Design and synthesis of rhodamine based chemosensors for the detection of Fe3+ ions

Article abstract of DOI:10.1016/j.dyepig.2012.05.025

The number and nature of coordinating entities as well as the size of chelating cavity in rhodamine based chemosensors were tuned to enhance the selectivity and sensitivity for Fe³⁺ ions. An intense pink color development and enhancement in flu

Full text of DOI:10.1016/j.dyepig.2012.05.025

Dyes and Pigments 95 (2012) 606e613
Contents lists available at SciVerse ScienceDirect
Dyes and Pigments
journal homepage: www.elsevier.com/locate/dyepig
Design and synthesis of rhodamine based chemosensors for the detection
of Fe3 ions
þ
Narendra Reddy Chereddy , Koorathota Suman , Purna Sai Korrapati , Sathiah Thennarasu ,*,
Asit Baran Mandal
a
a
a
b
a
c
,
**
Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600 020, India
Biomaterials Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai 600 020, India
Chemical Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai 600 020, India
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 February 2012
Received in revised form
The number and nature of coordinating entities as well as the size of chelating cavity in rhodamine based
chemosensors were tuned to enhance the selectivity and sensitivity for Fe ions. An intense pink color
3þ
development and enhancement in fluorescence emission intensity of chemosensor 5 upon complex
20 May 2012
3þ
formation at pH 7$4 enabled the detection of Fe ions in the presence of other competitive metal ions
Accepted 21 May 2012
Available online 9 July 2012
þ
þ
þ
þ
2þ
2þ
2þ
3þ
2þ
2þ
2þ
2þ
2þ
2þ
2þ
2þ
2þ
like Li , Na , K , Cs , Mg , Ca , Sr , Cr , Mn , Fe , Cu , Co , Ni , Zn , Cd , Hg , and Pb . A
3
þ
plausible application of chemosensor 5 in the imaging of live fibroblast cells exposed to Fe ions is also
demonstrated.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Rhodamine
Chemosensors
Fe selectivity
3þ
Size of chelating cavity
Naked eye detection
Live cell imaging
1. Introduction
[13e17] and polymeric chemosensors [18,19] for the detection of
heavy metal ions. However, only a few chemosensors are available
Selective detection of Fe3þ assumes importance because iron
plays an important role in cellular metabolism [1] and enzyme
catalysis [2e4]. Iron is an essential trace element for both plants
and animals, including humans. Consequently, deficiency in Fe3þ
leads to anemia, liver and kidney damages, diabetes, and heart
diseases [5]. Several techniques like atomic absorption spectros-
copy [6], colorimetry [7], spectrophotometry [8e10], and voltam-
in literature for Fe detection [20e48], and some of the chemo-
3þ
3þ
sensors developed for selective detection of Fe suffer from cross-
2
þ
3þ
sensitivity toward competitive metal ions like Cu
and Cr
even in the
presence of high concentrations of Cu and Cr would be more
3þ
[41e48]. Hence, a chemosensor that detects Fe
2
þ
3þ
3
þ
attractive. Since Fe
is a fluorescence quencher because of its
paramagnetic nature [49], development of chemosensors that
3
þ
3þ
metry [11] have been developed for Fe
detection, but these
exhibit fluorescence enhancement upon binding with Fe would
require sophisticated equipments, tedious sample preparation
procedures, and trained analysts. Therefore, chemosensors which
allow naked-eye detection, have advantages over other methods in
being easy to operate, portable, and not requiring sophisticated
instrumentation.
Rhodamine is one of the most attractive fluorochromes because
of its photo physical properties [12]. Recently, much effort has been
focused on the development of rhodamine based chemosensors
be very much attractive. According to the theory of hard and soft
acids and bases (HSAB theory), a stable complex is formed between
3
þ
a hard base and a hard acid such as Fe ions. This theory offers
a possibility to develop ligands with improved selectivity toward
a particular metal ion depending upon the strengths of hard and
soft acids and bases. The nature and number of the external
chelating moieties incorporated with the rhodamine [41,50] play an
important role for tuning metal ion selectivity. We used these
advantages for developing new chemosensors that show selectivity
for a single metal ion of interest over other competitive metal ions.
For the present study, we synthesized six rhodamine based
chemosensors bysubtlychanging the number, nature and size of the
coordinating entities. 5 showed the highest degree of sensitivity and
*
Corresponding author. Tel.: þ91 44 24913289; fax: þ91 44 24911589.
*
* Corresponding author.
E-mail addresses: thennarasu@gmail.com (S. Thennarasu), abmandal@clri.res.in
(
A.B. Mandal).
