New calix[4]arene based oxalylamido receptors for recognition of copper(II)

Article abstract of DOI:10.1016/j.tetlet.2013.02.034

New calix[4]arene derivatives with oxalylamido loops on their upper and lower rim (7, 8) have been designed and synthesized. It has been determined that molecular receptor 8 is more efficient than 7 for recognition of copper ions in preference to other me

Full text of DOI:10.1016/j.tetlet.2013.02.034

Tetrahedron Letters 54 (2013) 2766–2769
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Tetrahedron Letters
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New calix[4]arene based oxalylamido receptors for recognition of copper(II)
⇑
Har Mohindra Chawla , Preeti Goel, Richa Shukla
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 calix[4]arene derivatives with oxalylamido loops on their upper and lower rim (7, 8) have been
designed and synthesized. It has been determined that molecular receptor 8 is more efficient than 7
for recognition of copper ions in preference to other metal ions through distinct ‘naked eye’ color change
and a significant change in absorption spectra and fluorescence characteristics. The reported work paves
the way for development of novel sensor materials for ubiquitous ions like copper at low concentrations.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 28 October 2012
Revised 11 February 2013
Accepted 13 February 2013
Available online 20 February 2013
Keywords:
Calix[4]arenes
Oxalylamido looping
Recognition
Fluorescence
Color change
Calix[4]arenes represent one of the most widely employed
molecular scaffolds for applications in ionic and molecular recogni-
tion.1 Selective ionic and molecular sensing through colorimetric
and change in fluorescence intensity have received considerable
attention from the scientific community due to comparative ease
of such operations and high selectivity and sensitivity.2,3 For in-
stance, while the former technique is useful to obtain ‘use and
throw type’ indicator strips,4 the latter is used to measure much
low concentrations present in biological samples.
We report herein the synthesis and evaluation of new oxalyl-
amidocalix[4]arene derivatives with loops at their upper and the
lower rim for ubiquitous ion recognition such as that of copper
ions. These ions are essential at low concentrations for sustenance
of important biological processes but are extremely toxic when
present in higher concentrations.5
Most sensors developed so far for detection of metal ions show
only fluorescence changes.6 Sensors based on both naked eye detec-
tion and fluorescence changes are rare especially the ones which
show specific selectivity toward a target metal ion(s) over other
competing metal ions with high efficiency in the spectral visible
region. There is an urgent demand for the development of novel fluo-
rescent chemosensors with improved efficiency. The advantage
associated with the designed molecular receptor being reported
here is that it acts as a dual fluorescence and visible light sensing
probe. It has a large Stoke shift, induces a color change visible to
the naked eye, has high binding constant, and emits in the visible re-
gion to promote least interference from background emissions.7
Calixarenes are known to undergo rapid conformational tran-
formations.8 When the target application is ionic or molecular
recognition, it is essential that the designed molecular receptor
possesses a judicious balance of rigidity and flexibility to interact
with the target ion or a molecule. Since calix[4]arene cavity is
not large enough to accommodate ions and molecules, the calixa-
rene macrocycle usually provides a rigid support system in which
the recognition elements could be incorporated through function-
alization at their upper or the lower rim.9 In this Letter we describe
our attempts at functionalization of calix[4]arene macrocycle to
provide oxalylamidocalix[4]arene derivatives which have shown
an excellent promise to develop molecular receptors for copper
ions in preference to many other related ions when present alone
or in mixtures without loss of selectivity.
A survey of the literature indicates that hydrazine derived
Schiff’s bases are useful for both colorimetric and fluorometric
metal ion detection.10 These two properties prompted us to take
up the design and synthesis of molecular receptors 7–8 which
was accomplished by a series of reactions given in Scheme 1.11–14
Diethyl o-phenylenedioxamate11 required for the designed
molecular receptors was synthesized by stirring the solution of
o-phenylenediamine with ethyl oxalyl chloride and Et3N in dry
DCM. This was further reacted with hydrazine hydrate in ethanol
to give 1.11 Reaction of bis-formyl derivative of calix[4]arene (5
and 6) with 1 in the presence of glacial acetic acid in ethanol
yielded products which were further washed with methanol to
give 7 and 8 in 82% and 75% yields, respectively.
The synthesized compounds were characterized by 1H NMR, 13
C
NMR, IR, and HRMS (SI, Fig. 1). For example, 8 showed a >C@N– sig-
nal at 1600 cmÀ1 in IR and a sharp pair of doublets at d 3.52 and d
4.24 in the 1H NMR spectrum which could be attributed to axial
⇑
Corresponding author. Tel.: +91 11 26591 517; fax: +91 11 26581 102.
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.2013.02.034

