Unique fluorogenic ratiometric fluorescent chemodosimeter for rapid sensing of CN- in water

Article abstract of DOI:10.1002/asia.201402923

A new benzimidazole-spiropyran conjugate chemosensor molecule (BISP) has been synthesized and characterized by ¹H NMR spectroscopy, mass spectrometry (ESI-MS), and elemental analysis. The two isomeric forms (BISPBIMC) were shown to be highly se

Full text of DOI:10.1002/asia.201402923

FULL PAPER
DOI: 10.1002/asia.201402923
Unique Fluorogenic Ratiometric Fluorescent Chemodosimeter for Rapid
ꢀ
Sensing of CN in Water
[
a]
[a]
[a]
[a]
Ajit Kumar Mahapatra,* Kalipada Maiti, Saikat Kumar Manna, Rajkishor Maji,
[b]
[a]
[a]
Chitrangada Das Mukhopadhyay, Bholanath Pakhira, and Sabyasachi Sarkar
Abstract: A new benzimidazole-spiro-
pyran conjugate chemosensor molecule
spectroscopy, high-resolution mass
spectrometry (HRMS), UV/Vis meas-
urements, and fluorescence spectrosco-
py in HEPES buffer of pH 7.4.
TDDFT calculations were performed
in order to correlate the electronic
properties of the chemosensor with its
in situ showed that it acts as a secon-
dary recognition ensemble toward
3
+
2+
(
BISP) has been synthesized and char-
Au and Cu by switch-on fluores-
cence. In addition, a reversible logic-
gate property of BIMC has been dem-
onstrated through a feedback loop in
1
acterized by H NMR spectroscopy,
mass spectrometry (ESI-MS), and ele-
mental analysis. The two isomeric
forms (BISP$BIMC) were shown to
be highly selective and sensitive to
ꢀ
3+
the presence of CN and Au ions, re-
spectively. Furthermore, the use of
cyanide complex. Further, titration
ꢀ
3+
ꢀ
CN among the ten anions studied in
against thiophilic metal ions like Au
,
BIMC to detect CN in live cells by
2
+
+
2+
aqueous HEPES buffer, as shown by
fluorescence and absorption spectros-
copy and even by visual color changes,
with a detection limit of 1.7 mm for
Cu , Ag , and Hg with [BIMC-CN]
fluorescence imaging has also been
demonstrated. Notably, test strips
based on BIMC were fabricated, which
could serve as convenient and efficient
Keywords: benzimidazole-spiro-
pyran · chemodosimeter · cyanide ·
living cells · logic gate · ratiometric
ꢀ
ꢀ
BIMC. The reaction of CN with
CN test kits.
1
BIMC was monitored by H NMR
Introduction
the blood. Other potential sources of cyanide causing harm
to humans and animals are sodium nitroprusside, succinoni-
trile, and organic thiocyanates. Consequently, cyanide is
a potential hazardous contaminant in the environment. Its
lethal toxicity even in trace quantity to humans drew serious
attention to develop highly selective and specific analytical
methods for the trace detection of cyanide.
ꢀ
[1]
[5]
Cyanide (CN ) is extremely toxic to living organisms and
is one of the most hazardous environmental pollutants. Its
effect as lethal poison is due to its strong binding at the
oxygen binding site of cytochrome c oxidase to prevent mo-
lecular oxygen to act as the terminal electron acceptor in
aerobic respiratory species in oxidative phosphorylation.
Cyanide can also affect many functions in the body, includ-
ing the vascular, visual, central nervous, cardiac, endocrine,
[
2]
Therefore, continuos efforts have been made with regard
ꢀ
to chemical and/or physical methods in detecting CN over
[6]
the last several decades. Several chemical sensors to detect
[
3,4]
ꢀ
[7]
and metabolic systems. Despite its toxicity to humans,
CN have been developed, and most of these are based on
chemical reactions that develop a color contrast for inexpen-
sive and rapid detection. Many of these sensors rely on the
hydrogen-bonding motif and display moderate selectivity
ionic cyanide and its derivatives are industrially made in
large quantities and used in electroplating, metallurgy, pro-
duction of organic chemicals, in plastics, photography fumi-
gation, and in mining. Tobacco smoke is also a source of cy-
anide and that can lead to its high level of concentration in
[8]
ꢀ
over other anions. Reaction-based CN receptors have re-
cently been developed. Photoswitchable molecular receptors
like spirooxazine for CN detection were developed by Tom-
ꢀ
asulo et al. to introduce a visible color change, however, its
application is restricted to two-phase (water/organic) detec-
tion. Recently, the group of Shiraishi reported some mero-
[
a] Dr. A. K. Mahapatra, K. Maiti, S. K. Manna, R. Maji, B. Pakhira,
Prof. S. Sarkar
Department of Chemistry
Indian Institute of Engineering Science and Technology, Shibpur
Howrah-711103 (India)
Fax : (+91)33-26684564
[9]
cyanine (MC)-formed spiropyran derivatives with an ex-
tended conjugation system, which could serve as the fluoro-
ꢀ
[10]
metric probe for CN detection. However, most spiropyr-
an-based probes are insoluble in water and could be used
only in organic solvents or at least in a mixture of organic
solvents and water. Such semi-aqueous detection media are
not very practical. Other disadvantages include either color
changes or fluorescence changes, individually, but there are
only a few cases showing simultaneous changes in both ab-
E-mail: mahapatra574@gmail.com
[
b] C. D. Mukhopadhyay
Department of Centre for Healthcare Science and Technology
Indian Institute of Engineering Science and Technology, Shibpur
Howrah-711103 (India)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402923.
