Synthesis and photophysical evaluation of charge neutral thiourea or urea based fluorescent PET sensors for bis-carboxylates and pyrophosphate

Article abstract of DOI:10.1039/b409018g

The synthesis of the fluorescent photoinduced electron transfer (PET) chemosensors 1-3 for bis-anions such as bis-carboxylates and pyrophosphate in organic solvents is described herein. These sensors are based on the receptor-spacer-fluorophore-spacer-rec

Full text of DOI:10.1039/b409018g

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A R T I C L E
Synthesis and photophysical evaluation of charge neutral thiourea or
urea based fluorescent PET sensors for bis-carboxylates and
pyrophosphate
a
a,b
a
a
Thorfinnur Gunnlaugsson,* Anthony P. Davis, John E. O’Brien and Mark Glynn
a
Department of Chemistry, Trinity College Dublin, Dublin 2, Ireland. E-mail: gunnlaut@tcd.ie;
Fax: 00 353 1 671 2826; Tel: 00 353 1 608 3459
School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK BS8 1TS
b
Received 15th June 2004, Accepted 27th September 2004
First published as an Advance Article on the web 9th November 2004
The synthesis of the fluorescent photoinduced electron transfer (PET) chemosensors 1–3 for bis-anions such as
bis-carboxylates and pyrophosphate in organic solvents is described herein. These sensors are based on the
receptor–spacer–fluorophore–spacer–receptor motif where the receptors are charge neutral aromatic thiourea or urea
1
receptors and the fluorophore is anthracene. The anion recognition was evaluated using H NMR as well as
absorption and fluorescence spectroscopy in DMSO. For simple anions such as acetate or fluoride, the recognition
was shown to be through hydrogen bonding of the corresponding anion to the receptors. This gave rise to only minor
changes in the absorption spectra, but significant changes in the fluorescence emission spectra, which was
substantially (70–95%) quenched. Analysis of these recognition events implied a 1 : 2 (sensor : anion) binding and
−
−
−
ideal PET behaviour for ions such as AcO and H
2
PO . For F , the luminescent quenching indicated a 1 : 1 binding,
4
but we deduced that this was due more to complete quenching of the excited state after the addition of one equivalent
of the anion. For all of the anions, the quenching contributed to enhanced efficiency of PET from the receptors to the
excited state of the fluorophore. In the case of the bis-anions (ambient), such as di-carboxylates, similar fluorescence
quenching was observed. However, here either a 1 : 1 or a 1 : 2 binding was observed depending on the length of the
spacer separating the two carboxylate moieties and the nature of the receptor. Whereas both pyrophosphate and
malonate gave rise to a 1 : 1 binding, glutarate gave rise to ∼1 : 2 binding for the thiourea sensors 1 and 2. However,
for the urea based sensor 3, the binding was found to be 1 : 1 for all the bis-anions. For such a 1 : 1 binding we
1
propose that the anion most likely bridges the fluorophore moiety. This was also evident from the H NMR
(
DMSO-d ) spectrum where the anthracene resonances were significantly affected. By simply modifying the
6
electronic structure of the receptor, the sensitivity of the recognition process could also be modified; e.g. compound 1,
bearing the trifluoromethyl substituent, showed stronger binding to the bis-anions than 2, which possessed a simple
phenyl moiety.
−
−
−
Introduction
employing anions such as AcO , H
2
−
PO
4
and F in DMSO,
−
−
−
whereas anions such as ClO
4
, Cl , Br and I were not detected,
The sensing and monitoring of ions and molecules is currently
of major interest, as anions are important from industrial (such
as fertilisers), biological/medicinal and environmental points
presumably due to the simple nature of the receptor. However,
the success of our original idea led us to extend our approach
to anion sensing to the detection of anions that have more than
one binding site, such as bis-carboxylates and phosphates such
1
2
of view. Unlike cationic recognition and sensing, which is
now a well-established area of research, anion recognition has
been much less explored. However, recently a large number of
excellent examples of anion receptors and luminescent sensors
for anions have been produced and several reviews have appeared
9,10
as pyrophosphate, etc. Such fluorescence sensing is of great
biological and medicinal relevance as many dicarboxylates take
part in metabolic processes together with pyrophosphate, which
itself is essential for energy formation as it is the product of the
hydrolysis of ATP under cellular conditions. Herein we present
3
over the last few years. Major challenges in anion sensing are;
11
they exhibit a variety of structures and conformations, they are
often highly hydrated and they may be pH dependent, making
the full results from these investigations.
Our approach, which we call second-generation PET anion
sensors, are based on the receptor–spacer–fluorophore–spacer–
receptor motif shown in Fig. 1, originally developed by de Silva
and coworkers for the sensing of bis-ammonium species and for
4
it difficult to detect them in an aqueous environment. Conse-
quently, structurally complicated and synthetically demanding
receptors have been developed, which may not be realistic for
use in practical anion sensors applicable to, for example, in vitro
12
mimicking logic gates. Here however, we have simply used two
anion receptors that are connected in a linear fashion via the
two spacers to an anthracene fluorophore through the 9 and 10
positions. This design gave the two thiourea based fluorescent
sensors 1 and 2, and the urea analogue 3.