0143-7208/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.dyepig.2012.05.025

N.R. Chereddy et al. / Dyes and Pigments 95 (2012) 606e613
607
selectivity for Fe3 over Cu
þ
2þ
as compared with the other five
addition red color developed immediately. Then the mixture was
refluxed in an oil bath for 3 h. After that, the solution was cooled to
room temperature. The resultant mixture was subjected to silica gel
3
þ
analogs. The selectivity and sensitivity of 5 for Fe were exploited
for the detection of live fibroblast cells exposed to Fe ions.
3þ
100e200 mesh column chromatography using 1:3 hexane-
2
. Experimental section
ethtylacetate as eluent to get 0.395 g (74%) of 2 in pure form as
colorless solid.
1
2
.1. General
H NMR (CDCl
3
, 500 MHz):
d
1.15 (12H, t, J ¼ 6.9 Hz, NCH
2 3
CH ),
3
.31 (8H, q, J ¼ 6.9 Hz, NCH
2
CH
3
), 6.25 (2H, d, J ¼ 2.3 Hz,
Dry acetonitrile and double distilled water were used
XantheneeH), 6.35 (1H, s, furaneH), 6.41 (2H, d, J ¼ 2.3 Hz,
XantheneeH), 6.54 (2H, d, J ¼ 9.1 Hz, XantheneeH), 6.59 (1H, s,
furaneH), 7.05 (1H, d, J ¼ 6.9 Hz, AreH), 7.37 (1H, s, imineeH), 7.44
(2H, m, AreH), 7.98 (1H, d, J ¼ 6.9 Hz, furaneH), 8.17 (2H, s, AreH);
throughout the experiment. All the materials for synthesis were
purchased from commercial suppliers and used without further
purification. The solutions of metal ions were prepared from the
corresponding chloride salts. Absorption spectra were recorded on
13
3
C NMR (CDCl , 125 MHz): d 12.7, 12.8, 44.4, 65.7, 98.0, 105.5, 108.2,
a
CARY BIO 50 UVeVIS spectrophotometer. Fluorescence
111.6, 112.3, 123.5, 123.6, 127.9, 128.1, 128.3, 133.6, 136.0, 143.9, 149.1,
measurements were performed on a Perkin Elmer LC 45 Lumi-
nescence spectrometer. All pH measurements were made with
a Systronics mpH System Model 361. NMR spectra were recorded
150.7, 152.6, 152.9, 165.3.
m/z (M ) 534.3, found (M þ H)þ
þ
ESI-MS: calcd for C33
H
34
N
4
O
3
535.4.
using a JEOL eECP500 MHz spectrometer operated at 500 MHz. ESI
MS spectra were obtained on a HP 1100 LC-MS Analyzer without
using the LC part. Fluorescence imaging experiments were per-
formed using Olympus CK 40 Fluorescence Microscope. All
measurements were carried out at room temperature (w298 K).
2.1.4. Synthesis of bis-salicylaldehyde derivatives (A, B, C and D)
Salicylaldehyde (5.0 mmol, 0.61 g) was dissolved in 20 mL DMF,
and potassium corbonate (12.5 mmol, 1.73 g) was added and the
mixture was stirred at room temperature. Methelenebromide
(2.5 mmol, 0.44 g), 1,2- dibromoethane (2.5 mmol, 0.47 g), 1,3-
2
.1.1. Synthesis of rhodamine hydrazide
Rhodamine hydrazide was synthesized following the reported
dibromopropane (2.5 mmol, 0.51 g) or 1,4- dibromobutane
(2.5 mmol, 0.55 g) was added drop wise and then the mixture was
stirred under reflux for 6 h. The resultant mixture was partitioned
between water and ethylacetate, ethylacetate layer was collected,
concentrated under reduced pressure and then subjected to silica
gel 100e200 mesh column chromatography using 1:9 hexane-
ethtylacetate as eluent to afford compounds A (0.96 g, 75%), B
(0.97 g, 72%), C (1.07 g, 75%) and D (1.17 g, 75%) in pure form.
procedure [31]. To rhodamine B hydrochloride (0.96 g, 2 mmol)
dissolved in 15 mL methanol, excess amount of hydrazine hydrate
(
1 mL, 6.98 mmol) was added and the reaction mixture was
refluxed till the pink color disappeared (w3e4 h). After that, the
reaction mixture was cooled to room temperature, poured into
distilled water and extracted with ethylacetate (6 ꢀ 25 mL). The
combined extract was washed with brine, dried with anhydrous
sodium sulfate, filtered, and then concentrated under reduced
2.1.4.1. NMR data of bis-salicylaldehyde (A). 1
500 MHz): 6.01 (2H, s, OCH
O), 7.17 (2H, t, J ¼ 6.9 Hz, AreH), 7.37
3
H NMR (CDCl ,
pressure to yield 0.62 g (68%) of rhodamine hydrazide.
