New chromogenic bis(isatin hydrazonyl)calix[4]arenes for dual recognition of fluoride and silver ions

Article abstract of DOI:10.1016/j.tetlet.2013.01.038

New calixarene based dual chromogenic receptors bearing isatin hydrazone units have been synthesized and evaluated for their ion recognition potential. The synthesized molecular receptors can effectively and selectively recognize fluoride and silver ions through visible color changes and pronounced bathochromic shifts in their UV-visible spectra. NMR titration data further support the preliminary conclusions.

Full text of DOI:10.1016/j.tetlet.2013.01.038

Tetrahedron Letters 54 (2013) 1794–1797
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
New chromogenic bis(isatin hydrazonyl)calix[4]arenes for dual recognition
of fluoride and silver ions
⇑
Har Mohindra Chawla , Tanu Gupta
Department of Chemistry, Indian Institute of Technology Delhi, Hauz Khas, New Delhi 110016, India
a r t i c l e i n f o
a b s t r a c t
Article history:
New calixarene based dual chromogenic receptors bearing isatin hydrazone units have been synthesized
and evaluated for their ion recognition potential. The synthesized molecular receptors can effectively and
selectively recognize fluoride and silver ions through visible color changes and pronounced bathochromic
shifts in their UV–visible spectra. NMR titration data further support the preliminary conclusions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 24 October 2012
Revised 5 January 2013
Accepted 10 January 2013
Available online 21 January 2013
Keywords:
Calixarenes
Ditopic receptors
Ionic recognition
Dual colorimetric probe
Silver and fluoride
The design and synthesis of ditopic receptors for selective bind-
ing of both cationic and anionic species have become exciting do-
mains of supramolecular chemistry.1,2 Macrocyclic compounds
such as calixarenes have been employed extensively for this pur-
pose by various workers.3 These versatile ditopic receptors may
possess the cation and anion binding sites on the opposite rims4
of calixarene structure or together on one5,6 side of the calixarene
scaffold. At the same time, chromogenic receptors that can under-
go a vivid color change upon guest interaction are preferred and
constitute an emanating territory of interest.7–9 Indeed, colorimet-
ric sensor molecules based on the formation of hydrogen bonding
or anion promoted deprotonation of the binding moiety have been
shown to be very efficient and highly sensitive.10–12
Amongst the range of commonly occurring anions, fluoride is of
special interest due to its proven role in prevention of dental car-
ies13,14 and treatment of osteoporosis.15 On the other hand,
amongst important metal ions, silver ion has attracted consider-
able attention16 during last few years due to its widespread appli-
cations in the organic synthesis, electronics, photography, and
imaging industry. However, unlike other transition metal ions
there are not many reports on silver ion receptors, probably due
to the fact that silver ion does not show a pronounced coordination
ability. This in turn makes discrimination of silver from other
chemically related cations more difficult.
In this Letter we report the synthesis and evaluation of two new
ditopic calix[4]arene based molecular receptors (6–7) bearing isat-
in hydrazone units in their molecular scaffold for dual colorimetric
recognition of Ag+ and FÀ. The synthesis of bis(isatin hydrazo-
nyl)calix[4]arenes involved the formation of a schiff base between
calixarene derivative 5 and isatin hydrazones 2a and 2b. The choice
of isatin hydrazone as chromogenic sensing molecule was driven
by the fact that as an indole derivative, isatin could not only serve
as an anion sensor based on H-bonding or deprotonation mecha-
nism but it could be linked to the calixarene framework to result
in an extended conjugated system to function as a color reporting
group. Strong coordination ability of schiff base moiety in the de-
signed receptors further augments the plausibility of their use in
metal ion recognition. To the best of our knowledge this is the first
report on an isatin functionalized calixarene based molecular
receptor for target applications. The designed receptors feature
cation binding sites (in the form of hydrazone nitrogens and amide
oxygens) and anion binding sites (in the form of amide NH and
phenolic OH groups) which facilitate the dual ionic recognition.
