Fluorinated Phenyl Rings Research Articles

Electrochemistry and Spin‐Crossover Behavior of Fluorinated Terpyridine‐Based Co(II) and Fe(II) Complexes

AbstractDue to their ability to form stable molecular complexes that have tailor‐made properties, terpyridine ligands are of great interest in chemistry and material science. In this regard, we prepared two terpyridine ligands with two different fluorinated phenyl rings on the backbone. The corresponding CoII and FeII complexes were synthesized and characterized by single‐crystal X‐ray structural analysis, electrochemistry and temperature‐dependent SQUID magnetometry. Single crystal X‐ray diffraction analyses at 100 K of these complexes revealed Co−N and Fe−N bond lengths that are typical of low spin CoII and FeII centers. The metal centers are coordinated in an octahedral fashion and the fluorinated phenyl rings on the backbone are twisted out of the plane of the terpyridine unit. The complexes were investigated with cyclic voltammetry and UV/Vis‐NIR spectroelectrochemistry. All complexes show a reversible oxidation and several reduction processes. Temperature dependent SQUID magnetometry revealed a gradual thermal SCO behavior in two of the complexes, while EPR spectroscopy provided further insights on the electronic structure of the metal complexes, as well as site of reduction.

Potent and biostable inhibitors of the main protease of SARS-CoV-2

Potent and biostable inhibitors of the main protease (Mpro) of SARS-CoV-2 were designed and synthesized based on an active hit compound 5h (2). Our strategy was based not only on the introduction of fluorine atoms into the inhibitor molecule for an increase of binding affinity for the pocket of Mpro and cell membrane permeability but also on the replacement of the digestible amide bond by a surrogate structure to increase the biostability of the compounds. Compound 3 is highly potent and blocks SARS-CoV-2 infection invitro without a viral breakthrough. The derivatives, which contain a thioamide surrogate in the P2-P1 amide bond of these compounds (2 and 3), showed remarkably preferable pharmacokinetics in mice compared with the corresponding parent compounds. These data show that compounds 3 and its biostable derivative 4 are potential drugs for treating COVID-19 and that replacement of the digestible amide bond by its thioamide surrogate structure is an effective method.

Tailoring the cavities of hydrogen-bonded amphidynamic crystals using weak contacts: towards faster molecular machines.

This work describes the use of C–H⋯F–C contacts in the solid-state from the stator towards the rotator to fine-tune their internal motion, by constructing a set of interactions that generate close-fitting cavities in three supramolecular rotors 1–3I. The crystal structures of these rotors, determined by synchrotron radiation experiments at different temperatures, show the presence of such C–H⋯F–C contacts between extended carbazole stators featuring fluorinated phenyl rings and the 1,4-diazabicyclo[2.2.2]octane (DABCO) rotator. According to the 2H NMR results, using deuterated samples, and periodic density functional theory computations, the rotators experience fast angular displacements (preferentially 120° jumps) due to their low rotational activation energies (Ea = 0.8–2.0 kcal mol−1). The higher rotational barrier for 1 (2.0 kcal mol−1) is associated with a larger number of weak C–H⋯F–C contacts generated by the stators. This strategy offers the possibility to explore the correlation among weak intermolecular forces, cavity shape, and internal dynamics, which has strong implications in the design of future fine-tuned amphidynamic crystals.

Exploiting the Reactivity of Fluorinated 2-Arylpyridines in Pd-Catalyzed C-H Bond Arylation for the Preparation of Bright Emitting Iridium(III) Complexes.

