Synthesis and Biological Studies of Novel Aminophosphonates and Their Metal Carbonyl Complexes (Fe, Ru).

The quest to find new inhibitors of biologically relevant targets is considered an important strategy to introduce new drug candidates for the treatment of neurodegenerative diseases. A series of (aminomethyl)benzylphosphonates 8a-c and their metallocarbonyl iron 9a-c and ruthenium 10a-c complexes were designed, synthesized, and evaluated for their inhibitory potentials against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) by determination of IC50. Metallocarbonyl derivatives, in general, did not show significant inhibition activity against these enzymes, the most potent inhibitor was the (aminomethyl)benzylphosphonate 8a (IC50 = 1.215 µM against AChE). Molecular docking analysis of AChE and (aminomethyl)benzylphosphonates 8a-c showed the strongest interactions of 8a and AChE compared to isomers 8b and 8c. Cytotoxicity studies of synthesized compounds towards the V79 cell line were also performed and discussed.

13C CP MAS NMR and DFT Studies of 6-Chromanyl Ethereal Derivatives.

Vitamin E consists of a group of compounds including α- ß- γ- and δ-tocopherols and α- ß- γ- and δ-tocotrienols, containing the chroman-6-ol system. The recognition of the structural and dynamic properties of this system, present in all vitamers, seems to be important for the full explanation of the mechanism of the biological activity of vitamin E. This paper presents results of the structural analysis of the chosen 6-chromanyl ethereal derivatives using experimental (13 C NMR-in solution and solid state, as well as variable temperature experiments; single crystal X-ray diffraction) and theoretical (DFT) methods. For one of the studied compounds, 2,2,5,7,8-pentamethyl-6-((tetrahydro-2H-pyran-2-yl)oxy) chroman, the splitting of some signals was observed in the 13C dynamic NMR spectra. This observation was explained by the application of a conformational analysis and subsequent DFT optimization, followed by the calculation of NMR properties.

Experimental and Theoretical Studies of the Optical Properties of the Schiff Bases and Their Materials Obtained from o-Phenylenediamine.

Two macrocyclic Schiff bases derived from o-phenylenediamine and 2-hydroxy-5-methylisophthalaldehyde L1 or 2-hydroxy-5-tert-butyl-1,3-benzenedicarboxaldehyde L2, respectively, were obtained and characterized by X-ray crystallography and spectroscopy (UV-vis, fluorescence and IR). X-ray crystal structure determination and DFT calculations for compounds confirmed their geometry in solution and in the solid phase. Moreover, intermolecular interactions in the crystal structure of L1 and L2 were analyzed using 3D Hirshfeld surfaces and the related 2D fingerprint plots. The 3D Hirschfeld analyses show that the most numerous interactions were found between hydrogen atoms. A considerable number of such interactions are justified by the presence of bulk tert-butyl groups in L2. The luminescence of L1 and L2 in various solvents and in the solid state was studied. In general, the quantum efficiency between 0.14 and 0.70 was noted. The increase in the quantum efficiency with the solvent polarity in the case of L1 was observed (λex = 350 nm). For L2, this trend is similar, except for the chloroform. In the solid state, emission was registered at 552 nm and 561 nm (λex = 350 nm) for L1 and L2, respectively. Thin layers of the studied compounds were deposited on Si(111) by the spin coating method or by thermal vapor deposition and studied by scanning electron microscopy (SEM/EDS), atomic force microscopy (AFM), spectroscopic ellipsometry and fluorescence spectroscopy. The ellipsometric analysis of thin materials obtained by thermal vapor deposition showed that the band-gap energy was 3.45 ± 0.02 eV (359 ± 2 nm) and 3.29 ± 0.02 eV (377 ± 2 nm) for L1/Si and L2/Si samples, respectively. Furthermore, the materials of the L1/Si and L2/Si exhibited broad emission. This feature can allow for using these compounds in LED diodes.

Amine-catalyzed substitution in CpFe(CO)2I by phosphine and bisphosphine ligands.

We have found that amines significantly accelerate iodide substitution in CpFe(CO)2I (1) (Cp = η5-cyclopentadienyl) with phosphines and allow the synthesis of new complexes that are not available through reactions carried out without an amine. The reaction of equimolar amounts of 1 and triphenylphosphine in toluene containing DIPA afforded [CpFe(CO)2PPh3]+I- within 5 min at room temperature in 72% yield (90% after 24 h). DIPA and pyrrolidine gave the highest yields of the tested amines. We performed a similar reaction using model bisphosphines 1,3-bis(diphenylphosphino)ethane (dppe) and 1,1'-bis(diphenylphosphino)ferrocene (dppf). The products depended on the reagent ratio and bore the CpFe(CO)2 moiety coordinated to one or two phosphine phosphorus atoms. Chelates [CpFe(CO)(dppe)]+I- (4) and [Cp2Fe2(CO)4(dppe)]2+2I- (5) were formed in 72% and 98% yield, respectively. We also performed the DIPA-catalyzed reaction of 1 with triethyl phosphite and obtained the product of an Michaelis-Arbuzov-like rearrangement, CpFe(CO)2[P(O)(OCH2CH3)2] (11). All complexes were characterized with spectroscopic analysis by NMR, FT-IR, and ESI-MS, and by XRD for three complexes. To clarify the reaction mechanism, we performed theoretical calculations of the intermolecular interactions between 1 and amine molecules. We propose two possible reaction mechanisms to explain the formation of products.