Isatin hydrazones 2a and 2b were synthesized by reaction of
corresponding isatin with hydrazine hydrate in ethanol. The syn-
thesis of receptors 6 and 7 is outlined in Scheme 1. N-alkylation
of isatin was carried out by reaction of isatin with propyl bromide
and potassium carbonate in DMF. The structures of compounds 6
and 7 were confirmed from their spectroscopic17,18 and analytical
data. The 1H NMR spectrum of 6 showed two doublets (4H each)
for calixarene methylene bridge protons, two singlets (4H each)
corresponding to calixarene aryl ring protons, two doublets (2H
each) and two triplets (2H each) corresponding to isatin aryl ring
⇑
Corresponding author. Tel.: +91 11 265 91517; fax: +91 11 265 81102.
E-mail addresses: hmchawla@chemistry.iitd.ernet.in, hmchawla@chemistry.iitd.
ac.in (H.M. Chawla).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.038

H. M. Chawla, T. Gupta / Tetrahedron Letters 54 (2013) 1794–1797
1795
NNH2
1.0
0.8
0.6
0.4
0.2
0.0
O
NH2NH2.2H2O
Ethanol/reflux
O
O
N
R
N
R
2a, R=H
2b, R=CH2CH2CH3
(i)
OH
OH
O
OH
OH
OH
O
HO
4
3
O
O
O
O
300
350
400
450
500
550
NR RN
Wavelength/nm
(ii
)
O
Figure 1. Variation in absorption spectrum of 6 (30 l
M) upon titration with Ag+ (0–
1.5 equiv). Inset: the color change of 6 upon silver addition.
O
N
N
N
N
CHO
CHO
dark yellow while no other cation gave colorimetric response.
Moreover, the absorbance at 410 nm got saturated in the presence
of 1 equiv of silver ions, suggesting the formation of a 1:1 complex
between 6 and silver ion, which is in good agreement with 1:1 stoi-
chiometry for the silver complex, as confirmed by the Job’s plot
analysis (Supplementary data, Fig. S9). The corresponding binding
constant on the basis of Benesi–Hildebrand plot19 was calculated
to be 8.4 Â 103 MÀ1 (Supplementary data, Fig. S5).
(iii)
OH
OH
OH
O
OH
5
O
O
O
6-7
O
O
O
O
O
O
O
O
6 R=H
7 R=CH2CH2CH3
In order to understand the binding mode of 6 with Ag+ ion, 1H
NMR titrations were performed in DMSO-d6. Upon addition of
1 equiv of silver to the receptor solution (0.01 M), the chemical
Scheme 1. Synthesis of 6 and 7. Reagents and conditions: (i) ethyl bromoacetate,
K2CO3, CH3CN, reflux; (ii) hexamethylenetetramine, trifluoroacetic acid, reflux; (iii)
isatin hydrazone, ethanol, reflux.
shift of amide protons exhibited
0.23 ppm from d 10.795 ppm (Fig. 3). Similarly azo-methine pro-
tons (HC@N) showed a downfield shift by d 0.18 ppm. These
a downfield shift by Dd
D
protons, and two singlets (2H each) corresponding to isatin NH and
calixarene OH, while 7 showed all these peaks except for the peak
of isatin NH. This was further confirmed by HRMS analysis which
showed peaks at 1073.4369 and 1157.5328 corresponding to 6
and 7, respectively. Additionally, distinct signals at 30.7 and 31.1
for 6 and 7, respectively in 13C NMR spectra confirm symmetric
cone conformation for 6 and 7.
In order to get an insight into the spectroscopic behavior of de-
signed receptors toward cations and anions, UV–visible and 1H
NMR titrations were performed.
spectral changes suggest that silver ion could be bound by hyd-
razonyl nitrogens and amide oxygens of 6.
To ascertain the practical applicability of 6 as a silver selective
sensor, competitive experiments were carried out in THF, where
in absorption spectra of transition metal ion/silver ion coexisted
systems were examined. No significant change in the absorption
value was seen even when other metal ions (1 equiv) were present
along with silver ion in the receptor solution (Fig. 2). Based on the
UV titrations and colorimetric response shown by sensor 6 with
Ag+, it could be inferred that 6 shows a pronounced selectivity
for Ag+ ion over other transition metal cations being tested.
In the absence of external analytes, UV–vis spectrum of 6 and 7
in THF could be characterized by absorption peaks at 373 and
369 nm, respectively, which could be attributed to intramolecular
charge transfer band. The cation binding and sensing ability of
receptor 6 was investigated in detail by following its absorption
spectral changes upon addition of various metal perchlorates. Fig-
ure S3 (Supplementary data) represents the UV–vis absorption
0.16
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
changes upon addition of different transition metal ions (Mn2+
Co2+, Cu2+, Fe2+, Ni2+, Hg2+, Ag+, Cd2+, and Zn2+) to the THF solution
of receptor 6 (30 M). It was found that the UV–vis spectrum of 6
exhibited a considerable red shift ( kmax 37 nm) only in the pres-
,
l
D
ence of silver ions while other tested cations did not produce any
substantial change in the absorption spectrum. Figure S4 (Supple-
mentary data) shows a comparative view when different metal
ions were added in 1.5 equiv amount to the THF solution of 6.
Upon successive addition of silver ion to the solution of receptor
6, the absorption band at 373 nm decreased while a new peak
gradually moving toward longer wavelength and finally reaching
a maximum value at 410 nm appeared. Figure 1 exhibits the UV–
silver + other metal ions
vis spectral changes for receptor 6 (30 lM) on gradual addition
of silver from 0 to 1.5 mol equiv. This change in absorption spectra
was accompanied by a visible color change from pale yellow to
Figure 2. Competitive selectivity and sensitivity of 6 for Ag+ in preference to other
related metal ions. Black bar represents the absorbance of 6 in the presence of Ag+
alone. Gray bar denotes absorbance of Ag+/Mn+ coexisting systems.

1796
H. M. Chawla, T. Gupta / Tetrahedron Letters 54 (2013) 1794–1797
blue. The color change was attributed to the fact that when receptor
binds with fluoride ions, the electron density in the supramolecular
system increases which in turn enhances the charge transfer inter-
actions between electron rich and deficient moieties.
Interestingly, addition of a protic solvent such as water or meth-
anol resulted in disappearance of the observed color of the com-
plex, suggesting that fluoride–calixarene interaction did not
involve covalent bond formation and that H-bonding interactions
are indeed involved. The binding stoichiometry between 6 and
fluoride was determined to be 1:2 (6: FÀ) by Job’s plot analysis
(Supplementary data, Fig. S10). The associated binding constant
calculated by employing modified Benesi–Hildebrand20 equation
is 33 Â 106 MÀ2 (Supplementary data, Fig. S8).
To further evaluate the nature of intermolecular interactions
between 6 and fluoride, 1H NMR spectral changes upon addition
of TBAF to DMSO-d6 solution of 6 (0.01 M) were investigated. The
1H NMR spectrum of 6 showed a singlet at d 8.88 ppm correspond-
ing to phenolic protons and a singlet at d 10.795 ppm correspond-
ing to amide protons. As expected, both NH and OH protons
underwent serious signal broadening followed by disappearance
upon addition of TBAF (Fig. 5). These data further confirmed the
conclusion that both isatin –CONH and calixarene phenolic OH
are involved in the interaction with fluoride as envisaged.
Figure 3. Partial 1H NMR spectra of 6 upon addition of 1 equiv of silver ion.
