Novel bis-crown ethers and their sodium complexes as antimicrobial agent: Synthesis and spectroscopic characterizations

Article abstract of DOI:10.1007/s00044-014-0937-9

A series of new compounds containing formyl and imine group were synthesized. New formyl-substituted compounds were prepared by the reaction of 1,2-bis(bromomethyl) benzene with benzaldehyde derivatives in the presence of NaOH. New bis-crown ether imine compounds were prepared by the condensation of corresponding aldehydes with 4′-aminobenzo-15-crown-5. Sodium complexes of the bis-crown ethers form crystalline 2:1 (Na⁺:ligand) stoichiometries were also been synthesized. The prepared compounds were structurally confirmed by analytical and spectral data and evaluated for their antibacterial and antifungal activities. The results show that the antibacterial activity of compounds including o-methoxy group was significantly higher against S. epidermis compared to the other studied antimicrobial group. Springer Science+Business Media 2014.

Full text of DOI:10.1007/s00044-014-0937-9

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-014-0937-9
ORIGINAL RESEARCH
Novel bis-crown ethers and their sodium complexes
as antimicrobial agent: synthesis and spectroscopic
characterizations
¨
•
•
•
˘
Zeliha Hayvalı Hu¨seyin Gu¨ler Hatice Ogu¨tcu¨
Nurs¸en Sarı
Received: 25 October 2013 / Accepted: 3 February 2014
Ó Springer Science+Business Media New York 2014
Abstract A series of new compounds containing formyl
and imine group were synthesized. New formyl-substituted
compounds were prepared by the reaction of 1,2-bis(bro-
momethyl)benzene with benzaldehyde derivatives in the
presence of NaOH. New bis-crown ether imine compounds
were prepared by the condensation of corresponding
aldehydes with 40-aminobenzo-15-crown-5. Sodium com-
plexes of the bis-crown ethers form crystalline 2:1
(Na?:ligand) stoichiometries were also been synthesized.
The prepared compounds were structurally confirmed by
analytical and spectral data and evaluated for their anti-
bacterial and antifungal activities. The results show that the
antibacterial activity of compounds including o-methoxy
group was significantly higher against S. epidermis com-
pared to the other studied antimicrobial group.
Introduction
It is known that macrocyclic compounds show high affinity
to alkali, alkaline earth, and transition metal cations forming
stable complexes with them (Pedersen, 1967; Dmitrieva
et al., 2011; Gu¨mu¨s¸ et al., 2010). Because macrocyclic ethers
have a hydrophilic cavity structure, medium polarity and
strong electronegative effect of heteroatoms on the macro-
cyclic ring. Many different modifications of the crown
ethers, such as changing the ring size, the kinds of substitu-
ents, and the types of donor atoms, have made to enhance
their complexation properties (Gromov et al., 2011; Izatt
et al., 1991). The cation–polyether complexes are formed by
ion–dipole interaction between the cation and the negatively
charged oxygens symmetrically arranged in the polyether
ring. From the earliest beginning of the development of
crown compounds, benzo-crown ethers have been a very
useful class of host molecules, forming the basis for more
complex macrocyclic ligand frameworks such as the bis-
crown ether compounds (Hayvali et al., 1999, 2000). Bis-
crown ethers are composed of two crown ether moieties
linked by different chains in the same molecule. The two
effective binding sites, the bis-crown ethers can form inter-
molecular and intramolecular complexes depending on the
relative size of the ion and the hole in the polyether ring, the
coplanirity of the oxygen atoms, and even the chain lengths
that bridge the two units. The linking of two crown ether units
can lead to the formation of sandwich complex. If the
diameter of the cation is too large to fit inside the available
crown cavity, formation of the so-called ‘‘sandwich’’ com-
plexes with metal:crown ether ratio at 1:1 can occur (Weber
et al., 1990; Kikukawa et al., 1987). The stability of such
complexes is higher with respect to the monocyclic crown
ether analogs owing to the so-called ‘‘bis-crown effect’’
(Kikukawa et al., 1987; Kimura et al. 1985).
Keywords bis-Crown ethers ꢀ Schiff bases ꢀ Aldehydes ꢀ
Antibacterial activity ꢀ Sodium complexes
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-014-0937-9) contains supplementary
material, which is available to authorized users.
Z. Hayvalı ꢀ H. Gu¨ler
Department of Chemistry, Faculty of Science, Ankara
˘
University, 06100 Tandogan, Ankara, Turkey
¨
H. Ogu¨tcu¨
˘
Department of Biology, Faculty of Arts and Science, Ahi Evran
University, 40100 Kırs¸ehir, Turkey
N. Sarı (&)
Department of Chemistry, Gazi University, Faculty of Science,
06500 Teknikokullar, Ankara, Turkey
e-mail: nursens@gazi.edu.tr
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Med Chem Res
Mono- and bis-crown ethers have been a topic of great
interest in chemical and biological research for more than
four decades (Supek et al., 2011; Tusek-Bozic et al., 2009;
class of compounds possessing wide range of biological
activities (Bandgar et al., 2012).
In this article, we describe the synthesis and charac-
terization of a series of new bis-crown ethers and com-
plexes. We report (i) the synthesis of new aldehyde
compounds which have bis-formyl group (1–4) (Fig. 1a);
(ii) the synthesis and characterization of Schiff bases
containing bis-benzo-15-crown-5 (5–8) (Fig. 1b); (iii)
complexation of sodium within the crown ether cavity
(5a–8a) (Fig. 2); (iv) analytical, physical, and spectral
˘
Ugras¸ et al., 2006; Marjanovic et al., 2007). They have
recently demonstrated function as antimicrobial agents
(Supek et al., 2011). Crown ethers exhibit ionophoric
properties in membranes, behaving very similarly to the
biologically important ionophores (such as gramicidin,
valinomycin, and nonactin) which makes crown ethers
particularly interesting and useful in chemical and bio-
logical study and their pharmaceutical potential remains
large (Gokel et al., 2004; Kralj et al., 2008). In addition,
methoxy derivatives have continued to attract attention for
their interesting biological activities. Their anticancer
(Ziedan et al., 2010), antifungal, anti-inflammatory (Sahoo
et al., 2011), and antimicrobial activities (Flipo et al.,
2011) including human immunodeficiency virus activities
are well known. Methoxy derivatives form an important
1
(IR, H, 13C NMR, and MS) data; and (v) all of these
compounds were examined for antimicrobial activity
against pathogenic strains Staphylococcus aureus, Shi-
gella dysenteria typ 7, Listeria monocytogenes 4b,
Escherichia coli, Salmonella typhi H, Staphylococcus
epidermis, Brucella abortus, Micrococcus luteus, Bacillus
cereus, Pseudomonas putida, and antifungal activity
against Candida albicans.
