Calix[6]arene-based cascade complexes of organic ion triplets stable in a protic solvent

Article abstract of DOI:10.1002/chem.201001193

Herein we report a D_3h-symmetric tail-to-tail bis-calix[6]arene 3 featuring two divergent cavities triply connected by ureido linkages. This calix[6]tube was synthesized by a domino Staudinger/aza-Wittig reaction followed by a macrocyclization reaction. This process also afforded a C _2h-symmetric isomer that represents a rare example of a self-threaded rotaxane based on calix[6]arene subunits. The binding properties of 3 have been evaluated by NMR studies. Thus, bis-calix[6]arene 3 is able to bind simultaneously two neutral ureido guests through an induced-fit process. The guests are located in the cavities and are recognized through multiple hydrogen-bonding interactions with the ureido bridges. Host 3 can also simultaneously bind multiple ions and is especially efficient for the complexation of organic ion triplets. The anion is recognized through hydrogen-bonding interactions at the ureido binding site and is thus located between the two ammonium ions accommodated in the cavities. The resulting [1+1+2] quaternary complexes represent rare examples of cascade complexes with organic cations. These complexes are unique: 1) They are stable even in a markedly protic solvent, 2) the recognition of the ion triplets proceeds in a cooperative way through an induced-fit process and with a high selectivity, linear cations and doubly charged anions being particularly well recognized, 3) the ions are bound as contact ion triplets thanks to the closeness of the three binding sites, 4) the cationic guests can be exchanged and thus mixed [1+1+1+1] complexes can be obtained, 5) the ureido linkers wrapped around the anion adopt a helical shape and the resulting chirality is sensed by the cations. In other words, bis-calix[6]arene 3 presents a selective inner tunnel in which multiple guests such as organic ion triplets can be aligned in a cooperative way through induced-fit processes.

Full text of DOI:10.1002/chem.201001193

DOI: 10.1002/chem.201001193
Calix[6]arene-Based Cascade Complexes of Organic Ion Triplets
Stable in a Protic Solvent
Steven Moerkerke, Mickaꢀl Mꢁnand, and Ivan Jabin*[a]
Abstract: Herein we report a D3h-sym-
metric tail-to-tail bis-calix[6]arene
multiple ions and is especially efficient
for the complexation of organic ion
triplets. The anion is recognized
through hydrogen-bonding interactions
at the ureido binding site and is thus
located between the two ammonium
ions accommodated in the cavities. The
resulting [1+1+2] quaternary com-
plexes represent rare examples of cas-
cade complexes with organic cations.
These complexes are unique: 1) They
are stable even in a markedly protic
solvent, 2) the recognition of the ion
triplets proceeds in a cooperative way
through an induced-fit process and
3
with a high selectivity, linear cations
and doubly charged anions being par-
ticularly well recognized, 3) the ions
are bound as contact ion triplets thanks
to the closeness of the three binding
sites, 4) the cationic guests can be ex-
changed and thus mixed [1+1+1+1]
complexes can be obtained, 5) the
ureido linkers wrapped around the
anion adopt a helical shape and the re-
sulting chirality is sensed by the cat-
ions. In other words, bis-calix[6]arene 3
presents a selective inner tunnel in
which multiple guests such as organic
ion triplets can be aligned in a cooper-
ative way through induced-fit pro-
featuring two divergent cavities triply
connected by ureido linkages. This cal-
ix[6]tube was synthesized by a domino
Staudinger/aza-Wittig reaction fol-
lowed by a macrocyclization reaction.
This process also afforded a C2h-sym-
metric isomer that represents a rare ex-
ample of
a self-threaded rotaxane
based on calix[6]arene subunits. The
binding properties of 3 have been eval-
uated by NMR studies. Thus, bis-cal-
ix[6]arene 3 is able to bind simultane-
ously two neutral ureido guests through
an induced-fit process. The guests are
located in the cavities and are recog-
nized through multiple hydrogen-bond-
ing interactions with the ureido bridges.
Host 3 can also simultaneously bind
Keywords: calixarenes
·
cascade
complexes · ion triplets · molecular
AHCTUNGTRENGNcUN esses.
recognition
chemistry
·
supramolecular
Introduction
nanomaterials for the storage of gases.[5] Head-to-head bis-
calix[4]arenes have served as stoppers in rotaxanes[6] and
the self-assembly of tetraureido-calix[4]arenes has led to
head-to-head dimeric capsules that can be exploited for the
elaboration of sophisticated molecular objects.[7] Supra-
molecular polymers[8] and selective ionophores[9] from bis-
calix[4]- or -[5]arenes covalently connected in a tail-to-tail
fashion have been reported, whereas head-to-head bis-cal-
ix[5]arenes bridged by a ureido spacer have been shown to
recognize long-chain ammonium salts.[10] However, so far,
only a few examples of double- or multi-calix[6]arenes have
been described.[11] This is mainly attributable to the high
flexibility of the calix[6]arene subunits, which makes the
control of their linkage more difficult.
There is a growing interest in the design of molecular recep-
tors featuring multiple concave hydrophobic cavities.
Indeed, depending on the nature of the concave subunits
and on the way they are linked, structures of different topol-
ogies such as capsules[1] or organic nanotubes[2] can be ob-
tained. In this context, readily available calixarenes have
emerged as very attractive building blocks.[3] Calix[4]arene
subunits linked in a 1,3-alternate conformation have led to
nanotubes that can be used for cation transport[4] or as
[a] S. Moerkerke, Dr. M. Mꢀnand, Prof. I. Jabin
Laboratoire de Chimie Organique
Universitꢀ Libre de Bruxelles (U.L.B.)
Av. F. D. Roosevelt 50, CP160/06, 1050 Brussels (Belgium)
Fax : (+32)2-650-27-98
We have previously shown that calix[6]arene-based het-
ACHUTNGERNeNUG roAHCTUNGTRNENdUGN itopic receptors decorated with ureido groups on the
narrow rim can display versatile host–guest properties to-
wards charged or neutral species. Indeed, calix[6]tris-
ureas[12] and calix[6]crypturea[13] can strongly bind a wide
E-mail: ijabin@ulb.ac.be
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001193.
