X-ray Crystal Structure Analysis Research Articles

Analytical characterization and differentiation between threo- and erythro-4-fluoroethylphenidate.

Methylphenidate analogs appeared on the drug market during the last years. Its analogs contain two chiral centers and, thus, have potential varying configurations (i.e., threo and erythro forms). This study presents the analytical characterization of 4-fluoroethylphenidate (4-FEP) and its differentiation between threo- and erythro-4-FEP. Analysis of the samples included high-performance liquid chromatography (HPLC), gas chromatography-electron ionization-mass spectrometry (GC-EI-MS), high-resolution mass spectrometry (HRMS) analyses, nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal structure analysis. NMR spectroscopic investigations confirmed the differences between threo- and erythro-4-FEP, and demonstrated that both isomers could be separated using HPLC and GC methods. Two samples obtained from one vendor in 2019 consisted of threo-4-FEP, whereas the other two samples obtained from a different vendor in 2020 consisted of a mixture of threo- and erythro-4-FEP. Several analytical approaches including HPLC, GC-EI-MS, HRMS analyses, NMR spectroscopy and X-ray crystal structure analysis enabled the unambiguous identification of threo- and erythro-4-FEP. The analytical data presented in this article will be useful for identifying threo- and erythro-4-FEP included in illicit products.

M-Quinodimethane-based fused-ring triplet hydrocarbons

Abstract Hydrocarbons with open-shell singlet and triplet ground states have long been studied. In contrast to studies of Kekulé hydrocarbons with an open-shell singlet ground state, studies of non-Kekulé and Kekulé hydrocarbons with a triplet ground state are quite limited, and no hydrocarbon with a triplet ground state has been isolated as single crystals. In this review, our work on the synthesis, isolation, and properties of m-quinodimethane-based non-Kekulé polycyclic hydrocarbon, a kinetically stabilized triangulene derivative, and Kekulé polycyclic hydrocarbon, a kinetically stabilized bisdibenzo[3,4:5,6]cyclohepta[1,2-a:2,1-d]benzene derivative, are described. Triplet ground states of these hydrocarbons were experimentally confirmed by ESR and magnetic measurements, and these are the first example of polycyclic hydrocarbons with a triplet ground state whose structures were characterized by X-ray crystal structural analysis. These studies will enable the development of various polycyclic hydrocarbon multi-radicals with high spin multiplicity.

Synthesis, separation, and characterization of spiro-fused cycloalkyl-embedded 5,15-porphodimethenes

The synthesis of cycloalkyl-fused porphodimethenes from a mixture of products was investigated. Each product was separated via silica gel column chromatography and characterized using nuclear magnetic resonance (NMR) and UV-visible absorption spectroscopies, and mass spectrometry. X-ray crystal structure analysis revealed their gable-like bent conformations bearing perpendicular cycloalkyl rings in which the dipyrrin pairs contacted closely so that the neighboring pyrrole rings formed circular hydrogen bonding networks, such as those in porphyrins. Such configurations also caused extreme downfield shifts of the methylene protons of the cycloalkyl rings in the 1H NMR spectra.

Phenylazothiazoles as Visible-Light Photoswitches.

A novel class of photoswitches based on a phenylazothiazole scaffold that undergoes reversible isomerization under visible-light irradiation is reported. The photoswitch, which comprises a thiazole heteroaryl segment directly connected to a phenyl azo chromophore, has very different spectral characteristics, such as a redshifted absorption maximum wavelength and well-separated absorption bands of the trans and cis isomers, than conventional azobenzene and other heteroaryl azo compounds. Substituents at the ortho and para positions of the phenyl ring of the photoswitch resulted in a further shift to longer wavelengths up to 525 nm at the absorption maximum with a small thermal stability compensation. These photoswitches showed excellent photostationary distributions of the trans and cis isomers, thermal half-lives of up to 7.2 h, and excellent reductant stability. The X-ray crystal structure analysis revealed that the trans isomers exhibited a planar geometry and the cis isomers exhibited a T-shaped orthogonal geometry. Detailed ab initio calculations further demonstrated the plausible electronic transitions and isomerization energy barriers, which were consistent with the experimental observations. The fundamental design principles elucidated in this study will aid in the development of a wide variety of visible-light photoswitches for photopharmacological applications.