d
2
1
H NMR (CDCl
3
, 500 MHz):
d
1.16 (t, J ¼ 7.5 Hz, 12H, NCH
CH ), 3.63 (bs, 2H, NH ), 6.28 (dd,
J ¼ 2.3 Hz, 2H, XantheneeH), 6.43 (d, J ¼ 2.3 Hz, 2H, XantheneeH),
.45 (d, J ¼ 9.2 Hz, 2H, XantheneeH), 7.10 (m, 1H, AreH), 7.44 (t,
2
CH
3
),
(2H, d, J ¼ 8.4 Hz, AreH), 7.61 (2H, t, J ¼ 8.4 Hz, AreH), 7.86 (2H, dd,
13
3
.32 (q, J ¼ 6.8 Hz, 8H, NCH
2
3
2
J ¼ 1.6 Hz, AreH), 10.46 (2H, s, AldehydeeH); C NMR (CDCl
125 MHz): 90.7, 115.0, 123.1, 125.8, 129.0, 136.1, 158.7, 189.2.
3
,
d
6
13
2.1.4.2. NMR data of bis-salicylaldehyde (B). 1
500 MHz): 4.52 (4H, s, OCH CH
J ¼ 3.5 Hz, 2H, AreH), 7.93 (m, 1H, AreH); C NMR (CDCl
3
,
H NMR (CDCl
O), 7.06 (4H, m, AreH), 7.57 (2H, t,
3
,
125 MHz): 12.7, 44.5, 66.0, 98.0, 104.5, 108.1, 123.1, 123.9, 128.1,
d
d
2
2
128.2, 130.1, 132.6, 148.9, 151.6, 153.9, 166.3.
J ¼ 7.6 Hz, AreH), 7.82 (2H, d, J ¼ 6.2 Hz, AreH), 10.43 (2H, s,
13
3
AldehydeeH); C NMR (CDCl , 125 MHz): d 67.1, 112.9, 121.5, 125.2,
2.1.2. Synthesis chemosensor 1
128.6, 136.1, 160.9, 189.5.
To a solution of rhodamine hydrazide (0.46 g, 1 mmol) dissolved
in 20 mL methanol, pyridine-2-aldehyde (0.11 g, 1 mmol) was
added. The red color mixture thus obtained was refluxed in an oil
bath for 3 h. After that, the solution was cooled to room tempera-
ture. The resultant mixture was subjected to silica gel 100e200
mesh column chromatography using 1:3 hexane-ethtylacetate as
2.1.4.3. NMR data of bis-salicylaldehyde (C). 1
500 MHz): 2.43 (2H, p, OCH CH CH
O), 4.33 (4H, t, J ¼ 7.6 Hz,
OCH CH2CH
O), 7.03 (4H, m, AreH), 7.55 (2H, t, J ¼ 7.7 Hz, AreH),
7.83 (2H, d, J ¼ 7.7 Hz, AreH), 10.49 (2H, s, AldehydeeH); C NMR
(CDCl , 125 MHz): 29.2, 64.7, 112.5, 121.0, 124.9, 128.8, 136.2, 161.0,
189.6.
3
H NMR (CDCl ,
d
2
2
2
2
2
13
3
d
eluent to yield 0.40 g (75%) of 1 as colorless solid.
1
H NMR (CDCl
3
, 500 MHz):
d
1.14 (12H, t, J ¼ 6.9 Hz, NCH
2 3
CH ),
3
.29 (8H, q, J ¼ 6.9 Hz, NCH
2
CH
3
), 6.25 (2H, d, J ¼ 2.3 Hz,
2.1.4.4. NMR data of bis-salicylaldehyde (D). 1
H
NMR (CDCl
O), 4.19 (4H, s,
O), 6.98 (4H, m, AreH), 7.52 (2H, t, J ¼ 6.9 Hz,
3
,
XantheneeH), 6.41 (2H, d, J ¼ 3.0 Hz, XantheneeH), 6.54 (1H, d,
J ¼ 9.1 Hz, XantheneeH), 7.11 (2H, m, AreH, imineeH), 7.46 (2H, m,
AreH), 7.60 (1H, d, J ¼ 6.9 Hz, pyridineeH), 8.00 (1H, t, J ¼ 6.9 Hz,
pyridineeH), 8.34 (1H, s, AreH), 8.45 (1H, d, J ¼ 4.6 Hz,
500 MHz):
OCH CH CH
d
2 2 2 2
2.10 (4H, s, OCH CH CH CH
2
2
2
CH
2
1
3
AreH), 7.83 (2H, d, J ¼ 6.9 Hz, AreH), 10.49 (2H, s, Aldehyde-H);
NMR (CDCl , 125 MHz): 26.0, 67.9, 112.5, 121.0, 124.9, 128.6, 136.1,
161.2, 189.7.
C
3
d
pyridineeH); 13C NMR (CDCl
, 125 MHz): d 12.7, 44.4, 65.9, 98.3,
3
105.5, 108.1, 120.8, 123.7, 123.8, 127.7, 128.0, 128.3, 133.9, 136.3,
1
45.7, 149.0, 149.1, 152.6, 152.9, 154.5, 165.7.