Pd-catalyzed C-H bond arylation applied to 2-(2,4-difluorophenyl)-5-(trifluoromethyl)pyridine (1) and 2-(3,5-difluorophenyl)-5-(trifluoromethyl)pyridine (5) allows the access to two families of Ir(III) complexes, charge-neutral and cationic species. The reaction is regioselective since only the C3- or C4-position of the fluorinated phenyl ring of 1 or 5 is readily functionalized - namely the C-H bond flanked by the two fluorine atoms which is the most acidic - which allows the electronic control of the reactive site. A range of electron-withdrawing (CN, CO2Et, C(O)Me) substituents on the aryl group has been incorporated leading to the pro-ligands (1, Ar-2,4-dFppy; 2, Ar = p-C6H4-CN; 3, Ar = p-C6H4-CO2Et; 4, Ar = p-C6H4-C(O)Me; 5, and Ar-3,5-dFppy; 6, Ar = p-C6H4-CO2Et). The unsubstituted complexes F1/G1 and F1/G5 featuring 1 and 5, respectively, as C^N ligands are used as reference complexes. The families of five charge-neutral [Ir(C^N)2(N^O)] complexes (C^N is 2-(5-aryl-(4,6-difluorophenyl)-5-(trifluoromethyl)pyridinato (F2-F4), and 2-(4-aryl-(3,5-difluorophenyl)-5-(trifluoromethyl)pyridinato (F5-F6), N^O = 2-picolinate) and five cationic [Ir(C^N)2(N^N)]PF6 complexes (N^N = dmbpy is 4,4'-dimethyl-2,2'-bipyridine) (G2-G6) were synthesized, and their structural and photophysical properties were studied with comparison to the unsubstituted analogues used as reference complexes. The appended aryl group provides large steric bulk as the biaryl fragment is twisted as shown by the X-ray crystal structures of F2, F5, F6, G3, and G5. These latter complexes display a wide variety of different Ir···Ir intermetallic distances in crystals, from 8.150 Å up to 15.034 Å. Moreover, the impact on the emission energy is negligible, as a result of the breaking of the conjugation between the two aryl groups. Charge-neutral complexes [Ir(C^N)2(N^O)] (N^O = 2-picolinate) show bright luminescence: F2-F4 (λem = 495-499 nm) are blue-green emitters, whereas F5 and F6 (λem = 537, 544 nm), where the fluorine substituents are located at the C3- and C5-positions, emit in the green region of the visible spectrum. In all cases, a unitary photoluminescence quantum yield is found. The improvement of Φ might be explained by an increase of the radiative rate constant due to a higher degree of rigidity of these congested molecules, compared to the unsubstituted complex F1. The same trends are observed for the family of complexes G. Complexes G1-G4 exhibit blue photoluminescence, and G5 and G6 lead to a red-shifted emission band, as also found for the related complexes F5 and F6 due to the similar fluorine substitution pattern. Their emission quantum yields are remarkably high for charged complexes in the CH2Cl2 solution. These results showed that Pd-catalyzed C-H bond arylation is a valuable synthetic approach for designing efficient emitters with tunable photophysical properties.

Stepwise Design of γ-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere.

Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel CF3-alkoxy groups as bioisosteric replacements of a fluorinated phenyl ring and properties such as lipophilicity, solubility, metabolic stability, and free fraction could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by reducing aromaticity, we prevented phototoxicity. Additional substitution in the triazolopyridine core disturbed the binding to phosphatidylinositol 4-kinase, catalytic β (PIK4CB). We also introduced less lipophilic head heterocycles devoid of covalent binding (CVB) liability. After these changes, further modifications to the trifluoroethoxy bioisosteric replacement allowed rebalancing of properties, such as lipophilicity, and also potency. Our optimization strategy culminated with in vivo active RO7101556 (18B) having excellent properties and being selected as an advanced candidate.

Synthesis, crystal structure and fluorination effects in vinylidenebis(diphenylphosphine)gold(I) thiolate coordination compounds

We report the synthesis and characterization of nine new gold(I) dinuclear compounds containing the bridging ligand vinylidenebis(diphenylphosphine) and terminal fluorophenylthiolates with the general formula [Au2(SR)2(μ-vdpp)] in which SR = SC6F5, SC6HF4, SC6H3F2-2,4, SC6H3F2-3,4, SC6H3F2-3,5, SC6H4F-2, SC6H4F-3, SC6H4F-4 together with the non-fluorinated derivative [Au2(SC6H5)2(μ-vdpp)]. In these compounds, we analyze the long-range influence of the fluorination patterns over the electronic structure in terms of the changes in the 31P-NMR chemical shifts, showing the different effects depending on the relative fluorination position. Additionally, we present the crystal structure of four of the compounds, showing the presence of supported aurophilic interactions in which the Au···Au distances are modified as a consequence of the lateral interactions formed by the fluorinated phenyl rings. Overall this work gives insights in the effects of ligand fluorination in gold coordination compounds.