The new coumarin derivative cyclotetraphosphazene fluorometric chemosensor with reversible, high selective and sensitive for Fe3+ ion detection

A new coumarin-based cyclotetraphosphazene molecule (OCCTP) that can show fluorescence and chemosensory properties has been designed and synthesized. For this purpose, the 7-hydroxy-3-(3,4,5-trimethoxyphenyl)coumarin (4) was synthesized.For the first time in this study, compound 4 which solid state structure and geometry were determined by using crystal X-ray structural analysis were crystallized in the orthorhombic Fdd2 space group. The purified compounds were structurally characterized by elemental analysis, NMR (1H, 13C and 31P) and FT-IR spectroscopy, and mass analysis. Photophysical and chemosensory properties of OCCTP against a range of analytes (various metal ions) were investigated by UV–vis and Fluorescent Spectrophotometer. As a result of fluorimetric studies, OCCTP was found to be a Turn-Off fluorescent chemosensor against Fe3+ ions. The limit of detection (LOD) of OCCTP for Fe3+ was calculated as 1.87 µM and its complex stoichiometry was determined as 1:2 (L/M) as a result of Job's plot. The reversibility study of the iron complex with EDTA showed that the free OCCTP chemosensor regenerated causing an increase in the fluorescence intensity of EDTA. The results showed that the newly synthesized coumarin-based cyclotetraphosphazene compound (OCCTP) can be used as a reversible, highly selective and sensitive fluorescent chemosensor (Turn- Off) which responds immediately against Fe3+ ions.

Syntheses, Characterizations, Crystal Structures, and Protonation Reactions of Dinitrogen Chromium Complexes Supported with Triamidoamine Ligands

A novel dinitrogen-dichromium complex, [{Cr(LBn)}2(μ-N2)] (1), has been prepared from reaction of CrCl3 with a lithiated triamidoamine ligand (Li3LBn) under dinitrogen. The X-ray crystal structure analysis of 1 revealed that it is composed of two independent dimeric Cr complexes bridged by N2 in the unit cell. The bridged N-N bond lengths (1.188(4) and 1.185(7) Å) were longer than the free dinitrogen molecule. The elongations of N-N bonds in 1 were also supported by the fact that the ν(N-N) stretching vibration at 1772 cm-1 observed in toluene is smaller than the free N2. Complex 1 was identified to be a 5-coordinated high spin Cr(IV) complex by Cr K-edge XANES measurement. The 1H NMR spectrum and temperature dependent magnetic susceptibility of 1 indicated that complex 1 is in the S = 1 ground state, in which two Cr(IV) ions and unpaired electron spins of the bridging N22- ligand are strongly antiferromagnetically coupled. Reaction of complex 1 with 2.3 equiv of Na or K gave chromium complexes with N2 between the Cr ion and the respective alkali metal ion, [{CrNa(LBn)(N2)(Et2O)}2] (2) and [{CrK(LBn)(N2)}4(Et2O)2] (3), respectively. Furthermore, the complexes 2 and 3 reacted with 15-crown-5 and 18-crown-6 to form the respective crown-ether adducts, [CrNa(LBn)(N2)(15-crown-5)] (4) and [CrK(LBn)(N2)(18-crown-6)] (5). The XANES measurements of complexes 2, 3, 4, and 5 revealed that they are high spin Cr(IV) complexes like complex 1. All complexes reacted with a reducing agent and a proton source to form NH3 and/or N2H4. The yields of these products in the presence of K+ were higher than those in the presence of Na+. The electronic structures and binding properties of 1, 2, 3, 4, and 5 were evaluated and discussed based on their DFT calculations.