X-ray studies of three 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals: an unexpected molecular conformation stabilized by hydrogen bonds.

The results of the X-ray structure analysis of three novel 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine cocrystals are presented. These are 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-2,4,6-tribromophenol (1/2), C12H8N6·2C6H3Br3O, 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-isonicotinic acid N-oxide (1/2), C12H8N6·2C6H5NO3, and 3,6-bis(pyridin-2-yl)-1,2,4,5-tetrazine-4-nitrobenzenesulfonamide (1/1), C12H8N6·C6H6N2O4S. Special attention is paid to a conformational analysis of the title tetrazine molecule in known crystal structures. Quantum chemistry methods are used to compare the energetic parameters of the investigated conformations. A structural analysis of the hydrogen and halogen bonds with acceptor aromatic tetrazine and pyrazine rings is conducted in order to elucidate factors responsible for conformational stability.

Mechanochemical synthesis and anticonvulsant activity of 3-aminopyrrolidine-2,5-dione derivatives.

A series of 3-aminopyrrolidine-2,5-dione derivatives was synthesized and tested for anticonvulsant activity. Succinimide derivatives were obtained from a simple solvent-based reaction and a mechanochemical aza-Michael reaction of maleimide or its N-substituted derivatives with selected amines. The structure of the compounds was confirmed by spectroscopic methods (NMR, FT-IR, HPLC, ESI-MS, EA and XRD for four compounds). The cytotoxic activity of the succinimide derivatives was evaluated using HepG2 cells for hepatocytotoxicity and SH-SY5Y cells for neurocytotoxicity. None of the studied compounds showed hepatocytotoxicity and two showed neurocytotoxicity. Initial anticonvulsant screening was performed in mice using the psychomotor seizure test (6 Hz, 32 mA). The selected compounds were evaluated in the following acute models of epilepsy: the maximal electroshock test, psychomotor seizure test (6 Hz, 44 mA), subcutaneous pentylenetetrazole seizure test, and acute neurotoxicity (rotarod test). The most active compound 3-((4-chlorophenyl)amino)pyrrolidine-2,5-dione revealed antiseizure activity in all seizure models (including pharmacoresistant seizures) and showed better median effective doses (ED50) and protective index values than the reference compound, ethosuximide. Furthermore, 3-(benzylamino)pyrrolidine-2,5-dione and 3-(phenylamino)pyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz and MES tests, and 3-(butylamino)-1-phenylpyrrolidine-2,5-dione and 3-(benzylamino)-1-phenylpyrrolidine-2,5-dione exhibited antiseizure activity in the 6 Hz test. All active compounds demonstrated low in vivo neurotoxicity in the rotarod test and yielded favourable protective indices.

(2R)-8-Benzyl-2-[(S)-hy-droxy(phen-yl)meth-yl]-8-aza-bicyclo-[3.2.1]octan-3-one.

The crystal of the title compound, C(21)H(23)NO(2), was chosen from a conglomerate formed by a racemic mixture. An intra-molecular hydrogen bond is formed between hy-droxy group and heterocyclic N atom of the aza-bicyclo-[3.2.1]octan-3-one system. The crystal structure is stabilized by C-H⋯O inter-actions between aliphatic C-H groups and the carbonyl O atom. For the title chiral crystal, the highly redundant and accurate diffraction data set collected with low energy copper radiation gave a Flack parameter of 0.12 (18) for anomalous scattering effects originating from O atoms.

A novel hydrogen-bonding N-oxide-sulfonamide-nitro N-H...O synthon determining the architecture of benzenesulfonamide cocrystals.

