transferred, and how 19F-specific spin properties and relaxation pathways govern attainable polarization levels and lifetimes. Key determinants—including magnetic-field dependence, scalar-coupling topology, chemical exchange and hydrogenation kinetics, and catalyst/ligand design—are summarized as mechanistic and practical design variables for optimizing performance. We also survey complementary hyperpolarization strategies, including dissolution and Overhauser-effect DNP, CIDNP, and photo-CIDNP, highlighting their scope, strengths, and limitations. Finally, we outline emerging opportunities and design principles for robust, quantitative hyperpolarized 19F NMR protocols that enable sensitive spectroscopy and analysis in complex chemical and biological environments.

Signal amplification by reversible exchange (SABRE), a parahydrogen-based hyperpolarization technique, stands out for its operational accessibility and exceptional sensitivity enhancement. However, the structure-dependent mechanisms underlying hyperpolarization efficiency remain elusive, hindering targeted optimization. Herein, we investigated the relationship between substrate structure and SABRE hyperpolarization efficiency by probing coordination thermodynamics between pyridine/pyrazine derivatives and iridium catalyst precursors using 1H NMR, 2D diffusion-ordered spectroscopy (DOSY), and T1 relaxation measurements. We found that substrates exhibiting large coordination equilibrium constants (Keq) and decreased self-diffusion coefficients upon ligation to the catalyst generally showed higher signal enhancement. Further hyperpolarization on a mixture of four pyridine derivatives confirmed a direct correlation between signal enhancement and Keq magnitudes, i.e., the higher the Keq, the stronger the SABRE enhancement. Furthermore, the rapid spin relaxation of the substrate, as evidenced by shortened T1 values upon ligation to the Ir catalyst, contributed to suboptimal hyperpolarization performance. These findings provide useful experimental insight into substrate-dependent SABRE performance by revealing the combined roles of substrate coordination to the catalyst precursor and relaxation-mediated polarization retention.

The study aimed to assess the influence of diverse solvent schemes on the qualitative analysis of white tea and to establish a more comprehensive quality evaluation. A systematic study of solvent optimization was carried out using the quality analysis of white tea as an exemplar, highlighting the critical role of selecting appropriate solvents in NMR-based sample preparation process. Six sample dissolution protocols, encompassing extraction and reconstitution solvents, were evaluated. The aqueous methanol solution proved effective as an extraction solvent, offering optimal metabolite coverage and spectral resolution. For reconstitution solvents, D2O facilitated identification of specific metabolites, such as amino acids, organic acids and carbohydrates, while DMSO-d6 exhibited better performance in detecting catechins, alkaloids and lipid resonances. Additionally, DMSO-d6 enabled better discrimination among various white tea varieties, whereas D2O system demonstrated better ability for estimating the storage duration of white tea. The characteristic metabolites were exactly those that each of the two solvents is suited to solubilize. Therefore, it can be concluded that solvents suitable for the detection of a class of metabolites are more likely to highlight differences in that type of metabolites and multi-solvent combination captures more comprehensive information, revealing the necessity of optimizing solvent protocols for different assay targets.

Pyrazines are key flavor compounds in various foods, and their detection is essential for assessing quality, authenticity, and potential adulteration. However, because food matrices are complex mixtures, detecting pyrazines typically requires complex pretreatment steps to eliminate interference from structurally similar molecules. In this study, we present a highly selective detection method for pyrazines in food using sensitive and quantitative hyperpolarized NMR. Trace pyrazine compounds in edible oils were detected on a benchtop NMR system (60 MHz, 1.4 T) utilizing signal amplification by reversible exchange (SABRE) hyperpolarization through cosubstrate strategy. Thanks to the high selectivity of SABRE toward pyrazines, our method requires only a simple extraction procedure to achieve accurate quantification of pyrazine with the concentration of 59.3 μmol/L in sesame oil, and the limit of quantification is as low as 21.0 μmol/L. Compared to conventional high-field NMR (500 MHz, 11.7 T), our approach demonstrates high sensitivity and accuracy on a low-field NMR spectrometer. Our works validate SABRE as a powerful tool for highly selective trace analysis, with potential applications in food quality assessment, flavor profiling, and bioactivity analysis.

