Sławomir Kaźmierski

Investigation of structure and motional behavior of 1,6:3,4-dianhydro-2-O-tosyl-β-d-galactopyranose in solution by means of multiple-field NMR spectroscopy

Abstract In this paper 1H NMR, density functional theory gauge invariant atomic orbital (DFT GIAO) calculation of proton shielding NMR parameters and multi-field, carbon-13 relaxation data for 1,6:3,4-dianhydro-2-O-tosyl-β- d -galactopyranose (1) are reported. From 1H NMR measurements, carried out in three solvents (chloroform, benzene and dimethylosulfoxide), it is apparent that the observed shifting of 1H resonances, among the other factors, is caused by an aromatic ring current effect related to different orientations of the tosyl group with respect to the sugar ring. DFT GIAO calculations are applied for analyzing the changes of 1H shielding parameters in relation to geometry of the compound 1. The relaxation of the quaternary carbons of tosyl group which relax via CSA mechanism is used to establish the mode of local motion. In the complementary approach, employing the 1H chemical shift, dynamic parameters analysis, as well as results from theoretical calculations, the changes of the geometry of 1 in different environments are deduced.

13C high-resolution solid state NMR studies of the structure and dynamics of 1,6:3,4-dianhydro-2-O-tosyl-β-d-galactopyranose

13C CP/MAS, dipolar dephasing MAS and theoretical GIAO calculations were employed to assign 13C resonances to the molecular structure of 1,6:3,4-dianhydro-2-O-tosyl-beta-D-galactopyranose 1. From spinning sideband intensities, employing the graphical method of Herzfeld and Berger the 13C delta(ii) parameters for aromatic residue were calculated. The experimental data were compared with computed results obtained by means of the B3PW91 hybrid method and 6-311G (df, p) basis set. The X-ray geometry of 1 with the correlated position of hydrogen atoms was taken as input data for theoretical calculations. As concluded from Cambridge Crystallographic Database (CSD) search, there are two reports describing the X-ray studies of 1 that show the slightly different geometry of the compound under investigation. This work shows that such discrepancies in geometry can generate differences between computed 13C delta(ii) parameters up to 6 ppm. 13C T1 and 1H T1rho relaxation times reveal that 1 is very rigid in crystal lattice. This structure is characterized by extremely long 1H T1rho, found to be in range ca. 200 ms.

Solid State NMR Characterization of Ibuprofen:Nicotinamide Cocrystals and New Idea for Controlling Release of Drugs Embedded into Mesoporous Silica Particles

Grinding and melting methods were employed for synthesis of pharmaceutical cocrystals formed by racemic (R/S) and entiomeric (S) ibuprofen (IBU) and nicotinamide (NA) as coformer. Obtained (R/S)-IBU:NA and (S)-IBU:NA cocrystals were fully characterized by means of advanced one- and two-dimensional solid state nuclear magnetic resonance (SS NMR) techniques with very fast magic angle spinning (MAS) at 60 kHz. The distinction in molecular packing and specific hydrogen bonding pattern was clearly recognized by analysis of 1H, 13C, and 15N spectra. It is concluded from these studies that both methods (grinding and melting) provide exactly the same, specific forms of cocrystals. Thermal solvent-free (TSF) approach was used for loading of (R/S)-IBU:NA and (S)-IBU:NA into the pores of MCM-41 mesoporous silica particle (MSP). The progress and efficiency of this process was analyzed by NMR spectroscopy. It has been confirmed that TSF method is an effective and safe technique of filling the MSP pores with active pharmaceutical ingredients (APIs). By analyzing the NMR results, it has been further proved that excess of IBU and NA components, which are not embedded into the pores during melting and cooling, crystallize on the MCM-41 walls preserving very specific arrangement, characteristic for crystalline samples. By investigating kinetic of release for (R/S)-IBU/MCM-41, (S)-IBU:NA/MCM-41, and (R/S)-IBU:NA/MCM-41 samples containing active components exclusively inside of the pores, it was revealed that release of IBU is much faster for the first of the samples compared to those containing IBU and NA inside the pores. The hypothesis that the rate of release of API can be controlled by specific composition of cocrystal embedded into the MSP pore was further supported by study of (R/S)-IBU:BA/MCM-41 sample with benzoic acid (BA) as coformer.

Influence of environmental humidity on organization and molecular dynamics of heteromacrocyclic assemblies.

1D and 2D NMR study, Car-Parrinello molecular dynamics, as well as classical molecular dynamics were employed to investigate three derivatives of benzodiazacoronands (achiral compounds which are able to form single crystals with a planar chirality) with intention to explain all subtle effects important during their preorganization, the step anticipating formation of crystals. The experimental study was carried out in two solvents: chloroform and DMSO either containing traces of water (commercial samples) or carefully dried over molecular sieves. Both methods revealed that environmental humidity has a dramatic influence on topology of solute-solvent interactions. Damping of the macrocycle dynamics by its diverse types of interactions with water molecules was shown by computational means. In the most spectacular experiment, we have proved that in chloroform-d during the low temperature measurements traces of water dramatically change the spectral pattern, leading to isochronous NMR signals of the AB spin system of benzodiazacoronand. The temperature of isochronous point (TIP) strongly depends on the benzodiazacoronand/water (BW) ratio. This observation opens a pathway to a new strategy based on variable temperature crystallizations and fitting of BW ratio with hope to optimize conditions for formation of chiral crystals.

Synthesis and Structural Studies ofSP andRP Diastereomers of Deoxyxylothymidyl-3′-O-acetylthymidyl (3′,5′)-O-(2-Cyanoethyl)phosphorothioate in Solution and in the Solid State

The synthesis and full assignment of the molecular structure of the diastereomers of deoxyxylothymidyl-3′-O-acetylthymidyl (3′,5′)-O-(2-cyanoethyl)phosphorothioate (1) in the liquid phase based on 1 H, 13C, 1D and 2D homo- and heteronuclear PFG (Pulse Field Gradient) NMR spectroscopic experiments are reported. The pseudorotation parameters of deoxyribose and deoxyxylose were analyzed by means of the PSEUROT program. The absolute configuration RP and SP of the phosphorus centers was deduced from 1H ROESY experiment. The 31P CP/MAS technique was used to establish the ratio between the amorphous and crystalline phases, and to test the progress of crystallization. The differences in the 31P δii principal elements of the chemical shift tensor, in particular the δ33 parameter, for crystalline and amorphous phases were calculated. Finally, the X-ray data for the SP diastereomer are reported. The influence of weak C−H···S hydrogen bonding on the molecular packing of both Rp-1 and SP-1, and the significance of this type of intermolecular interaction for phosphorothioate systems is discussed.

Nucleophilic N1 → N3 Rearrangement of 5′-O-Trityl-O2,3′-Cycloanhydrothymidine

Abstract 5′-O-Trityl-O2,3′-cycloanhydrothymidine (1) heated at 150°C in the presence of O,O-diethyl phosphate or O,O-diethyl phosphorothioate anions undergoes rearrangement into N3-isomer (2); its structure was established by both advanced NMR methods and X-ray crystallographic studies. The most probable mechanism of 1→2 rearrangement relies upon reversibility of glycosidic bond cleavage process.