Coordination-driven switching of a preorganized and cooperative calix[4]pyrrole receptor

Article abstract of DOI:10.1002/chem.201203319

The study of preorganization in receptors, particularly in cooperative receptors, and their reversible control by external stimuli is important for elucidating design strategies that can lead to increased sensitivity and external control of molecular recognition. In this work we present the design, synthesis, and operation of an asymmetric tetrathiafulvalene (TTF)-calix[4]pyrrole receptor appended with a pyridine moiety. ¹H NMR spectroscopy was employed to demonstrate that intramolecular complexation between the receptor and the pyridine moiety leads to a preorganized receptor. Absorption and ¹H NMR spectroscopy along with a computational investigation were used to demonstrate the ability of the receptor to complex the substrate 1,3,5-trinitrobenzene (TNB) and that the receptor can be reversibly modulated between negative and positive cooperativity by employing external stimuli in the form of Zn^II. Fitting procedures incorporating multiple datasets and fitting to multiple equilibria simultaneously have been employed to quantitatively determine the preorganization effects. Zinc's a turn on! The molecular recognition of an asymmetric tetrathiafulvalene (TTF)-calix[4]pyrrole receptor can be reversibly switched between positive and negative cooperativity, when binding 1,3,5-trinitrobenzene (TNB), by chemical stimuli in the form of Zn^II (see figure). An intramolecular complexation promotes a preorganized receptor with an increased affinity for TNB with a 237-fold increase in the first complexation (K₁). Copyright

Full text of DOI:10.1002/chem.201203319

DOI: 10.1002/chem.201203319
Coordination-Driven Switching of a Preorganized and Cooperative
Calix[4]pyrrole Receptor
Steffen Bꢀhring, Gunnar Olsen, Paul C. Stein, Jacob Kongsted, and Kent A. Nielsen*[a]
Abstract: The study of preorganization
in receptors, particularly in cooperative
receptors, and their reversible control
by external stimuli is important for elu-
cidating design strategies that can lead
to increased sensitivity and external
control of molecular recognition. In
this work we present the design, syn-
thesis, and operation of an asymmetric
ployed to demonstrate that intramolec-
ular complexation between the recep-
tor and the pyridine moiety leads to a
preorganized receptor. Absorption and
1H NMR spectroscopy along with a
computational investigation were used
to demonstrate the ability of the recep-
tor to complex the substrate 1,3,5-trini-
trobenzene (TNB) and that the recep-
tor can be reversibly modulated be-
tween negative and positive coopera-
tivity by employing external stimuli in
the form of ZnII. Fitting procedures in-
corporating multiple datasets and fit-
ting to multiple equilibria simultane-
ously have been employed to quantita-
tively determine the preorganization
effects.
Keywords: allosterism · calix[4]pyr-
role · molecular recognition · supra-
molecular chemistry · tetrathiaful-
valene
tetrathiafulvalene
(TTF)–calix[4]pyr-
role receptor appended with a pyridine
1
moiety. H NMR spectroscopy was em-
Introduction
receptor 1 appended with a pyridine moiety and demon-
strate how a coordination-driven switching mechanism can
be utilized to control the function of the receptor between
negative and positive cooperativity. The mechanistic scheme
for the proposed coordination-driven switching of receptor 1
is illustrated in Scheme 1. Calix[4]pyrrole macrocycles are
known to adopt four limiting conformations, namely the
cone, partial cone, 1,2-alternate, and the 1,3-alternate con-
formation, in which the 1,3-alternate conformation is fa-
vored in solution. Theoretical studies[12] have provided in-
sight into the conformational distribution of calix[4]pyrroles,
for which the 1,3-alternate conformation is preferred, fol-
lowed by the partial cone conformation, then the 1,2-alter-
nate conformation and the least stabile conformation being
the cone conformation. In solution, molecular receptor 1
exists predominantly in a preorganized[13] conformation (1,3-
alternate) due to self-complexation between the host part
(calix[4]pyrrole) and the guest part (pyridine) of the recep-
tor. This leads to negative cooperativity of the receptor,
whereby the first substrate (e.g., 1,3,5-trinitrobenzene, TNB)
binds better (TNBꢀ1) to the preorganized receptor than the
second substrate (TNB2ꢀ1), which has to compete with the
pyridine guest for the second binding site. Addition of ZnII
results in a coordination-driven switching of the receptor
from preorganized to random[13] conformation 1·ZnII. This
event also switches the function of the receptor from nega-
tive to positive cooperativity. This can be observed as a
weak binding of the first substrate and a strong binding of
the second substrate.