Synthesis, X-ray Structure, and Catalytic Activity in the Hydrosilylation Process of Platinum Complexes Bearing Buchwald Ligands

The controlled reaction between [Pt2(DVTMS)3], where DVTMS represents 1,3-divinyl-1,1,3,3-tetramethyldisiloxane, and dialkylbiaryl phosphines (Buchwald ligands) 2-(di-tert-butylphosphino)biphenyl (JohnPhos, 1), 2-(dicyclohexylphosphino)biphenyl (CyJohnPhos, 2), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (tBuXPhos, 3), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos, 4), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (SPhos, 5), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (DavePhos, 6), and 2-dicyclohexylphosphino-2′,4′,6′-trimethoxybiphenyl (MeOSPhos, 7) generates an efficient platinum catalyst of type [Pt(DVTMS)(L)] (1a–7a), where L represents the Buchwald ligand, applied for hydrosilylation of phenylacetylene by diphenylsilane. The X-ray crystal structure analysis of the obtained Pt catalysts showed the presence of specific Pt-aryl interactions with the phenyl group of the dialkylbiarylphosphine ligand in complex 1a, while the same effect was not observed for the related 2′,4′,6′-triisopropyl substituted aromatic ring in 3a. The evaluation of the steric parameters from X-ray diffraction analysis (XRD) showed the increase of the steric hindrances around the platinum atom improves the selectivity and the yield of the β(E)-product.

Switching of Guest Selectivity for the Inclusion of Regioisomers of Monosubstituted Phenols with Crystals of p-tert-Butylcalix[4]arene

To develop an inclusion method for hard-to-separate organic molecules with wide guest scopes, we examined the control of guest selectivity via external factors such as solvents, temperature, and additives for the competitive inclusion of monosubstituted phenol isomers with crystals of p-tert-butylcalix[4]arene 1. Guest selectivity was thus switched between two isomers in the inclusion of cresol, fluorophenol, and bromophenol and between three isomers in the inclusion of chlorophenol. The mechanism of guest selectivity in chlorophenol inclusion was mainly determined using X-ray crystal structural analysis and a comparison of the thermal stabilities and the formation rates of inclusion crystals with each isomer. Under kinetic control, the inclusion from decane at a low temperature selectively yielded type-A (host/guest = 1:1) inclusion crystals of p-isomer (1·p-chlorophenol) in which the host and guest molecules exhibited CH−π and OH–π interactions. In aqueous solutions at high temperatures, where water molecules inhibited the inclusion of m-isomer, thermally stable type-B (host/guest = 2:1) crystals of o-isomer (12·o-chlorophenol), in which a guest molecule was included in a capsule constructed by two host molecules, selectively formed. Furthermore, the inclusion from decane in the presence of methanol produced a co-inclusion crystal of type-C (host/guest/additive = 2:1:1) in which a 1:1 complex of m-isomer and methanol, connected via an intermolecular hydrogen bond, was selectively included by the distorted capsule of two host molecules to form 12·m-chlorophenol·CH3OH.

Elucidation of Drug Transport Mechanism by Serum Protein and Development for Pancreatic Cancer Treatment

