2-Aminopyridine derivative as fluorescence 'On-Off' molecular switch for selective detection of Fe3+/Hg2+

Article abstract of DOI:10.1016/j.tetlet.2012.02.094

2-Amino-6-methyl-4-phenyl-nicotinonitrile 1, a 2-aminopyridine-based fluorescent compound, was found to be a fluorescent chemosensor for the detection of Fe³⁺ and Hg²⁺ ions over a number of other metal ions. Compound 1 was synthesized in one step using a multicomponent reaction, and characterized using common spectroscopic tools. During Fe ³⁺/Hg²⁺ sensing the compound 1 followed a 'switch-off' mechanism. Further, compound 1 could sense Fe³⁺ over Hg²⁺ by its distinct absorption and fluorescence quenching behaviors. 1:1 complex formation of 1 with Fe³⁺ and Hg²⁺ was clearly understood from Job's plot. The present work brings additional evidence on the importance of multicomponent reactions which could lead to the development of fluorescence chemosensor in one step for the selective detection of biologically important metal ions.

Full text of DOI:10.1016/j.tetlet.2012.02.094

Tetrahedron Letters 53 (2012) 2302–2307
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2
-Aminopyridine derivative as fluorescence ‘On–Off’ molecular switch
3
+
2+
for selective detection of Fe /Hg
⇑
⇑
Rik Rani Koner, Sougata Sinha, Sunil Kumar, Chayan K. Nandi , Subrata Ghosh
School of Basic Sciences, Indian Institute of Technology Mandi, Mandi 175001, HP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Amino-6-methyl-4-phenyl-nicotinonitrile 1, a 2-aminopyridine-based fluorescent compound, was
found to be a fluorescent chemosensor for the detection of Fe and Hg ions over a number of other
Received 26 December 2011
Revised 20 February 2012
Accepted 21 February 2012
Available online 27 February 2012
3+
2+
metal ions. Compound 1 was synthesized in one step using a multicomponent reaction, and characterized
3+
2+
using common spectroscopic tools. During Fe /Hg sensing the compound 1 followed a ‘switch-off’
mechanism. Further, compound 1 could sense Fe3 over Hg by its distinct absorption and fluorescence
+
2+
3
+
2+
quenching behaviors. 1:1 complex formation of 1 with Fe and Hg was clearly understood from Job’s
plot. The present work brings additional evidence on the importance of multicomponent reactions which
could lead to the development of fluorescence chemosensor in one step for the selective detection of bio-
logically important metal ions.
Keywords:
Fluorescence chemosensor
Molecular switch
Quenching
Ó 2012 Elsevier Ltd. All rights reserved.
Aminopyridine
The development of new fluorescence chemosensor for sensi-
tive and selective detection of biologically important heavy and
transition metal ions has attracted a great attention in recent years.
In the last few decades a number of small molecule based fluores-
cence chemosensors have been developed, and reported in the lit-
CHO
CN
CN
CH COCH , NH OAc
N
3
3
4
+
Benzene, reflux, 4 h, 45%
1
erature. However, the main drawback of most of these developed
H C
N
NH2
3
sensors is their multistep chemical synthesis. Therefore, the one
step synthesized fluorescence chemosensors using common chem-
icals are highly desirable.
1
Scheme 1. One step synthesis of 2-amino-6-methyl-4-phenyl-nicotinonitrile (1).
The promising biological responses of 2-amino-3-cyanopyridine
derivatives have made them an important class of substituted N-
heterocyles. For example, they have been found to be IKK-b and
Iron is one of the most abundant metals in the human body and
many biological events are regulated by it. The iron concentration
2
7
HIV-1 integrase inhibitors, A2A adenosine receptor antagonists,
antiviral, and antimicrobial.3 Apart from their potential biological
applications they have widely been used as important building
blocks toward the syntheses of nitrogen heterocycles.4 Recently,
these pyridine derivatives have been used as material precursors
is an important factor in human health because a higher concentra-
tion may induce disorders like Alzheimer’s, Parkinson’s, and other
8
various diseases. On the other hand Hg and its derivatives possess
a high degree of toxicity, and as consequences the mercury inhala-
9
tion or accumulation may cause serious health problem. Therefore
5
for the production of functional paper sheets. Due to their numer-
the development of suitable and cost-effective methods/tech-
niques for the efficient detection of mercury, and iron is always
desirable. A number of small molecule-based fluorescence chemo-
ous applications in various fields a number of synthetic methods
6
have been developed over the years for their easy preparation.
In this Letter we report a new application of one aminopyridine
derivative 2-amino-6-methyl-4-phenyl-nicotinonitrile 1 (Scheme 1),
which could be synthesized in one step following a multicomponent
condensation reaction, as a chemosensor for the detection of iron (Fe)
and mercury (Hg) metal ions.
2+
3+
sensors for the easy detection of Hg and Fe have been devel-
oped in recent years10,11, particularly based on switch-off
10c–e,11i–k
mechanism.
Although enough efforts have been devoted to study the chemi-
cal, spectral, and biological properties of various 2-amino-3-cyano-
pyridine derivatives, to the best of our knowledge there is no report
in the literature dealing with their use as metal selective fluores-
cence chemosensor. In comparison to various traditional and te-
dious analytical methods, optical based fluorescence, absorption
measurements show very promising toward the selective detection
⇑
Corresponding authors. Tel.: +91 1905 237917; fax: +91 1905 237924 (C.K.N);
tel.: +91 1905 237926; fax: +91 1905 237924 (S.G.).
E-mail addresses: chayan@iitmandi.ac.in (C.K. Nandi), subrata@iitmandi.ac.in (S.
Ghosh).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.02.094

