Pentaquinone based probe for nanomolar detection of zinc ions: Chemosensing ensemble as an antioxidant

Article abstract of DOI:10.1039/c2dt31341c

A pentaquinone based compound 3a has been synthesized which undergoes significant fluorescence enhancement in the presence of Zn²⁺ ions with a detection limit up to nanomolar range in THF. Further, the zinc ensemble of 3a is evaluated for its anti-oxidizing property which is better than commercially available antioxidants. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2dt31341c

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Pentaquinone based probe for nanomolar detection of
zinc ions: Chemosensing ensemble as an antioxidant†
Cite this: Dalton Trans., 2013, 42, 975
Vandana Bhalla,* Roopa and Manoj Kumar*
Received 22nd June 2012,
A pentaquinone based compound 3a has been synthesized which undergoes significant fluorescence
enhancement in the presence of Zn2+ ions with a detection limit up to nanomolar range in THF. Further,
the zinc ensemble of 3a is evaluated for its anti-oxidizing property which is better than commercially
available antioxidants.
Accepted 1st November 2012
DOI: 10.1039/c2dt31341c
www.rsc.org/dalton
development of chemosensors that can discriminate Zn2+ from
Cd2+ is still a challenge as they are in the same group of the
Introduction
Recently, the development of fluorescent chemosensors for Periodic table and have similar properties. Further, chemo-
Zn(II) have received considerable attention as it is the second sensors which exhibit fluorescence enhancement in response
most abundant heavy metal ion after iron present in the to Zn2+ ions with nanomolar selectivity are still limited.
human body with its total content of 2–3 g in the whole body Recently, we reported a triphenylene based Zn2+ ensemble that
and its concentration as high as 10 μM in serum.1 It is an scavenges reactive oxidation species {hydroperoxide anions
essential nutrient required for normal growth2 and develop- (OOH−)} and behaves as an antioxidant.12 In continuation of
ment, and for key cellular processes such as DNA repair3 and this work on zinc selective artificial fluorescent sensors, we
apoptosis.4 The deficiency of zinc causes unbalanced metab- were interested in the development of a highly selective ‘turn
olism, which in turn can induce retarded growth in children, on’ chemosensor for zinc that could show emission at longer
brain disorders and high blood cholesterol5 and also be impli- wavelengths (>450 nm) with a detection limit up to the nano-
cated in various neurodegenerative disorders such as molar range. In this context, pentaquinone moiety is a scaffold
Alzheimer’s disease, epilepsy, ischemic stroke, and infantile of interest. Pentaquinone derivatives are found to emit around
diarrhea.6 Further, in the human body zinc is complexed to 500 nm in the fluorescence spectrum as indicated by our pre-
different peptides like albumin or alpha macroglobulin and in vious studies on these derivatives.13 Moreover, pentaquinone
enzymes like δ-aminolevulinate and acts as an antioxidant and derivatives have found immense utility in the design and syn-
protects specific regions thus preserving their stability and thesis of solution processable functionalized pentacene deriva-
activity.7 It is found that oxidative stress and decrease in anti- tives.14 Thus, in the present investigation, we designed and
oxidant activity of zinc is responsible for several pathological synthesized chemosensor 3a in which pentaquinone scaffold
conditions such as atherosclerosis, carcinogenesis, and is appended with β-hydroxynaphthaldehyde moieties through
macular degeneration.8 Thus, the role of zinc complexes as imine linkages which can coordinate and stabilize metal ions
antioxidants in living systems provides sufficient impetus to in a variety of oxidation states.15 Further, this type of structural
develop artificial receptors for Zn2+ ions showing bio-mimetic arrangement can undergo excited state intramolecular proton
applications. Up to now, a variety of zinc sensors based on qui- transfer (ESIPT) leading to enol-imine to keto-amine tautomer-
noline, fluorescein, coumarin, dansyl, naphthalimide, peptide ism which will give emission at longer wavelengths. It was
and proteins have been developed9,10 and many of these found that derivative 3a exhibits remarkable fluorescence
sensors exhibit bio-mimetic applications.11 However, most of enhancement (Φ = 0.33) and upholds high selectivity towards
these sensors suffer from interference of heavy transition Zn2+ ions over the various metal ions tested in comparison to
metal ions such as Fe2+, Ni2+, Cu2+ and Hg2+. In addition, the sensors reported in the literature and also detects Zn2+ ions at
the nanomolar level.16 Further, the zinc ensemble of 3a has
been evaluated for its anti-oxidizing property17 and it was
Department of Chemistry, UGC Sponsored-Centre for Advanced Studies-I, Guru
observed that the 3a–Zn ensemble scavenges reactive oxygen
species (ROS) {hydroperoxide anions (OOH−)} and behaves as
Nanak Dev University, Amritsar-143005, Punjab, India.
