The packing of the units is dominated by C—H⋯O hydrogen bonding and weak dispersion forces, with a minor contribution from C—H⋯π bonds and π–π stacking interactions.The structure of tellurium(VI)], [Sb3Te(C6H5)9O6], the hexaoxidotellurate(VI) ion is coordinated to three SbV ions via pairs of cis-positioned O atoms to form a discrete molecular unit. The TeVI and SbV central ions exhibit distorted octahedral [TeO6] and distorted trigonal–bipyramidal [SbC3O2] coordination geometries, respectively. The linking of these polyhedra, by sharing the dioxide edges, results in the Te-based octahedron having a mer-configuration. The packing of the molecules is dominated by C—H⋯O hydrogen bonding and weak dispersion forces, with a minor contribution from C—H⋯π bonds and π–π stacking interactions. According to the Hirshfeld surface analysis, the contributions of the H⋯H, H⋯C/C⋯H and H⋯O/O⋯H contacts are 58.0, 32.6 and 7.8%, respectively. The title structure provides a model for the bonding of triorganoantimony dications to octahedral oxoanions, and the observed doubly bridged motifs, Te(μ-O)2Sb, may find application in the functionalization of polyoxometalate species.In the structure of the title compound [systematic name hexa-μ-oxido-1:2κ The latter are formally similar to 1,2-benzenediolate chelates, which have been observed in molecular organoantimony compounds 3TeO6, which features the formation of discrete clusters, [Te{(μ-O)2SbPh3}3].At the same time, PhC2/c, and contains the discrete molecular unit shown in Fig. 16] octahedron and three [Ph3SbO2] polyhedra sharing oxide edges. Thus two oxide bridges are formed from TeVI to each of the three SbV ions with Te—O—Sb angles in the range 99.33 (13)–102.41 (13)°  Å, which occurs in the Te1(μ-O)2Sb2 unit. Such fully substituted organometallic hexaoxotellurate(VI) units are exceedingly rare, with the only known example being an aliphatic SnIV derivative 4Te(OH)2] and [(Ph3SnO)2Te(OMe)4] –174.49 (13)°. The fivefold coordination around each of three Sb-atoms can best be described as distorted trigonal bipyramidal, with the O2—Sb1—C7 = 161.09 (15)°, O4—Sb2—C19 = 164.73 (16)° and O5—Sb3—C37 = 165.43 (16)° bond angles defining the principal axes of the trigonal bipyramids. This assignment is supported by the calculated five-coordinate τ-indices, which are 0.69, 0.75 and 0.65 for Sb1, Sb2 and Sb3, respectively –2.110 (3) Å] than the equatorial Sb—Oeq bonds, Sb1—O1, Sb2—O3 and Sb3—O6 [in the range 1.966 (3)–1.992 (3) Å]. This observation coincides with the differentiation of the Te—O bond lengths; three of which, Te1—O2, Te1—O4 and Te1—O5, lie in the range 1.904 (3)–1.918 (3) Å and three, Te1—O1, Te1—O3 and Te1—O6, lie in the range 1.949 (3)–1.968 (3) Å. Thus when considering the six Te—O—Sb bridges, the shorter Sb—O bonds are accompanied by the longer Te—O bonds and vice versa. The distribution of the Te—OaxSb and Te—OeqSb bonds indicates that the coordination octahedron around the Te atom has the mer-configuration 3Te(OH)3]  Å; symmetry code (ii) x, y + 1, z; Table 2b direction iii and C41—H41⋯Cg(C13–C18)iv  x, −y + 2, x − x, −y + 1, z + bc plane. In addition, to further consolidate the bilayers, there are weak slipped π–π stacking interactions between pairs of inversion-related phenyl rings, with a centroid-to-centroid distance, Cg(C1–C6)⋯Cg(C1–C6)v = 3.807 (6) Å, an interplanar distance of 3.603 (5) Å and a slippage angle of 18.8 (5)° . There are no specific interactions between the bilayers, and the shortest of their C⋯C contacts [3.404 (6) Å] is not accompanied by any π–π overlap.Very weak mutual C—H⋯O bonding  and trans-[(Ph3SnO)2Te(OMe)4] 2[CH2(Ph2SnO)2]2Te -octakis(trimethylsilyloxy)ditellurium and orthotelluric acid trisester 3Te(OH)3, 4Te(μ-O)2Te(OR)4 . The latter contains double Te—O—Te bridges, which are formally similar to the double Te—O—Sb bridges found in the title compound. No tetrahedral TeO4 fragments have been reported in organometallic series to date. The only known example of a tetrahedral tellurate is the ionic salt [NEt4]2TeO4·2H2O . These results are consistent with the weakness of the C—H⋯O bonds in the structure. It is evident that only a few of the H⋯C/C⋯H contacts correspond to C—H⋯π bonding. Therefore, the H⋯C/C⋯H plot represents a rather diffuse collection of points between the pair of poorly resolved features and there no ‘wings’ at the upper left and lower right, which are characteristic of C—H⋯π interactions  bromide as follows:In previously reported syntheses, a range of silver salts were used in ion-exchange reactions to form Ph3H3TeO6, was synthesized according to the method of Gospodinov (19923H3TeO6 were added to a solution containing 0.612 g (1.2 mmol) of Ph4SbBr in 20 mL of acetonitrile. The mixture was stirred for 3 h and then the AgBr precipitate removed by filtration. Evaporation of the solution yielded a colourless glassy material, which was then dissolved in 10 mL of a 1:1 v/v mixture of benzene and butyl acetate. Slow evaporation of the solution to a volume of 2–3 mL afforded 0.138 g (27%) of the product in the form of long colourless prisms. The crystals were filtered and dried in air. Analysis (%) for C54H45O6Sb3Te: Found: C 50.12, H 3.39; Calculated: C 50.56, H 3.54. IR : 454s, 520m, 610s, 692vs, 732vs, 772w, 996w, 1066m, 1434s, 1478m, 1576w, 2824w, 3052m.The starting material, Aginov 1992. 0.220 gUiso(H) = 1.2Ueq(C).Crystal data, data collection and structure refinement details are summarized in Table 310.1107/S2056989021011294/cq2048sup1.cifCrystal structure: contains datablock(s) global, I. DOI: 10.1107/S2056989021011294/cq2048Isup2.hklStructure factors: contains datablock(s) I. DOI: 2118082CCDC reference:  crystallographicinformation; 3D view; checkCIF reportAdditional supporting information:


The asymmetric unit of 2-(2-hydroxyphenyl)quinoline-6-sulfonamide contains two crystallographically independent molecules. The crystal structure features hydrogen bonding and π–π stacking interactions. 15H12N2O3S, there are two molecules (A and B) in the asymmetric unit. The attached phenol and quinoline moieties of each molecule are almost coplanar with a dihedral angle of 6.05 (15)° for molecule A and 1.89 (13)° for molecule B. The crystal structure features N—H⋯O and C—H⋯O hydrogen bonds, C—H⋯π interactions and π–π stacking interactions. Hirshfeld surface analysis indicates that the most significant contacts in the crystal packing are C⋯H/H⋯C (29.2%), O⋯H/H⋯O (28.6%) and H⋯H (28.5%).In the title compound, C This compound was prepared in a two-step reaction, A and B). The C6A—C7A and C6B—C7B bond lengths of 1.472 (5) and 1.470 (5) Å, respectively, are notably shorter than the normal C—C single bond due to conjugation but are comparable to those observed in related structures ortho-position of each independent molecule in (I)S(6) ring motifs , with a dihedral angle between their planes of 4.0 (2)° for molecule A and 1.49 (17)° for molecule B.The hydroxyl group in the fs Fig. 1, which sA and 1.89 (13)° for molecule B , indicating a significant electron delocalization within the molecules. The sulfonamide groups are twisted away from the attached quinoline fragment with an C11A—C12A—S1A—N2A torsion angle of 91.8 (4)° for molecule A and C11B—C12B—S1B—N2B torsion angle of − 79.9 (3)° for molecule B. The sulfonamide atoms S1A and S1B deviate by 0.228 (1) and 0.054 (1) Å from the planes of the quinoline fragment in molecules A and B respectively.The attached quinoline and phenol moieties are almost coplanar with a dihedral angle of 6.05 (15)° for molecule  B Fig. 2b, indica). The packing diagram of the title compound viewed down the a axis  shows that the layers are stacked perpendicular to the b axis at  and . These layers are formed by aggregation of c). In addition, the hydroxyl group of each molecule is involved in a C—H⋯O hydrogen bond, forming an inversion dimer with an d). Weak intermolecular C—H⋯π interactions are also observed in the crystal packing, forming a chain along the a-axis direction .In the crystal of (I)is Fig. 3b shows fs Fig. 3c. In adup Fig. 3d. Weak on Fig. 3e.Cg2⋯Cg3 = 3.779 (2) Å  for A molecules and Cg6⋯Cg7 = 3.6636 (18) Å  for B molecules where Cg2, Cg3, Cg6 and Cg7 are the centroids of the C1A–C6A, C10A–C15A, C1B–C6B and C10B–C15B rings, respectively]. These result in the formation of a supramolecular ribbon parallel to the a axis based on the stacked molecules .Cohesion of the crystal structure is enhanced by the presence of π–π stacking interactions, the most significant being between the 2-hydroxyphenyl and benzene rings of the quinoline groups of each molecule .Crystal data, details of data collection, and results of structure refinement are summarized in Table 310.1107/S2056989022002870/zn2017sup1.cifCrystal structure: contains datablock(s) I. DOI: 10.1107/S2056989022002870/zn2017Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989022002870/zn2017Isup3.cmlSupporting information file. DOI: 2158517CCDC reference:  crystallographicinformation; 3D view; checkCIF reportAdditional supporting information:


Apart from a slight site occupancy difference for the water molecule of crystallization, compounds (I) and (II) are isostructural, featuring isolated tetrahedral cations of copper(I) ions coordinated by two dmbpy ligands and centrosymmetric, octahedral anions of fluorinated early transition metals.The syntheses and crystal structures of two bimetallic molecular compounds, namely, biscopper(I) hexafluoridozirconate(IV) 1.134-hydrate, [Cu(dmbpy) 2]2[ZrF6]·1.134H2O , (I), and bis[biscopper(I)] hexafluoridohafnate(IV) 0.671-hydrate, [Cu(dmbpy)2]2[HfF6]·0.671H2O, (II), are reported. Apart from a slight site occupany difference for the water molecule of crystallization, compounds (I) and (II) are isostructural, featuring isolated tetrahedral cations of copper(I) ions coordinated by two dmbpy ligands and centrosymmetric, octahedral anions of fluorinated early transition metals. The tetrahedral environments of the copper complexes are distorted owing to the steric effects of the dmbpy ligands. The extended structures are built up through Coulombic interactions between cations and anions and π–π stacking interactions between heterochiral Δ- and Λ-[Cu(dmbpy)2]+ complexes. A comparison between the title compounds and other [Cu(dmbpy)2]+ compounds with monovalent and bivalent anions reveals a significant influence of the cation-to-anion ratio on the resulting crystal packing architectures, providing insights for future crystal design of distorted tetrahedral copper compounds.The syntheses and crystal structures of two bimetallic molecular compounds, namely, bis[biscopper(I)] hexafluoridozirconate(IV) 1.134-hydrate, [Cu(dmbpy) The octahedral coordination environment of Zr1 is slightly distorted, with Zr1—F bond lengths ranging from 1.9955 (13) to 2.0183 (12) Å  Fig. 1. The strd Table 1. To quaÅ Table 1. The min2 Table 2].2]2[HfF6]·0.671H2O and crystallizes in the triclinic space group P2]+ cations also have C2 symmetry, with the angle between the least squares planes containing Cu1 and each ligand being 84.14 (8)° ° between the N1/C1–C5 and