Synthesis, crystal structure and spectroscopic and Hirshfeld surface analysis of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde

The title molecule is planar with an r.m.s. deviation for all non-hydrogen atoms of 0.018 Å. An intramolecular O1—H1⋯O5 hydrogen bond involving the adjacent hydroxyl and nitro groups closes an S(6) ring motif.


Chemical context
The title compound is a key starting material in the preparation of entacapone (Srikanth et al., 2012;Mantegazza et al., 2008;Chinnapillai Rajendiran et al., 2007;Deshpande et al., 2010). Entacapone, (E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)propenamide (II), whose crystal structure has been reported by Leppä nen et al. (2001), is a selective and reversible catechol-O-methyltransferase inhibitor used in the treatment of Parkinson's disease in combination with levodopa and carbidopa (Najib, 2001;Pahwa & Lyons, 2009). Entacapone (II), prevents metabolism and inactivation of levodopa and carbidopa, which allows better bio-availability of these compounds. Several synthetic routes for the synthesis of entacapone have been reported (Bartra Sanmarti et al., 2008;Harisha et al., 2015;Jasti et al., 2005;Cziá ky, 2006); however, only a few intermediates/starting materials have been characterized crystallographically (Keng et al., 2011;Babu et al., 2009;Vladimirova et al., 2016). Knowledge of the crystal structure is beneficial for understanding the properties of the starting materials as well as being the gold standard for the identification of starting materials. Recently, we have synthesized and studied the influence of different entacaponerelated compounds on the crystallization of the final forms of entacapone. As part of this work, the title compound, 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (I), was synthesized and its spectroscopic and structural features were studied. There are two reasons for this study, one is connected with the utilization of crystal structures in the identification of mate-rials in the solid state, and the other is to build a library of structurally related compounds of entacapone that will be utilized in a future crystallization study.

Structural commentary
The molecular structure of the title compound I is illustrated in Fig. 1. The intramolecular O1-H1Á Á ÁO5 hydrogen bond (Table 1), involving the adjacent hydroxyl and nitro groups, forms an S(6) ring motif. The molecule is planar (r.m.s. deviation for all non-hydrogen atoms is 0.018 Å ) with the maximum deviation from the mean plane being 0.038 (1) Å for atom O5. The bonds lengths and bond angles are close to those found for similar structures (see x4. Database survey).

Figure 2
A partial view along the a axis of the crystal packing of compound I, illustrating the two different ring motifs. The hydrogen bonds (Table 1) are shown as dashed lines.

Hirshfeld surface analysis
Intermolecular interactions in the crystal of compound I were further investigated by the Hirshfeld surfaces. Calculations were performed using CrystalExplorer17 (Turner et al., 2017). The d norm values were mapped onto the Hirshfeld surface over the whole molecule (Fig. 5). Red areas represent contacts of the atoms shorter then the sum of the van der Waals radii, such as hydrogen bonds, or C OÁ Á Á contacts, whereas blue areas represent contacts between atoms longer then the sum of the van der Waals radii. White areas represent contacts equal to the sum of the van der Waals radii.
The two-dimensional fingerprint plots show intermolecular contacts and distances between atoms (Fig. 6). The most abundant contacts are between oxygen and hydrogen atoms,     comprising almost half of the Hirshfeld surface area (47.3%). This finding is not surprising having in mind the number of oxygen atoms located on the edges of the molecule with respect its size, each of them is involved in one or more hydrogen bonds. Also, because of the large number of oxygen atoms and C OÁ Á Á contacts, there is a high proportion of CÁ Á ÁO/OÁ Á ÁC contacts, which comprise 12.0% of the surface area. Since there is no stacking of the aromatic rings, only 3.9% of the surface derives from CÁ Á ÁC contacts.
Electrostatic potentials were calculated using TONTO with a 3-21G basis set at the Hartree-Fock level of theory and were mapped on the Hirshfeld surface (Fig. 7) in the energy range between À0.0923 and 0.1232 a.u.. The most positive region is around the hydroxyl hydrogen atom (Fig. 7a), while the most negative region is around the carbonyl oxygen atom (Fig. 7b). Those two atoms are involved in the shortest intermolecular hydrogen bond in the crystal structure (O1-H1Á Á ÁO3 i ), where O1Á Á ÁO3 i = 2.6989 (12) Å ; see Table 1.

Synthesis and crystallization
4-Hydroxy-3-methoxybenzaldehyde (20 g; 131.4 mmol) was dissolved in acetic acid (200 ml) and the solution was cooled to 283-288 K and 65% HNO 3 (10.5 ml) was added dropwise over 30 min. The reaction mixture was stirred for 30 min at 283-288 K and 30 min at 293-298 K. The suspension was then filtered and the crystals obtained were washed with water (3 Â 20 ml). The crystals were dried in a vacuum dryer (10 mbar, 313 K, 16 h) to obtain pure yellow compound I (yield 20.28 g; 78.3%). Yellow block-like crystals, suitable for X-ray diffraction analysis, were obtained by slow evaporation of a solution in acetone after 10 d at room temperature.
Spectroscopic analysis: The structure of compound I (Fig. 8) was confirmed by 1 H and 13 C NMR, recorded on a Bruker Avance DRX 500 at 500.1 MHz ( 1 H) and 125.8 MHz ( 13 C) in CD 3 OD ( Fig. 9a and 9b, respectively); see Tables 2 and 3 for further details.

Thermal analysis
The thermal stability of compound I was investigated in the solid state by differential scanning calorimetry (DSC) and by thermogravimetric analysis (TGA). Calculated electrostatic potentials over the Hirshfeld surface of compound I. Electrostatic potential was mapped in the energy range À0.0923 to 0.1232 a.u.. The blue area around the hydroxyl oxygen atom in (a) represents the most positive part, while the red area around the carbonyl oxygen atom in (b) represents the most negative part of the molecule.

Figure 8
Structure of compound I in relation to the NMR data in Tables 2 and 3.

Table 2
Chemical shifts of protons (DMSO-d 6 ) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (I).  performed on a TA Instruments Discovery DSC in a closed aluminium pan (40 mL) under nitrogen flow (50 ml min À1 ) and a heating rate of 10 C min À1 in the temperature range 25-300 C (Fig. 10). Thermogravimetric analysis was performed on a TA Instruments Discovery TG in a closed aluminium pan (40 mL) under nitrogen flow (50 ml min À1 ) and a heating rate of 10 C min À1 in the temperature range 25-300 C (Fig. 11). DSC analysis shows one endotherm at about 176 C that corresponds to the melting point of the title compound. Thermogravimetric analysis does not show any weight loss during heating up to 140 C where a change in mass can be observed that can be attributed to the thermal decomposition of the sample.

IR spectroscopy
The IR spectrum (Fig. 12)   DSC curve of compound I.

Figure 11
TG curve of compound I.

Refinement details
Crystal data, data collection and structure refinement details are summarized in Table 4. Hydrogen atoms were located in a difference-Fourier map and refined as riding on their parent atom: O-H = 0.82 Å , C-H = 0.93-0.96 Å , with U iso (H) = 1.5U eq (O) and 1.2U eq (C) for other H atoms.

Funding information
VV and EM acknowledge PLIVA for financial support.