Second generation of calix[6]aza-cryptands: Synthesis of heteroditopic receptors for organic ion pairs

Article abstract of DOI:10.1021/ol8021726

(Chemical Equation Presented) The efficient syntheses of calix[6]azacryptands decorated with anion-binding groups on the narrow rim have been achieved from an 1,3,5-tris-protected calix[6]hexa-amine. These heteroditopic receptors can bind ammonium ions or organic ion pair salts with a positive cooperativity. In regard to their functionalization at the 1,3,5-phenolic positions, these compounds constitute the first examples of a second generation of C_3v symmetrical calix[6]azacryptands.

Full text of DOI:10.1021/ol8021726

ORGANIC
LETTERS
2008
Vol. 10, No. 22
5195-5198
Second Generation of Calix[6]aza-
Cryptands: Synthesis of Heteroditopic
Receptors for Organic Ion Pairs
Ste´phane Le Gac,† Mickae¨l Me´nand,‡ and Ivan Jabin*,‡
URCOM, UniVersite´ du HaVre, FST, 25 rue Philippe Lebon, BP 540, 76058 Le HaVre
cedex, France, and Laboratoire de Chimie Organique, UniVersite´ Libre de Bruxelles
(U.L.B.), AV. F. D. RooseVelt 50, CP160/06, B-1050 Brussels, Belgium
ijabin@ulb.ac.be
Received September 17, 2008
ABSTRACT
The efficient syntheses of calix[6]azacryptands decorated with anion-binding groups on the narrow rim have been achieved from an 1,3,5-
tris-protected calix[6]hexa-amine. These heteroditopic receptors can bind ammonium ions or organic ion pair salts with a positive cooperativity.
In regard to their functionalization at the 1,3,5-phenolic positions, these compounds constitute the first examples of a second generation of
C3v symmetrical calix[6]azacryptands.
The design of molecular receptors from concave macrocyclic
compounds is particularly attractive. Indeed, these artificial
hosts can find applications in various areas such as sensing,
modeling of enzyme-active sites, catalysis, drug delivery,
and separation science.1 Due to their hydrophobic cavity that
is well-adapted for the encapsulation of organic guests,
calix[6]arenes2 constitute an ideal platform for the design
of such receptors.3 In this context, we have developed a
family of C3V symmetrical calix[6]arene-based receptors,
namely the calix[6]azacryptands, bearing a tripodal nitrog-
enous cap on the narrow rim (Figure 1).4 The azacryptand
cap constrains the calixarene in a cone conformation and
constitutes a tunable binding site for either neutral or charged
species (i.e., neutral molecules, anions, ammonium ions,
organic ion pairs or metal ions), allowing versatile host-guest
processes that can be controlled by the environment (presence
of metal ions, acids, or bases).5 Despite these remarkable
properties, this first generation of receptors is limited by the
lack of efficient methodologies for their selective function-
alization. Indeed, chemical modifications at the level either
of the nitrogenous binding site or of the wide rim alter the
(3) Reinaud, O.; Le Mest, Y.; Jabin, I. In Calixarenes in the Nanoworld;
Vicens, J. et al., Eds.; Springer: Dordrecht, The Netherlands, 2006; pp
259-285. For recent examples, see: Le Gac, S.; Marrot, J.; Reinaud, O.;
Jabin, I. Angew. Chem., Int. Ed. 2006, 45, 3123–3126. Arduini, A.; Credi,
A.; Faimani, G.; Massera, C.; Pochini, A.; Secchi, A.; Semeraro, M.; Silvi,
S.; Ugozzoli, F. Chem. Eur. J. 2008, 14, 98–106.
† Universite´ du Havre.
‡ Universite´ Libre de Bruxelles.
(1) Functional Synthetic Receptors; Schrader, T., Hamilton, A. D., Eds.;
Wiley-VCH: Weinheim, Germany, 2005.
(4) (a) Jabin, I.; Reinaud, O. J. Org. Chem. 2003, 68, 3416–3419. (b)
Zeng, X.; Hucher, N.; Reinaud, O.; Jabin, I. J. Org. Chem. 2004, 69, 6886–
6889. (c) Zeng, X.; Coquie`re, D.; Alenda, A.; Garrier, E.; Prange´, T.; Li,
Y.; Reinaud, O.; Jabin, I. Chem.sEur. J. 2006, 12, 6393–6402. (d) Le Gac,
S.; Zeng, X.; Girardot, C.; Jabin, I. J. Org. Chem. 2006, 71, 9233–9236.
