research communications
5,5-Dichloro-6-hydroxydihydropyrimidine-2,4(1H,3H)-dione: molecular and Hirshfeld surface analysis and the new route for synthesis with Mg(ReO4)2 as a new catalyst
aPeoples' Friendship University of Russia, 6 Miklukho-Maklaya St, 117198, Moscow, Russian Federation, bA. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, 31 Leninsky Prospekt bldg 4, 119071 Moscow, Russian Federation, and cMedical University REAVIZ, Moscow branch, Krasnobogatyrskaya 2, 107564 Moscow, Russian Federation
*Correspondence e-mail: tony.novickoff@yandex.ru
The molecular and crystal structures of the title compound, C4H4Cl2N2O3, were investigated by single-crystal X-ray diffraction and a Hirshfeld surface analysis. 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. The six-membered ring adopts a half-chair conformation. In the crystal, hydrogen bonds connect the molecules into double layers, which are connected to each other by halogen bonds. The Hirshfeld surface analysis revealed that the most important contributions for the crystal packing are from O⋯H/H⋯O (35.8%), Cl⋯Cl (19.6%), Cl⋯H/H⋯Cl (17.0%), H⋯H (8.3%), C⋯O/O⋯C (4.3%), Cl⋯O/O⋯Cl (4.2%) and O⋯O (4.1%) contacts.
Keywords: crystal structure; uracil; pyrimidine; hydrogen bonds; halogen bonds; Hirshfeld surface analysis.
CCDC reference: 2025758
1. 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 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 Cl2 in H2O (Johnson et al., 1943) or (2) by addition of Na2S2O8 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(ReO4)2 as a catalyst. The reaction scheme is shown in Fig. 1.
2. Structural commentary
The title compound crystallizes in the C2/c with eight molecules in the The 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 P. 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 sp2-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 −0.275 (2) and 0.411 (3) Å, respectively, forming the above mentioned half-chair.
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3. 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 O1i and O2ii atoms [symmetry codes: (i) x, y + 1, z; (ii) x, −y + 2, z + ] of different molecules. The C4—H4A⋯O1i hydrogen bond also involves O1i with a H4A⋯O1i distance of 3.058 (2) Å (Table 2). In the similar compound ZEQYIF (Kasradze et al., 2012), the OH group participates as proton donor in a very strong hydrogen bond with the O atom of one of the CO groups of a neighbouring molecule. In our such strong hydrogen bonds are absent. N3—H3A forms a bifurcated hydrogen bond weaker than O3—H3 with atoms O2iv and O3v [symmetry codes: (iv) −x, −y + 2, −z + 1; (v) x, −y + 2, z − ] of different molecules. The strongest hydrogen bond is N1—H1A⋯O2iii [symmetry code: (iii) −x, −y + 1, −z + 1] with an N1⋯O2iii distance of 2.793 (2) Å. The hydrogen bonds connect the molecules into double layers parallel to the (100) plane, as shown in Fig. 4. Halogen bonds Cl1⋯Cl1vi [3.3670 (9) Å] and Cl2⋯Cl2vii [3.3568 (8) Å; symmetry codes: (vi) − x, − y, 2 − z; (vii) − x, − y, 1 − z] connect the layers, forming a three-dimensional framework.
4. Hirshfeld surface analysis
The Crystal Explorer 17.5 (Turner et al., 2017) program was used to analyse the interactions within the crystal. The donor–acceptor groups are visualized using a standard (high) surface resolution and dnorm surfaces are mapped over a fixed colour scale of −0.640 (red) to 0.986 (blue) a.u., as illustrated in Fig. 5. Red spots on the surface of the dnorm plot indicate intermolecular contacts involving the hydrogen and halogen bonds. The brightest red spots correspond to the strongest hydrogen bonds, N1—H1A⋯O2 and O3—H3⋯O2 (Table 2). There are no π–π interactions in the molecule, as can be seen from Fig. 5b by the absence of characteristic triangles. The fingerprint plots (Fig. 6) show that the O⋯H/H⋯O 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—H⋯O and N—H⋯O types are predominantly formed in the crystal. Then, the Cl⋯Cl (19.6%) and Cl⋯H/H⋯Cl (17.0%) contacts make approximately the same contribution. H⋯H (8.3%) contacts make an insignificant contribution, similarly for the C⋯O/O⋯C (4.3%), Cl⋯O/O⋯Cl (4.2%) and O⋯O (4.1%) contacts, which make approximately the same contribution. Other contacts make weaker contributions to the packaging and are not shown in Fig. 6.
