A bifunctional calixarene designed for immobilisation on a natural polymer and for metal complexation

Article abstract of DOI:10.1016/S0040-4039(02)02203-7

The present work describes the multi-step synthesis of a new bifunctional calix[4]arene designed for grafting on natural polymeric materials, such as water-soluble dextrans, and for metal complexation. The podand was then anchored to the polymer by means

Full text of DOI:10.1016/S0040-4039(02)02203-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8863–8866
A bifunctional calixarene designed for immobilisation on a
natural polymer and for metal complexation
Philippe Engrand and Jean-Bernard Regnouf-de-Vains*
GEVSM, UMR 7565 CNRS-UHP, Faculte´ de Pharmacie, 5, rue Albert Lebrun, F-54001 Nancy Cedex, France
Received 18 September 2002; revised 2 October 2002; accepted 3 October 2002
Abstract—The present work describes the multi-step synthesis of a new bifunctional calix[4]arene designed for grafting on natural
polymeric materials, such as water-soluble dextrans, and for metal complexation. The podand was then anchored to the polymer
by means of a cyanuric linker. The resulting material showed an interesting ability to complex copper(I), giving stable yellowish
light orange solids and aqueous solutions. © 2002 Elsevier Science Ltd. All rights reserved.
The dextrans are natural hydrosoluble carbohydrate
polymers mainly composed of linear chains of glucose
units with a-1,6 linkages. Their bioavailability and their
potent biocompatibility can explain the interest taken
in these structures by various industrial fields. They are
mainly used in the formulation of cosmetics, pharma-
ceuticals, imaging agents and other domains in which
they can act as carriers and/or protective agents for
other compounds. The presence of secondary alcoholic
functions confers to these materials a good ability for
chemical transformation, allowing cross-linking such as
in Sephadex, and the conjugation, via direct methods or
via a pre-activation, of various types of active com-
pounds.1 The use of dextrans in the field of metal
complexation has been essentially developed for the
preparation of new image-enhancing agents, notably
with lanthanides2 and other paramagnetic ions via the
grafting of amine–acetic acid derivatives (DTPA)2 or of
macrocyclic chelates.3
polymers as supporting matrices has not been, as far as
we know, investigated. We thus present here our pre-
liminary results on the synthesis of a new metal-com-
plexing dextran-supported calixarene. Thus, our first
goal was to prepare a polyfunctional calixarene species
bearing a complexing subunit and one anchoring sub-
stituent, both introduced at the lower rim for an easier
synthetic accessibility. Using the base-strength driven
regioselective functionalisation approach,10 the intro-
duction of the anchoring group was performed on the
residual hydroxyl group of the previously described
tris-bipyridyl calixarene podand I.11 Among the various
types of covalent linkages available in the chemistry of
cellulose and parent polymers, we have chosen the
cyanuryl chloride, employed notably in dying processes
or covalent coating of bioactive amino compounds,12
and which can be used as co-reactant in one-pot syn-
thetic pathways.13 Thus, the calixarene was activated by
the introduction of an amino group separated from the
macrocyclic platform by an alkylaromatic propyl-
eneoxyphenyl linker, which was preferred to simple
alkyl ones for analytical reasons, notably for NMR and
UV spectroscopies.
As calixarenes are known to be good candidates for
complexing neutral or ionic organic guests in their
cavities,4 or, when modified by incorporation of chelat-
ing arms, of various metal species,5 we were interested
in the development of materials able to display these
specific behaviours, but in a way that allows the recov-
ery of the complexing agent and its intrinsic properties.
This approach has been developed by immobilisation of
various calixarenes on silica6 and on synthetic poly-
mers,7 or by direct polymerisation of calixarenes
monomers8 but, except for chitosan9 the use of natural
The tris-bipyridyl calixarene 1 initially prepared in a
low-yield two-step process from p-tert-butyl-
calix[4]arene
and
6-bromomethyl-6%-methyl-2,2%-
bipyridine was obtained here with a much better yield
(ca. 90%) from the same reactants and the couple
BaO:Ba(OH)2 as base in DMF.14 The p-nitrophen-
oxypropyl spacer was introduced at the residual calix-
arene hydroxyl group by reaction of its bromo
analogue15 with 1 in dry DMF and NaH as base,
affording the nitro calixarene 2 with a yield of 93%
(Scheme 1). The reaction of 2 with SnCl2 in EtOH at
* Corresponding author. Fax: (33)3 83 68 23 45; e-mail:
jean-bernard.regnouf@pharma.u-nancy.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02203-7

