Design, synthesis and photophysical studies of simple fluorescent anion PET sensors using charge neutral thiourea receptors.

Article abstract of DOI:10.1039/b404706k

The synthesis of four fluorescent photoinduced electron transfer (PET) chemosensors 1-4 for anions is described. These are all based on a simple design employing charge neutral aliphatic or aromatic thiourea anion receptors connected to an anthracene fluo

Full text of DOI:10.1039/b404706k

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Design, synthesis and photophysical studies of simple fluorescent
anion PET sensors using charge neutral thiourea receptors
Thorfinnur Gunnlaugsson,*a Anthony P. Davis,a,b Gillian M. Hussey,a Juliann Tierneya
and Mark Glynna
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
b School of Chemistry, University of Bristol, Cantock’s Close, Bristol, UK BS8 1TS
Received 30th March 2004, Accepted 13th May 2004
First published as an Advance Article on the web 16th June 2004
The synthesis of four fluorescent photoinduced electron transfer (PET) chemosensors 1–4 for anions is described.
These are all based on a simple design employing charge neutral aliphatic or aromatic thiourea anion receptors
connected to an anthracene fluorophore via a methylene spacer. Here the anion recognition occurred through 1 : 1
hydrogen bonding between the thiourea protons and the anion, as demonstrated by observing the changes in the 1H
NMR in DMSO-d6 where the two thiourea protons were shifted downfield upon addition of anions. Whereas 1–3
were designed for the detection of anions such as fluoride, acetate or phosphate, 4 was made for the recognition of
N-protected amino acids. All the sensors showed ‘ideal’ behaviour where only the fluorescence emission was quenched
upon anion recognition, due to enhanced efficiency of electron transfer quenching from the receptor to the excited
state of the fluorophore. By simply varying the nature of the thiourea substituent it was possible to modulate, or
tune, the acidity of the thiourea receptor moiety, altering the sensitivity of the anion recognition. For 1, the anion
selectivity and the degree of the fluorescence quenching were in the order of FϪ > AcOϪ > H2PO4Ϫ, with ClϪ or BrϪ
not being detected.
where the anion recognition would give rise to ideal PET anion
Introduction
sensing, i.e. only the quantum yield (ΦF) and the fluorescence
Anions play a major role in many biological processes and in
lifetime would be affected upon ion recognition.16,17 Hence, no
biological structures, such as amino acids, neurotransmitters,
other spectral changes such as exciplex or excimer emission or
enzyme substrates, co-factors and nucleic acids.1 They are also
changes in the absorption spectra should be observed.18 Here
important components in a variety of industries, such as in the
we give a full account of our investigation, where we developed
production of fertilisers, in food additives and in the water
the charge neutral PET sensors 1–3, for the detection of simple
supply.1 Consequently, many anions are also major pollutants
anions such as halides, acetates or phosphates.10 Furthermore,
both industrially and environmentally. The recognition and
we describe a chiral PET sensor 4 aimed at the enantioselective
sensing of carboxylates such as N-acetyl protected amino acids.
Even though we were unable to achieve enantioselectivity, we
demonstrate the potential feasibility of such sensing, as the
fluorescence of 4 was highly modulated upon addition of
N-acetyl protected amino acids.
sensing of anions are of current interest in the field of supra-
molecular chemistry.2–8 Whereas the sensing of cations is a well
established field of research,2 it is only recently that the same
can be said for anion sensing.3–5 This stems from the fact that
in contrast to biologically important cations, such as Naϩ, Ca2ϩ
or NH4ϩ, anions often exhibit a variety of structures and
conformations, and are often highly pH sensitive as well as
hydroscopic.6 In view of this fact, the recognition of anions
frequently requires the use of structurally complicated hosts,
furnished with anion recognition motifs7 that often require
elaborate and lengthy synthesis,3,8 or the use of metal ion
coordination centres.9 All of these features have to be carefully
considered and implemented in the design strategy of efficient
anion recognition motifs. Due to these drawbacks the develop-
ment of simple luminescent sensors for anions has only recently
been explored.10 We are interested in the design of luminescent
devices, and we have developed fluorescent11 as well as
lanthanide luminescent12 chemosensors, switches and logic-
gate mimics. We are particularly interested in the development
of luminescent sensors for anions and have developed several
simple lanthanide based sensors for the detection of carb-
oxylates.13 Having developed several photoinduced electron
transfer (PET) sensors for cations,11 we set out to develop
simple and easy to make PET anion sensors,10 based on the use
of the fluorophore–spacer–receptor motif developed by de
Silva.2 Even though Fabbrizzi et al.14 and Czarnick et al.15 have
developed PET sensors for anions using positively charged
receptors, to the best of our knowledge, no fluorescent PET
sensors using charge neutral receptors have been developed.
Our aim was thus to demonstrate the feasibility of such sensing,
Results and discussion
Design and synthesis of 1–4
We chose to use thiourea as a receptor moiety with the aim of
demonstrating anion PET sensing. Thioureas and ureas are well
known hydrogen bonding donors and have been used by several
researchers as anion recognition sites for anion detection,16,17,19
or in organic synthesis as catalysts.20 They are easily made from
commercially available isocyanates or isothiocyanates, raising
the possibility of developing a range of (thio)urea receptors
where the acidity of the hydrogen bonding donor can be tuned.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
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 4
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This would lead to different receptor:anion stabilities and
subsequently provide different affinity and selectivity.10 To
demonstrate such PET sensing we chose to use anthracene as a
fluorophore, as this moiety had been used previously by several
researchers to demonstrate PET sensing.1,14,15,21 All the sensors
contain the thiourea receptor connected to the anthracene via a
methyl spacer, giving rise to a fluorophore–spacer–anion receptor
motif. Scheme 1 shows the synthesis of 1–3, which was carried
out in dry CH2Cl2 at room temperature. All the sensors were
easily made from 9-(aminomethyl)anthracene 5 (see discussion
below) and an equimolar amount of 4-(trifluoromethyl)phenyl-
(7), phenyl- (6) and methyl isothiocyanate (8) respectively. The
resulting products all precipitated upon formation (instantly),
but stirring was continued for 12 hours. After reducing the
volume, the precipitates were isolated by filtration and
recrystallised from hot CHCl3, giving 1 and 2 in 84% and 77%
yield respectively. For 3, the final product was purified by silica
flash chromatography with 100% ethyl acetate as the eluent,
giving 3 in 67% yield.
insoluble amine complex, which was isolated by filtration and
dispersed in a solution of ethanol, water and concentrated HCl
in a ratio of 20 : 4 : 5. The complex dissolved on heating to
70 ЊC and was refluxed for a subsequent hour. After this time a
precipitate of the HCl salt began to form. Once removed from
the heat the solution was then allowed to stand at room temper-
ature overnight and the product was isolated by filtration in
ca. 90% yield.