E-mail: vanmanan@yahoo.co.in, mksharmaa@yahoo.co.in;
an antioxidant. Reactive oxidation species (ROS)18 are a class
of radical or non-radical oxygen-containing molecules that
show high reactivity to bio-molecules19 and are responsible for
Fax: +91 (0)1832258820; Tel: +91 (0) 1832258820 9 ext. 3205
†Electronic supplementary information (ESI) available: 1H NMR, IR, mass
spectra, UV-vis and fluorescence. See DOI: 10.1039/c2dt31341c
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causing oxidation. Excessive generation of ROS is involved in NvCH). MALDI-TOF m/z: 799.43 (M + H)+. C56H34N2O4: Calcd
the pathogenesis of many diseases, including cardiovascular C 84.19%; H 4.29%; N 3.51%. Found C 84.16%; H 4.53%; N
disease, cancer and neurological disorders.20 In this context, 3.32%. 13C NMR spectrum of 3a could not be recorded
regulation of generation of reactive oxidation species is highly because of its poor solubility in all the organic deuterated
significant. Further, anti-oxidant activity of 3a–Zn ensemble is solvents.
found to be even better than that of the previously reported tri-
phenylene based zinc ensemble from our laboratory12 as well
Synthesis of 2,3-bis(4-((2-methoxynaphthalen-2-yl)-
methyleneamino)phenyl)-6,13-pentacenequinone (3b)
2-Methoxynaphthaldehyde 2b24 (0.025 g, 0.13 mmol) was
as five commercially available anti-oxidants.21 To the best of
our knowledge, this is the first report where a pentaquinone
based receptor works as a selective chemosensor for nano-
molar detection of Zn2+ ions. In addition, the 3a–Zn ensemble
scavenges reactive oxygen species and behaves as an
antioxidant.
added to the stirred solution of 2,3-bis(4-aminophenyl)-6,13-
pentacenequinone 1 (0.03 g, 0.06 mmol) in dry THF and absol-
ute ethanol (2 : 1). The reaction mixture was refluxed for 48 h.
After the completion of the reaction a yellow colored solid pre-
cipitated, that was filtered, washed with ethanol and recrystal-
lized from ethanol and tetrahydrofuran to give pure
compound 3b in 70% yield (35 mg). Mp: >250 °C. 1H NMR
(300 MHz, CDCl3, ppm): δ 4.07 (s, 6H, OCH3), 7.63–7.66 (m,
2H, ArH), 7.77–7.79 (m, 4H, ArH), 7.84–7.87 (m, 2H, ArH),
7.99–8.03 (m, 2H, ArH), 8.19–8.21 (m, 4H, ArH), 8.27–8.29 (m,
2H, ArH), 9.02–9.07 (m, 10H, ArH), 9.39 (s, 2H, ArH), 9.61 (d,
2H, J = 7.5, ArH). ESI-MS m/z: 827.29 (M + H)+. C58H38N2O4:
Calcd C 84.24%; H 4.63%; N 3.39%. Found C 84.19%; H
4.49%; N 3.28%. 13C NMR spectrum of 3b could not be
recorded because of its poor solubility in all the organic deut-
erated solvents.
Experimental
General experimental methods
All reagents were purchased from Aldrich and were used
without further purification. THF (AR grade) was used to
perform analytical studies. UV-vis spectra were recorded on a
SHIMADZU UV-2450 spectrophotometer, with a quartz cuvette
(path length, 1 cm). The fluorescence spectra were recorded
with a SHIMADZU RF 5301 PC spectrofluorimeter. 1H spec-
trum was recorded on a JEOL-FT NMR-AL 300 MHz using
CDCl3 as solvent and tetramethylsilane SiMe4 as internal stan-
dards. Data are reported as follows: chemical shifts in ppm (δ),
multiplicity (s = singlet, d = doublet, q = quartet, br = broad
singlet, m = multiplet, dd = doublet of doublet), coupling con-
stants (Hz), integration, and interpretation. Silica Gel 60
(60–120 mesh) was used for column chromatography.