Fig. 1 Structures of the novel
bis-aldehydes (1–4) (a) and
Schiff bases (5–8) (b)
A
B
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Med Chem Res
Fig. 2 Structures of the sodium
complexes (5a–8a)
Materials and methods
susceptibility test was used by C. albicans Y-1200-NIH,
Tokyo. The ligands and the complexes were tested for their
antimicrobial activity by the well-diffusion method (Sari
et al., 2013). Each ligand and complex was kept dry at room
temperature and dissolved (103 lM) in DMF. DMF was used
as solvent and also for control. It was found to have no
antimicrobial activity against any of the tested organisms.
1 % (v/v) of a 24-h broth culture containing 106 CFU/ml was
placed in sterile Petri dishes. Mueller–Hinton Agar (15 ml)
kept at 45 °C was then poured into the Petri dishes and
allowed to solidity. Then 6-mm diameter wellswere punched
carefully by using a sterile cork borer and were entirely filled
with the test solutions. The plates were incubated for 24 h at
37 °C. On completion of the incubation period, the mean
value obtained for the two holes was used to calculate the
zone of growth inhibition of each sample.
Reagents and equipments
4-Hydroxy-3-methoxybenzaldehyde (vanillin), 2-Hydroxy-
3-methoxybenzaldehyde (o-vanillin), 2-hydroxy-4-meth-
oxybenzaldehyde, and 2-hydroxy-5-methoxybenzaldehyde
were purchased from Aldrich and used without further
purification. 1,2-bis(bromomethyl)benzene was prepared
according to the literature (Zhu et al., 2011). Solvents were
dried and distilled before use according to the standard
procedure. Melting points were measured on a Thomas–
Hoover apparatus using a capillary tube. 1H and 13C NMR
spectra were recorded on a Varian Mercury, High Perfor-
mance Digital FT-NMR (400 MHz) spectrometer (SiMe4
as an internal standard). Chemical shifts for proton and
carbon resonances were reported in ppm (d). IR spectra
were obtained from PEL-DATA spectrum 100 series
spectrometer. Carbon, nitrogen, and hydrogen analyses
were performed on LECO CHNS-932 elemental analyzer.
Mass spectrometric analyses were performed on the Waters
2695 Allonce ZQ LC/MS spectrometer.
General method for prepare of novel bis-aldehydes
(1–4)
The corresponding vanillin or methoxysalicylaldehyde
derivatives (0.35 g, 2.30 mmol) were dissolved in EtOH
(15 mL). NaOH (0.09 g, 2.30 mmol) was added in small
amounts and the resulting reaction mixture was refluxed for
1 h. Subsequently, 1,2-bis(bromomethyl)benzene (0.30 g,
1.15 mmol) in EtOH (15 mL) was added dropwise to the
reaction mixture. The resulting solution was refluxed for
24 h, and the complete consumption of the starting material
was observed by TLC (silica; eluent; CHCl3). The white
precipitate was isolated and recrystallized from ethanol.
Detection of antimicrobial activity
The bacterial subcultures chosen were S. aureus RSKK-
07035, S. dys. typ 7 NCTC-9363, L. monocytogenes 4b ATCC
19115, E. coli ATCC 1280, S. typhi H NCTC 901.8394, S.
epidermis sp., B. abortus RSKK-03026, M. luteus ATCC-
9341, B. cereus sp., and P. peptide sp. An antifungal
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Med Chem Res
2,20-[1,2- Phenylenebis(methyleneoxy)]
General method for prepare of bis-crown ether Schiff
bis(3-methoxybenzaldehyde) (1)
bases (5–8)
White; m.p. 159–160 °C; IR (KBr) mmax 2,949–2,846 (w),
10 mL of methanol was added to a solution of corre-
sponding bis-aldehyde (1–4) (0.20 g, 0.49 mmol) with
continuous stirring of 40-aminobenzo-15-crown-5 (0.27 g,
0.98 mmol). The resulting solution was stirred under reflux
for 5 h, and then the reaction mixture was allowed to stand
for 2 h at room temperature. The yellow product was re-
crystallized from CH3OH.
1,691 (s), 1,584 (s), 1,251, 1,183, 1,067 (s), 1,059 (s) cm-1
;
1H NMR (CDCl3, 500 MHz,): d = 10.25 (2H, s),
7.54–7.13 (10H, m), 5.32 (s, 4H), 3.86 (s, 6H); 13C NMR
(CDCl3, 125 MHz,): d = 190.6 (C, CHO),153.0 (C, C-4),
151.6 (C, C-5), 142.8 (C, C-3), 130.0 (C, C-1), 129.1 (C,
C-2), 122.3 (C, C-8), 130.2 (C, C-9), 119.2 (C,C-7), 115.1
(C, C-6), 57.1 (C, OCH2), 69.9 (C, OCH3); Anal. Calcd. for
C24H22O6: C, 70.92; H, 5.46. Found: C, 71.21; H, 5.67.
