Crystal structures, vibrational spectra, and fungicidal activity of 1,5-diaryl-3-oxypyrazoles

Article abstract of DOI:10.3390/molecules19011302

The aryloxypyrazole structure is present in a number of bioactive molecules. Four 1,5-diaryl-3-oxypyrazoles containing benzoyl (I), thiazolidinethione (II and III) or per-O-Acetylated glucopyranosyl (IV) moieties were characterized by single-crystal X-ray

Full text of DOI:10.3390/molecules19011302

Molecules 2014, 19, 1302-1316; doi:10.3390/molecules19011302
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Crystal Structures, Vibrational Spectra, and Fungicidal Activity
of 1,5-Diaryl-3-oxypyrazoles
Yi Li 1, Yuanyuan Liu 2,*, Yihuang Xiong 3 and Xiaohui Xiong 1,*
1
College of Food Science and Light Industry, Nanjing University of Technology,
Nanjing 211816, China; E-Mail: liynj2012@njut.edu.cn
2
Department of Chemical and Pharmaceutical Engineering,
Southeast University ChengXian College, Nanjing 210088, China
3
Department of Materials Science and Engineering, the Pennsylvania State University,
University Park, Pennsylvania, PA 16802, USA; E-Mail: yyx5048@psu.edu
* Authors to whom correspondence should be addressed; E-Mails: liuyuanyuan@cxxy.seu.edu.cn (Y.L.);
xxh@njut.edu.cn (X.X.); Tel.: +86-137-7061-9279 (Y.L.); +86-25-5813-9432 (X.X.).
Received: 4 November 2013; in revised form: 9 January 2014 / Accepted: 14 January 2014 /
Published: 21 January 2014
Abstract: The aryloxypyrazole structure is present in a number of bioactive molecules.
Four 1,5-diaryl-3-oxypyrazoles containing benzoyl (I), thiazolidinethione (II and III) or
per-O-acetylated glucopyranosyl (IV) moieties were characterized by single-crystal X-ray
diffraction. Compounds I and II crystallize in a triclinic P-1 system, whereas III and IV
crystallize in an orthorhombic Pbca and a monoclinic P21 space groups, respectively.
The dihedral angles between the two benzene rings of the pyrazole are 61.33° (I), 62.87° (II),
57.09° (III) and 70.25° (IV). The structures were stabilized by classical intra- (C-H···S for
II and III, C-H···O for IV) and intermolecular (C-H···O for I and IV) H-bonds, as well as
intermolecular C-H···π stacking interactions. The theoretical FTIR results showed good
agreement with the experimental data. Compounds IV, II and III showed moderate
fungicidal activity against Sclerotinia sclerotiorum and Gibberella zeae. The structure-activity
relationships were discussed.
Keywords:
1,5-diaryl-3-oxypyrazoles;
crystal
structure;
fungicidal
activity;
structure-activity relationship

Molecules 2014, 19
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1. Introduction
Since the discovery of the fungicide pyraclostrobin by BASF scientists [1–3], aryloxypyrazoles
have attracted enormous attention due to their diverse bioactivities in fungicide [4,5], insecticide [6],
and herbicide [7]. We have also devoted considerable effort to develop this series of fungicide, and
found several 1,5-diaryl-3-oxypyrazoles containing alkyloxyacetate, heterocycle, glucopyranosyl or
benzoyl moieties with fungicidal activity [8–12]. However, their detailed structural properties and
structure-activity relationship have not been reported.
In this paper, we report the crystal structures and FTIR spectra of four 1,5-diaryl-3-oxypyrazoles
bearing benzoyl (I), thiazolidinethione (II and III) or per-O-acetylated glucopyranosyl (IV) moieties
(Figure 1). Meanwhile, their in vitro fungicidal activity against Sclerotinia sclerotiorum and
Gibberella zeae has been investigated, and their structure-activity relationshipe were also discussed.
Figure 1. The four 1,5-diaryl-3-oxypyrazoles I, II, III, and IV.
2. Results and Discussion
2.1. Structural Description
The detailed crystal and structure refinement data of I–IV are listed in Table 1. Compounds I and II
crystallize in a triclinic p-1, whereas III and IV crystallize in an orthorhombic Pbca and a monoclinic
P21 space groups, respectively. Selected bond lengths and angles/torsion angles for I–IV are given in
Table 2. The bond lengths of N1-C4 (1.417(7) Å) and N3-C17 (1.412(6) Å) in II and III are longer
than normal N-C amide bond (1.325-1.352 Å) [13]. The C7-Cl bond length in II is 1.732(6) Å, which
is similar to the aryl-Cl value of 1.730(7) Å (C11-Cl) in III. The C16-F bond length in IV is 1.380(7) Å,
representing a typical alkyl-F bond, and the value is similar to those (1.371(3) Å) reported for other
related derivatives [14]. The bond angle of C9-C10-C11 in I is 104.2(3)°, whereas the corresponding