The three sensors were characterised using conventional
1
methods. The H NMR of 2 when recorded in DMSO-d6 is
shown in Fig. 1, clearly demonstrating the C2 symmetry of the
anthracene moiety. Here the three most characteristic reson-
ances are the two thiourea hydrogens marked as a and b, at 9.62
ppm and 8.36 ppm respectively and the methylene spacer
marked as c, at 5.72 ppm. It can be seen that the methylene
resonance appears as a doublet, coupling to the adjacent thio-
urea proton b. Similar results were observed for 1 and 3. The
13C NMR of 2 also clearly demonstrated the presence of the
thiourea carbon, appearing at 179.6 ppm. We were however
unable to characterise these sensors using ESMS due to
fragmentation.
Scheme
1
Synthesis of the anion PET sensors 1–3, from 9-
(aminomethyl)anthracene 5, and phenyl-, 4-(trifluoromethyl)phenyl-,
and methyl isothiocyanates, giving 1, 2 and 3 respectively. Carried out in
dry CH2Cl2 at room temperature for 12 hours.
The synthesis of 5 is worthy of comment. A previously
reported preparation of 9-(aminomethyl)anthracene employed
the Gabriel synthesis (Scheme 2).22 9-Anthraldehyde was
reduced with NaBH4 to the corresponding methyl alcohol 9,
which was then converted to 9-(chloromethyl)anthracene using
thionyl chloride. Treatment with potassium phthalimide gave
10, and reaction with NH2NH2 in DMF gave 5. However,
this method is both lengthy and low yielding due to the poor
solubility of 10. Consequently we set out to improve the yield
of 5, using two alternative methods.
Fig. 1 The 1H NMR (400 MHz, DMSO-d6) of 2. The two resonances
corresponding to the thiourea protons are marked as a and b and the
methylene spacer as c. The remaining resonances can be assigned to the
aromatic receptor and the anthracene protons.
In the case of 4, we firstly made 9-(isothiocyanatomethyl)-
anthracene 11, which was then reacted with the enantio-
merically pure (S)-1-phenylethylamine 12, in dry CHCl3 at
room temperature, Scheme 3. The isothiocyanate 11 has
recently been made by Suzuki et al.25 We made 11 from 5, by
reacting it with thiophosgene in a biphasic mixture of saturated
NaHCO3 and THF. The product was obtained as an oil and
was subjected to purification on neutral flash silica using ethyl
acetate–hexane (9 : 1) as the eluent, after which 11 was obtained
as an orange solid in 20% yield.
Scheme 2 Synthesis of the 9-methylamine anthracene 5, using the
classical Gabriel amine synthesis.
We firstly carried out numerous attempts to reduce the
commercially available 9-cyanoanthracene to 5, using reagents
such as NaBH4, LiAlH4 or B2H6 in solvents such as THF or
DMF at either room temperature or at elevated temperatures.
Of the different methods employed, the use of B2H6 (using
borane–THF complex) in either refluxing THF or DMF gave
5 in the best yields of 68% and 65% respectively, after
aqueous acid–base workup. However, the yield of 5 was highly
dependent on the quality of the borane–THF complex.
Consequently, another method was investigated, which
involved the transformation of 9-(bromo- or 9-(chloro-
methyl)anthracene23 with hexamethylenetetramine24 in dry
CHCl3 at 60 ЊC. This amine is cheap and easy to use. It reacted
readily with 9-(halomethyl)anthracene in CHCl3 to yield an
Scheme 3 Synthesis of the chiral sensor 4.
The chemosensor 4 was obtained as a yellow powder that
precipitated upon reacting 11 with 12, under conditions similar
to those described above for 1–3. The 1H NMR of 4 had
characteristic resonances for the two thiourea protons at
6.24 ppm and 6.22 ppm, the latter of these appearing as a
doublet due to the coupling to the benzylic proton. As in the
case of 1–3, we were unable to obtain HRMS of this product
as it fragmented in the ESMS. To investigate the effect of
the anion recognition on the receptor moieties themselves, we
also synthesised 13, Scheme 4, which mimics the structural
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
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in the absorption spectra of these compounds upon titration
with any of the aforementioned anions. Hence, the ground
state results fulfilled the PET criteria that there should be no
significant changes in the absorption spectra.
We next investigated the effect of the excited state of 1–3
upon titration of several anions. This was carried out in an
identical way to that described above for the ground state
investigation in DMSO. In contrast to the above results, the
changes in the fluorescence emission spectra of 1–3 were very
different. In the case of 2, significant fluorescence emission was
observed upon excitation at 370 nm. Here a typical anthracene
emission was observed, with emission bands at 443 nm, 419 nm
and 397 nm, and a shoulder at 473 nm respectively. Using
9-methylanthracene as a reference,26 the quantum yield of
fluorescence (ΦF) was determined as 0.104. In comparison, the
ΦF of 9-methylanthracene, which lacks the anion receptor was
0.284 in DMSO. This would indicate that some quenching is
occurring in 2, which might suggest that there was an active
quenching of the anthracene exited state by the receptor moiety
via photoinduced electron transfer prior to any anion
Scheme 4 Synthesis of the anion receptor 13.
features of the receptor used in 2. This was achieved in a similar
manner to that of 1–3, by reacting 4-(trifluoromethyl)phenyl
isothiocyanate with ethylene amine (2 M in THF) in anhydrous
CH2Cl2 at room temperature.
