Crystal structure and Hirshfeld surface analysis of (Z)-3-methyl-4-(thiophen-2-ylmethylidene)isoxazol-5(4H)-one

The title compound, C9H7NO2S, crystallizes with two independent molecules (A and B) in the asymmetric unit with Z = 4.In the molecular skeleton of title compound, the angle between mean planes of the two molecules A and B is 4.09 (1)°. The two molecules A and B are involved in intermolecular C—H⋯O and C—H⋯N hydrogen bonds.


Chemical context
Isoxazolones show some interesting biological properties. They are inhibitors of the factorization of tumor necrosis alpha (TNF-) (Laughlin et al., 2005) and antimicrobial (Mazimba et al., 2014). They are used for the treatment of cerebrovascular disorders and as muscle relaxants. They are also herbicides (Tomita et al., 1977) and fungicides (Miyake et al., 2012). On other hand, isoxazolone derivatives constitute excellent intermediates for the synthesis of various heterocycles such as pyridopyrimidines (Tu et al., 2006), quinolines (Abbiati et al., 2003) and undergo various chemical transformations (Batra & Bhaduri, 1994). Some cycloaddition reactions are also described and provide access to several types of polycycles (Badrey & Gomha, 2014). For these reasons, these compounds have been the subject of several investigations. The present method for their synthesis is a three-component polycondensation between an aromatic aldehyde, ethyl acetoacetate and hydroxylamine hydrochloride under different conditions and for our part we propose here the use of K 2 CO 3 , a food additive, tolerated in organic agriculture, very inexpensive, highly available and a safe catalyst, in an aqueous medium. In the present study, we report on the synthesis, molecular and crystal structure together with a Hirshfeld surface analysis of the title isoxazole derivative.

Structural commentary
The molecular structure of the title compound is shown in (Fig. 1). It crystallizes with two independent molecules (A and B) in the asymmetric unit. The molecular structure adopts a The bond lengths in the two molecules are practically equal, while there are slight differences in bond angles; with for example C2-C3-C4 (molecule A) and C11-C12-C13 (molecule B) differing by 0.8 (2) . Also, a slight difference of 0.3 (2) is observed between the angles C2-C5-C6 and C11-C14-C15. In molecule A, the angle between the normal of the molecular plane (O2A/N1A/C1A-C3A) and the normal of the (S1A/C6A-C9A) plane is 3.67 (2) . An important difference is observed in molecule B, where the angle between the normal of the molecular plane (O3B/N2B/C10B-C12B) and the normal of the (S2B/C15B-C18B) plane is 10.00 (1) . In the molecular skeleton, the angle between the mean planes of the molecules A and B is 4.09 (1) . Each of the two methyl groups, C4 and C13, has a C-H bond lying in the mean plane of the molecular skeleton, and they are oriented toward the thiophene group.

Figure 1
The molecular structure of the title compound, with atom labelling and displacement ellipsoids drawn at the 50% probability level.