Allosteric controlled systems play a ubiquitous role in bio-
logical processes, in which events must be efficiently regulat-
ed in response to external stimuli. Well-known examples in-
clude the allosteric binding of oxygen to haemoglobin,[1]
feed-back mechanisms of enzymes such as the inhibition of
the biosynthesis of isoleucine in bacteria,[2] and positive
stimulation of the lactose operon in the metabolism of
E. coli.[2] A desire to mimic the key features of allosterism
in artificial systems has long been a goal within the chemical
community because it is appreciated that such efforts can
lead to new advances in biomimetic design.[3] There are nu-
merous examples[3b,4] of simple synthetic allosteric host–
guest systems using ions or neutral guest as effectors. How-
ever, homotropic allosteric receptors[5] are considerably
more difficult to achieve.[3b] In these systems the first bind-
ing event induces a nonlinear positive or negative response
to subsequent guest binding.[5b,f] Some of the earliest systems
were reported by Rebek,[6] Traylor,[7] and Tabushi.[8] In
recent years Sessler,[5f,9] Setsune,[10] and Lee,[11] among
others, have been successful in developing receptors that
display a positive allosteric mechanism of binding.
Herein, we report the design, synthesis, and characteriza-
tion of a tetrathiafulvalene (TTF)-substituted calix[4]pyrrole
[a] S. Bꢀhring, G. Olsen, Prof. Dr. P. C. Stein, Prof. Dr. J. Kongsted,
Prof. Dr. K. A. Nielsen
Department of Physics, Chemistry and Pharmacy
University of Southern Denmark
Campusvej 55, 5230 Odense M (Denmark)
Fax : (+45)66-15-87-80
E-mail: kan@sdu.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201203319.
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Chem. Eur. J. 2013, 19, 2768 – 2775

FULL PAPER
ternate conformation, along
with the intramolecular com-
plexed 1,2-alternate and partial
cone conformations to estab-
lish the most stable conforma-
tion (Figure 1). By employing
the M05-2X/6-31G*[14] level of
quantum chemical geometry
optimization and single point
energy calculations in CH2Cl2,
we were able to show that the
preorganized conformation of
1
is more stable than the
random nonbinding conforma-
tion of
by 54.39 kJmolꢁ1
1
(Table 1). The stability of the
proposed conformations follow
the trend reported for calix[4]-
pyrrole.[12a]
The receptor 1 was synthe-
sized as outlined in Scheme 2.
Treatment
ethylthio)-5-methylthio-1,3-di-
thiolo-2-thione[15]
(2) with
of
4-(2-cyano-
CsOH·H2O generated the cor-
responding thiolate, which was
subsequently alkylated with 4-
(3-bromopropyl)-pyridine[16]
(3) affording the 4-methylthio-
5-[3-(4-pyridyl)propylthio]-1,3-
dithiolo-2-thione (4) in 66%
yield. Triethyl phosphite medi-
ated cross-coupling of 4 with
N-tosyl-(1,3)-dithioloACTHNUTRGNE[NUG 4,5-c]pyr-
role-2-one[17] (5) in neat trieth-
yl phosphite gave the tosyl-
protected
monopyrrolotetra-
thiafulvalene (MPTTF) deriva-
tive 6 in 52% yield. Removal
of the tosyl protecting group
was completed with an excess
of NaOMe in a mixture of
THF/MeOH to afford the
MPTTF derivative 7 in 86%
yield. Reaction of 7 and four
equivalents of MPTTF deriva-
tive 8[18] in a CH2Cl2/acetone
mixture in the presence of tet-
Scheme 1. Mechanistic scheme illustrating the ZnII coordination-driven switching of receptor 1 and stepwise
complexation of the analyte TNB with the receptor in its preorganized 1 and random 1·ZnII conformations,
along with their energy-minimized structures.
rabutylammonium
chloride
(TBACl) and stoichiometric
Results and Discussion
amounts of methanesulfonic acid (MSA) afforded a mixture
of the desired asymmetric receptor 1 bearing one pyridine
moiety in 16% yield, and the symmetric TTF–calix[4]pyrro-
le[5a,f,19] receptor 10 in 13% yield, after basic aqueous
workup and column chromatographic purification.
To design a functional switching system, it is very important
to know the relative energies of its conformations; there-
fore, we undertook a computational study on receptor 1 in
its proposed preorganized (self-complexed) 1,3-alternate
conformation and a conformationally rather mobile 1,3-al-
The asymmetry of receptor 1 is readily seen in the
1H NMR spectrum (400 MHz, CDCl3, 298 K; Figure 1 and
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2769

K. A. Nielsen et al.
can be assigned to the four chemically nonequivalent NH
protons. The meso-methyl groups are found to split into
three singlets in the ratio 1:1:2 at d=1.53, 1.54, and
1.56 ppm, respectively, and multiplets are found to arise
from the six thiopropyl groups in the aliphatic part of the
spectrum.
Initial evidence for the interactions between the host part
(calix[4]pyrrole) and the guest part (pyridine) came from
1
comparing the H NMR spectrum of receptor 1 with those
of the model compound 4-methylpyridine (9) and receptor
10 (Figure 2). In the spectrum of receptor 1 the signals cor-
responding to the resonances from the aromatic protons of
the guest part (pyridine) are found to be upfield shifted
(Dd=0.14–0.47 ppm), relative to those of model compound
9, due to shielding of the guest between two TTF sub-
units.[5a,20] Furthermore, one of the four NH (d=9.50 ppm)
protons was found to be highly downfield shifted (Dd=
2.36 ppm), relative to that of the NH protons of receptor 10.
This pronounced shift is caused by hydrogen bonding taking
place between the NH proton of the host part of receptor 1
and the nitrogen lone pair of the guest part of receptor 1.
Further support for the proposed complexation came from
NOESY NMR studies; in the case of receptor 1 the pres-
ence of cross-peaks corresponding to close noncovalent con-
tacts between the host and guest part were observed
(Figure 2). To establish whether the preferred complexation
Figure 1. M05-2X/6-31G* geometry optimized structures of the random
nonbinding conformation and the three possible intramolecular hydro-
gen-bonding conformations.
Table 1. M05-2X/6-31G*[14] single point energy calculations of the three
intramolecular hydrogen-bonding conformations and the non-hydrogen-
bonding random conformation.
Conformation
Energy
[a.u.]
Relative energy
[a.u.]
Relative energy
[kJmolꢁ1
G
E
N
]
nonbinding
1,3-alternate
1,3-alternate
1,2-alternate
Partial cone
ꢁ12583.780520
–
–
ꢁ12583.801042
ꢁ12583.779758
ꢁ12583.792694
ꢁ2.052ꢂ10ꢁ2
ꢁ7.62ꢂ10ꢁ4
ꢁ1.217ꢂ10ꢁ2
ꢁ54.39
2.020
ꢁ32.27
Figure 2. Partial 1H NMR spectra (400 MHz, 298 K) recorded in CDCl3
of a) receptor 1 (2.00 mm), b) 9 (2.00 mm), and c) receptor 10 (2.00 mm).
is intra- or inter-molecular in nature, a dilution experi-
1
ment[21] was carried out and monitored by H NMR spectro-
scopic analysis (Figure S17 in the Supporting Information).
Upon dilution of a concentrated solution (30.0–0.10 mm)
only small peak shifts (Dd<0.06 ppm) were observed, indi-
cating that intramolecular complexation (Scheme 1) is
taking place. Collectively, these data provide support for a
preorganization of receptor 1 that is affected by an intramo-
lecular complexation between the guest part and one of the
two host sites of the receptor. Importantly, the preorganiza-
tion of the receptor leaves one of the two host sites vacant
for substrate binding and, as a consequence of the positive
homotropic allosteric nature of the receptor, an increased
sensitivity for target substrate is to be expected.
Scheme 2. Synthesis of the receptors 1 and 10 along with the chemical
structures of model compound 9 and [Zn(hfac)2]. Reagents and condi-
tions: a) 4-(3-bromopropyl)-pyridine (3; 1.1 equiv) and then CsOH·H2O
(1.05 equiv), DMF/MeOH, RT, 24 h, 66%; b) N-tosyl-(1,3)-dithiolo[4,5-
c]pyrrole-2-one (5; 0.5 equiv), P(OEt)3, 1308C, 2 h, 52%; c) NaOMe
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(13 equiv), THF/MeOH, 358C, 0.5 h, 86%; d) MSA, TBACl, CH2Cl2/ace-
tone, RT, 1 h, then excess Et3N, 16%.
The preorganization of receptor 1 can be ”turned off” by
a coordination-driven switching event using zinc(II)-hexa-
Figure S7 in the Supporting Information), which shows four
singlets resonating at d=7.04, 7.13, 7.24, and 9.50 ppm that
fluoro-acetylacetonate [ZnACTHUNGRETNNU(G hfac)2]. This is evident from a
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Switching of a Calix[4]pyrrole Receptor
FULL PAPER
1H NMR titration experiment (400 MHz, CDCl3, 298 K; Fig-
ure S18–S20 in the Supporting Information) in which step-
wise addition of [ZnACTHNUTRGNEUNG
(hfac)2][22] results in a downfield shift
(Dd=0.48 ppm) of the aromatic pyridine protons Ha and Hb
(d=6.96 and 7.99 ppm, respectively). After addition of one
equivalent of [ZnACHTUNGTRENNUNG(hfac)2], the protons were found to reso-
nate close to the same position as the complex formed be-
tween the model compound 9 and one equivalent of [Zn-
ACHTUNGTRENNUNG(hfac)2] (Figure S18 in the Supporting Information). This
corresponds to the guest part of receptor 1 being complexed
with zinc (1·ZnII)[23] outside the host part of the receptor,
showing that a coordination-induced intramolecular decom-
plexation has taken place.[24]
Figure 4. Partial 1H NMR spectra (400 MHz, 298 K) recorded in CDCl3
of a) 1 (1.0 mm), b) 1+[ZnACTHNUTRGNE(NUG hfac)2] (1.0 equiv), c) after washing the solu-
tion in b) with H2O, and d) after addition of [Zn
solution in c).