N,N0-{1,2-phenylbis[methyleneoxy(3-methoxy-2,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin) (5)
2,20-[1,2- Phenylenebis(methyleneoxy)]
bis(4-methoxybenzaldehyde) (2)
Yellow; m.p. 82–83 °C; IR (KBr) mmax 2,922–2,867 (w),
1,621 (s), 1,577, 1,511 (s), 1,260, 1,125–1,069 (s) cm-1; 1H
NMR (CDCl3, 500 MHz,): d = 8.69 (2H, s), 7.68–6.61
(16H, m), 5.24 (4H, s), 4.12–3.75 (32H, m) 3.79 (6H, s);
13C NMR (CDCl3, 125 MHz,): d = 155.7 (C, CH=N),
152.3 (C, C-1), 150.1 (C, C-2), 149.1 (C, C-3), 148.1 (C,
C-4), 146.1 (C, C-5), 136.1 (C, C-6), 130.9 (C, C-7), 130.5
(C,C-8), 128.7 (C, C-9), 124.6 (C, C-10), 119.2 (C, C-11);
115.0 (C, C-12), 114.9 (C, C-13), 113.9 (C, C-14); 108.0
(C, C-15); 73.5 (C, OCH2) 71.4–68.9 (C, OCH2CH2O),
56.9 (C, OCH3); Anal. Calcd. for C52H60O14N2: C, 66.65;
H, 6.45; N, 2.99. Found: C, 66.89; H, 6.46; N, 3.02.
White; m.p. 129–130 °C; IR (KBr) mmax 2,928–2,866 (w),
1,676 (s), 1,595, 1,577 (s), 1,260, 1,164,1,044 (s), 1,030
(s) cm-1; 1H NMR (CDCl3, 500 MHz,): d = 10.31 (2H, s),
7.87–7.23 (10H, m), 5.31 (s, 4H), 3.83 (s, 6H); 13C NMR
(CDCl3, 125 MHz,): d = 189.1 (C, CHO),166.7 (C, C-4),
166.2 (C, C-5), 139.5 (C, C-3), 130.8 (C, C-2), 130.1 (C,
C-8), 128.6 (C, C-1), 122.8 (C, C-9), 108.7 (C,C-7), 101.5
(C, C-5), 68.6 (C, OCH2), 56.1 (C, OCH3); Anal. Calcd. for
C24H22O6: C, 70.92; H, 5.46. Found: C, 70.99; H, 5.45.
2,20-[1,2- Phenylenebis(methyleneoxy)]
bis(5-methoxybenzaldehyde) (3)
N,N0-{1,2-phenylbis[methyleneoxy(4-methoxy-2,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin) (6)
White; m.p. 143–144 °C; IR (KBr) mmax 2,963–2,842 (w),
1,677 (s), 1,586 (s), 1,256, 1,164 (s), 1,043 (s) cm-1; H
1
NMR (CDCl3, 500 MHz,): d = 10.41 (2H, s), 7.53–6.97
(10H, m), 5.22 (s, 4H), 3.79 (s, 6H); 13C NMR (CDCl3,
125 MHz,): d = 189.3 (C, CHO),154.92 (C, C-8), 153.9
(C, C-4), 134.1 (C, C-3), 128.8 (C, C-2), 128.6 (C, C-1),
125.9 (C, C-9), 123.9 (C, C-6), 114.2 (C,C-5), 111.1 (C,
C-8), 69.5 (C, OCH2), 56.0 (C, OCH3); Anal. Calcd. for
C24H22O6: C, 70.92; H, 5.46. Found: C, 70.69; H, 5.32.
Yellow; m.p. 129–128 °C; IR (KBr) mmax 2,917–2,865 (w),
1,610 (s), 1,585, 1,511 (s), 1,259, 1,118–1,036 (s) cm-1; 1H
NMR (CDCl3, 500 MHz,): d = 8.75 (2H, s), 8.06–6.46
(16H, m), 5.22 (4H, s), 4.11–3.74 (32H, m) 3.75 (6H, s);
13C NMR (CDCl3, 125 MHz,): d = 156.2 (C, CH=N),
153.2 (C, C-1), 149.4 (C, C-2), 149.1 (C, C-3), 147.6 (C,
C-4), 146.2 (C, C-5), 137.3 (C, C-6), 129.1 (C, C-7), 129.9
(C,C-8), 126.4 (C, C-9), 124.7 (C, C-10), 118.5 (C, C-11);
115.6 (C, C-12), 114.1 (C, C-13); 112.8 (C, C-14); 107.7
(C, C-15); 72.3 (C, OCH2) 70.9–68.3 (C, OCH2CH2O),
72.3 (C, OCH3); 56.2 (C, OCH2); Anal. Calcd. for
C52H60O14N2: C, 66.65; H, 6.45; N, 2.99. Found: C, 66.63;
H, 6.87; N, 2.89.
4,40-[1,2-Phenylenebis(methyleneoxy)]bis(3-
methoxybenzaldehyde) (4)
White; m.p. 137–138 °C; IR (KBr) mmax 2,946–2,814 (w),
1,675 (s), 1,583, 1,513 (s), 1,267, 1,134 (s), 1,032 (s) cm-1
;
1H NMR (CDCl3, 500 MHz,): d = 10.36 (2H, s),
7.54–6.96 (10H, m), 5.29 (s, 4H), 3.82 (s, 6H); 13C NMR
(CDCl3, 125 MHz,): d = 189.1 (C, CHO),156.1 (C, C-4),
151.1 (C, C-5), 141.2 (C, C-3), 131.9 (C, C-2), 129.4 (C,
C-1), 126.0 (C, C-7), 128.8 (C, C-6), 126.0 (C,C-7), 113.2
(C, C-9), 69.4 (C, OCH2), 55.2 (C, OCH3); Anal. Calcd. for
C24H22O6: C, 70.92; H, 5.46. Found: C, 71.02; H, 5.63.
