Anion-induced dimerization in p-squaramidocalix[4]arene derivatives

Article abstract of DOI:10.1021/jo500422u

Spherical anions induce the dimerization of calix[4]arene derivatives 3 and 4 bearing squaramide moieties at the exo rim (p-squaramidocalixarenes). ¹H NMR titration experiments showed that unlike the distal isomer 3, proximal p-squaramidocalixa

Full text of DOI:10.1021/jo500422u

Note
pubs.acs.org/joc
Anion-Induced Dimerization in p‑Squaramidocalix[4]arene
Derivatives
Carmine Gaeta,*,† Carmen Talotta,† Paolo Della Sala,† Luigi Margarucci,‡ Agostino Casapullo,‡
and Placido Neri†
†Dipartimento di Chimica e Biologia, Universita
̀
di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano (Salerno), Italy
‡Dipartimento di Farmacia, Universita
̀
di Salerno, Via Giovanni Paolo II 132, I-84084 Fisciano (Salerno), Italy
S
* Supporting Information
ABSTRACT: Spherical anions induce the dimerization of
calix[4]arene derivatives 3 and 4 bearing squaramide moieties
1
at the exo rim (p-squaramidocalixarenes). H NMR titration
experiments showed that unlike the distal isomer 3, proximal
p-squaramidocalixarene 4 is also able to form dimeric
complexes with trigonal-planar anions.
he development of efficient artificial receptors for the
Tselective binding of biologically or environmentally
important anionic species has been the object of an extensive
research effort in the past decade.1 Among the possible artificial
anionic hosts, electroneutral species have been particularly
investigated because of their ability to recognize anions over a
large interval of pH.2 The most common electroneutral anionic
hosts generally contain polarized N−H fragments of amide,3
urea/thiourea4 (1a/1b; Chart 1) or pyrrole groups,5 and very
often display remarkable host properties.
calixarene hosts bearing electroneutral H-bond-donor units
such as amide11 and urea groups,12 which often display
remarkable recognition properties. In regard to hybrid
calixarene−squaramide hosts, Jiang and co-workers13 very
recently reported the first examples of calix[4]arene-based
receptors in which two squaramide moieties were introduced at
the endo (or lower) rim. These hybrid hosts were able to
recognize and sense H2PO4 , AcO−, and F− anions.
−
As an alternative to functionalization of the the endo rim, the
introduction of functionalities at the exo (or upper) rim of the
calixarene skeleton plays a special role because it is considered
the best way to exploit the preformed calixarene cavity in
recognition processes evocating the use of calixarenes as
enzyme mimics, as already precognized by Gutsche in his early
papers.14 Unexpectedly, no examples of hybrid exo-rim-linked
calix[4]arene−squaramide hosts have been reported to date.
This observation prompted us to investigate the introduction of
squaramide moieties at the exo rim of the calix[4]arene
macrocycle and to study the recognition properties of these
novel p-squaramidocalix[4]arene derivatives 3 and 4 (Scheme
1) toward anionic guests.
The synthesis of 3 and 4 is outlined in Scheme 1. In
particular, the known precursors 5,17-diaminocalix[4]arene (5)
and 5,11-diaminocalix[4]arene (6), obtained according to the
procedure of Reinhoudt and co-workers15 (see Scheme S1),16
were coupled with squaramido ester 7 in MeOH as the solvent
to give 3 and 4 in 30% and 35% yield, respectively.
Chart 1
In the last years, the squaramide subunit6 2 (Chart 1) has
been considered as a novel H-bond-donating group that can
coordinate anionic7 guests because of its ability to establish
bifurcated hydrogen bonds like urea/thiourea groups do. With
respect to urea/thiourea groups, recent reports have shown that
the squaramide ring presents structural and electronic
diversities that make it superior as a H-bond-donating group.8
The calix[4]arene macrocycle9 is greatly used as a molecular
scaffold in the design of artificial anion receptors because of its
ready availability and easy chemical modification, which allows
the introduction of appropriate functional groups to create a
suitable complementarity with anionic10 guests. Thus, increas-
ing attention has been devoted to the synthesis of hybrid
The structures of regioisomeric p-squaramidocalix[4]arenes
3 and 4 were readily confirmed by spectral analysis.16 In
Received: February 22, 2014
Published: March 19, 2014
© 2014 American Chemical Society
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Note
K
1:1 and K2:1 values are 500 and 230 M−1, respectively, with K1:1
Scheme 1. Synthesis of p-Squaramidocalix[4]arene
> K2:1 (see Table 1).
