Information transfer in calix[4]arenes: influence of upper rim substitution on alkaline metal complexation at the lower rim

Article abstract of DOI:10.1016/j.tetlet.2008.07.128

Novel calix[4]arene amides have been synthesized and their interaction with alkaline cations has been evaluated through extracting aqueous solutions of Li-, Na- and K-picrates with solutions of calix[4]arene amides in CH₂Cl₂. Electro

Full text of DOI:10.1016/j.tetlet.2008.07.128

Tetrahedron Letters 49 (2008) 5800–5803
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Information transfer in calix[4]arenes: influence of upper rim substitution
on alkaline metal complexation at the lower rim
Daniel T. Schühle a,b, Sascha Klimosch b, Jürgen Schatz b,c,
*
a Biocatalysis and Organic Chemistry, Department of Biotechnology, Delft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands
b Division of Organic Chemistry 1, University of Ulm, Albert-Einstein-Allee 11, D-89069 Ulm, Germany
c Organic Chemistry 1, Friedrich-Alexander-University Erlangen-Nuremberg, Henkestr. 42, D-91054 Erlangen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel calix[4]arene amides have been synthesized and their interaction with alkaline cations has been
evaluated through extracting aqueous solutions of Li-, Na- and K-picrates with solutions of calix[4]arene
amides in CH2Cl2. Electron-withdrawing groups on the upper rim of the calix[4]arene scaffold were found
to have a negative effect on the absolute amount of metal ions extracted. The decreased extraction ability
is accompanied by a higher selectivity towards sodium cations.
Received 25 June 2008
Revised 21 July 2008
Accepted 23 July 2008
Available online 29 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Calix[4]arene
Metal receptor
Binding selectivity
Substitution effect
Ion channels play a key role in the transport of ions across cell
membranes. The best known result of such transport is the differ-
ence in concentration of alkaline metal ions between the inside
and the outside of cells: the extracellular concentrations of Na+
and K+ are 140 mM and 5 mM, respectively, whereas the intracel-
lular concentrations in humans have about the opposite magnitude
(5 mM and 150 mM).1 Nature has developed very effective strate-
gies to control this concentration difference in order to ensure a
proper functioning of cells.
Previously, it has been shown that cone-calix[4]areneamides are
able to complex metal ions and therefore, they found applications
in various fields.4–14 Especially, calix[4]arenetetraamides (Scheme
1) show interesting features in the complexation of Li+, Na+ and
K+ ions and therefore, they were used as lead structures in artificial
transmembrane ion transport systems.1,15,16
An easy and fast way to screen the binding abilities of this type
of compounds is by performing extraction experiments of metal
To gain more insight into the mechanism of these natural sys-
tems, supramolecular chemists try to develop artificial model sys-
tems mimicking the action of ion channels or ion transportation
systems. Some of the major challenges are the design of synthetic
channels with high metal binding selectivity, the possibility to
include these compounds into artificial bilayers and the need to
completely span this bilayer (ꢀ40 Å).1 An approach to fulfil these
requirements is to include molecules that have proven to bind ions
with good selectivity into liposomal bilayers that serve as model
compounds for cell membranes.2 Amongst other good chelators
such as crown ethers, some calix[4]arene derivatives are known
to bind ions while maintaining their hydrophobicity and thus their
ability to be included into bilayers. Therefore, it is not surprising
that this class of compounds found some application in the design
of artificial transmembrane ion transporters.1,3
O
O
O
O
O
O
O
O
O
NR2
O
O
NEt2
O
R2N
O
NR2
Et2N
O
NEt2
R2N
O
Et2N
O
1 a R = Et
2
b R = (CH2)4
c R = Pr
d R = Bu
e R = Allyl
f R = Propargyl
g R = Benzyl
* Corresponding author. Tel.: +49 9131 85 25766; fax: +49 9131 85 24707.
E-mail address: juergen.schatz@chemie.uni-erlangen.de (J. Schatz).
Scheme 1.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.128