N2/C6–C10 rings and 7.97 (8)° between the N3/C13–C17 and N4/C18–C22 rings. Moreover, the octahedral coordination environment of Hf1 is also slightly distorted, with Hf1—F bond lengths ranging from 1.9945 (10) to 2.0111 (11) Å. Like in compound (I)trans position of HfF62− anions, but the geometry of the hydrogen bond is slightly different from that in compound (I)B⋯F2 (Table 4Compound (II) Fig. 2. Compoun° Table 3 and the 2 Table 4].2]+ cations and octahedral MF62− anions are closely packed via Coulombic interactions  of 3.6967 (12) and 3.7016 (8) Å, for compounds (I)2]+ pairs pack into racemic chains along the c-axis direction with heterochiral parallel displaced π–π interactions between the N3/C13–C17 and N4/C18–C22 rings with an interplanar angle of 0°, interplanar distances of 3.708 and 3.678 Å, and centroid–centroid distances (dpy–py) of 5.3726 (13) and 5.3777 (11) Å, for compounds (I)MF62− anions with hydrogen-bonded water molecules are interlaced between the racemic chains to form the extended three-dimensional structure. Compared to other molecular compounds with MF62− anions in an extended and complicated hydrogen network In the extended structures of compounds (I)ns Fig. 3. The Δ/Λet al., 20162]+ complexes: [Cu(dmbpy)2][BF4]  et al., 2015A survey of compounds related to compounds (I)MF62−, the compounds reported in the CSD are charge-balanced by monovalent anions and display two different types of packing architectures distinct from those of the title compounds: [Cu(dmbpy)2][BF4], [Cu(dmbpy)2][PF6], and [Cu(dmbpy)2][ClO4] are isostructural, crystallizing in space group 1/cP2. Compared to compounds (I)Unlike compound (I)2][C16H9O8]·H2O, which crystallizes in space group P2]+ cations, π–π interactions in the compound [Cu(dmbpy)2][C16H9O8]·H2O are dominant between [Cu(dmbpy)2]+ cations and [C16H9O8]− anions instead of between [Cu(dmbpy)2]+ cations. In this compound, the [Cu(dmbpy)2]+ cations and [C16H9O8]− anions are packed into charge-neutral chains via Coulombic interactions and π–π interactions along c axis and inversion centers are present between the chains. Additionally, the [C16H9O8]− anions and free water molecules generate a three-dimensional network via O—H⋯O hydrogen bonding interactions, resulting in a different architecture.Another type of packing architecture is found in [Cu(dmbpy)et al., 1993−1 to 423 K and held at 423 K for 24 h. The autoclaves were allowed to cool to room temperature at a rate of 6 K h−1. Orangish red solid products were recovered by vacuum filtration with a moderate yield. Compound (I)2, 0.835 mmol of 6,6′-dimethyl-2,2′-bipyridyl, 0.15 ml (4.14 mmol) of HF (aq) (48%), and 0.1 ml (5.5 mmol) of deionized H2O. Compound (II)2, 0.835 mmol of 6,6′-dimethyl-2,2′-bipyridyl, 0.05 ml (1.38 mmol) of HF (aq) (48%), and 0.2 ml (11 mmol) of deionized H2O.The compounds reported here were synthesized by the hydrothermal pouch method (Harrison Uiso(H) = 1.2Ueq(C) within OLEX2  I, II. DOI: 10.1107/S2056989021007295/hb7977Isup2.hklStructure factors: contains datablock(s) I. DOI: 10.1107/S2056989021007295/hb7977IIsup3.hklStructure factors: contains datablock(s) II. DOI: 2096336, 2096335CCDC references:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


Both the organic cation and the quasi-regular octahedral inorganic anion are located about inversion centres. The organic cations and [SnCl6]2− anions lie in layers parallel to the ac plane with p-anisaldehyde molecules occupying the space between the layers. A network of classical N—H⋯Cl and N—H⋯O hydrogen bonds exists between the ethylenediammonium cations and the [SnCl6]2− anions and p-anisaldehyde molecules. These interactions, together with non-classical C—H⋯O interactions between the ethylenediammonium cations and the p-anisaldehyde molecules, serve to hold the structure together. The crystal studied was refined as a two-component twin.The asymmetric unit of the title organic–inorganic hybrid complex , (C The Sn—Cl2 bond involved in hydrogen bonding is slightly longer, at 2.4322 (11) Å, than the other Sn—Cl bonds [Sn—Cl1 = 2.4100 (12)Å and Sn—Cl3 = 2.4220 (11) Å]. These results are comparable to those reported by other research groups  dianion, [SnClde Fig. 1. The envac plane in which each [SnCl6]2− dianion is surrounded by four ethylenediammonium cations  Å for N1⋯O2iii to 3.404 (4) Å for N1⋯Cl3v. Non-classical interactions between the p-anisaldehyde molecules and the ethylenediammonium cations, C9—H9⋯O2vi at 2.62 Å, further serve to hold the structure together.The packed crystal structure contains sheets lying parallel to the ns Fig. 2. The p-ats Fig. 3. The cryts Fig. 3. The NH36H22N4)[SnCl6]Cl2·2H2O and (C8H24N4)[SnCl6]Cl2·2H2O [SnCl6] 2[SnCl6], and (C7H10N)2[SnCl6] 3SnBr6·Br ] were purchased from Sigma-Aldrich and were used without any further purification. The solvent use for the synthesis was ethanol (96%).Chemicals ·2C8H8O2 crystallizes in the space group P21/n with the monoclinic angle, β, close to 90°. The crystals formed as non-merohedral twins with about one quarter of reflections overlapping. The twin law corresponds to rotation about c*. For the crystal investigated, the relative domain sizes amounted to 0.790 (4): 0.210 (4). The structure was solved by intrinsic phasing  = 1.2Uiso(C) or 1.5Uiso(C-methyl)]. H atoms attached to N were located as local maxima in a difference-Fourier map and refined with a distance restraint N—H = 0.9 Å and an isotropic displacement parameter Uiso(H) = 1.2Uiso(N).Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S205698902100579X/cq2042sup1.cifCrystal structure: contains datablock(s) I. DOI: 10.1107/S205698902100579X/cq2042Isup2.hklStructure factors: contains datablock(s) I. DOI: 2063269CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


ARs) make them an attractive target for selective and persistent modulation of neuronal excitability. However, the availability of selective modulators targeting δ-GABAARs remains limited. AA29504 -phenyl]-carbamic acid ethyl ester), an analog of K+ channel opener retigabine, acts as an agonist and a positive allosteric modulator (Ago-PAM) of δ-GABAARs. Based on electrophysiological studies using recombinant receptors, AA29504 was found to be a more potent and effective agonist in δ-GABAARs than in γ2-GABAARs. In comparison, AA29504 positively modulated the activity of recombinant δ-GABAARs more effectively than γ2-GABAARs, with no significant differences in potency. The impact of AA29504's efficacy- and potency-associated GABAAR subtype selectivity on radioligand binding properties remain unexplored. Using [3H]4'-ethynyl-4-n-propylbicycloorthobenzoate ([3H]EBOB) binding assay, we found no difference in the modulatory potency of AA29504 on GABA- and THIP -induced responses between native forebrain GABAARs of wild type and δ knock-out mice. In recombinant receptors expressed in HEK293 cells, AA29504 showed higher efficacy on δ- than γ2-GABAARs in the GABA-independent displacement of [3H]EBOB binding. Interestingly, AA29504 showed a concentration-dependent stimulation of [3H]muscimol binding to γ2-GABAARs, which was absent in δ-GABAARs. This was explained by AA29504 shifting the low-affinity γ2-GABAAR towards a higher affinity desensitized state, thereby rising new sites capable of binding GABAAR agonists with low nanomolar affinity. Hence, the potential of AA29504 to act as a desensitization-modifying allosteric modulator of γ2-GABAARs deserves further investigation for its promising influence on shaping efficacy, duration and plasticity of GABAAR synaptic responses.The unique pharmacological properties of δ-containing γ-aminobutyric acid type A receptors (δ-GABA AR), members of the Cys-loop ligand-gated ion channels superfamily, are the major sites for fast-acting synaptic inhibition in the mammalian brain pyridin-3-yl]benzamide), a selective positive allosteric modulator of α4/6βδ receptors, is a widely used pharmacological tool to probe δ-GABAesponses , 22. It lability . AA29504,2-apyridtrations –27. In rtrations , 25, 28.subtypes –27. AA29le cells , 25. In  potency , 27. How potency . Earlierce versa . Hence, ARs. The selectivity of AA29504 to δ-GABAARs was confirmed using wild-type (WT) and δ subunit knockout (δKO) C57BL/6 J mice forebrains, as well as recombinant receptors expressed in human embryonic kidney 293 (HEK293) cell line. Radioligands employed , a non-competitive blocker of GABA-gated chloride channel [3H]GABA, and [3H]muscimol, a universal GABAAR agonist with exceptionally high affinity to δ-GABAARs Muscimol (22 Ci/mmol) and [3H]EBOB (48 Ci/mmol) were purchased from PerkinElmer Life and Analytical Sciences . [3H]GABA (30 Ci/mmol) was purchased from Moravek Biochemicals . Unlabeled GABA and picrotoxin were from Sigma Chemicals Co. . AA29504 and THIP were from Tocris Biosciences .muscimol (2 nM) and [3H]GABA (5 nM) were measured in assay buffer  at room temperature (22 ºC) in a total volume of 300 µl. Individually pooled triplicate membrane samples  were incubated with shaking for 15 min. The effect of AA29504 on binding was determined in the presence of various concentrations of AA29504. Non-specific binding was determined in the presence of 100 µM GABA. The incubation was terminated by filtration of the samples with a Brandel Cell Harvester  onto Whatman GF/B filters .The binding of [3H]muscimol (2 nM) binding to the membrane homogenates were as follows: WT , δKO , α1β2γ2 , α6β2γ2  and α6β2δ . For [3H]GABA (5 nM) the binding values were: WT  and δKO .The samples were rinsed twice with 4–5 ml of ice-cold assay buffer. Filtration and rinsing steps took a total time of 15 s. The filters were air-dried and immersed in 3 ml of Optiphase HiSafe 3 scintillation fluid  and vortexed. The radioactivity was determined in a Wallac model 1410 liquid scintillation spectrometer . The average specific counts per minute (CPM) and % specific [3H]muscimol binding was measured essentially as described by Benkherouf et al. [3H]muscimol was performed essentially as described by Uusi-Oukari and Korpi [3H]muscimol (1–50 nM) at room temperature (22 ºC) for 60 min in the absence and presence of 10 µM AA29504. Non-specific binding was determined in the presence of 100 µM GABA. The incubation was terminated by filtration and the radioactivity of the air-dried filters was measured using a scintillation spectrometer as described above.The effect of AA29504 on the association and dissociation of [f et al. . Saturatnd Korpi . Triplic3H]EBOB binding was measured in [3H]EBOB assay buffer  at room temperature (22 ºC) in a total volume of 400 µl in the absence and presence of various concentrations of GABA or THIP with and without 10 µM AA29504. Triplicate samples were incubated with shaking for 2 h. Non-specific binding was determined in the presence of 100 µM picrotoxin. The incubations were terminated as described above for [3H]muscimol binding. The average CPM and % specific [3H]EBOB (1 nM) binding to the membrane homogenates were as follows:WT , δKO , α6β3γ2 , α6β3δ , α6β3: .The displacement of 1 nM EBOB displacement from 0.20 ± 0.11 mM to 15.8 ± 6.5 µM in WT mice (p < 0.01) and from 0.22 ± 0.05 mM to 12.1 ± 1.5 µM in δKO mice . There were no significant differences between WT and δKO mouse binding values in the effects of GABA or THIP on forebrain GABAARs in the absence or presence of AA29504 .