Anion sensing using colorimetric amidourea based receptors incorporated into a 1,3-disubstituted calix[4]arene

Article abstract of DOI:10.1016/j.tetlet.2006.10.112

The synthesis of amidourea-based colorimetric anion sensors 1 and 2 and the evaluation of these sensors using anions such as acetate (CH₃ CO₂^-), fluoride (F^-), hydrogen phosphate (H₂ PO₄

Full text of DOI:10.1016/j.tetlet.2006.10.112

Tetrahedron Letters 47 (2006) 9333–9338
Anion sensing using colorimetric amidourea based
receptors incorporated into a 1,3-disubstituted calix[4]arene
Eoin Quinlan,a Susan E. Matthewsb,* and Thorfinnur Gunnlaugssona,*
aSchool of Chemistry, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland
bSchool of Chemical Sciences and Pharmacy, University of East Anglia, Norwich NR4 7TJ, United Kingdom
Received 15 August 2006; revised 10 October 2006; accepted 19 October 2006
Available online 9 November 2006
Abstract—The synthesis of amidourea-based colorimetric anion sensors 1 and 2 and the evaluation of these sensors using anions
such as acetate ðCH3CO2ꢀÞ, fluoride (Fꢀ), hydrogen phosphate ðH2PO4ꢀÞ and hydrogenpyrophosphate (pyr) in DMSO is described.
While 1 has a single amidourea moiety, 2 has two such receptors incorporated into a lower-rim 1,3-disubstituted calix[4]arene scaf-
fold. Whilst both sensors gave rise to red shifts in their absorption spectra upon anion recognition, the sensing of Fꢀ and pyr gave
rise to large changes with concomitant colour changes from yellow to purple, which were visible to the naked eye.
Ó 2006 Published by Elsevier Ltd.
The recognition of anions using luminescent or colori-
metric methods has become an active area of research.1,2
In particular, charged or charge neutral receptors such
as metal based macrocycles,3 amides,4 carbamides,5
ureas6 or thioureas7 have been employed for the selective
recognition of anions in relatively simple structural
motifs.8 Such binding sites have also been incorporated
into structural frameworks such as steroids,9 calixa-
renes10 and polynorbornanes11 giving rise to more pre-
organized anion recognition motifs. Moreover, such
designs can give rise to larger supramolecular assemblies
as demonstrated elegantly by Gale et al.,12 Kruger
et al.13 and Beer et al.14 to name just a few. Anion recep-
tors have also been employed for medicinal purposes
and as biological mimics for the transport of anions or
ion pairs across cell membranes.15
that can hydrogen bond to anions such as acetate, phos-
phate and potentially halides. Furthermore, using 4-
nitrobenzene as part of the receptor enables us to mon-
itor this binding spectroscopically in the visible region.
We have previously used related amidothioures as a part
of naphthalimide based colorimetric sensors.20 Simi-
larly, both Gale et al., using pyrrolylamidoureas,21 and
Jiang et al.22 using N-benzamido-thiourea, have devel-
oped many excellent examples of receptors for anion
recognition. However, to the best of our knowledge, 2
is the first example of an amidourea based 1,3-disubsti-
tuted calix[4]arene based colorimetric sensor for anions.
O
O
OH
O
OH
We are interested in the development of sensors for
anions and have demonstrated such sensing based on
the use of charge neutral photoinduced electron transfer
(PET) sensors16 as well as colorimetric anion sensors
based on the use of internal charge transfer chromo-
phores.17,18 In this letter, we build upon these earlier
successes and present 1, which can also be incorporated
into a preorganized scaffold, such as at the lower-rim
of a 1,3-disubstituted calix[4]arene, for example, 2.19
Our receptors are based on a simple amidourea structure
HN
HN
O
HN
HN
O
O
NH
NH
O
O
O
HN
HN
NH
NO2
NO2
O2N
1
2
The synthesis of 1 was achieved in two steps as shown in
Scheme 1. This involved the use of 2-phenoxy-acetohyd-
razide 3, which was made from ethyl 2-phenoxyacetate
*
Corresponding authors. Tel.: +353 1 608 3459; fax: +353 1 671 2826
(T.G.); e-mail addresses: susan.matthews@uea.ac.uk; gunnlaut@
tcd.ie
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.10.112

9334
E. Quinlan et al. / Tetrahedron Letters 47 (2006) 9333–9338
as a white powder. We have also employed this method
NO2
for the conversion of the tetra ester of calix[4]arene into
the tetra hydrazidocarbonyl in good yield. The synthesis
of the desired sensor was then achieved by reacting 6 in
dry THF with 2 equiv of 4. The mixture was stirred
overnight at room temperature after which it was
quenched by the addition of methanol, and the off-yel-
low precipitate filtered and washed with methanol to
yield 2 as a pale yellow powder in a 95% yield.ꢀ The
1H NMR (400 MHz, DMSO-d6) of 2, Figure 1, shows
the formation of the desired amidourea sensor with
characteristic resonances appearing at 10.17, 9.59 and
8.62 ppm for the three N–H protons. Figure 1 also
4
NH2NH2
Ethanol
NCO
THF
O
O
1
O
O
HN
NH2
EtO
3
1
Scheme 1. Synthesis of 1.
shows the simplicity of the H NMR caused by the C2
symmetry of 2 (see Scheme 2).
by reaction with hydrazine hydrate in ethanol under
reflux for 3 h, followed by cooling to room temperature
overnight, upon which a solid was formed. Reacting 3
with 4-nitrophenyl isocyanate 4 under an inert atmo-
sphere at room temperature overnight gave 1 as a light
yellow precipitate in a 62% yield after filtration and
washing with methanol. The 1H NMR (400 MHz, in
DMSO-d6) clearly showed the presence of the two urea
protons, and the amide urea proton.ꢀ
The ability of both 1 and 2 to recognize anions was eval-
uated in DMSO by observing the changes in the absorp-
tion spectra of both compounds. For the current study,
Upper rim
Calix[4]arene
Nitrophenol
CH
2
N-H
Calix[4]arene
urea
N-H
urea
-CH -
2
N-H
amide
The rationale behind 2 was to incorporate two anion
receptors into a single calixarene scaffold with the aim
of achieving colorimetric sensing of anions such as phos-
phate or pyrophosphate, where the binding of the anion
would be in a 1:1 stoichiometry. The synthesis of the
desired sensor 2, commenced with the synthesis of the
hydrazine intermediate 6, which was achieved in one-
step from 25,27-bis[(ethoxy-carbonyl)methoxy]-26,28-
dihydroxy calix[4]arene, 5, previously synthesized by
Reinhoudt et al.,23 through treatment with an excess
of hydrazine hydrate. Following cooling to room tem-
perature, the solution was evaporated to dryness under
reduced pressure and the resulting residue triturated
with methanol, collected by suction filtration and
washed with distilled water providing 6 in a 94% yield
10.0 9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
(ppm)
Figure 1. The 1H NMR (400 MHz, DMSO-d6) of 2.
O
OH
O
OH
5
O
O
OEt
EtO
ꢀ Compound 1: Mp 208–211 °C. Anal. Calcd for C15H14N4O5Æ0.3THF:
C, 55.36; H, 4.74; N, 15.81. Found: C, 55.41; H, 4.41; N, 16.24%. 1H
NMR (400 MHz, DMSO-d6) dH: 10.11 (s, 1H, NH), 9.55 (s, 1H, NH),
8.54 (s, 1H, NH), 8.18 (d, J = 9.0 Hz, 2H, Ar–H(nitrophenyl)), 7.73
(d, J = 7.0 Hz, 2H, Ar–H(nitrophenyl)), 7.32 (t, J = 8.0 Hz, 2H, Ar–
Hortho), 7.00 (m, 3H, Ar–Hmeta,para), 4.63 (s, 2H, OCH2C(O)). 13C
NMR (100 MHz, DMSO-d6) dC: 167.8, 157.7, 146.4, 141.1, 129.5,
125.0, 121.2, 118.0, 117.8, 114.7,66.0. IR mmax (cmꢀ1, solid): 3326,
3228, 3107, 2903, 1728, 1720, 1676, 1660, 1616, 1598, 1567, 1508,
1459, 1412, 1426, 1343, 1333, 1300, 1239, 1202, 1175.
