Selective and tuneable recognition of anions using C3v- symmetrical tripodal urea-amide receptor platforms

Article abstract of DOI:10.1039/c1cc15233e

The synthesis and binding investigations of first generation C _3v-symmetrical hydrogen bonding urea-amide based tripodal receptors, 1-6, with various anions such as acetate, phosphate, sulfate and chloride in DMSO-d₆ are presented. Analysis of the ¹H NMR titrations of 1-6 showed on all occasions the selective formation of 1:1 stoichiometries. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc15233e

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COMMUNICATION
Selective and tuneable recognition of anions using C3v-symmetrical
tripodal urea-amide receptor platformsw
Cidalia Maria Gomes dos Santos,a Elaine M. Boyle,a Stefano De Solis,ab Paul E. Krugerc
and Thorfinnur Gunnlaugsson*a
Received 23rd August 2011, Accepted 29th September 2011
DOI: 10.1039/c1cc15233e
The synthesis and binding investigations of first generation
C3v-symmetrical hydrogen bonding urea-amide based tripodal
receptors, 1–6, with various anions such as acetate, phosphate,
sulfate and chloride in DMSO-d6 are presented. Analysis of the
1H NMR titrations of 1–6 showed on all occasions the selective
formation of 1 : 1 stoichiometries.
The design and synthesis of receptors for the selective recognition
and sensing of anions, through the use of weak interactions
such as hydrogen bonding, is an active area of research within
supramolecular chemistry.1–4 Structures based on urea and
thiourea recognition sites are of particular interest due to their
strong, and tuneable hydrogen binding abilities,4–7 and their
relatively easy syntheses, which facilitates their use in both
simple and complex systems.8 Incorporation of such moieties
into the tripodal molecular platform can give rise to the
formation of preorganised structures,9 which can allow for
cooperative hydrogen bonding interactions to take place from
several binding sites.10 Hence, such systems have also been
employed for studying transport of anions11 such as sulfate
across lipid bilayers.12 To date, only a limited number of
tripodal anion receptors have been reported in the literature,
but these are highly attractive for the formation of anion
receptors that possess high coordination requirements such as
halides, sulfates and phosphates.13,14 We have recently demon-
strated that simple amido-urea15 and thiourea16 receptors can
be designed that enable positive cooperative binding of anions.
Herein we present the synthesis and anion binding studies of
six new tripodal receptors, 1–6, Fig. 1. Each receptor consists
of three urea moieties, connected to a central C3v symmetrical
phenyl platform via amide linkage. This central N-arylbenzamide
motif has previously been identified by Lewis et al.,17 as a
candidate for developing extended geometries18 for molecular
recognition, but to the best of our knowledge, have not been used
Fig. 1 Structures 1–6 employed in the current study.
as part of an anion receptor platform of the kind presented
here. We anticipated that for 1–6, this central platform would
enable cooperative or synergetic binding of anions by all three
urea sites. We also foresaw that this binding would affect the
chemical shifts of the amide protons in the 1H NMR due to the
conformational changes that these structures would undergo.
While 1 and 2 possess electron withdrawing groups, 3–6 all
have long alkyl chains which we hoped would facilitate the use
of these structures as potential membrane transporters.
The synthesis of receptors 1–6 (see Scheme S1 in ESIw) was
achieved in a few steps from 1,3,5-benzenetricarbonyl trichloride.
In general, these were first reacted with either meta or para
nitroaniline, followed by reduction to the corresponding
amines, using 10% Pd/C and hydrazine monohydrate. The
final receptors 1–6 were then formed by suspending these
amines into hot CH3CN followed by the addition of the
desired isocyanates, and heating the resulting mixtures at
reflux under an inert atmosphere overnight. This resulted in
the formation of precipitates, which were filtered and washed
with cold CH3CN giving 1–6 in 91%, 85%, 89%, 95%, 91%
and 67% yields respectively (see ESIw).
In order to evaluate the binding affinity of 1–6 for various
anions, we initially carried out UV-Vis absorption studies
using acetate (AcOÀ), sulfate (SO42À), dihydrogen phosphate
(H2PO4À) and chloride (ClÀ), respectively, as their TBA
(tetrabutyl ammonium) salt solutions. However, to our surprise,
the changes in the absorption spectra were minor, and it was
difficult to assess the binding affinity of these receptors for the
above anions accurately. Consequently, the anion recognition
of 1–6 was instead examined by using 1H NMR titrations
a School of Chemistry, Centre for Synthesis and Chemical Biology,
Trinity College Dublin, Dublin 2, Ireland. E-mail: gunnlaut@tcd.ie;
Fax: +353 1 671 2826; Tel: +353 1 896 3459
b Department of Chemistry, University of Perugia,
via Elce Di Sotto 8, 06123 Perugia, Italy
c Department of Chemistry, University of Canterbury,
Private Bag 4800, Christchurch 8041, New Zealand
w Electronic supplementary information (ESI) available: Experimental
part, detailed photophysical studies. See DOI: 10.1039/c1cc15233e
c
12176 Chem. Commun., 2011, 47, 12176–12178
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Table 1 Binding constants determined for 1–6 from NMR titrations
in DMSO-d6
Receptor
1
Anion
AcOÀ
log K1 : 1 (N–H urea)
2.81 Æ 0.07
2.78 Æ 0.05
3.10 Æ 0.10
2.39 Æ 0.06
2.79 Æ 0.07
3.70 Æ 0.20
4.20 Æ 0.10
2.10 Æ 0.07
3.70 Æ 0.10
2.15 Æ 0.08
3.19 Æ 0.08
2À
SO4
H2PO4
À
À
À
À
À
À
ClÀ
2
3
4
5
6
AcOÀ
SO4
2À
H2PO4
ClÀ
AcOÀ
SO4
Fig. 2 The 1H NMR (400 MHz) titration of receptor 6 with H2PO4
(0 - 3 eq.) in DMSO-d6.
À
2À
H2PO4
ClÀ
a
—
AcOÀ
SO4
3.25 Æ 0.04
2.10 Æ 0.10
3.50 Æ 0.10
2.81 Æ 0.07
3.70 Æ 0.10
2.06 Æ 0.09
3.20 Æ 0.10
in DMSO-d6, which allowed the changes in the chemical
environment of all of the N–Hs of 1–6 to be monitored upon
anion recognition. An example of such a titration is shown as
a stack plot in Fig. 2, for the titration of 6, where it is clear that
the anion binding is in fast exchange on the NMR time scale.19
The anion induced changes for the N–H resonances of 1–6
were analysed by non-linear regression analysis, and fitted to
various host : guest stoichiometries. The changes observed for
the urea N–H resonancesÀ(only one of each shown) of 1 and 2
2À
H2PO4
ClÀ
AcOÀ
SO4
2À
H2PO4
ClÀ
a
—
—
—
AcOÀ
SO4
a
2À
a
H2PO4
ClÀ
2.84 Æ 0.07
2À
2.05 Æ 0.04
Isotherm could not be fitted to a 1 : 1 or 1 : 2 binding model.
upon binding of H2PO4 and SO4 are shown in Fig. 3,
a
expressed as Dd vs. anion equivalents. From these changes, it
can be clearly seen that both structures bind these anions in a
1 : 1 stoichiometry, where the N–H protons are shifted by
1.5–2.5 ppm upon hydrogen binding to the anions. Similar
behaviour was observed for ClÀ and AcOÀ for both receptors
(see ESIw), where the largest changes in the 1H NMR were
observed upon the addition of one equivalent of these anions.
As we had observed in our previous work,15,16 the amide
proton (meta to the urea) of 1 also experieÀnced a significant
downfield shift upon titration with H2PO4 and ClÀ, being
shifted by ca. 0.6 ppm within the addition of one equivalent of
these anions. In contrast, these chemical shifts were less
significant upon titration with SO42À and AcOÀ, being shifted
by ca. 0.1 ppm (see ESIw). Moreover, for the structural para
isomer 2, only ClÀ gave rise to such shifts, being ca. 0.15 ppm,
after the addition of one equivalent. Molecular modeling
using MM2 of the binding of 1 and 2 (see Graphical Abstract)
to these anions showed the formation of closely associated
host–guest complexes, where the amide protons are directed
away from the anion-binding side (i.e. ‘receptor pocket’).
Hence, these shifts are conformationally induced, signifying
the binding of the anions to the urea moieties, and are not
due to direct binding of the anions to the amides themselves.
From the titration profiles in Fig. 3, it is also clear that the
recognition of H2PO4À did not result in any further measurable
shifts in the urea N–H resonance after the formation of the
1 : 1 host : guest complex. This 1 : 1 stoichiometry was also
confirmed using MALDI-TOF mass spectrometry, (see ESI)
for the binding of 2 to H2PO4À, with a m/z peak observed
at 1138.2332, which had an isotopic distribution pattern
matching that calculated for [2 + H2PO4]À. The binding
affinity of 1 and 2 for the aforementioned anions was further
assessed by fitting the changes in the N–H resonances of the
urea protons using the program WinEq NMR19 to 1 : 1 and
1 : 2 binding stoichiometries. On all occasions the best fit was
obtained using a 1 : 1 stoichiometry and the binding constants
obtained from this analysis (expressed as log K1 : 1) are shown
in TabÀle 1, where the binding constants of anions such as
H2PO4 which displayed high affinity for these receptors are
displayed in bold. Moreover, similar results were obtained for
fitting either of the two N–H urea protons (see ESIw). With
the exception of ClÀ, 2 gave rise to higher binding affinity
for these ions than 1, which in the case of H2PO4À resulted in a
log K1 : 1 = 4.20 (Æ0.10), for 2, while an order of magnitude
lower binding constant, of log K1 : 1 = 3.10 (Æ0.10), was
observed for 1. This clearly demonstrates the importance of
the substituted pattern of the di-aryl urea part (e.g. meta vs.
para) of these receptors and that 1 and 2 have high affinity
for tetrahedral anions. For both, the highest affinity was
À
also found to be for H2PO4 of the anions tested. However,
2À
the interaction between 2 and SO4 was also strong with log
K1 : 1 = 3.70 (Æ0.20), again, being a magnitude larger than that
seen for 1.
Next the electron donating receptors m- and p-urea-phenyl-
alkoxy chain derivatives, 3 and 4, were investigated. The
Fig. 3 Changes in the chemical shifts (Dd) of one of the urea protons
of 1 (’) and 2 (m) (7 Â 10À3 M) upon titration with H2PO4À (left) and
2À
interaction with AcOÀ and SO4 showed very similar results
2À
SO4 (right) in DMSO-d6.
with the urea protons experiencing a large downfield shift of
c
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2.5–3 ppm before reaching a plateau. In contrast, the amide
proton of both receptors experienced, however, a significantly
smaller shift to that seen for 1 and 2 above. The formation
of only the 1 : 1 species for receptor 4 with AcOÀ was also
evident in the MALDI-TOF mass spectrum (ESIw). Similar
shifts were seen for H2PO4À. The smallest spectral changes
were observed upon titration with ClÀ. The results from these
NMR titrations were fitted to 1 : 1 binding, from which log
K1 : 1 was determined, Table 1. Here, receptor 4 showed a
slightly higher affinity for these anions than 3; albeit the
difference in log K1 : 1 was to a lesser extent than seen for 1
and 2. Interestingly, the binding of AcOÀ was significantly
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higher for both compared to 1 and 2. For both, the smallest
2À
log K1 : 1 was observed for SO4
.
With the view of further investigating the effect that the
various substituents had on the anion affinity of these tripodal
systems, the m-urea-phenyl-alkyl chain and the p-urea-alkyl
chain based receptors 5 and 6 were also analysed in an
analogous manner. Here, 5, a slightly modified version of 3,
was determined to have higher affinity for the anions than 6,
which is to be expected, as 6 lacks the second aryl group, which
through inductive effects makes the protons in 5 more acidic
and hence, better hydrogen bonding donors, Table 1. In fact,
comparison of 3 and 5 showed that both display similar
affinity for these anions. Analysis of the binding of AcOÀ
2À
and SO4 to 6 did not result in a full plateau being reached
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being of similar magnitude, to that seen for 1 and 3 above. In
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2À
contrast the binding of SO4 was significantly weaker for 5
than seen for 1; but of similar to that seen forÀ3. Receptor 6 also
showed a significant interaction with H2PO4 and ClÀ, but in
contrast to that seen for 1–5 it was the lowest in the series.
In summary, we have developed six novel tripodal receptors,
1–6, possessing highly organised urea binding sites, and deter-
mined their binding properties with various anions using
1H NMR titrations. These showed high binding affinities
for H2PO4À and AcOÀ. Moreover, 2 also showed high affinity
for SO42À. The results clearly show that our simple design
principle facilitates the development of novel anion receptors
possessing tuneable cooperative binding. We are currently
developing this anion binding motives in greater details.
We thank the Science Foundation Ireland for SFI RFP 2008
and 2009 grants, HEA-PRTLI Cycle 4 (CSCB), TCD and
Ministero per l’ Universitae la Ricerca Scientifica e Tecnologica
(Rome, Italy) for financial support.
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This journal is The Royal Society of Chemistry 2011