Self-assembly of dimeric tetrathiafulvalene-calix[4]pyrrole: Receptor for 1,3,5-trinitrobenzene

Article abstract of DOI:10.1021/ol2025586

The synthesis and binding properties of a tetrathiafulvalene (TTF)-calix[4]pyrrole receptor 2 appended with one 3,5-dinitrobenzoate guest moiety are reported. The preliminary studies revealed that the receptor is self-complexing into a dimer receptor 2?2.

Full text of DOI:10.1021/ol2025586

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6176–6179
Self-Assembly of Dimeric
Tetrathiafulvalene-Calix[4]pyrrole:
Receptor for 1,3,5-Trinitrobenzene
Kent A. Nielsen* and Paul C. Stein
Department of Physics and Chemistry, University of Southern Denmark, Campusvej 55,
DK-5230 Odense M, Denmark
kan@ifk.sdu.dk
Received September 21, 2011
ABSTRACT
The synthesis and binding properties of a tetrathiafulvalene (TTF)-calix[4]pyrrole receptor 2 appended with one 3,5-dinitrobenzoate guest moiety
are reported. The preliminary studies revealed that the receptor is self-complexing into a dimer receptor 2•2. The self-complexation of the receptor
leads to preorganization;in its 1,3-alternate conformation;and as a result hereof, the dimer receptor 2•2 is displaying a 2 order higher binding
affinity toward analytes (e.g., 1,3,5-trinitrobenzene) than the model tetrathiafulvalene (TTF)-calix[4]pyrrole receptor 3.
The design of novel synthetic receptors that mimic the
binding processes in biological systems has recently at-
tracted considerable interest. In many biological systems,
change in activity is affected by self-assembly of identical,
or nearly identical, subunits into larger aggregates.1 These
aggregates often show enhanced binding properties or
formation of catalytically active sites as a result of self-
assembly.1,2 Although there are numerous examples of
synthetic systems that self-assemble into dimers or larger
aggregates, such as cyclodextrins,3 porphyrins,4 and en-
capsulation complexes,5 we are unaware of any examples
where self-assembly of two identical receptors into a novel
dimer receptor has been exploited to demonstrate an
enhanced binding response to a nitroaromatic analyte.
The motivation for the present work was the finding that
TTF6-substituted calix[4]pyrrole7 showed positive homo-
tropic allosteric binding of electron-deficient guests8 (e.g.,
1,3,5-trinitrobenzene, TNB). After binding of the first
TNB guest, the flexible TTF-calix[4]pyrrole receptor was
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Nielsen, K.; Thorup, N.; Becher, J. J. Org. Chem. 2000, 65, 5794–5805.
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2011, 17, 11001–11007. (b) Park, J. S.; Derf, F. L.; Bejger, C. M.; Lynch,
V. M.; Sessler, J. L.; Nielsen, K. A.; Johnsen, C.; Jeppesen, J. O. Chem.ꢀ
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r
10.1021/ol2025586
Published on Web 11/01/2011
2011 American Chemical Society

