Synthesis and crystal structure of a compound with two conformational isomers: 2-(2,6-Difluorobenzamido)-4-methyl-N-o-tolylthiazole-5-carboxamide

Article abstract of DOI:10.1007/s10870-009-9608-y

The single crystal of the title compound (C₁₉H ₁₅F₂N₃O₄S) with two conformational isomers was obtained from the solution of the title compound dissolved in the ethyl acetate by slow evaporation at room temperature. The crystal is Orthorhombic, space group Pca2(1) with a = 21.840(2) A, b = 7.5321(8) A, c = 22.365(2) A, α = 90.00°, β = 90.00°, γ = 90.00°, empirical formula is C₃₈H₃₀F ₄N₆O₄S₂, Mr = 774.80, V = 3,679.2(6) A³, Z = 4, D _c = 1.399 g/cm³, μ(MoKα) = 0.215 mm^-1, F(000) = 1,600, S = 1.032, the final R = 0.0328, wR ₂ = 0.0811 for 4,708 observed reflections with I > 2σ(I). In the unit cell, there are two independent molecules having only slightly different bond lengths, torsion angles and the corresponding dihedral angles of the two molecules are also different. In the crystal structure, molecules are linked through aromatic π-π stacking and intermolecular N-H???N hydrogen bonds interactions, forming 1D chain structure.

Full text of DOI:10.1007/s10870-009-9608-y

J Chem Crystallogr (2010) 40:100–103
DOI 10.1007/s10870-009-9608-y
ORIGINAL PAPER
Synthesis and Crystal Structure of a Compound with Two
Conformational Isomers: 2-(2,6-Difluorobenzamido)-4-methyl-N–
o-tolylthiazole-5-carboxamide
Hua Cai Æ Ying Guo Æ Jian-Gang Li Æ
Yun-Ling Zou
Received: 17 December 2008 / Accepted: 8 August 2009 / Published online: 25 August 2009
Ó Springer Science+Business Media, LLC 2009
Abstract The single crystal of the title compound
(C19H15F2N3O4S) with two conformational isomers was
obtained from the solution of the title compound dissolved
in the ethyl acetate by slow evaporation at room temper-
ature. The crystal is Orthorhombic, space group Pca2(1)
growth of xanthomonas and as ingredients of herbicides,
antischistosomicidal, and anthelmintic drugs [5]. Amino-
thiazoles are known to be ligands of the estrogen receptor
and as a novel class of adenosine receptor antagonists [6].
As a continuous work, in this paper, the authors report the
synthesis and crystal structure of a new 2-Aminothiazole
compound, 2-(2,6-difluorobenzamido)-4-methyl- N–o-tol-
ylthiazole- 5-carboxamide, in which there are two confor-
mational isomers in the unit cell.
˚
with a = 21.840(2) A, b = 7.5321(8) A, c = 22.365(2) A,
˚
˚
a = 90.00°, b = 90.00°, c = 90.00°, empirical formula is
3
˚
C38H30F4N6O4S2, Mr = 774.80, V = 3,679.2(6) A , Z =
4, Dc = 1.399 g/cm3, l(MoKa) = 0.215 mm-1, F(000) =
1,600, S = 1.032, the final R = 0.0328, wR2 = 0.0811 for
4,708 observed reflections with I [ 2r(I). In the unit cell,
there are two independent molecules having only slightly
different bond lengths, torsion angles and the correspond-
ing dihedral angles of the two molecules are also different.
In the crystal structure, molecules are linked through aro-
matic p–p stacking and intermolecular N–HꢀꢀꢀN hydrogen
bonds interactions, forming 1D chain structure.
Experimental
Reagents and Apparatus
All the reagents were purchased commercially and used
without further purification. The melting point was deter-
mined using a WRS-1B digital melting-point apparatus and
uncorrected. The C, H, and N elemental analyses were
carried out with a CE-440 (Leemanlabs) analyzer. Fourier
transform (FT)-IR spectra (KBr pellets) were taken on an
AVATAR-330 (Nicolet) spectrometer. 1H NMR spectra
were recorded on a Varian-300 spectrometer using TMS as
an internal reference.
Keywords Thiazole ꢀ Dihedral angle ꢀ Hydrogen bond ꢀ
Crystal structure
Introduction
The thiazole ring unit is a common structural feature in
various bioactive molecules [1]. This heterocyclic system
has been employed in the preparation of different important
drugs required for treatment of inflammations [2], bacterial
infections [3], and hypertension [4]. Some of the thiazole
analogues are used as fungicides, inhibiting in vivo the
Synthesis of the Title Compound
The title compound was prepared in two stages as shown in
Scheme 1 [7]. To a solution 2-(2,6-difluorobenzamido)-4-
methylthiazole-5-carboxylic acid (2.98 g, 10 mmol) in
dichloromethane (20 mL) was added oxalyl dichloride
(0.54 g, 20 mmol). Two drops of DMF were added to the
reaction mixture after 10 min. The reaction mixture was
stirred at room temperature for 2 h. Then the solvent was
evaporated, afforded acyl chloride, as a yellow solid. The
H. Cai (&) ꢀ Y. Guo ꢀ J.-G. Li ꢀ Y.-L. Zou
College of Science, Civil Aviation University of China,
300300 Tianjin, People’s Republic of China
e-mail: caihua-1109@163.com
123

