Crystal structure and Hirshfeld surface analysis of (Z)-4-(4-hy-droxy-benzyl-idene)-3-methyl-isoxazol-5(4H)-one.

The title compound, C11H9NO3, contains an isoxazole and a hy-droxy-benzyl-idene ring, which are inclined to each another by 3.18 (8)°. There is an intra-molecular C-H⋯O contact forming an S(7) ring. In the crystal, mol-ecules stack head-to-tail in columns along the b-axis direction, linked by offset π-π inter-actions [inter-centroid distances of 3.676 (1) and 3.723 (1) Å]. The columns are linked by O-H⋯O and O-H⋯N hydrogen bonds, forming layers parallel to the ab plane. The layers are linked by C-H⋯O hydrogen bonds, forming a supra-molecular three-dimensional framework. An analysis of the Hirshfeld surfaces points to the importance of the O-H⋯O and O-H⋯N hydrogen bonding in the packing mechanism of the crystal structure.

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/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—H11⋯O2 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 1

The mol­ecular structure of the title compound, with atom labelling and displacement ellipsoids drawn at the 50% probability level. The intra­molecular C—H⋯O contact (see Table 1 ▸) is shown as a dashed line.

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C11—H11⋯O2	0.93	2.15	2.989 (2)	149
O3—H3O⋯O1i	0.86 (2)	2.41 (2)	2.9119 (18)	118 (2)
O3—H3O⋯N1i	0.86 (2)	2.00 (2)	2.7984 (19)	154 (2)
C5—H5⋯O2ii	0.93	2.47	3.3655 (17)	162
C7—H7⋯O2ii	0.93	2.55	3.4038 (19)	152

Symmetry codes: (i) ; (ii) .

Supra­molecular features

In the crystal, mol­ecules stack head-to-tail along the b-axis direction (Fig. 2 ▸), and are linked by offset π–π inter­actions: Cg1⋯Cg2iii,iv inter­centroid distances are 3.676 (1) and 3.723 (1) Å, inter­planar distances are 3.426 (1) and 3.489 (1) Å, slippages are 1.287 and 1.458 Å with the rings inclined to each other by 3.18 (8)°; symmetry codes: (iii) −x + , −y + , −z + 1; (iv) −x + , −y − , −z + 1. The mol­ecular columns are linked by O—H⋯O and O—H⋯N hydrogen bonds (Table 1 ▸), forming layers parallel to (001). The layers are linked by C—H⋯O hydrogen bonds, forming a supra­molecular three-dimensional framework (Table 1 ▸ and Fig. 2 ▸).

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.

Analysis of the Hirshfeld surfaces

Additional insight into the inter­molecular inter­actions was obtained from an analysis of the Hirshfeld surface (Spackman & Jayatilaka, 2009 ▸) and the two-dimensional fingerprint plots (McKinnon et al., 2007 ▸). The program CrystalExplorer (Turner et al., 2017 ▸) was used to generate Hirshfeld surfaces mapped over d norm, d e and the electrostatic potential for the title compound.

The analysis of the Hirshfeld surface mapped over d norm is shown in Fig. 3 ▸. The O3—H3⋯O1i and O3—H3⋯N1i 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—H5⋯O2ii and C7—H7⋯Oii 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 ▸).

Figure 3

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

Figure 4

Two views of the Hirshfeld surface mapped over d norm.

Figure 5

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

The overall two-dimensional fingerprint plot is illustrated in Fig. 6 ▸ a, and the H⋯O/O⋯H, H⋯H, C⋯H/H⋯C, and N⋯H/H⋯N contacts are illustrated in Fig. 6 ▸ b–f, respectively. The H⋯O/O⋯H contacts (Fig. 6 ▸ b) 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 H⋯H contacts (Fig. 6 ▸ c), 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 H⋯C/C⋯H contacts (9.6% contribution; Fig. 6 ▸ d) 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 H⋯N/N⋯H contacts (Fig. 6 ▸ e), 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 C⋯C contacts (Fig. 6 ▸ f), which account for 11.7% of the Hirshfeld surface with d e + d i = 3.4 Å, indicate the presence of π–π stacking.

Figure 6

Two-dimensional fingerprint plots: (a) overall, and delineated into contributions from different contacts: (b) H⋯O/O⋯H, (c) H⋯H, (d) H⋯C/C⋯H, (e) H⋯NN⋯H, (f) C⋯C.

