Synthetic receptors for neutral nitro derivatives

Article abstract of DOI:10.1016/j.tetlet.2008.11.015

Different arylurea-based receptors with similar substitution pattern and one guanidine-based receptor were synthesised and studied concerning their binding capability towards the title functional group; specific binding of neutral nitro groups is revealed

Full text of DOI:10.1016/j.tetlet.2008.11.015

Tetrahedron Letters 50 (2009) 359–362
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthetic receptors for neutral nitro derivatives
Umporn Athikomrattanakul a,b, Chamras Promptmas b, Martin Katterle a,
*
a Fraunhofer Institute for Biomedical Engineering, Am Mühlenberg 13, Potsdam 14476, Germany
b Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Different arylurea-based receptors with similar substitution pattern and one guanidine-based receptor
were synthesised and studied concerning their binding capability towards the title functional group; spe-
cific binding of neutral nitro groups is revealed with relatively high binding constants in DMSO ranging
from 470 to 1370 Mꢀ1 for urea and 730–990 Mꢀ1 for guanidine-based binding partners.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 August 2008
Revised 30 October 2008
Accepted 5 November 2008
Available online 8 November 2008
Keywords:
Nitro derivatives
Arylurea-based receptor
Guanidine-based receptor
Binding constants
The utilisation of host–guest chemistry for a target is a well-
established area of research and currently directed towards
tailor-made receptors to bind suitable substrates in polar and
non-polar solvents, respectively. A large number of receptors have
been described in particular for the selective binding of anionic
fragments.1 Oxoanionic substrates such as carboxylic acids and
carboxylates are important functional groups in biological and
in self-assembled supramolecular systems.2 Several binding
receptors in particular for both simple and complex carboxylic
compounds have been developed, in non-polar as well as in polar
solvents.3 Aryl(thio)urea derivatives build up bifurcate hydrogen
donor–acceptor interactions, and therefore they are used as
excellent neutral receptors for these oxoanions.4,5 Moreover, urea
and thiourea can act as an organocatalyst to activate the alkylation
of aromatic compounds with nitroalkenes via the bidentate hydro-
gen bonding.6 Various guanidium salts have also been successfully
employed for the molecular recognition of carboxylates (amino
acids) or phosphates (nucleotides).7,8 Recently, guanidinocarbonyl
pyrrolereceptorsweredescribedaswell, whichdisplayedhighaffin-
ities for carboxylates due to the combination of the electrostatic
interaction and the binding via a bidentate hydrogen bonding.3,9,10
The neutral nitro group is one of the isosters of the mono-anio-
nic carboxylate because of structural similarity.3,11 Therefore, this
group should be able to build up hydrogen donor–acceptor net-
works based on the nitro-urea and nitro-guanidine interactions.
The combination of multiple weak interactions like in carboxyl-
ate-receptor systems leads to high binding affinities in polar
solvent systems.9 Many synthetic receptors have been constructed
for mono-anionic carboxylate moieties, but surprisingly there are
only few examples of synthetic receptors for the recognition of
its isosteric anions, for example, phosphates, sulfonates groups
and only one for the specific molecular recognition of the neutral
nitro group.10 However, there is one previous report that revealed
the interaction between the nitro anions compound (nitronate) via
hydrogen bond with the 1,3-dimethylthiourea by weak binding
(Ka = 120 Mꢀ1), but quite strong binding with bicyclic guanidinium
(Ka = 3200 Mꢀ1) in DMSO.12 For this reason, we designed chromo-
genic receptor units and provided an assessment of their relative
affinity in polar or non-polar solvent systems. We applied two
strategies to the design of the receptors: one was based on
aryl(thio)urea derivatives with increasing electron-deficient aryl
moieties (1–3). In a second approach, we employed the zwitter-
ionic guanidinium derivative 4, which has never been used for
the neutral nitro group recognition. As before, the urea moiety is
a capable host for oxoanions,11 and the binding can be tuned up
by increasing the acidity of the hydrogen bond donor site by using
strong withdrawing substituents on the aromatic ring and/or by
substitution of the oxygen atom by a sulfur atom in the urea unit.
Therefore, the thiourea derivatives were designed and synthesised
to use as receptors for this purpose.
Herein, we report on the synthesis and binding characteristics
of the nitro moiety of new unsymmetrically substituted aromatic
(thio)urea derivatives, which were obtained by condensation of
the corresponding aryl iso- and thioisocyanates with 4-vinylaniline
in a single reaction step. These aryl(thio)urea-based receptors yield
in chromogenic systems which are used as a signalling unit for the
binding events. Compounds 1 and 4 were synthesised as described
earlier,9,13 and the novel compounds 2 and 3 were prepared in
analogy with moderate to good yields (Fig. 1).
* Corresponding author. Tel.: +49 0331 58187 503; fax: +49 0331 58187 299.
E-mail address: martin.katterle@ibmt.fraunhofer.de (M. Katterle).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.015