Proton (1H) NMR spectroscopy presents a powerful tool for biomass mixture studies by revealing the involved chemical compounds with identified ingredients and molecular structures. However, conventional 1H NMR generally suffers from spectral congestion when measuring biomass mixtures, particularly biomass carbohydrate samples, that contain various physically and chemically similar compounds. In this study, a targeted detection NMR approach, DREAMTIME, is exploited for studying biomass carbohydrate mixtures by spectroscopically targeting the desired compounds in separate 1D NMR spectra. From three model mixtures, namely, the C6 sugar isomerization mixture, C5 sugar catalytic hydrogenation mixture, and d-glucose and d-xylose fermentation mixture, to a real reaction mixture of sucrose hydrolysis, DREAMTIME achieves satisfactory performance in compound identification and mixture analysis even when mixture signals are crowded and overlapped in conventional 1H NMR. Additionally, DREAMTIME is performed in a rapid 1D acquisition manner, making it available for highly efficient analysis on various biomass reactions. Our results suggest that DREAMTIME provides an effective method for wide applications to complex biomass mixture analysis with explicit compound identification, targeted component monitoring, and conversion reaction detection.

Micellar solubilization is considered as a key factor affecting the recovery efficiency in chemically enhanced oil recovery (cEOR). However, it is poorly understood how polymers in surfactant-polymer (SP) flooding influences the micellar solubilization. Guar gum (GG) and hydroxyethyl cellulose (HEC) are two important and widely used polysaccharide polymers. In this work, the effect of GG and HEC on the solubilization of a crude oil model compound methyl benzoate (MB) in anionic sodium dodecyl sulfate (SDS) micelles and the underlying mechanism were explored at the molecular scale by NMR spectroscopy. GG and HEC slightly increased the MB solubility in SDS micelles but did not change the solubilization capacity. No correlation peak was observed to demonstrate the attractive interaction between polymer and SDS. After examination, there is weak electrostatic repulsion between HEC/GG and SDS, which made the polymer independent from SDS micelles and was unable to participate in the formation of micelles to alter micellar structure and solubilization behavior. Although the solubility of MB was slightly increased, this increase should originate from weak molecular interactions between polymers, surfactants and hydrophobic molecules, including hydrogen bonding, van der Waals forces and hydrophobic interactions, etc. In summary, without strong electrostatic attraction between polymer and surfactant, the solubilization of polymers and the solubilization of micelles proceed independently, resulting in that the solubilization capacity of SDS micelles was not improved.

Nuclear magnetic resonance (NMR) is a promising tool to provide reproducible metabolite fingerprinting and biomarker discovery for biological products such as white tea. However, one-dimensional NMR spectra of complex biological samples may suffer from severe peak overlapping issue and random drift of chemical shifts. By allowing fine-tuning of chemical shift and line width of peaks, a novel peak fitting strategy is proposed to reduce negative effects of these two nuisance issues, and to extract more informative features from NMR spectra. Experimental results demonstrated that the proposed strategy is more robust to chemical shift drift and peak overlapping issues than the commonly used strategies including spectral binning and characteristic peak quantification. More informative features are extracted, and more powerful models are built for storage year prediction of white tea samples, demonstrating that the peak fitting strategy offers a promising approach for identifying biomarkers and metabolite fingerprinting in NMR-based metabolomics.