Photophysical evaluation of 1–3 in DMSO
The photophysical properties of 1–3 were initially measured in
DMSO. We first investigated the ground state properties of 2
(1 × 10Ϫ5 M) upon anion recognition in HPLC grade DMSO,
using tetrabutylammonium acetate (TBAOAc). In accordance
with ideal PET sensor design, we did not expect to see many
changes in the ground state properties for the anthracene moi-
ety of 2 upon anion recognition on the receptor site as stated
above. The absorption spectra of the free sensor 2 gave rise to
typical anthracene absorption bands at 390, 370, 352 and 336
nm respectively. These transitions appear at almost identical
positions to that of 9-methylanthracene. The changes in the
absorption spectra of 2 upon addition of AcOϪ are shown in
Fig. 2. As can be seen from this titration, only minor changes
occur in the anthracene absorption spectra. However there are
some changes occurring at short wavelength, which are due to
the thiourea receptor. Hence upon anion recognition, through
hydrogen bonding, Scheme 5, the charge density of the aromatic
moiety is substantially affected as the anion increases the reduc-
tion potential of the receptor. To investigate this further we
carried out an identical absorption titration using AcOϪ and 13.
This confirmed that the changes at shorter wavelengths, as in
the spectra of 2 were indeed due to the hydrogen bonding
interactions of the anion with the thiourea protons. These
results confirm that there are no significant ground state inter-
actions between the anthracene fluorophore and the thiourea
receptor, as the methylene spacer prevents any π–π or n–π
interactions between the two moieties. We also investigated the
effect of the addition of several other anions such as FϪ, ClϪ,
recognition. Upon addition of AcOϪ (0
32 mM), Fig. 3, the
intensity of the anthracene emission bands gradually decreased
with no other spectral changes being observed i.e. no spectral
shifts or formation of new emission bands, such as red shifted
exciplex formation. Teramae et al.16 have recently shown that
pyrene based chemosensors having aliphatic thiourea anion
receptors (similar to 3) give rise to long wavelength emission
bands. These were due to the formation of intramolecular
exciplex emission after anion recognition, hence these related
examples can be considered as a ratiometric anion indicator.16
In our case, using PET nomenclature, the emission can be said
to have been approximately 70% (at 419 nm) ‘switched off’ with
ΦF = 0.0070. The fluorescent excited state lifetime of the free
ligand, or in the presence of AcOϪ, was unfortunately too short
for us to obtain an accurate estimate.
Ϫ
BrϪ, and H2PO4 (as their TBA salts) upon the absorption
spectra of 2. Similar results were observed for these anions as
for AcOϪ. In an analogous way the absorption spectra of 1 and
3 were also recorded. As for 2, no significant changes were seen
Fig. 3 Changes in the fluorescence emission spectra of 2 upon addition
of TBAOAc (0
32 mM) in DMSO.
In a similar way to that described above, the fluorescence
emission was also substantially affected upon titrating 2 with
H2PO4Ϫ and FϪ, Figs. 4 and 5 respectively, whereas neither ClϪ
nor BrϪ gave rise to any substantial changes in the fluorescence
emission (less than 5%). As for the AcOϪ titration, only the
emission intensities of 2 are affected upon anion recognition.
The changes in the fluorescence spectra vary significantly. For
Fig. 2 The changes in the absorption spectra of 2 upon titration with
TBAOAc (0
32 mM) in DMSO.
Ϫ
H2PO4 the fluorescence emission was quenched by approx-
imately 50% (ΦF = 0.0156), whereas for FϪ the quenching (at
443 nm) was much more pronounced, being ca. 90% (ΦF
=
0.0011) quenched. For ClϪ (ΦF = 0.108) or BrϪ (ΦF = 0.088) the
quenching is poor, ruling out any quenching by heavy atom
effect. We propose that this difference in quenching between
these anions is due to their ability to form strong receptor:anion
complexes with 2. FϪ is a small spherical anion with high charge
Scheme 5 The formation of linear hydrogen bonding between the
thiourea protons of the receptor of 2 with AcOϪ in DMSO.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
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a
Table 1
1
2
3
b
c
b
c
b
c
Sensor
ΦF
% Fred
Log βd
ΦF
% Fred
Log βd
ΦF
% Fred
Log βd
Free
0.187
0.16
0.101
0.067
0.173
0.172
0.108
0.007
0.0156
0.0011
0.108
0.088
0.340
0.200
0.110
0.230
0.300
0.250
AcOϪ
73
46
64
8
2.15
1.82
2.90
75
50
90
7
2.33
2.05
3.35
43
38
55
12
14
1.75
2.05
2.37
Ϫ
H2PO4
FϪ
ClϪ
—
—
—
e
e
e
BrϪ
7
—
12
—
—
e
e
e
a All measurements carried out in DMSO at room temperature. b We estimate the error in these measurements to be 5%. c The % of fluorescent
quenching (reduction). d We estimate the error in these measurements to be 0.1. e These changes were too small for the determination of accurate
binding.
‘switched on’, as the thermodynamic pathway for PET is
removed.
To investigate the sensitivity and the selectivity of 2 towards
the above anions we investigated the intensity changes as a
function of the anion concentration. This is shown in Fig. 6,
where the relative intensity at 419 nm has been plotted as a
function of the Ϫlog [Anion]. From these changes, it is obvious
Ϫ
that the binding profiles for AcOϪ, H2PO4 and FϪ are all
sigmoidal, whereas no significant changes are seen for ClϪ and
BrϪ. Moreover, as quenching occurs over ca. two log units, it
can be deduced that the sensing is due to a simple equilibrium
and 1 : 1 binding, both features that are commonly seen
for PET cation sensors. From the equation: log [(Imax Ϫ IF)/
(IF Ϫ Imin)] = log [anion] Ϫ log β, these were evaluated to be
3.35 ( 0.05) for FϪ, 2.55 ( 0.05) for AcOϪ and 2.05 ( 0.05) for
H2PO4Ϫ. These results are summarised in Table 1 for all the
sensors. Importantly, even though the structure of the receptor
of 2 is simple it shows good anion selectivity with AcOϪ over
H2PO4Ϫ, both anions representing families of biologically
Fig. 4 Changes in the fluorescence emission spectra of 2 upon addition
important anions. The fact that 2 shows higher affinity and
more efficient quenching for FϪ than AcOϪ is not surprising,
since fluoride’s high charge density and small size enable it
to form strong hydrogen bonds with the thiourea receptor, as
previously discussed.
of TBA H2PO4 (0
32 mM) in DMSO.
