The preparation and analysis of fluoro-polyphosphates by F, P, 2D F-P HETCOR and 2D P-P COSY NMR

A complex mixture of fluoro-polyphosphates (FPPs) and polyphosphates was prepared by heating a mixture of NaF and sodium tripolyphosphate (STPP) at 600 °C in nitrogen atmosphere. Two-dimensional ³¹P-¹⁹F heteronuclear correlation spectroscopy (HETCOR) NMR was developed in identifying the atomic connection between F and P in the mixed FPPs. ¹⁹F, ³¹P and ³¹P-³¹P correlation spectroscopy (COSY) NMR methods were employed to identify the components of the mixture and measure the chain length of each FPP ingredient. NMR results clearly demonstrated that the mixture contains four kinds of fluoro-phosphates with different chain length of polyphosphate, which are monofluoro-phosphate (MFP), monofluoro-dipolyphosphate (MFDPP), monofluoro-tripolyphosphate (MFTPP) and difluoro-tripolyphosphate (DFTPP). Other phosphates and polyphosphates also were found in the mixture.     

Potentiometric measurement of ionic, acid-labile and covalently bound fluorine

Fluoride (F⁻) is the predominant chemical form of F in serum and bone, during administration of NaF as cariostatic agent or in the treatment of osteoporosis. In the treatment with sodium monofluorophosphate (MFP), F⁻, F bound to proteins by acid-labile linkage and non-volatile covalently bound F are detected. Only F⁻ is detectable with the ion-selective electrode. This paper describes a method for the measurement of non-volatile covalently bound F with the ion-selective electrode, which has a detection limit of 0.8 ± 0.6 nmol, within-run standard deviation of 7 nmol and a between-run standard deviation of 13 nmol at 100 nmol F and has a linear behaviour above 1 nmol. This paper also reports a methodology for the potentiometric measurement of F⁻, acid-labile F and covalently bound F in biological samples.     

Bioavailability of fluoride administered as sodium fluoride or monofluorophosphate to humans

A double-bind cross-over study was conducted on four healthy subjects, aged 19-29 years, in order to determine the relative bioavailability and other pharmacokinetics features of fluoride (F) after single oral administration in fasting conditions of 2 mg F as sodium F (NaF) or sodium monofluorophosphate (MFP). The bioavailability was evaluated on the basis of the plasma levels and of the urinary excretion of F. Blood was sampled before and during the 8 h after the administration of the test solutions. For F excretion urine was sampled 12 h before the study and over the 8 h after the administration. Data were tested for statistically significant differences by ANOVA and Tukey's post hoc tests, and also by Student's t-test (p < 0.05). For the two formulations, the pharmacokinetics of F in plasma was characterized by a rapid absorption and by a peak (C_max = 0.1 μg/mL) which was reached 20 min after administration, followed by a biphasic elimination. In the 8 h following the administration the urinary excretion of F accounted for 35-41% of the administered dose, without significant differences between the two formulations. The AUCs (±S.D.) for NaF and MFP were 21.15 (±0.58) and 19.04 (±1.75) min μg mL⁻¹, respectively, and were not significantly different (p = 0.079). Based on the AUC and C_max of F in plasma and on the urinary excretion of F during the 8 h following administration, the relative bioavailabilities of the two F formulations were equivalent.     

C-F?M interaction in anionic α-fluorovinyl rhenium oxycarbene complexes and their β-fluoroenolate analogs

The C-F?M⁺ interaction in anionic σ-(α-fluorovinyl)rhenium oxycarbene complexes, [RCFCFReC(O)R′(CO)₄]M (1-6), M = Na, Li, K is studied by ¹⁹F NMR in THF and Et₂O. The coordination of α-F to M⁺ results in an upfield shift of the corresponding ¹⁹F NMR signal and a decrease of ¹J_CF. The maximum shift is found for the Li salt of complex 4 in Et₂O (Δδ_Fα = 36.4 ppm), in which case a ⁷Li-¹⁹F spin-spin coupling is also observed (J_LiF = 40 Hz). The ΔE of C-F?M⁺ interaction and its effect on ¹⁹F shielding was further studied by DFT calculations using β-fluoroenolates as models, which confirmed a strong impact of CF-bond environment on the coordination ability of fluorine in these F,O-chelates. A compound with a β-fluoroenolate backbone but without rhenium, o-(α-fluorovinyl)phenolate 12, was prepared and studied by ¹⁹F NMR, and similarly showed indications of C-F?M⁺ interaction in THF solution. It is concluded that the donor ability of fluorine in the studied system is enhanced because of the conjugation of α-fluorovinyl group with the enolate π-system and back donation from the transition metal.     

