Partial charge transfer in the salt co-crystal of l-ascorbic acid and 4,4′-bipyridine

In the title 1:2 co-crystal, l-ascorbic acid (LAA) and 4,4′-bipyridine (bpy) co-crystallize with two molecules of LAA, and one molecule of bpy in the asymmetric unit. The structure was modeled in two parts due to possible proton transfer from LAA to the corresponding side of the bpy molecule having an occupancy of approximately 0.25 and part 2 with an occupancy of approximately 0.75.


Chemical context
l-Ascorbic acid (LAA) is an antioxidant and integral vitamin, vitamin C, for many biological systems (Frei et al., 1989;Yogeswaran et al., 2007). Since humans cannot synthesize LAA naturally, vitamin C is often obtained from digesting fruits and vegetables, including citrus fruits, tomatoes and potatoes (Medicine, 2000;Yu et al., 2016). Vitamin C is also produced through the ingestion of dietary supplements composed of LAA or many other ascorbate-containing derivatives including calcium ascorbate, dehydroascorbate, and calcium threonate (Johnston et al., 1994).
Co-crystallization, a process in which two or more molecules form a crystalline single phase material generally in a stoichiometric ratio (Trask, 2007), can tailor pharmaceutically important physical properties including solubility, hygroscopicity, and, active lifetime without altering the active pharmaceutical ingredient (Rodriquez-Honedo et al., 2007;Ross et al., 2016;Shan & Zaworotko, 2008;Thipparaboina et al., 2016). Co-crystal structures are key to identifying important structure-directing interactions in the solid-state (Childs et al., 2007). In this paper, we report the synthesis and single crystal structure determination of a salt co-crystal containing LAA and a commonly used co-former, 4,4 0 -bipyridine (BPy) (Aakerö y et al., 2015, Cherukuvada et al., 2016, which is known to be a secondary building component often used as a pillaring ligand to give three-dimensionality in what would ISSN 2056-9890 normally be stacking of two-dimensional sheets in crystalline systems (Dinesh et al., 2015;Ló pez-Cabrelles et al., 2015).

Structural commentary
LAA and BPy co-crystallize in the chiral space group P2 1 with two molecules of LAA, and one molecule of BPy in the asymmetric unit (Fig. 1). While the lattice is composed of molecules in a variety of charge states (vide infra), the neutral molecule abbreviations (LAA and BPy) provide a convenient method for describing the structure in terms of these fragments.
The overall three-dimensional structure is formed by interlocking sheets of LAA bridged by BPy molecules. Initial attempts to refine the structure as neutral molecules were not satisfactory and suggested the presence of disorder in the positions of the protons involved in intermolecular hydrogen bonding between LAA and Bpy (H4 and H10). Fourier difference maps produced following a refinement using all atoms except the suspected disorders protons (H4, H10) revealed the presence of two peaks of electron density between the two pairs of heavy atoms involved in the hydrogen bonding (N1 and O4; N2 and O10, Fig. 2). The positions of the two protons were initially modeled independently (model 1) in two parts to account for the disorder arising from proton transfer from LAA to Bpy. In this model, the occupancy of H10 and its disorder partner atom H2 refined to 0.22736 and 0.70972, respectively. The occupancy of H4 and its disorder partner atom H1 refined to 0.70972 and 0.23932, respectively. The similarity of the occupancies for the two pairs indicated that the disorder was likely correlated.
An additional refinement was performed in which the occupancies were constrained to be identical for the pairs of atoms (single part command for both pairs, model 2). The occupancies for model 2 were determined to be 0.73718 and 0.26282 for the pairs, similar to what was observed in model 1. The R 1 values for both model 1 and model 2 were found to be 3.94%. Given the same values for R 1 for both models, the model with the fewer parameters, model 2, will be reported. There has been an active debate in the community whether an organic salt due to proton transfer is considered a co-crystal However, as we cannot rule out the presence of a non-ionized species within the lattice, we will refer to the obtained product as a salt co-crystal (Cherukuvada et al., 2016).

Supramolecular features
In the structure, LAA forms hydrogen bonds with neighboring LAA molecules, giving rise to extended sheets of LAA mol- Fourier difference map of the LAA-BPy salt co-crystal showing two peaks of electron density between N1Á Á ÁO4 (upper) and N2Á Á ÁO10 (lower).

Figure 1
Asymmetric unit of the title compound, showing the numbering scheme.

Figure 3
Diagram illustrating the hydrogen-bonding interactions (dashed lines, see

Database survey
Recently the co-crystal structure of LAA and 3-bromo-4pyridone (BrPyd) was reported (Wang et al., 2016). While the LAA molecules in each structure contain similar interactions, LAA-BPy and LAA-BrPyd demonstrate important differences with regard to the three-dimensional structure because of the different binding synthons of BrPyd compared to BPy (Fig. 5). In the structure of LAA-BrPyd, the carbonyl on the BrPyd hydrogen bonds with both hydroxyl groups located on the five-membered ring of LAA, whereas the carbonyl located on the five-membered ring of LAA hydrogen bonds with the pyridinium group of BrPyd. The corresponding hydrogenbond network results in two-dimensional sheets. The threedimensional aspect of LAA-BrPyd arises from stacking of the sheets, which are held together by hydrogen bonding of the terminal hydroxyl group of the aliphatic carbon chain with the hydroxyl group on the five-membered ring on the LAA in the adjacent sheet.

Synthesis and crystallization
All chemicals were obtained commercially and used as received. Solid l-ascorbic acid (0.0450 g, 0.256 mmol) and 4,4 0bipyridine (0.0200 g, 0.128 mmol) were added to a 25 ml scintillation vial. To this were added approximately 12 ml of 200 proof ethanol followed by gentle heating. The loosely capped vial was then placed into a dark cabinet. Plate crystals of the title compound suitable for single crystal X-ray diffraction measurements were obtained.

Special details
Refinement. X-ray diffraction data was collected on a Bruker SMART APEX2 CCD diffractometer installed at a rotating anode source (MoKα radiation, λ=0.71073 Å), and equipped with an Oxford Cryosystems (Cryostream700) nitrogen gasflow apparatus. The data were collected by the rotation method with a 0.5° frame-width (ω scan) and a 15 second exposure per frame. Three sets of data (360 frames in each set) were collected, nominally covering complete reciprocal space. The structure was solved in the Olex2 (Dolomanov, O. V. B. et al., 2009) crystallography program using the XS structure solution program (Sheldrick,G. M, 2008) using the Charge Flipping method and refined using the olex2.refine refinement package (Bourhis, L. J., et al., 2015) using least-squares minimization.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (