A single molecular probe for multi-analyte (Cr3+, Al3+ and Fe3+) detection in aqueous medium and its biological application

Article abstract of DOI:10.1039/c4cc04731a

An ESIPT based fluorescent sensor 1 was developed, which could selectively detect and differentiate trivalent metal ions Cr³⁺, Al³⁺ and Fe³⁺ in aqueous medium. The cell imaging experiments confirmed that 1 can be used for

Full text of DOI:10.1039/c4cc04731a

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A single molecular probe for multi-analyte
(Cr3+, Al3+ and Fe3+) detection in aqueous
medium and its biological application†
Cite this: Chem. Commun., 2014,
50, 12258
Received 21st June 2014,
Accepted 22nd August 2014
Junfeng Wang,a Yingbo Li,b Nikul G. Patel,c Ge Zhang,c Demin Zhoub and
Yi Pang*ad
DOI: 10.1039/c4cc04731a
www.rsc.org/chemcomm
An ESIPT based fluorescent sensor 1 was developed, which could and Fe(III)10 have been reported, and far fewer find application
selectively detect and differentiate trivalent metal ions Cr3+
,
in cell imaging.3c,9d,10h In contrast, Al3+ is diamagnetic, whose
Al3+ and Fe3+ in aqueous medium. The cell imaging experiments binding to sensors often enhances the fluorescence.11 Due to strong
confirmed that 1 can be used for monitoring intracellular Cr3+ and hydration of Al3+ in water, however, most reported dyes for Al3+ are
Al3+ levels in living cells.
required to be used in organic solvents or mixed solvents, with very
few being suitable for Al3+ imaging applications.11a,e Recently, the
Trivalent cations have important biological properties and are study by Costero et al.9a reported a fluorescein derivative, whose
directly involved in the cell function where there is a critical control fluorescence at 475 nm could be turned on by Cr3+, Fe3+ and Al3+ in
of M3+ levels.1 For example, Cr3+ has direct impacts on the dry CH3CN. The presence of 4% of water in CH3CN, however, will
metabolism of carbohydrates, fats, proteins and nucleic acids by quench the fluorescence of the fluorescein complex with Cr3+ and
either activating certain enzymes or stabilizing proteins and nucleic Fe3+ ions. It remains a challenge to design a fluorescent sensor that
acids.2 Chromium deficiency can increase the risk factors asso- not only can recognize but also differentiate the trivalent cations
ciated with diabetes and cardiovascular diseases.3 Al3+ could also (Al3+, Cr3+ and Fe3+), especially in aqueous solution. Herein, we
have adverse effects on human health, as an excessive amount of disclose a sensor that can simultaneously detect Cr3+, Al3+ and
Al3+ in the brain is believed to cause neurodementia, including Fe3+ ions by the naked eye in an aqueous medium.
neurological disorders such as Parkinson’s disease, Alzheimer’s
The sensor design incorporates the 2-(20-hydroxyphenyl)
disease and dialysis encephalopathy.4 Fe3+ plays an indispensable benzoxazole (HBO) unit as an emitting fluorophore, whose
role in many biochemical processes at the cellular level,5 and in emission has a large Stokes shift (4150 nm) arising from the
the oxygen transport processes in all tissues in the form of excited-state intramolecular proton transfer (ESIPT). As shown
hemoglobin.6 The deficiencies or excesses of Fe3+ can lead to a in Fig. 1, the cation binding is expected to occur by using two
variety of diseases, such as Alzheimer’s, Huntington’s, and stronger ligands 2-(pyridin-20-yl)hydrozono groups (2). Due to
Parkinson’s diseases.7 Thus, there is an urgent need to develop steric hindrance by the Ha atom, the CQN will be twisted away
chemical sensors that are capable of detecting the presence of from the coplanarity (with HBO) upon binding metal cations, result-
Cr3+, Al3+ and Fe3+ ions in biological samples.
ing in a decrease of the conjugation length (absorbance hypsochromic
shift). It is assumed that only those metal cations that can bind
Due to their paramagnetic nature, trivalent chromium (Cr3+
)
and iron (Fe3+) are among the most effective fluorescent strongly to the imine bonds will be able to compete, thus separating
quenchers,8 which makes it difficult to develop a fluorescence the trivalent cations from the divalent and monovalent ones. In
turn-on sensor. For this reason, very few sensors for Cr(III)3c,8,9 addition, the cation binding removes the adverse effect of Schiff
base on fluorescence, thereby turning on the emission. The proposed
metal complex 2 has four-coordination, which should be more stable
than 3 (three coordination). The two different binding modes
a Department of Chemistry, The University of Akron, Akron, Ohio 44325, USA.