H. M. Chawla et al. / Tetrahedron Letters 54 (2013) 2766–2769
2767
O
O
O
O
NH2
NH2
O
NH
OEt
NH
NHNH2
OEt
(i)
(ii)
Cl
NH
O
OEt
O
NH
O
NHNH2
O
O
(1)
(vi)
(iii)
OH
OH
O
O
OH
OH
O
O
OH
OH
OH
OH
O
O
(4)
(2)
(3)
O
O
Br
Br
(iv)
(vii)
CHO
CHO
OH
OH
O
O
OH
O
OH
o
O
O
O
O
O
O
(6)
(v)
(5)
CHO
CHO
(v)
O
O
HN
NH
O
O
O
O
O
O
H
(H2C)3
H
(CH2)3
O
HN
NH
N
O
N
C
H
C
H
N
N
O
O
O
O
NH
HN
OH
O
OH
o
O
O
NH
HN
O
O
(8)
(7)
Scheme 1. Synthesis of novel calixarene derivatives. Reagents and conditions: (i) Et3N, anhyd DCM, 0 °C, N2 atm; (ii) NH2NH2Á2H2O, ethanol, reflux; (iii) 1,3-dibromopropane,
K2CO3, reflux; (iv) p-hydroxy-benzaldehyde, K2CO3, reflux; (v) (1),11 acetic acid, ethanol reflux; (vi) ethyl bromoacetate, K2CO3, reflux; (vii) HMTA, TFA, reflux.
and equatorial protons respectively. A distinct signal at d 30.83 for
the methylene carbons in its 13C NMR spectrum indicated a sym-
metric cone conformation for the calix[4]arene scaffold. It was fur-
ther confirmed by observing two D2O exchangeable singlets at d
10.70 and d 12.06 for –NH and –OH protons, respectively. The
azo-methine (–N@CH) proton was observed as a non-deuterable
singlet at d 8.44 (Scheme 1).
The cation binding ability of the synthesized receptors 7 and 8
was first investigated by examining their UV–Vis spectrum in dry
THF solution in the presence of various metal ions (Na+, Li+, K+, Cs+,
Ag+, Ca2+, Mn2+, Zn2+, Co2+, Cd2+, Pb2+, Hg2+, Fe3+, Ni2+, and Cu2+) as
their perchlorate salts. While selectivity observed through 7 was
limiting (see later discussion and Supplementary information), 8
showed a strong absorption band at 327 nm which on addition of

