Acid/base controllable molecular recognition

Article abstract of DOI:10.1002/chem.201101266

The study of controllable molecular recognition in supramolecular receptors is important for elucidating design strategies that can lead to external control of molecular recognition applications. In this work, we present the design and synthesis of an asymmetric (TTF) tetrathiafulvalene-calix[4]pyrrole receptor and show that its recognition of 1,3,5-trinitrobenzene (TNB) can be controlled by an acid/base input. The new receptor is composed of three identical TTF units and a fourth TTF unit appended with a phenol moiety. Investigation of the host-guest complexation taking place between the TTF-calix[4]pyrrole receptor and the TNB guests was studied by means of absorption and ¹H NMR spectroscopy; this revealed that the conformation of the molecular receptor can be switched between locked and unlocked states by using base and acid as the input. In the unlocked state, the receptor is able to accommodate two TNB guest molecules, whereas the guests are not able to bind to the receptor in the locked state. This work serves to illustrate how external control (acid/base) of a receptor may be used to direct the molecular recognition of guests (TNBs). It has led to a new controllable molecular recognition system that functions as an acid/base switch.

Full text of DOI:10.1002/chem.201101266

FULL PAPER
DOI: 10.1002/chem.201101266
Acid/Base Controllable Molecular Recognition
Kent A. Nielsen,* Steffen Bꢀhring, and Jan O. Jeppesen[a]
Abstract: The study of controllable
a fourth TTF unit appended with a
phenol moiety. Investigation of the
host–guest complexation taking place
between the TTF-calix[4]pyrrole recep-
tor and the TNB guests was studied by
means of absorption and 1H NMR
spectroscopy; this revealed that the
conformation of the molecular receptor
can be switched between locked and
molecular recognition in supramolec-
ular receptors is important for elucidat-
ing design strategies that can lead to
external control of molecular recogni-
tion applications. In this work, we pres-
ent the design and synthesis of an
asymmetric (TTF) tetrathiafulvalene-
calix[4]pyrrole receptor and show that
its recognition of 1,3,5-trinitrobenzene
(TNB) can be controlled by an acid/
base input. The new receptor is com-
posed of three identical TTF units and
unlocked states by using base and acid
as the input. In the unlocked state, the
receptor is able to accommodate two
TNB guest molecules, whereas the
guests are not able to bind to the re-
ceptor in the locked state. This work
serves to illustrate how external control
(acid/base) of a receptor may be used
to direct the molecular recognition of
guests (TNBs). It has led to a new con-
trollable molecular recognition system
that functions as an acid/base switch.
Keywords: anion recognition · cal-
ix[4]pyrrole · molecular devices ·
receptors · self-complexation
Introduction
pended (Schemes 1 and 2) with a phenol moiety and demon-
strate how deprotonation/protonation at a “remote” site can
be utilized to lock/unlock the molecular receptor. Deproto-
nation of the phenol moiety in the calix[4]pyrrole receptor 1
changes its ability to bind guest molecules as a result of a
conformational change induced by a self-complexation[14]
event taking place between the phenolate anion “tail”[15]
and the calix[4]pyrrole “head”.[16]
The mechanistic scheme for the proposed locking/unlock-
ing of the molecular receptor 1 is illustrated in Scheme 1. In
its neutral form, the molecular receptor 1 exists predomi-
nantly in the 1,3-alternate conformation[17] allowing elec-
tron-deficient guests, such as 1,3,5-trinitrobenzene
(TNB),[11a,e,18] to access the two cavities of 1 leading to the
formation of the 2:1 complex TNB2ꢀ1. Deprotonation of
the phenol moiety leads to the formation of TNB2ꢀ1À,
which undergos conformational changes, from the 1,3-alter-
nate to the self-complexing conformation 1À with a concomi-
tant release of the two TNB guests since no cavities in the
self-complexing conformation 1À are available for binding.
Finally, protonation of 1À regenerates the neutral 1,3-alter-
nate conformation of the receptor. Since this receptor
design allows the calix[4]pyrrole “head” to bite its own
“tail” (phenolate), it seems appropriate to name it an ouro-
boros (“tail-eater” in Greek).
Allosteric change in activity is characteristic for many bio-
logical receptors.[1] In these systems an effector typically en-
hances or reduces the binding efficiency and eventually
switches the activity fully ON or OFF. One of the ultimate
challenges in supramolecular chemistry is to obtain external
control of a molecular receptor, thus enabling the release
and/or uptake of guest molecules to be induced at will. Pio-
neering work in this field has been reported by Rebek and
Shinkai among others.[2] Calix[4]pyrroles[3] are well-known
for their ability to bind a variety of different anions through
intermolecular hydrogen-bonding interactions taking place
between the four NH protons and the anion in quest. Al-
though several groups have explored this recognition motif
and used it for the synthesis of strapped calix[4]pyrroles,[4]
extractants for halide anion salts,[5] colorimetric sensors,[6]
ion-selective electrodes,[7] electrochemical sensors,[8] anion-
pair receptors,[9] selective encapsulation systems,[10] molecu-
lar sensors,[8a,11] and catalysts,[12] the creation of unique intra-
molecular self-complexation[13] systems based on the ca-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
tion of a tetrathiafulvalene-calix[4]pyrrole receptor 1 ap-
[a] Dr. K. A. Nielsen, S. Bꢀhring, Prof. J. O. Jeppesen
Department of Physics and Chemistry
University of Southern Denmark, Campusvej 55
5230 Odense M (Denmark)
Results and Discussion
The neutral receptor 1 was synthesized in four steps as out-
lined in Scheme 2. Treatment of the cyanoethyl-protected
monopyrrolotetrathiafulvalene[19] (MPTTF) building block 2
with one equivalent of CsOH·H2O generated the corre-
Fax : (+45)66-15-87-80
E-mail: kan@ifk.sdu.dk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101266.
