Crystal structure and Hirshfeld surface analysis of ethyl 5-phenyl-isoxazole-3-carboxyl-ate.

The title compound, C12H11NO3, is an inter-mediate used in the synthesis of many drug-like mol-ecules. The mol-ecule is almost planar, with the phenyl ring inclined to the isoxazole ring by 0.5 (1)°. The ester moiety has an extended conformation and is almost in the same plane with respect to the isoxazole ring, as indicated by the O-C-C-N torsion angle of -172.86 (18)°. In the crystal, mol-ecules are linked via pairs of C-H⋯O hydrogen bonds with the same acceptor atom, forming inversion dimers with two R21(7) ring motifs. The mol-ecules stack in layers lying parallel to (10-3). Analysis using Hirshfeld surface generation and two-dimensional fingerprint plots explores the distribution of weak inter-molecular inter-actions in the crystal structure.

Chemical context

Nitro­gen-containing heterocyclic rings are of great importance in medicinal and organic chemistry (Dou et al., 2013 ▸). Isoxazole derivatives are important heterocyclic pharmaceuticals having a broad spectrum of biological activity, which includes antagonism of the NMDA receptor, anti-inflammatory (Panda et al., 2009 ▸), anti-tumour, anti­convulsant, anti-psychotic, anti-depressant and anti HIV activity (Conti et al., 2005 ▸; Srivastava et al., 1999 ▸). Considerable attention has been paid to isoxazole derivatives as a result of their prominent biological properties (Dou et al., 2013 ▸). Valdecoxib (Bextra), a selective cyclo­oxygenase-2 (COX-2) inhibitor used in the treatment of arthritis, contains an isoxazole moiety which is responsible for its biological activity (Waldo & Larock, 2007 ▸; Dadiboyena & Nefzi, 2010 ▸). In addition, isoxazole derivatives are also important inter­mediates in the preparation of various heterocyclic biologically active drugs (Dou et al., 2013 ▸). As part of our ongoing studies on isoxazole derivatives as kinase inhib­itors, we have synthesized the title compound, and report herein on its crystal structure and the qu­anti­tative analysis of inter­molecular inter­actions using the Hirshfeld surface and 2D fingerprint plot analysis.

Structural commentary

The mol­ecular structure of the title compound, (I), is illus­trated in Fig. 1 ▸. The mol­ecule consists of three almost flat units: the phenyl ring, the isoxazole ring and the ester. The phenyl (C1–C6) and isoxazole (O1/N1/C7–C9) rings are almost coplanar, as indicated by the torsion angle C5—C6—C7—O1 = 0.1 (3)°. The ester unit has an extended conformation and is almost in the same plane as the isoxazole ring, as indicated by the torsion angle O2—C10—C9—N1 = −172.86 (18)°.

Figure 1

The mol­ecular structure of compound (I), with the atom labelling and displacement ellipsoid drawn at the 50% probability level.

Supra­molecular features

In the crystal of (I), mol­ecules are linked via pairs of C—H⋯O hydrogen bonds, both involving atom O2 as acceptor, forming inversion dimers with two (7) ring motifs (Table 1 ▸ and Fig. 2 ▸). The mol­ecules stack in layers lying parallel to (10), as illustrated in Fig. 3 ▸.

Table 1

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C1—H1⋯O2i	0.93	2.52	3.447 (2)	171
C8—H8⋯O2i	0.93	2.36	3.260 (2)	163

Symmetry code: (i) .

Figure 2

Crystal packing of compound (I), viewed along the a axis. Hydrogen bonds are shown as dashed lines (see Table 1 ▸).

Figure 3

Crystal packing of compound (I) viewed along the b axis. Hydrogen bonds are shown as dashed lines and, for clarity, H atoms have been omitted.