ACHTUNGTNER(NNUG hfac)2] (1.0 equiv) to the
To examine whether the receptor can be switched be-
tween its preorganized 1 and random 1·ZnII conformations,
1
a H NMR experiment (400 MHz, CDCl3, 298 K; Figure 3)
1
using H NMR spectroscopy (400 MHz, CDCl3, 298 K). Ad-
dition of up to one equivalent of TNB to a solution of re-
ceptor 1 caused a large downfield shift (Dd=0.23–0.41 ppm;
Figure 5a–d and Figure S35 in the Supporting Information)
Figure 3. An expanded region of the 2D NOESY NMR spectrum of re-
ceptor 1, showing the NOE between the aliphatic meso-Me protons and
those of the aromatic pyridine and the four distinct NH protons. Some of
the NOE signals have been omitted in the structure of receptor 1 for
clarity.
Figure 5. Partial 1H NMR spectra (400 MHz, 298 K) recorded in CDCl3
of
1 with addition of an increasing amount of TNB a) receptor 1
was carried out that involved repeated addition of first [Zn-
ACHTUNGTRENNUNG(hfac)2] followed by aqueous extraction of zinc ions. Initially,
(2.0 mm), b) with TNB (0.25 equiv), c) with TNB (0.50 equiv), d) with
TNB (1.0 equiv), and e) with TNB (3.7 equiv). f) Changes in chemical
*
shift values of the aromatic protons Ha ("), Hb (3), Hc (&), Hd
(
), He
the preorganized receptor 1 was converted into the random
~
!
(
) and Hf ( ) together with the simultaneously fitted binding isotherm.
conformation (Figure 4b) by addition of one equivalent of
[Zn
phase allows the system to revert to the preorganized con-
formation (Figure 4c). Repeated addition of [Zn(hfac)2] and
ACHTUNGTRENNUNG
(hfac)2]. Extraction[25] of the zinc ions into an aqueous
T
of the four NH protons as expected. However, when exceed-
ing one equivalent of TNB, an upfield shift of the NHc
proton and a continued downfield shift of the remaining
three NH protons was observed (Figure 5e). The upfield
shift of the NHc proton is rationalized as an increased com-
petition between the pyridine “guest” and the substrate
TNB for the second binding site (Scheme 1). In the second
aqueous extraction resulted in a continuation of the control-
led switching of the receptor, as can be inferred from
Figure 4.
The binding event between our substrate of choice,
namely 1,3,5-trinitrobenzene (TNB), and the receptor in its
two limiting conformations (Scheme 1) were studied by
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2771

K. A. Nielsen et al.
experiment, addition of TNB to the receptor in the random
conformation 1·ZnII was carried out under identical condi-
tions (Figure S37 in the Supporting Information). The data-
sets for the receptor in its preorganized and random confor-
mations, and the model receptor 10 titrated with TNB were
fitted with multiple equilibria[26] (Figure 5 f and Figure S36,
S38 and S39 in the Supporting Information) using the chem-
ical shift changes of the NH protons and the aromatic pyri-
dine protons Ha and Hb, using a downhill simplex method[27]
with a least squares metric.
ceptor—due to intramolecular complexation—leads to a
large increase of the first substrate binding, and a decrease
of the second substrate binding.