Molecules 2014, 19
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bond angles in II–IV are 106.3(5)° (C6-C7-C8), 104.9(4)° (C13-C14-C15), and 104.4(5)° (C10-C11-C12),
respectively. These values are similar to the typical angle values of five-membered rings (108.0°).
Table 1. Crystal data and structure refinements for I, II, III and IV.
I
II
819778
III
918082
IV
925316
C32H35FN2O10
626.62
CCDC
Empirical formula
Formula weight
Temperature
Wavelength (Å)
Crystal system
Space group
a (Å)
906894
C24H20N2O4
400.42
C21H18ClN3O3S2
459.95
C20H16ClN3O2S2
429.93
293(2)
293(2)
293(2)
293(2)
0.71073
Triclinic
P-1
0.71073
Triclinic
P-1
0.71073
Orthorhombic
Pbca
0.71073
Monoclinic
P21
9.3040(19)
10.507(2)
12.075(2)
68.70(3)
81.40(3)
67.99(3)
1,019.5(4)
2
6.0180(12)
8.2370(16)
21.600(4)
87.08(3)
87.46(3)
82.30(3)
1,058.9(4)
2
13.698(3)
7.6260(15)
38.908(8)
90.00
11.838(2)
9.4500(19)
14.514(3)
90.00
b (Å)
c (Å)
α (°)
β (°)
90.00
100.41(3)
90.00
γ (°)
Volume (Å3)
90.00
4,064.4(14)
8
1,596.9(6)
2
Z
Calculated density (Mg/m3)
Absorption coefficient
(mm−1)
1.304
1.443
1.405
1.303
0.090
0.406
0.414
0.101
F(000)
420
476
1,776
660
Crystal size (mm)
θ range for data collection
(°)
0.10 × 0.20 × 0.30
0.05 × 0.05 × 0.10
0.10 × 0.20 × 0.30
0.10 × 0.20 × 0.30
1.81–25.36
1.89–25.28
1.05–25.28
1.43–25.25
0 ≤ h ≤ 11
−11 ≤ k ≤ 12
−14 ≤ l ≤ 14
4002
0 ≤ h ≤ 7
−9 ≤ k ≤ 9
0 ≤ h ≤ 16
0 ≤ k ≤ 9
−14 ≤ h ≤ 13
0 ≤ k ≤ 11
Index ranges
−25 ≤ l ≤ 25
4239
0 ≤ l ≤ 46
0 ≤ l ≤ 17
Reflections collected
Independent reflections
[R(int)]
3688
3091
3750
3843
3688
3091
[R(int) = 0.045]
[R(int) = 0.061]
0.9800 and 0.9605
Full-matrix
least-squares
3843/0/272
1.002
[R(int) = 0.034]
0.9597 and 0.8857
Full-matrix
least-squares
3688/0/253
1.032
[R(int) = 0.052]
0.9900 and 0.9704
Full-matrix
least-squares
3091/7/388
1.004
Max. and min. transmission 0.9911 and 0.9736
Full-matrix
Refinement method on F2
least-squares
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices
3750/0/271
1.005
R1 = 0.0688
wR2 = 0.1508
R1 = 0.1452
wR2 = 0.1835
R1 = 0.0854
wR2 = 0.1592
R1 = 0.1766
wR2 = 0.1897
R1 = 0.0740
wR2 = 0.1616
R1 = 0.1359
wR2 = 0.1922
R1 = 0.0656
wR2 = 0.1567
R1 = 0.1000
wR2 = 0.1798
[I > 2σ(I)]; R1, wR2
R1, wR2 (all data)
Largest diff. peak and hole
(e·Å−3)
0.149 and −0.169
0.451 and −0.266
0.325 and −0.358
0.226 and −0.577