Human serum albumin (HSA) and α1-acid glycoprotein (AGP) are the major drug-binding proteins in the blood and regulate the tissue transfer of bound drugs. We succeeded in clarifying the three-dimensional structure of AGP for the first time in the world from X-ray crystal structure analysis. Using a site-directed mutagenesis method by constructing yeast expression systems as well as the three-dimensional structure, we elucidated the properties of drug binding sites of AGP. We also found that structural change due to the interaction between AGP and cell membranes causes the release of bound drugs and reported an "AGP-mediated drug transport process." Pancreatic cancer has an extremely low response rate to anticancer drugs compared to other cancers and is resistant to starvation of nutrients including fatty acids. We clarified that glutamine metabolism is involved in this tolerance. Furthermore, aiming at efficient drug delivery and effective treatment for pancreatic cancer, we focused on nitric oxide (NO) which increases pancreatic blood flow and has a cell-killing effect on tumors and surrounding stromal tissues. We successfully synthesized nitrated phenylbutyrate (NPB), which binds to HSA and has an antitumor effect in vitro and vivo. The binding of NPB to HSA is considered to be useful for delivery to tumors through the enhanced permeability and retention (EPR) effect and HSA receptors.

Significantly reduced lattice thermal conductivity with anharmonic lattice vibrations and band edge effect in electronic thermal conductivity in Ag2S1-xSex (0 ≤ x ≤ 0.6)

The composition dependence of the unusual behaviors in electronic and lattice thermal conductivity, κele and κlat, in Ag2S1-xSex (x = 0–0.6 in steps of 0.1, 300 K) is investigated in detail by means of precise electron and heat transport properties measurement, synchrotron X-ray crystal structure and electron density distribution analyses, and sound velocity measurement. We reveal that the κele of Ag2S1-xSex is strongly affected by the fine electronic structure of the conduction band edge near the chemical potential and the thermoelectric motive force; therefore, these effects make the κele of Ag2S1-xSe far different from that calculated by the Wiedemann–Franz law, κele = L0σT, with the Lorentz number L0 = π2kB2/(3e2). It is also clearly demonstrated that the κlat of Ag2S1-xSex is greatly reduced by anharmonic lattice vibrations and that the magnitude of κlat is quantitatively reproduced by an equation representing the thermal conductivity under the strongest scattering limit. The κlat decreases with increasing x and saturates at 0.4 W m−1 K−1 at x ≥ 0.4. This is caused by the increasing anharmonic lattice vibrations with x, and its saturating behavior is determined by the strongest scattering limit. On the other hand, a negligibly small κele at x = 0 turns out to be non-trivial at x ≥ 0.4 owing to the increasing carrier density with x, most likely contributed by the increasing interstitial Ag defects. Consequently, the total thermal conductivity of Ag2S1−xSex becomes minimum not at x = 0.5 (composition of the maximum structure entropy) but at x = 0.3.

Reactions of PNCNP and POCOP Pincer Platinum Hydride Complexes with Phenylacetylene and Carbon Disulfide: The Influence of the Pincer Backbone on the Structures of Unsaturated Auxiliary Ligands

In order to get information about the influence of the pincer backbone on the structure and reactivity of a pincer complex, bisphosphiamine PNCNP and bisphosphinite POCOP pincer platinum hydride complexes, [2,6-(tBu2PY)2C6H3]PtH (Y = NH, 1a; O, 2a), were reacted with phenylacetylene and carbon disulfide. The reactions with phenylacetylene in the presence of CuI/Et2NH produced the corresponding σ-alkynyl complexes [2,6-(tBu2PY)2C6H3]PtC≡CPh (Y = NH, 1b; O, 2b). The reactions with carbon disulfide produced the corresponding dithioformato complexes [2,6-(tBu2PY)2C6H3]PtSC(S)H (Y = NH, 1c; O, 2c). The PNCNP complex 1a is easier to react with carbon disulfide than the POCOP complex 2a. X-ray crystal structure analysis indicated that the PNCNP pincer backbone influences the phenylacetylido and dithioformato auxiliary ligands in the resulting complexes more significantly than the POCOP pincer backbone. The dithioformato auxiliary ligand adopts different coordination modes in complexes 1c and 2c. The results provide useful information about how PNCNP and POCOP pincer backbones influence the reactivity of the metal center and the coordination of unsaturated auxiliary ligands.

Synthesis and characterisation of new antimalarial fluorinated triazolopyrazine compounds.

