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

Vusak, V.; Vusak, D.; Molcanov, K.; Ernest, M.

doi:10.1107/S2056989020000225

research communications

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ISSN: 2056-9890

Volume 76| Part 2| February 2020| Pages 239-244

https://doi.org/10.1107/S2056989020000225

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

Vitomir Vusak,^a ^* Darko Vusak,^b Kresimir Molcanov ^c and Mestrovic Ernest ^a ‡

^aPLIVA Croatia Ltd., Prilaz baruna Filipovića 29, HR-10000 Zagreb, Croatia, ^bDepartment of Chemistry, Faculty of Science, University of Zagreb, Horvatovac, 102a, HR-10000 Zagreb, Croatia, and ^cDepartment of Physical Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia
^*Correspondence e-mail: vitomir.vusak@pliva.com

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 17 December 2019; accepted 9 January 2020; online 21 January 2020)

The title compound, C₈H₇NO₅, is planar with an r.m.s. deviation for all non-hydrogen atoms of 0.018 Å. An intramolecular O—H⋯O hydrogen bond involving the adjacent hydroxy and nitro groups forms an S(6) ring motif. In the crystal, molecules are linked by O—H⋯O hydrogen bonds, forming chains propagating along the b-axis direction. The chains are linked by C—H⋯O hydrogen bonds, forming layers parallel to the bc plane. The layers are linked by a further C—H⋯O hydrogen bond, forming slabs, which are linked by C=O⋯π interactions, forming a three-dimensional supramolecular structure. Hirshfeld surface analysis was used to investigate intermolecular interactions in the solid state. The molecule was also characterized spectroscopically and its thermal stability investigated by differential scanning calorimetry and by thermogravimetric analysis.

Keywords: crystal structure; entacapone; hydrogen bonding; Hirshfeld surface analysis.

CCDC reference: 1957893

1. 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 Leppänen 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 ; Cziáky, 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 entacapone-related 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 materials 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.

2. Structural commentary

The molecular structure of the title compound I is illustrated in Fig. 1. The intramolecular O1—H1⋯O5 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 §4. Database survey).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
O1—H1⋯O3ⁱ	0.82	2.12	2.6989 (12)	128
O1—H1⋯O5	0.82	1.94	2.6247 (14)	140
C7—H7⋯O4ⁱⁱ	0.93	2.50	3.4018 (16)	163
C8—H8A⋯O3ⁱⁱⁱ	0.96	2.60	3.4733 (18)	152
C8—H8B⋯O4^iv	0.96	2.58	3.476 (2)	156
Symmetry codes: (i) x, y, z-1; (ii) $[x, -y+{\script{3\over 2}}, z+{\script{1\over 2}}]$ ; (iii) $[x, -y+{\script{1\over 2}}, z-{\script{1\over 2}}]$ ; (iv) $[-x+1, y-{\script{1\over 2}}, -z+{\script{5\over 2}}]$ .

Figure 1
The molecular structure of compound I, with atom labelling. Displacement ellipsoids are drawn at the 50% probability level. The intramolecular O1—H1⋯O5 hydrogen bond is shown as a dashed line (Table 1

3. Supramolecular features

In the crystal of compound I, molecules are linked by intermolecular bifurcated hydrogen bonds involving the hydroxyl group. Details of the hydrogen bonding together with the symmetry codes are given in Table 1. The O1—H1⋯O3ⁱ_aldehyde hydrogen bonds [2.6989 (12) Å] link the molecules into chains with a C(8) motif. Each oxygen atom is involved in one or more intermolecular hydrogen bonds, except for the O5_nitro atom, which is involved only in the intramolecular hydrogen bond. Each molecule is connected by six adjacent molecules through strong O1—H1⋯O3_aldehyde and weak C7—H7⋯O4ⁱⁱ_nitro and C8—H8A⋯O3ⁱⁱⁱ_aldehyde hydrogen bonds, forming undulating layers parallel to the bc plane, enclosing two type of ring motifs – R₃²(16) and R₃³(16) (Fig. 2). The layers are linked by a further C—H⋯O hydrogen bond, C8—H8B⋯O4^iv_nitro, forming slabs (Fig. 3). Moreover, C7=O3⋯π [oxygen–centroid distance = 3.4028 (12) Å] and C2—O1⋯π [3.353 (su?) Å] close contacts (Fig. 4) are present, linking the slabs to form a three-dimensional supramolecular structure.