Chem. Eur. J. 2011, 17, 11001 – 11007
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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The asymmetry of the neutral
receptor 1 is clearly evident
from the 1H NMR spectrum
(400 MHz) recorded in CDCl3
at 298 K. The spectrum (Fig-
ure 1a) shows three singlets res-
onating at d=7.21, 7.19, and
7.18 ppm—integrating to 1H,
1H, and 2H, respectively—
which can be assigned to the
three chemically nonequivalent
NH protons. In agreement with
the asymmetric nature, multip-
lets arising from the six thio-
propyl and eight meso-methyl
groups are observed (see Fig-
ure S7 in the Supporting Infor-
mation) to resonate in the ali-
phatic part of the spectrum.
Scheme 1. Mechanistic scheme for the acid/base controllable conformational locking and unlocking of the mo-
lecular receptor 1, directing decomplexation and complexation of the TNB guests.
Scheme 2. Synthesis of the neutral receptor 1 and the model receptor 8:
a) 1 equiv CsOH·H2O, THF/MeOH, RT, 1 h; b) 4-(3-bromopropyl)phenol
(3), RT, 16 h, 86%; c) 10 equiv NaOMe, THF/MeOH, 508C, 1 h, 93%;
d) TFA, TBACl, CH2Cl2/Me2CO, RT, 16 h, then Et3N, RT, 20 min, 10%;
Figure 1. Partial 1H NMR spectra (400 MHz, 298 K) recorded in CDCl3
of a) 1 (1.5 mm), b) 1+0.25 equiv DBU, c) 1+0.50 equiv DBU, d) 1+
0.75 equiv DBU, and e) 1+1.00 equiv DBU.
e) Et3N, benzoyl chloride, CH2Cl2, RT, 30 min, 79%.
sponding MPTTF-thiolate, which was alkylated with 4-(3-
bromopropyl)phenol[20] (3) affording the MPTTF derivative
4 in 86% yield. The tosyl protecting group on the MPTTF
compound 4 was removed with an excellent yield (93%) by
using sodium methoxide (NaOMe) in a THF/MeOH mix-
ture. Reaction of the MPTTF derivative 5 appended with
the phenol moiety and four equivalents of the MPTTF de-
rivative[21] 6 in a CH2Cl2/Me2CO mixture in the presence of
tetrabutylammonium chloride (TBACl) and excess trifluoro-
acetic acid (TFA) afforded a mixture of the desired receptor
1 in 10% yield, and the tetraTTF-calix[4]pyrrole[8a,11] 7 (see
Figure S10 in the Supporting Information) in 10% yield,
after basic aqueous workup and column chromatographic
purification. Reaction of the receptor 1 with benzoyl chlo-
ride in a CH2Cl2 solution in the presence of Et3N afforded
the model receptor tetraTTF-calix[4]pyrrole 8 in 79% yield.
Formation of the ouroboros 1À was followed by using
1H NMR
spectroscopy.
The
base
1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU) was used to deprotonate the
phenol moiety in the receptor 1 and the resulting self-com-
plexing event (Scheme 1) taking place between the pheno-
late anion “tail” and the calix[4]pyrrole “head” is clearly
evident from the 1H NMR spectra (Figure 1) recorded in
CDCl3 at 298 K. Stepwise addition of DBU reveals that the
resonances associated with the NH protons (d=7.21–
7.18 ppm) in the 1,3-alternate conformation of 1 are ob-
served to decrease in intensity concurrent with an increase
in the intensity of the NH signals associated with the ouro-
boros 1À. As a consequence of the inherent asymmetry of
the ouroboros 1À, a multiplet of NH signals are observed to
resonate between d=12.64–12.40 ppm.[22,6a] The phenol pro-
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Chem. Eur. J. 2011, 17, 11001 – 11007

Acid/Base Controllable Molecular Recognition
FULL PAPER
Table 1. Binding constants[a] (Ka, mÀ1) corresponding to the interactions
between the receptors 1 and 8 and the ClÀ and p-cresolate anions in the
form of their TBA+ salts as determined by absorption spectroscopy[b] at
298 K in CH2Cl2 and formation constant[a] (Kf) for the self-complexing
tons are found to resonate as two doublets at d=7.04 and
6.72 ppm in the neutral receptor 1. Upon addition of DBU,
the signals associated with these protons are also seen to de-
crease in intensity concurrent with the appearance of two
new multiplets resonating at d=7.02–6.95 and 6.95–
6.88 ppm, respectively. These shifts (Dd=À0.06 and
0.20 ppm, respectively) can most likely be accounted for by
the apparent proximity between the phelolate moiety and
the MPTTF unit and the meso-methyl groups of the calix[4]-
pyrrole macrocycle in the ouroboros 1À. To confirm that
these shifts are associated with the formation of the self-
complexing system 1À rather than the formation of dimers
or supramolecular oligomers, the complex between the p-
cresolate anion and the model system tetraTTF-calix[4]pyr-
1
ouroboros 1À, determined by H NMR spectroscopy[c] at 298 K in CDCl3.
Receptor
ClÀ
p-Cresolate
Self-complexation
1
8
1.9ꢂ106
1.3ꢂ106
–
1.5ꢂ106
–
1.4ꢂ105
[a] Estimated errors are <15%. [b] Receptors 1 and 8 were titrated with
a concentrated TBA·Cl or TBA·p-cresolate solution containing the corre-
sponding receptor at its initial concentration to give the corresponding
complexation. [c] Determined from competitive binding experiments.[24]
An average Krel of 1.5 for the 1·ClÀ/1À was obtained by analyzing a
CDCl3 solution of 1 (1.5 mm) containing 0.5 equiv of ClÀ and 1.0 equiv of
DBU.
1
role 8 was also investigated by using H NMR spectroscopy.