Figure 3
Two views of the Hirshfeld surface mapped over d norm .
( McKinnon et al., 2007) were generated with CrystalExplorer (Turner et al., 2017). The analysis of Hirshfeld surface mapped over d norm is shown in (Fig. 3). The interactions between the corresponding donor and acceptor atoms are visualized as bright-red spots on both sides (zones 1, 2, 3 and 4) of the Hirshfeld surfaces (Fig. 3), corresponding to C17-H17Á Á ÁN2, C4-H4CÁ Á ÁN2, C16-H16Á Á ÁO2 and C18-H18Á Á ÁO4 hydrogen bonds, respectively. Two other red spots exist, corresponding to C4-H4AÁ Á ÁO interactions (Fig. 3, zone 5), are considered to be very weak interactions, comparing them to the van der Waals radii. The overall two-dimensional fingerprint plot of the structure and HÁ Á ÁS/SÁ Á ÁH, HÁ Á ÁH, HÁ Á ÁO/OÁ Á ÁH, HÁ Á ÁN/NÁ Á ÁH and CÁ Á ÁC contacts are illustrated in Fig. 4a-m). The HÁ Á ÁH contacts, accounting for about 35.4% of the Hirshfeld surface ( Fig. 4b) represent the largest contribution and are seen in the fingerprint plot as a pair of shorts pikes at d e + d i = 2.2 Å ; comparing this to van der Waals radius, we find the difference between them is about 1 Å , which means it is a very powerful interaction. HÁ Á ÁO/OÁ Á ÁH contacts (Fig. 4c) make a contribution of 28.7%, with a distinctive peak in the fingerprint plot at d e + d i = 2.4 Å ; the van der Waals radius sum for this interaction is about 2.7 Å . The pair of short peaks at d e + d i = 3.1, i.e. almost equal to the sum of the van der Waals radius, in the fingerprint plot delineated into HÁ Á ÁS/SÁ Á ÁH contacts are indicative of short interatomic contacts in the crystal (6% contribution, Fig. 4d). Although the HÁ Á ÁN /NÁ Á ÁH interactions have a notable contribution of 12% to the Hirshfeld surface ( Fig. 4e), their interatomic distances (d e + d i = 2.4 Å ) are less than their van der Waals radius (2.7 Å ), which means that it is a very strong interaction in this structure. The presence ofstacking reflects the presence of CÁ Á ÁC contacts (Fig. 4f), which account for 7.9% of the Hirshfeld surface with d e + d i = 3.4 Å ; the van der Waals radius is 3.4 Å , so we can confirm the presence ofstacking. Two further views of the Hirshfeld surface are shown in Fig   Two views of the Hirshfeld surface mapped over d norm , with interactions to neighbouring molecules shown as green dashed lines. The asymmetric unit of the title compound contains two crystallographically independent molecules, as found for ERIXIN and WOYPIL while in AJESAK, MBYIOZ01 and VIDSAF, there is only one molecule per asymmetric unit. The configuration about the C C bond is Z in all five compounds and in each molecule, the oxazol and thiophene rings are inclined to one another by 3.67 (2), 10.00 (1), 0.86 (9), 7.02 (8), 2.65 (16), 4.55 (15), 6.50 (1), 7.98 (8) and 3.18 (8) , respectively.

Database survey
In the crystal of WOYPIL, the individual molecules are linked via C-HÁ Á ÁO hydrogen bonds, forming ABAB chains along the [101] direction, similarly in the crystal of the title compound, the packing of molecules A and B is of an ABABÁ Á Á type along the [100] direction. In our compound, the cohesion of the crystal is ensured by interactions of the type C-HÁ Á ÁO, C-HÁ Á Á and -[intercentroid distances of 3.701 (2) and 3.766 (2) Å compared with 3.811 (2) and 3.889 (2) Å in ERIXIN and 3.767 (2) and 3.867 (2) Å in WOYPIL].

Synthesis and crystallization
Thiophene-2-carbaldehyde (C 5 H 4 OS, 1 mmol), hydroxylamine hydrochloride (ClH 4 NO, 1 mmol), ethyl acetoacetate (C 6 H 10 O 3 ,1 mmol) and K 2 CO 3 (5 mol%) were mixed in a 25 mL flask equipped with a magnetic stirrer. The mixture was refluxed in 5 mL of water for 3h (followed by TLC). When the reaction was judged to be finished, the mixture was gradually poured into ice-cold water. Stirring was maintained for a few minutes and the obtained solid was filtered and purified by crystallization from ethanol (yield 72%).

Refinement details
Crystal data, data collection and structure refinement details for the title compound are summarized in Table 2. H atoms were placed in calculated positions (C-H = 0.93-0.96 Å ) and refined as riding with U iso (H) = 1.2-1.5U eq (C).   (Macrae et al., 2020); software used to prepare material for publication: WinGX publication routines (Farrugia, 2012).

(Z)-3-Methyl-4-(thiophen-2-ylmethylidene)isoxazol-5(4H)-one
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.60 e Å −3 Δρ min = −0.54 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.