N,N0-{1,2-phenylbis[methyleneoxy(5-methoxy-2,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin) (7)
Green; m.p. 95–96 °C; IR (KBr) mmax 2,921–2,866 (w),
1,623 (s), 1,579, 1,508 (s), 1,262, 1,125–1,029 (s) cm-1; 1H
123

Med Chem Res
Table 1 1H-NMR spectral data
Compound
–OCH3
–OCH2
–CHO
HC=N
–OCH2CH2O–
Ar–H
1
3.86 (s, 6H)
3.83 (s, 6H)
3.79 (s, 6H)
3.82 (s, 6H)
3.79 (s, 6H)
3.75 (s, 6H)
3.81 (s, 6H)
3.93 (s, 6H)
3.82 (s, 6H)
3.76 (s, 6H)
3.86 (s, 6H)
3.97 (s, 6H)
5.32 (s, 4H)
5.31 (s, 4H)
5.22 (s, 4H)
5.29 (s, 4H)
5.24 (s, 4H)
5.22 (s, 4H)
5.20 (s, 4H)
5.35 (s, 4H)
5.21 (s, 2H)
5.25 (s, 4H)
5.21 (s, 4H)
5.32 (s, 4H)
10.25 (s, 2H)
–
–
7.54–7.13 (m, 10H)
7.87–7.23 (m, 10H)
7.53–6.97 (m, 10H)
7.54–6.96 (m, 10H)
7.68–6.61 (m, 16H)
8.06–6.46 (m, 16H)
7.64–6.67 (m, 16H)
7.56–6.74 (m, 16H)
7.67–6.24 (m, 16H)
8.01–6.48 (m, 16H)
7.61–6.79 (m, 16H)
7.53–6.71 (m, 16H)
2
10.31 (s, 2H)
–
–
3
10.41 (s, 2H)
–
–
4
10.36 (s, 2H)
–
–
5
–
–
–
–
–
–
–
–
8.69 (s, 2H)
8.75 (s, 2H)
8.84 (s, 2H)
8.33 (s, 2H)
8.57 (s, 2H)
8.66 (s, 2H)
8.74 (s, 2H)
8.24 (s, 2H)
4.12–3.75 (m, 32H)
4.11–3.74 (m, 32H)
4.13–3.75 (m, 32H)
4.19–3.76 (m, 32H)
4.19–3.70 (m, 32H)
4.15–3.70 (m, 32H)
4.17–3.69 (m, 32H)
4.24–3.72 (m, 32H)
6
7
8
5a
6a
7a
8a
Chemical shifts (d) are reported in ppm (in CDCl3)
s singlet, m multiplet
NMR (CDCl3, 500 MHz,): d = 8.84 (2H, s), 7.64–6.67
(16H, m), 5.20 (4H, s), 4.13–3.75 (32H, m) 3.81 (6H, s);
13C NMR (CDCl3, 125 MHz,): d = 155.9 (C, CH=N),
152.8 (C, C-1), 149.0 (C, C-2), 148.6 (C, C-3), 147.3 (C,
C-4), 145.0 (C, C-5), 137.5 (C, C-6), 128.8 (C, C-7), 128.0
(C,C-8), 126.2 (C, C-9), 125.2 (C, C-10), 117.5 (C, C-11);
115.2 (C, C-12), 114.0 (C, C-13); 112.9 (C, C-14); 106.1
(C, C-15); 73.2 (C, OCH2) 71.33–68.2 (C, OCH2CH2O),
56.5 (C, OCH3); Anal. Calcd. for C52H60O14N2: C, 66.65;
H, 6.45; N, 2.99. Found: C, 66.42; H, 6.49; N, 2.91.
(0.02 g, 0.21 mmol) was slowly added in methanol (5 mL)
with stirring for 1 h. The crude complexes were filtered and
then left to dry in open air. For characteristic peaks, see Table 1.
N,N0-{1,2-phenylbis[methyleneoxy(3-methoxy-2,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin)
sodium complex (5a)
Compound (5a) White; m.p. 132–133 °C; IR (KBr) mmax
2,919–2,876 (w), 1,620 (s), 1,577, 1,508 (s), 1,265 (s),
1,080, 622 (s) cm-1; 1H NMR (CDCl3, 500 MHz,): d = 8.
57 (2H, s), 7.67–6.24 (16H, m), 5.21 (4H, s), 4.19–3.70
(32H, m) 3.82 (6H, s); 13C NMR (CDCl3, 125 MHz,): d =
155.6 (C, CH=N); 153.9, 151.69, 148.7, 148.0, 145.9, 136.
2, 130.5, 129.6, 129.2, 125.5, 118.1, 114.7, 113.2, 112.7,
106.2 (C, C1-15); 72.7 (C, OCH2); 71.5–69.2 (C, OCH2-
CH2O); 52.9 (C, OCH3); Anal. Calcd. for C52H60O22N2-
Na2Cl2: C, 52.84; H, 5.12; N, 2.37. Found: C, 52.58; H, 5.
32; N, 2.38.
N,N0-{1,2-phenylbis[methyleneoxy(3-methoxy-4,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin) (8)
Green; m.p. 95–96 °C; IR (KBr) mmax 2,925–2,865 (w),
1,619 (s), 1,586, 1,506 (s), 1,261, 1,118–1,046 (s) cm-1; 1H
NMR (CDCl3, 500 MHz,): d = 8.75 (2H, s), 7.56–6.74
(16H, m), 5.35 (4H, s), 4.19–3.76 (32H, m) 3.93 (6H, s);
13C NMR (CDCl3, 125 MHz,): d = 156.05 (C, CH=N),
151.9 (C, C-1), 151.0 (C, C-2), 148.7 (C, C-3), 148.0 (C,
C-4), 147.2 (C, C-5), 136.2 (C, C-6), 131.1 (C, C-7), 130.1
(C,C-8), 128.1 (C, C-9), 125.3 (C, C-10), 118.2 (C, C-11);
114.2 (C, C-12), 113.2 (C, C-13); 112.9 (C, C-14); 106.2
(C, C-15); 72.2 (C, OCH2) 70.9–68.6 (C, OCH2CH2O),
55.6 (C, OCH3); Anal. Calcd. for C52H60O14N2: C, 66.65;
H, 6.45; N, 2.99. Found: C, 66.74; H, 6.67; N, 3.12.