5
or in vivo monitoring.
We have recently focused our research towards the devel-
opment of structurally simple sensors for anion recognition;
developing lanthanide luminescent sensors, where coordinated
6
unsaturated Tb(III) complexes were used to detect carboxylates
Even though these are structurally simple sensors, by simply
altering the nature of the receptor site, e.g. by incorporating
3
such as salicylic acid in water at pH 7; as well as using
charge neutral PET (photoinduced electron transfer) anion
electron withdrawing substituents such as CF , we hoped to be
7
8
sensors, which employ thiourea based receptors. For the latter,
able to ‘tune’ the selectivity and sensitivity of anion recognition.
recognition occurs through hydrogen bonding between the
thiourea protons and the anion. This causes the fluorescence
of the fluorophore to be quenched by electron transfer from
This would be due to a modulation of the strength of the
hydrogen bonding interactions between the thiourea/urea N–H
and the anions, resulting in a receptor–anion complex which
would be substantially affected and would subsequently affect
8
the anion–receptor complex. We have demonstrated this by
4
8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5

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tion of MS-analysis due to fragmentations (see Experimental
1
section). The H NMR spectra (400 MHz) of 1–3, when recorded
in either DMSO-d
6
or CDCl , showed that the sensors were all
3
highly symmetrical, as is evident from Fig. 2 (for 2), where only
two resonances for the thiourea protons are observed at 9.36
and 8.06 ppm respectively. The latter is observed as a triplet due
to the coupling of the methylene spacer, which is observed as a
doublet at 5.75 ppm (the NMR of 1 is discussed later).
Fig. 1 The receptor–spacer–fluorophore–spacer–receptor model used
and the corresponding sensors 1–3.
13
the PET quenching of the fluorophore. To the best of our
knowledge, these chemosensors are the first examples of charge
neutral fluorescent PET sensors that show ideal PET behaviour
13,14
for bis-anions.
1
Fig. 2 The H NMR (DMSO-d
6
, 400 MHz) of 2.
Results and discussion
The synthesis of the starting material 4 was more troublesome
than expected. A preparation described previously employed the
Synthesis of 1–4
15
classical Gabriel synthesis. We, however, found that the first
step in this synthesis resulted in the formation of the insoluble
bis-phthalimide anthracene derivative and the conversion of this
intermediate to 4 was extremely poor. More successful was
an alternative method (Scheme 1) which involved the initial
synthesis of 9,10-bisbromomethylanthracene 8 in one step from
anthracene (75% yield) using a method derived by Altava et al.1
This involved reacting anthracene with 48% HBr and 1,3,5-
trioxane, in glacial acetic acid in the presence of a catalytic
amount of tetradecyltrimethyl ammonium bromide. The desired
The chemosensors 1–3 were prepared from the corresponding
isothiocyanates (5, 6 and 7) and 9,10-diaminomethylanthracene
4
in CH
products were formed as precipitates that were isolated by
filtration, washed with cold CH Cl and recrystallised from
CHCl , giving 1–3 in ca. 80% yield. The isothiocyanates used
in the synthesis of 1 and 2 were 4-(trifluoromethyl)-phenyl-
and phenyl-isothiocyanate 6 respectively, whereas for 3, 4-
trifluoromethyl)phenyl-isocyanate 7 was used. All the sensors
2
Cl
2
by stirring at room temperature (Scheme 1). The
2
2
6a
3
5
(
were characterised using conventional methods, with the excep-
product was removed by filtration and dried over P
2
5
O followed
by recrystallisation from toluene. From 8, 4 could be formed
in ca. 85% yield as a crude product that could be used without
further purification. This synthesis involved the treatment of
8
with hexamethylenetetramine in anhydrous CHCl under an
3
inert atmosphere, followed by refluxing the resulting solution for
five hours before the off-white precipitate formed was isolated
by filtration.1 The resulting solid was then treated with a 20 : 4 :
6b
5
7
mixture of EtOH, H
0 C for twelve hours, causing the HCl salt to redissolve. Upon
2
O and concentrated HCl and heated at
◦
cooling the mixture to room temperature a yellow precipitate
was formed which was filtered and washed with 10% KHCO
and then extracted into CHCl . As stated earlier, the quality of
3
3
this crude material was sufficient for use in the synthesis of 1–3.
Photophysical evaluation of 1–3 using monodentate anions
The ground and the excited state properties of 1–3 were
investigated in DMSO. The absorption spectrum for 1, shown in
Fig. 3, exhibits the same fine structure as is commonly observed
for anthracene at 400, 379 and 359 nm respectively, with an
5
−1
−1
extinction coefficient e = 4 × 10 cm M . For comparative
purposes the absorption spectrum for 9,10-dimethyl-anthracene
(DMA) is superimposed on the spectrum of 1 in Fig. 3. DMA
spectra has peaks at 397, 375 and 356 nm respectively, illustrating
that the two thiourea receptors in 1 have a slight but significant
influence on the absorption bands, which become red-shifted.
In comparison, the fluorescence emission spectra of 1 consisted
of three bands at 409, 430 and 455 nm when excited at 379 nm
1
7
(
with quantum yield of fluorescence, U
F
= 0.047) . These were
significantly more red-shifted than those observed for DMA,
which had emission bands at 395, 419 and 444 nm. However, a
Scheme 1 The synthesis of sensors 1–3. i) 1,3,5-Trioxane, HBr,
CH
ethylenetetramine in anhydrous CHCl
iii) CH Cl room temperature.
3 2
CO H; tetradecyltrimethyl ammonium bromide; ii) hexam-
followed by HCl, ethanol, H
2
O;
U
F
= 0.87 was measured under the same conditions for DMA,
3
2
2
indicating significant quenching of the excited state of 1 which
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6
4 9

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enhancements in PET quenching. This process was reversible, as
upon addition of competitive hydrogen bonding solvents, such
as ethanol or water, the emission was restored (switched on),
indicating that the anion–receptor complexes were broken and
hence reversible.
Fig. 3 The absorption spectra of 1 (solid) and DMA (dashed) in
DMSO.
we assign to photoinduced electron transfer (PET) quenching
taking place from the receptors in 1 to the excited state of the
anthracene. For 2 (kabs = 400, 379 and 360 nm and k = 409, 431
F
and 454 nm), the quantum yield was measured to be 0.11, which
is substantially higher than that determined for 1, suggesting
that the rate of PET is somewhat less in the free sensor of 2 in
comparison to that observed for 1.
Fig. 5 The changes in the fluorescence emission spectra of 1 in DMSO
upon addition of AcO ([AcO ] = 0–58 mM). The emission is switched
off upon ion recognition.
−
−
The effect on the absorption and the fluorescence emission
spectra was recorded in the presence of several anions, using
tetrabutyl ammonium (TBA) salts in DMSO. The absorption
spectrum of 1 in the presence of increasing concentrations
of TBAOAc (in DMSO) is shown in Fig. 4. As can be seen
from this titration, there are only minor changes observed for
the anthracene absorption, indicating that insignificant ground
state interactions occur between the two receptors and the
fluorophore, as no p–p or n–p interactions occur owing to the
presence of the covalent spacers. Unfortunately, these changes
were so small that we were unable to obtain a reliable binding
profile from these results.
As these are monodentate anions we expected them to bind in
the ratio of 1 : 2 (sensor : anions) as each receptor can recognise
the acetate. This was indeed found to be the case as can be seen
in Fig. 6 for the changes in fluorescence at 430 nm, where the
emission is switched off over ca. four logarithmic units, from
−
–
log[Ac ] 2–6. In contrast to our earlier work, a 1 : 1 binding
occurs over two concentration units. We thus conclude that this
binding is 1 : 2 (see later in Fig. 14). It is also important to notice
that no other significant spectral changes occur in the emission
spectrum and, as a result, the presence of any red- or blue-
shifts, or exiplex or eximer emission formation is not observed.
Hence, only the intensity, and subsequently the quantum yield,
of fluorescence is modulated upon anion sensing. Similar results
−
were observed using H
2
PO
4
. From these results it is clear that
13,14,18
the sensor is behaving like an ideal PET sensor.
Fig. 4 The changes (uncorrected for dilution) in the absorption spectra
−
−
of 1 in DMSO upon addition of AcO ([AcO ] = 0–58 mM).
In contrast to these results, the changes in the fluorescence
emission spectra were very different, as can be seen in Fig. 5,
upon excitation of the anthracene fluorophores at 378 nm. From
these changes it can be seen that emission was substantially
quenched, ca. 70% at 430 nm, upon anion recognition at the
receptor sites and the subsequent formation of the electron
rich anion–receptor complexes. These changes are due to an
enhanced photoinduced electron transfer (PET) rate from the
anion bound receptors to the excited state of the anthracene.
Fig. 6 The changes in the fluorescence emission spectra of 1 at 430 nm
−
in DMSO upon addition of AcO . From these changes it can be deduced
that the recognition of the anion occurs in a two-step process over four
logarithmic concentration units.
To confirm the selectivity of these sensors towards linear
anions such as acetates, we also titrated the sensors with other
−
−
anions. Upon addition of spherical anions such as Cl or Br ,
no significant quenching was observed excluding quenching by
−
Furthermore, the addition of 10 mM of AcO to a solution of
DMA did not affect the U
F
of DMA; hence the emission was not
the heavy atom effect. Moreover, no quenching was observed
−
quenched by either electron transfer or other dynamic processes,
confirming that the quenching of 1 was indeed due to the
recognition of the anion on the receptor site, with concomitant
upon addition of ClO
AcO over Cl , a known amount of AcO was added to a
4
. To investigate the selectivity of 1 for
−
−
−
−
solution of 1 with a 40 mM background concentration of Cl .