Tin(IV) Tetrachloride Complexes with Bis-(Dialkylamino)phosphoryl Fluoride: A Multinuclear (119Sn, 31P, 19F,and 1H) NMR Characterization in Solution

The two octahedral complexes SnCl₄·2(O)PF(NR₂)₂ (R = Me or Et) were prepared from reaction of SnCl₄ with the ligand (R₂N)₂P(O)F in anhydrous CHCl₃. The new adducts have been characterized by elemental analysis, IR, and multinuclear (¹¹⁹Sn, ³¹P, ¹⁹F, and ¹H) NMR spectroscopy. The NMR data show that the adducts exist in solution as a mixture of cis and trans isomers with markedly different proportions. When compared with previously described hexamethylphosphoramide (HMPA) and trimethylphosphate (TMPA) analogues, our results indicate that the cis isomer is the predominant species in solution. Low temperature ³¹P and ¹¹⁹Sn NMR spectra show that the compounds partially dissociate in dichloromethane.     

Phosphate additives determination in meat products by 31-phosphorus nuclear magnetic resonance using new internal reference standard: hexamethylphosphoroamide

New ³¹P NMR internal reference standard - hexamethylphosphoroamide (HMPA) was applied for determination of added polyphosphates and their ionic forms in raw pork meat and meat products. Phosphate species were determined after extraction with a boric acid buffer (pH = 9) and EDTA solution, using internal standard (HMPA) procedure. Hexamethylphosophoroamide was also used as the NMR reference standard. Linear correlations between phosphates and polyphosphate concentrations and ³¹P NMR signal areas were found in the range 81-5236 mg P/dm³, presenting 95-99% recovery and variation coefficient (CV) ≤ 5%. Studied HMPA procedure revealed shorter analysis time and the same recovery (>95%) and precision (CV = 1.3-2.7%) in comparison to MDPA method. Results of phosphate determination by both ³¹P NMR methods were tested against the molybdenumvanadate yellow spectrophotometric method (standard PN-ISO 13730, 1999) using standard reference material (certified phosphate solution).     

Synthesis, structural and spectral properties of novel octakis(3,5-bis-trifluoromethyl-benzylthio) substituted porphyrazine derivatives

[Octakis(3,5-bis-trifluoromethyl-benzylthio)porphyrazinato] magnesium carrying eight (3,5-bis-trifluoromethyl-benzylthio) groups on the peripheral positions have been synthesized by cyclotetramerization of 1,2-bis(3,5-bis-trifluoromethyl-benzylthio)maleonitrile in the presence of magnesium butanolate. Its demetalation by the treatment with trifluoroacetic acid resulted in the metal-free derivative. Further reaction of this product with copper(II) acetate, zinc(II) acetate and cobalt(II) acetate have led to the metallo derivatives M = Cu(II), Zn(II), Co(II). These novel complexes were characterized by elemental analysis, together with FT-IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR, UV-vis and mass spectral data.     

13C and19F NMR study of α,β-difluorostyryl derivatives of transition metal carbonylates. A method of signal assignment based on the carbon—fluorine spin-spin coupling constants

The¹³C and¹⁹F NMR spectra ofZ- andE-isomers of β-X-substituted α,β-difluorostyrenes (X=F, Cl, CpFe(CO)₂, Re(CO)₅, Re₂(CO)₉Na) were studied. Direct and long-range (across 1–5 bonds) spin-spin coupling constants and the (¹³C−¹²C) isotope shifts in the¹⁹F NMR spectra were determined. The study of the¹³C satellites in the¹⁹F NMR spectra of substituted difluorostyrenes permitted assignment of the¹³C NMR signals of the vinylic carbon atoms. Similarly, the signals in¹⁹F NMR spectra were assigned based on coupling constants of fluorine withipso-carbon. These assignments were found to be in good agreement with the data available from the literature (X=F, Cl). The developed approach was applied to the elucidation of the structure ofZ−PhCF=CClFe(CO)₂Cp. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya. No. 8, pp. 1575–1579, August, 1998.     