[3H]EBOB binding to recombinant GABAARs expressed in HEK293 cells as an indicator for allosteric agonist activity. The receptor subunit combinations α6β3γ2, α6β3δ, and α6β3 were selected to further examine the influence of γ and δ subunits on [3H]EBOB binding displacement by AA29504. The results indicate that AA29504 was able to displace [3H]EBOB binding to all three receptor subtypes in a concentration-dependent manner .We assessed the potential of AA29504 to directly displace HEBOB binARs expressed in WT and δKO mice. The binding of [3H]muscimol and [3H]GABA was measured at room temperature (22 °C) with increasing concentrations of AA29504, where individually pooled forebrain membrane samples were incubated for 15 min. Figure 3H]muscimol and [3H]GABA binding to both WT and δKO mice forebrains. Two-way ANOVA followed by Tukey's post hoc analysis indicated that AA29504 was more potent in stimulating [3H]muscimol (p < 0.01) and [3H]GABA (p < 0.001) binding in δKO than in WT mice.We further examined the modulatory effects of AA29504 on the high-affinity agonist binding to native GABAARs expressed in WT and δKO mice forebrains, we compared the role of γ and δ subunits on AA29504 modulation of [3H]muscimol binding in recombinant α1β2γ2, α6β2γ2, and α6β2δ receptors expressed in HEK293 cells. As illustrated in Fig. 3H]muscimol binding to α1β2γ2 and α6β2γ2 receptor subtypes in a concentration-dependent manner (p < 0.05). In contrast, it had no significant effect on the binding to α6β2δ receptor subtype (Two-way ANOVA followed by Tukey’s post hoc test).Under the same conditions performed for native GABA3H]muscimol binding is due to alterations in receptor-ligand binding kinetics as we assessed the influence of AA29504 on [3H]muscimol association and dissociation rates in WT and δKO forebrain membranes. The results indicate that [3H]muscimol association at 22 °C was faster in δKO compared to WT in the absence of AA29504, where the calculated association rate constants Kon were 5.9 ± 0.6 × 108 M−1 × min−1 and 2.2 ± 0.3 × 108 M−1 × min−1, respectively  . Co-incubation with AA29504 did not significantly affect [3H]muscimol Kon in either δKO (4.8 ± 0.9 × 108 M−1 × min−1) or WT mice (3.9 ± 1.1 × 108 M−1 × min−1) , but it notably increased the amount of specific radioligand binding in both mouse lines (p < 0.001). The increased binding was maximally 240 ± 23% of control binding without AA29504 in δKO mice, significantly higher than that in WT mice (166 ± 5% of control)   than in WT (0.38 ± 0.02 min−1) , reflecting a faster radioligand dissociation in the former mouse line . However, no evident effects were observed with AA29504 on [3H]muscimol.Similar to the association, the dissociation rate constant Koff in δKO (0.64 ± 0.05 min−1) and WT forebrains (0.43 ± 0.02 min−1)   , in the absence (control) or presence of AA29504, all tested groups except control WT membranes were best fit to the one-site binding model. Binding to control WT membranes was best fit to the two-site binding model , displaying two binding affinities at distinguishable receptor densities (Table (1) + Bmax(2)) in WT membranes, however, was equivalent to control δKO Bmax (no AA29504). The presence of 10 µM AA29504 in WT membranes rendered [3H]muscimol binding more favorable to one-site model as it displayed a single apparent affinity that was intermediate between the affinities obtained in control WT membranes. On the other hand, AA29504 significantly decreased the equilibrium dissociation constant (KD) reflecting an enhancement of [3H]muscimol binding affinity in δKOs (p < 0.001). Moreover, AA29504 increased [3H]muscimol Bmax in δKO (p < 0.05) as well as WT mouse lines (p < 0.01) (Two-way ANOVA followed by Tukey's post hoc test). The calculated [3H]muscimol Bmax and KD values are summarized in Table As a probable mechanism for AA29504-induced stimulation of EBOB binding to recombinant GABAARs in this study, and similar to the earlier findings with electrophysiological measurements [3H]EBOB directly (in the absence of GABA) in the former subtype  and dissociation (Koff) rate constants in either mouse line. Hence, the link between AA29504-induced stimulation of [3H]muscimol binding and alterations in receptor-ligand binding kinetics was not established.Modulating GABAed state , 65. Thu-GABAARs , 67 and -GABAARs . DespiteARs muscimol saturation analysis revealed AA29504-induced GABAAR shift to the high-affinity states. In WT mice, [3H]muscimol displayed two high-affinity receptor populations in the absence of AA29504: low-nanomolar (KD = 4.1 ± 3.6 nM) for δ-GABAARs as earlier reported muscimol [AR population was suggested to rise from desensitized γ2-GABAARs [3H]muscimol binding, especially in the forebrain region muscimol binding  EBOB radioligand as a unique probe for assessing drug enhancement of GABAAR function, we demonstrated for the first time the non-differential AA29504 modulatory potency on native GABAARs expressed in WT and δKO C57BL/6J mice. We further displayed AA29504’s GABA-independent activity on recombinant GABAARs expressed in HEK293 cells, indicating higher selective agonist efficacy on δ-GABAARs in relation to γ2-GABAARs. Interestingly, AA29504 showed a concentration-dependent stimulation of GABAA agonist binding to γ2 GABAARs but not to δ-GABAARs. This newly revealed selective modulation by AA29504 is attributed to its ability to shift the low-affinity γ2-GABAARs towards a higher affinity desensitized state, thereby rising new sites capable of binding GABAAR agonists with low nanomolar affinity. Hence, the potential of AA29504 to act as a desensitization-modifying allosteric modulator (DAM) of γ2-GABAARs deserves further investigation for its promising influence on shaping efficacy, duration and plasticity of GABAAR synaptic responses [This study sheds light on AA29504's modulatory activity, its direct actions and interactions with agonists in GABAesponses , 84, 85.


The molecular and crystal structures were studied and a Hirshfeld surface analysis undertaken for the title benzothiazine derivative, which has potential non-steroidal anti-inflammatory activity. 22H22ClN3O4S, which has potential non-steroidal anti-inflammatory activity, the benzothiazine and cyclohexenone rings both adopt a distorted sofa conformation while the 4H-pyrane ring adopts a very flattened sofa conformation. The two bicyclic fragments are skewed to each other, with the dihedral angle between their least-squares planes being 72.8 (1)°. In the crystal, the molecules form a hydrogen-bonded chain parallel to the a axis due to N—H⋯O and N—H⋯Cl hydrogen bonds. Neighbouring chains are linked by C—H⋯N, C—H⋯O and π–π stacking interactions. Hirshfeld surface analysis was used to investigate the importance of the different types of intermolecular interactions whose contributions are: H⋯H = 44.7%, O⋯H/H⋯O = 21.8%, N⋯H/H⋯N = 11.9%, C⋯H/H⋯C = 9.5%, Cl⋯H/H⋯Cl = 7.2%. Parts of the molecule, viz. the phenyl ring and the ethyl side chain, are equally disordered over two sets of sites.In the title compound, C H-benzo[c]thiazine 2,2-dioxide moiety and its derivatives have been the focus of chemists and pharmacologists for decades  of the ‘oxicame’ group , Θ = 52.5 (1)°, Ψ = 20.3 (1)°. The S1 and C8 atoms deviate from the least-squares plane of the remaining atoms of the ring by 0.863 (6) and 0.244 (2) Å respectively. The phenyl ring of the benzothiazine fragment is disordered over two positions (A and B) with equal occupancy. The partially saturated carbocycle has the same conformation as the hydrothiazine ring, with puckering parameters of S = 0.67 (1), Θ = 41.9 (1)°, Ψ = 11.8 (1)°. The deviations of the C13 and C14 atoms from the least-squares plane of the remaining atoms in the ring are 0.717 (2) and 0.132 (2) Å, respectively. The 4H-pyran ring adopts a very flattened sofa conformation with puckering parameters of S = 0.11 (1), Θ = 59.3 (1)°, Ψ = 3.2 (1)°, where the C9 atom deviates by 0.118 (2) Å from the plane of the remaining atoms in this ring. The C8—C9 bond is elongated to 1.525 (3) Å [the mean value °]. The presence of the vicinal substituents on the 4H-pyran moiety results in an elongation of the C16—C17 bond to 1.347 (3) Å .The dihydrothiazine ring of compound on Fig. 2 with puc4 form hydrogen-bonded chains parallel to the a axis  1 + x, y, z; Table 1In the crystal, molecules of is Fig. 3 due to NH-pyran rings of molecules belonging to neighbouring layers are found [the distance between ring planes is 3.38 (1) Å and the plane shift is 1.247 (1) Å]. Molecules are arranged in a head-to-tail manner in both types of stacking dimers. Additional C—H⋯N and C—H⋯O hydrogen-bonding interactions of a weak nature  is provided by O⋯H/H⋯O interactions , while the highest contribution is from H⋯H contacts (44.7%). The contributions of N⋯H/H⋯N (11.9%), C⋯H/H⋯C (9.5%) and Cl⋯H/H⋯Cl (7.2%)  interactions are similar, but the presence of sharp spikes on the fingerprint plot containing only N⋯H/H⋯N or Cl⋯H/H⋯Cl interactions suggests that the latter contacts are much stronger.All of the hydrogen bonds and short contacts of the title compound are evident on the two-dimensional fingerprint plot presented in Fig. 5ns Fig. 5c, whileet al., 2016et al., 2014aet al., 2016et al., 2018et al., 2014bet al., 2017et al., 2018A search of the Cambridge Structural Database  , malononitrile (2)  and 5,5-dimethylcyclohexane-1,3-dione (3)  was dissolved in 20 ml of i-PrOH and then triethylamine (0.1 mol%) was added ; colourless crystals; m.p. > 523 K.A mixture of 4-chloro-1-ethyl-1ed Fig. 1. The mixsp3—Csp3 = 1.54 Å for the ethyl side chain C21—C22; Csp2—Csp2 = 1.38 Å for the phenyl ring C1–C6), and with an equal occupancy for the two sets of sites. All hydrogen atoms were located in difference-Fourier maps. They were included in calculated positions and treated as riding with C—H = 0.96 Å, Uiso(H) = 1.5Ueq(C) for methyl groups and with Car—H = 0.93 Å, Csp3—H = 0.97 Å, Uiso(H) = 1.2Ueq(C) for all other hydrogen atoms. The hydrogen atoms of the amino group were refined freely.Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989021002085/wm5596sup1.cifCrystal structure: contains datablock(s) I. DOI: 10.1107/S2056989021002085/wm5596Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989021002085/wm5596Isup3.cmlSupporting information file. DOI: 2064493CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