D. T. Schühle et al. / Tetrahedron Letters 49 (2008) 5800–5803
5801
salts from an aqueous solution into a solution of the metal binding
compound in an organic solvent. The absolute values of the extrac-
tion efficiency are of minor importance for application as ion trans-
porters, but the selectivity factors for certain ions are governing the
desired properties. The preference of compounds for particular
metal ions can be expressed by selectivity factors S. For example,
the selectivity for alkaline metal ions by 1 can be given by the ratio
of the mole percent extraction Na+/mol % extraction M+ (M = Li,
K).17 As shown in Table 1, variation of the N-substituents in 1 leads
to significant changes in the selectivity in picrate extraction
experiments.
The finding that weaker complexation might lead to enhanced
selectivity inspired us to synthesize new calix[4]arenetetraamides
bearing different substituents on the upper rim of the skeleton. We
introduced electron-withdrawing groups (Br, CN) to decrease the
electron density at the phenolic oxygen atoms or phenyl rings to
mimic steric effects that might occur upon changing the substitu-
tion pattern.
Tetrabromo-calix[4]arene 3 was obtained by bromination of 2
using N-bromosuccinimide (NBS). The Pd(PPh3)4-catalyzed Suzuki
reaction with phenylboronic acid in a toluene/methanol mixture
yielded 4 (Scheme 2).
The influence of upper rim substitution on the metal complexa-
tion at the lower rim is demonstrated by the selectivity factors of 2
compared to those of its alkylated derivative 1a: both selectivity
factors show that 2 has a higher selectivity for Na+ than 1a. This
difference has been attributed to the larger conformational mobil-
ity of 2 and to its better solvation which decreases its binding
ability towards alkaline cations.18
Diprotected calix[4]arene 5 was prepared by bisbenzoylation of
tetrahydroxycalix[4]arene in distal position (Scheme 3). During the
subsequent bromination to the dibromo derivative 6, it turned out
that the excess of bromine in the reaction mixture could be more
easily removed by cyclohexene than with the commonly applied
sulfur-based quenching agents. Deprotection in boiling ethanol/
water proceeded smoothly, and calixarene 7 was obtained after
alkylation with N,N-diethylbromoacetamide in dmf/thf using a
standard protocol.19
Table 1
N,N-Diethylbromoacetamide was prepared by a modified litera-
ture procedure enabling us to synthesize this compound on a large
scale and with high purity.20 Whereas a previous attempt of an-
other group to synthesize dicyano-calix[4]arene 8 by a palla-
dium-catalyzed reaction was not successful, we could obtain this
compound using CuCN in NMP although the yield was rather
poor.19,21 We did not optimize this reaction further, since a suffi-
cient amount of 8 could be achieved by this methodology.
Extraction of metal picrate salts from aqueous into organic solu-
tion is a powerful, fast, reliable and well-established method in
supramolecular chemistry. From its early days until today, this
technique found many applications.22,23
Selectivity factors S for picrate extraction of alkali picrates from H2O into CH2Cl2 at
20 °C
S (Na+/K+)a
S (Na+/Li+)a
1a
1b
1c
1d
1e
1f
1.3
1.6
1.2
1.2
1.4
6.7
1.4
1.7
1.5
1.9
1.3
1.4
2.3
8.8
2.2
2.5
1g
2
a
Values calculated from Refs. 17 and 18.
Br
Br
Br
Br
a.
O
O
O
O
O
O
O
O
51%
O
NEt2
O
O
NEt2
O
Et2N
O
Et2N
Et2N
O
Et2N
NEt2
NEt2
O
O
2
3
Ph
Ph
Ph
Ph
b.
O
O
O
72%
O
O
NEt2
O
Et2N
O
Et2N
NEt2
O
4
Scheme 2. Synthesis of 3 and 4. Reagents and conditions: (a) NBS, butanone, 5 d, rt; (b) PhB(OH)2, Pd(PPh3)4, Cs2CO3, PhCH3, MeOH, 16 h, 70 °C.

