19F NMR Signals Research Articles

A novel in-situ strategy for enantiomeric discrimination and selective identification of multicomponent carboxylic acids in foods

Chiral carboxylic acids are ubiquitous in nature and are of pivotal importance in practical applications in the field of food science and pharmaceuticals. Simultaneous enantiomeric analysis of carboxylic acids mixtures is a significant research goal. Herein, we demonstrate a new strategy involving the use of the highly selective chiral derivatizing agent (R)-2-amino-1,1,1-trifluoropropane ((R)-TFPA) for the enantiomeric discrimination and selective identification of carboxylic acids in mixtures, even structurally similar drugs. The key success of this sensing approach lies in the distinguishable 19F NMR signals of diastereoisomers formed via derivatization of the substrates by (R)-TFPA. The utility of this approach was demonstrated by simultaneously differentiating 20 chiral carboxylic acids in a complicated mixture with accurate determination of the enantiomeric excess (ee). Most importantly, our approach can be applied to food analysis, where the diverse carboxylic acids in real samples without separation were unambiguously identified, such as vinegar, yogurt, and grape.

Guiding the High-Yield Synthesis of NHC-Ligated Gold Nanoclusters by 19F NMR Spectroscopy.

Optimizing the synthesis of atomically precise metal nanoclusters by virtue of molecular tools is highly desirable but quite challenging. Herein we report how 19F NMR spectroscopy can be used to guide the high-yield synthesis of N-heterocyclic carbene (NHC)-stabilized gold nanoclusters. In spite of little difference, 19F NMR signals of fluoro-incorporated NHCs (FNHC) are highly sensitive to the tiny change in their surrounding chemical environments with different N-substituents, metals, or anions, thus providing a convenient strategy to discriminate species in reaction mixtures. By using 19F NMR, we first disclosed that the one-pot reduction of FNHC-Au-X (X is halide) yields multiple compounds, including cluster compounds and also a large amount of highly stable [Au(FNHC)2]+ byproduct. The detailed quantitative 19F NMR analyses over the reductive synthesis of NHC-stabilized Au nanoclusters reveal that the formation of the di-NHC complex is deleterious to the high-yield synthesis of NHC-stabilized Au nanoclusters. With the understanding, the reaction kinetic was then slowed by controlling the reduction rate to achieve the high yield of a [Au24(FNHC)14X2H3]3+ nanocluster with a unique structure. The strategy demonstrated in this work is expected to provide an effective tool to guide the high-yield synthesis of organic ligand-stabilized metal nanoclusters.

Composites of (C4F)n and (CF)n Synthesized by Uncatalyzed Fluorination of Graphite

A new solid-state 19F magic-angle spinning NMR signal at an isotropic 19F chemical shift of −53 ppm is measured from graphite fluoride synthesized by reaction of graphite with F2 at temperatures above 750 K with no catalyst. Two-dimensional NMR suggests the −53 ppm 19F NMR signal originates from covalent fluoromethanetriyl groups belonging to ordered (CyF)n bulk domains composited with the major (CF)n domains. Quantitative 19F and 13C NMR find y=4.32±0.64. DFT calculations of NMR chemical shifts for unsaturated fluorographene models show that a (C4F)n phase with fluorine bound covalently to a single side of the carbon layer best explains the observed NMR chemical shifts. We assign the new phase to this (C4F)n structure, which constitutes up to 15% of the carbon in our graphite fluoride composites. The (C4F)n content of the composite affects bulk electrochemical properties in a manner similar to graphite fluorides produced by conventional, catalyzed fluorination processes.

Janus-Type Dendrimers Based on Highly Branched Fluorinated Chains with Tunable Self-Assembly and 19F Nuclear Magnetic Resonance Properties

