5,5-Dichloro-6-hydroxydihydropyrimidine-2,4(1H,3H)-dione: molecular and crystal structure, Hirshfeld surface analysis and the new route for synthesis with Mg(ReO4)2 as a new catalyst

The title compound was synthesized by a new type of reaction using Mg(ReO4)2 as a new catalyst and a possible mechanism for this reaction is proposed. In the crystal, hydrogen bonds connect the molecules into double layers, which are connected to each other by halogen bonds.


Chemical context
Nitrogen heterocycles and pyrimidines are examples of the most important biologically active compounds and find a wide use in modern medicine (Pałasz et al., 2015;Takeshita et al., 2006;Henderson et al., 2003). Uracil is widespread in nature as a pyrimidine derivative, and is found as a part of nucleic acids. Uracil derivatives are used for therapeutic purposes (Smith et al., 2004;Kasradze et al., 2012) . Halogen derivatives of uracil serve as convenient intermediates for the preparation of compounds with various functional groups (Wamhoff et al., 1992). Halogen-halogen bonding has recently attracted attention as it expands the possibilities of understanding the new properties of compounds containing halogens and their applications (Szell et al., 2017). Pyrimidine derivatives are used as intermediates for the production of various complex organic molecules for the treatment of cancer and AIDS (Fawcett et al., 1996). Several pyrimidine derivatives belong to the class of central nervous system depressants (Soayed et al., 2015). 5,5-Dichloro-6-hydroxydihydropyrimidine-2,4(1H,3H)-dione (1) was earlier synthesized by two reaction schemes starting with uracil: (1) by addition of Cl 2 in H 2 O (Johnson et al., 1943) or (2) by addition of Na 2 S 2 O 8 and NaCl in acetic acid (Itahara et al., 1986). We have found a new reaction for the synthesis of 1 by the reaction of uracil with hydrochloric acid and water in the presence of Mg(ReO 4 ) 2 as a catalyst. The reaction scheme is shown in Fig. 1.

Structural commentary
The title compound crystallizes in the space group C2/c with eight molecules in the unit cell. The asymmetric unit is illustrated in Fig. 2. A similar compound with a methyl group instead of an H atom at C5 (ZEQYIF; Kasradze et al., 2012;ZEQYIF01;Sharutin, 2016) crystallizes in the space group P1. The six-membered ring adopts a half-chair conformation, as in ZEQYIF (Kasradze et al., 2012). The largest angle at nitrogen atom, C6-N1-C2, is 126.69 (13) . The angle involving the two chlorine atoms, Cl1-C5-Cl2, is 109.29 (8) . The two C-N bonds at the N1 atom are similar in length while those at N3 differ because of the N3-C2 sp 2 -conjugation, the latter bond being only 1.344 (2) Å ( Table 1). The six atoms N3, C2, O2, N1, C6 and O1 are almost planar (r.m.s. deviation of fitted atoms = 0.0462 Å ) while the two other ring atoms of the ring C4 and C5 are displaced from this plane by À0.275 (2) and 0.411 (3) Å , respectively, forming the above mentioned halfchair.

Supramolecular features
The hydrogen-bond system is shown in Fig. 3. In the structure, there are two bifurcated hydrogen bonds. O3-H3 forms a bifurcated hydrogen bond with the O1 i and O2 ii atoms [symmetry codes: (i) x, y + 1, z; (ii) x, Ày + 2, z + 1 2 ] of different molecules. The C4-H4AÁ Á ÁO1 i hydrogen bond also involves O1 i with a H4AÁ Á ÁO1 i distance of 3.058 (2) Å ( Molecular structure of the title compound, including atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Figure 1
Synthesis scheme of 1.

Figure 4
Crystal packing of 1 showing the double layers with halogen bonds between them.