J Chem Crystallogr (2010) 40:100–103
101
acyl chloride was added dropwise to a solution of o-tolu-
idine (1.07 g, 10 mmol) and Et3N (1.06 g, 10.5 mmol) in
dichloromethane (20 mL) at 0 °C. The mixture was stirred
at room temperature for 3 h. The reaction mixture was
evaporated at reduced pressure. The residue was extracted
with CH2Cl2 (2 9 30 mL), washed with a solution of
NaHCO3, NaCl, dried over anhydrous magnesiumsulfate,
the solvent evaporated again. The residue was purified by
column chromatography (50% EtOAc in hexanes as eluent)
to afford the target compound as a white crystalline solid
(3.29 g, 85% yield). The single crystals suitable for
determination were obtained by slow evaporation from the
solution of the title compound dissolved in ethyl acetate at
room temperature. m.p: 162.4–164.0 °C. IR(KBr, cm-1):
3469(m), 3170(w), 3024(w), 2939(w), 2802(w), 1696(m),
1658(m), 1623(m), 1525(s), 1452(s), 1320(s), 1252(m),
1007(s), 806(m), 752(s). The elemental analysis found for
C38H30F4N6O4S2: C, 58.85; H, 3.99; N, 10.82%. Calcd.: C,
58.91; H, 3.90; N, 10.85%. 1H NMR(300 MHz, DMSO-d6)
d(ppm): 2.26 (s, 3H, CH3), 2.60 (s, 3H, CH3), 7.15–7.39
(m, 6H, Ar–H), 7.61–7.71 (m, 1H, AR–H), 9.62 (s, 1H,
NH), 13.6 (s, 1H, NH).
Results and Discussion
The bond lengths and angles are in normal range [10]
(Table 2), and in agreement with 2-[(Benzoyl)-amino]-4-
methyl-N-(2-chloro-6-methylphenyl)-1,3-thiazole-5-carbox-
amide [7]. In the unit cell of the title compound, there are
two independent molecules (A and B, Fig. 1) having only
slightly different bond lengths, torsion angles and dihedral
angles between them. The C11–C12 and N3–12 bond
˚
lengths are 1.494(4) and 1.338(5) A, respectively, compa-
rable with C30–C31 = 1.475(4) and N6–C31 = 1.357(4)
˚
A, respectively. The S–C–C–O torsion angles, which are
the only note worthy difference in bond geometry between
A and B, namely, 4.8°[S(1)–C(11)–C(12)–O(2)] versus
-16.2° [S(2)–C(30)–C(31)–O(3)] for a difference of 21°.
The methylthiazole, 2-methylphenyl and 2, 6-difluoroben-
zene rings of each molecule are not coplanar. In molecule
A, the dihedral angle formed by the least-squares planes of
the methylthiazole and 2-methylphenyl rings being equal to
3.8°. The dihedral angles between the 2, 6-difluorobenzene
and methylthiazole rings are 49.2°. However, in molecule
X-ray Crystallography
Table 1 Crystal data and structure refinement
Single crystal X-ray diffraction data collection for the title
compound (0.32 9 0.28 9 0.26 mm) was performed on a
Bruker Apex II CCD diffractometer at 293(2) K with Mo
Empirical formula
Mr
C19H15F2N3O2S
387.40
Crystal size/mm
Crystal system
Space group
0.32 9 0.28 9 0.26
Orthorhombic
Pca2(1)
21.840(2)
7.5321(8)
22.365(2)
90
˚
Ka radiation (k = 0.71073 A). A total of 4,708 reflections
was collected, of which 3,962 are independent. The
structure was solved by direct methods and refined by full-
matrix least squares techniques (SHELXTL97) [8, 9]. The
empirical absorption corrections by SADABS were carried
out. All non-hydrogen atoms were located by direct
methods and subsequent difference Fourier syntheses. The
hydrogen atoms were positioned geometrically and refined
using a riding model, with Uiso(H) = 1.2 Ueq(C, N) and
˚
a (A)
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
90
90
3
˚
V (A )
3,679.2(6)
8
U
iso(H) = 1.5 Ueq(C). Crystal and structure refinement
Z
data are shown in Table 1. Selected bond lengths and bond
angles are listed in Table 2, and the hydrogen bond lengths
and bond angles in Table 3.
Dc [g cm-3
]
1.399
l [mm-1
]
0.215
F(000)
1,600
Flack parameter
Fiedel opposites
Total/independent reflections
Parameters
0.06(7)
CH3
O
CH3
O
1,374
F
O
F
N
F
O
F
N
4,708/3,962
491
ClCOCOCl
DMF
Cl
OH
N
S
N
S
H
H
Rint
Ra, Rbw
GOFc
0.0282
0.0328, 0.0803
1.031
CH3
O
NH2
CH3
CH3
F
O
F
N
H
-3
˚
Residuals [e A
]
0.180, -0.189
N
N
S
P
GOF ¼
P
a
H
R ¼ kF0jꢁjFck= jF0j
Et3N
h
h
i
i
1=2
ꢀ
ꢁ
ꢀ
ꢁ
P
n
P
2
2
b
c
Rw
¼
w F02 ꢁ Fc2
=
w F02
h
i
o
1=2
ꢀ
ꢁ
P
2
w F02 ꢁ Fc2 =ðn ꢁ pÞ
Scheme 1 Synthetic process of the title compound
123