R. R. Koner et al. / Tetrahedron Letters 53 (2012) 2302–2307
2303
of very low concentration of metal ions.1 Either enhancement or
ganic fluorophores by opening
a
non-radiative deactivation
2+
reduction of fluorescence/absorption makes it easy for the quantita-
tive detection of a particular metal ion over several other ions. Our
results showed that 2-amino-6-methyl-4-phenyl-nicotinonitrile 1
channel. However, the quenching mechanism of Hg is likely
due to the heavy metal ion effect, which in principle participates
in spin spin coupling. There was no evidence of any longer wave-
length bands associated with the exciplex formation. This should
3
+
2+
can selectively detect both Fe and Hg over a wide range of metal
ions, and also can distinguish Fe3 over Hg ions by both UV and
+
2+
be noted that 1-Fe complex was associated with more non-
3+
fluorescence data.
The pyridine derivative 2-amino-6-methyl-4-phenyl-nicotino-
nitrile 1 was synthesized following the literature reported one step
synthetic procedure which has been outlined in Scheme 1. The
product was characterized by common spectroscopic techniques,
and the spectral data were in agreement with the reported data.
The compound was column purified in order to get analytical grade
product. The compound purity was determined using HPLC, and
was found to be more than 97% pure.
radiative decay channels which in turn led to the fluorescence
2
+
quenching in a greater extent than 1-Hg complex. This was pos-
3+
sibly due to the different types of binding mechanism of Fe and
6
g
2+
Hg with 1. While the quantum yield of pure 1 was found to be
2 4
0.15 (0.5 M H SO solution of quinine was used as standard), the
3
+
2+
quantum yields of 1-Fe and 1- Hg were calculated as 0.037
and 0.10, respectively. These results also indicated a substantial
3+
2+
quenching of fluorescence of 1 in the presence of Fe /Hg , and
3
+
2+
also the stronger quenching effect of Fe in comparison to Hg
.
The selectivity and sensitivity of the compound 1 against differ-
ent metal ions were detected by UV–vis absorption and fluores-
cence measurements. Figure 1a shows the UV–vis Spectra of
compound 1 in the presence of different metal ions. The UV–Vis
To determine the quantitative sensitivity range, and to get more
3
+
2+
information on binding mechanism of 1 toward Fe /Hg spectro-
metric titration experiments were performed in the presence of
these two ions. Figure 2 shows the gradual change in fluorescence
À4
3+
2+
spectra of 1 in methanol solution (1 Â 10 M) showed two peaks
intensity of 1 upon progressive addition of Fe /Hg in various
3
+
at 246 and 335 nm (molar extinction coefficient: 2.368 Â
concentration ranges. Addition of 6 equiv of Fe showed quench-
ing close to 100% (Fig 2a) with 6 nm red shift. Four nanometer
1
04 M cm and 7.86 Â 10 M cm respectively). These bands
À1
À1
3
À1
À1
⁄
3+
may be assigned to the electronic transition from
p
to
p
of the
red shift was also observed during UV titration of 1 with Fe (Sup-
aromatic ring. Addition of 2 equiv of Fe3 led to increase in the
+
plementary data, Fig. S1a). These data probably suggested Photoin-
duced Electron Transfer (PET). PET sensors usually exhibit little or
absorption intensity both in 246 and 335 nm (molar extinction
4
À1
À1
4
À1
À1
12
coefficient: 3.064 Â 10 M cm
,
and 1.344 Â 10 M cm
,
no spectral shift with increase or decrease in emission intensity.
respectively), which indicated the interaction between 1 and the
On the other hand, addition of 10 equiv or more of Hg2+ showed
70% fluorescence quenching (Fig. 2b) with approximately 2 nm
red shift. The UV titration data (Supplementary data, Fig. S1b) sug-
gested an 8 nm red shift with a isobastic point at 345 nm, which
probably also suggested PET with different type of binding for
Fe ion. Further, the addition of two equivalents of Hg2+ led to a
3+
decrease in absorption intensity (molar extinction coefficient:
4
À1
À1
3
À1
À1
1
.448 Â 10 M cm
and 4.69 Â 10 M cm ). In addition to
that, there was a little red shift of about 8 nm in the absorption
band. These data seemed to indicate different types of binding
2
+
Hg complex. Further, from the spectrometric titration data it
seemed the presence of only dynamic quenching in case of interac-
3+
2+
between compound 1 and Fe /Hg . These spectral data could be
used to discriminate Fe3 over Hg . Addition of other metal ions
+
2+
tion of 1 with Fe , however, the Stern-Volmer plot (Fig. 3a) for Fe
complex showed little upward curvature. This probably
suggested not only dynamic but also the involvement of static
3+
3+
showed no significant changes in absorption intensity of 1 indicat-
a
ing its high sensing capability toward Fe3 /Hg
+
2+
.
1
3
The selectivity of 1 was also investigated by measuring the fluo-
rescence emission spectra against different metal ions in methanol
solution. Figure 1b shows clearly a very little change in fluores-
cence intensity resulted by the addition of different metal ions ex-
quenching.
Considering both static and dynamic quenching,
we further fit the Stern-Volmer plot using the equations (I
0
/
2
I = (1 + K
(K + K ) + K
fit. While the intercept gave the value of K
D
[Q])(1 + K
S
[Q]) = (K
D
+ K
[Q]. Plot of [I
/IÀ1]1/[Q] vs [Q] showed a linear
+ K , the slope gave
KS. Solving the above two equations we obtained the value of
S
)[Q] + K
D
K
S
[Q] or [I
0
/I À 1]1/Q =
1
3
D
S
D
K
S
0
3
+
2+
cept in case of Fe and Hg . These data explicitly showed the
selectivity of toward these two particular metal ions
ex = 330 nm and kem = 410 nm). While the addition of two equiv-
D
S
1
K
K
D
3
À1
3
À1
(
k
D
= 1.68 Â 10 M and K = 3.16 Â 10 M . The interaction of 1
S
3
+
2+
alents of Fe ion showed substantial quenching of fluorescence of
1
ing of 55%. The quenching caused by Fe can be explained by the
paramagnetic nature of Fe3 transition metal ion which easily par-
ticipates in energy transfer or electron transfer processes with or-
with Hg probably involved only static quenching as major part
of the fluorescence quenching was due to the decrease in absorp-
tion intensity in the ground state (Fig. 1a). Further, the Stern-Vol-
2+
upto 81%, the addition of same amount of Hg showed a quench-
3+
+
2+
mer plot for 1-Hg complex using the simple model of static
0 0
quenching I /I = 1 + Ksv[Q] showed a linear fit [I stands for initial
À4
Figure 1. (a) Absorption spectra of 1 (1 Â 10 M) in methanol solution upon addition of 2 equiv of various metal ions. (b) Fluorescence spectra of 1, upon addition of 2 equiv
of various metal ions (kex = 330 nm, kem = 410 nm).