The complexation between receptor 1—in its two limiting
conformations—and the substrate TNB were also investigat-
ed in CH2Cl2 by using absorption spectroscopy. Addition of
ten equivalents of TNB to a solution of 1 (Figure 6b) result-
ed in an immediate color change from yellow to green, due
to the presence of charge transfer (CT) interactions between
the electron-donating TTF subunits and the electron-defi-
cient substrate. The intensity of the CT band centered at
680 nm is approximately half that formed between 10 and
ten equivalents of TNB (Figure 6 f). However, addition of
The fitting procedure for the Connors[26] 2:1 is based on
that the actual host and guest concentrations (½Hꢂ and ½Gꢂ)
can be calculated from the starting concentrations (½Hꢂ0 and
½Gꢂ0) via:
one equivalent of [ZnACHTNUGTRNEUNG(hfac)2] to the solution of receptor 1
containing ten equivalents of TNB resulted in a coordina-
tion-driven intramolecular decomplexation event, which was
observed as an increase of the CT band (Figure 6d) to
almost the same intensity as that of the model receptor 10
containing ten equivalents of TNB. This is in agreement
with 1 being preorganized, having only one free binding site
for TNB, whereas 1·ZnII and 10 has two binding sites. Fitting
the titration data to the Hill equation[28] gave the Hill coeffi-
cients (Table 1, and Figure S45 and Table S1 in the Support-
ing Information) with a good correlation coefficient (R2 >
0.999). From Table 1 it can be seen that a coordination-
driven switching of the receptor between its two limiting
conformations results in switching between positive and neg-
ative cooperativity.
2
½Hꢂ0¼ ð1 þ KaÞ½Hꢂ þ ðKb þ KaKdÞ½Hꢂ½Gꢂ þ KbKc½Hꢂ½Gꢂ
2
½Gꢂ0¼ ½Gꢂ þ ðKb þ KaKdÞ½Hꢂ½Gꢂ þ 2KbKc½Hꢂ½Gꢂ
with the condition that 0ꢃ½Hꢂꢃ ½Hꢂ0 and 0ꢃ½Gꢂꢃ½Gꢂ0. The
chemical shift for a site (i) is obtained from:
2
½Hꢂ
½Hꢂ½Gꢂ
½Hꢂ0
½Hꢂ½Gꢂ
½Hꢂ0
di ¼ di;0 þ Ka
di;a þ Kb
di;b þ 2KbKc
di;c
½Hꢂ0
½Hꢂ½Gꢂ
þKaKd
di;d
½Hꢂ0
for i=a…f; and where di,0 are the chemical shift of the site
at infinite dilution and di,a…di,d are the chemical shifts of the
different complexes (Scheme 3). In the complexation event
between the preorganized receptor 1 and TNB, multiple
equillibria have been taken into consideration, in which the
self-complexed preorganized receptor is in equilibrium with
the noncomplexed conformation (Scheme 3), which also
contributes to the complexation of TNB. Based on the fitted
data, we were able to delineate the complex behavior of re-
ceptor 1 (Scheme 3). The fitted values of the macroscopic
constants K1 and K2 (Table 2) show that receptor 1 in its
preorganized conformation has a 291-fold increase in the
first complexation (K1) with TNB when compared with the
random conformation. In the second complexation (K2) with
TNB, the competition between the pyridine “guest” and the
TNB substrate results in a 38-fold decrease of the binding.
These results demonstrate that a preorganization of the re-
Conclusion
We have demonstrated the operation of a molecular recep-
tor 1 that—in the presence or absence of ZnII—adjusts its
ability to complex guest molecules. In the absence of ZnII
a
self-complexation between the pyridine guest part and the
calix[4]pyrrole host part occurs, resulting in a higher level of
preorganization of the receptor. In this conformation the re-
ceptor shows negative cooperativity with initial high binding
towards TNB guest molecules. Addition of ZnII results in a
coordination-induced switching of the receptor into its
random conformation, in which it shows positive cooperativ-
ity towards TNB.
Experimental Section
Table 2. Binding constants[a] [K1 and K2 (Mꢁ1)] corresponding to the in-
teractions between the receptors 1, 1·ZnII, and 10 and the analyte TNB
General methods: All chemicals were purchased from Sigma–Aldrich
and used as received unless indicated otherwise. Compounds 2,[15] 3,[16]
5,[17] and 8[18] were synthesized according to literature procedures. All re-
actions were carried out under an atmosphere of anhydrous nitrogen.
THF and MeOH were distilled from sodium-benzophenone and Mg, re-
spectively, immediately prior to use. CH2Cl2 was distilled immediately
prior to use and, if necessary, stored over molecular sieves (4 ꢃ).
(EtO)3P was distilled prior to use and stored over molecular sieves (4 ꢃ).
Acetone was stored over Drierite for at least three days. Analytical thin-
layer chromatography (TLC) was performed by using aluminum sheets
precoated with silica gel 60F (Merck 5554), which were inspected by UV-
light (254 nm) prior to development with I2 vapor. Column chromatogra-
1
as determined by H NMR spectroscopy[b] at 298 K in CDCl3 and Hill co-
efficient[c] (n) for the cooperative binding of TNB, determined by absorp-
tion spectroscopy[b] at 298 K in CH2Cl2.