Tricritical point in ferroelastic ammonium titanyl fluoride: NMR study

Ionic mobility and phase transitions in ammonium titanyl pentafluoride (NH₄)₃TiOF₅ were studied using the ¹⁹F and ¹H NMR data. The high-temperature phase (I) is characterized by spherically symmetric (isotropic) reorientation of [TiOF₅]³⁻ anions and by uniaxial reorientation of these anions in the ferroelastic phase II. A previously unknown second-order phase transition to the low-temperature modification (NH₄)₃TiOF₅(III) was found at 205 K. The transition is accompanied by hindering of uniaxial rotations of [TiOF₅]^3- anions and by noticeable change of ¹⁹F magnetic shielding tensor associated with the influence of pseudo-Jahn-Teller effect. A pressure-induced tricritical point with coordinates p_TCR≈2 kbar and T_TCR≈170 K is estimated on the base of ¹⁹F NMR chemical shift data, and previously studied p-T diagram of (NH₄)₃TiOF₅.     

Chiral selectors for enantioresolution and quantitation of the antidepressant drug fluoxetine in pharmaceutical formulations by (19)F NMR spectroscopic method

¹⁹F NMR spectroscopy was applied to the quantitative determination of fluoxetine enantiomers using different chiral recognition agents in pharmaceutical formulations. Several parameters affecting the enantioresolution including the type and concentration of chiral selector, concentration of fluoxetine and temperature were studied. The chiral selectors investigated are the cyclic oligosaccharides α-, β- and γ-cyclodextrin and a diamino derivative of methylated α-cyclodextrin (DAM-α-CD), linear polysaccharides (maltodextrin with dextrose equivalents of 4.0-7.0, 13.0-17.0 and 16.5-19.5) and the macrocyclic antibiotic vancomycin. Among the chiral selectors used, DAM-α-CD turned out to give the best resolution of the ¹⁹F NMR signals of (R)- and (S)-fluoxetine. The calibration curve was linear for (R)- and (S)-fluoxetine over the range 0.10-1.35 mg mL⁻¹, the detection limits (S/N = 3) being 5.9 and 7.5 μg mL⁻¹ for the pure solutions of (R)- and (S)-fluoxetine, respectively. The recovery studies performed on pharmaceutical samples ranged from about 90 to 110% with relative standard deviations of <8%. The results showed that the proposed method is rapid, precise and accurate. Applying statistical Student's t-test revealed insignificant difference between the real and measured contents at the 95% confidence level.     

Determination of the second-order H NMR parameters for the aromatic protons in 4-fluoroaniline and application to the analysis of the H NMR spectra for the aromatic protons in N-(4′-fluorophenyl)succinamic acid and in N-(4′-fluorophenyl)-3,3-difluorosuccinamic acid

Four studies of the ¹H NMR spectrum for the aromatic protons of 4-fluoroaniline between 1958 and 1974 give three very different solutions to the second-order, AA′BB′X, spectrum. A re-evaluation of the second-order spectrum was done at 300 MHz. Simultaneous simulations of the ¹H NMR spectrum and ¹⁹F NMR spectrum for 4-fluoroaniline were done using WINDNMR-Pro, and a new set of parameters for the six coupling constants was obtained from the optimized simulations. This new set of parameters was used as a basis to evaluate the AA′BB′X spectrum for the aromatic protons in N⁴-(4′-fluorophenyl)succinamic acid and in N⁴-(4′-fluorophenyl)-3,3-difluorosuccinamic acid by simultaneous simulations of the ¹H NMR spectrum and ¹⁹F NMR spectrum for each using WINDNMR-Pro. Formation of the amide bond results in small, but significant, changes in the values for the set of parameters in both molecules. These results confirm that second-order analyses as an AA′BB′X system are required for derivatives of 4-fluoroaniline, rather than first-order analyses that have been used in previous reports.     