E-mail: yp5@uakron.edu
b State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical
Sciences, Peking University, Beijing 100191, China
c Department of Biomedical Engineering, The University of Akron, Akron,
Ohio 44325, USA
could be easily identified by their ESIPT ON–OFF properties (large
or smaller Stokes shift). The design also includes a phenol group,
whose participation in the cation binding event could act as a switch
to manipulate the ESIPT properties. By using the dual channel control
(i.e., fluorescence intensity and ESIPT), the study aims to differentiate
the trivalent cations, since the ESIPT of the HBO unit is quite sensitive
to electronic perturbation from the cation binding.12
d Maurice Morton Institute of Polymer Science, The University of Akron, Akron,
Ohio 44325, USA
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc04731a
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(at 195 nm for Cr3+ and at 170 nm for Al3+ respectively), which
indicates the existence of the free phenol group and ruled out the
binding mode 3. All these facts point to the formation of the metal
complex 2, where Al3+ and Fe3+ showed a similar binding mode.
Mass spectral studies revealed that ligand 1 disappeared
(TOF-MS-ES+ at peaks 472.1815 and 494.1637) upon addition of
Cr3+ (ESI,† Fig. 8d). The newly formed positively charged peak
of TOF-MS-ES+ at 577.1374 matched [1 + Cr3+ + MeOꢀ + EtOꢀ]+ =
577.1507, indicating the formation of 2 (ESI,† Fig. S8) with a
1 : 1 ratio of the ligand to trivalent metal ions. In aqueous
solution, TOF-MS-ES+ also detected the formation of 2 where
LQL0QOH (ESI,† Fig. S8a) with six-coordination geometry.
1H NMR spectra revealed consistent evidence to support the
formation of 2. Upon addition of 1.0 equiv. of Cr(NO3)3, the
turbid solution of 1 in CD3OD/DMSO-d6 became transparent,
indicating the Cr3+ complex formation. The characteristic pyridine
signal Hb and imine Hf (at B8.5 ppm) were shifted downfield to
about B8.7 ppm, supporting the assumption that both pyridine
units and imine groups were bound to the Cr3+ ion, as shown in
complex 2 (ESI,† Fig. S19).
Fig. 1 Top: dye 1 and its Cr3+ complex 2 (3 is possible but not preferred).
The cation in
2 is likely to adopt six-coordination geometry with
two additional ligands (L & L0). Bottom: fluorescence response of 1
upon addition of 10 equiv. of different metal ions in aqueous solution
(8 : 2 = water : EtOH).
To gain a better understanding of M3+ binding mode,
compounds 4 and 5 were prepared (Fig. 2). UV-vis absorption of 4
exhibited nearly no change (at B417 nm, Fig. 2a) upon addition of
The absorption of 1 revealed a major peak (at 315 nm, the M3+ cations, in comparison with 1. In sharp contrast, UV-vis
attributed to p–p*) and a minor peak (at 432 nm, attributed absorption of 5 showed a clear blue shift upon addition of M3+
to n–p*) (ESI,† Fig. S1b). The fluorescence response of 1 was (Fig. 2b). This observation supported the proposed binding mode
examined in aqueous medium (H2O : EtOH = 8 : 2) by addition of that the cation binds to both Schiff base groups as shown in 2,
various metal ions (Fig. 1). Sensor 1 showed weak red fluorescence whose formation caused the twisting of imine bonds. This was also
(FF = 0.1) with a large Stokes shift (180 nm), attributed to emission consistent with the hypsochromic shift in UV-vis absorption.