5
0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6

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−
1
Whereas in the presence of Cl the emission was switched on,
H NMR of 1 and 2 very simple, as seen in Fig. 2 for 2. For 1,
−
it was quenched upon the addition of AcO clearly confirming
the thiourea protons appeared as two characteristic resonances
at 9.68 and 8.38 ppm, respectively, Fig. 8 (top spectrum) and,
as for 2 (Fig. 2), the spacer appears as a doublet. The position
of the thiourea protons changed dramatically upon addition of
−
−
that 1 was selectively binding AcO over Cl . The same results
were obtained for 2 when studied under identical experimental
conditions.
−
−
Even though these spherical anions did not give rise to any
anions such as AcO and H
2
PO
4
to a solution of the sensors in
change in either the ground or the excited states, the titration of
DMSO-d . With either of these anions (0–5 equivalents of TBA
6
−
1
or 2 with F was very different as the fluorescence emission
salts), the thiourea resonances were gradually shifted downfield
by 2.5–3 ppm, confirming the formation of the anion–receptor
complexes through hydrogen bonding. Analysis of the change
−
was almost fully quenched (ca. 98%) after F recognition. This
was due to its small size and high charge density, which makes
the hydrogen bonding between the receptors and the anion
strong and, hence, the efficiency of the PET process is enhanced.
However, the 1 : 2 binding was not so clear in this case as for
the acetate or the phosphate titration. This could possibly be
due to effective quenching of the excited state by only one of the
at 8.38 ppm as a function of concentration is shown in Fig. 9 for
−
titration of H
2
PO
4
. These results clearly show that after only
−
two equivalents of H
2
PO
4
the thiourea resonance stops shifting,
indicating that a 1 : 2 binding is observed in this case (some line
broadening was also observed). Similar results were seen for the
−
−
−
receptor–F complexes, prior to the binding of the second F .
titration of AcO . However, the clear plateau after the addition
19
Such an effect has recently been shown by Lippard et al. to
occur in PET chemosensors for Zn(II), e.g. the sensor had two
receptors but only 1 : 1 binding was confirmed by luminescence,
as the emission was fully switched on after one equivalent of
Zn(II). Here, a similar effect is possible, e.g. the emission is fully
of two equivalents of the anion was not as sharp. In addition to
monitoring these changes, the position and characteristics of the
resonances assigned to the aromatic protons and the methylene
spacers were also monitored (see Fig. 8). In comparison to
the changes in the two thiourea protons, these resonances
did not change significantly, except for those assigned to the
phenyl ring of the receptor as the anion recognition effects
the electron density of the ring upon anion recognition. This
indicates that there were only minor interactions between the
anion–receptor complex and the anthracene moiety. From these
results we conclude that for the simple monodentate anions the
stoichiometry between the sensor and the anion is 1 : 2. We did
not however determine the binding constant for this anion re-
cognition event.
−
quenched by F after only one equivalent. We do not believe
that the changes observed in the fluorescence spectra are due
to deprotonation of one or more of the thiourea protons as
could possibly occur. We base this on the fact that we have
recently developed naphthalimide based sensors that show dual
−
fluorescence/colorimetric changes by F , where the former was
caused by hydrogen bonding recognition at a thiourea receptor
and the colorimetric changes were due to deprotonation of an
−
7b
aryl amine by F . Similar results were seen for 3 (kabs = 398,
3
77 and 358 nm and k
F
= 404, 427 and 453 nm) as observed
for 1, upon titrations with these anions in DMSO. The changes
for the titration of the latter using AcO is shown in Fig. 7.
−
Analysis of these changes indeed gave rise to a 1 : 2 binding as
seen previously for 1 and 2, where the changes occurred from ca.
−
−
log[Ac ] of 1.8–4.8 (see later in Fig. 15 and Fig. 16). However,
here the quenching is only ca. 60% as the urea–acetate complex
is somewhat less effective in PET processes, most likely due
to weaker binding as the urea protons are less acidic than the
thiourea protons of 1.
1
Fig. 8 The changes in the H NMR (400 MHz) spectra of 1 in
−
DMSO-d
6
upon addition of H
2
PO
4
using, 0, 0.5 and 1 equivalent of
the anion.
Fig. 7 The changes in the fluorescence emission spectra of 3 in DMSO
−
−
upon addition of AcO ([AcO ] = 0–40 mM). As in the case of 1, the
emission of 3 is switched off upon ion recognition.
1
Evaluating the 1 : 2 binding of 1 using H NMR
To confirm the 1 : 2 binding observed in the above investigations,
1
for both acetate and phosphate, we conducted a H NMR
titration of 1 using various anions and observed the changes
1
in the H NMR of the thiourea protons in DMSO-d
6
. As
Fig. 9 The changes in the
1
H NMR resonance (Dd) of the 8.38 ppm pro-
−
mentioned previously, the high level of symmetry makes the
ton of 1 in DMSO-d
6
upon addition of H
2
PO
4
(shown in equivalents).
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6
5 1

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Photophysical evaluation of 1–3 using bidentate anions
In a similar manner to that described above, the ground state
and the excited state of 1–3 were investigated in the presence of
biologically important bis-anions such as glutarate, malonate,
and pyrophosphate [using tris(tetrabutylammonium) hydrogen
20
pyrophosphate] in DMSO. The changes in the absorption
spectra of 1 in the presence of pyrophosphate are shown in
Fig. 10. As previously observed, there are only minor changes
observed in the anthracence region upon anion recognition. In
comparison to that observed in Fig. 4, the changes here are
more pronounced particularly in the 358 and 378 nm transitions.
Furthermore, analysis of the changes at longer wavelengths
clearly showed that an isosbestic point was observed at 406 nm
(
Fig. 11). This indicates that the anthracence moiety experiences
some perturbation in its electronic structure, most likely due to
direct interactions with the anion. Similar results were observed
for both 2 and 3.
Fig. 12 The changes in the fluorescence spectrum of 1 upon titration
with pyrophosphate, which is switched off upon anion recognition.
pyrophosphate. As before the emission is switched off similarly
to that seen for the mono-anions. This efficient fluorescence
quenching is due to the enhancements in the reduction potential
of the thiourea receptor moieties upon anion recognition. Hence,
the rate of the electron transfer from the HOMO of the receptor
to the anthracene excited state is increased as DGET becomes
more thermodynamically favourable. As in previous cases, the
emission was switched on again upon addition of EtOH.
The changes in the fluorescence emission of 1 upon titration
with glutarate in DMSO were similar to that observed in
pyrophosphate (Fig. 12). As previously demonstrated, the
emission was switched off (U
this anion. The fluorescence emission of 1 was also switched off
when using malonate (U
F
= 0.012) upon recognition of
F
= 0.011) ([anion] = 40 mM in all
cases). No other spectral changes were observed in the emission
spectra. Similar results were seen using 2, where the emission
Fig. 10 The changes (corrected for dilution) in the absorption spectrum
of 1 upon titration with pyrophosphate.
was however, less affected, with U
F
= 0.039 and 0.035 after
the addition of 40 mM of glutarate and malonate respectively.
This is not surprising as the receptor is less electron deficient
compared to 1 and consequently the hydrogen bonding to the
anion can be predicted to be weaker. The changes in 3 were
similar to those observed for 1 and 2. However, the quenching
was somewhat smaller than that seen for 1 because the urea
protons are less acidic than the thiourea protons. This means
that by simply changing the nature of the substituent and the
substituent pattern can have substantial affect on both the
binding sensitivity as well as the selectivity. On each occasion
the reversibility of this binding was demonstrated by adding
competitive solvents to the media.
To evaluate the selectivity and the sensitivity of this anion
sensing, the changes at different wavelengths were monitored.
The relative fluorescence changes for the anions tested for 1 are
−
−
shown in Fig. 13 (Cl and Br are omitted as the fluorescence
changes were too small), when observed at 430 nm as a function
of −log[anion]. As can be seen from these changes, all the
anions give rise to sigmoidal curves. Importantly, the emission
is switched off over two logarithmic units for pyrophosphate
and malonate, which would suggest a 1 : 1 binding and a simple
Fig. 11 The changes in the absorption spectrum of 1 upon titration
−
with H
2
PO
4
between 390–410 nm only.
equilibrium. From these changes, using the equation log[(Imax
−
13,22
The concomitant changes in the fluorescence emission spectra
of 1 are shown in Fig. 12. Unlike that seen for the changes in the
ground state, the excited state of the anthracene is substantially
affected upon anion recognition, being switched off by ca. 95%.
As before in the case of the mono-anions, no other significant
spectral changes were observed in the emission spectra, i.e. no
change in the emission wavelength or the formation of excimer
emission bands. Similar changes were seen for 2, the quenching
I
F
)/(I
F
− Imin)] = log[anion] − logb,
the binding constants
(logb) of 2.34 (± 0.05) and 3.40 (± 0.05) were determined, for
malonate and pyrophosphate respectively, for 1.
As stated earlier, the changes in the fluorescence were
modulated over more than two logarithmic units for the mono-
13
anions. These results are also included in Fig. 13 for 1. Similar
trends were found for 2 and 3, as shown in Figs. 14 and 15 re-
spectively. For the 1 : 1 binding of the bis-anions to 2, the binding
constant was measured to be 3.07 (± 0.05) and 2.02 (± 0.05) for
pyrophosphate and malonate respectively. The gluatarte binding
was also observed but not with a clear 1 : 1 binding. These
for 2 being ca. 90%. For these changes the U values of 0.001
F
and 0.017 were determined after these titrations for 1 and 2
respectively. Similar changes were seen for 3 upon titration with
5
2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6

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Table 1 Binding constants for the proposed 1 : 1 binding to 1, 2 and
ab
3
1
2
3
−
F
4.13
3.40
2.34
3.74
3.03
3.07
3.15
3.27
3.30
2.72
2.66
3.77
Pyrophosphate
Malonate
Glutarate
a
All measured in DMSO at room temperature and were repeated 2 or
3
times. Using data from different wavelengths gave, on all occasions,
b
same binding constants with in 5–10% error. Determined using the
equation: log[(Imax − I
22
F
)/(I
F
− Imin)] = log[anion] − logb.
glutarate is of similar magnitude to that observed for Hamilton’s
receptors.