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H. M. Chawla et al. / Tetrahedron Letters 54 (2013) 2766–2769
a solution of various metal ions exhibited negligible shift for Na+, Li+,
K+, Cs+, Ag+, Ca2+, Mn2+, Zn2+, Co2+, Cd2+, Pb2+, Hg2+, Fe3+, and a little
shift for Ni2+. However, a significant change in the absorption profile
of 8 was observed on addition of Cu2+ (SI, Fig. 2).
Upon gradual addition of Cu2+ ion to receptor 8, the absorption
at 327 nm gradually decreased with the concurrent increase in the
intensity in the new absorption band centered at 345 nm with
appearance of an isosbestic point at 350 nm (Fig. 1) accompanied
by a noticeable color change from colorless to light yellow. Thus,
it could be used as a naked eye visible sensor for Cu2+. Job’s contin-
uous variation plot was deduced to determine the stoichiometry of
the interaction between the Cu2+ ion and receptor 8. Analysis of the
data obtained from Job’s plot revealed the formation of a 1:1
molecular complex (Fig. 2).
Sensitivity and selectivity of the synthesized receptor 8 were
evaluated by observing changes in their fluorescence emission
spectra in THF solution. The fluorescence emission spectrum of 8
was recorded from 350 to 800 nm by exciting it at 327 nm when
the emission maximum was observed at 443 nm. From this data,
we inferred that it could be employed as a fluorescence sensor
which required a thorough study of 8 through fluorescence
spectroscopy in the presence of various ions. The spectral measure-
ments were accomplished in the presence of competing metal ions
in THF solution to evaluate the utility of synthesized molecular
receptors to function as fluorescence based cation sensors. Figure 3
shows a relative change in the fluorescence intensity of molecular
receptor 8 upon addition of various metal ions. It has been
observed from the data given in Figure 3 that while other metal
ions do not confer significant change in the emission spectra of
the receptor 8, addition of Cu2+ induces a remarkable quenching
on its emission band. The observed quenching might be due to
electron transfer in the excited state as reported earlier.15
Figure 2. Job’s plot of Cu2+ complex formation. {[8]/[8]+[Cu2+] is the mole fraction
of ligand 8}.
To analyze the mode of interaction between Cu2+ and 8, fluores-
cence titration was performed by using increasing concentration of
Cu2+ (Fig. 4). A plot of F0/F versus [Cu2+] was found to be linear
thereby confirming the interaction to be of 1:1 type interaction (in-
set Fig. 3). These data sets were further confirmed by mass spectro-
metric analysis. A peak at m/z 1170.5413 in ESI-MS data showed
the formation of 1:1 complex [8+Cu2++ClO4]+ (SI, Fig. 1). Moreover,
the quenching of fluorescence intensity occurring in this case
seems to be static quenching15 which could be inferred from a
careful examination of the absorption spectra of synthesized
receptor 8. The detection limit16 calculated by using the semi-log-
arithmic plot of (F0ÀF)/F0 (where F0 and F are emission intensities
at 443 nm) against log [Cu2+] was found to be 6.02 Â 10À6 M (SI,
Fig. 3). Using the fluorescence titration data, the Stern Volmer
quenching constant15 Ksv of 8–Cu2+ complex in THF solution was
Figure 3. Change in the fluorescence intensity of 8 upon addition of 7.5 equiv of
various metal ions in THF (kexcitation = 327 nm). Inset: a plot of F0/F versus [Cu2+] for
ligand 8.
0.50
0.45
0.40
1.2
0.35
0.30
1.0
0.25
0.20
0.15
0.8
0
20
40
60
2+
80 100 120 140
in µM
Cu
conc
A
0.6
0.4
0.2
240
300
350
400
450
500
550
600
nm
Figure 4. Quenching of fluorescence intensity of 8 (20
of Cu2+ (kexcitation = 327 nm). Inset: shows change in the fluorescence intensity of the
ligand 8 with varying concentrations of Cu2+
lM) in THF in the presence
Figure 1. Change in the UV–Vis spectra of 8 (20
lM) upon addition of 7.5 equiv of
Cu2+ in THF. Inset: changes in the absorption as a function of Cu2+ added.
.

