Tuning the strength and selectivity of ion-pair recognition using heteroditopic calix[4]arene-based receptors

Article abstract of DOI:10.1039/b615873k

The syntheses, characterisation and ion binding properties of two novel heteroditopic calix[4]arene receptors are reported. These systems were found to demonstrate cooperative binding of certain ion-pairs, with the selectivity depending critically on the structure of the receptors. Furthermore, a macrocyclic effect for ion-pair recognition was observed to operate. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Full text of DOI:10.1039/b615873k

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/njc | New Journal of Chemistry
Tuning the strength and selectivity of ion-pair recognition using
heteroditopic calix[4]arene-based receptorswz
Michael D. Lankshear, Ian M. Dudley, Kar-Man Chan and Paul D. Beer*
Received (in Durham, UK) 1st November 2006, Accepted 28th November 2006
First published as an Advance Article on the web 20th December 2006
DOI: 10.1039/b615873k
The syntheses, characterisation and ion binding properties of two novel heteroditopic
calix[4]arene receptors are reported. These systems were found to demonstrate cooperative
binding of certain ion-pairs, with the selectivity depending critically on the structure of the
receptors. Furthermore, a macrocyclic effect for ion-pair recognition was observed to operate.
was investigated as this should impact significantly on the ion-
Introduction
pair binding affinity.
The field of ion-pair recognition has attracted much attention
in recent years, stimulated by the multiple possible applica-
tions of ditopic receptors for salt solubilisation, extraction,
and membrane transport,1 and the opportunity for the fine
tuning of their strengths and selectivities of association.2 In
particular, the preparation of receptors capable of the recogni-
tion of contact ion-pairs is an attractive prospect, as this
avoids the otherwise energetically unfavourable separation
of the two ions.3 The design of these receptors normally hinges
on the proximal arrangement of known cation and anion
binding domains within a given molecular framework. The
calix[4]arene structural motif represents an attractive anchor
point for such systems, owing to its ease of functionalisation
and high degree of preorganisation.4,5
Taking the above considerations into account, we detail
herein the syntheses and binding properties of new hetero-
ditopic calix[4]arene bisester compounds 2 and 3 (Fig. 1),
which are shown to demonstrate biased selectivity towards
sodium and lithium containing ion pairs, as well as a macro-
cyclic effect in ion-pair recognition.
Receptor syntheses
The synthesis of receptor 2 was achieved through further
reaction of the previously described calix[4]arene bisamine
Recently, we reported the heteroditopic calix[4]diquinone–
isophthalamide receptor 1 (Fig. 1), which was shown to be
capable of the cooperative recognition of contact alkali metal
and ammonium ion-pairs.6 Such a recognition process was
mediated by placing the calix[4]diquinone7 cation and iso-
phthalamide8,9 anion binding sites within the confines of a
single macrobicycle. Importantly, the ion pair recognition was
shown to occur in a manner consistent with AND logic,10
whereby the receptor displayed no affinity for either of selected
free ions, binding only to the contact ion-pair species. The
receptor was not particularly discriminatory between the ion-
pairs of different cations, however.
In order to address this issue of cation selectivity, it was
decided to alter the nature of the cation binding unit appended
to the calix[4]arene motif. Lower-rim ester-substituted calix[4]-
arene derivatives have been demonstrated to enforce selectivity
for sodium cations,11 and this unit was consequently used in
these studies. Additionally, the impact of the preorganisation
of the anion binding site, whether chelating or macrocyclic,
Inorganic Chemistry Laboratory, South Parks Road, Oxford, UK.
E-mail: paul.beer@chem.ox.ac.uk; Fax: (+44) 01865 272960
Tel: (+44) 01865 285142
w George Gokel 60th birthday special issue article.
z Electronic supplementary information (ESI) available: Synthesis and
brief characterisation for previously described compounds, as well as
description of titration protocols. See DOI: 10.1039/b615873k
Fig. 1 Calix[4]diquinone receptor 1 and calix[4]arene diester recep-
tors 2 and 3.
ꢀc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
684 | New J. Chem., 2007, 31, 684–690

View Article Online
Fig. 2 Perturbations of the aliphatic region of the 1H NMR spectrum
of 2 on addition of sodium cation: (a) 2 and, (b) 2 ꢁ NaClO4. Solvent:
acetone-d6, 298 K. For proton assignments see Fig. 1.
Scheme 1 Synthesis of receptor 2.
compound 4 (Scheme 1).6 Condensation of this bisamine with
an excess of hexanoyl chloride and triethylamine in dichloro-
methane gave the bisamide compound 5 in 84% yield. Heating
this species under reflux in acetone with ethyl bromoacetate
and potassium carbonate for four days gave the desired
receptor 2 in 78% yield.
Ion binding results
Anion and group 1 cation binding properties of the new
receptors were studied by 1H NMR spectroscopic methods.
The addition of sodium or lithium perchlorate salts to a
solution of receptor 2 in acetone-d6 induced significant
changes in the aliphatic region of the spectrum (Fig. 2),
indicating an interaction of the components. The stoichiome-
try of interaction was verified to be 1 : 1, through a Job Plot
analysis, and the change in chemical shift of the signal arising
from the ethyl ester methylene proton f was monitored as a
function of added cation concentration to obtain association
constant data using the winEQNMR computer program
(Table 1).13 It may clearly be observed from these data that
2 binds sodium strongly in this solvent, lithium less strongly,
and displays no affinity for the larger alkali metal cation
potassium, or ammonium. When sodium or lithium perchlo-
rate were added to a 1 : 1 solution of 2 and TBA chloride or
bromide salts, however, precipitation was observed, prevent-
ing the calculation of association constant data.
Receptor 3 required a slightly longer preparative route
(Scheme 2). The disubstitution of para-tert-butylcalix[4]arene
with two equivalents of the known compound 612 was accom-
plished in 60% yield by heating the two components under
reflux in acetonitrile for four days, in the presence of potas-
sium carbonate. The reductive cleavage of the phthalimide
protecting functionality was then carried out by heating 7
under reflux in ethanol in the presence of excess hydrazine to
give the bisamine compound 8 in 95% yield. Under high
dilution conditions, condensation of 8 with isophthaloyl
dichloride and triethylamine in dichloromethane gave the
macrobicyclic species 9 in 69% yield, following silica gel
chromatographic purification. Finally, 3 was prepared in
55% yield by heating 9 under reflux in acetonitrile, in the
presence of an excess of ethyl bromoacetate and potassium
carbonate.
The anion binding properties of 2 were therefore studied in
an alternative solvent, acetonitrile-d3. It was found that the
addition of TBA halide salts induced small downfield shifts in
the signals arising from the amide protons (m) of the receptor.
Importantly, the chemical shift change induced on addition of
Both new compounds 2 and 3 were characterised by NMR
spectroscopy, elemental analysis and electrospray mass spec-
trometry (see Experimental section).
Scheme 2 Formation of cyclic receptor 3. Reagents and conditions: (a) 6, K2CO3, CH3CN, heat, 4 d; (b) N2H4 ꢁ H2O, EtOH, heat, 16 h; (c)
isophthaloyl dichloride, NEt3, CH2Cl2, 16 h; (d) ethyl bromoacetate, K2CO3, CH3CN, heat, 4 d.
ꢀc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
New J. Chem., 2007, 31, 684–690 | 685

View Article Online
Table 1 Cation binding properties of receptor 2a
Table 2 Anion binding properties of receptor 2a
Li+ b
Na+ b
ꢂ0.064
K+ c
NH4
2
2 ꢁ NaClO4
DdNH/ppm
+ c
Cation
DdNH/ppm
K11/Mꢂ1
K11/Mꢂ1
DdH/ppm
K11/Mꢂ1
a
0.078
470
ꢂ0.002
ꢂ0.003
d
d
3500
—
—
TBACl
TBABr
TBAI
0.055
0.045
0.003
o5
0.203
0.139
0.016
20
20
Solvent: acetone-d6, 298 K. DdH (ppm) values correspond to the
chemical shift change of the ester methylene proton signal (f) induced
on addition of one equivalent of cation. Association constant errors
10
b
—
b
—
a
Solvent: CD3CN, 298 K. DdNH (ppm) values correspond to the
chemical shift change of the amide proton signal (m) induced on
addition of one equivalent of anion. Association constant errors
b
c
o10%. Cation added as perchlorate salt. Cation added as hexa-
d
fluorophosphate salt. No interaction could be inferred.
b
o10%. No interaction could be inferred.
of lithium binding, an enhancement both in the induced
chemical shift and resulting association constant was ob-
served, indicating that bromide enhances the affinity of 3 for
this cation. For sodium, however, the chemical shift change
and association constant obtained were reduced in the pre-
sence of bromide, indicating that this anion exerts an anti-
cooperative effect on cation binding. This is interesting as
sodium enhances the binding of bromide (vide infra). It is also
notable that addition of sodium or lithium cations to a 1 : 1
solution of 3 and TBA chloride did not reveal any cation
binding interaction.
one equivalent of halide anion was larger in the case of
2 ꢁ NaClO4 than for 2 alone, suggesting that the bound cation
enhances anion recognition. The dependence of the amide
proton chemical shift on added anion concentration (Fig. 3)
was used to obtain association constant data (Table 2).13 It
can be seen that, although the interaction of 2 with halide
anions in this solvent is weak, a definite cooperative enhance-
ment of anion recognition is affected by the presence of
sodium cations. No such enhancement was observed for
2 ꢁ KPF6, with the chemical shift changes observed being
consistent with first the ion-pair association of potassium
and halide anion remote of the receptor, followed by the
subsequent binding of the ‘free’ anion by 2.