Chem. Asian J. 2014, 9, 3623 – 3632
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Ajit Kumar Mahapatra et al.
[
11]
sorption and emission spectra. Moreover, those dual spec-
tral change-based sensors showed fluorescence quenching
nature of the substituent at position 5 of the indoline frag-
ment. The nucleophilic interaction of CN with the positive-
ꢀ
ꢀ
[12]
(
on-off) after the addition of CN . However, water-solu-
ble CN sensors are still very scarce.
In view of the need for CN detection exclusively in an
aqueous medium and as a part of our research devoted to
ion recognition, herein, we report a highly selective, chro-
mogenic and fluorogenic chemodosimeter, BIMC, for CN
ly charged spirocarbon of BIMC form produces the BIMC–
CN species with a new absorption at 573 nm. Similarly, the
chemosensor BISP, a thioimidazole-appended spiropyran
(Scheme 2), displays a red fluorescence, but shows a green
ꢀ
ꢀ
[13]
ꢀ
fluorescence via a nucleophilic interaction with CN under
ꢀ
irradiation with UV light.
with a low limit of detection (1.7 mm). Unlike the usual irre-
versible chemodosimeters, an
In order to understand the selective and sensitive anion-
interesting reversible phenom-
3
+
enon triggered by Au , which
is the first of its kind was also
observed. This has provided
a new approach for the unde-
veloped fluorescent sensing of
[14]
gold ions to date. To achieve
fluorescence ratiometric sensing
and overcome the limitations,
herein,
a
benzthioimidazole
group is introduced into the spi-
ropyran system to fabricate
a novel highly selective and
ꢀ
sensitive optical probe for CN
detection in water.
ꢀ
3+
Scheme 2. Colorimetric and fluorometric sensing of CN and Au by chemosensor BIMC and its ensemble
BIMC-CN.
Results and Discussion
The chemosensor molecule, BISP, was synthesized in three
known steps (Scheme 1). It was synthesized starting from
a condensation reaction between o-aminothiophenol and
binding behavior of BISP$BIMC isomers, absorption and
fluorescence titrations were carried out.The absorption spec-
ꢀ
4
trum of BISP (1ꢁ10 m) in water (HEPES buffer, pH 7.4)
exhibited a band centered at
4
25 nm under dark conditions,
indicating that BISP exists as
a SP form. Upon irradiation
with UV light (254 nm) BISP
showed two characteristic UV/
Vis absorbance bands centered
at 425 nm (low intensity) and
Scheme 1. Synthetic route of BISP. [a] Reagents and conditions: (a) Salicylaldehyde, CdS cat., MeOH, hn, rt, 573 nm (high intensity), respec-
2
h; (b) hexamine, toluene-acetic acid, reflux, 12 h (c) N-2,3,3-tetramethyl indolium cation, EtOH, reflux.
tively (Supporting Information,
Figure S8a) in water, assigned
to the BIMC form with the
salicylaldehyde to produce benzthioimidazole 1, followed by
photostationary state attained after 10 min irradiation (Sup-
porting Information, Figure S8b and Figure S8c). Very re-
[15]
formylation
bond formation as shown in Scheme 1.
to result in 2, and subsequent CꢀC double
[16]
cently, Chernyshev et al. reported that the cyclic isomers
of benzothiazolyl-spironaphthopyran derivatives possess
a longest wavelength absorption band at 381–404 nm. Upon
irradiation of these cyclic compounds with UV light in ace-
The stability and spectral properties of the zwitterionic
BIMC form depends on the nature of the functional groups
attached on the nonionic spiropyran derivative (BISP) plat-
form. The new thioimidazole-based spiropyran (BISP) che-
mosensor is pale yellow and, upon irradiation with UV light,
is isomerized to the purple-colored merocyanine (BIMC)
form. It is quite similar to recent work by Chernyshev et
[17]
tone, the photomerocyanine was formed as expected with
a new absorption band centered at 640 nm, and these results
corroborate our study.
Upon addition of increasing amounts of Bu NCN to this
4
[
16]
al. , who showed that acetone solutions of the investigated
spiropyrans are weakly yellow colored at ambient tempera-
ture and that the intensity of the color depends on the
solution, a new absorption band appeared at 407 nm and the
band at 573 nm completely disappeared (Figure 1a), imply-
ing a destruction of the p-conjugation that had resulted in
Chem. Asian J. 2014, 9, 3623 – 3632
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Ajit Kumar Mahapatra et al.
(
Supporting Information, Fig-
ure S14). Furthermore, the 1:1
stoichiometric reaction was
confirmed by ESI-MS analysis
where a CH CN solution of
3
ꢀ
BIMC with CN showed a peak
at m/z 437.1491, assigned to the
ꢀ
[
BIMC+CN ] ion (Supporting
Information, Figure S7). The as-
sociation constant for this reac-
tion was determined by UV/Vis
4
ꢀ1
spectroscopy to be 1.5ꢁ10 m .