Transforming growth factor beta (TGF‐β) plays an important role in the viral liver disease progression via controlling viral propagation and mediating inflammation‐associated responses. However, the antiviral activities and mechanisms of TGF‐β isoforms, including TGF‐β1, TGF‐β2 and TGF‐β3, remain unclear. Here, we demonstrated that all of the three TGF‐β isoforms were increased in Huh7.5 cells infected by hepatitis C virus (HCV), but in turn, the elevated TGF‐β isoforms could inhibit HCV propagation with different potency in infectious HCV cell culture system. TGF‐β isoforms suppressed HCV propagation through interrupting several different stages in the whole HCV life cycle, including virus entry and intracellular replication, in TGF‐β/SMAD signalling pathway–dependent and TGF‐β/SMAD signalling pathway–independent manners. TGF‐β isoforms showed additional anti‐HCV activities when combined with each other. However, the elevated TGF‐β1 and TGF‐β2, not TGF‐β3, could also induce liver fibrosis with a high expression of type I collagen alpha‐1 and α‐smooth muscle actin in LX‐2 cells. Our results showed a new insight into TGF‐β isoforms in the HCV‐related liver disease progression. The expressions of TGF‐β isoforms are promoted by HCV infection in cultured hepatocytes and in livers of HCV‐infected patients, which might be caused by HCV‐induced endoplasmic reticulum stress, unfolded protein response activation or HCV core expression.22.1The human hepatoma cell line Huh7.5 cells and the plasmid pFL‐J6/JFH/JC1 (HCV‐2a) containing the full‐length chimeric HCV complementary DNA (cDNA) were kindly provided by Vertex Pharmaceuticals Inc.2.2TGF‐β1 (100‐21‐10 μg), TGF‐β2 (100‐35B‐10 μg) and TGF‐β3 (100‐36E‐10 μg) proteins were purchased from PeProtech Inc (Peprotech). All TGF‐β isoforms were dissolved according to the manufacturer's protocol and the cell viability after TGF‐β isoforms treatment was determined by a methyl thiazolyl tetrazolium  assay.2.3The plasmids pcDNA3.1(+)‐TGF‐β1 expressing TGF‐β1, pcDNA3.1(+)‐TGF‐β3 expressing TGF‐β3, pcDNA3.1(+)‐TGF‐β1‐His expressing TGF‐β1 with His tag at the C‐terminal, pcDNA3.1(+)‐TGF‐β3‐His expressing TGF‐β3 with His tag at the C‐terminal and the part truncated mutant plasmids of pcDNA3.1(+)‐TGF‐β1‐His or pcDNA3.1(+)‐TGF‐β3‐His were generated by amplification of cDNA from Huh7.5 cell using primers shown in Table 2.4−ΔΔCT method. Glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) was served as the internal control for the quantification. The primer and probe sequences used for quantitative real‐time reverse transcriptase polymerase chain reaction (qRT‐PCR) are provided in Table The cellular RNAs harvested by RNeasy Mini Kit (QIAGEN) from Huh7.5 cells were detected using the AgPath‐ID One‐Step RT‐PCR Kit (Applied Biosystems). Fluorescent signals were identified with 7500 fast real‐time PCR system (Applied Biosystems) according to the procedure recommended by the manufacturer. HCV RNA level was calculated according with the 2TGFB1, TGFB2, TGFB3, type I collagen alpha 1 (COL1A1) or alpha‐smooth muscle actin (α‐SMA) were quantified using GoTaq qPCR Master Mix according to the procedure. The primers are shown in Table For mRNA quantitation by SYBR Green method, total RNAs were reverse‐transcribed with PrimeScript RT Master Mix , and the mRNAs of 2.5Huh7.5 cells were treated with HCV viral stock at different multiplicity of infection  for 72 hours or at MOI = 0.2 for 0, 3 days or 6 days, and then, intracellular mRNAs or proteins were extracted and quantified by qRT‐PCR or Western blot (WB) analysis.2.6Huh7.5 cells were inoculated with HCV viral stock (MOI = 0.5) and simultaneously treated with TGF‐β isoforms or sofosbuvir. At 72 hours, intracellular proteins were harvested by the CytoBuster Protein Extraction Reagent  containing 1 mmol/L protease inhibitor cocktail (Roche Applied Science) and HCV core protein level in cells was determined by WB analysis.−1 to 10−8 and simultaneously treated with 0.5 nmol/L of TGF‐β1, TGF‐β2 and TGF‐β3. At 72 hours post‐infection, HCV‐positive wells were examined using a microscope after immunostaining against HCV core protein.For measuring HCV infectivity, Huh7.5 cells were incubated with HCV viral stock at 10‐fold dilutions ranged from 10de novo HCV particle production, Huh7.5 cells were inoculated with HCV viral stock (MOI = 0.7) and 0.5 nmol/L of TGF‐β1, TGF‐β2 or TGF‐β3 for 24 hours. The newly released infectious virus particles were collected at 48 hours and then quantified by 50% tissue culture infective dose (TCID50) assay. The infectivity titre was shown as TCID50 per mL.To identify the effects of TGF‐β isoforms on GS4.3 cells were treated with 0.5 nmol/L of TGF‐β isoforms or sofosbuvir (0.5 μmol/L) for 72 hours. Then, intracellular proteins were extracted by PER and HCV NS3 protein level was detected by WB analysis.2.7To evaluate the antiviral effective stages of TGF‐β isoforms, Huh7.5 cells were pre‐treated with TGF‐β isoforms (0.5 nmol/L) for 2 hours followed by HCV infection for 2 hours, simultaneously treated with TGF‐β isoforms (0.5 nmol/L) and HCV for 2 hours, or infected with HCV (MOI = 0.5) for 2 hours followed by TGF‐β isoforms (0.5 nmol/L) 2 hours treatment. At 72 hours, intracellular HCV core protein level was detected by WB analysis. In order to further characterize the inhibition stages, a time‐of‐addition assay was performed. In brief, Huh7.5 cells were inoculated with HCV (MOI = 0.5) at 37°C for 2, 4, 6, 8 hours or 10 hours, and then, the HCV‐containing medium was replaced by TGF‐β isoforms (0.5 nmol/L) or sofosbuvir (0.5 μmol/L) containing medium. After 2 hours of treatment, the medium was replaced by fresh medium. At 72 hours, HCV core protein level in cells was determined by WB analysis.2.8HCV viral stock (MOI = 0.5) was pre‐treated with 0.2 nmol/L TGF‐β1, 0.5 nmol/L TGF‐β2 or 0.5 nmol/L TGF‐β3 at 37°C and used to infect cells after 25‐fold dilution of the inoculum. Infection with untreated HCV stock was performed in parallel in the presence of TGF‐β isoforms at indicated concentrations. At 72 hours, intracellular proteins were harvested and HCV core protein level was determined by WB.2.9Huh7.5 cells were incubated with HCV viral stock (MOI = 0.5) for 16 hours, and then, the cells were treated with TGF‐β isoforms (0.5 nmol/L), sofosbuvir (0.5 μmol/L) or 0.1% BSA for 48 hours. The culture medium was replaced by adding fresh culture medium. After 24 hours, the cell viability was tested using MTT assay, the culture medium was collected for incubation to naïve Huh7.5 cells, and intracellular RNA was extracted and quantified by qRT‐PCR. Meanwhile, naïve Huh7.5 cells were incubated with above culture supernatants for 72 hours. Then, the intracellular RNA of Huh7.5 cells was extracted and quantified by qRT‐PCR.2.10q value was calculated with the improved Bürgi formula (Jin's equation), with q < 0.85, 0.85 ~ 1.15, and >1.15 indicating antagonism, addition and synergy, respectively.Huh7.5 cells were inoculated with HCV viral stock (MOI = 0.5) and simultaneously treated with 0.04 nmol/L TGF‐β1, 0.05 nmol/L TGF‐β2, 0.1 nmol/L TGF‐β3 alone, in combination or double concentration (2×), or sofosbuvir (0.5 μmol/L). At 72 hours, intracellular proteins were extracted and determined by WB analysis. To evaluate their combined effect, the combination index (CI) showed with 2.11Huh7.5 cells were incubated with TβRI or TβRII kinase inhibitors (20 μmol/L LY2109761 or 50 μmol/L RepSox) for 6 hours, and then, TGF‐β isoforms (0.5 nmol/L) and HCV (MOI = 0.5) were simultaneously added. After 72 hours incubation, intracellular HCV core protein was determined by WB analysis.2.12Huh7.5 cells were transfected with TGF‐β1, TGF‐β1‐His, TGF‐β3, TGF‐β3‐His, the mutants of TGF‐β plasmids or plasmid control pcDNA3.1(+) applying HD transfection reagent (Promega), or transfected with siRNA for TβRI or SMAD2/3 or negative control siRNA‐A applying RNAiMAX transfection reagent (Invitrogen). After 48 hours, the cells were sub‐cultured and part of intracellular proteins was harvested to detect His tag or corresponding protein expression with WB. After 24 hours, cells were infected with HCV (MOI = 0.5) or added TGF‐β isoforms (0.5 nmol/L) and HCV (MOI = 0.5). After 48 hours, intracellular proteins were extracted to detect HCV core protein level by WB.2.13COL1A1 and α‐SMA mRNA was quantified with qRT‐PCR.LX‐2 cells were cultured in high glucose DMEM without FBS for 12 hours. Then, the cell supernatant was replaced by fresh medium with 2% FBS containing 0.5 nmol/L TGF‐β isoforms. After 24 hours, intracellular RNA was extracted and 2.14The Western blot analysis was performed as previously described.2.15t test; P < 0.05 was considered as statistically significant.The data were presented as means ± standard deviation (SD) more than three independent experiments. Statistical analyses were performed in GraphPad Prism 7 (GraphPad) using ANOVA analysis followed by the Student’s 33.1In infectious HCV cell culture (HCVcc) system, the three TGF‐β isoforms at mRNA Figure , left anDe novo HCV production, Huh7.5 cells were infected with HCV and simultaneously treated with TGF‐β isoforms for 24 hours, and newly released infectious virus particles were collected at 48 hours and then quantified by TCID50 assay. De novo produced HCV yielded a viral titre of about 104.17 TCID50 per mL, whereas treatment with TGF‐β isoforms significantly decreased the TCID50 of the De novo produced HCV ‐TGF‐β2 could not well express TGF‐β2 in Huh7.5 cells as TGF‐β1 and TGF‐β3 did. Therefore, we only test the ant‐HCV effects caused by overexpressing TGF‐β1 and TGF‐β3 to investigate which regions or amino acid residues of TGF‐β isoforms were responsible for their anti‐HCV capacities. Overexpressing TGF‐β1 and TGF‐β3 with His tag at C‐terminal had equal anti‐HCV effects as TGF‐β1 and TGF‐β3, respectively Figure , suggestCys77 or Cys109 in TGF‐β isoforms is important to form homodimer for activation of their signalling activities.The amino acid residues Arg25, Val92 and Arg94 of TGF‐β1 and TGF‐β3 are responsible for their high‐affinity interaction with TβRII, once they are exchanged with Lys25, Ile92 and Lys94, respectively, TGF‐β signalling activities of TGF‐β1 and TGF‐β3 are reduced.The α‐helix 3 of TGF‐β isoforms is response for their binding surface for TβRI and truncating α‐helix 3 of TGF‐β2 suppresses its signalling activity.Interestingly, by blocking the TGF‐β receptor kinase activity or silencing SMAD2/3, we presumed the anti‐HCV activities of TGF‐β1 and TGF‐β2 might be through TGF‐β/SMAD signalling pathway, while TGF‐β3 inhibited HCV replication independent on TGF‐β/SMAD signalling pathway Figure . This di3.5COL1A1 and α‐SMA mRNA expression ; Data curation (lead); Methodology (lead); Writing‐original draft ; Writing‐review & editing (lead). Jian‐Rui Li: Data curation (lead); Methodology (lead). Hu Li: Methodology (supporting); Writing‐review & editing (supporting). Jia‐Li Tan: Data curation (supporting); Methodology (supporting); Writing‐review & editing (supporting). Mei‐Xi Wang: Writing‐review & editing (supporting). Nan‐Nan Liu: Writing‐review & editing (supporting). Rong‐Mei Gao: Data curation (supporting); Methodology (supporting). Hai‐Yan Yan: Data curation (supporting); Methodology (supporting). Xue‐Kai Wang: Writing‐review & editing (supporting). Biao Dong: Methodology (supporting). Yu‐Huan Li: Methodology (supporting). Zonggen Peng: Conceptualization (lead); Data curation (lead); Formal analysis (lead); Funding acquisition (lead); Methodology (lead); Project administration (lead); Writing‐review & editing (lead).