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.

Figure 3
A view along the c axis of the crystal packing of compound I. The hydrogen bonds (Table 1

) are shown as dashed lines. For clarity, only the H atoms involved in hydrogen bonding have been included.

Figure 4
Short C—O_hydroxy⋯π and C=O_aldehyde⋯π contacts.

4. Database survey

A search of the Cambridge Structural Database (CSD, Version V5.41, last update November 2019; Groom et al., 2016 ), for crystal structures containing a nitro group on the benzene ring, oxygen atoms bonded on carbon position 2 and 3, and the –C=O group located on position 5, gave three hits, out of which only one entry contained the title molecule, viz. a tin complex of the 4-hydroxy-3-methoxy-5-nitrobenzaldehyde with a deprotonated hydroxyl group and benzyl anions (CSD refcode EREWII; Keng et al., 2011). The other two entries do not contain an aldehyde group, but a methylketo (MUCDOE; Babu et al., 2009) and carboxylic group (TAFSAX; Vladimirova et al., 2016) instead.

A second search of the CSD for a nitro group on a benzene ring, OH groups on carbon atoms 2 and 3, and a carbon atom on position 5 gave eight hits for seven structures. These include the structure of entacapone II (OFAZUQ; Leppanen et al., 2001), and four of its acyl esters, viz. (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione monohydrate (XIPNOC; Bommaka et al., 2018 ), (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide pyridine-4-carboxamide (XIPNUI; Bommaka et al., 2018), (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide pyrazine-2-carboxamide (XIPPAQ; Bommaka et al., 2018), and (E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethylprop-2-enamide acetamide (XIPPEU; Bommaka et al., 2018). These four compounds were prepared by solvent-assisted grinding, and the study was aimed at improving the aqueous solubility, diffusion permeability, and co-crystal stability of entacapone.

5. 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=O⋯π 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.

Figure 5
A view of the Hirshfeld surface of compound I, mapped over d_norm in the colour range −0.448 to 1.186 a.u.. Red areas show intermolecular contacts shorter than the sum of the van der Waals radii of the atoms. The shortest intermolecular O—H⋯O hydrogen bond is also shown.

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=O⋯π contacts, there is a high proportion of C⋯O/O⋯C 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 C⋯C contacts.

Figure 6
(a) Two-dimensional fingerprint plot for compound I, and the fingerprint plots delineated into (b) H⋯O/O⋯H (47.3%), (c) H⋯H (19.8%), (d) C⋯O/O⋯C (12.0%), (e) C⋯H/H⋯C (8.5%), (f) O⋯O (4.6%), (g) C⋯C (3.9%), (h) N⋯O/O⋯N (3.1%), (i) H⋯N/N⋯H (0.6%).

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 −0.0923 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—H1⋯O3ⁱ), where O1⋯O3ⁱ = 2.6989 (12) Å; see Table 1.

Figure 7
Calculated electrostatic potentials over the Hirshfeld surface of compound I. Electrostatic potential was mapped in the energy range −0.0923 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.

6. 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% HNO₃ (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 × 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 ¹H and ¹³C NMR, recorded on a Bruker Avance DRX 500 at 500.1 MHz (¹H) and 125.8 MHz (¹³C) in CD₃OD (Fig. 9a and 9b, respectively); see Tables 2 and 3 for further details.

Table 2
Chemical shifts of protons (DMSO-d₆) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (I)

Chemical shift (δ, p.p.m.)	Multiplicity	Number of protons	Assignment
3.962	s	3	H9
7.622–7.626	d	1	H3
8.095–8.098	d	1	H5
9.867	s	1	H10

Table 3
Chemical shifts of carbons (DMSO-d₆) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (I)

Chemical shift (δ, p.p.m.)	Number of carbons	Assignment
56.78	1	C9
112.52	1	C3
120.87	1	C5
126.81	1	C4
137.04	1	C6
147.73	1	C1
150.03	1	C2
190.42	1	C10

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

and 3

Figure 9
¹H NMR spectra of compound I (CD₃OD); (b) ¹³C NMR spectra of compound I (CD₃OD)

7. Thermal analysis

The thermal stability of compound I was investigated in the solid state by differential scanning calorimetry (DSC) and by thermogravimetric analysis (TGA). DSC analysis was performed on a TA Instruments Discovery DSC in a closed aluminium pan (40 µL) under nitrogen flow (50 ml min⁻¹) and a heating rate of 10°C min⁻¹ 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 µL) under nitrogen flow (50 ml min⁻¹) and a heating rate of 10°C min⁻¹ 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.