Receptor
n
K1
5.8ꢂ103
20
4.6ꢂ102
K2
K2/K1
1
0.86
1.27
1.24
3.2ꢂ102
1.2ꢂ104
1.6ꢂ103
0.05
600
3.49
1·ZnII
10
[a] Estimated errors are <15%. [b] Receptors 1, 1·ZnII, and 10 were ti-
trated with a concentrated TNB solution containing the corresponding
receptor at its initial concentration. [c] Estimated errors are <10%.
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Switching of a Calix[4]pyrrole Receptor
FULL PAPER
tus and are uncorrected. 1D and
2D NMR spectra were recorded with
a Bruker AVANCE III 400 MHz spec-
trometer; 1H NMR spectra were re-
corded at 400 MHz (298 K) and
13C NMR was recorded at 100 MHz
(298 K). Low temperature 1H NMR
spectra were recorded with a Varian
Unity 500 MHz spectrometer. The
NMR samples were dissolved in deu-
terated solvents purchased from Cam-
bridge Isotope Labs or Sigma–Aldrich,
and TMS or the residual solvent were
used as internal standard. Solvent sig-
nals were assigned according to Nudel-
man et al.,[29] IR spectra were record-
ed with a Perkin-Elmer 580 spectro-
photometer. Isothermal titration calo-
rimetry was performed with a VP-ITC
from MicroCal. Matrix-assisted laser-
desorption (MALDI)/ionization mass
spectrometry was performed with
Bruker Autoflex III Smartbeam
(MALDI-TOF) utilizing 2,5-dihy-
a
a
droxybenzoic acid (DHB) matrix.
Electrospray ionization mass spectra
(HR-ESI) were recorded with
a
Thermo Finnigan MAT SSQ710 single
stage quadropole. Elemental analyses
were performed by Atlantic Microlab,
Inc., Atlanta, Georgia, USA.
Synthesis of 4-methylthio-5-(3-(4-pyri-
dyl)propylthio)-1,3-dithiolo-2-thione
(4):
4-(2-Cyanoethylthio)-5-methyl-
thio-1,3-dithiolo-2-thione[15] (2, 8.87 g,
33.2 mmol) and 4-(3-bromopropyl)pyr-
idine[16] (3, 7.36 g, 36.8 mmol) were
dissolved in anhydrous DMF (300 mL)
and degassed with N2 for 15 min,
before
a
solution of CsOH·H2O
(5.89 g, 35.1 mmol) in anhydrous
MeOH (5 mL) was added dropwise
over 1 h. The reaction was stirred at
RT overnight before being concentrat-
ed in vacuo to a red oil, which was re-
dissolved in CH2Cl2 (400 mL) and
Scheme 3. Mechanistic scheme illustrating the equilibria present in the complexation of receptor 1 and TNB.
Ke is calculated based on Ka, Kb and Kd. Kf is calculated based on Kc and Ke.
washed with brine (3ꢂ200 mL) and H2O (2ꢂ200 mL) before being dried
(MgSO4). The solution was evaporated onto silica and purified by
column chromatography (800 mL SiO2, 8 cm Ø; CH2Cl2/MeOH 49:1 v/v).
The orange band (Rf =0.3) was collected and concentrated to give com-
pound 4 (7.26 g, 66%) as a red oil. 1H NMR (400 MHz, CDCl3, 298 K,
TMS): d=2.01 (quintet, J=7.0 Hz, 2H), 2.50 (s, 3H), 2.78 (t, J=7.0 Hz,
2H), 2.86 (t, J=7.0 Hz, 2H), 7.13 (d, J=6.0 Hz, 2H), 8.52 ppm (d, J=
6.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, 298 K, TMS): d=19.2, 29.9,
33.5, 35.9, 123.8, 131.4, 140.3, 149.5, 149.9, 210.7 ppm; HRMS (ESI): m/z:
·+
calcd for C12H14NS5 331.9724 [M·+]; found 331.9739; IR (KBr): n˜ =3065
(w), 3023 (w), 2917 (m), 1673 (w), 1600 (s), 1414 (s), 1067 cmꢁ1 (s); ele-
mental analysis calcd (%) for C12H13NS5 +1/3ꢂCH2: C 44.06, H 4.10, N
4.17, S 47.68; found: C 44.07, H 4.05, N 4.30, S 47.31.