2.1.5. Synthesis of bis-rhodamine chemosensors 3, 4, 5 and 6
Rhodamine hydrazide (0.46 g, 1 mmol) was dissolved in 20 mL
methanol, and bis-salicylaldehyde derivative A (0.13 g, 0.5 mmol), B
m/z (M ) 545.3, found (M þ H)þ
þ
35 5 2
ESI-MS: calcd for C34H N O
5
46.4.
(0.14 g, 0.5 mmol), C (0.15 g, 0.5 mmol) or D (0.16 g, 0.5 mmol) was
2
.1.3. Synthesis chemosensor 2
Rhodamine hydrazide (0.46 g, 1 mmol) was dissolved in 20 mL
methanol and furan-2-aldehyde (0.10 g, 1 mmol) was added. Upon
added. The mixture was refluxed in an oil-bath for w3 h and then
cooled to room temperature. The resultant mixture was subjected
to silica gel 100e200 mesh column chromatography using 1:3

608
N.R. Chereddy et al. / Dyes and Pigments 95 (2012) 606e613
hexane-ethtylacetate as eluent to afford 3 (0.425 g, 75%), 4 (0.435 g,
125 MHz):
d 12.7, 25.8, 44.4, 65.8, 67.7, 98.0, 106.1, 108.2, 112.0,
7
5%),5 (0.44 g, 75%) and 6 (0.45 g, 75%) as colorless solids.
120.7, 123.4, 123.7, 124.1, 126.4, 127.9, 128.3, 128.9, 131.0, 133.4,
1
42.7, 148.9, 152.4, 153.0, 157.6, 165.2.
þ
2
.1.5.1. NMR and Mass analytical data of chemosensor 3. 1H NMR
ESI MS: calcd for C74
1175.5.
78 8 6
H N O
m/z (M ) 1174.4, found (M þ H)þ
(
CDCl
3
, 500 MHz):
d
1.08 (24H, t, J ¼ 7.5 Hz, NCH
2 3
CH ), 3.24 (16H, q,
O), 6.22 (4H, dd, J ¼ 2.3 Hz,
J ¼ 6.9 Hz, NCH
2
CH
3
), 5.29 (2H, s, OCH
2
XantheneeH), 6.41 (4H, d, J ¼ 2.3 Hz, XantheneeH), 6.53 (4H, d,
J ¼ 9.2 Hz, XantheneeH), 7.00 (2H, t, J ¼ 7.5 Hz, AreH), 7.08 (2H, d,
J ¼ 6.9 Hz, AreH), 7.12 (2H, d, J ¼ 8.6 Hz, AreH), 7.39 (2H, t,
J ¼ 7.5 Hz, AreH), 7.45 (4H, p, J ¼ 7.5 Hz, AreH), 7.93 (2H, d,
J ¼ 6.9 Hz, AreH), 8.01 (2H, d, J ¼ 6.9 Hz, AreH), 8.67 (2H, s,
2.2. Preparation of solutions for absorption and fluorescence
measurements
Stock solutions of chemosensors were prepared by dissolving
the required amounts of chemosensors (5.46 mg, 5.35 mg,11.33 mg,
11.47 mg, 11.61 mg and 11.75 mg of chemosensors 1, 2, 3, 4, 5 and 6
respectively, 1.0 mmol) in 1:1 v/v 0.01 M Tris HCleCH CN (pH 7$4)
and making up to the mark in a 10 mL volumetric flask. Further
dilutions were made to prepare 100
ments. To 1.0 mL of this solution in a 10 mL volumetric flasks was
added 9.0 mL 1:1 v/v 0.01 M Tris HCleCH CN (pH 7$4) containing
different concentrations of metal ions, so as to get an overall dye
concentration of 10 M for the experiments. Absorption and fluo-
rescence measurements were made using a 3.0 mL cuvette.
imineeH); 13C NMR (CDCl
, 125 MHz): d 12.7, 44.4, 65.7, 91.6, 97.9,
3
105.7, 108.2, 114.7, 122.4, 123.5, 123.8, 124.7, 126.6, 128.1, 128.3,
3
128.7, 131.1, 133.5, 141.9, 149.0, 152.5, 153.0, 156.0, 165.3.
þ
þ
ESI MS: calcd for C71
H
72
N
8
O
6
m/z (M ) 1132.4, found (M þ H)
mM solutions for the experi-
1133.3.
3
2
.1.5.2. NMR and Mass analytical data of chemosensor 4. 1H NMR
, 500 MHz): CH ), 3.20 (16H, q,
1.03 (24H, t, J ¼ 7.5 Hz, NCH
J ¼ 4.6 Hz, NCH CH ), 4.19 (4H, s, OCH CH O), 6.21 (4H, dd,
(
CDCl
3
d
2
3
m
2
3
2
2
J ¼ 2.3 Hz, XantheneeH), 6.39 (4H, d, J ¼ 2.9 Hz, XantheneeH), 6.54
(
(
4H, d, J ¼ 9.2 Hz, XantheneeH), 6.95 (2H, t, J ¼ 7.5 Hz, AreH), 7.00
2H, d, J ¼ 8.6 Hz, AreH), 7.06 (2H, d, J ¼ 6.9 Hz, AreH), 7.31 (2H, t,
3. Results and discussion
J ¼ 8.1 Hz, AreH), 7.45 (4H, p, J ¼ 7.5 Hz, AreH), 8.02 (4H, t,
Rhodamine hydrazide was prepared as described previously
13
J ¼ 6.9 Hz, AreH), 8.69 (2H, s, imineeH); C NMR (CDCl
25 MHz): 12.6, 44.4, 65.6, 66.3, 97.8, 105.6, 108.2, 112.4, 121.4,
23.5, 123.8, 124.3, 126.5, 128.2, 128.3, 128.8, 131.0, 133.5, 141.4,
3
,
[51]. Chemosensors 1 and 2 were facilely synthesized by the
1
1
d
condensation of rhodamine hydrazide with pyridine-2-aldehyde
and furan-2-aldehyde, respectively, as shown in Scheme 1, and
characterized by NMR and Mass analyses (Supporting data,
Fig. S3eS8). The existence of spirocyclic ring structure in 1 and 2
149.0, 152.6, 152.9, 157.1, 165.3.
þ
ESI MS: calcd for C72
H
74
N
8
O
6
m/z (M ) 1146.4, found (M þ H)þ
1147.5.
13
were confirmed by the observation of C NMR resonances at
w65.88 and w65.66 ppm, respectively (Supporting data, Fig. S4
and S6). Although both 1and 2 contain the rhodamine moiety,
they were colorless in 0.01 M Tris HCleCH CN mixture (pH 7.4) as
3
well as in other organic solvents confirming the existence of the
ring-closed spirolactam as the predominant species [52]. The
limited solubility of rhodamine derivatives in water and aqueous
buffer necessitated the use of other organic solvents miscible with
2
.1.5.3. NMR and Mass analytical data of chemosensor 5. 1H NMR
, 500 MHz): CH ), 2.05 (2H, p,
1.07 (24H, t, J ¼ 7.5 Hz, NCH
CH CH CH ), 3.99
O), 3.22 (16H, q, J ¼ 7.5 Hz, NCH
CH
O), 6.22 (4H, dd, J ¼ 2.3 Hz, XantheneeH), 6.41
4H, d, J ¼ 1.7 Hz, XantheneeH), 6.56 (4H, d, J ¼ 9.2 Hz,
(
CDCl
3
d
2
3
J ¼ 6.3 Hz, OCH
2
2
2
2
3
(
(
4H, s, OCH
2
CH
2
2
XantheneeH), 6.85 (4H, m, AreH), 7.04 (2H, d, J ¼ 6.9 Hz, AreH),
.20 (2H, t, J ¼ 7.5 Hz, AreH), 7.40 (4H, p, J ¼ 7.5 Hz, AreH), 7.95
2H, d, J ¼ 8.1 Hz, AreH), 7.98 (2H, d, J ¼ 6.3 Hz, AreH), 8.81 (2H, s,
7
(
water. Between CH
miscible with water, the rhodamine derivatives 1 and 2 were more
soluble in CH CN than in MeOH. On studying the absorbance
properties of 1 and 2 in aqueous buffer containing different
proportions of CH CN, we inferred that the 1:1 mixture of aqueous
buffer and CH CN would contain the minimum amount of organic
3
CN and MeOH, the two organic solvents highly
13
imine-H); C NMR (CDCl
9
3
, 125 MHz): d 12.8, 29.6, 44.4, 64.9, 65.7,
3
8.0, 106.0, 108.2, 112.1, 120.7, 123.5, 123.7, 124.0, 126.5, 127.9, 128.3,
128.5, 131.0, 133.5, 142.5, 148.9, 152.6, 152.9, 157.6, 165.3. ESI MS:
3
þ
þ
calcd for C73
H
76
N
8
O
6
m/z (M ) 1160.4, found (M þ H) 1161.5.
3
solvent and display excellent solubility of rhodamine derivatives.