N,N0-{1,2-phenylbis[methyleneoxy(4-methoxy-2,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin)
sodium complex (6a)
Compound (6a) White; m.p. 142–143 °C; IR (KBr) mmax
2,927–2,878 (w), 1,606 (s), 1,591, 1,509 (s), 1,262 (m),
1,085, 623 (s) cm-1; 1H NMR (CDCl3, 500 MHz,): d = 8.
66 (2H, s), 8.01–6.48 (16H, m), 5.25 (4H, s), 4.15–3.70
(32H, m) 3.76 (6H, s); 13C NMR (CDCl3, 125 MHz,): d =
155.12 (C, CH=N); 152.8, 150.5, 149.1, 147.7, 144.9, 137.
8, 131.6, 130.2, 129.6, 126.2, 119.5, 113.8, 112.2, 111.5,
General methods for prepare of NaClO4 complexes
(5a–8a)
To a solution of corresponding ligand (5–8) (0.10 g,
0.10 mmol) in methanol (10 mL), a solution of NaClO4
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Med Chem Res
105.9 (C, C1-15); 72.2 (C, OCH2); 71.1–68.8 (C, OCH2-
CH2O); 56.6 (C, OCH3); Anal. Calcd. for C52H60O22N2-
Na2Cl2: C, 52.84; H, 5.12; N, 2.37. Found: C, 52.66; H, 5.
27; N, 2.58.
aldehydes in 2:1 molar ratio in methanol. The sodium
complexes (5a–8a) were carried out by combining the
respective bis-crown ethers with two molar NaClO4 in
methanol. In the proposed structures, the ligands have bis-
benzo-15-crown-5 cores to form dinuclear metal com-
plexes. Ligands have bis-benzo-15-crown-5 cores are form
dinuclear metal complexes.
N,N0-{1,2- phenylbis [methyleneoxy(5-methoxy-2,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin)
sodium complex (7a)
The spectroscopic data indicated that the stoichiometry
of the complex formed between Na? benzo-15-crown-5
(M:L) is 2:1 (Fig. 2). Analytical and physical data of
aldehydes (1–4), crown ether Schiff bases (5–8), and
sodium complexes (5a–8a) are presented in ‘‘Materials and
methods’’ section. The structures of all compounds were
fully characterized by using melting points, elemental
analysis (C, H, N), FT-IR, 1H-, and 13C NMR spectral data.
There are selected spectra as supplementary data for studied
compounds (Figs S1–S8).
Compound (7a)
Yellow; m.p. 138 °C; IR (KBr) mmax
2,925–2,882 (w), 1,625 (m), 1,588, 1,509 (m), 1,252 (m),
1,082, 623 (s) cm-1; 1H NMR (CDCl3, 500 MHz,): d = 8.
74 (2H, s), 7.61–6.79 (16H, m), 5.21 (4H, s), 4.17–3.69
(32H, m) 3.86 (6H, s); 13C NMR (CDCl3, 125 MHz,): d =
155.8 (C, CH=N); 153.6, 151.2, 148.2, 147.2, 145.34, 138.
7, 130.9, 130.1, 128.7, 125.5, 118.2, 113.9, 113.0, 111.7,
105.6 (C, C1-15); 77.9 (C, OCH2); 71.9–69.2 (C, OCH2-
CH2O); 56.2 (C, OCH3); Anal. Calcd. for C52H60O22N2-
Na2Cl2: C, 52.84; H, 5.12; N, 2.37. Found: C, 53.08; H, 5.
16; N, 2.61.
1
FT-IR spectra, H and 13C NMR spectra
Selected IR spectral data for the aldehydes (1–4), bis-
crown ethers (5–8), and sodium complexes (5a–8a) are
listed in ‘‘Materials and methods’’ section. For the alde-
hydes (1–4), characteristic aldehyde t(C=O) vibrations for
carbonyl groups were detected at 1,691, 1,676, 1,677, and
1,675 cm-1, respectively. In the imine compounds (5–8),
the relatively strong bands attributable to t(C=N), were
observed at 1,621, 1,610, 1,623, and 1,619 cm-1, respec-
tively. The tas(C–O–C)arom. and ts(C–O–C)aliph. vibrations
appear between 1,262 and 1,029 cm-1 in the spectra of the
crown ethers (5–8). The aliphatic t(C–H) vibrations exer-
ted by –OCH2 and –OCH3 groups for compounds (1–8)
were observed in the range of 2,963–2,814 cm-1. For
N,N0-{1,2-phenylbis[methyleneoxy(3-methoxy-4,1-
phenyl)methylene]}bis(2,3,5,6,8,9,11,12-octahydro-
1,4,7,10,13-benzopentaoxocyclopentadien-15-amin)
sodium complex (8a)
Compound (8a) Green; m.p. \200 °C (decompose); IR
(KBr) mmax 2,920–2,879 (w), 1,606 (m), 1,591, 1,509 (m),
1,263 (m), 1,085, 623 (s) cm-1
;
1H NMR (CDCl3,
500 MHz,): d = 8.24 (2H, s), 7.53–6.71 (16H, m), 5.32
(4H, s), 4.24–3.72 (32H, m) 3.97 (6H, s); 13C NMR
(CDCl3, 125 MHz,): d = 156.1 (C, CH=N); 152.1, 151.4,
147.9, 147.1, 146.9, 137.1, 128.2, 127.9, 127.22, 125.36,
119.22, 114.69, 112.19, 111.23, 107.78 (C, C1-15); 72.12
(C, OCH2); 70.97–68.63 (C, OCH2CH2O); 56.11 (C,
OCH3); Anal. Calcd. for C52H60O22N2Na2Cl2: C, 52.84; H,
5.12; N, 2.37. Found: C, 52.79; H, 5.36; N, 2.19.
