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Literature News

In this section we propose a selection of articles from some of the major scientific publications, aimed at updating the topic of: Fluorine Chemistry


Emulating Natural Product Conformation by Cooperative, Non-Covalent Fluorine Interactions

Pervasive in Nature, the propane unit is an essential component of numerous bioactive molecules. These range from acyclic systems, such as the neurotransmitter γ-aminobutyric acid, through to the bicyclic nuclei of various chromanes and dihydrobenzofurans. In the latter case, cyclisation via cyclic ether formation ensures a highly pre-organised structure, whilst linear scaffolds display more dynamic conformational behaviour resulting from rotation about the two internal C(sp3 )-C(sp3 ) bonds. In this study, the replacement of -[CH2 ]- units by -[CHF]- centres is evaluated as a strategy to achieve acyclic conformational control by hindering these internal rotations. Reinforcing, non-covalent fluorine interactions are validated as powerful design features that result in programmable conformational behaviours: These are encoded by the relative configuration of each centre. By exploiting cooperative neighbouring stereoelectronic effects in a multi-vicinal fluoroalkane it is possible to emulate the overall conformation of the dihydrobenzofuran scaffold found in a variety of natural products with an acyclic mimic. This is described as a function of two bond vectors at the chain termini and validated by combined theoretical, crystallographic and spectroscopic analyses. In view of the favourable physicochemical properties associated with fluorine introduction, this approach to bioactive scaffold design may prove to be expansive.

Source: Scheidt F. et al. Chemistry. 2016 Oct 27.
DOI: 10.1002/chem.201604632.


X-Ray Induced and Thermostimulated Luminescence of New Fluorine Containing Compounds (Potential Luminophores, Scintillators and Dosimeters)

X-ray induced luminescence spectra in optical range of wave-lengths (200-700 nm) and thermoluminescence curves for fluoride, fluorosulphate, fluorophosphate and fluorooxalate compounds of the titanium subgroup elements with alkali metals and ammonium have been obtained. Influence of annealing and repeated X-raying on luminescence (XRL) spectra of a number of compounds has been examined. Alloy additives influence on fluorine compounds XRL spectra has been examined. Most of compounds being under study may be used as X-ray luminophores, scintillators and dosimeters. The highest intensity of luminescence was achieved for such compounds as K2ZrF6, Cs2ZrF6, Rb2ZrF6 (especially for doped K2ZrF6), K2HfF6 and CsZr2(PO4)3. Radiation drifting to long-wave range for a number of fluorophosphatezirconates in comparison with fluorides may be a positive moment in making luminophores on their base.

Source: Boroznovskaya N.N. et al. J Fluoresc. 2016 Dec 30.
DOI: 10.1002/chem.201604632.


The unique fluorine effects in organic reactions: recent facts and insights into fluoroalkylations

Fluoroalkylation reaction, featuring the transfer of a fluoroalkyl group to a substrate, is a straightforward and efficient method for the synthesis of organofluorine compounds. In fluoroalkylation reactions, fluorine substitution can dramatically influence the chemical outcome. On the one hand, the chemistry of alkylation with non-fluorinated reagents may not be applicable to fluoroalkylations, so it is necessary to tackle the fluorine effects to achieve efficient fluoroalkylation reactions. On the other hand, fluorine substitution may bring about new reactivities and transformations that cannot be realized in alkylation with non-fluorinated reagents; thus, fluorine substitution can be used to explore new synthetic methods. This tutorial review provides a brief overview of the unique fluorine effects in recently developed nucleophilic, electrophilic, radical, and transition metal-mediated fluoroalkylation reactions by comparing with either their non-fluorinated counterparts or fluorinated counterparts with different numbers of fluorine substituents.