360
U. Athikomrattanakul et al. / Tetrahedron Letters 50 (2009) 359–362
CF3
NO2
CF3
O
O
O
N
N
S
H
H
O2N
C
H
N
C
H
N
N
O
N
HO
N
N
CF3
N
H
N
CF3
H
H
O
H
O
O
6
5
7
Br
1
2
Figure 2. Substrates used in the binding studies; 4-nitrobenzylbromide 5, N-(5-
F
F
nitro-2-furfurylidene)-1-aminohydantoin
6
and 3-carboxybenzyl-1-methineami-
F
F
F
O
S
no-2,4-imidazolidinedione 7.
N
H
HN
NH2
N
N
H
H
-
+
NH
2 Cl
3
1000
4
20
10
0 mM
Figure 1. Structures of aryl(thio)urea—1, 2, 3 and guanidine 4 based receptors used
800
in the study.
I
600
Fluorescence spectroscopy has been utilised for the assessment
of the association constants (Ka) of the nitro derivatives 5 and 6
(nitrofurantoin) with aryl(thio)ureas (1–3) and the guanidium pyr-
role 4 in DMSO and CHCl3. Fluorescence spectroscopy benefits
from the strong quenching by the nitro group while binding to
the chromophoric receptor (Scheme 1), and it is more sensitive
than other spectroscopical methods in this case.14 Newly synthes-
ised substrate 7 was used in this study as a reference compound,
because of its structural similarities with 6; instead of the nitro
group it bears a carboxylate group in order to compare the binding
interactions with the receptors relative to the nitro compounds 5
and 6 (Fig. 2).
As shown in Figure 3, addition of substrate 5 to a solution of
receptor 3 in DMSO caused significant quenching of the fluores-
cence intensity of receptor 3, which is accompanied by a batho-
chromic shift from 373 nm to 404 nm of the emission. In
addition to 5, nitrofurantoin 6 acted as a similar quencher by
decreasing the intensity of the fluorescence emission of all recep-
tors. All association constants that were listed in Table 1 were cal-
culated using Stern–Volmer plots of fluorescence titration data.
Furthermore, NMR studies were used to reveal more detailed
structural information about the nitro-receptor binding. The 1H
NMR experiments confirmed the proposed formation of a biden-
tate hydrogen-bound complex between nitro group and (thio)urea
moieties. Our presumed interactions of nitro-urea/guanidine using
nitrobenzylbromide 5 as a model compound are shown in Scheme
1. It demonstrates the binding pattern with two parallel hydrogen
bonds in addition to the electrostatic attraction. As depicted in Fig-
ure 4, the 1H NMR spectra exhibit upfield shifts of the urea NH pro-
ton resonances (ꢁ0.5 ppm) after adding substrate 5 to receptor 1
solution. This indicates the existence of interactions between oxy-
gen atoms of the nitro group and the protons of the urea moiety.
The changes of chemical shifts are due to the negative charge that
is transferred onto the receptor framework after the hydrogen-
bonding interaction with oxoanion.4,5 Accordingly, but minor
10 mM
350
400
450
500
550
λ
em / nm
I
400
200
0
350
400
450
500
550
λ
em /nm
Figure 3. Fluorescence emission spectra obtained by titration of receptor 3 (1 mM)
with substrate 5 (0 (top), 0.5, 1, 2, 3, 4, 5, 7.5, 10 mM (bottom)) in DMSO. Inset:
emission spectrum of 5 (1 mM) (kex = 310 nm).
Table 1
Association constants (Ka/Mꢀ1) of receptors with various substrates and solutiona
Entry
5/DMSO
5/CHCl3
270
480 17
950 38
n.s.
6/DMSO
7/DMSO
1
2
3
4
470 21
1560 112
440b
6
1370 55
450 33
280 18
990 38
1470 89
470 44
430 36
640 37
730 43
a
Determined by fluorescence titration of 1 mM receptor with substrate from 0 to
10 mM at 25 °C in DMSO or CHCl3.
b
Ks + Kd ffi association constant from static + dynamic case (n.s = not soluble).
changes of chemical shifts of the proton urea NH resonances were
observed after the assembly of aryl(thio)urea 3 and guanidine 4
based receptors with nitro compounds 5 and 6. Furthermore, the
complexation by hydrogen bonds of a simple guanidinium deriva-
tive with nitroalkane was previously reported by X-ray crystal
structure.15
Surprisingly, the nitro group of nitrofurantoin 6 or nitro-
benzylbromide
5
has good binding affinities in (relatively)
F
F
F
F
S
-
O
O
+
F
F
N
N
H
N
H
F
F
F
Ka (Table 1)
S
F
+
-
N
O
O
+
N
H
N
H
Br
5
3
Br
Scheme 1.