5. Database survey
A search of the Cambridge Structural Database (CSD, Version 5.41, update of November 2019; Groom et al., 2016) for different possible substituents at C4 and C5 atoms gave only a few results. A similar compound was found with a methyl group instead of an H atom at C5 (ZEQYIF; Kasradze et al., 2012; ZEQYIF01; Sharutin, 2016). In cis-thymine glycol (THYGLY10; 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.
6. Synthesis and crystallization
The title compound was synthesized by adding 5 mg of uracil (Sigma Aldrich) to 1 ml of 1 mol l−1 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, ReO4− does not react with HCl while TcO4− is actively reduced (German et al., 2002). We found that in the presence of Mg2+, the ReO4− being distorted according to (Khrustalev, 2000; Ravi et al., 2018) attacks the HCl, forming Cl2 that is readily reacted with water to form HOCl. In the air and in low acidic HCl·H2O solution, the Re is then oxidized back to ReVII. Cl2 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 Cl2 + H2O = 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 Cl2 by electrophilic (more likely in an aqueous medium) and possibly through radical substitution.
7. Refinement
Crystal data, data collection and structure . The C-bound hydrogen atom was placed at a calculated position (C—H = 1.00 Å) and refined using a riding-atom model [Uiso(H) = 1.2Ueq(C)]. O- and N-bound H atoms were refined isotropically [Uiso(H) = 1.2Ueq(O, N)].
details are summarized in Table 3
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Supporting information
CCDC reference: 2025758
https://doi.org/10.1107/S2056989020011809/zq2257sup1.cif
contains datablocks I, global. DOI:Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020011809/zq2257Isup2.hkl
Supporting information file. DOI: https://doi.org/10.1107/S2056989020011809/zq2257Isup3.cml
Data collection: APEX2 (Bruker, 2012); cell
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).C4H4Cl2N2O3 | F(000) = 800 |
Mr = 198.99 | Dx = 1.898 Mg m−3 |
Monoclinic, C2/c | Mo Kα radiation, λ = 0.71073 Å |
a = 19.9042 (10) Å | Cell parameters from 3314 reflections |
b = 6.6243 (4) Å | θ = 3.8–34.7° |
c = 10.5636 (7) Å | µ = 0.89 mm−1 |
β = 90.819 (4)° | T = 100 K |
V = 1392.68 (14) Å3 | Needle, colourless |
Z = 8 | 0.50 × 0.10 × 0.02 mm |
Bruker Kappa APEXII area-detector diffractometer | 2128 reflections with I > 2σ(I) |
φ and ω scans | Rint = 0.045 |