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P. Engrand, J.-B. Regnouf-de-Vains / Tetrahedron Letters 43 (2002) 8863–8866
Scheme 1. Synthetic pathway (5: proposition of structure).
70°C16 gave the amino calixarene 3 with a yield of 64%.
In order to understand the reaction mechanisms
involved in the next grafting step, but also in order to
try direct coupling reactions on dextran polymers, we
synthesised the chlorocyanuryl derivative 4, by reacting
3 with cyanuryl chloride and K2CO3 in acetone.17 The
calixarenes 1–4 gave satisfactory NMR, mass and ele-
focused on polar aprotic organic solvents. Pure DMF,
which is recommended for this synthetic approach,13
does not solubilise dextran 10,000; the grafting reaction
which must occur in this case at the surface of the
polymeric material was not observed (based on the
absence of an evident orange colouring after addition
of Cu(I) salt). Pure DMSO, which is an excellent sol-
vent for dextran 10,000, promised good operating con-
ditions. Nevertheless, we found that this solvent did not
favour the grafting: the compound 4, which, on the
base of TLC analyses, was formed in situ, remained
unchanged and the resulting solid gave no reaction with
Cu(I). We thus supposed that DMF was essential to the
reaction, and found that the presence of 10% of DMSO
in DMF was sufficient to solubilise dextran 10,000.
Under these conditions, the grafting reaction occurred,
giving, after treatment, solid materials which reacted, in
the solid state or in aqueous solution with Cu(I); the
resulting complexes remained stable over 2 weeks in
ambient conditions (Fig. 1). Three different ratios of
calixarene versus sugar units, 5, 10 and 30% (3, 6 and
18 calixarene units by dextran chain), were tested,
giving the solid materials 5a–c. Attempts to evaluate
mental analyses. According to de Mendoza et al.,18 13
C
NMR confirmed that the cone conformation was pre-
served, with Ar-CH2-Ar resonance signals appearing
between 31 and 32 ppm.
Various dextrans have been tested as supporting poly-
mers, but the quasi-insolubility of high-molecular-
weight species in standard organic solvent brought us,
for analytical reasons, to give most of our attention to
dextran 10,000, its good solubility in DMSO being
useful for UV–vis and NMR spectroscopies. A one pot
procedure involving the direct mixing of the amino
compound 3, cyanuryl chloride, polymer and base in
the adapted solvent was chosen.13 The preliminary eval-
uation of the grafting was monitored by the reaction of
Cu(MeCN)4PF6 on the resulting material, that should
give an orange-to-red colouring due to the formation of
a tetrahedral bipyridine/Cu(I) complex. The main prob-
lem in this strategy was the choice of the solvent
system: as water was prohibited due to the insolubility
of the calixarene and to the risks of hydrolysis, we
1
the amounts of grafted calixarenes involved H NMR
and UV–vis spectroscopies.
1H NMR experiments, performed in DMSO-d6, showed
the apparition of aromatic signals between 5.5 and 8.5

P. Engrand, J.-B. Regnouf-de-Vains / Tetrahedron Letters 43 (2002) 8863–8866
8865
Figure 1. Visualisation of the complexation. (a) Solid 5c; (b)
solid 5c+Cu(I) in MeCN; (c) aq. soln of 5c+Cu(I) in MeCN.
ppm, and alkyl ones at ca. 0.9 and 1.2 ppm which were
attributed to the calixarene moieties (Fig. 2). The inte-
grations of calixarene and dextran parts were com-
pared, resulting in an evaluation of grafting ratios
(calixarene versus dextran chains) of 11, 59 and 48% for
5a–c, respectively. At the same time, the amount of
water associated to the polymers was evaluated to be
33, 16 and 27%, respectively. This allowed us to calcu-
late the real mass of polymer involved in the following
UV–vis experiments.
Figure 3. UV–vis titration of 5b by Cu(MeCN)4PF6; DMSO.
(a) free ligand; (f) free ligand+1 equiv. of Cu(I).
Titration with Cu(MeCN)4PF6, (Fig. 3), gave, on the
base of the MLCT band which appeared at 455 nm,
ratios of 12, 50 and 60%, for 5a–c, respectively.
Attempts to directly graft the pre-activated calixarene 4
were unsuccessful in DMSO, and resulted in a rapid
degradation process of 4 in DMF.
UV spectroscopy in H2O confirmed the presence of
chromophoric material with an absorption band at 285
nm attributed to the grafted bipyridyl calixarene. The
controlled addition of Cu(MeCN)4PF6 resulted in the
apparition of the expected MLCT (metal-to-ligand
charge-transfer; orange-to-red colour) band at 455 nm.
The ratios of grafting were thus evaluated, on the base
of one Cu(I) ion for one calixarene unit,11 to ca. 29, 54
and 58% for 5a–c, respectively. Nevertheless, the irregu-
lar increase of absorbance at this wavelength suggested
that mixing problems occurred and led us to operate in
DMSO. In this solvent, the three species exhibited an
absorption maximum at 279 nm. The absorbance val-
ues, directly correlated to the presence of the calixarene,
were compared to 4 (m=54,000 mol−1 L cm−1; DMSO).
According to these measurements, the ratio of grafting
was evaluated to 30, 57 and 55% for 5a–c, respectively.
FT-IR analysis of 5 in KBr pellet showed that the
1800–1350 cm−1 region increased strongly, while the
1200–900 cm−1 region remained unchanged, with
regards to pure dextran 10,000. Attempts to quantify
the grafting process by this method were unsuccessful
at this time.
We have prepared a bifunctional calixarene species
dedicated to the complexation of transition metal
cations and able to be fixed covalently on carbohydrate
polymers. We have shown by spectroscopic methods
and complexation experiments that the grafting was
efficient, but in low yields. Improvement of the reaction
conditions and development of new and more efficient
synthetic strategies with soluble and insoluble polymers
are under current investigations.
1
Figure 2. Comparison of H NMR spectra of compounds 4 (CDCl3) and 5b (DMSO-d6).

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P. Engrand, J.-B. Regnouf-de-Vains / Tetrahedron Letters 43 (2002) 8863–8866
Polym. 1996, 31, 81; (d) Ohto, K.; Tanaka, Y.; Inoue, K.
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to SAFAS (Monaco) for UV spectroscopy. The authors
thank Mrs. N. Marshall for correcting the manuscript.
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