Hirshfeld surface and fingerprint plot analysis

To explore the weak inter­molecular inter­actions in (I), Hirshfeld surfaces and 2D fingerprint plots were generated using Crystal Explorer 3.1 to qu­antify the inter­molecular inter­actions (McKinnon et al., 2007 ▸; Spackman & Jayatilaka, 2009 ▸). Hirshfeld surfaces are produced through the partitioning of space within a crystal where the ratio of promol­ecule to procrystal electron density is equal to 0.5, generating continuous, non-overlapping surfaces which are widely used to visualize and study the significance of weak inter­actions in the mol­ecular packing (McKinnon et al., 2007 ▸). The Hirshfeld surface of title compound was mapped over d norm, shape index and curvedness. The d norm surface is the normalized function of d i and d e (Fig. 4 ▸ a), with white-, red- and blue-coloured surfaces. The white surface indicates those contacts with distances equal to the sum of the van der Waals (vdW) radii, red indicates shorter contacts (< vdW radii) and blue the longer contact (> vdW radii). The Hirshfeld surface was also mapped over electrostatic potential (Fig. 4 ▸ b) using a STO-3G basis set at the Hartee–Fock level of theory (Spackman & McKinnon, 2002 ▸; McKinnon et al., 2004 ▸). In the Hirshfeld surface, a pair of inter­actions between the aromatic C—H⋯O=C atoms can be seen as the bright-red area (1) in Fig. 5 ▸ a. The 2D fingerprint plot analysis of the O⋯H inter­actions revealed significant hydrogen-bonding spikes (d i = 1.3, d e = 0.9 Å and d e = 1.9, d i = 2.6 Å); Fig. 6 ▸ c.

Figure 4

Hirshfeld surface mapped over (a) d norm and (b) electrostatic potential.

Figure 5

Hirshfeld surface mapped over (a) d norm highlighting the regions of C—H⋯O hydrogen bonding and (b) d norm highlighting the region of C—H⋯N hydrogen bonding.

Figure 6

Two-dimensional fingerprint plot analysis (a) all inter­actions, (b) H⋯H contacts, (c) O⋯H contacts, (d) N⋯H contacts, (e) C⋯H contacts and (f) C⋯C contacts.

The analysis indicates that there is a weak N⋯H inter­molecular inter­action between the nitro­gen atom of the isoxazole ring and the methyl­ene hydrogen atom of the phenyl ring of a neighbouring mol­ecule (Fig. 5 ▸ b). The fingerprint plot analysis of N⋯H contacts reveals a significant wing-like structure (d i = 1.2, d e = 1.5 Å and d e = 2.2, d i = 2.4 Å) Fig. 6 ▸ d.

The relative contributions to the Hirshfeld surface area for each type of inter­molecular contact are illustrated in Figs. 6 ▸ and 7 ▸. The H⋯H inter­actions appear as scattered points over nearly the entire plot and have a significant composition of 41% of the Hirshfeld surface. The H⋯O contacts comprise of 18.7% and the C⋯C inter­actions comprise 1.6% of the total Hirshfeld surface. The C⋯H and N⋯H inter­actions cover 23.2% and 9.2% of the surface, respectively. Thus, these weak inter­actions contribute significantly to the packing of (I).

Figure 7

Relative contribution of each inter­action in the two-dimensional fingerprint analysis.

Database survey

A search of the Cambridge Structural Database (CSD, V5.38; last update November 2016; Groom et al., 2016 ▸) for similar isoxazole derivatives, revealed only one hit, viz. ethyl 5-(4-amino­phen­yl) isoxazole-3-carboxyl­ate (CSD refcode YAVRIY; Zhao et al., 2012 ▸). This compound crystallizes with two independent mol­ecules in the asymmetric unit. One mol­ecule is slightly more planar than the other, with the phenyl ring being inclined to the isoxazole ring by 1.77 (10) and 5.85 (10)°. In the title compound, (I), this dihedral angle is 0.5 (1)°.

Synthesis and crystallization

There are several methods available in the literature for the preparation of isoxazole derivatives. We have followed a simple preparation from a diketoester (Tourteau et al., 2013 ▸; Bastos et al., 2015 ▸). After the reaction of aceto­phenone with diethyoxalate in a basic solution (sodium ethoxide) of ethanol for 8 h, 1N HCl was added to neutralize the sodium ethoxide to obtain the diketoester (ethyl 2,4-dioxo-4-phenyl­butano­ate; see Fig. 8 ▸) as a yellow liquid. 1 g (4.5 mmol) of the diketoester in ethanol was added to hydroxyl amine hydro­chloride (0.315 g, 4.5 mmol) at room temperature and the resulting mixture was stirred at 353 K for 12 h. The progress of the reaction was monitored by TLC. After the completion of starting materials, the reaction mixture was cooled to room temperature and the excess of ethanol removed. The resulting residue was dissolved in water and extracted with ethyl acetate. The organic layer was dried with Na2SO4, filtered and the concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (3% ethyl acetate: Pet-ether) to afford the title compound, (I) (yield 76.9%, 0.75 g; m.p. 325–327 K).

