Crystal structure of 2-(2,5-di-meth-oxy-phen-yl)benzo[d]thia-zole.

The title compound, C15H13NO2S, was synthesized efficiently in the solid state by exploiting pepsin catalysis. The ring systems are nearly coplanar [inter-planar angle of 5.38 (2)°] with an associated intra-molecular S⋯O=C short contact of 2.7082 (4) Å. The packing involves C-H⋯O, C-H⋯π and π-π contacts. © Metwally et al. 2022.

Chemical context

Although countless synthetic methods are widely available, new and more efficient procedures or approaches are always needed. Enzymes, as ‘green’ catalysts for modern organic synthesis, have attracted increased attention because they may provide alternative and sustainable processes, thus helping to minimize the release of haza­rdous substances into the environment (Witayakran & Ragauskas, 2009 ▸). Pepsin, a kind of hydro­lase, belongs to the family of aspartic acid proteases and is involved in chemical digestion of protein (Cooper et al., 1990 ▸; Lin et al., 1989 ▸). Pepsin-catalysed aldol (and other) reactions have been developed (Li et al., 2010 ▸; He et al., 2016 ▸; Zongbo et al., 2017 ▸).

2-Aryl-benzo­thia­zoles are a class of nitro­gen-containing heterocyclic compounds that can be found in a variety of natural and synthetic compounds. In view of their biological and pharmacological characteristics, we are inter­ested in developing synthetic strategies for heterocyclic ring systems containing a benzo­thia­zole moiety; these have shown significant biological activity as novel anti­viral and anti­microbial agents. (Azzam et al. 2017a ▸,b ▸, 2020a ▸,b ▸,c ▸, 2021 ▸; Elgemeie et al., 2000a ▸,b ▸, 2020 ▸). The conventional synthesis of 2-aryl-benzo­thia­zoles, which involves heating a mixture containing 2-amino­thio­phenol (1), is disadvantageous because 1 is extremely unstable in air and highly toxic. In a continuation of our recent research in developing ‘green’ and simple syntheses of novel heterocyclic compounds (Metwally et al., 2020 ▸, 2021a ▸,b ▸), we have now synthesized 2-(2,5-di­meth­oxy­phen­yl)benzo[d]thia­zole (3) using pepsin as the ‘green’ catalytic reaction. Thus, a mixture of 1 and 2,5-di­meth­oxy­benzaldehyde 2 was ground in a mortar with 0.05 g pepsin for 10 minutes, providing the desired product 3 in 97% yield. The nature of compound 3 was confirmed by spectroscopic analysis and by the single-crystal X-ray structure reported here.

Structural commentary

The structure of 3 is shown in Fig. 1 ▸. Mol­ecular dimensions may be regarded as normal; a brief selection is presented in Table 1 ▸. Both ring systems are effectively planar (r.m.s. values of 0.01 Å for the benzo­thia­zole and 0.004 Å for the phenyl ring, respectively), with an inter­planar angle of 5.38 (2)°. The approximate coplanarity leads to the short intra­molecular contacts S1⋯O1 = 2.7082 (4) and H16⋯N3 = 2.48 Å; the C16—H16⋯N3 angle is 101°.

Figure 1

The mol­ecule of 3 in the crystal. Ellipsoids represent 50% probability levels.

Table 1

Selected geometric parameters (Å, °)

S1—C7A	1.7327 (6)	N3—C3A	1.3820 (7)
S1—C2	1.7642 (5)	C3A—C7A	1.4082 (8)
C2—N3	1.3064 (7)
C7A—S1—C2	89.40 (3)	N3—C3A—C7A	115.25 (5)
N3—C2—S1	114.72 (4)	C3A—C7A—S1	109.23 (4)
C2—N3—C3A	111.39 (5)