2
304
R. R. Koner et al. / Tetrahedron Letters 53 (2012) 2302–2307
3
+
3+
Figure 2. (a) Fluorescence titration spectra upon addition of Fe ion (0.0–6.0 equiv) to a solution of 1. Inset: Ratiometric curve as a function of Fe concentration. (b)
2
+
2+
Fluorescence titration spectra upon addition of Hg ion (0.0–10.0 equiv) to a solution of 1. Inset: Ratiometric curve as a function of Hg concentration.
Figure 3. Stern-Volmer plot for 1 in the presence of (a) Fe3+, and (b) Hg2+
.
Figure 4. Job’s plot for determination of the stoichiometry of (a) 1-Fe3+, and (b) 1-Hg2+
.
intensity, I indicates final intensity after addition of metal, Q is the
quencher concentration and Ksv is the static Stern-Volmer con-
from Benesi-Hildebrand equation (Supplementary data),15
3
À1
3
À1
2.66 Â 10 M
and 1.02 Â 10 M
,
respectively (Fig. S2,
1
4
2+
3+
2+
stant] (Fig. 3b). The rate constant for Hg complex calculated
Supplementary data). The stoichiometry of 1-Fe /Hg complexes
3
À1
16
from the Stern-Volmer plot was 2.89 Â 10 M . Further, the quan-
was determined using Job’s plot (Fig. 4a and b), which indicated
titative binding constants for Fe3 and Hg
+
2+
were obtained
the formation of 1:1 complexes.