Figure 8

Synthesis of the title compound, (I).

Colourless crystals were obtained by slow evaporation of a solution in ethyl acetate. Spectroscopic data: 1H NMR (500 MHz, chloro­form-d) δ 7.80 (m, 2H), 7.50 (m, 3H), 6.92 (s, 1H), 4.47 (q, 2H), 1.44 (t, 3H). 13C NMR (126 MHz, chloro­form-d) δ 171.66, 159.98, 156.96, 130.76, 129.11, 126.61, 125.89, 99.92, 62.18, 14.15.

Refinement

Crystal data, data collection and structure refinement parameters are given in Table 2 ▸. All H atoms were positioned geometrically and refined as riding: C—H = 0.95–0.99 Å with U iso(H) = 1.2U eq(C).

Table 2

Experimental details

Crystal data
Chemical formula	C12H11NO3
M r	217.22
Crystal system, space group	Monoclinic, P21/n
Temperature (K)	100
a, b, c (Å)	5.4447 (7), 17.180 (2), 11.7603 (19)
β (°)	94.508 (5)
V (Å3)	1096.6 (3)
Z	4
Radiation type	Mo Kα
μ (mm−1)	0.10
Crystal size (mm)	0.4 × 0.2 × 0.2
Data collection
Diffractometer	Bruker APEXII CCD
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	14119, 2813, 1889
R int	0.075
(sin θ/λ)max (Å−1)	0.676
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.064, 0.177, 1.09
No. of reflections	2813
No. of parameters	146
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.27, −0.30

Computer programs: APEX2 and SAINT (Bruker, 2006 ▸), SHELXS97 and SHELXTL (Sheldrick 2008 ▸), SHELXL2014 (Sheldrick, 2015 ▸), and Mercury (Macrae et al., 2008 ▸).

Crystal structure: contains datablock(s) I, Global. DOI: 10.1107/S2056989017003127/su5350sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989017003127/su5350Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989017003127/su5350Isup5.cml

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989017003127/su5350sup3.png

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989017003127/su5350sup4.png

CCDC reference: 1534636

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

C12H11NO3	F(000) = 456
Mr = 217.22	Dx = 1.316 Mg m−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 5.4447 (7) Å	Cell parameters from 5392 reflections
b = 17.180 (2) Å	θ = 2.4–30.5°
c = 11.7603 (19) Å	µ = 0.10 mm−1
β = 94.508 (5)°	T = 100 K
V = 1096.6 (3) Å3	Blocks, colourless
Z = 4	0.4 × 0.2 × 0.2 mm

Bruker APEXII CCD diffractometer	Rint = 0.075
φ and ω scans	θmax = 28.7°, θmin = 2.4°
14119 measured reflections	h = −5→7
2813 independent reflections	k = −23→23
1889 reflections with I > 2σ(I)	l = −15→14

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)] = 0.064	Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.177	H-atom parameters constrained
S = 1.09	w = 1/[σ2(Fo2) + (0.1P)2] where P = (Fo2 + 2Fc2)/3
2813 reflections	(Δ/σ)max < 0.001
146 parameters	Δρmax = 0.27 e Å−3
0 restraints	Δρmin = −0.30 e Å−3