Laplace nuclear magnetic resonance (NMR) exploits relaxation and diffusion phenomena to reveal information regarding molecular motions and dynamic interactions, offering chemical resolution not accessible by conventional Fourier NMR. Generally, the applicability of Laplace NMR is subject to the performance of signal processing and reconstruction algorithms involving an ill-posed inverse problem. Here, we propose a proof-of-concept of a deep-learning-based method for rapid and high-quality spectra reconstruction from Laplace NMR experimental data. This reconstruction method is performed based on training on synthetic exponentially decaying data, which avoids a vast amount of practically acquired data and makes it readily suitable for one-dimensional relaxation and diffusion measurements by commercial NMR instruments.

Utilizing para-hydrogen (p-H2)-induced hyperpolarization to increase the sensitivity of nuclear magnetic resonance, especially signal amplification by reversible exchange (SABRE), has been widely studied. Here, we achieved hyperpolarization of exchangeable protons in methanol-d4 by introducing dynamic covalent bonds as reversible exchange following the SABRE process. To release the hyperpolarized CD3OH, the pyridine-based ligands with aldehyde groups underwent acetal exchange between the aldehyde and hydroxyl groups of CD3OH after being first hyperpolarized by SABRE. Our mechanistic study highlights the importance of the reversible exchange of functional groups and chemical kinetics in realizing hyperpolarization of exchangeable protons in methanol-d4. Our work broadens SABRE's chemical system compatibility and possible applications.

The micellar solubilization mechanism of curcumin by mixed surfactants of SDS and Brij35 was investigated at the molecular scale by NMR spectroscopy. Through the investigation of the micelle formation process, types and structures of mixed micelles and solubilization sites, the intrinsic factors influencing the solubilization capacity were revealed. For systems with αSDS = 0.5 and 0.2, the obtained molar solubilization ratios (MSRs) are consistent with the MSRideal values. However, for αSDS = 0.8, the solubilization capacity of curcumin is weakened compared to the MSRideal. Furthermore, only one single mixed SDS/Brij35 micelles are formed for αSDS = 0.5 and 0.2. However, for αSDS = 0.8, there are separate SDS-rich and Brij35-rich mixed micelles formed. In addition, NOESY spectra show that the interaction patterns of SDS and Brij35 in mixed micelles are similar for three systems, as are the solubilization sites of curcumin. Therefore, for αSDS = 0.5 and 0.2 with single mixed micelles formed, the solubility of curcumin depends only on the mixed micelle composition, which is almost equal to the surfactant molar ratio. Although curcumin is solubilized in both separate micelles at αSDS = 0.8, a less stable micelle structure may be responsible for the low solubility. This study provides new insights into the investigation and application of mixed micelle solubilization.

The synergism/inhibition level, solubilization sites and the total solubility (St) of co-solubilization systems of phenanthrene, anthracene and pyrene in Tween 80 and sodium dodecyl sulfate (SDS) are studied by 1H-NMR, 2D nuclear overhauser effect spectroscopy (NOESY) and rotating frame overhauser effect spectroscopy (ROESY). In Tween 80, inhibition for phenanthrene, anthracene and pyrene is observed in most binary and ternary systems. However, in SDS, synergism is predominant. After analysis, we find that the different synergism or inhibition situation between Tween 80 and SDS is related to the different types of surfactants used and the resulting different co-solubilization mechanisms. In addition, we also find that three polycyclic aromatic hydrocarbons (PAHs) have similar solubilization sites in both Tween 80 and SDS, which are almost unchanged in co-solubilization systems. Due to the similar solubilization sites, the chemical shift changes of surfactant and PAH protons follow the same pattern in all solubilization systems, and the order of chemical shift changes is consistent with the order of changes in the St of PAHs. In this case, it is feasible to evaluate St of PAHs by chemical shift. In both Tween 80 and SDS solutions, the ternary solubilization system has relatively high St rankings. Therefore, in practical applications, a good overall solubilization effect can be expected.

