Synthesis, photophysical and NMR evaluations of thiourea-based anion receptors possessing an acetamide moiety

Article abstract of DOI:10.1080/10610278.2010.506539

The synthesis and photophysical evaluation of three diaryl thiourea-based anion receptors (4-6) for comparison with their urea counterparts (1-3) is outlined. These anion receptors posses an acetamide functionality on one of the aryl groups and an electron-withdrawing CF3 group on the other. By varying the position of the acetamide group, in the o-, m- and p-positions of 4-6, respectively, the anion binding ability was both tuneable and found to be, in some cases, significantly different from that seen for the urea analogues 1-3. The binding affinities of the receptors 4-6, as well as the binding stoichiometries, were evaluated using UV-vis absorption spectroscopy in MeCN. However, these receptors were not sufficiently emissive to quantify the anion recognition using fluorescence. The results confirmed strong binding of these receptors to anions such as fluoride, acetate, phosphate, pyrophosphate and chloride. Nevertheless, the overall results obtained did not conform to the anticipated trends seen for 1-3, which is most likely due to the enhanced binding affinity of the thiourea analogues 4-6. The binding interactions were also investigated by using 1H NMR which confirmed that these receptors interacted with the anions in a stepwise manner, where the primary anion binding interaction occurred at the thiourea side, which led to an activation of the acetamide moiety towards the second anion binding interaction, an example of an allosteric activation mode.

Full text of DOI:10.1080/10610278.2010.506539

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Supramolecular Chemistry
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Synthesis, photophysical and NMR evaluations
of thiourea-based anion receptors possessing an
acetamide moiety
Elaine M. Boyle a , Thomas McCabe a & Thorfinnur Gunnlaugsson a
a School of Chemistry, Trinity College Dublin, Centre for Synthesis and Chemical Biology ,
Dublin 2, Ireland
Published online: 31 Aug 2010.
To cite this article: Elaine M. Boyle , Thomas McCabe & Thorfinnur Gunnlaugsson (2010) Synthesis, photophysical and NMR
evaluations of thiourea-based anion receptors possessing an acetamide moiety, Supramolecular Chemistry, 22:10, 586-597,
DOI: 10.1080/10610278.2010.506539
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Supramolecular Chemistry
Vol. 22, No. 10, October 2010, 586–597
Synthesis, photophysical and NMR evaluations of thiourea-based anion receptors possessing an
acetamide moiety
Elaine M. Boyle, Thomas McCabe and Thorfinnur Gunnlaugsson*
School of Chemistry, Trinity College Dublin, Centre for Synthesis and Chemical Biology, Dublin 2, Ireland
(Received 14 April 2010; final version received 23 June 2010)
The synthesis and photophysical evaluation of three diaryl thiourea-based anion receptors (4–6) for comparison with their
urea counterparts (1–3) is outlined. These anion receptors posses an acetamide functionality on one of the aryl groups and an
electron-withdrawing CF3 group on the other. By varying the position of the acetamide group, in the o-, m- and p-positions of
4–6, respectively, the anion binding ability was both tuneable and found to be, in some cases, significantly different from that
seen for the urea analogues 1–3. The binding affinities of the receptors 4–6, as well as the binding stoichiometries, were
evaluated using UV–vis absorption spectroscopy in MeCN. However, these receptors were not sufficiently emissive to
quantify the anion recognition using fluorescence. The results confirmed strong binding of these receptors to anions such as
fluoride, acetate, phosphate, pyrophosphate and chloride. Nevertheless, the overall results obtained did not conform to the
anticipated trends seen for 1–3, which is most likely due to the enhanced binding affinity of the thiourea analogues 4–6. The
binding interactions were also investigated by using 1H NMR which confirmed that these receptors interacted with the anions
in a stepwise manner, where the primary anion binding interaction occurred at the thiourea side, which led to an activation of
the acetamide moiety towards the second anion binding interaction, an example of an allosteric activation mode.
Keywords: anions; sensing; recognition; thiourea; amide
Introduction
example of such a combination are the acetamide-
functionalised diaryl urea-based receptors 1–3, previously
synthesised within our research group (29), which
demonstrated for the first time that the recognition and
sensing of anions could occur through ‘positive allosteric
effects’ in addition to the synergetic action of more than one
hydrogen-bonding donors. These samples have an electron-
withdrawing CF3 substituent in the para position of one of
these rings, which will make the urea moiety more electron
deficient and hence, a better anion receptor. In the case of 1
and 2, the binding of the anions at the urea moiety was shown
to enhance or activate the recognition ability of the amide
moiety (e.g. an allosteric effect). This enabled these
receptors to bind anions in a 1:1 as well as a 1:2 binding
stoichiometry; the latter occurring via the amide functional
group. However, this second anion binding interaction (i.e.
at the amide site) only occurred after this primary
recognition at the urea site took place. The third receptor
3, with the amide functionality ortho to the urea moiety, only
gave rise to a 1:1 binding stoichiometry, where the amide
moiety cooperatively participated in the initial anion binding
event at the urea site. The receptors 1–3 were found to
interact strongly with anions such as AcO2, H2PO42,
H2P2O372 and F2 in MeCN as determined by changes in their
respective absorption spectra. Recently, Jiang and co-
workers have demonstrated the use of additional functional
The recognition and sensing of anions in both organic and
aqueous solutions has become an active field of research
within supramolecular chemistry (1–4). Much effort has
been devoted to the detection of anions due to the important
roles they play in physiology, industry and in the
environment (5). The recognition and sensing of anions
using luminescent and colorimetric methods and, in
particular, charge neutral receptors such as ureas and
thioureas is of particular interest (6–15). Urea and thiourea
groups have been widely used as anion receptor moieties as
they are excellent hydrogen-bond donors (16–24). The
anions usually form strong directional hydrogen-bonding
complexes with the NZH protons, which are better
hydrogen-bonding donors than simple amides; allowing
the urea and thiourea moiety to be more selective in its
binding (25). However, of these two functionalities, the
thiourea is generally considered to form more stable
complexes with anions than their urea counterparts, due to
their enhanced NZH acidity (21).
The combination of either ureas or thioureas in
conjunction with amides as hydrogen-bonding receptors
within the same structure has only recently been explored,
but this combination has given rise to significant
enhancements in anion binding affinity (26–28). An
*Corresponding author. Email: gunnlaut@tcd.ie
ISSN 1061-0278 print/ISSN 1029-0478 online
q 2010 Taylor & Francis
DOI: 10.1080/10610278.2010.506539
http://www.informaworld.com

