Synthesis, crystal structure and antibacterial activity of N,N′-Bis(4-methoxy-benzylidene)-1,4-bis(3-aminopropyl)piperazine

Article abstract of DOI:10.1007/s10870-012-0338-1

A new Schiff base, N,N′-bis(4-methoxy-benzylidene)-1,4-bis(3- aminopropyl)piperazine (BMBA), has been synthesized by the reaction of 1,4-bis(3-aminopropyl)piperazine and 4-methoxy-benzaldehyde in methanol solution. The title compound was characterized by elemental analysis, IR spectrum, ¹H NMR, ¹³C NMR and X-ray single crystal diffraction analyses. The compound crystallizes in the monoclinic system with space group C2/c and a = 24.071(5), b = 9.4035(19), c = 11.263(2) A, β = 96.787(2)°, V = 2531.6(9) A³, D _c = 1.193 g/cm³, M _r = 454.60, Z = 4, F (000) = 984, μ = 0.079 mm^-1, R ₁ = 0.0693, and ωR ₂ = 0.2269. In the crystal structure, molecules of BMBA and water of crystallization are linked through intermolecular O2W-H2′???N2 hydrogen bond, forming a 1D hydrogen bonding network that generates planar ribbons running parallel to the c-axis. Furthermore, the antibacterial activity of title compound was investigated preliminary by agar diffusion method, and it exhibited certain inhibited effect against Escherichia coli, Staphylococcus aureus and Bacillus subtilis.

Full text of DOI:10.1007/s10870-012-0338-1

J Chem Crystallogr (2012) 42:928–932
DOI 10.1007/s10870-012-0338-1
ORIGINAL PAPER
Synthesis, Crystal Structure and Antibacterial Activity of N,
N0-Bis(4-methoxy-benzylidene)-1,4-bis(3-aminopropyl)piperazine
•
Rui-Bo Xu Na Zhang Hong-Ying Zhou
•
•
•
•
Shu-Ping Yang Yu-Yang Li Da-Hua Shi
•
•
Wei-Xing Ma Xing-You Xu
Received: 19 June 2011 / Accepted: 6 June 2012 / Published online: 21 June 2012
Ó Springer Science+Business Media, LLC 2012
Abstract A new Schiff base, N,N0-bis(4-methoxy-ben-
zylidene)-1,4-bis(3-aminopropyl)piperazine (BMBA), has
been synthesized by the reaction of 1,4-bis(3-aminopro-
pyl)piperazine and 4-methoxy-benzaldehyde in methanol
solution. The title compound was characterized by ele-
mental analysis, IR spectrum, 1H NMR, 13C NMR and
X-ray single crystal diffraction analyses. The compound
crystallizes in the monoclinic system with space group
Keywords Synthesis ꢀ Crystal structure ꢀ N,N0-Bis(4-
methoxy-benzylidene)-1,4-bis(3-aminopropyl)piperazine ꢀ
Schiff base ꢀ Antibacterial activity
Introduction
Schiff base can be conveniently obtained by the conden-
sation reaction of primary amine with active carbonyl
[1, 2]. It is well known that Schiff bases can be widely used
as versatile ligands, and exhibit a wide range of biological
activities (such as antimicrobial, antitumor and so on) and
intriguing applications in many fields [2–6]. Therefore, the
chemistry of Schiff base have been attracted comprehen-
sive attention since Hugo Schiff synthesized the first Schiff
base in 1864 [2, 7, 8]. While piperazine derivatives have
good pharmacological activity and often be used as inter-
mediates of medicine, dyes, etc. [9–11], so investigation on
the synthesis and biological activity of Schiff bases derived
from piperazine are of importance.
˚
C2/c and a = 24.071(5), b = 9.4035(19), c = 11.263(2) A,
3
b = 96.787(2)°, V = 2531.6(9) A , Dc = 1.193 g/cm3,
˚
Mr = 454.60, Z = 4, F (000) = 984, l = 0.079 mm-1
,
R1 = 0.0693, and xR2 = 0.2269. In the crystal structure,
molecules of BMBA and water of crystallization are linked
through intermolecular O2W–H20ꢀꢀꢀN2 hydrogen bond,
forming a 1D hydrogen bonding network that generates
planar ‘‘ribbons’’ running parallel to the c-axis. Further-
more, the antibacterial activity of title compound was
investigated preliminary by agar diffusion method, and it
exhibited certain inhibited effect against Escherichia coli,
Staphylococcus aureus and Bacillus subtilis.
At present, reports on Schiff bases derived from piper-
azine are relatively rare, especially 1,4-bis(3-aminopro-
pyl)-piperazine (BAPP) Schiff bases [11–13]. Our group
had designed and synthesized two 1,4-bis(3-aminopro-
pyl)piperazine Schiff bases, and their crystal structures had
been published [11, 12]. Furthermore, their antibacterial
activities and interaction with bio-macromolecules DNA
and BSA were undertaken. As our continuous work, we
synthesized another novel BAPP Schiff base, N,N0-bis(4-
methoxy-benzylidene)-1,4-bis(3-aminopropyl)piperazine
(BMBA), by the reaction of BAPP with 4-methoxy-benz-
aldehyde in methanol solution. The route of synthesis is
given in Scheme 1. In this paper, we reported the synthesis,
crystal structure and antibacterial activity of the title
compound BMBA.
R.-B. Xu ꢀ H.-Y. Zhou ꢀ S.-P. Yang ꢀ Y.-Y. Li ꢀ D.-H. Shi ꢀ
W.-X. Ma
Chemical Engineering School, Huaihai Institute of Technology,
Lianyungang 222005, People’s Republic of China
N. Zhang
College of Pharmacy, Liaoning University of Traditional
Chinese Medicine, Dalian 116600, People’s Republic of China
X.-Y. Xu (&)
Huaiyin Institute of Technology, Huaian 223003,
People’s Republic of China
e-mail: xuxy@hyit.edu.cn
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J Chem Crystallogr (2012) 42:928–932
929
NH2
(E)
O
N
MeOH
N
N
O
O
+
N
N
N
O
(E)
H2N
Scheme 1 The synthesis route of title compound
Experimental
Table 1 Crystal data and structure refinement for title compound
All reagents were purchased as analytical grade and used
without further purification. Elemental analyses (C, H, N)
were determined with a Perkin-Elmer 240C instrument. IR
spectrum was recorded on a Spectrum One BFT-IR spec-
trophotometer using KBr pellet in the range of
CCDC deposition number
Expeirical formula
Formula weight
829,572
26H38N4O3
C
454.60
Temperature (K)
298(2)
˚
Wavelength (A)
0.71073
4,000–450 cm-1 1H NMR and 13C NMR spectra were
.
Crystal system
Space group
Monoclinic
recorded on a Bruker DRX300 MHz spectrometer.
Synthesis of the Title Compound
C2/c
˚
a (A)
24.071(5)
˚
b (A)
9.4035(19)
˚
c (A)
11.263(2)
A solution of BAPP (3 mmol) in 6 mL methanol was added
dropwise to the solution of 4-methoxy benzaldehyde
(6 mmol) in 10 mL methanol. The mixture solution was
stirred and heated under reflux about 4 h. The resulting
solutionwas filtered. After cooling, the filtrate was evaporated
at ambient environment. 3 days later, pale yellow crystals
suitable for X-ray analysis were collected, and washed with
small amount of methanol. Yield: 87.7 %. m.p.: 86–87 °C.
Anal. Calcd. (%) for C26H38N4O3: C 68.69, H 8.43, N 12.32;
Found (%): C 68.43, H 8.72, N 12.67. Main IR bands (KBr,
cm-1): 3244 (w), 2933 (m), 2826 (m), 1639 (s), 1604 (s), 1575
(s), 1510(s), 1468(m), 1357(w), 1241(vs), 1051(m), 840(m),
848 (w), 598 (w), 519 (w). 1H NMR (300 MHz, CDCl3, ppm):
8.20 (s, 1H, HC=N), 6.92–7.66 (d, 4H, Ar–CH), 3.83 (dd, 3H,
–OCH3), 1.89–3.6 (t, dd, 6H, BAPP-H). 13C NMR: 28.26,
53.30, 55.45, 56.42, 59.65, 114.06, 129.29, 129.68, 160.67
and 161.64.
a (°)
b (°)
c (°)
90
96.787(2)
90
3
˚
V (A )
2531.6(9)
Z
4
D
calc. (mg m-3
)
1.193
Absorption coefficient (mm-1
)
0.079
F(000)
984
h range for data collection (°)
Limiting indices
2.33–27.43
–31 B h B 31
-12 B k B 12
-14 B l B 14
11,192/2,878 (Rint = 0.0313)
2,878/0/226
Reflections collected/unique
Data/restraints/parameters
Goodness-of-fit on F2
1.212
Final R indices [I [ 2r(I)]
R indices (all data)
R1 = 0.0693, wR2 = 0.2269
R1 = 0.0906, wR2 = 0.2386
0.238, -0.369
-3
)
˚
Largest diff. peak and hole (e. A
Structure Determination
placed in their calculated positions and refined freely. The
details of crystal data and refinement for MBMA are given
in Table 1.
A selected crystal was mounted on a glass fiber. X-ray
diffraction intensity data were collected on a BRUKER
SMART CCD diffractometer equipped with a graphite-
˚
monochromatized Mo Ka (k = 0.71073 A) radiation by
Antibacterial Activity Determination
using the x-2h scan mode at 298(2) K. The crystal struc-
ture was solved by direct methods and Fourier synthesis
with the program SHELXS-97 and refined by full-matrix
least-squares techniques on F2 using program SHELXL-97
[14]. The non-hydrogen atoms were refined anisotropically.
The hydrogen atoms of water molecule were located in a
difference Fourier map and included in the refinement
using the riding model, while other hydrogen atoms were
The antibacterial activity of title compound and 4-methoxy
benzaldehyde against Escherichia coli, Staphylococcus
aureus and Bacillus subtilis were evaluated by the modified
agar diffusion method [15]. The compounds were dissolved
in DMF. Nutrient agar thawed by heating in water bath was
transferred to plates and froze at 37 °C. After the test
123

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J Chem Crystallogr (2012) 42:928–932
strains were spread on the solid nutrient agar surface,
stainless steel tubes (7.8 mm 9 6 mm 9 10 mm) were
spread on the surface. 0.05 mL compound with certain
concentration were injected to the steel tubes allowed to
incubate at 37 °C for 24 h. Inhibit zones around the disc
were calculated as zone diameter in mm. Blank tests
showed that DMF in the preparation of the test solutions
does not affect the test organisms. All tests were repeated
three times and average data were taken as the final result.
formation of Schiff base. Furthermore, in the 1H NMR
spectrum of the title compound, the chemical shift
observed at d 8.20 is assigned to the proton of imine
(CH–N) as singlet. And the 13C NMR shows peaks at
range of 28.26–161.64 ppm, attributed to the carbons of
benzene, methoxyl, propyl piperazine and imine (CH–N,
160.67 ppm) in MBMA. The above analyses coincided
with the X-ray diffraction analysis.
Crystal Structure Description
Results and Discussion
The molecular structure of the title compound is shown in
Fig. 1 and the packing diagram in a unit cell in Fig. 2. The
selected bond lengths and bond angles are given in Table 2.
The crystal system is monoclinic, and the asymmetric unit
of the cell contains half of N,N0-bis(4-methoxy-benzyli-
dene)-1,4-bis(3-aminopropyl)piperazine (i.e. BMBA) mol-
ecule and half of water molecule. While BMBA is
centrosymmetry and the water molecule is located on a
crystallographic twofold rotation axis. As depicted in
Fig. 1, the compound contains one BMBA and one water
molecule of crystallization. In BMBA molecule, the bond
General Characterization
The starting materials BAPP and 4-methoxybenzaldehyde
are liquid at room temperature, while BMBA is in solid
state, and its melting point is 86–87 °C. The IR spectrum
shows a broad band around 3,244 cm-1, which can be
assigned to the stretching vibrations, m(O–H), of the
hydroxyl group in the crystallization water of MBMA [16].
The strong band at 1,685 cm-1, attributed to stretching
vibrations of carbonyl group m(O=C) in the IR of
4-methoxybenzaldehyde is disappeared and a new middle
strong peak at 1,639 cm-1 in that of MBMA is charac-
teristic of the imine m(C=N) group [17], indicating the
˚
length of C8–N1 [1.259(4) A] is slightly shorter than that
˚
of C=N (1.28 A) [9], longer than that of C:N
˚
(1.14–1.16 A) [11, 12] and belongs to typical C–N double
bond, coinciding with the above spectral characterization.
Fig. 1 The molecular structure
of title compound with 50 %
probability displacement
ellipsoids. Symmetry operation
codes A: -x, -y ? 2, -z
Fig. 2 Packing diagram in a
unit cell of title compound
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J Chem Crystallogr (2012) 42:928–932
931
˚
and propyl piperazine are on the opposite sides of the C=N
bond, showing an E configuration.
Table 2 Selected bond lengths (A) and bond angles (°)
Bond
Dist.