Results and discussion
The condensation of pentaquinone diamine 123 with β-hydoxy-
naphthaldehyde 2a22 in THF-ethanol furnished compound 3a
1
in 82% yield (Scheme 1). The H NMR spectrum of compound
UV-vis and fluorescence titrations
3a showed four doublets at 7.07, 7.70, 7.80 and 8.10 ppm,
four multiplets at 7.30–7.42, 7.48–7.52, 7.73–7.75 and
8.14–8.17 ppm and three singlets at 8.22, 8.98 and 9.03 ppm
corresponding to aromatic protons and one doublet at
9.37 ppm corresponding to imino protons (NvCH). The IR
spectrum of compound 3a showed a stretching band at
1622 cm−1 corresponding to the NvCH group. The mass spec-
trum of compound 3a showed a parent ion peak at m/z 799.43
(M + H)+. These spectroscopic data corroborate with structure
3a for this compound (ESI, Fig. S1–S3†).
Solutions of compounds 3a, 3b, 2a, metal perchlorates and
antioxidants were prepared in dry THF. In titration experi-
ments, each time a 3 mL solution of ligand (5 μM) was filled in
a quartz cuvette (path length, 1 cm) and metal ions were
added into the quartz cuvette by using a micro-pipette. For flu-
orescence measurements, excitation was provided at 390 nm,
and emission was collected from 350 to 650 nm.
Synthesis of 2,3-bis(4-((2-hydroxynaphthalen-2-yl)-
methyleneamino)phenyl)-6,13-pentacenequinone (3a)
β-Hydoxynaphthaldehyde 2a22 (0.023 g, 0.13 mmol) was added
to the stirred solution of 2,3-bis(4-aminophenyl)-6,13-penta-
cenequinone 123 (0.03 g, 0.06 mmol) in dry THF and absolute
ethanol (2 : 1). The reaction mixture was refluxed for 48 h.
After completion of the reaction, a yellow colored solid precipi-
tated out, that was filtered, washed with ethanol and recrystal-
lized from ethanol and tetrahydrofuran to give pure
compound 3a in 82% yield (40 mg). Mp: >250 °C. IR (KBr) νmax
Binding studies
The binding behaviour of compound 3a toward different
cations (Zn2+, Cu2+, Hg2+, Fe2+, Fe3+, Co2+, Pb2+, Ni2+, Cd2+, Ag+,
1
= 1622 cm−1. H NMR (300 MHz, CDCl3, ppm): δ 7.07 (d, 2H, J
= 9, ArH), 7.30–7.42 (m, 6H, ArH), 7.48–7.52 (m, 2H, ArH), 7.70
(d, 2H, J = 7.8, ArH), 7.73–7.75 (m, 2H, ArH), 7.80 (d, 2H, J = 9,
ArH), 8.10 (d, 2H, J = 7.8, ArH), 8.14–8.17 (m, 2H, ArH), 8.22 (s,
2H, ArH), 8.98 (s, 2H, ArH), 9.03 (s, 2H, ArH), 9.37 (s, 2H,
Scheme 1
976 | Dalton Trans., 2013, 42, 975–980
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Scheme 2
imino nitrogen atoms to photoexcited pentaquinone moiety is
inhibited as the lone pair of electrons on the nitrogen atoms
are involved in coordination with the Zn2+ ions, leading to a
significant increase (584%) in the fluorescence emission
(Fig. 2). The emission intensity of compound 3a increased line-
arly as a function of Zn2+ ion concentration as shown in inset
B Fig. 2. A green fluorescence emission of the solution can be
easily observed by the naked eye by UV-irradiation (inset A;
Fig. 2). The detection limit of compound 3a as a fluorescent
sensor for the analysis of Zn2+ ions was found to be 3.5 × 10−9
mol L−1 which is sufficiently low for the detection of nano-
molar range of Zn2+ ions found in many chemical systems
(ESI, Fig. S5†). The fluorescence quantum yields (Φfs) of com-
pound 3a in the free state was found to be 0.08 and Zn2+-
bound state was found to be 0.33. Fitting the changes in the
fluorescence spectra of compound 3a with Zn2+ ions using the
nonlinear regression analysis program SPECFIT27 gave a good
fit and demonstrated that 1 : 1 stoichiometry (host : guest) was
Fig. 1 UV-vis spectra of 3a (5 μM) in the presence of Zn2+ ions (0–10 equiv.) in
THF.
Fig. 2 Fluorescence response of receptor 3a (5 μM) on addition of Zn2+ ions the most stable species in the solution with the binding con-
(0–1.0 equiv.) in THF; λex = 390 nm. Inset: (A) fluorescence before and after the
stant (log β) = 6.37 0.36. The method of continuous variation
addition of Zn2+ ions (B) change in the fluorescence intensity of receptor 3a as a
(Job’s plot)28 was also used to prove the 1 : 1 stoichiometry
function of Zn2+ ion concentration.