Molecules 2014, 19
Table 2. Selected bond lengths (Å), bond angles/torsion angles (°) for I, II, III, and IV.
1305
Comp. Bond lengths (Å)
X-ray
Bond angles/Torsion angles (°)
C9-C10-C11
X-ray
104.2(3)
173.5(3)
−172.8(3)
5.0(5)
I
C11-O3
N1-N2
C5-C9
1.391(4)
1.374(3)
1.472(4)
1.360(4)
N2-N1-C11-O3
N1-N2-C9-C5
O3-C18
C1-O1-C8-C7
C2-O2-C3-C4
−2.7(5)
II
C6-O2
N1-C4
C7-Cl
N2-N3
C8-C9
O2-C5
1.326(8)
1.417(7)
1.732(6)
1.357(6)
1.479(8)
1.414(7)
C6-C7-C8
N3-N2-C6-O2
N2-N3-C8-C9
C15-O3-C12-C11
C4-N1-C3-S2
106.3(5)
−179.7(6)
−176.1(6)
1.1(11)
−1.0(10)
III
C15-O1
N3-C17
C11-Cl
N1-N2
1.351(5)
1.412(6)
1.730(7)
1.365(5)
1.477(7)
1.424(5)
C13-C14-C15
N1-N2-C15-O1
N2-N1-C13-C7
C17-N3-C18-S1
104.9(4)
178.1(4)
177.8(4)
9.4(7)
C7-C13
O1-C16
IV
C10-O1
C16-F
1.392(6)
1.380(7)
1.388(5)
1.499(7)
1.404(6)
C10-C11-C12
N2-N1-C10-O1
N1-N2-C12-C13
O1-C19-O2-C20
O2-C19-C23-O10
C21-C20-C26-O4
C19-O1-C10-C11
104.4(5)
177.4(6)
−176.3(6)
−173.8(4)
−174.2(4)
−61.0(6)
160.7(6)
N1-N2
C12-C13
O1-C19
X-ray diffraction studies indicated that the dihedral angles between the C-linked benzene ring A and
N-linked benzene ring B of I, II, III, and IV are 61.33°, 62.87°, 57.09°, and 70.25°, respectively.
Rings A, B and benzoyloxy ring C in I are twisted 50.95°, 40.62°, and 64.18°, respectively, from the
plane of the pyrazole ring. The dihedral angle between rings A and C is 32.20°, whereas the
corresponding angle between rings B and C is 47.99°. The N2-N1-C11-O3 and N1-N2-C9-C5 torsion
angles are 173.5(3)° and −172.8(3)°, whereas the corresponding angles in II, III, and IV are
−179.7(6)° (N3-N2-C6-O2) and −176.1(6)° (N2-N3-C8-C9), 178.1(4)° (N1-N2-C15-O1) and
177.8(4)° (N2-N1-C13-C7), 177.4(6)° (N2-N1-C10-O1) and −176.3(6)° (N1-N2-C12-C13),
respectively. The methoxyl groups in I and II are almost co-planar with the benzene ring. The torsion
angles of C1-O1-C8-C7, C2-O2-C3-C4 and C15-O3-C12-C11 are found to be 5.0(5)°, −2.7(5)°, and
1.1(11)°, respectively, which are consistent with the literature value of 174.9(4)° [15]. Rings A, B and
thiazolidine-2-thione ring D in II are twisted 64.12°, 38.34°, and 79.22°, respectively, from the plane
of the pyrazole ring, whereas the corresponding angles in III are 45.00°, 50.49°, and 69.94°. Rings D
in II and III both adopt envelope conformation, with the C1 and C19 atoms displaced by 0.240 Å and

Molecules 2014, 19
1306
0.368 Å from the plane of the other ring atoms. The torsion angle of C4-N1-C3-S2 in II is −1.0(10)°,
whereas the corresponding torsion angle in III is 9.4(7)° (C17-N3-C18-S1). Rings A and B in IV are
twisted 59.92° and 43.65°, respectively, from the plane of the pyrazole ring. An ORTEP view of IV
4
reveals that the saccharide moiety in IV is a glucopyranose ring in the usual C1 conformation.
The anomeric center of the saccharide has the β configuration, which is also confirmed from the
torsion angles of O1-C19-O2-C20 −173.8(4)° and O2-C19-C23-O10 −174.2(4)°. The torsion angle
C21-C20-C26-O4 of −61.0(6)° indicates the acetyl group attached to the primary hydroxyl group is in
the gt position, which is known to be the favored orientation for a glucopyranose. The pyrazole ring is
nearly coplanar with the anomeric C19 atom by making a torsion angle of C19-O1-C10-C11 160.7(6)°,
and this orientation facilitates the delocalization of electrons from the lone-pair orbitals of O1 with the
π orbitals of the pyrazole ring.
The atom numbering schemes and arrangements for I-IV are shown in Figure 2. The molecules are
organized in the crystal lattice by classical intramolecular (C-H···S for II and III, and C-H···O for IV)
and intermolecular (C-H···O for I and IV) H-bonds (Table 3a), as well as intermolecular C-H···π
stacking interactions (Table 3b). For I (Figure 3), there is an intermolecular C-H···O H-bond, between
the pyrazole hydrogen and the oxygen atom of the methoxyl group, as well as six C-H···π interactions,
between the ring B hydrogen (H17A) and the center of the pyrazole ring (C17-H17A···Cg1), the
methoxyl hydrogen (H2B), ring A hydrogen (H4A), or phenyl hydrogen (H24A) and the center of the
ring B (C2-H2B···Cg2, C4-H4A···Cg2, and C24-H24A···Cg2), as well as the phenyl hydrogen
(H22A) or the methoxyl hydrogen (H2C) to the center of the ring A (C22-H22A···Cg3 and
C2-H2C···Cg3), to form a three-dimensional network. For II (Figure 4), the intramolecular
C5-H5A···S2 H-bond results in the formation of one non-planar pseudo ring (C5/H5A/S2/C3/N1/C4),
with H5A atom displaced by 0.580 Å from the plane of the other ring atoms. Five C-H···π
interactions, between the methylene hydrogen (H2C) and the center of the ring D (C2-H2C···Cg4), the
methylene hydrogen (H1A) or the phenyl hydrogen (H14A) and the center of the ring B
(C1-H1A···Cg2 and C14-H14A···Cg2), and the phenyl hydrogens (H17A and H18A) and the center of
the pyrazole ring (C17-H17A···Cg1 and C18-H18A···Cg1), form dimers. For III (Figure 5), the
structure is stabilized by the intramolecular C-H···S H-bond, between the methylene hydrogen and the
sulfur atom of the ring D to form a non-planar pseudo ring (H16B/C16/C17/N3/C18/S1) bearing
envelope conformation, with H16B atom displaced by 0.604 Å from the plane of the other atoms, and
three C-H···π interactions, one is between the methylene hydrogen (H19B) and the center of the ring B
(C19-H19B···Cg2), and the others are from the pyrazole hydrogen (H14A) or the methylene
hydrogen (H19C) to the center of the pyrazole ring (C14-H14A···Cg1 and C19-H19C···Cg1). For IV
(Figure 6), five intra- and four intermolecular H-bonds, and six C-H···π interactions, between
the phenyl hydrogens (H14A and H18A) to the center of the pyrazole ring (C14-H14A···Cg1 and
C18-H18A···Cg1), and the methyl hydrogens (H27A-C and H31C) to the centers of the rings A or
B (C27-H27A···Cg2, C27-H27C···Cg2, C27-H27B···Cg3, and C31-H31C···Cg3), reinforce the
crystal packing.

Molecules 2014, 19
Table 3. Parameters (Å, °) for the intra- and intermolecular interactions in I, II, III, and IV.
1307
Comp.
D-H…A
D-H
H···A
D···A
D-H···A
(a) Intermolecular and intramolecular hydrogen bond
I
C10-H10A···O1 a
C5-H5A···S2
0.9300
0.9700
0.9700
0.9800
0.9800
0.9800
0.9800
0.9800
0.9300
0.9800
0.9600
0.9600
C-H
2.5100
2.5900
2.5800
2.5300
2.2700
2.4000
2.4000
2.2600
2.5200
2.4100
2.5100
2.4200
H···Cg
3.442(5)
3.033(8)
3.094(5)
2.897(8)
2.645(8)
2.975(8)
2.958(7)
2.659(9)
3.440(10)
3.363(9)
3.375(11)
3.320(10)
C···Cg
175.00
108.00
113.00
102.00
102.00
117.00
116.00
103.00
170.00
163.00
150.00
155.00
C-H···Cg
II
III
C16-H16B···S1
C21-H21A···O4
C21-H21A···O5
C21-H21A···O7
C23-H23A···O7
C23-H23A···O9
C17-H17A···O3 b
C20-H20A···O3 c
C24-H24B···O9 d
C29-H29C···O7 e
C-H···Cg
IV
Comp.
(b) C-H…π interactions
I
C17-H17A···Cg1 f
0.9300
0.9600
0.9300
0.9300
0.9600
0.9300
0.9700
0.9700
0.9300
0.9300
0.9300
0.9700
0.9300
0.9700
0.9300
0.9300
0.9600
0.9600
0.9600
0.9600
3.2873
3.1975
3.3208
3.3983
2.9016
3.1317
3.0259
3.2864
3.0647
3.2738
3.0448
3.3425
2.8623
3.3978
3.2004
3.3184
3.0282
3.2317
2.7786
3.3687
3.900(4)
4.050(5)
4.113(4)
4.143(5)
3.706(5)
3.866(6)
3.812(8)
3.927(8)
3.906(7)
3.550(7)
3.418(9)
4.032(6)
3.725(6)
3.940(6)
3.780(9)
3.865(7)
3.571(9)
3.571(9)
3.647(9)
4.192(9)
125.39
148.87
144.40
138.64
142.02
137.15
139.03
125.25
151.31
99.63
C2-H2B···Cg2 f
C4-H4A···Cg2 f
C24-H24A···Cg2 g
C2-H2C···Cg3 a
C22-H22A···Cg3 h
C2-H2C···Cg4 i
II
C1-H1A···Cg2 i
C14-H14A···Cg2 j
C17-H17A···Cg1 k
C18-H18A···Cg1 k
C19-H19B···Cg2 l
C14-H14A···Cg1 m
C19-H19C···Cg1 n
C14-H14A···Cg1 o
C18-H18A···Cg1 p
C27-H27A···Cg2 c
C27-H27C···Cg2 c
C27-H27B···Cg3 q
C31-H31C···Cg3 o
105.87
129.74
154.68
117.46
122.32
119.69
117.24
102.94
150.82
144.97
III
IV
Symmetry codes: a 1-x, 2-y, −z; b x, y, −1+z; c 1-x, 1/2+y, 1-z; d 2-x, −1/2+y, 1-z; e 2-x, 1/2+y, 1-z; f 1-x, 1-y, −z;
g
h
i
j
k
l
m
2-x, 1-y, −z; 1+x, y, −1+z; 1-x, -y, 1-z; 1+x, y, z; −1+x, y, z; 2-x, 1/2+y, 1/2-z; 3/2-x, 1/2+y, z;
n
o
p
q
2-x, −1/2+y, 1/2-z; 1-x, 1/2+y, −z; 1-x, −1/2+y, −z; x, y, 1+z; Cg1, Cg2, Cg3, and Cg4 are the
centroids of the pyrazole ring, N-linked benzene ring B, C-linked benzene ring A, and thiazolidine-2-thione
ring D, respectively.

Molecules 2014, 19
1308
Figure 2. X-ray crystal structures of I, II, III, and IV.
Figure 3. (1) A packing diagram of I; (2) Intermolecular C-H···π interactions of I.
Figure 4. (1) A packing diagram of II; (2) Intermolecular C-H···π interactions of II.

Molecules 2014, 19
Figure 5. (1) A packing diagram of III; (2) Intermolecular C-H···π interactions of III.
1309
Figure 6. (1) A packing diagram of IV; (2) Intermolecular C-H···π (pyrazole) interactions of IV;
(3) Intermolecular C-H···π (phenyl) interactions of IV.
2.2. Experimental and Theoretical FTIR Results
The experimental and theoretical FTIR spectra for I–IV are shown in Figure 7, where the intensity
is plotted against the vibrational frequencies. The primary vibrational frequencies with assignments are
listed in Table 4. The main signals are grouped in three regions, including the ranges of 2800–3200 cm−1,
1000–1800 cm−1 and 500–1000 cm−1. The second region shows strongly mixed vibrational bands.
The C=O stretching vibrations of I–IV were found at 1739 cm−1, 1714 cm−1, 1708 cm−1, and 1755 cm−1,

Molecules 2014, 19
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whereas they were calculated at 1737 cm−1, 1718 cm−1, 1711 cm−1, and 1752 cm−1, respectively.
The experimental and theoretical C=C stretching vibrations of the phenyl rings were found in the
region of 1440–1630 cm−1, which were consistent with the literature value of 1,430–1,625 cm−1 [16].
The bands observed in the region of 1000–1300 cm−1 corresponded to the symmetric and asymmetric
C-O stretching vibrations. The region below 1000 cm−1 exhibited the out of plane bending C-H
vibrations of the aromatic rings, and the region in 3000–3200 cm−1 was the characteristic absorption of
the aromatic C-H stretching vibrations. The C-Cl stretching vibration in II was consistent with the
aromatic C-Cl stretching vibration in III. The experimental C-F stretching vibration at 1330 cm−1 in
IV was consistent with its theoretical value of 1332 cm−1. These results indicated that the observed and
calculated FTIR data were in good agreement with each other.
Table 4. Primary vibrations of experimental and theoretical FTIR for I, II, III, and IV (cm−1).
I
II
B3LYP/
III
B3LYP/
IV
Vibration
ν=CH
B3LYP/
6-31G *
3090
Exp.
Exp.
Exp.
Exp.
B3LYP/6-31G *
3068
6-31G *
6-31G *
3069
3066
3076
3058
3073
3069
νC-H
2958
2838
2953
2842
2932
2842
2935
2847
2927
2848
2936
2845
2963
2898
2958
2896
νC=O
νC=C
1739
1596
1549
1507
1444
1737
1593
1548
1509
1440
1714
1616
1521
1456
1718
1624
1521
1458
1708
1627
1595
1551
1502
1466
1711
1623
1604
1552
1508
1459
1755
1610
1556
1515
1466
1752
1603
1555
1514
1463
νC-O
1259
1167
1147
1088
1066
1027
1264
1168
1130
1095
1071
1020
1280
1255
1226
1179
1134
1027
1267
1267
1222
1185
1147
1024
1280
1225
1187
1054
1266
1240
1183
1053
1230
1161
1080
1055
1234
1163
1081
1054
γ=C-H
864
811
768
703
869
807
764
703
837
773
698
828
782
695
881
790
767
696
672
888
787
774
701
676
845
779
846
770
νC-Cl
νC-F
734
736
734
737
1330
1332

Molecules 2014, 19
Figure 7. Experimental (above) and theoretical (below) FTIR spectra for I, II, III, and IV.
1311
1000
500
1000
500
3500
3000
2500
2000
1500
3500
3000
2500
2000
1500
Wavenumber(cm-1)
Wavenumber (cm-1)
1000
500
3000
2500
2000
500
3500
3000
2500
2000
1500
3500
1500
1000
Wavenumber(cm-1)
Wavenumber(cm-1)
2.3. Fungicidal Activity
Compounds I–IV were evaluated for in vitro fungicidal activity against Sclerotinia sclerotiorum
and Gibberella zeae, at a dosage of 10 μg/mL. As can be seen in Table 5, for Sclerotinia sclerotiorum,
Compound IV (29%) possessing a per-O-acetylated glucopyranosyl moiety, displayed better activity
than I (0%), II (21%), and III (14%).
Table 5. In vitro fungicidal activities of I, II, III, and IV (% inhibition).
Inhibition rate (%)
Comp.
X
Y
S. sclerotiorum
G. zeae
I
3,4-(OCH3)2
p-OMe
m-Cl
H
0
4
II
H
H
21
14
29
32
29
11
III
IV
p-F
p-Me2CH
The reason was speculated that the glucopyranosyl moiety could form more H-bonds (Figure 2) to
improve the hydrophilicity of molecule, which could balance the HLB value and then increase the
systemic of molecule within plant. Within the series of thiazolidinethione derivatives, compound II
(21%, 32%) with an electron-withdrawing chloro group on the pyrazole ring displayed better
fungicidal activity against the two fungi than III (14%, 29%), and both compounds showed better

Molecules 2014, 19
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inhibitory activity against Gibberella zeae than I (4%) and IV (11%). The results might imply that the
introduction of the heterocycle moiety by full consideration of the electronic effects was important for
improving its fungicidal activity. However, compound I containing a benzoyloxy moiety showed the
worst activity (0, 4%), which indicated switching the C3-substituent of the pyrazole ring from
thiazolidinethione to benzoyloxy moiety had no effective impact on the inhibition rates. The
structure-activity relationship revealed that the improvement of bioactivity might require a reasonable
design of molecules (e.g., considering H-bonds effect and heterocycle) and full consideration of the
electronic effects of electron-withdrawing groups to balance the HLB value and enhance the systemic
of the whole molecule.
3. Experimental
3.1. General Information
Melting points were measured on an X-4 microscope electrothermal apparatus (Taike, Nanjing,
1
China) and were uncorrected. H-NMR spectra were recorded on a Bruker spectrometer (Bruker,
Leipzig, Germany) at 300 or 500 MHz using CDCl3 or DMSO-d6 as solvent, with tetramethylsilane as
an internal standard. Elemental analyses were performed on a Flash EA-1112 elemental analyzer
(Thermo, Illinois, USA). FTIR spectra of compounds I–IV were recorded in the region of 4000–400 cm−1
on a Nicolet 380 FT-IR spectrophotometer (Thermo, Waltham, MA, USA) using the KBr pellet technique.
3.2. Synthesis and Characterization
Compounds I–IV were prepared from 1,5-diaryl-1H-pyrazol-3-ols via a series of reactions that
included substitution, hydrolysis, condensation, chlorination, glycosylation, or esterification [8–12].
3.2.1. Preparation of Compound I
To a solution of 5-(3,4-dimethoxyphenyl)-1-phenyl-1H-pyrazol-3-ol (0.59 g, 2.0 mmol) in CHCl3
(50 mL) was added Et3N (0.41 g, 4.0 mmol). The mixture was stirred for 10 min and benzoyl chloride
(0.42 g, 3.0 mmol) was added. Then, the mixture was stirred at r.t. for 2 h. The solvent was removed
under reduced pressure and the residue was recrystallized from ethanol to give the white solid product
5-(3,4-dimethoxyphenyl)-1-phenyl-3-benzoyloxy-1H-pyrazole (I). Yield: 87%; M.p. 133–134 °C;
1H-NMR (300 MHz, DMSO-d6) δ: 8.16 (d, J = 7.2 Hz, 2H, Ar-H), 7.79 (t, J = 7.3 Hz, 1H, Ar-H),
7.65 (t, J = 7.3 Hz, 2H, Ar-H), 7.48–7.31 (m, 5H, Ar-H), 7.00–6.80 (m, 3H, Ar-H), 6.67 (s, 1H, CH),
3.76 (s, 3H, OCH3), 3.57 (s, 3H, OCH3); Anal. Calcd for C24H20N2O4: C 71.99, H 5.03, N 7.00; found
C 71.75, H 5.01, N 7.03.
3.2.2. Preparation of Compound II
SOCl2 (5 mL) was put into a round-bottom flask and then 2-((5-(4-methoxyphenyl)-1-phenyl-1H-
pyrazol-3-yl)oxy)-1-(2-thioxothiazolidin-3-yl)ethanone (0.43 g, 1.0 mmol) as well as catalytic amount
of DMF (0.1 mmol) was added. The mixture was heated under reflux for 4 h. Then excess SOCl2 was
evaporated under reduced pressure and H2O (200 mL) was added with good stirring. The precipitate

