Peter Luger

Structure and physicochemical properties of meloxicam, a new NSAID

Abstract The physicochemical properties of meloxicam, a new NSAID, were investigated. Dependent on pH and solvents used, X-ray crystallography showed that meloxicam crystallized in four different prototropic forms; the anion, the acidic enol, the zwitterion and the cation forms. As determined by 1H- and 13C-NMR, meloxicam in neutral or weakly basic solution exists in the anion form. An equilibrium between the enol and zwitterion forms, dependent upon solvent polarity, was indicated. Meloxicam was soluble at neutral pH but became rapidly insoluble with decreasing pH. At very low pH its solubility increased, indicating a second pKa value and the existen of a cation species. The very low solubility of meloxicam in acidic environments suggests it may cause few local gastrointestinal adverse events. The n-octanol-water partition coefficients (log P values) of meloxicam and other NSAIDs were estimated. At low pH meloxicam was more lipophilic than piroxicam or tenoxicam and similar to ketoprofen and naproxen.

MolIso – a program for colour-mapped iso-surfaces

The program MolIso allows the visualization of colour-mapped iso-surfaces from XD grid or GAUSSIAN CUBE files. It is written in C++ and uses the OpenGL and GLUT libraries, and is therefore portable. Linux and Windows versions are currently available. Optically correct looking, transparent visualizations are possible. The molecule inside the iso-surface can be depicted as ball-and-stick or atomic displacement parameter ellipsoid–line models. Screenshots can easily be taken in Portable Pix Map format. Short video clips, with various codecs for presentations, are easy to create.

The invariom model and its application: refinement of d,l-serine at different temperatures and resolution

Three X-ray data sets of the same D,L-serine crystal were measured at temperatures of 298, 100 and 20 K. These data were then evaluated using invarioms and the Hansen & Coppens aspherical-atom model. Multipole populations for invarioms, which are pseudoatoms that remain approximately invariant in an intermolecular transfer, were theoretically predicted using different density functional theorem (DFT) basis sets. The invariom parameters were kept fixed and positional and thermal parameters were refined to compare the fitting against the multi-temperature data at different resolutions. The deconvolution of thermal motion and electron density with respect to data resolution was studied by application of the Hirshfeld test. Above a resolution of sin theta/lambda approximately 0.55 A-1, or d approximately 0.9 A, this test was fulfilled. When the Hirshfeld test is fulfilled, a successful modeling of the aspherical electron density with invarioms is achieved, which was proven by Fourier methods. Molecular geometry improves, especially for H atoms, when using the invariom method compared to the independent-atom model, as a comparison with neutron data shows. Based on this example, the general applicability of the invariom concept to organic molecules is proven and the aspherical density modeling of a larger biomacromolecule is within reach.

Automation of invariom and of experimental charge density modelling of organic molecules with the preprocessor program InvariomTool

The program InvariomTool can be used to obtain high-quality X-ray structures of organic molecules by automating both invariom modelling and the modelling process employed in experimental charge density studies. InvariomTool is a preprocessor program for the XD package [Koritsanszky et al. (2003), Technical Report, Freie Universitat Berlin] and allows the analysis of a structure in terms of the local atomic bonding environment in order to assign Hansen–Coppens pseudoatoms that are transferable from one molecule to another (invarioms). It relies on a database of invariom entries, each containing the invariom name, local atomic site symmetry, coordinate system, model-compound name and theoretically predicted multipole population parameters. The information on chemical equivalence and local atomic site symmetry determines which multipole parameters are to be refined in the least-squares procedure of an experimental charge density study. InvariomTool allows the user to generate input files either for invariom refinement, where parameters are fixed and taken from the database, or for an experimental refinement of multipole parameters.

How to Make the Ionic Si―O Bond More Covalent and the Si―O―Si Linkage a Better Acceptor for Hydrogen Bonding

Variation of a bond angle can tune the reactivity of a chemical compound. To exemplify this concept, the nature of the siloxane linkage (Si-O-Si), the most abundant chemical bond in the earths crust, was examined using theoretical calculations on the molecular model compounds H(3)SiOSiH(3), (H(3)Si)(2)OHOH, and (H(3)Si)(2)OHOSiH(3) and high-resolution synchrotron X-ray diffraction experiments on 5-dimethylhydroxysilyl-1,3-dihydro-1,1,3,3-tetramethyl-2,1,3-benzoxadisilole (1), a molecular compound that gives rise to the formation of very rare intermolecular hydrogen bonds between the silanol groups and the siloxane linkages. For theoretical calculations and experiment, electronic descriptors were derived from a topological analysis of the electron density (ED) distribution and the electron localization function (ELF). The topological analysis of an experimentally obtained ELF is a newly developed methodology. These descriptors reveal that the Si-O bond character and the basicity of the siloxane linkage strongly depend on the Si-O-Si angle. While the ionic bond character is dominant for Si-O bonds, covalent bond contributions become more significant and the basicity increases when the Si-O-Si angle is reduced from linearity to values near the tetrahedral angle. Thus, the existence of the exceptional intermolecular hydrogen bond observed for 1 can be explained by its very small strained Si-O-Si angle that adopts nearly a tetrahedral angle.