2
(
OCH
OCH
.1.5.4. NMR and Mass analytical data of chemosensor 6. 1H NMR
CDCl , 500 MHz): CH ), 1.91 (4H, s,
CH ), 3.93 (4H, s,
O), 6.22 (4H, dd, J ¼ 2.3 Hz, XantheneeH), 6.41
The absorbance and fluorescence characteristics of 1 and 2 were
3
d
1.09 (24H, t, J ¼ 6.9 Hz, NCH
2
3
greatly influenced by the addition of Cu or Fe ions. A clear pink
color with a good fluorescence emission developed (Supporting
2þ
3þ
2
CH
CH
2
CH
CH
2
2
CH
CH
2
O), 3.27 (16H, q, J ¼ 6.9 Hz, NCH
2
3
2
2
2
data, Fig. S9) upon addition of 50
mM concentrations of either
(
4H, d, J ¼ 2.3 Hz, XantheneeH), 6.55 (4H, d, J ¼ 9.2 Hz,
2þ
3þ
þ
þ
þ
Cu or Fe ions, while other competitive metal ions (Li , Na , K ,
XantheneeH), 6.77 (2H, d, J ¼ 8.0 Hz, AreH), 6.86 (2H, t, J ¼ 7.5 Hz,
AreH), 7.08 (2H, d, J ¼ 6.9 Hz, AreH), 7.19 (2H, t, J ¼ 8.0 Hz, AreH),
þ
2þ
2þ
2þ
2þ
2þ
3þ
2þ
2þ
2þ
2þ
2þ
2þ
Cs , Mg , Ca , Sr , Cr , Mn , Fe , Co , Ni , Zn , Cd
,
Hg , and Pb ) showed negligible effect. The UVeVisible absorp-
tion spectrum of 1 and 2 are shown in the Fig. S10 (Supporting
7
.44 (4H, p, J ¼ 7.5 Hz, AreH), 7.95 (2H, d, J ¼ 6.9 Hz, AreH), 7.99
13
(
2H, d, J ¼ 7.5 Hz, AreH), 8.81 (2H, s, imineeH); C NMR (CDCl
3
,
data). The 10
mM solutions of 1 and 2 in 1:1 v/v 0.01 M Tris
N
O
N N
O
CHO
R=
R
R
1
N NH2
Methanol, Reflux
O
N
O
N
R=
N
O
N
2
Scheme 1. Synthesis of rhodamine based chemosensors 1e2.

N.R. Chereddy et al. / Dyes and Pigments 95 (2012) 606e613
609
OH
Br(CH ) Br
2
n
O(CH ) O
2
n
DMF, K CO , Reflux
2
3
CHO
CHO
OHC
A n=1, B n=2, C n=3, D n=4
N
O
N
O(CH ) O
2
n
A, B, C, D
N
N
N NH2
N
N
O
Methanol, Reflux
O
O
O
N
O
N
N
N
3
n=1, 4 n=2, 5 n=3, 6 n=4
Scheme 2. Synthesis of bis-rhodamine based chemosensors 3e6.
HCleCH
in 500e600 nm region. However, addition of either Cu or Fe
ions (50 M) induced a new peak centered at w 555 nm with
3
CN pH 7.4 were colorless and did not show any absorbance
in entropy between chelate and non-chelate complex reactions
significantly influences metal ion selective chelation [54]. In the
case of rhodamine derivatives, even a slight change in the steric
requirement or puckering of chelating ring drastically alters metal-
donor atom interactions and completely change the metal ion
selectivity [50,55e60]. Achievement of such steric effects requires
considerable rigidity in the ligand. The rigid positioning of donor
atoms in a ligand (the OeNeO combination of donor atoms in the
present study), can best be obtained in aromatic ligands as
compared with aliphatic analogs.
2
þ
3þ
m
a shoulder peak at 520 nm. Other competitive metal ions did not
influence the absorption characteristics of 1 and 2. The enhance-
2
þ
3þ
ment in the absorbance of 1 upon addition of Cu and Fe were
5
3 and 57 fold respectively, and indicated that 1 had nearly equal
2
þ
3þ
and Fe . However, the enhancement
sensitivity for both Cu
factor of absorbance of 2 upon addition of Cu and Fe were 38
2
þ
3þ
and 154, respectively. This observation indicated that the furan O-
3
þ
2þ
atom in 2 could favor the binding of Fe ions over Cu ions. It was
also clear from Job plot (Supporting data, Fig. S11eS12) that both
2
þ
3þ
chemosensors 1 and 2 formed complexes with Cu and Fe ions
in 2:1 stoichiometry (Supporting data, Scheme 1). Thus, the
3þ
2þ
observed selectivity for Fe over Cu in the case of 2 could be
explained in terms of the theory of hard and soft acids and bases
(
HSAB theory). The furan O-atom in 2 being a stronger hard base
than the pyridine N-atom in 1, the former is likely to form a more
3
þ
stable complex with Fe (a stronger hard acid as compared to
2
þ
Cu ) than the latter. Moreover, it seems likely that compared to the
chelating ligand of 1 that contains OeNeN combination of donor
atoms, the chelating ligand of relatively rigid molecule 2 containing
3
þ
OeNeO combination of donor atoms might fit better with Fe
than with Cu2
þ
.