The detection limit of 1.7 mm,
obtained by fluorescence spec-
troscopy, is below the CN con-
centration of the WHO (World
Health Organization) guide-
ꢀ
4
Figure 1. (a) UV/Vis spectral changes of BIMC (1.0ꢁ10 m) in CH
3
CN/H
2
O (1:9 v/v; pH 7.4) upon addition of
CN (1.0
O (1:9 v/v; pH 7.4). (b) Absorbance of BIMC at 407 nm and 573 nm as a function of
ꢀ
3
ꢀ4
NBu
4
CN (1.0ꢁ10 m). Inset: Solutions of BIMC (1.0ꢁ10 m) in the absence and presence of NBu
4
ꢀ
ꢀ
3
x10 m) in CH
3
CN/H
2
ꢀ
CN concentration.
lines
for
drinking
water
ꢀ
a blue shift. It is understandable that in BIMC an ICT (in-
ternal charge transfer) takes place from the phenoxide O
atom to the positive charged indolyl cation through the
double bond-conjugated spacer. This ICT is, however, dis-
(1.9 mm), showing that BIMC is an excellent probe for CN
detection. To investigate any possible interference by other
anions, we have done competitive anion tests using UV/Vis
ꢀ
titration; the results suggest that CN ion sensing occurs
ꢀ
rupted by the reaction of CN with BIMC (within 40s, Sup-
very well in the presence of other anions (Figure 3b).
The reactive BIMC isomer exhibits a strong fluorescence
emission at 583 nm upon excitation at 425 nm in HEPES
buffer (pH 7.4). Upon addition of an increasing amount of
porting Information, Figure S9) simply because the nucleo-
philic addition of the cyanide anion towards the indolyl-
cation moiety of BIMC induces breaking of the indole con-
jugation as depicted in Scheme 2. Thus, the reaction weak-
ens its ICT to develop an apparent color change of BIMC
from purple to greenish-yellow.
nBu NCN to the solution under irradiation at 425 nm, the
4
emission at 583 nm faded gradually with the concomitant
appearance of a new strong fluorescence at 445 nm (Fig-
ure 2a). The switch off-on fluorescence emission is due to
the exchange of either an electron or energy between the
excited state of a benzthiaimidazole fluorophore and one of
the two interconvertable states BISP$BIMC of a indolyl
photochrome, which deactivates the former nonradiatively
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2ꢀ
A series of anions (viz. F , Cl , Br , I , SCN , SO
,
4
ꢀ
ꢀ
ꢀ
AcO , HS , and H PO , respectively) with more or less nu-
2
4
cleophilic property were added to the solution containing
BIMC, and the change in the absorption spectral feature
with each addition was monitored. Upon the addition
[18]
2
0 equivalents of each anion, the absorption spectra of
to cause a decrease in the intensity of fluorescence.
In
BIMC did not significantly change, except upon the addition
of cyanide ion (Figure 3a) where a remarkable color change
from purple to greenish-yellow and a fluorescence change
from reddish-pink to intense green occurred. BIMC reacts
contrast, a remarkable contribution has been provided by
[19]
Micheauꢂs group,
who adopted the spiropyran–merocya-
nin system for selective cation detection in acetonitrile solu-
2
+
2+
tion. When Ni and Co cations were added to the solu-
tion, no fluorescence change was detected. On the other
ꢀ
with CN in a 1:1 stoichiometry as observed by a Jobꢂs plot
ꢀ
4
Figure 2. (a) Fluorescence spectral changes [lex =425 nm] of BIMC (1.0ꢁ10 m) in CH
3
CN/H
2
O (1:9 v/v; pH 7.4) upon addition of NBu
4
CN (1.0ꢁ
ꢀ
3
ꢀ3
ꢀ
ꢀ2
1
0
m). Inset: fluorescence of BIMC (1.0ꢁ10 m) before and after addition of CN (1.0ꢁ10 m). (b) Fluorescence of BIMC at 445 nm and 583 nm as
ꢀ
a function of CN concentration.
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Ajit Kumar Mahapatra et al.
check whether BIMC is selec-
ꢀ
tive and sensitive to only CN
or even responds to other ions,
similar fluorescence titrations
were carried out with other
ꢀ
ꢀ
ꢀ
ꢀ
anions, that is, F , Cl , Br , I ,
ꢀ
2ꢀ
ꢀ
ꢀ
SCN , SO , AcO , HS , and
H PO in the same medium.
4
ꢀ
2
4
No significant fluorescence en-
hancement was caused by any
of these ions (Supporting Infor-
mation, Figure S11b).
ꢀ
4
Figure 3. (a) Competitive absorption spectra of BIMC (1.0ꢁ10 m) in the presence of tetrabutyl ammonium
Owing to the strong affinity
ꢀ
3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2ꢀ
ꢀ
ꢀ
and sodium salts of different anions (1.0ꢁ10 m) (CN , F , Cl , Br , I , SCN , SO
O(1:9 v/v; pH 7.4) (b) Change in absorbance of BIMC (at 407 nm) (c=1ꢁ10 m) upon
addition of 2 equiv. of CN (c=1ꢁ10 m) or 7 equiv. of other anions (c=1ꢁ10 m) (black bars) and upon ad-
4
, AcO , HS , and
ꢀ
of CN
toward cyanophilic
ꢀ
ꢀ4
H
2
PO
4
) in CH
3
CN/H
2
ꢀ
ꢀ3
ꢀ3
metal ions, the fluorescent
BIMC-CN complex was studied
for secondary sensing property
ꢀ
dition of a mixture of 7 equiv. of other anions and 2 equiv. of CN (gray bars).
3
+
2+
+
toward Au , Cu , Ag , and
2
+
hand, a bright luminescence around 700 nm was recorded in
the presence of Zn due to the d electronic configuration
of the zinc(II) ion, suppressing LMCT.