In the case of the 8·p-cresolate complex (see Figure S10 in
the Supporting Information), one broad NH signal is ob-
served to resonate at d=12.6 ppm, which indicates a higher
degree of symmetry relative to the self-complexing system
1À. Furthermore, the signals corresponding to the SCH2 and
meso-methyl groups were found to split into different signals
for the self-complexing system 1À, whereas for the 8·p-creso-
late complex only a shift and a broadening of the signals
were observed.[23] Finally, the 1H NMR spectra (400 MHz,
298 K) recorded of 1À in CDCl3 at different concentra-
tions[13f–i,m] did not show any concentration dependence from
1.7 down to 0.12 mm. These observations indicate that the
phenol “tail” and the calix[4]pyrrole macrocycle “head” of
the receptor 1 upon deprotonation forms an intramolecular
complex that can be ascribed as the ouroboros 1À and it is
unlikely, therefore, that supramolecular oligomers are
formed to any significant extent under the conditions stud-
ied.
respectively, allow the relative binding constant (Krel) to be
determined. Finally, the Kf value can be calculated by using
the Ka value for the 1·ClÀ complex. Analysis of the data
gave a Kf value of 1.5ꢂ106 for the formation of the ouro-
boros 1À. For comparison, the binding constant for the inter-
molecular complexation between the model system tet-
raTTF-calix[4]pyrrole 8 and p-cresolate was determined by
using absorption spectroscopy and gave a Ka value of 1.4ꢂ
105 mÀ1 in CH2Cl2 at 298 K. A comparison[27] of the Ka value
for the 8·p-cresolate complex and the Kf value for the ouro-
boros 1À revealed that the binding in the intramolecular
self-complexating system 1À is eleven times stronger than
the binding in the intermolecular 8·p-cresolate complex, an
observation that also supports the hypothesis that 1À is a
self-complexing system.
To examine whether the receptor can be switched be-
tween its neutral 1,3-alternate conformation 1 and the self-
1
complexing ouroboros 1À conformation, an H NMR spec-
1
No significant changes appear in the H NMR spectra re-
troscopic experiment (Figure 2) was carried out that in-
corded of the receptor 1 after addition of more than one
equivalent of DBU, which indicates that the formation con-
stant (Kf) for the ouroboros 1À is very strong. Consequently,
the Kf value cannot be determined by traditional titration
techniques, because the titration plot tended towards lineari-
ty with increasing DBU concentration, which makes the
nonlinear curve fitting procedure unreliable. Instead, the Kf
value for the ouroboros 1À was determined by a competitive
method.[24] Initially, the binding constant (Ka) for the com-
plexation between the neutral receptor 1 and ClÀ (as its
TBA+ salt; Table 1) was determined by using absorption
spectroscopy, which gave a Ka value of 1.9ꢂ106 mÀ1 in
CH2Cl2 at 298 K.[25] Subsequently, the Kf value for the for-
mation of the ouroboros 1À was determined from a competi-
1
tive H NMR spectroscopic experiment with ClÀ ions under
conditions of negligible free receptor conditions. The cal-
ix[4]pyrrole receptor 1 was brought to self-complex by the
addition of one equivalent of DBU; then ClÀ anions (as its
TBA+ salt) were added[26] until approximately 50% of the
ouroboros 1À was converted (see Figure S8 in the Support-
ing Information) into the 1·ClÀ complex. Integration of the
resonances associated with the CH3 protons in the TBA+
cation and the CH3 protons in the calix[4]pyrrole receptor,
Figure 2. Partial 1H NMR spectra (400 MHz, 298 K) recorded in CDCl3
of a) the receptor 1 (1.5 mm), b) the mixture obtained after adding
1.0 equiv of DBU to the solution in a), c) the mixture obtained after
adding 1.0 equiv of MSA to the solution in b), d) the mixture obtained
after adding 1.0 equiv of DBU to the solution in c), e) the mixture ob-
tained after adding 1.0 equiv of MSA to the solution in d), and f) the
mixture obtained after adding 1.0 equiv of DBU to the solution in e).
Chem. Eur. J. 2011, 17, 11001 – 11007
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K. A. Nielsen et al.
volved the repeated addition of first base followed by acid
to a solution of the receptor 1. Initially, the neutral receptor
1 was converted (Figure 2b) to the ouroboros 1À by addition
of one equivalent of base (DBU). Addition of one equiva-
lent of methanesulfonic acid (MSA) to the solution of the
conformation. This change in conformation happens essen-
tially instantaneously and is observed as a color change
from green to yellow concomitant with the disappearance
(Figure 3c) of the CT absorption band centered at 677 nm in
the absorbance spectrum, which indicates that the TNB
guests have been released (Scheme 1) from the receptor
since no cavities are available for TNB binding in the ouro-
boros 1À. Finally, addition of one equivalent of MSA to the
solution of the ouroboros 1À and TNB resulted in a color
change from yellow to green and an absorption spectrum
(Figure 3d) similar to that recorded of the original mixture
of the receptor 1 and TNB (Figure 3b), which suggests that
the TNB2ꢀ1 complex has been regenerated in the CH2Cl2
solution as a result of protonation of the phenolate moiety
in the ouroboros 1À. Analyses of this sequence of events
were also carried out by using 1H NMR spectroscopy
(Figure 4) in CDCl3 at 298 K. Upon addition (Figure 4a,b)
of two equivalents of TNB to a solution of the neutral re-
ceptor 1, the signals associated with the NH protons—reso-
nating at d=7.21, 7.19, and 7.18 ppm—are downfield-shifted
to d=7.82 and 7.80 ppm as a result of hydrogen-bonding in-
teractions taking place between the NH protons of the re-
ceptor 1 and the TNB guests. In this mixture, the CH pro-
tons of the TNB guests are found to resonate at d=
9.28 ppm and are upfield-shifted relative to their initial posi-
tion at d=9.37 ppm. These observations are in complete
agreement[11c] with the formation of the TNB2ꢀ1 complex in
which the two TNB guests are being sandwiched between
the TTF subunits. Upon addition of one equivalent of DBU
(Figure 4c) to the solution of the TNB2ꢀ1 complex, the CH
protons of the TNB guests are observed to revert back to es-
sentially their initial position (d=9.38 ppm) and the NH
protons are found to resonate at d=12.64–12.40 ppm, which
clearly indicates that the self-complexing ouroboros 1À con-
1
ouroboros 1À reprotonates the phenolate anion. A H NMR
spectrum (Figure 2c) recorded subsequently revealed that
the aromatic phenol protons reverted back to essentially
their initial positions (d=7.04 and 6.73 ppm, respectively),[28]
which indicates that the neutral 1,3-alternate conformation
of the receptor 1 has been regenerated. Repeated additions
of base (DBU) followed by the subsequent addition of acid
(MSA) resulted in the continuation of the controlled switch-
ing of the receptor 1 between its neutral 1,3-alternate (un-
locked) and its ouroboros 1À (locked) conformations, as can
be inferred from Figure 2.