forced to adopt a more rigidified 1,3-alternate conforma-
tion, thereby providing a preorganized framework for the
subsequent binding of the second TNB guest. This resulted
in weak binding of the first TNB and stronger binding of
the second TNB guest. The purpose of the present study
was to design a TTF-calix[4]pyrrole receptor that is pre-
organized in the 1,3-alternate conformation, thus eliminat-
ing the inherent low binding of the first TNB guest, and to
show that this receptor displays an enhanced binding for
our testsubstrate TNB. If the TTF-calix[4]pyrrole receptor
could be modified by covalently linking it to one nitroaro-
matic guest (Scheme 1), the resulting receptor might pre-
organize itself into the 1,3-alternate conformation, through
intra/intermolecular hostꢀguest complexation and at the
same time present the “second” and strongest binding site
for TNB complexation, resulting in enhanced binding.
Figure 1. Schematic illustration of dimer receptor 2•2 formation
and the following complexation with TNB.
1
came by comparing the H NMR spectrum of receptor 2
Scheme 1. Chemical Structure of the Receptors 1, 2, and 3 and
the Model Compound 4, and Synthesis of the Receptor 2
(20.0 mM, Figure S6) with the spectra of receptor 1 and the
model compound p-methylphenyl-3,5-dinitrobenzoate (4).9
In the spectrum of receptor 2 (Figure S6), the signals
corresponding to the resonances of the NH protons are
downfield shifted Δδ = 0.51ꢀ0.59 ppm, relative to that of
receptor 1 as a result of the hydrogen bonding taking place
between the NH protons of the host part of receptor 2and the
nitro groups of the guest part of receptor 2. The aromatic
protons of the guest part of receptor 2 are found to be upfield
shifted Δδ = 0.09ꢀ0.32 ppm, relative to that of the model
compound 4, as a consequence of being sandwiched between
two shielding TTF subunits.8d Due to the covalent link
between the guest part and the host part of receptor 2, the
receptor might form intra-10 or intermolecular11 complexes.
To establish whether the complexation between the host
part and guest part of receptor 2 were intra-10 or inter-
molecular11 in nature, a dilution experiment was carried out
employing 1H NMR spectroscopy (Figure 2 and Figure S7).
Upon dilution of a concentrated solution of receptor 2
(44.0ꢀ0.15 mM), significant peak shifts were observed
throughout the spectrum. In particular, the peaks corre-
sponding to the NH protons shifted upfield Δδ = 0.49ꢀ0.55
ppm and the aromatic protons from the guest part shifted
downfield Δδ = 0.13ꢀ0.41 ppm. These results indicate that
receptor 2 forms intermolecular aggregates in solution. To
determine if the intermolecular aggregates are dimers,
The receptor 2 was synthesized as outlined in Scheme 1.
Reaction of the asymmetric TTF-calix[4]pyrrole receptor 18a
appended with one phenol moiety and 3,5-dinitrobenzoyl
chloride in a CH2Cl2 solution in the presence of Et3N
afforded the desired asymmetric TTF-calix[4]pyrrole recep-
tor 2 in 70% yield after aqueous workup and column
chromatographic purification. The asymmetry of receptor 2
1
is clearly evident from the H NMR spectrum (400 MHz,
CDCl3, 298 K). The spectrum (Figure S1 in Supporting
Information) shows three singlets resonating at δ = 7.80,
7.74, and 7.69 ppm;integrating to 1 H, 2 H, and 1 H,
respectively;which can be assigned to the chemically non-
equivalent NH protons. Multiplets corresponding to the six
thiopropyl and eight meso-methyl groups (Figure S1) are
observed to resonate in the aliphatic part of the spectrum.
Initial evidencefor the interactions between the hostpart
(calix[4]pyrrole) and the guest part (3,5-dinitrobenzoate)
of receptor 2 came from absorption spectroscopy. The
resulting spectra (Figure S13) revealed a charge transfer (CT)
band centered around λ = 560 nm, which is characteristic8
for the interactions between TTF-calix[4]pyrrole receptors
and nitroaromatic guests. Further, support for the interaction
(9) Um, I.-H.; Han, H.-J.; Ahn, J.-A.; Kang, S.; Buncel, E. J. Org.
Chem. 2002, 67, 8475–8480.
(10) (a) Hooley, R. J.; Rebek, J., Jr. Org. Lett. 2007, 9, 1179–1182.
(b) Cooke, G.; Woisel, P.; Bria, M.; Delattre, F.; Garety, J. F.; Hewage,
S. G.; Rabani, G.; Rosair, G. M. Org. Lett. 2006, 8, 1423–1426. (c) Liu,
Y.; Flood, A. H.; Moskowitz, R. M.; Stoddart, J. F. Chem.ꢀEur J. 2005,
11, 369–385.
(11) (a) Baldini, L.; Sansone, F.; Faimani, G.; Massera, C.; Casnati,
A.; Ungaro, R. Eur. J. Org. Chem. 2008, 869–886. (b) Haino, T.; Fujii,
T.; Fukazawa, Y. J. Org. Chem. 2006, 71, 2572–2580. (c) Miyauchi, M.;
Takashima, Y.; Yamaguchi, H.; Harada, A. J. Am. Chem. Soc. 2005,
127, 2984–2989.
(12) The rational for formation of inter- rather than intramolecular
complexation was found in the rather rigid linker connecting the host
part and guest part of receptor 2. A CoreyꢀPaulingꢀKoltun (CPK)
model analysis showed that the geometry of the guest part (p-alkylphe-
nyl-3,5-dinitrobenzoate) of receptor 2 makes it unfavorable to form
intramolecular complexation.
Org. Lett., Vol. 13, No. 23, 2011
6177