Hg . Upon the addition of these metal ions to an aqueous
2
+
10
3+
solution of the BIMC-CN complex, only Au caused a re-
markable increase in the fluorescence emission band at
583 nm, which provides an alternative ensemble-based new
ꢀ
Therefore, BIMC is selective to CN among the other
[20]
ions studied. Visual fluorescent color change experiments
have been carried out to examine the behavior of BIMC in
the presence of various anions.
Under UV light, the solution of BISP (intense red fluo-
rescence) transformed to BIMC (weak red fluorescence),
whereas in the presence of CN , it shows an intense green
color fluorescence (Figure 2a inset) which is otherwise not
present in case of the other anion studies (Supporting Infor-
approach for fluorescent sensing of gold ions. The addi-
2
+
+
tion of Cu and Ag also led to an increase in the emission
intensity, albeit to a small extent (Supporting Information,
Figure S20c).
2
+
+
The weak response toward Cu and Ag could be attrib-
uted to a similar affinity to cyanide, as they belong to the
ꢀ
3
+
same group. Next, fluorescence titrations of Au were car-
3
+
ried out (Figure 4a). Upon the addition of Au to an aque-
ous solution of the BIMC-CN complex, the fluorescence of
the complex gradually decreased at 445 nm, while it in-
creased at 583 nm until saturation was attained.
ꢀ
mation, Figure S15b). Therefore, CN can easily be differ-
entiated by visual color change among the other anions.
These studies reveal that the CN -induced fluorescence
ꢀ
enhancement at 445 nm was unaffected in the presence of
The maximum fluorescence intensity was observed when
3
+
other anions. Thus, it is notable that BIMC can be used as
about 1 equivalent of Au was present, and a further in-
ꢀ
3+
a selective CN sensor in the presence of most of the other
crease in the concentration of Au did not lead to further
anions, which can be proved by UV/Vis measurements (Fig-
ure 3a, 3b) and fluorescence titration (Supporting Informa-
tion, Figure S11b).
fluorescence enhancement. Similar fluorescence titrations
were performed with other cations, and no significant
ꢀ
Titration of BIMC with CN
results in an enhancement of
the fluorescence intensity at
4
45 nm as a function of the
ꢀ
added CN concentration (Sup-
porting
Information,
Fig-
ure S12b), and the increase is
saturated with ꢁ1 equiv of
ꢀ
CN . A plot of the fluorescence
intensity (I/I0) versus the
ꢀ
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[CN ]/
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
[BIMC] mole ratio (Sup-
porting
Information, Fig-
ure S12a) suggests that BIMC
ꢀ
interacts with CN in a 1:1 stoi-
ꢀ
4
Figure 4. (a) Fluorescence spectral changes of BIMC-CN (1.0 x10 m) in CH
3
CN/H
2
O (1:9 v/v; pH 7.4) upon
chiometry with an association
constant K =1.0ꢁ10 m as de-
rived from the Benesi–Hilde-
brand equation. In order to of other metal ions and 2 equiv. of Au (gray bars).
3
+
ꢀ3
addition of Au (c=1.0ꢁ10 m). Inset: fluorescenc of BIMC-CN (at 583 nm) in the absence and presence of
Au . (b) Change in the fluorescence of BIMC-CN (c=1ꢁ10 m) upon addition of 2 equiv. of Au (c=1ꢁ
0 m) and 7 equiv. of other metal ions (c=1ꢁ10 m) (black bars) and upon addition of a mixture of 7 equiv.
4
ꢀ1
a
3+
ꢀ4
3+
ꢀ3
ꢀ3
1
3
+
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Ajit Kumar Mahapatra et al.
changes in the fluorescence intensity of BIMC-CN during
tion occurs in the absorption and emission maxima in the
BISP and BIMC isomers.
2
+
+
the titration were observed, except for Cu and Ag (Sup-
porting Information, Figure S20c). The corresponding
changes in the UV/Vis spectra were also recorded (Support-
ing Information, Figure S21a). With increasing concentra-
The cyano adduct BIMC-CN has an orthogonal (tilted)
conformation due to the presence of a nearly 908 dihedral
angle, with an sp3-hybridized carbon bond in the perpendic-
ular direction to the phenoxide ring. This structural differ-
ence gives rise to a significant difference in p-conjugation
between BIMC and BIMC-CN, hence no ICT was observed
in BIMC-CN (Figure 5).
3
+
tion of Au , the absorption peak at about 425 nm gradually
decreased. Competition experiments (Supporting Informa-
3
+
tion, Figure S20c), which were carried out by adding Au
to a solution of BIMC-CN in the presence of other metal
ions, revealed that there was no significant interference
The frontier molecular orbitals of BIMC-CN are mainly
localized on the phenoxide and benzthiazole part, and the
main contribution comes from the HOMO-1!LUMO tran-
sition (Figure 6), providing a calculated absorption band at
2
+
(
with the exception of Cu , which slighly interfered) of the
3
+
Au -induced fluorescent response by commonly coexistent
metal ions (Figure 4b).
To understand the absorption and fluorescence properties
of BISP and BIMC, and changes of BIMC by the reaction
ꢀ
with CN , density functional theory (DFT) calculations were
[21]
performed with a suite of Gaussian 03 package. The cal-
culated lmax, main orbital transition, and oscillator strength
(
f) are listed in Figure S23 and Table S2 in the Supporting
Information. The optimized structures of BISP are shown in
Figure S24a in the Supporting Information, while those of
BIMC and BIMC-CN are shown in Figure 5.
Figure 5. The energy-optimized structures of BIMC and BIMC-CN.