The structures of novel cocrystals of 4-nitropyridine N-oxide with benzenesulfonamide derivatives, namely, 4-nitrobenzenesulfonamide-4-nitropyridine N-oxide (1/1), C5H4N2O3·C6H6N2O4S, and 4-chlorobenzenesulfonamide-4-nitropyridine N-oxide (1/1), C6H6ClNO2S·C5H4N2O3, are stabilized by N-H...O hydrogen bonds, with the sulfonamide group acting as a proton donor. The O atoms of the N-oxide and nitro groups are acceptors in these interactions. The latter is a double acceptor of bifurcated hydrogen bonds. Previous studies on similar crystal structures indicated competition between these functional groups in the formation of hydrogen bonds, with the priority being for the N-oxide group. In contrast, the present X-ray studies indicate the existence of a hydrogen-bonding synthon including N-H...O(N-oxide) and N-H...O(nitro) bridges. We present here a more detailed analysis of the N-oxide-sulfonamide-nitro N-H...O ternary complex with quantum theory computations and the Quantum Theory of Atoms in Molecules (QTAIM) approach. Both interactions are present in the crystals, but the O atom of the N-oxide group is found to be a more effective proton acceptor in hydrogen bonds, with an interaction energy about twice that of the nitro-group O atoms.

Trithiocyanuric acid: novel cocrystals and analysis of its tautomeric forms.

Cocrystals of trithiocyanuric acid with 2,2'-bipyridyl [1,3,5-triazinane-2,4,6-trithione-2,2'-bipyridine (2/1), 2C3H3N3S3·C10H8N2, (I)] and 4-methylbenzohydrazide [1,3,5-triazinane-2,4,6-trithione-4-methylbenzohydrazide (1/1), C8H10N2O·C3H3N3S3, (II)] crystallize in the monoclinic crystal system. In the crystals, molecules of both components are linked by hydrogen bonds. The trithiocyanuric acid molecules are connected by N-H...S hydrogen bonds forming R22(8) synthons, which are further organized into chain motifs. Computations based on quantum chemistry methods have been performed for a more detailed description of the observed tautomerism of trithiocyanuric acid.

New dinuclear zinc(ii) complexes with Schiff bases obtained from o-phenylenediamine and their application as fluorescent materials in spin coating deposition.

Two Zn(ii) complexes, K1 and K2, obtained from the template reaction of zinc(ii) acetate dihydrate with o-phenylenediamine and 2-hydroxy-5-methylisophthalaldehyde (K1) or 2-hydroxy-5-tert-butyl-1,3-benzenedicarboxaldehyde (K2), respectively, were characterized by X-ray crystallography, spectroscopic (UV-vis, fluorescence and IR), and thermal methods. In the complex [Zn2(MeO)1.4(OH)0.6(L1)]·2H2O K1, there are two binding sites in the macrocyclic ligand and they are occupied by zinc(ii) cations found in slightly distorted square pyramidal environment. The zinc(ii) cations are connected by slightly asymmetric oxo bridges with a Zn1-O14-Zn1[-x, -y + 1, -z + 1] angle of 104.8(2)°. In the dimer [Zn2(CH3COO)2(L2)]·2EtOH K2, there are two crystallographically independent binding sites both occupied by zinc(ii) cations. There is a significant difference between both complexes, since in K1 only one site is independent and the second is occupied due to the application of symmetry rules, and the geometry of both sites is identical. Thin layers of the obtained Zn(ii) complexes were deposited on Si(111) by the spin coating method and studied by scanning electron microscopy (SEM/EDS), atomic force microscopy (AFM), fluorescence spectroscopy and ellipsometry. In the non-absorbing range, the value of the refractive index exhibits normal dispersion between 1.8 and 2.1 for K1_1-K1_3; and between 2.3 and 2.6 for the K2 series of samples established for long wavelengths (longer than 500 nm). The Zn(ii) complexes and their thin layers exhibited fluorescence between 534-573 nm and 495-572 nm for the compounds and the layers, respectively. The highest quantum yield of fluorescence was achieved for K2 in benzene and in the solid state ϕ = 0.78 and 0.58, respectively. The influence of the solvent polarity on the fluorescence properties of the obtained complexes was studied. Additionally, DFT calculations were performed to explain the structures and electronic spectral properties of the complexes.

Intramolecular double proton transfer from 2-hydroxy-2-iminoacetic acid to 2-amino-2-oxoacetic acid.

The double intramolecular proton transfer process which transforms 2-hydroxy-2-iminoacetic acid into 2-amino-2-oxoacetic acid is analyzed. The MP2 and DFT calculations were performed for different tautomers and conformers of these species. Pople style (6-311++G(d,p), 6-311++G(3df,3pd)) and Dunning type (aug-cc-pVTZ) basis sets were applied. O-H...O, N-H...O, and O-H...N intramolecular hydrogen bonds were also analyzed with the use of Quantum Theory of "Atoms in Molecules" (QTAIM) as well as Natural Bond Orbitals (NBO) method. Different criteria of the hydrogen bonding existence were applied here for intramolecular interactions. It was found that some of N-H...O hydrogen bonds may be treated as blue-shifting ones.

C-Br...S halogen bonds in novel thiourea N-oxide cocrystals: analysis of energetic and QTAIM parameters.

Cocrystals of thiourea with 4-nitropyridine N-oxide, C5H4N2O3·2CH4N2S, (I), and 3-bromopyridine N-oxide, C5H4BrNO·CH4N2S, (II), crystallize in the monoclinic space group P21/c. In the crystals, molecules of both components are linked by N-H...O hydrogen bonds, creating R21(6) synthons. The bromine substituent of the N-oxide component in (II) is a centre for C-Br...S halogen bonding to the thiourea molecule. Computations based on quantum chemistry methods (quantum theory of atoms in molecules, QTAIM) and atoms in molecules (AIM) theory were performed for a more detailed description of the observed type of halogen-bonding interaction.

A new look at two polymorphic crystal structures of dibenzoylmethane: relationship between the crystal packing and the hydrogen atom position revealed by quantum chemistry and quantum crystallography methods.

Chalcones, including dibenzoylmethane, are an important subgroup of natural polyphenolic compounds that exhibit a wide spectrum of pharmacological and industrial applications. Dibenzoylmethane was isolated from Hottonia palustris L. (Primulaceae). The compound was crystallized in two polymorphic forms: in monoclinic space group P21/c and orthorhombic space group Pbca. Crystal structures of the polymorphs were solved and refined against diffraction data measured at 100 and 293 K. In both crystal structures, the chalcone occurs in its keto-enol tautomeric form with the hydroxyl H atom mutually bound by two oxygen atoms rather than covalently attached to a particular oxygen atom. To explain this phenomenon in more detail, density functional theory and quantum theory of atoms in molecules based quantum chemistry calculations were applied. Additionally, high-resolution experimental data of very high quality measured for the monoclinic and orthorhombic crystals at 100 K allowed the engagement of the quantum crystallography method, based on Hirshfeld atom refinement, to determine the position of each individual H atom. It is suggested that the presence of the particular tautomeric form of dibenzoylmethane with a centred H atom position results from the π-stacking interaction between the phenyl ring and the malondialdehyde quasi-ring causes delocalization of the electron density in the latter.

Crystal structure of 3,6-bis-(pyridin-2-yl)-1,4-di-hydro-1,2,4,5-tetra-zine.

The structure of the title compound, C12H10N6, at 100 K has monoclinic (P21/n) symmetry. Crystals were obtained as a yellow solid by reduction of 3,6-bis-(pyridin-2-yl)-1,2,4,5-tetra-zine. The structure displays inter-molecular hydrogen bonding of the N-H⋯N type, ordering mol-ecules into infinite ribbons extending along the [100] direction.

N-Oxide-N-oxide interactions and Cl...Cl halogen bonds in pentachloropyridine N-oxide: the many-body approach to interactions in the crystal state.

Pentachloropyridine N-oxide, C5Cl5NO, crystallizes in the monoclinic space group P21/c. In the crystal structure, molecules are linked by C-Cl...Cl halogen bonds into infinite ribbons extending along the crystallographic [100] direction. These molecular aggregates are further stabilized by very short intermolecular N-oxide-N-oxide interactions into herringbone motifs. Computations based on quantum chemistry methods allowed for a more detailed description of the N-oxide-N-oxide interactions and Cl...Cl halogen bonds. For this purpose, Hirshfeld surface analysis and the many-body approach to interaction energy were applied.

Performance of Møller-Plesset second-order perturbation theory and density functional theory in predicting the interaction between stannylenes and aromatic molecules.

The performances of Møller-Plesset second-order perturbation theory (MP2) and density functional theory (DFT) have been assessed for the purposes of investigating the interaction between stannylenes and aromatic molecules. The complexes between SnX2 (where X = H, F, Cl, Br, and I) and benzene or pyridine are considered. Structural and energetic properties of such complexes are calculated using six MP2-type and 14 DFT methods. The assessment of the above-mentioned methods is based on the comparison of the structures and interaction energies predicted by these methods with reference computational data. A very detailed analysis of the performances of the MP2-type and DFT methods is carried out for two complexes, namely SnH2-benzene and SnH2-pyridine. Of the MP2-type methods, the reference structure of SnH2-benzene is reproduced best by SOS-MP2, whereas SCS-MP2 is capable of mimicking the reference structure of SnH2-pyridine with the greatest accuracy. The latter method performs best in predicting the interaction energy between SnH2 and benzene or pyridine. Among the DFT methods, ωB97X provides the structures and interaction energies of the SnH2-benzene and SnH2-pyridine complexes with good accuracy. However, this density functional is not as effective in reproducing the reference data for the two complexes as the best performing MP2-type methods. Next, the DFT methods are evaluated using the full test set of SnX2-benzene and SnX2-pyridine complexes. It is found that the range-separated hybrid or dispersion-corrected density functionals should be used for describing the interaction in such complexes with reasonable accuracy.