The anion binding properties of receptor 3 were probed in
acetone-d6. The addition of TBA anion salts induced down-
field shifts in the amide (o) and isophthalyl (p) protons,
revealing a 1 : 1 receptor/anion stoichiometry. Treatment of
the concentration dependence of these shifts on added anion
salt yielded winEQNMR association constant values (Table
4).13 These show that 3 binds halide anions in the expected
selectivity order of Clꢂ 4 Brꢂ 4 Iꢂ.8
In the presence of one equivalent of cation the binding
properties of 3 were considerably modulated. The addition of
chloride to 3 ꢁ M+ did not initially lead to any significant
changes in the 1H NMR spectrum, but after one equivalent of
For 3, as in the case of 2, it was possible to ascertain the
cation binding strength of the bisester cavity by 1H NMR
methods, in acetone-d6. As expected, the addition of lithium
and sodium perchlorate induced perturbations in the aliphatic
1
region of the H NMR spectrum of the receptor, but was not
affected by the addition of potassium, rubidium or ammo-
nium. Job Plot analysis revealed that this had 1 : 1 stoichio-
metry, and through monitoring the dependence of the
chemical shift of the ester CH2CO f proton on added cation
concentration (Fig. 4), it was possible to obtain winEQNMR-
derived association constants (Table 3).13 These confirm that
the receptor is selective for sodium and lithium cations.
Furthermore, when lithium and sodium perchlorate were
added to a 1 : 1 mixture of 3 and TBA bromide, it was found
that the cation binding behaviour was influenced. In the case
Fig. 3 Dependence of chemical shift of the amide proton signal of 2
on added TBA bromide concentration, in the presence and absence of
one equivalent of sodium perchlorate; lines correspond to theoretical
1 : 1 anion binding isotherms. Solvent: acetone-d6 at 298 K. Endpoint
corresponds to ten equivalents of added anion.
Fig. 4 Dependence of the chemical shift of the ester CH2CO (f)
proton of 3 on added cation concentration, in the presence and
absence of one equivalent of TBA bromide guest; lines correspond
to theoretical 1 : 1 cation binding isotherms. Solvent: acetone-d6,
298 K.
ꢀc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
686 | New J. Chem., 2007, 31, 684–690

View Article Online
Table 3 Cation binding properties of receptor 3a
3
3 ꢁ TBABr
DdH/ppm
DdH/ppm
K11/Mꢂ1
K11/Mꢂ1
LiClO4
NaClO4
KPF6
NH4PF6
a
0.296
ꢂ0.071
ꢂ0.003
0.004
2840
3350
—
0.383
ꢂ0.041
ꢂ0.007
ꢂ0.008
4104
740
b
b
—
—
b
b
—
Solvent: acetone-d6, 298 K. DdH (ppm) values correspond to the
chemical shift change of the ester methylene proton signal (f) induced
on addition of one equivalent of cation Association constant errors
b
o10%. No interaction could be inferred.
Fig. 5 Perturbations in the aromatic region of the 1H NMR spectrum
of 3 on the addition of one equivalent of (a) TBABr, (b) nothing, (c)
NaClO4 and (d) NaBr. Solvent: acetone-d6, 298 K.
anion had been added downfield shifts in the amide and
isophthalyl protons were observed, consistent with the binding
of chloride. This was ascribed to the sequestration of cation by
the first equivalent of added anion, followed by unassisted
binding of the remainder. Although not accompanied by
precipitation in this case, the behaviour is consistent with that
observed for receptor 2 in this solvent. Similar behaviour was
observed when TBA bromide or iodide were added to 1 : 1
mixtures of 3 and potassium, rubidium or ammonium salts;
this is due to ion-pairing rather than sequestration as these
cations are not bound by the receptor in the first place.
Conversely, on the addition of TBA bromide and iodide
salts to a 1 : 1 mixture of 3 and lithium or sodium cations,
significant downfield shifts in the amide and isophthalyl pro-
tons o and p were observed (Fig. 5). These were larger than the
corresponding changes in chemical shift induced on addition
of anion to the free receptors, suggesting an increased strength
of interaction. Job Plot analysis indicated a 1 : 1 binding
stoichiometry, and by monitoring the dependence of the
chemical shift of the amide proton (o) as a function of added
anion concentration it was possible to obtain winEQNMR-
derived association constant values (Table 4).13 These anion
association constants indicated a cooperative binding effect for
lithium and sodium bromide and iodide. Indeed, anion affinity
is increased by nearly an order of magnitude.
bind ion pairs in a cooperative fashion, given the correct
conditions. This can be lent credence by a consideration of
the results as a function of the potential equilibria that may
occur in solution, summarised in Fig. 6.14 For the case of
‘pure’ anion binding, it is normally assumed that when the
counter-cation is non-coordinating (such as TBA), Kip, K2 and
K3 are negligible; thus any measurable changes in spectra of
the receptor consistent with binding are defined by K1. The
same applies to cation binding in the presence of a non-
coordinating anion (K3).