H. M. Chawla et al. / Tetrahedron Letters 54 (2013) 2766–2769
2769
References and notes
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Figure 5. Comparative study of molecular receptor 8 in THF of peak at 443 nm in
the presence of 7.5 equiv of various metal ions + 7.5 equiv of Cu2+ by exciting at
327 nm.
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(b) Gutsche, C. D.; Iqbal, M. Org. Synth. 1990, 68, 234; (c) Gutsche, C. D.; Iqbal,
M.; Steward, D. J. Org. Chem. 1986, 51, 742–745; (d) Chawla, H. M.; Shrivastava,
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Srivastava, B.; Upreti, S. Org. Lett. 2006, 8, 2237–2240.
13. Procedure for the synthesis of 8: To a solution of bis formyl calix[4]arene (6) in
ethanol was added 1 and a catalytic amount of acetic acid. The reaction
mixture was refluxed for 24 h. After completion of the reaction (TLC), the
precipitate was filtered and washed with water. The structure of 4 was
confirmed by 1H NMR and 13C NMR spectra as well as ESI MS analysis.
14. Analytical data for 8: White solid; melting point: 340 °C (decomposed); UV
(kmax, THF): 327 nm. IR (KBr pellet, cmÀ1): 3445, 1682, 1600, 756; 1H NMR
(300 MHz, DMSO-d6, d in ppm): 12.065 (s, 2H, NH, D2O exchangeable), 10.704
(s, 2H, NH, D2O exchangeable), 8.440 (s, 2H, @CH), 8.12 (s, 2H, OH, D2O
exchangeable), 7.628(d, 2H, ArH1), 7.520(s, 4H, ArH), 7.311 (d, 2H, ArH1), 6.916
(s, 4H, ArH), 4.754 (s, 4H, –OCH2), 4.252–4.229 (m, 8H, –CH2+–OCH2CH3), 3.517
(dd, 4H, CH2), 1.266 (t, 6H, –CH3), 0.999 (s, 18H, –C(CH3)3); 13C NMR (75 MHz,
DMSO-d6, d in ppm): 168.89, 158.55, 155.58, 155.14151.78, 150.49, 146.75,
131.80, 129.94, 128.79, 128.01, 126.14, 125.71, 124.69, 71.90, 60.84, 33.69,
30.93, 30.83, 13.94; HRMS (ESI-MS) m/z: calcd 1031.4161, found 1031.4173
(M+Na+).
calculated to be 3.92 Â 104 MÀ1 (Inset Fig. 3). To calculate associa-
tion constant,17 a plot of log (F0ÀF/F) versus log [Cu2+] yielded the
value of K as 1.655 Â 106 MÀ1 which represents efficient binding of
Cu2+ and 8 (SI, Fig. 10).
Under identical conditions, addition of Cu2+ to 7 resulted in 80%
quenching of the fluorescence intensity of the synthesized receptor
(SI, Fig. 5) with less Ksv and binding constant (1.981 Â 104 MÀ1) as
compared to 8 (SI, Figs. 6 and 11) revealing superiority of 8 over 7
for binding Cu2+
.
The practical application of synthesized receptor 8 as fluores-
cence ‘turn off’ probe for Cu2+ was examined by recording its
fluorescence response to Cu2+ in the presence of other competing
ions. As shown in Figure 5, most of the competing ions such as
Co2+, Hg2+, Zn2+, Ni2+, Cd2+, Mn2+, Fe3+, Ag+, exhibited negligible
interference in the detection of Cu2+ in the presence of other metal
ions. Thus 8 can be used for selective detection of Cu2+ even in the
presence of these competing ions. The same selectivity was deter-
mined by UV–Vis spectroscopic studies (SI, Fig. 8).
The binding of Cu2+ with receptor 8 could not be monitored
through NMR titrations owing to the paramagnetic nature of
copper which leads to the broadening of peaks.
In conclusion, we have designed, synthesized and evaluated
novel calix[4]arene based oxalylamide receptors (7, 8) as chemo-
sensors for Cu2+ ions through fluorescence and chromogenic
probes. The detection has been found to be selective in the micro-
molar range without interference from other competing ions in
coexisting systems. It appears that upper rim oxalylamido looping
of the calixarene scaffold is advantageous for Cu2+ recognition.
Acknowledgments
P.G. and R.S. thank UGC and CSIR, India for a research fellow-
ship. Financial assistance from DST, MoFPI, MoEF, and MoRD is
gratefully acknowledged.
15. Lakowicz, J. R. Principles of Fluorescence Spectroscopy, 3rd ed.; Kluwer Academics/
Plenum: New York, 2006.
16. Mashraqui, S. H.; Ghorpade, S. 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.2013.02.034.
17. (a) Mishra, B.; Barik, A.; Priyadarsini, K. I.; Mohan, H. J. Chem. Sci. 2005, 117, 641–
647; (b) Ding, J.; Yuan, L.; Gao, L.; Chen, J. J. Lumin. 2012, 132, 1987–1993.