Figure 10
DSC curve of compound I.

Figure 11
TG curve of compound I.

8. IR spectroscopy

The IR spectrum (Fig. 12) of compound I was recorded on a Thermo Scientific Nicolet instrument by ATR (attenuated total reflectance) technique. It shows a broad band at about 3200 cm⁻¹, which corresponds to the O—H stretching vibrations. Strong stretching vibrations of C=O (aldehyde) and C—O (aromatic ether) appear at 1683 and 1266 cm⁻¹, respectively. Bands corresponding to N—O asymmetric and symmetric stretching modes can be found at 1547 and 1366 cm⁻¹, respectively. Characteristic weak overtones of the aromatic ring can be seen at 1800–1700 cm⁻¹.

Figure 12
IR spectra (ATR) of compound I.

9. 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.

Table 4
Experimental details

Crystal data
Chemical formula	C₈H₇NO₅
M_r	197.15
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	293
a, b, c (Å)	6.8249 (2), 14.3395 (5), 8.9089 (3)
β (°)	106.678 (4)
V (Å³)	835.21 (5)
Z	4
Radiation type	Cu Kα
μ (mm⁻¹)	1.16
Crystal size (mm)	0.30 × 0.15 × 0.13

Data collection
Diffractometer	Rigaku Xcalibur Ruby Nova
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2018 $[Rigaku OD, (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Rigaku Corporation, Oxford, England.]$ )
T_min, T_max	0.647, 1
No. of measured, independent and observed [I > 2σ(I)] reflections	3633, 1697, 1574
R_int	0.016
(sin θ/λ)_max (Å⁻¹)	0.629

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.040, 0.174, 0.81
No. of reflections	1697
No. of parameters	127
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.27, −0.17
Computer programs: CrysAlis PRO (Rigaku OD, 2018 $[Rigaku OD, (2018). CrysAlis PRO. Rigaku Oxford Diffraction, Rigaku Corporation, Oxford, England.]$ ), SHELXS97 (Sheldrick, 2008 ), Mercury (Macrae et al., 2008 ), SHELXL2017 (Sheldrick, 2015 ), PLATON (Spek, 2020 ) and publCIF (Westrip, 2010 ).

Supporting information

CCDC reference: 1957893

Crystal structure: contains datablocks global, I. DOI: https://doi.org/10.1107/S2056989020000225/su5534sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989020000225/su5534Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989020000225/su5534Isup3.cml

checkCIF report

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2018); cell refinement: CrysAlis PRO (Rigaku OD, 2018); data reduction: CrysAlis PRO (Rigaku OD, 2018); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2017 (Sheldrick, 2015); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2017 (Sheldrick, 2015), PLATON (Spek, 2020) and publCIF (Westrip, 2010).

4-Hydroxy-3-methoxy-5-nitrobenzaldehyde top

Crystal data top

C₈H₇NO₅	F(000) = 408
M_r = 197.15	D_x = 1.568 Mg m⁻³
Monoclinic, P2₁/c	Cu Kα radiation, λ = 1.54184 Å
Hall symbol: -P 2ybc	Cell parameters from 2167 reflections
a = 6.8249 (2) Å	θ = 3.2–75.6°
b = 14.3395 (5) Å	µ = 1.16 mm⁻¹
c = 8.9089 (3) Å	T = 293 K
β = 106.678 (4)°	Block, yellow
V = 835.21 (5) Å³	0.30 × 0.15 × 0.13 mm
Z = 4

Data collection top

Rigaku Xcalibur Ruby Nova diffractometer	1697 independent reflections
Radiation source: micro-focus sealed X-ray tube	1574 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.016
Detector resolution: 10.4323 pixels mm^-1	θ_max = 76.0°, θ_min = 6.8°
ω scans	h = −8→8
Absorption correction: multi-scan (CrysAlis PRO; Rigaku OD, 2018)	k = −16→17
T_min = 0.647, T_max = 1	l = −7→11
3633 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.040	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.174	H-atom parameters constrained
S = 0.81	w = 1/[σ²(F_o²) + (0.2P)²] where P = (F_o² + 2F_c²)/3
1697 reflections	(Δ/σ)_max = 0.001
127 parameters	Δρ_max = 0.27 e Å⁻³
0 restraints	Δρ_min = −0.16 e Å⁻³