The Significance of Ionic Bonding in Sulfur Dioxide: Bond Orders from X‐ray Diffraction Data

A novel refinement technique for X‐ray diffraction data has been employed to derive S-O bond orders in sulfur dioxide experimentally. The results show that ionic S-O bonding dominates over hypervalency.

Charge Transfer via the Dative N-B Bond and Dihydrogen Contacts. Experimental and Theoretical Electron Density Studies of Small Lewis Acid-Base Adducts

The electronic characteristics of the dative N−B bond in three Lewis acid−base adducts, hydrazine borane, hydrazine bisborane, and ammonia trifluoroborane, are analyzed by an approach combining experimental electron density determination with a broad variety of theoretical calculations. Special focus is directed to the weak dihydrogen contacts in hydrazine borane. The Atoms In Molecules partitioning scheme is complemented by additional methods like the Source Function, and the Electron Localizability Indicator. For the multipole-free theoretical models of hydrazine borane and hydrazine bisborane, a weak charge donation from Lewis base to acid of about 0.05 e is found, whereas multipole refinement of theoretical and experimental structure factors resulted in opposite signs for the Lewis acid and base fragments. For ammonia trifluoroborane, the donation from Lewis base to acid is slightly larger (about 0.13 e) in the multipole-free models, and the charges obtained by multipole refinement retain the direction of the charge donation but show quite large variations. The natural population analysis charges predict larger charge donations (0.35 e) from the Lewis bases to the acids for the three title complexes. Although the three compounds exhibit intermolecular interactions of different types and strengths, including classical hydrogen bonds, F···H contacts and the already mentioned dihydrogen bonds, almost no charge transfer is detected between different molecules within the crystal environment. The main electronic effect of the formation of the Lewis acid-base adducts and of the crystallization is an increase in the charge separation within the ammonia/hydrazine fragments, which is supported by all investigated bond and atomic properties. The nature of the dative N-B bond is found to be mainly electrostatic, but with a substantial contribution of covalency. The F-B bonds show similarities and differences from the N-B bonds, which makes a distinction of coordinative (or dative) bonds from polar covalent interactions possible.

Experimental electron density of sumanene, a bowl-shaped fullerene fragment; comparison with the related corannulene hydrocarbon

The experimental electron density of sumanene, C(21)H(12), was extracted from a high resolution X-ray data set measured at 100 K and topologically analyzed. In addition to bond topological and atomic properties, information about the density distribution between adjacent molecules, which show close C···C approaches of ~3.4 Å within the columnar π-stacks in the crystal lattice, are discussed. A comparison is made with the electron density of the related corannulene molecule based also on the analysis of Electron Localizability Indicator (ELI-D) calculations.

Charge transfer via the dative N-B bond and dihydrogen contacts. Experimental and theoretical electron density studies of four deltahedral boranes.

In an approach combining high resolution X-ray diffraction at low temperatures with density functional calculations, two closo-borates, B12H12(2-) (1) and B10H10(2-) (2), and two arachno-boranes, B10H12L2 (L = amine (3) or acetonitrile (4)), are studied by means of Atoms In Molecules (AIM) theory and Electron Localizability Indicator (ELI-D). The charge transfer via the dative N-B bonds in the arachno-boranes and via dihydrogen contacts in the closo-borates is quantified. The dative N-B bond in 4 is significantly shorter and stronger than that in 3 and in small N-B Lewis acid base adducts from the literature. It is even shorter in the gas phase than in the crystal environment in contrast to the bond shortening in the crystal generally found for N-B Lewis acid-base adducts. Furthermore, the calculated charge transfer in terms of AIM charges is opposite to the expected N → B direction but still weak as found for all other N-B bonds. The intramolecular charge redistributions due to intermolecular interactions are quantified by the AIM and ELI-D analysis of contact ion pairs. The latter method gives a deeper understanding of delocalization effects in the borane cages as well as in the counterions. Since dihydrogen bonds are rarely found in crystal structures, one focus was directed to the topologies of the large number of 58 experimentally found contacts of this type. The analysis reveals that the electron density at the bond critical point, the corresponding Laplace function, and the curvature along the bond path (λ3) show a behavior that clearly discriminates these interactions from classical hydrogen bonds, confirming earlier theoretical findings.

How to easily replace the independent atom model – the example of bergenin, a potential anti-HIV agent of traditional Asian medicine

Bergenin, which has been isolated from a variety of tropical plants, has several pharmacological applications in traditional Asian medicine. Its electron-density distribution was obtained from a room-temperature low-resolution X-ray data set measured with point detection making use of multipole populations from the invariom library. Two refinement models were considered. In a first step, positional parameters and ADPs were refined with fixed library multipoles (model E1). This model was suitable to be input into a second refinement of multipoles (model E2), which converged smoothly although based on Cu Kalpha room-temperature data. Quantitative results of a topological analysis of the electron density from both models were compared with Hartree-Fock and density-functional calculations. With respect to the independent atom model (IAM) more information can be extracted from invariom modelling, including the electrostatic potential and hydrogen-bond energies, which are highly useful, especially for biologically active compounds. The reliability of the applied invariom formalism was assessed by a comparison of bond-topological properties of sucrose, for which high-resolution multipole and invariom densities were available. Since a conventional X-ray diffraction experiment using basic equipment was combined with the easy-to-use invariom formalism, the procedure described here for bergenin illustrates how it can be routinely applied in pharmacological research.