Efficient synthesis and anion recognition of a colorimetric preorganized tripodal thiourea compound

Article abstract of DOI:10.1016/j.tetlet.2012.02.069

A preorganized colorimetric tripodal thiourea receptor was synthesized in high yield utilizing a thiol-ene reaction as a primary step. The interaction of the receptor with dihydrogen phosphate, acetate, chloride, and fluoride anions was investigated using

Full text of DOI:10.1016/j.tetlet.2012.02.069

Tetrahedron Letters 53 (2012) 2181–2184
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis and anion recognition of a colorimetric preorganized
tripodal thiourea compound
⇑
Abby R. Jennings, David Y. Son
Department of Chemistry, Southern Methodist University, Dallas, TX 75275-0314, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A preorganized colorimetric tripodal thiourea receptor was synthesized in high yield utilizing a thiol-ene
reaction as a primary step. The interaction of the receptor with dihydrogen phosphate, acetate, chloride,
and fluoride anions was investigated using UV–vis. and 1H NMR spectroscopic titration techniques. The
binding stoichiometry of the receptor with dihydrogen phosphate and acetate was found to be 1:2, and
1:1 with chloride and fluoride. The binding constants for the receptor and dihydrogen phosphate, acetate,
chloride, and fluoride were determined using HypNMR2008 and HypSpec.
Received 16 December 2011
Revised 9 February 2012
Accepted 14 February 2012
Available online 20 February 2012
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
Tripodal receptors
Thiourea compound
Preorganization
Colorimetric
Thiol-ene reaction
Introduction
O
O
Anions play a vital role in many biological, chemical, and envi-
ronmental processes.1 Moreover, anion receptors are valuable
components in areas such as catalysis, biological imaging, and an-
ion scavenging and removal.1–4 As a result of these factors, there is
growing need for the design and efficient synthesis of compounds
that will selectively recognize and bind anions.
N
O
N
N
Figure 1. 1,3,5-Triacrylolylhexahydro-1,2,5-s-triazine (TAT).
Many types of anion receptors have been described, but some of
the most widely studied are the charge-neutral receptors. These
receptors are electrically neutral, unhindered by a counterion,
and bind to anions through hydrogen bonding, which is generally
weaker than the interactions between anions and a charged recep-
tor.5,6 The latter characteristic can be alleviated by using electron
withdrawing groups as part of the framework of the receptor. This
feature makes the anion receptor more acidic and increases its
ability to hydrogen bond.7 Moreover, by incorporating a chromo-
phore into the structure, one can synthesize an anion receptor
capable of ‘naked eye’ detection.7,8 Another strategy used when
designing anion receptors is to construct them in such a manner
that they are predisposed to a specific geometry, or make them
preorganized. In doing so, one not only encourages cooperative
hydrogen bonding from several sites, but also reduces the entropic
cost of binding. Calixarenes and macrocyclics are examples of
preorganized rigid receptors which have binding sites that are held
in place.9,10 Other types of preorganized receptors offer more
conformational flexibility, allowing for the receptor to arrange in
a fashion that allows for complexation to occur.5,11
This Letter describes the efficient synthesis, characterization,
and binding studies of a charge-neutral preorganized anion recep-
tor recently developed in our laboratory. This receptor utilizes
thioureas as the hydrogen bond donors, which are known to be
more acidic than ureas in solvents such as dimethyl sulfoxide.12
Moreover, our receptor incorporates 4-nitrophenyl groups that
act as electron withdrawing groups as well as chromophores,
which allows for the visible and spectral detection of anions such
as dihydrogen phosphate, acetate, and fluoride. The synthesis of
the receptor utilizes 1,3,5-triacryloylhexahydro-1,3,5-s-triazine,
also known as TAT, as a starting material (Fig. 1).
TAT is stable, inexpensive, highly reactive in thiol-ene reactions,
and its tripodal nature makes it ideal for recognizing non-spherical
anions such as acetate and dihydrogen phosphate. Another addi-
tional benefit is the preorganized nature of the TAT core. As a result
of the planar character of the nitrogen atoms, the arms extend on
the same side of the ring, confirmed by the published crystal struc-
tures of compounds with the 1,3,5-triazine-triamido core.13–16
⇑
Corresponding author. Tel.: +1 214 768 8813; fax: +1 214 768 4089.
E-mail address: dson@smu.edu (D.Y. Son).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.069