(e) Le Gac, S.; Jabin, I. Chem.sEur. J. 2008, 14, 548–557.
(2) Gutsche, C. D. Calixarenes ReVisited, Monographs in Supramo-
lecular Chemistry; Stoddart, J. F., Eds.; The Royal Society of Chemistry:
Cambridge, U.K., 1998. Lu¨ning, U.; Lo¨ffler, F.; Eggert, J. In Calixarenes
2001; Asfari, Z., et al., Eds.; Kluwer Academic: Dordrecht, The Netherlands,
2001; pp 71-88.
10.1021/ol8021726 CCC: $40.75
Published on Web 10/22/2008
2008 American Chemical Society

Figure 1. First and second generation of calix[6]azacryptands.
Among the different calix[6]azacryptands, calix[6]tac 1
(tac ) 1,3,5-triazacyclohexane) has shown a remarkable
ability to bind small ammonium ions inside its cavity.9 Thus,
we were interested in introducing anion-coordinating groups
(i.e., amido or urea groups) on the calix[6]tac skeleton in
order to obtain neutral heteroditopic receptors for organic
ion pairs. Such receptors capable of simultaneous binding
of cations and anions are intensively studied since they can
lead to cooperative processes and present the advantage of
avoiding the competitive ion-pairing of the guest salt.10
Scheme 1. Syntheses and Host-Guest Properties of
1,3,5-Tris-functionalized Calix[6]tacs 58 and 6
Herein, we report on the use of compound 2 for the
synthesis of the first members of a second generation of
calix[6]azacryptands based on the calix[6]tac skeleton.
The synthesis of the 1,3,5-tris-acetyl-calix[6]hexa-amine
3 was previously reported in an efficient two step sequence
from the C3V molecular platform 2 (75% overall yield)
(Scheme 1).8 Addition of an excess of phenylisocyanate (6
equiv) to a solution of 2 in CH2Cl2 led to the intermediate
1,3,5-tris-Boc-2,4,6-tris-phenylurea-calix[6]hexa-amine which
was purified by flash chromatography.11 The subsequent
removal of the Boc groups by acidic treatment (TFA)
affordedtheC3Vsymmetrical1,3,5-tris-phenylurea-calix[6]hexa-
amine 412 in 88% overall yield from 2. Finally, the [1 + 3]
macrocyclization reaction of compounds 3 or 4 with aqueous
HCHO in CH2Cl2 gave the expected 1,3,5-tris-acetamido-
binding event. In addition, the selective removal of the
methyl groups at the 1,3,5-phenolic positions remains chal-
lenging.6 Until now, the 1,3,5-tris-methoxy-calix[6]arene
(X6H3Me3) intermediate was the only readily available
calixarene-based building block displaying a 1,3,5-substitu-
tion pattern.7 However, we have recently described an
efficient strategy for the selective 1,3,5-tris-protection of a
hexa-aminocalix[6]arene, yielding the molecular platform 2
(Figure 1).8 This calix[6]arene possesses three alternating
free amino groups accessible for a chemical transformation
and thus constitutes an interesting alternative to the use of
X6H3Me3 since functionalized calix[6]cryptands could be
easily obtained through macrocyclization reactions.
(8) Le Gac, S.; Marrot, J.; Jabin, I. Chem.sEur. J. 2008, 14, 3316–
3322.
(9) Darbost, U.; Giorgi, M.; Reinaud, O.; Jabin, I. J. Org. Chem. 2004,
69, 4879–4884.
(10) For a review on receptors for ion pairs, see: Sessler, J. L.; Gale,
A. P.; Cho, W.-S. In Anion Receptor Chemistry; The Royal Society of
Chemistry: Cambridge, 2006; pp 259-293. For recent articles dealing with
related heteroditopic receptors from calixarenes, see: Hamon, M.; Me´nand,
M.; Le Gac, S.; Luhmer, M.; Dalla, V.; Jabin, I. J. Org. Chem. 2008, 73,
7067–7071. Lankshear, M. D.; Dudley, I. M.; Chan, K.-M.; Cowley, A. R.;
Santos, S. M.; Felix, V.; Beer, P. D. Chem.sEur. J. 2008, 14, 2248–2263.