Database survey

A search of the Cambridge Structural Database (CSD, V3.59, last update February 2018; Groom et al., 2016 ▸) for 4-substituted 3-methyl-isoxzol-5(4H)-ones gave 22 hits. Of these, six compounds involve a benzyl­idene substituent. The configuration about the C=C bond is Z in all six compounds and the benzene ring is inclined to the isoxazole ring by angles as small as 1.14° in (Z)-4-benzyl­idene-3-methyl­isoxazol-5(4H)-one (MBYIOZ01; Chandra et al., 2012 ▸) compared to ca 11.59° in (Z)-4-(4-meth­oxy­benzyl­idene)-3-methyl-1,2-oxazol-5(4H)-one (YIMWIC; Saikh et al., 2013 ▸). The most relevant structure is the 2-hy­droxy­benzyl­idene analogue, viz. (Z)-4-(2-hy­droxy­benzyl­idene)-3-methyl­isoxazol-5(4H)-one (AJESAK; Cheng et al., 2009 ▸), in which the two rings are inclined to each other by ca 6.53°, compared to 3.18 (8)° in the title compound. The Z configuration of all six mol­ecules indicates that there is an intra­molecular C—H⋯O contact present forming an S(7) ring motif, as in the title compound (Fig. 1 ▸ and Table 1 ▸).

Synthesis and crystallization

4-Hy­droxy­benzaldehyde (1 mmol), hydroxyl­amine hydro­chloride (1 mmol), ethyl­aceto­acetate (1 mmol) and K2CO3 (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.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2 ▸. The hydroxyl H atom was located in a difference-Fourier map and freely refined. The C-bound H atoms were included in calculated positions and treated as riding: C—H = 0.93–0.96 Å with U iso(H) = 1.5U eq(C-meth­yl) and 1.2U eq(C) for other H atoms.

Table 2

Experimental details

Crystal data
Chemical formula	C11H9NO3
M r	203.19
Crystal system, space group	Monoclinic, C2/c
Temperature (K)	293
a, b, c (Å)	21.191 (2), 7.2352 (11), 12.9569 (14)
β (°)	103.920 (11)
V (Å3)	1928.2 (4)
Z	8
Radiation type	Mo Kα
μ (mm−1)	0.10
Crystal size (mm)	0.36 × 0.23 × 0.11
Data collection
Diffractometer	Agilent Technologies Xcalibur, Eos
Absorption correction	Multi-scan (CrysAlis PRO; Agilent, 2013 ▸)
T min, T max	0.551, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	4536, 1891, 1465
R int	0.021
(sin θ/λ)max (Å−1)	0.617
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.040, 0.113, 1.04
No. of reflections	1891
No. of parameters	142
H-atom treatment	H atoms treated by a mixture of independent and constrained refinement
Δρmax, Δρmin (e Å−3)	0.19, −0.13

Computer programs: CrysAlis PRO (Agilent, 2013 ▸), SIR92 (Altomare et al., 1994 ▸), PLATON (Spek, 2009 ▸), Mercury (Macrae et al., 2008 ▸), SHELXL2018/3 (Sheldrick, 2015 ▸) and publCIF (Westrip, 2010 ▸).

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S2056989018007867/zp2027sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989018007867/zp2027Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989018007867/zp2027Isup3.cml

CCDC reference: 1845567

Additional supporting information: crystallographic information; 3D view; checkCIF report

C11H9NO3	F(000) = 848
Mr = 203.19	Dx = 1.400 Mg m−3
Monoclinic, C2/c	Mo Kα radiation, λ = 0.71073 Å
a = 21.191 (2) Å	Cell parameters from 1714 reflections
b = 7.2352 (11) Å	θ = 4.1–32°
c = 12.9569 (14) Å	µ = 0.10 mm−1
β = 103.920 (11)°	T = 293 K
V = 1928.2 (4) Å3	Needle, pale yellow
Z = 8	0.36 × 0.23 × 0.11 mm

Agilent Technologies Xcalibur, Eos diffractometer	1891 independent reflections
Radiation source: Enhance (Mo) X-ray Source	1465 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.021
ω scans	θmax = 26.0°, θmin = 3.2°
Absorption correction: multi-scan (CrysalisPro; Agilent, 2013)	h = −26→23
Tmin = 0.551, Tmax = 1.000	k = −8→8
4536 measured reflections	l = −15→12