5802
D. T. Schühle et al. / Tetrahedron Letters 49 (2008) 5800–5803
a.
OH
OH
O
O
70%
OH
OH
O
O
HO
OH
Ph
Ph
5
b., c.
85%, 95%
Br
Br
Br
Br
d.
O
O
O
54%
O
OH
OH
HO
OH
O
NEt2
O
Et2N
O
Et2N
NEt2
O
7
6
e.
11%
Ph
HN
CN
CN
HN
S
O
O
O
O
O
O
O
O
O
O
NEt2
O
O
NEt2
O
Et2N
O
Et2N
Et2N
NEt2
NEt2
O
Et2N
O
8
9
Scheme 3. Synthesis of 7 and 8. Reagents and conditions: (a) PhCOCl, TEA, MeCN, 3 d, rt; (b) Br2, CHCl3, 1 d, rt; (c) NaOH, EtOH, H2O, 3d, 70 °C; (d) BrCH2CONEt2, NaH, dmf,
thf, 4 d, rt; (e) CuCN, NMP, 22 h, 200 °C.
Table 2
Our main interest lies in the complexation of physiologically
Mole percent extraction (%E)a of alkali picrates from H2O into CH2Cl2 at 20 °C
relevant alkaline metal ions, so we performed the extraction
Li+
Na+
K+
S (Na+/Li+)
Srel
S (Na+/K+)
Srel
experiments with lithium, sodium and potassium picrate. The
extractions were performed from aqueous solution into dichloro-
methane at 20 °C (Table 2).18
The binding stoichiometry of the complex between the calixa-
renetetraamide and the metal ions is 1:1, which was exemplarily
confirmed by a Job’s plot analysis for 2 (data not shown) as well
as by literature data.16,21 The extraction percentages obtained for
ligand 2 are consistent with the literature.18
2
3
4
7
8
38.5
6.3
31.
17.5
5.6
91.4
54.7
87.7
78.1
41.8
55.
8.5
36.5
23.3
4.1
2.4
8.7
2.8
4.5
7.5
1
1.7
6.4
2.4
3.4
10.2
1
3.6
1.2
1.9
3.1
3.8
1.4
2.0
6.0
a
Mean value of at least three independent experiments. Errors of %E generally
62%.
To the best of our knowledge, the influence of chemical modifi-
cations on one side of the calix[4]arene backbone on the guest
binding on its other side is rarely studied. An early example pub-
lished by Ungaro and co-workers is the complexation of anions
by 9 bearing a thiourea unit as a binding motive for anions and
the tetraamide pattern also used in the present work.21 In the
presence of Na+-ions, it binds anions stronger and shows a lower
selectivity towards acetate than in the absence of Na+-ions. The

D. T. Schühle et al. / Tetrahedron Letters 49 (2008) 5800–5803
5803
authors attributed this to an electron-withdrawing effect and
rigidification of the calixarene backbone upon complexation. Fur-
thermore, changes in the solvation might contribute to the ob-
served increase in binding capability.18
The changes in the extraction behavior as shown in Table 2 are a
consequence of the same phenomena, which make a quantitative
evaluation impossible. Qualitatively, it can be concluded that also
in 3, 4, 7 and 8 an ‘information transfer’ occurs between the two
different rims of the calixarene backbone.
potential to be included into liposomes giving access to models
for cation transportation across lipid bilayers.
Experimental: The extraction studies were performed according
to Ungaro and co-workers.18 Compound 2 was prepared using a
slightly modified literature procedure (see Supplementary data).24
Tetrahydroxycalix[4]arene is readily available following a known
method.25
Acknowledgement
Comparison of the sodium selectivity of the benchmark ligand 2
with the functionalized ligands 3, 4, 7 and 8 shows that electron-
withdrawing substituents increase the sodium selectivities
roughly by a factor of 2–6. This can be rationalized by the elec-
tron-withdrawing effects of the bromo and cyano groups in 3, 7
and 8, which decrease the electron density at the phenolic oxygen
atoms and therefore, weaken the binding ability of the receptors
towards cations. The strong decrease in mainly Li+- and K+-binding
leads to better Na+ selectivity in all cases. The selectivity for Na+
binding is qualitatively correlated with the number of such elec-
tron-withdrawing groups, for example, dibromo ligand 7 exhibits
only about double the Na+ selectivity compared to the unsubstitut-
ed ligand 2, whereas tetrabromo-calix[4]arene 3 has about fourfold
selectivity. Comparison of ligands 7 and 8 clearly shows that the
mesomeric effect of the nitrile groups on the binding abilities of
the phenolic oxygen atoms is more effective than the inductive
effects caused by bromo substitution and leads to a better sodium
selectivity towards both lithium and potassium. Dicyano-calixa-
rene 8 is the only compound studied which shows a higher Na+/
K+ than Na+/Li+ selectivity. This may be explained by additional
steric reasons and eventually different solvations. The CN-group
has a strong electron-withdrawing effect paralleled by less steric
demand compared to the bromo group. Therefore, the ligand
sphere located at the lower rim is less distorted by the nitrile
substituent and the general sodium selectivity resulting from an
increasing electron-withdrawing effect can be deployed more
effectively.
The authors want to thank Dr. Joop Peters, TU Delft, for fruitful
discussions.
Supplementary data
Supplementary data (synthetic details as well as characteriza-
tion of all novel compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.07.128.
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