Fig. 13 The relative intensity changes in the fluorescence spectrum of
1
H
, when measured at 430 nm, upon addition of: ×= malonate; ꢀ =
−
−
−
2
PO
4
; ꢀ = AcO ; ᭜ = pyrophosphate; * = glutarate; ᭺ = F .
For 3, the binding of the anions was similar to that seen for
both 1 and 2. The changes for the binding of both the mono- and
the bis-anions are shown in Fig. 15. As mentioned previously, the
−
−
mono-anions gave rise to a 1 : 2 binding for AcO and H
2
PO .
4
−
It is also clear that for F the emission is ca. 90% quenched after
one equivalent of the anion. For malonate and pyrophosphate
the binding was also determined to be in a 1 : 1 stoichiometry,
with logb values of 2.6 (± 0.05) and 2.8 (± 0.05) respectively.
However, unlike that seen for either 1 or 2, the detection of
glutarate gives rise to ca. 1 : 1 binding. These binding results are
summarized in Table 1.
Fig. 14 The relative intensity changes in the fluorescence spectrum of
These results indicate that for 1 and 2 there is a clear trend,
where all the anions were detected at a lower concentration for
2
, when measured at 430 nm, upon addition of: ×= malonate; ꢀ =
−
−
−
H
2
PO
4
; ꢀ = AcO ; ᭜ = pyrophosphate; * = glutarate; ᭺ = F .
1
in comparison to 2, with the exception of malonate. This is
due to the electron withdrawing effect of the CF substituent
3
on the receptor, making the N–H more acidic. However, for 3
the binding is usually weaker than for either 1 or 2. Overall,
the presence of the second binding site in 1–3 gives rise to the
selective 1 : 1 binding of anions that can potentially bridge
the anthracene moiety. We foresee this occuring in a manner
as shown in Scheme 2. This is supported by the fact that an
isosbestic point was observed for these titrations, whereas in the
1
: 2 binding of the more simple anions, such as acetate and
phosphate, it was absent. We also showed that this 1 : 2 binding
1
was observed in the H NMR, where the resonances assigned
to the anthracene fluorophore were not affected. Consequently,
1
we evaluated the changes in the H NMR spectra of 1 in the
presence of pyrophosphate, which had shown the best fit to 1 :
1
binding for 1–3.
Fig. 15 The relative intensity changes in the fluorescence spectrum of
3
H
, when measured at 430 nm, upon addition of: ×= malonate; ꢀ =
−
−
−
2
PO
4
; ꢀ = AcO ; ᭜ = pyrophosphate; * = glutarate; ᭺ = F .
overall changes can be seen in Figs. 13–15, and treading the
data observed using a 1 : 1 fitting gave binding constants of
3
.74, 3.15 and 3.77 for 1, 2 and 3 respectively. Hamilton et al.
have investigated the binding of structurally similar systems, 8
10
and 9. The anion binding constants for 8 with the TBA salt
2
−1
of glutaric acid in DMSO-d
6
was determined as 6.4 × 10 M ,
a
whereas for the thiourea system 9 a fifteen-fold increase, K
.0 × 10 M , was observed. Hence, the binding of 1 and 3 by
=
Scheme 2 The possible binding of the bis-anions by 2 in a 1 : 1 binding
stoichiometry.
4
−1
1
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6
5 3

View Online
1
Evaluating the 1 : 1 binding of pyrophosphate by 1 using H
NMR
have been demonstrated between the two pyrene units and
21
pyrophosphate.
1
The H NMR titrations were carried out in the same manner
as described for the mono-anions. As before, the position of the
thiourea protons changed dramatically upon addition (greater
Conclusion
We have demonstrated the synthesis of several new PET sensors
for anions. These sensors were designed to target anions
flanked with two binding sites such as bis-carboxylates and
pyrophosphate. The anion sensing of these compounds was
demonstrated using fluorescence. For sensors 1–3 the emission
was switched off upon titration with various anions. This was
due to the enhancement in the PET quenching of the anthracene
excited state upon anion recognition, which occurred through
hydrogen bonding between the thio or the urea protons and
the anions. This binding mode was confirmed by observing the
changes in the thiourea protons of 1 upon titration with several
anions. By monitoring the changes in the fluorescence emission
spectra as a function of anion concentration, we demonstrated
than 3 ppm) of pyrophosphate in DMSO-d . There was also a
6
substantial line broadening observed at the later stage of the
titration. These changes are seen in Fig. 16 for 1. By plotting
the changes in the thiourea proton at 8.38 as a function of the
added anion, a binding profile was observed (Fig. 17) which
demonstrated the formation of 1 : 1 binding between the anion
and the sensor. From these changes, a logb of 3.61(± 0.05)
was determined, with a clear 1 : 1 binding, which is in good
agreement with that seen using fluorescence (logb of 3.45). For
such recognition to take place the anion would have to bridge the
anthracene moiety in the manner we have proposed in Scheme 2.
