Solid-state 19F NMR Research Articles

Structural Investigation of α- and β-Sodium Hexafluoroarsenate, NaAsF6, by Variable Temperature X-ray Powder Diffraction and Multinuclear Solid-State NMR, and DFT Calculations

We report the phase transition between the α- and β-phases of NaAsF6 monitored by DTA, variable temperature 19F solid-state NMR and temperature controlled X-ray powder diffraction (XRPD) as well as their crystalline structures determined from XRPD data. The structural type of β-NaAsF6 has been determined thanks to 19F and 75As solid-state NMR experiments. 19F, 23Na, and 75As NMR parameters, including 19F–75As 1J coupling, have been measured for both phases. The 19F, 23Na, and 75As solid-state NMR investigations are in full agreement with both crystalline structures from a qualitative point of view. Chemical shielding tensors have been calculated from the gauge including projector augmented wave approach. The electric field gradient tensors of 23Na and 75As have been calculated in α-NaAsF6 from the all-electrons method and the projector augmented-wave approach. Two difficulties were encountered: the libration of the rigid and regular AsF6– anions in the β-phase, highlighted by the atomic anisotropic displacement parameters for F, which leads to erroneous shortened As–F bond length, and the overestimation of the As–F bond length with the PBE functional used in the density functional theory calculations. We show that both difficulties can be overcome by full optimization and rescaling of the cell parameters of the crystalline structures. Additionally, a linear correlation is observed between experimental 23Na δiso values and calculated 23Na σiso values from previously reported data and from our own measurements and calculations.

Alignment of Druglike Compounds in Lipid Bilayers Analyzed by Solid-State 19F-NMR and Molecular Dynamics, Based on Dipolar Couplings of Adjacent CF3 Groups

Solid-state (19)F-NMR spectroscopy is frequently used to analyze the structure and dynamics of lipophilic drugs and peptides embedded in biomembranes. The homonuclear dipolar couplings of trifluoromethyl (CF3) labels can provide valuable parameters such as orientational constraints and/or distances. To characterize the complex dipolar patterns of multiple (19)F spin interactions, three different model compounds carrying two CF3 groups in meta-position on a phenyl ring were incorporated in macroscopically aligned DMPC bilayers. The dipolar patterns obtained with the CPMG (Carr-Purcell-Meiboom-Gill) multipulse sequence were analyzed to yield simultaneously the intra-CF3 and intergroup dipolar coupling values. The fluorine-fluorine distances were predicted by a density functional calculation, and the alignment of the labeled molecular segment could be determined from these distances and the dipolar coupling values. The different compounds were found to align in the lipid bilayer according to their amphiphilic properties, though with a weak anisotropic preference that is typical of solutes in liquid crystals. The residual dipolar couplings were used to calculate Saupe order parameters. For the least complex molecule, (CF3)2-BA, an orientational probability function for the solute in the lipid matrix could be derived. The overall description of how (CF3)2-BA is embedded in the bilayer was independently assessed by molecular dynamics simulations, and compared in structural and dynamical terms with the results of the NMR experiments.

Self-Assembly of the Membrane-Bound β-Stranded Peptide (KIGAKI)3 into Immobilized Amyloid Fibrils Observed by Solid-State 19F-NMR

The structure and membrane alignmentof β-stranded antimicrobial peptide KIGAKI [(KIGAKI)3-NH2] has been determined in oriented DMPC bilayers using circular dichroism and solid state 19F-NMR spectroscopy. CF3-Bpg was used as a reporter group to label the peptide, where several IIe or Ala residues were individually replaced one by one. At high peptide-to-lipid molar ratios (P/L) of 1:200 or above, the 19F dipolar coupling of all five labels exhibits the maximum possible value, which is indicative of a parallel alignment of the Cα-CF3 bond vector with respect to the bilayer normal. This finding suggests that at high concentration KIGAKI self-assembles into immobilized -sheets, which lie flat on the membrane surface. Transmission electron microscopy images reveal that the aggregated KIGAKI forms amyloid like fibrils. At low peptide concentrations, on the other hand, the dipolar couplings of the CF3-groups indicate that their time-averaged alignment is still parallel to the bilayer normal, but the mobility of the peptides increases drastically and reflects a monomeric state. Correspondingly, the flexible β-strands float on the membrane surface and undergo motional averaging in the 2-dimensional membrane plane, similar to intrinsically unstructured proteins in solution. This is the first example of concentration dependent transition of a flexible β-strand to an amyloid like fibril in membranes that is directly observed by solid state NMR.

Short Stories - on Antimicrobial Peptides that are Too Short to Span the Membrane

Solid-state 19F-NMR structure analysis of membrane-bound peptides is routinely feasible now in macroscopically oriented samples. For many long amphiphilic α-helices, their membrane-induced folding, re-alignment and insertion into the lipid bilayer has been characterized as a series of consecutive steps, ultimately leading to pore-formation across the membrane. More recently, however, we have examined various short peptides that are not long enough to span the lipid bilayer, and whose biological action cannot be explained in terms of classical models of oligomeric pore formation.

Borane-Induced Dehydration of Silica and the Ensuing Water-Catalyzed Grafting of B(C6F5)3 To Give a Supported, Single-Site Lewis Acid, ≡SiOB(C6F5)2

A supported, single-site Lewis acid, ≡SiOB(C(6)F(5))(2), was prepared by water-catalyzed grafting of B(C(6)F(5))(3) onto the surface of amorphous silica, and its subsequent use as a cocatalyst for heterogeneous olefin polymerization was explored. Although B(C(6)F(5))(3) has been reported to be unreactive toward silica in the absence of a Brønsted base, we find that it can be grafted even at room temperature, albeit slowly. The mechanism was investigated by (1)H and (19)F NMR, in both the solution and solid states. In the presence of a trace amount of H(2)O, either added intentionally or formed in situ by borane-induced dehydration of silanol pairs, the adduct (C(6)F(5))(3)B·OH(2) hydrolyzes to afford C(6)F(5)H and (C(6)F(5))(2)BOH. The latter reacts with the surface hydroxyl groups of silica to yield ≡SiOB(C(6)F(5))(2) sites and regenerate H(2)O. When B(C(6)F(5))(3) is present in excess, the resulting grafted boranes appear to be completely dry, due to the eventual formation of [(C(6)F(5))(2)B](2)O. The immobilized, tri-coordinate Lewis acid sites were characterized by solid-state (11)B and (19)F NMR, IR, elemental analysis, and C(5)H(5)N-TPD. Their ability to activate two molecular C(2)H(4) polymerization catalysts, Cp(2)ZrMe(2) and an (α-iminocarboxamidato)nickel(II) complex, was explored.

A risk-based statistical investigation of the quantification of polymorphic purity of a pharmaceutical candidate by solid-state 19F NMR

The DMAIC (Define, Measure, Analyse, Improve and Control) framework and associated statistical tools have been applied to both identify and reduce variability observed in a quantitative 19F solid-state NMR (SSNMR) analytical method. The method had been developed to quantify levels of an additional polymorph (Form 3) in batches of an active pharmaceutical ingredient (API), where Form 1 is the predominant polymorph. In order to validate analyses of the polymorphic form, a single batch of API was used as a standard each time the method was used. The level of Form 3 in this standard was observed to gradually increase over time, the effect not being immediately apparent due to method variability. In order to determine the cause of this unexpected increase and to reduce method variability, a risk-based statistical investigation was performed to identify potential factors which could be responsible for these effects. Factors identified by the risk assessment were investigated using a series of designed experiments to gain a greater understanding of the method. The increase of the level of Form 3 in the standard was primarily found to correlate with the number of repeat analyses, an effect not previously reported in SSNMR literature. Differences in data processing (phasing and linewidth) were found to be responsible for the variability in the method. After implementing corrective actions the variability was reduced such that the level of Form 3 was within an acceptable range of ±1% w w −1 in fresh samples of API.

Tuning the discharge potential of fluorinated carbon used as electrode in primary lithium battery

When the carbon lattice of the starting material exhibits a curvature as in the case of fullerenes and derivatives, the C–F bonding in the compounds resulting from the fluorination using molecular fluorine is strongly affected and the covalence is significantly weakened. 19F solid state NMR underlines that the higher the curvature the lower the C–F bonding covalence is. The electrochemical discharge potentials of these materials used as electrode in primary lithium batteries can be then tuned according to the curvature, i.e. the diameter of the outer tubes. The potential decreases from 2.9 to 2.3 V versus Li +/Li° according to the following classification: SWCNTs, MWCNTs and carbon nanofibres, which can be described as MWCNTs with large diameter due to the high number of walls. The case of highly fluorinated fullerenes is different because several types of bonding coexist and are progressively broken during the electrochemical process at potentials ranged in between 2.0 and 3.6 V. The behaviour of fluorinated nanocarbons is also compared to conventional graphite fluorides.

Orientation of the Calcium Sensitizing Agent dfbp-o, when Bound to Troponin in a Muscle Fiber as Determined by Solid-State NMR Spectroscopy

Heart failure is characterized by the inability of the heart to supply the body with oxygenated blood. There is a large range of treatment strategies employed by physicians; however, many of these options are limited in their ability to improve mortality during acute heart failure. A more recently identified therapeutic option involves a class of pharmaceuticals termed “calcium sensitizers”. These molecules enhance the contractile apparatus's response to calcium, instead of increasing the concentration of cytosolic calcium. Levosimendan is the most widely used calcium sensitizer, but since it is unstable, its exact mode of action has yet to be identified. Recently, we have determined that the stable structural analog of levosimendan, dfbp-o, functions as a calcium sensitizer in a similar manner as levosimendan [Robertson et al., J Mol Cell Cardiol. 2010 Aug 27. [Epub ahead of print]]. Two fluorine atoms are present on dfbp-o which can be used to elucidate useful structural information via 19F-NMR spectroscopy. 19F is a particularly attractive nucleus for study by NMR spectroscopy because like 1H it is ∼100% naturally abundant, has a spin of 1/2, and possesses a large gyromagnetic ratio. We have used 19F solid-state NMR spectroscopy to study the orientation of dfbp-o in demembranated rabbit psoas muscle fibers. Upon incubating the muscle fiber in relaxing solution containing dfbp-o, the length of the fiber decreased approximately three fold, presumably due to the calcium sensitizing nature of dfbp-o. This approach will allow us to establish the orientation of the dfbp-o:troponin complex with respect to the thin filament axis. In addition, the results give us further evidence that dfbp-o binds muscle fibers to elicit its calcium sensitization effect.

Iridium(iii)–surfactant complex immobilized in mesoporous silica via templated synthesis: a new route to optical materials

In this work we report the preparation of a new blue-emitting material based on the templated synthesis of mesoporous silica (MCM-41) using micellar solutions of the newly synthesized monocationic metallosurfactant complex bis[1-benzyl-4-(2,4-difluorophenyl)-1H-1,2,3-triazole](4,4′-diheptadecyl-2,2′-bipyridine)–iridium(III) chloride in hexadecyl-trimethyl-ammonium bromide (CTAB). Under ambient conditions, significant increases in excited state lifetime and quantum yield values (up to 45%), were obtained for the solid materials in comparison to the corresponding micellar solutions. Solid state 1H and 19F NMR spectroscopies were successfully employed for quantifying the luminophore content in terms of Ir–surfactant to CTAB and Ir–surfactant to silica ratios.

End-functionalization of a vinylidene fluoride oligomer in coordination nanochannels

The utility of basic sites of porous coordination polymers (PCPs) for the end-functionalization of oligo(vinylidene fluoride) (OVDF) is demonstrated. Densely arranged carboxylate moieties on the PCP pore walls act as basic sites and allow the efficient elimination reaction of the terminal group of OVDF to proceed. The progress of the reaction of an OVDF precursor in the PCP nanochannels was evidenced using solid state 19F NMR spectroscopy. From 19F and 1H NMR and IR measurements of the product isolated from the composite obtained, the terminal –CH2CF2I moiety of OVDF was shown to be successfully converted to a –CHCF2group. Because of the large surface area of the PCP materials, the OVDF precursor easily accessed the basic sites, resulting in a large increase in the rate of the elimination reaction. In addition, a notable effect of the porous structure of PCPs upon the elimination reaction was observed.

Effect of SiO2 on the dynamics of proton conducting [Nafion/(SiO2)X] composite membranes: a solid-state 19F NMR study

Composite membranes, consisting of Nafion and inorganic oxide additives, are frequently discussed alternative materials to overcome the known low conductivity of pure Nafion at temperatures above 100 °C and at low relative humidity. It has been reported that under dry conditions, these membranes show enhanced water uptake and diffusion as compared to filler-free Nafion. This work focuses on the polymer mobility in Nafion/SiO(2) composites and on the impact of the silica particles on the polymer dynamics. [Nafion/(SiO(2))(X)] composite membranes (with X ranging from 0 to 15 wt%) in the dry and wet states were investigated by variable temperature solid-state (19)F NMR spectroscopy. (19)F T(1) and T(1ρ) relaxation times, and NMR lineshapes (linewidths and spinning sideband intensities) were analyzed to get information about the polymer mobility. It is found that Nafion composite membranes, in general, possess a higher mobility as compared to recast Nafion which is in agreement with previous results from conductivity studies. These findings are attributed to the ability of the SiO(2) particles to keep more water inside the composite membranes which also leads to a higher mobility of the polymer component. The results are further supported by the experimental (19)F{(1)H} CP/MAS NMR spectra. It is also shown that the structure of the composite membranes is more stable after dehydration, and possible condensation reactions are diminished in these membranes. In addition, the decrease in ionic exchange capacity after dehydration is less pronounced for the composite membranes as compared to filler-free Nafion.

A NMR study of the hydration of sulfo and carboxyl groups in perfluorinated cation exchange membranes

The mobility of the polymer matrix and the structure of the hydration complex in the acid forms of perfluorinated ion exchange membranes MF-4SK and F-4KF depending on moisture content were studied by 1H, 13C, and 19F solid-state high-resolution NMR. A correlation between an increase in mobility of separate polymer matrix segments under hydration conditions and their hydrophilic properties was observed. Carboxyl groups in F-4KF membranes were shown to exist as dimers C(OOH)2C, and the main hydrated complex form in MF-4SK membrane under low moisture content conditions was the hydroxonium ion H5O2+.

Evaluating chemical degradation of proton conducting perfluorosulfonic acid ionomers in a Fenton test by solid-state 19F NMR spectroscopy

Chemical degradation and stability of perfluorosulfonic acid (PFSA) ionomers against radical attack were investigated by an (ex situ) Fenton test. Solid-state and solution NMR as well as ATR-FTIR studies were performed on the samples before and after the Fenton reaction. By changing the concentration of the Fenton's solution it is found that the metallic catalyst (Fe2+) is a critical factor which may affect the solid-state NMR results. After adjusting the experimental conditions, i.e., by reducing the Fe2+ concentration, it was possible to detect by solid-state 19F NMR spectroscopy the structural changes of the perfluorosulfonic acid ionomers during the ex situ Fenton test.A comparative study was made on the degradation of Nafion and Hyflon Ion membranes which differ in the length of the side chains. It is shown that the Hyflon Ion membrane with shorter side chains is more stable against side chain attack, most probably because of the absence of an additional tertiary carbon in the side chain. At the same time, there is evidence for enhanced main chain degradation in membranes with unprotected backbone chain ends.

Detection of low-level PTFE contamination: An application of solid-state NMR to structure elucidation in the pharmaceutical industry

We report a novel use of solid-state 19F nuclear magnetic resonance to detect and quantify polytetrafluoroethylene contamination from laboratory equipment, which due to low quantity (up to 1% w/w) and insolubility remained undetected by standard analytical techniques. Solid-state 19F NMR is shown to be highly sensitive to such fluoropolymers (detection limit 0.02% w/w), and is demonstrated as a useful analytical tool for structure elucidation of unknown solid materials.

Chemical Degradation of Nafion Membranes under Mimic Fuel Cell Conditions as Investigated by Solid-State NMR Spectroscopy

A new ex situ method has been developed to mimic the degradation of the polymer membranes in polymer electrolyte membrane fuel cells (PEMFCs), caused by the cross-leakage of H2 and O2. In this ex situ setup, it is possible to expose membranes to flows of different gases with a controlled temperature and humidity. H+-form Nafion films with and without an electrode layer (Pt) have been treated in the presence of different gases in order to simulate the anode and cathode side of a PEMFC. The changes of the chemical structure occurring during the degradation tests were primarily examined by solid-state 19F NMR spectroscopy. For completion, liquid-state NMR studies and ion-exchange capacity measurements were performed. The molecular mobility changes of the ionomer membrane upon degradation were examined for the first time by variable-temperature 19F NMR line-shape, T1 and T1ρ relaxation experiments. It was found that degradation occurs only when both H2 and O2 are present (condition of gas cross-leakage) and when the membrane is coated with a Pt catalyst. The chemical degradation rate is found to be highest for H2-rich mixtures of H2 and O2, which corresponds to the anode under OCV conditions. It is further shown that side-chain disintegration is very important for chemical degradation, although backbone decomposition also takes place. The temperature-dependent line-width and spectral anisotropy alterations were explained by the reduction of static disorder in the Nafion membrane. From the relaxation data, there is evidence for structural annealing, which is independent of the chemical degradation. Chemical degradation is considered to reduce the chain flexibility, as expressed by smaller motional amplitudes, most probably due to chain cross-linking.

Orientation, dynamics, and lipid interaction of an antimicrobial arylamide investigated by 19F and 31P solid-state NMR spectroscopy.

A number of arylamides have been synthesized and found to exhibit potent antimicrobial activities against a broad spectrum of Gram-positive and Gram-negative bacteria while exhibiting low toxicity toward eukaryotic cells. These facially amphiphilic foldamers have a relatively rigid intramolecular hydrogen-bonded arylamide as a framework, which places trifluormethyl versus positively charged amino and guanidino groups along opposite faces of the elongated molecule, facilitating interactions with lipid membranes. To better understand the mechanism of action of these antimicrobial foldamers, we have investigated the lipid interaction, depth of insertion, orientation, and dynamics of an arylamide, PMX30016, using (31)P and (19)F solid-state NMR spectroscopy. Static (31)P NMR line shapes of lipid membranes with a range of compositions indicate that PMX30016 does not disrupt the lamellar order of the lipid bilayer but perturbs the lipid headgroup conformation. This headgroup perturbation, manifested as systematic (31)P chemical shift anisotropy increases, is consistent with the well documented "electrometer" effect of lipid membranes in response to the addition of positive charges to membrane surfaces. Paramagnetic relaxation enhancement experiments indicate that the arylamide inserts into the membrane-water interface, just below the headgroup region. Measurement of (19)F-(19)F dipolar couplings within each CF(3) moiety revealed that PMX30016 is oriented with the molecular plane 20 degrees and 30 degrees from the membrane normal of neutral and anionic bilayers, respectively, and the long molecular axis lies parallel to the membrane plane. Thus, this arylamide inserts into the bilayer in a knife-like fashion, consistent with previous vibrational spectroscopy results. Moreover, (19)F NMR line shapes indicate that this molecular knife undergoes fast uniaxial rotation around the bilayer normal. These results suggest that antimicrobial arylamides destabilize anionic lipid membranes primarily by altering the membrane electric potential profile, and the spinning molecular knife may additionally create transient defects in the lipid membrane. Compared to typical antimicrobial peptides, this arylamide has more subtle effects on and is less disruptive of the structure of lipid bilayers.

Solid-State 19F MAS NMR Investigation of Fluoride Ion Mobility in Lead Fluorides: Correlation with Anionic Conductivity

A study of the fluoride ion mobility in Pb5Ga3F19 and β-Pb2ZnF6, combining data from high-resolution magic-angle-spinning variable-temperature one-dimensional solid-state 19F NMR, two-dimensional exchange NMR experiments, temperature-controlled X-ray diffraction and complex impedance spectroscopy measurements, is presented. In Pb5Ga3F19, a mutual chemical exchange occurs, above 30 °C, between all the fluorine sites within the isolated Ga1F63− octahedra. At higher temperature, a chemical exchange between these ions and some of the free fluoride ions is observed. At least up to 186 °C, fluoride sites belonging to the Ga2F63− octahedra chains are not involved in the dynamic process, which results in the absence of anionic conductivity. In β-Pb2ZnF6, the fluoride anionic mobility depends on the sample. For T > 70 °C, a tridimensional diffusive process takes place in this Aurivillius-type phase due to chemical exchange between the overall fluoride sites, which is confirmed by the occurrence of macroscopic fluo...