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	0.1048 (2)	0.62026 (7)	0.20002 (11)	0.0221 (4)
O3	−0.4360 (3)	0.73867 (7)	0.01862 (12)	0.0230 (4)
O2	−0.6161 (2)	0.62208 (7)	−0.01700 (11)	0.0243 (4)
C10	−0.4499 (3)	0.66119 (10)	0.02530 (16)	0.0184 (4)
C6	0.1914 (3)	0.48387 (10)	0.22525 (16)	0.0181 (4)
N1	−0.0666 (3)	0.67215 (8)	0.14685 (14)	0.0225 (4)
C4	0.5520 (4)	0.44302 (11)	0.34137 (19)	0.0256 (5)
H4	0.692513	0.455560	0.387897	0.031*
C7	0.0322 (4)	0.54579 (9)	0.17410 (16)	0.0174 (4)
C9	−0.2320 (3)	0.62718 (10)	0.09196 (15)	0.0180 (4)
C5	0.4000 (4)	0.50161 (10)	0.29503 (17)	0.0234 (5)
H5	0.438869	0.553372	0.311094	0.028*
C3	0.4941 (4)	0.36559 (11)	0.31817 (17)	0.0249 (5)
H3	0.596502	0.326217	0.348598	0.030*
C1	0.1308 (4)	0.40540 (10)	0.20262 (16)	0.0203 (4)
H1	−0.010182	0.392615	0.156628	0.024*
C12	−0.5855 (4)	0.86283 (11)	−0.04174 (18)	0.0273 (5)
H12A	−0.579681	0.880375	0.035929	0.041*
H12B	−0.711938	0.890614	−0.086440	0.041*
H12C	−0.429204	0.872225	−0.071751	0.041*
C8	−0.1780 (3)	0.54715 (9)	0.10639 (16)	0.0185 (4)
H8	−0.267753	0.504983	0.075862	0.022*
C11	−0.6410 (4)	0.77721 (11)	−0.04635 (18)	0.0243 (5)
H11A	−0.794720	0.766468	−0.012878	0.029*
H11B	−0.654755	0.759053	−0.124690	0.029*
C2	0.2846 (4)	0.34724 (10)	0.24996 (17)	0.0237 (5)
H2	0.245566	0.295307	0.235394	0.028*

	U11	U22	U33	U12	U13	U23
O1	0.0236 (8)	0.0114 (6)	0.0300 (8)	0.0009 (5)	−0.0065 (6)	0.0016 (5)
O3	0.0239 (8)	0.0128 (6)	0.0314 (8)	0.0024 (5)	−0.0047 (6)	0.0009 (5)
O2	0.0233 (8)	0.0170 (6)	0.0319 (8)	−0.0022 (5)	−0.0028 (6)	−0.0018 (6)
C10	0.0199 (10)	0.0140 (8)	0.0215 (10)	−0.0001 (7)	0.0026 (8)	−0.0025 (7)
C6	0.0190 (10)	0.0150 (8)	0.0207 (10)	0.0016 (7)	0.0047 (8)	0.0019 (7)
N1	0.0246 (10)	0.0139 (7)	0.0280 (9)	0.0031 (6)	−0.0052 (7)	0.0029 (7)
C4	0.0195 (11)	0.0220 (10)	0.0345 (12)	−0.0005 (8)	−0.0036 (8)	0.0034 (8)
C7	0.0234 (11)	0.0102 (8)	0.0190 (10)	−0.0019 (7)	0.0041 (8)	−0.0019 (7)
C9	0.0209 (10)	0.0131 (8)	0.0204 (10)	−0.0019 (7)	0.0035 (8)	0.0001 (7)
C5	0.0211 (11)	0.0146 (9)	0.0345 (12)	−0.0003 (7)	0.0017 (9)	0.0006 (8)
C3	0.0224 (11)	0.0195 (9)	0.0331 (11)	0.0057 (8)	0.0038 (9)	0.0064 (8)
C1	0.0218 (11)	0.0161 (8)	0.0228 (10)	−0.0003 (7)	0.0005 (8)	−0.0010 (7)
C12	0.0294 (12)	0.0197 (9)	0.0320 (12)	0.0047 (8)	−0.0019 (9)	0.0042 (8)
C8	0.0208 (10)	0.0108 (8)	0.0243 (10)	−0.0014 (7)	0.0032 (8)	−0.0020 (7)
C11	0.0219 (11)	0.0197 (9)	0.0300 (11)	0.0041 (8)	−0.0055 (8)	0.0009 (8)
C2	0.0276 (11)	0.0150 (8)	0.0289 (11)	0.0020 (8)	0.0042 (8)	−0.0001 (8)