R. R. Koner et al. / Tetrahedron Letters 53 (2012) 2302–2307
2305
Figure 5. Competitive experiments towards the fluorescence quenching effect of Fe3+/Hg2+ (2 equiv) in presence of a large number of other cations (10 equiv) [except for Co3+
(
4 equiv), higher equivalents of which made the whole solution turbid].
was clear that other ions’ interference was negligibly small during
3
+
2+
the detection of Fe and Hg . Further, the data showed excellent
3
+
2+
selectivity for Fe over Hg . These results further suggested that 1
3
+
could be used as a chemosensor for Fe over a wide range of cat-
2
+
ions including Hg
.
We then investigated the reversible binding nature of the pres-
3
+
ent sensor 1. While the addition of 2 equiv of Fe to a methanolic
solution of 1 resulted more than 80% quenching of fluorescence,
upon further addition of an excess amount (500 equiv) of strong
À
coordinating fluoride anions (F ) to this methanolic solution of
3
+
1
-Fe the fluorescence intensity of compound 1 was regenerated
(
Fig. 6). This happened possibly due to the decomplexation of [1-
3
+
nÀ
y
Fe] and formation of [FeF
]
. Interestingly, further addition of
3
+
another 2 equiv of Fe to the same solution resulted ꢀ70% fluores-
3+
cence quenching indicating the regeneration of [1-Fe] species.
For further detailed information on the complexation of 1 with
Fe3+ and Hg we performed H NMR experiments (Fig. 7). While
2+
1
the NH
2
protons of 1 in absence of any metal ions showed a sharp
1
signal in H NMR at 6.82 ppm, we observed a broad signal for NH
protons at 7.01 ppm in the presence of Fe , and a very weak broad
signal at 7.10 ppm in the presence of Hg . These changes in the nat-
ure of signals of NH protons in the presence of iron and mercury
could be due to the coordination of NH functionality with metal
2
3
+
2
+
Figure 6. Fluorescence titration profile of 1-Fe3+ complex in presence of NaF.
2
2
ions during complexation. This fact was also supported by the theo-
To establish the selectivity of 1 toward Fe3+/Hg over a range of
2+
retical calculations performed for the compound 1 both in the ab-
+
+
+
2+
2+
3+
various metallic and non-metallic cations (Na , Li , K , Ca , Mg
,
sence and the presence of Fe ion to understand the binding
2
+
+
2+
2+
2+
2+
2+
3+
3+
+, and Pb
2+
3+
Cd , Ag , Co , Ni , Mn , Zn , Cu , Co , Al , NH
4
)
nature of the compound 1 with Fe . All the calculations were per-
we carried out the competitive recognition studies where the other
cations were used in higher concentrations (Fig. 5). From the bar
diagram, one could easily understand that the effects on emission
intensity of 1 upon the addition of higher concentrations of various
formed at B3LYP level of theory using 6-31G basis set. The geome-
tries were optimized without any symmetry constrain. The
optimized geometry for both compound 1 and its Fe complex
3+
(Fig. 8) showed that pyridine nitrogen and partially amine nitrogen
cations were almost negligible except for Fe3 /Hg . Therefore, it
+
2+
3+
were mainly responsible for the binding of Fe ion. Thermal proper-
Figure 7. Partial 1H NMR spectra of 1, 1-Fe3+ and 1-Hg2+
.

2
306
R. R. Koner et al. / Tetrahedron Letters 53 (2012) 2302–2307
Figure 8. Optimized structure of aminopyridine derivative 1, and 1-Fe3+ complex.
ties of 1 and its complexes with Fe3+ and Hg threw some light on
2+
fellowship. We thankfully acknowledge Dr. Prasenjit Pandey for
his help during theoretical studies. We are thankful to the Director,
IIT Mandi for research facilities. The reviewers are thankfully
acknowledged for their valuable comments.
the complexation affinity of 1 with Fe3 and Hg . Thermogravimet-
ric analysis (at a heating rate of 10 °C/min under nitrogen atmo-
sphere) curves of these three different entities showed entirely
different degradation behaviors. While compound 1 had only one
starting thermal decomposition temperature and showed one-stage
thermal decomposition (182 °C), both the complexes decomposed
thermally in a two-stage process (Figs. S3, S4 and S5, Supplementary
data). From these experimental results it seemed that due to the
+
2+
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.02.094.
3
+
2+
formation of 1-Fe /Hg complexes the thermal property of 1 was
changed. Finally, and as an important proof toward the formation
References and notes
3
+
2+
of 1-Fe and 1-Hg complexes mass spectrometric characteriza-
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3
)
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]
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3
+
2+
3+
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Fe /Hg ions. The Fe /Hg sensing by 1 followed a fluorescence
switch-off mechanism. The sensing selectivity and sensitivity of
3
+
2+
this molecule toward Fe /Hg ions were established by a number
of spectroscopy-based experiments. It is worth mentioning that
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