Fluoride Acceptor Research Articles

¹⁸F-labeled silicon-based fluoride acceptors: potential opportunities for novel positron emitting radiopharmaceuticals.

Background. Over the recent years, radiopharmaceutical chemistry has experienced a wide variety of innovative pushes towards finding both novel and unconventional radiochemical methods to introduce fluorine-18 into radiotracers for positron emission tomography (PET). These “nonclassical” labeling methodologies based on silicon-, boron-, and aluminium-18F chemistry deviate from commonplace bonding of an [18F]fluorine atom (18F) to either an aliphatic or aromatic carbon atom. One method in particular, the silicon-fluoride-acceptor isotopic exchange (SiFA-IE) approach, invalidates a dogma in radiochemistry that has been widely accepted for many years: the inability to obtain radiopharmaceuticals of high specific activity (SA) via simple IE. Methodology. The most advantageous feature of IE labeling in general is that labeling precursor and labeled radiotracer are chemically identical, eliminating the need to separate the radiotracer from its precursor. SiFA-IE chemistry proceeds in dipolar aprotic solvents at room temperature and below, entirely avoiding the formation of radioactive side products during the IE. Scope of Review. A great plethora of different SiFA species have been reported in the literature ranging from small prosthetic groups and other compounds of low molecular weight to labeled peptides and most recently affibody molecules. Conclusions. The literature over the last years (from 2006 to 2014) shows unambiguously that SiFA-IE and other silicon-based fluoride acceptor strategies relying on 18F− leaving group substitutions have the potential to become a valuable addition to radiochemistry.

A New SiF–Dipropargyl Glycerol Scaffold as a Versatile Prosthetic Group to Design Dimeric Radioligands: Synthesis of the [18F]BMPPSiF Tracer to Image Serotonin Receptors

A novel SiX-dipropargyl glycerol scaffold (X: H, F, or (18) F) was developed as a versatile prosthetic group that provides technical advantages for the preparation of dimeric radioligands based on silicon fluoride acceptor pre- or post-labeling with fluorine-18. Rapid conjugation with the prosthetic group takes place in microwave-assisted click conjugation under mild conditions. Thus, a bivalent homodimeric SiX-dipropargyl glycerol derivatized radioligand, [(18) F]BMPPSiF, with enhanced affinity was developed by using click conjugation. High uptake of the radioligand was demonstrated in 5-HT1A receptor-rich regions in the brain with positron emission tomography. Molecular docking studies (rigid protein-flexible ligand) of BMPPSiF and known antagonists (WAY-100635, MPPF, and MefWAY) with monomeric, dimeric, and multimeric 5-HT1A receptor models were performed, with the highest G score obtained for docked BMPPSiF: -6.766 as compared with all three antagonists on the monomeric model. Multimeric induced-fit docking was also performed to visualize the comparable mode of binding under in vivo conditions, and a notably improved G score of -8.455 was observed for BMPPSiF. These data directly correlate the high binding potential of BMPPSiF with the bivalent binding mode obtained in the biological studies. The present study warrants wide application of the SiX-dipropargyl glycerol prosthetic group in the development of ligands for imaging with enhanced affinity markers for specific targeting based on peptides, nucleosides, and lipids.

Microscopic nature of mobile fluoride anions on sp2 carbon surfaces

We use ab initio theories to investigate the configuration of the mobile fluoride acceptor anions on sp2-bonded carbon materials. We find that trifluoride anion (F3-1) is bound onto the graphene plane through ionic interaction, shifting the Fermi level rigidly without perturbing the π electron structures. This suggests that the F3-1 can easily migrate, generating hole carriers in graphitic materials. On the other hand, the monatomic fluoride anion is not stable against the formation of the C–F bond, and F2 molecule does not adsorb. We suggest that the widely debated semi-ionic C–F bond is not a relevant model for fluorinated graphites.

18F]Fluoride labelling of macromolecules in aqueous conditions: silicon and boroaryl‐based [18F]fluorine acceptors, [18F]FDG conjugation and Al18F chelation

[18F]Fluorination is usually carried out by nucleophilic substitution reactions entailing the use of stringent conditions. A number of novel techniques including silicon and boron‐based fluoride acceptor molecules, [18F]fluoro‐2‐deoxy‐ d‐glucose and chelation of the Al18F complex have been employed recently to achieve [18F]radiolabelling of macromolecules. These approaches are reviewed herein. Copyright © 2012 John Wiley & Sons, Ltd.