When both cation and anion are coordinating it is no longer
possible to neglect the other equilibria in Fig. 6. Therefore, on
addition of for example halide anion to a 1 : 1 mixture of
ditopic receptor and metal salt of a non-coordinating anion,
the behaviour observed depends on all four of these processes.
If the system is an appropriately designed ditopic receptor,
then the observed anion association constant, Kobs(anion),
which is itself a conflation of K1 and K2, will be larger than
that observed when the counter-cation is non-coordinating,
demonstrating that the receptor behaves in a cooperative
manner. If the system is not ideally suited to the binding of
an ion-pair (K2), then the competing equilibrium defined by
Kip will result in a Kobs reduced in comparison to that observed
Discussion
in the absence of a coordinating counter-cation. Should Kip be
the dominant contributor, then the changes observed will be
consistent primarily with sequestration of the metal cation,
followed by binding of the free anion defined by K1. Needless
to say, the solvent is highly influential on which situation
dominates.
The anion, cation and ion-pair binding observations outlined
above demonstrate that both of these ditopic receptors will
Table 4 Anion binding properties of receptor 3a
TBACl
TBABr
TBAI
DdNH
ppm
/
K11
/
DdNH
ppm
/
K11
/
DdNH
ppm
/
K11/
Mꢂ1
Mꢂ1
Mꢂ1
3
1.135
1550
—
0.406
0.975
0.936
0.192
250
2320
2150
0.044
0.205
0.150
0.032
45
420
290
b
3 ꢁ LiClO4 0.037
3 ꢁ NaClO4 0.022
3 ꢁ KPF6 0.007
a
b
—
—
b
b
b
—
—
Solvent: acetone-d6, 298 K. DdNH (ppm) values correspond to the
chemical shift change of the amide proton signal (o) induced on
addition of one equivalent of anion. Association constant errors
b
o10%. No association constant could be determined due to ion-
Fig. 6 Summary of potential solution equilibria on binding ion-pair
pairing phenomena on addition of first equivalent of TBA anion salt.
species.
ꢀc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
New J. Chem., 2007, 31, 684–690 | 687

View Article Online
All three of these potential behaviours are observed in the
binding properties of 2 and 3. For 2, a modest cooperative
interaction can be inferred in acetonitrile-d3 solution from the
halide binding properties in the presence and absence of
sodium cations, but the association constants observed were
very small. Investigations in the less polar solvent acetone-d6
were not possible due to precipitation problems.
vacuum in a desiccator containing phosphorus pentaoxide and
self-indicating silica. Elemental analyses were carried out by
the service at the Inorganic Chemistry Laboratory, University
of Oxford. Mass spectra were obtained on a Micromass LCT
(ESMS) instrument. NMR spectra were recorded on a Varian
Mercury 300, Oxford Instruments Venus 300, or Varian Unity
Plus 500 spectrometer, with the solvent as serving as the lock
and internal reference. Coupling constants (J values) quoted
below are in Hertz.
Receptor 3 demonstrated somewhat different binding prop-
erties towards ion pairs. For chloride-containing species, anti-
cooperative behaviour consistent with strong ion-pairing was
observed, as in the case of 2 in acetone-d6; this was ascribed to
ion-sequestration phenomena. For the association of bromide
and iodide, however, a definite cooperative effect was seen,
indicating a significant contribution of K2 to the observed
anion binding constant. This cooperativity extended to the
binding of lithium, but interestingly sodium binding was found
to be inhibited by the presence of bromide ion. This latter
phenomenon is not easy to rationalise. For the larger alkali
metal cation potassium, and ammonium, the behaviour of 3
was decidedly anti-cooperative in nature, such that the pre-
sence of these cations inhibited anion binding completely. This
is because the receptor does not bind these cations (K3 tends to
zero).
Syntheses
Receptor 2. A solution of compound 5 (0.43 g, 0.42 mmol),
anhydrous K2CO3 (0.29 g, 2.1 mmol) and ethyl 2-bromoace-
tate (0.28 mL, 2.52 mmol) was heated under reflux in acetone
(10 mL) for 4 days, under a nitrogen atmosphere. The reaction
mixture was then allowed to cool to room temperature,
filtered, and the precipitate washed with copious CH2Cl2.
The combined filtrate was subsequently concentrated in vacuo,
and the resulting off-white crude product purified by silica gel
chromatography (CH2Cl2–MeOH 95 : 5 v/v) to give 2 as a
white solid (0.40 g, 78%) (Found: C, 70.5; H, 8.6; N, 2.2.
1
2
C72H106N2O12 ꢁ CH2Cl2 requires: C, 70.6; H, 8.7; N, 2.3%);
d
H (300 MHz; CDCl3) 0.87 (6H, t, 3J = 6.7, Hr), 1.04 (18H, s,
As a result, receptor 3 provides an example of a system
wherein the ion-pair cooperativity is highly selective for
certain salts, namely the bromide and iodide salts of sodium
and lithium, while displaying little or no affinity for other ion
pairs. Such a selectivity may be very useful in the design of
molecular devices, and suggests a use for ditopic receptors in
the fine-tuning of ion-recognition processes. Furthermore,
although impossible to compare directly the binding proper-
ties of the two receptors detailed here due to the different
solvents used to measure their anion association constants, it is
nonetheless evident that 3, wherein the anion and cation
binding sites may be considered as being enclosed within the
same macrocycle motif, behaves as a superior binder for ion-
pairs, being less prone to solvent ion-pairing or precipitation
effects. This suggests a macrocyclic effect for ion-pair recogni-
tion, which is in turn consistent with the binding of both ions
as a single unit, or a contact ion pair.
H
a/b), 1.05 (18H, s, Ha/b), 1.27 (14H, m, Hh, Hp and Hq), 1.61
(4H, m, Ho), 2.14 (4H, t, 3J = 7.6, Hn), 3.15 (4H, d, 2J = 12.9,
3
3
H
e,out), 3.44 (4H, t, J = 4.7, Hk), 3.56 (4H, t, J = 4.7, Hl),
3.92 (4H, t, 3J = 5.3, Hj), 4.20 (8H, m, Hi and Hg), 4.59 (4H, d,
2J = 12.9, He,in), 4.68 (4H, s, Hf), 6.29 (2H, br, Hm), 6.75 (4H,
s, Hc/d), 6.79 (4H, s, Hc/d); dC (75.5 MHz; CDCl3) 13.97, 14.23,
22.43, 25.45, 31.33, 31.41, 31.49, 31.51, 33.85, 36.61, 39.33,
60.62, 69.84, 70.46, 71.30, 72.99, 76.63, 125.12, 125.33, 133.23,
133.67, 138.19, 145.24, 152.49, 153.58, 170.37, 173.33; m/z
(ES+): 1191.78 (M + H+), 1213.76 (M + Na+).
Receptor 3. Compound 9 (0.20 g, 0.19 mmol), ethyl 2-
bromoacetate (0.09 g, 0.5 mmol) and K2CO3 (0.06 g, 0.5
mmol) were suspended in CH3CN (10 mL), and the mixture
heated under reflux under a nitrogen atmosphere for 18 h. The
reaction mixture was allowed to cool, then filtered. The
precipitate was washed with copious CH2Cl2, and the com-
bined filtrate was reduced in vacuo. The resulting crude
product was purified by silica gel chromatography
(CHCl3–MeOH 90 : 10) to give the white solid 3 (0.12 g,
55%) (Found: C, 66.0; H, 7.5; N, 1.9. C72H96N2O14 ꢁ CHCl3
requires: C, 65.8; H, 7.3; N, 2.1%); dH (300 MHz, CDCl3) 0.90
Conclusions
The two new receptors 2 and 3 demonstrate that the strength
and selectivity of ion-pair recognition may be tuned by the
appropriate design of cation and anion binding sites within a
given motif. In particular, the inclusion of these two sites
within a macrocycle appears to support a contact ion-pair
recognition process which maximises the electrostatic forces
between cation and anion within the receptor ꢁ MX complex,
and therefore the cooperativity of interaction.
3
(18H, s, Ha/b), 1.09 (18H, s, Ha/b), 1.15 (6H, t, J = 7.5, Hh),
3.06 (4H, d, 2J = 12.9, He,out), 3.58 (16H, m, Hk, Hl, Hm and
2
Hn), 4.02 (12H, m, Hi, Hj and Hg), 4.43 (4H, d, J = 12.9,
He,in), 4.58 (4H, s, Hf), 6.59 (4H, s), 6.81 (4H, s, Hc/d), 7.47
3
(3H, m, Ho and Hr), 8.02 (2H, d, J = 7.9, Hq), 8.13 (1H, s,
Hp); dC (75.5 MHz; CDCl3) 14.12, 30.99, 31.23, 31.49, 31.63,
33.75, 40.04, 60.77, 70.16, 70.28, 70.52, 72.44, 124.08, 125.11,
125.24, 125.38, 131.17, 131.23, 132.73, 134.06, 134.17, 134.47,
143.47, 145.06, 166.90, 189.44, 192.31. m/z (ES+) 1235.63
(M + Na+).