(ESI, Fig. S6†). To elucidate the binding mode of receptor 3a
with Zn2+, the IR spectrum of 3a–Zn complex was recorded
Ba2+, Mg2+, K+, Na+ and Li+) as their perchlorate salts was
(ESI, Fig. S7†). The important change was in the absorption
band corresponding to the imino group which shifts from
1622.02 to 1604.66 cm−1. There was no absorption band corre-
sponding to the perchlorate anion in the IR spectrum of the
complex which indicates the perchlorate counter anion is not
present in the complex. This is supported by the mass spec-
trum of the complex which showed the molecular ion peak at
m/z = 861.35 corresponding to 1 : 1 complex [3a + Zn + H]+
between 3a and Zn2+ (ESI, Fig. S8†). Further, the parent ion
peak at m/z = 861.35 in the mass spectrum and absence of
absorption bands corresponding to perchlorate anion in the
IR spectrum of the complex indicate that deprotonation of
phenolic groups take place in the presence of zinc perchlorate.
This type of deprotonation of phenolic groups in the presence
of zinc perchlorate has been previously reported.29 A quality
1H NMR spectrum of the zinc complex could not be recorded
due to the poor solubility of the complex in common organic
solvents. Thus, on the basis of IR and mass data we may con-
clude that the imino nitrogen atoms and phenolic oxygens are
involved in coordination with Zn2+ ions (Scheme 3). Under the
same conditions as used above for the Zn2+ ions, we also
tested the fluorescence response of receptor 3a for other metal
ions. (Fig. 3A; ESI, Fig. S9†). No significant change in emission
investigated by UV-vis and fluorescence spectroscopy. The titra-
tion experiments were carried out in THF by adding aliquots
of different metal ions. The absorption spectrum of compound
3a (5 μM) is characterized by the presence of typical absorption
bands at 298 nm and 391 nm due to the naphthol moiety
(Fig. 1). Upon addition of Zn2+ ions (0–10 equiv.), the band at
391 nm is decreased slightly, accompanied by a red shift to
408 nm. The formation of a red shifted band is attributed to
an intramolecular charge transfer (ICT)25 mechanism occur-
ring in the presence of Zn2+ ions (Fig. 1). However, no signifi-
cant variation in the absorption spectra was observed in the
presence of other metal ions (Cu2+, Hg2+, Fe2+, Fe3+, Co2+, Pb2+,
Ni2+, Cd2+, Ag+, Ba2+, Mg2+, K+, Na+ and Li+) (ESI, Fig. S4†). In
the fluorescence spectrum, compound 3a (5 μM) showed a
weak emission at 500 nm when excited at 390 nm (Fig. 2),
which is attributed to very fast enol-imine (3a) to keto-amine (4)
tautomerism involving the phenomenon of excited state intra-
molecular proton transfer (ESIPT)26 (Scheme 2). This weak flu-
orescence emission of compound 3a is due to photoinduced
electron transfer (PET) from the nitrogen atom to the photo-
excited pentaquinone moiety. Upon addition of 1.0 equiv. of
Zn2+ ions to a solution of compound 3a in THF, PET from
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Scheme 3
Fig. 4 Fluorescence spectrum of 2a (3 μM) upon addition of 66 μM of H2O2 in
THF.
Scheme 4
Fig. 3 Fluorescence response of receptor 3a (5 μM) on addition of various
cations in THF, λex = 390 nm. Bars represent the emission intensity ratio (I − Io/Io)
× 100. ‘Io’ is the fluorescence intensity of each free host and ‘I’ is the fluore-
scence intensity after the addition of metal ions. (A) Red bars represent the
addition of various metal ions (1 equiv.) to the solution of 3a (5 μM). (B) The
blue bars represent the competitive selectivity of Zn2+ (1 equiv.) in the presence
of other metal ions (100 equiv.).
of a metal coordinated ligand using an organic template is
rare.12 We investigated the zinc ensemble of 3a for its anti-
oxidant activity by utilizing β-hydroxynaphthaldehyde22 as a
template, carried out its Dakin oxidation12,31 and observed its
fluorescence behaviour in the presence and absence of 3a–Zn.
