Inversion of selectivity in anion recognition with conformationally blocked calix[4]pyrroles

Article abstract of DOI:10.1039/c2ob26309b

Two calixpyrrole derivatives were synthesised. A p-dimethylaminobenzoyl group was electronically attached to a pyrrole ring, establishing an intramolecular hydrogen bond in a 1,3-alternate conformation. The formation of the H-bond was corroborated by IR,

Full text of DOI:10.1039/c2ob26309b

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PAPER
Inversion of selectivity in anion recognition with conformationally blocked
calix[4]pyrroles†
Raúl Gotor,a Ana M. Costero,*a Salvador Gil,a Margarita Parra,a Luis E. Ochandob and Katherine Chulvia
Received 9th July 2012, Accepted 6th September 2012
DOI: 10.1039/c2ob26309b
Two calixpyrrole derivatives were synthesised. A p-dimethylaminobenzoyl group was electronically
attached to a pyrrole ring, establishing an intramolecular hydrogen bond in a 1,3-alternate conformation.
The formation of the H-bond was corroborated by IR, NMR, and X-ray measurements. NMR titration
studies reveal that the H-bond is strong enough to block the conversion to a cone conformation, allowing
them to only acquire a partial cone conformation. Affinity constants for several anions were calculated,
and a noticeable increase was observed for tridentate tetrahedral anions, while the Ka of spheric or
bidentate anions decreased. In the presence of several acids, the synthesised compounds can act as
chemosensors by a double process: protonation of the amino group and coordination of the generated
anion. In addition, a displacement approach gives rise to a proof of concept for sulphonate recognition.
electron-accepting groups increase the acidity of the N–H
Introduction
protons, giving rise to higher affinity constants.4
meso-Octamethylcalix[4]pyrrole (OMCP) was reported in 1996
by Gale et al. to strongly bind to different anions (specially F−)
and neutral guests.1 The ability of calix[4]pyrroles to form com-
plexes is related to the NH array present in their structure. These
compounds possess a 1,3-alternate conformation in solution, but
this conformation changes in the presence of several guests to a
cone-like structure due to coordination. For this reason, calix-
pyrrole functionalization can be used to either increase affinity
for certain anions or perturb intrinsic substrate binding selectivities.
For instance, as steric bulkiness increases at the meso position, it
generally results in a lower affinity towards most tested ions.2
In contrast, when substituents form a cavity, the affinity for well-
fitting anions increases if compared to larger ones.3 On the other
hand, changes in the affinity constants in C-rim functionalised
calixpyrroles are also governed by electronic effects. Thus,
Here we report a different way of controlling calixpyrrole
complexation by blocking the macrocycle conformation through
intramolecular hydrogen bond formation. So it was that two
novel C-rim mono and disubstituted calix[4]pyrroles (1 and 2,
Chart 1) were synthesised and their selectivities towards different
anions were studied. In addition, their sensing properties in the
presence of several acids and anions were also evaluated. The
inversion in the relative complexation of anions observed with
these ligands suggests their possible use as sulphonate sensors.
Detection of sulphonates is of interest given their environmental
aCentro de Reconocimiento Molecular y Desarrollo Tecnológico,
Unidad Mixta Universidad de Valencia - Universidad Politécnica de
Valencia, Departamento de Química Orgánica, Facultad de Ciencias
Químicas, Universidad de Valencia, Doctor Moliner 50, 46100
Burjassot, Valencia, Spain. E-mail: ana.costero@uv.es
bA Centro de Reconocimiento Molecular y Desarrollo Tecnológico,
Unidad Mixta Universidad de Valencia - Universidad Politécnica de
Valencia, Departamento de Geología, Facultad de Ciencias Biológicas,
Universidad de Valencia, Doctor Moliner 50, 46100 Burjassot,
Valencia, Spain
†Electronic supplementary information (ESI) available: 1D and 2D
NMR spectra of compounds 1 and 2. IR of 1, 2, 3 and 1·TBACl, NMR
titration data, crystallographic data of compounds 1 and 2. CCDC
879852 (1) and 879855 (2). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c1cc11949d
Chart 1 Chemical structures of C-rim monosubstituted calixpyrroles
presenting carbonyl groups conjugated with the pyrrole ring (1–3, 5)
and separated by a –CH2– spacer 4.
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toxicity.5 Linear alkylbenzene sulphonates (LAS) constitute a
group of widely used anionic surfactants, which are often
present in soils due to the use of compost generated in waste-
water treatment plants. From the environmental point of view,
the LAS concentration in the dry material used as fertilisers is
important information. The most generally used techniques
for detecting these compounds are biosensors,6 potentiometric
methods7 or liquid chromatography-mass spectrometry.8
However, as far as we know, there are no examples in the litera-
ture of chromogenic or fluorogenic chemosensors able to detect
sulphonates. For all these reasons we have explored the possible
use of ligand 1 in sulphonate sensing as a proof of concept.