As regards the origin of metal ion selectivity, higher negative
charge of the ligand and higher number of chelate rings, greatly
increase the stabilities of the metal chelates formed, but decrease
selectivity [53]. Chelate effect which originates from the difference
M) to Cu2 (50
þ
m
M) and Fe
3þ
Fig. 2. Comparison of absorbance (a) and fluorescence (b) characteristics of 5 (10
m
M).
M)
Fig. 1. Relative sensitivities of chemosensors (10
50 M) ions.
m
(
m
in 1:1 v/v 0.01 M Tris HCleCH CN pH 7.4 in response to different metal ions (50 m
3

610
N.R. Chereddy et al. / Dyes and Pigments 95 (2012) 606e613
in 1:1 stoichiometry as opposed to the 2:1 stoichiometry observed
for 2. Accordingly, four bis-rhodamine probes 3, 4, 5 and 6 with
similar coordinating moieties and incremental spacer lengths were
synthesized as shown in Scheme 2 and characterized by NMR and
Mass analyses (Supporting data, Fig. S13eS24). Despite the presence
of two rhodamine moieties, all four bis-rhodamine probes 3e6 gave
3
a colorless solution in 1:1 v/v 0.01 M Tris HCleCH CN pH 7.4 as well
as other organic solvents, indicating their spirocyclic structure. The
non-fluorescent spirocyclic form of 3, 4, 5 and 6 was further
13
confirmed by C NMR analysis. While all four bis-rhodamine probes
e6 (10 M each) were colorless and insensitive to 50 M concen-
tration of different metal ions (Li , Na , K , Cs , Mg , Ca , Sr
3
m
m
þ
2þ
þ
þ
2þ
þ
þ
2þ
2þ
2þ
2þ
2þ
,
3þ
2þ
2þ
2þ
2þ
Cr , Mn , Fe , Co , Ni , Zn , Cd , Hg , and Pb ), they
showed the characteristic color only to Fe and Cu ions (Fig.1 and
3
2þ
Fig. 3. Metal-ion selectivity of 5 (10
dark bars represent the fluorescence emission of a solution of 5 (10
the cation of interest. The light bars show the fluorescence change that occurs upon
addition of 1 equiv of Fe(III) to the solution containing 5 (10 M)and the cation
50 M).
m
M) in 1:1 v/v 0.01 M Tris HCleCH
3
CN pH 7.4. The
Supporting data, Fig. S25). The UVeVisible absorption patterns of
3e6 were measured in 1:1 v/v 0.01 M Tris HCleCH CN pH 7.4.
3
Solutions of all four bis-rhodamine probes 3e6 did not show any
mM) and 5 equiv of
m
2þ
absorbance above 500 nm. But, addition of 50
m
M of either Cu or
(
m
3
þ
Fe induced a new peak centered at w555 nmwith a shoulder peak
at 520 nm. Other competitive metal ions did not influence the
absorption characteristics of 3e6 (Supporting data, Fig. S25).
Predictably, all the four bis-rhodamine probes 3e6 showed nearly
equal enhancement (400e407 fold increase) in the absorbance
intensity upon addition of Fe ions. Under identical conditions the
enhancement factors of absorbance of 3, 4, 5 and 6 for Cu were 99,
209, 49, and 150, respectively. This remarkable reduction in Cu
In our previous work we successfully demonstrated that a bisr-
hodamine chemosensor was more sensitive than its monorhod-
3
þ
amine analog [51]. Based on the observed selectivity for Fe over
2
þ
3þ
Cu in the case of 2 and the results of our previous work, we
speculated that the spatial disposition of OeNeO donor atoms
combined with an appropriate spacer in a bis-rhodamine analog
would result in a sensor with enhanced sensitivityand selectivity for
2
þ
2þ
induced absorbance of bis-rhodamine probes 3e6 could be ascribed
3
þ
3þ
2þ
Fe ions. Such a chemosensor should form a complex with Fe ion
to the low affinity of chelating ligands for Cu which in turn would
O(CH ) O
N
N
2 3
O(CH ) O
N
N
2 3
N
N
N
N
N
N
N
N
O
O
Fe3+
O
O
O
O
O
O
N
N
N
N
5, colour less
Pink colour
EDTA
O(CH ) O
N
N
2 3
O(CH ) O
N
N
2 3
N
N
N
N
N
N
N
N
O
O
Fe3+
O
O
O
O
O
O
N
N
N
N
colour less
+
Pink colour
+
EDTA-Fe3+
3
+
EDTA-Fe
Scheme 3. Perspective mechanism of 5-Fe3 complex formation.
þ

N.R. Chereddy et al. / Dyes and Pigments 95 (2012) 606e613
611
2
2
1
1
50
00
50
00
each) were 446 and 23, respectively (Fig. 2b). Thus, owing to the
reduced affinity of the bis-rhodamine probe 5 for Cu ions, Fe
ions could be selectively detected. The concentration dependant
240
220
200
180
160
140
120
100
2þ
3þ
variations in the fluorescence emission intensity of 5 upon addition
3þ
2þ
of Fe and Cu ions are shown in the Fig. S30 (Supporting data).