Synthesis of monopyrrolotetrathiafulvalene 6: N-Tosyl-(1,3)-dithioloACHTUNGTRENNUNG[4,5-
c]pyrrole-2-one[17] (5, 3.15 g, 10.1 mmol) was dissolved in triethyl phos-
phite (50 mL) and heated to 1308C, whereafter 4-methylthio-5-(3-(4-pyri-
dyl)propylthio)-1,3-dithiolo-2-thione (4) was added in portions after
0 min (4.98 g, 14.9 mmol), 7 min (1.15 g, 3.45 mmol) and 14 min (0.96 g,
2.88 mmol). The reaction mixture was stirred for 2 h before being cooled
to RT and concentrated in vacuo to a dark-yellow oil, which was redis-
solved in CH2Cl2 (200 mL) and washed with brine (200 mL) and H2O
(3ꢂ200 mL) before being dried (MgSO4). After evaporation of the sol-
vent, the dark-yellow oil was purified by column chromatography
Figure 6. Absorption spectra recorded in CH2Cl2 at 298 K of a) receptor 1
(0.20 mm; d), b) 1+TNB (10 equiv; b), c) receptor 1·ZnII (0.20 mm;
l), d) 1·ZnII +TNB (10 equiv; black c), e) receptor 10 (0.20 mm;
g), and f) 10+TNB (10 equiv; dark grey c).
phy was performed by using silica gel 60F (Merck 9385, 0.040–0.063 mm).
Melting points (mp) were determined with a Bꢄchi melting point appara-
Chem. Eur. J. 2013, 19, 2768 – 2775
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2773

K. A. Nielsen et al.
(500 mL SiO2, 6 cm Ø; CH2Cl2/MeOH 49:1 v/v). The yellow band (Rf =
0.4) was collected and concentrated to give 6 (3.14 g, 52%) as a yellow
solid (m.p. 100–1058C). 1H NMR (400 MHz, CDCl3, 298 K, TMS) d=
1.96 (quintet, J=7.0 Hz, 2H), 2.41 (s, 3H), 2.42 (s, 3H), 2.76 (t, J=
7.0 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 6.94 (s, 2H), 7.11 (dd, J=5.9,
1.6 Hz, 2H), 7.30 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.2 Hz, 2H), 8.50 ppm
(dd, J=5.9, 1.6 Hz, 2H); 13C NMR (100 MHz, CDCl3, 298 K, TMS) d=
19.3, 21.8, 30.0, 33.6, 35.4, 111.4, 114.6, 117.5, 124.1 (two signals), 127.1,
127.2, 127.2, 130.3, 130.8, 135.5, 145.7, 150.0 ppm, two signals are overlap-
Acknowledgements
This work was supported by the Danish Natural Science Research Coun-
cil (FNU, projects no. 272-08-0047), the Center for Fundamental Living
Technology (FLinT), the University of Southern Denmark (SDU), and
the Villum Foundation.
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·+
ping or missing; HRMS (ESI): m/z: calcd for C24H23N2O2S7 594.9799
[M·+]; found 594.9806; IR (KBr): n˜ =3154 (w), 3132 (w), 3064 (w), 2985
(m), 2916 (m), 1599 (s), 1493 cmꢁ1 (m); elemental analysis calcd (%) for
C24H23N2O2S7: C 48.45, H 3.73, N 4.71, S 37.73; found: C 48.32, H 3.77, N
4.67, S 37.54.
Synthesis of monopyrrolotetrathiafulvalene 7: Monopyrrolotetrathiaful-
valene 6 (1.35 g, 1.78 mmol) was dissolved in a mixture of anhydrous
THF (150 mL) and anhydrous MeOH (50 mL) and degassed with N2 for
20 min. Sodium methoxide (25 wt% in MeOH, 1.22 g, 22.7 mmol) was
added in one portion, and the reaction mixture was heated to 358C.
After 1 h, the reaction was quenched with H2O (100 mL) and extracted
with CH2Cl2 (2ꢂ100 mL). The combined organic phases were washed
with H2O (2ꢂ100 mL) and dried (MgSO4). After evaporation of the sol-
vent, the dark-yellow oil was purified by column chromatography
(500 mL SiO2, 6 cm Ø; CH2Cl2/MeOH 49:1 v/v). The yellow band (Rf =
0.3) was collected and concentrated to give 7 (678 mg, 86%) as a yellow
solid (m.p. 157–1588C). 1H NMR (400 MHz, CDCl3, 298 K, TMS): d=
1.98 (quintet, J=7.2 Hz, 2H), 2.43 (s, 3H), 2.77 (t, J=7.2 Hz, 2H), 2.81
(t, J=7.2 Hz, 2H), 6.61 (d, J=2.8 Hz, 2H), 7.13 (dd, J=4.5, 1.5 Hz, 2H),
8.33 (br. s, 1H), 8.50 ppm (d, J=4.5, 1.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3, 298 K, TMS): d=19.2, 29.9, 33.5, 35.3, 109.8, 119.9, 119.9, 121.3,
124.0, 130.7, 149.9, 150.1 ppm, three signals are overlapping or missing;
·+
HRMS (ESI): m/z: calcd for C17H17N2S6
440.9710 [M·+]; found
440.9710; IR (KBr): n˜ =3401 (s), 3122 (s), 3058 (m), 2919 (s), 2857 (s),
1604 (s), 1417 cmꢁ1 (s); elemental analysis calcd (%) for C17H17N2S6: C
46.33, H 3.66, N 6.36, S 43.65; found: C 46.54, H 3.67, N 6.36, S 43.46.