Arduini, A.; Ferdani, R.; Pochini, A.; Secchi, A.; Ugozzoli, F. Angew.
Chem., Int. Ed. 2000, 39, 3453–3456. Ballistreri, F. P.; Notti, A.; Pappalardo,
S.; Parisi, M. F.; Pisagatti, I. Org. Lett. 2003, 5, 1071–1074. For other
ureidocalix[6]arenes, see: Gonzalez, J. J.; Ferdani, R.; Albertini, E.; Blasco,
J. M.; Arduini, A.; Pochini, A.; Prados, P.; de Mendoza, J. Chem.sEur. J.
2000, 6, 73–80.
(5) Darbost, U.; Rager, M-.N.; Petit, S.; Jabin, I.; Reinaud, O. J. Am.
Chem. Soc. 2005, 127, 8517–8525.
(6) Only one example of selective removal of the methyl groups has
been reported with a sodium complex of a 1,3,5-trismethoxycalix[6]arene
bearing amido groups; see: van Duynhoven, J. P. M.; Janssen, R. G.;
Verboom, W.; Franken, S. M.; Casnati, A.; Pochini, A.; Ungaro, R.; de
Mendoza, J.; Nieto, P. M.; Prados, P.; Reinhoudt, D. N. J. Am. Chem. Soc.
1994, 116, 5814–5822.
(7) For the synthesis of X6H3Me3 in 27% yield, see: Arduini, A.; Casnati,
A. In Macrocycle Synthesis, A Practical Approach; D. Parker, Eds.; Oxford
University Press: Oxford, 1996; pp 145-173. The related 1,3,5-trisbenzyl
derivatives have been obtained in 25-35% yields; see: Neri, P.; Consoli,
G.; Cunsolo, F.; Piattelli, M Tetrahedron Lett. 1994, 35, 2795–2798.
(11) The 1H NMR spectrum of this compound showed a complex
mixture of conformers even at high temperature (CD3OD, 330 K) (see the
Supporting Information).
(12) See the Supporting Information for the conformational properties
of 4.
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Org. Lett., Vol. 10, No. 22, 2008

+
Table 1. Selected Complexation Induced Shifts (CISs) of the Calixarene Hosts 1, 5, and 6 and Guest PrNH3
.
a
host (∆δ/ppm)a
+
guest PrNH3 (∆δ/ppm)
entry
host-guest complex
CH3CH2
CH3CH2
CH2N
PhNHCO
CH2NHCO
1
2
3
4
5
6
[1⊃PrNH3+],Pic-
[1⊃PrNH3+],Cl-
[5⊃PrNH3+],Pic-
[5⊃PrNH3+,Cl-]
[6⊃PrNH3+],Pic-
[6⊃PrNH3+,Cl-]
-2.33b
-2.38
-2.35
-2.34
-2.41
-2.46
-2.96b
-3.05
-3.09
-3.07
-3.15
-3.08
-2.43b
-2.44
-2.44
ndc
-2.54
-2.45
-0.18
+0.65
+0.23
+0.53
+0.16
+1.34
a CISs calculated at 294 K in CDCl3 and defined as ∆δ ) δ(host-guest complex) - δ (free). b Determined in CDCl3/CD3OD 92:8. c nd ) not determined.
+
Figure 2
.
1H NMR spectra (CDCl3, 294 K) of (a) 6; (b) 6 + 1 equiv of PrNH3+,Pic-; (c) 6 + 1 equiv of PrNH3+Cl-. 1: included PrNH3
.
S ) solvents (CHCl3, CH2Cl2), W ) water.
calix[6]tac 5 and 1,3,5-tris-phenylurea-calix[6]tac 6 in re-
markably high yields (78% and 98% yield, respectively).
out exchange process on the NMR time scale (see Figure
2b for [6⊃PrNH3 ],Pic-).