Figure 6. Molecular orbitals and electronic contribution of the relevant
excitations of BIMC and BIMC-CN.
The time-dependent density functional theory (TDDFT)
studies suggest that the vertical major transitions observed
at about 566 nm are comparable to those of the experimen-
tally observed spectra at about 573 nm for the BIMC
isomer. The calculated band at 566 nm is assigned to the
HOMO!LUMO transition; the highest observed oscillator
strength (f) corresponds to the experimental lmax (~573 nm),
which is assigned to the p!p* transition from the benz-
thioimidazole-appended phenoxide to the electron-deficient
indolyl cation (Supporting Information, Figure S23 and
about 413 nm, which mainly corresponds to the absorbance
band obtained experimentally at 407 nm. Figure S25b and
S25c in the Supporting Information show simulated absorp-
tion spectra of BIMC and BIMC-CN, respectively.
Eventually, theoretical UV/Vis spectra calculated by
TDDFT were found to agree well with the experimental ob-
servations. The calculated HOMO–LUMO energy gaps of
BIMC and BIMC-CN are 2.60 and 3.08 eV, respectively
(Supporting Information, Figure S22 and Table 1). We no-
ticed that BIMC and BIMC-CN have separated lmax bands.
Thus, it could be expected that the maximum peak of
2
Table S2). As BIMC has a conjugated sp -hybridized C=C
ꢀ
bond between phenoxide and indole groups, it shows an in-
tramolecular charge transfer (ICT) transition. The groups of
BIMC at 573 nm would gradually decrease upon CN addi-
tion, whereas that of BIMC-CN at 407 nm would be in-
creased. Notably, the ICT blocking in BIMC-CN is due to
breaking of the conjugation between the benzothiazole-ap-
pended phenoxide ion and indole groups, which could be
the main reason for the local emission (LE) from the benzo-
thiazole moiety at 445 nm in the BIMC-CN complex.
[22]
[16]
Champagne and Chernyshev reported pioneering works
in this area by performing an experimental and theoretical
study on different isomers of benzothiazolyl-spiropyran de-
rivatives to investigate the chelation of transition metal ions.
Indeed, our theoretical study confirmed that a similar transi-
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Ajit Kumar Mahapatra et al.
1
In addition, we monitored the H NMR spectra of BISP
by BIMC, as reported in this paper, allow for the design of
combinatorial molecular logic gates with INH and IMP
logic functions based on two sets of input signals (Fig-
ure 8).With respect to inputs, the presence and absence of
[23]
[24]
and BIMC in the presence of cyanide anions. The addition
reaction of CN to BIMC was confirmed by the comparison
of H NMR spectra of BIMC without and with the addition
ꢀ
1
ꢀ
of CN in [D ]DMSO (Figure 7).
6
Figure 8. Truth table and symbolization of a complementary output IMP/
INH circuit.
ꢀ
3+
CN and Au are defined as ’’1’’ and ’’0’’, respectively. Ad-
ditionally, we define high and low signals of fluorescence as
outputs ’’1’’ and ’’0’’, respectively. When both inputs are
zero, the output signal is one and the gate is ON at 583 nm.
1
Figure 7. H NMR spectra (300 MHz, [D
(
(
6
]DMSO, 0.5 mL) of BIMC
ꢀ
ꢀ
10 mg) measured (a) without CN and (b) with addition of CN
2.5 equiv)
3
+
BIMC treated with Au alone does not show any change
in fluorescence at 445 nm but emission at 583 nm remains
3
+
The olefinic H proton of the MC form of spiropyran is
unchanged and thus upon addition of Au , the output
i
magnetically deshielded and shifts downfield as compared
to the SP form (Supporting Information, Figures S3 and S6).
However, the product of BIMC-CN leads to an upfield shift
of the olefinic proton (0.2 ppm), indicating that the elec-
tron-withdrawing effect by the indole quaternary N atom
signal is one. On the other hand, if BIMC is treated with
CN alone as input, the fluorescence is significantly en-
ꢀ
hanced at 445 nm, and the output signal readout is one (i.e.,
the gate is ON). However, if both inputs are present at the
same time, the fluorescence of BIMC is quenched signifi-
cantly at 445 nm, with the output readout as zero (i.e., the
gate is OFF). Therefore, these studies clearly demonstrate
decreases. As reported, the NꢀCH protons of the BIMC
3
form are also magnetically deshielded due to the decreased
electron density of the indole ring by quaternization of the
nitrogen atom and shift downfield as compared to the SP
form (0.5 ppm) (Figure 7). This is because the interaction of
ꢀ
that BIMC is switched on only in the presence of CN at
445 nm. The mode of the fluorescence variation of BIMC in
ꢀ
3+
the presence of CN /Au mimics the performance of an
ꢀ
3+
spirocarbon with CN reduces the positive charge on the
INH logic gate. Similarly, in the presence of Au , fluores-
quaternary nitrogen atom of the indole ring.
cence emission of BIMC-CN was enhanced and a significant
output signal was observed at 583 nm. As the emission band
of BIMC at 583 nm remained unchanged upon addition of
The data indicate that nucleophilic interaction between
the positively charged spirocarbon of the MC form of BIMC
ꢀ
3+
and CN produces the BIMC-CN species (Scheme 2). The
Au only, the data are in accordance with the IMP logic.
1
:1 reaction is confirmed by the analysis of the ESI mass
The truth table and the pictorial representation of the com-
binatorial complex molecular switch for the corresponding
INH and IMP logic gates are given in Figure 8.
spectrum where the peak at m/z 437.1462 is assigned to the
[BIMC-CN] ion.
As noted above from the fluorescence, absorption, and
ESI-MS results, the highly fluorescent ensemble, BIMC-CN,
The capability of UV/Vis and fluorescence color changes
in the presence of cyanide strongly suggests that these sen-
sors can be used in kits for the detection of cyanide. To
check the feasibility of using chemosensor BIMC in practi-
cal applications, test strips were prepared by immersing
shows fluorescence quenching at 445 nm when titrated with
3
+
Au in water.
The logic gate properties of BIMC have been studied
ꢀ
3+
ꢀ2
using two sets of input signals, that is, CN and Au , by
monitoring two outputs in the fluorescence emission at
TLC plates into a water solution of BIMC (c=1.0ꢁ10 m),
followed by drying them in air. The test strips containing
445 nm and 583 nm, respectively. The properties exhibited
BIMC were then immersed in an aqueous solution of differ-
Chem. Asian J. 2014, 9, 3623 – 3632
3628
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Ajit Kumar Mahapatra et al.
ꢀ
ent cyanide concentrations to sense CN ; as controls, there
the probe BIMC-CN complex in live cells, it would be pru-
dent to choose a working concentration of 10–20 mm for the
probe.
were immersed in solutions of other anions. As shown in
Figure 9, an obvious color change was observed only with
the CN solution under irradiation with UV light at 254 nm.
ꢀ
Hence, to assess the effectiveness of compound BIMC as
ꢀ
a probe for intracellular detection of CN by confocal mi-
ꢀ
croscopy, RAW cells were treated with 20 mm CN for 1 h,
followed by treatment with 10 mm probe solution to promote
formation of probe BIMC-CN. Confocal microscopic studies
revealed the absence of a fluorescence signal for RAW cells
ꢀ
treated with CN alone (Figure 10b); cells became red fluo-
Figure 9. Fluorescence color changes visualized on TLC plate strips of
ꢀ
2
ꢀ
(
1
CH
a) BIMC (c=1.0ꢁ10 m) alone and after addition of CN at (b) 1.0ꢁ
0
ꢀ
6
ꢀ5
ꢀ4
ꢀ3
ꢀ2
m; (c) 1.0ꢁ10 m; (d) 1.0ꢁ10 m (e) 1.0ꢁ10 m and (f) 1.0ꢁ10 m in
CN/H O=1:9 (v/v).
3
2
ꢀ
When the concentration of CN ion was increased, the fluo-
rescent color of the test strips changed from deep red to in-
tense green (Figure 9). The potentially competitive anions
ꢀ
did not influence the detection of CN by the test strips.
Therefore, the test strips could conveniently detect CN
ꢀ
Figure 10. Confocal fluorescence images of the probe in Raw 264.7 cells
in solution. The above result suggests that this system may
be used as a sensitive and practical ’’dip-in’’ naked-eye cya-
nide sensor in the near future.
(40ꢁ objective lens) (a) Bright-field image of the cells; (b) Only Bu NCN
4
at 2.0ꢁ10m concentration and nuclei counterstained with DAPI
ꢀ
1
ꢀ6
(
1 mgmL ); (c) Stained with probe BIMC at a concentration 1.1ꢁ10
m
(
green filter); (d) Overlay image of images shown in (b, c); (e) Cells
To demonstrate the practical application of the probe
3+
ꢀ5
4
treated sequentially with Bu NCN, probe, and Au (c=1.0ꢁ10 m). Dis-
ꢀ
BIMC to detect even a minute amount of CN , we carried
appearance of green fluorescent signals and appearance of red fluores-
cent signals was observed.
out experiments in living cells. In vitro studies established
ꢀ
that the newly synthesized BIMC probe can detect CN
with excellent selectivity even up to 10 mm. Hence, to assess
the effectiveness of BIMC as a probe for in vitro detection
rescent upon treatment with BIMC alone (Supporting Infor-
mation, Figure S26). Upon incubation with CN followed by
ꢀ
ꢀ
of CN by confocal microscopy, RAW cells were used to
ꢀ
detect CN ions in live cells. However, to achieve this objec-
addition of BIMC, a striking green fluorescence was ob-
served inside RAW cells, which indicated formation of the
BIMC-CN complex, as observed earlier in solution studies
in vitro (Figure 10c). Further, an intense green fluorescence
was noticeable in the perinuclear region of RAW cells, and
again a red fluorescence reappeared upon treatment with an
tive it is a prerequisite to assess the cytotoxic effect of probe
ꢀ
BIMC, CN , and the complex on live cells. We therefore
used the MTT assay, which is based on the mitochondrial
dehydrogenase activity of viable cells to study the cytotoxic-
ity of the above-mentioned compounds at the various con-
centrations mentioned in the Experimental Section. Fig-
ure S27 in the Supporting Information shows that probe
BIMC did not exert any significant effect on cell viability;
3
+
Au solution (Figure 10e). The confocal microscopic analy-
sis strongly suggested that the probe BIMC could readily
cross the membrane barrier of the RAW cells and rapidly
ꢀ
ꢀ
however, CN ions had a dose-dependent adverse effect on
sense intracellular CN at very low concentration.
the cells. The CN–probe complex also had a significant ad-
verse effect on the cell viability at concentrations >75 mm.