Having established the ability of 6 to interact with cations, we
investigated the utility of 7 as a cation sensor under identical con-
ditions. Upon titration with silver (0–2 equiv), the absorption spec-
trum of 7 too shifted to a longer wavelength but with an isobestic
point at 401 nm (Supplementary data, Fig. S15). The corresponding
binding constant has been calculated to be 37.5 Â 103 MÀ1
.
To quantitatively study the anion sensing ability of 6 in THF,
UV–vis monitoring was performed by adding a standard solution
of tetrabutylammonium salts of anions. The tested anions included
FÀ, ClÀ, BrÀ, IÀ, HSO4À, and H2PO4À. All the representative anions,
except fluoride produced a negligible change in the absorption
UV–vis titration of 7 with anions under identical conditions re-
vealed the role of isatin NH in anion binding. The absorption spec-
trum of 7 underwent a red shift from 369 to 588 nm (Dkmax
219 nm) upon addition of tetrabutylammonium fluoride(TBAF)
while other anions did not produce any change. Figure S16
(Supplementary data) shows the UV–vis spectral changes of 7 upon
successive addition of fluoride from 0 to 4 equiv. It was determined
that 7 with fully N-substituted isatin hydrazonyl functionality
shows much less significant UV–vis changes than 6. Moreover, 7
in the absence of binding amide group shows comparatively little
color change upon addition of fluoride. For instance, addition of
spectrum of 6 (30 lM) (Supplementary data, Fig. S6). Addition of
fluoride to the receptor solution resulted in an instantaneous
change in the absorption band of receptor accompanied by a visible
color change displaying higher selectivity of 6 toward fluoride over
other commonly occurring anions. It was determined that the UV–
vis spectrum of 6 was red shifted to 593 nm (Dkmax 220 nm) as
fluoride ions came in contact with the receptor solution.
Figure S7 (Supplementary data) shows a comparative view
when different anions were added in 4 equiv amount to a THF solu-
tion of 6. Figure 4 displays the absorption spectral changes for 6
1 equiv of TBAF to a 30 lM solution of 7 in THF results in much
smaller color changes compared to the color changes seen with 6.
The detection limit21 of 6 toward fluoride and silver ions was
obtained from UV–visible titration experiments. The interaction
(30 lM) on gradual addition of fluoride ion from 0 to 4 mol equiv.
of 6 with fluoride could be detected down to at least 4.0
lM, while
While, the original absorption peak at 373 nm got gradually weak-
ened, a new bathochromically shifted peak at 593 nm resulted from
binding of 6 and FÀ. These spectral changes could be attributed to
H-bonding between amide N–H and phenolic O–H of 6 and fluoride
ion followed by deprotonation. The interaction was accompanied
by a color change of receptor solution from pale yellow to dark
with silver the detection limit was determined to be 3.98
lM (Sup-
plementary data, Figs. S11, S12).
To investigate the binding ability of one ion in the presence of
its competing ion, two sets of UV–vis binding studies of 6 and 7
were performed with Ag+ and FÀ ions. When 6ÁAg+ complex was ti-
trated with TBAF (0–10 equiv), it was observed that the red shifted
absorption maxima of 6ÁAg+ complex underwent a blue shift along
with the appearance of a new band around 600 nm. This suggests
that silver ions are sequestered out of the receptor as FÀ binds with
it (Supplementary data, Fig. S17). When 6ÁFÀ was titrated with Ag+,
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
300
400
500
600
700
Wavelength/nm
Figure 4. Variation in the absorption spectra of 6 on titration with tetrabutylam-
monium fluoride (0–4 equiv). Inset: the color change of 6 upon addition of TBAF.
Figure 5. Partial 1H NMR spectra of sensor 6 in the presence of 1 equiv of fluoride
ion.