Synthesis of 4-(2-fluorophenyl)-7-methoxycoumarin: experimental and computational evidence for intramolecular and intermolecular C-F···H-C bonds.

4-(2-Fluorophenyl)-7-methoxycoumarin (6) was synthesized by Pechmann reaction under mild conditions via a three-step reaction. The solution-state 1H NMR spectra of 6 showed a strong intramolecular interaction between F and H5 (JFH = 2.6 Hz) and 13C NMR suggested that this C–F···H–C coupling is a through-space interaction. The 2D 19F-{1H} HOESY and 1H-{19F} 1D experiments were done to confirm this F···H interaction. The single crystal X-ray structure and the DFT-optimized structure showed that the fluorinated phenyl ring favors the orientation with the fluorine atom closer to H5 than H3. The X-ray structure also showed the existence of the intermolecular C–F···H–C interaction.

Coordination Polymers with Intramolecular Fluorine-Involved Contacts in Two-Dimensional Sheet Windows

Six two-dimensional polymeric complexes of [Hg(L2-F)2]n, 1, [Hg(L2,5-F)2]n, 2, [Hg(L3-F)2]n, 3, [Hg(L2,3,4-F)2]n, 4, [Hg(L3,4,5-F)2]n, 5, and [Hg(L2,3,4,5-F)2]n, 6 and a discrete complex of [Hg(L2,6-F)2], 7, in which Ln-F ligands are N-(fluorinatedphenyl)-2-pyrazinecarboxamides carrying fluorine atoms on the different positions of phenyl ring, have been synthesized and characterized. The crystal structures from X-ray diffraction reveal that all polymeric complexes have similar two-dimensional (2D) sheet windows. From a topological perspective, each metal atom can be viewed as 4-connected nodes and Ln-F ligands can be considered as linkers in the formation of these 2D windows. Because of the flexibility of the ligand, fluorinated-phenyl rings as hanging groups in the windows are pointed toward the adjacent groups to generate different fluorine-involved intramolecular interactions. One of the common features in the crystal structures of these complexes is the presence of a strong tendency to form intramolec...

Stereoselective and quantitative [2 + 2] photodimerization of a symmetrical octafluoro stilbene in the solid state: Face-to-face stacking of the fluorinated rings in trans-1,2-bis(2,3,5,6-tetrafluorophenyl)ethylene

Abstract The symmetrical octafluoro stilbene trans -1,2-bis(2,3,5,6-tetrafluorophenyl)ethylene ( 1 ) undergoes a stereoselective and quantitative [2 + 2] photodimerization in the solid state. The olefin self-assembles via C-H⋯F and face-to-face interactions of the fluorinated phenyl rings into a geometry for a topochemical photodimerization. The crystal structure and stereochemistry of the photoproduct rctt -1,2,3,4-tetrakis(2,3,5,6-tetrafluorophenyl)cyclobutane ( 2 ) has been determined.

Fluorine Scan of Inhibitors of the Cysteine Protease Human Cathepsin L: Dipolar and Quadrupolar Effects in the π-Stacking of Fluorinated Phenyl Rings on Peptide Amide Bonds.

The π-stacking of fluorinated benzene rings on protein backbone amide groups was investigated, using a dual approach comprising enzyme-ligand binding studies complemented by high-level quantum chemical calculations. In the experimental study, the phenyl substituent of triazine nitrile inhibitors of human cathepsin L (hCatL), which stacks onto the peptide amide bond Gly67-Gly68 at the entrance of the S3 pocket, was systematically fluorinated, and differences in inhibitory potency were measured in a fluorimetric assay. Binding affinity is influenced by lipophilicity (clog P), the dipole and quadrupole moments of the fluorinated rings, but also by additional interactions of the introduced fluorine atoms with the local environment of the pocket. Generally, the higher the degree of fluorination, the better the binding affinities. Gas phase calculations strongly support the contributions of the molecular quadrupole moments of the fluorinated phenyl rings to the π-stacking interaction with the peptide bond. These findings provide useful guidelines for enhancing π-stacking on protein amide fragments.