Experimental
Materials and instrumentation
All commercial grade chemicals were used without further
purification. TBA anion salts, as well as hexafluorophosphate
and perchlorate cation salts were stored prior to use under
Calixarene bishexylamide 5. A solution of compound 4 (0.5
g, 0.61 mmol), and NEt3 (0.34 mL, 2.43 mmol) in dry CH2Cl2
(50 mL) was cooled to 0 1C, then a solution of hexanoyl
ꢀc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
688 | New J. Chem., 2007, 31, 684–690

View Article Online
chloride (0.26 mL, 1.83 mmol) in dry CH2Cl2 (50 mL) was
added dropwise, under a nitrogen atmosphere. Once addition
was complete, the reaction mixture was allowed to warm to
room temperature, and stirred for a further 16 h under an
atmosphere of nitrogen. The reaction mixture was then
washed consecutively with 1 M HCl(aq) (2 ꢃ 100 mL), 1 M
NaOH(aq) (2 ꢃ 100 mL), H2O (100 mL) and saturated NaCl(aq)
(100 mL). The organic phase was subsequently dried over
MgSO4, filtered, and the solution concentrated in vacuo to
afford compound 5 as a white solid (0.52 g, 84%); dH (300
MHz, CDCl3) 0.83 (6H, t, 3J = 7.1, CH2CH3), 1.10 (18H, s, t-
Bu), 1.17 (8H, m, CH2CH2CH3), 1.22 (18H, s, t-Bu), 1.43 (4H,
m, NCOCH2CH2), 1.84 (4H, t, 3J = 7.0, NCOCH2), 3.33 (4H,
d, 2J = 12.9, ArCHinHoutAr), 3.60 (4H, t, 3J = 4.1,
CH2CH2N), 3.73 (4H, m, CH2N), 3.99 (4H, m, CH2CH2OAr),
4.20 (4H, m, CH2OAr), 4.38 (4H, d, 2J = 12.9, ArCHin
HoutAr), 6.97 (4H, s, ArH), 7.01 (4H, s, ArH), 7.24 (2H, br,
NH), 8.38 (2H, s, OH); dC (75.5 MHz; CDCl3) 14.01, 22.44,
25.51, 31.15, 31.28, 31.53, 31.97, 33.85, 34.12, 36.09, 39.53,
69.80, 70.09, 75.14, 76.22, 125.39, 125.88, 128.41, 133.31,
142.64, 147.51, 149.20, 149.80, 173.97; m/z (ES+): 1019.71
(M + H+), 1041.68 (M + Na+).
2J = 13.1, ArCHinHoutAr), 6.58 (s, 4H, ArH), 7.02 (4H, s,
ArH); m/z (ES+): 911.61 (M + H+), 937.58 (M + Na+).
Calixarene macrobicycle 9. Separate solutions of 8 (1.0 g, 1.1
mmol) in dry CH2Cl2 (100 mL) and isophthaloyl chloride
(0.22 g, 1.1 mmol) in dry CH2Cl2 (100 mL) were added
dropwise, simultaneously, to a stirred solution of NEt3
(1 mL, excess) in dry CH2Cl2 (800 mL) over the period of 1
h. The reaction mixture was then left to stir for 18 h before
being reduced in vacuo to approximately 150 mL in volume.
This solution was washed with 1 M HCl(aq) (150 mL), H2O
(100 mL), 1 M NaOH(aq) (100 mL) and saturated NaCl(aq)
(100 mL), then dried over MgSO4 and reduced in vacuo.
Purification by silica gel chromatography (EtOAc–acetone
95 : 5) gave the white solid 9 (0.79 g, 69%) (Found: C, 71.6;
H, 7.9; N, 2.5. C64H84N2O10 ꢁ 2H2O requires: C, 71.4; H, 8.2;
N, 2.6%); dH (300 MHz; CDCl3) 0.89 (18H, s, t-Bu), 1.30
2
(18H, s, t-Bu), 3.25 (4H, d, J = 13.1, ArCHinHoutAr), 3.69
(20H, m, CH2OCH2CH2OCH2CH2N), 4.03 (4H, m, ArOCH2),
4.28 (4H, d, 2J = 13.1, ArCHinHoutAr), 6.70 (4H, s, calixArH),
3
7.05 (4H, s, calixArH), 7.58 (1H, t, J = 7.6, ArH), 7.69 (2H,
3
br, NH), 8.11 (2H, d, J = 7.6, ArH), 8.39 (1H, s, ArH). m/z
(ES+): 1041.63 (M + H+), 1063.60 (M + Na+).
