research communications Acta Cryst. (2020). E76, 239–244 https://doi.org/10.1107/S2056989020000225 239 Received 17 December 2019 Accepted 9 January 2020 Edited by H. Stoeckli-Evans, University of Neucha ˆtel, Switzerland ‡ Current address: Xellia Ltd, Slavonska avenija 24/6, HR-10000 Zagreb, Croatia. Keywords: crystal structure; entacapone; hydrogen bonding; Hirshfeld surface analysis. CCDC reference: 1957893 Supporting information: this article has supporting information at journals.iucr.org/e 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 ‡ a PLIVA Croatia Ltd., Prilaz baruna Filipovic ´a 29, HR-10000 Zagreb, Croatia, b Department of Chemistry, Faculty of Science, University of Zagreb, Horvatovac, 102a, HR-10000 Zagreb, Croatia, and c Department of Physical Chemistry, Ru¤er Bos ˇkovic ´ Institute, Bijenic ˇka cesta 54, HR-10000 Zagreb, Croatia. *Correspondence e-mail: [email protected]The title compound, C 8 H 7 NO 5 , is planar with an r.m.s. deviation for all non- hydrogen atoms of 0.018 A ˚ . An intramolecular O—HO hydrogen bond involving the adjacent hydroxy and nitro groups forms an S(6) ring motif. In the crystal, molecules are linked by O—HO hydrogen bonds, forming chains propagating along the b-axis direction. The chains are linked by C—HO hydrogen bonds, forming layers parallel to the bc plane. The layers are linked by a further C—HO hydrogen bond, forming slabs, which are linked by C Ointeractions, 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. 1. Chemical context The title compound is a key starting material in the prepara- tion 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-dihy- droxy-5-nitrophenyl)propenamide (II), whose crystal struc- ture has been reported by Leppa ¨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; Czia ´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 entacapone- related compounds on the crystallization of the final forms of entacapone. As part of this work, the title compound, 4-hy- droxy-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- ISSN 2056-9890
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Synthesis, crystal structure and spectroscopic and …Synthesis, crystal structure and spectroscopic and Hirshfeld surface analysis of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde Vitomir
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Figure 1The molecular structure of compound I, with atom labelling. Displace-ment ellipsoids are drawn at the 50% probability level. The intra-molecular O1—H1� � �O5 hydrogen bond is shown as a dashed line(Table 1).
Figure 2A 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 3A view along the c axis of the crystal packing of compound I. Thehydrogen bonds (Table 1) are shown as dashed lines. For clarity, only theH atoms involved in hydrogen bonding have been included.
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; Vladi-
mirova 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-
Figure 5A view of the Hirshfeld surface of compound I, mapped over dnorm in thecolour range�0.448 to 1.186 a.u.. Red areas show intermolecular contactsshorter than the sum of the van der Waals radii of the atoms. The shortestintermolecular O—H� � �O hydrogen bond is also shown.
Figure 7Calculated electrostatic potentials over the Hirshfeld surface ofcompound 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 thecarbonyl oxygen atom in (b) represents the most negative part of themolecule.
Figure 8Structure of compound I in relation to the NMR data in Tables 2 and 3.
Table 2Chemical shifts of protons (DMSO-d6) of 4-hydroxy-3-methoxy-5-nitro-benzaldehyde (I).
Chemical shift (�, p.p.m.) Multiplicity Number of protons Assignment
3.962 s 3 H97.622–7.626 d 1 H38.095–8.098 d 1 H59.867 s 1 H10
Table 3Chemical shifts of carbons (DMSO-d6) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (I).
Chemical shift (�, p.p.m.) Number of carbons Assignment
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 A, C—H = 0.93-0.96 A, with Uiso(H) =
1.5Ueq(O) and 1.2Ueq(C) for other H atoms.
Funding information
VV and EM acknowledge PLIVA for financial support.
References
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Primary atom site location: structure-invariant direct methods
Secondary atom site location: difference Fourier map
Hydrogen site location: inferred from neighbouring sites
H-atom parameters constrained
supporting information
sup-2Acta Cryst. (2020). E76, 239-244
w = 1/[σ2(Fo2) + (0.2P)2]
where P = (Fo2 + 2Fc
2)/3(Δ/σ)max = 0.001
Δρmax = 0.27 e Å−3
Δρmin = −0.16 e Å−3
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 (Å2)