Ar(Ar′)I][N(CF3)2], effect of fluorine substituents on aryl groups of iodonium cations and of coordinating bases on the fluoride transfer from the anion to the cation

Three prototypical fluoroaryliodonium salts with the [N(CF3)2]− anion were obtained by metathesis in the corresponding tetrafluoroborate salts [Ar(Ar′)I][BF4] (Ar/Ar′=C6H5/4-FC6H4, 3-FC6H4/4-FC6H4, C6F5/C6F5) with in situ generated Rb[N(CF3)2]. The kinetic lability of the [N(CF3)2]− anion (potential fluoride donor like [OCF3]−) in combination with the gradual change in fluoride affinity of the three [Ar(Ar′)I]+ fluoroaryliodonium cations allowed to distinguish the fluoride acceptor property of the three [Ar(Ar′)I]+ fluoroaryliodonium cations. Coordinating solvents or ligands suppressed the fluoride transfer from the [N(CF3)2]− anion to the fluoroaryliodonium cation.

SiFA Azide: A New Building Block for PET Imaging Using Click Chemistry

We present a new highly potent building block for PET imaging based on silicon fluoride acceptors (SiFA) which can easily be coupled to bioactive compounds by means of click chemistry. Owing to a remarkable chemoselectivity, short reaction times, and high yields the labeling reactions thoroughly meet the stringent demands for PET investigations.

SiFA‐Modified Phenylalanine: A Key Compound for the Efficient Synthesis of 18F‐Labelled Peptides

AbstractBoth the racemic and the stereoselective synthesis of the silicon‐modified amino acid p‐(tBu2FSi)C6H4CH2(NH2)COOH (SiFA‐phenylalanine, 6) and its derivatives p‐(tBu2FSi)C6H4CH2(NHBoc)COOH (10) and p‐(tBu2FSi)C6H4CH2(NHFmoc)COOH (11) are reported. The latter two compounds are valuable building blocks for the convenient introduction of silicon‐based fluoride acceptors (SiFAs) into peptides by solid‐phase peptide syntheses (SPPS). As prove of principle, the Tyr3‐octreotate derivatives 12, 13 and 14 were prepared by using standard protocols of the solid‐phase peptide synthesis (SPPS). They were labelled with 18F‐fluorine by isotopic exchange in radiochemical yields of up to 70 % (with radiochemical purity ranging between 92 and 99 %). The incorporation of 18F‐fluorine into the SiFA‐modified amino acid 6 was studied as the latter may also serve as a tracer in PET. After purification, [18F]‐6 showed a remarkable stability in an isotonic solution. Also reported is the molecular structure, as determined by single‐crystal X‐ray diffraction analysis, of p‐(tBu2FSi)C6H4CHCH[C(O)OMe]NHC(O)OCH2Ph (8), which serves as a precursor for the stereoselective synthesis of compound 6.

Long‐Lived Radical Cations of Monocyclic Arenes at Room Temperature Obtained by NbF5 Acting as an Oxidizing Agent and Counterion Precursor

Salt of the earth: Radical cation salts of monocyclic arenes, including benzene, have been obtained in a reaction where niobium pentafluoride behaves both as an oxidizing agent (conversion into NbF4) and fluoride acceptor (to afford the counterion [Nb2F11]−, see picture). Anion–π-electron density interactions, as revealed by experimental and computational studies, are crucial in providing unprecedented inertness to the radical cations.

