Redetermination of bis{(1S,2S,4S,5R)-2-[(R)-hydroxy(6-methoxy-4-quinolyl)methyl]-5-vinylquinuclidinium} sulfate dihydrate

The structure of the title compound, known as quinine sulfate dihydrate, 2C20H25N2O2 +·SO4 2−·2H2O, was previously reported by Mendel [Proc. K. Ned. Akad. Wet. (1955), 58, 132–134], but only the [010] projection was determined. Hence, we have redetermined its crystal structure at 100 K using three-dimensional data. The asymmetric unit consists of a quininium cation, viz. (R)-(6-methoxyquinolinium-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidinium-2-yl]methanol, one half of a sulfate anion and a water molecule. The S atom occupies a special position on a twofold axis. The packing is characterized by infinite columns, consisting of sulfate anions and water molecules, linked through hydrogen bonds along the b axis, and further stabilized by hydrogen bonds to quininium cations. The quininium cations interact further through C—H⋯O and C—H⋯π interactions.


Related literature
For the biological activity of quinoline-based antimalarial drugs, see: Chou et al. (1980). For related structures and a previous determination of the title compound, see: Mendel (1955 Table 1 Hydrogen-bond geometry (Å , ).

Comment
Malaria is the most widespread and deadly humain infectious disease that is presently endemic in tropical and subtropical countries, covering approximately half of the world population. Its treatement is sometimes complicated with the appearence of antimalarial-resistant Plasmodium falciparum strains, arising in regions due to a long time use of a specific antimalarial drug molecule. Quinine, a quinoline core alkaloid extracted from the bark of cinchona tree, is considered in certain countries as medication of last resort against malaria and it is solely used to fight parasite strains that had resisted to other available antimalarial drug molecules.
According to Chou et al. (1980) the biological activity of quinoline-based antimalarial drugs is based on the formation of cytotoxic complexes between the latter molecules and ferriprotoporphyrin IX (hematin or hemin). The knowledge of the three-dimensional structure of such complexes should be a significant step towards the elucidation of its mechanism of action and the design of new antimalarial drugs. In an attempt to crystallize porphyrin-quinine complexes, quinine sulfate dihyrate was cocrystallized with the acidic form of [Fe(III) meso-tetra(4-sulfonatophenyl)porphine]chloride at pH 4.8 from a water/propyleneglycol mixture. However, the title compound was obtained of which the [010] projection of the crystal structure has previously been determined (Mendel, 1955). Hence, we have redetermined the structure at 100 K (Fig. 1).

Experimental
Quinine sulfate dihydrate, purchased from Acros Organics (Geel, Belgium), was added to the acid form of [Fe(III)mesotetra(4-sulfonatophenyl)porphine]chloride (FeTSPP) in the mixture of water and propyleneglycol 6:4 to induce reaction between the two compounds at room temperature. The pH was fixed at 4.8 using 0.01 M acetate buffer and adjusted with either HCl or NaOH. Colourless plate-like crystals, suitable for X-ray diffraction, were obtained within five to six h.
supplementary materials sup-2 Refinement Hydrogen atoms attached to N2 and O3 were located in a difference Fourier map. The other hydrogen atoms were positioned with idealized geometry using a riding model with C-H = 0.95-0.99 Å. All hydrogen atoms were further refined with isotropic temperature factors fixed at 1.2 or 1.5 times U eq of the parent atoms. Fig. 1. The molecular structure of the title compound with the atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are presented as small spheres of arbitrary radius.

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.
Refinement. Refinement of F 2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The threshold expression of F 2 > σ(F 2 ) is used only for calculating Rfactors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.