After it has been established that the sequential addition
of DBU and MSA to a solution of the receptor 1 can be
used to switch the receptor between its neutral 1,3-alternate
and ouroboros states, it was investigated how the acid/base
controllable switching event affects the binding ability of the
receptor 1 toward TNB. The binding between the receptor 1
and TNB was studied (Figure 3) in CH2Cl2 solution by using
Figure 3. Absorption spectra recorded in CH2Cl2 at 298 K of a) the recep-
tor 1 (0.83 mm; c), b) 1+2 equiv TNB (b), c) the mixture obtained
after adding 1 equiv of DBU to the solution in b) (g), d) the mixture
obtained after adding 1 equiv of MSA to the solution in c) (a), and
e) the mixture obtained after adding 1 equiv of DBU to the solution in
d) (d).
absorption spectroscopy. Neither the receptor 1 or TNB
gave rise to any notable visible absorption bands at l>
500 nm. Addition of two equivalents of TNB to a CH2Cl2 so-
lution of 1 resulted in an immediate color change from
yellow to green and the appearance (Figure 3b) of a charge-
transfer (CT) absorption band centered at 677 nm in the ab-
sorption spectrum, a situation that is characteristic[11c] for
the inclusion of TNB guests inside the two cavities of a te-
Figure 4. Partial 1H NMR spectra (400 MHz, 298 K) recorded in CDCl3
of a) the receptor 1 (1.5 mm), b) 1+2 equiv TNB, c) the mixture obtained
after adding 1.0 equiv of DBU to the solution in b), d) the mixture ob-
tained after adding 1.0 equiv of MSA to the solution in c), and e) the
mixture obtained after adding 1.0 equiv of DBU to the solution in d).
ACHTUNGTRENNUNGtraTTF-calix[4]pyrrole receptor. The addition of one equiva-
lent of DBU to the CH2Cl2 solution of the TNB2ꢀ1 complex
results (vide supra) in a base-mediated conformational
change of the receptor 1 to its self-complexing ouroboros 1À
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Acid/Base Controllable Molecular Recognition
FULL PAPER
4-(3-bromopropyl)phenol[20] 3 (212 mg, 1.32 mmol) was added in one por-
tion. The reaction mixture was stirred overnight, after which time the sol-
vent was evaporated in vacuo. The resulting yellow residue was dissolved
in CH2Cl2 (200 mL), washed with H2O (3ꢂ100 mL), and dried (MgSO4).
Evaporation of the solvent gave a yellow solid which was purified by
column chromatography (silica gel). The yellow band was collected and
formation has been formed. Acidification of the ouroboros
1À and TNB mixture by addition of one equivalent of MSA
revealed (Figure 4d) that the CH protons of the TNB guests
resonate at d=9.29 ppm signaling that the TNB2ꢀ1 complex
has been re-established. In this mixture, the NH protons of
the receptor are found to resonate as a broad singlet at d=
7.94 ppm. Although the signal is broad,[29] it is clear that the
NH protons have reverted back to the position expected for
the TNB2ꢀ1 complex.
concentrated to give
4 as a yellow solid (630 mg, 86%). Rf =0.2
1
(CH2Cl2); m.p. 65–688C; H NMR (400 MHz, CDCl3, 298 K): d=7.72 (d,
J=8.3 Hz, 2H), 7.29 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H), 6.93 (s,
2H), 6.74 (d, J=8.4 Hz, 2H), 4.82 (s, 1H), 2.77 (t, J=7.2 Hz, 2H), 2.67
(t, J=7.2 Hz, 2H), 2.41 (s, 3H), 2.39 (s, 3H), 1.90 ppm (p, J=7.2 Hz,
2H); 13C NMR (100 MHz, CDCl3, 298 K): d=153.8, 145.5, 135.3, 133.1,
130.2, 129.7, 129.6, 127.3, 127.2, 127.0, 125.1, 115.3, 115.3, 114.9, 111.3,
35.4, 33.3, 31.3, 21.7, 19.2 ppm, one signal missing or overlapping; HRMS
(ESI): m/z: calcd for C25H23NO3S7 +Na+: 631.9616 [M+Na+]; found:
631.9622; elemental analysis calcd (%) for C25H23NO3S7: C 49.23, H 3.80,
N 2.30, S 36.80; found: C 49.46, H 3.85, N 2.40, S 36.51.
Conclusion
We have demonstrated the operation of a molecular recep-
tor 1—which through an acid/base input—adjusts its ability
to complex guest molecules. In the unlocked state, the re-
ceptor is able to accommodate two TNB guest molecules,
whereas the guests are not able to bind to the receptor in
the locked state. The locked state of the receptor 1 is ob-
tained by a base-mediated conformational change from a
1,3-alternate conformation to an ouroboros 1À conformation
in which the phenolate anion “tail” and the calix[4]pyrrole
“head” forms a self-complexing system. These results repre-
sent an important step towards the construction of more ad-
vanced molecular devices and to achieve control of motion
at the single-molecule level. The uses of such supramolec-
ular systems add attractive features to the construction of
advanced nanoscale molecular machinery because of their
potential to undergo controllable intramolecular complexa-
tion in response to a particular stimulus.