+
All the signals of the 1H NMR spectra of calix[6]arenes 5
and 6 recorded in CDCl3 (294 K) were assigned through 2D
NMR analyses (COSY, HMQC, HMBC). It is noteworthy
that the 1H signals belonging either to the calixarene core or
to the tac cap of 5 and 6 were found close to those reported
for the parent calix[6]tac 1, indicating very similar confor-
mational properties for these three rigidified calix[6]arenes.
Thus, 5 and 6 stand in a C3V symmetrical flattened cone
conformation (∆δArH and ∆δtBu > 0.6 ppm, see Figure 2a
for 6)4a with the bulky urea or amido arms directed toward
the outside of the cavity (see the structures displayed in
Scheme 1), the cone-cone inversion being prevented thanks
to the presence of the tac cap. Hence, the 1,3,5-tris-
functionalized calix[6]tac 5 and 6 possess a well-defined
cavity suitable for guest inclusion.
The spectra of these host-guest complexes are quasi-
superposable to the one observed in the case of the parent
calix[6]tac (i.e., [1⊃PrNH3 ],Pic-), and in particular, the
+
+
complexation induced shifts (CISs) of the included PrNH3
are close in all cases (Table 1, entries 1, 3, and 5).13 This
shows a similar positioning of the ammonium ion in the
cavity and thus a priori a similar way of binding, i.e. a
combination of H-bonding, CH-π, and cation-π interac-
tions between PrNH3 and its host.14
+
Very interestingly, while the NH chemical shifts of the
amido and urea groups of the host-guest complexes
[5⊃PrNH3 ],Pic- and [6⊃PrNH3 ],Pic- were only slightly
different from those of the free hosts (Figure 2b), a strong
downfield shift of these protons was observed when
+
+
PrNH3 Cl- was used in place of the picrate salt (Table 1,
+
entries 3 vs 4 and 5 vs 6) (Figure 2c for [6⊃PrNH3 ,Cl-]).
+
The host-guest properties of receptors 5 and 6 toward
This clearly indicates that, in the presence of an appropriate
the picrate and chloride salts of propylammonium ion were
coordinating anion such as Cl-, calix[6]tac 5 and 6 can
1
studied by H NMR spectroscopy at rt. Thus, addition of 1
equiv of PrNH3 Pic- to CDCl3 solutions of 5 or 6 led to the
+
(13) Moreover, HMQC spectra allowed us to determine the carbon
resonances of the included PrNH3+. For [5⊃PrNH3+],Pic-: δ (ppm) CH3
) 10.6, CH2 ) 17.5, CH2N ) 38.0; for [6⊃PrNH3+,Cl-]: δ (ppm) CH3 )
10.8, CH2 ) 18.0, CH2N ) 38.2.
(14) These interactions have been evidenced in the case of the complex
[1⊃PrNH3+],Pic- thanks to an X-ray structure; see ref 9.
quantitative formation of the corresponding endocomplexes
[5⊃PrNH3 ],Pic- and [6⊃PrNH3 ],Pic- (Scheme 1), as
+
+
indicated by the presence of high-field signals corresponding
to the inclusion of 1 equiv of PrNH3 , with a slow in and
+
Org. Lett., Vol. 10, No. 22, 2008
5197

+
behave as heteroditopic receptors able to simultaneously
encapsulate the ammonium ion in the cavity and bind its
counteranion at the level of the amido or urea moieties
through H bonding interactions (see the structure depicted
in Figure 2c). It is noteworthy that differentiated signals for
binding of PrNH3 .17 In both cases, progressive addition of
the ammonium salt (up to 1 equiv/calix total) to a 1:1 solution
of 1 and 6 in CDCl3 led to a mixture of the corresponding
endocomplexes.18 With X ) Pic-, [1⊃PrNH3 ],Pic- and
+
[6⊃PrNH3+],Pic- were formed in equal amounts in all cases,
indicating a similar binding constant. This result is highly
compatible with the low affinity of the picrate anion for the
urea groups. In contrast, with X ) Cl-, in comparison with
[1⊃PrNH3+],Cl-, a much larger amount of [6⊃PrNH3+,Cl-]
the free host 6 and for the complex [6⊃PrNH3 ,Cl-] were
+
observed when less than 1 equiv of PrNH3 Cl- was added.