Special details top

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 (Å²) top

	x	y	z	U_iso*/U_eq
O1	0.24420 (14)	0.44411 (6)	0.92251 (10)	0.0442 (3)
H1	0.258885	0.488242	0.868197	0.066*
O2	0.19059 (16)	0.31818 (6)	1.10856 (11)	0.0506 (3)
O3	0.23301 (16)	0.48763 (7)	1.62543 (10)	0.0508 (3)
O4	0.3265 (2)	0.72037 (7)	1.06656 (14)	0.0655 (4)
O5	0.29317 (17)	0.62262 (8)	0.87895 (11)	0.0547 (3)
N1	0.30056 (15)	0.64166 (7)	1.01585 (12)	0.0422 (3)
C1	0.27609 (15)	0.56669 (8)	1.11855 (13)	0.0353 (3)
C2	0.24838 (14)	0.47461 (7)	1.06403 (13)	0.0347 (3)
C3	0.22165 (16)	0.40479 (8)	1.17059 (14)	0.0375 (3)
C4	0.22427 (16)	0.42865 (8)	1.32044 (13)	0.0386 (3)
H4	0.206582	0.382706	1.389078	0.046*
C5	0.25347 (16)	0.52194 (8)	1.37123 (13)	0.0377 (3)
C6	0.27967 (15)	0.59084 (8)	1.27155 (13)	0.0376 (3)
H6	0.299441	0.652439	1.305155	0.045*
C7	0.25478 (19)	0.54494 (9)	1.53231 (14)	0.0424 (3)
H7	0.273358	0.60689	1.564115	0.051*
C8	0.1668 (2)	0.24460 (10)	1.21046 (17)	0.0577 (4)
H8A	0.145807	0.186668	1.154094	0.086*
H8B	0.287788	0.240337	1.297763	0.086*
H8C	0.05098	0.257453	1.247879	0.086*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
O1	0.0671 (5)	0.0406 (5)	0.0279 (5)	−0.0002 (3)	0.0184 (4)	−0.0015 (3)
O2	0.0823 (6)	0.0336 (5)	0.0392 (6)	−0.0058 (4)	0.0229 (5)	−0.0032 (3)
O3	0.0749 (6)	0.0513 (6)	0.0302 (5)	−0.0034 (4)	0.0214 (4)	−0.0005 (3)
O4	0.1106 (9)	0.0351 (6)	0.0529 (7)	−0.0071 (5)	0.0268 (6)	0.0028 (4)
O5	0.0838 (7)	0.0512 (6)	0.0326 (6)	−0.0033 (4)	0.0223 (5)	0.0063 (4)
N1	0.0540 (5)	0.0378 (6)	0.0353 (6)	−0.0005 (4)	0.0135 (4)	0.0052 (4)
C1	0.0423 (5)	0.0336 (6)	0.0304 (6)	0.0017 (4)	0.0112 (4)	0.0029 (4)
C2	0.0415 (5)	0.0366 (6)	0.0274 (6)	0.0017 (4)	0.0120 (4)	0.0014 (4)
C3	0.0481 (5)	0.0335 (7)	0.0318 (6)	−0.0002 (4)	0.0126 (4)	0.0002 (4)
C4	0.0517 (6)	0.0353 (6)	0.0316 (6)	−0.0014 (4)	0.0163 (5)	0.0022 (4)
C5	0.0453 (6)	0.0396 (7)	0.0296 (6)	0.0012 (4)	0.0131 (4)	−0.0015 (4)
C6	0.0469 (6)	0.0340 (6)	0.0325 (7)	0.0010 (4)	0.0124 (5)	−0.0017 (4)
C7	0.0575 (6)	0.0407 (7)	0.0312 (6)	0.0001 (4)	0.0162 (5)	−0.0024 (4)
C8	0.0881 (9)	0.0352 (7)	0.0513 (8)	−0.0040 (6)	0.0225 (7)	0.0040 (5)