Fluconazole–malonic acid (1/1)

Co-crystallizaton of the anti­fungal drug fluconazole [2-(2,4-difluoro­phen­yl)-1,3-bis­(1H-1,2,4-triazol-1-yl)propan-2-ol] with malonic acid in acetonitrile solution resulted in the formation of the title 1:1 co-crystal, C13H12F2N6O·C3H4O4. The geometry around the central fluconazole atom is distorted tetrahedral. The dihedral angles between the triazole rings and the fluorinated phenyl ring are 30.64 (7) and 61.91 (5)°. In the crystal, the basic packing motif may be envisioned as a cyclic aggregate formed of two fluconazole mol­ecules linked by two malonic acid mol­ecules through O—H⋯N and O—H⋯O hydrogen bonds. Such aggregates are further connected into (001) layers by further O—H⋯N hydrogen bonds. The structure also features weak non-classical C—H⋯O and C—H⋯N inter­actions.

Highly efficient deep-blue organic electroluminescent devices (CIEy ≈ 0.08) doped with fluorinated 9,9′-bianthracene derivatives (fluorophores)

A series of new fluorinated 9,9′-bianthracene derivatives (BAnFs) have been designed and synthesized to serve as deep-blue dopants in organic electroluminescent (EL) devices. With the different substitution patterns of the electron-withdrawing groups, such as F and CF3, the photophysical properties, the energy levels and thermal stability of these BAnFs are tuned, which are supported by a density functional study of their geometry and electronic structure. In the thin film state, the fluorescent emissions of the BAnFs are fine-tuned from 448 to 439 nm, with varied fluorinated phenyl rings attached to the 9,9′-bianthracene core. All the BAnFs show a considerable thermal stability, which have high Tg values, above 150 °C. A pure blue emission at the Commission Internationale de l'Eclairage (CIE) coordinates (0.156, 0.083), has been achieved using the host 4,4′-bis(N-carbazolyl)biphenyl (CBP) doped with 10,10′-bis(3,5-bis(trifluoromethyl)phenyl)-9,9′-bianthracene (BAn-(3,5)-CF3). The maximum current efficiency and power efficiency of the BAn-(3,5)-CF3-doped device are 3.05 cd A−1 and 2.62 lm W−1, corresponding to 5.02% of the maximum external quantum efficiency. The synthesized new fluorinated 9,9′-bianthracene derivatives show potential applications as highly efficient pure blue emitters for organic light emitting devices.

Highly efficient deep-blue organic electroluminescent devices doped with hexaphenylanthracene fluorophores

Fluorescent 2,3,6,7,9,10-hexaphenylanthracene-based derivatives (HPhAn) were synthesized to serve as deep-blue dopants in organic electroluminescent (EL) devices. The fluorescent emissions of HPhAn fluorophores, fine-tuned from 462 to 449 nm with varied fluorinated phenyl rings attached to the central carbons of the anthracene core, produced photoluminescence quantum yields of 82–88% in the solid state. Unlike the known monostyrylamine deep-blue dopant, these blue dopants in dilute solutions showed no pronounced spectral red shift with increasing solvent polarity; the emission color of HPhAn dopants is thus insensitive to the polarity of the medium. The highest-occupied molecular orbital (HOMO) and lowest-unoccupied molecular orbital (LUMO) energy levels calculated from the oxidation potentials and optical energy gaps are 5.61–5.70 eV and 2.73–2.89 eV, respectively. These thermally robust compounds undergo thermal decomposition at temperatures greater than 300 °C. The relationships among current density, voltage and luminance, the EL efficiency and the operational stability of devices based on the blue HPhAn dopants were examined. These HPhAn-doped EL devices are activated at voltages less than 3.5 V and attained an external quantum efficiency as much as 5.3% in the deep-blue light region with Commission Internationale d'Éclairage (CIE) coordinates (0.14, 0.10), near the National Television System Committee (NTSC) standard blue coordinates (0.14, 0.08).