Monitoring of the insecticide trichlorfon by phosphorus-31 nuclear magnetic resonance (31P NMR) spectroscopy

Trichlorfon is an organophosphorus insecticide, which is extensively being used for protection of fruit crops. Trichlorfon is a thermal labile compound, which cannot be easily determined by gas chromatography (GC) and has no suitable group for sensitive detection by high performance liquid chromatography (HPLC). In this study, a ³¹P nuclear magnetic resonance (³¹P NMR) has been described for monitoring of trichlorfon without any separation step. The quantitative works of ³¹P NMR spectroscopy has been performed in the presence of an internal standard (hexamethylphosphoramide). Limit of detection (LOD) for this method has been found to be 55 mg L⁻¹, without any sample preparation, and the linear working range was 150-5500 mg L⁻¹. Relative standard deviation (R.S.D.%) of the method for three replicates within and between days was obtained ≤9%. The average recovery efficiency was approximately 99-112%. This method was applied for monitoring trichlorfon in a commercial insecticide sample and tomato sample.     

Synthesis and H NMR spectroscopic properties of substituted (η-tetraarylcyclobutadiene)(η-cyclopentadienyl)cobalt metallocenes

The reaction of diarylacetylenes with CoCl(PPh₃)₃ and sodium cyclopentadienylide or sodium carbomethoxycyclopentadienylide gave (η⁴-tetra-arylcyclobutadiene)(η⁵-cyclopentadienyl)cobalt and (η⁴-tetra-arylcyclobutadiene)(η⁵-carbomethoxycyclopentadienyl)cobalt, respectively, where aryl = para-XC₆H₄ (X = CF₃, F, MeO). The reaction was unsuccessful for the synthesis of (η⁴-tetra(para-methoxyphenyl)cyclobutadiene)(η⁵-cyclopentadienyl)cobalt, which was synthesised instead from dicarbonyl(η⁵-cyclopentadienyl)cobalt. In all of the examples starting with CoCl(PPh₃)₃ an intermediate (η⁵-cyclopentadienyl)- or (η⁵-carbomethoxycyclopentadienyl)(triphenylphosphine)-2,3,4,5-tetraarylcobaltacyclopentadiene complex was isolated, and two examples were characterised by X-ray crystallography. Heating the (η⁵-cyclopentadienyl)- or (η⁵-carbomethoxycyclopentadienyl)(triphenylphosphine)-2,3,4,5-tetraarylcobaltacyclopentadiene complexes resulted in clean conversion to the corresponding metallocenes. The influence of the para-aryl substituents on the ¹H NMR of the cyclopentadienyl moiety is tabulated, together with the influence of a range of R substituents in (η⁴-tetraphenylcyclobutadiene)(η⁵-RC₅H₄)cobalt (R = CO₂Me, CH₂OH, Me, CHO, CCH, CO₂H, CN, CONHR¹, 2-oxazolinyl, NH₂, NHAc, HgCl, Br, I, SiMe₃, SnMe₃, Ph).     

Intramolecular mobility and phase transitions in ammonium oxofluoroniobates (NH4)2NbOF5 and (NH4)3NbOF6, a NMR and DFT study

Molecular structure, ionic mobility and phase transitions in six- and seven-coordinated ammonium oxofluoroniobates (NH₄)₂NbOF₅ and (NH₄)₃NbOF₆ were studied by ¹⁹F, ¹H NMR and DFT calculations. Equatorial fluorine atoms (F_eq) in [NbOF₅]²⁻ and [NbOF₆]³⁻ are characterized by high ¹⁹F NMR chemical shifts while axial fluorine atoms (F_ax) have those essentially lower. The high-temperature ionic mobility in (NH₄)₂NbOF₅ does not stimulate the ligand exchange F_eq ↔ F_ax, whereas it is observed in (NH₄)₃NbOF₆ as pseudorotation typical for seven-coordinated polyhedra. The transformation of pentagonal bipyramidal structure (BP) of [NbOF₆]³⁻ into capped trigonal prismatic (CTP) one takes place during the phase transition (PT) at 260 K. The PT of order-disorder type in (NH₄)₂NbOF₅ is accompanied by transition of anionic sublattice to a rigid state. The ¹⁹F and ¹H NMR data corroborate the independent motions of NH₄ groups and anionic polyhedra in (NH₄)₂NbOF₅ while they are coordinated in (NH₄)₃NbOF₆.     