Calixarene diphthalimide 7. para-Tert-butylcalix[4]arene
(4.70 g, 7.24 mmol) and K2CO3 (2.10 g, 15.2 mmol) were
suspended in dry CH3CN (200 mL), and stirred under a
nitrogen atmosphere for 30 min. Compound 6 (7.85 g, 18.1
mmol) was then added, and the resulting mixture was heated
under reflux under a nitrogen atmosphere for 4 days. After this
time, the suspension was allowed to cool, and the solvent
carefully removed in vacuo to give a sticky solid material which
was triturated with 1 M HCl(aq) (200 mL). The resulting
suspension was extracted with CH2Cl2 (3 ꢃ 100 mL), and
the organic extracts combined, washed with H2O (2 ꢃ 100
mL), dried over MgSO4, filtered and concentrated in vacuo.
Purification by silica gel chromatography (CHCl3–acetone 95 :
5) gave the white solid 7 (4.97 g, 60%); dH (300 MHz, CDCl3)
0.93 (18H, s, t-Bu), 1.26 (18H, s, t-Bu), 3.24 (4H, d, 2J = 13.2,
ArCHinHoutAr), 3.72 (12H, m, ArOCH2CH2OCH2CH2O),
3.85 (4H, t, 3J = 6.6, ArOCH2), 3.89 (4H, t, 3J = 4.6,
CH2CH2N), 4.07 (4H, t, 3J = 4.6, CH2N), 4.31 (4H, d, 2J
= 13.2, ArCHinHoutAr), 6.75 (4H, s, calixArH), 7.07 (4H, s,
calixArH), 7.18 (2H, s, OH), 7.67 (2H, dd, 3J = 5.5, 4J = 3.0,
PhthH), 7.80 (2H, dd, 3J = 5.5, 4J = 3.0, PhthH); m/z (ES+):
1193.61 (M + Na+).
Acknowledgements
We would like to thank the EPSRC and GE Healthcare,
Amersham for the provision of a CASE-supported student-
ship (M. L.).
References
1 (a) D. M. Rudkevich, J. D. Mercer-Chalmers, W. Verboom, R.
Ungaro, F. de Jong and D. N. Reinhoudt, J. Am. Chem. Soc.,
1995, 117, 612; (b) N. Pelizzi, A. Casnati, A. Friggeri and R.
Ungaro, J. Chem. Soc., Perkin Trans. 2, 1998, 1307; (c) F. W.
Kotch, V. Sidorov, Y.-F. Lam, K. J. Kayser, H. Li, M. S. Kaucher
and J. T. Davis, J. Am. Chem. Soc., 2003, 125, 15140; (d) P. A.
Tasker and V. Gasperov, in Macrocyclic Chemistry–Current
Trends and Future Perspectives, ed. K. Gloe, Springer, Heidelberg,
2005, p. 365; (e) S. G. Galbraith, L. F. Lindoy, P. A. Tasker and P.
G. Plieger, Dalton Trans., 2006, 1134; (f) A. Cazacu, C. Tong, A.
van der Lee, T. M. Fyles and M. Barboiu, J. Am. Chem. Soc., 2006,
128, 9541.
2 (a) P. R. A. Webber and P. D. Beer, Dalton Trans., 2003, 2249; (b)
R. Custelcean, H. D. Laetitia, B. A. Moyer, J. L. Sessler, W.-S.
Cho, S. Gross, G. W. Bates, S. J. Brooks, M. E. Light and P. A.
Gale, Angew. Chem., Int. Ed., 2005, 44, 2537; (c) A. Mele, P.
Metrangolo, H. Neukirch, T. Pilati and G. Resnati, J. Am. Chem.
Soc., 2005, 127, 14972; (d) J. Gong and B. C. Gibb, Chem.
Commun., 2005, 1393; (e) F. Oton, A. Tarraga, A. Espinosa, M.
D. Velasco and P. Molina, Dalton Trans., 2006, 30, 3685; (f) J. L.
Sessler, P. A. Gale and W.-S. Cho, Anion Receptor Chemistry,
RSC, Cambridge, 2006.
3 (a) J. M. Mahoney, A. M. Beatty and B. D. Smith, J. Am. Chem.
Soc., 2001, 123, 5847; (b) J. M. Mahoney, A. M. Beatty and B. D.
Smith, Inorg. Chem., 2004, 43, 5902; (c) J. M. Mahoney, K. A.