Supra­molecular features

There are no markedly short inter­molecular contacts. One borderline ‘weak’ C—H⋯O hydrogen bond can be identified (Table 2 ▸), which links mol­ecules via the c-glide operator x, −y +  , z −  . This is reinforced by a C—H⋯π contact from H14 to the centroid of the phenyl ring (H14⋯Cg = 2.67 Å, C14—H14⋯Cg = 138°; Cg is the centroid of the C11–C16 ring). Additionally, the mol­ecules are linked in pairs, related by c-axis translation, in which the benzo­thia­zole ring system of one mol­ecule lies opposite the phenyl ring of the other; the inter­centroid distances are 3.5651 (3) Å for benzo⋯phenyl, and 3.6022 (3) Å for thia­zole⋯phenyl (phenyl operator x, y, −1 + z). The net effect is to form a somewhat flattened herringbone pattern parallel to the c axis (Fig. 2 ▸; the π–π inter­actions are not shown explicitly). The contact C18—H18C⋯N3 (Table 2 ▸), involving a methyl group, connects the chains in the third dimension via the operator −x + 1, −y + 1, −z.

Table 2

Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C13—H13⋯O1i	0.95	2.65	3.5113 (7)	151
C18—H18C⋯N3ii	0.98	2.60	3.4867 (8)	151

Symmetry codes: (i) ; (ii) .

Figure 2

Crystal packing of 3, viewed perpendicular to (100) in the region x ≃ 0.25. Dashed lines indicate ‘weak’ C—H⋯O hydrogen bonds or C—H⋯π contacts. Atom labels correspond to the asymmetric unit.

Database survey

A search of the Cambridge Database (Version 2021.3.0; Groom et al., 2016 ▸) gave four hits for purely organic, neutral species in which one benzo[d]thia­zole is bonded at its 2-position to an aromatic C6 ring with oxygen substituents at the ortho (2-) and meta (5-) positions. These were CEFWOB [Yousuf et al., 2012 ▸; 2-hy­droxy, 5-meth­oxy; no S⋯O contact because of an intra­molecular O—H⋯N hydrogen bond; inter­planar angle 1.23 (9)°]; NOYSOM [Wang et al., 2019 ▸; 2,5-dimeth­oxy with an additional 4-(2-pyrid­yl) substituent; two independent mol­ecules; S⋯O = 2.650, 2.715 Å; inter­planar angles of 6.0, 5.5°]; UFAHUF [Chen, 2007 ▸; 2,4,5-trimeth­oxy; S⋯O = 2.671 Å, inter­planar angle of 4.5 (2)°] and WACPUO (Sakai et al., 2016 ▸; 2-hy­droxy, 5-meth­oxy with an additional 3-imidazole substituent; S⋯O = 2.695 Å, inter­planar angle of 1.6°). Where not given in the original publications, these values were calculated using the CCDC program Mercury (Macrae et al., 2020 ▸).

Synthesis and crystallization

A mixture of o-amino­thio­phenol 1 (0.01 mol), 2,5-di­meth­oxy­benzaldehyde 2 (0.01 mol) and pepsin (0.05 g) was ground together at room temperature for 10 min. The viscous mixture was poured onto ice–water; the solid that formed was filtered off and recrystallized from ethanol to give pale-yellow crystals of 3 in 97% yield, m.p. 414 K; IR (KBr, cm−1): νmax 1581 (C=N); 1H NMR (DMSO-d 6): δ = 3.82 (s, 3H, OCH3), 4.0 (s, 3H, OCH3), 7.13–7.15 (m, 1H, Ar), 7.22 (d, 1H, J = 8.8 Hz, Ar), 7.41 (t, 1H, J = 7.6 Hz, Ar), 7.51 (t, 1H, J = 7.6 Hz, Ar), 7.96 (s, 1H, Ar), 8.07 (dd, 2H, J = 8.0 Hz, Ar), 13C NMR (DMSO-d 6): δ = 56.0, 57.0, 112.5, 114.7, 119.1, 122.1, 122.2, 122.9, 125.4, 126.7, 136.0, 151.9, 153.8, 154.4, 162.3; m/z = 271 (M +, 100%), 238 (61.4%), 185 (27.6%), 136 (79.0%); Analysis: calculated for C15H13NO2S (271.33) C 66.40, H 4.83, N 5.16, S 11.82%; found C 66.58, H 4.65, N 5.39, S 11.68%.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 3 ▸. Methyl groups were refined as idealized rigid groups allowed to rotate but not tip (AFIX 137), with C—H = 0.98 Å, H—C—H = 109.5°. Other hydrogen atoms were included using a riding model starting from calculated positions (C—Haromatic = 0.95 Å). The U(H) values were fixed at 1.5 or 1.2 × U eq of the parent carbon atoms for methyl and aromatic hydrogens, respectively.

Table 3

Experimental details

Crystal data
Chemical formula	C15H13NO2S
M r	271.32
Crystal system, space group	Monoclinic, P21/c
Temperature (K)	100
a, b, c (Å)	14.6666 (2), 13.8922 (2), 6.26063 (10)
β (°)	100.1273 (14)
V (Å3)	1255.74 (3)
Z	4
Radiation type	Mo Kα
μ (mm−1)	0.25
Crystal size (mm)	0.22 × 0.22 × 0.15
Data collection
Diffractometer	XtaLAB Synergy, HyPix
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2021 ▸)
T min, T max	0.927, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	123768, 6759, 6156
R int	0.023
(sin θ/λ)max (Å−1)	0.871
Refinement
R[F 2 > 2σ(F 2)], wR(F 2), S	0.027, 0.084, 1.04
No. of reflections	6759
No. of parameters	174
H-atom treatment	H-atom parameters constrained
Δρmax, Δρmin (e Å−3)	0.62, −0.19

Computer programs: CrysAlis PRO (Rigaku OD, 2021 ▸), SHELXT (Sheldrick, 2015a ▸), SHELXL2018/3 (Sheldrick, 2015b ▸) and XP (Siemens, 1994 ▸).

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S2056989022003279/vm2262sup1.cif

Structure factors: contains datablock(s) I. DOI: 10.1107/S2056989022003279/vm2262Isup2.hkl

Click here for additional data file.

Supporting information file. DOI: 10.1107/S2056989022003279/vm2262Isup3.cml

CCDC reference: 2161465

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

C15H13NO2S	F(000) = 568
Mr = 271.32	Dx = 1.435 Mg m−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 14.6666 (2) Å	Cell parameters from 88513 reflections
b = 13.8922 (2) Å	θ = 2.8–38.4°
c = 6.26063 (10) Å	µ = 0.25 mm−1
β = 100.1273 (14)°	T = 100 K
V = 1255.74 (3) Å3	Block, colourless
Z = 4	0.22 × 0.22 × 0.15 mm

XtaLAB Synergy, HyPix diffractometer	6759 independent reflections
Radiation source: micro-focus sealed X-ray tube	6156 reflections with I > 2σ(I)
Detector resolution: 10.0000 pixels mm-1	Rint = 0.023
ω scans	θmax = 38.3°, θmin = 2.0°
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2021)	h = −24→25
Tmin = 0.927, Tmax = 1.000	k = −23→23
123768 measured reflections	l = −10→10

Refinement on F2	Primary atom site location: dual
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.027	H-atom parameters constrained
wR(F2) = 0.084	w = 1/[σ2(Fo2) + (0.0489P)2 + 0.2455P] where P = (Fo2 + 2Fc2)/3
S = 1.03	(Δ/σ)max = 0.001
6759 reflections	Δρmax = 0.62 e Å−3
174 parameters	Δρmin = −0.19 e Å−3
0 restraints

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. Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane) - 0.2606 (0.0025) x + 11.3686 (0.0009) y - 3.5208 (0.0006) z = 4.3561 (0.0009) * -0.0113 (0.0003) S1 * 0.0122 (0.0004) C2 * 0.0073 (0.0004) N3 * -0.0022 (0.0005) C3A * -0.0178 (0.0004) C4 * 0.0029 (0.0005) C5 * 0.0151 (0.0005) C6 * -0.0033 (0.0005) C7 * -0.0029 (0.0005) C7A Rms deviation of fitted atoms = 0.0101 - 1.6150 (0.0031) x + 11.4261 (0.0017) y - 3.3180 (0.0011) z = 4.1087 (0.0012) Angle to previous plane (with approximate esd) = 5.381 ( 0.023 ) * -0.0035 (0.0003) C11 * 0.0058 (0.0004) C12 * -0.0025 (0.0004) C13 * -0.0031 (0.0004) C14 * 0.0054 (0.0004) C15 * -0.0020 (0.0004) C16 -0.0003 (0.0008) O1 0.0801 (0.0011) C17 0.0285 (0.0008) O2 0.1636 (0.0010) C18 Rms deviation of fitted atoms = 0.0040

	x	y	z	Uiso*/Ueq
S1	0.13465 (2)	0.49165 (2)	0.34350 (2)	0.01451 (4)
C2	0.24674 (4)	0.47726 (4)	0.28209 (8)	0.01188 (8)
N3	0.31247 (3)	0.52002 (3)	0.41668 (7)	0.01347 (7)
C3A	0.27752 (4)	0.56826 (4)	0.57771 (8)	0.01360 (8)
C4	0.33134 (4)	0.62033 (4)	0.74630 (9)	0.01695 (9)
H4	0.396755	0.623486	0.758537	0.020*
C5	0.28692 (5)	0.66707 (4)	0.89466 (9)	0.01963 (10)
H5	0.322334	0.703577	1.008219	0.024*
C6	0.19042 (5)	0.66133 (5)	0.87976 (10)	0.02095 (11)
H6	0.161650	0.694472	0.982862	0.025*
C7	0.13610 (5)	0.60805 (4)	0.71696 (10)	0.01924 (10)
H7	0.071002	0.603042	0.709129	0.023*
C7A	0.18087 (4)	0.56196 (4)	0.56475 (9)	0.01468 (8)
C11	0.26660 (3)	0.42388 (3)	0.09270 (8)	0.01131 (7)
C12	0.19879 (3)	0.37320 (4)	−0.05164 (8)	0.01179 (8)
C13	0.22303 (4)	0.32478 (4)	−0.22766 (8)	0.01295 (8)
H13	0.177114	0.290066	−0.323243	0.016*
C14	0.31402 (4)	0.32648 (4)	−0.26592 (8)	0.01283 (8)
H14	0.329903	0.293120	−0.386674	0.015*
C15	0.38132 (3)	0.37743 (4)	−0.12577 (8)	0.01215 (8)
C16	0.35765 (4)	0.42522 (4)	0.05254 (8)	0.01240 (8)
H16	0.404004	0.459248	0.148423	0.015*
O1	0.11061 (3)	0.37347 (3)	−0.00594 (7)	0.01587 (7)
C17	0.04056 (4)	0.32676 (5)	−0.15693 (10)	0.01998 (10)
H17A	0.036645	0.356648	−0.300050	0.030*
H17B	−0.019153	0.333071	−0.108453	0.030*
H17C	0.056005	0.258430	−0.166186	0.030*
O2	0.47191 (3)	0.38509 (3)	−0.15047 (7)	0.01691 (8)
C18	0.49545 (4)	0.34434 (5)	−0.34295 (10)	0.01952 (10)
H18A	0.454902	0.371139	−0.470203	0.029*
H18B	0.487554	0.274329	−0.340465	0.029*
H18C	0.560067	0.359596	−0.350301	0.029*