U. Athikomrattanakul et al. / Tetrahedron Letters 50 (2009) 359–362
361
CF3
O
O
NH2
S
H
N
N
H
N
H
N
H
CF3
-
N
+
Cl
H
2
4
H
-
N
-
N
O
O
+
O
+
5
5
Br
Br
Scheme 2.
association constants of the aryl(thio)urea moiety and substrates
in DMSO is in the order decreasing from 1 > 2 > 3 unlike in CHCl3.
Thus, the urea derivative 1 has the highest affinity for both nitro
substrates 5 and 6 with Ka = 470 21 and 1370 55 Mꢀ1 in DMSO,
respectively. But the insolubility of the receptor 4 as well as sub-
strates 6 and 7 required the use of a non-protic polar solvent like
DMSO.
Figure 4. 1H NMR titration of a 1 mM solution of receptor 1 with 0–10 mM (top to
bottom) solution of substrate 5 in CDCl3 and circles indicate the shift of urea proton
resonances.
Analogous binding studies of guanidine-based receptor 4 show
similarly remarkable recognition of 5, 6 and 7 in the range of 640–
990 Mꢀ1 in DMSO (Table 1). These high Ka values can be explained
by multiple hydrogen-bonding interactions paired with ionic inter-
actions, which further gains in binding energy (Scheme 2) com-
pared to the corresponding urea systems. Moreover, in host 4,
the H-bond donor sites are in very close proximity, which result
in a less effective solvation than when widely spaced. The pro-
posed multiple bonding structure of the host–guest complex was
supported by the downfield shifts (ꢁ0.1 ppm) of all four NH proton
resonances of the guanidine receptor (Fig. S17). In addition, the
binding efficiency of the two receptors unit classes with nitro
compounds 5 and 6 gave associations constants in range of 470–
730 Mꢀ1 and 280–1370 Mꢀ1 in DMSO, respectively, which are
a 2- to 9-fold increase in stability compared to the previous
report.11
In summary, we have shown that different urea-based synthetic
receptors can be utilised for the recognition of neutral nitro group
derivatives and that manipulation of the electronical properties of
the urea derivatives leads to high binding in highly competitive
solvents like DMSO. The urea derivative receptor 1 and guanidi-
nium receptor 4 are superior candidates with high affinity to nitro
groups. The association constants of the two receptor unit classes
with nitro compounds in DMSO are increased by one order of mag-
nitude compared to previous report.11 Moreover, the study re-
vealed that the competition of the solvent during the binding
process cannot be neglected, which makes the development of
the receptors with high pKa values unnecessary while working in
DMSO. In accomplishment, most of receptors show slightly higher
binding to the substrates in aqueous solvent system, DMSO, mim-
icking biological system and leading to a large range of applications
in molecular imprinting process or biosensors.
non-polar and polar solvents to both receptors unit classes with
some Ka values larger than 103 Mꢀ1. These results are in contrast
to a previous report where no evidence of binding of nitrobenzene
to unsymmetrically substituted urea derivatives was detected in