Two crystallographically independent molecules are present in the asymmetric unit. O—H⋯O, N—H⋯O and C—H⋯O hydrogen bonds form rings and chains and π–π stacks further connect molecules in the crystal. 14H11NO2, with virtually identical geometries. The carbazole units are planar. The hydroxy group at position 1, carbaldehyde group at position 2, and methyl group at position 8 (with the exception of two H atoms) are coplanar with the attached benzene rings. The dihedral angle between the two benzene rings is 2.20 (9)° in molecule A and 2.01 (9)° in molecule B. The pyrrole ring makes dihedral angles of 0.82 (10) and 1.40 (10)° [0.84 (10) and 1.18 (10)° in molecule B] with the (–CH3)-substituted and (–OH and –CHO) substituted benzene rings, respectively. The molecular structure is stabilized by the intramolecular O—H⋯O hydrogen bonds, while the crystal structure features N—H⋯O and C—H⋯O hydrogen bonds. A range of π–π contacts further stabilizes the crystal structure.Two crystallographically independent molecules are present in the asymmetric unit of the title compound, C Murraya koenigii spreng (Rutaceae) is a rich source of carbazole alkaloids ° in molecule B. The pyrrole ring makes dihedral angles of 0.82 (10) and 1.40 (10)° for molecule A and 0.84 (10) and 1.18 (10)° for molecule B with the methyl-substituted and hydroxide/carbaldehyde-substituted benzene rings, respectively. The compound exhibits intramolecular O—H⋯O hydrogen bonding between the hydroxide and aldehyde groups  ring motifs, have previously been observed  and N2—H2⋯O2 hydrogen bonds. A C14—H14⋯O3 hydrogen bond is also present. A range of π–π contacts is also observed  = 3.4604 (13) Å, Cg1⋯Cg3  = 3.4896 (13) Å and Cg7⋯Cg9  = 3.6279 (13) Å, where Cg1, Cg2, Cg3, Cg7 and Cg9 are the centroids of the N1/C7/C6/C10/C9, C2–C7, C8–C13, N2/C21/C20/C24/C23 and C22–C27 rings, respectively.In the crystal, molecules are connected into chains parallel to the s Table 1. Both cred Fig. 4. The diset al., 2016H-carbazole-2-carbaldehyde gave two hits, viz. 2,2,10-trimethyl-2,3-dihydropyranocarbazol-4(11H)-one ethanone  in dry benzene (25 ml) was added slowly and the reaction mixture was allowed to stir for another 36 h. The reaction was monitored by TLC. After completion of the reaction, benzene was removed in vacuo and the contents in the flask were transferred to a beaker containing water. It was neutralized with dilute HCl, filtered, washed with water and dried to get crude 1-hydroxy-8-methyl-9H-carbazole-2-carbaldehyde. It was purified by column chromatography over silica using petroleum ether:ethyl acetate (95:5) as eluant. The brown pure product obtained was recrystallized using glacial acetic acid , m.p. 414 K  was washed with dry benzene and taken into a round-bottom flask containing dry benzene (100 ml). The flask was kept in an ice bath under stirring. Ethyl formate (8 ml) was added dropwise to the solution over a period of 10 minutes. Then 8-methyl-2,3,4,9-tetrahydro-1 K Fig. 5.D and H3A were located in a difference-Fourier map and freely refined. The remaining hydrogen atoms were placed in calculated positions with C—H bond distances of 0.93 Å (aromatic H), or 0.96 Å (methyl H) and were refined with anisotropic displacement parameters 1.2 and 1.5 times that of the parent carbon atoms.Crystal data, data collection and structure refinement details are summarized in Table 210.1107/S2056989021007210/yy2001sup1.cifCrystal structure: contains datablock(s) I. DOI: 10.1107/S2056989021007210/yy2001Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989021007210/yy2001Isup3.cdxSupporting information file. DOI: Click here for additional data file.10.1107/S2056989021007210/yy2001Isup4.cmlSupporting information file. DOI: 1540679CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information:


We report here the following nucleotide incorporations opposite Ua by various DNA polymerases: DNA polymerase α, dATP and dGTP (dATP > dGTP); DNA polymerase δ, dATP; DNA polymerase ζ, dATP; Kf exo−, dATP; Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4), dGTP and dATP (dGTP > dATP); and DNA polymerase η, dCTP, dGTP, dATP, and dTTP (dCTP > dGTP > dATP > dTTP). DNA polymerases β and ε were blocked by Ua. Elongation by DNA polymerases δ and ζ stopped after inserting dATP opposite Ua. Importantly, the elongation efficiency to full-length beyond Ua using DNA polymerase η and Dpo4 were almost the same as that of natural DNA.Urea (Ua) is produced in DNA as the result of oxidative damage to thymine and guanine. It was previously reported that Klenow fragment (Kf) exoThe online version contains supplementary material available at 10.1186/s41021-022-00236-3. Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) have not been analyzed to date. Herein, we describe our studies of nucleotide incorporations and translesion synthesis in relation to Ua with DNA polymerases α, δ, ε, η, ζ and Dpo4. Also, we confirmed nucleotide incorporation and extension in relation to Ua using Kf exo− and DNA polymerase β.DNA damage is a major cause of cell death, mutations, cancer, neurological disease, and aging. Urea (Ua) is produced in DNA by ionizing radiation  due to o− was purchased from Fermentas . Yeast DNA polymerase ζ was purchased from Enzymax . Human DNA polymerase δ [Saccharomyces cerevisiae DNA polymerase ε [T4 polynucleotide kinase was purchased from New England Biolabs . T4 DNA ligase was purchased from Takara . Calf thymus DNA polymerase α and human DNA polymerase β were purchased from Chimerx . Klenow fragment exonucleasemerase δ , human Dmerase δ , and Sacmerase ε  were purThe DNA template , Alexa 680-labeled 15-mer primer (5′-Alexa680-TATTGATTGTGAATT-3′), 6-mer oligonucleotide containing 8oxoG (5′-CTT8oxoGAA-3′), 13-mer oligonucleotide (5′-TTCACAATCAATA-3′), and 11-mer oligonucleotide (5′-CTCATCAACAT-3′) were constructed by Japan Bio Services Co., Ltd. .2 and KI [The 30-mer DNA template containing Ua (30-merUa)  was constructed as follows. A 6-mer oligonucleotide containing 8oxoG (5′-CTT8oxoGAA-3′) was oxidized to a 6-mer oligonucleotide containing oxaluric acid (Oxa) using I2 and KI , then Ox2 and KI . This 6-2, 10 mM NaCl, 45 mM KCl, 1 mM DTT, 100 μg/mL bovine serum albumin (BSA); (for DNA polymerase β) 50 mM Tris-HCl (pH 8.8), 10 mM MgCl2, 1 mM DTT, 100 μg/mL BSA; (for DNA polymerase δ) 50 mM Tris-HCl (pH 7.4), 2 mM MgCl2, 2 mM DTT, 100 μg/mL BSA; (for DNA polymerase ε) 50 mM Tris-HCl (pH 7.4), 8 mM MgCl2, 2 mM DTT, 100 μg/mL BSA; (for DNA polymerases ζ and η) 50 mM Tris-HCl (pH 8.0), 2 mM MgCl2, 5 mM DTT, 100 μg/mL BSA; (for Kf exo−) 50 mM Tris-HCl (pH 8.0), 5 mM MgCl2, 1 mM DTT, 100 μg/mL BSA; (for Dpo4) 20 mM HEPES (pH 6.5), 10 mM MgCl2, 1 mM MnCl2 100 mM NaCl, 100 μg/mL BSA.Polymerization reactions (5 μL) were carried out using the following mixtures: (for DNA polymerase α) 40 mM Tris-HCl (pH 8.0), 5 mM MgCl− and Dpo4 contained 100 fmol of the template and 50 fmol of 5′-Alexa680-labeled 15-mer primer. Other conditions and the concentrations of dNTPs and DNA polymerases are specified in the figure legends. Reactions were performed at 30 °C for 30 min for DNA polymerases α, β, δ, ε, ζ, Kf exo− and Dpo4, and at 37 °C for 30 min for DNA polymerase η. All reactions were stopped by adding 5 μL of stop buffer , and 100 μM rhodamine 6G). Aliquots (2.5 μL) were subjected to electrophoresis in a denaturing 16% polyacrylamide (v/v) gel containing 8 M urea at 30 W for 90 min. The fluorescence intensity of each n-mer band (In) was quantified using an Odyssey infrared imaging system from LI-COR  for 5′-Alexa 680-labeled products. The nucleotide incorporation efficiency was calculated using the formula: Σ In (n ≥ 16) / Σ In (n ≥ 15). The DNA synthesis efficiency was calculated using the formula: I30 / Σ In (n ≥ 15).The reaction mixtures for DNA polymerases α, β, δ, ε, η, ζ, Kf exoDNA polymerase α was used for in vitro nucleotide insertion and the analysis of primer extension of template oligonucleotides containing Ua. Under the reaction condition in which DNA polymerase α inserted only dCTP opposite guanine Fig. A, lane 8We investigated whether DNA polymerase α extends the primer beyond Ua. DNA polymerase α slightly elongated the 15-mer primer to 30-mer (3%) across the Ua lesion  opposite Ua under the condition that incorporated only dCTP into guanine in the template Fig. B, lane 7DNA polymerase ζ predominantly inserted mainly dATP 3%) opposite Ua Fig. A, lane 7% opposit− [−, we re-analyzed nucleotide incorporation and translesion synthesis opposite Ua. The results of elongation efficiency by DNA polymerase β beyond Ua -oxazolone (Oz) using DNA polymerase ζ was approximately the same as that of natural DNA [DNA polymerase ζ plays a critical role in an error-prone lesion bypass pathway –37. We pural DNA . AnalysiDNA polymerase η can efficiently and accurately extend the primer beyond the cyclobutane pyrimidine dimer , as wellDpo4 is a thermostable translesion synthesis polymerase and elongated the primer to full-length across Ua  were obtained . However, these two products equilibrate with each other and thus could not be isolated separately. In a previous report [289H370N103O176P29) was confirmed by ESI-MS (m/z 9000.727) and then was used as 30-merUa in our experiment.s report , Dubey, Additional file 2: Fig. S2. DNA synthesis across urea (Ua) by Kf exo−. DNA synthesis in Fig. S2 was conducted under the same condition as in Fig. − (75 μU) was incubated with templates containing G (lane 3) or Ua (lane 4) and 100 μM of each of the four dNTPs (lanes 1–4). Lanes 1 and 2 contained no enzyme and are negative controls. The background darkness of panel A is adjusted in Panel B. Fig. S3. DNA synthesis across urea (Ua) by DNA polymerase η. DNA synthesis in Fig. S3 was conducted under the same condition as in Fig.  Ua lane  and 100