Fig. 5 Changes in the fluorescence emission spectra of 2 upon addition
of TBAF (0 32 mM) in DMSO.
density and can hydrogen bond strongly to the receptor,
whereas AcOϪ can form a stronger linear-directed hydrogen
bonding complex than H2PO4Ϫ. The results obtained for the
other halides are simply explained due to size exclusion, and
smaller charge density than for FϪ, e.g. these ions are too big to
give rise to strong hydrogen bonding to the thiourea. We
propose that these hydrogen bonding receptor:anion complexes
affect the reduction potential of the thiourea receptor, which in
turn will enhance the free energy of PET (∆GPET) quenching.
Hence the rate of PET from the HOMO of the receptor to the
anthracene excited state, is greatly increased as the reduction
potential of the thiourea is increased upon anion recognition.
This will thus cause the fluorescence emission to be more
quenched, or ‘switched off’. These systems operate in reverse
to the classical PET cation sensing,2,11 where the oxidation
potential of the receptor is increased causing the emission to be
Fig. 6 Changes in the relative fluorescence emission at 419 nm of 2
upon addition of TBAOAc (᭜); TBA H2PO4 (×); TBAF (*); TBACl
(ꢀ) and TBABr (᭿) in DMSO.
We carried out identical titrations to those described above
using 1 and 3. As expected, the binding affinity for the anions of
these sensors was not as strong relative to that of 2 due to the
lower electron withdrawing ability of the skeleton groups of
1 and 2. Furthermore, these results demonstrated that although
using simple thiourea moieties, we were able to ‘tune’ the sensi-
tivity of the ion recognition. The absorption and fluorescence
spectra were similar to that of 2 shown above, due to the com-
mon anthracene ring with only a slight shift in the absorption
λmax ca. ∼2 nm for 1 and 3 respectively. Furthermore, similar
changes in the emission and absorption effects were observed
for 1 and 3 as seen for the titrations of 2 with the various TBA
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
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salts i.e. no significant changes were seen in the absorption
spectra. Whereas the fluorescence emission was quenched for
both upon anion recognition, with no other spectral changes
being observed. Hence, as in the case of 2, both sensors behaved
like ideal PET sensors, as only the intensity or the ΦF was
modulated. For these, the ΦF was measured to be 0.187 and
0.34 for the two sensors respectively prior to the anion sensing.
This clearly supports our earlier findings that the emission is
quenched prior to the anion recognition, as the magnitude of
ΦF follows the same order as the ability of the receptors to
participate in PET, hence, the electron density of the receptors
is 2 > 1 > 3. We attempted to evaluate the changes in the
reduction potentials of the receptor 13, as a function of
[AcOϪ] using cyclic voltammetry with the aim of evaluating
∆GPET. Unfortunately, the CV measurements on 13 showed two
irreversible oxidative waves, and hence accurate ∆GET could not
be determined from these measurements.
The changes in the relative fluorescence emission of 1 and 3
as a function of Ϫlog [anion] are shown in Figs. 7 and 8 respect-
ively. As can be seen from these titration profiles, all gave rise to
sigmoidal curves over two log units, which as discussed before,
signify the formation of 1 : 1 binding. From the changes shown
in Fig. 7 and Fig. 8, we were able to determine log β in an
analogous way to that described above for 2. These results are
summarised in Table 1, as well as the degree of quenching
(% FQUE) and ΦF. It is also interesting to see that for all of these
sensors the quenching was most pronounced for FϪ, giving rise
to ca. 73% and 43% ‘switching off’ for 1 and 3 respectively,
followed by AcOϪ (which in the case of 1 is close to that of FϪ)
and H2PO4Ϫ. The binding of ClϪ and BrϪ was, however, in both
cases too weak to be measurable. Figs. 6, 7 and 8 demonstrate
the above trend for 1–3, where the magnitude of the fluor-
escence quenching correlates well with the order of the binding
affinity. Only for 3 is the binding affinity trend not so clear. This
demonstrates clearly the inability of the aliphatic thiourea in 3
to inflict any significant degree of selectivity, possibly due to
steric as well as electronic effects. Hence we believe that the
above results support the hypothesis that the affinities of
the anion binding can be manipulated by simply changing the
acidity of the thiourea protons even in such simple PET
sensors. Hence the more electron withdrawing the thiourea
substituent the stronger the binding, furthermore, the more
electron rich receptors give rise to a larger degree of quenching.
We also investigated the PET affect in other solvents. When
the fluorescence titrations of 1–3 were carried out in CH3CN,
CH3CO2Et or THF, the emission was also quenched upon
addition of AcOϪ but the degree of quenching was somewhat
smaller. In ethanol, which is a highly competitive hydrogen
bonding solvent, no binding was observed between 2 and
AcOϪ, whereas there was a notable degree of quenching
observed when CH3CN was used. The binding was found to be
reversible by simply adding ethanol to either the CH3CN or the
DMSO solutions. Whereas CHCl3 has been extensively used for
anion recognition studies,27 it was not employed in the current
studies as the sensors were only soluble upon heating.
Investigating the anion recognition using 1H NMR
To investigate the nature of the anion sensing we also evaluated
the anion recognition using 1H NMR in DMSO-d6 and AcOϪ.