Stucker, H. Jiang, I. Carmichael, N. R. Brinkmann, A. M. Beatty,
B. C. Noll and B. D. Smith, J. Am. Chem. Soc., 2005, 127, 2922; (d)
B. D. Smith, in Macrocyclic Chemistry: Current Trends and Future
Perspectives, ed. K. Gloe, Springer, Dordrecht, 2005, p. 137; (e) M.
Cametti, M. Nissinen, A. Dalla Cort, L. Mandolini and K.
Rissanen, J. Am. Chem. Soc., 2005, 127, 3831.
Calixarene bisamine 8. Compound 7 (3.40 g, 2.9 mmol) was
suspended in EtOH (70 mL), and hydrazine monohydrate (3
mL, excess) added. This suspension was then heated under
reflux for 18 h, during which time the white suspension was
seen to dissolve. The reaction mixture was then allowed to cool
to room temperature, then added to H2O (200 mL) to give a
white suspension which was extracted with EtOAc (3 ꢃ 50
mL). The organic extracts were combined, dried over MgSO4,
filtered, then concentrated in vacuo to give the white solid 8
(2.51 g, 95%); dH (300 MHz, CDCl3) 0.78 (18H, s, t-Bu), 1.23
(18H, s, t-Bu), 3.06 (4H, m, CH2NH2), 3.24 (4H, d, 2J = 13.1,
ArCHinHoutAr), 3.76 (12H, m, OCH2CH2OCH2CH2N), 3.85
(4H, m, ArOCH2CH2), 4.12 (4H, m, ArOCH2), 4.26 (4H, d,
4 (a) Calixarenes In Action, ed. L. Mandolini and R. Ungaro,
Imperial College Press, London, UK, 2000; (b) Calixarenes 2001,
ed. Z. Asfari, V. Bohmer, J. Harrowfield and J. Vicens, Kluwer,
ꢀc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
New J. Chem., 2007, 31, 684–690 | 689

View Article Online
Dordrecht, Netherlands, 2001; (c) P. Lhotak, Top. Curr. Chem.,
2005, 255, 65; (d) P. D. Beer and S. E. Matthews, Supramol. Chem.,
2005, 17, 411.
5 (a) P. Tongraung, N. Chantarasiri and T. Tuntulani, Tetrahedron
Lett., 2002, 44, 29; (b) S. O. Kang and K. Y. Nam, Bull. Korean
Chem. Soc., 2002, 23, 640; (c) A. Arduini, E. Brindani, G. Giorgi,
A. Pochini and A. Secchi, J. Org. Chem., 2002, 67, 6188; (d) G.
Tumcharern, T. Tuntulani, S. J. Coles, M. B. Hursthouse and J. D.
Kilburn, Org. Lett., 2003, 5, 4971; (e) A. J. Evans and P. D. Beer,
Dalton Trans., 2003, 4451.
8 (a) K. Kavallieratos, S. R. de Gala, D. J. Austin and R. H.
Crabtree, J. Am. Chem. Soc., 1997, 119, 2325; (b) K. Kavallieratos,
C. M. Bertao and R. H. Crabtree, J. Org. Chem., 1999, 64, 1675.
9 P. A. Gale, Acc. Chem. Res., 2006, 39, 465.
10 (a) A. P. de Silva, H. Q. N. Gunaratne and C. P. McCoy, J. Am.
Chem. Soc., 1997, 119, 7891; (b) D. C. Magri, G. J. Brown, G. D.
McClean and A. P. de Silva, J. Am. Chem. Soc., 2006, 128, 4950.
11 (a) F. Arnaud-Neu, E. M. Collins, M. Deasy, G. Ferguson, S. J.
Harris, B. Kaitner, A. J. Lough, M. A. McKervey, E. Marques, B.
L. Ruhl, M.-J. Schwing-Weill and E. M. Seward, J. Am. Chem.
Soc., 1989, 111, 8681; (b) T. Nabeshima, T. Saiki, J. Iwabuchi and
S. Akine, J. Am. Chem. Soc., 2005, 127, 5507.
6 M. D. Lankshear, A. R. Cowley and P. D. Beer, Chem. Commun.,
2006, 612.
7 (a) P. D. Beer, P. A. Gale, Z. Chen, M. G. B. Drew, J. A. Heath,
M. I. Ogden and H. R. Powell, Inorg. Chem., 1997, 36, 5880; (b) M.
Gomez-Kaifer, P. A. Reddy, C. D. Gutsche and L. Echegoyen, J.
Am. Chem. Soc., 1997, 119, 5222.
12 S. Botros, A. W. Lipkowski, A. E. Takemori and P. S. Portoghese,
J. Med. Chem., 1986, 29, 874.
13 M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311.
14 R. Shukla, T. Kida and B. D. Smith, Org. Lett., 2000, 2, 3099.
ꢀc
This journal is the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007
690 | New J. Chem., 2007, 31, 684–690