H. M. Chawla, T. Gupta / Tetrahedron Letters 54 (2013) 1794–1797
1797
it was observed that a band corresponding to 6 and Ag+ complex-
References and notes
ation was formed around 400 nm, but the long wavelength band
corresponding to 6 and FÀ binding did not disappear completely
even after addition of 55 equiv of Ag+ (Supplementary data,
Fig. S18). These observations could be attributed to a stronger
interaction of 6 with FÀ in comparison to that in Ag+ because of
which FÀ is not completely sequestered out of 6. Upon titration
of 7ÁAg+ with FÀ, the absorption maxima of 7ÁAg+ gradually shifted
to smaller wavelength and a new red shifted band developed
around 557 nm instead of 588 nm as seen in the absence of Ag+.
On this basis it was assumed that 7ÁAg+ complex could be involved
in further complexation with FÀ to give a mixed complex. The
spectral change reached its limiting value upon addition of 3 equiv
of FÀ (Supplementary data, Fig. S19). In the reverse experiment,
upon addition of Ag+ into 7ÁFÀ complex, the peak at 557 nm was
observed again, indicating the formation of a mixed complex. How-
ever, when the amount of Ag+ was increased beyond 1 equiv, the
absorbance at 557 nm decreased and the spectra eventually chan-
ged to that of 7ÁAg+ (Supplementary data, Fig. S20).
1. Tumcharern, G.; Tuntulani, T.; Coles, S. J.; Hursthouse, M. B.; Kilburn, J. D. Org.
Lett. 2003, 5, 4971–4974.
2. Webber, P. R. A.; Beer, P. D. Dalton Trans. 2003, 2249–2252.
3. (a) Pelizzi, N.; Casnati, A.; Friggeri, A.; Ungaro, R. J. Chem. Soc., Perkin Trans. 2
1998, 1307–1312; (b) Yang, H.; Song, H.; Zhu, Y.; Yang, S. Tetrahedron Lett.
2012, 53, 2026–2029.
4. Lee, J. W.; Park, S. Y.; Cho, B. K.; Kim, J. S. Tetrahedron Lett. 2007, 48, 2541–2546.
5. Chawla, H. M.; Sahu, S. N.; Shrivastava, R.; Kumar, S. Tetrahedron Lett. 2012, 53,
2244–2247.
6. Chawla, H. M.; Pant, N.; Kumar, S.; Kumar, N.; Black David St, C. Calixarene-
based materials for chemical sensors In Chemical Sensors Fundamentals of
Sensing Materials; Korotcenkov, G., Ed.; Momentum Press: New York, 2010; Vol.
3, p 300.
7. Kim, H. J.; Kim, S. K.; Lee, J. Y.; Kim, J. S. J. Org. Chem. 2006, 71, 6611–6614.
8. Martínez-Máñez, R.; Sancenón, F. Chem. Rev. 2003, 103, 4419–4420.
9. (a) Tsui, Y. K.; Devaraj, S.; Yen, Y. P. Sens. Actuators, B 2012, 161, 510–519; (b)
Chawla, H. M.; Srinivas, K. J. Org. Chem. 1996, 61, 8464–8467.
10. Kumar, M.; Babu, J. N.; Bhalla, V. Talanta 2010, 81, 9–14.
11. Bao, X.; Yu, J.; Zhou, Y. Sens. Actuators, B 2009, 140, 467–472.
12. Sessler, J. L.; Gale, P. A.; Cho, W. S. Anion Receptor Chemistry; Royal Society of
Chemistry: Cambridge, UK, 2006.
13. Mahoney, J. M.; Nawaratna, G. U.; Beatty, A. M.; Duggan, P. J.; Smith, B. D. Inorg.
Chem. 2004, 43, 5902–5907.