Source: Ni C. et al. Chem Soc Rev. 2016 Oct 21;45(20):5441-5454. 
DOI: 10.1039/c6cs00351f


Targeted synthesis of novel b-lactam antibiotics by laccase-catalyzed reaction of aromatic substrates selected by pre-testing for their antimicrobial and cytotoxic activity

The rapidly increasing problem of antimicrobial-drug resistance requires the development of new antimicrobial agents. The laccase-catalyzed amination of dihydroxy aromatics is a new and promising method to enlarge the range of currently available antibiotics. Thirty-eight potential 1,2- and 1,4-hydroquinoid laccase substrates were screened for their antibacterial and cytotoxic activity to select the best substrates for laccase-catalyzed coupling reaction resulting in potent antibacterial derivatives. As a result, methyl-1,4-hydroquinone and 2,3-dimethyl-1,4-hydroquinone were used as parent compounds and 14 novel cephalosporins, penicillins, and carbacephems were synthesized by amination with amino-β-lactam structures. All purified products were stable in aqueous buffer and resistant to the action of β-lactamases, and in agar diffusion and broth micro-dilution assays, they inhibited the growth of several Gram-positive bacterial strains including multidrug-resistant Staphylococcus aureus and Enterococci. Their in vivo activity and cytotoxicity in a Staphylococcus-infected, immune-suppressed mouse model are discussed.

Source: Mikolasch A. et al. Appl Microbiol Biotechnol. 2016 Jun;100(11):4885-99.
DOI: 10.1007/s00253-016-7288-z.


Regioselective Synthesis of a-Fluorinated Cyclopentenones by Organocatalytic Difluorocyclopropanation and Fluorine-Directed and Fluorine-Activated Nazarov Cyclization

Silyl dienol ethers, prepared from a,b-unsaturated ketones, underwent proton sponge-catalyzed difluorocyclopropanation with trimethylsilyl 2,2-difluoro-2-fluorosulfonylacetate in a regioselective manner, leading to 1,1-difluoro-2-siloxy-2-vinylcyclopropanes in good yields. The cyclopropanes thus obtained were in turn subjected to fluoride-ion-catalyzed ring opening to afford 1-fluorovinyl vinyl ketones (i.e., Nazarov precursors). Treatment of the precursors with Me3 Si+ B(OTf)4- regioselectively promoted the Nazarov cyclization, the rate and regioselectivity of which were drastically enhanced by the fluoro substituent, which thus facilitated efficient synthesis of biologically promising α-fluorocyclopentenone derivatives.

Source: Fuchibe K. et al. Chemistry. 2017 Feb 24;23(12):2831-2838.
DOI: 10.1002/chem.201604578.


Crystal Structures of Diaryliodonium Fluorides and Their Implications for Fluorination Mechanisms

The radiofluorination of diaryliodonium salts is of value for producing radiotracers for positron emission tomography. We report crystal structures for two diaryliodonium fluorides. Whereas diphenyliodonium fluoride (1 a) exists as a tetramer bridged by four fluoride ions, 2-methylphenyl(phenyl)iodonium fluoride (2 a) forms a fluoride-bridged dimer that is further halogen bonded to two other monomers. We discuss the topological relationships between the two and their implications for fluorination in solution. Both radiofluorination and NMR spectroscopy show that thermolysis of 2 a gives 2-fluorotoluene and fluorobenzene in a 2 to 1 ratio that is in good agreement with the ratio observed from the radiofluorination of 2-methylphenyl(phenyl)iodonium chloride (2 b). The constancy of the product ratio affirms that the fluorinations occur via the same two rapidly interconverting transition states whose energy difference dictates chemoselectivity. From quantum chemical studies with density functional theory we attribute the "ortho-effect" to the favorable electrostatic interaction between the incoming fluoride and the o-methyl in the transition state.
By utilizing the crystal structures of 1 a and 2 a, the mechanisms of fluoroarene formation from diaryliodonium fluorides in their monomeric, homodimeric, heterodimeric, and tetrameric states were also investigated. We propose that oligomerization energy dictates whether the fluorination occurs through a monomeric or an oligomeric pathway.

Source: Lee Y. S. et al. Chemistry. 2017 Mar 28;23(18):4353-4363.
DOI: 10.1002/chem.201604803.


Importance of fluorine in 2,3-dihydroquinazolinone and its interaction study with lysozyme

The main aim of this study is to investigate the interaction of 7-fluoro-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-one with lysozyme through various spectrophotometric studies. The graph such as Stern-Volmer plot, modified Stern Volmer plot, double logarithmic plot and Van't Hoff plot were plotted to determine the various parameters essential for predicting the interaction. The interaction of the ligand with the protein was further confirmed by circular dichroism and NMR study. The molecular docking was performed and the results obtained were correlated with the other studies. The importance of fluorine was justified through the prediction of pKa values and the possible metabolic pathway using the in silico tools. In addition, the cytotoxicity of the compound was carried out using HeLa cancer cell.