Nine new fluorinated analogues were synthesised by late-stage functionalisation using Diversinate™ chemistry on the Open Source Malaria (OSM) triazolopyrazine scaffold (Series 4). The structures of all analogues were fully characterised by NMR, UV and MS data analysis; three triazolopyrazines were confirmed by X-ray crystal structure analysis. The inhibitory activity of all compounds against the growth of the malaria parasite Plasmodium falciparum (3D7 and Dd2 strains) and the cytotoxicity against a human embryonic kidney (HEK293) cell line were tested. Some of the compounds demonstrated moderate antimalarial activity with IC50 values ranging from 0.2 to >80 µM; none of the compounds displayed any cytotoxicity against HEK293 cells at 80 µM. Antimalarial activity was significantly reduced when C-8 of the triazolopyrazine scaffold was substituted with CF3 and CF2H moieties, whereas incorporation of a CF2Me group at the same position completely abolished antiplasmodial effects.

Synthesis, Crystal, and Electronic Structure of (HpipeH2)2[Sb2I10](I2), with I2 Molecules Linking Sb2X10 Dimers into a Polymeric Anion: A Strategy for Optimizing a Hybrid Compound's Band Gap.

In searching for a tool for optimizing the band gap of a hybrid compound capable of serving as a light-harvesting material in lead-free photovoltaics, we synthesized a new polyiodoantimonate (HpipeH2)2[Sb2I10](I2) and analyzed its crystal and electronic structure by application of X-ray crystal structure analysis, Raman and diffuse reflectance spectroscopies, and quantum chemical calculations. It was demonstrated that I2 molecules link Sb2I10 edge-sharing octahedra into zig-zag chains, whereas the organic cations link inorganic anionic chains into a 3D structure featuring a complex pattern of covalent bonds and non-covalent interactions. Overall, these features provide the background for forming the electronic structure with a narrow band gap of 1.41 eV, therefore being a versatile tool for optimizing the band gap of a potential light-harvesting hybrid compound.

Pictet-Spengler synthesis of twisted quinoline-fused BODIPYs as heavy-atom-free photosensitizers.

Singly and doubly quinoline-fused BODIPYs were effectively synthesized through a reaction sequence consisting of the reduction of nitrophenyl-substituted BODIPYs and subsequent Pictet-Spengler cyclization. The combination of the BODIPY core and fused quinoline rings imposed significantly twisted conformations in the quinoline-fused BODIPYs (around 20.0° deviation from coplanarity obtained from X-ray crystal structure analysis). These twisted BODIPYs showed significantly reduced LUMO, redshifted absorption/emission bands, high molar extinction coefficients and satisfactory reactive oxygen species generation efficiency up to 0.56, indicating potential use as heavy-atom-free photosensitizers.

Time-resolved in-situ X-ray diffraction and crystal structure analysis of porous coordination polymer CPL-1 in CO2 adsorption

The phase transition from the degassed phase to the gas adsorption phase in a copper porous coordination polymer with pillared-layer structure CPL-1 was observed using time-resolved in-situ synchrotron radiation X-ray powder diffraction. The time evolution of the gas adsorption phase and the structural change of the framework were simultaneously observed. As regards CO2 adsorption, the results suggest two-step adsorption stages in the early stage of the gas adsorption process and the energy barrier of framework deformation required to incorporate gas molecules. Further, we determined the CO2 adsorption structure of CPL-1.

Thermodynamic characterization of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its acyclic analogs.

Cyclization of small molecules is a widely applied strategy in drug design for ligand optimization to improve affinity, as it eliminates the putative need for structural preorganization of the ligand before binding, or to improve pharmacokinetic properties. In this work, we provide a deeper insight into the binding thermodynamics of a macrocyclic Zika virus NS2B/NS3 protease inhibitor and its linear analogs. Characterization of the thermodynamic binding profiles by isothermal titration calorimetry experiments revealed an unfavorable entropy of the macrocycle compared to the open linear reference ligands. Molecular dynamic simulations and X-ray crystal structure analysis indicated only minor benefits from macrocyclization to fixate a favorable conformation, while linear ligands retained some flexibility even in the protein-bound complex structure, possibly explaining the initially surprising effect of a higher entropic penalty for the macrocyclic ligand.