Substitution of CO by phosphanes influences the bond parameters more than replacing the C5H5 ligand by C5H4Cl.The syntheses and structures of the cymantrenes [(C 3] (Cp = π-C5H5 or π-C5H4Cl) in the presence of the phosphanes PPh3 or PCy3 (Cy = cyclohexyl) and Ph2PCH2CH2PPh2 yields the substitution products [CpMn(CO)2PR3] (R = Ph or Cy) and [CpMn(CO)(Ph2PCH2CH2PPh2)], namely, dicarbonyl(η5-cyclopentadienyl)(triphenylphosphane-κP)manganese(I), [Mn(C5H5)(C18H15P)(CO)2], 1a, dicarbonyl(η5-1-chlorocyclopentadienyl)(triphenylphosphane-κP)manganese(I), [Mn(C5H4Cl)(C18H15P)(CO)2], 1b, dicarbonyl(η5-cyclopentadienyl)(tricyclohexylphosphane-κP)manganese(I), [Mn(C5H5)(C18H33P)(CO)2], 2a, dicarbonyl(η5-1-chlorocyclopentadienyl)(tricyclohexylphosphane-κP)manganese(I), [Mn(C5H4Cl)(C18H33P)(CO)2], 2b, carbonyl(η5-cyclopentadienyl)manganese(I), [Mn(C5H5)(C26H24P2)(CO)], 3a, and carbonyl(η5-1-chlorocyclopentadienyl)manganese(I), [Mn(C5H4Cl)(C26H24P2)(CO)], 3b, The crystal structure determinations show a very small influence of the chlorine substitution and a moderate influence of the phosphane substitution on the bond lengths. The PR3 groups avoid being eclipsed with the C—Cl bonds. All the compounds employ weak C—H⋯O interactions for intermolecular association, which are enhanced by C—H⋯Cl contacts in the chlorinated products.UV irradiation of tetrahydrofuran solutions of [CpMn(CO) Limitation of the search to the fragment [(C5H5)Mn(CO)2PPh2] gave 10 hits, of which most contained unsymmetrical mono- or dinuclear diphosphanes. Relevant in the context of this study were an early determination of the structure of [(C5H5)Mn(CO)2(PPh3)] Mn(CO)2PPh2CH2Ph]  by other donor ligands, particularly phosphanes, is one of the most important textbook examples for the reactivity of metal carbonyl complexes Mn(CO)3] (I) and a slight molar excess of the phosphane in tetrahydrofuran  was irradiated for 7 h under argon. The colours of the solutions changed from yellow to red with concomitant gas evolution. After further stirring for 16 h, the solvent was evacuated and the residue dissolved in diethyl ether (Et2O) and filtered through a plug of silica gel. The solvent was evaporated again and the residue dissolved in the minimum amount of petroleum ether. This solution was placed on top of a silica gel chromatography column  and the products were eluted with a petroleum ether/Et2O (9:1 v/v) mixture. Evaporation of the eluate yielded the products as yellow powders. Recrystallization from petroleum ether (with some added Et2O) by slow evaporation in a refrigerator at 5 °C yielded crystals of all three compounds.A solution of   and PCy3  in THF (120 ml) was irradiated for 7 h. After the usual work up (see above), a yellow solid was obtained, consisting of a 7:3 mixture of 2b and 2a. Recrystallization from petroleum ether (with some added Et2O) by slow evaporation in a refrigerator at 5 °C yielded crystals. 1H NMR : δ 4.63 (2H), 4.33 (2H), 2.02–1.07 (33H). 31P{1H} NMR : δ 91.8. MS : m/z = 490.4 (M+), 434.4 (M+ − 2CO).A solution of impure [(C5H4Cl)Mn(CO)3]  and dppe  in THF (120 ml) was irradiated for 7 h. After usual work up, 3b  was isolated as an orange powder. 0.05 g of the starting material  was recovered. Recrystallization from petroleum ether (with some added Et2O) by slow evaporation in a refrigerator at 5 °C yielded crystals. 1H NMR : δ 7.82–7.75 (4H), 7.47–7.35 (6H), 7.33–7.22 (6H), 7.19–7.09 (4H), 4.44 (2H), 3.56 (2H), 2.53–2.41 (2H), 2.36–2.22 (2H). 13C{1H} NMR : δ 232.8 , 142.9 , 139.83–138.89 (m), 133.1 , 131.4 , 129.4, 128.6, 128.1 , 97.5, 78.0, 77.9, 77.6, 30.6 . 31P{1H} NMR : δ 117.6. IR : ν (CO) = 1847. MS : m/z = 580.3 (M+), 552.3 (M+ − CO), 398.2 (C26H24P2), 183.0 (PPh2), 108.0 (PPh). HRMS (EI): m/z calculated 580.0684, found: 580.0681 (M+).A solution of  in the presence of PPh3 leads to 1a and 1b in moderate yields of 40–60%  Å] is significantly longer (>20σ) than the Mn1—P1 bond [2.2259 (6) Å]. All other bond lengths are identical in the two molecules (Table 2The major difference between the two molecules is in the relative orientation of the Mn(CO)s Table 2.supporting information). Three of them involve arene C—H bonds, and carbonyl atom O22 accepts two of them .There are five intermolecular C—H⋯O hydrogen bonds  shorter in 1b. The most important bond parameters can be found in Table 2The Mn→P vector is nearly perpendicular to the C—Cl bond (torsion angle C1—Ct—Mn—P1 is 77.6°). The individual bond lengths are nearly identical to those in supporting information). The Cl atoms always bridge two different H atoms of the same symmetry-related arene ring along the a screw axis. Apparently, this interaction enforces the orientation of this particular arene ring and generates the chirality.There is only one intramolecular C—H⋯Cl hydrogen bond with a length shorter than the sum of the van der Waals radii (H16⋯Cl1). Additionally, there is one weak intramolecular and three intermolecular C—H⋯O hydrogen bonds, and one intermolecular C—H⋯Cl hydrogen bond  and protonation studies followed soon afterwards  in very low yield. Despite long irradiation times, large amounts of the starting material could be recovered. In contrast to 1a, it was not possible to lithiate 2a with n-BuLi or t-BuLi and chlorinate the presumed intermediate lithium compound with C2Cl6 to give 2b. It was possible, however, to obtain crystals of both compounds suitable for X-ray diffraction.We prepared both compounds according to Scheme 12a crystallizes in the monoclinic space group P21/n, with one molecule in the asymmetric unit   Table 2. The dis3 ligand and carbonyl atom O1. A packing diagram shows that these interactions mainly  join the individual molecules in the c direction .There is one intramolecular and two intermolecular C—H⋯O hydrogen bonds involving exclusively methylene H atoms of the PCy2b crystallizes in the monoclinic space group P21/c, with one molecule in the asymmetric unit  than in 2a and have the same lengths as in 1b. This is also true for the distance of the Mn atom from the centroid of the cyclopentadienyl ring. More bond parameters can be found in Table 2Compound it Fig. 3. The Mn→X interactions involving two methylene H atoms of the PCy3 ligand and either the Cl atom or one carbonyl O atom. Additionally, an intermolecular C—H⋯Cl hydrogen bond joins glide-plane-related molecules along the b axis .There are intramolecular C—H⋯3a was first prepared by the photochemical reaction of cymantrene with bis(diphenylphosphanyl)ethane (dppe) in benzene (ca 85% yield after 50 h irradiation), while the same reaction in cyclohexane produced the dppe-bridged dinuclear complex {[(C5H5)Mn(CO)2]2[μ-dppe]} , again with substantial recovery of the starting material. Some weak signals in the NMR spectra showed small amounts of other products, most likely dinuclear ones. However, the influence of prolonged reaction times on product yields and distribution was not examined. In contrast to the reactivity of 1b, it was not possible to deprotonate 3b  and introduce more chlorine substituents via addition of C2Cl6. However, again it was possible to obtain crystals suitable for X-ray diffraction for both compounds.Irradiation of THF solutions of the corresponding tricarbonyl complexes in the presence of dppe for 7 h yields 3a crystallizes in the monoclinic space group C2/c, with one molecule in the asymmetric unit. Fig. 4Compound 3 ligand or one C—H group of the cyclopentadienyl ring. The packing diagram shows that these interactions connect the individual molecules in the a direction .There are two intermolecular hydrogen bonds involving the carbonyl O atom and one methylene H atom of the PCy3b crystallizes in the triclinic space group P3a. The same holds for the relative distances between manganese and the cyclopentadienyl centroids, while the Mn—CO bonds are virtually identical .There is one intermolecular C—H⋯Cl hydrogen bond involving an arene H atom, which joins the individual molecules in the 3 system, where a substantial elongation occurs. When comparing the two triads with different phosphanes, the Mn—Ct (Ct describes the centroid of the cyclopentadienyl ring) and Mn—P distances show a slight increase in the order 3→1→2. The C—O bonds follow the trend 1 ≃ 2 < 3 and the C—Cl bonds follow the trend 2b < 1b ≃ 3b. The average C—C bond lengths are the same within 2σ for all six compounds. Comparison with the PPh2CH2Ph compound GIXRIO and the ferrocenylbisphosphane chelate compound EFUHAO shows more similarities with the PPh3 complexes 1 than with the dppe chelates 3. The tendency of the Mn—P bonds to eclipse one cyclopentadienyl C—H bond is obvious in all the compounds. In all the chloro compounds, the Mn—P bonds avoid being eclipsed with the C—Cl bond of the cyclopentadienyl ring.The introduction of a chlorine substituent in the cyclopentadienyl ring leads to a slight increase in the Mn—Ct and Mn—P distances for all the title phosphanes, while both the Mn—CO and the C—O bonds are only affected in the PCyvia the formation of C—H⋯Cl hydrogen bonds.Apparently, the introduction of one chlorine substituent has only a small influence on the bond lengths, despite the relatively large effect on the spectroscopic data. Steric hindrance within the phosphanes seems to be of greater importance for the bond parameters than the differences in electronic effects. However, the presence of chlorine in the cyclopentadienyl ring leads to additional lattice stabilization 10.1107/S2053229621009177/dv3012sup1.cifCrystal structure: contains datablock(s) compd1a, compd1b, compd2a, compd2b, compd3a, compd3b, global. DOI: 10.1107/S2053229621009177/dv3012compd1asup2.hklStructure factors: contains datablock(s) compd1a. DOI: 10.1107/S2053229621009177/dv3012compd1bsup3.hklStructure factors: contains datablock(s) compd1b. DOI: 10.1107/S2053229621009177/dv3012compd2asup4.hklStructure factors: contains datablock(s) compd2a. DOI: 10.1107/S2053229621009177/dv3012compd2bsup5.hklStructure factors: contains datablock(s) compd2b. DOI: 10.1107/S2053229621009177/dv3012compd3asup6.hklStructure factors: contains datablock(s) compd3a. DOI: 10.1107/S2053229621009177/dv3012compd3bsup7.hklStructure factors: contains datablock(s) compd3b. DOI: 10.1107/S2053229621009177/dv3012sup8.pdfAdditional figures and table. DOI: 2107491, 2107490, 2107489, 2107488, 2107487, 2107486CCDC references:


In this work, practically important relationships between Eint and electron density, its Laplacian, curvature, potential, kinetic, and total energy densities at the bond critical point as well as bond length were derived for the structures of the [Z–I···Hal]− and [Z–Hal···I]− types bearing halogen bonds and involving iodine as interacting atom(s) . The mean absolute deviations for the correlations found were 2.06–4.76 kcal/mol.Bond energy is the main characteristic of chemical bonds in general and of non-covalent interactions in particular. Simple methods of express estimates of the interaction energy, E The halogen bond is one of the most important types of non-covalent interactions being second only to hydrogen bonds in its significance. According to the IUPAC definition, “a halogen bond occurs when there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity” . Weak inThe supramolecular and cluster chemistry of halide anions currently attracts much attention ,27,28,29b) is a difficult task. Experimental methods  are usually associated with complex technical procedures and can be applied to a very limited number of structures. The direct theoretical calculations of Eb for the A···B bond as the energy difference between the structure A···B and the isolated molecules A and B may be successfully applied to intermolecular non-covalent interactions in the gas phase. However, in the condensed phase, molecules are usually bound with each other by a network of several non-covalent interactions, and an adequate fragmentation which affects only the bond of interest is often impossible. In such a situation, an approximation of Eb through other parameters easily accessible from experiment becomes very important − and [(A)nZ–Y···I]− types  were calculated. The correlations between Eint and the electron density (ρb), its Laplacian (∇2ρb), the curvature of ρ(r) which is parallel to the bond path direction (positive) , the potential, kinetic, and total energy densities  at BCP, and the halogen bond length (dY···X) were established.Recently, the author started a project to establish practically useful correlations between the interaction energy and properties which could be easily determined from experiment for halogen bonds of various types, including those formed by a halide anion. In the previous work , such renZ–Y···X]− which include different types of second-order atoms Z and third-order groups A, otherwise, the relationships found may suffer a significant overfitting. Therefore, a large statistically significant set of 412 structures bearing twelve different types of the Z atom was used in this work.Two points should be mentioned here. First, the interactions with the iodine atom as a halogen bond donor are the most important among all halogen bonds since the existence of a prominent σ-hole at the iodine atom provides particularly high stability of these interactions. Second, reliable relationships can be obtained only for sufficiently large sets of the structures [(A)Full geometry optimization of the main set of structures was carried out at the density functional theory (DFT) level by using the M06-2X functional  with thenZ–Y···X]− structures  [int(Vb) correlations for the [(A)nZ–Y···X]− structures  obtained at the M06-2X level of theory have similar parameters as those for the MP4, CCSD, and CCSD(T) methods. On the other hand, it was found − were calculated using Equation (1):nZ–Y fragments were unrelaxed and corresponded to those in [(A)nZ–Y···X]−. The topological analysis of the electron density distribution was performed with the help of the Atoms in Molecules (AIM) method developed by Bader − and [(A)nZ–Y···I]− types  were selected for the calculations. Among them, 70 structures were in each series [(A)nZ–I···X]− with X = F, Cl, or Br and [(A)nZ–Br···I]−, 65 structures were in the [(A)nZ–I···I]− series, and 67 structures were in the [(A)nZ–Cl···I]− series. For Z = C and N, different orbital hybridizations of these atoms were considered. For Z = S and P, different oxidation states of these atoms were considered. The groups A  vary from the electron donor to the electron acceptor ones providing a broad span of interaction energies for the halogen bond. The complete list of the calculated structures is given in Structures of the [(A)nZ–I···F]− type O2S–I…F]−, [F3Si–I…F]−, [p-H2N-C6H4-Br–I…F]−, [Me3Si–I…F]−, [MeO–I…F]−, [(Me)O2S–I…F]−, [Ph–I…F]−, and [(p-Me-C6H4)2N–I…F]−), which provide the Eint span from –9 to –73 kcal/mol.The M06-2X/ADZP–DKH method was validated toward the reproduction of the experimental electron densities for the set of eleven structures bearing halogen bonds of different types  and for which the experimental electron densities are known. Performance of the M06-2X and PBE0-D3BJ functionals was also compared for the set of ten structures of the −, HO–H···Cl−, HO–H···I−, H3C–H···I−, and [I–I–I]−). As can be seen in −. The experimental error is in the range of 0.1–1.6 kcal/mol, and theoretical M06-2X values fall within the 3σ interval for four of six structures. The interaction energies calculated at the CCSD and CCSD(T) levels were strongly underestimated when the CP correction was applied. The CCSD method performed worse than M06-2X for H3C–H···F− and HO–H···Cl− even with the aug-cc-pVTZ basis set, and only the CCSD(T) level with the triple-zeta basis set and without the CP correction provided better results than the DFT approach . Thus, considering that typical MAD values for the Eint property relationships found for the structures [(A)nZ–Hal1···Hal2]− are 2–4 kcal/mol . cations . Here, tructures . The calty 1.07, . The PBEint(Vb) relationships obtained for the small set of ten structures of the [(A)nZ–I···F]− type were similar for both M06-2X and PBE0-D3BJ functionals  and it was 3.96 kcal/mol at Vb = 100 kcal/(mol•bohr3). These deviations were lower than MAD for the whole set of seventy [(A)nZ–I···F]− structures . All these results indicate that the relationships found in this work at the M06-2X/ADZP–DKH level are reliable for the determination of Eint using experimental electron density properties.Correspondingly, the Ectionals . The devnZ–I···X]− and [(A)nZ–Y···I]− types and the corresponding Eint property relationships were discussed (in this and the following sections). The calculated BSSE-corrected interaction energies for the halogen bonds in these structures varied between 2.53 and −88.43 kcal/mol. These bonds were the strongest for the [(A)nZ–I···F−] series. The highest dispersion of Eint was found for the [(A)nZ–I···F]− and [(A)nZ–Cl···I]− series. The halogen bonds in the series [(A)nZ–I···Cl]−, [(A)nZ–I···Br]−, and [(A)nZ–I···I]− have similar strengths and dispersion.After validation of the computational method, the interaction energies calculated for 412 structures of the [(A)int for the hydrogen bonds X–H…O and FH…FR [nZ–Y···X]−  bearing halide anions [int and Vb were found for all series except [(A)nZ–Cl···I]− (int(Gb) relationship was linear only for the [(A)nZ–I···F]− series and it was approximated by a binominal function for [(A)nZ–I···X]−  and [(A)nZ–Br···I]−. Finally, the Eint(ρb) dependence was quadratic for all series.These types of relationships were recommended for the predictions of End FH…FR ,83 and fe anions . Here, tCl···I]− . The EinnZ–Cl···I]− series (int(Vb), Eint(Gb), or Eint(ρb) function. Instead, the horizontal branch is clearly visible in the range of Eint of 10–20 kcal/mol. The interaction energy could be reasonably approximated by polynomial fourth-order functions, but such an approximation is usually associated with significant overfitting and cannot be recommended for practical use. The reasons of this peculiar situation are discussed below.An interesting relationship distinct from all other bonds with halide anions was obtained for the [(A)− series . These snZ–Y···X]− in this and previous −. Third, the slope of the relationships is strongly affected by the nature of the Y and X atoms. For instance, for the Vb estimator, the lowest slope (0.69–0.84) and the highest negative intercept (−3.68 ÷ −6.50) were found for X = F. The highest slopes were detected for [(A)nZ–I···I]− (2.34) as well as for the [(A)nZ–Y···X]−  series (1.55–2.12). The series with (X or/and Y) = Cl but (X and Y) ≠ F exhibited an intermediate slope (1.26–1.46). Such a behavior can be qualitatively interpreted by the different properties of the halogen atoms forming the Y···X bond. First of all, the electronegativity of the X atom decreases along the series F > Cl > Br > I. There is a clear trend between the slope of the Eint(Vb) dependence and the difference of the electronegativities of X and Y nZ group on the Y···X bond are more pronounced if the electron shells of X are more diffuse, i.e., from X = F to I. Since the higher dispersion contribution and more diffuse electron shells are associated with lower concentration of electron or energy density at BCP, Eint values are higher for most electron acceptor groups (A)nZ at a given value of Eint in the case of heavier atom X.Analysis of the relationships obtained for the structures − + [(A)nZ–I···Br]− + [(A)nZ–Br···I]−, (ii) [(A)nZ–I···Cl]− + [(A)nZ–Cl···Cl]− + [(A)nZ–Br···Cl]− + [(A)nZ–Cl···Br]−, and (iii) [(A)nZ–I···F]− + [(A)nZ–Br···F]− + [(A)nZ–Cl···F]− groups. Each of them may be approximated by a linear function . The Eint(Gb) and Eint(ρb) dependences are characterized by a higher dispersion between series. They are more sensitive to the nature of the Y and X atoms and, therefore, such a grouping is not efficient for those relationships.Fourth, some series form distinct groups which can be approximated by a single relationship of a reasonable quality. There are three such groups when considering the EnZ–Y···X]− structures were significantly different from those obtained previously for the hydrogen bonds X–H…O and FH…FR − (this work) and [(A)nZ–Br···F]− [int(∇2ρb) functions for other series are not well-defined nZ–I···F]−, [(A)nZ–I···Cl]−, and [(A)nZ–I···Br]−  relationship for the first of these series is linear and of a lower quality compared to the Eint(Vb), Eint(Gb), and Eint(ρb) functions. The last two series are very well approximated by two exponential functions . For the series [(A)nZ–I···I]− and [(A)nZ–Br···I]−, the λ||,b parameter is not sensitive to determine Eint at high values   fittings at lower Eint are also not reasonable. Finally, the Eint function is not well-defined for [(A)nZ–Cl···I]−.The curvature of the electron density distribution can serve for the estimates of EI···Br]− . The Eincal/mol) . The Einint depends on the nature of the Y and X atoms. It cannot be used for the [(A)nZ–I···F]− series due to high dispersion of the Eint(Hb) function at lower Eint and its low sensitivity at higher Eint (int(Hb) relationship is not sensitive for the weakest interactions with Eint < 10 kcal/mol. However, for stronger interactions, good linear dependences were observed , except for the [(A)nZ–Cl···I]− series which was approximated by a quadratic function  nZ–I···I]−, [(A)nZ–Br···I]−, [(A)nZ–Cl···Cl]−, [(A)nZ–Cl···Br]−, and [(A)nZ–Br···Br]−) are described together by a single linear function of the reasonable quality   . Six sercal/mol) .nZ–Cl···I]− demonstrate reasonable exponential relationships between interaction energy and the length of the halogen bond nZ–I···Br]– + [(A)nZ–Br···I]− and [(A)nZ–Br···Cl]− + [(A)nZ–Cl···Br]−. For other series, the fitting parameters are quite different from each other. Similarly to the other estimators, the Eint(dY…X) dependence is complex for the [(A)nZ–Cl···I]− series. There is a horizontal branch for the interval of Eint 5–15 kcal/mol. Meanwhile, in this case, the dependence may be quite reasonably approximated by a two-exponential function .All series except for [(A)gen bond . The quaint–property relationships for the [(A)nZ–Cl···I]− series have a peculiar character. The more detailed analysis shows that such behavior is due to the tremendous effect of the second-order atom Z and the third-order groups A. First, the Eint values are low and do not exceed 14 kcal/mol when Z = C, P, Si, B, or H  and those with Z = O, N, or S have a significant span of Eint .As was mentioned above, the E B, or H . The strint(Vb) trend slope for the combined series [(A)nZ–Cl···I]− (Z = Si + B) is 6.75 while the slope of the linear correlation for the series [(A)nZ–Cl···I]−  is 1.43  are not linear but exponential. The tangent slopes