Geometric parameters (Å, º) top

O1—C2	1.3271 (14)	C3—C4	1.3733 (16)
O1—H1	0.82	C4—C5	1.4080 (17)
O2—C3	1.3510 (15)	C4—H4	0.93
O2—C8	1.4310 (15)	C5—C6	1.3740 (15)
O3—C7	1.2068 (16)	C5—C7	1.4700 (16)
O4—N1	1.2097 (15)	C6—H6	0.93
O5—N1	1.2367 (15)	C7—H7	0.93
N1—C1	1.4520 (15)	C8—H8A	0.96
C1—C6	1.3998 (15)	C8—H8B	0.96
C1—C2	1.4008 (17)	C8—H8C	0.96
C2—C3	1.4270 (15)

C2—O1—H1	109.5	C5—C4—H4	119.7
C3—O2—C8	116.83 (9)	C6—C5—C4	120.54 (10)
O4—N1—O5	122.31 (11)	C6—C5—C7	120.27 (11)
O4—N1—C1	119.11 (11)	C4—C5—C7	119.18 (11)
O5—N1—C1	118.58 (10)	C5—C6—C1	118.84 (11)
C6—C1—C2	122.25 (11)	C5—C6—H6	120.6
C6—C1—N1	117.22 (11)	C1—C6—H6	120.6
C2—C1—N1	120.52 (10)	O3—C7—C5	123.43 (12)
O1—C2—C1	127.16 (10)	O3—C7—H7	118.3
O1—C2—C3	115.39 (10)	C5—C7—H7	118.3
C1—C2—C3	117.46 (10)	O2—C8—H8A	109.5
O2—C3—C4	125.69 (11)	O2—C8—H8B	109.5
O2—C3—C2	114.08 (10)	H8A—C8—H8B	109.5
C4—C3—C2	120.22 (11)	O2—C8—H8C	109.5
C3—C4—C5	120.69 (11)	H8A—C8—H8C	109.5
C3—C4—H4	119.7	H8B—C8—H8C	109.5

O4—N1—C1—C6	1.36 (17)	O1—C2—C3—C4	179.72 (9)
O5—N1—C1—C6	−178.32 (10)	C1—C2—C3—C4	−0.22 (16)
O4—N1—C1—C2	−179.20 (11)	O2—C3—C4—C5	−178.50 (10)
O5—N1—C1—C2	1.12 (16)	C2—C3—C4—C5	−0.07 (17)
C6—C1—C2—O1	−179.40 (10)	C3—C4—C5—C6	0.07 (17)
N1—C1—C2—O1	1.19 (17)	C3—C4—C5—C7	179.82 (10)
C6—C1—C2—C3	0.52 (16)	C4—C5—C6—C1	0.22 (16)
N1—C1—C2—C3	−178.89 (8)	C7—C5—C6—C1	−179.52 (10)
C8—O2—C3—C4	−2.73 (18)	C2—C1—C6—C5	−0.53 (16)
C8—O2—C3—C2	178.76 (10)	N1—C1—C6—C5	178.90 (8)
O1—C2—C3—O2	−1.68 (14)	C6—C5—C7—O3	−179.85 (11)
C1—C2—C3—O2	178.39 (9)	C4—C5—C7—O3	0.40 (19)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
O1—H1···O3ⁱ	0.82	2.12	2.6989 (12)	128
O1—H1···O5	0.82	1.94	2.6247 (14)	140
C7—H7···O4ⁱⁱ	0.93	2.50	3.4018 (16)	163
C8—H8A···O3ⁱⁱⁱ	0.96	2.60	3.4733 (18)	152
C8—H8B···O4^iv	0.96	2.58	3.476 (2)	156

Symmetry codes: (i) x, y, z−1; (ii) x, −y+3/2, z+1/2; (iii) x, −y+1/2, z−1/2; (iv) −x+1, y−1/2, −z+5/2.

Chemical shifts of protons (DMSO-d₆) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (I) top

Chemical shift (δ, ppm)	Multiplicity	Number of protons	Assignment
3.962	s	3	H9
7.622–7.626	d	1	H3
8.095–8.098	d	1	H5
9.867	s	1	H10

Chemical shifts of carbons (DMSO-d₆) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (I) top

Chemical shift (δ, ppm)	Number of carbons	Assignment
56.78	1	C9
112.52	1	C3
120.87	1	C5
126.81	1	C4
137.04	1	C6
147.73	1	C1
150.03	1	C2
190.42	1	C10

Footnotes

‡Current address: Xellia Ltd, Slavonska avenija 24/6, HR-10000 Zagreb, Croatia.

Funding information

VV and EM acknowledge PLIVA for financial support.

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