Para‐Functionalized Aryl‐di‐tert‐butylfluorosilanes as Potential Labeling Synthons for 18F Radiopharmaceuticals

Broad spectrum: Novel para-functionalized aryl-di-tert-butylfluorosilanes, p-(tBu(2)FSi)C(6)H(4)X (X=functional group), have been made available and broaden the spectrum of silicon-based (18)F acceptors (SiFAs) for potential PET applications. For example, the [(18)F]maleimido derivative 1 has been employed for the synthesis of [(18)F]1- labeled rat serum albumin (RSA), the applicability of which for PET has been verified by in vivo experiments.The syntheses of the functionalized triorganofluorosilanes tBu(2)(p-XC(6)H(4))SiF (3 a, X=SH; 4 a, X=NCS; 4 b, X=NCO; 5, X=NC(4)H(2)O(2); 7, X=COOH; 8 a, X=COONC(4)H(4)O(2); 8 b, X=COOC(6)F(5)) are reported. These compounds display potential as silicon-based fluoride acceptors (SiFAs). The molecular structures of compounds 5, 7, and 8 a have been determined by single-crystal X-ray diffraction studies. With the exception of compounds 8 a and 8 b, all of the compounds could be (18)F-labeled by isotopic exchange in good to high radiochemical yields (RCY) with good to excellent specific activities. As proof of applicability, the maleimido-functionalized SiFA derivative 5, which is specific for thiol groups, has been used for the labeling of rat serum albumin (RSA) that had been derivatized with 2-iminothiolane. The incorporation of [(18)F]5 into the derivatized RSA reached a maximum yield after 30 min at ambient temperature. After purification, the [(18)F]RSA was evaluated in a healthy rat by means of muPET and displayed an expedient in vivo stability over 180 min.

Mono‐ and Perfluoroaryliodine(III) Cyano Compounds – Synthesis, Reactivity, and Structure

AbstractC6F5I(CN)2 and x‐FC6H4I(CN)2 (x = 2, 3, 4) were isolated from reactions of the corresponding aryliodine difluorides ArIF2 and a stoichiometric excess of Me3SiCN in CCl3F (0 °C) or CH2Cl2 (20 °C), respectively. In addition, x‐FC6H4I(CN)2 compounds were synthesized in good yields on alternative routes, namely from 3‐ or 4‐FC6H4I(OC(O)CH3)2 or 4‐FC6H4I(OC(O)CF3)2 or from 4‐FC6H4IO and Me3SiCN in CH2Cl2 at 20 °C. In the 1 : 1 reaction of C6F5IF2 and Me3SiCN a lower temperature was necessary to suppress partial disubstitution and to obtain the first example of a new type of aryliodine(III) cyanide compounds, C6F5I(CN)F. 4‐FC6H4I(CN)F could be isolated from the equimolar reaction of 4‐FC6H4IF2 and Me3SiCN in CH2Cl2 even at 20 °C. The new products were characterized by multi‐NMR and Raman spectroscopy. The molecular structures of C6F5I(CN)2, 3‐ and 4‐FC6H4I(CN)2, C6F5I(CN)F, and 4‐FC6H4I(CN)F are discussed and compared with that of C6F5IF2. The reactivity of C6F5I(CN)F towards fluoride acceptors EFn (BF3, AsF5) and RxEX−x (C6F5SiF3, C6H5SiF3, C6H5PF4, Me3SiCl, Me3SiC6F5) were investigated and showed differing reaction patterns (fluoride abstraction, aryl transfer, chloride transfer). Besides the molecular entities C6F5I(CN)F and C6F5I(CN)Cl, the corresponding iodonium salts [C6F5(CN)I][BF4] and [C6F5(CN)I][AsF6] were isolated. The thermal stability of ArI(CN)2 and ArI(CN)F, neat and in solution, as well as the reactivity of 4‐FC6H4I(CN)2 towards the Lewis acid BF3 are reported.

The first examples of germanium tetrafluoride and tin tetrafluoride complexes with soft thioether coordination—synthesis, properties and crystal structures

The first thioether complexes of the hard Lewis acidic GeF(4) and SnF(4) have been prepared by reaction of [GeF(4)(MeCN)(2)] or [SnF(4)(MeCN)(2)] respectively with the thioether ligand in rigorously anhydrous CH(2)Cl(2) solution. The isolated compounds were characterised spectroscopically (IR, (1)H and (19)F{(1)H} NMR) and by microanalyses. Crystal structures of four representative examples, [GeF(4){MeS(CH(2))(2)SMe}], [GeF(4){EtS(CH(2))(2)SEt}], [SnF(4){EtS(CH(2))(2)SEt}] and [SnF(4){(i)PrS(CH(2))(2)S(i)Pr}], reveal distorted octahedral adducts with chelating thioethers, and weak, secondary Ge-S and Sn-S bonds. These compounds are the first reported examples of thioether complexes with any main group metal/metalloid fluoride acceptor.