Thin Hydrogel Films With Nanoconfined Surface Reactivity by Photoinitiated Chemical Vapor Deposition

Several property requirements have led to the modification of hydrogels by incorporating functional groups. The current work seeks to achieve graded functional group incorporation into hydrogel thin films using the one-step technique of photoinitiated CVD (piCVD). The functional group pentafluorophenylmethacrylate (PFM) is copolymerized with hydroxyethyl methacrylate (HEMA). Because PFM reacts easily with amine groups, the incorporation of PFM results in a platform for subsequent functionalization. The graded copolymer confines the PFM to the near surface region (∼20 nm) allowing the control of the hydrogel film properties independently of the surface reactivity. Although homogeneous incorporation of PFM in the hydrogel matrix inhibits swelling, the swollen water content of pure pHEMA is nearly preserved in the graded copolymer. FTIR spectroscopy shows that the absorption peaks corresponding to the fluorinated phenyl ring in the graded copolymer disappear after functionalization with O,O-bis (2-aminoethyl) polyethylene (PEG-diamine), suggesting a nearly complete conversion of the PFM bonds.

( P-Bis(pentafluorophenyl) substituted) PCP-pincer Ru(II) complexes: A theoretical study of the molecular structure and electronic properties

The differences between the molecular structures of the PCP-pincer complex [RuCl{C 6H 3(CH 2P(C 6H 5) 2) 2-2,6}(PPh 3)] ([RuCl(PCP H)(PPh 3)], 1) and its tetrakis-pentafluorophenyl substituted analogue [RuCl{C 6H 3(CH 2P(C 6F 5) 2) 2-2,6}(PPh 3)] ([RuCl(PCP F20)(PPh 3)], 2) have been rationalised by performing calculations on the cations [Ru(PCP H)(PPh 3)] + ( 1cat) and [Ru(PCP F20)(PPh 3)] + ( 2cat). The molecular interactions between the chloride ligand and the axial rings, as found in 1 and 2, respectively, have been studied computationally in the model systems [(C 6X 5PH 2) 2Cl −] (X = H, F). The calculations on 2cat show that in 2 it is most likely the attractive electrostatic interaction between the chloride ligand and the fluorinated phenyl rings that forces the C ipso atom to occupy an axial position rather than an equatorial one in the observed (X-ray of 2) square pyramidal arrangement. In 1, however, repulsive steric hindrance forces the PPh 3 ligand to take the apical position. The applicability of the TD-DFT method for the calculation of the electronic spectra of the PCP-pincer compounds 1 and 2 has been tested. The results indicate that the excitation energies calculated for both complexes are in a reasonable agreement with the experimental absorption maxima. However, for 1, all the calculated transition energies are underestimated.

New deuterium isotope effects on 13C and 19F chemical shifts across intramolecular hydrogen bonds of non-resonance assisted systems

A series of thioanilides and corresponding anilides, some of which contain fluorinated phenyl rings, have been synthesized as model compounds. They all contain rather strong intramolecular hydrogen bonds, the strength of which varies. Deuterium isotope effects on 19F and 13C chemical shifts due to deuteriation at the NH proton show interesting new long-range isotope effects on chemical shifts that may be related to the existence of an intramolecular hydrogen bond and to transmission of the isotope effect due to an electric field effect. Deuterium isotope effects on chemical shifts report on variations in hydrogen bonding, for example, as a function of changes in substituents or temperature. Deuteriation leads to a strengthening of the hydrogen bond.

The structure and dynamic behaviour of disubstituted derivatives of [Rh 6(CO) 16] containing bidentate phosphorus ligands

