Colorimetric and luminescent sensors for chloride: Hydrogen bonding vs deprotonation

Article abstract of DOI:10.1021/ol402500q

The synthesis and photophysical properties of four squaramide based fluorescent anion sensors (1-4) are described. These luminescent compounds showed selectivity for Cl^- over various other anions with concomitant changes in both their UV/visible and fluorescence properties upon Cl ^- addition, attributed to initial H-bonding followed by NH deprotonation in the presence of excess Cl^-, signaled by a color change. The nature of the electron withdrawing aryl substituents is directly related to the H-bonding ability/acidity of the squaramide protons and can be used to tune the deprotonation behavior.

Full text of DOI:10.1021/ol402500q

ORGANIC
LETTERS
2013
Vol. 15, No. 22
5638–5641
Colorimetric and Luminescent Sensors for
Chloride: Hydrogen Bonding vs
Deprotonation
Robert B. P. Elmes, Peter Turner, and Katrina A. Jolliffe*
School of Chemistry (F11), The University of Sydney, NSW 2006, Australia
kate.jolliffe@sydney.edu.au
Received September 4, 2013
ABSTRACT
The synthesis and photophysical properties of four squaramide based fluorescent anion sensors (1ꢀ4) are described. These luminescent compounds
showed selectivity for Clꢀ over various other anions with concomitant changes in both their UV/visible and fluorescence properties upon Clꢀ addition,
attributed to initial H-bonding followed by NH deprotonation in the presence of excess Clꢀ, signaled by a color change. The nature of the electron withdrawing
aryl substituents is directly related to the H-bonding ability/acidity of the squaramide protons and can be used to tune the deprotonation behavior.
Colorimetric and luminescent sensors provide a visual
method for detection of a wide range of chemical species.
Substantial effort has recently been invested in the synthe-
sis of such chemosensors for detection of anions in many
diverse areas including biology, industry, and the environ-
ment.1ꢀ3 In particular, the design of charge neutral
sensors capable of binding anions in competitive media,
where the spectroscopic properties arising from the sen-
sors, e.g. a color change, are modulated by addition of the
external analyte has become a popular method of sensing
chemical species.4 Anion recognition has been successfully
achieved through the use of numerous neutral receptors
including imidazoles,5,6 pyrroles,7 calixarenes,8 amides,9
ureas,10ꢀ13 thioureas,14ꢀ19 amidothioureas,20 and recently
thiosemicarbazides21 leading to a large body of research in
the area. More recently, a characteristically different class
of compounds, the squaramides, have been explored for their
(10) Sambrook, M. R.; Hiscock, J. R.; Cook, A.; Green, A. C.;
Holden, I.; Vincent, J. C.; Gale, P. A. Chem. Commun. 2012, 48, 5605.
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Brooks, S. J.; Light, M. E.; Herniman, J.; Langley, G. J.; Soto-Cerrato,
V.; Perez-Tomas, R.; Marques, I.; Costa, P. J.; Felix, V.; Gale, P. A.
Chem. Sci. 2013, 4, 103.
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Gunnlaugsson, T. Chem. Commun. 2011, 47, 12176.
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39, 3889.
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Gunnlaugsson, T. Org. Biomol. Chem. 2009, 7, 3447.
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2012, 24, 585.
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J. Org. Chem. 2012, 77, 3115.
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Biomol. Chem. 2008, 6, 4089.
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(2) Cametti, M.; Rissanen, K. Chem. Soc. Rev. 2013, 42, 2016.
(3) Gale, P. A. Chem. Commun. 2011, 47, 82.
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Pfeffer, F. M. Coord. Chem. Rev. 2006, 250, 3094. (b) Yu, G.; Zhang, Z.;
Han, C.; Xue, M.; Zhou, Q.; Huang, F. Chem. Commun. 2012, 48, 2958–
2960.
(5) Wang, J.; Yang, L.; Hou, C.; Cao, H. Org. Biomol. Chem. 2012,
10, 6271.