at the lowest energy points are 9.2 and 8.7.Second, the E is 1.43 . DependenN–Cl···I]− structures could be divided into two distinct groups  and those with a stronger Cl···I interaction  imine and nitro compounds, Group II). The trend slope for these two groups is similar (2.1) but the intercept is very different . The different behavior of these two groups is apparently associated with a different nature of the (A)nN part of the molecule. In Group I, (A)nN exhibits either electron donor or weak electron acceptor properties. In Group II, (A)nN is a strong electron acceptor. Furthermore, the structures of Group II have more extended conjugation systems compared to those of Group I. All these relationships considered together provide such a peculiar trend for the whole [(A)nZ–Cl···I]− series. Interestingly, this effect of Z and A is much smaller for other series making possible the existence of linear correlations. Similar behavior was also found for the Gb and ρb estimators.Third, the − series. However, for the more narrow series −, [(A)nC–Cl···I]−, and [(A)nP–Cl···I]−, these relationships are of a good quality  and they may be useful for practical applications. The d(Y…X) estimator is much better for the description of the [(A)nZ–Cl···I]− series because it permits the reasonable approximation of Eint by a single two-exponent function.The great effect of the Z atom and A group on Eint for the condensed phases is a much more difficult task than that for the gas phase. Both periodic solid state and cluster approaches often do not allow direct estimates of Eint as an energy difference because fragments may have multiple mutual weak intermolecular interactions. When it is possible, the adequate computational model is usually exceedingly large. For instance, accurate calculations of Eint for the A···B bond in a solid-state structure within the cluster approach requires explicit consideration of all intermolecular interactions which molecules A and B are involved in. An example of an adequate cluster for the direct estimates of Eint between the simple fragments I–C4F8–I and Cl− in the X-ray structure ACIPOU is shown in 4F8–I···Cl− surrounded by all molecules which form short contacts with the I–C4F8–I or Cl− fragments).The estimate of EConsidering this situation, the practice of utilization of small bimolecular clusters which include only two molecules forming a contact of interest becomes increasingly popular. In other words, there are multiple attempts to approximate the properties of solid-state structures by gas phase calculations.int calculated for the I–CF2CF2–I···Cl− halogen bond in the X-ray structure ACIPIO using the bimolecular approach is 20.07 kcal/mol. However, when four molecules are considered .There are two points which invalidate this practice. First, such a bimolecular model ignores other intermolecular interactions in which both considered molecules participate. These secondary interactions may significantly affect the energy of the contact under study. For instance, Eint has little physical meaning.The second point is that geometry of bimolecular clusters is usually not optimized but taken from the X-ray structures since optimization often leads to the collapse of the structure compared to X-ray. In such calculations, the geometry considered is not equilibrium and does not belong to a minimum energy path for either adiabatic or vertical bond cleavage, and, hence, the resulting Eint in the condensed phase is free from the difficulties discussed above since it requires a single parameter  directly obtained from experiment.Application of the correlations established in this work for the rapid estimates of EnZ–I···Hal]− and [(A)nZ–Hal···I]− bearing the iodine atom . Thus, together with the results published previously −, those with X = F demonstrate quite poor approximations of Eint with MAD of 3.29–4.76 kcal/mol. For other structures, except [(A)nZ–Cl···I]−, more reasonable correlations were obtained . Meanwhile, the approximations of Eint for halogen bonds formed by halide anions are worse than those obtained for homohalogen bonds formed by two neutral fragments − type. In fact, only two parameters were found to be able to adequately estimate Eint for this bond, i.e., Hb  and dY…X.Second, the most difficult case is the structures of the [(A)int for all structures [(A)nZ–Y···X]−. For the electron density-based properties, the highest slopes (linear correlations) or curvatures (non-linear correlations) were found for the bonds formed by heavy halogens (I and Br) while the lowest slopes and curvatures were observed for X = F.Third, there is no unique equation to approximate EFourth, the correlations derived for halogen bonds with halide anions are very different from those established for some hydrogen bonds and halogen bonds formed by two neutral fragments . This anb, Vb, Gb, and dY···X estimators behave similarly. In contrast, the ∇2ρb, λ||,b, and Hb parameters have limited significance as Eint estimators and they may be used only for some series or a certain range of the Eint values.Fifth, the ρint of the structures [(A)nZ–Y···I]− and [(A)nZ–I···X]− are given in The relationships recommended for practical use to estimate E


The distorted KO6 octahedra share edges, resulting in chains running in the [010] direction.The title compound, C E)-2-{4-[3-(thiophen-3-yl)acryloyl]phenoxy}acetic acid are described. Crystallization from an ethanol–water mixture resulted in the title compound, C30H23KO8S2 or [K(C15H11O4S)(C15H12O4S)]n, containing one molecule of the acid and one molecule of the potassium salt in the asymmetric unit. Both molecules share the H atom between their carboxyl groups and a potassium ion. The C=C bonds display an E configuration. The thiophene and phenyl rings in the two molecules are inclined by 43.3 (2) and 22.7 (2)°. The potassium ion is octahedrally coordinated by six O atoms. This distorted octahedron shares on opposite sides two oxygen atoms with inversion-related octahedra, resulting in chains of octahedra running in the [010] direction, which form ladder-like chains by C—H⋯π interactions. A Hirshfeld surface analysis indicates that the highest contributions to the surface contacts arise from interactions in which H atoms are involved, with the most important contribution being from H⋯H (31.6 and 31.9% for the two molecules) interactions.The synthesis and spectroscopic data of ( This compound is considered to be a good monomer for the synthesis of water-soluble polythiophene-based conjugated polyelectrolytes. A single-crystal structure determination indicates that after crystallization, crystals were obtained containing one molecule of the acid and one molecule of the potassium salt in the asymmetric unit.° for molecule B. The C=C bonds display an E configuration, resulting in short intramolecular C6—H6⋯O9 and C26—H26⋯O29 interactions , K41⋯O36ii = 3.347 (3) Å, symmetry codes: (ii) −x + 2, −y + 2, −z + 1, (iv) −x + 1, −y + 1, −z + 1].Potassium ion K41 is octahedrally coordinated by six O atoms with K—O distances between 2.672 (2) and 2.906 (3) Å Fig. 3 and an oii, at the other side O20i and O20iv; symmetry codes: (i) x + 1, y, z, (ii) −x + 2, −y + 2, −z + 1, (iv) −x + 1, −y + 1, −z + 1] with inversion-related octahedra  and 4.8353 (14) Å .In the crystal packing, the potassium ion K41 interacts with six molecules of which two occur in the carboxylic acid form Fig. 4. The disa Figs. 3 and 5 ▸.Cg1v contacts .Despite the presence of many aromatic rings, the crystal packing of the title compound does not show πany –π interactions. The shortest centroid–centroid distance is 4.735 (3) Å between thiophene rings S1/C2–C5 and S21/C22–C25 with an angle between the rings of 52.3 (3)°. However, C—H⋯π interactions are present and give rise to a ladder-like chain also running in the [010] direction Table 1. In addiThe packing does not show any residual solvent-accessible voids.et al., 2007CrystalExplorer . The sharp tips at de + di ≃ 1.4 Å arise from the O19—H19⋯O39 hydrogen bond. The principal contribution to the Hirshfeld surfaces involves H⋯H contacts at 31.6 and 31.9% for molecules A and B, respectively. These are followed by C⋯H/H⋯C (21.1 and 20.0%) O⋯H/H⋯O (17.4 and 17.3%) and S⋯H/H⋯S (8.8 and 9.9%) contacts.The Hirshfeld surface analysis —p-C6H4—R2 gave 619 hits (with C atoms double-bond acyclic). For only 33 cases (5.3%), the double bond has the Z configuration . The histogram of the dihedral angle between the planes of the double bond and the phenyl ring shows values between 0.0 and 86.2° . A search with thiophene as R1 resulted in only four hits . Only one structure was found for which R2 is the same as in the title compound -2-{4-[3-(thiophen-3-yl)acryloyl]phenoxy}acetic acid, is given in Fig. 9The synthetic pathway to synthesize the target compound, (A mixture of ethyl 2-(4-acetylphenoxy)acetate (5 mmol), 3-thiophenecarbaldehyde (5 mmol) and 50 mL of ethanol was stirred in ice-cold water for 20 minutes. Then, 5 mL of 50% KOH solution was added dropwise to the reaction mixture, which was then stirred continuously for 5 h. At the end of the reaction, water was added to the reaction mixture and stirring was continued until all solids in the mixture were dissolved. Concentrated HCl was slowly added to the obtained solution until the solution changed from brown to yellow. The solution was then heated until crystals appeared. The solid then began to crystallize when the solution temperature started to decrease. The crystallized solid was filtered off, washed thoroughly with water and recrystallized from an ethanol–water mixture to give 2-{4-[3-(thiophen-3-yl)acryloyl]phenoxy}acetic acid (yield 62%) in the form of pale-yellow crystals (m.p. 455 K).−1): 1017, 980 (=C—H bend), 1597 (C=C), 1659 (C=O), 3457 .IR , J (Hz)]: 7.60 , 7.42 , 7.38 , 7.81 , 7.34 , 8.03 , 7.02 , 4.77 .13C NMR : 121.81 (C2), 128.75 (C3), 127.01 (C4), 125.41 (C5), 132.67 (C6), 130.87 (C7), 171.85 (C8), 169.73 (C9), 138.39 (C10 and C14), 137.96 (C11 and C13), 114.65 (C12), 64.68 (C15), 189.09 (C16). Calculation for C15H11O4S: M = 287 au.Uiso(H) value of 1.5Ueq of the parent atom O19. The other H atoms were placed in idealized positions and included as riding contributions with an Uiso(H) values of 1.2Ueq of the parent atom, with C—H distances of 0.93 (aromatic) and 0.97 Å (CH2). In the final cycles of refinement, 12 outliers with |error/e.s.d.| > 5.0 were omitted.Crystal data, data collection and structure refinement details are summarized in Table 310.1107/S2056989021004801/ey2007sup1.cifCrystal structure: contains datablock(s) I. DOI: 10.1107/S2056989021004801/ey2007Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S2056989021004801/ey2007Isup3.cmlSupporting information file. DOI: 2082049CCDC reference:  crystallographic information; 3D view; checkCIF reportAdditional supporting information: