Synthesis, crystal structure and biological activity of novel diester cyclophanes

Article abstract of DOI:10.1590/S0103-50532012005000045

A series of novel diester cyclophanes was synthesized by esterification of 1,2-benzenedicarbonyl chloride with eight different diols under high dilution conditions. The structures of the compounds were verified by elemental analysis, 1H nuclear magnetic resonance (NMR), IR spectroscopy and high resolution mass spectrometry (HRMS). The crystal structures of two compounds were characterized by single crystal X-ray diffractometry (XRD). All the new cyclophanes were evaluated for biological activities and the results showed that some of these compounds have low antibacterial or antifungal activities.

Full text of DOI:10.1590/S0103-50532012005000045

J. Braz. Chem. Soc., Vol. 23, No. 10, 1771-1775, 2012.
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Article
A
Synthesis, Crystal Structure and Biological Activity of Novel Diester Cyclophanes
Pengfei Zhang, Bingqin Yang,* Xianwen Fang, Zhao Cheng and Meipan Yang
Department of Chemistry, Key Laboratory of Synthetic and Natural Functional Molecule Chemistry,
Northwest University, Xi’an 710069, Shaanxi, P. R. China
Uma série de novos ciclofanos diésteres foi sintetizada por esterificação de cloreto de 1,2
benzenodicarbonilo com oito diferentes dióis sob condições de elevada diluição. As estruturas dos
compostos foram verificadas por análise elementar, ressonância magnética nuclear (NMR) de 1H,
espectroscopia IR e espectrometria de massas de alta resolução (HRMS). As estruturas cristalinas
de dois dos compostos foram caracterizadas por difratometria de raios X (XRD) de monocristais.
Todos os novos ciclofanos foram avaliados com relação a suas atividades biológicas e os resultados
mostraram que alguns destes compostos têm baixas atividades antibacterianas e antifúngicas.
A series of novel diester cyclophanes was synthesized by esterification of 1,2-benzenedicarbonyl
chloride with eight different diols under high dilution conditions. The structures of the compounds
were verified by elemental analysis, 1H nuclear magnetic resonance (NMR), IR spectroscopy and high
resolution mass spectrometry (HRMS). The crystal structures of two compounds were characterized
by single crystal X-ray diffractometry (XRD).All the new cyclophanes were evaluated for biological
activities and the results showed that some of these compounds have low antibacterial or antifungal
activities.
Keywords: synthesis, ester cyclophanes, crystal, antibacterial activity, antifungal activity
Introduction
So far, scientists have synthesized a wide variety of
cyclophanes with numerous modes of ring attachments.
Medium-sized ring cyclophanes generally have a ring size
of 8 to 11 atoms.14 Herein, it is reported the synthesis and
biological activity of several diester cyclophanes. In
continuation with our interest in cyclophane synthesis,15
an effective method for the synthesis of cyclophane
compounds was designed, and a series of medium-sized
cyclophanes 4a-4h was obtained by esterification of
1,2-benzenedicarbonyl chloride with some diols under
high dilution conditions. Their antibacterial and antifungal
activities are also described.
Cram and Steinberg1 opened the field of cyclophane
chemistry by their work in 1951. Since then, cyclophanes
have attracted a great deal of attention from organic
scientists, various kinds of compounds have been
synthesized and their structures and properties have been
studied.2-6 Cyclophanes play an important role in host-guest
chemistry because they can recognize specific molecules
or ions by forming various inclusion complexes.7-9 In some
reaction systems, the host-guest complex can simulate
the high efficiency of enzyme catalysis, which means the
reaction yield can be greatly improved.10,11 Besides, some
ester cyclophanes were also used in the perfume industry
because of their aromatic properties. Cyclophanes have
so many important applications that it can be predicted
a promising future in this field. However, the biological
activities of cyclophanes were scarcely reported.12,13
Therefore, there is a continuous need to synthetize novel
cyclophanes through efficient and simple routes and to
study their biological activities.
Results and Discussion
O-Phthalic acid undergoes a reaction with SOCl2 and
catalytic DMF (dimethylformamide) to form the diacid
chlorides 1 (Scheme 1).16 Diols 3a-3h were also prepared and
used for the synthesis of cyclophanes. 4-Methylaniline was
treated with oxirane and catalytic propanoic acid by stirring
at room temperature for 24 h. Diol 3a was obtained as white
solid.17 Diols 3b, 3c, 3d, 3e and 3f were also prepared by
similar procedures. Compounds 3g and 3h were obtained
*e-mail: yangbq@nwu.edu.cn

1772
Synthesis, Crystal Structure and Biological Activity of Novel Diester Cyclophanes
J. Braz. Chem. Soc.
O
O
OH
OH
SOCl2
DMF
Cl
Cl
O
O
1
O
O
NH2
Py, DMAP
R
R
R
O
N
CH2Cl2, reflux
OH
OH
R
O
O
2a-2f
N
NH2
Cyclophanes 4a-4h
3a-3h
2g-2h
a: R = p-CH3 b: R = p-OCH3
c: R = p-Cl
d: R = m-CH3
e: R = m-Cl
f: R = 3,5-(CH3)2 g: R = m-NO2 h: R = p-Br
Scheme 1. Synthesis of medium-sized cyclophanes 4a-4h.
using CaCO3, KI and 2-chloroethanol according to Lin et al.18
Different catalysts showed different catalytic effect in the
cyclization procedure. The inorganic base K2CO3 showed no
catalytic activity. The reaction could be improved by adding
pyridine, but the product yield was still low. It was found
that a high cyclization yield was achieved in the presence
of pyridine and 4-dimethylaminopyridine (DMAP). The
reaction 1 equiv. of diol 3a with 1.5 equiv. of diacid chloride
1 in CH2Cl2 and in the presence of pyridine and DMAP
afforded the cyclophane 4a in 56% yield.19-24 Using the
new dual catalyst system not only increased the yield of the
product, but also improved the reaction rate. The 1H NMR
spectrum of cyclophane 4a displayed the aromatic methyl
protons as a singlet at d 2.27, OCH2CH2 protons as two triplet
at d 3.80 and 4.55 with J 4.0 Hz, in addition to aromatic
protons. Cyclophanes 4b-4h were also accessed by a familiar
method from the reaction of diols 3b-3h with diacid chloride
1. In order to avoid polymerization, the cyclization procedure
was run under high dilution conditions and the reaction
solution had to be vigorously stirred.
[H(18) O(4) = 2.607 Å, C(18)-H(18) O(4) = 153.84°];
…
…
…
…
…
[H(10B) O(4) = 2.577Å, C(10)-H(10B) O(4) = 135.39°];
…
[H(11A) O(6)=2.614Å, C(11)-H(11A) O(6)=143.53°];
…
…
[H(10A) O(5) = 2.630 Å, C(10)-H(10A) O(5) =
163.21°] and [H(9B) O(5) = 2.552Å, C(9)-H(9B) O(5) =
159.46°]. The crystal structure X-ray analysis of 4h revealed
cyclophanes connected by four intermolecular CH
hydrogen bonding (Figure 2c): [H(3) O(1) = 2.410 Å,
C(3)-H(3) O(1) = 153.69°]; [H(7B) O(2) = 2.699 Å,
C(7)-H(7B) O(2) = 158.01°]; [H(17B) O(4) = 2.587 Å,
C(17)-H(17B) O(4) = 133.99°] and [H(18A) O(2) =
2.642Å, C(18)-H(18A) O(2) = 164.49°]. The compounds
…
…
…
O
…
…
…
…
…
…
…
…
were further stabilized by H-bond stacking interaction to
construct supramolecular architectures (Figures 1b and 2b).
Biological activity
The synthesized novel compounds 4a-4h were screened
for their in vitro antibacterial activity against Staphylococcus
aureus (ATCC 25923), Bacillus subtilis (ATCC 6633),
Escherichia coli (ATCC 25922), Pseudomonas aeruginosa
(ATCC 27853) and Salmonella typhi (ATCC 14028).
The new compounds 4a-4h were also evaluated for
their antifungal activity against Candida albicans
(ATCC 10231). The results of preliminary antibacterial
activity of the compounds are shown in Table 2. A control
test was performed with sterile DMSO. This revealed
no inhibiting activity. The compounds 4a, 4b, 4c and 4h
were found to exhibit higher antifungal activity against
C. albicans among the new compounds.
Theminimuminhibitoryconcentration(MIC)fortheactive
compounds is presented in Table 3. Chloramphenicol and
fluconazole were chosen as standard drugs whose MIC
values are also provided in Table 3. The antibacterial activity
(MIC of 128 μg mL-1) of compound 4g against E. coli showed
relatively better results than the other new compounds. This is
The carbonyl absorption of cyclophanes in the IR was
in 1700-1720 cm-1 region, at lower frequency than that of
normal esters due to the formation of a large p bonding. This
peak was the strongest peak compared with all other peaks
in the IR spectrum.
Crystal and molecular structures
Crystals of compounds 4g and 4h were obtained
from a mixture of petroleum ether and ethyl acetate (5:1).
Crystal data collection and refinement parameters for the
two compounds are shown in Table 1. The structures of
compounds are presented in Figures 1a and 2a. The crystal
structure X-ray analysis of 4g showed that there are six
…
intermolecular CH OH-bonding interactions (Figure 1c):
…
…
[H(2) O(1) = 2.697 Å, C(2)-H(2) O(1) = 126.18°];

Vol. 23, No. 10, 2012
Zhang et al.
1773
Table 1 Crystallographic data and structure refinement parameters for the compounds 4g and 4h
Compound
4g
4h
C18H16BrNO4
white
Empirical formula
Color
C18H16N2O6
yellow
Formula weight
Temperature / K
Wavelength / Å
Crystal system
Space group
356.33
390.23
296(2)
296(2)
0.71073
monoclinic
P2(1)/n
0.71073
monoclinic
P 21/c
Unit cell dimensions
a = 7.925(2) Å
b = 15.854(4) Å
c = 13.208(3) Å
α = 90°
a = 21.197(4) Å
b = 4.8526(9) Å
c = 16.152(3) Å
α = 90°
β = 90.813(4)°
γ = 90°
β = 99.692(3)°
γ = 90°
Volume / Å3
1659.4(7)
1637.7(5)
Z
4
1.426
4
1.583
Density / (mg m-3)
Absorption coefficient / mm−1
F (000)
0.109
2.532
744
792
Crystal size / mm
Range for data collection
Limiting indices
0.33 × 0.27 × 0.15
2.01° to 25.10°
0.33 × 0.24 × 0.15
1.95° to 25.10°
–9 ≤ h ≤8,
–17 ≤ k ≤ 18,
–12≤ l ≤ 15
–24 ≤ h ≤25,
–5 ≤ k ≤ 5,
–16≤ l ≤ 19
Reflections collected/unique
Completeness to theta = 25.10
Refinement method
6678/2930[R (int) = 0.0329]
7769/2897[R (int) = 0.0268]
99.0%
99.7%
Full-matrix least-squares on F2
2930/0/236
Full-matrix least-squares on F2
2897/0/218
Data/restraints/parameters
Goodness-of-fit on F2
1.026
1.039
Final R indices [I > 2 sigma (I)]
R indices (all data)
Largest diffraction peak , hole / (e Å−3)
R1 = 0.0494, wR2 = 0.1158
R1 = 0.0779, wR2 = 0.1322
0.191, –0.197
R1 = 0.0318, wR2 = 0.0674
R1 = 0.0478, wR2 = 0.0728
0.275, –0.388
Figure 1. (a) Crystal structure of compound 4g, (b) packing diagrams of 4g and (c) the arrangement of 4g showing the hydrogen bonding interactions.
attributed to the nitro unit substituent at the 4-position of the
aryl ring. But the MIC value is relatively low for cyclophane
4g as compared with chloramphenicol. Compounds 4a and
4b had relatively higher activity against C. albicans (MIC of
128 μg mL-1) when compared with compounds 4c and 4h.
However, cyclophanes 4a and 4b were less effective than
fluconazole. It is clear that all the synthesized cyclophanes
have low antibacterial or antifungal activity.

