Showing papers by "Louis J. Farrugia published in 2016"

Electron density, disorder and polymorphism:high-resolution diffraction studies of the highly polymorphic neuralgic drug carbamazepine

Abstract: Analysis of neutron and high-resolution X-ray diffraction data on form (III) of carbamazepine at 100 K using the atoms in molecules (AIM) topological approach afforded excellent agreement between the experimental results and theoretical densities from the optimized gas-phase structure and from multipole modelling of static theoretical structure factors. The charge density analysis provides experimental confirmation of the partially localized π-bonding suggested by the conventional structural formula, but the evidence for any significant C—N π bonding is not strong. Hirshfeld atom refinement (HAR) gives H atom positional and anisotropic displacement parameters that agree very well with the neutron parameters. X-ray and neutron diffraction data on the dihydrate of carbemazepine strongly indicate a disordered orthorhombic crystal structure in the space group Cmca, rather than a monoclinic crystal structure in space group P21/c. This disorder in the dihydrate structure has implications for both experimental and theoretical studies of polymorphism.

Cascade Metathesis Reactions for the Synthesis of Taxane and Isotaxane Derivatives

Abstract: Tricyclic isotaxane and taxane derivatives have been synthesized by a very efficient cascade ring-closing dienyne metathesis (RCDEYM) reaction, which formed the A and B rings in one operation. When the alkyne is present at C13 (with no neighboring gem-dimethyl group), the RCEDYM reaction leads to 14,15-isotaxanes 16 a,b and 18 b with the gem-dimethyl group on the A ring. If the alkyne is at the C11 position (and thus flanked by a gem-dimethyl group), RCEDYM reaction only proceeds in the presence of a trisubstituted olefin at C13, which disfavors the competing diene ring-closing metathesis reaction, to give the tricyclic core of Taxol 44.

High resolution X-ray and neutron diffraction studies on molecular complexes of chloranilic acid and lutidines

Abstract: A total of 18 molecular complexes of chloranilic acid (H2CA) and various isomeric dimethylpyridine (lutidine) bases (B) in a 1 : 1 and 1 : 2 stoichiometric ratio have been prepared and characterised structurally; 10 of the structural determinations used high resolution crystallography. Since proton transfer between the acid and base occurs in all the crystalline forms, they are most appropriately described as salts between the lutidinium cations [BH+] and the chloranilate mono- and dianions [HCA−] and [CA2−]. The formation of bifurcated or non-bifurcated charge-assisted hydrogen bonds is described and the influence of the different functional groups on symmetrical or asymmetrical bifurcated hydrogen bond formation are investigated. Previously unreported salts of the composition [BH+][HCA−] with 2,3- and 3,5-lutidine, and [BH+]2[CA2−] with 2,3-, 2,4-, 2,5-, 2 ,6- and 3,4-lutidine are reported, as well as di- and trihydrate forms of the latter salt type with 2,4- and 3,4-lutidine respectively. For the 2,4- and 3,5-lutidines only, molecular complexes containing co-existing charged and neutral chloranilic acid molecules are also observed. The charge delocalisation in the chloranilate anions, which has an influence on the hydrogen bond distances, is confirmed by the deformation density plots, atomic net charge calculations and the density at the bond critical points. The QTAIM molecular graphs, which show the presence of bifurcated or non-bifurcated hydrogen bonds, are highly dependent on the exact refinement model. Lattice energy calculations based on the experimental charge densities also show a high dependence on the refinement strategy, while theoretical lattice energy calculations using different approaches provide no consistency in the rank order stabilities. We conclude that neither experimental nor theoretical approaches are currently sufficiently accurate to determine a definitive stability order for such isomeric complexes.