Source: Hemalatha K. et al. J Photochem Photobiol B. 2016 Sep;162:176-88.
DOI: 10.1016/j.jphotobiol.2016.06.036.


A Heck-Matsuda Process for the Synthesis of b-Arylethenesulfonyl Fluorides: Selectively Addressable Bis-electrophiles for SuFEx Click Chemistry

A Heck-Matsuda process for the synthesis of the otherwise difficult to access compounds, β-arylethenesulfonyl fluorides, is described. Ethenesulfonyl fluoride (i.e., vinylsulfonyl fluoride, or ESF) undergoes β-arylation with stable and readily prepared arenediazonium tetrafluoroborates in the presence of the catalyst palladium(II) acetate to afford the E-isomer sulfonyl analogues of cinnamoyl fluoride in 43-97 % yield. The β-arylethenesulfonyl fluorides are found to be selectively addressable bis-electrophiles for sulfur(VI) fluoride exchange (SuFEx) click chemistry, in which either the alkenyl moiety or the sulfonyl fluoride group can be the exclusive site of nucleophilic attack under defined conditions, making these rather simple cores attractive for covalent drug discovery.

Source: Qin H.L. et al. Angew Chem Int Ed Engl. 2016 Nov 2;55(45):14155-14158.
DOI: 10.1002/anie.201608807


Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood

Series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and FeII, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic 19F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial-up to 100-fold-decrease in the longitudinal relaxation time (T1) of the fluorine nuclei. The shorter T1 allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T2/T1 ratio. In water, the optimal metal complexes for imaging applications are those containing HoIII and FeII, and to a lesser extent TmIII and YbIII. Whereas T1 of the lanthanide complexes are little affected by blood, the T2 are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, HoIII-DOTAm-F12, could not be detected in blood. TmIII yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of FeII-DOTAm-F12 are similar in water and in blood. That complex has the highest T2/T1 ratio (0.57) and the lowest limit of detection (300 μM) in blood. The combination of high water solubility, single fluorine signal, and high T2/T1 of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.

Source: Srivastava K. et al. Inorg Chem. 2017 Feb 6;56(3):1546-1557.
DOI: 10.1021/acs.inorgchem.6b02631


From secondary alcohols to tertiary fluoro substituents: A simple route to hydroxymethyl branched sugars with a fluorine substituent at the branching point

From a secondary hydroxyl group, by the simple sequence of oxidation, Wittig reaction of the obtained ulose with methoxymethylene triphenyl phosphorane, exposure of the resulting exocyclic enol ether to Selectfluor and subsequent reduction of the α-fluoro aldehyde thus obtained, tertiary fluoro substituents can be introduced into carbohydrate and carbohydrate-related scaffolds at a branching point now bearing a new hydroxymethyl group.

Source: Schalli M. et al. Carbohydr Res. 2016 Dec 21;436:11-19.
DOI: 10.1016/j.carres.2016.10.013.


Novel fluorinated ligands for gold nanoparticle labelling with applications in 19F-MRI

Novel fluorinated ligands for gold nanoparticle labelling have been designed and synthesised. Several types of gold nanoparticles have been prepared in the presence of these fluorinated ligands alone, or in combination with non-fluorinated ligands. Their colloidal stability in water and other solvents was tested and the magnetic resonance properties of the so-obtained nanoparticles were also assessed in detail. 1H and 19F-NMR spectra were evaluated and MRI phantoms of the most promising nanoparticles were successfully measured in 19F-MRI. The MRI signal to noise ratio was related to the fluorine concentration and compared with ICP-MS data to correlate the real concentration of fluorine grafted onto the nanoparticles with the actually active fluorine in MRI.

Michelena O. et al. Chem Commun (Camb). 2017 Feb 21;53(16):2447-2450.
DOI: 10.1039/c6cc08900c.

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