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Chem. Eur. J. 2010, 16, 11712 – 11719

FULL PAPER
range of anions through induced-fit processes, but can also
behave as unique receptors for organic contact ion pairs[14]
with a positive cooperativity in the complexation process,
the anion acting as an allosteric effector. It has also been
shown that the calix[6]crypturea host is able to complex
neutral guests and its binding properties can be chemically
controlled by an external stimulus (addition of acid or base
to the medium). In the course of developing multitopic, ver-
satile calix[6]arene-based receptors, we became interested in
the synthesis of a tubular tail-to-tail bis-calix[6]arene pos-
sessing a well-defined inner tunnel able to complex simulta-
neously multiple-charged or neutral species. This calix[6]-
tube was designed in such a way that it should display two
divergent hydrophobic cavities triply connected by short
ureido linkages.[15] Indeed, such a heterotritopic receptor
was expected to possess unique recognition properties, nota-
bly towards tight ion triplets,[16] as a result of the original
combination of the three different binding sites in close
proximity, that is, the convergent hydrogen-bonding donor
ureido groups (anion-binding site) located between the two
cavities (ammonium ion binding sites). Furthermore, this
calix[6]tube was also particularly attractive because it has
been shown that the simultaneous binding of multiple guests
in a tubular structure could provide allosteric regulation of
the recognition process.[17]
Herein we report the synthesis and binding properties of
the first tail-to-tail bis-calix[6]arene featuring a tris-ureido
recognition site. This calix[6]tube can strongly bind organic
ion triplets even in the presence of a protic solvent, leading
to rare examples of metal-free cascade complexes.[18]
Results and Discussion
Synthesis and characterization of the calix[6]tube: The de-
sired tail-to-tail bis-calix[6]arene 3 was obtained from the
known[19] calix[6]tris-azide 1 and calix[6]tris-amine 2 by a
domino Staudinger/aza-Wittig reaction followed by a [1+1]
macrocyclization step. Indeed, the reaction of calix[6]tris-
azide 1 with PPh3/CO2 led in situ to the reactive intermedi-
ate calix[6]tris-isocyanate, which immediately reacted with
calix[6]tris-amine 2 under high dilution conditions. Purifica-
tion of the crude mixture by flash chromatography led to a
1:1 mixture of the D3h-symmetric bis-calix[6]arene 3 and its
unexpected C2h-symmetric isomer 4 (Scheme 1).[20] These
two compounds were easily separated as a result of their
highly different solubility in EtOH. Thus, both 3 and 4 were
obtained in an overall yield of 26% from 1. The formation
of these two isomers originates from the existence of two
possible patterns for the formation of the macrocycle after
the first two linkages (i.e., syn and anti patterns[21]). Note
that the tail-to-tail bis-calix[6]arene 4 represents a rare ex-
ample of a self-threaded rotaxane based on calix[6]arene
subunits.[22]
The tail-to-tail bis-calix[6]arenes 3 and 4 were character-
ized by NMR spectroscopy in CDCl3. The isomer 4 displays
1
a complex H NMR pattern in agreement with a C2h-sym-
metrical structure with 1) one ureido linkage threading
through the macrocycle formed by the other two and
2) both calixarene cavities filled by an inward methoxy
group (dOMe =1.76 ppm compared with dOMe =3.72 ppm for
the outward OMe groups; Scheme 1).[23] The bis-calix[6]ar-
ene 3 exhibits a broad NMR signature that can be ascribed
Scheme 1. Synthesis of D3h- and C2h-symmetric tail-to-tail bis-calix[6]arenes 3 and 4.
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I. Jabin et al.
to the intramolecular self-association of the ureido
groups.[24] However, a well-resolved NMR pattern indicative
of a D3h-symmetric structure was observed at 330 K, which
confirms the tubular architecture of this compound.[23] At
this high temperature (T), the signals of the calixarene sub-
ACHTUNGTRENNUNGunits of 3 are characteristic of an averaged straight cone
conformation (DdtBu =0.14 ppm, dOMe =3.02 ppm).[25] In the
presence of a protic solvent [i.e., CD3OD/CDCl3 (3:1)],[26]
the NH ureido protons of 3 experience a downfield shift
(dNH =6.49 vs. 6.13 ppm in CDCl3) and its calixarene sub-
ACHTUNGTRENNUNGunits adopt a flattened averaged cone conformation with the
hydrophobic cavity filled by the OMe groups (dOMe
=
2.30 ppm; Figure 1a, Scheme 1).
Neutral molecule recognition: The binding properties of the
bis-calix[6]arenes 3 and 4 were investigated by NMR spec-
troscopy. As expected given its self-threaded structure, 4 did
not exhibit any host properties towards either neutral or
charged guests (anions or ion pairs). In the case of 3, no evi-
dence was obtained for the endo complexation of either
small alcohols (i.e., MeOH, EtOH), amides (i.e., DMF), or
apolar molecules (i.e., CH2Cl2) in CDCl3. However, upon
the progressive addition of imidazolidin-2-one (Imi), increas-
ing NMR signals corresponding to a new D3h-symmetric spe-
cies were observed. When the titration was performed at
low T (263 K), a highfield signal at 0.20 ppm showing the in-
tracavity inclusion of Imi was clearly apparent.[23] Integra-
tion of this highfield signal indi-
Figure 1. 1H NMR spectra (300 MHz, 298 K) of a) 3 in CD3OD/CDCl3
2À
(3:1); b) 3ꢀ
G
2À
2À
addition of 6 equiv of (PrNH3+)2SO4 to 3; c) 3ꢀ
ACHTUNGTRENNUNG
CDCl3 obtained after extraction of 1 equiv of (HexNH3+)2SO4 by 3.
2À
+
+
+
!
