Jolanta Natalia Latosińska

Structural study of selected polyhalogenated benzimidazoles (protein kinase CK2 inhibitors) by nuclear quadrupole double resonance, X-ray, and density functional theory.

Protein kinase CK2 inhibitors, polyhalogenated benzimidazoles, have been studied experimentally in solid state by NMR-NQR double resonance and X-ray and theoretically by the density functional theory (DFT). Six resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in each polyhalogenated benzimidazole molecule. The effects of prototropic annular tautomerism and polymorphism related to stable cluster formation due to intermolecular hydrogen bonding interactions on the (14)N NQR parameters have been analyzed within the DFT and AIM (atoms in molecules) formalism. The studies suggest that all polyhalogenobenzimidazoles are isostructural and can exhibit polymorphism and that (14)N NQR is very sensitive to hydrogen bondings but less sensitive to the specific arrangement of the hydrogen bonded molecules. NQDR and DFT results suggest the presence of the prototropic annular tautomerism 50:50, which is in a good agreement with the X-ray and (1)H NMR data.

Analysis of the NQR parameters in 2-nitro-5-methylimidazole derivatives by quantum chemical calculations

The present study involves nitrogen NMR-NQR measurements and semiempirical as well as ab initio calculations at the different levels in three 2-nitro-5-methylimidazole derivatives. The NMR-NQR data were compared with the results of the quantum chemical calculations with the geometry optimization by seven semiempirical and a few ab initio methods. Since the use of a finite basis set is always a source of uncertainties in the electric field gradient (EFG) tensor components, the calculations were performed in different basis sets, and—regarding the effect of the functional—also at different levels of the theory. The results closest to experimental ones were obtained at the BLYP level of theory.

Hydrogen Bonding and Stacking π−π Interactions in Solid 6-Thioguanine and 6-Mercaptopurine (Antileukemia and Antineoplastic Drugs) Studied by NMR-NQR Double Resonance Spectroscopy and Density Functional Theory

A chemotherapeutic drug 6-thioguanine (2-amino-1,7-dihydro-6H-purine-6-thione, 6-TG) has been studied experimentally in the solid state by NMR-NQR double resonance and theoretically by the density functional theory. Fourteen resonance frequencies on (14)N have been detected and assigned to particular nitrogen sites in the 6-TG molecule. A valid assignment of NQR frequencies for 6-mercaptopurine (6-MP) has been proposed. The effects of molecular aggregations, related to intermolecular hydrogen bonding and stacking pi-pi interactions on the NQR parameters have been analyzed within the DFT and AIM (atoms in molecules) formalism for 6-TG and 6-mercaptopurine (6-MP). The so-called global reactivity descriptors have been calculated to compare the properties of molecules of 6-TG and 6-MP, to check the effect of -NH(2) group as well as to identify the differences in crystal packing.

The tautomeric equilibria of cytosine studied by NQR spectroscopy and HF, MP2 and DFT calculations

A study was undertaken to check if such parameters as NQR frequencies, quadrupole coupling constants and the asymmetry parameters determined from the 14 N NQR spectra can provide sufficient information to infer about the tautomeric form of a compound studied. The influence of the choice of functional on the 14 N NQR parameters calculated by ab initio and DFT methods was analysed. Moreover, the influence of the neighbouring molecules on the NQR parameters was checked for the assumed symmetric planar environment of the cytosine molecule in which it is hydrogen-bonded to four other cytosine molecules. Since the use of a finite basis set is always a source of uncertainties in the electric field gradient tensor components, the final calculations for a layer were performed in two different basis sets: middle and extended. q 2002 Elsevier Science B.V. All rights reserved.

Conformations and intermolecular interactions pattern in solid chloroxylenol and triclosan (API of anti-infective agents and drugs). A 35Cl NQR, 1H-14 N NQDR, X-ray and DFT/QTAIM study

Two antibacterial and antifungal agents, chloroxylenol (4‐chloro‐3,5‐dimethyl‐phenol) and triclosan (5‐chloro‐2‐(2’,4’‐dichlorophenoxy)‐phenol), were studied experimentally in solid state with an X‐ray, 35Cl‐nuclear quadrupole resonance (NQR) and 17O‐nuclear quadrupole double resonance (NQDR) spectroscopies and, theoretically, with the density functional theory/quantum theory of atoms in molecules (DFT/QTAIM). The crystallographic structure of triclosan, which crystallises in space group P31 with one molecule in the asymmetric unit [a = 12.64100(10), b = 12.64100(10), c = 6.71630(10) Å], was solved with an X‐ray and refined to a final R‐factor of 2.81% at room temperature. The NQR frequencies of 35Cl and 17O were detected with the help of the density functional theory (DFT) assigned to particular chlorine and oxygen sites in the molecules of both compounds.

14N NQR, 1H NMR and DFT/QTAIM study of hydrogen bonding and polymorphism in selected solid 1,3,4-thiadiazole derivatives

The 1,3,4-thiadiazole derivatives (2-amino-1,3,4-thiadiazole, acetazolamide, sulfamethizole) have been studied experimentally in the solid state by (1)H-(14)N NQDR spectroscopy and theoretically by Density Functional Theory (DFT). The specific pattern of the intra and intermolecular interactions in 1,3,4-thiadiazole derivatives is described within the QTAIM (Quantum Theory of Atoms in Molecules)/DFT formalism. The results obtained in this work suggest that considerable differences in the NQR parameters permit differentiation even between specific pure association polymorphic forms and indicate that the stronger hydrogen bonds are accompanied by the larger η and smaller ν(-) and e(2)Qq/h values. The degree of π-electron delocalization within the 1,3,4-thiadiazole ring and hydrogen bonds is a result of the interplay between the substituents and can be easily observed as a change in NQR parameters at N atoms. In the absence of X-ray data NQR parameters can clarify the details of crystallographic structure revealing information on intermolecular interactions.

