Structural and theoretical studies of 4-chloro-2-methyl-6-oxo-3,6-dideuteropyrimidin-1-ium chloride (d 6)

The crystal structure of 4-chloro-2-methyl-6-oxo-3,6-dideuteropyrimidin-1-ium chloride exhibits unusual angles about an sp 2 C atom, which are confirmed by theoretical calculations.


Chemical context
Heterocycles containing the pyrimidine moiety are of great interest because they constitute an important class of natural and non-natural products, many of which exhibit useful biological activities and clinical applications (Brown, 1984;Elderfield, 1957). Substituted purines and pyrimidines occur very widely in living organisms and were some of the first compounds studied by organic chemists (Bruice, 2007).
In light of these unusual bond angles for an sp 2 C atom, a theoretical analysis of the cation was undertaken. The geometries of the isolated cation, two neutral variants, and a tautomer of the cation were optimized using the PBE0 exchange-correlation functional (Adamo & Barone, 1999;Perdew et al., 1996) and aug-cc-pVTZ basis set (Dunning, 1989;Kendall et al., 1992;Woon & Dunning 1993;Davidson, 1996) via NWChem (Aprà et al., 2020). The geometry of the cation was also optimized as a scan was made of the nuclear charge of the hydrogen bound to N2. Diagram showing the cation and anion and the atom-numbering scheme (only the major component of the disorder is shown) with atomic displacement parameters drawn at the 30% probability level. The N-HÁ Á ÁCl hydrogen bond is shown by a dashed line.
Figs. 2-5 show the optimized geometries for the cation 1, two neutral structures, 3 and 4, which are tautomers of each other, and a tautomer of the cation, 5. When N2 is protonated, as in 1 (Fig. 2) and 4 (Fig. 4), the carbonyl moiety is tilted towards N2. When N2 is not protonated, as in 3 (Fig. 3) and 5 (Fig. 5), the carbonyl moiety assumes a normal orientation for an sp 2 C atom. This suggests an electrostatic interaction between oxygen and hydrogen may be responsible for the unusual angles. To explore this further, the geometry of 1 was optimized as the nuclear charge of the hydrogen bound to N2 was scanned from 0.7 to 1.3 e. As can be seen from the plot (Fig. 6), the two angles converge with decreasing nuclear charge on the hydrogen and diverge with increasing nuclear charge. This lends further support to the idea that the origin of the angle difference is an electrostatic interaction between the O1 and the hydrogen on N2.
392 Butcher et al.     Diagram showing the results of calculations for the neutral molecule, 3 (tautomer 1). Relevant angles are displayed.

Figure 6
Diagram showing a plot of the variation in the C-C-O and N-C-O angles around the sp 2 C atom as the nuclear charge of the hydrogen attached to the nitrogen is varied while keeping all other nuclear charges fixed at their normal values and keeping the number of electrons fixed.

Supramolecular features
In the crystal, the cations and anions pack into sheets in the ab plane linked by N-HÁ Á ÁCl hydrogen bonds, as well as ClÁ Á ÁO and weak C-HÁ Á ÁO interactions (Table 1). In graph-set notation (Etter et al., 1990), these make R 3 3 (11) and R 3 2 (9) rings as seen in Fig. 7. Interestingly there are no N-HÁ Á ÁO hydrogen bonds.

Synthesis and crystallization
Inside a dry box, one side of an H-tube (with no filter between the sides) was charged with 250 mg triphosgene (Aldrich) and the other side was loaded with 20 mg tetramethylammonium chloride in 3 mL dry tetraglyme. Once attached to a vacuum line with Cajon flexible tubing, the components were mixed and the phosgene was collected in a vacuum trap. In one NMR tube, 0.36 mmol of phosgene were measured on the vacuum line, condensed into 0.75 mL of dry CD 3 CN, and the tube was sealed as an NMR reference. In another tube, 0.36 mmol of phosgene was condensed onto 0.06 g (0.20 mmol) of silver oxalate in CD 3 CN and the tube was sealed to attempt to prepare a CO 2 polymer. Upon warming, the 13 C NMR of the reaction tube showed gaseous CO 2 and solvent only. After standing unobserved for three years, the reference tube was observed to be filled with crystals of the title compound, which is completely insoluble in acetonitrile, and the tube was opened in a drybox to keep the crystals dry. The 13 C{ 1 H} NMR spectrum of the crystals in D 2 O (DSS ref) is 167.07 (s), 164.11 (s), 161.28 (s), 113.05 (C3, t, 1 J C-D = 27.5 Hz) , 22.35 (CD 3 , septet, 1 J C-D = 19.8 Hz) . The previous report (Yanagida et al., 1968) involved a reaction of phosgene, CH 3 CN and HCl at 338 K. In contrast to a previous report for the structure of the monoclinic polymorph (Kawai et al., 1973), all crystals had the same habit and appearance and one suitable for X-ray diffraction studies was chosen for further study.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The cation is disordered and was refined as two equivalent forms with occupancies of 0.750 (4)/ 0.250 (4), while the chloride anion is triply disordered with occupancies of 0.774 (12), 0.12 (2), and 0.11 (2). The locations of all deuterium atoms for the major component except one attached to N1 were located in difference-Fourier maps and refined in idealized positions using a riding model with atomic displacement parameters of U iso (D) = 1.2U eq (C, N) [1.5U eq (C) for CD 3 ], and C-D and N-D distances of 0.95 and 0.88 Å , respectively. The deuterium atoms for the methyl substituent were refined isotropically. The packing viewed along the c axis showing how the cations and anions pack into sheets in the ab plane linked by N-HÁ Á ÁCl hydrogen bonds and ClÁ Á ÁO and weak C-HÁ Á ÁO interactions, forming R 3 3 (11) and R 3 2 (9) rings.

4-Chloro-2-methyl-6-oxo-3,6-dihydropyrimidin-1-ium chloride
Crystal data 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 )