*
*
: PrNH3 in; : PrNH3 out; : HexNH3 in; W: water; S: residual sol-
vent; *: residual grease.
groups from the cavities. The overall binding constant b2 for
the formation of 3ꢀ
(Imi)2 was estimated to be >1.1ꢂ104 mÀ2
ACHTUNGTRENNUNG
(see the Experimental Section). The high selectivity for Imi
can be rationalized by a four hydrogen-bond recognition
cated a 1:2 host–guest associa-
tion, which attests to the forma-
tion of the ternary complex[3ꢀ-
ACHTUNGTRENNUNG
(Imi)2 (Scheme 2).[27] Over the
course of the titration, slight
shifts of the signals of the free
host 3 were observed in addi-
tion to the separate peaks cor-
responding to[3ꢀ
ACHTUNGTRENNUNG(Imi)2. These
shifts are likely due to the for-
mation of the intermediate
complex 3ꢀImi experiencing
fast host–guest exchange on the
NMR timescale with 3. The
complex 3ꢀ
ACHTUNGTRENNUNG(Imi)2 displays a
flattened cone conformation
with the OMe groups expelled
from
the
cavity
(dOMe =
3.92 ppm). The complexation-
induced shift (CIS) of the meth-
ylenic protons of the included
Imi (CISCH2 =À3.34 ppm) indi-
cates a positioning of this guest
in the heart of the cavity.[28]
Thus, host 3 is able to complex
simultaneously two neutral
ureido guests, one in each
cavity, through an induced-fit
process that ejects the OMe Scheme 2. Host–guest properties of the calix[6]tube 3 towards neutral guests and ion triplets.
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Chem. Eur. J. 2010, 16, 11712 – 11719

Calix[6]arene-Based Cascade Complexes
FULL PAPER
process between each guest and its calixarene subunit, as
well as CH–p interactions between the methylenic protons
of Imi and the aromatic walls of the host. Such an efficient
mode of recognition for Imi has already been described for
closely related calix[6]arene-based systems[29] and has been
rationalized by an X-ray structure analysis.[30] Finally, upon
the addition of 2% of CD3OD, only 25% of the complex
À1.5 ppm) corresponding to the alkyl chain of the ammoni-
um ion deeply included inside the cavity. The CISs of the in-
cluded ammonium ions are displayed in Table 1. As a repre-
sentative
example,
the
1H NMR
spectrum
of
+
2À
3ꢀ(PrNH3 )2SO4 is displayed in Figure 1b. The “normal”
G
chemical shifts of the OMe of both complexes (dOMe
>
4 ppm) reveal an induced-fit recognition process, the alter-
nating aromatic units having interchanged their in and out
positions upon complexation (see the structures depicted in
Scheme 2).
3ꢀ
ACHTUNGTRENNUNG(Imi)2 survived. For comparison, the parent calix[6]cryp-
turea receptor was able to complex Imi in pure CD3OD,
whereas calix[6]tris-ureas were insensitive to neutral guests.
The intermediate host–guest behavior of 3 is likely due to
the intermediate preorganization of its tris-ureido binding
site in terms of flexibility.
Note that the resonances of the methylenic protons of the
ureido bridges are very broad and also a variable-tempera-
2À
ture NMR study undertaken with 3ꢀ
(PrNH3+)2SO4
ACHTUNGTRENNUNG
showed a coalescence phenomenon for other resonances of
the complex in the 293–263 K temperature range (Figure 2).
At 243 K, a large splitting of the ArH and CH2 resonances
of the host was observed together with a splitting of the
methylenic resonances of the guest.[23] Similarly to previous
results,[32] this phenomenon can be attributed to the freezing
of the helical twisting of the three ureido linkages. Indeed,
the host–guest complex exists as a pair of D3-symmetric heli-
cal enantiomers that are in conformational equilibrium (see
Anion recognition: The progressive addition of tetra-n-bu-
ACHTUNGTRENNUNGtylACHTUNGTRENNUNG
ammonium salts of various anions (i.e., TBA+XÀ with
À
À
À
XÀ =ClÀ, BrÀ, IÀ, CNÀ, N3 , HSO4 , SO42À, AcOÀ, or NO3 )
to 3 in CDCl3 in some cases (i.e., XÀ =ClÀ and AcOÀ) only
caused tiny shifts of the signals and in particular of the
ureido NH protons. The association constants Ka for all
these anions were estimated by1H NMR titrations to be
<1mÀ1.[31] Again, if compared with the calix[6]crypturea re-
ceptor, the poor ability of 3 to coordinate anions can be ra-
tionalized by the large size of the macrocycles formed by
the ureido linkages. Indeed, this structural difference results
in a much greater flexibility of the tris-ureido recognition
site as well as a lack of the chelate effect. Concerning the
parent calix[6]tris-ureas, the higher acidity of their ureido
protons contributes largely to their better efficiency in the
recognition of anions.
Ion-triplet recognition: It was found that calix[6]tube 3 be-
haves as a remarkable receptor for the simultaneous com-
plexation of ammonium ions and anions even in a markedly
protic solvent. Indeed, the addition of a few equivalents of
2À
an ammonium sulfate salt (RNH3+)2SO4 (with R=Et or
Pr) to 3 in CD3OD/CDCl3 (3:1) led quantitatively to the
+
2À
D3h-symmetric complex 3ꢀ
(RNH3 )2SO4
(Scheme 2).[23]
Upon the progressive addition of the ammonium salts, only
signals belonging to 3 and the [1+1+2] quaternary com-
plexes were observed, which suggests a much lower stability
of the intermediate complexes.[23] In both cases, the quater-
nary complexes were characterized by highfield signals (i.e.,
Figure 2. Variable-temperature
1H NMR
spectra
(600 MHz)
of
2À
3ꢀ
G
+
+
!
!
d) 263, and e) 243 K.
W: Water.
: PrNH3
in;
: PrNH3
out; S: Solvent;
Table 1. Complexation-induced shifts (CISs) and cumulative formation constants b3 of the ion-triplets in the case of 3ꢀ
ACHTUNGTRENNUNG
2À
G
.