18F‐Labeling of Peptides by means of an Organosilicon‐Based Fluoride Acceptor

Fluorine-18 is among the most commonly used radionuclides for positron emission tomography (PET). This non-invasive imaging technique is capable of providing in vivo information about the distribution of radiolabeled biomolecules by 1808 coincidence detection of two simultaneously emitted photons from positron–electron annihilation. Although a number of different radiotracers have been successfully employed in PET, only a few, such as 2-[F]fluoro-2-deoxy-d-glucose (FDG) and [F]fluorodopa, have gained widespread application in nuclear medicine. The reason for this is that the regioselective introduction of F into tracer molecules is often non-specific and radiochemical yields (RCY) of the Flabelled product are low. The introduction of F into tracer molecules requires high temperatures and often leads to undesired by-products. The research over the last decade clearly indicates that the success of PET in nuclear medicine justifies the intense search for versatile labeling formulations for the syntheses of F-radiopharmaceuticals. Especially the development of rational F-labelling strategies for peptides, until now characterized by multistep procedures, is considered to be one of the most important tasks. As an alternative to conventional F-labelling chemistry, the use of [F]fluorosilanes as labeling synthons was first proposed by Rosenthal et al. who treated chlorotrimethylsilane with n.c.a. (no carrier added) F in aqueous acetonitrile isolating the corresponding [F]fluorosilane in 65% yield. A preliminary in vivo evaluation revealed fast hydrolysis of the compound accompanied by high radioactivity (F) uptake by the bone making it unsuitable as a labeling synthon. Another approach is based on the work by Pilcher et al. who fluorinated organosilanoles with nonradioactive HF in high yields. An analogous labeling strategy was proposed in a symposium abstract. However, so far no labeling experiments using aqueous F /[F]HF solutions have been reported. Most recently Ting et al. used organotriethoxysilanes as labeling precursors for the synthesis of [F]fluorosilanes but no practical application for the synthesis of potential radiopharmaceuticals has been demonstrated. Herein we report the syntheses of substituted [F]organofluorosilanes using organochlorosilanes as labeling precursors and their in vitro and in vivo stability. As an alternative labeling approach we also describe the F–F isotopic exchange using [F]di-tert-butylphenyl fluorosilane as a highly efficient silicon-based fluoride acceptor (SiFA compound). As proof of applicability we transferred the SiFA approach to the development of a simple and practical formulation for the synthesis of a F-labelled SiFA derivatized Tyr-octreotate, a peptide used in oncology for the visualization of neuro-endocrine tumors. We synthesized three [F]organofluorosilanes, namely [F]fluorotriphenylsilane (1), [F]fluoro-tert-butyldiphenylsilane (2), and [F]fluorodi-tert-butylphenylsilane (3), and evaluated their in vitro stability in human serum as well as their in vivo stability in rats, studied by animal-PET. These data are essential for finding the most suitable compound and for evaluating the labeling concept. The reaction in acetonitrile of the triorganochlorosilanes (5–11.8 mmolmL ) Ph3SiCl, tBuPh2SiCl, and tBu2PhSiCl, with the azeotropically dried complex F /Kryptofix2.2.2./ K at room temperature provided almost quantitatively the corresponding [F]triorganofluorosilanes 1–3 (Figure 1), as demonstrated by means of radio-HPLC. Their identities were confirmed by coelution of the radioactive probes spiked with the related nonradioactive F-analogues. The specific activity of 1, 2, and 3 was determined using UV-calibration curves and was in the range 1500–1700 GBqmmol . To investigate the applicability of the F-labelled compounds for the development of Si–F containing radiopharmaceuticals, their in vitro stability in human serum was investigated (Figure 1). In agreement with previously published data, the [F]triphenylfluorosilane 1 was found to be stable for 4 h in neutral water (data not shown) but unstable at pH 7.4–7.6 in human serum. In contrast, the tert[*] Dr. R. Schirrmacher, Dr. E. Schirrmacher, J. Tillmanns, Dr. T. Siessmeier, Dipl.-Ing. H. G. Buchholz, Prof. Dr. P. Bartenstein Klinik und Poliklinik f1r Nuklearmedizin Johannes Gutenberg Universit6t Mainz 55131 Mainz (Germany) Fax: (+49)6131-172386 E-mail: schirrmacher@klinik.nuklearmedizin.uni-mainz.de Dipl.-Chem. G. BradtmBller, Prof. Dr. K. Jurkschat Lehrstuhl f1r Anorganische Chemie Universit6t Dortmund 44221 Dortmund (Germany) Fax: (+49)231-755-5048 E-mail: klaus.jurkschat@uni-dortmund.de

Selective Protonation at a C−F Bond in the Presence of an Iridium−Methyl Bond Gives Diastereoselective Carbon−Fluorine Bond Activation and Carbon−Carbon Bond Formation. A New Path to Carbon Stereocenters Bearing Fluorine Atoms

Reaction of iridium−fluoroalkyl complexes with fluoride acceptors occurs with completely diastereoselective activation of a C−F bond and formation of a new C−C bond. Protonation occurs with complete selectivity at the C−F bond without any detectable formation of methane by protonation at the Ir−CH3 group.

Lewis Acid Behavior of ReO2F3: Synthesis of (ReO2F3)∞, ReO2F4-, Re2O4F7-, Re3O6F10-, and ReO2F3(CH3CN) and Study by NMR Spectroscopy, Raman Spectroscopy, and Density Functional Theory Calculations; and X-ray Structures of [Li][ReO2F4], [K][Re2O4F7], [K][Re2O4F7]·2ReO2F3, [Cs][Re3O6F10], and ReO3F(CH3CN)2·CH3CN

The reaction of Re2O7 with XeF6 in anhydrous HF provides a convenient route to high-purity ReO2F3. The fluoride acceptor and Lewis base properties of ReO2F3 have been investigated leading to the formation of [M][ReO2F4] [M = Li, Na, Cs, N(CH3)4], [K][Re2O4F7], [K][Re2O4F7]·2ReO2F3, [Cs][Re3O6F10], and ReO2F3(CH3CN). The ReO2F4-, Re2O4F7-, and Re3O6F10- anions and the ReO2F3(CH3CN) adduct have been characterized in the solid state by Raman spectroscopy, and the structures [Li][ReO2F4], [K][Re2O4F7], [K][Re2O4F7]·2ReO2F3, [Cs][Re3O6F10], and ReO3F(CH3CN)2·CH3CN have been determined by X-ray crystallography. [Li][ReO2F4] crystallizes in the tetragonal system, space group P421m, with a = 4.727(3) A, c = 8.880(7) A, V = 198.4(7) A3, and Z = 2 at 24 °C, R1 = 0.0378, and wR2 = 0.1029. [K][Re2O4F7] crystallizes in the monoclinic system, space group P2/n, with a = 5.4990(11) A, b = 5.1530(10) A, c = 14.753(3) A, β = 95.68°, V = 415.99(14) A3, and Z = 2 at 20 °C, R1 = 0.0473, and wR2 = 0.1200. [K][Re2O4F7]·2ReO2F3...

Unexpected Reactions of (Heptafluoro-1,4-cyclohexadien-1-yl)xenon(II) Hexafluoroarsenate with Sodium Fluoride and Antimony Pentafluoride

The reactivity of (heptafluoro-1,4-cyclohexadien-1-yl)xenon(ii) hexafluoroarsenate 1 towards a fluoride donor and acceptor has been investigated; the interaction of 1 with NaF led to perfluoro-3-methylenecyclopentene and xenon. No dication [C 6 F 6 Xe] 2+ was detected by 19 F NMR spectroscopy when [1-Xe + -1,4-C 6 F 7 ] [AsF 6 ] – was treated with SbF 5 –SO 2 , SbF 5 –SO 2 FCI or neat SbF 5 .