(6) Amendola, V.; Boiocchi, M.; Fabbrizzi, L.; Fusco, N. Eur. J. Org.
Chem. 2011, 6434.
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2971.
Commun. 2013, 49, 264.
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2664. (b) Young, P. G.; Clegg, J. K.; Jolliffe, K. A. Supramol. Chem.
2011, 24, 77.
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Biomol. Chem. 2012, 10, 2824.
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Chem.;Eur. J. 2011, 17, 5972.
Int. Ed. 2006, 45, 7882.
r
10.1021/ol402500q
Published on Web 10/29/2013
2013 American Chemical Society

molecular recognition properties.22 Comprising a conforma-
tionally rigid cyclobutene structure in combination with a
strong hydrogen bond donor ability,23 these moieties have
been exploited in numerous applications ranging from medic-
inal chemistry to catalysis24 and more recently in the design of
new anion receptors and transporters.25ꢀ29
charge delocalization being extended to the entire molecular
framework. Considering the unique properties of the squar-
amide functional group, we set out to exploit their strong
anionic recognition potential by synthesizing a family of
spectroscopically responsive receptors for anions. Herein,
we describe the synthesis of receptors 1ꢀ4 based on a squar-
amide recognition moiety covalently tethered to a lumines-
cent anthracene reporter group, which has been used exten-
sively in the field of luminescent anion recognition, including
in previously reported urea and thiourea analogues of 1 ꢀ4.4
By incorporating various electron withdrawing substituents,
such as trifluoromethyl and nitro groups, on the squaramide
aryl substituent we envisaged being able to ‘tune’ both the
selectivity and sensitivity of the anion recognition.
Scheme 1. Synthesis of AnthraceneꢀSquaramide Conjugates 1ꢀ4
Unsymmetrical squaramides 1ꢀ4 were synthesized by
the reaction of 9-aminomethyl anthracene30 with the cor-
responding squarate monoesters (5ꢀ8) to afford 1ꢀ4 in
75%, 79%, 94%, and 96% yield, respectively (Scheme 1).
The monoesters were assembled via a room-temperature
coupling of diethyl squarate (9) with the appropriate
29
anilines (10ꢀ13) in the presence of Zn(OTf)2 (see Sup-
porting Information (SI) for experimental details). Crys-
tals suitable for single crystal X-ray analysis were obtained
for 1ꢀ3 by recrystallization from concentrated DMSO
solutions allowing the evaluation of their solid-state behav-
ior (Figure 1). Tables of H-bonds, data collection, and
refinement details can be found in the SI. 1, 2, and 3 were
each found to be H-bonded to a DMSO molecule in the
solid state with the squaramide moiety acting as both a
H-bond donor and acceptor to a pair of DMSO molecules
in the crystal lattice. Stacking interactions between the
anthracene moieties were also clearly evident in the packing
structure of each analogue (SI). With receptors 1ꢀ4 in hand,
we next evaluated their ability to detect anions in solutioꢀn by
titration of ‘nonbasic’ anions Clꢀ, Brꢀ, Iꢀ, and NO3 as
their tetrabutylammonium salts (TBAþ), observing any
changes in both their ground and excited state properties.
In contrast to studies by Taylor et al.,29 the presence of only a
single electron withdrawing aryl group on the squaramide
did not result in deprotonation in DMSO. Upon titration of
these sensors with Brꢀ, Iꢀ, and NO3ꢀ, very minor changes
were seen in the absorption spectra of 1ꢀ4 suggesting that
little interaction of these anions is occurring at the squar-
amide. In contrast, much more significant changes were seen
upon addition of Clꢀ. Large modulations were observed in
the absorption spectra of 1ꢀ3 but only minor changes were
observed for 4. The absorption spectrum of 1 changed
significantly upon incremental additions of Clꢀ with a
44% increase in absorption of its band at 393 nm being
observed and a concomitant decrease in the band at 355 nm
resulting in an isosbestic point at 360 nm. Similarly, 2showed
a 55% increase at 393 nm and a decrease of the 355 nm band
also resulting in an isosbestic point at 360 nm. The changes
for both 1 and 2 culminated in a color change from colorless
to yellow, observable to the naked eye upon addition of
excess Clꢀ. The nitro derivative 3 displayed more dramatic
Figure 1. (a) X-ray structure of 3 bound to DMSO and (b) self-
assembly network showing the H-bond donor and acceptor ability of 3.