Monopyrrolotetrathiafulvalene 5: A solution of the monopyrrolotetra-
thiafulvalene 4 (1.22 g, 2.00 mmol) in anhydrous THF (300 mL) and an-
hydrous MeOH (100 mL) was degassed (N2, 15 min) before sodium
methoxide (25% w/w solution in MeOH, 4.0 mL, 1.08 g, 20.0 mmol) was
added in one portion. The yellow mixture was heated to 508C for 1 h and
cooled to room temperature. H2O (200 mL) was added and the mixture
extracted with CH2Cl2 (3ꢂ100 mL). The combined organic phases were
washed with H2O (2ꢂ100 mL) and dried (MgSO4). After evaporation of
the solvent, the yellow oil was purified by column chromatography (silica
gel). The yellow band was collected and concentrated to give 5 as a pure
yellow solid (0.85 g, 93%). Rf =0.4 (CH2Cl2/MeOH/Et3N 97.9:2.0:0.1);
m.p. 51–548C; 1H NMR (400 MHz, CDCl3, 298 K): d=8.21 (brs, 1H),
7.01 (d, J=8.3 Hz, 2H), 6.74 (d, J=8.3 Hz, 2H), 6.60 (d, J=2.6 Hz, 2H),
4.70 (s, 1H), 2.79 (t, J=7.2 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.42 (s, 3H),
1.91 ppm (p, J=7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3, 298 K): d=
153.7, 133.3, 129.6, 125.1, 120.7, 119.9, 119.8, 115.3, 110.8, 109.8, 109.8,
35.4, 33.3, 31.3, 19.2 ppm, one signal missing or overlapping; HRMS
(ESI): m/z: calcd for C18H17NOS6: 454.9629 [M+]; found: 454.9620; ele-
mental analysis calcd (%) for C18H17NOS6: C 47.44, H 3.76, N 3.07;
found: C 47.61, H 3.73, N 3.05.
TetraTTF-calix[4]pyrrole 1: A solution of the monopyrrolotetrathiafulva-
lene
6 (1.41 g, 3.60 mmol), monopyrrolotetrathiafulvalene 5 (0.41 g,
0.90 mmol), and tetrabutylammonium chloride (1.25 g, 4.50 mmol) in a
mixture of CH2Cl2 (600 mL) and Me2CO (200 mL) was degassed (N2,
20 min) before TFA (3.4 mL) was added to the yellow solution. The reac-
tion mixture was stirred at room temperature for 16 h, whereupon Et3N
(6 mL) was added slowly. The reaction mixture was concentrated to ap-
proximately 150 mL, whereupon CH2Cl2 (250 mL) was added and the
mixture was washed with H2O (3ꢂ150 mL) before being dried (MgSO4).
After evaporation of the solvent, the yellow solid was purified by column
chromatography (silica gel). The first yellow band (Rf =0.85) was collect-
ed and concentrated to give the symmetric tetraTTF-calix[4]pyrrole 7 as
a yellow solid. Recrystallization from CH2Cl2/Me2CO gave 7 as fine
yellow needles (0.20 g, 10%).[30] Subsequently, the second yellow band
was collected and concentrated to give 1 as a yellow solid (0.16 g, 10%).
Rf =0.25 (CH2Cl2/hexanes 3:1); m.p. 143–1458C (melts with decomposi-
tion); 1H NMR (400 MHz, CDCl3, 298 K): d=7.21 (brs, 1H), 7.19 (brs,
1H), 7.18 (brs, 2H), 7.04 (d, J=7.2 Hz, 2H), 6.72 (d, J=7.2 Hz, 2H),
4.55 (s, 1H), 2.83–2.77 (m, 14H), 2.69 (t, J=7.2 Hz, 2H), 2.42 (s, 3H),
1.93 ppm (p, J=7.2 Hz, 2H), 1.72–1.62 (m, 12H), 1.60–1.57 (m, 24H),
Experimental Section
General methods: Chemicals were purchased from Aldrich and used as
received unless indicated otherwise. Tetrabutylammonium chloride
(TBACl) was dried under vacuum at 408C for 24 h before use. The com-
pounds 2,[19e] 3,[20] and 6[21] were prepared according to literature proce-
dures. All reactions were carried out under an inert N2 atmosphere. THF
was distilled from sodium-benzophenone immediately prior to use.
MeOH was distilled from Mg and I2. TLC was carried out by using alu-
minum 336 sheets precoated with silica gel 60F (Merck 5554). The plates
were inspected under UV light (254 nm) and developed with I2 vapor.
Column chromatography was carried out by using silica gel 60F (Merck
9385, 0.040–0.063 mm). Melting points were determined with a Bꢃchi
melting point apparatus. 1H NMR spectra were recorded with a Bruker
Avance III 341 (400 MHz) instrument by using the residual solvent as
the internal standard. 13C NMR spectra were recorded at room tempera-
ture with a Bruker Avance III (100 MHz) by using the residual solvent
as the internal standard. Samples were prepared by using CDCl3 pur-
chased from Cambridge Isotope Labs. Mass spectra were obtained by
using a Bruker Autoflex III smart beam (MALDI-TOF) utilizing a 2,5-di-
hydroxybenzoic acid (DHB) matrix or by using a Thermo Finnigan MAT
SSQ710 (ESI-MS). Absorption spectroscopic data was recorded by using
a Shimadzu UV-1601PC apparatus. Microanalyses were performed by the
Atlantic Microlab, Inc., Atlanta, Georgia.
1.04–0.98 ppm (m, 18H); HRMS (MALDI): m/z: calcd for C72H84N4OS24
:
1787.9937 [M+]; found: 1787.9896; elemental analysis calcd (%) for
C72H84N4OS24: C 48.28, H 4.73, N 3.13, S 42.97; found: C 48.23, H 3.82, N
3.12, S 42.69.