Hence, such bridging would most likely affect the resonances
of the anthracene moiety. As discussed earlier, the anthracene
−
−
that for simple anions such as AcO and H
2
PO
4
the recognition
−
resonances were not affected upon addition of either AcO or
was due to the formation of a 1 : 2 binding between the sensors
−
H
2
PO
4
(Fig. 8). However, as can be seen in Fig. 16, this is not the
−
−
and the anions. For halides such as Cl and Br no significant
case for pyrophosphate, where both shifts and line broadening
occur upon anion recognition. Therefore, these results support
the possibility that the anion bridges across the anthracene,
ruling out the possibility of obtaining the 1 : 1 ratio via two
sensors binding to two anions simultaneously.
−
fluorescence changes occurred. However, for F the emission was
almost fully quenched after only one equivalent of the anion.
The recognition of bis-anions such as pyrophosphate, mal-
onate and glutarate was also demonstrated. For the first two
of these anions, the sensing was shown to be in the 1 : 1
stoichiometry, whereas for glutarate the binding was most likely
1
: 2 for 1 and 2. The 1 : 1 binding of pyrophosphate was also
1
demonstrated using H NMR.
To the best of our knowledge these are the first PET sensors
for such bis-anions where the anion recognition occurs through
hydrogen bonding between the anion and the charge neutral
receptors, with concomitant enhancements in the quenching of
the fluorophore excited state. We are currently developing other
anion sensors for bis-anions with the aim of improving both
selectively and the sensitivity of the sensors, as well as making
this sensing process possible in aqueous environments.
Experimental
1
General
Fig. 16 The changes in the H NMR (400 MHz) spectra of 1 in
DMSO-d upon addition of pyrophosphate using 0, 0.5, 1 and equivalent
6
Reagents (obtained from Aldrich) and solvents were purified
using standard techniques. Solvents were dried over the ap-
propriate drying agent before use using standard procedures.
Melting points were determined using a GallenKamp melting
point apparatus. Infrared spectra were recorded on a Mattson
Genesis II FTIR spectrophotometer equipped with a Gateway
of the anion. Unlike that seen in Fig. 8, the aromatic resonances are
substantially affected upon binding.
2
000 4DX2-66 workstation. Oils were analysed using NaCl
plates and solid samples were dispersed in KBr and recorded as
1
clear pressed discs. H NMR spectra were recorded at 400 MHz
1
3
using a Bruker Spectrospin DPX-400 instrument. C NMR
were recorded at 100 MHz using a Bruker Spectrospin DPX-400
instrument. Fluorescent measurements were made on a Perkin
Elmer LS 50B. UV-Vis absorption spectra were recorded at room
temperature using a Shimadzu UV-2401PC.
Syntheses of 1–4
9
,10-Bis (aminomethyl) anthracene, 4. 9,10-Bis-bromom-
ethylanthracene, 8 (0.37 g, 1.02 mmol) was dissolved in an-
hydrous CHCl (15 mL). This solution was added drop-wise
to a solution of hexamethylenetetramine (0.2848 g, 2.03 mmol)
in 10 mL of anhydrous CHCl and the resulting solution was
3
3
1
Fig. 17 The changes in the H NMR resonance (Dd) of the 8.38 ppm
refluxed for 5 hours with vigorous stirring. The precipitate
was removed by filtration and washed several times with water,
before adding to a mixture of ethanol, water and concentrated
hydrochloric acid (20 : 4 : 5). This mixture was heated at
6
proton of 1 in DMSO-d upon addition of pyrophosphate.
As we did not obtain the formation of any excimer emis-
sion in the fluorescence spectra, it also supports the notion
that a 2 : 2 binding is not occurring. Recently however the
interactions between pyrophosphate and pyrene fluorophores
◦
70 C overnight. The precipitate dissolved initially and then
re-precipitated out of solution after 1 hour. This precipitate was
removed by filtration then dispersed in 10% KHCO (20 mL) and
3
5
4
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6

View Online
extracted into CHCl
3
(2 × 20 mL). The organic layer was then
cooling, the green solid formed was filtered and washed with
dried over MgSO . Excess solvent was removed under reduced
4
water and ethanol. The resulting crude product was recrystalized
◦
pressure and the residue was dried over P
2
O
5
overnight (0.2005 g,
: C, 81.32%;
from toluene (15.32 g, 75%). Mp 300 C (dec.); CHN calculated
◦
8
3%). Mp 238 C; CHN calculated for C16
H
16
N
2
for C16
H
12Br : C, 52.78%; H, 3.32%; found C, 52.79%; H, 3.30%;
2
H, 6.32%; N, 11.85%; found C, 81.29%; H, 6.33%; N, 11.82%;
(100 MHz, CDCl ): 4.43 (s, 4H, 15-H, 16-H), 7.55 (dd, J
3.0 Hz, J = 3.0 Hz, J
= 2.5 Hz, 4 H, Ar-H), 8.53 (dd, J
.5 Hz, 4 H, Ar-H); d (400 MHz, CDCl ): 45.6, 124.7, 126.2,
30.4, 131.7; IR (KBr) cm ; 3458, 3048, 1953, 1622, 1528, 1195.