from its keto tautomer associated with its ESIPT properties. Sensor Fluorescence of 5 also exhibited a similar blue shift as 1 upon
1 was silent toward monovalent and divalent metal ions. Surpris- interaction with the M3+ cation (ESI,† Fig. S20). The fluorescence of
ingly, the fluorescence of 1 showed immediate turn-on upon metal complex 5-M3+ exhibited a small Stokes shift (B60 nm), which
addition of trivalent ions Cr3+, Al3+ and Fe3+, although Cr3+ and is far smaller than that of 1 + M3+ (B190 nm). The results thus
Fe3+ are widely known to be fluorescence quenchers. The sample indicate the formation of complex 2, whose ESIPT remains on.
with Fe3+ showed the initial fluorescence turn-on but quickly
In an effort to seek additional evidence for the binding mode,
decays within 5 minutes (ESI,† Fig. S5b), while the yellow fluores- 4 was further examined with addition of Zn2+ cations, as its
cence of Cr3+ complexes was quite stable (ESI,† Fig. S3). The complex can involve the adjacent phenol as observed.12d While
fluorescence of Al3+ complexes changed to blue-green (527 nm). ligand 4 exhibited weaker interaction with Zn2+ in an aqueous
The distinctive feature in optical response thus allowed us to medium (ESI,† Fig. S16 and S17b), it reacted readily with Zn2+ in
distinguish Fe3+ (which gives pulse-like fluorescence) from Cr3+ ethanol to form stable 4-Zn complexes (ESI,† Fig. S9e and S18).
(emission lem B 556 nm, yellow green) and Al3+ (lem B 527 nm, As a consequence of the removal of the phenolic proton, the
blue-green). In summary, different response to trivalent ions UV-vis absorption of 4 (lmax E 375 nm) was notably shifted to
enabled the naked eye detection of Cr3+, Fe3+ and Al3+ cations
lmax E 417 nm via forming 4-Zn (Scheme 1, and ESI,† Fig. S18a). In
(Cr: FF = 0.63; Al: FF = 0.31). It was noted that the sensor also addition, the weak emission of 4 at B582 nm (assigned to ESIPT
showed different responses for Fe2+ and Fe3+, as Fe2+ only slightly from the keto tautomer) disappeared, which was accompanied
quenched the fluorescence without showing initial turn-on.
To elucidate the metal binding mode, the UV-vis spectra of 1
were recorded upon addition of different equiv. of Cr3+ (ESI,†
Fig. S2). As is known, the deprotonation of the phenol upon
metal binding will lead to large spectral bathochromic shift
together with fluorescence blue shift, resulting in a smaller
Stokes shift.12a,d Upon addition of Cr3+, the absorption band at
432 nm (n–p*) progressively decreased, indicating that the
cation binds to the Schiff base. The new p–p* absorption band
was observed at about 358 nm. It should be noted that the
emission of the metal complex exhibited a large Stokes shift
Fig. 2 UV-vis response of 4 (a) and 5 (b) upon addition of 10 equiv. of
different metal ions in aqueous solution (8 : 2 = water : EtOH).
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Scheme 1 Structures of 4 and its metal complexes.
by a stronger new emission at B477 nm upon formation of the
zinc complex. It was clear that participation of phenol in cation
binding would result in a large spectral shift with a small
Stokes shift (60 nm). Since no large spectral shift was observed
when ligand 1 binds to the trivalent Cr3+ cation, it is not likely
that the phenol participated in binding. Therefore, the proposed
binding mode 2 was predominant for the Cr3+ complex of 1. For
the Al3+ cation, the resulting complex with 1 initially formed via
binding mode 2, while some of the Al3+ complex might adopt
binding mode 3 to give blue-green emission as suggested from
its fluorescence in EtOH (ESI,† Fig. S15). In the sensing of Fe3+
ions, the formation of complex 2 initially turned on the fluores-
cence. However, the tautomerization of 2 took place quickly
within 5 min leading to the formation of 20 (ESI,† Scheme S1),
which was captured by TOF-MS-ES+: the positively charged peak
of TOF-MS-ES+ at 503.0999 matched [1 + Fe3+ ꢀ 2H+]+ = 503.0762
(see ESI,† Fig. S21). The formation of 20 could be responsible for
the observed fluorescence quenching.