Exposure of HCT cells to probe the BIMC-CN complex re-
sulted in a decline in cell viability above a concentration of
It is significant to mention here that bright-field images of
treated cells did not reveal any gross morphological changes,
which suggested that RAW cells were viable. These findings
open up an avenue for future in vivo biomedical applica-
tions of this sensor.
20 mm. The effect was more pronounced at higher concentra-
tions and showed an adverse cytotoxic effect in a dose-de-
[25]
pendent manner. The viability of HCT cells was not influ-
enced by the solvent (DMSO) (Supporting Information, Fig-
ure S27), leading to the conclusion that the observed cyto-
toxic effect could be attributed to the BIMC-CN complex.
The results obtained in the in vitro cytotoxic assay sug-
gested that, in order to pursue confocal imaging studies with
Conclusions
A
benzthioimidazole-appended spiropyran compound
(BISP) has been synthesized and characterized. BISP exhib-
its a fluorescence turn-on response at 445 nm for CN ,
ꢀ
Chem. Asian J. 2014, 9, 3623 – 3632
3629
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Ajit Kumar Mahapatra et al.
among the ten different anions studied in aqueous HEPES
buffer solution. The selectivity and sensitivity was demon-
strated on the basis of fluorescence, absorption, and
H NMR spectroscopic measurements, ESI mass spectrome-
try data, and visual UV/Vis and fluorescent color changes.
chased from local suppliers and were distilled by standard procedure
before use.
The substrate-binding interaction was calculated according to the
Benesi–Hildebrand equation.
1
ꢀ
ꢁ ꢀ
ꢁ
2
A0
A ꢀ A
e0
ꢀ e
1
¼
þ 1
2
BIMC has been shown to be sensitive with a detection limit
0
e
0
K
B
½Substrateꢂ
ꢀ
of 1.7 mm CN by switch-on fluorescence, suggesting its ap-
ꢀ
where A
the absorbance recorded in the presence of added guest, e
corresponding molar absorption co-efficients, and K represents the sub-
0
is the absorbance of the receptor in the absence of guest, A is
plicability to detect CN ions in aqueous buffer medium.
0
and e are the
The BIMC-CN ensemble has been subjected to studies of
their secondary sensing properties toward various cations. It
was found to be selective toward cyanophilic cations and is
B
strate-binding interaction with the guest. The binding constant of the che-
mosensor BIMC can also be calculated through the emission method by
using the following equation.
3
+
sensitive as well as selective, in particular to Au among all
2
+
+
the cations studied, including Cu and Ag . The selectivity
has been shown on the basis of fluorescence and absorption
spectroscopic studies. TDDFT calculations were carried out
to demonstrate the electronic properties of BISP and BIMC
and its corresponding cyanide complex. DFT/TDDFT calcu-
1
=ðIꢀI
0
Þ ¼ 1=KðImaxꢀI
0
Þ½Gꢂ þ 1=ðImaxꢀI
0
Þ
where I
0
, Imax, and I represent the emission intensity of free BIMC, the
maximum emission intensity observed in the presence of added anion at
ꢀ
4
45 nm for CN (lext =425 nm), and the emission intensity at a certain
concentration of the anion added, respectively, and [G] is the concentra-
tion of the guest anions.
ꢀ
lations indicate that upon the addition of CN the fluores-
cence enhancement of BIMC at 445 nm is mainly due to the
blocking of the conjugation-based ICT process. Further,
BIMC has been utilized to demonstrate the combinational
Cellular Imaging Methodology
Frozen human colorectal carcinoma cells (cell line HCT 116, ATCC:
CCL-247) were obtained from the American Type Culture Collection
(Rockville, MD, USA) and maintained in Dulbeccoꢂs modified Eagleꢂs
medium (DMEM, Sigma Chemical Co., St. Louis, MO, USA) supple-
mented with 10% fetal bovine serum (Invitrogen), penicillin
ꢀ
logic gate properties based on two inputs (i.e., CN and
3
+
Au ), and the output is the fluorescence response of
BIMC. In addition, test strips based on BIMC were fabricat-
ꢀ1
ꢀ1
(
100 mgmL ), and streptomycin (100 mgmL ). The RAW 264.7 macro-
phages were obtained from NCCS, Pune, India and maintained in
DMEM containing 10% (v/v) fetal calf serum and antibiotics in a CO
ꢀ
ed, which also exhibit a good selectivity to CN in water.
We believe that the test strips could serve as a convenient
2
2
ꢀ
incubator. Cells were initially propagated in a 25 cm tissue culture flask
in an atmosphere of 5% CO and 95% air at 378C humidified air until
0–80% confluency.
Synthesis of BIMC
,3,3-Trimethyl-3H-indole (1.25 mmol, 200 mg) was dissolved in dry
CHCl (10 mL). Subsequently, methyl iodide (1.87 mmol, 266 mg) was
and efficient CN test kit. Using RAW cells, BIMC was also
2
demonstrated as a potential live-cell fluorescence imaging
agent. A strong fluorescence was observed in RAW cells in
7
ꢀ
the presence of CN .
2
3
added dropwise, and the mixture was stirred at room temperature over-
night upon which a pale pink precipitate appeared. The cationic salt pre-
Experimental Section
cipitate was filtered, washed with CHCl
Benzothiazole-2-yl-2-hydroxy-benzaldehyde (0.39 mmol, 100 mg) and N-
,3,3-tetramethyl indolium cationic salt (0.4 mmol, 69.6 mg) were re-
3
several times, and collected. 3-
General Information and Materials
2
fluxed in 10 mL ethanol for 5 h. The mixture was then stirred at room
temperature for 1 h. The resulting orange precipitate was filtered and
washed with EtOH. It was then recrystallized by EtOAc/hexane to afford
Unless otherwise mentioned, materials were obtained from commercial
suppliers and were used without further purification. H and C NMR
spectra were recorded on a Brucker 300 MHz instrument. For NMR
1
13
the pure product (BISP) as an orange-yellow solid (129 mg, 80%). M.p.