NH2NH2
Ethanol
O
OH
O
OH
Compound 2: Mp 242–245 °C Anal. Calcd for C46H40N8O12ÆCH3OH:
C, 60.77; H, 4.77; N, 12.06. Found: C, 60.26; H, 4.48; N, 12.09%. 1H
NMR (400 MHz, DMSO-d6) dH: 10.17 (s, 2H, NHurea), 9.59 (s, 2H,
NHurea), 8.62 (s, 2H, NHamide), 8.14 (d, J = 9 Hz, 4H, Ar–Hnitro-
phenyl), 7.71 (d, J = 9 Hz, 4H, Ar–Hnitrophenyl), 7.17 (d, J = 7 Hz, 4H,
ArH), 7.05 (d, J = 7 Hz, 4H, ArH), 6.81 (t, J = 8.0 Hz, 2H, Ar–H),
6.62 (t, J = 7.0 Hz, 2H, Ar–H), 4.68 (s, 4H, ArO–CH2–C(O)), 4.33 (d,
J = 13 Hz, 4H, Ar–CH2–Ar), 4.46 (d, J = 13 Hz, 4H, Ar–CH2–Ar).
13C NMR (100 MHz, DMSO-d6) dC: Quaternary not visible, 152.4,
152.3, 146.2, 141.2, 133.5, 129.1, 128.7, 127.5, 125.6, 125.4,125.0,
119.3, 117.8, 73.3, 30.6. IR mmax (cmꢀ1, solid): 3314, 3097, 1658, 1633,
1595, 1567, 1510, 1466, 1434, 1329, 1302, 1215.
6
O
O
NH
HN
NH2
NH2
4
THF
2
Scheme 2. Synthesis of 2.

E. Quinlan et al. / Tetrahedron Letters 47 (2006) 9333–9338
9335
0.2
0.18
0.16
0.14
0.12
0.1
tetrabutylammonium (TBA) anions such as acetate
ðCH3CO ꢀÞ,
fluoride
(Fꢀ),
hydrogenphosphate
ðH2PO4ꢀ2Þ and hydrogenpyrophosphate (pyr) were
employed. In DMSO, the two receptors 1 and 2 had
absorptions bands centred at 338 nm (e = 17,641
cmꢀ1 Mꢀ1) and 336 nm (e = 29802 cmꢀ1 Mꢀ1), respec-
tively. These were assigned to the internal charge trans-
fer (ICT) nature of the chromophore. Both compounds
showed significant changes in their absorption spectra
upon addition of the above anions, demonstrating the
formation of an anion-receptor complex utilizing hydro-
gen bonding. Figure 2 shows the changes observed for
the titration of 1 with acetate. Here, significant spectral
changes were observed for the 336 nm transition, which
was hypsochromically shifted upon anion recognition.
The changes in the 440 nm wavelength were used to
evaluate the binding affinity of 1 and these changes are
shown as an inset in Figure 2. Fitting these changes
using the nonlinear least squares regression program
SPECFIT, gave a good fit, with two binding constants,
logb1 = 4.20 ( 0.03) and logb2 = 3.21 ( 0.09). This
indicates that the binding of acetate is not a 1:1 stoichio-
metry as might be expected. Examining the changes in
the main transition in Figure 2, it can be seen that no
clear isosbestic point is observed, which suggest that
there is more than one simple 1:1 binding process occur-
ring. This can possibly be viewed as one of the anions
forming linear hydrogen bonds to the urea part of the
receptor, with a second binding occurring at the amide.