Guest ion-triplet
CIS [ppm][a]
a
b
g
d
e
z
h
q to m
0:1
1:10
3:1
2À
(EtNH3+)2SO4
E
À1.13[c]
À0.67[c]
À0.57[d]
À0.59[d]
À0.60[d]
À1.34[d]
À3.02
À2.97
À2.85
À2.79
À2.79
À3.04
–
–
–
–
–
–
–
–
–
–
–
–
–
>3.2ꢂ1013
>3.2ꢂ1013
>1.5ꢂ109
>9.5ꢂ1012
>2.4ꢂ1012
>1.0ꢂ1010
>3.4ꢂ1013
>1.2ꢂ1014
4.6ꢂ104
no inclusion
no inclusion
67
9.5ꢂ109
1.3ꢂ109
nd[e]
2À
À2.90
À3.03
À2.65
À2.50
–
N
2À
(HexNH3+)2SO4
À2.10
À2.06
–
À1.85
À1.70
–
À0.84
À0.84
–
–
<À0.45
–
nd[e]
2À
(DodecNH3+)2SO4
À0.50
nd[e]
2À
(PyrNH2+)2SO4
nd[e]
[a] CIS is defined as Dd=d(complexed ammonium ion)Àd(free ammonium ion). [b] b3 determined at 298 K by integration of the different species in
(PyrNH2+)2SO42À]/([3] 2[SO42À]) in the case of (PyrNH2+)2SO42À. Ini-
ACHTUNGTRENUNNG AHCTUNGETRN[GNUN PyrNH2 ] ACUTHNGTRENNUNG
+
+
equilibrium. b3 is defined as [3ꢀ
E
N
]
U
tial host concentration [3]i =1.7–2.5ꢂ10À3 m; error estimated to be Æ15%. [c] CIS calculated at 298 K in CD3OD/CDCl3 (3:1). [d] CIS calculated at
298 K in CDCl3. [e] Not determined.
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I. Jabin et al.
2À
the structures depicted in Figure 2). At low temperature,
this equilibrium is slow on the NMR timescale and thus the
diastereotopic aromatic and methylenic protons of the
whole edifice are differentiated. In other words, the guest
ammonium ions sense the helical chirality of the host. Note
that an enantiomerization barrier of 57.5(1) kJmolÀ1 was de-
termined for the coalescence processes.[23]
Altogether, these results show that calix[6]tube 3 can act
as a heterotritopic receptor able to recognize efficiently a
contact ion triplet through a cooperative three-step binding
process. Remarkably, high cumulative constants b3 were
found for the formation of the two complexes
excess (2 equiv) of (PrNH3+)2SO4 to 3 in CD3OD/CDCl3
(3:1). Upon the subsequent and progressive addition of
(EtNH3+)2SO42À, guest-exchange occurred as evidenced by
increasing signals corresponding to the cascade complexes
+
+
2À
+
2À [23]
3ꢀ(EtNH3 )
E
and
3ꢀACHTNUGETNR(NUNG EtNH3 )2SO4 .
Owing to the overlapping of signals, it was not possible to
determine precisely the proportions of the different species,
but neither of the two different types of quaternary com-
plexes (i.e., [1+1+1+1] vs. [1+1+2]) seemed to be fa-
vored. Nonetheless, this result shows that the included am-
monium ions can be displaced by others and mixed [1+1+
1+1] cascade complexes can be easily obtained.
+
2À
3ꢀ
G
Interestingly, despite the insolubility of ammonium sulfate
salts in pure CDCl3, cascade complexes of various ammoni-
the amount of CD3OD [i.e., CD3OD/CDCl3 (1:10)], it was
possible to observe the complexation of the pyrrolidinium
sulfate salt (PyrNH2+)2SO42À, but with a low cumulative for-
mation constant (Table 1). However, in this solvent mixture,
the calix[6]tube 3 was not sensitive to the addition of larger
um sulfate salts as large as (PyrNH2+)2SO42À, (Hex
A
SO42À, or (DodecNH3+)2SO4 were identified in this solvent
2À
(Figure 1c).[23] In all cases, the CISs indicate a deep inclusion
of the ammonium ions inside the cavity (Table 1) and the
ammonium salts, that is, (HexNH3+)2SO42À or (DodecN
signals of the NH3 protons of these bound ions are clearly
+
SO42À. Such selectivity for the smaller ammonium salts can
be rationalized by the important steric hindrance generated
by the introverted tBu groups closing the cavities. Very in-
terestingly, when propylammonium picrate (PrNH3+PicÀ,
2 equiv) and several TBA+XÀ salts of monocharged anions
apparent at around 7 ppm. Moreover, the significant down-
field shifts of the ureido NH protons (Dd>1.4 ppm) are in
2À
good agreement with the coordination of SO4 through hy-
drogen-bonding interactions with the ureido linkages. In the
case of the primary ammonium ions, prolonged heating (>
6 h) was necessary for the complexation to be completed
and no trace of the free salt was observed in solution.[35]
These highly efficient solid–liquid extractions denote a
strong binding process. In addition, it is known that, with p-
tBu-calix[6]arene-based receptors, the complexation of
guests possessing an alkyl chain longer than propyl can only
be observed in the case of host–guest systems that display
very high association constants. Indeed, in all cases, remark-
ably high estimated cumulative formation constants b3 were
found, even for the dodecylammonium ion, the alkyl chain
of which protrudes out of the cavity (Table 1). Note that the
complexation of the sulfate salt prepared from 2-(3,4-dime-
thoxyphenyl)ethylamine was not observed, which indicates a
high selectivity for linear ammonium ions.
Finally, the complexation of an ammonium ion associated
with a monocharged anion, that is, PrNH3+ClÀ, was also
studied by NMR spectroscopy. In CDCl3, signals corre-
sponding to the intermediate C3v-symmetric ternary complex
3ꢀPrNH3+ClÀ were clearly apparent upon the addition of
0.5 equiv of PrNH3+ClÀ to 3.[23] The two calixarene subunits
of this ternary complex exhibit separate signals, one of the
calixarene cavities being filled by the methoxy groups
(dOMe =2.46 ppm), the other hosting the ammonium ion with
À
(XÀ =FÀ, ClÀ, AcOÀ, or NO3 , ca. 1.5 equiv) were subse-
+
quently added to 3, only a trace of PrNH3 was detected in
the calixarene cavity.[33] However, the subsequent addition
2À
of 1 equiv of (TBA+)2SO4 to this complex mixture gave
rise to the selective and quasi-quantitative formation of the
2À [23]
quaternary complex 3ꢀ
(PrNH3+)2SO4
.
Thus, in a protic
solvent, the complexation of the sulfate anion can only pro-
ceed efficiently when ammonium ions are present in the cal-
2À
ixarene cavities (see above) and conversely, without SO4
,
host 3 is inefficient at binding the two ammonium ions. This
allosterically coupled binding process is made possible by
the unique structure of 3 that 1) is sufficiently flexible to
allow induced-fit processes and 2) displays two hydrophobic
cavities and a recognition site for anions in close proximity,
which favors a high cooperativity. Indeed, the closeness of
the three binding sites is crucial in the recognition process
because it avoids the unfavorable separation of the com-
plexed ions.