Derivatives 3 and 4
An insight into the structure of the dimeric Br−·(3)2 complex
was obtained by molecular mechanics calculations using the
MacroModel 9.0 program20 with the optimized potentials for
liquid simulations (OPLS) force field and H2O as the solvent.
In the structure with the lowest OPLS energy (Figure 2a), the
calixarene macrocycle is locked in the cone conformation by
the four propyl groups at the lower rim. The molecular model
suggests that the stabilization of the dimeric Br−·(3)2 complex
is obtained by H-bonding interactions between the squaramide
NHs and the bromide anion. In particular, two squaramidoca-
lixarene molecules (Figure 2b) can assume a relative orientation
that brings the two squaramide rings of two different
calixarenes into approximately the same plane, promoting
their square-planar coordination around the bromide anion. A
comparable dimerization induced by a spherical anion was
previously reported by Lhotak
and co-workers21 for a
calix[4]arene derivative bearing proximally located ureido
moieties at the exo rim.
Similar results were obtained for the chloride anion. In
particular, the formation of the dimeric Cl−·(3)2 complex was
evidenced by the ESI(−) mass spectrum and by Job plot
analysis, which showed a 2:1 binding stoichiometry. In this case
also, K1:1 (325 M−1) was larger than K2:1 (70 M−1).
́
particular, the presence of a pseudomolecular ion peak at m/z
1265 (MH+) in their ESI(+) mass spectra confirmed the
molecular formula, while the 1H and 13C NMR spectra (Figures
S1−S3) and the 2D COSY NMR spectra (Figures S4−S6)
confirmed the distal and proximal disubstitutions in 3 and 4,
respectively.16,17
The ability of p-squaramidocalix[4]arene 3 to bind anionic
18
1
guests was studied by standard H NMR titrations in which
the host concentration was kept constant while the guest
concentration was varied (Table 1). DMSO-d6 containing 0.5%
D2O was used as the solvent in order to minimize the effect of
atmospheric water absorption during the titrations.
Thus, we can conclude here that spherical anions such as
chloride and bromide induce dimerization of calix[4]arene 3
1,3-difunctionalized at the exo rim with squaramide rings. It is
likely that the dimerization process is thermodynamically driven
by the favorable square-planar coordination of two squaramide
rings of different calixarenes around at the spherical anion.
Interestingly, to the best of our knowledge, these are the first
examples in the literature in which spherical anions induce a
dimerization of squaramide-based hosts. Previously, Costa and
co-workers22 reported the dimerization of a squaramide-based
host in a protic solvent induced by the tetrahedral sulfate anion.
Unlike distal p-squaramidocalix[4]arene 3, the proximal
regioisomer 4 showed good solubility in CDCl3. Thus, its
binding properties (Figures S8−S10) were studied in CDCl3
containing 1% DMSO-d6 and 0.5% D2O.16 Interestingly, Job
plots of 4 and spherical guests such as Br− and Cl− showed
maxima at a mole fraction of 0.67 in each case (Figure S9b,c).16
These results indicate that host 4 also binds spherical anions
with a 2:1 stoichiometry, forming dimeric complexes. The
formation of the Br−·(4)2 complex was also evidenced by the
ESI(−) mass spectrum of 4 in the presence of 1 equiv of Br−
(Figure S11, top),16 which evidenced the presence of a sharp
pattern centered at m/z 2609 [2M + Br]− corresponding to the
dimeric complex. Analogously, the ESI(−) mass spectrum
obtained for a mixture of 4 and Cl− (Figure S11, bottom)16
corroborated the presence of the dimeric complex Cl−·(4)2.
Titrations of 4 with bromide and chloride anions (Figures S8−
S10) gave binding isotherms for the squaramide NHa proton, in
which a downfield shift was observed until a plateau was
reached at about 1 equiv of anion (Figure S9a). The titration
chemical shift data were analyzed by nonlinear least-squares
fitting procedures using the EQNMR program19 to give the
association constants reported in Table 1. In particular, a total
association constant Ktot = K1:1K2:1 = (9.1 0.2) × 107 M−2
(Table 1) was determined for the Cl−·(4)2 complex, a value
significantly higher than that observed for the bromide-induced
dimerization of 4 [Ktot = (2.2 0.2) × 106 M−2].
