Synthesis, crystal structures and antibacterial activities of benzohydrazone derivatives from 4-diethylaminosalicylaldehyde

Article abstract of DOI:10.4067/S0717-97072013000200027

A series of three new benzohydrazone compounds, C₁₈H ₂₁N₃O₃ (1), C₁₉H₂₃N ₃O₃ (2), and C₁₈H₂₀ClN ₃O₂ (3), derived from the c

Full text of DOI:10.4067/S0717-97072013000200027

J. Chil. Chem. Soc., 58, Nº 2 (2013)
SYNTHESIS, CRYSTAL STRUCTURES AND ANTIBACTERIAL ACTIVITIES OF BENZOHYDRAZONE
DERIVATIVES FROM 4-DIETHYLAMINOSALICYLALDEHYDE
ZHIGANG WANG1,∞, FENG ZHI2,∞, RONG WANG2, LIAN XUE2, YI ZHANG2, QIANG WANG2, YI-LIN YANG2,*
1 Department of Respiratory Medicine, Third Affiliated Hospital of Soochow University, Changzhou 213000, P. R. China;
2 Modern Medical Research Center, Third Affiliated Hospital of Soochow University, Changzhou 213000, P. R. China
∞ These authors contributed equally to this work.
(Received: November 23, 2012 - Accepted: January 14, 2013)
ABSTRACT
A series of three new benzohydrazone compounds, C18H21N O3 (1), C19H23N3O3 (2), and C18H20ClN3O2 (3), derived from the condensation of
4-diethylaminosalicylaldehyde with 2-hydroxybenzohydrazide, 4-m3ethoxybenzohydrazide, and 4-chlorobenzohydrazide, respectively, in methanol, were
prepared. The compounds were characterized by elemental analysis, IR spectra, 1H NMR spectra, and single crystal X-ray diffraction. Compound 1 crystallizes in
the monoclinic space group P2 with unit cell dimensions a = 6.2656(6) Å, b = 21.873(2) Å, c = 6.6362(7) Å, β = 114.025(2)°, V = 830.70(15) Ǻ3, Z = 2, R1 = 0.0323
and wR2 = 0.0784. Compound 12 crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 13.8966(17) Å, b = 13.1402(15) Å, c = 9.8043(12)
Å, β = 90.768(2)°, V = 1790.1(4) Ǻ3, Z = 4, R1 = 0.0670 and wR2 = 0.1671. Compound 3 crystallizes in the triclinic space group P-1 with unit cell dimensions a
= 9.884(2) Å, b = 11.781(3) Å, c = 15.990(4) Å, α = 95.916(5)°, β = 99.520(5)°, γ = 104.147(4)°,V = 1760.5(7) Ǻ3, Z = 4, R = 0.0698 and wR2 = 0.1250. Crystal
structures of the compounds are stabilized by hydrogen bonds and π···π stacking interactions. The preliminary antibacterial1tests against Staphylococcus aureus,
Escherichia coli, Klebsiella pneumoniae, and Candida albicans were assayed.
Keywords: benzohydrazone; crystal structure; X-ray diffraction; antibacterial activity; hydrogen bonds.
days, colorless block-shaped single crystals were formed. The crystals were
INTRODUCTION
collected by filtration, washed three times with methanol. Yield, 0.29 g (89%).
Anal. Calcd. (%) for C18H21N3O3: C, 66.0; H, 6.5; N, 12.8. Found (%): C, 65.8;
H, 6.5; N, 12.9. Characteristic IR data (KBr, cm–1): 3412 (w) (vO-H), 3183 (m)
(vN-H), 1637 (s) (v ), 1602 (s) (vC=N). 1HNMR data (d-DMSO, ppm): δ = 1.14
(m, 6H), 3.40 (m,C4=HO ), 6.32 (s, 1H), 6.39 (d, 1H), 6.9-7.9 (m, 5H), 8.72 (s, 1H),
11.17 (s, 1H), 11.56 (s, 1H), 12.78 (s, 1H).
The condensation of carbonyl-containing compounds with primary
amines produce Schiff base compounds bearing C=N double bonds, which
is an essential structural requirement for biological activities, especially
for antibacterial, antimicrobial, antifungi, and antitumor activities.1-4
Benzohydrazone derivatives are a kind of special Schiff bases bearing –
C=N–NH–CO–Ph functional groups. As is well known, Schiff bases derived
from salicylaldehyde and its derivatives have interesting biological activities.
In recent years, considerable attention has been focused on the preparation
and biological activities of benzohydrazone derivatives.5-8 During the search
of literature, we observed that benzohydrazone derivatives have effective
antibacterial activities; yet, the number of such compounds is relatively less
than the usual Schiff bases. In order to investigate the crystal structures and
antibacterial activities of benzohydrazone derivatives, in the present paper,
4-diethylaminosalicylaldehyde, a compound bearing lipophilic group, was
used to prepare three benzohydrazone derivatives, C18H21N3O3 (1), C19H23N3O3
Synthesis
methoxybenzohydrazide
of
N’-(4-Diethylamino-2-hydroxybenzylidene)-4-
(2) and 4-Chloro-N’-(4-diethylamino-2-
hydroxybenzylidene)benzohydrazide (3): Compounds 2 and 3 were synthesized
by the same method as that described for 1, with 2-hydroxybenzohydrazide
replaced by 4-methoxybenzohydrazide (1.0 mmol, 0.166 g) for 2, and by
4-chlorobenzohydrazide (1.0 mmol, 0.171 g) for 3. The filtrates for the two
compounds were stood still in air to slow evaporate of the solvent to yield
colorless block-shaped single crystals. For 2: Yield, 0.28 g (82%). Anal. Calcd.
(%) for C19H23N3O3: C, 66.8; H, 6.8; N, 12.3. Found (%): C, 67.0; H, 6.9; N,
12.2. Characteristic IR data (KBr, cm–1): 3403 (w) (vO-H), 3170 (m) (vN-H), 1636
1
(s) (vC=O), 1602 (s) (v ).. HNMR data (d-DMSO, ppm): δ = 1.14 (m, 6H),
3.40 (m, 4H), 3.85 (s,C3=HN ), 6.32 (s, 1H), 6.39 (d, 1H), 7.1-7.9 (m, 5H), 8.72 (s,
1H), 11.32 (s, 1H), 12.40 (s, 1H). For 3: Yield, 0.31 g (90%). Anal. Calcd. (%)
for C18H20ClN3O2: C, 62.5; H, 5.8; N, 12.2. Found (%): C, 62.6; H, 5.8; N, 12.3.
Characteristic IR data (KBr, cm–1): 3427 (w) (vO-H), 3162 (m) (vN-H), 1638 (s)
(vC=O), 1601 (s) (v ).. 1HNMR data (d-DMSO, ppm): δ = 1.14 (m, 6H), 3.41
(m, 4H), 6.31 (s, 1CH=N), 6.39 (d, 1H), 7.4-8.0 (m, 5H), 8.72 (s, 1H), 11.51 (s, 1H),
12.82 (s, 1H).
X-ray Crystallography: Suitable single crystals of the three compounds
were mounted on glass fibers for X-ray measurement. Reflection data were
collected at room temperature on a Bruker AXS SMART APEX II CCD
diffractometer with graphite monochromatized Mo-Kα radiation (λ = 0.71073
Å). Crystal structures of the three compounds were solved by direct method.
All non-hydrogen atoms were refined anisotropically. The amino H atoms
were located from difference Fourier maps and refined isotropically, with N–H
distances restrained to 0.90(1) Å. The remaining hydrogen atoms were fixed at
calculated positions and refined by using riding models. All calculations were
performed using SHELX-97.9 Crystal data and details of the data collection and
the structure refinement are given in Table 1. Hydrogen bonding information
is given in Table 2.
Antibacterial Test: The compounds were tested for their in vitro
antibacterial activities against Staphylococcus aureus var. Oxford 6538,
Escherichia coli ATCC 10536, Klebsiella pneumoniae ATCC 100131 and
Candida albicans ATCC 10231 strains using the paper disc diffusion method
(for the qualitative determination) and the serial dilutions in liquid broth method
(for determination of the MIC).10 Tetracycline was used as the reference drug.
(2), and C18H20ClN3O2 (3).
EXPERIMENTAL
Materials
and
Methods:
4-Diethylaminosalicylaldehyde,
and
2-hydroxybenzohydrazide,
4-methoxybenzohydrazide,
4-chlorobenzohydrazide were obtained commercially from Lancaster Research
Chemicals. Solvents used were of analytical grade. Elemental analyses (CHN)
were performed on a Perkin-Elmer 240C elemental analyzer. IR spectra
were recorded on a Perkin Elmer Paragon 1000 spectrophotometer. H NMR
spectra were recorded on a Bruker DPX-400 instrument at 400 MHz with
1
tetramethylsilane as the internal reference.
Synthesis
of
N’-(4-Diethylamino-2-hydroxybenzylidene)-2-
hydroxybenzohydrazide (1): 4-Diethylaminosalicylaldehyde (1.0 mmol, 0.193
g) was added with stirring to 2-hydroxybenzohydrazide (1.0 mmol, 0.152
g) in methanol. The mixture was heated under reflux for 1 h, and cooled to
room temperature. After filtration and slow evaporation in air for a few
e-mail: yangyilin_szu@126.com
1763

J. Chil. Chem. Soc., 58, Nº 2 (2013)
TABLE 1. Crystal Data and Refinement Parameters for the Compounds.
Compound
1
2
3
Empirical formula
Molecular weight
Crystal color, habit
Crystal size (mm3)
Crystal system
Space group
C18H21N3O3
327.4
C19H23N3O3
341.4
C18H20ClN3O2
345.8
Colorless, block
0.20 × 0.20 × 0.17
Monoclinic
P21
Colorless, block
0.20 × 0.17 × 0.15
Monoclinic
P21/c
Colorless, block
0.30 × 0.27 × 0.27
Triclinic
P-1
Unit cell dimensions
a (Ǻ)
6.2656(6)
21.873(2)
6.6362(7)
90
13.8966(17)
13.1402(15)
9.8043(12)
90
9.884(2)
b (Ǻ)
11.781(3)
15.990(4)
95.916(5)
99.520(5)
104.147(4)
1760.5(7)
4
c (Ǻ)
α (°)
β (°)
114.025(2)
90
90.768(2)
90
γ (°)
V (Ǻ3)
830.70(15)
2
1790.1(4)
4
Z
Dcalc (g cm–3)
1.309
1.267
1.305
Absorption coefficient (μ, mm–1)
θ range collected (°)
Tmin and Tmax
0.091
0.087
0.232
3.3 – 27.9
0.982 and 0.985
4369/2982 (0.0127)
2982/2/224
2721
2.6 – 24.3
0.983 and 0.987
17156/3311 (0.0407)
3311/1/233
2093
2.3 – 24.5
0.934 and 0.940
14382/7318 (0.0690)
7318/6/463
2860
Reflections collected/unique (Rint)
Data/restraints/parameters
Observed reflections [I ≥ 2 σ (I)]
R1, wR2 [I ≥ 2σ(I)]
R1, wR2 (all data)
Goodness of fit (GOF) on F2
0.0323, 0.0784
0.0365, 0.0818
1.037
0.0670, 0.1671
0.1105, 0.1968
1.034
0.0698, 0.1250
0.1881, 0.1648
0.916
Largest differences in peak/hole (e/Ǻ3) 0.102 and –0.160
0.632 and –0.277
0.175 and –0.220
TABLE 2. Geometrical Parameters for Hydrogen Bonds.
D–H···A
D–H (Ǻ)
H···A (Ǻ)
1
D···A (Ǻ)
D–H···A (°)
O1–H1∙∙∙N2
N3–H3B∙∙∙O3
O3–H3∙∙∙O2i
0.82
0.90(1)
0.82
1.92
2.642(2)
2.643(2)
2.673(2)
147
140(2)
167
1.90(2)
1.87
2
N3–H3A∙∙∙O2ii
O1–H1∙∙∙N2
0.90(1)
0.82
2.00(2)
1.92
2.879(3)
2.641(3)
167(3)
147
3
N4–H4∙∙∙O1iii
N1–H1∙∙∙O3
O4–H4A∙∙∙N5
O2–H2∙∙∙N2
0.90(1)
0.90(1)
0.82
1.93(1)
2.12(2)
1.93
2.829(4)
3.004(4)
2.650(4)
2.594(4)
173(4)
164(3)
146
0.82
1.87
146
Symmetry transformation used to generate the symmetry related atoms: (i) x, y, 1 + z; (ii) x, 1/2 – y, –1/2 + z; (iii) 1 + x, y, z.
In 2, the dihedral angle between C1-C6 and C13-C18 benzene rings is 72.5(2)°.
RESULTS AND DISCUSSION
In 3, the dihedral angle between C1-C6 and C9-C14 benzene rings is 18.4(2)°;
the dihedral angle between C19-C24 and C27-C32 benzene rings is 31.1(2)°.
It is notable that the molecule of 1, except for the diethylamino group, is much
more planar than those of 2 and 3, which is better attributed to the formation
of intramolecular O1–H1···N2 and N3–H3B···O3 hydrogen bonds in 1 (Table
2). In each molecule of 2 and 3, there only exists one intramolecular O–H···N
hydrogen bond (Table 2). The corresponding bond lengths in the three
compounds are comparable to each other, and also within normal values.6,8,11-14
For 3, all the bond values are similar to the positional isomer structure.15
In the crystal structure of 1, molecules are linked through intermolecular
O–H···O hydrogen bonds, to form chains running along c axis (Figure 4). In
the crystal structure of 2, molecules are linked through intermolecular N–H···O
hydrogen bonds, to form chains running along c axis (Figure 5). In the crystal
Structure Description of the Compounds: The molecular structures
of compounds 1, 2, and 3 are shown in Figures 1, 2, and 3, respectively. In
each compound, the benzohydrazone molecules adopts an E configuration
with respect to the C=N double bonds. The distances between C11 and N2
[1.287(2) Å in 1, 1.280(4) Å in 2] in 1 and 2, as well as those between C8 and
N2 [1.282(4) Å] and C26 and N5 [1.289(4) Å] in 3, conform them as typical
double bonds. The distances between C12 and N3 [1.335(2) Å in 1, 1.342(4)
Å in 2] in 1 and 2, as well as those between C7 and N1 [1.344(4) Å] and C25
and N4 [1.355(5) Å] in 3, are intermediate between single and double bonds,
due to the conjugation effects of the C···N···N···C···O moieties. Hence it can
conclude that the molecules of the compounds are in the keto tautomeric form.
In 1, the dihedral angle between C1-C6 and C13-C18 benzene rings is 3.1(2)°.
1764

J. Chil. Chem. Soc., 58, Nº 2 (2013)
structure of 3, molecules are linked through intermolecular N–H···O hydrogen
bonds, to form chains running along a axis (Figure 6). In addition, π···π
stacking interactions are observed among the benzene rings in the compounds
ranging from 4.1 to 4.9 Å, as specified in Table 3.
Antibacterial Activity: The antibacterial activities of the compounds as
well as the reference drug are summarized in Table 4. The results indicated that
the compounds show from weak to moderate to effective activities against the
growth of the tested strains. It is obvious that the activities of 3 are much more
effective than those of 1 and 3, which might be caused by the Cl substituent
of the compound. The Cl-containing compounds have been proved to have
interesting biological properties. The activities for 1 and 2 are not good enough,
and show no obvious rules. Compound 3 show moderate activities against
Staphylococcus aureus and Klebsiella pneumoniae. However, it has effective
activity against Escherichia coli, which is even stronger than Tetracycline.
In addition, compound 3 is more effective than Tetracycline against Candida
albicans.
Fig. 4. Packing diagram for 1, viewed along the a axis. Hydrogen bonds
are drawn as dashed lines.
Fig. 1. Thermal ellipsoid plot (30% probability level) of 1 showing the
numbering scheme. Hydrogen bonds are shown as dashed lines.
Fig. 2. Thermal ellipsoid plot (30% probability level) of 2 showing the
numbering scheme. Hydrogen bond is shown as a dashed line.
Fig. 5. Packing diagram for 2, viewed along the b axis. Hydrogen bonds
are drawn as dashed lines.
Fig. 3. Thermal ellipsoid plot (30% probability level) of 3 showing the
numbering scheme. Hydrogen bonds are shown as dashed lines.
Fig. 6. Packing diagram for 3, viewed along the b axis. Hydrogen bonds
are drawn as dashed lines.
1765

J. Chil. Chem. Soc., 58, Nº 2 (2013)
TABLE 3. Parameters Between the Planes for the Compounds
Distance between ring
Perpendicular distance of
Perpendicular distance of
Cg
Dihedral angle (°)
centroids (Å)
Cg(I) on Cg(J) (Å)
Cg(J) on Cg(I) (Å)
1
Cg1···Cg2iv
4.801
3.19
0.00
3.348
3.632
3.253
3.632
2
Cg3···Cg3v
3
4.874
Cg4···Cg4vi
Cg4···Cg5vii
4.166
4.853
0.02
3.566
3.781
3.566
2.929
18.97
For 1: Cg1 and Cg2 are the centroids of C1-C2-C3-C4-C5-C6 and C13-C14-C15-C16-C17-C18, respectively. Symmetry code: (iv) 1 + x, y, z. For 2: Cg3 is
the centroid of C13-C14-C15-C16-C17-C18. Symmetry code: (v) 1 – x, 2 – y, 2 – z. For 3: Cg4 and Cg5 are the centroids of C1-C2-C3-C4-C5-C6 and C9-C10-
C11-C12-C13-C14, respectively. Symmetry codes: (vi) 1 – x, – y, – z; (vii) 1 – x, 1 – y, – z.
TABLE 4. Antibacterial Activity of the Compounds as MIC Values (μg/mL).
Test material
Staphylococcus aureus
Escherichia coli
Klebsiella pneumoniae
Candida albicans
1
32
16
32
32
256
128
8.0
1.2
128
256
2
3
4.0
0.22
1.0
1.5
64
Tetracycline
> 1024
2. V.S.V. Satyanarayana, M. Rakshit, A. Sivakumar, Asian J. Chem. 23,
1295, (2011).
CONCLUSION
3. Z.H. Chohan, S.H. Sumrra, M.H. Youssoufi, T.B. Hadda, Eur. J. Med.
Chem. 45, 2739, (2010).
Three new benzohydrazone compounds derived from the condensation
4-diethylaminosalicylaldehyde with 2-hydroxybenzohydrazide,
of
4. K. Cheng, Q.-Z. Zheng, Y. Qian, L. Shi, J. Zhao, H.-L. Zhu, Bioorg. Med.
Chem. 17, 7861, (2009).
5. A. Ozdemir, G. Turan-Zitouni, Z.A. Kaplancikli, Y. Tunali, J. Enzyme
Inhib. Med. Chem. 24, 825, (2009).
6. W.W. Wardakhan, E.M. Samir, J. Chil. Chem. Soc. 57, 1118, (2012).
7. G. Kucukguzel, A. Kocatepe, E. De Clercq, F. Sahin, M. Gulluce, Eur. J.
Med. Chem. 41, 353, (2006).
4-methoxybenzohydrazide, and 4-chlorobenzohydrazide, respectively,
in methanol, were prepared and structurally characterized. The
preliminary biological tests indicated that 4-chloro-N’-(4-diethylamino-2-
hydroxybenzylidene)benzohydrazide has effective activity against Escherichia
coli, which deserves further study.
SUPPLEMENTARY MATERIAL
8. M. Zhang, D.-M. Xian, H.-H. Li, J.-C. Zhang, Z.-L. You, Aust. J. Chem.
65, 343, (2012).
9. G.M. Sheldrick, Acta Crystallogr. A64, 112, (2008).
10. A.Barry,Proceduresandtheoreticalconsiderationsfortestingantimicrobial
agents in agar media. in: Lorian (Ed.), Antibiotics in Laboratory Medicine,
5th ed. Williams and Wilkins, Baltimore, (1991).
CCDC – 908607 for 1, 908608 for 2, and 908609 for 3 contain the
supplementary crystallographic data for this paper. These data can be obtained
free of charge at http://www.ccdc.cam.ac.uk/const/retrieving.html or from the
Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk.
11. R.B.N. Bessy, K.M.R. Prathapachandra, E. Suresh, Struct. Chem. 17, 201,
(2006).
ACKNOWLEDGEMENTS
12. Y.-M. Cui, Y.-J. Cai, W. Chen, J. Coord. Chem. 64, 1385, (2011).
13. Q.-Y. Zhu, Y.-J. Wei, F.-W. Wang, Polish J. Chem. 83, 1233, (2009).
14. K. Pyta, P. Przybylski, A. Huczyński, A. Hoser, K. Wozniak, W. Schilf,
B. Kamienski, E. Grech, B. Brzezinski, J. Mol. Struct. 970, 147, (2010).
15. T.-Y. Li, B.-B. Li, Acta Crystallogr. E67, o383, (2011).
The authors thank the Third Affiliated Hospital of Soochow University for
supporting this work.
REFERENCES
1. M.M. Kamel, H.I. Ali, M.M. Anwar, N.A. Mohamed, A.M. Soliman, Eur.
J. Med. Chem. 45, 572, (2010).
1766