d
H
(400 MHz, CDCl
3.4 Hz, J
= 6.9 Hz, 4 H, Ar-H), 8.38 (dd, J
6.9 Hz, 4 H, Ar-H); d (400 MHz, CDCl
IR (KBr) cm 3048, 1953, 1622, 1528, 1442, 1195
3
): 5.50 (s, 4H, 15-H, 16-H), 7.68 (dd, J
1
=
d
H
3
1
2
1
= 3.4 Hz, J
2
=
=
2
1
2
=
C
3
): 26.6, 124.4, 126.7;
−
1
2
1
C
3
−
1
9,10-Diaminomethylanthracene 4. The bis-bromomethyl-
9
,10-Bis-trifluoromethylphenyl-thioureamethyl anthracene, 1.
anthracene 8 (0.37 g, 1.02 mmol) was dissolved in anhydrous
CHCl (15 mL). This solution was added drop-wise to a solution
9
,10-Bis-aminomethyl anthracene 4 (0. 6 g, 2.54 mM) was
3
dissolved in 30 mL of dry DCM. To this solution was added
-trifluoromethylphenylisothiocyanate (1.03 g, 5.09 mM, 1.01
of hexamethylenetetramine (0.2848 g, 2.03 mmol) in 10 mL of
4
anhydrous CHCl and the resulting solution was refluxed for
3
eq.). A creamy yellow precipitate was immediately formed upon
addition of the isothiocyanate. However, it is believed that this
precipitate was the mono-thiourea. Therefore, the reaction was
allowed to stir vigorously overnight at room temperature. The
resulting precipitate was removed by filtration, washed with dry
5 hours with vigorous stirring. The precipitate was removed by
filtration and washed several times with water. The precipitate
was added to a mixture of ethanol, water and concentrated
hydrochloric acid (20 : 4 : 5). This mixture was heated at
◦
70 C overnight. The precipitate dissolved initially and then re-
CHCl
3
and dried over P
2
O
5
, followed by recrystallisation from
precipitated out of solution after 1 hour. This precipitate was
◦
chloroform (0.999 g, 89% yield). Mp 256 C; CHN calculated
removed by filtration then dispersed in 10% KHCO (20 mL) and
3
for C32
H
24
F
6
N
4
S
2
: C, 59.80%; H, 3.76%; N, 8.72%; found C,
9.81%; H, 3.74%; N, 8.75%; d (400 MHz, CDCl ): 5.75 (s,
H, 15-H, 24-H), 7.63 (d, J
= 8.5 Hz, 4 H, Ar-H), 7.70 (dd,
= 3.5 Hz, J = 3.0 Hz, 4 H, Ar-H), 7.82 (d, J = 8.5 Hz,
H, Ar-H), 8.53 (dd, J = 3.0 Hz, 4 H, Ar-H);
= 3.5 Hz, J
(400 MHz, CDCl ): 179.9, 139.6, 132.1, 130.0, 128.7, 126.5,
25.5, 125.1, 121.5, 122.5, 67.4; F NMR: 60.9; MS m/z (ES):
extracted into CHCl (2 × 20 mL). The organic layer was then
3
5
2
J
4
H
3
dried over MgSO . Excess solvent was removed under reduced
4
1
pressure and the residue was dried over P O overnight (0.2005 g,
2
5
◦
1
2
1
83%). Mp. 238 C; CHN calculated for C H N : C, 81.32%; H,
1
6
16
2
1
2
6.32%; N, 11.85%; found C, 81.29%; H, 6.33%; N, 11.82%; dH
(400 MHz, CDCl ): 4.43 (s, 4H, 15-H, 16-H), 7.55 (dd, J =
d
C
3
3
1
1
9
1
6
3.0 Hz, J = 2.5 Hz, 4 H, Ar-H), 8.53 (dd, J = 3.0 Hz, J =
C 3
2
1
2
+
−1
43 ([M] ); IR (KBr) cm ; 3400, 2922, 1533, 1328, 835.
2.5 Hz, 4 H, Ar-H); d (400 MHz, CDCl ): 45.6, 124.7, 126.2,
1
−
1
30.4, 131.7; IR (KBr) cm 3458, 3048, 1953, 1622, 1528, 1195.
9
,10-Bis-trifluoromethylphenyl-ureamethyl anthracene, 2.
−
3
9
,10-Bis-aminomethyl anthracene 4 (0.6 g, 2.54 × 10 mol) was
Acknowledgements
dissolved in 20 mL of dry DCM. To this solution was added
−
3
4
1
-trifluoromethylphenylisocyanate (0.95 g, 5.09 × 10 mol,
We thank Enterprise Ireland, Kinerton Ltd and TCD for
financial support and Dr Hazel Moncrieff and Dr Juliann
Tierney for their help.
.01 eq.). A creamy yellow precipitate was immediately formed
upon addition of the isocyanate. However, it is believed that this
precipitate was the mono-thiourea. Therefore, the reaction was
allowed to stir vigorously overnight at room temperature. The
resulting precipitate was removed by filtration, washed with dry
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2
O
5
, followed by recrystallisation from
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(
removed by filtration, washed with dry CHCl
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1
0 (a) Urea receptors have been used to bind bis-anions where the
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5
6
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 4 8 – 5 6