The intense coloration observed with sensors that make
use of amide, urea, and thiourea moieties is often a result of
deprotonation in the presence of basic anions and deloca-
lization of the resulting anion throughout the receptor.
Similarly, recent reports from the groups of Fabbrizzi
et al.26 and Taylor et al.29 have suggested that deprotonation
of the squaramide moiety by basic anions such as AcOꢀ,
H2PO4ꢀ, and Fꢀ is even more favorable due to the negative
(23) Storer, I. R.; Aciro, C.; Jones, L. H. Chem. Soc. Rev. 2011, 40.
ꢀ
(24) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K. A. Chem.;Eur.
J. 2011, 17, 6890.
(25) Busschaert, N.; Kirby, I. L.; Young, S.; Coles, S. J.; Horton,
P. N.; Light, M. E.; Gale, P. A. Angew. Chem., Int. Ed. 2012, 51, 1.
(26) Amendola, V.; Bergamaschi, G.; Boiocchi, M.; Fabbrizzi, L.;
Milani, M. Chem.;Eur. J. 2010, 16, 4368.
(27) Jin, C.; Zhang, M.; Wu, L.; Guan, Y.; Pan, Y.; Jiang, J.; Lin, C.;
Wang, L. Chem. Commun. 2013, 49, 2025.
(28) Porel, M.; Ramalingam, V.; Domaradzki, M. E.; Young, V. G.;
Ramamurthy, V.; Muthyala, R. S. Chem. Commun. 2013, 49, 1633.
(29) Rostami, A.; Colin, A.; Li, X. Y.; Chudzinski, M. G.; Lough,
A. J.; Taylor, M. S. J. Org. Chem. 2010, 75, 3983.
(30) Gunnlaugsson, T.; Davis, A. P.; O’Brien, J. E.; Glynn, M. Org.
Biomol. Chem. 2005, 3, 48.
Org. Lett., Vol. 15, No. 22, 2013
5639

In general, the observation of large changes in the ground
state properties of neutral anion sensors is a result of a
deprotonation event. Fꢀ is one of the more basic anions and
is known to deprotonate ureas, thioureas, and squar-
amides.2,26 However, to the best of our knowledge, Clꢀ
anions have not previously been shown to result in depro-
tonation of a H-bond receptor. To determine whether the
changes we observed upon addition of Clꢀ to receptors 1ꢀ3
were due to deprotonation or H-bonding, a series of Fꢀ
titrations were also undertaken. Upon addition of Fꢀ to 1
and 2, a stark color change was immediately observed from
colorless to yellow in a manner analogous to that described
for Clꢀ. Such changes suggest that deprotonation is respon-
sible for the color changes observed with excess Clꢀ. Sensor
3 also exhibited a color change from orange to deep pink at
low concentrations of Fꢀ as was seen with Clꢀ, but further
additions of Fꢀ resulted in a second color change from pink
to blue/purple suggesting a second deprotonation event
(Figure 2) as has been previously observed for bis(4-
nitrophenyl) substituted squaramides in the presence of
excess Fꢀ.29 We confirmed this deprotonation behavior
by titration of 3 with TBAOH, which resulted in analogous
changes (SI) where the formation of a band at 540 nm
corresponding to the mono-deprotonated species (red) was
observed initially but was followed by a decrease in the band
at 540 nm and the concomitant formation of a new absorp-
tion band at 675 nm corresponding to the doubly deproto-
nated derivative (blue). These results indicate for the first
time that, when strong electron withdrawing groups are
attached to the squaramide moiety, it is possible to detect
Clꢀ ions by a color change induced by deprotonation.