-
sodium complexes (5a–8a), the anion ClO4 gives rise to
IR absorption bands at 1,080; 622, 1,085; 623, 1,082; 623;
and 1,085; 623 cm-1, respectively. These bands attribut-
able to the asymmetric tas(Cl–O) stretching modes ca.
between 1,085 and 1,080 cm-1 and the asymmetric tas(O–
Cl–O) bending modes ca. between 623 and 622 cm-1
,
suggest that both bounded and uncoordinated free anions
are present.
Results and discussion
The 1H-NMR spectral data for the aldehydes (1–4), bis-
crown ethers (5–8), and sodium complexes (5a–8a) are
summarized in Table 1. The 1H-NMR spectra of the
compounds indicated singlets between 3.75 and 3.97 ppm
and between 5.20 and 5.35 ppm, corresponding to the
–OCH3 and –OCH2 protons, respectively. The singlet at
10.25, 10.31, 10.41, and 10.36 ppm belong to aldehyde
protons (–CHO) (for 1–4). The aromatic protons of alde-
hydes, crown ether imine compounds, and sodium com-
plexes appear as multiplets in the ranges of 8.06–6.46 ppm
(for 1–4), 8.06–6.46 ppm (for 5–8), and 8.01–6.24 ppm
(for 5a–8a), respectively. For the bis-crown ether Schiff
Characterization of Schiff bases and their Na
Complexes
The new aldehydes (1–4) were synthesized in 82–92 %
yields from the reaction of 1,2-bis(bromomethyl)benzene
with 2-hydroxy-3-methoxybenzaldehyde (o-vanillin),
2-hydroxy-4-methoxybenzaldehyde, 2-hydroxy-5-methox-
ybenzaldehyde, and 4-hydroxy-3-methoxybenzaldehyde in
EtOH, in the presence of NaOH (Fig. 1). Crown ether
Schiff bases (5–8) (Fig. 2) were prepared by the conden-
sation of 40-aminobenzo-15-crown-5 with corresponding
123

Med Chem Res
bases (5–8), the characteristic imine protons (HC=N) were
observed as singlets at 8.69, 8.75, 8.84, and 8.33 ppm,
respectively. The absence of aldehyde proton signal and
detecting azomethine (HC=N) signal indicate the presence
aldehyde carbons (–CHO) for compounds (1–4) were
observed at 190.63, 189.13, 189.32, and 189.08 ppm,
respectively. As expected, the imine carbons (HC=N) of
the compounds 5–8 were detected at 155.72, 156.19,
155.97, and 156.05 ppm, respectively. The signals of the
eight crown ether –OCH2CH2O– carbons were observed
between at 71.35 and 68.17 ppm, as expected. The signals
of the aromatic carbons were detected in the expected
region, and were equal to the number in the proposed
structures of aldehydes and bis-crown ethers. In the 13C
NMR spectra of sodium complexes (5a–8a), the small up
field chemical shifts were detected for the crown ether
protons (–OCH2–CH2O–). In addition, the spectra indi-
cated the characteristic signals for the –OCH3, –OCH2,
–HC=N and aromatic carbons.
1
of imine compounds. The H NMR spectra indicated that
substituted –OCH3 group was effective for the imine pro-
ton shift, because imine proton was seen at 8.33 ppm for 8,
while this peak was detected at 0.36, 0.42, and 0.51 ppm
upfield (d = 8.69, 8.75 and 8.84 ppm) for compounds 5–7,
respectively. The imine protons for sodium complexes
were approximately the same for the ligands imine protons.
Bis-crown ether protons (–OCH2–CH2O–) appeared as
multiplets between 4.19 and 3.74 ppm for compounds
1
(5–8). In the H-NMR spectra of sodium complexes (5a–
8a), the small downfield or upfield chemical shifts were
detected for the crown ether protons (–OCH2–CH2O–).
These small shifts may be attributed to the differences in
the longer distances between Na? and the five oxygen
atoms of the benzo-15-crown-5 (Hayvalı et al., 2003;
Atkinson et al., 1907).
The 13C NMR data for compounds (1–4), (5–8) and (5a–
8a) were recorded in CDCl3 solution (Table 2). In all of the
ligands (1–8), the characteristic aliphatic –OCH3 carbons
were detected between at 55.18 and 57.14 ppm. The
Mass spectra
The API-ES and APCI mass spectra of compounds were
recorded. Compounds examined provided nice quality mass
spectra, and the molecular weight of the ligands and com-
plexes have been confirmed. In the API-ES mass spectra of
all aldehydes (1–4), the respective molecular ion peaks
[M?H]? were detected at m/z 407.5 (100 %). The major
Table 2 13C NMR spectral data. Chemical shifts (d) are reported in ppm (in CDCl3)
Comp -OCH3
-OCH2
-CHO
HC=N
190.6
-
189.1
-
189.3
OCH2CH2O-
Ar-C1-3
Ar-C4-9
1
2
3
57.1
69.8
56.1
68.6
56.0
69.5
55.2
69.4
-
-
-
-
130.0; 129.1; 142.8
128.6; 130.8; 139.5
128.6; 128.8; 134.1
129.4; 131.9; 141.2
153.0, 151.7, 115.1 119.2, 122.3,
130.2
166.7, 101.5, 166.2 108.7, 130.1,
122.8
153.9, 114.2, 123.9
154.9, 111.1, 125.9
156.1, 151.1, 110.3
128.8, 126.0, 113.1
Ar-C1-C15
1
2
3
4
O
9
5
4
O
H
OC
H
3CO
6
3
H
O
C
H
O
C
7
8
(1-4)
-
189.1
-
56.9
73.5
56.2
72.3
56.5
73.2
55.6
72.2
56.9
72.7
56.6
72.2
56.2
71.9
56.1
72.1
-
71.4-68.9
70.9-68.3
71.3-68.2
70.9-68.6
71.5-69.2
71.1-68.8
71.9-69.2
70.9-68.6
152.3; 150.1; 149.1; 148.1; 146.1; 136.1; 130.9; 130.5; 128.7; 124.6; 119.2; 115.0; 114.9; 113.9; 108.0
153.2; 149.4; 149.1; 147.6; 146.2; 137.3; 129.1; 129.9; 126.4; 124.7; 118.5; 115.6; 114.1; 112.8; 107.7
152.8; 149.0; 148.6; 147.3; 145.0; 137.5; 128.8; 128.0; 126.2; 125.2; 117.5; 115.2; 114.0; 112.9; 106.1