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A. R. Jennings, D. Y. Son / Tetrahedron Letters 53 (2012) 2181–2184
appearing in the 1H-NMR spectrum near 16 ppm, attributed to the
Synthesis
HFÀ2 ion.6,20 The binding stoichiometry for 2 and fluoride was inves-
tigated by the method of continuous variations using UV–vis
spectroscopy and was found to be 1:1 (see Supplementary data).
There exists a wide variety of tripodal anion receptors; how-
ever, their syntheses are quite complex.5,17,18 One of the benefits
of our receptor is the ease with which it can be made. The complete
synthesis of the anion receptor, compound 2, can be performed in
less than 2 h under ambient conditions (Scheme 1). The product is
purified and isolated in high yield by simple precipitation, and can
be easily synthesized in multigram quantities. The synthesis of the
precursor, compound 1, is achieved in minutes via a thiol-ene click
reaction.13 Compound 2 is a stable, slightly hygroscopic yellow
crystalline powder that is soluble in dimethyl sulfoxide and
acetone.
Results and discussion
The binding stoichiometries of receptor 2 with dihydrogen
phosphate, acetate, and chloride anions in DMSO-d6 were investi-
gated by the method of continuous variations using 1H NMR spec-
troscopy.19 As illustrated by Job plots in Figures 2 and 3, the
binding stoichiometry between the receptor and anion was found
to be 1:2 for both dihydrogen phosphate and acetate.
The 1:2 binding stoichiometry indicates that 2 does not bind
these non-spherical anions cooperatively with all three arms. This
is believed to be the result of having a relatively bulky phenyl
group attached directly to the binding site.5 To illustrate this, a
binding study was performed on the spherical anion, chloride. As
seen in Figure 4, the Job plot shows a 1:1 binding stoichiometry,
Figure 2. Job plot for 2 and dihydrogen phosphate.
which implies that in this case the three arms of
cooperatively.
2 bind
The binding stoichiometry between 2 and fluoride could not be
determined using 1H NMR spectroscopy. As more fluoride ion is
added to the receptor, the –NH– resonances become broad and
eventually disappear. This result is likely due to deprotonation.6,7
Adding increased amount of fluoride ion also results in a new peak
O
O
H2N
NH2
S
N
N
O
S
N
Compound 1
S
Figure 3. Job plot for 2 and acetate.
NH2
NO2
SCN
DMSO, 23 °C
86% Yield
O
O
HB HA
HA HB
N
N
N
N
R
S
N
N
O
S
R
S
S
N
S
Compound 2
R=
NO2
S
R
NHA
NHB
Scheme 1. Synthesis of compound 2.
Figure 4. Job plot for 2 and chloride.

A. R. Jennings, D. Y. Son / Tetrahedron Letters 53 (2012) 2181–2184
2183
The interaction of 2 with dihydrogen phosphate, acetate, and
fluoride was also investigated through UV–vis spectroscopic titra-
tions. Figure 5 shows the family of spectra taken over the course of
the titration of 2 with dihydrogen phosphate.
As more equivalents of anion are added, the absorption band
near 350 nm increases in intensity while undergoing a slight bath-
ochromic shift. This red shift is the result of the formation of a
hydrogen bonding complex between the neutral receptor and an-
ion.8,21 The color of the solution also changes from light yellow
to light orange over the course of the titration.
ruling out the possibility of intermolecular hydrogen bonding.
Figure 7 shows the family of spectra taken over the course of the
titration of 2 with chloride.
As a result of complex formation, a downfield shifting and
broadening of the –NH– resonances of 2 is observed and progresses
Figure 6 shows the UV–vis spectra obtained over the course of
the titration of 2 with acetate.
As more equivalents of acetate are added, the intensity of the
band near 355 nm decreases and the absorption band also under-
goes a bathochromic shift to 363 nm, again implying complexation
through hydrogen bonding.8,21 One noticeable difference between
the spectra for phosphate and acetate is the appearance of a new
band near 475 nm that increases in intensity as more equivalents
of acetate are added to the receptor. The formation of the new
red-shifted absorption band indicates the formation of a thioureido
anion, which occurs as the result of deprotonation of the thiourea
groups.5,8,22,23 Upon proton transfer, complexation can occur
between the conjugate acid and the thioureido anion.5 Over the
course of the titration with acetate, the color of the solution
changes from light yellow to dark orange.
Similar trends to that of acetate were seen for the titration of 2
with fluoride ion; however, sharp isosbestic points were observed
in the titration profile (see Supplementary data). The occurrence of
sharp isosbestic points indicates the presence of two discrete
species at equilibrium.22 The isosbestic points observed are be-
lieved to be due to complex formation and complete deprotonation
as a result of the formation of the highly stable HFÀ2 ion, or self
complex.8,20 Self complex formation depends on the acidity of
the receptor and the stability of the self complex, HXÀ2 , and
increases in the order of X = H2PO4À < CH3COOÀ < FÀ.7,24 Over the
course of the titration with fluoride the color of the solution
changes from light yellow to red.
Figure 6. UV–vis spectral change of a DMSO solution of 2 upon the addition of
tetrabutylammonium acetate ([2] = 2.5 Â 10À5 M, 0 6 [anion] 6 1.25 Â 10À4 M).
Table 1
Binding constants for 2 determined from UV–vis spectroscopic data
a
b
Anion
LogK11
LogK12
Dihydrogen phosphate
Acetate
Chloride
1.35
5.62
NAc
6.45
9.51
Fluoride
5.11
a
b
c
Refers to a 1:1 host:guest binding mode.
Refers to a 1:2 host:guest binding mode.
UV–vis spectroscopy could not be used to determine the binding constant.
Using the data obtained from the UV–vis titrations, binding con-
Upon binding with chloride, 2 does not elicit a colorimetric response.
stants were determined using HypSpec (Table 1).25
The interaction of 2 with chloride, dihydrogen phosphate, and
acetate was also investigated through 1H NMR spectroscopic
titrations. Prior to performing the titrations, the possibility of inter-
molecular hydrogen bond formation for 2 was investigated.5 The
chemical shifts due to 2 showed no dependence on concentration,
Figure 5. UV–vis spectral change of a DMSO solution of 2 upon the addition of
tetrabutylammonium dihydrogen phosphate ([2] = 5.0 Â 10À5 M, 0 6 [anion] 6
2.5 Â 10À4 M).
Figure 7. 1H NMR spectral change of a DMSO-d6 solution of 2 upon the addition of
tetrabutylammonium chloride ([2] = 5.0 Â 10À3 M, 0 6 [anion] 6 2.5 Â 10À2 M). The
bottom spectrum corresponds to 0 M tetrabutylammonium chloride.