0.50
0.40
0.30
0.20
0.10
0.00
data
fit
0.08
0.06
0.04
0.02
0
0.0000 0.0002 0.0004 0.0006 0.0008 0.0010
[Fluoride]
295
320
345
370
395
420
445
470
495
520
545
Wavelength [nm]
Figure 3. The changes in the absorption spectra of 1 upon titration
with fluoride in DMSO. Inset: The changes at 439 nm and the result of
fitting the data to 1:1 binding using SPECFIT.
selves17 and Gale et al.,24 and more recently by Fab-
brizzi et al.25), one would have expected that such a
deprotonation should occur within the addition of the
2 equiv of Fꢀ to 1. However, this does not seem to be
the case and only upon addition of a large excess of
Fꢀ (>40 equiv) does such deprotonation occur. Such
deprotonation would give rise to the formation of
HF2ꢀ8 with concomitant changes in the absorption spec-
tra, which would be shifted to longer wavelengths.17 In-
deed this was found to be the case for 1 at such high Fꢀ
concentrations. Hence, we can conclude that for Fꢀ, the
binding occurs only through hydrogen bonding within
the concentration range shown in Figure 3. From these
changes at 440 nm (Inset Fig. 3), a logb = 3.31 ( 0.03)
value was determined, which is significantly smaller than
that obseꢀrved for CH3CO2ꢀ. However, in contrast to the
CH3CO2 titration, the changes in the absorption spec-
tra were also clearly visible to the naked eye, where a
yellow colour was observed upon binding of the anion
to the receptor. When these titrations were repeated
using chloride or bromide, no significant binding was
In a similar manner, the titration of Fꢀ revealed some
interesting results, as here the binding was determined
to be mostly 1:1. Figure 3 shows the changes observed
in the absorption spectra upon the addition of Fꢀ. As
can be seen from these changes the absorption band at
338 nm is significantly reduced in intensity, with
concomitant formation of a new band centred at ca.
420 nm and an isosbestic point at 369 nm. This signifies
a 1:1 binding interaction, which is somewhat surpris-
ing.17 Given the fact that Fꢀ is a strong Lewis base
and can deprotonate one, or more, of the N–H protons
of the receptor (as previously demonstrated by our-
ꢀ
observed. In a similar manner, using H2PO4 gave rise
to changes in the absorption spectra. However, in con-
trast to that observed above, the changes in the absorp-
tion spectra were smaller. For H2PO4ꢀ, only a small red
shift was observed, from which a binding constant value
logb1 = 4.73 ( 0.17) was determined. It was also possi-
ble to determine a second binding constant from these
changes, assigned to the formation of 2:1 complex
between two anions and 1, with logb2 = 3.55 ( 0.30),
however, these values carry a significant error.
0.120
0.70
0.100
data
fit
0.080
0.060
0.040
0.020
0.000
0.60
0.50
0.40
0.30
0.20
0.10
0.00
0.0000 0.0005 0.0010 0.0015 0.0020 0.0025 0.0030
[Acetate]/M
In contrast to these results, titration with pyr, gave rise
to large changes in the absorption spectra (Fig. 4), sim-
ilar to those observed for Fꢀ. However, analysis of these
data using a 1:1 stoichiometry gave, on all occasions,
unsatisfactory results, where the fitted data carried a
large error. Hence, alternative binding modes were con-
sidered. The best data fit was observed for the scenario
where 2 equiv of 1 and a single anion formed a complex.
The speciation distribution diagram for this fitting is
280 305 330 355 380 405 430 455 480 505 530 555 580
Wavelength [nm]
Figure 2. Changes in the absorption spectra upon titration with
acetate in DMSO. The arrows show the red shift observed upon anion-
complex formation. Inset: The changes at 440 nm and the fitted data
observed using SPECFIT.