In summary, two new bis(isatin hydrazonyl) calix[4]arene
based dual receptors 6 and 7 have been designed and synthesized
for selective detection of fluoride and silver ions. 6 can be utilized
as a visible chemosensor owing to the noticeable color change in
the presence of these ions. 6 could bind Ag+ and FÀ while display-
ing significant bathochromic shifts in UV–vis spectroscopy. While
6 binds Ag+ with 1:1 stoichiometry, it binds FÀ with 1:2 stoichiom-
etry. It interacts with fluoride through amide and phenolic protons
while binding of silver takes place through hydrazonyl nitrogens
and amide oxygens. Moreover, as expected the absence of isatin
NH in 7 interfered with the possible interaction between the recep-
tor and fluoride. Further work to explore utility of isatin hydrazo-
nyl calix[4]arenes is in progress.
14. Kirk, K. L. Biochemistry of the Halogen and Inorganic Halides; Plenum Press: New
York, 1991. p 58.
15. Kleerekoper, M. Endocrinol. Metab. Clin. North Am. 1998, 27, 441.
16. (a) Ni, X. L.; Zeng, X.; Redshaw, C.; Yamato, T. Tetrahedron 2011, 67, 3248–
3253; (b) Ye, J.-H.; Duan, L.; Yan, C.; Zhang, W.; He, W. Tetrahedron Lett. 2012,
53, 593–596.
17. Analytical data for 6: Yield: 72%; Mp: 190–192 °C; UV (kmax, THF):373 nm,
HRMS (ESI-MS) m/z: calcd 1073.4420, found 1073.4369; 1H NMR (300 MHz,
DMSO, d in ppm): 10.795 (s, 2H, NH, D2O exchangeable), 8.88 (s, 2H, OH, D2O
exchangeable), 8.43 (s, 2H), 8.1 (d, 2H), 7.8 (s, 4H), 7.38 (t, 2H), 7.24 (s, 4H), 7.0
(t, 2H), 6.86 (d, 2H), 4.9 (s, 4H), 4.38 (d, 4H), 4.31 (q, 4H), 3.66 (d, 4H), 1.30 (t,
6H),1.12(s,18H); 13C NMR (300 MHz, DMSO, d in ppm) 14.04, 30.782, 34.006,
61.013, 71.904, 110.61, 116.732, 122.256, 124.949, 126.142, 129.107, 129.463,
130.096,
132.481,133.253,144.731,147.529,150.435,156.539,162.79,164.846,169.193.
18. Analytical data for 7: Yield: 65%; Mp: 178–180 °C; UV (kmax,THF): 369 nm,
HRMS (ESI-MS) m/z: calcd 1157.5359, found 1157.5328; 1H NMR (300 MHz,
CDCl3, d in ppm): 8.6 (s, 2H, OH, D2O exchangeable), 8.5 (s, 2H), 8.27 (d, 2H), 7.6
(s, 4H), 7.38 (t, 2H), 7.07 (s, 4H), 6.98 (t, 2H), 6.85 (d, 2H), 4.85 (s, 4H), 4.5 (d,
4H), 4.36 (q, 4H), 3.7 (t, 4H), 3.54 (d, 4H), 1.7 (m, 4H), 1.40 (t, 6H), 1.12 (s,18H),
0.969 (t, 6H); 13C NMR (300 MHz, DMSO, d in ppm) 11.314, 14.152, 20.783,
31.145, 34.156, 41.531, 61.468, 72.151, 108.726, 117.044, 122.650, 125.303,
126.268, 129.348, 130.195, 132.313, 132.605, 132.911, 145.989, 148.358,
150.618, 157.101, 164.665, 169.112.
Acknowledgments
Tanu Gupta thanks CSIR, India for fellowship. Financial
assistance from DST, DBT, MOEF, MRD, and MFPI is gratefully
acknowledged.
19. Benesi, H. A.; Hildebrand, J. H. J. Am. Chem. Soc. 1949, 71, 2703–2707.
20. Shiraishi, Y.; Sumiya, S.; Kohno, Y.; Hirai, T. J. Org. Chem. 2008, 73, 8571–8574.
21. Mashraqui, S. H.; Ghorpade, S.; Tripathi, S.; Britto, S. Tetrahedron Lett. 2012, 53,
765–768.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.038.