either CDCl3 or DMSO, whereas in CCl4 was bound very weakly
(Ka ꢂ 180 Mꢀ1).11 This observation can be explained by the rela-
tively poor hydrogen-bonding ability, which is due to the low
pKa value of the neutral nitro group.
It increases in the order 1 < 2 < 3 in both non-polar solvent
(CHCl3) and non-protic polar solvent (DMSO) because of it is com-
pensated by the higher acidity of the urea receptors. Moreover, this
is caused by a higher acidity of thiourea derivatives (pKa = 21.0)
than the corresponding urea derivatives (pKa = 26.9).4 The pKa
can be amplified by introducing electron-withdrawing substitu-
ents at the aryl moiety. These findings are in agreement with pre-
vious reports on carboxylate–urea interactions proving again that
on varying the substitution of monourea systems, the Ka values
in DMSO increase dramatically.4,16,17 Titration experiments in
DMSO were carried out because of solubility reasons, which re-
vealed from the association constants that the binding of nitro sub-
strates 5 and 6 was slightly weaker to most receptors than
carboxylate 7. We further assessed the complexation properties
of carboxylate 7, because of its structural and electronical similar-
ities to 6. Moreover, this study demonstrated that all substrates
were bound more efficiently to urea hosts in the highly polar sol-
vent DMSO with a decreasing binding in the order 1 > 2 > 3. The
high electron deficiency in 2 and 3 of the urea moiety leads to a
competition of binding between the DMSO and the substrate. Thus,
the solvation of the hydrogen bond acceptor sites were occupied
results in the disruption of the complex.4,5,18 These findings were
supported by 1H NMR titration of receptor 3 with substrate 5 in
DMSO, which is reflected by very small upfield shift of the thiourea
NH proton resonances (ꢁ0.01 ppm) (Fig. S16). A X-ray crystal
structure of urea compound with DMSO19 supports the solvation
of solvent to the receptor and the formation of a dimer of the urea
receptor in DMSO that lead to the competition and interruption of
binding between receptor and substrate.19 From this, we can draw
the conclusion that there are less interactions between oxygen
atoms of nitro group and the protons of the thiourea moiety as
compared to 1 + 5, where urea NH proton resonances were shifted
0.5 ppm (Fig. 4.). In addition, the Stern–Volmer plot of the fluores-
cence quenching of receptor 3 by substrate 5 in DMSO shows a
non-linear correlation, which is associated with static and dynamic
quenching mechanism20 (Fig. S15). Therefore, the tendency of the
Acknowledgements
Financial support from the Thailand Research Fund through the
Royal Golden Jubilee Ph.D. Programme (Grant No. PHD/0090/2546)
to Umporn Athikomrattanakul and Chamras Promptmas, and the
BMBF (0311993) is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.11.015.

362
U. Athikomrattanakul et al. / Tetrahedron Letters 50 (2009) 359–362
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