Methyl 1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-1H-benzo[d]imidazole-7-carboxylate: a combined X-ray and DFT study

The crystal and molecular structures of methyl 1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-1H-benzo[d]imidazole-7-carboxylate,obtained as a side product during the synthesis of the previously reported antitubercular agent N-(2-fluoroethyl)-1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-1H-benzo[d]imidazole-4-carboxamide, are reported.

The title compound, C 16 H 16 N 4 O 3 , was obtained as a side product during the synthesis of the previously reported antitubercular agent N-(2-fluoroethyl)-1-[(6-methoxy-5-methylpyrimidin-4-yl)methyl]-1H-benzo [d]imidazole-4-carboxamide and structurally characterized by X-ray crystallography and computational methods. In the crystal (space group P2 1 /n, Z = 4), the title compound adopts a twisted conformation with a dihedral angle between the benzimidazole and pyrimidine mean planes of 84.11 (3) . The carboxylate group and the 5-methyl group on the pyrimidine ring exhibit partial disorder. The DFT-optimized molecular structure resembles the structure of the minor component in the crystal.
The solid-state structure of 3 appears to be governed by close packing. The packing index calculated with PLATON (Spek, 2020) for the major disorder part is 73.8%, indicating a dense crystal packing (Kitaigorodskii, 1973). As shown in Fig. 4, face-to-facestacking each between the benzimidazole and pyrimidine systems of adjacent molecules is a dominating structural motif. It is interesting to note that, in contrast to DEVGEU, the benzimidazole C2-H2 group does not form short C-HÁ Á ÁX (X = N, O) contacts in the crystal structure of 3.

Synthesis and crystallization
We obtained compound 3 as a side product in the deliberate synthesis of its structural isomer 2, following the route   Structure overlay plot of the molecular structure of 3 in the crystal (green; displacement ellipsoids with 50% probability) and the DFT-optimized molecular structure (orange). The respective benzimidazole moieties were superimposed (r.m.s deviation for non-hydrogen atoms: 0.024 Å ).

Figure 4
Section of the crystal structure of 3. Colour scheme: carbon, grey; nitrogen, blue; oxygen, red. Hydrogen atoms and O2 0 are omitted for clarity.
published by Manjunatha et al. (2019). The isomers were separated by flash chromatography (Richter et al., 2022). Crystals of 3 suitable for X-ray crystallography were obtained as follows: Slow evaporation of a solution of the compound in chloroform-d to dryness yielded a powder, which was redissolved in methanol. The solution thus obtained was again set aside at room temperature, and the solvent was allowed to evaporate slowly. Colourless crystals appeared after the vessel had been left undisturbed for a couple of weeks.

Refinement
Crystal data, data collection and structure refinement details are listed in Table 1. Initial independent-atom model refinement was carried out with SHELXL2018 (Sheldrick, 2015b). The final structure refinement was carried out by Hirshfeld atom refinement with non-spherical atomic form factors factors using NoSpherA2 Midgley et al., 2021) (Becke, 1993;Lee et al., 1988) and a def2-TZVPP basis set (Weigend & Ahlrichs, 2005). The carbonyl oxygen atom (O2) and the methyl hydrogen atoms on C16 were found to be disordered over two positions in each case. Standard similar distance restraints were applied to the C8-O2 and C8-O2 0 distances as well as on the 1,2-and 1,3-distances of the disordered methyl hydrogen atoms. The ratio of occupancy was refined by means of a free variable for each disordered group to give 0.63 (4):0.37 (4) for the carbonyl oxygen atom and 0.646 (12):0.354 (12) for the hydrogen atoms of the methyl group. U iso values of hydrogen atoms were refined freely, except for those affected by disorder, for which U iso (H) = 1.5U eq (C) was set.
DFT structure optimization of an isolated molecule of 3 was undertaken using ORCA (version 5.0; Neese et al., 2020) with a B3LYP(G) (VWN1) hybrid functional (20% HF exchange) (Becke, 1993;Lee et al., 1988;Hertwig & Koch, 1997), using a def2-TZVPP basis set (Weigend & Ahlrichs, 2005) utilizing the auxiliary basis def2/J (Weigend, 2006). The input structure was generated from the major disorder component in the crystal structure. Optimization of the structures used the BFGS method from an initial Hessian according to Almoef's model with a very tight self-consistent field convergence threshold (Fletcher, 2000). The optimized local minimumenergy structure exhibited only positive frequencies.