The addition of spherical bromide anions, in the form of the
tetrabutylammonium salt (TBABr), to the solution of receptor
3 caused downfield shifts of the NMR signals of both the NHb
and NHa squaramide protons. This indicated that these groups
were engaged in H-bonding interactions with the anionic guest
with a fast complexation equilibrium. Surprisingly, a Job plot for
3 and Br− (Figure S7)16 showed a maximum at a mole fraction
of 0.67,18 thus indicating a 2:1 calixarene/bromide binding
stoichiometry. The formation of the dimeric Br−·(3)2 complex
was also evidenced by the ESI(−) mass spectrum (Figure 1),
Figure 1. ESI(−) mass spectrum of a 1:1 mixture of 3 and Br− in
CHCl3.
which evidenced a sharp isotope pattern centered at m/z
2609.17 [2M + Br]− in good agreement with the dimeric
complex. The binding constants were estimated by NMR
titrations carried out with a 1 mM solution of 3 using 0.1−4.0
mM TBABr at 25 °C. Nonlinear least-squares fitting for the
NHa proton was performed using the EQNMR program.19 The
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Note
a
b
Table 1. Complexation Constants (K1:1 and K2:1) of Receptors 3 and 4 toward Chloride, Bromide, Benzoate, and Nitrate
1
Anions As Determined by H NMR Titrations (400 MHz) at 298 K
Cl−
325 20
Br−
500 65
PhCOO−
NO3
−
a
c
c
3
4
K1:1
K2:1
K1:1
K2:1
−
−
70 30
230 40
b
(3.6 0.4) × 104
(3.10 0.34) × 103
(2.47 0.37) × 103
102 12
(1.25 0.2) × 103
78 10
(2.54 0.2) × 103
720 30
b
a
c
1H NMR titrations were carried out in DMSO-d6/0.5% D2O. 1H NMR titrations were carried out in CDCl3/1% DMSO-d6/0.5% D2O. No
changes in the H NMR spectra were observed.
1
Figure 3. (a) Model of the energy-minimized structure of the
PhCOO−·(4)2 complex. (b) View of the NHa disposition above the
aromatic 3,5-trifluoromethylphenyl ring.
Figure 2. (a) CPK model of the energy-minimized structure of the
Br−·(3)2 complex (OPLS force field, H2O, GB/SA solvent model). (b)
View of the square-planar coordination of the two squaramide rings
around the Br− anion (green).
squaramide units of two different calixarene caps. Close
inspection of the lowest-energy structure of the PhCOO−·
(4)2 complex (Figure 3b) revealed that the NHa squaramide
protons lie directly above the aromatic ring of the
trifluoromethylphenyl moieties (Figure 3b). This accounts for
the previously mentioned initial upfield shift of the NHa
protons in the titration of 4 with PhCOO− (Figure S12 top).
The surprising differences in the binding behavior toward
trigonal-planar anions of the seemingly similar regioisomeric
receptors 3 and 4 can be explained in terms of a balance
between inter- and intramolecular H-bonds.23 In fact, the more
symmetrical distal isomer 3 has a strong tendency to give
intermolecular H-bonding interactions, as evidenced by its
aggregating tendency in the less polar CDCl3 solvent, which
reduces its binding affinities. On the other hand, the less
symmetrical proximal isomer 4 is less prone to give
intermolecular H-bonding interactions, as evidenced by its
higher solubility in CDCl3, leading to intramolecular H-bonds
(Figure S13),16,23 which favor both the 1:1 and 2:1 complex-
ation with trigonal-planar anions. This indicates that intra-
molecular H-bonding interactions can be advantageous for
receptor efficiency.23
The addition of trigonal-planar anions such as nitrate and
benzoate, in the form of their tetrabutylammonium salts, to
solutions of 1,3-disubstitued p-squaramidocalix[4]arene recep-
1
tor 3 did not cause significant shifts of the H NMR signals of
the host, indicating that no appreciable interactions were
established between distal regioisomer 3 and the benzoate or
nitrate anion. In contrast to 3, the proximal regioisomer 4
exhibited good binding abilities toward trigonal-planar anionic
guests. In fact, the addition of benzoate (Figure S12, top) or
nitrate (Figure S12, bottom),16 in the form of the TBA salt, to
the solution of 4 caused a shift of both squaramide NHb and
1
NHa signals in the H NMR spectrum. In particular, a close
inspection of the binding isotherms in Figure S1216 revealed an
initial upfield shift of the NHa proton up to the addition of 0.5
equiv of anionic substrate. Above 0.5 equiv, the direction of the
shift changed to downfield. As previously reported by
Hamilton,24 these type of complexation induced shifts (CISs)
are due to two complexation equilibria. In the first one, at the
beginning of the titration, the macrocycle is in excess with
respect to the anion and the prevalent species is the dimeric
complex X−·(4)2. In the second one, as the anion concentration
increases, the equilibrium shifts to the monomeric X−·4
complex and reaches the saturation point toward the end of
the titration. Also in these cases, nonlinear fitting of the
titration data using the EQNMR program19 gave the following
association constants (Table 1): K1:1 = (2.47 0.37) × 103 and
K2:1 = 102 12 for benzoate; K1:1 = (1.25 0.17) × 103 and
In conclusion, we have here reported the anion-induced
dimerization of p-squaramidocalix[4]arene derivatives 3 and 4.