102
J Chem Crystallogr (2010) 40:100–103
˚
Table 2 Selected bond lengths (A), angles (°) and torsion angles (°)
S(1)–C(8)
1.720(3)
1.729(4)
1.714(3)
1.730(3)
1.362(5)
1.352(5)
1.369(5)
1.344(4)
1.217(4)
1.213(4)
1.229(4)
1.208(4)
1.351(4)
1.385(4)
1.301(4)
1.375(4)
1.338(5)
1.428(4)
1.357(4)
1.376(4)
1.309(4)
1.373(4)
1.357(4)
1.424(4)
1.495(5)
1.486(5)
1.494(4)
1.503(6)
1.506(5)
1.501(5)
1.475(4)
1.515(6)
N(1)–C(7)–C(6)
114.3(3)
122.6(3)
123.1(3)
124.3(3)
117.4(3)
116.2(3)
119.3(4)
124.5(3)
129.7(3)
122.4(3)
113.9(3)
123.3(3)
122.8(3)
125.0(2)
116.4(2)
116.7(3)
119.7(3)
123.6(3)
130.1(3)
123.1(3)
177.2(3)
-4.3(5)
129.8(4)
180.0(3)
0.3(6)
S(1)–C(11)
S(2)–C(27)
S(2)–C(30)
F(1)–C(1)
O(1)–C(7)–C(6)
O(1)–C(7)–N(1)
C(7)–N(1)–C(8)
N(2)–C(9)–C(10)
F(2)–C(5)
N(3)–C(12)–C(11)
O(2)–C(12)–C(11)
O(2)–C(12)–N(3)
F(3)–C(20)
F(4)–C(24)
O(1)–C(7)
O(2)–C(12)
O(3)–C(31)
O(4)–C(26)
N(1)–C(7)
N(1)–C(8)
N(2)–C(8)
N(2)–C(9)
N(3)–C(12)
N(3)–C(13)
N(4)–C(26)
N(4)–C(27)
N(5)–C(27)
N(5)–C(28)
N(6)–C(31)
N(6)–C(32)
C(6)–C(7)
C(12)–N(3)–C(13)
C(13)–C(18)–C(19)
N(4)–C(26)–C(25)
O(4)–C(26)–C(25)
O(4)–C(26)–N(4)
Fig. 1 Molecular structure of the title compound. (Dotted lines
indicate p–p stacking interactions)
C(26)–N(4)–C(27)
N(5)–C(28)–C(29)
N(6)–C(31)–C(30)
O(3)–C(31)–C(30)
O(3)–C(31)–N(6)
C(31)–N(6)–C(32)
C(32)–C(37)–C(38)
C(8)–N(1)–C(7)–C(6)
C(8)–N(1)–C(7)–O(1)
C(5)–C(6)–C(7)–N(1)
C(13)–N(3)–C(12)–C(11)
C(13)–N(3)–C(12)–O(2)
S(1)–C(11)–C(12)–O(2)
C(27)–N(4)–C(26)–C(25)
C(20)–C(25)–C(26)–O(4)
C(20)–C(25)–C(26)–N(4)
C(32)–N(6)–C(31)–C(30)
C(32)–N(6)–C(31)–O(3)
S(2)–C(30)–C(31)–O(3)
Fig. 2 1-D chain structure along [100] direction via multiple N–
HꢀꢀꢀN and p–p stacking interactions
The dimers are further linked by the intermolecular
N–HꢀꢀꢀN hydrogen bonds (Table 3), which form the R22 (8)
rings. This creates 1D chain in the [100] direction (Fig. 2).
C(9)–C(10)
C(11)–C(12)
C(18)–C(19)
C(25)–C(26)
C(28)–C(29)
C(30)–C(31)
C(37)–C(38)
4.8(4)
-176.1(3)
52.4(5)
Supplementary Material
-128.6(4)
172.0(3)
-7.7(5)
-16.3(4)
CIF file has been deposited with the Cambridge Crystal-
lography Data Center. Supplementary data are available
from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK, on request, quoting the deposition numbers 712255.
Acknowledgments We acknowledge financial support by the Sci-
entific Research Foundation of Civil Aviation University of China
(No. 08CAUC-S01, No. 07KYS05) and Natural Science Foundation
of Tianjin (09JCYBJC04200).
˚
Table 3 Hydrogen bond lengths (A) and bond angles (°)
˚
˚
˚
D–HꢀꢀꢀA (A)
DꢀꢀꢀA (A)
HꢀꢀꢀA (A)
D–HꢀꢀꢀA (°)
N1–H1ꢀꢀꢀN5i
2.9284
2.9371
2.07
2.08
175
174
N4–H4ꢀꢀꢀN2ii
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