Crystal structure and Hirshfeld surface analysis of (Z)-4-(4-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one

In the crystal of the title compound, molecules stack head-to-tail in columns along the b-axis direction, and are linked by offset π–π interactions [intercentroid distances of 3.676 (1) and 3.723 (1) Å].


Chemical context
The isoxazole ring system is a component of many natural and medicinally active molecules that exhibit interesting biological activities (Wang et al., 2012). Isoxazole derivatives have been shown to possess anticonvulsant (Balalaie et al., 2000), antifungal (Santos et al., 2010), HDAC inhibitory (Conti et al., 2010), analgesic (Kano et al., 1967), antimicrobial (Padmaja et al., 2009), antituberculosis (Lee et al., 2009), antimycobacterial (Mao et al., 2010) and many other biological properties. They are also used for the treatment of leishmaniasis (Changtam et al., 2010) and for the treatment of patients with active arthritis (Suryawanshi et al., 2012). Furthermore, the isoxazole unit can be used as the basis for the design and construction of merocyanine dyes, which are used in optical recording and non-linear optical research (Zhang et al., 2011). In the present study, we report on the synthesis, crystal structure and Hirshfeld surface analysis of the title isoxazole derivative.

Structural commentary
The molecular structure of the title compound is shown in Fig. 1. The molecule is composed of an isoxazole ring (O1/N1/ ISSN 2056-9890 C1-C3) that is almost coplanar with the benzene ring (C6-C11) of the 4-hydroxybenzylidene substituent; the two rings are inclined to each other by 3.18 (8) . The configuration about the C2 C5 bond is Z, and within the molecule there is a short intramolecular C11-H11Á Á ÁO2 contact (Table 1), forming an S(7) ring motif. The bond lengths and bond angles agree well with those observed for a similar compound, the 2-hydroxybenzylidene analogue, (Z)-4-(2-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (Cheng et al., 2009). Here the hydroxyl group is in the ortho position, compared to the para position in the title compound.

Figure 2
A view along the b axis of the crystal packing of the title compound. Only the H atoms (grey balls) involved in hydrogen bonding (see Table 1) have been included.

Figure 3
A view of the Hirshfeld surface mapped over d norm , with neighbouring interactions shown as green dashed lines.

Figure 1
The molecular structure of the title compound, with atom labelling and displacement ellipsoids drawn at the 50% probability level. The intramolecular C-HÁ Á ÁO contact (see Table 1) is shown as a dashed line.
The analysis of the Hirshfeld surface mapped over d norm is shown in Fig. 3. The O3-H3Á Á ÁO1 i and O3-H3Á Á ÁN1 i interactions between the corresponding donor and acceptor atoms are visualized as bright-red spots on both sides (zones 1 and 2) of the Hirshfeld surfaces ( Fig. 4). Two other red spots exist, corresponding to the C5-H5Á Á ÁO2 ii and C7-H7Á Á ÁO ii interactions ( Fig. 4, zones 3 and 4); these are considered to be weak interactions by comparing them to the sum of the van der Waals radii. The donors and acceptors of intermolecular hydrogen bonds appear as blue and red regions, respectively, around the participating atoms on the Hirshfeld surface mapped over the calculated electrostatic potential (Fig. 5).
The overall two-dimensional fingerprint plot is illustrated in Fig. 6a, and the HÁ Á ÁO/OÁ Á ÁH, HÁ Á ÁH, CÁ Á ÁH/HÁ Á ÁC, and NÁ Á ÁH/HÁ Á ÁN contacts are illustrated in Fig. 6b-f, respectively. The HÁ Á ÁO/OÁ Á ÁH contacts (Fig. 6b) account for 33.9% of the Hirshfeld surface, representing the largest contribution and is displayed on the fingerprint plots by a pair of short spikes at d e + d i = 2.3 Å . This distance is ca 0.5 Å shorter than the sum of the van der Waals radii of the individual atoms, which means it is a very strong interaction. A contribution of 31.0% was found for the interatomic HÁ Á ÁH contacts (Fig. 6c), with a distinctive peak in the fingerprint plot at d e + d i = 2.2 Å ; the van der Waals radius for this interaction is 2.4 Å . The HÁ Á ÁC/ CÁ Á ÁH contacts (9.6% contribution; Fig. 6d) are indicated by a pair of short peaks at d e + d i = 2.7 Å , equal to the sum of the van der Waals radii. The HÁ Á ÁN/NÁ Á ÁH contacts (Fig. 6e), which account for only 8.4% of the Hirshfeld surface, are displayed on the fingerprint plot as a pair of long spikes at d e + d i = 2.0 Å . This distance differs by ca 0.7 Å from the sum of the van der Waals radii, which means it is the strongest interaction present. The CÁ Á ÁC contacts (Fig. 6f) Two views of the Hirshfeld surface mapped over d norm .

Figure 5
Two views of the Hirshfeld surface mapped over the electrostatic potential.

Synthesis and crystallization
4-Hydroxybenzaldehyde (1 mmol), hydroxylamine hydrochloride (1 mmol), ethylacetoacetate (1 mmol) and K 2 CO 3 (5 ml) were mixed in a 25 ml flask equipped with a magnetic stirrer. The mixture was refluxed in 5 ml of water for 1 h (the reaction was monitored by TLC). On completion of the reaction, 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 83%), yielding pale-yellow needle-like crystals on slow evaporation of the solvent.