Synthesis of tetrathiafulvalene–calix[4]pyrrole 1: A solution of monopyr-
rolotetrathiafulvalene 7 (345 mg, 0.783 mmol), monopyrrolotetrathiaful-
valene 8[18] (915 mg, 2.34 mmol), and tetrabutylammonium chloride
(0.227 g, 0.817 mmol) in anhydrous CH2Cl2 (300 mL) and anhydrous ace-
tone (150 mL) was degassed with argon for 20 min, before methanesul-
fonic acid (1.4 mL, 2.1 g, 30 mmol) was added to the yellow solution. The
reaction mixture was stirred at RT for 45 min, whereupon triethylamine
(2.0 mL, 1.5 g, 14 mmol) was added slowly. H2O (100 mL) was added and
the solution was extracted with CH2Cl2 (3ꢂ100 mL). The combined or-
ganic phases were washed with H2O (5ꢂ100 mL) before being dried
(MgSO4). After evaporation of the solvent, the dark-yellow oil was puri-
fied by column chromatography (600 mL SiO2, 6 cm Ø; CH2Cl2 until the
first band eluted, then CH2Cl2/MeOH 33:1 v/v). The first band containing
the symmetric tetrathiafulvalene–calix[4]pyrrole[5a, f,19] 10, was isolated.
The yellow band (Rf =0.3) was collected and concentrated to give 1
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ing conformations: 1,3-alternate, partial cone, 1,2-alternate, cone,
and all conformations in between. The preorganized conformation
consists of all the same conformations. However, the equilibrium is
shifted in favor of the 1,3-alternate conformation, due to the intra-
molecular complexation between the guest (pyridine)and the host
(calix[4]pyrrole) parts of the receptor.
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2006, 2, 364–382.
1
(220 mg, 16%) as an orange solid (m.p. 124–1268C). H NMR (400 MHz,
CDCl3, 298 K, TMS): d=0.99–1.05 (m, 18H), 1.53 (s, 6H), 1.54 (s, 6H),
1.56 (s, 12H), 1.63–1.70 (m, 12H), 2.01 (quintet, J=7.0 Hz, 2H), 2.49 (s,
3H), 2.73 (t, J=7.0 Hz, 2H), 2.74–2.83 (m, 14H), 6.96 (dd, J=5.9,
1.3 Hz, 2H), 7.04 (s, 1H), 7.13 (s, 1H), 7.24 (s, 1H), 7.99 (dd, J=5.9,
1.3 Hz, 2H), 9.50 ppm (s, 1H); 13C NMR (100 MHz, CDCl3, 298 K,
TMS): d=13.2, 19.3, 23.2, 27.8, 28.0, 28.1, 28.4, 29.7, 32.7, 36.0, 36.1, 36.2
(two signals), 38.1, 38.2, 109.2, 111.9, 112.2, 114.6, 115.1, 115.3, 115.7,
116.5, 123.8, 127.1, 127.2 (two signals), 127.4, 128.0, 128.3, 129.1, 130.6,
130.9, 148.4, 150.0 ppm, signals are overlapping and/or missing; HRMS
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·+
(ESI): m/z: for C71H83N5S24 1772.9940 [M·+]; found 1772.980; IR (KBr):
n˜ =3401 (s), 3122 (s), 3058 (m), 2919 (s), 2857 (s), 1604 (s), 1417 cmꢁ1 (s);
elemental analysis calcd (%) for C71H83N5S24 +C5H10: C 49.44, H 5.08, N
3.79, S 41.68; found: C 49.14, H 5.03, N 3.75, S 41.22.
2774
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ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 2768 – 2775

Switching of a Calix[4]pyrrole Receptor
FULL PAPER
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conditions.
[20] For the intermolecular complex 10ꢀ92 small shifts were observed in
the 1H NMR spectrum (Figure S23 in the Supporting Information).
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tion of the organic phase and drying over MgSO4 before a subse-
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7512–7515.
[22] Association constants for Zinc hexafluoroacetylacetonate [Zn-
Received: September 17, 2012
Published online: January 7, 2013
(hfac)2] and 4-methylpyridine
9
are K1 =4.27ꢂ104 mꢁ1 and K2 =
Chem. Eur. J. 2013, 19, 2768 – 2775
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2775