Synthesis of TetraTTF-calix[4]pyrrole 8: TetraTTF-calix[4]pyrrole
1
(5.0 mg, 2.8 mmol) and Et3N (0.6 mg, 6.0 mmol) were dissolved in CH2Cl2
(5 mL) before a solution of benzoylchloride (0.6 mg, 4.3 mmol) in CH2Cl2
(0.5 mL) was added in one portion. The mixture was stirred for 30 min,
after which time the reaction mixture was washed with H2O (3ꢂ5 mL)
and dried (MgSO4). Evaporation of the solvent gave a yellow oil that was
purified by column chromatography (silica gel). The yellow band was col-
Monopyrrolotetrathiafulvalene 4: A solution of the monopyrrolotetra-
thiafulvalene 2 (635 mg, 1.20 mmol) was dissolved in anhydrous THF
(500 mL) and degassed (N2, 10 min) before a solution of CsOH·H2O
(212 mg, 1.26 mmol) in anhydrous MeOH (1 mL) was added dropwise
via a syringe over a period of 1 h. The mixture was stirred for 15 min and
Chem. Eur. J. 2011, 17, 11001 – 11007
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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K. A. Nielsen et al.
lected and concentrated to give 8 as a yellow solid (4.2 mg, 79%). Rf =
0.4 (CH2Cl2/hexanes 2:1); m.p. 148–1538C; 1H NMR (400 MHz, CDCl3,
298 K): d=8.22–8.17 (m, 2H), 7.66–7.61 (m, 1H), 7.54–7.48 (m, 2H),
7.28–7.24 (m, 2H), 7.16–7.10 (m, 6H), 2.83–2.77 (m, 16H), 2.43 (s, 3H),
1.99 (p, J=7.2 Hz, 2H), 1.72–1.62 (m, 12H), 1.61–1.56 (m, 24H), 1.04–
[9] K. Kim, J. L. Sessler, D. E. Gross, C.-H. Lee, J. S. Kim, V. M. Lynch,
L. H. Delmau, B. P. Hay, J. Am. Chem. Soc. 2010, 132, 5827–5836.
[10] a) G. Gil-Ramꢆrez, M. Chas, P. Ballester, J. Am. Chem. Soc. 2010,
132, 2520–2521; b) B. Verdejo, G. Gil-Ramꢆrez, P. Ballester, J. Am.
Chem. Soc. 2009, 131, 3178–3179; c) P. Ballester, G. Gil-Ramꢆrez,
Proc. Natl. Acad. Sci. USA 2009, 106, 10455–10459.
[11] a) J. S. Park, F. L. Derf, C. M. Bejger, V. M. Lynch, J. L. Sessler,
K. A. Nielsen, C. Johnsen, J. O. Jeppesen, Chem. Eur. J. 2010, 16,
848–854; b) K. A. Nielsen, L. Martꢆn-Gomis, G. H. Sarova, L. San-
guinet, D. E. Gross, F. Fernꢅndez-Lꢅzaro, P. C. Stein, E. Levillain,
J. L. Sessler, D. M. Guldi, ꢇ. Sastre-Santos, J. O. Jeppesen, Tetrahe-
dron 2008, 64, 8449–8463; c) K. A. Nielsen, W.-S. Cho, G. H.
Sarova, B. M. Petersen, A. D. Bond, J. Becher, F. Jensen, D. M.
Guldi, J. L. Sessler, J. O. Jeppesen, Angew. Chem. 2006, 118, 7002–
7007; Angew. Chem. Int. Ed. 2006, 45, 6848–6853; d) K. A. Nielsen,
W.-S. Cho, J. O. Jeppesen, V. M. Lynch, J. Becher, J. L. Sessler, J.
Am. Chem. Soc. 2004, 126, 16296–16297.
0.98 ppm (m, 18H); HRMS (MALDI): m/z: calcd for C79H88N4O2S24
:
1892.0204 [M+]; found: 1892.0170.
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), University of Southern Denmark (SDU), and the
Villum Foundation.
[12] G. Cafeo, M. D. Rosa, F. H. Kohnke, A. Soriente, C. Talotta, L. Val-
enti, Molecules 2009, 14, 2594–2601.
[13] a) F. Durola, J. Rebek, Jr., Angew. Chem. 2010, 122, 3257–3259;
Angew. Chem. Int. Ed. 2010, 49, 3189–3191; b) D.-H. Qu, B. L. Fer-
inga, Angew. Chem. 2010, 122, 1125–1128; Angew. Chem. Int. Ed.
2010, 49, 1107–1110; c) I. Aprahamian, O. Miljanic, W. R. Dichtel,
K. Isoda, T. Yasuda, T. Kato, J. F. Stoddart, Bull. Chem. Soc. Jpn.
2007, 80, 1856–1869; d) S. Nygaard, Y. Liu, P. C. Stein, A. H. Flood,
J. O. Jeppesen, Adv. Funct. Mater. 2007, 17, 751–762; e) H. Wu, D.
Zhang, L. Su, K. Ohkubo, C. Zhang, S. Yin, L. Mao, Z. Shuai, S. Fu-
kuzumi, D. Zhu, J. Am. Chem. Soc. 2007, 129, 6839–6846; f) R. J.
Hooley, J. Rebek, Jr., Org. Lett. 2007, 9, 1179–1182; g) G. Cooke, P.
Woisel, M. Bria, F. Delattre, J. F. Garety, S. G. Hewage, G. Rabani,
G. M. Rosair, Org. Lett. 2006, 8, 1423–1426; h) Y. Liu, A. H. Flood,
R. M. Moskowitz, J. F. Stoddart, Chem. Eur. J. 2005, 11, 369–385;
i) Y. Liu, A. H. Flood, J. F. Stoddart, J. Am. Chem. Soc. 2004, 126,
9150–9151; j) L. Fabbrizzi, F. Foti, M. Licchelli, P. M. Maccarini, D.
Sacchi, M. Zema, Chem. Eur. J. 2002, 8, 4965–4972; k) V. Balzani, P.
Ceroni, A. Credi, M. Gꢈmez-Lꢈpez, C. Hamers, J. F. Stoddart, R.
Wolf, New J. Chem. 2001, 25, 25–31; l) M. B. Nielsen, J. G. Hansen,
J. Becher, Eur. J. Org. Chem. 1999, 2807–2815; m) R. Wolf, M. Asa-
kawa, P. R. Ashton, M. Gꢈmez-Lꢈpez, C. Hamers, S. Menzer, I. W.