151.9; 151.0; 148.7; 148.0; 147.2; 136.2; 130.1; 131.1; 128.1; 125.3; 118.2; 114.2; 113.1; 112.9; 106.2
153.9; 151.7; 148.7; 148.0; 145.7; 136.2; 130.5; 129.6; 129.2; 125.5; 118.1; 114.7; 113.2; 112.7; 106.2
152.8; 150.5; 149.1; 147.7; 144.9; 137.8; 131.6; 130.2; 129.6; 126.2; 119.5; 113.8; 112.2; 111.5; 105.9
153.6; 151.2; 148.2; 147.2; 145.3; 138.7; 130.9; 130.1; 128.7; 125.5; 118.2; 113.88; 113.0; 111.7; 105.6
5
6
155.7
-
156.2
-
155.9
-
156.1
-
155.6
-
155.1
-
155.8
-
156.1
7
8
5a
6a
7a
8a
152.1; 151.4; 147.9; 147.0; 146.9; 137.1; 128.2; 127.9; 127.2; 125.4; 119.2; 114.7; 112.2; 111.2; 107.8
1
2
3
O
6
4
8
O
5
15
12
O
10
O
14
13
O
O
N
C
H
N
C
H
O
9
O
11
7
O
O
O
O
H
OC
H
3CO
3
(5-8)
123

Med Chem Res
fragments for compounds (1–4) were obtained at m/z 104.1
(49.4, 51.1, 50.3, and 48.3 %) corresponding to the [C8H8].
In the APCI mass spectra of the Schiff bases (5–8), the
molecular ion peaks were recorded at m/z 938.2 (29.1, 32.1,
20.3, and 28.3 %, respectively). The major fragments were
obtained at m/z 974.0 (58.1 %), 974.1 (54.1 %), 974.2
(51.1 %), and 974.2 (52.5 %) corresponding to the
[M?2H2O]?, for the Schiff bases. The fragmentation pat-
tern proceeding by the loss of ether chains is in accordance
with previous papers (Coco et al., 2008; Bush and Truter,
1972; Fenton et al., 1981).
(Table 3). All of the compounds were active against Sh.
dys. typ and B. cereus.
Effective of methoxy substituent in the bis-aldehydes As
shown in Fig. 1, three electron-donor derivatives were
prepared, containing 3-methoxy, 4-methoxy, and 5-meth-
oxy. The pharmacology test revealed that their activity
order was 3-methoxy \ 4-methoxy \ 5-methoxy for L.
monocytogenes, Br. abortus, and C. albicans. As shown in
Table 3, the compound (3) that has 5-methoxy substituent
showed a significant activity against M. luteus; however,
S. aureus did not display any activity against.
In the API-ES mass spectra of sodium complexes (5a–
8a), the dominant peak at m/z 961.3 (55.1 %), 961.1
(52.1 %), 961.5 (53.1 %), and 961.2 (54.2 %) corresponds
to the ligand plus sodium [M?Na]?. The molecular ion
peaks and fragments of the ligands and complexes support
the proposed structures.
Effective of methoxy substituent in Schiff bases Table 3
and Fig. 2 were analyzed together; the antibacterial activity
order was 3-methoxy \ 4-methoxy \ 5-methoxy for B.
cereus. The compound (7) (Schiff bases including
5-methoxy) was highly active against Gram-positive and
Gram-negative bacteria with a 103 lM.
Effective of methoxy substituent in sodium complexes:
Regular order was not observed in none of studied bacteria
species and fungal effective of methoxy substituent in
sodium complexes.
Antibacterial studies
The ligands and their sodium complexes were screened for
antimicrobial activity in DMF solvent as a control sub-
stance. The compounds were tested with the same con-
centrations in DMF solution (103 lM). All the synthesized
compounds and antibiotic exhibited varying degree of
inhibitory effects on the growth of different tested strains
In general, the sodium complexes are more potent bac-
tericides than the ligand. This enhancement in activity may
be explained on the basis of chelation theory (Sarı et al.,
2013). As shown in Table 3, complexes (5a), (7a), and (8a)
showed a significant activity against S. epidermis. S. aureus
Table 3 Antimicrobial activity of studied compounds (103 lM) and standard reagents (diameter of zone inhibition (mm))
1
2
3
4
5
5a
6
6a
7
7a
8
8a
Control
S. aureus
–
–
–
–
13
11
–
–
–
–
15
13
11
14
14
20
19
12
18
–
–
15
19
12
20
13
21
–
–
–
–
–
–
–
–
–
–
–
–
–
Sh.dys. typ 7
L. monocytogenes
E. coli
16
11
14
12
20
17
20
18
19
24
15
12
15
11
16
15
15
13
–
16
14
13
14
18
22
26
16
15
27
17
13
15
13
18
20
20
15
14
26
15
12
16
13
33
23
25
28
19
24
15
11
–
17
11
18
14
16
19
20
15
20
20
20
12
17
14
25
24
19
20
24
23
15
11
–
–
S. typhi H
S. epidermis
Br. abortus
M. luteus
–
–
14
25
15
23
19
20
22
–
–
–
25
–
–
16
18
13
21
B. cereus
12
–
15
–
P. putida
C. albicans
20
12
–
21
Positive control
S. aureus
L. monocytogenes
E. coli
S. typhi H
Br. abortus
C. albicans
K30
25
24
30
30
–
15
11
16
22
–
25
18
10
14
–
20
17
11
19
–
–
–
SXT25
AMP10
AMC30
NYS100
SCF
–
–
–
–
–
–
–
20
–
–
–
–
–
12
K30 kanamycin 30 lg, SXT25 sulfamethoxazol 25 lg, AMP10 ampicillin 10 lg, CIP5 Ciprofloxacin 5 lg, AMC30 amoxycillin 30 lg, NYS100
nystatin 100 lg, SCF sulbactam (30 lg)
123

Med Chem Res
Dmitrieva SN, Sidorenko NI, Kurchavov NA, Vedernikov AI,
Freidzon AY, Kuz’mina LG, Buryak AK, Buslaeva TM,
Bagatur’yants AA, Strelenko YA, Howard JAK, Gromov SP
(2011) Macrocyclic complexes of palladium(II) with benzothia-
crown ethers: synthesis, characterization, and structure of cis and
trans Isomers. Inorg Chem 50:7500–7510
did not display any activity against them. The results of
antifungal and antibacterial screening indicated that the
complexes of (3) showed more activity than the other
complexes for B. cereus.