Figure 5
Hirshfeld surface mapper over (a) d norm and (b) shape-index to visualize the interactions in the title compound.  molecular contacts involving the hydrogen and halogen bonds. The brightest red spots correspond to the strongest hydrogen bonds, N1-H1AÁ Á ÁO2 and O3-H3Á Á ÁO2 (Table 2). There are nointeractions in the molecule, as can be seen from Fig. 5b by the absence of characteristic triangles. The fingerprint plots (Fig. 6) show that the OÁ Á ÁH/HÁ Á ÁO contacts (35.8%) make the largest contribution to the overall packing of the crystal, which is due to the fact that hydrogen bonds of the O-HÁ Á ÁO and N-HÁ Á ÁO types are predominantly formed in the crystal. Then, the ClÁ Á ÁCl (19.6%) and ClÁ Á ÁH/ HÁ Á ÁCl (17.0%) contacts make approximately the same contribution. HÁ Á ÁH (8.3%) contacts make an insignificant contribution, similarly for the CÁ Á ÁO/OÁ Á ÁC (4.3%), ClÁ Á ÁO/ OÁ Á ÁCl (4.2%) and OÁ Á ÁO (4.1%) contacts, which make approximately the same contribution. Other contacts make weaker contributions to the packaging and are not shown in Fig. 6.  Flippen, 1973), one of the chlorine atoms is replaced by an OH group, and the second chlorine atom is replaced by a methyl group. FUFDIT (Flippen-Anderson, 1987) is the same as cis-thymine glycol, except that the H atom in the hydroxyl group is replaced by OH group and water of crystallization is present.

Synthesis and crystallization
The title compound was synthesized by adding 5 mg of uracil (Sigma Aldrich) to 1 ml of 1 mol l À1 hydrochloric acid aqueous solution in the presence of magnesium perrhenate. This solution was heated in a water bath (at 348 K) until the components were completely dissolved. Crystallization occurred with isothermal evaporation of the resulting solution at room temperature for several weeks, giving colourless needle-shaped crystals, composition according to chemical analysis (obs./calc.): C, 24.12/24.14; H, 2.04/2.03; Cl,35.64/ 35.63;N,14.07/14.08;O,24.13/24.12. Crystals suitable for a X-ray structural analysis were extracted manually from this batch. We suggest a possible mechanism of the observed reaction. Typically, ReO 4 À does not react with HCl while TcO 4 À is actively reduced (German et al., 2002). We found that in the presence of Mg 2+ , the ReO 4 À being distorted according to (Khrustalev, 2000;Ravi et al., 2018) attacks the HCl, forming Cl 2 that is readily reacted with water to form HOCl. In the air and in low acidic HClÁH 2 O solution, the Re is then oxidized back to Re VII . Cl 2 is thus formed by the action of hydrochloric acid on the rhenium salt as a result of a redox reaction. The process of hypohalogenation is then likely to occur. Since the reaction takes place in an aqueous medium, the formation of hypohalogenic acid is possible by the reaction Cl 2 + H 2 O = HOCl + HCl. Hypohalogenation is usually carried out with an aqueous solution of halogen. The addition to positions 5 and 6 is electrophilic, in accordance with the electron-density distribution. The partially positively charged halogen atom is directed towards carbon C5, which has a higher partial negative charge compared to the C6 atom, towards which the hydroxyl is directed. Then, at position C5, hydrogen is possibly replaced by Cl 2 by electrophilic (more likely in an aqueous medium) and possibly through radical substitution.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. The C-bound hydrogen atom was placed at a calculated position (C-H = 1.00 Å ) and refined using a riding-atom model [U iso (H) = 1.2U eq (C)]. O-and Nbound H atoms were refined isotropically [U iso (H) = 1.2U eq (O, N)].

Acknowledgements
The X-ray diffraction experiment was carried out at the Centre of Shared Use of Physical Methods of Investigation of IPCE RAS.  Computer programs: APEX2 and SAINT-Plus (Bruker, 2012), SHELXS97 (Sheldrick, 2008) and SHELXL2018 (Sheldrick, 2015).

Computing details
Data collection: APEX2 (Bruker, 2012); cell refinement: SAINT-Plus (Bruker, 2012); data reduction: SAINT-Plus (Bruker, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015). 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.