Tuning the self-assembly of dendritic amphiphiles represents a major challenge for the design of advanced nanomaterials for biomimetic applications. The morphology of the final aggregates, in fact, critically depends on the primary structure of the dendritic building blocks as well as the environmental conditions. Here we report a new family of fluorinated Janus-type dendrimers (FJDs), based on a short-chain and branched fluorinated synthon with 27 magnetically equivalent fluorine atoms, linked to bis-MPA polyester dendrons of different generations. Increasing size, flexibility, and number of peripheral hydroxyl groups, we observed a peculiar self-assembly behavior in bulk and in aqueous media as a consequence of the subtle balance between their fluorinated and hydrophilic portions. The lowest generation FJDs formed spherical nanoparticles in water, e.g., micelles, showing a single 19F NMR peak with good signal-to-noise ratio and over time stability, making them promising as 19F-MRI traceable probes. The highest generation FJD, instead, presented an interesting morphological transition from multilamellar dendrimersomes to tubules as a consequence of a subtle balance of intra- and intermolecular forces that compete at the interface. Interestingly, a reduction of the local mobility of CF3 groups passing from dendrimersomes to tubules switches off the 19F NMR signal. The transition mechanism has been rationalized by coarse-grain simulations as well as demonstrated by using cosolvents of different nature (e.g., fluorinated) that promote conformational changes, ultimately reflected in the self-assembly behavior. Short and branched fluorinated chains have here been demonstrated as new moieties for the design of FJDs with tunable self-assembly behavior for potential applications as biocompatible 19F MRI probes in the construction of theranostic platforms.

Electrostatic effects on 19F NMR chemical shifts in N-phenyl γ-lactam derivatives

Covalently identical ortho-F nuclei display dual 19F NMR signals in di-ortho-F substituted N-phenyl γ-lactams. Structural variations at C9-substituent on the γ-lactam lead to larger chemical shift changes at downfield 19F signals (δdown) than those at upfield 19F signals (δup). A “reverse” correlation between downfield 19F chemical shifts and electron-withdrawing abilities of C9-phenylamides is observed. Electrostatic effects are the major forces between C9-substituents and ortho-F nuclei, and Hammett parameters can be used to describe such through-space interactions. Structural factors influencing ortho-19F shielding among diverse C9-substituted N-phenyl γ-lactams are discussed.

Spectroscopic study of cyclen-based 19F NMR probe for detection of hydrogen sulfide.

A cyclen-based 19F NMR probe (F-cyclen) for hydrogen sulfide (H2S) has been prepared and evaluated for its complex formation ability with Cu2+ ions and responsivity to H2S. F-Cyclen was readily synthesized by reacting cyclen with 4-(trifluoromethyl)benzyl bromide. Visible absorption spectrophotometry showed that, same as the original cyclen, F-cyclen formed a 1:1 complex with Cu2+ ions. The 19F NMR signal of F-cyclen at 16.5ppm gradually decreased in intensity with increasing CuCl2 concentration, with trifluoromethane sulfonic acid sodium salt (TFMSNa) used as an internal standard (0ppm). When the Cu2+-F-cyclen complex was subjected to an increasing concentration of Na2S (as H2S donor), its corresponding 19F NMR signal of F-cyclen at 16.5ppm gradually increased in intensity. The regression curve between the 19F NMR signal intensity ratio of F-cyclen to TFMSNa and Na2S concentration showed good linearity (r = 0.986) over the Na2S concentration range of 25-150μM.

Triplet Dynamic Nuclear Polarization of Guest Molecules through Induced Fit in a Flexible Metal–Organic Framework**

AbstractDynamic nuclear polarization utilizing photoexcited triplet electrons (triplet‐DNP) has great potential for room‐temperature hyperpolarization of nuclear spins. However, the polarization transfer to molecules of interest remains a challenge due to the fast spin relaxation and weak interaction with target molecules at room temperature in conventional host materials. Here, we demonstrate the first example of DNP of guest molecules in a porous material at around room temperature by utilizing the induced‐fit‐type structural transformation of a crystalline yet flexible metal–organic framework (MOF). In contrast to the usual hosts, 1H spin‐lattice relaxation time becomes longer by accommodating a pharmaceutical model target 5‐fluorouracil as the flexible MOF changes its structure upon guest accommodation to maximize the host–guest interactions. Combined with triplet‐DNP and cross‐polarization (CP), this system realizes an enhanced 19F NMR signal of guest target molecules.

Effects of fluorine bonding and nonbonding interactions on 19F chemical shifts.

19F-NMR signals are sensitive to local electrostatic fields and are useful in probing protein structures and dynamics. Here, we used chemically identical ortho-F nuclei in N-phenyl γ-lactams to investigate the relationship between 19F NMR chemical shifts and local environments. By varying the structures at the C5- and C7-substituents, we demonstrated that 19F shifts and Hammett coefficients in Hammett plots follow typical relationships in bonding interactions, while manifesting reverse correlations in nonbonding contacts. Quantum mechanics calculations revealed that one of the ortho-F nuclei engages in n → π* orbital delocalization between F lone pair electrons (n) and a C[double bond, length as m-dash]O/Ar[double bond, length as m-dash]N antibonding orbital (π*), and the other ortho-F nucleus exhibits n ↔ σ orbital polarization between the n electrons and the C-H σ bonding orbital. As 19F NMR spectroscopy find increasing use in molecular sensors and biological sciences, our findings are valuable for designing sensitive probes, elucidating molecular structures, and quantifying analytes.

Relating Conformational Equilibria to Conformer-Specific Lipophilicities: New Opportunities in Drug Discovery.

Efficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation–activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer‐specific lipophilicities (logp) is much less explored. Here we show how conformer‐specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.

Relating Conformational Equilibria to Conformer‐Specific Lipophilicities: New Opportunities in Drug Discovery

AbstractEfficient drug discovery is based on a concerted effort in optimizing bioactivity and compound properties such as lipophilicity, and is guided by efficiency metrics that reflect both aspects. While conformation–activity relationships and ligand conformational control are known strategies to improve bioactivity, the use of conformer‐specific lipophilicities (logp) is much less explored. Here we show how conformer‐specific logp values can be obtained from knowledge of the macroscopic logP value, and of the equilibrium constants between the individual species in water and in octanol. This is illustrated with fluorinated amide rotamers, with integration of rotamer 19F NMR signals as a facile, direct method to obtain logp values. The difference between logp and logP optimization is highlighted, giving rise to a novel avenue for lipophilicity control in drug discovery.

Modes of Disorder in Poly(carbon monofluoride).

Poly(carbon monofluoride), or (CF)n, is a layered fluorinated graphite material consisting of nanosized platelets. Here, we present experimental multidimensional solid-state NMR spectra of (CF)n, supported by density functional theory (DFT) calculations of NMR parameters, which overhauls our understanding of structure and bonding in the material by elucidating many ways in which disorder manifests. We observe strong 19F NMR signals conventionally assigned to elongated or "semi-ionic" C-F bonds and find that these signals are in fact due to domains where the framework locally adopts boat-like cyclohexane conformations. We calculate that C-F bonds are weakened but are not elongated by this conformational disorder. Exchange NMR suggests that conformational disorder avoids platelet edges. We also use a new J-resolved NMR method for disordered solids, which provides molecular-level resolution of highly fluorinated edge states. The strings of consecutive difluoromethylene groups at edges are relatively mobile. Topologically distinct edge features, including zigzag edges, crenellated edges, and coves, are resolved in our samples by solid-state NMR. Disorder should be controllable in a manner dependent on synthesis, affording new opportunities for tuning the properties of graphite fluorides.

Development of Off-On Switching 19F MRI Probes for Cathepsin K Activity Detection

Abstract Cathepsin K is a protease expressed in osteoclasts that degrades bone tissue, such as type I collagen fibers. Overexpression of cathepsin K is involved in osteoporosis, rheumatoid arthritis, and bone metastasis. Therefore, detecting cathepsin K activity is important for understanding the mechanism of these diseases and developing new drugs. However, current chemical probes cannot be employed for the detection of cathepsin K activity in animal deep-tissue. In this study, we developed novel 19F magnetic resonance imaging (MRI) probes (FLAME-(Gd-X), X = Acp, Deg, Deg2) to detect cathepsin K. In FLAME-(Gd-X), the Gd3+ complex was modified on the surface of perfluorocarbon-encapsulated silica nanoparticles through cathepsin K substrate and three different hydrophobic/hydrophilic linkers. The 19F NMR signal intensities of these probes were suppressed by the paramagnetic relaxation enhancement (PRE) effect of the Gd3+ complexes. The 19F MRI signal intensities of FLAME-Gd-Acp and FLAME-Gd-Deg specifically increased with the substrate cleavage by cathepsin K. The 19F MRI probes based on the PRE effect can be applied to the in vivo detection of cathepsin K activity.

Tailoring Sensors and Solvents for Optimal Analysis of Complex Mixtures Via Discriminative 19F NMR Chemosensing.

Separation-free analytic techniques capable of providing precise and real-time component information are in high demand. 19F NMR-based chemosensing, where the reversible binding between analytes and a 19F-labeled sensor produces chromatogram-like output, has emerged as a valuable tool for the rapid analysis of complex mixtures. However, the potential overlap of the 19F NMR signals still limits the number of analytes that can be effectively differentiated. In this study, we systematically investigated the influence of the sensor structure and NMR solvents on the resolution of structurally similar analytes. The substituents adjacent and distal to the 19F labels are both important to the resolving ability of the 19F-labeled sensors. More pronounced separation between 19F NMR peaks was observed in nonpolar and aromatic solvents. By using a proper sensor and solvent combination, more than 20 biologically relevant analytes can be simultaneously identified.