3þ
Addition of incremental concentrations of Fe
emission w579 nm. The limit of detection of 5 for Fe ions was
induced a new
3
þ
5
0
0
ꢁ7
5
ꢁ7
5
4 ꢀ 10 M ( I4 ꢀ 10
/
I
0
¼ 4.25) [50]. The metal competition assay
3
þ
carried out by adding Fe ions (10
m
M) to 5 (10
m
M) in the presence
of other metal ions (50
metal ions did not show any interference on the Fe induced
fluorescence emission of 5 as shown in Fig. 3. Only Cu induces
mM) revealed that the commonly coexistent
8
6
4
2
0
0
0
0
0
3
þ
0
2
4
6
8
10
2
þ
pH
3þ
a little fluorescence emission but addition of Fe to the solution of
2þ
5
-Cu complex leads to a greater enhancement in the fluorescence
3þ
emission of 5 indicating the high binding affinity of 5 for Fe and,
600
650
700
750
3
þ
suggests that 5 can be used to detect Fe even in the presence of
2
þ
2þ
Wavelength (nm)
Cu at high concentrations. Since the concentrations of Cu ions
3þ
are lower than those of Fe ions in biological tissues, and the fact
that 5 displays a lower affinity for Cu ions, the presence of Fe
ions in biological tissues could be selectively detected using 5.
The mechanism for the changes in the fluorescence character-
istics of 5 upon addition of Fe ions is shown in the Scheme 3. As it
Fig. 4. pH dependant variation in fluorescence intensity of chemosensor 5 (5 mM).
2
þ
3þ
contribute to the selectivity for Fe3 ions (Fig.1 and Supporting data,
Fig. S25). Unlike the mono-rhodamine probes 1 and 2, the bis-
rhodamine probes 3e6, formed complexes with Fe and Cu
þ
3þ
3
þ
2þ
3þ
would be expected, the Fe
binds with 5, and opens the spi-
ions in 1:1 stoichiometry as determined by Job plot (Supporting
data, Fig. S26eS29). As it is apparent that all four bis-rhodamine
probes 3e6 contain the same OeNeO combination of donor
atoms, the selectivity displayed by 5 (Fig. 2a) can only be ascribed to
the spacer length that appears to provide the required chelating ring
size and flexibility and, thereby, favor the formation of the complex
rolactam ring that results in the fluorescence enhancement and
development of pink color (Supporting data, Fig. S31). The pink
3
þ
color formed by the addition of Fe ions becomes colorless upon
addition of EDTA, confirming the reversibility of complex formation
and the formation of 5 (Supporting data, Fig. S32). This colorless
3
þ
solution regains its pink color upon addition of excess Fe ions,
with Fe3 rather than with Cu
The fluorescence characteristics of 5 were studied in 1:1 v/v
.01 M Tris HCleCH CN pH 7.4. In the absence of metal ions, 5 alone
was fluorescently inactive in the rhodamine emission range
550e650 nm) indicating the existence of the spirocyclic form. The
þ
2þ
.
suggesting that the color development is due to the formation 5-
3
þ
3þ
Fe complex and not due to any catalytic action of Fe ions. Such
0
3
a complex formation should involve the carbonyl oxygen atom of 5.
13
The C NMR spectra of 5 recorded in the presence of different
3
þ
(
concentrations of Fe
ions clearly show the involvement of
metal ion dependent variations in the fluorescence emission
intensity of 5 is shown in Fig. 2b. The fluorescence emission of 5
carbonyl oxygen of 5 in complex formation. The reduction in the
13
C-resonance at 66.12 ppm confirms the opening of spirolactam
3
þ
3þ
was highly enhanced upon injection of Fe ions. Other competitive
ring upon complex formation with Fe
ions (Supporting data,
2
þ
metal ions did not show any considerable influence except Cu
which showed little interference. Interestingly, the fluorescence
Fig. S33). The formation a distorted octahedral complex is sup-
ported by theoretical calculations (Supporting data, Fig. S34) and in
agreement with the observed spectrometric evidence.
3
þ 2þ
enhancement factors of 5 (10 mM) for Fe and Cu ions (10 mM
M) and Fe3 (5
þ
mM), and, fluorescence microscopic images
Fig. 5. Microscopic images of (a) untreated fibroblast cells, (b) cells incubated with 5 (1
þ
of (d) untreated cells, (e) cells incubated with 5 (1 M), and (f) cells incubated with 5 (1 mM) and Fe (5 mM).
m
M), (c) cells incubated with 5 (1
m
3
m

612
N.R. Chereddy et al. / Dyes and Pigments 95 (2012) 606e613
The stability at physiological pH is a prerequisite for any che-
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