Absorption correction: multi-scan (SADABS; Bruker, 2008) | θmax = 35.0°, θmin = 4.1° |
Tmin = 0.802, Tmax = 0.983 | h = −32→31 |
12430 measured reflections | k = −9→10 |
3046 independent reflections | l = −17→16 |
Refinement on F2 | 3 restraints |
Least-squares matrix: full | Hydrogen site location: mixed |
R[F2 > 2σ(F2)] = 0.042 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.103 | w = 1/[σ2(Fo2) + (0.0468P)2 + 0.922P] where P = (Fo2 + 2Fc2)/3 |
S = 1.02 | (Δ/σ)max < 0.001 |
3046 reflections | Δρmax = 0.91 e Å−3 |
109 parameters | Δρmin = −0.55 e Å−3 |
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. |
x | y | z | Uiso*/Ueq | ||
Cl1 | 0.18354 (2) | 0.69299 (6) | 0.90632 (4) | 0.02208 (10) | |
Cl2 | 0.22188 (2) | 0.68819 (7) | 0.64394 (4) | 0.02409 (11) | |
O1 | 0.11148 (7) | 0.36996 (19) | 0.76917 (14) | 0.0270 (3) | |
O2 | 0.01449 (6) | 0.75547 (19) | 0.46558 (12) | 0.0218 (3) | |
O3 | 0.07140 (7) | 0.9344 (2) | 0.82106 (14) | 0.0296 (3) | |
H3 | 0.0619 (12) | 1.052 (3) | 0.828 (2) | 0.036* | |
N1 | 0.05958 (6) | 0.57272 (19) | 0.62634 (13) | 0.0142 (2) | |
H1A | 0.0352 (10) | 0.469 (3) | 0.598 (2) | 0.017* | |
N3 | 0.08836 (7) | 0.9086 (2) | 0.60091 (15) | 0.0209 (3) | |
H3A | 0.0803 (11) | 1.010 (4) | 0.564 (2) | 0.025* | |
C2 | 0.05203 (8) | 0.7500 (2) | 0.55987 (15) | 0.0160 (3) | |
C4 | 0.11860 (8) | 0.9140 (2) | 0.72628 (16) | 0.0177 (3) | |
H4A | 0.152164 | 1.026060 | 0.731982 | 0.021* | |
C5 | 0.15341 (7) | 0.7110 (2) | 0.74935 (15) | 0.0135 (3) | |
C6 | 0.10627 (7) | 0.5334 (2) | 0.71907 (15) | 0.0148 (3) |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.02396 (18) | 0.0258 (2) | 0.01618 (18) | −0.00256 (15) | −0.01093 (14) | 0.00345 (15) |
Cl2 | 0.01459 (16) | 0.0329 (2) | 0.0248 (2) | −0.00212 (15) | 0.00148 (14) | −0.00355 (17) |
O1 | 0.0290 (6) | 0.0180 (6) | 0.0334 (8) | −0.0055 (5) | −0.0147 (5) | 0.0107 (5) |
O2 | 0.0269 (6) | 0.0176 (5) | 0.0204 (6) | −0.0034 (4) | −0.0153 (5) | 0.0025 (5) |
O3 | 0.0226 (6) | 0.0338 (7) | 0.0323 (8) | 0.0093 (5) | −0.0071 (5) | −0.0185 (6) |
N1 | 0.0149 (5) | 0.0114 (5) | 0.0160 (6) | −0.0017 (4) | −0.0059 (4) | 0.0003 (5) |
N3 | 0.0280 (7) | 0.0099 (6) | 0.0242 (8) | −0.0025 (5) | −0.0163 (6) | 0.0042 (5) |
C2 | 0.0174 (6) | 0.0133 (6) | 0.0169 (7) | −0.0003 (5) | −0.0075 (5) | 0.0008 (5) |
C4 | 0.0195 (7) | 0.0133 (6) | 0.0200 (7) | 0.0019 (5) | −0.0104 (6) | −0.0028 (6) |
C5 | 0.0122 (5) | 0.0149 (6) | 0.0132 (6) | 0.0001 (5) | −0.0038 (5) | 0.0013 (5) |