These results represent a rare example of cascade com-
plexes involving organic cations in place of classical metal
ions.[34] Moreover, there is a big difference between 3 and
the previously described cascade receptors. These latter usu-
ally coordinate two metal ions and then the anionic species
form a bridge between the metal centers. Thus, whereas
these dimetallic receptors are highly efficient for the recog-
nition of anions in water, in contrast to 3, they do not dis-
play a specific binding site for anions in the absence of the
cations.
CISs slightly different to those of the quaternary complex
+
3ꢀ
G
through the further addition of an excess (4 equiv) of
PrNH3+ClÀ. Note that a similar NMR signature was ob-
tained quantitatively on addition of 1 equiv of PrNH3+ClÀ
and 1 equiv of PrNH3+PicÀ to 3, which indicates the pres-
ence of only one ClÀ bound to the tris-ureido binding site.[23]
Interestingly, notable differences can be observed in the
The possibility of making mixed [1+1+1+1] quaternary
+
+
2À
complexes such as 3ꢀ
(EtNH3 )
N
was also
studied through a competitive NMR experiment between
(EtNH3+)2SO4 and (PrNH3+)2SO42À. First, the complex
NMR
spectra
of
the
two
cascade
complexes
2À
2À
+
+
2À
3ꢀ
(PrNH3+)2SO4 was prepared by the addition of an
3ꢀ
N
ACHTUNGTRENNUNG
11716
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11712 – 11719

Calix[6]arene-Based Cascade Complexes
FULL PAPER
ular, the protons of the ureido groups and of the included
ammonium ions (only those that are close to the anion, that
ronment for the guest ammonium ions. We do believe that
these examples of cascade complexes, made of organic cat-
ions strongly bound in two divergent cavities, open new per-
spectives for the elaboration of sophisticated self-assembled
systems such as supramolecular polymers. Further research
in our laboratory will be directed towards the complexation
of other dicharged anions, quaternary or ditopic ammonium
ions, as well as towards the grafting of water-soluble groups
onto the calixtube.
+
is, CH2CH2NH3 protons) display different resonances
(Table 1).[23] Furthermore, the signals of the ureido bridges
+
are much broader in the case of 3ꢀ
(PrNH3 )2SO42À. Again,
all these NMR data confirm the coordination of the anion
to the tris-ureido recognition site and the high proximity be-
tween the anion and the ammonium ions accommodated
inside the cavity. A strong cumulative formation constant
+
was estimated for 3ꢀ
G
expected, in the presence of a small amount of a protic sol-
vent [CD3OD/CDCl3 (1:10)], the formation of this quaterna-
ry complex was less favorable although still observed
(Table 1). Interestingly, a variable-temperature NMR study
Experimental Section
General: All reactions were performed under an inert atmosphere. THF
was distilled over Na/benzophenone. Silica gel (230–400 mesh) was used
in CDCl3 undertaken in the presence of 1 equiv of PrNH3
1
for flash chromatography purification. H NMR spectra were recorded at
ClÀ showed that the equilibrium was displaced in favor of
the ternary complex 3ꢀPrNH3+ClÀ when the temperature
was lowered.[23] In addition, 1H NMR competitive binding
600, 400, or 300 MHz and 13C NMR spectra were recorded at 75 MHz.
Chemical shifts are expressed in ppm. Traces of residual solvent were
used as the internal standard and CDCl3 was filtered through a short
column of basic alumina to remove traces of HCl. Most of the 1H NMR
signals were assigned on the basis of 2D NMR analyses (COSY, HSQC,
HMBC). Mass spectra were recorded with an ESI-MS apparatus
equipped with an ion-trap using the following settings: Flow rate:
10 mLminÀ1, spray voltage: 5 kV, capillary temperature: 1608C, capillary
voltage: À15 V, tube lens offset voltage: À30 V. The calix[6]tris-azide 1
and calix[6]tris-amine 2 were prepared as previously described.[19] NMR
spectra were recorded on Bruker Avance 300 MHz and Varian Unity
600 MHz spectrometers, IR spectra were recorded on a Bruker IFS 25
spectrometer, and HRMS spectra were recorded with a Water Q-TOF 2
spectrometer (at the University Mons-Hainaut, Belgium).
studies between ClÀ and SO4 were performed either in
CDCl3 or CD3OD/CDCl3 (1:10) to estimate the importance
of the charge of the anion on complex stability. Thus, in
2À
both cases, only the complex 3ꢀ
(PrNH3+)2SO4 was detect-
ed upon the addition of 1 equiv of (PrNH3+)2SO4 and a
2À
large excess of TBA+ClÀ (>110 equiv) to 3, thereby show-
ing a remarkable selectivity for the bicharged anion (KSO 2À
/
4
>104 in both cases).[23] All in all, these results show that
ClÀ
the formation of cascade complexes from calix[6]tube 3 is
also possible with monocharged anions, however, in compar-
ison with the sulfate anion, the required ion-pair dissocia-
tion and the weaker electrostatic interactions make this pro-
cess more difficult, especially in a protic solvent.
Bis-calix[6]arenes 3 and 4: Triphenylphosphine (322 mg, 1.23 mmol) as
added to a solution of calix[6]tris-azide 1 (250 mg, 0.20 mmol) in anhy-
drous THF (5 mL). Then CO2 was bubbled into the solution for 2 min
and the reaction mixture was stirred at room temperature under CO2
overnight. The reaction medium was drained with argon, placed in a sy-
ringe and the volume was adjusted to 10 mL with anhydrous THF. A
second syringe containing calix[6]tris-amine 2 (234 mg, 0.20 mmol) in an-
hydrous THF (10 mL) was prepared. The two solutions were simultane-
ously added dropwise through a syringe pump (0.793 mLhÀ1) to anhy-
drous THF (100 mL) and the resulting solution was stirred at room tem-
perature overnight. After evaporation of the solvent to remove Ph3PO,
Conclusion
The straightforward synthesis of the first tail-to-tail bis-cal-
ix[6]arene 3 that incorporates two divergent hydrophobic
cavities linked by ureido groups has been achieved. Al-
though the endo complexation of neutral guests has been
evidenced, it has been shown that this heterotritopic recep-
tor is especially efficient for the cooperative binding of or-
ganic ion triplets. The recognition process takes advantage
of the flexibility of the calix[6]arene platform and leads to a
high selectivity for linear ammonium ions associated with
doubly charged anions. The remarkable robustness of the
cascade complexes in the presence of a protic solvent stress-
es the importance of the proximity of the three binding
sites. Indeed, the charged guests are accommodated as tight
ion triplets and thus the highly energetically unfavorable
dissociation of the ions is avoided. Therefore this work illus-
trates well the synergistic effect of combining two hydropho-
bic pockets connected by a recognition site. Another re-
markable feature of these cascade complexes is their chirali-
ty due to the helical arrangement of the ureido linkers that
surround the anion. This helicity is efficiently transmitted to
the calixarene cavities, which hence provide a chiral envi-
the resulting solid was suspended in a 1:1 ethanol/water mixture
(150 mL), sonicated for 20 min, heated at reflux for 20 min, filtered, and
dried under vacuum. Flash chromatography (CH2Cl2/AcOEt, 80:20) of
the resulting solid afforded a white solid corresponding to a 1:1 mixture
of 3 and 4. This solid was suspended in EtOH, sonicated, and centrifuged.