Fig. 1 1H NMR spectrum (selected region) of OMCP (top), compound
1 (middle), and compound 2 (bottom), all measured in CD2Cl2 at
400 MHz.
Results and discussion
Synthesis
Calixpyrrole 1 was synthesised through acylation of the parent
calixpyrrole polyanion with p-dimethylaniline benzoyl chloride.
OMCP polyanions were generated by treating the macrocycle
with 3–4 equiv. of butyl lithium. Even though OMCP has
already been reported to have been subjected to the electro-
philicity of benzoyl chloride with no positive results,9 when
p-dimethylaniline benzoyl chloride is employed, the acylation
reaction takes place with moderate yields. Thus, even if a poly-
anion is used, when working at low temperatures and with
amounts below an equivalent of acid chloride, the mono-functio-
nalized product is obtained as the main product.
Synthesis of calixpyrrole 2 was carried out using the same
procedure used with 1, but with the addition of 2 equiv. of acid
chloride. Surprisingly with this procedure, only one regioisomer
is obtained (Chart 1). It seems that the introduction of the first
acyl group directs the next group to the most stable position to
yield compound 2 as the main product. In any case, compound 1
is always obtained as a by-product in the synthesis of 2.
Fig. 2 Proposed 1,3-alternate favourable conformations of free ligands
1 and 2 in dichloromethane solution.
around 20 kcal mol−1 more stable than the corresponding confor-
mation without this interaction.
Regarding compound 2, NMR spectra reveal that the N–Ha
proton shifts to 9.49 ppm, a positive Δδ = 0.59 ppm in relation
to 1 and Δδ = 2.41 ppm if compared with OMCP. Such a displa-
cement proves that the N–Ha proton is involved in an even stron-
ger hydrogen bond interaction. The simplicity of the spectra
indicates a high level of symmetry, which simplifies structure
elucidation: the two attached substituents (the signals at 7.88 and
6.68 ppm) are equivalents, as well as the corresponding functio-
nalised pyrrole rings (5.95 ppm). These substituted pyrroles, as
revealed by the COSY experiments, couple with the N–H signals
at 7.27 ppm. Thus, there are three sets of pyrrole signals: two
equivalent pyrroles supporting the substituents, this being a
pyrrole in which the N–H proton is possibly double bonded to
two ketones, and the other free pyrrole with normal shifts. These
data suggest that the hydrogen bond interaction can be formed
with any of the carbonyl groups and that a change from one car-
bonyl group to the other is fast on the NMR time scale.
Conformational studies
Compound 1 in dichloromethane solutions adopts a restricted
conformation with one pyrrole ring involved in a hydrogen bond
interaction with the carbonyl group of the substituent. The inten-
sity of the hydrogen bond interaction is expected to be strong
given the electron donor properties of the dimethylaniline
moiety.
The presence of this hydrogen bond was confirmed by NMR
studies (Fig. 1). Thus, while Hb, Hc, and Hd displacements (7.45,
7.07, 7.02 ppm, respectively) appear at the normal position for
these labile protons,2 Ha appears at 8.90 ppm. This unusual shift
is presumably due to the hydrogen bond. In this aprotic solvent
(0.01 M in CD2Cl2), the only group able to establish a hydrogen
bond with the N–Ha proton is the aromatic ketone group,
reinforced by the electron donor power of the p-dimethylamino
group. Consequently, compound 1 in dichloromethane solutions
seems to adopt a restricted conformation with one pyrrole ring
involved in a hydrogen bond interaction with the carbonyl group
of the substituent (Fig. 2). This suggestion agrees with the theor-
etical results (at RHF-3-21G level) that show the 1,3-alternate
conformation stabilized by the proposed hydrogen bond is
The IR spectra of compounds 1 and 2 (see ESI†) support this
hypothesis: for instance, the CvO stretching band shifts to a
lower wavelength in both cases, 1592 and 1593 cm−1, respect-
ively. If compared with the tabulated wavelength, an aromatic
ketone of a similar substitution normally vibrates at 1640 cm−1
.
This decrease indicates a minor loss of double bond character
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due to the interaction with the adjacent N–H proton. In fact,
when the IR spectrum for methylated compound 3 is registered,
the CvO band appears at the expected position (1642 cm−1),
which reasserts the fact that when no electron donor groups are
connected to the ketone, the intramolecular hydrogen bond is
much less favourable.