The stabilization of the dimeric architectures was brought by
the square-planar coordination of two squaramide rings around
the anionic guests to give H-bonding interactions between
1
squaramide NH protons and the anion. H NMR titration
experiments showed that both distal and proximal p-
squaramidocalixarenes 3 and 4, respectively, are able to form
dimeric capsules in the presence of spherical anions such as
chloride and bromide. However, significant complexation of
trigonal-planar benzoate and nitrate anions was observed only
with the proximal isomer 4, which also forms stable dimeric X−·
(4)2 complexes, probably because of favorable intramolecular
H-bonding interactions and greater complementarity with
respect to the distal isomer 3. To the best of our knowledge,
K
2:1 = 78 10 for nitrate. Regarding the dimeric PhCOO−·(4)2
complex, molecular mechanics calculations (MacroModel 9.0
program, AMBER force field, CHCl3 as the solvent) revealed a
structure (Figure 3a) that is slightly different with respect to
that observed for the dimeric Br−·(3)2 complex. In particular,
the benzoate ring is almost perpendicular to the two
squaramide planes, with the oxygen atoms of the carboxylate
group engaged in four H-bonds with the NH groups of two
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Note
concentration was kept constant while the guest concentration was
varied [e.g., 1 mM host (3 or 4) using 0.1−2.5 mM TBAX]. In all
cases, the signals of the host were followed and the data were analyzed
by nonlinear regression analysis.19
Job Plot Experiments. Complexation stoichiometries were
determined from Job plots using 1H NMR spectroscopy.18 Stock
solutions of host (5 mM) and guest (5 mM) in CDCl3 were prepared.
Ten NMR spectra were obtained in the following volume ratios (host/
guest): 100:400, 150:350, 200:300, 250:250, 300:200, 350:150,
40:100, 450:50, 500:0 (μL/μL). The chemical shift of NH squaramide
protons was recorded for each sample, and the corresponding
concentration of the complex was determined for each sample. The
Job plot was obtained by plotting the complex concentration as a
function of the mole fraction of the host.
the above cases are the first examples in which a spherical anion
induces dimerization of a squaramide-based receptor. The
above-mentioned favorable intramolecular H-bonding inter-
actions can be considered a new and interesting approach to
optimize and tune the recognition properties of molecular
receptors.
EXPERIMENTAL SECTION
■
General Information. High-resolution ESI-MS spectra were
performed on a Q-ToF mass spectrometer equipped with an
electrospray ion source. Each compound was analyzed by direct
infusion using 80:18:2 CH2Cl2/CH3OH/HCOOH as the solvent. The
instrument was calibrated using [Glu1]-Fibrinopeptide B. All of the
chemicals were reagent-grade and used without further purification.
Anhydrous solvents were used as purchased from the supplier. When
necessary, compounds were dried in vacuo over CaCl2. Reaction
temperatures were measured externally. Derivatives 5,15 6,15 and 725
were synthesized according to literature procedures. NMR spectra
were recorded on a 400 MHz spectrometer; chemical shifts are
reported relative to the residual solvent peak. One-dimensional 1H and
13C spectra, COSY-45, and NOESY were used for NMR peak
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR and 2D COSY spectra of derivatives 3 and 4,
NMR titration data, and detailed results of the molecular
mechanics calculations. This material is available free of charge
via the Internet at http://pubs.acs.org.
assignment. COSY-45 spectra were recorded using a relaxation delay
of 2 s with 30 scans and 170 increments of 2048 points each. NOESY
spectra were recorded in phase-sensitive mode using a mixing time
(tm) of 200 ms. Monte Carlo conformational searches (10 000 steps)
were performed with the MacroModel 9.0/Maestro 4.1 program20
using the OPLS force field and H2O or CHCl3 solvent (GB/SA
model). The starting structures were built on the basis of the cone
conformation adopted by the tetrapropoxycalix[4]arene skeleton.