β-Hydroxynaphthaldehyde 2a (3 μM) shows an emission at
434 nm in THF when excited at 318 nm (Fig. 4). This emission
behaviour of compound 2a may be ascribed to persistence of
the excited state intramolecular proton transfer (ESIPT)
phenomenon (Scheme 4). To carry out Dakin oxidation we con-
sequently added alkaline H2O2 (pH = 8) to the solution of 2a
(3 μM). Upon addition of 0.3 μM of H2O2, the emission band is
shifted to 383 nm accompanied by enhancement of the emis-
sion intensity. This blue shift in fluorescence emission is
attributed to the interaction between compound 2a and alka-
line H2O2, which inhibits the enol to keto tautomerism and
results in the appearance of a fluorescence emission at a
shorter wavelength (383 nm). Further addition of 66 μM of
H2O2 leads to quenching of fluorescence emission (Fig. 4).
This quenching is ascribed to the oxidative conversion of 2a to
species 6 (Scheme 4). In species 6, PET from oxygen atom to
naphthalene moiety becomes operational; as a result fluore-
scence quenching is observed (Scheme 4). To investigate the
anti-oxidation effect of 3a–Zn ensemble, we carried out fluore-
scence titration of 2a (β-hydroxy naphthaldehyde) with H2O2
under similar conditions in the presence of 2 μM of 3a–Zn
ensemble (Fig. 5). In addition to the emission band of 2a at
434 nm, we observed another emission band at 500 nm corre-
sponding to 3a–Zn ensemble. Interestingly, in the presence of
spectra was observed in the presence of other metal ions. The
probable reason for the high selectivity towards Zn2+ ions is
due to the fact that zinc is neither soft nor hard metal ion i.e.
it is a borderline case and hence can interact with both hard
and soft binding sites. Since compound 3a has a combination
of both hard (oxygen atoms) and soft (imino nitrogen atoms)
binding sites as a result of which it shows high selectivity for
Zn2+ ions. To check out the practical applicability of receptor
3a as a Zn2+ selective fluorescent sensor, we carried out com-
petitive experiments in the presence of 1.0 equiv. of Zn2+
mixed with 100 equiv. (Pb2+, Cu2+, Fe2+, Fe3+, Ni2+, Hg2+, Cd2+,
Co2+, Mg2+, Ba2+, Ag+, K+, Na+ and Li+) of various metal ions
(Fig. 3B), and no significant variation in the fluorescence
intensity change was found by comparison with or without the
other metal ions. To confirm the phenomenon of tauto-
merism, we also prepared compound 3b in which the phenolic
hydroxyl groups of compound 3a were protected by methyl
groups (ESI, Fig. S10 and S11†). On excitation at 390 nm, the
compound 3b did not exhibit any band at 500 nm and no
change in emission intensity was observed upon the addition
of Zn2+ ions (ESI, Fig. S12 and S13†). This result confirms the
presence of ESIPT phenomenon in compound 3a.
Recently, new fluorescent probes have been reported for the
detection of ROS.30 However, evaluation of anti-oxidant activity
978 | Dalton Trans., 2013, 42, 975–980
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ions. Derivative 3a showed significant fluorescence enhance-
ment in the presence of Zn2+ ions in THF with a detection
limit up to the nanomolar range. Further, anti-oxidant proper-
ties of the Zn2+ ensemble of 3a was demonstrated by carrying
out fluorescence studies using β-hydroxynaphthaldehyde as an
organic template and performing its Dakin oxidation in the
absence and presence of the 3a–Zn ensemble. Though 3a is
not soluble in water we believe that by introduction of suitable
hydrophilic moieties it can be made soluble in water or in
mixed aqueous media. However, the Zn2+ ensemble of 3a
showing anti-oxidation properties may be used in the real
world by diluting with THF prior to the hydroperoxide assay.
Fig. 5 Fluorescence response of β-hydroxynaphthaldehyde 2a (3 μM) on
addition of H2O2 (350 μM) in the presence of 2 μM of 3a–Zn in THF.
Acknowledgements
We are thankful to CSIR (New Delhi) for financial support
(Ref. No. CSIR Scheme 01(2167)07/EMR-II). We are also thank-
ful to Advanced Instrumentation Research Facility (AIRF), JNU
for MALDI-TOF mass spectra and Guru Nanak Dev University
for providing research facilities. Roopa is thankful to CSIR
(New Delhi) for senior research fellowship.
Notes and references
Fig. 6 Comparison of % anti-oxidation activity of 3a–Zn with various commer-
cial antioxidants.
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to quench the fluorescence than in the absence of 3a–Zn
ensemble (Fig. 5). This may be ascribed to the preferential
binding of in situ generated hydroperoxide anions (−OOH) to
the positively charged zinc centre of the 3a–Zn ensemble. As a
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Fig. S19†).
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In conclusion, we have designed and synthesized a highly
selective pentaquinone based fluorogenic receptor 3a for Zn2+
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