Furthermore, the antibacterial activity of these com-
pounds was also compared with seven commercial antibi-
otics, namely, kanamycin, sulfamethoxazol, ampicillin,
ciprofloxacin, amoxycillin, sulbactam, and nystatin. It was
seen that the synthesized compounds were effective as the
antibiotics above mentioned.
Fenton DE, Parkin D, Newton RF (1981) The synthesis of adrenaline
crown ethers. J Chem Soc Perkin Trans 1:449–454
Flipo M, Desroses M, Lecat-Guillet N, Diri B, Carette X, Leroux F,
Piveteau C, Demirkaya F, Lens Z, Rucktooa P, Villeret V,
Christophe T, Jeon HK, Locht C, Brodin P, Deprez B, Baulard
AR, Willand N (2011) Ethionamide boosters: synthesis, biolog-
ical activity, and structure activity relationships of a series of
1,2,4-oxadiazole EthR inhibitors. J Med Chem 54:2994–3010
Gokel GW, Leevy WM, Weber E (2004) Crown Ethers: sensors for
ions and molecular scaffolds for materials and biological models.
Chem Rev 104:2723–2750
Conclusion
Gromov SP, Vedernikov AI, Lobova NA, Kuz’mina LG, Basok SS,
Strelenko YA, Alfimov MV, Howard JAK (2011) Controlled
self-assembly of bis(crown)stilbenes Into unusual bis-sandwich
complexes: structure and stereoselective [2?2] photocycloaddi-
tion. New J Chem 35:724–737
In conclusion, new formyl-substituted compounds (1–4)
were prepared by reacting with the appropriate hydroxy
benzaldehydes with 1,2-bis(bromomethyl)benzene in EtOH
in the presence of NaOH. These compounds reacted with
40-aminobenzo-15-crown-5 to afford the corresponding bis-
crown ethers (5–8). Dinuclear sodium complexes (5a–8a)
of the bis-crown ethers were prepared with NaClO4. Most
of the compounds had potential antibacterial activities
against studied bacteria. In particular, compound (5a) was
found to have the most antibacterial effective. Previous
papers on bioactive properties of methoxy derivatives
highlight importance substituent in the 5-position (Fenton
et al., 1981; Husain et al., 2011). This study shows that
crown ether compounds that have 5-methoxy derivatives
may have presented greater antimicrobial properties. These
results suggested that further development of such com-
pounds may be of interest.
˘
¨
Gu¨mu¨s¸ A, Karadeniz S¸, Ugras¸ HI, Bulut M, C¸ akır U, Goren AC
(2010) Synthesis, complexation, and biological activity studies
of 4-aminomethyl-7,8-dihydroxy coumarines and their crown
ether derivatives. J Heterocyclic Chem 47:1127–1133
Hayvali Z, Gunduz N, Kilic Z, Weber E (1999) Synthesis and
characterization of new bis(crown ether)s of Schiff base type
containing recognition sites for sodium and nickel guest cations.
J Prakt Chem 341:568–573
Hayvalı Z, Gu¨ndu¨z N, Kılıc¸ Z, Weber W (2000) Synthesis, complex
formation and spectral investigation of new tritopic bis(crown
ether) compounds containing recognition sites for sodium and
nickel guest cations. Z Naturforsch 55b:975–981
¨
Hayvalı Z, Hayvalı M, Kılıc¸ Z, Hokelek T, Weber E (2003) New
benzo-15-crown-5 ethers featuring salicylic Schiff base Substi-
tutions-synthesis, complexes and structural study. J Incl Phenom
Macrocycl Chem 45:285–294
Husain A, Drabu S, Kumar N, Alam MA, Ahmad A (2011) Synthesis
and biological Evaluation of some new pyridazinone derivatives.
J Enzy Inhib Med Chem 26:742–748
Izatt RM, Pawlak K, Bradshaw JS (1991) Thermodynamic and kinetic
data for macrocyclic interaction with cations and anions. Chem
Rev 91:1721–2085
Acknowledgments The authors gratefully acknowledge the finan-
cial assistance of the Scientific and Technical Research Council of
Turkey (TUBITAK), Grant No: TBAG 210T122 and Ahi Evran
University, Grant No: SBA-11-23.
Kikukawa K, He G-X, Abe A, Goto T, Arata R, Ikeda T, Wada F,
Matsuda T (1987) New applications of crown ethers. Part 6.
Structural effects of bis(benzocrown ether)s and substituted
benzocrown ethers on solvent extraction and complexation of
alkali-metal cations. J Chem Soc Perkin Trans 2:135–141
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sensitive cation selectivities of bis(monoazacrown ether) deriv-
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crown ethers: prospective antitumor agents. Chem Med Chem
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Tusek-Bozic T (2007) Antitumor potential of crown ethers:
structure–activity relationships, cell cycle diturbances, and Cell
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