Supramolecular Chemistry
587
collected by suction filtration and washed with cold
CHCl3 to give 4–6 in 89, 89 and 42% yield, respectively.
The three receptors were fully characterised by using 1H
NMR, 13C NMR, mass spectrometry and elemental analysis.
For instance, the 1H NMR spectrum (600MHz, DMSO-d6)
for receptor 4 showed the presence of two broad resonances,
one appearing at 9.98ppm, assigned to one of the thiourea
protons, while a second resonance, appearing at 9.94ppm,
corresponded to the second thiourea proton and the amide
proton, respectively. In contrast, for 5, the thiourea protons
appeared as a single broad signal at 10.06 ppm, while the
amide proton resonated at 9.97ppm. The spectrum for 6
displayed three separate resonances at 10.41, 9.74 and
9.20ppm for the two thiourea and the amide protons,
respectively. The methyl peak was observed at 2.04ppm for
4 and 5 and at 2.08ppm for 6. Both the thiourea and the
amide stretches were clearly distinguishable in the FTIR.
Scheme 1. Synthesis of receptors 4, 5 and 6.
groups to enhance the hydrogen-bonding ability of anion
receptors, by developing N-(o-methoxybenzamido)-based
thioureas, where the anion binding at the urea moiety was
greatly enhanced by the introduction of the methoxy
substituent (30). Based on these encouraging results, and the
fact that the allosteric mode of action had not been, to the
best of our knowledge, previously explored using thiourea-
based anion receptors, we synthesised receptors 4–6. These
anion receptors are structural analogues of 1–3, possessing a
diaryl thiourea moiety, with the acetamide, substituent in the
para, meta and ortho positions of 4–6, respectively, and we
investigated their anion binding affinity and mode of action
using UV–vis absorption and 1H NMR spectroscopies.
The X-ray crystal structure analysis of 6
It was found that the receptors 4–6, formed crystalline
material; however, of these, we were only able to obtain
suitable crystals for X-ray crystallographic analysis of 6
(31). In the case of 6, colourless crystals were obtained
from a mixture of CHCl3 and MeOH at room temperature
Results and discussion
and the resulting X-ray crystal structure is shown in
Figure 1(A), while Figure 1(B) demonstrates that the two
aryl groups are significantly twisted out of the plane of the
thiourea moiety.
Synthesis of compounds 4–6
The synthesis of compounds 4–6 is shown in Scheme 1. The
first step was achieved by reacting the commercially
available nitroaniline derivatives 7–9 (the para, meta and
ortho isomers, respectively) with neat acetic anhydride
overnight at room temperature to form the desired
acetamide functionalities 10–12, in 67, 57 and 71% yields,
respectively. Subsequent reduction of the nitro group in 10–
12 to the corresponding amine was achieved by refluxing
10–12 in EtOH overnight with hydrazine monohydrate
(N2H4·H2O) in the presence of 10% Pd/C catalyst, giving
rise to 13–15 in 73, 80 and 84% yield, respectively. Finally,
the anion receptors 4–6 were formed by reacting 13–15 in
CHCl3 with the commercially available trifluoro-p-tolyl
isothiocyanate at room temperature overnight under an
atmosphere of argon. The resulting precipitates were
The packing diagram viewed down the crystallographic
a-axis is shown in Figure 2, illustrating an extensive
intermolecular hydrogen-bonding network that exists
between the amide protons and one of the NHs of the
thiourea moiety; while no p–p stacking was observed for
the aromatic moieties, most likely prevented by the CF3
groups. Theoverall packing diagram wasquitesimilartothat
observed for 3.
Photophysical evaluation of 4–6
The absorption spectra of 4–6, when recorded at room
temperature in MeCN, are shown in Figure 3. All three

588
E.M. Boyle et al.
Figure 1. (A) The X-ray crystal structures of 6 showing the thiourea moiety flanked by the two aryl groups. (B) The side view,
demonstrating that the two aryl groups are significantly twisted out of the thiourea plane.
receptors showed similar characteristic absorption bands
tetrabutylammonium (TBA) salts. The absorption spectra
of 4, upon titration with the various anions, all exhibited a
bathochromic shift upon binding to these anions. The
spectral data obtained from the titration of 4 with AcO2
are presented in Figure 4(A).
centred at ca. 280–283 nm with 1283 ¼ 28,220M21 cm21
,
1282 ¼ 19,220M21 cm21 and 1280 ¼ 19,260M21 cm21 and
for 4, 5 and 6, respectively. A second band was also observed
at ca. 248 nm for 5 and at ca. 235 nm for 6. Upon excitation at
these lmax, the receptors only gave rise to weak fluorescence
emission. Hence, the anion recognition was only monitored
by observing the changes in the ground state of 4–6.
Figure 4(A) shows that the band centred at ca. 283 nm
was shifted to ca. 294 nm with the formation of a ‘pseudo
isosbestic point’ at ca. 282 nm. It can be seen from Figure
4(B) that the number of equivalents of anion required to
reach a plateau is approximately 2 with only minor
changes occurring thereafter (e.g. 2–5 equiv.). The same
behaviour was observed for HP2O372 and F2, indicating
the rapid formation of a very stable host–guest species in
solution. In the case of H2PO24 , the band centred at ca.
283 nm exhibited a slightly smaller red shift of ca. 7 nm
with the plateau being reached upon ca. 15 equiv. of anion.
The spectral changes observed for Cl2, were, however,
less significant and occurred only at relatively higher
Anion binding evaluations of compounds 4–6
The anion binding ability of receptors 4–6, as well as the
stoichiometries for the resulting binding interactions, was
investigated by titrations of a stock solution of the receptor
(ca. 1 £ 1025 M) with various anion solutions in MeCN at
room temperature. The anions studied were dihydrogen
phosphate (H2PO24 ), acetate (AcO2), hydrogenpyropho-
sphate (HP2O372), fluoride (F2) and chloride (Cl2) as their
Figure 2. Packing diagram of 6 viewed down the crystallographic a-axis.

Supramolecular Chemistry
589
It can be seen from Figure 5(A) that the absorption
spectrum of 5 was red-shifted from ca. 282 nm to ca.
287 nm with the concomitant loss of the band centred at ca.
252 nm at higher concentrations of the anion; while Figure
5(B) indicates that a plateau was reached before the
addition of 5 equiv. of the anion (insert is the result of the
full titration).
0.4
0.3
0.2
0.1
0.0
4
5
6
Similar behaviour was also observed upon addition of
anions such as H2PO24 , F2 and AcO2. The spectral
changes observed for Cl2 again occurred only at higher
concentrations, and the bathochromic shift caused by the
interaction with Cl2 was the smallest among the anions
studied. The observed changes strongly indicate that the
interaction between 5 and the various anions is due to H-
bonding. By fitting the changes for each titration, the
binding constants for these anions and 5 were determined
using SPECFITe, the results of which are shown in Table 2.
It can be seen that the changes observed for each anion
were best fitted to 1:1 and 2:1 stoichiometries. It appeared
that the formation of the 1:1 species was the most
dominant species in solution for AcO2 and Cl2, with a
much smaller contribution from the 2:1 stoichiometry at
higher equivalent of the anion, as shown in Figure 6.
The results obtained for 5 were significantly different
than those observed for its urea counterpart 2. The binding
constants determined for 2 and anions such as F2, H2PO42
and HP2O372 were all best fitted to 1:1, 1:2 and 2:1
stoichiometries with the anion becoming ‘sandwiched’
between the urea moieties of the two ligands before the
activation of the acetamide functionality led to the
formation of the 2:1 species. This behaviour was not
observed between 5 and any of the anions studied. It was
also noted that while AcO2 gave rise to slightly higher 1:1
binding to 5 (log K1:1 ¼ 5.61 (^0.11)) than to 2
(log K1:1 ¼ 5.41 (^0.02)), Cl2 gave a lower binding
constant of log K1:1 ¼ 3.69 (^0.05) and log K1:1 ¼ 4.86
(^0.09) for 5 and 2, respectively.
The third receptor 6, with the acetamide functionality
in the ortho position, was studied in the same manner as
above. This analogue showed the most interesting results
as it was anticipated that only a 1:1 species between the
host and anion would be formed, as only this receptor
offers the possibility of direct cooperative binding between
the amide and the thiourea functionality, as was previously
observed with the urea analogue 3. However, analysis of
the data obtained, as shown in Table 3, indicated that this
was not the case. Indeed, the changes observed for all of
the anions were best fitted to both 1:1 and 2:1
stoichiometries. This is most likely due to the enhanced
anion binding ability of the thiourea moiety.
200
250
300
350
400
450
Wavelength (nm)
Figure 3. The absorption spectra of receptors 4–6 in MeCN (ca.
1 £ 1025 M).
concentrations of the anion, indicating a weaker binding
interaction in comparison to the above anions.
From the changes observed, binding constants (log K)
for complex formation between the anions (G) and 4 (L)
were determined by fitting the absorption data using the
non-linear least-squares regression program SPECFITe.
The obtained stoichiometries and corresponding log K
values are listed in Table 1.
The first binding mode was ascribed to the interaction
between the anions and the thiourea moiety of 4 through H-
bonding. Upon further addition of the anion, a second
binding interaction was observed. This interaction was
attributed to the anion binding to the amide functionality
para to the urea moiety. When the results of 4 were
compared to the corresponding urea receptor 1, it was
found that the binding affinity of 4 with the various anions
was generally stronger, which is the anticipated trend, as
discussed above. For example, AcO2 and H2PO42 gave rise
to binding constants of log K1:1 ¼ 6.31 (^0.17) and
log K1:1 ¼ 5.34 (^0.24), respectively, for receptor 4, while
the binding constants for the urea analogue 1 were
determined to be log K1:1 ¼ 5.29 (^0.03) and
log K1:1 ¼ 4.93 (^0.05) for these anions, respectively. It
is also worth noting that the presence of two G:L
complexes, namely the 1:1 and 2:1 species between 4 and
Cl2, were found to exist while the urea receptor 1 only
formed a 1:1 complex. This is most likely due to the
enhanced acidity of the thiourea receptor in comparison to
the urea analogue.
Having established the anion binding ability of 4, the
structural isomer 5 was next investigated. Besides the
characteristic absorption band lmax ¼ 282 nm, receptor 5
also had a band centred at ca. 252 nm. The largest spectral
changes observed were those between 5 and HP2O372, as
illustrated in Figure 5(A).
The titration of 6 with H2PO24 is shown in Figure 7(A).
The band centred at ca. 280 nm was shifted to ca. 290 nm
(with the formation of an isosbestic point at ca. 235 nm).
As can be seen from Figure 7(B), an excellent fit was
obtained for the changes observed in Figure 7(A).

590
E.M. Boyle et al.
A
B
0.4
0.3
0.2
0.1
0.0
0.34
0.32
0.30
0.28
0.26
0.24
0.34
0.32
0.30
0.28
0.26
0.24
0
5
10 15 20 25 30 35 100 200 300 400 500
eq AcO–
250
300
350
400
0
1
2
3
4
5
–
Wavelength (nm)
eq AcO
Figure 4. (A) Changes observed in the absorption spectra of 4 (8.98 £ 1026 M) upon titration with AcO2 (0–4.67 mM) in MeCN. (B)
The changes in the absorbance at 294 nm as a function of equivalents of AcO2. The inset shows the changes observed between 0 and 500
equiv. of AcO2.
A
B
0.3
0.2
0.1
0.0
0.25
0.24
0.23
0.22
0.21
0.20
0.19
0.18
0.25
0.24
0.23
0.22
0.21
0.20
0.19
0.18
0
5
10 15 20 25 30 35 40100 200 300 400 500
3–
eq HP2O7
250
300
350
400
0
1
2
3
4
5
3–
Wavelength (nm)
eq HP2O7
Figure 5. (A) Changes in the absorption spectra of 5 (1.1 £ 1025 M) upon titration with HP2O732 (0–4.58 mM) in MeCN. (B) The
changes in the absorbance at 294 nm as a function of equivalents of HP2O372. The inset shows the changes observed between 0 and 500
equiv. of HP2O372
.
A
B
100
80
60
40
20
0
100
80
60
40
20
0
L
G:L
G2:L
L
G:L
G2:L
0
50
100
150
200
0
100
200
300
400
500
eq AcO–
eq Cl–
Figure 6. (A) Speciation distribution diagram for the absorption titration of 5 (L) with AcO2. (B) Speciation distribution diagram for the
absorption titration of 5 (L) with Cl2.
From these changes two binding constants were
determined, where the 1:1 stoichiometry resulted in a
log K1:1 ¼ 4.81 (^0.01) and a second strong binding
interaction with a log K2:1 ¼ 4.60 (^0.14) was also
determined. Both AcO2 and F2 exhibited a strong 1:1
binding interaction, with log K1:1 ¼ 5.46 (^0.05) and
log K1:1 ¼ 5.30 (^0.05), respectively. The binding inter-
action for the 2:1 species for these anions was not as strong

Supramolecular Chemistry
591
Table 1. Binding constants and binding modes between anions
and receptor 4.
Table 3. Binding constants and binding modes between anions
and receptor 6.
Binding mode
Gn:Lm
Standard
deviation (^)
Binding
mode Gn:Lm
Standard
deviation (6)
log Kn:m
Anion (G)
log Kn:m
AcO2
F2
G:L
G2:L
G:L
G2:L
G:L
G2:L
G:L
G2:L
G:L
G2:L
6.31
5.12
4.84
4.3
5.34
4.66
5.76
1.52
4.1
0.17
0.37
0.1
0.28
0.24
0.46
0.007
0.13
0.13
0.31
AcO2
G:L
G2:L
G:L
G2:L
G:L
G2:L
G:L
G2:L
G:L
G2:L
5.46
3.44
5.30
3.47
4.81
4.60
6.33
2.13
3.20
2.0
^0.05
^0.28
^0.05
^0.21
^0.01
^0.14
^0.06
^0.19
^0.07
^0.01
F2
H2PO24
HP2O372
Cl2
H2PO24
HP2O372
Cl2
3.26
binding constants obtained for AcO2 are almost identical
with log K1:1 ¼ 5.45 (^0.02) and log K1:1 ¼ 5.46 (^0.02)
for 3 and 6, respectively. The results for Cl2 are also
comparable with log K1:1 ¼ 3.60 (^0.05) and
log K1:1 ¼ 3.20 (^0.07) for 3 and 6, respectively. This
pattern is repeated with the other anions studied. However,
the main anomaly is the 2:1 stoichiometries obtained for 6
with all of the anions investigated. This is in stark contrast
with the results obtained for the urea analogue 3 as it
appears that the amide functionality of receptor 3 is
orientated such that a 2:1 species is possible.
Table 2. Binding constants and binding modes between anions
and receptor 5.
Binding
mode Gn:Lm
Standard
deviation (^)
Anion (G)
log Kn:m
AcO2
G:L
G2:L
G:L
G2:L
G:L
G2:L
G:L
G2:L
G:L
G2:L
5.61
2.93
5.39
3.71
4.42
4.945
5.46
2.77
3.69
1.90
^0.11
^0.23
^0.07
^0.25
^0.19
^0.39
^0.15
^0.30
^0.05
F2
H2PO24
HP2O372
Cl2
In summary, the interaction between the three
receptors 4–6 and various anions was investigated using
UV–vis absorption spectroscopy. Receptor 4 was found to
generally bind to the anions more strongly than its urea
counterpart 1, as anticipated. Receptor 5 was found to
interact with the anions in a different manner to its urea
analogue 2, with the changes observed for each anion best
fitted to 1:1 and 2:1 stoichiometries while receptor 2 was
also found to bind the anions in a 1:2 stoichiometry by
a
–
a Value fixed, as the affinity is low.
as that seen for H2PO24 , as illustrated in Figure 8. Once
again, the smallest spectral changes observed were for
Cl2, where the 280 nm band was red-shifted by only 5 nm.
When these results were compared to that of urea
receptor 3, some similarities were found. For instance, the
A
B
0.3
0.28
0.26
0.28
0.24
0.2
0.1
0.0
0.26
0.22
0.24
Data
Fit
0.22
0.20
0.18
0.16
0.20
0.18
0.16
0
50
100 150 200 250 300 350
–
eq H2PO4
250
300
eq H2PO4
350
400
0
5
10
15
20
25
–
–
eq H2PO4
Figure 7. (A) Changes in the absorption spectra of 6 (1.09 £ 1025 M) upon titration with H2PO24 (0–4.72 mM) in MeCN. (B) Fit to the
experimental binding isotherm obtained using SPECFITe. The inset shows the fit between 0 and 350 equiv. of H2PO42.

592
E.M. Boyle et al.
A
B
100
80
60
40
20
0
100
L
G:L
G2:L
L
G:L
G2:L
80
60
40
20
0
0
10
20
30
40
50
0
20
40
60
80
100
eq AcO–
–
eq H2PO4
Figure 8. (A) Speciation distribution diagram for the absorption titration of 6 (L) with AcO2. (B) Speciation distribution diagram for the
absorption titration of 6 (L) with H2PO24 .
0 eq
sandwiching the anion between two urea moieties. Finally,
receptor 6 was shown to have the acetamide functionality
free to bind the anions in a 2:1 stoichiometry, while it is
cooperatively involved in binding with the urea moiety of
receptor 3. With the view of further analysing the binding
interactions of these thiourea derivatives with the above
H1 H2 and H3
0.5 eq
1 eq
1
anions, we next carried out H NMR titrations.
1H NMR analysis of 4–6 on the binding of various
anions
1H NMR spectroscopy is a useful technique to directly
observe the effect of anion complexation on the NH
protons of sensors such as 4–6. The 1H NMR titrations of
4–6 were all carried out in DMSO-d6, which enabled us to
clearly follow the changes in the chemical environment of
all of the NZHs in these structures upon binding to the
anions. The stack plot of the 1H NMR spectra of 4
upon addition of various equivalents of Cl2 is shown in
Figure 9, which clearly demonstrates the dramatic changes
observed in the structure of 4 upon anion recognition. It
can be seen that the thiourea protons experience a
significant downfield shift upon binding to Cl2, and
interestingly, the thiourea protons become two separate
resonances upon addition of Cl2. The amide proton also
experiences a shift, however this is less significant, and in
contrast, only minor changes were observed for the
aromatic protons.
2 eq
3 eq
4 eq
5 eq
The changes in the thiourea and amide resonances (Dd)
were plotted against the equivalents of anion added, shown
in Figure 10(A) and (B), respectively. The thiourea protons
are shifted downfield, with changes still occurring even at
higher concentrations of Cl2. The amide proton is also
immediately shifted downfield with the more significant
changes occurring after ca. 2 equiv. These results confirm
the results previously observed from the absorption
studies.
11
10
9
8
7
[ppm]
Figure 9. Stack plot of the 1H NMR (400 MHz, DMSO-d6)
spectra of 4 upon addition of 0.5, 1, 2, 3, 4 and 5 equiv. of Cl2. H1
and H2 are the thiourea protons, while H3 is the amide NH.

Supramolecular Chemistry
593
A
B
1.0
0.8
0.6
0.4
0.2
0.0
0.14
0.12
0.10
0.08
0.06
0.04
0.02
0.00
NHthiourea 1
NHthiourea 2
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
eq Cl–
eq Cl–
Figure 10. (A) Changes in the H1 resonance of 4 (as Dd) upon titration with Cl2. Similar changes were seen for the H2 proton. (B)
Changes seen for the H3 resonance during the same titration.
A
B
0.06
0.04
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
0.02
0.00
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
eq AcO–
–0.02
–0.04
–0.06
–0.08
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
eq AcO–
Figure 11. (A) Changes in the H1 resonance of 4 (as Dd) upon titration with AcO2. (B) Changes seen for the H3 resonance during the
same titration.
A
B
1.2
1.0
0.8
0.6
0.4
0.2
0.0
2.0
1.5
1.0
0.5
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
0.0
0.5
1.0
1.5
2.0
2.5
–
3.0
3.5
4.0
–
eq H2PO4
eq H2PO4
Figure 12. (A) Changes in the H1 resonance of 5 (as Dd) upon titration with H2PO24 . (B) Changes seen for the H3 resonance during the
same titration.
The results observed between 4 and AcO2, illustrated
in Figure 11(A), show that the binding of the anion had a
major effect on the NZH protons, which in the case of the
thiourea NZHs occurred within the addition of 0–1.5
equiv. of AcO2. It can be seen from Figure 11(B) that the
amide proton is shifted upfield initially. However, beyond
1.5 equiv. is shifted downfield as a function of an increased
AcO2 concentration. This phenomenon was also observed
for the urea analogues 1–3, and was attributed to the anion
initially binding at the urea moiety via H-bonding with the
amide functionality becoming activated at higher concen-
trations of the anion. These results also correlate with the

594
E.M. Boyle et al.
A
B
2.5
2.0
1.5
1.0
0.5
0.0
1.0
0.8
0.6
0.4
0.2
0.0
0.0
0.2
0.4
0.6
0.8
1.0
1.2
0.0
0.5
1.0
1.5
2.0
2.5
–
3.0
3.5
4.0
–
eq H2PO4
eq H2PO4
Figure 13. (A) Changes in the H1 resonance of 6 (as Dd) upon titration with H2PO24 . (B) Changes seen for the H3 resonance during the
same titration.
absorption studies carried out with 4–6 and the various
anions discussed above.
broadening of the thiourea protons. Figure 14 shows the
1
stack plot of the H NMR spectra of 6 upon addition of
various equivalents of Cl2, and also demonstrated that
significantly more pronounced changes were observed in
the aromatic region of 6 upon binding to this anion.
Receptors 4–6 also showed significant shifts when
titrated with F2. The thiourea protons of all three receptors
showed a broadening of the resonances, making it difficult
to track the changes. At higher concentrations, deprotona-
tion of the thiourea protons occurred, signified by the
appearance of a triplet at ca. 16 ppm. However, the amide
proton was clearly visible even at higher concentrations of
F2. Figure 15 shows the plot of the changes in the
amide resonances of 4 and 5 (Dd) against the equivalents
of F2 added.
The changes observed in the NZH protons of receptor
5 when titrated with H2PO42 are shown in Figure 12. It can
be seen that the thiourea protons, Figure 12(A), experience
the majority of the changes between 0 and 1 equiv.
However, the amide proton, Figure 12(B), continues to
experience a shift even at higher concentrations of the
anion, indicating a second binding event. Again, these
results confirm the results previously determined from the
absorption studies.
Similar results were seen for the titration between 5
and AcO2, with the majority of the changes occurring
between 0 and 1.5 equiv. for the thiourea protons. The
amide proton was again initially shifted upfield but at
higher concentrations of the anion it experienced a
downfield shift.
The amide proton was found to experience an upfield
shift until ca. 2 equiv. of F2 after which it shifted
downfield. It was also at this point that the appearance of
the HF22 triplet at ca. 16 ppm appeared, a clear indication
of a deprotonation event (24).
These 1H NMR studies are in agreement with the data
obtained from the UV–vis absorption titrations. It was
found that the position of the acetamide functionality on
the ring greatly influenced the anion binding affinity of
receptors 4–6, especially for receptor 6 where it is
available as a second binding site for the various anions but
is unavailable to bind them in the urea analogue 3. This
second binding event is a direct consequence of the
thiourea moiety present in receptor 6.
The third receptor, 6 which demonstrated the most
unusual results in the absorption studies out of the three
receptors, was also investigated by 1H NMR. The interaction
with this receptor with the various anions was indeed quite
strong. In general, the thiourea protons experienced a
large downfield shift with a concomitant broadening of the
two resonances. For example, Figure 13(A) shows the
plot of the changes in the thiourea resonance (Dd) against
the equivalents of H2PO42 added. Even at lower concen-
trations of the anion, the protons were so broadly shifted
that the resonances were not visible. However, it appeared
that a plateau was beginning to form at ca. 1 equiv. of
H2PO24 . The amide proton was therefore the only resonance
which could be followed, Figure 13(B).
Conclusion
Similar changes were seen between 6 and AcO2 and
HP2O372. In contrast, the results seen for the Cl2 titration
were slightly less significant, leading to only small
In conclusion, three novel anion receptors 4–6 have been
synthesised and fully characterised, and their various
spectroscopic properties analysed in the presence of

Supramolecular Chemistry
595
several biologically important anions. All of the receptors
were found to interact via H-bonding with anions such as
AcO2, F2, H2PO42, HP2O372 and Cl2 as determined by the
changes in their respective absorption spectra. A possible
conformation for the hydrogen-bonding complex formed
between 4–6 and AcO2 is illustrated in Figure 16.
0 eq
0.5 eq
1 eq
H3
H2
H1
When compared to their urea counterparts, 1–3, many
of the anticipated trends were not observed. For example,
it was expected that the thiourea receptors would show
increased binding affinity to the various anions compared
to the urea analogues, however in some instances this was
not found to be the case. Also, receptor 3 was only
expected to bind in a 1:1 stoichiometry due to cooperative
binding between the amide and thiourea functionalities,
but all of the anions formed a 2:1 species with this
receptor. It has been suggested that thioureas are
conformationally more flexible than their urea analogues,
leading to the possibility that any conformational changes
within the thiourea receptors may affect, to a certain
extent, their anion binding properties (32). We have also
compared the binding affinity of 4 and 5 in particularly
with that of 1 and 2, respectively. These demonstrate that
the thiourea receptors are in general stronger anion
binders. We have also compared the ratio between log K1:1
and log K2:1 (as log K2:1/log K1:1) for these receptors.
These results show that for 4, the binding of AcO2, F2,
H2PO24 and Cl2 gave log K1/log K2 values of 0.71, 0.83,
0.87 and 0.79 for these anions, respectively, while for the
urea analogue 1, this ratio was 0.66, 0.51, 0.62 and 0.58.
Similar trends were also seen for 5 upon comparison with
2. This seems to suggest that the ‘allosteric effect’ might
be stronger in the thiourea systems. We are currently
investigating this allosteric phenomenon further.
2 eq
3 eq
4 eq
5 eq
11
10
9
8
7
[ppm]
1
Figure 14. Stack plot of the H NMR (400 MHz, DMSO-d6)
spectra of 6 upon addition of 0.5, 1, 2, 3, 4 and 5 equiv. of Cl2. H1
and H2 are thiourea protons, while H3 is the amide NH.
A
B
0.2
0.1
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
eq F–
–0.1
0.0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0
–0.2
–0.3
–0.4
–0.1
eq F–
–0.2
–0.3
–0.4
Figure 15. (A) Changes in the H3 resonance of 4 (as Dd) upon titration with F2. (B) Changes seen for the H3 resonance of 5 upon
titration with F2.

596
E.M. Boyle et al.
Synthesis
O
O
General experimental procedure for compounds 4–6
H
H
N
The relevant amino acetamide (13–15) (1 equiv.) was
placed in a 50 ml round bottom flask and dissolved with
CHCl3. Trifluoro-p-tolyl isocyanate (1.1 equiv.) was
added, and the solution was then stirred at room
temperature overnight under an argon atmosphere. The
resulting precipitate was filtered and washed with cold
CHCl3. The obtained solid was then dried under vacuum
followed by crystallisation.
N
O
S
N
H
CF3
4–6
O
O
Figure 16. Possible hydrogen-bonding complex between 4–6
and AcO2.
Experimental
N-(4-(3-(4-(Trifluoromethyl)phenyl)thioureido)
phenyl)acetamide (4)
General
Reagents (obtained from Sigma-Aldrich Ireland Ltd.) and
solvents were purified using standard techniques. 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. 1H NMR spectra
were recorded at 400 MHz using a Bruker Spectrospin DPX-
400 instrument. 13C NMR spectra wererecorded at100 MHz
using a Bruker Spectrospin DPX-400 instrument.
Receptor 4 was synthesised according to the above
procedure using N-(4-aminophenyl)-acetamide (13)
(0.28 g, 1.89 mmol) and trifluoro-p-tolyl isothiocyanate
(0.57 g, 2.83 mmol). The resulting precipitate was then
filtered and washed with cold CHCl3 to yield the pure
compound as an off white solid (0.59 g, 89% yield). Mp
209–2118C. Calculated for C16H14N3OF3S·0.05CHCl3: C,
53.50; H, 3.93; N, 11.65%. Found C, 53.34; H, 3.79; N,
11.64%; HR-MS (m/z) (ESþ) calculated for
C16H13N3OF3S m/z ¼ 352.0731 [M 2 H]2. Found
1
m/z ¼ 352.0731; H NMR (600 MHz, d6-(CD3)2SO) dH:
Spectroscopic studies
9.98 (br s, 1H, NHthiourea), 9.94 (br s, 1H, NHthioureaþamide),
7.76 (d, 2H, Ar-H, J ¼ 8.5 Hz), 7.68 (d, 2H, Ar-H,
J ¼ 8.5 Hz), 7.56 (d, 2H, Ar-H, J ¼ 8.5 Hz), 7.37 (d, 2H,
Ar-H, J ¼ 8.5 Hz), 2.04 (s, 3H, CH3); 13C NMR
(150 MHz, d6-(CD3)2SO) dC: 179.5, 168.0, 143.4, 136.3,
133.9, 125.5 (q, J13C –19F ¼ 4 Hz), 125.3 (q, J13C–
All measurements were made at room temperature. UV–
vis absorption spectra were recorded using a Varian Cary
50 spectrophotometer. The solvents used were of HPLC
grade. The wavelength range was 200–600 nm with a scan
rate of 600 nm min21. The blank used was a sample of the
solvent system the titration was undertaken in. Baseline
correction measurements were used in all spectra. All
stock solutions were prepared freshly before measurement.
Data analysis was conducted using Origin 7.5w and
SPECFITe. The effect of anions on the sensors was
investigated by the addition of different volumes of an
anion (H2PO24 , AcO2, HP2O732, F2, Cl2) solution in
MeCN, with different concentrations (5 £ 1023–0.1 M),
to a 2.7 ml solution of 4–6 in MeCN. In each case,
additions were accompanied with magnetic stirring. All
titrations were repeated twice to ensure reproducibility. All
the anions were used in the form of their TBA salts,
(C4H9)4Nþ. These salts were purchased from Aldrich and
used without further purification.
¼ 26 Hz), 125.2, 124.5, 124.3 (q, J13C –
19F
¼ 270 Hz), 122.7, 119.0, 23.8; IR nmax (cm21) 3302,
19F
3206, 3094, 1669, 1618, 1599, 1567, 1521, 1330, 1304,
1158, 1130, 1112, 1072, 1014, 839, 404.
N-(3-(3-(4-(Trifluoromethyl)phenyl)thioureido)
phenyl)acetamide (5)
Receptor 5wassynthesisedaccordingtotheaboveprocedure
using N-(3-aminophenyl)-acetamide (14) (0.16 g,
1.08 mmol) and trifluoro-p-tolyl isothiocyanate (0.33 g,
1.63mmol). The resulting precipitate was then filtered and
washed with cold CHCl3 to yield the pure compound as an
off white solid (0.34 g, 89% yield). Mp 169–1718C. Found
m/z ¼ 352.0707; calculated for C16H14N3OF3S·0.05CHCl3:
C, 53.64; H, 3.94; N, 11.69%. Found C, 53.76; H, 3.87; N,
11.59%; HR-MS (m/z) (ESþ) calculated for C16H14N3OF3-
SNa m/z ¼ 376.0731 [M þ Na]þ; 1H NMR (600MHz, d6-
(CD3)2SO) dH: 10.06 (s, 2H, NHthiourea), 9.97 (s, 1H,
NHacetamide), 7.77 (d, 2H, Ar-H, J ¼ 8.2 Hz), 7.76 (dd, 1H,
Ar-H, J ¼ 2.0 Hz, 2.0 Hz), 7.68 (d, 2H, Ar-H, J ¼ 8.2 Hz),
7.37 (dd, 1H, Ar-H, J ¼ 8.0 Hz, 2 Hz), 7.25 (t, 1H, Ar-H,
J ¼ 8.0 Hz), 7.20 (dd, 1H, Ar-H6, J ¼ 8.0 Hz, 2.0 Hz), 2.04
NMR titrations
The experiments were carried out by using a known amount
of the host dissolved in 0.6 ml of solvent
([host] < 7.4 £ 1023 M). The anion guest solutions were
prepared such that 2 ml of the solution would give 0.1 equiv.
of anion ([anion] < 0.22 £ 1021 M). After each addition of
the anion guest to the NMR tubes, the 1H NMR spectra were
recorded (400MHz) after 5 min equilibration.

Supramolecular Chemistry
597
(s, 3H, CH3); 13C NMR (150MHz, d6-(CD3)2SO) dC: 179.4,
168.3, 143.4, 139.6, 139.3, 128.7, 125.5 (q, J13C–
(6) Ali, H.D.P.; Quinn, S.J.; McCabe, T.; Kruger, P.E.;
Gunnlaugsson, T. New J. Chem. 2009, 33, 793–800.
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Hussey, G.M.; Pfeffer, F.M.; dos Santos, C.M.G.; Tierney,
J. J. Fluoresc. 2005, 15, 287–299.
(8) Veale, E.B.; Gunnlaugsson, T. J. Org. Chem. 2008, 73,
8073–8076.
(9) Veale, E.B.; Tocci, G.M.; Pfeffer, F.M.; Kruger, P.E.;
Gunnlaugsson, T. Org. Biomol. Chem. 2009, 7, 3447–3454.
(10) Quinlan, E.; Matthews, S.E.; Gunnlaugsson, T. J. Org.
Chem. 2007, 72, 7497–7503.
¼ 4 Hz), 124.4 (q, J13C–19F ¼ 272 Hz), 123.8 (q, J13C-
19F
¼ 32Hz), 122.8, 118.2, 115.4, 114.1, 23.9; IR nmax
19F
(cm21) 3320, 3232, 3180, 3126, 3064, 1654, 1597, 1573,
1545, 1453, 1417, 1320, 1305, 1288, 1254, 1161, 1104,
1063, 1016, 840, 785, 713, 680.
N-(2-(3-(4-(Trifluoromethyl)phenyl)thioureido)
phenyl)acetamide (6)
(11) Ali, H.D.P.; Kruger, P.E.; Gunnlaugsson, T. New J. Chem.
2008, 32, 1153–1161.
(12) Pfeffer, F.M.; Kruger, P.E.; Gunnlaugsson, T. Org. Biomol.
Chem. 2007, 5, 1894–1902.
(13) Duke, R.M.; Gunnlaugsson, T. Tetrahedron Lett. 2007, 48,
8043–8047.
(14) dos Santos, C.M.G.; McCabe, T.; Gunnlaugsson, T.
Tetrahedron Lett. 2007, 48, 3135–3139.
(15) dos Santos, C.M.G.; Glynn, M.; McCabe, T.; de Melo,
J.S.S; Burrows, H.D.; Gunnlaugsson, T. Supramol. Chem.
2008, 20, 407–418.
(16) Gunnlaugsson, T.; Davis, A.P.; Glynn, M. Chem. Commun.
2001, 2556–2557.
(17) Lowe, A.J.; Dyson, G.A.; Pfeffer, F.M. Org. Biomol. Chem.
2007, 5, 1343–1346.
(18) Pfeffer, F.M.; Lim, K.F.; Sedgwick, K.J. Org. Biomol.
Chem. 2007, 5, 1795–1799.
(19) Quinlan, E.; Matthews, S.E.; Gunnlaugsson, T. Tetrahedron
Lett. 2006, 47, 9333–9338.
(20) Palacios, M.A.; Nishiyabu, R.; Marquez, M.; Anzenbacher,
P., Jr. J. Am. Chem. Soc. 2007, 129, 7538–7544.
(21) Gomez, D.E.; Fabbrizzi, L.; Licchelli, M.; Monzani, E. Org.
Biomol. Chem. 2005, 3, 1495–1500.
(22) Pfeffer, F.M.; Buschgens, A.M.; Barnett, N.W.; Gunn-
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6579–6584.
(23) Pfeffer, F.M.; Gunnlaugsson, T.; Jensen, P.; Kruger, P.E.
Org. Lett. 2005, 7, 5357–5360.
Receptor 6 was synthesised according to the above
procedure using N-(2-aminophenyl)-acetamide (15)
(0.14 g, 0.92 mmol) and trifluoro-p-tolyl isothiocyanate
(0.28 g, 1.38 mmol). The resulting precipitate was then
filtered and washed with cold CHCl3 to yield the pure
compound as an off white solid (0.14 g, 42% yield). Mp
179–1828C. Found m/z ¼ 352.0707; calculated for C16-
H14N3OF3S·0.04CHCl3: C, 53.79; H, 3.95; N, 11.73%.
Found C, 53.81; H, 3.99; N, 11.60%; HRMS (m/z) (ESþ)
calculated for C16H14N3OF3SNa m/z ¼ 376.0700
[M þ Na]þ; 1H NMR (600 MHz, d6-(CD3)2SO) dH:
10.41 (br s, 1H, NHthiourea), 9.74 (s, 1H, NHamide), 9.20
(br s, 1H, NHthiourea), 7.82 (d, 2H, Ar-H, J ¼ 8.5 Hz), 7.69
(d, 2H, Ar-H, J ¼ 8.5 Hz), 7.55 (d, 1H, Ar-H, J ¼ 7.1 Hz),
7.47 (d, 1H, Ar-H, J ¼ 7.1 Hz), 7.21 (t, 1H, Ar-H,
J ¼ 7.1 Hz), 7.18 (t, 1H, Ar-H, J ¼ 7.1 Hz), 2.08 (s, 3H,
CH3); 13C NMR (150 MHz, d6-(CD3)2SO) dC: 180.1,
169.1, 143.3, 132.6, 132.0, 128.2, 126.1 (q, J13C–
¼ 4 Hz), 125.7, 125.6 125.5 (q, J13C–19F ¼ 272 Hz),
19F
124.8, 124.4 (q, J13C-19F ¼ 272 Hz), 122.7, 23.4; IR nmax
(cm21) 3197, 3110, 3012, 1642, 1598, 1537, 1500, 1481,
1442, 1319, 1296, 1260, 1239, 1166, 1156, 1106, 1064,
1016, 845, 762, 736, 700.
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Pfeffer, F.M.; Hussey, G.M. Tetrahedron Lett. 2003, 44,
6575–6578.
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Glynn, M. Org. Biomol. Chem. 2004, 2, 1856–1863.
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41, 4344–4346.
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9235–9244.
Acknowledgements
We thank Trinity College Dublin, Science Foundation Ireland
(SFI RFP 2008 grant), and PRTLI Cycle 4 (CSCB funding) for
financial support, and Drs Steve Comby and Emma Veale for
their help and suggestions.
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