Table 1. Dimerization Constant (K1) of Receptor 2 and Binding
Constants (Ka) for Guest Complexes of Receptor 2 and 38d with
the Analyte 1,3,5-Trinitrobenzene Determined by 1H NMR
Spectroscopy in CDCl3 at 298 K
receptor K1 (Mꢀ1
)
K2 (Mꢀ1
)
K3 (Mꢀ1
)
K4 (Mꢀ1
)
K6 (Mꢀ1
)
2
3
1950
3500
20
3500
660
3100
900
Figure 2. Partial 1H NMR spectra (400 MHz, CDCl3, 298 K) of
receptor 2 at various concentrations (44.0ꢀ0.15 mM).
Scheme 2. Complexes and Equilibria Taken into Account for
the Data Analysis
Figure 3. Job plot for the NH and Ha protons ([2] þ [TNB] =
2.0 mM). The data points (b for NH and 2 for Ha) are obtained
from the Job plot experiment, whereas the curves are predicted
from known association constants and chemical shifts (Table 1
and Table S1 in Supporting Information).
First, a Job’s14 plot analysis (Figure 3) was carried out
in order to determine the stoichiometry between the dimer
receptor 2•2 and TNB. The analysis showed 1:1 stoichiome-
try for the NH protons, indicating that the dimer receptor 2•2
is complexing two TNB guests (Figure 1). However, the Ha
protons showed a maximum in the area between 0.2 and
0.3 indicating that more complexes are involved in the
equlibria.15 1H NMR spectroscopic titration methods were
used to determine the binding constants (Ka) corresponding
to the interaction between the dimer receptor 2•2 and TNB.
As expected, addition of TNB to a solution of the dimer
receptor 2•2 (0.78 mM) did cause a large downfield shift
(Δδ = 0.53ꢀ0.59 ppm) for the NH protons of the host part
of receptor 2(Figure 4a). The aromatic signals from the guest
part of receptor 2 experienced a downfield shift (Δδ =
0.06ꢀ0.12 ppm). Analyses of the NMR data were carried
out by considering the equilibria shown in Scheme 2, and
for each equilibrium, the set of eqs 1a, 1b, and 2 was
considered.16 In the fast exchange regime, each complex
oligomers, or polymers, the equilibrium expressed by eqs 1a
and 1b was considered with q = 0. From the dilution
experiment and the equilibrium (eqs 1a and 1b), the number
of units in the aggregate was determined to be p ∼ 1.9ꢀ2.1,
indicating dimer12 (2•2, Figure 1) rather than oligomer or
polymer formation.13 By fitting the data (Figure S10), assum-
ing a monomer to dimer equilibrium, a dimerization constant
KD = 1950 Mꢀ1 (K1 in Scheme 2 and Table 1) was obtained.
pH þ qG h HpGq
ð1aÞ
(
P
[H]0 ¼
p,qp[HpGq]
P
ð1bÞ
[G]0 ¼ p,qq[HpGq]
X
X
[HpGq]
[H]o
[HpGq]
[H]o
δ ¼
pδpq ¼ δH þ
pΔpq ð2Þ
p,q
p,q¼f1,0g
The complexation between the dimer receptor 2•2, pre-
organized in the 1,3-alternate conformation, and the analyte
TNB was studied in CDCl3 solution using 1H NMR spectro-
scopy and in CH2Cl2 solution using absorption spectroscopy.
(14) Job, A. Annales de Chemie (10th series), 2008, 9, 113ꢀ203.
(15) The NH proton is describing the situation (TNB2⊂2•2) where
two TNB molecules are complexed by the dimer receptor 2•2 (1:1
stoichiometry). However, excess TNB is needed to expel the guest part
(Ha) from the host part of receptor 2 (Figure 1) leading to formation of
the TNB2⊂2 complex and therefore is a maximum in the area between
0.2 and 0.3 observed for the Ha proton.
(13) It was not possible to rule out polymer formation; however,
under the condition studied, dimer formation was favored, probably as a
consequence of the two hostꢀguest complexations leading to dimer 2•2
formation, rather than only one hostꢀguest complexation leading to
polymer formation.
(16) Connors, K. A. Binding Constants; Wiley: New York, 1987.
(17) Nelder, J. A.; Mead, R. Comput. J. 1965, 7, 308–313.
6178
Org. Lett., Vol. 13, No. 23, 2011

