A study of the crystal structures, supramolecular patterns and Hirshfeld surfaces of bromide salts of hypoxanthine and xanthine

Two new crystalline salts, namely, hypoxanthinium bromide monohydrate, C5H5N4O+·Br−·H2O (I) and xanthinium bromide monohydrate, C5H5N4O2 +·Br−·H2O (II), were synthesized and characterized by single-crystal X-ray diffraction technique and Hirshfeld surface analysis. The hypoxanthinium and xanthinium cations in salts I and II are both in the oxo-N(9)–H tautomeric form. The crystal packing of the two salts is governed predominantly by N—H⋯O, N—H⋯Br, C—H⋯Br and O—H⋯Br interactions described by (9) and (8) synthons.

Two new crystalline salts, namely, hypoxanthinium bromide monohydrate, C 5 H 5 N 4 O + ÁBr À ÁH 2 O (I) and xanthinium bromide monohydrate, C 5 H 5 N 4 O 2 + ÁBr À ÁH 2 O (II), were synthesized and characterized by single-crystal X-ray diffraction technique and Hirshfeld surface analysis. The hypoxanthinium and xanthinium cations in salts I and II are both in the oxo-N(9)-H tautomeric form. The crystal packing of the two salts is governed predominantly by N-HÁ Á ÁO, N-HÁ Á ÁBr, C-HÁ Á ÁBr and O-HÁ Á ÁBr interactions described by R 2 3 (9) and R 2 2 (8) synthons. The crystal packing is also consolidated by carbonylÁ Á Á interactions between symmetry-related hypoxanthinium (HX + ) cations in salt I and xanthinium cations (XA + ) in salt II. The combination of all these interactions leads to the formation of wave-and staircase-like architectures in salts I and II, respectively. The largest contributions to the overall Hirshfeld surface are from BrÁ Á ÁH/HÁ Á ÁBr contacts (22.3% in I and 25.4% in II) .

Chemical context
Over the past several decades, non-covalent interactions have been found to play a prominent role in coordination chemistry, materials science and pharmaceutical science (Č erný & Hobza, 2007;Desiraju, 2013;Perumalla & Sun, 2014). Understanding the role of non-covalent interactions is important in the context of crystal engineering (Aakerö y et al., 2010;Pogoda et al., 2018;Cavallo et al., 2016;Desiraju et al., 2013) in order to design solids with desired properties. When it comes to pharmaceutics, active pharmaceutical ingredients (APIs) are known to exist in different solid forms such as salts, co-crystals, solvates, polymorphs and amorphous solids (Aaltonen et al., 2009). The salt and co-crystal forms of APIs have improved their solubility and bioavailability when compared to pure APIs (Thackaberry, 2012;Xu, et al., 2014). Drugs with low solubility/bioavailability are usually converted to their salts or crystallized in their co-crystal/polymorphic/ solvate forms to enhance their properties. Herein, we report two new salts of hypoxanthine (HX) and xanthine (XA).
Hypoxanthine (C 5 H 4 N 4 O) [systematic name: 1,9-dihydropurine-6-one] and xanthine (C 5 H 4 N 4 O 2 ) [systematic name: 3,7-dihydro-purine-2,6-dione] are well-known purine-based nucleotides (Emel'yanenko et al., 2017) present in t-RNA and DNA in the form of the nucleoside inosine (Plekan et al., 2012). Purine derivatives are widely known for their therapeutic applications such as antagonization of the adenosine receptor, anti-inflammatory, antimicrobial, antioxidant, antitumour, anti-asthmatic and psycho-stimulant drug activity (Meskini et al., 1994;Burbiel et al., 2006). HX and XA are also found as intermediates in the biological degradation of nucleic acid to uric acid. Furthermore, HX is used as an indicator of hypoxia and it is known to inhibit the effect of several drugs (Dubler et al., 1987a,b). It is also used to destroy harmful agents such as cancer cells (Susithra et al., 2018). Purine-based derivatives of HX and XA bind with the DNA base pairs through weak hydrogen bonds (Latosiń ska et al., 2014;Rutledge et al., 2007). Additionally, hypoxanthine-guanine phosphoribosyl transferase plays an important role in activating antiviral drugs in the human body and xanthine has been used as a mild stimulant drug (Faheem et al., 2020).
In the hypoxanthinium salts, the hypoxanthine molecule is usually also protonated at the N7 position, resulting in the oxo-N(9)-H tautomer. Similarly, xanthinium nitrate monohydrate, xanthinium hydrogensulfate monohydrate (Sridhar, 2011) and xanthinium perchlorate dihydrate (Biradha et al., 2010) are also in the oxo-N(9)-H tautomeric form and are therefore protonated on the N7 position. Studies of noncovalent interactions involving hypoxanthine and xanthine bases with inorganic acids have increased because their hydrogen-bonding patterns are similar to those of purine bases (Maixner & Zachova, 1991;Sridhar, 2011;Kistenmancher & Shigematsu, 1974). In the current work, the crystal structures, supramolecular packing patterns and Hirshfeld surface analyses of hypoxanthinium bromide monohydrate (I) and xanthinium bromide monohydrate (II) are reported.