Thermodynamic stability of indazole studied by NMR–NQR spectroscopy and ab initio calculations

The aim of this study was to verify whether NQR can be the method of identification as to which of the tautomeric forms 1H or 2H of indazole occurs in a given solid‐state substance. For this purpose, the enthalpy of formation and parameters characterizing the NQR spectra were calculated and compared with experimental data. The results prove that the calculations allow unambiguous identification of the two tautomeric forms. Copyright

Electron density distribution in 2‐nitro‐5‐methylimidazole derivatives studied by NMR–NQR double resonance

An NMR–NQR spectroscopic study of three 2‐nitroimidazole derivatives was performed, prompted by the prospective medical applications of these compounds. A comparison of the NMR–NQR spectra of the derivatives taken at 193 and 296 K was made. Moreover, the electronic structure of each derivative was referred to that of pure imidazole, which was possible on the basis of analysis of the bond populations. The effect of substitution of the imidazole ring at the 1 H position was analysed. Copyright

Quantum-Chemical Insight into Structure–Reactivity Relationship in 4,5,6,7-Tetrahalogeno-1H-benzimidazoles: A Combined X-ray, DSC, DFT/QTAIM, Hirshfeld Surface-Based, and Molecular Docking Approach

The weak interaction patterns in 4,5,6,7-tetrahalogeno-1H-benzimidazoles, protein kinase CK2 inhibitors, in solid state are studied by the X-ray method and quantum chemistry calculations. The crystal structures of 4,5,6,7-tetrachloro- and 4,5,6,7-tetrabromo-1H-benzimidazole are determined by X-ray diffraction and refined to a final R-factor of 3.07 and 3.03%, respectively, at room temperature. The compound 4,5,6,7-tetrabromo-1H-benzimidazole, which crystallizes in the I41/a space group, is found to be isostructural with previously studied 4,5,6,7-tetraiodo-1H-benzimidazole in contrast to 4,5,6,7-tetrachloro-1H-benzimidazole, which crystallizes as triclinic P1̅ with 4 molecules in elementary unit. For 4,5,6,7-tetrachloro-1H-benzimidazole, differential scanning calorimetry (DSC) revealed a second order glassy phase transition at Tg = 95°/106° (heating/cooling), an indication of frozen disorder. The lack of 3D isostructurality found in all 4,5,6,7-tetrahalogeno-1H-benzimidazoles is elucidated on the basis of the intra- and intermolecular interactions (hydrogen bonding, van der Waals contacts, and C-H···π interactions). The topological Baders Quantum Theory of Atoms in Molecules (QTAIM) and Spackmans Hirshfeld surface-based approaches reveal equilibration of electrostatic matching and dispersion van der Waals interactions between molecules consistent with the crystal site-symmetry. The weakening of van der Waals forces accompanied by increasing strength of the hydrogen bond (N-H···N) result in a decrease in the crystal site-symmetry and a change in molecular packing in the crystalline state. Crystal packing motifs were investigated with the aid of Hirshfeld surface fingerprint plots. The ordering 4,5,6,7-tetraiodo > 4,5,6,7-tetrabromo > 4,5,6,7-tetrachloro > 4,5,6,7-tetrafluoro reflects not only a decrease in crystal symmetry but also increase in chemical reactivity (electronic activation), which could explain some changes in biological activity of compounds from the 4,5,6,7-tetrahalogeno-1H-benzimidazole series. The ability of formation of a given type of bonds by 4,5,6,7-tetrahalogeno-1H-benzimidazole molecules is the same in the crystal and in CK2. Analysis of the interactions in the crystal permits drawing conclusions on the character (the way) of connections between a given 4,5,6,7-tetrahalogeno-1H-benzimidazole as a ligand with CK2 protein to make a protein-ligand complex.

Supramolecular synthon pattern in solid clioquinol and cloxiquine (APIs of antibacterial, antifungal, antiaging and antituberculosis drugs) studied by 35Cl NQR, 1H-17O and 1H-14N NQDR and DFT/QTAIM

AbstractThe quinolinol derivatives clioquinol (5-chloro-7-iodo-8-quinolinol, Quinoform) and cloxiquine (5-chloro-8-quinolinol) were studied experimentally in the solid state via 35Cl NQR, 1H-17O and 1H-14N NQDR spectroscopies, and theoretically by density functional theory (DFT). The supramolecular synthon pattern of O–H···N hydrogen bonds linking dimers and π–π stacking interactions were described within the QTAIM (quantum theory of atoms in molecules) /DFT (density functional theory) formalism. Both proton donor and acceptor sites in O–H···N bonds were characterized using 1H-17O and 1H-14N NQDR spectroscopies and QTAIM. The possibility of the existence of O–H···H–O dihydrogen bonds was excluded. The weak intermolecular interactions in the crystals of clioquinol and cloxiquine were detected and examined. The results obtained in this work suggest that considerable differences in the NQR parameters for the planar and twisted supramolecular synthons permit differentiation between specific polymorphic forms, and indicate that the more planar supramolecular synthons are accompanied by a greater number of weaker hydrogen bonds linking them and stronger π···π stacking interactions. FigureThe 1H-14N solid effect double resonance spectra and the relief map of the Laplacian of electron density in the OH...N plane for clioquinol and cloxiquine