BaY16Si4O33 containing Ba(SiO4)4 orthosilicates

Single crystals of a new quaternary oxide, barium hexadecayttrium tetrasilicon tritriacontaoxide, BaY16Si4O33, were obtained from a melt-solidified sample prepared by heating a mixture of BaCO3, Y2O3, and SiO2 at 2073 K. X-ray crystal structure analysis revealed that Ba(SiO4)4 orthosilicate clusters in which a Ba atom is surrounded by four SiO4 tetrahedra were isolated in a framework composed of Y and O in the structure of BaY16Si4O33. The dielectric constant measured for polycrystalline ceramics of BaY16Si4O33 sintered at 1953 K was 13 (298 K, 1 MHz), and the thermal expansion coefficient was 8.70 × 10 −6 K−1 (298–873 K), which are close to the values previously reported for Y2O3.

Construction of 5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles via the One-Pot Reaction of Alkyl Isocyanides with Aryl/Alkyl Carbonyl Chlorides and Diaminomaleonitrile: Fluorescence and Antimicrobial Activity Evaluation

5-(Alkylamino)-6-aryl/alkylpyrazine-2,3-dicarbonitriles were successfully synthesized in good to moderate yields by reacting alkyl isocyanides with aryl/alkyl carbonyl chlorides, followed by the addition of diaminomaleonitrile. The synthesized pyrazines were fully characterized in this investigation, and X-ray crystal structure analysis was performed on some derivatives. The antibacterial and antifungal activities of the newly synthesized pyrazine-2,3-dicarbonitriles were assessed in addition to their UV and fluorescence results. All the compounds showed similar UV-Vis spectral features with absorption peaks (λmax) around 267, 303, and 373 nm.

Intramolecular Cyclization During Bromination of the Quinoline Alkaloid Haplophyllidine.

Bromination of the furanoquinoline alkaloid haplophyllidine by molecular bromine and N-bromosuccinimide was accompanied by intramolecular cyclization to form mixtures of new compounds containing additional penta-, hexa-, and spirocyclic rings incorporating the prenyl group of haplophyllidine. The structures and absolute configurations of the chiral centers of all four bromo-derivatives were elucidated using a combination of NMR spectroscopic methods and X-ray crystal structure analyses.

Exploration of Molecular Structure, DFT Calculations, and Antioxidant Activity of a Hydrazone Derivative.

The hydrazine derivatives are known to possess several biological activities including anticancer, antibacterial and anti-fungal, anticonvulsant, and antioxidant. This communication presents the synthesis, X-ray crystal structure analysis, DFT calculations, cell cytotoxicity, and antioxidant activity of the Schiff base 4,4'-((1E,1'E)-hydrazine-1,2-diylidenebis(ethan-1-yl-1-ylidene))bis(benzene-1,3-diol) (compound 2). We have also isolated the side product compound 1 and characterized it using single X-ray crystallography. The crystal structure of compound 1 depicts that the ensuing C-H···N hydrogen bonding interaction is presented and discussed herein. In addition, the calculations using density functional theory (DFT) approximation supported by experimental 1H and 13C NMR studies on the key compound 2 are reported. The results of theoretical and experimental 1H and 13C NMR were concordant. The antioxidant activity of compound 2 was determined by using 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS•+) radical cation assays and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical assay. Compound 2 demonstrated excellent antioxidant activity in ABTS assay (IC50 = 4.30 ± 0.21 µM) and DPPH assay (IC50 = 81.06 ± 0.72 µM) with almost no cytotoxicity below 25 µM.