Role of Peptide Folding and Aggregation in Triggering Membrane Perturbation

Many membrane-active antimicrobial peptides are cationic and fold into amphiphilic structures upon binding to the lipid bilayer of the bacterial envelope, which thereupon gets permeabilized. Peptides with an alpha-helical conformation have been thoroughly studied by solid state NMR and other biophysical techniques. A concerted re-alignment of several monomers is supposed to lead to the formation of a transient pore, i.e. a local oligomeric assembly with anionic lipids that is called toroidal wormhole. Yet, several designer-made “helical” peptides have been found to undergo a rapid membrane-induced concentration-dependent aggregation as beta-strands. Given that such H-bonded aggregate is thermodynamically more stable, the question arises whether membrane perturbation involves only the “classical” helical structures under kinetic control, or whether oligomeric beta-sheets may also contribute, as proposed e.g. for the cytotoxic Alzheimer's peptide. Even more intriguing is the same question when referring to designated beta-stranded peptides, such as the (KIGAKI)3 system designed by Blazyk et al. as a complement to the helical (KIAGKIA)3, both of which have comparable antimicrobial activity. We have studied these and other representative antimicrobial peptides with alpha-helical and beta-stranded character using solid state 19F-NMR and circular dichroism. In macroscopically oriented samples, a combination of these two methods can reveal not only the conformation and alignment of a peptide in the lipid bilayer, but also its local dynamic behavior and global aggregation kinetics. Structural results and their correlation with antimicrobial activity will be presented, in an attempt to address the mechanistic questions raised above.

Fluorinated nanocarbons using fluorinating agent: Strategies of fluorination and applications

The fluorination method strongly influences the physical properties of the resulting fluorinated carbon materials. Two fluorination ways, direct fluorination under pure fluorine gas and controlled fluorination by the decomposition of TbF4, have been used for the fluorination of particular nanocarbons: carbon nanofibers and a mixture of carbon nanodiscs and nanocones. Then, fluorocarbon matrix structures have been determined owing to solid state 19F NMR for MAS conditions at a spinning speed of 30 kHz. It reveals that the fluorination mechanism depends on the fluorination conditions but not on the starting nanocarbons morphology, i.e. tubular or planar. Finally, the electrochemical properties of carbon nanofibers fluorinated by the two ways are detailed. Controlled fluorination allows an increase of the power densities of fluorinated carbon nanofibers used as electrode in primary lithium batteries.

Structural analysis of 5-fluorouracil and thymine solid solutions

Solid-state analysis with powder X-ray diffraction (PXRD), solid-state NMR (SSNMR), and other spectroscopic and physical methods can provide detailed structural information about organic and pharmaceutical cocrystals. In this study, a range of solid-state analysis methods are used to characterize co-crystallized solid solutions of 5-fluorouracil and thymine. 1H, 13C and 19F SSNMR and PXRD methods are used to study the structure and disorder present in a solid solution previously prepared by solution evaporation methods; here the solid solution is prepared over a wider stoichiometric range by solvent-drop grinding techniques. Long-range perturbations of key chemical shifts are detectable by SSNMR, indicating that the solid solution is not random. Cross-polarization and heteronuclear correlation SSNMR experiments between 1H, 13C, and 19F nuclei offer insight into the structure of this solid solution, and density functional theory (DFT) methods are applied to calculate lattice energies and NMR properties in order to understand the population of the two primary disordered sites in the crystal structure. In addition, a second solid solution of 5-fluorouracil and thymine is reported and analyzed. This solid solution, which was produced by solvent-drop grinding experiments and characterized by SSNMR and powder X-ray diffraction methods, is determined to be an isostructural phase to that of anhydrous thymine with the inclusion of 5-fluorouracil defects. A similar effect does not occur under excess 5-fluorouracil conditions; instead, phase-separated Form 1 of 5-fluorouracil and anhydrous thymine are obtained. DFT calculations are applied to offer a possible explanation for this disparity.