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was filtered off, washed with water and dried. It was then purified by flash column chromatography
(eluent: ethyl acetate/petroleum ether, 1:6 v/v) to afford the yellow solid product 2-((4-chloro-5-(4-
methoxyphenyl)-1-phenyl-1H-pyrazol-3-yl)oxy)-1-(2-thioxothiazolid-in-3-yl)ethanone (II). Yield: 65%;
1
M.p. 193–194 °C; H-NMR (500 MHz, CDCl3) δ: 7.26–7.15 (m, 7H, Ar-H), 6.88 (d, J = 8.8 Hz, 2H,
Ar-H), 5.78 (s, 2H, CH2), 4.61 (t, J = 7.6 Hz, 2H, CH2), 3.82 (s, 3H, OCH3), 3.38 (t, J = 7.6 Hz, 2H,
CH2); Anal. Calcd for C21H18ClN3O3S2: C 54.84, H 3.94, N 9.14; found C 54.95, H 3.95, N 9.17.
3.2.3. Preparation of Compound III
2-((5-(3-Chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)oxy)acetic acid (0.33 g, 1.0 mmol) was dissolved
in a solution of DCC (0.22 g, 1.05 mmol) in CH2Cl2 (50 mL), and the mixture was stirred at 0 °C for 1 h.
Then, thiazolidine-2-thione (0.12 g, 1.0 mmol) and DMAP (0.01 g, 0.1 mmol) was added.
The solution was stirred at 0 °C for 2 h and then at room temperature for 12 h. The white precipitate
was filtered off and the solvent was evaporated under reduced pressure. The residue was purified by
flash column chromatography over silica gel eluting with petroleum ether/ethyl acetate 3:1 to gain the
the yellow solid product 2-((5-(3-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)oxy)-1-(2-thioxothiazolidin-
3-yl)ethanone (III). Yield: 73%; M.p. 143–144 °C; 1H-NMR (500 MHz, CDCl3) δ: 7.30–7.05 (m, 9H,
Ar-H), 6.05 (s, 1H, CH), 5.72 (s, 2H, CH2), 4.60 (t, J = 7.6 Hz, 2H, CH2), 3.37 (t, J = 7.6 Hz, 2H,
CH2); Anal. Calcd for C20H16ClN3O2S2: C 55.87, H 3.75, N 9.77; found C 55.78, H 3.74, N 9.80.
3.2.4. Preparation of Compound IV
A mixture of CHCl3 (20 mL), Bu4N+Br− (0.23 g, 0.7 mmol), and H2O (2 mL) was heated to 55 °C,
and then a solution of 1-(4-fluorophenyl)-5-(4-isopropylphenyl)-1H-pyrazol-3-ol (0.30 g, 1.0 mmol)
in CHCl3 (15 mL) and 5% aqueous NaOH (6 mL) were added dropwise. The pH value was adjusted
to 8–10, and acetobromo-α-D-glucose (0.54 g, 1.3 mmol) was added under vigorously stirring. The
mixture was stirred at 55 °C for another 4 h, and then left to cool to room temperature. The organic
layer was separated, washed with 5% aqueous NaOH, and dried. Then, the solvent was removed
in vacuo and the residue was recrystallized from ethanol to give the white solid product 3-(2′,3′,4′,
6′-tetra-O-acetyl-β-D-glucopyranosyloxy)-1-(4-isopropylphenyl)-5-(4-fluorophenyl)-1H-pyrazole (IV).
Yield: 46%; M.p. 151–152 °C. 1H-NMR (500 MHz, CDCl3) δ: 7.26–6.97 (m, 8H, Ar-H), 5.99 (s, 1H,
CH), 5.67 (d, J = 7.7 Hz, 1H, H1′), 5.32–5.26 (m, 2H, H2′, H3′), 5.19 (t, J = 9.5 Hz, 1H, H4′),
4.28 (dd, J = 4.7, 12.4 Hz, 1H, H6′b), 4.18 (dd, J = 2.4, 12.4 Hz, 1H, H6′a), 3.91–3.88 (m, 1H, H5′),
2.93–2.87 (m, 1H, CH), 2.05, 2.04, 2.03, 2.01 (4× s, 12H, 4× COCH3), 1.23 (d, J = 6.9 Hz, 6H, CH3);
Anal. Calcd for C32H35FN2O10: C 61.34, H 5.63, N 4.47; found C 61.52, H 5.61, N 4.45.
3.3. X-ray Crystallography
Suitable crystals of I–IV were obtained by slow evaporation of ethyl acetate solutions at r.t. Crystal
data were performed on a Nonius CAD-4 diffractometer (Enraf-Nonius, Rotterdam, The Netherlands)
by using MoKα (λ = 0.71073 Å) irradiation. All of the structures were solved by direct methods using
SHELXS-97 and refined by full-matrix least-squares on F2 for all data using SHELXL-97 [17]. All
non-H-atoms were refined anisotropically, and H-atoms were introduced at calculated positions. The