2 orders higher than the first binding (K2) of TNB to the
parent TTF-calix[4]pyrrole receptor 3 (Table 1), studied
under nearly8d identical conditions. This enhancement is
believed to arise from the preorganization of the receptor 2
into a dimer receptor 2•2. In the preorganization step, the
guest part of the receptor 2 is complexed (recognized) by
the first binding site of the host part of receptor 2, thereby
exposing the second binding site with a higher binding
affinity for the analyte in quest (TNB). In order to check
the robustness of the fitting procedures, the Job plots were
predicted using the equilibrium constants and changes in
chemical shift as fitted above. The resulting curves are
depicted in Figure 3 and describe the experimental data for
the Ha proton very well and for the NH proton reasonably
well.
The interactions between the dimer receptor 2•2 and
TNB were also investigated in CH2Cl2 at 298 K using
absorption spectroscopy. The TNB guest did not give rise
to any notable absorption bands at λ > 500 nm. However,
the dimer receptor 2•2 showed a charge transfer (CT)
absorption band centered at λ = 560 nm. Upon addition
of TNB to a solution of the dimer receptor 2•2, an increase
in intensity (Figure S13) and a shift of the CT band (λ =
633 nm) were observed,10 signaling that complexation
between the dimer receptor 2•2 and the TNB guests has
occurred.
In summary, we have synthesized an asymmetric TTF-
calix[4]pyrrole receptor appended with one 3,5-dinitro-
benzoate guest and investigated its self-complexation into
a dimer receptor 2•2. The dimer receptor 2•2 showed an
increased binding for the analyte TNB, asa consequenceof
preorganization of the receptor in its 1,3-alternate con-
formation. This work serves to illustrate how self-com-
plexation of two identical synthetic receptors;intoa novel
dimer receptor;may be used to enhance the recognition
ability toward analytes.
Figure 4. (a) Partial 1H NMR spectra (400 MHz, 298 K) of the
dimer receptor 2•2 ([2] = 0.78 mM) titrated with increasing
amounts of TNB in CDCl3. (b) Binding curves of the NH and
Ha protons obtained from two different titration experiments
(1.5 mM (solid line) and (0.78 mM, dotted line) of receptor 2.
contributes to the average chemical shift, and therefore, the
chemical shifts of the complexes are expressed by δpq = δH þ
Δpq and the average chemical shift (δ) can be expressed by
eq 2, where the summation is over all relevant complexes (see
Supporting Information). The chemical shift changes were
fitted using a downhill simplex method17 with a least-squares
metric, while we limit ourselves to the NH proton with the
largest chemical shift change and to Ha.
Acknowledgment. This work was supported by the
Danish Natural Science Research Council (FNU, Project
No. 272-08-0047) and the University of Southern Denmark
(SDU).
Two titration experiments were subsequently used to fit the
association constants (Ka) for the equilibria expressed by K2,
K3, K4, and K6, and this gave the Ka values listed in Table 1.
From Table 1, it can be seen that the binding of the TNB
substrates to the dimer receptor 2•2 (K2 and K3) is around
Supporting Information Available. Supporting fig-
ures, experimental and fitting details. This material
is available free of charge via the Internet at http://
pubs.acs.org.
Org. Lett., Vol. 13, No. 23, 2011
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