NMR investigations of polytrifluoroethylene (PTrFE) synthesized by RAFT

Identification of the 1H, 19F, and 13C NMR signals of the end-groups of polytrifluoroethylene synthesized by RAFT polymerisation.

Synthesis and application of a 19F-labeled fluorescent nucleoside as a dual-mode probe for i-motif DNAs.

Because of their stable orientations and their minimal interference with native DNA interactions and folding, emissive isomorphic nucleoside analogues are versatile tools for the accurate analysis of DNA structural heterogeneity. Here, we report on a bifunctional trifluoromethylphenylpyrrolocytidine derivative (FPdC) that displays an unprecedented quantum yield and highly sensitive 19F NMR signal. This is the first report of a cytosine-based dual-purpose probe for both fluorescence and 19F NMR spectroscopic DNA analysis. FPdC and FPdC-containing DNA were synthesized and characterized; our robust dual probe was successfully used to investigate the noncanonical DNA structure, i-motifs, through changes in fluorescence intensity and 19F chemical shift in response to i-motif formation. The utility of FPdC was exemplified through reversible fluorescence switching of an FPdC-containing i-motif oligonucleotide in the presence of Ag(i) and cysteine.

New fluorinated manganese carbonyl complexes for light controlled carbon monoxide (CO) release and the use of benchtop 19F-NMR spectroscopy

Carbon monoxide (CO) is used as an essential therapeutic agent. Control delivery and tracking of CO is the important concern for using in therapeutics. We report fluorinated manganese(I) tricarbonyl complexes PF-DPA.Mn and CF-DPA.Mn as a new photoCORMs for the photo-controlled CO release. For the first time, the benchtop 19F-NMR “on-off” signal has been used to monitor light-controlled CO release along with other traditional methods. 19F-NMR signal was initially “on” which attenuates on irradiating with blue light due to conversion of Mn(I) to Mn(II). CO release behaviour of new complexes also supported by Myoglobin assay, time-dependent IR study and UV–Vis experiments. Fluorinated manganese carbonyl complexes with 19F-NMR open up vast opportunities for researchers to develop a fast and reliable technique for tracking CO release.

(Invited) Novel Approaches for the Study of Local Processes in Rocksalt Oxyfluoride Cathodes

Cation-disordered rocksalt (DRX) lithium transition metal oxides have recently emerged as a new class of high energy density lithium-ion cathodes, but in most cases suffer from rapid performance degradation upon electrochemical cycling. Unlike layered lithium transition metal oxides, these DRXs are amenable to bulk fluorination (as demonstrated by 19F NMR spectroscopy) and significant improvements in their electrochemical properties, especially cyclability, have been observed upon partial oxygen substitution by fluorine.1 We present here our findings on the impact of fluorine doping on the local cation order and structural and electrochemical properties of several DRX cathodes, using a combination of solid-state NMR experiments and theoretical calculations. Specifically, the impact of F insertion on the distribution of Li and F species in the as-synthesized cathodes is evaluated, and changes in the local structure upon electrochemical cycling are monitored. Ex situ 19F NMR spectra collected on cathode samples stopped at different stages of (dis)charge are particularly difficult to interpret, due to the presence of paramagnetic transition metals leading to very large shifts and broad resonances. In addition, the intrinsic disorder on the cation sublattice leads to a large number of F environments with similar shifts, resulting in broad and overlapping signals. To assist the interpretation of the NMR data, we use Monte Carlo simulations and ab initio calculations of the paramagnetic NMR parameters to determine the distribution of F environments in the materials and predict the chemical shift for these various F sites.Monte Carlo simulations clearly indicate short-range order in the as-synthesized materials, with the incorporation of F in octahedral anion sites with at least five Li nearest-neighbors, in good agreement with 19F NMR results (see Fig. 1). Yet, first principles calculations of NMR parameters reveal that 19F NMR signals from F nuclei directly bonded to the redox-active (and paramagnetic) transition metal species are too broad to be observed.2 Hence, all experimentally-observed 19F NMR signals arise from F sites that are not directly bonded to the paramagnetic metal. These initial insights clearly reveal the strength of our combined experimental and theoretical approach but also suggest that further insight into short-range order in these complex materials requires new experimental (NMR) approaches and complementary techniques. Figure 1. a) Distribution of F environments in the model Li1.166Ni0.333Ti0.5O1.833F0.166 DRX structure obtained from Monte Carlo simulations at an equilibration temperature of 973 K. This distribution is used as a proxy for the distribution of F environments in the Li1.15Ni0.45Ti0.3Mo0.1O1.85F0.15material synthesized at 700°C. b) 19F spin echo NMR spectrum obtained at 11.7 T and at a magic angle spinning (MAS) speed of 60 kHz. The observed 19F signal arises from F nuclei with no Ni nearest-neighbor. Figures adapted from Clément et al.2

Fluorinated ZnFeIII Hollow Metal-Organic Framework as a 19F NMR Probe for Highly Sensitive and Selective Detection of Hydrogen Sulfide.