Molecules 2014, 19
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isotropic temperature factors were fixed to 1.2 times (1.5 times for methyl group) the equivalent
isotropic displacement parameters of the C-atom the H-atom is attached to CCDC-906894 (I),
CCDC-819778 (II), CCDC-918082 (III) and CCDC-925316 (IV) contain the supplementary
crystallographic data for this paper. These data can be obtained free of charge via
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2
1EZ, UK; Fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
3.4. FTIR Spectra
The structures in the ground state (in vacuo) were optimized by the Gaussian 03 program using the
B3LYP (DFT) method with the 6-31G (d) basis set [18–20]. The initial configurations for calculation
were constructed according to the X-ray data. Frequency calculations at the same levels of theory
revealed no imaginary frequencies, indicating that the B3LYP/6-31G (d) method was the optimal one
in our system.
3.5. Fungicidal Activity Assays
The in vitro fungicidal activity of compounds I–IV against Sclerotinia sclerotiorum and Gibberella zeae
was investigated at a dosage of 10 μg/mL, according to a reported method [10]. The fungi were
obtained from Jiangsu Pesticide Research Institute Co., Ltd., Nanjing, China. The tested compounds
I–IV were dissolved in acetone and added to a sterile agarized Czapek-Dox medium at 45 °C. In
preliminary screenings, the compounds were used in a concentration of 10 μg/mL. The control sample
contained only one equivalent of acetone. The media were poured onto 8-cm Petri dishes (10 mL for
each dish) and after 2 days inoculated with 5-mm PDA discs of overgrown mycelium. In the case of
Sclerotinia sclerotiorum, the medium was inoculated by a prick of laboratory needle containing fungus
spores. The Petri dishes were incubated at r.t. in the dark. After 4 days, the diameters of the
inoculation of the cultures were measured. The percentage inhibition of fungal growth was determined
by comparison between the development of fungi colonies on media containing compounds and on the
control. Three replicates of each test were carried out.
4. Conclusions
Four 1,5-diaryl-3-oxypyrazoles containing benzoyl (I), thiazolidinethione (II and III) or
per-O-acetylated glucopyranosyl (IV) moieties have been analyzed by X-ray diffraction. The
molecules were stabilized by classical intra- and intermolecular H-bonds, as well as intermolecular
C-H···π stacking interactions. Compound IV with more H-bonds in the crystal displayed better activity
(29%) against Sclerotinia sclerotiorum than I (0%), II (21%), and III (14%). Compound II (21%, 32%)
showed better fungicidal activity against the two fungi than III (14%, 29%), and both II and III exhibited
better inhibitory activity against Gibberella zeae than I (4%) and IV (11%). The structure-activity
relationship revealed that the improvement of bioactivity might require full consideration of H-bonds
effect, heterocycle, and electronic effects of electron-withdrawing groups to balance the HLB value
and enhance the systemic of molecule.

Molecules 2014, 19
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Acknowledgments
This work was supported by the Project of Food Fast Detection Technology (BM2012026), the
supporting project of the Twelfth Five Year Plan of China (2012BAK17B09), the Science Foundation
for Young Scholars of Jiangsu Province of China (BK20130749), and the Youths Foundation of
Southeast University ChengXian College (7303600001).
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are available from the authors.
© 2014 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
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(http://creativecommons.org/licenses/by/3.0/).