2184
A. R. Jennings, D. Y. Son / Tetrahedron Letters 53 (2012) 2181–2184
Table 2
thiourea groups could be achieved with acetate, resulting in com-
plex formation through the thioureido anion and the neutral acid.
After forming a hydrogen bond complex with fluoride, complete
deprotonation was achieved which resulted in the formation of
the stable HFÀ2 self complex. The 1H NMR titrations showed that
2 interacted with chloride, dihydrogen phosphate, and acetate
through hydrogen bonding. Deprotonation of 2 with dihydrogen
phosphate and acetate was also observed.
Binding constants for 2 determined from 1H NMR spectroscopic data
a
b
Anion
LogK11
LogK12
Dihydrogen phosphate
Acetate
Chloride
3.00
2.20
1.40
NAc
5.62
4.61
Fluoride
a
b
c
Refers to a 1:1 host:guest binding mode.
Refers to a 1:2 host:guest binding mode.
1H NMR spectroscopy could not be used to determine the binding constant.
Acknowledgment
Upon addition of more than 1 equiv of fluoride, the –NH– resonances of 2 are
undetectable.
The authors thank the Southern Methodist University for sup-
port of this work.
as more equivalents of the anion are added.7,22,26 Similar trends
were seen for the titration of 2 with dihydrogen phosphate and
acetate; however these changes were more dramatic (see Supple-
mentary data). Upon the addition of more than two equivalents
of anion in the titration of 2 with dihydrogen phosphate and ace-
tate, the resonance for the more acidic –NH–, –NHB–, is only
detectable when the spectrum is magnified. Moreover, this reso-
nance no longer integrates for the three protons, implying that
deprotonation is occurring in the 1H NMR experiment.6,20,26
Using the data obtained from the 1H NMR spectral titrations,
binding constants were determined using HypNMR2008 (Table 2).25
There is a difference between the binding constants that were
determined for dihydrogen phosphate and acetate using the UV–
vis and 1H NMR data. This could be attributed to a number of factors
including, oligomerization, self aggregation, and self complex
formation.5,6 Having ruled out the possibility of intermolecular
hydrogen bonding for 2, the variations in the constants are believed
to be due to self complex formation, HXÀ2 .5 The 1H NMR experi-
ments are performed at concentrations two orders of magnitude
greater than the UV–vis titrations. With a higher concentration of
anion present, self complex formation would occur more readily
than in the UV–vis experiments. There would thus be less anion
available to bind with 2, yielding lower binding constants. This
would also explain why the deprotonation of 2 by dihydrogen
phosphate was observed in the 1H NMR experiment and not in
the UV–vis titration.
Supplementary data
Supplementary data (complete experimental and characteriza-
tion details for compound 2; 1H and 13C NMR spectra and elemen-
tal analysis) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2012.02.069.
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In summary, we have designed an efficient synthesis for a col-
orimetric preorganized tripodal thiourea anion receptor. This com-
pound shows a selective coloration upon binding with dihydrogen
phosphate, acetate, and fluoride ions. Moreover, 2 binds non-
spherical ions with a 1:2 binding stoichiometry, but can bind
spherical ions cooperatively with all three arms. Based on UV–vis
spectroscopic studies, 2 was found to interact with dihydrogen
phosphate through hydrogen bonding. Deprotonation of the
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