Supramolecular features
In I, the protonated HX + cation interacts with another inversion-related HX + and Br À pair via N1-H1Á Á ÁBr1, C8-H8Á Á ÁBr1 ii and N9-H9Á Á ÁO6 ii hydrogen bonds (Table 1). These interactions lead to the formation of a nine-membered ring with R 2 3 (9) (type D) primary graph-set motif (Sletten & Jensen, 1969). Along with this, the HX + cation interacts with another inversion-related HX + cation and a water molecule through O1W-H1WÁ Á ÁN3 iii and N7-H7Á Á ÁO1W ii hydrogen bonds. The combination of these interactions leads to the formation of an eleven-membered R 3 3 (11) (type I) ring motif. The interaction is very similar to the water-mediated base pairs observed in the crystal structure of hypoxanthinium chloride and the nucleobase pairs in DNA and RNA (Sletten & Jensen, 1969;Reddy et al., 2001;Brandl et al., 2000). Here the O1W atom of the water molecule acts as both a hydrogenbond donor and a hydrogen-bond acceptor. The R 2 3 (9) and R 3 3 (11) ring motifs combine to form a supramolecular ribbon. Adjacent ribbons are connected through pairs of O1W-H2WÁ Á ÁBr1 hydrogen bonds with R 4 6 (16) and R 4 6 (14) (types N

Figure 5
Formation of a supramolecular ribbon with a DADA array in salt II via N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds between cations and water molecules.

Figure 6
Supramolecular ribbons connecting adjacent ribbons through N-HÁ Á ÁBr interactions. [Symmetry codes: . In this regard, the contribution of the interatomic contacts to the d norm surface map can help differentiate whether the contact is longer (blue) or shorter (red) than the sum of the van der Waals radii of the two interacting atoms. The Hirshfeld surfaces of salts I and II are shown in Fig. 9a and 10a, respectively and the hydrogen-bonding interactions between the hydrated ion pairs I and II and the respective neighbouring moieties are shown in Fig. 9b and 10b
A comparison between some related purine-based chloride and bromide salts revealed that type A, B and C hydrogenbond motifs are predominant. The commonly observed motifs in purine based salts are shown in the scheme. A comparison of salts I and II with the reported crystal structures revealed that the bromide and chloride salts of I are isomorphous and therefore, one might predict, the unreported xanthinium chloride monohydrate could be isomorphous with its bromide salt II.

Figure 12
Hirshfeld surface analysis and two-dimensional fingerprint plots for salt II plotted over d norm , with interactions to neighbouring fragments shown as dashed lines.

Figure 11
Hirshfeld surface analysis and two-dimensional fingerprint plots for salt I plotted over d norm , with interactions to neighbouring fragments shown as dashed lines.
anthine molecule is protonated at the N7 position and interacts with the anion through N-HÁ Á ÁCl/O and C OÁ Á Á interactions. In the xanthinium salts, the xanthine molecules are protonated at the N7 position in xanthinium nitrate monohydrate and xanthinium hydrogensulfate monohydrate and at the N9 position in xanthinium perchlorate monohydrate. In all of the crystal structures, the xanthinium cation interacts with the anion through N-HÁ Á ÁO, O-HÁ Á ÁO and C OÁ Á Á interactions.

Synthesis and crystallization
A general method was used for the preparation and crystallization of the hypoxanthinium bromide monohydrate (I) and xanthinium bromide monohydrate (II) using the following quantities: 0.0340 mg (0.25mmol) of hypoxanthine for I and 0.0380 mg (0.25 mmol) of xanthine for II. The indicated amount of the base was dissolved in 20 mL of distilled water and 2 mL of hydrobromic acid (5% in water) were added. The reaction mixture was heated to 358 K for 30 min using a water bath. The resulting solution was allowed to slowly evaporate at room temperature. After a few days, colourless plate-like crystals were obtained.

Refinement
Crystal data, data collection and structure refinement details for salts I and II are summarized in Table 4. All C-bound hydrogen atoms were placed in idealized positions and refined using a riding model, with C-H = 0.93 Å and U iso (H) = 1.2U eq (C). The H atoms of the water molecule were located in a difference-Fourier map and refined with the O-H distance restrained to 0.85-0.86 Å and with U iso (H) = 1.5 U eq (O). The hydrogen atoms bound to the nitrogen atoms in salts I and II were located in difference-Fourier maps and either refined freely (in I) or with the distance restraint N-H = 0.82 Å and with U iso (H) = 1.2U eq (N) (in II).

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.

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.

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