The substitution of germanium for silicon in AST-type zeolite

The substitution of silicon by germanium in the AST zeolite framework type, [Si_nGe_40−nO₈₀]*4(SDA⁺F⁻) expressed as unit cell content in its cubic F-centered symmetry, has been studied. Three different kinds of templates, dimethyldiethylammonium, dimethyldiisopropylammonium and isopropyltrimethylammonium cations, were used in the hydrothermal synthesis process in fluoride medium. The products were identified with XRD, MAS NMR, SEM and thermal analysis. The analysis of the X-ray powder diagrams shows that AST crystallizes in different space group symmetries depending on the nature of the SDA and the degree of Ge-substitution. The resonance signals of ¹⁹F in MAS NMR experiments for the pure Si- and Ge-end members are at −38.2 and −15 ppm, respectively, indicating that the F⁻-anion is located as co-template in the double-four-ring (D4R) of the tetrahedral framework. This is confirmed by Rietveld analysis of powder diffraction data of the pure Ge-end member. The peak splitting of the ¹⁹F NMR signal in pure GeO₂AST-type material is related to the displacement of F⁻ location inside the D4R. Two more distinct signals at −8 and −19 ppm, respectively, are observed for X-ray pure AST-samples of intermediate compositions and assigned to fluoride in D4R built of 4[GeO₄]- and 4[SiO₄]-tetrahedra (4Ge, 4Si) and to (2Ge, 6Si)-D4R, respectively. An ordered distribution of Ge in the AST-framework is proposed for cubic AST with compositions around Si/Ge=1.5–1 by correlating the intensities of ¹⁹F NMR signals and the results from chemical analysis. This model is further confirmed by the quantitative analyses of the corresponding ²⁹Si MAS NMR spectra.     

Poly(ethylene-glycol)-based fluorinated esters: a readily available entry for novel F-MRI agents

Readily available, low cost, hydrosoluble poly(ethylene-glycol) derivatives of 2-(trifluoromethyl)-3,3,3-trifluoro-propanoic acid were easily synthesized and their properties as MRI agents are preliminarily investigated. Two novel polymers, of 2356 Da and 756 Da, respectively, both showing a single ¹⁹F signal at NMR in deuterated chloroform and D₂O were fully characterized; both compounds were shown to be soluble in water. However when experiments of in vitro MR imaging were conducted a clear imaging was obtained only with the sample of 756 MW, pointing at the importance of the fluorine content of the carrier.     

Synthesis of [F]xenon difluoride as a radiolabeling reagent from [F]fluoride ion in a micro-reactor and at production scale

[¹⁸F]Xenon difluoride ([¹⁸F]XeF₂), was produced by treating xenon difluoride with cyclotron-produced [¹⁸F]fluoride ion to provide a potentially useful agent for labeling novel radiotracers with fluorine-18 (t_1/2 = 109.7 min) for imaging applications with positron emission tomography. Firstly, the effects of various reaction parameters, for example, vessel material, solvent, cation and base on this process were studied at room temperature. Glass vials facilitated the reaction more readily than polypropylene vials. The reaction was less efficient in acetonitrile than in dichloromethane. Cs⁺ or K⁺ with or without the cryptand, K 2.2.2, was acceptable as counter cation. The production of [¹⁸F]XeF₂ was retarded by K₂CO₃, suggesting that generation of hydrogen fluoride in the reaction milieu promoted the incorporation of fluorine-18 into xenon difluoride. Secondly, the effect of temperature was studied using a microfluidic platform in which [¹⁸F]XeF₂ was produced in acetonitrile at elevated temperature (≥85 °C) over 94 s. These results enabled us to develop a method for obtaining [¹⁸F]XeF₂ on a production scale (up to 25 mCi) through reaction of [¹⁸F]fluoride ion with xenon difluoride in acetonitrile at 90 °C for 10 min. [¹⁸F]XeF₂ was separated from the reaction mixture by distillation at 110 °C. Furthermore, [¹⁸F]XeF₂ was shown to be reactive towards substrates, such as 1-((trimethylsilyl)oxy)cyclohexene and fluorene.     

Preparation,Optimisation, and In Vitro Evaluation of [18F]AlF-NOTA-Pamidronic Acid for Bone Imaging PET

[¹⁸F]sodium fluoride ([¹⁸F]NaF) is recognised to be superior to [⁹⁹mTc]-methyl diphosphate ([^99mTc]Tc-MDP) and 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) in bone imaging. However, there is concern that [¹⁸F]NaF uptake is not cancer-specific, leading to a higher number of false-positive interpretations. Therefore, in this work, [¹⁸F]AlF-NOTA-pamidronic acid was prepared, optimised, and tested for its in vitro uptake. NOTA-pamidronic acid was prepared by an N-Hydroxysuccinimide (NHS) ester strategy and validated by liquid chromatography-mass spectrometry analysis (LC-MS/MS). Radiolabeling of [¹⁸F]AlF-NOTA-pamidronic acid was optimised, and it was ensured that all quality control analysis requirements for the radiopharmaceuticals were met prior to the in vitro cell uptake studies. NOTA-pamidronic acid was successfully prepared and radiolabeled with ¹⁸F. The radiolabel was prepared in a 1:1 molar ratio of aluminium chloride (AlCl₃) to NOTA-pamidronic acid and heated at 100 °C for 15 min in the presence of 50% ethanol (v/v), which proved to be optimal. The preliminary in vitro results of the binding of the hydroxyapatite showed that [¹⁸F]AlF-NOTA-pamidronic acid was as sensitive as [¹⁸F]sodium fluoride ([¹⁸F]NaF). Normal human osteoblast cell lines (hFOB 1.19) and human osteosarcoma cell lines (Saos-2) were used for the in vitro cellular uptake studies. It was found that [¹⁸F]NaF was higher in both cell lines, but [¹⁸F]AlF-NOTA-pamidronic acid showed promising cellular uptake in Saos-2. The preliminary results suggest that further preclinical studies of [¹⁸F]AlF-NOTA-pamidronic acid are needed before it is transferred to clinical research.     

Di- and triazidation of 3-chlorotetrafluoropyridine

3-Chlorotetrafluoropyridine and pentafluoropyridine readily react with an excess of sodium azide in dimethylsulfoxide at room temperature to give corresponding 2,4,6-triazido-3-chloro-5-fluoropyridine and 2,4,6-triazido-3,5-difluoropyridine in high yields. The reaction of asymmetric 3-chlorotetrafluoropyridine with two equimolar amounts of sodium azide under similar reaction conditions occurs regioselectively to give 2,4-diazido-5-chloro-3,6-difluoropyridine as a sole product. ¹⁹F, ¹³C and ¹⁵N NMR spectral characteristics of the triazides suggest that these compounds can be of interest as cross-linking reagents for polymer chemistry and as starting materials for organic synthesis.     

In and F MAS NMR study of (NH4)3InF6 phases

This study presents for the first time an NMR spectroscopic characterization of the room and high temperature phases of (NH₄)₃InF₆ using ¹⁹F and ¹¹⁵In as probe nuclei. The reversible phase transition to the cubic phase at 353 K was followed by MAS NMR in situ. Static NMR experiments of the room temperature phase and MAS NMR experiments of the high temperature phase allowed the determination of the NMR parameters of both nuclei. Finally, the scalar In-F coupling, rarely observed in solid state NMR, is evidenced in both room and high temperature phases of (NH₄)₃InF₆, and measured in the high temperature phase.