Refinement on F2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: mixed
R[F2 > 2σ(F2)] = 0.040	H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.113	w = 1/[σ2(Fo2) + (0.0595P)2] where P = (Fo2 + 2Fc2)/3
S = 1.04	(Δ/σ)max = 0.001
1891 reflections	Δρmax = 0.19 e Å−3
142 parameters	Δρmin = −0.13 e Å−3
0 restraints	Extinction correction: (SHELXL-2018/3; Sheldrick, 2015), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0020 (6)

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.

	x	y	z	Uiso*/Ueq
O1	0.62276 (5)	0.14571 (16)	0.60644 (8)	0.0492 (4)
O2	0.72284 (6)	0.0722 (2)	0.69282 (8)	0.0626 (4)
O3	0.99352 (6)	−0.2162 (2)	0.60528 (10)	0.0613 (4)
H3O	1.0132 (11)	−0.237 (3)	0.5558 (16)	0.092 (8)*
N1	0.58554 (6)	0.16143 (18)	0.49783 (10)	0.0448 (4)
C1	0.68443 (8)	0.0886 (2)	0.60805 (12)	0.0392 (4)
C2	0.68735 (7)	0.06174 (19)	0.49745 (11)	0.0308 (3)
C3	0.62309 (7)	0.11381 (19)	0.43784 (12)	0.0347 (4)
C4	0.59837 (9)	0.1192 (2)	0.32016 (13)	0.0521 (5)
H4A	0.558271	0.187052	0.302307	0.078*
H4B	0.591061	−0.004561	0.293277	0.078*
H4C	0.629819	0.178707	0.289026	0.078*
C5	0.73584 (7)	0.00370 (18)	0.45337 (10)	0.0321 (4)
H5	0.723867	0.000592	0.379466	0.039*
C6	0.80178 (7)	−0.05397 (19)	0.49675 (11)	0.0309 (3)
C7	0.83942 (7)	−0.0968 (2)	0.42463 (11)	0.0374 (4)
H7	0.820742	−0.088293	0.352088	0.045*
C8	0.90318 (8)	−0.1508 (2)	0.45834 (12)	0.0407 (4)
H8	0.927260	−0.178127	0.409006	0.049*
C9	0.93153 (7)	−0.1646 (2)	0.56651 (13)	0.0391 (4)
C10	0.89502 (8)	−0.1264 (2)	0.63930 (12)	0.0414 (4)
H10	0.913860	−0.136911	0.711693	0.050*
C11	0.83143 (7)	−0.0732 (2)	0.60553 (11)	0.0374 (4)
H11	0.807415	−0.049326	0.655426	0.045*

	U11	U22	U33	U12	U13	U23
O1	0.0342 (7)	0.0808 (8)	0.0351 (6)	0.0182 (6)	0.0132 (5)	0.0031 (5)
O2	0.0413 (7)	0.1180 (11)	0.0271 (6)	0.0283 (7)	0.0056 (5)	−0.0015 (6)
O3	0.0259 (6)	0.1075 (11)	0.0490 (8)	0.0214 (6)	0.0061 (6)	−0.0077 (7)
N1	0.0290 (8)	0.0631 (8)	0.0410 (8)	0.0122 (7)	0.0057 (6)	0.0029 (6)
C1	0.0271 (8)	0.0580 (9)	0.0335 (8)	0.0104 (7)	0.0091 (7)	0.0017 (7)
C2	0.0256 (8)	0.0372 (7)	0.0289 (7)	0.0031 (6)	0.0050 (6)	0.0010 (6)
C3	0.0274 (8)	0.0405 (7)	0.0363 (8)	0.0049 (7)	0.0076 (7)	0.0005 (6)
C4	0.0392 (10)	0.0710 (11)	0.0397 (9)	0.0134 (9)	−0.0027 (8)	−0.0004 (8)
C5	0.0294 (8)	0.0403 (7)	0.0263 (7)	0.0033 (6)	0.0061 (6)	−0.0002 (6)
C6	0.0258 (8)	0.0373 (7)	0.0297 (7)	0.0036 (6)	0.0067 (6)	−0.0021 (6)
C7	0.0324 (9)	0.0516 (9)	0.0283 (7)	0.0051 (7)	0.0075 (6)	−0.0001 (6)
C8	0.0297 (9)	0.0582 (9)	0.0374 (8)	0.0057 (7)	0.0141 (7)	−0.0051 (7)
C9	0.0225 (8)	0.0503 (9)	0.0435 (8)	0.0067 (7)	0.0062 (7)	−0.0045 (7)
C10	0.0323 (9)	0.0588 (9)	0.0304 (8)	0.0081 (7)	0.0025 (7)	−0.0033 (7)
C11	0.0292 (8)	0.0531 (9)	0.0310 (8)	0.0083 (7)	0.0093 (6)	−0.0032 (6)