C6 | 0.0147 (6) | 0.0143 (6) | 0.0152 (7) | −0.0011 (5) | −0.0048 (5) | 0.0025 (5) |
Cl1—C5 | 1.7592 (15) | N1—H1A | 0.89 (2) |
Cl2—C5 | 1.7787 (16) | N3—C2 | 1.344 (2) |
O1—C6 | 1.2086 (19) | N3—C4 | 1.447 (2) |
O2—C2 | 1.2371 (18) | N3—H3A | 0.79 (2) |
O3—C4 | 1.389 (2) | C4—C5 | 1.531 (2) |
O3—H3 | 0.805 (16) | C4—H4A | 1.0000 |
N1—C6 | 1.3658 (19) | C5—C6 | 1.536 (2) |
N1—C2 | 1.375 (2) | ||
C4—O3—H3 | 109.1 (19) | O3—C4—H4A | 110.0 |
C6—N1—C2 | 126.69 (13) | N3—C4—H4A | 110.0 |
C6—N1—H1A | 117.2 (13) | C5—C4—H4A | 110.0 |
C2—N1—H1A | 115.5 (13) | C4—C5—C6 | 111.48 (12) |
C2—N3—C4 | 121.97 (14) | C4—C5—Cl1 | 110.91 (11) |
C2—N3—H3A | 113.8 (17) | C6—C5—Cl1 | 110.09 (10) |
C4—N3—H3A | 120.2 (17) | C4—C5—Cl2 | 108.90 (11) |
O2—C2—N3 | 123.56 (15) | C6—C5—Cl2 | 106.02 (11) |
O2—C2—N1 | 119.77 (14) | Cl1—C5—Cl2 | 109.29 (8) |
N3—C2—N1 | 116.65 (13) | O1—C6—N1 | 122.56 (14) |
O3—C4—N3 | 112.65 (13) | O1—C6—C5 | 123.13 (13) |
O3—C4—C5 | 106.26 (14) | N1—C6—C5 | 114.24 (13) |
N3—C4—C5 | 107.77 (13) | ||
C4—N3—C2—O2 | 164.69 (16) | O3—C4—C5—Cl2 | −172.67 (10) |
C4—N3—C2—N1 | −17.2 (2) | N3—C4—C5—Cl2 | 66.35 (14) |
C6—N1—C2—O2 | 169.06 (16) | C2—N1—C6—O1 | −176.62 (17) |
C6—N1—C2—N3 | −9.1 (3) | C2—N1—C6—C5 | 0.6 (2) |
C2—N3—C4—O3 | −70.5 (2) | C4—C5—C6—O1 | −152.65 (17) |
C2—N3—C4—C5 | 46.4 (2) | Cl1—C5—C6—O1 | −29.1 (2) |
O3—C4—C5—C6 | 70.70 (16) | Cl2—C5—C6—O1 | 88.98 (18) |
N3—C4—C5—C6 | −50.28 (18) | C4—C5—C6—N1 | 30.10 (19) |
O3—C4—C5—Cl1 | −52.36 (14) | Cl1—C5—C6—N1 | 153.63 (12) |
N3—C4—C5—Cl1 | −173.35 (11) | Cl2—C5—C6—N1 | −88.27 (14) |
D—H···A | D—H | H···A | D···A | D—H···A |
O3—H3···O1i | 0.81 (2) | 2.41 (2) | 3.045 (2) | 136 (2) |
O3—H3···O2ii | 0.81 (2) | 2.16 (2) | 2.8076 (18) | 138 (2) |
N1—H1A···O2iii | 0.89 (2) | 1.91 (2) | 2.7932 (17) | 178 (2) |
N3—H3A···O2iv | 0.79 (2) | 2.46 (2) | 3.0978 (19) | 138 (2) |
N3—H3A···O3v | 0.79 (2) | 2.60 (2) | 3.147 (2) | 128 (2) |
C4—H4A···O1i | 1.00 | 2.45 | 3.058 (2) | 119 |
Symmetry codes: (i) x, y+1, z; (ii) x, −y+2, z+1/2; (iii) −x, −y+1, −z+1; (iv) −x, −y+2, −z+1; (v) x, −y+2, z−1/2. |
Acknowledgements
The X-ray diffraction experiment was carried out at the Centre of Shared Use of Physical Methods of Investigation of IPCE RAS.
Funding information
Funding for this research was provided by: Ministry of Science and Higher Education of the Russian Federation (subject No. AAAA-A18-118040590105-4).
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