In order to examine the selectivity of 1, some other cations were
added to a solution of 1 under the same conditions. Addition of M+
and M2+ cations (10 equiv.) induced almost no change in the UV-vis
spectra of 1 (except Cu2+, see ESI,† Fig. S1). The results indicated
weak binding between dye 1 and the mono- and divalent metal
ions. Physiologically important metal ions, which exist in living
cells, such as Ca2+, Mg2+, Na+ and K+, gave negligible fluorescence
response. Upon addition of one of the metal ions with the
subsequent addition of Cr3+/Al3+, the green-yellow fluorescence
was turned on (see ESI,† Fig. S10). Therefore, 1 is a highly selective
chemosensor for Cr3+/Al3+ with the detection limits of 0.2 mM and
0.5 mM for Cr3+ and Al3+, respectively.
Fig. 3 Confocal fluorescence images of Human mesenchymal stem cells
(hMSCs) excited with a Diode laser (405 nm) on an Olympus FV-1000 laser
scanning microscope. The images were collected at bright field (a–c) and
fluorescent channels (d–f). (a–d): the cells were incubated with dye 1 in
PBS for 60 min; (b–e) the cells were first treated with Cr3+ (30 mM) for
30 min and further exposed to dye 1 (10 mM) in PBS for another 60 min, and
image e was collected from 535 to 565 nm; (c–f) the cells were first treated
with Al3+ (30 mM) for 30 min and further exposed to dye 1 (10 mM) in PBS for
another 60 min, and image (f) was collected from 505 to 525 nm.
In conclusion, we have demonstrated a single fluorescent mole-
cular probe that can specifically detect trivalent ions (Cr3+, Al3+ and
Fe3+) in aqueous medium. In the molecular design, the sensor
cleverly utilized two ‘‘hydrazone Schiff bases’’ (binding mode 2) to
bind trivalent cations Al3+, Cr3+ and Fe3+ (M3+ cations), while being
silent to mono- and divalent metal ions. Simultaneous binding
to two ‘‘hydrazone Schiff bases’’ by M3+ cations removed the
fluorescence ‘‘quenching effect’’ associated with Schiff base,
thereby leading to great fluorescence turn-on. Large response
from both fluorescence intensity and spectral shift provided
distinctly different profiles for each of the three trivalent metal
ions, thereby allowing their naked eye detection. By using the
different cation binding modes to switch the ESIPT ON and OFF,
the study further illustrates an effective and novel strategy to
differentiate Al3+, Cr3+ and Fe3+. Cell imaging of confocal fluores-
cence microscopy further demonstrated that 1 can be used for
monitoring intracellular Cr3+ and Al3+ levels in living cells.
This work was supported by National Institute of Health
(Grant No: 1R15EB014546-01A1). We also thank the Coleman
endowment from the University of Akron for partial support.
The potential application of 1 for both Cr3+ and Al3+ in biological
samples was examined by using confocal fluorescence microscopy.
In the control experiment, staining human mesenchymal stem cells
(hMSCs) with 10 mM dye 1 for 30 min led to a negligible intracellular
fluorescence (Fig. 3d). When the cells were first incubated with
30 mM of metal ions (Cr3+ or Al3+) for 30 min, and then further
treated with 10 mM sensor 1 for another 30 minutes, a significant
increase in the fluorescence from the intracellular area was observed
(Fig. 3e and f). Bright-field measurements confirmed that the cells,
after being treated with Cr3+/Al3+ and 1, were viable throughout the
imaging experiments. These results demonstrate that the probe is
permeable to cells, binds to intracellular Cr3+ and Al3+, and emits
strong fluorescent light, thus it is highly suitable for determining
intracellular Cr3+ and Al3+ ions. Response to Cr3+ and Al3+ ions with
distinctly different colors (yellow-green and cyan, respectively) from
the cell samples raised the prospect that the Cr3+ and Al3+ ions could
be simultaneously determined.
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