O1—C1	1.3660 (19)	C5—C6	1.4370 (19)
O1—N1	1.4426 (15)	C5—H5	0.9300
O2—C1	1.2054 (18)	C6—C7	1.401 (2)
O3—C9	1.3417 (18)	C6—C11	1.4053 (19)
O3—H3O	0.86 (2)	C7—C8	1.373 (2)
N1—C3	1.2860 (19)	C7—H7	0.9300
C1—C2	1.462 (2)	C8—C9	1.389 (2)
C2—C5	1.357 (2)	C8—H8	0.9300
C2—C3	1.445 (2)	C9—C10	1.384 (2)
C3—C4	1.489 (2)	C10—C11	1.368 (2)
C4—H4A	0.9600	C10—H10	0.9300
C4—H4B	0.9600	C11—H11	0.9300
C4—H4C	0.9600
C1—O1—N1	109.59 (11)	C6—C5—H5	113.2
C9—O3—H3O	112.2 (14)	C7—C6—C11	117.27 (13)
C3—N1—O1	107.22 (11)	C7—C6—C5	117.34 (13)
O2—C1—O1	118.53 (14)	C11—C6—C5	125.39 (13)
O2—C1—C2	134.54 (15)	C8—C7—C6	121.68 (13)
O1—C1—C2	106.93 (12)	C8—C7—H7	119.2
C5—C2—C3	124.58 (13)	C6—C7—H7	119.2
C5—C2—C1	131.96 (13)	C7—C8—C9	119.66 (14)
C3—C2—C1	103.46 (13)	C7—C8—H8	120.2
N1—C3—C2	112.79 (13)	C9—C8—H8	120.2
N1—C3—C4	119.70 (14)	O3—C9—C10	117.26 (14)
C2—C3—C4	127.50 (14)	O3—C9—C8	122.99 (14)
C3—C4—H4A	109.5	C10—C9—C8	119.75 (14)
C3—C4—H4B	109.5	C11—C10—C9	120.49 (14)
H4A—C4—H4B	109.5	C11—C10—H10	119.8
C3—C4—H4C	109.5	C9—C10—H10	119.8
H4A—C4—H4C	109.5	C10—C11—C6	121.12 (14)
H4B—C4—H4C	109.5	C10—C11—H11	119.4
C2—C5—C6	133.54 (13)	C6—C11—H11	119.4
C2—C5—H5	113.2
C1—O1—N1—C3	0.71 (16)	C1—C2—C5—C6	0.4 (3)
N1—O1—C1—O2	178.29 (14)	C2—C5—C6—C7	−176.83 (15)
N1—O1—C1—C2	−1.37 (16)	C2—C5—C6—C11	4.0 (3)
O2—C1—C2—C5	1.7 (3)	C11—C6—C7—C8	−1.6 (2)
O1—C1—C2—C5	−178.74 (15)	C5—C6—C7—C8	179.15 (14)
O2—C1—C2—C3	−178.13 (19)	C6—C7—C8—C9	0.2 (2)
O1—C1—C2—C3	1.45 (16)	C7—C8—C9—O3	−179.90 (15)
O1—N1—C3—C2	0.28 (17)	C7—C8—C9—C10	1.0 (2)
O1—N1—C3—C4	−178.93 (13)	O3—C9—C10—C11	−179.90 (14)
C5—C2—C3—N1	179.09 (14)	C8—C9—C10—C11	−0.7 (2)
C1—C2—C3—N1	−1.08 (17)	C9—C10—C11—C6	−0.7 (2)
C5—C2—C3—C4	−1.8 (2)	C7—C6—C11—C10	1.8 (2)
C1—C2—C3—C4	178.06 (14)	C5—C6—C11—C10	−178.97 (14)
C3—C2—C5—C6	−179.81 (14)

D—H···A	D—H	H···A	D···A	D—H···A
C11—H11···O2	0.93	2.15	2.989 (2)	149
O3—H3O···O1i	0.86 (2)	2.41 (2)	2.9119 (18)	118 (2)
O3—H3O···N1i	0.86 (2)	2.00 (2)	2.7984 (19)	154 (2)
C5—H5···O2ii	0.93	2.47	3.3655 (17)	162
C7—H7···O2ii	0.93	2.55	3.4038 (19)	152