Understanding the water state in Nafion is not only crucial for operating a proton-exchange membrane (PEM)-based fuel cell, but also intimately related to the elucidation of the proton transport mechanism in a PEM. Although many studies have been published on this subject, some controversies and ambiguities remain unresolved. In this work, we design three different types of Nafion samples by substituting protons with lithium or sodium cations. We also pay special attention to the preparation of samples for carrying out broad-range variable temperature solid state NMR experiments so that no membrane dehydration occurs during the long experimental time at low temperatures. With these precautions and improvements, clear and largely straightforward information could be obtained to ensure minimal ambiguity and complexity in the interpretation of the experimental data. Our results show that about 40-60% of water remains unfrozen at -70 °C, depending on the type of the substituting cation. Both the 1H and 2H spectral and relaxation results indicate that water freezing starts from the center of the nanopores inside Nafion and increases gradually as the temperature decreases. The protons remain dissociated with sulfonate groups even at the lowest temperature we reached (-70 °C), whereas both lithium and sodium are associated with sulfonate groups at most temperatures below 0 °C. The experimental data also suggest that besides frozen and unfrozen water, there is broad distribution of water state and dynamics in Nafion as the temperature is lowered from above zero down to -70 °C. The effect of the size of the substituting cation significantly affects the properties of supercooled water by modifying the cation-water interaction and impeding the rotation of sulfonate groups. These novel results not only help us in establishing a better understanding of the water state in Nafion and its performance as a proton exchange mebrane, but also provide insights into water freezing, antifreeze and supercooling in other nanoscopic environments.

Different submicellar solubilization mechanisms of two systems, Triton X-100 (TX-100)/tetradecane and sodium dodecyl sulfate (SDS)/butyl methacrylate, are revealed on the molecular scale by 1H NMR spectroscopy and 2D diffusion ordered spectroscopy (DOSY). It is evident that the apparent solubilities of both tetradecane and butyl methacrylate are enhanced, even at much lower surfactant concentrations than the CMCs. Solubilized solutes also contribute to the early formation of surfactant micelles. In general, the molar solubilization ratios (MSRs) of both solutes linearly increase as the surfactant concentrations increase. However, variations in MSRs of the two systems are different below and above the CMC, which is probably related to the different solubilization mechanisms. For TX-100/tetradecane, as the TX-100 concentration increases, the tetradecane resonance in the independent state transforms into that of the aggregated state and the corresponding evolution of diffusions is shown in the 2D DOSY spectra. These results demonstrate that below the CMC, tetradecane is first solubilized in TX-100 solutions, and then solubilized in TX-100 micelles above the CMC. For SDS/butyl methacrylate, the appearance of oligomeric SDS resonances below the CMC indicates that butyl methacrylate is partially solubilized in SDS oligomers. Then, when the CMC is reached, the dominant, monomeric SDS molecules aggregate into oligomers, and the similar diffusivity trend of butyl methacrylate with that of SDS indicates that a proportion of butyl methacrylate molecules are solubilized in it. Finally, the fusion of SDS resonances in the two states and the tendency of co-diffusion of SDS and butyl methacrylate indicate that all the SDS molecules gradually aggregate into micelles, and almost all the butyl methacrylate molecules are solubilized in them. In conclusion, above the CMCs, the solubilization manners of these two systems are similar. However, they are different below CMCs. The solubilization of tetradecane by TX-100 is driven by the intermolecular hydrophobic interaction, i.e., molecular-pair formation. However, the polar interaction between functional groups of butyl methacrylate and the polar head of SDS contributes to the solubilization of butyl methacrylate. The different submicellar solubilization mechanisms are mainly caused by the different properties of solutes and surfactants, which also results in different MSRs and solubilization sites in the micelles.

After mixing a sulfonated NIR-I organic dye (IR820) with human serum albumin (HAS), fluorescence in the biological NIR-II window of the IR820–HSA organic complex increases dramatically, as shown by Yaming Li, Zhen Cheng and co-workers in article number 1901471. In vivo NIR-II imaging with IR820–HSA can noninvasively and dynamically be used to visualize and monitor the physiological and pathological conditions of the vascular system, lymphatic drainage system, and tumor-bearing mice, as well as allow image-guided tumor resection.