O1—C7	1.366 (2)	C9—C8	1.413 (2)
O1—N1	1.4018 (19)	C5—H5	0.9300
O3—C10	1.336 (2)	C3—C2	1.379 (3)
O3—C11	1.461 (2)	C3—H3	0.9300
O2—C10	1.203 (2)	C1—C2	1.391 (3)
C10—C9	1.489 (3)	C1—H1	0.9300
C6—C5	1.382 (3)	C12—C11	1.502 (2)
C6—C1	1.408 (2)	C12—H12A	0.9600
C6—C7	1.471 (2)	C12—H12B	0.9600
N1—C9	1.317 (2)	C12—H12C	0.9600
C4—C3	1.389 (3)	C8—H8	0.9300
C4—C5	1.387 (3)	C11—H11A	0.9700
C4—H4	0.9300	C11—H11B	0.9700
C7—C8	1.342 (3)	C2—H2	0.9300
C7—O1—N1	108.98 (13)	C4—C3—H3	120.1
C10—O3—C11	115.97 (14)	C2—C1—C6	119.14 (18)
O2—C10—O3	125.19 (16)	C2—C1—H1	120.4
O2—C10—C9	122.75 (16)	C6—C1—H1	120.4
O3—C10—C9	112.06 (15)	C11—C12—H12A	109.5
C5—C6—C1	119.53 (17)	C11—C12—H12B	109.5
C5—C6—C7	120.93 (16)	H12A—C12—H12B	109.5
C1—C6—C7	119.54 (17)	C11—C12—H12C	109.5
C9—N1—O1	104.55 (14)	H12A—C12—H12C	109.5
C3—C4—C5	119.89 (19)	H12B—C12—H12C	109.5
C3—C4—H4	120.1	C9—C8—C7	104.35 (15)
C5—C4—H4	120.1	C9—C8—H8	127.8
O1—C7—C8	109.53 (15)	C7—C8—H8	127.8
O1—C7—C6	115.78 (16)	O3—C11—C12	106.35 (15)
C8—C7—C6	134.68 (16)	O3—C11—H11A	110.5
C8—C9—N1	112.59 (16)	C12—C11—H11A	110.5
C8—C9—C10	126.49 (16)	O3—C11—H11B	110.5
N1—C9—C10	120.92 (15)	C12—C11—H11B	110.5
C6—C5—C4	120.69 (17)	H11A—C11—H11B	108.7
C6—C5—H5	119.7	C3—C2—C1	120.87 (17)
C4—C5—H5	119.7	C3—C2—H2	119.6
C2—C3—C4	119.87 (18)	C1—C2—H2	119.6
C2—C3—H3	120.1
C11—O3—C10—O2	−0.4 (3)	O3—C10—C9—N1	7.3 (2)
C11—O3—C10—C9	179.40 (15)	C1—C6—C5—C4	1.1 (3)
C7—O1—N1—C9	−0.10 (19)	C7—C6—C5—C4	−178.82 (18)
N1—O1—C7—C8	0.15 (19)	C3—C4—C5—C6	−0.4 (3)
N1—O1—C7—C6	−179.04 (15)	C5—C4—C3—C2	−0.6 (3)
C5—C6—C7—O1	0.1 (3)	C5—C6—C1—C2	−0.9 (3)
C1—C6—C7—O1	−179.73 (15)	C7—C6—C1—C2	179.02 (17)
C5—C6—C7—C8	−178.8 (2)	N1—C9—C8—C7	0.1 (2)
C1—C6—C7—C8	1.3 (3)	C10—C9—C8—C7	−178.89 (17)
O1—N1—C9—C8	0.0 (2)	O1—C7—C8—C9	−0.13 (19)
O1—N1—C9—C10	179.04 (15)	C6—C7—C8—C9	178.9 (2)
O2—C10—C9—C8	6.0 (3)	C10—O3—C11—C12	179.89 (15)
O3—C10—C9—C8	−173.78 (16)	C4—C3—C2—C1	0.8 (3)
O2—C10—C9—N1	−172.86 (18)	C6—C1—C2—C3	0.0 (3)

D—H···A	D—H	H···A	D···A	D—H···A
C1—H1···O2i	0.93	2.52	3.447 (2)	171
C8—H8···O2i	0.93	2.36	3.260 (2)	163