Having observed such stark colorimetric changes in the
ground state properties of 1ꢀ4 we were also keen to
investigate their excited state properties in the presence
of each of the anions described above. Gunnlaugsson and
co-workers have published a number of examples of PET
sensors based on the combination of anthracene and both
ureas and thioureas;30,31,33 however, to the best of our
knowledge such sensors taking advantage of the squara-
mide moiety have not yet been reported. As such, we
expected that interaction of anionic guests with the squar-
amide based receptors would result in significant changes
totheirexcited state properties. Again, minorchanges were
observed in the emission spectra of 1ꢀ4 upon titration with
Brꢀ, Iꢀ, and NO3ꢀ, further confirming the minimal nature
of interaction of these anions with any of the receptors.
Titration with Clꢀ, however, led to much more significant
changes as shown in Figure 3 for 1, where fluorescence
quenching was observed. The observed excimer emission
centered at 530 nm was significantly ‘‘switched off’’ by
66% in the presence of Clꢀ ions. A similar effect was
observed for 2 but with a smaller emission decrease of 28%
being exhibited. Although the excimer emission at 530 nm
was less obvious in the case of 3, it too underwent an
emission decrease and these changes corresponded well to
those observed for 1 (SI). The emission spectrum of
Figure 2. Changes observed in the absorption spectrum of 1 (1 ꢁ
10ꢀ5 M) upon addition of TBACl (0ꢀ0.03 M) in DMSO. (Inset):
Absorbance changes observed at 393 nm ([) vs 540 nm (9) and
the corresponding changes seen by the naked eye with various
halide anions.
Figure 3. Changes observed in the fluorescence emission spectrum
of 1 (1 ꢁ 10ꢀ5 M) upon addition of TBACl (0ꢀ0.03 M) in DMSO.
(Inset): Relative emission measured at 530 nm in the presence of
increasing concentrations of Clꢀ ([),Brꢀ (9),Iꢀ (2),andNO3ꢀ (ꢁ).
changes. As shown in Figure 2, addition of Clꢀ resulted in
the decreasing absorbance of the bands at 380 and 400 nm
coupled to absorbance increases in the bands at 360 and
540 nm with the emergence of a new band at 325 nm. More-
over, each of the bands also exhibited blue shifts of ∼5ꢀ10 nm
for each of the anthracenyl transitions. These changes resulted
in a color change from orange to deep pink/red. From these
titrations we estimated the stability constants (log β) for
chloride to be ∼2.93, 2.06, and 2.83 for squaramides 1, 2,
and 3, respectively, which are considerably higher than those
of the urea and thiourea analogues for which a log β value for
Clꢀ could not be calculated under the same conditions.31
(31) Dos Santos, C. M. G.; Glynn, M.; McCabe, T.; Seixas de Melo,
J. S.; Burrows, H. D.; Gunnlaugsson, T. Supramol. Chem. 2008, 20, 407.
(32) Nishizawa, S.; Kato, Y.; Teramae, N. J. Am. Chem. Soc. 1999,
121, 9463.
5640
Org. Lett., Vol. 15, No. 22, 2013

Figure 5. (a) Single crystal X-ray structure of the chloride
complex of compound 1 and (b) self-assembly network formed
between Clꢀand 1. Counterions have been omitted for clarity.
Figure 4. Stack plot of H NMR spectra of 3 (2.5 ꢁ 10ꢀ3 M)
1
of Clꢀ led to the disappearance of the NH signals and stark
color changes of the titration solutions of 1ꢀ3 but not of 4
providing further evidence of deprotonation of these sensors
in the presence of Clꢀ at high concentrations, a phenomenon
usually only reported for the more basic Fꢀ, AcOꢀ,
or H2PO4ꢀ anions. Similarly, mass spectrometry analysis
of these solutions confirmed the presence of [M ꢀ H]ꢀ ions
further supporting the observations described above (SI).
