Synthesis and crystallographic characterization of 6-hydroxy-1,2-dihydropyridin-2-one

The synthesis of the title compound as a formic acid salt, rather than the standard hydrochloride salt that is commercially available, and its spectroscopic and crystallographic characterization are described.


Chemical context
6-Hydroxy-1,2-dihydropyridin-2-one, more commonly known as 2,6-dihydroxypyridine (2,6-DHP), is a derivative of nicotinic acid, a common compound found within personal care products (Behrman & Stanier, 1957;Hicks et al., 2016;Nakamoto et al., 2019).Recent work has focused on the bacterial hydrolysis of nicotinic acid for use in bioremediation efforts (Bokor et al., 2022).Synthesis of 2,6-DHP can be accomplished by reaction between 2,6-dichloropyridine and potassium tert-butoxide to afford 2,6-di-tert-butoxypyridine (1) followed by reaction with formic acid to produce the product 2 as the pyridone tautomer (Scheme 1; Kocienski, 1994).The identification of 2 was confirmed by 1 H, 13 C and IR spectroscopy.The 1 H NMR spectrum suggested a nonsymmetric pyridone molecule with an N-H proton at � = 11.47 ppm.The aromatic region of the spectrum suggested that each of the three protons on the aromatic backbone of 2 were in different chemical environments highlighted by their different chemical shifts of � = 7.66, 6.91 and 6.60 ppm.These shifts, along with their splitting patterns and coupling constants, are consistent with the structure of 2. IR spectroscopic data of 2 were also consistent with the overall structure of a pyridone tautomer.Crystals of 2 were grown from slow evaporation of a saturated methanol solution.The solid-state structure of 2 was consistent with the solution state as the title molecule crystallized as the keto tautomer.

Structural commentary
The structure of 2,6-dihydroxypyridine (Fig. 1) shows the expected 2,6-disubstitution of the pyridine ring.The bond lengths and angles are routine for nitrogen-containing aromatic compounds (Table 1).

Supramolecular features
There are six independent molecules in the asymmetric unit of 2; of these, two pairs of molecules are each held together by O-H� � �O hydrogen bonds.In both instances, the H atoms in the hydrogen bonds are disordered over two positions with refined occupancies of 0.51 (3) and 0.49 (3) at the O6 and O7 sites, respectively, and 0.39 (3) and 0.61 (3) at the O2 and O3 sites, respectively.The molecules pack together in the solid state with intermolecular O-H� � �O and N-H� � �O interactions (Table 2 and Fig. 2).The crystal packing of the title compound involves no �-� ring interactions (Fig. 3).

Hirshfeld surface analysis
The Hirshfeld surface analysis of 2 was performed and the associated two-dimensional fingerprint plots were generated using Crystal Explorer 21.5 software (Spackman et al., 2021).Visualizations used a red-white-blue color scheme where red indicates shorter contacts, while blue indicates longer contacts.There are four red spots on the d norm surface (Fig. 4a) and these spots indicate the direction and strength of the inter- Figure 2 A view of the intermolecular interactions in 2.
Figure 3 A view of the molecular packing in 2.

Database survey
A search for the pyridone tautomers of relatively simple dihydroxy-substituted pyridines in the Cambridge Structure Database (CSD version 5.44, last update April 2023; Groom et al., 2016) revealed 23 crystal structures.Nearly all these structures have N-H� � �O and O-H� � �O hydrogen-bonding motifs, similar to those observed in the title compound.The structures with dissimilar motifs involve intermolecular interactions with solvent molecules or intramolecular hydrogen bonding.The closest analogues to 2 were found to be GUBKIZ and NOQGOR (Gerhardt & Bolte, 2015); these structures contain N-H� � �O and O-H� � �O(solvent) hydrogen-bonding motifs.

Synthesis and crystallization
1: A 100 mL round-bottom flask equipped with a stir bar was charged with 2,6-dichloropyridine (1.00 g, 6.80 mmol, 1 eq) and 15 mL of mesitylene solvent.To the solution was added potassium tert-butoxide (1.52 g, 13.6 mmol, 2.1 eq).The solution was then refluxed under N 2 for 18 h.A color change from colorless to deep red was observed.After 18 h, the solution was allowed to cool to room temperature and the solution was washed with water (3 � 20 mL).The organic layer was collected, dried over sodium sulfate and used without purification in step 2.
Crystals suitable for X-ray analysis were grown from slow evaporation of a saturated methanol solution.The melting point of 2,6-DHP was measured at 460-465 K.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3.All non-hydrogen atoms were refined anisotropically.Hydrogen atoms bonded to carbon were included in calculated positions and refined using a riding model.Hydrogen atoms bound to N and O were located in the difference-Fourier map, and refined semi-freely with the help of distance restraints.

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.

Figure 1 A
Figure 1A view of 2 showing the atom-numbering scheme for one independent molecule.Displacement ellipsoids are drawn at the 50% probability level.

Figure 4 (
Figure 4 (a) Hirshfeld surface representations of 2 with the function d norm plotted onto the surface indicating the E-H� � �O (E = N, O) interactions; (b) two-dimensional fingerprint plot.

Table 3
Experimental details.