+
Upon the progressive addition of PrNH3 Cl- (from 0 to 12
+
equiv), the chemical shifts of the downfield-shifted NHCO
was produced with less than 1 equiv of PrNH3 Cl- (Figure
+
signals of [6⊃PrNH3 ,Cl-] were not affected and no species
+
other than the free host and [6⊃PrNH3 ,Cl-] were observed
+
3). This highlights that the simultaneous binding of the anion
by the urea groups of the ditopic receptor 6 enhances the
endocomplexation of the ammonium ion.
(see the Supporting Information). These NMR data indicate
a strong complexation of the Cl- at the level of the ureas
and are highly consistent with a 1:1 calixarene/Cl- binding
stoichiometry.
Moreover,
in
comparison
to
[6⊃PrNH3 ],Pic-, the NCH2N and CH2N protons of the cap
+
of [6⊃PrNH3 ,Cl-] are significantly downfield shifted (see
+
Figure 2c vs 2b), the other protons of the receptor being
weakly affected. This may indicate that the chloride stands
in close proximity to the tac cap when this anion is
simultaneously coordinated by the ureas. All these results
taken together may support a cooperative complexation of
15
the Cl- by the ureas of the endocomplex [6⊃PrNH3 ].
+
The interaction of PrNH3+ and Cl- with both 5 and 6 was
1
also investigated by mass spectrometry. ESI-MS spectra of
Figure 3
.
Competitive H NMR study conducted with 1 and 6
5 or 6 in the presence of 10 equiv of PrNH3 Pic- displayed
+
toward the complexation of PrNH3+Cl- (CDCl3, 294 K, ArHin
region): 1:1 mixture of 1 and 6 before (a) and after addition of 0.6
equiv (b), 1.4 equiv (c) and 2 equiv (d) of PrNH3+Cl-.
ion peaks at m/z ) 1453.3 and 1684.1 corresponding,
respectively, to [5+PrNH3]+ and [6+PrNH3]+.16 When the
analyses were carried out under the same conditions with
bulkier ammonium picrate salts (phenylethylammonium and
hexylammonium) unable to be accommodated into the cavity
of 5 and 6, only protonated species [5+H]+ and [6+H]+
were observed. This indicates the presence of specific
interactions between PrNH3+ and the receptors 5 and 6 which
are likely due to the inclusion of the ammonium ion. A
different complexation behavior toward Cl- was observed
between 5 and 6 (using 10 equiv of TBACl). Indeed, while
the [6+Cl]- ion peak at m/z ) 1658.9 was detected as the
major signal, the peak corresponding to [5+Cl]- was not
observed. This result shows the weaker coordination proper-
ties of the amido groups toward anions.
In conclusion, the selective introduction of anion binding
groups on the narrow rim of a calix[6]azacryptand has led
to heteroditopic receptors able to bind either ammonium ions
or organic ion pair salts with a positive cooperativity. Thus,
the 1,3,5-tris-protected-calix[6]hexa-amine 2 constitutes a
promising intermediate for the preparation of sophisticated
calix[6]cryptand based receptors.
Acknowledgment. This research was supported by the
Agence Nationale de la Recherche (Calixzyme Project ANR-
05-BLAN-0003) and the Bureau des Relations internationales
(U.L.B.).
Finally, a competitive NMR experiment between receptor
Supporting Information Available: General experimental
methods; 1D, 2D NMR spectra of 4-6, and ESI-MS
spectra.This material is available free of charge via the
Internet at http://pubs.acs.org.
6 and the parent calix[6]tac 1 toward the complexation of
PrNH3 X- (with X ) Pic- and Cl-) has been performed to
+
see whether the coordination of the anion could enhance the
OL8021726
(15) At 263 K, only one resonance was observed for the three NHPhurea
protons of [6⊃PrNH3+,Cl-] (see the Supporting Information). The chloride
ion may be either simultaneously bound by the three urea groups or by
two of the ureas with an overall fast exchange process on the NMR time
scale even at low temperature.
(17) Because of strong association constants (K > 106 M-1, see ref 9),
accurate determination of the affinity of 6 toward PrNH3+X- was not
possible by NMR spectroscopy.
(16) See the Supporting Information for the experimental conditions of
the ESI-MS analyses.
(18) The ArHin region of the NMR spectra was well appropriate for the
observation of the different species.
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Org. Lett., Vol. 10, No. 22, 2008