1774
Synthesis, Crystal Structure and Biological Activity of Novel Diester Cyclophanes
J. Braz. Chem. Soc.
Figure 2. (a) Crystal structure X-ray analysis of 4h, (b) packing diagrams of 4h and (c) the arrangement of 4h showing the hydrogen bonding interactions.
Table 2 Antimicrobial activity of the cyclophanes (Ccyclophane = 200 μg mL-1)
Bacteria
Fungus
Compound
S. aureus
B. subtilis
E. coli
P. aeruginosa
S. typhi
C. albicans
4a
–
–
–
–
–
–
–
–
–
+
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
++
++
++
–
4b
4c
+
–
4d
–
–
4e
–
–
–
4f
–
–
–
4g
++
+
++
–
–
4h
++
–
Control
–
–
++: good inhibition; +: moderate inhibition; −: no inhibition.
Table 3. MIC values of antibacterial activity and antifungal activity
recorded on an INOVA-400 NMR spectrometer, using
TMS as internal standard and CDCl3 as the solvent. High
resolution mass spectrometry (HRMS) were obtained with
a MALDI-TOF mass spectrometer (Kratos Analytical
Inc.). Column chromatography was performed on silica
gel (200-300 mesh).
(μg mL-1)
Compound
B. subtilis
E. coli
NA
NA
NA
128
NA
8
C. albicans
4a
NA
NA
NA
NA
NA
8
128
128
NA
NA
NA
-
4b
4c
4g
Antibacterial and antifungal assays
4h
Chloramphenicol
Fluconazole
NA: not active (> 128 μg mL-1).
-
-
16
The bacteria and fungi were obtained from Shaanxi
Province Institute of Microbiology (Xi’an, China) and
maintained on Luria-Bertani (LB) medium consisting of the
following: yeast extract 5.0 g, peptone 10.0 g, NaCl 10.0 g,
distilled H2O 1 L, pH 7.5 in slants or Petri plates at room
temperature.
Experimental
Materials and equipment
Preliminary antimicrobial activities of compounds 4a-4h
were tested as follows: the new compound was dissolved in
DMSO at the concentration of 200 μg mL-1 and placed on the
LB plates that had been previously inoculated separately with
the microorganisms. The plates were incubated at 35 °C, and
the growth-inhibition zones were measured after 12 h in the
case of bacteria/fungi.
The MIC values of the compound assays were carried out
using the broth microdilution method. The tested compounds
were dissolved in DMSO to afford 128 μg mL-1. Two fold
All reagents and solvents were purchased from
Sinopharm Chemical Reagent Co., Ltd. The solvents
were purified under conventional conditions or distilled
immediately before use. The melting points were determined
using an XT-4B micro-melting-point apparatus and are
informed uncorrected. The elemental analyses for the
compounds were carried out on a Vario EL III CHNOS
instrument. The IR spectra (KBr) were recorded on an
1
Equinox-55 spectrophotometer. H NMR spectra were

Vol. 23, No. 10, 2012
Zhang et al.
1775
dilutions of the solution were prepared (64, 32, 16, 8, 4,
2, 1, 0.5, 0.25 and 0.125 μg mL-1). The bacterial cultures
(ca. 108 CFU mL-1) in Müller-Hinton medium were added
to the corresponding tubes. The plates were incubated at
35 °C for 12 h. Chloramphenicol and fluconazole were
used as reference agents. Suitable solvent control (DMSO),
positive growth control and standard drug control were also
run simultaneously. The MIC values of the compounds
were recorded as the lowest concentration of each chemical
compound in the tubes with no turbidity of inoculated
bacteria/fungus.
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Eight novel compounds (4a-4h) were synthesized. XRD
studies were carried out for compounds 4g and 4h, which
were further stabilized by H-bond stacking interaction. These
new compounds 4a-4h represent a novel class of compounds
that incorporate an 11-membered ring lactone type structure.
Some of the synthesized cyclophanes have low antibacterial
or antifungal activities, providing stimulus for further studies.
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This work was financially supported by the National
Natural Science Foundation of China (Grant No. 21172178
P. R. China).
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Submitted: July 11, 2012
Published online: September 25, 2012