General Procedure for the Synthesis of p-Squaramidocalix-
[4]arene Derivatives 3 and 4. The appropriate aminocalix[4]arene
derivative 5 or 615 (0.10 g, 0.16 mmol) was dissolved in dry methanol
(5 mL), and then derivative 725 (0.25 g. 0.71 mmol) was added. The
reaction mixture was stirred at room temperature for 48 h, filtered, and
concentrated under reduced pressure. The residue was dissolved in
CH2Cl2 and washed with 1 N HCl and H2O. The organic phase was
dried on Na2SO4 and filtered, and the solvent was removed under
reduced pressure. The crude product was purified by column
chromatography on silica gel.
Derivative 3. CH2Cl2/MeOH (9:1 v/v), white solid, 0.061 g, 30%
yield. ESI(+) MS: m/z 1265 (MH+). 1H NMR (DMSO-d6, 400 MHz,
298 K): δ 0.94 (t, OCH2CH2CH3, J = 6.9 Hz, 6H), 1.02 (t,
OCH2CH2CH3, J = 6.9 Hz, 6H), 1.85−1.92 (m, OCH2CH2CH3, 8H),
3.12 and 4.32 (AX, ArCH2Ar, J = 12.8 Hz, 8H), 3.69 (br t,
OCH2CH2CH3, 4H), 3.84 (br t, OCH2CH2CH3, 4H), 4.97 (s, OCH2,
4H), 6.40 (br t, ArH, 2H), 6.48 (br d, ArH, 4H), 6.96 (br s, ArH, 4H),
7.94 (br s, NH, 2H), 8.05 (s, ArH, 2H), 8.11 (s, ArH, 4H), 9.45 (s,
NH, 2H). 13C NMR (DMSO-d6, 100 MHz, 298 K): δ 10.1, 10.5, 22.7,
22.9, 30.4, 46.2, 76.4, 76.6, 118.7, 121.5, 122.0, 124.7, 127.8, 128.7,
130.4, 130.7, 132.8, 133.6, 136.3, 142.6, 152.8, 155.3, 164.3, 168.3,
180.7, 183.9. Anal. Calcd for C66H60F12N4O8: C, 62.66; H, 4.78.
Found: C, 62.75; H, 4.69.
AUTHOR INFORMATION
Corresponding Author
*E-mail: cgaeta@unisa.it.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Italian MIUR (PRIN 20109Z2XRJ_006) for
financial support.
■
DEDICATION
■
This paper is dedicated to Professor A. Zambelli on the
occasion of his 80th birthday.
REFERENCES
■
(1) (a) Sessler, J. L.; Gale, P. A.; Cho, W.-S. Anion Receptor
Chemistry; Royal Society of Chemistry: Cambridge, U.K., 2006.
(b) Gale, P. A. Coord. Chem. Rev. 2003, 240, 191−221. (c) Steed, J. W.
Chem. Soc. Rev. 2009, 38, 506−519. (d) Katayev, E. A.; Ustynyuk, Y.
A.; Sessler, J. L. Coord. Chem. Rev. 2006, 250, 3004−3037.
(2) (a) Gale, P. A. In Encyclopedia of Supramolecular Chemistry;
Atwood, J. L., Steed, J. W., Eds.; Marcel Dekker: New York, 2004; p
3141. (b) Amendola, V.; Fabbrizzi, L.; Mosca, L. Chem. Soc. Rev. 2010,
39, 3889−3915. (c) Dydio, P.; Lichosyt, D.; Jurczak, J. Chem. Soc. Rev.
2011, 40, 2971−2985.
(3) (a) Choi, K.; Hamilton, A. D. J. Am. Chem. Soc. 2003, 125,
10241−10249. (b) Kang, S. O.; Llinares, J. M.; Powell, D.;
VanderVelde, D.; Bowman-James, K. J. Am. Chem. Soc. 2003, 125,
10152−10153. (c) Otto, S.; Kubik, S. J. Am. Chem. Soc. 2003, 125,
7804−7805. (d) Bondy, C. R.; Loeb, S. J. Coord. Chem. Rev. 2003, 240,
77−99.
Derivative 4. CH2Cl2/MeOH (9:1 v/v), white solid, 0.071 g, 35%
1
yield. ESI(+) MS: m/z 1265 (MH+). H NMR (CDCl3/DMSO-d6,
99:1 v/v, 400 MHz, 298 K): δ 0.93 (overlapped, OCH2CH2CH3, 6H),
1.83 (overlapped, OCH2CH2CH3, 8H), 3.06 and 4.29 (AX, ArCH2Ar,
J = 12.8 Hz, 2H), 3.10 and 4.32 (AX, ArCH2Ar, J = 13.6 Hz, 4H), 3.16
and 4.33 (AX, ArCH2Ar, J = 12.8 Hz, 2H), 3.75 (overlapped,
OCH2CH2CH3, 4H), 4.98 (s, OCH2, 4H), 6.37 (broad, ArH, 2H),
6.51 (broad, ArH, 2H), 6.66 (broad, ArH, 2H), 7.73 (broad, ArH,
2H), 7.77 (broad, ArH, 2H), 7.79 (overlapped, ArH, 6H), 8.06 (br s,
NH, 2H), 9.11 (s, NH, 2H). 13C NMR (DMSO-d6, 100 MHz, 298 K):
δ 10.2, 22.7, 22.8, 30.2, 30.4, 30.6, 46.0, 76.2, 76.3, 79.1, 121.2, 121.5,
121.6, 121.9, 124.6, 127.8, 127.9, 128.5, 130.3, 130.6, 132.6, 134.1,
134.3, 134.6, 134.9, 135.4, 142.3, 152.3, 156.1, 164.2, 168.2, 180.9,
183.4. Anal. Calcd for C66H60F12N4O8: C, 62.66; H, 4.78. Found: C,
62.78; H, 4.68.
(4) (a) Smith, P. J.; Reddington, M. V.; Wilcox, C. S. Tetrahedron
Lett. 1992, 33, 6085−6088. (b) Fan, E.; van Arman, S. A.; Kincaid, S.;
Hamilton, A. D. J. Am. Chem. Soc. 1993, 115, 369−370. (c) Evans, A.
J.; Matthews, S. E.; Cowley, A. R.; Beer, P. D. Dalton Trans. 2003,
4644−4650. (d) Miyaji, H.; Collinson, S. R.; Prokes, I.; Tucker, J. H.
R. Chem. Commun. 2003, 64−65. (e) Takemoto, Y. Org. Biomol. Chem.
2005, 3, 4299−4306.
́
(5) (a) Gale, P. A.; Sessler, J. L.; Kral, V.; Lynch, V. J. Am. Chem. Soc.
1996, 118, 5140−5141. (b) Cafeo, G.; Kohnke, F. H.; LaTorre, G. L.;
White, A. J. P.; Williams, D. J. Chem. Commun. 2000, 1207−1208.
́
(c) Anzenbacher, P., Jr.; Try, A. C.; Miyaji, H.; Jursíkova, K.; Lynch, V.
Determination of Association Constants by 1H NMR
M.; Marquez, M.; Sessler, J. L. J. Am. Chem. Soc. 2000, 122, 10268−
10272. (d) Sessler, J. L.; Anzenbacher, P., Jr.; Jursíkova, K.; Miyaji, H.;
1
Titrations. H NMR titrations were performed at 298 K. The host
́
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Note
Genge, J. W.; Tvermoes, N. A.; Allen, W. E.; Shriver, J. A.; Gale, P. A.;
(15) Kelderman, E.; Verboom, W.; Engbersen, J. F. J.; Reinhoudt, D.
N.; Heesink, G. J. T.; van Hulst, N. F.; Derhaeg, L.; Persoons, A.
Angew. Chem., Int. Ed. Engl. 1992, 8, 1075−1077.
Kral
P. A. Chem. Commun. 2000, 1129−1130.
(6) (a) Prohens, R.; Tomas, S.; Morey, J.; Deya,
́
, V. Pure Appl. Chem. 1998, 70, 2401−2408. (e) Camiolo, S.; Gale,
(16) See the Supporting Information for further details.
́
́
P. M.; Ballester, P.;
(17) In accordance with the C2v-symmetric structure of distal
regioisomer 3, its 1H NMR spectrum (Figure S1 top) (400 MHz, 298
K, DMSO-d6) showed one AX system at 4.32 and 3.12 ppm (J = 12.8
Hz; see the COSY spectrum in Figure S4) for the four equivalent
ArCH2Ar groups. The proximal functionalization of regioisomer 4 was
readily proved by three AX systems for ArCH2Ar protons at 3.06/4.29
Costa, A. Tetrahedron Lett. 1998, 39, 1063−1066. (b) Prohens, R.;
Martorell, G.; Ballester, P.; Costa, A. Chem. Commun. 2001, 1456−
́
1457. (c) Prohens, R.; Rotger, M. C.; Pina, M. N.; Deya, P. M.; Morey,
̃
J.; Ballester, P.; Costa, A. Tetrahedron Lett. 2001, 42, 4933−4936.
(d) Amendola, V.; Bergamaschi, G.; Boiocchi, M.; Fabbrizzi, L.;
Milani, M. Chem.Eur. J. 2010, 16, 4368−4380. (e) Amendola, V.;
Fabbrizzi, L.; Mosca, L.; Schmidtchen, F.-P. Chem.Eur. J. 2011, 17,
(2H), 3.10/4.32 (4H), and 3.16/4.33 ppm (2H)16 in its H NMR
1
spectrum (Figure S1 bottom; also see the COSY spectrum in Figure
S6) (400 MHz, CDCl3/1%-DMSO-d6, 298 K). The NHb and NHa
(see Scheme 1) squaramide protons of both 3 and 4 were assigned on
the basis of 2D NOESY spectra.
́
5972−5981. (f) Aleman, J.; Parra, A.; Jiang, H.; Jørgensen, K. A.
Chem.Eur. J. 2011, 17, 6890−6899.
(7) (a) Jin, C.; Zhang, M.; Wu, L.; Guan, Y.; Pan, Y.; Jiang, J.; Lin, C.;
Wang, L. Chem. Commun. 2013, 49, 2025−2027. (b) Rostami, A.; Wei,
(18) Hirose, K. In Analytical Methods in Supramolecular Chemistry;
Schalley, C. A., Ed.; Wiley-VCH: Weinheim, Germany, 2007; Chapter
2, pp 17−54.
C. J.; Guar
2062.
(8) (a) Garau, C.; Frontera, A.; Ballester, P.; Quinonero, D.; Costa,
́
in, G.; Taylor, M. S. Angew. Chem., Int. Ed. 2011, 50, 2059−
̃
(19) Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311−312.
A.; Deya,
́
P. M. Eur. J. Org. Chem. 2005, 179−183. (b) Quinonero, D.;
̃
(20) Macromodel, version 9.0; Schrodinger, LLC: New York, 2005.
̈
Frontera, A.; Suner, G. A.; Morey, J.; Costa, A.; Ballester, P.; Deya,
M. Chem. Phys. Lett. 2000, 326, 247−254. (c) Quinonero, D.; Prohens,
R.; Garau, C.; Frontera, A.; Ballester, P.; Costa, A.; Deya,
Phys. Lett. 2002, 351, 115−120. (d) Neus Pina, M.; Rotger, M. C.;
́
Costa, A.; Ballester, P.; Deya, P. M. Tetrahedron Lett. 2004, 45, 3749−
́
P.
̃
Mohamadi, F.; Richards, N. G.; Guida, W. C.; Liskamp, R.; Lipton, M.;
Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. J. Comput. Chem.
1990, 11, 440−467.
̃
́
P. M. Chem.
̃
(21) Lang, K.; Curí
̌
nova,
, P. Tetrahedron Lett. 2005, 46, 4469−4472.
P. M.;
́ ̌ ̌ ́
P.; Dudic, M.; Proskova, P.; Stibor, I.;
́
́
̌
St’astny, V.; Lhotak
́
́
3752. (e) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X. N.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119−125. (f) Malerich, J. P.; Hagihara,
K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416−14417.
(22) Pina, M. N.; Rotger, C.; Soberats, B.; Ballester, P.; Deya,
́
̃
Costa, A. Chem. Commun. 2007, 963−965.
(23) We thank one of the unknown referees for important
suggestions in this regard. For some examples of advantageous
intramolecular H-bonds for recognition efficiency, see: (a) Gale, P. A.
Chem. Commun. 2011, 47, 82−86. (b) Gale, P. A. Acc. Chem. Res.
2011, 44, 216−226. (c) Ramalingam, V.; Domaradzki, M. E.; Jang, S.;
Muthyala, R. S. Org. Lett. 2008, 10, 3315−3318.
(24) Choi, K. A.; Hamilton, D. J. Am. Chem. Soc. 2003, 125, 10241−
10249.
(25) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc.
2008, 130, 14416−14417.
(9) For general reviews of calix[n]arenes, see: (a) Bohmer, V. Angew.
̈
Chem., Int. Ed. Engl. 1995, 34, 713−745. (b) Gutsche, C. D.
Calixarenes Revisited; Royal Society of Chemistry: Cambridge, U.K.,
1998. (c) Calixarenes 2001; Asfari, Z., Bohmer, V., Harrowfield, J.,
̈
Vicens, J., Eds.; Kluwer: Dordrecht, The Netherlands, 2001.
(d) Bohmer, V. In The Chemistry of Phenols; Rappoport, Z., Ed.;
̈
Wiley: Chichester, U.K., 2003; Chapter 19. (e) Calixarenes in the
Nanoworld; Vicens, J., Harrowfield, J., Eds.; Springer: Dordrecht, The
Netherlands, 2007.
(10) (a) Edwards, N. Y.; Anthony, P. L. Supramol. Chem. 2013, 25,
446−463. (b) Matthews, S. E.; Beer, P. D. In Calixarenes 2001; Asfari,
Z., Bohmer, V., Harrowfield, J., Vicens, J., Eds.; Kluwer: Dordrecht,
̈
́
The Netherlands, 2001; pp 421−439. (c) Lhotak, P. Top. Curr. Chem.
2005, 255, 65−95. (d) Matthews, S. E.; Beer, P. D. Supramol. Chem.
2005, 17, 411−435.
́ ́ ́
(11) (a) Flídrova, K.; Tkadlecova, M.; Lang, K.; Lhotak, P.
Tetrahedron Lett. 2012, 53, 678−680. (b) Kim, H. J.; Kim, S. K.;
Lee, J. Y.; Kim, J. S. J. Org. Chem. 2006, 71, 6611−6616. (c) Troisi, F.;
Russo, A.; Gaeta, C.; Bifulco, G.; Neri, P. Tetrahedron Lett. 2007, 48,
7986−7989. (d) Troisi, F.; Gaeta, C.; Pierro, T.; Neri, P. Tetrahedron
Lett. 2009, 50, 5113−5115.
(12) (a) Budka, J.; Lhotak
Lett. 2001, 42, 1583−1586. (b) Dudic,
K.; Proskova, P. Org. Lett. 2003, 5, 149−152. (c) Quinlan, E.;
́
, P.; Michlova,
́
V.; Stibor, I. Tetrahedron
̌
M.; Lhotak
́
, P.; Stibor, I.; Lang,
̌
́
Matthews, S. E.; Gunnlaugsson, T. Tetrahedron Lett. 2006, 47, 9333−
9338. (d) Yakovenko, A. V.; Boyko, I. V.; Kalchenko, V. I.; Baldini, L.;
Casnati, A.; Sansone, F.; Ungaro, R. J. Org. Chem. 2007, 72, 3223−
3231.
(13) Jin, C.; Zhang, M.; Deng, C.; Guan, Y.; Gong, J.; Zhu, D.; Pan,
Y.; Jiang, J.; Wang, L. Tetrahedron Lett. 2013, 54, 796−801.
(14) (a) Gutsche, C. D. Acc. Chem. Res. 1983, 16, 161−170. For
recent reports in which the calixarene cavity was exploited in
recognition processes, see: (b) Gaeta, C.; Talotta, C.; Farina, F.;
Camalli, M.; Campi, G.; Neri, P. Chem.Eur. J. 2012, 18, 1219−1230.
(c) Gaeta, C.; Talotta, C.; Farina, F.; Teixeira, F. A.; Marcos, P. M.;
Ascenso, J. R.; Neri, P. J. Org. Chem. 2012, 77, 10285−10293.
(d) Moerkerke, S.; Men
11712−11719. (e) Coquier
Prange, T.; Reinaud, O. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 10449−
10454.
́
and, M.; Jabin, I. Chem.Eur. J. 2010, 16,
̀
e, D.; de la Lande, A.; Martì, S.; Parisel, O.;
́
3708
dx.doi.org/10.1021/jo500422u | J. Org. Chem. 2014, 79, 3704−3708