The white solid was dried under vacuum to afford 3 (124 mg, 26%) and
the supernatant was evaporated to dryness to give 4 (126 mg, 26%) as a
white solid.
Compound 3: M.p. ca. 2608C (dec.); IR (KBr): n˜ = 3400, 1659 cmÀ1
;
1H NMR (300 MHz, CDCl3, 298 K): d=1.00 (s, 54H, tBu), 1.14 (s, 54H,
tBu), 2.95 (brs, 18H, OCH3), 3.37 (d, J=15 Hz, 12H, ArCH2), 3.59 (brs,
12H, CH2N), 3.71 (brs, 12H, OCH2), 4.50 (d, J=15 Hz, 12H, ArCH2),
6.09 (brs, 6H, NH), 6.83 (s, 12H, ArH), 7.02 ppm (s, 12H, ArH);
1H NMR (300 MHz, CDCl3/CD3OD, 3:1, 298 K): d= 0.60 (s, 54H, tBu),
1.19 (s, 54H, tBu), 2.08 (s, 18H, OCH3), 3.25 (d, J=15 Hz, 12H, ArCH2),
3.41 (brs, 12H, CH2N), 3.71 (brs, 12H, OCH2), 4.39 (d, J=15 Hz, 12H,
ArCH2), 6.17 (brs, 6H, NH), 6.45 (s, 12H, ArH), 7.10 ppm (s, 12H,
ArH); 13C NMR (75 MHz, CDCl3/CD3OD, 3:1, 298 K): d=29.2, 30.8,
31.2, 33.7, 34.0, 40.3, 60.0, 72.3, 123.4, 128.0, 132.7, 133.0, 145.9, 146.3,
149.2, 151.4, 153.7 ppm;[36] HRMS: calcd for C153H204N6O15Na: 2388.5282;
found: 2388.5332.
Compound 4: M.p. ca. 2608C (dec.); IR (KBr): n˜ =3382, 1659 cmÀ1
;
1H NMR (300 MHz, CDCl3, 298 K): d=0.75 (s, 36H, tBu), 1.04 (s, 36H,
tBu), 1.34 (s, 18H, tBu), 1.39 (s, 18H, tBu), 1.76 (s, 6H, OCH3), 3.11 (d,
J=15 Hz, 4H, ArCH2), 3.20–3.32 (m, 8H, ArCH2 +OCH2), 3.37 (d, J=
Chem. Eur. J. 2010, 16, 11712 – 11719
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11717

I. Jabin et al.
15 Hz, 4H, ArCH2), 3.44 (brs, 4H, CH2N), 3.72 (brs, 20H, OCH3 +
CH2N), 3.95 (brs, 4H, OCH2), 4.03 (brs, 4H, OCH2), 4.28 (d, J=15 Hz,
4H, ArCH2), 4.39 (d, J=15 Hz, 4H, ArCH2), 4.47 (d, J=13 Hz, 4H,
ArCH2), 5.27 (brs, 2H, NH), 6.42 (brs, 4H, ArH), 6.51 (brs, 4H, NH),
6.75 (s, 4H, ArH), 6.81 (s, 4H, ArH), 7.06 (s, 4H, ArH), 7.09 (s, 4H,
KSO
KSO
was estimated according to the following equation:
2À/ClÀ
2À/ClÀ
4
2À
[3ꢀ
G
]
N
(PrNH3+)2ClÀ][SO42À]).
ACHUTGTNRENNUG CAHTUNGTRENNUGN
4
ArH), 7.10 ppm (s, 4H, ArH); HRMS: calcd for
2388.5282; found: 2388.5264.
C153H204N6O15Na:
Acknowledgements
Estimation of the cumulative formation constant b2 of 3 towards Imi in
CDCl3: The cumulative formation constant b2 in CDCl3 was estimated ac-
cording to the following procedure: Suitable aliquots of a solution of Imi
were added to a solution of receptor 3 (2.5ꢂ10À3 m) in such a way that
the corresponding 1H NMR spectra recorded at 263 K revealed the total
disappearance of the free receptor 3. The concentration of the undetecta-
This research was supported by the Universitꢀ Libre de Bruxelles
(U.L.B.).
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[11] a) T. Arimura, S. Matsumoto, O. Teshima, T. Nagasaki, S. Shinkai,
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Am. Chem. Soc. 1998, 120, 12226–12231; c) A. Arduini, R. Ferdani,
A. Pochini, A. Secchi, Tetrahedron 2000, 56, 8573–8577; d) W.-C.
Zhang, Y. Zhu, E.-C. Li, T.-J. Liu, Z.-T. Huang, Tetrahedron 2000,
56, 3365–3371; e) H. Galꢃn, M. T. Murillo, R. Quesada, E. C. Escu-
dero-Adan, J. Benet-Buchholz, P. Prados, J. de Mendoza, Chem.
Commun. 2010, 46, 1044–1046; for the only example of a tail-to-tail
bis-calix[6]arene featuring a triple linkage, see: f) S. Le Gac, X.
Zeng, O. Reinaud, I. Jabin, J. Org. Chem. 2005, 70, 1204–1210.
[12] a) M. Hamon, M. Mꢀnand, S. Le Gac, M. Luhmer, V. Dalla, I. Jabin,
J. Org. Chem. 2008, 73, 7067–7071; b) calix[6]arenes bearing three
long (thio)ureido arms have also been described but, in this case,
the calixarene framework was only used as a molecular platform for
the preorganization of a binding site for anions far away from the
cavity, see: J. Scheerder, J. F. J. Engbersen, A. Casnati, R. Ungaro,
D. N. Reinhoudt, J. Org. Chem. 1995, 60, 6448–6454.
[13] a) M. Mꢀnand, I. Jabin, Chem. Eur. J. 2010, 16, 2159–2169. See also:
b) S. Le Gac, M. Mꢀnand, I. Jabin, Org. Lett. 2008, 10, 5195–5198.
[14] For a review on anion and ion-pair receptors, see: J. L. Sessler, P. A.
Gale, W.-S. Cho in Anion Receptor Chemistry, RSC, Cambridge,
2006; examples of the metal-free complexation of contact ion-pairs
are still rare, see: a) S. Kubik, J. Am. Chem. Soc. 1999, 121, 5846–
5855; b) J. M. Mahoney, J. P. Davis, A. M. Beatty, B. D. Smith, J.
Org. Chem. 2003, 68, 9819–9820; c) S. Le Gac, I. Jabin, Chem. Eur.
J. 2008, 14, 548–557.
ble species (i.e., 3) and the concentration of 3ꢀ
ACHTUNGRTEN(NUGN Imi)2 were estimated to
be 5 and 95% of the starting host concentration, respectively. The cumu-
lative formation constant b2 was estimated according to the following
equation: b2 >[3ꢀ
[Imi]2).
ACHTUNGTRENNUNG(Imi)2]/([3]ACHUTNGTRENNGUN
Estimation of the cumulative formation constants b3 of
3
towards
(1:10):
2À
(RNH3+)2XnÀ or (PyrNH2+)2SO4 in CDCl3 or CD3OD/CDCl3
U
The cumulative formation constants b3 were estimated according to the
following procedure: Suitable aliquots of a solution of the chloride or sul-
fate salt were added to a solution of receptor 3 (1.7–2.5ꢂ10À3 m) in such a
way that the corresponding 1H NMR spectra recorded at 298 K revealed
the total disappearance of the free receptor 3. The concentration of the
undetectable species (i.e., 3) and the concentration of the quaternary
complex were estimated to be 5 and 95% of the starting host con-
centration, respectively. The cumulative formation constants b3 were esti-
mated according to the following equation: b3 >[3ꢀ
([3][RNH3 [PyrNH2
2[XnÀ]) or [3ꢀ(PyrNH2+)2SO42À]/([3] 2[SO42À].
Determination of the cumulative formation constants b3 of 3 towards
(RNH3+)2XnÀ]/
ACHTUNGTERNNUNG
+
] ACHTUNGTRENNUNG
+
]
G
R
G
N
2À
2À
(PyrNH2+)2SO4
in CD3OD/CDCl3
G
and
2À
(PrNH3+)2SO4 in CD3OD/CDCl3
AHCTUNGTRENNUNG
fate salt was added to 3 (1.7–2.5 ꢂ10À3 m) in such a way that the H NMR
spectrum recorded at room temperature showed the resonances of both
species (3 and the corresponding quaternary complex) in addition to the
signals corresponding to the free ammonium ion. Integration of the sig-
nals of the different species (i.e., 3, the corresponding quaternary com-
plex, and the free ammonium ion) allowed us to calculate the cumulative
formation constants b3 according to the following equation: b3 =
+
[3ꢀ
([3][PyrNH2
Determination of the cumulative formation constant b3 of 3 towards
(RNH3+)2SO42À]/([3]
N
]
R
or
[3ꢀ
(PyrNH2+)2SO42À]/
ACHTUNGTRENNUNG
+
T
] ACHTUNGTRENNUNG
2[SO42À].
+
(PrNH3+)2ClÀ in CD3OD/CDCl3
ACTHNUTRGNEN(UG 1:10): A solution containing PrNH3
ClÀ was added to 3 (1.7ꢂ10À3 m) in such a way that the 1H NMR spec-
trum recorded at room temperature showed the resonances correspond-
ing to 3 and the ternary complex 3ꢀPrNH3+ClÀ in addition to the signals
of the free ammonium ion. Integration of the signals of the different spe-
cies (i.e., 3, 3ꢀPrNH3+ClÀ, and the free ammonium ion) allowed us to
calculate the cumulative formation constants b2 according to the follow-
+
ing equation: b2 =[3ꢀPrNH3+ClÀ]/([3]
[PrNH3
]
E
a
subse-
quent addition of the solution containing PrNH3+ClÀ, the H NMR spec-
1
trum showed only the resonances of 3ꢀPrNH3+ClÀ and 3ꢀ
in addition to the signals corresponding to the free ammonium ion. Inte-
gration of the signals of the different species allowed us to calculate the
association constants Ka according to the following equation: Ka =
[3ꢀ
A
[PrNH3+]). The cumulative formation
ACHTUNGTRENNUNG
constants b3 was thus defined as b3 =b2Ka.
(PrNH3+)2XÀ
ACHTUNGTRENNUNG
2À/ClÀ
Estimation of the relative affinity KSO
in the case of 3ꢀ
4
through 1H NMR competitive binding studies in CDCl3 or CDCl3/
2À
CD3OD (10:1) at 298 K: (PrNH3+)2SO4 (1 equiv) was added to a
CDCl3 or CDCl3/CD3OD (10:1) solution containing 3 (1.7ꢂ10À3 m) lead-
ing to the quantitative formation of 3ꢀ
(PrNH3+)2SO42À. Then a large
ACHTUNGTRENNUNG
excess of TBA+ClÀ (113–238 equiv) was added to the solution. The con-
centration of the undetectable species (i.e., 3ꢀ
ACHTUNGTRENNUNG
2À
SO4
3ꢀ
)
and the concentration of the other species (i.e.,
) were estimated to be 5 and 95%
free
of the starting host concentration, respectively. The relative affinity
[15] An example of a head-to-tail bis-calix[6]arene triply bridged by
ureido linkages that can form a pseudo-rotaxane has recently been
described: A. Arduini, A. Credi, G. Faimani, C. Massera, A. Pochi-
free
2À
(PrNH3+)2SO4
and ClÀ
11718
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11712 – 11719

Calix[6]arene-Based Cascade Complexes
FULL PAPER
ni, A. Secchi, M. Semeraro, S. Silvi, F. Ugozzoli, Chem. Eur. J. 2008,
14, 98–106.
small amount of a protic solvent can break the intramolecular hy-
drogen bonds between the ureido groups of 3, this spreading of the
ureido linkages leading to the highly favorable self-inclusion of the
OMe groups.
[16] For examples of calix[6]arene-based receptors that can bind ion trip-
lets (two anions and one cation), see ref. [15] and A. Arduini, R.
Ferdani, A. Pochini, A. Secchi, F. Ugozzoli, Angew. Chem. 2000,
112, 3595–3598; Angew. Chem. Int. Ed. 2000, 39, 3453–3456.
[17] a) T. Nabeshima, T. Saiki, K. Sumitomo, S. Akine, Tetrahedron Lett.
2004, 45, 4719–4722; b) U. Darbost, O. Sꢀnꢄque, Y. Li, G. Bertho, J.
Marrot, M. N. Rager, O. Reinaud, I. Jabin, Chem. Eur. J. 2007, 13,
2078–2088.
[18] The term “cascade complex” usually refers to aza-cryptands that
bind two metal ions through a bridging anion (see ref. [34]). Only a
few examples of metal-free cascade complexes have been described,
see: M. A. Hossain, P. Morehouse, D. Powell, K. Bowman-James,
Inorg. Chem. 2005, 44, 2143–2149, and references therein.
[19] M. Mꢀnand, I. Jabin, Org. Lett. 2009, 11, 673–676.
[25] I. Jabin, O. Reinaud, J. Org. Chem. 2003, 68, 3416–3419.
[26] Calix[6]tube 3 is insoluble in pure CD3OD.
[27] Similarly, the inclusion of pyrrolidin-2-one (Pyro) was observed in
CDCl3 at 263 K (highfield signals at d=0.05 and À1.22 ppm). How-
ever, only a trace of the D3h-symmetric complex 3ꢀ
ACHTUNGTERNUN(NG Pyro)2 was ob-
served upon addition of a large excess (175 equiv) of Pyro, which
denotes an extremely low formation constant.
[28] Owing to the broadness of most of the signals even at low T, the
signal corresponding to the NH ureido protons of 3ꢀ
ACHTUNGRTENUN(NG Imi)2 was not
clearly identified.
[29] a) S. Le Gac, X. Zeng, C. Girardot, I. Jabin, J. Org. Chem. 2006, 71,
9233–9236; b) S. Le Gac, M. Luhmer, O. Reinaud, I. Jabin, Tetrahe-
dron 2007, 63, 10721–10730; c) D. Coquiꢄre, S. Le Gac, U. Darbost,
O. Sꢀnꢄque, I. Jabin, O. Reinaud, Org. Biomol. Chem. 2009, 7,
2485–2500.
[20] The bis-calix[6]arenes 3 and 4 display identical Rf values and ESI-
MS spectra.
[21] The syn pattern refers to the unreacted amino and isocyanate
groups on the same side of the macrocycle formed by the first two
linkages, whereas in the anti pattern, the two unreacted groups are
on opposite sides (see the Supporting Information). The syn and
anti patterns lead to compounds 3 and 4, respectively.
[30] S. Le Gac, J. Marrot, O. Reinaud, I. Jabin, Angew. Chem. 2006, 118,
3195–3198; Angew. Chem. Int. Ed. 2006, 45, 3123–3126.
[31] In CD3CN/CDCl3 (1:2), the association constant Ka was still estimat-
2À
ed to be <1mÀ1 for SO4
.
[22] For previous examples of self-threaded rotaxanes with calix[6]ar-
enes, see: a) S. Kanamathareddy, C. D. Gutsche, J. Am. Chem. Soc.
1993, 115, 6572–6579; b) A. Casnati, P. Jacopozzi, A. Pochini, F.
Ugozzoli, R. Cacciapaglia, L. Mandolini, R. Ungaro, Tetrahedron
1995, 51, 591–598; a few examples of self-threaded molecules with
homo-oxacalix[3]arene and calix[4]arene subunits have also been
described, see: c) Z. Zhong, A. Ikeda, S. Shinkai, J. Am. Chem. Soc.
1999, 121, 11906–11907; d) T. Tuntulani, S. Poompradub, P. Thavor-
nyutikarn, N. Jaiboon, V. Ruangpornvisuti, N. Chaichit, Z. Asfari, J.
Vicens, Tetrahedron Lett. 2001, 42, 5541–5544.
[32] a) S. Blanchard, M.-N. Rager, A. F. Duprat; O. Reinaud, New J.
Chem. 1998, 22, 1143–1146; O. Reinaud, New J. Chem. 1998, 22,
1143–1146; b) U. Darbost, M.-N. Rager, S. Petit, I. Jabin, O. Rein-
aud, J. Am. Chem. Soc. 2005, 127, 8517–8525.
+
[33] This trace of included PrNH3 likely corresponds to a trace of the
ternary complex 3ꢀ
(PrNH3+)XÀ.
ACHTUNGTRENNUNG
[34] For a review on cascade complexes with dimetallic cryptates, see: V.
Amendola, L. Fabbrizzi, C. Mangano, P. Pallavicini, A. Poggi, A. Ta-
glietti, Coord. Chem. Rev. 2001, 219–221, 821–837.
[35] In the case of (DodecNH3+)2SO42À, only 0.6 equiv of the salt was ex-
tracted even after prolonged heating (see the Supporting Informa-
tion).
[23] See the Supporting Information.
[24] Indeed, the addition of a small amount (3 mL) of water to 3 in
CDCl3 led to a well-resolved 1H NMR spectrum very similar to the
one obtained in CD3OD/CDCl3 (3:1) (see below), that is, resonances
indicative of a flattened averaged cone conformation with introvert-
ed OMe groups and downfield NH ureido protons (see the Support-
ing Information). These data are in agreement with the fact that a
[36] The signal of C=O was not clearly identified.
Received: May 4, 2010
Published online: September 8, 2010
Chem. Eur. J. 2010, 16, 11712 – 11719
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11719