	U11	U22	U33	U12	U13	U23
S1	0.01415 (6)	0.01602 (6)	0.01373 (6)	0.00148 (4)	0.00352 (4)	−0.00175 (4)
C2	0.01436 (18)	0.01083 (17)	0.01076 (17)	0.00014 (14)	0.00307 (14)	0.00011 (13)
N3	0.01641 (18)	0.01302 (17)	0.01139 (16)	−0.00157 (13)	0.00354 (13)	−0.00175 (13)
C3A	0.0193 (2)	0.01086 (18)	0.01120 (17)	−0.00042 (15)	0.00426 (15)	−0.00038 (14)
C4	0.0236 (2)	0.0142 (2)	0.01336 (19)	−0.00312 (17)	0.00403 (17)	−0.00254 (15)
C5	0.0314 (3)	0.0140 (2)	0.0142 (2)	−0.00201 (19)	0.00606 (19)	−0.00317 (16)
C6	0.0321 (3)	0.0161 (2)	0.0167 (2)	0.0025 (2)	0.0097 (2)	−0.00306 (17)
C7	0.0239 (2)	0.0180 (2)	0.0176 (2)	0.00356 (19)	0.00846 (19)	−0.00219 (18)
C7A	0.0190 (2)	0.01267 (19)	0.01312 (18)	0.00175 (15)	0.00489 (15)	−0.00059 (15)
C11	0.01340 (17)	0.01037 (17)	0.01029 (16)	0.00010 (13)	0.00241 (13)	−0.00034 (13)
C12	0.01206 (17)	0.01134 (18)	0.01187 (17)	0.00064 (13)	0.00182 (14)	−0.00025 (13)
C13	0.01318 (18)	0.01267 (18)	0.01268 (18)	0.00015 (14)	0.00138 (14)	−0.00222 (14)
C14	0.01418 (18)	0.01223 (18)	0.01217 (18)	0.00012 (14)	0.00257 (14)	−0.00183 (14)
C15	0.01276 (18)	0.01177 (18)	0.01232 (17)	−0.00073 (14)	0.00333 (14)	−0.00073 (14)
C16	0.01365 (18)	0.01212 (18)	0.01161 (17)	−0.00128 (14)	0.00273 (14)	−0.00118 (14)
O1	0.01170 (15)	0.01927 (18)	0.01672 (16)	−0.00048 (12)	0.00270 (12)	−0.00411 (13)
C17	0.01240 (19)	0.0272 (3)	0.0192 (2)	−0.00078 (18)	−0.00011 (17)	−0.0035 (2)
O2	0.01379 (16)	0.02132 (19)	0.01681 (17)	−0.00358 (13)	0.00599 (13)	−0.00600 (14)
C18	0.0175 (2)	0.0238 (3)	0.0190 (2)	−0.00194 (19)	0.00813 (18)	−0.00580 (19)

S1—C7A	1.7327 (6)	C15—O2	1.3686 (6)
S1—C2	1.7642 (5)	C15—C16	1.3941 (7)
C2—N3	1.3064 (7)	O1—C17	1.4243 (7)
C2—C11	1.4704 (7)	O2—C18	1.4276 (7)
N3—C3A	1.3820 (7)	C4—H4	0.9500
C3A—C4	1.4027 (8)	C5—H5	0.9500
C3A—C7A	1.4082 (8)	C6—H6	0.9500
C4—C5	1.3862 (8)	C7—H7	0.9500
C5—C6	1.4043 (10)	C13—H13	0.9500
C6—C7	1.3912 (9)	C14—H14	0.9500
C7—C7A	1.4032 (8)	C16—H16	0.9500
C11—C16	1.4017 (7)	C17—H17A	0.9800
C11—C12	1.4091 (7)	C17—H17B	0.9800
C12—O1	1.3728 (6)	C17—H17C	0.9800
C12—C13	1.3896 (7)	C18—H18A	0.9800
C13—C14	1.3969 (7)	C18—H18B	0.9800
C14—C15	1.3930 (7)	C18—H18C	0.9800
C7A—S1—C2	89.40 (3)	C15—O2—C18	116.63 (4)
N3—C2—C11	121.40 (5)	C5—C4—H4	120.7
N3—C2—S1	114.72 (4)	C3A—C4—H4	120.7
C11—C2—S1	123.86 (4)	C4—C5—H5	119.5
C2—N3—C3A	111.39 (5)	C6—C5—H5	119.5
N3—C3A—C4	124.55 (5)	C7—C6—H6	119.4
N3—C3A—C7A	115.25 (5)	C5—C6—H6	119.4
C4—C3A—C7A	120.20 (5)	C6—C7—H7	121.2
C5—C4—C3A	118.50 (6)	C7A—C7—H7	121.2
C4—C5—C6	121.05 (6)	C12—C13—H13	119.6
C7—C6—C5	121.30 (5)	C14—C13—H13	119.6
C6—C7—C7A	117.66 (6)	C15—C14—H14	120.2
C7—C7A—C3A	121.26 (5)	C13—C14—H14	120.2
C7—C7A—S1	129.51 (5)	C15—C16—H16	119.5
C3A—C7A—S1	109.23 (4)	C11—C16—H16	119.5
C16—C11—C12	118.61 (4)	O1—C17—H17A	109.5
C16—C11—C2	117.91 (4)	O1—C17—H17B	109.5
C12—C11—C2	123.47 (4)	H17A—C17—H17B	109.5
O1—C12—C13	123.26 (5)	O1—C17—H17C	109.5
O1—C12—C11	116.71 (4)	H17A—C17—H17C	109.5
C13—C12—C11	120.02 (5)	H17B—C17—H17C	109.5
C12—C13—C14	120.88 (5)	O2—C18—H18A	109.5
C15—C14—C13	119.54 (5)	O2—C18—H18B	109.5
O2—C15—C14	124.24 (5)	H18A—C18—H18B	109.5
O2—C15—C16	115.90 (4)	O2—C18—H18C	109.5
C14—C15—C16	119.85 (5)	H18A—C18—H18C	109.5
C15—C16—C11	121.10 (5)	H18B—C18—H18C	109.5
C12—O1—C17	117.16 (4)
C7A—S1—C2—N3	0.85 (4)	S1—C2—C11—C16	174.46 (4)
C7A—S1—C2—C11	−177.67 (4)	N3—C2—C11—C12	177.18 (5)
C11—C2—N3—C3A	177.97 (4)	S1—C2—C11—C12	−4.38 (7)
S1—C2—N3—C3A	−0.60 (6)	C16—C11—C12—O1	179.80 (5)
C2—N3—C3A—C4	179.57 (5)	C2—C11—C12—O1	−1.36 (7)
C2—N3—C3A—C7A	−0.08 (7)	C16—C11—C12—C13	0.89 (7)
N3—C3A—C4—C5	178.64 (5)	C2—C11—C12—C13	179.73 (5)
C7A—C3A—C4—C5	−1.73 (8)	O1—C12—C13—C14	−179.65 (5)
C3A—C4—C5—C6	1.12 (9)	C11—C12—C13—C14	−0.81 (8)
C4—C5—C6—C7	0.50 (10)	C12—C13—C14—C15	−0.03 (8)
C5—C6—C7—C7A	−1.46 (9)	C13—C14—C15—O2	−178.84 (5)
C6—C7—C7A—C3A	0.83 (9)	C13—C14—C15—C16	0.78 (8)
C6—C7—C7A—S1	−179.51 (5)	O2—C15—C16—C11	178.96 (5)
N3—C3A—C7A—C7	−179.57 (5)	C14—C15—C16—C11	−0.69 (8)
C4—C3A—C7A—C7	0.76 (8)	C12—C11—C16—C15	−0.14 (7)
N3—C3A—C7A—S1	0.70 (6)	C2—C11—C16—C15	−179.05 (5)
C4—C3A—C7A—S1	−178.96 (4)	C13—C12—O1—C17	−4.35 (8)
C2—S1—C7A—C7	179.48 (6)	C11—C12—O1—C17	176.78 (5)
C2—S1—C7A—C3A	−0.82 (4)	C14—C15—O2—C18	5.35 (8)
N3—C2—C11—C16	−3.97 (7)	C16—C15—O2—C18	−174.28 (5)

D—H···A	D—H	H···A	D···A	D—H···A
C13—H13···O1i	0.95	2.65	3.5113 (7)	151
C18—H18C···N3ii	0.98	2.60	3.4867 (8)	151