As discussed earlier, the thiourea protons can be used to
observe the hydrogen bonding interactions between the
receptor and the anion, giving useful information on
the structure of the receptor:anion complex. Furthermore, the
information within the 1H NMR spectra can give details of the
rate of association and dissociation as well as conformational
changes that can occur upon binding.28
All the sensors were analysed and all showed that the anion
binding was a fast exchange process, where both the thiourea
resonances were shifted down field upon anion recognition.
1
As previously stated, the H NMR of 2 in DMSO-d6 showed
two sharp signals at 9.62 ppm and 8.36 ppm for the thiourea
hydrogens. The changes in the resonance of the thiourea proton
adjacent to the aromatic ring are shown in Fig. 9, as a function
of the equivalents of AcOϪ. Here the main resonance shifts
were observed between 0
1 equivalents of AcOϪ, signifying
the formation of a 1 : 1 complex. From these changes a binding
constant of Kass of 1507 MϪ1 was determined.29 Whereas
the thiourea protons were significantly shifted upon anion
recognition, the position of the methylene protons and the
resonances for the aromatic protons were only slightly affected,
however all the resonances did become significantly broad upon
anion binding. This suggests that the anion recognition indeed
occurs at the thiourea moiety through hydrogen bonding
and that there are no interactions with the anthracene ring,
confirming the results obtained from the absorption spectra
shown in Fig. 2. This further confirms that the changes seen in
Fig. 7 Changes in the relative fluorescence emission at 419 nm of 1
upon addition of TBAOAc (*); TBA H2PO4 (᭿); TBAF (᭜); TBACl
(ꢀ) and TBABr (×) in DMSO.
Fig. 8 Changes in the relative fluorescence emission at 419 nm of 3
upon addition of TBAOAc (᭜); TBA H2PO4 (*); TBAF (᭿); TBACl
(ꢀ) and TBABr (×) in DMSO.
Fig. 9 The changes in the thiourea resonance (appearing at 9.62 ppm
in the free sensor) upon titration with AcOϪ in DMSO-d6.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
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the fluorescence emission spectra of these sensors are due to the
modulation of the electronic properties of the receptor after
recognition of the anions, which gives rise to enhanced through
space PET quenching. Similar effects were observed when the
other two sensors were employed.
receptor was either an aryl (1 and 2) or an aliphatic (3 and 4)
based thiourea moiety. All the sensors were characterised using
conventional methods. Investigation into the ground and
excited state properties of the anthracene fluorophore of 1–4
clearly showed that in several solvents these sensors behaved as
ideal PET sensors, i.e. only the fluorescent quantum yield was
affected upon the anion sensing. No other significant spectral
changes were observed, and there was no evidence for any
charge transfer complex formation between the fluoro-
phore and the thiourea receptor or the anion:receptor complex.
Analysis of the recognition process using 1H NMR indeed
confirmed that the recognition process was due to 1 : 1
hydrogen bonding binding between the anion and the receptor.
We propose that this will increase the reduction potential of the
receptor, which consequently gives rise to increased quenching
through PET from the anion:receptor complex to the anthra-
cene excited state. We also demonstrated that by simply tuning
the acidity of the thiourea protons, the strength of this
hydrogen bonding interaction could be modulated and hence,
the sensitivity of the anion sensing, i.e. 2 showed stronger
binding than 1, which gave stronger binding than 3. We further
demonstrated that the anion sensing followed the trend that
FϪ was most strongly bound and gave rise to the most efficient
Evaluation of 4 for the enantioselective recognition of N-protected
amino acids
The recognition of N-protected amino acids has recently been
explored by several researchers.30 However, these often involve
the use of structurally complicated hosts. As the fluorescence of
sensors 1–3 was on all occasions substantially quenched upon
sensing of AcOϪ, we considered using our simple design to
attempt the chiral recognition of such N-acetal protected amino
acids. With this in mind we synthesised 4 as described above.
In this first generation of such chiral sensors, only a single
asymmetric carbon was introduced into the receptor.
The absorption spectrum of 4 was similar to that seen for 1–3
above, with typical anthracene absorption bands at 335 nm, 351
nm, 370 nm and 390 nm respectively. Upon titration with AcOϪ
or TBA alanine no significant changes were observed in the
absorption spectra, demonstrating no ground state interactions.
In contrast to these results, the fluorescence emission spectra,
with emission bands at 395 nm, 417 nm, 442 nm, and a shoulder
at 469 nm respectively, were significantly affected. As discussed
above no other spectral changes were observed and this
quenching can be assigned to PET from the chiral receptor to
the anthracene excited state. However, as can be seen from
Fig. 10, for the change in the 419 nm transition as a function of
Ϫlog [AcOϪ] the binding is weak in comparison to 1 and 2, but
of a similar magnitude to that seen for 3. We next evaluated the
sensing of (S)- and (R)-N-acetylalanine as their TBA salts in
DMSO. As in the case of AcOϪ the fluorescence emission of 4
was substantially quenched for both of these amino acids.
However, as can be clearly seen from Fig. 10, the chiral
recognition of these amino acids was not achieved efficiently.
Furthermore, as the receptor is aliphatically based, the thiourea
protons are not acidic enough to give rise to strong hydrogen
bonding and hence the sensitivity of the sensing is rather low.
These results, however, are encouraging and clearly demon-
strate that the potential recognition of such amino acids should
be feasible, as the fluorescence was on both occasions reduced
by ca. 60%. Hence the design of more enantioselective receptors
is necessary. We are currently working towards developing such
systems using receptors that have two stereogenic centres as
part of their design.
Ϫ
quenching. This was followed by AcOϪ and H2PO4 respect-
ively, but the sensing of ClϪ and BrϪ was not feasible using this
simple design. We also attempted to apply our simple design to
the enantioselective sensing of N-protected amino acids. While
this was not successful, the anion recognition indeed gave rise
to PET quenching which strongly supports that such selective
sensing is possible, provided that more enantioselective
receptors are employed, i.e. the introduction of another chiral
centre is necessary.
From the above combined measurements it is clear that the
anion recognition occurs through hydrogen bonding of the
thiourea receptors to the anions. This gives rise to quenching of
the excited state. From these fluorescence changes an accurate
binding constant can be determined for ions such as AcOϪ,
H2PO4Ϫ and FϪ. Similarly, the change in the 1H NMR provides
us with information about the nature of the binding as well
as the strength of these interactions. The final analytical
method employed to investigate this sensing, the ground state
investigation, however, gives only very minor information as the
changes only occur at short wavelengths. Hence, only in the case
of 1, 2 and 4, where the aromatic receptors absorb do we
observe any significant spectral changes, e.g. no such changes
occur in 3.
The above results demonstrate the fluorescent PET sensing
of biologically important anions using charge neutral receptors.
To the best of our knowledge these were the first examples of
such anion PET sensors that gave rise to ideal PET behaviour.
We are currently working towards modifying our systems for use
in more competitive environments, as well as developing more
anion enantioselective and sensitive fluorescent PET sensors.
Experimental
General
Reagents (obtained from Aldrich) and solvents were purified
using standard techniques. Solvents were dried over the
appropriate 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
2000 4DX2-66 workstation. Oils were analysed using NaCl
plates, solid samples were dispersed in KBr and recorded as
clear pressed discs. 1H NMR spectra were recorded at 400 MHz
using a Bruker Spectrospin DPX-400 instrument. 13C NMR
were recorded at 100 MHz using a Bruker Spectrospin
DPX-400 instrument. Fluorescent measurements were made
Fig. 10 The changes in the fluorescent emission at 419 nm for 4 upon
titration of TBAOAc (ꢀ); TBA -Ala (᭿); TBA -Ala (᭜).
Conclusion
In this paper we have demonstrated the feasibility of anion
sensing using fluorescent PET sensors, using the simple
fluorophore–spacer–receptor design. For all of these, the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
1861

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on a Perkin Elmer LS 50B and on a Varian Cary Eclipse
fluorimeter. UV-Vis absorption spectra were recorded at room
temperature using a Shimadzu UV-2401PC.
9-(Methyl-thioureidomethyl)anthracene, 3. 9-(Aminomethyl)-
anthracene, 5 (0.3 g, 1.45 mM) was dissolved in 20 mL of dry
CH2Cl2. To this solution was added methyl isothiocyanate,
8 (0.18 g, 2.6 mM, 1.8 equiv.). The reaction was allowed to stir
vigorously overnight at room temperature. The excess solvent
was removed under reduced pressure. The residue was purified
by silica flash chromatography with 100% ethyl acetate as the
eluent (Rf 0.67). The product was dried over P2O5 followed by
recrystallisation from CHCl3 (0.155 g, 67% yield). mp 190 ЊC
dec; CHN calculated for C17H16N2S: C, 72.82%; H, 5.75%; N,
9.99%; found C, 72.79%; H, 10.01%; N, 9.98%; δH(400 MHz,
CDCl3): 8.49 (s, 1H, 10-H), 8.30 (d, 2H, J = 8.5 Hz, Ar-1H,
Ar-8H), 8.05 (d, 2H, J = 8.0 Hz, Ar-4H, Ar-5H), 7.59 (t, 2H,
J1 = 6.5 Hz, J2 = 8.5 Hz, Ar-2H, Ar-7H), 7.51 (t, 2H, J1 = 7.0 Hz,
J2 = 8.0 Hz, Ar-3H, Ar-6H), 5.66 (s, 2H, 15-H), 2.85 (s, 3H,
17-H); δC(100 MHz, CDCl3): 129.1, 128.5, 126.8, 125.16, 123.63,
42.0, 30.2; IR (KBr) cmϪ1 3204, 3056, 1545, 1333, 1114, 738.
Synthesis of 1–4
Improved synthesis of: 9-(aminomethyl)anthracene, 5. 9-
(Bromomethyl)anthracene (1 g, 3.68 mmol) was dissolved in
anhydrous CHCl3 (15 mL). This solution was added drop-wise
to a solution of hexamethylenetetramine (0.515 g, 3.68 mmol)
in 10 mL of anhydrous CHCl3. The resulting solution was
refluxed for 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 HCl (20 : 4 : 5), 29 mL. This mixture was heated
at 70 ЊC, after 1 hour the precipitate had completely dissolved,
the solution was kept stirring at 70 ЊC overnight. Once removed
from the heat the solution was then allowed to stand at room
temperature overnight and the product precipitated out of
solution as a HCl salt. This salt was washed with 10% KHCO3
(10 mL) and extracted into CHCl3 (35 mL). The organic layer
was dried over MgSO4. Excess solvent was removed under
reduced pressure and the residue was dried over P2O5 overnight
to give a pale yellow solid (0.708 g, 93%). mp 102 ЊC (dec.);
δH(400 MHz, CDCl3): 8.43 (s, 1H, Ar-10H), 8.39 (d, 2H, J = 9.0
Hz, Ar-8H, Ar-1H), 8.06 (s, 2H, J = 8.0 Hz, Ar-4H, Ar-5H),
7.58 (d, 2H, J1 = 7.5 Hz, J2 = 7.5 Hz, Ar-2H, Ar-7H), 7.50 (d,
2H, J1 = 7.5 Hz, J2 = 8.0 Hz, Ar-3H, Ar-6H), 4.88 (s, 2H,
Ϫ15H); δC(100 MHz, CDCl3): 132.0, 130.9, 130.2, 129.7, 127.7,
126.0, 123.7, 122.9, 35.1; MS m/z (ES): 207 ([M]ϩ).
9-(Isothiocyanatomethyl)anthracene 11. 9-(Aminomethyl)-
anthracene (600 mg, 2.46 mmol) was added to a biphasic
solution of THF (10 mL) and sat. NaHCO3 (10 mL) that was
cooled in an ice bath. The mixture was stirred at 0 ЊC for
20 min. Stirring was stopped and the layers were allowed to
separate. Thiophosgene (0.20 mL, 2.66 mmol) was added via
syringe into the organic phase in one portion. The cool reaction
mixture (0 ЊC) was stirred for a subsequent 3 h to ensure
the reaction had gone to completion. The layers were then
separated and the aqueous phase was extracted with chloro-
form (3 × 10 mL). The organic layers were combined and dried
over Na2SO4, filtered and evaporated to dryness. The crude
product was purified by column chromatography on silica gel
(9 : 1 hexane–ethyl acetate) to yield the desired product as a
yellow solid in 20% yield. The experimental results were in
accordance with reference 25. δH(CDCl3, 400 MHz): 8.55 (s,
1H, An-10H), 8.26 (d, 2H, J = 8.8 Hz, An-8H and An-1H), 8.09
(d, 2H, J = 8.8 Hz, An-4H and An-5H), 7.65 (m, 2H, An-2H
and An-7H), 7.54 (m, 2H, An-3H and An-6H), 5.61 (s, 2H,
CH2); δC(CDCl3, 100 MHz): 132.2, 130.9, 129.5, 128.9, 128.94,
126.8, 124.8, 124.1, 122.5, 40.9.
9-[4-(Trifluoromethyl)phenyl-thioureidomethyl]anthracene, 2.
9-(Aminomethyl)anthracene, 5 (0. 1 g, 0.483 mM) was dissolved
in 20 mL of dry CH2Cl2. To this solution was added
4-(trifluoromethyl)phenyl isothiocyanate, 7 (0.098 g, 0.485 mM,
1.01 equiv.). A creamy yellow precipitate was immediately
formed upon addition of the isothiocyanate. The reaction was
allowed to stir vigorously overnight at room temperature. The
resulting precipitate was removed by filtration, washed with dry
CHCl3 and dried over P2O5, followed by recrystallisation from
CHCl3 (0.166 g, 84% yield). mp 197–198 ЊC; CHN calculated
for C23H17F3N2S: C, 67.30%; H, 4.17%; N 6.82%; found C,
67.28%; H, 4.17%; N, 6.86%; δH(400 MHz, CDCl3): 8.53 (s, 1H,
10-H), 8.32 (d, 2H, J = 8.5 Hz, Ar-8H, Ar-1H), 8.09 (s, 2H,
Ar-4H, Ar-5H), 7.63 (d, 2H, J1 = 6.5 Hz, J2 = 8.5 Hz, Ar-2H,
Ar-7H), 7.54 (d, 2H, J1 = 7.5 Hz, J2 = 7.5 Hz, Ar-3H, Ar-6H),
7.45 (d, 2H, J = 8.5 Hz, 19-H, 20-H,), 7.16 (d, 2H, J = 8.0 Hz,
18-H, 21-H), 5.83 (s, 2H, 15-H); δC(100 MHz, CDCl3): 179.6,
139.56, 131.5, 130.5, 129.5, 127.2, 127.0, 126.6, 123.5, 123.2,
42.7; δF(D6-DMSO, 376.46 MHz); Ϫ63.16; IR (KBr) cmϪ1
3241, 3056, 1542, 1333, 1114, 728.
1-Anthracen-9-ylmethyl-3-(1-phenyl-ethyl)thiourea
4.
9-
(Isothiocyanatomethyl)anthracene (2.33 g, 9.36 mmol) was
added to anhydrous THF (20 mL). The mixture was stirred
at room temperature under an inert environment. (S)-(Ϫ)-
1-phenylethylamine (1.5 mL, 11.6 mmol) was added to the
mixture dropwise. The mixture was then refluxed for 12 h, after
which a yellow precipitate had formed. The precipitate was
isolated by filtration and was washed with THF (3 × 7 mL) to
remove any unreacted starting material. The yellow solid was
dissolved in chloroform and washed with 1 M HCl (3 × 10 mL)
and water (3 × 5 mL), dried over NaHCO3, filtered and concen-
trated. The desired product was isolated as a yellow solid (310
mg) and did not require any further purification. δH(D6-DMSO,
400 MHz): 8.36 (s, 1H, An), 8.11 (d, J = 8.2 Hz, 2H, An), 7.59
(d, J = 6.8 Hz, 2H, An), 7.55 (m, 4H, 2 × An and 2 × Ar), 7.22
(m, 5H, 2 × An and 3 × Ar), 6.29 (m, 1H, NH), 6.24 (d, J = 7.5
Hz, 1H, NH), 5.19 (m, 2H, CH2), 4.77 (m, 1H, CH), 1.26 (d,
J = 6.8 Hz, 3H, CH3); δC(D6-DMSO, 100 MHz): 157.2, 145.5,
131.1, 129.6, 128.9, 128.3, 127.1, 126.5, 126.3, 125.6, 125.3,
124.3, 48.7, 35.3, 23.3; IR vmax (cmϪ1): 3340, 3303, 2360, 2343,
1616, 1571, 1240, 731, 696.
9-(Phenyl-thioureidomethyl)anthracene, 1. 9-(Aminomethyl)-
anthracene, 5 (0.1 g, 0.483 mM) was dissolved in 20 mL of dry
CH2Cl2. To this solution was added phenyl isothiocyanate, 6
(59 µl, 0.483 mM, 1 equiv.). The resulting solution was stirred
overnight at room temperature. The resulting precipitate was
removed by filtration, washed with cold CH2Cl2 and dried over
P2O5 and was then recrystallised from CHCl3 (0.127 g, 77%
yield). mp 205–207 ЊC; CHN calculated for C22H18N2S: C,
77.16%; H, 5.30%; N 8.18%; found C, 77.20%; H, 5.29%; N,
8.18%; δH(400 MHz, CDCl3): 8.49 (s, 1H, Ar-10H), 8.31 (d, 2H,
J = 9.0 Hz, Ar-1H, Ar-8H), 8.05 (d, 2H, J = 8.5 Hz, Ar-4H,
Ar-5H), 7.61 (t, 2H, J1 = 7.5 Hz, J2 = 7.5 Hz, Ar-2H, Ar-7H),
7.5 (t, 2H, J1 = 8.5 Hz, J2 = 7.5 Hz, Ar-3H, Ar-6H), 7.18 (t, 1H,
J1 = 7.5 Hz, J2 = 8.0 Hz, 20H), 7.10 (d, 1H, J = 7.5 Hz, 18H),
7.04 (d, 1H, J = 7.5 Hz, 19H), 5.82 (d, 2H, J1 = 4 Hz, 15-H);
1-Ethyl-3-(4-trifluoromethyl-phenyl)thiourea 13. 4-(Trifluoro-
methyl)phenyl isothiocyanate (130 mg, 0.64 mmol) was added
to anhydrous DCM (5 mL). The mixture was stirred at room
temperature under an inert environment. Ethylamine (2 M in
THF, 0.5 mL) was added dropwise to the mixture. The reaction
was stirred at room temperature overnight after which time
TLC of the reaction mixture confirmed reaction of the starting
isocyanate. The reaction was washed with 1 M HCl (2 × 15 mL)
and extracted with DCM. The organic layer was dried over
δ (100 MHz, CDCl ): 180.05 (C᎐S), 139.53, 131.61, 130.26,
᎐
C
3
129.44, 128.67, 128.43, 126.42, 125.15, 123.92, 129.50, 67.41
(CH2); IR (KBr) cmϪ1 3412, 2922, 1509, 1495, 1345, 1256, 717.
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
1862

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S. Ishihara, M. Tsukahara and S. Tokita, J. Chem. Soc., Perkin
MgSO4, filtered and concentrated. The desired product was
isolated by precipitation from chloroform as a white solid
(100 mg, 63%). Anal. Calc. for C10H11F3N2S: C, 48.38; H, 4.47;
N, 11.28. Found: C, 48.42; H, 4.37; N, 11.37%. δH(D6-DMSO,
400 MHz): 9.80 (br s, 1H, NH), 8.06 (br s, 1H, NH), 7.68 (d,
J = 8.52 Hz, 4H, Ar), 3.49 (m, 2H, CH2), 1.14 (t, J = 7.04 Hz,
CH3); δC(D6-DMSO, 100 MHz): 179.9, 143.4, 125.8, 123.3,
121.7, 39.4, 13.9; δF(D6-DMSO, 376.46 MHz): Ϫ60.8.
Trans. 2, 2002, 1455; D. H. Lee, H. Y. Lee and J. P. Hong,
Tetrahedron Lett., 2002, 34, 7273; S. O. Kang, S. Jeon and K. C.
Nam, Supramol. Chem., 2002, 14, 405; P. E. Kruger, P. R. Mackie
and M. Nieuwenhuysen, J. Chem. Soc., Perkin Trans. 2, 2001, 1079;
Y. Kubo, M. Tsukahara, S. Ishihara and S. Tokita, Chem. Commun.,
2000, 653; P. Anzenbacher, Jr., K. Jursíková and J. L. Sessler, J. Am.
Chem. Soc., 2000, 122, 9350; H. Miyaji, P. Anzenbacher, Jr.,
J. L. Sessler, E. R. Bleasdale and P. A. Gale, Chem. Commun., 1999,
1723; H. Xie, S. Yi, X. Yang and S. Wu, New J. Chem., 1999, 23,
1105; C. B. Blake, B. Andrioletti, A. C. Try, C. Ruiperez and
J. L. Sessler, J. Am. Chem. Soc., 1999, 121, 10438; C. R. Cooper,
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Acknowledgements
We thank Enterprise Ireland, Kinerton Ltd, and TCD for
financial support, Dr Hazel M. Moncrieff for helpful
discussions and Dr John E. O’Brien for assisting with the
NMR titrations.
18 Since the publication of our communication (ref. 10) several PET
anion sensors have been reported: T. Gunnlaugsson, P. E. Kruger,
T. Clive Lee, R. Parkesh, F. M. Pfeffer and G. M. Hussey,
Tetrahedron Lett., 2003, 35, 6575; K. Kim, N. J. Singh, S. J. Kim,
H. G. Kim, J. K. Kim, L. W. Lee, K. S. Kim and J. A. Yoon,
Org. Lett., 2003, 54, 2083; A. Coskun, B. T. Baytekin and E. U. S.
Akkaya, Tetrahedron Lett., 2003, 35, 5649; K. Kim and J. T. Yoon,
Chem. Commun., 2002, 770; T. Gunnlaugsson, A. P. Davis,
J. E. O’Brien and M. Glynn, Org. Lett., 2002, 4, 2449; S. Sasaki,
D. Citterio, S. Ozawa and K. S. Suzuki, J. Chem. Soc., Perkin Trans.
2, 2001, 2309 (See also reference 25 for PET sensors).
19 K. H. Choi and A. D. Hamilton, Coord. Chem. Rev., 2003, 240, 101;
K. Kumamoto, Y. Misawa, S. Tokita, Y. Kubo and H. Kotsuki,
Tetrahedron Lett., 2003, 44, 1035; B. R. Linton, M. S. Goodman,
E. Fan, S. A. van Arman and A. D. Hamilton, J. Org. Chem., 2001,
66, 7313; C. K. Lam and T. C. W. Mak, Tetrahedron, 2000, 56, 6657;
B. R. Linton, M. S. Goodman and A. D. Hamilton, Chem.
Eur. J., 2000, 6, 2449; T. Hayashita, T. Onodera, R. Kato,
S. Nishizawa and N. Teramae, Chem. Commun., 2000, 775; J. L. J.
Blanco, J. M. Benito, C. O. Mellet and J. M. G. Fernandez, Org.
Lett., 1999, 1, 1217; A. Casnati, L. Pirondini, N. Pelizzi and
R. P. Ungaro, Supramol. Chem., 2000, 12, 53; K. P. Xiao,
P. Buhlmann and Y. Umezawa, Anal. Chem., 1999, 71, 1183; J. W. M.
Nissink, H. Boerrigter, W. Verboom, D. N. Reinhoudt and J. H. van
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29 These changes were fitted using a non-linear least squares regression
algorithm.
30 Recent examples: M. V. Rekharsky, H. Yamamura, M. Kawai and
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 1 8 5 6 – 1 8 6 3
1863