The solution structure and dynamic behaviour of [Rh 6(CO) 14(μ,η 2-dppm)] ( 1), [Rh 6(CO) 14(μ,η 2-dppe)] ( 2) and [Rh 6(CO) 14(μ,η 2-dppe f)] ( 3) containing bridging diphosphine ligands have been examined using 1D 13C, 31P and 2D 13C–{ 103Rh}, 31P–{ 103Rh} HMQC and 13C EXSY NMR techniques. It has been shown that the solid state structure of these clusters remains unchanged in solution, including the close non-bonding intramolecular interactions of the perfluorinated phenyl rings with adjacent terminal carbonyls. In solution, two different dynamic processes have been found: for 2 and 3, the P–CH 2–CH 2–P chain of the coordinated dppe and dppe f is non-rigid and this leads to the interchange of the two enantiomeric forms of the clusters through a ‘rocking’ motion of the bridging diphosphine; the rate of this exchange depends strongly on the non-bonding van der Waal's interactions between the phosphorus substituents and adjacent carbonyl ligands which results in substantially slower dynamics for 3 because the steric requirements of the fluorinated phenyl rings considerably hinder this racemization. The second type of dynamics found in 1– 3 involves exchange of terminal/face-bridging CO's associated with the unsubstituted rhodium atoms. Regioselectivity of these exchanges is essentially similar for all three clusters, whereas the rates of these CO-exchanges are substantially higher in 3, which may be due to the lower net donicity of the per-fluorinated diphosphine.

Influence of quadrupolar interactions on the crystal packing of organic compounds: the pentafluorophenyl ester of a tricyclic α,β-unsaturated-γ-amino acid

The single crystal X-ray diffraction structure of (−)-pentafluorophenyl( Z, S, S)-2-(6-oxo-1,3,4,6,11,11a-hexahydro-2 H-pyrido[1,2- b]isoquinolin-11-yliden)acetate ( 1) is reported. We have found that the crystal packing of the α,β-unsaturated-γ-amino acid derivative 1 is mainly determined by the interaction between the two aromatic rings, namely the benzenic type and the pentafluorinated ring. The crystal packing of 1 shows a herringbone (zig-zag) structure, that is quite typical of aromatic compound with intermolecular arene–arene interactions. The benzenic and the fluorinated phenyl rings in 1 are in a matched face-to-face arrangement. The origin of this interaction can be ascribed to a favourably quadrupolar interaction between both types of aromatic ring. The results reported in the present paper indicate that the pentafluorophenyl ester functionality can be a useful building block in crystal engineering.

Conformational and Electronic Effects of Phenyl-Ring Fluorination on the Photophysical Properties of Nonplanar Dodecaarylporphyrins

Static and time-resolved optical measurements have been performed on a number of free-base and zinc dodecaarylporphyrins with varying degrees of fluorination of the peripheral aryl rings. These studies were performed in a variety of solvents of differing polarity and metal-ligating ability and at room and low temperatures. All of the compounds are deduced to be nonplanar based on their perturbed photophysical properties relative to planar analogues and on the X-ray data available for these molecules. The dodecaarylporphyrins studied generally separate into two classes based on their photophysical properties and the presence or absence of meso-pentafluorophenyl rings. The photophysical properties are clearly affected by the electron-withdrawing characteristics of these fluorinated phenyl rings, but structural effects derived from the interaction of the phenyl rings with each other, the macrocycle, and the solvent are also apparent. Many of the differences in properties among the molecules studied and the p...

A Molecular Dynamics Simulation Study of Dipole Correlation in the Isotropic Phase of the Mesogens me5NF and GGP5Cl

Molecular dynamics simulations of the molecules me5NF and GGP5Cl have been undertaken to study dipole correlation in the isotropic phase. The simulations use an all-atom force field developed specifically for these molecules, together with a full treatment of the long range electrostatic interactions via an Ewald sum. me5NF exhibits a preference for anti-parallel dipole association as seen through the distance dependent correlation function g1(r). However, GGP5Cl shows no marked preference for parallel or anti-parallel dipole association. Both molecules show the presence of distinct parallel and anti-parallel dipole dimers in the liquid phase. For me5NF the dominant molecular pair configurations arise from favourable quadrupolar interactions between an unsubstituted phenyl ring and a second phenyl ring with fluorine and cyano substituents. In GGP5Cl, which has two fluorinated phenyl rings, molecules in the liquid phase show an intramolecular preference for an anti-parallel arrangement of C-F bond dipoles, which is absent in the gas phase. Kirkwood correlation factors, g1, have been calculated from the simulations data. For me5NF, the g1 result is in excellent agreement with existing experimental data. However, the g1 result for GGP5Cl is in error. It is suggested that this discrepancy arises due to a failure to model correctly the dipole-induced dipole interactions that arise in this molecule.