Parsons, N. Spencer, J. F. Stoddart, M. S. Tolley, D. J. Williams,
Angew. Chem. 1998, 110, 1018–1022; Angew. Chem. Int. Ed. 1998,
37, 975–979; n) L. Fabbrizzi, M. Licchelli, P. Pallavicini, L. Parodi,
Angew. Chem. 1998, 110, 838–841; Angew. Chem. Int. Ed. 1998, 37,
800–802; o) M. B. Nielsen, S. B. Nielsen, J. Becher, Chem. Commun.
1998, 475–476; p) P. R. Ashton, R. Ballardini, V. Balzani, S. E.
Boyd, A. Credi, M. T. Gandolfi, M. Gomez-Lopez, S. Iqbal, D.
Philp, J. A. Peece, L. Prodi, H. G. Ricketts, J. F. Stoddart, M. S.
Tolley, M. Venturi, A. J. P. White, David J. Williams, Chem. Eur. J.
1997, 3, 152–169; q) R. Corradini, A. Dossena, R. Marchelli, A.
Panagia, G. Sartor, M. Saviago, A. Lombardi, V. Pavone, Chem.
Eur. J. 1996, 2, 373–381; r) M. Nakamura, A. Ikeda, N. Ise, T. Ikeda,
H. Ikeda, F. Toda, A. Ueno, J. Chem. Soc. Chem. Commun. 1995,
721–722.
[14] It should be mentioned that self-complexation in a calix[2]furan[4]-
pyrrole receptor has been suggested in the conclusion of the follow-
ing article: G. Cafeo, A. Kaledkowski, F. H. Kohnke, A. Messina,
Supramol. Chem. 2006, 18, 273–279.
[15] It has previously been reported that the parent calix[4]pyrrole is
able to form a 1:1 complex with the p-nitrophenolate anion, see:
a) P. A. Gale, L. J. Twyman, C. I. Handlin, J. L. Sessler, Chem.
Commun. 1999, 1851–1852; b) G. Cafeo, F. H. Kohnke, L. Valenti,
A. J. P. White, Chem. Eur. J. 2008, 14, 11593–11600.
[16] Conformational control of the tetraTTF-calix[4]pyrrole system 7 has
previously been described with successive chloride and sodium addi-
tions, see reference [11b]. However, acid/base control of the recep-
tor conformation and self-complexation are novel concepts.
[17] J. R. Blas, J. M. Lꢈpez-Bes, M. Mꢅrquez, J. L. Sessler, F. J. Luque,
M. Orozco, Chem. Eur. J. 2007, 13, 1108–1116.
[1] a) L. Stryer, Biochemistry 4th ed., Freeman, New York, 1995; b) A.
Livitzki, Quantitative Aspects of Allosteric Mechanism, Springer,
Berlin, 1978.
[2] a) J. Rebek, Jr., Angew. Chem. 2005, 117, 2104–2115; Angew. Chem.
Int. Ed. 2005, 44, 2068–2078; b) L. Kovbasyuk, R. Krꢀmer, Chem.
Rev. 2004, 104, 3161–3187; c) F. Hof, S. L. Craig, C. Nuckolls, J. Re-
bek, Jr., Angew. Chem. 2002, 114, 1556–1578; Angew. Chem. Int.
Ed. 2002, 41, 1488–1508; d) M. Takeuchi, M. Ikeda, A. Sugsaki, S.
Shinkai, Acc. Chem. Res. 2001, 34, 865–873; e) S. Shinkai, M. Ikeda,
A. Sugasaki, M. Takeuchi, Acc. Chem. Res. 2001, 34, 494–503; f) T.
Nabeshima, Coord. Chem. Rev. 1996, 148, 151–169.
[3] a) D. Canevet, M. Sallꢄ, G. Zhang, D. Zhang, D. Zhub, Chem.
Commun. 2009, 2245–2269; b) D. E. Gross, F. P. Schmidtchen, W.
Antonius, P. A. Gale, V. M. Lynch, J. L. Sessler, Chem. Eur. J. 2008,
14, 7822–7827; c) J. L. Sessler, D. E. Gross, W.-S. Cho, V. M. Lynch,
F. P. Schmidtchen, G. W. Bates, M. E. Light, P. A. Gale, J. Am.
Chem. Soc. 2006, 128, 12281–12288; d) J. L. Sessler, P. A. Gale,
W. S. Cho in Synthetic Anion Receptor Chemistry, RSC, London,
2006, Chapter 5; e) P. A. Gale, P. Anzenbacher, Jr., J. L. Sessler,
Coord. Chem. Rev. 2001, 222, 57–102; f) P. A. Gale, J. L. Sessler, V.
Krꢅl, Chem. Commun. 1998, 1–8.
[4] a) M. G. Fisher, P. A. Gale, J. R. Hiscock, M. B. Hursthouse, M. E.
Light, F. P. Schmidtchen, C. C. Tonga, Chem. Commun. 2009, 3017–
3019; b) D.-W. Yoon, D. E. Gross, V. M. Lynch, C.-H. Lee, P. C. Ben-
nett, J. L. Sessler, Chem. Commun. 2009, 1109–1111; c) D.-W. Yoon,
D. E. Gross, V. M. Lynch, J. L. Sessler, B. P. Hay, C.-H. Lee, Angew.
Chem. 2008, 120, 5116–5120; Angew. Chem. Int. Ed. 2008, 47, 5038–
5042; d) D.-W. Yoon, H. Hwang, C.-H. Lee, Angew. Chem. 2002,
114, 1835–1837; Angew. Chem. Int. Ed. 2002, 41, 1757–1759.
[5] a) A. Aydogan, D. J. Coady, S. K. Kim, A. Akar, C. W. Bielawski, M.
Marquez, J. L. Sessler, Angew. Chem. 2008, 120, 9794–9798; Angew.
Chem. Int. Ed. 2008, 47, 9648–9652; b) A. Aydogan, D. J. Coady,
V. M. Lynch, A. Akar, M. Marquez, C. W. Bielawski, J. L. Sessler,
Chem. Commun. 2008, 1455–1457.