Recently, much attention has been focused on the development of second near‐infrared window (NIR‐II, 1000–1700 nm) fluorescence imaging because of its reduced scattering, minimal absorption, and negligible autofluorescence. NIR‐II bioimaging allows the visualization of deep anatomical features with an unprecedented degree of clarity. In addition to the construction of a variety of new NIR‐II fluorophores, using a fluorescence tail emission greater than 1000 nm for conventional NIR‐I dyes represents a promising strategy for developing an NIR‐II imaging technique. Herein, the authors report tailoring a supramolecular assembly of human serum albumin (HSA) protein complexed with a sulfonated NIR‐I organic dye (IR820) to produce a brilliant 21‐fold increase in fluorescence for NIR‐II imaging. In vivo NIR‐II imaging with IR820–HSA allows noninvasive and dynamic visualization and monitoring of physiological and pathological conditions of the vascular system, lymphatic drainage system, and tumor‐bearing mice, as well as image‐guided tumor resection with high spatial and temporal resolution. Furthermore, photoacoustic imaging (PAI) of IR820–HSA in mouse tumor models also demonstrate good tumor accumulation. Overall, an IR820–protein complex with high biocompatibility can be easily constructed using a conventional NIR‐I dye that provides a new theranostic tool with high clinical translation potential.

The micellar solubilization process and mechanism with thymol and Tween 80 as the model drug and surfactant were studied by the tensiometric study, 1H NMR spectroscopy, 2D diffusion ordered spectroscopy (DOSY) and NOESY. First of all, changes in chemical shifts and line shapes of thymol and Tween 80 in mixed solutions compared with those in pure solutions, the co-diffusion of thymol and Tween 80 molecules, and cross peaks between them prove that thymol molecules are solubilized in Tween 80 micelles. The thymol-incorporated Tween 80 micelles form, and its critical micellar concentration (CMC) was obtained. Almost synchronously, the independent diffusion of thymol molecules was observed. These indicate that when the CMC of thymol-incorporated Tween 80 micelles is reached, a portion of thymol molecules are solubilized in Tween 80 micellar solutions. Finally, with the continuous increase of thymol concentration, there is another resonance group of Tween 80 shown up, accompanied by turbid solutions. The independent diffusion of the new Tween 80 resonance group, and its cross peaks with thymol indicate the formation of another aggregate-emulsions, meanwhile, which are coexisted with thymol molecules solubilized in micelles and those dissolved in solutions. The solubilization of thymol in Tween 80 aqueous solutions follows the order of micelles> solutions> emulsions. Besides, different cross peak patterns suggest that solubilization sites of thymol in micelles and emulsions are different. In micelles, thymol molecules are likely to be wrapped in the folded alkane chains of Tween 80. However, in emulsions, they are possibly solubilized in the core of emulsions made of stretched hydrophobic chains. The surface tension results are consistent with the conclusions obtained from NMR studies.

High-resolution nuclear magnetic resonance (NMR) spectroscopy is an indispensable technique for obtaining chemical structure information. Its quantitative and noninvasive properties have led to its growing popularity as an analytical tool in many fields, including biology, chemistry, medicine, and food science. During transportation and storage, chemical reactions among the many nutrients lead to a loss of food quality. In these circumstances, portable NMR spectrometers can readily be used for food inspection and quality control. Because of the heterogeneous tissue distribution in food, a high-resolution NMR method is required for detailed food inspection. Therefore, in this study, we demonstrated the feasibility of using an intermolecular double-quantum coherence signal to obtain high-resolution metabolic profiles of several fruits, including grape, cantaloupe, tomato, and watermelon. The resulting high-resolution NMR spectra facilitate the identification of important metabolites, which can be used as biomarkers for food quality control. The method established here may be adapted for food inspection using portable NMR equipment.