6
spectra, [D ]DMSO was used as solvent using TMS as an internal stan-
1
>
2508C; H NMR ([D
6
]DMSO, 300 MHz): d=8.15 (d, 1H, J=6.3), 7.85
1
1
1
dard. Chemical shifts are expressed in d ppm units and H- H and H-C
coupling constants in Hz. Mass spectra were carried out using a Waters
QTOF Micro YA 263 mass spectrometer. Fluorescence spectra were re-
corded on a PerkinElmer Model LS 55 spectrophotometer. UV spectra
were recorded on a JASCO V-530 spectrophotometer. Elemental analysis
of the compounds was carried out on a PerkinElmer 2400 series CHNS/
(
1
(
1
1
1
2
d, 1H J=6.9), 7.74(d, 1H, J=6.3) 7.67 (d, 1H, J=7.67),7.48 (t, 1H, J=
1.4), 7.25(t, 1H, J=5.4), 7.15 (d, 2H, J=8.7), 7.04 (t, 1H, J=11.8), 6.96
t, 1H, J=5.7), 6.88 (d, 1H, J=12.8), 5.80 (d, 1H, J=10.8), 3.62 (s, 3H),
.84 ppm (s, 6H); C NMR ([D ]DMSO, 75 MHz): d=181.8, 167.9,
6
57.4, 150.6, 146.2, 143.4, 141.8, 133.6, 132.4, 129.5, 129.0, 127.3, 126.3,
23.0, 122.9, 122.6, 122.1, 120.5, 115.3, 113.9, 107.1, 52.1, 51.4, 34.6, 28.9,
1
3
O Analyzer. Salts of different anions, that is, Bu
Bu NBr, Bu NCl, Bu NCN, NaH PO , Na SO , NaSH, and NaNO
purchased from Spectrochem Pvt Ltd. (India). Salts of all the cations,
4
NF, Bu
4
OAc, Bu
4
NI,
2
5.7 ppm; elemental anal. calcd. for C26H22ON S: C 76.10, H 5.41, N 3.90,
4
4
4
2
4
2
4
2
were
S 7.80; found: C 76.23, H 5.52, N 3.72, S 7.83; MS (ESI MS): (m/z,%):
+
4
2
11.1462 [(BISP+H ), 100%]; calculated for C26H22ON S: 410.6788.
that is, Hg
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(ClO
O, Co(ClO
O, Mn(ClO
4
)
2
·xH
·6H
·6H
2
O, Cu
O, Fe
O, AgNO
A
H
U
G
R
N
U
G
4
)
2
·H
·6H
, and AuCl
3
2
O, Cd
O, Ni
were obtained from
A
H
U
G
R
N
U
G
4
)
2
·H
2
O, Zn-
The orange-yellow solid of BISP was dissolved in dry acetonitrile in
a 100 mL beaker. The beaker was then exposed to irradiation with UV
light (l=254 nm) in a UV chamber for 15 min under stirring. The orange
yellow solution turned purple due to the formation of BIMC and evapo-
A( ClO
C
H
T
U
N
G
T
R
E
N
N
U
N
G
4
)
)
2
·6H
·6H
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
4
)
2
2
4
)
2
2
A
T
N
R
N
G
4
)
2
·6H
2
O, Mg-
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(ClO
4
2
2
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
4
)
2
2
3
Sigma–Aldrich Chemical Co. (USA).
Bulk solutions of BIMC and anionic and cationic salts were made in ace-
ration of the solvent gives dark red BIMC. It was then directly placed
tonitrile/water (1:9, v/v). For UV/Vis and fluorescence titrations, a stock
1
under NMR for its characterization. H NMR ([D
6
]DMSO, 300 MHz):
ꢀ
4
3 2
solution of BIMC was prepared (c=1ꢁ10 m) in CH CN/H O (1:9, v/v).
d=8.26 (d, 2H, J=8.1), 8.19 (d, 1H J=12.3), 8.15 (d, 1H, J=11.4) 7.62
t, 1H, J=4.5), 7.53 (t, 1H, J=7.5), 7.30 (t, 1H, J=8.7), 7.26 (d, 1H, J=
.1), 7.23 (d, 1H, J=7.8), 7.12 (t, 1H, J=5.7), 7.06 (t, 1H, J=6.0), 6.70
ꢀ
3
A solution of the salts of guest anions in the order of 1ꢁ10 m was pre-
pared in deionized water. To examine the reversibility of the BIMC-CN
(
5
ꢀ
4
ꢀ
ꢀ3
complex, first BIMC (1ꢁ10 m) was titrated with CN (1ꢁ10 m) until
(
d, 1H, J=16.5), 6.05 (d, 1H, J=16.5), 4.15 (s, 3H), 2.08 ppm (s, 6H).
3
+
ꢀ3
saturation was obtained, and then an Au (c=1ꢁ10 m) solution was
slowly added to afford the BISP compound. This procedure was also
used for UV/Vis and fluorescence titrations. All the solvents were pur-
Chem. Asian J. 2014, 9, 3623 – 3632
3630
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Ajit Kumar Mahapatra et al.
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