9336
E. Quinlan et al. / Tetrahedron Letters 47 (2006) 9333–9338
3.5E-06
3.0E-06
2.5E-06
2.0E-06
1.5E-06
1.0E-06
5.0E-07
0.0E+00
1.5E-05
1.2E-05
9.0E-06
6.0E-06
3.0E-06
0.0E+00
0.900
0.800
0.700
0.600
0.500
0.400
0.300
0.200
0.100
0.000
0.45
0.40
0.35
0.30
0.25
0.0E+00 1.0E-04 2.0E-04 3.0E-04 4.0E-04
[pyr] (M)
0.0E+00
3.0E-04 6.0E-04 9.0E-04
0.20
0.15
0.10
0.05
0.00
[Fluoride]
270
320
370
420
470
520
570
620
275
325
375
425
475
525
575
Wavelength [nm]
Wavelength [nm]
Figure 4. The changes in the absorption spectra of 1 upon titration
with pyr in DMSO. Inset: Speciation distribution diagram for the
Figure 5. Changes in the absorption spectra of 2 upon titration with
fluoride in DMSO. Inset: The species distribution diagram for the
____
____
____
___ ___
___
titration of 1 with pyr in DMSO:
1;
1:1 and
2:1.
titration:
2,
1:1 and
2:1 (anion:2).
logb = 3.24 ( 0.15) value being determined for 2:1
complex.
seen as an inset in Figure 4. From this fit, two binding
constants can be determined for 2:1 (1:anion) and 1:1
anion binding, where at a lower concentration, the
2 equiv of 1 bind to pyr, but with increasing concentra-
tion of the anion, the self-assembly brakes down to give
the 1:1 complex as the dominant stoichiometry (Fig. 4).
For the 1:1 binding, a value of logb = 5.78 ( 0.30) was
determined, which is quite strong binding; while for the
2:1 self-assembly, a binding constant of logb = 7.59
( 0.8) was determined. However, it is worth pointing
out that this latter binding carries a large error.
The titrations of 2 using H2PO4ꢀ also gave rise to hypso-
chromic shifts in the absorption spectra. However, as for
the titration of 1, these changes were not as pronounced
as those for CH3CO2ꢀ and Fꢀ. However, here the preor-
ganization of the sensor was evident as only 1:1 binding
was observed, with logb = 4.86 ( 0.03) being deter-
mined. This is somewhat stronger binding than that ob-
served for 1, demonstrating the advantage of the use of
the receptors as part of the calix[4]arene scaffold.
Having established the ability of 1 to interact with anions
in 1:1, 2:1 or 1:2 stoichiometries, we investigated the use
of 2 under identical conditions. In the case of 2, the anion
receptors are more preorganized, and as such should be
The most striking results were however, once again ob-
served for the titration with pyr. The changes in the
absorption spectra are shown in Figure 6, and clearly
show that the band centred at 336 nm is initially shifted
to longer wavelengths, in a similar manner to that seen
for 1 giving rise to the formation of a new band at ca.
377 nm, and a shoulder at ca. 500 nm. However, at a
higher concentration (not shown), the 377 nm absorp-
tion gave way to even further changes with the forma-
tion of two new bands at 346 and 384 nm,
respectively. Moreover, the shoulder previously ob-
ꢀ
able to bind anions such as H2PO4 or pyr in a more
cooperative manner, giving rise to an exclusive 1:1 bind-
ing of these anions. We first evaluated the ability of 2 to
sense CH3CO2ꢀ, which would be expected to bind in a
2:1 manner (anion:2) as each of the amidoureas would
be expected to act independently. Upon titration with
CH3CO2ꢀ, the absorption spectrum of 2 was shifted to
longer wavelengths in a similar manner to that observed
for 1. Analysis of the changes at 440 nm indeed revealed
two binding constants for the 1:1 and the 1:2 (2:anion)
complexes, with logb1 = 5.64 ( 0.07) and logb2 = 4.39
( 0.27), both of which are significantly larger than ob-
served for 1. However, unlike that seen for 1, we believe
that these binding constants represent binding of the ace-
tate directly to the urea parts of the receptors alone (cf.
results from 1 above). In a similar manner, the titration
of 2 with Fꢀ gave rise to significant spectral changes
(Fig. 5), that were also clearly visible to the naked eye.