Crystals of both 1 and 4 suitable for X-ray diffraction
were obtained in the presence of 5 equiv of tetrabutylam-
monium chloride (TBACl) (Figure 5). Analysis revealed
that 1 forms a 1:1 (receptor/anion) complex with Clꢀ at this
concentration where the encapsulated anion is bound by
two H-bonding interactions with both available squaramide
NH groups. Similarly, the unfunctionalized aryl squaramide
4 also forms a 1:1 complex with chloride, where the anion is
again bound by two H-bonding interactions with both
available squaramide NH groups. Interestingly, in the case
of 1, the NꢀCl distance is shortest on the 3,5-trifluoro-
methylphenyl side of the squaramide, again demonstrating
the effect of the more electron withdrawing substituent on
the H-bond donor ability of the squaramide NH.
upon addition of TBACl (0ꢀ12 equiv) in DMSO-d6 at 25 °C.
compound 4 did not change significantly upon addition of
Clꢀ. Interestingly, in all cases, the monomer emission of
the anthracene moiety itself remained largely unchanged,
even upon addition of large concentrations of anion, and
this suggests that these sensors are not PET sensors; rather
their sensing ability is due to their ability to modulate
excimer formation, a phenomenon described in a number
of reports by Teramae et al.32,34
We performed 1H NMR spectroscopic investigations in
DMSO-d6 with each of the sensors 1ꢀ4 to establish the
stoichiometry of their anion complexes while gaining an
understanding of the mechanism of hostꢀguest interac-
tions. Similarly, we sought to investigate the effect of the
substitution pattern of the phenyl substituents. The data
obtained from these titrations, where possible, were
plotted as the cumulative changes in chemical shift (Δδ)
against the equivalents of anion added, and the resulting
plots were analyzed using Hyperquad. Figure 4 shows the
changes observed in the 1H NMR spectrum of 3 upon the
addition of Clꢀ. These changes together with the solid state
analysis of these compounds (see below) clearly support
a classical H-bonding interaction between the anions and
the NH protons of the sensors at low Clꢀ concentrations.
The binding constants (log β) of 1ꢀ4 (determined by
Hyperquad) with Clꢀ were calculated as ∼2.25, 2.13,
2.02, and 1.75 for 1, 2, 3, and 4, respectively. On all
occasions a good fit to a 1:1 binding isotherm was ob-
served; this was further supported by Job’s plot analysis
which confirmed a 1:1 binding stoichiometry (SI). The
overall results from the Clꢀ NMR titrations demonstrate
the same trend as observed for the ground and excited state
studies described above, and highlight the effect the sub-
stituents have on the anion affinity of these sensors. More-
over, addition of a large number of equivalents (30 equiv)
Insummary, wehavesuccessfully synthesizeda familyof
receptors capable of distinguishing between halide anions by
both colorimetric and luminescent modulations. We have
demonstrated that the acidity of the squaramide can be
effectively tuned by various aryl substituents and this
provides for a novel method of selectively recognizing Clꢀ
anions via deprotonation of the squaramide NH proton. We
are currently investigating these and related systems in more
detail, and results will be reported in due course.
Acknowledgment. We thank the ARC (DP110100682)
and USyd for financial support.
Supporting Information Available. Experimental proce-
dures and spectral data for 1ꢀ4as well as spectroscopic titration
curves, Job plots, and crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(33) Gunnlaugsson, T.; Davis, A. P.; Glynn, M. Chem. Commun.
2001, 2556.
(34) Nishizawa, S.; Kaneda, H.; Uchida, T.; Teramae, N. J. Chem.
The authors declare no competing financial interest.
Soc., Perkin Trans. 2 1998, 2325.
Org. Lett., Vol. 15, No. 22, 2013
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