The extensive calixpyrrole library includes very few C-rim
monosubstituted calixpyrroles with carbonyl groups. For
instance, compound 59 (Chart 1) has an aldehyde carbonyl con-
jugated with the pyrrole ring. The NMR data for this compound
show that the most unshielded N–H protons shift at 7.35 ppm
(2H), followed by two other N–H shifts at 7.23 and 6.93 ppm.
These N–H shifts appear in the common area for N–H calix-
pyrrole protons, where no H-bond seems to occur. In addition,
compound 4 (Chart 1) displays the greatest N–H shift at 8.56 ppm.9
Even though this signal is not assigned by the author, it presum-
ably shifts due to the formation of the hydrogen bond with the
ester carbonyl. However, lack of rigidity in the system because
of the presence of the –CH2– spacer may be the reason for this
not-so-great shift observed. In addition, the nature of the carbo-
nyl group, which is less electron-donating than that in 1 and 2,
may also play an important role in the intensity of the hydrogen
interactions.
Fig. 3 (left) Asymmetric unit of compound 1. (right) Asymmetric unit
of compound 2. Thermal ellipsoids indicate the atom positions at prob-
ability levels of 50%. H atoms are omitted for clarity purposes.
(0.13)° for compound 1 and 2.81 (0.30)° for 2. The difference
lies in the angle between the planes formed by N(4) and the
opposite N(2), which is 24.78 (0.14)° for 1 and 33.55 (0.30)° for
2. This is due to the presence of the H-bond, which provides a
gentle folding of the box framework (see ESI†).
Complexation studies
In order to determine the influence that the electron donor
characteristics of the dimethylamino group have on the intensity
of the hydrogen bond, compound 3 was studied by NMR
spectroscopy. The quaternary ammonium group should deacti-
vate the hydrogen bond acceptor ability of the carbonyl oxygen
by an inductive effect. This is corroborated by the 1H-NMR
spectrum of 3, where the N–Ha proton appears at 8.29 ppm, this
being a decrease of 0.61 ppm if compared with 1. Thus, a com-
parison made among these five compounds evidences the
relationship between the donating power of the groups linked to
the carbonyl group and the N–Ha shift.
Before starting the complexation studies, the possibility of any
type of self-assembly in compounds 1 and 2 was considered.
Thus, NMR experiments at different concentrations (from 0.5 ×
10−1 to 10−4 M in CD2Cl2) were carried out. Concentration
seems not to have any influence on the chemical shift of the
different hydrogen atoms (pyrrole and phenyl rings) which
suggests that there is no appreciable association between differ-
ent molecules of the ligands. In that sense, NMR spectra at low
temperature were registered and the changes observed (from 296
to 200 K) agree with a reinforcement of the hydrogen bond but
not with any inclusion of the phenyl group into the calixpyrrole
cavity (see ESI†).
After establishing that no appreciable intermolecular associ-
ation was observed in the ligands and in order to gain a better
understanding of the influence that the conformational restriction
has on complexing properties, complexation studies in CD2Cl2
with different anions (F−, Cl−, AcO−, H2PO4−, HSO4−, BzO−,
p-TsO−, all of them as TBA salts) were carried out. Thus, the
0.01 M solutions of compound 1 in CD2Cl2 in the presence of
increasing amounts of anions were studied by 1H NMR (Fig. 4).
As expected, as the anion concentration increases, the N–Hb,c,d
proton signals shift downfield, which indicates an effective
coordination of the anion with these protons. However, N–Ha
X-ray diffraction studies
Slow evaporation of a CH3CN solution of 1 allows the isolation
of high quality crystals. On the other hand, weak single crystals
of compound 2 are also obtained by slow CH3CN–hexane solu-
tion evaporation. Both bulk crystals are useful for X-ray studies.
The X-ray data reveal that calixpyrrole compounds 1 and 2
adopt a 1,3-alternate conformation in the solid state (Fig. 3).
As expected, the crystal structures of compounds 1 and 2
show the presence of a strong intramolecular H-bond in both
cases, which involves the acyl oxygen of the carbonyl group and
the N(4)–H proton of the adjacent pyrrole ring. As a result, the
distance C(10c)–O⋯H in 1 and 2 is longer than that specified
for aromatic ketones (1.218 Å)10 (Table 1).