From these changes, it can be seen that the 1:1 complex
is initially formed exclusively, but after addition of ca.
one equiv of Fꢀ, the 2:1 complex was also formed. As
in the case of 1, we do not seem to have a direct evidence
for the deprotonation of the receptor moieties of 2 by Fꢀ
within the concentration range shown in Figure 5. Con-
sequently, we can conclude that Fꢀ is being recognized as
the hydrogen bonding complex, mirroring that observed
for 1. From these changes a value of logb = 5.1 ( 0.05)
was determined for the 1:1 complex formation, with a
1.2E-05
1.0E-05
8.0E-06
0.45
6.0E-06
0.40
4.0E-06
0.35
2.0E-06
0.30
0.0E+00
2.00E-06
5.20E-05
1.02E-04
[pyr]
[phy
0.25
0.20
0.15
0.10
0.05
0.00
270
320
370
420
470
520
570
Wavelength [nm]
Figure 6. The changes in the absorption spectra of 2 upon titration with
pyr in DMSO. Inset: The species distribution diagram for the titration
___ ___
___
of 2 with pyrophosphate:
2,
1:1 and
1:2 (anion:2).

E. Quinlan et al. / Tetrahedron Letters 47 (2006) 9333–9338
9337
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served at 500 nm developed into a full transition. We
attribute these overall changes to: (i) formation of the
hydrogen bonding anion:receptor complex, at lower
concentrations, (ii) deprotonation of the anion receptors
at higher pyr concentrations. Such deprotonation has
also been shown to be possible with anions other than
Fꢀ by Gale et al.21
Analysis of the initial changes in Figure 6, showed that
the pyr is bound to 2 in the desired 1:1 stoichiometry,
with logb = 5.72 ( 0.11). This binding can possibly
occur in such a manner that the pyr anion bridges the
two receptors in 2, across the calix[4]arene cavity. How-
ever, a second binding constant can also be determined
from these changes, assigned to the 1:2 (2:anion) stoichi-
ometry, with logb = 3.81 ( 0.31). The speciation distri-
bution diagram for the binding of pyr to 2 is shown in
Figure 6 as an inset. From these changes, it can be seen
that the recognition of pyr initially involves the forma-
tion of a 1:1 self-assembly, with the formation of the
1:1 and the 1:2 binding stoichiometries at higher concen-
trations. We are currently evaluating these binding
possibilities in a greater detail.
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In summary, we have developed calixarene 2 as a novel
colorimetric sensor for anions, by incorporating amido-
urea based receptors, used in model compound 1, into
1,3-disubstituted calix[4]arene in short and high yielding
synthesis. We have demonstrated that these receptors
can bind Fꢀ in a 1:1 stoichiometry with concomitant
colorimetric changes, where the binding occurs through
hydrogen bonding and that no deprotonation of the
receptors in either 1 or 2 occurs until high Fꢀ concentra-
tions are reached. We have also shown that a strong
ꢀ
1:1 binding is observed for H2PO4 and pyr, where the
latter binding occurs by bridging the anion across the
lower-rim cavity of the 1,3-functionalized calix[4]arene
scaffold 2. We are currently working towards developing
other analogues of 2 with the aim of achieving a more
selective anion sensing and the formation of anion tem-
plate self-assembly structures.
Acknowledgement
17. (a) Gunnlaugsson, T.; Kruger, P. E.; Lee, T. C.; Parkesh,
R.; Pfeffer, F. M.; Hussey, G. M. Tetrahedron Lett. 2003,
44, 6575; (b) Gunnlaugsson, T.; Kruger, P. E.; Jensen, P.;
Pfeffer, F. M.; Hussey, G. M. Tetrahedron Lett. 2003, 44,
8909.
We like to thank TCD and Enterprise Ireland for finan-
cial support and Dr. John E. O’Brien for assisting with
NMR measurements.
18. Other recent examples include: (a) Winstanley, K. J.;
Sayer, A. M.; Smith, D. K. Org. Biomol. Chem. 2006, 4,
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J.; Yoon, J. Y. Tetrahedron Lett. 2006, 47, 3103; (c)
Thiagarajan, V.; Ramamurthy, P.; Thirumalai, D.; Rama-
krishnan, T. Org. Lett. 2005, 7, 657; (d) Jose, D. A.;
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