Hydrogen sulfide (H2S) is considered as a highly toxic environmental pollutant and an important signal transmitter in physiological processes, and the selective and reliable detection of H2S is of great concern and remains challenging. Herein, we report a smart sensitive “off–on” 19F NMR sensor for H2S by partially introducing a fluorinated ligand to construct a hollow dual metal–organic framework (MOF) nanosystem, F-ZnFeIII hMOF, in which the fluorinated ligand acts as the 19F signal source but is initially quenched due to the strong paramagnetic relaxation enhancement (PRE) effect from neighboring Fe3+ nodes. Upon exposure to sulfide ions, reduction of Fe3+ to Fe2+ is specifically triggered, which attenuates PRE efficiency, thus turning on the 19F NMR signal. The unique hollow MOF architecture benefits the mobility of 19F atoms, thereby improving the response sensitivity. Meanwhile, the desirable H2S-sorption feature and appropriate redox potential of Fe3+/Fe2+ account for the favorable selectivity. The increase in the 19F signal is linear with the concentration of sulfide in the range of 20 to 150 μM with a detection limit of 2.8 μM. The probe is well demonstrated by analyzing H2S in complex matrixes such as biological and foodstuff samples.

4'-Fluorinated RNA: Synthesis, Structure, and Applications as a Sensitive 19F NMR Probe of RNA Structure and Function.

Fluorinated RNA molecules, particularly 2'-F RNA, have found a wide range of applications in RNA therapeutics, RNA aptamers, and ribozymes and as 19F NMR probes for elucidating RNA structure. Owing to the instability of 4'-F ribonucleosides, synthesis of 4'-F-modified RNA has long been a challenge. In this study, we developed a strategy for synthesizing a 4'-F-uridine (4'FU) phosphoramidite, and we used it to prepare 4'-F RNA successfully. In the context of an RNA strand, 4'FU, which existed in a North conformation, was reasonably stable and resembled unmodified uridine well. The 19F NMR signal of 4'FU was sensitive to RNA secondary structure, with a chemical shift dispersion as large as 4 ppm (compared with <1 ppm for 2'FU), which makes it a valuable probe for discriminating single-stranded RNA and A-type, B-type, and mismatched duplexes. In addition, we demonstrated that because RNA-processing enzymes treated 4'FU the same as unmodified uridine, 4'FU could be used to monitor RNA structural dynamics and enzyme-mediated RNA processing. Taken together, our results indicate that 4'-F RNA represents a probe with wide utility for elucidation of RNA structure and function by means of 19F NMR spectroscopy.

Al(III)-NTA-fluoride: a simple model system for Al-F binding with interesting thermodynamics.

Al(iii) complexes are extensively studied as [18F]fluoride carriers in positron emission tomography. However, our limited knowledge on their thermodynamic and kinetic properties has hindered efforts to easily prepare radiochemically pure compounds while simultaneously reducing the overall labeling time. Thus, to improve our understanding of fluoride binding to coordinatively unsaturated Al(iii) complexes, we investigated the ternary system Al(iii)-H3NTA-F- (H3NTA = nitrilo-triacetic acid) by NMR, potentiometry and X-ray diffraction. Our results show that the [Al(NTA)] complex binds two water molecules, which are replaced by fluorides. Individual species and isomers show separate 19F NMR signals and different stability constants. The two available positions on the [Al(NTA)] complex feature significantly different properties in terms of basicity of the coordinated water molecules and preferential binding of fluoride anions. Fluorides are effectively bound in weakly acidic or neutral solutions, whereas hydroxido species are preferentially formed in alkaline solutions. Our experimental observations were rationalized by theoretical calculations: predictions of the energy ordering of complexes and isomers, interpretation of 19F NMR chemical shifts, and natural bonding orbital analysis. Radiolabeling of [Al(NTA)] with [18F]fluoride gave low yields that confirmed a high affinity of the complex for hydroxide anions.