[6] a) S.-J. Hong, J. Yoo, S.-H. Kim, J. S. Kim, J. Yoonc, C.-H. Lee,
Chem. Commun. 2009, 189–191; b) G. V. Zyryanov, M. A. Palacios,
P. Anzenbacher Jr., Angew. Chem. 2007, 119, 7995–7998; Angew.
Chem. Int. Ed. 2007, 46, 7849–7852.
[7] a) T. V. Shishkanova, R. Volf, V. Krꢅl, J. L. Sessler, S. Camiolo, P. A.
Gale, Anal. Chim. Acta 2007, 587, 247–253; b) V. Krꢅl, J. L. Sessler,
T. V. Shishkanova, P. A. Gale, R. Volf, J. Am. Chem. Soc. 1999, 121,
8771–8775.
[8] a) K. A. Nielsen, W.-S. Cho, J. Lyskawa, E. Levillain, V. M. Lynch,
J. L. Sessler, J. O. Jeppesen, J. Am. Chem. Soc. 2006, 128, 2444–
2451; b) K. A. Nielsen, J. O. Jeppesen, E. Levillain, J. Becher,
Angew. Chem. 2003, 115, 197–201; Angew. Chem. Int. Ed. 2003, 42,
187–191; c) P. A. Gale, M. B. Hursthouse, M. E. Light, J. L. Sessler,
C. N. Warriner, R. S. Zimmerman, Tetrahedron Lett. 2001, 42, 6759–
6762; d) J. L. Sessler, A. Gebauer, P. A. Gale, Gazz. Chim. Ital.
1997, 127, 723–726.
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Chem. Eur. J. 2011, 17, 11001 – 11007

Acid/Base Controllable Molecular Recognition
FULL PAPER
[18] D.-S. Kim, V. M. Lynch, K. A. Nielsen, C. Johnsen, J. O. Jeppesen,
J. L. Sessler, Anal. Bioanal. Chem. 2009, 395, 393–400.
[24] a) S. Liu, C. Ruspic, P. Mukhopadhyay, S. Chakrabarti, P. Y. Zavalij,
L. Isaacs, J. Am. Chem. Soc. 2005, 127, 15959–15967; b) L. Fielding,
Tetrahedron 2000, 56, 6151–6170; c) W. L. Mock, N.-Y. Shih, J. Org.
Chem. 1986, 51, 4440–4446; d) J. A. A. de Boer, D. N. Reinhoudt, J.
Am. Chem. Soc. 1985, 107, 5347–5351.
[19] a) J. O. Jeppesen, M. B. Nielsen, J. Becher, Chem. Rev. 2004, 104,
5115–5131; b) J. O. Jeppesen, J. Becher, Eur. J. Org. Chem. 2003,
3245–3266; c) J. L. Segura, N. Martꢆn, Angew. Chem. 2001, 113,
1416–1455; Angew. Chem. Int. Ed. 2001, 40, 1372–1409; d) M. R.
Bryce, J. Mater. Chem. 2000, 10, 589–598; e) J. O. Jeppesen, K. Taki-
miya, F. Jensen, T. Brimert, K. Nielsen, N. Thorup, J. Becher, J. Org.
Chem. 2000, 65, 5794–5805.
[20] Y. Sato, H. Sakakibara, J. Organomet. Chem. 1979, 166, 303–307.
[21] J. A. Hansen, J. Becher, J. O. Jeppesen, E. Levillain, M. B. Nielsen,
B. M. Petersen, J. C. Petersenc, Y. S¸ahin, J. Mater. Chem. 2004, 14,
179–184.
[22] Splitting of the NH signal(s) for asymmetric calix[4]pyrrole systems
upon complexation with anions has previously been reported; a) A.
Aydogan, J. L. Sessler, A. Akar, V. Lynch, Supramol. Chem. 2008,
20, 11–21; b) G. Bruno, G. Cafeo, F. H. Kohnke, F. Nicol, Tetrahe-
dron 2007, 63, 10003–10010; c) S.-D. Jeong, J. Yoo, H.-K. Na, D. Y.
Chi, C.-H. Lee, Supramol. Chem. 2007, 19, 271–275; d) R. Nishiya-
bu, M. A. Palacios, W. Dehaen, P. Anzenbacher, Jr., J. Am. Chem.
Soc. 2006, 128, 11496–11504; e) R. Nishiyabu, P. Anzenbacher, Jr.,
Org. Lett. 2006, 8, 359–362.
[23] The complex between the p-cresolate anion and the model system
tetraTTF-calix[4]pyrrole 7 was also investigated by using 1H NMR
spectroscopy. The results show (see Figure S10 in the Supporting In-
formation) that the 7·p-cresolate complex has the same high degree
of symmetry as observed for the 8·p-cresolate complex.
[25] The Ka value corresponding to the interaction between 1 and ClÀ
anions is too strong to be determined by using 1H NMR spectrosco-
py and was therefore determined by using absorption spectroscopy.
[26] This resulted in the appearance of a new signal in the 1H NMR spec-
trum (d=10.9 ppm) corresponding to formation of the 1·ClÀ com-
plex, see the Supporting Information. This confirms the competition
between phenolate and chloride anions for the complexation to the
NH protons.
[27] It should be noted that the ouroboros 1À are expected to be found
in the partial cone conformation (Scheme 1), whereas the 7·p-creso-
late complexes are expected to be found in the cone conformation
(see Figure S10 in the Supporting Information).
[28] The labile OH and NH protons are not observed under the acidic
conditions.
[29] The fact the NH protons are observed as a broad singlet can most
likely be accounted for by an exchange process taking place be-
tween the NH protons and the solvent under the acidic conditions
1
in which the H NMR spectrum has been recorded.
[30] Analytical data for 7 are identical with those reported in the litera-
ture, see reference [11d].
Received: April 26, 2011
Published online: August 18, 2011
Chem. Eur. J. 2011, 17, 11001 – 11007
ꢁ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11007