Fluoride ion affinities of germanium tetrafluoride and boron trifluoride from thermodynamic and structural data for (SF3)2GeF6, ClO2GeF5, and ClO2BF4

Results of studies to determine the fluoride ion affinity in GeF/sub 4/ and BF/sub 3/ are presented herein. Thermodynamic and structural data for (SF/sub 3/)/sub 2/GeF/sub 6/, ClO/sub 2/GeF/sub 2/, and ClO/sub 2/BF/sub 4/ are tabulated. The first fluoride ion affinity of GeF/sub 4/ was found to be 4-8kcal more energetic than that of BF/sub 3/. The packing volume of the BF/sub 4//sup -/ ion was found to be 16 +/- 2 A/sup 3/ which is less than the smaller GeF/sub 5//sup -/. It is noted that in small-cation structures, with close-packed ion arrangements, the lattice energy of fluoroborates can be approximately 5kcal mol/sup -1/ more favorable than for related fluorogermanates. Thus for this type of salts, the better fluoride acceptor ability of GeF/sub 4/ is largely offset by a poorer lattice energy, with the lattice difference decreasing as the cation becomes larger.

Fluorine exchange in some phosphorus and arsenic compounds

The rate of intermolecular fluorine exchange in the system PhPF 4 + PhPF − 5 ⇌ PhPF 4FPhPF − 4 was studied by 19F and 31P dynamic NMR techniques. The anion PhPF − 5 was generated by adding potassium fluoride in crown ether to PhPF 4. Attempts to initiate exchange in Ph 2AsF 2Me by adding fluoride ion donors were unsuccessful, instead, fluoride acceptors such as HF produced rapid intermolecular fluorine exchange in Ph 2AsF 2Me, presumably via an intermediate cation Ph 2AsFMe +. Experimental results and proposed mechanisms of fluorine exchange will be discussed.

ChemInform Abstract: THE CRYSTAL STRUCTURE OF TRIFLUOROXENON(IV) HEXAFLUOROBISMUTHATE(V)‐ THE FLUORIDE‐ACCEPTOR STRENGTH OF BISMUTH PENTAFLUORIDE

Abstract(XeF3)(BiF6) kristallisiert triklin in der Raumgruppe P1 mit Z=2.

The crystal structure of trifluoroxenon(IV) hexafluorobismuthate(V): the fluoride-acceptor strength of bismuth pentafluoride

The crystal structure of [XeF3][BiF6] has been determined from three-dimensional X-ray counter data. Crystals are triclinic with a= 5.698(3), b= 7.811(3), c= 8.854(4)A, α= 99.45(5), β= 110.09(5), γ= 92.84(5)°, U= 362.7 A3, Z= 2, and Dc= 4.69 g cm–3. The structure has been refined in the space group P to a final conventional R′ of 0.097 for 1 238 independent reflections. The structure consists of [XeF3]+ and [BiF6]– ions with a close contact of 2.25(2)A between the xenon atom of the T-shaped cation and fluorine atom of the octahedral anion. The bridging fluorine is shown to be more strongly associated with the xenon in [XeF3][BiF6] than in [XeF3][SbF6], indicating that BiF5 is a weaker fluoride acceptor than SbF5.

The Preparation and Properties of Complexes of Antimony and Bismuth Trifluorides with Strong Fluoride Acceptors

The reactions of antimony and bismuth trifluorides with the pentafluorides of antimony and arsenic in liquid sulfur dioxide yield the adducts SbF3•SbF5 (type A), SbF3•AsF5, BiF3•3SbF5, and BiF3•AsF5; no adducts of the trifluorides with BF3 were isolated. Antimony metal reacts with excess of antimony pentafluoride and arsenic pentafluoride in liquid sulfur dioxide giving a second form of SbF3•SbF5 (type B) and the same form of SbF3•AsF5 as produced from SbF3, respectively. BiF3•3SbF5 can be formulated as Bi(SbF6)3, but its Raman spectrum indicates the presence of extensive cation–anion fluorine-bridging. Their Raman spectra suggest that BiF3•AsF5, SbF3•AsF5, and SbF3•SbF5 (type B) have similar structures, possibly containing polymeric fluorine-bridged cations, but that SbF3•SbF5 (type A) has a different structure probably like that of AsF3•SbF5. The 121Sb Mössbauer spectra of the SbF3 adducts support the assignment of similar structures to SbF3•AsF5 and SbF3•SbF5 (type B), and the suggestion that SbF3•AsF5 and both forms of SbF3•SbF5 contain antimony (III) fluoro-cations. 19F n.m.r. shows that SbF3 has appreciable solubility in SO2 solutions of SbF5 and indicates the possible formation of "fluxional" SbF2–SbnF5n+1 molecules in SbF3–SbF5 solutions.