The X-ray data of compounds 1 and 2 reveal that, in both
cases, coplanarity between pyrrole N(1) and the aniline ring is
sacrificed in order to adopt the optimal geometry to establish the
H-bond. In compound 2, the substituent of pyrrole N(3), which
does not form the H-bond, presents non-coplanarity due to the
steric effects related with the dimethylamino ring of the other
substituent.
exhibits a less marked shift than those for N–Hb,c,d, (i.e., ΔδHa
/
ΔδHc,d = 0.52 after addition of 5 equiv. of TBACl). This fact
suggests that the N–Ha proton participates less in the bonding
process. Furthermore, the slight displacement that N–Ha under-
goes may be due to the coordination of the anion with N–Hb,
which makes the aromatic ketone system more electron-donating
and reinforces the hydrogen bond at the same time (Fig. 5). This
suggestion agrees with the CvO stretching band in the corres-
ponding complexes that show a similar value to that of the
free ligand (for example, 1592 cm−1 for the complex with
1
In both compounds 1 and 2, the planes formed by the oppos-
ing pyrrole rings N(1) and N(3) are practically parallel: 11.73
chloride). In addition, H NMR experiments at low temperature
demonstrated that even though all the NH signals are lowfield
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Table 1 Summary of the atomic distances and angles between planes
1
2
Atomic distances (Å)
dH-bond
2.879
2.862
C(10c)–O(11c)⋯H
Dimethylamino ring : pN1
pN1 : pN3
1.2414 (0.0031)
57.62 (0.11)
11.73 (0.13)
24.78 (0.14)
1.2442 (0.0087)
64.26 (0.27)
11.73 (0.13)
33.55 (0.30)
Angle between dimethylamino and pyrrole ring plane (°)
Angle between the planes formed by the pyrrole rings (°)
pN2 : pN4
Table 2 Association constants (Ka, M−1) of the parent OMCP and
synthesised calixpyrrole derivatives 1 and 2 with different anions
determined by 1H NMR at 298 Ka
OMCP
1
2
b
b
F−
17 170 900
Cl−
350
128
97
140
<5
<2
7
5
9
4
4
50
68 11
11
32
22
4
2
29
58
2
11
29
22
24
1
5
1
1
3
3
4
AcO−
H2PO4
−
1
1
3
1
5
2−
HPO4−
HSO4
p-TsO−
MsO−
1
46
a Anions were added as 0.1 M dichloromethane-d2 solutions of their
Bu4N+ (TBA) salts to 0.01
solutions of the receptor in
M
dichloromethane-d2. Binding constants were calculated using the
EQNMR software.12 b The measured proton signal broadens due to
deprotonation.
Fig. 4 1H NMR titrations of 0.01 M CD2Cl2 calixpyrrole 1 solutions
with (top) nothing, (middle) 2 equiv. TBACl, (bottom) 5 equiv.
Fig. 5 Hydrogen bond reinforcement after anion complexation.
Fig. 6 Relative increment of the complexation constants of calixpyrroles
1 and 2 for diverse anions when compared with the OMCP results.
shifted as the temperature decreases, the changes observed in
N–Ha are lower than in the other signals. In the same sense, the
signal width for N–Ha is kept in opposition to the other signals
that are becoming broader. Finally, it has been reported that in
the chlorine complex with the parent calixpyrrole the difference
of energy between the cone and the partial-cone complex in
However, when comparing the Ka values with the parent
OMCP under the same conditions, some surprising results can
be seen (Table 2). Thus if ((Ka − Ka(OMCP))/Ka(OMCP)) is plotted
and normalised, the Ka of the tetrahedral tridentate ligands based
on sulphur atoms rises towards compound 1, at around 100% for
CH2Cl2 is 8.1 kcal mol−1 11
In compound 1 this difference of
.
energy seems to be compensated by the hydrogen-bond with the
carbonyl group.
−
p-TsO−, 350% for HSO4 and 550% for MsO−, while the Ka of
The fact that the N–Ha proton remains H-bonded to the ketone
group, even in the presence of large amounts of anionic guests,
may lead to new possibilities in host–guest affinity constant
tuning: when N–Ha is H-bonded with the ketone group, the
rotation of the whole pyrrole ring supporting N–Ha is blocked
around the C3–C4 axis. Thus in the presence of an anion, only
three pyrrole rings can effectively be oriented to match the best
position for guest coordination. In principle, this should result in
a considerable reduction of the affinity constants towards all
guests.
the remaining studied anions lowers in the order of 50–100%
(Fig. 6). This fact can be related to the new tridentate nature of
the host, which would prove a better match for the geometry of
the tetrahedral anion.
When compound 2 is titrated with the same anions, a similar
tendency on the affinity for these species is observed. The pres-
ence of two H-bond acceptors near N–Ha should further stabilise
the 1,3-alternate conformation by leaving just one ring with
rotational freedom. This restriction gives rise to even higher
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Fig. 7 Decrease in the absorption band of the p-nitrophenolate anion
(1 × 10−5 M in CH2Cl2) upon the addition of calixpyrrole 1 in CH2Cl2
(from 0 to 20 equiv. at 25 °C).
Fig. 8 UV spectra of p-nitrophenolate·calixpyrrole-1 complex (1 ×
10−5 M and 2 × 10−4 M in CH2Cl2) upon the addition of tetrabutyl-
ammonium mesylate in CH2Cl2 (from 0 to 50 equiv. from a 1 × 10−2
stock solution) at 25 °C.
M
−
complexing constants for HSO4 and p-TsO−. However, this
marked tendency is not observed for MsO−.
Sensing experiments
Displacement chemosensor for sulphonates. The affinity of 1
and 2 for sulphonate and alkylsulphonate anions led us to specu-
late about the capacity of these calixpyrroles to act as a new
branch of chemosensors to detect these species.
As displacement chemosensors involving calixpyrroles have
proven to yield good results,13,14 a displacement chemosensor
complex involving compound 1 and the p-nitrophenolate anion
was built and its sensing possibilities were evaluated. Thus,
aliquots of 1 × 10−3 M solutions of calixpyrrole 1 were added to
a 1 × 10−5 M solution of tetrabutylammonium p-nitrophenolate
in dichloromethane at 25 °C until the principal absorption band
of the yellow coloured anion disappeared (20 equiv. of 1).
Fig. 7 shows the change in the main absorption band of the
p-nitrophenolate at 430 nm during titration. This decrease in absor-
bance is attributed to the formation of the p-nitrophenolate·(1)
complex (Ka = 37 9 M−1).
Fig. 9 UV spectra of compound 1 (1 × 10−4 M in acetonitrile) in the
presence of 10 equiv. of different acids.
Firstly, these experiments demonstrate that the protonation
reaction under these conditions is a slow process in non-polar
solvents, while it is practically instantaneous in water. This fact
seems to relate to the strong hydrogen bond present in the
sensors, which has to be broken for protonation to take place. In
the presence of acids, protonation of the amino group occurs; as
this reaction changes the electronic properties of the amino
group, a charge transfer band of around 500 nm appears (Fig. 9).
In addition, some sensing selectivity, related to the anion com-
plexation in the calixpyrrole cavity, is observed. Thus, no coordi-
nating anions, such as ClO4−, show the new band at 512 nm
due to protonation, although other coordinating anions give rise
to a hypsochromic shift (500.0, 504.5, 506.0, 506.5 nm for Cl−,
At this point, aliquots of a 1 × 10−2 M solution of methyl-
sulphonate in dichloromethane (as TBA salt) were added, and
the solution recovered its original yellow colour, indicating the
effective binding of sulphonate after the displacement of the
p-nitrophenolate (Fig. 8). The minimum detectable absorbance
change for this system was recorded after the addition of
0.25 equiv. of mesylate, which indicates a detection limit of
238 ppb according to the equation DL = K × Sb1/S, where
K = 3, Sb1 is the standard deviation of the blank solution and
S is the slope of the calibration curve.15
−
p-TsO−, PhSO3 and HSO4−). The changes observed in the
absorption band are not due to acidity, but to the association con-
stants between the ligand and the corresponding anion generated
in the protonation process (see ESI†). Even though the observed
modifications are not overly large, the colour change is clear
enough to be detected by the naked eye.
Acid chemosensor. Compounds 1 and 2 were evaluated in
sensing experiments in the presence of some acids (HCl, HClO4,
H2SO4, p-toluenesulphonic acid, benzenesulphonic acid in
acetonitrile solutions) (Fig. 9).
The sensing paradigm is based on the presence of two active
sites in the molecule: the amino group, which can be protonated
with a concomitant colour change, and the calixpyrrole moiety,
able to coordinate the corresponding anion, giving rise to a
colour modulation.
Conclusions
Two new calix[4]pyrroles, mono- (1) and di- (2), substituted in
the C-rim, were prepared. The strong hydrogen bond formed
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between the carbonyl group of the substituent with a hydrogen
atom of the pyrrole moiety precludes the usual conformation
change (from 1,3-alternate to cone) in the complexation process.
This fact leads to an inversion in the complexation affinity when
compared with the parent compound. The most marked increase
in affinity is observed in the tridentate anions based on a sulphur
atom. This selectivity can be used in sensing alkylsulphonates
following the displacement approach. The prepared ligands are
also able to detect different acids. In this case, sensing selectivity
is based on protonation, followed by coordination of the gen-
erated anion, and can be observed by the naked eye.
(s, 6H), 1.61 (s, 6H), 1.60 (s, 6H), 1.53 (s, 6H), 1.51 (s, 6H)
ppm. 13C NMR (126 MHz, CD2Cl2) δ 193.39, 153.44, 139.96,
139.18, 138.69, 138.66, 138.62, 137.76, 137.63, 135.41, 132.36,
126.60, 119.31, 110.46, 107.33, 102.92, 102.80, 102.31, 102.19,
101.93, 39.91, 36.53, 35.14, 35.02, 34.85, 28.78, 28.28,
28.06, 27.23 ppm. HRMS: calculated for C37H46N5O [M + H]+
576.3697, found 576.3704.
Synthesis of calixpyrrole 2. 2 g (4.66 mmol) of OMCP was
dissolved in 250 mL of dry THF in an argon atmosphere. Then
the mixture was cooled to −78 °C, and after 5 min, 18.66 mmol
of a 1.43 M BuLi in hexanes solution was slowly added. After
1 h, the mixture was heated to 0 °C for 2 min, and cooled back
down to −78 °C. At that time, a p-dimethylaminobenzoyl chlor-
ide solution (1.715 g (9.32 mmol) in 50 mL of dry THF)
was dropwise added, and the reaction was allowed to warm
overnight. TLC revealed the formation of the desired product
(Rf: 0.37 EtOAc : Hex 4 : 6). Next, 1 mL of water was added and
THF was evaporated. Later, the residue was dissolved in EtOAc,
washed twice with 10% NH4Cl, and the aqueous layer was
extracted with EtOAc (3 × 50 mL). Combined organic layers
were washed with a NaCl (sat) solution and dried with MgSO4.
The solvent was evaporated and the mixture was purified by
column chromatography (EtOAc : Hex 2 : 8 to 4 : 6) over an
Et3N-neutralised silica. The yellow solid product weighed
620 mg, yielding 18.4%. RF: 0.37 (4 : 6 EtOAc : Hex, silica). m.
p.: 132 °C (decomp). IR (cm−1): 3455, 3430, 3372, 3202, 3153,
3097, 2969, 2929, 2879, 2805, 1704, 1593, 1427, 1372, 1259,
Experimental section
General methods
All the synthetic manipulations were performed in a dry argon
atmosphere using standard techniques. meso-Octamethylcalix[4]-
pyrrole (OMCP) was prepared according to the procedures
described in the literature. The tetrabutylammonium salts of
methanesulphonic acid and p-nitrophenol were prepared by the
addition of 1 equiv. of tetrabutylammonium hydroxide to the
neutral compound in dichloromethane. After solvent evapo-
ration, all the TBA salts were kept in a vacuum oven at 40 °C for
at least 24 h prior to use. Tetrahydrofuran was distilled over Na
prior to use. The other materials were purchased and used as
1
received. The H and 13C NMR spectra were recorded using a
1
Bruker DRX-500 spectrometer (500 MHz for H and 126 MHz
1
1231, 1165, 1047, 893, 769. H NMR (400 MHz, CD2Cl2) δ
1
for 13C) and a Bruker Avance 400 MHz (400 MHz for H and
9.49 (s, 1H), 7.86 (d, J = 9.1 Hz, 4H), 7.32 (s, 2H), 7.26 (s, 1H),
6.70 (d, J = 9.0 Hz, 4H), 6.04 (d, J = 3.0 Hz, 2H), 6.00 (d, J =
2.7 Hz, 2H), 5.97 (d, J = 2.7 Hz, 2H), 3.08 (s, 12H), 1.70 (s,
12H), 1.54 (s, 12H) ppm. 13C NMR (101 MHz, CD2Cl2) δ
192.99, 153.23, 140.37, 138.68, 137.84, 135.35, 132.20, 127.13,
118.91, 110.42, 107.23, 103.62, 102.59, 39.83, 36.82, 35.01,
28.67, 26.88 ppm. HRMS: calculated for C46H55N6O2 [M + H]+
723.4374, found 723.4395.
100 MHz for 13C). HRMS were recorded using a Shimadzu
QP5050A. Absorption spectra were recorded with a Shimadzu
UV-2101PC spectrophotometer.
Synthesis of calixpyrrole 1. 2 g (4.66 mmol) of OMCP was
dissolved in 250 mL of dry THF in an argon atmosphere. The
mixture was cooled to −78 °C, and after 5 min, 18.66 mmol of a
1.43 M BuLi in hexane solution was slowly added. After 1 h,
the mixture was heated to 0 °C for 2 min, and cooled back down
to −78 °C. At that time, a p-dimethylaminobenzoyl chloride
solution (600 mg (3.26 mmol) in 50 mL of dry THF) was drop-
wise added, and the reaction was allowed to warm overnight.
TLC revealed the formation of the desired product (Rf: 0.35
EtOAc : Hex 2 : 8). Next, 1 mL of water was added, and THF
was evaporated. Later, the residue was dissolved in EtOAc,
washed twice with 10% NH4Cl, and the aqueous layer was
extracted with EtOAc (3 × 50 mL). Combined organic layers
were washed with a NaCl (sat) solution and dried with MgSO4.
The solvent was evaporated and the mixture was purified by
column chromatography (Hex : EtOAc 9 : 1 as an eluent) over an
Et3N-neutralised silica. Later, products (disubstitution isomers)
were eluted with EtOac : Hex mixtures (2 : 8 to 4 : 6). The
yellowish foamy product weighed 549 mg, yielding 29.2%. RF:
0.35 (2 : 8 EtOAc : Hex, silica). m.p.: 118 °C (decomp). IR
(cm−1): 3553, 3330, 3317, 3300, 2967, 2930, 2869, 2810, 1590,
Synthesis of calixpyrrole 3. Firstly, 100 mg (0.17 mmol) of 1
was dissolved in 25 mL of dry CH3CN in an argon atmosphere.
Then, 200 μL (3.22 mmol) of CH3I was added and the mixture
was refluxed for 24 h. After this time, the red precipitate was
filtered off, obtaining 29 mg, 23.2%. IR (cm−1): 3316(b),
3295(b), 3106, 2970, 2926, 2872, 1716(w), 1642, 1494, 1462,
1
1428, 1362, 1253, 1049, 773. H NMR (400 MHz, CD3CN) δ
8.17 (s, 1H), 8.02 (d, J = 9.0 Hz, 2H), 7.93 (s, 1H), 7.88 (d, J =
8.7 Hz, 2H), 7.79 (s, 1H), 7.36 (s, 1H), 6.05–5.78 (m, 7H), 3.61
(s, 9H), 1.69 (s, 6H), 1.56 (d, J = 6.5 Hz, 12H), 1.48 (s, 6H) ppm.
NMR titration studies. They were carried out in a Bruker
Avance 400 MHz spectrometer at 298 K. Titration was performed
by addition of different TBA salt aliquots (0.1 M dichloro-
methane-d2) to 0.5 mL of a 0.01 M solution of OMCP, calix-
pyrrole derivatives 1 or 2 in dichloromethane-d2. The data
analysis and stability constants were obtained by least-squares
fitting with the EQNMR12 software. The N-Hb proton shift was
measured and the binding profile was fitted to a 1 : 1 complex
model.
1
1428, 1359, 1261, 1229, 1164, 1039, 919, 890, 769. H NMR
(500 MHz, CD2Cl2) δ 8.90 (s, 1H), 7.92 (d, J = 9.1 Hz, 2H),
7.47 (s, 1H), 7.12 (s, 1H), 7.05 (s, 1H), 6.74 (d, J = 9.1 Hz, 2H),
6.02 (d, J = 3.0 Hz, 1H), 5.97–5.93 (m, 1H), 5.92 (d, J =
2.7 Hz, 2H), 5.91 (d, J = 2.9 Hz, 1H), 5.90–5.82 (m, 2H), 3.10
Crystal structure data collection and refinement. Intensity
data were collected at 120(2) K with an Oxford Diffraction
8450 | Org. Biomol. Chem., 2012, 10, 8445–8451
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S Ultra diffractometer equipped with a Mo co-mounted (λ =
0.71073 Å) enhance X-ray sapphire CCD detector. Structures
were solved by direct methods and refined by full-matrix least-
squares using SHELX-97.16,17 All the non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were geometrically con-
structed with fixed displacement parameters, except Ha, which
was isotropically refined. Molecular graphics of the structures
(Fig. 3) were produced with Crystalmaker. Solution, refinement,
geometrical calculations and graphics were performed with the
WinGX package.18 The experimental data are shown below.
(1) CCDC 879852 and (2) CCDC 879855 contain the sup-
plementary crystallographic data for this paper.
pre-doctoral FPU fellowship. SCSIE and ICMOL (Universidad
de Valencia) are gratefully acknowledged for all the equipment
employed.
Notes and references
1 (a) P. A. Gale, J. L. Sessler and V. Král, Chem. Commun., 1998, 1–8;
(b) P. A. Gale, P. Anzenbacher Jr. and J. L. Sessler, Coord. Chem. Rev.,
2001, 222, 57–102.
2 P. A. Gale, J. L. Sessler, V. Kral and V. Lynch, J. Am. Chem. Soc., 1996,
118, 5140–5141.
3 J. L. Sessler, P. Anzenbacher, Jr., H. Miyaji, K. Jursikova, E. R. Bleasdale
and P. A. Gale, Ind. Eng. Chem. Res., 2000, 39, 3471–3478.
4 (a) H. Miyaji, D. An and J. Sessler, Supramol. Chem., 2001, 13, 661–669;
(b) R. Nishiyabu and P. Anzenbacher, Jr., Org. Lett., 2006, 8, 359–362;
(c) M. A. Palacios, R. Nishiyabu, M. Marquez and P. Anzenbacher, Jr.,
J. Am. Chem. Soc., 2007, 129, 7538–7544; (d) S. M. S. Chauhan, B. Garg
and T. Bisht, Supramol. Chem., 2009, 21, 394–400.
5 S. D. Dyer, J. R. Lauth, S. W. Morrall, R. R. Herzog and D. S. Cherry,
ETWQ, 1997, 12, 295–303.
6 Y. Nomura, K. Ikebukuro, K. Yokoyama, T. Takeuchi, Y. Arikawa,
S. Ohno and I. Karube, Biosens. Bioelectron., 1998, 13, 1047–1053.
7 D. Madunić-Čačić, M. Sak-Bosner, R. Matešić-Puać and Z. Grabarić,
Sensor Lett., 2008, 6, 339–346.
8 A. Di Corcia, J. Chromatogr., A, 1998, 794, 165–185.
9 P. Anzenbacher, Jr., K. Jursíková, J. A. Shriver, M. Hidekazu,
V. M. Lynch, J. L. Sessler and P. A. Gale, J. Org. Chem., 2000, 65,
7641–7645.
10 F. H. Allen, O. Kennard, D. G. Watson, L. Brammer, A. G. Orpen and
R. Taylor, J. Chem. Soc., Perkin Trans. 2, 1987, S1–S19.
11 y.-D. Wu, D.-F. Wang and J. L. Sessler, J. Org. Chem, 2001, 66,
3739–3746.
Single-crystal structure of 1. C37H45N5O, Mr = 575.78, T =
120(2) K, monoclinic, space group P21/c, a = 13.1700(7) Å, b =
12.2955(5) Å, c = 20.5036(9) Å, α = γ = 90°, β = 103.669(5)°,
V = 3226.15 Å3, Z = 4, ρcalcd = 1.185 g cm−3, crystal size =
0.13 × 0.08 × 0.04 mm, μ = 0.0072 mm−1, reflections collected
15 338, unique reflections = 5686, data/restraints/parameters
5686/0/404, GOF on F2 1.0350, Rint for independent data
0.0584, final R1 = 0.0603, R indices (all data): R1 = 0.1243,
wR2 = 0.1513, largest diff. peak and hole: 0.20 and −0.236 e Å−3
.
Single-crystal structure of 2. C46H54N6O2, Mr = 722.95, T =
ˉ
120(2) K, triclinic, space group P1, a = 10.051(3) Å, b =
10.220(5) Å, c = 20.088(7) Å, α = 76.98(4)°, β = 76.86(3)°, γ =
86.88(3)°, V = 1957.7(13) Å3, Z = 2, ρcalcd = 1.226 g cm−3
,
crystal size = 0.06 × 0.03 × 0.02 mm, μ = 0.076 mm−1, reflec-
tions collected 8850, unique reflections = 5810, data/restraints/
parameters 5810/84/508, GOF on F2 0.972, Rint for independent
data 0.0957, final R1 = 0.1000, R indices (all data): R1 = 0.2362,
wR2 = 0.1997, largest diff. peak and hole: 0.271 and −0.292 e Å−3.
12 M. J. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311–312.
13 P. A. Gale, L. J. Twyman, C. I. Handlin and J. L. Sessler, Chem.
Commun., 1999, 1851–1852.
14 N. Saki and E. U. Akkaya, J. Inclusion Phenom. Macro, 2005, 53,
269–273.
15 M. Zhu, M. Yuan, X. Liu, J. Xu, J. Lv, C. Huang, H. Liu, Y. Li, S. Wang
and D. Zhu, Org. Lett., 2008, 10, 1481–1484.
16 G. M. Sheldrick, SHELX97, Programs for Crystal Structure Analysis
(Release 97–2). University of Göttingen, Germany, 1997.
17 G. M. Scheldrick, Acta Crystallogr., Sect. A: Fundam. Crystallogr., 2008,
64, 112–122.
Acknowledgements
We thank the Spanish Government (DGICYT projects
MAT2009-14564-C03) for support. R.G. thanks MEC for a
18 L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837–838.
This journal is © The Royal Society of Chemistry 2012
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