There is only one kind of intermolecular H-bond
between the water of crystallization and BMBA molecule
in the crystal structure: O–HꢀꢀꢀN. The H(20)ꢀꢀꢀN(2) (sym-
N1–C8
N2–C13
N2–C12
O1–C7
C9–C10
N1–C9
N2–C11
O1–C6
C3–C8
1.259(4)
1.462(4)
1.467(4)
1.420(4)
1.513(4)
1.464(4)
1.466(3)
1.368(4)
1.464(4)
1.527(4)
˚
metry code: -x, -y ? 2, -z) bond length is 2.10(4) A, the
0
˚
N(2)ꢀꢀꢀO(2W) is 2.919(3) A and the C(2W)–H(2 )ꢀꢀꢀN(2)
angel is 168(4)°. According to Jeffrey criterion for H-bond
[18], the above intermolecular hydrogen bond is a rela-
tively stronger one. H(20) and H(20A) atoms from the
crystallization water are hydrogen bonded to N2A and N2
atoms of different piperazine rings, respectively. Thus the
BMBA and crystallization water can be linked by the
intermolecular H-bonding interactions to form a 1D
hydrogen bonding network that generates planar ‘‘ribbons’’
running parallel to the c-axis, as described in Fig. 3.
C10–C11
Angle
(°)
C8–N1–C9
117.1(3)
108.8(2)
118.3(3)
110.4(2)
109.5(2)
111.7(2)
122.9(3)
111.1(2)
C13–N2–C12
C6–O1–C7
Antibacterial Activity
N2–C12–C13#1
C13–N2–C11
C11–N2–C12
N1–C8–C3
It can be seen from Table 3 that the title compound and
4-methoxy benzaldehyde are all active against the three test
organisms, showing similar antibacterial activity. And the
activity of these compounds against the strains enhanced
with the increase of the concentration in the test range.
Compared with 4-methoxy benzaldehyde, the antibacterial
activity of title compound is higher against Escherichia
coli, lower against Staphylococcus aureus and somewhat
complex against B. subtilis (that is, when the concentration
is 1.0 and 5.0 mg mL-1, 4-methoxy benzaldehyde exhibits
more stronger antibacterial effect, while the concentration
is 0.1 and 0.01 mg mL-1, the title compound exhibits more
active inhibition effect).
N2–C13–C12#1
Symmetry transformations used to generate the equivalent atoms: #1:
-x, -y ? 2, -z
While other C–N bond distances in the compound are in
˚
the range of 1.462(4)–1.467(4) A, close to the mean C–N
˚
single bond length of 1.470 A, indicating they are single
bond. The two phenyl rings (C1–C6 and C1A–C6A) are
parallel to each other, similar to other BAPP Schiff bases
we reported [11, 12]. The piperazine ring can be regarded
as three moieties: plane A composed of N(2)–C(12)–C(13),
ring B composed of C(12)–C(13)–C(12A)–C(13A) and
plane C composed of N(2A)–C(12A)–C(13A). The dihe-
dral angle between the plane A and B is 127.5°, equal to
that of B and C, and that of A and C is 0°. Therefore plane
A and C parallel to each other, indicating that the pipera-
zine ring in BMBA adopts the stable chair conformation,
not the boat conformation. Furthermore, the benzene ring
Supplementary Material
CCDC-829572 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free
of charge at www.ccdc.cam.ac.uk/conts/retriving.html [or
from the Cambridge Crystallographic Data Centre
Fig. 3 The 1D ribbons
structure of title compound
linked by hydrogen bonding
interaction running parallel to
c axis
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J Chem Crystallogr (2012) 42:928–932
Table 3 Antibacterial activity
of title compound and
4-methoxy benzaldehyde
Compound
Concentration
mg mL-1
Diameter of inhibition zone(mm)
Escherichia
coli
Staphylococcus
aureus
Bacillus
subtilis
Title compound
5.0
1.0
12.3 0.74
11.3 0.61
10.5 0.41
9.5 0.37
11.7 0.34
10.2 0.65
9.3 0.79
8.5 0.25
7.8 0.02
13.2 0.29
12.5 0.87
10.5 0.34
9.7 0.49
14.2 0.34
12.8 0.58
11.8 0.49
10.8 0.60
7.8 0.05
11.8 0.69
10.8 0.33
9.5 0.42
8.3 0.37
12.5 0.59
11.7 0.37
9.3 0.50
7.8 0.09
7.8 0.03
0.1
0.01
5.0
4-Methoxy benzaldehyde
1.0
0.1
0.01
Note The diameter of the
stainless steel tube is 7.8 mm
DMF
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Acknowledgments This work is supported by the Opened Funds of
Jiangsu Key Laboratory of Marine Biotechnology of Huaihai Institute
of Technology (2009HS06), Science and Technique Foundation of
Lianyungang (CG1132), College students’ practice and innovation
training project of Jiangsu Province, Doctor Science Initial Funding
of Huaihai Institute of Technology (KQ10130) and by Qing Lan
Project of Jiangsu Province (2008).
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