Synthesis and recognition behaviour of allosteric hemicarcerands

Article abstract of DOI:10.1016/S0040-4039(02)00086-2

Bipyridine bridged bis(resorcinarenes) have been prepared. Upon co-ordinating to a transition metal ion, e.g. Ag⁺, the respective metal complex forms a hemicarcerand-like structure with the two resorcinarene moieties capable of binding non-polar organic molecules in a co-operative fashion, as shown qualitatively by NMR spectroscopy.

Full text of DOI:10.1016/S0040-4039(02)00086-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1807–1811
Synthesis and recognition behaviour of allosteric hemicarcerands
Arne Lu¨tzen,* Oliver Haß and Torsten Bruhn
University of Oldenburg, Department of Chemistry, PO Box 2503, D-26111 Oldenburg, Germany
Received 21 December 2001; accepted 11 January 2002
Abstract—Bipyridine bridged bis(resorcinarenes) have been prepared. Upon co-ordinating to a transition metal ion, e.g. Ag+, the
respective metal complex forms a hemicarcerand-like structure with the two resorcinarene moieties capable of binding non-polar
organic molecules in a co-operative fashion, as shown qualitatively by NMR spectroscopy. © 2002 Elsevier Science Ltd. All rights
reserved.
Although known for almost 130 years now,1 resor-
cinarenes had to face the fate of being considered more
or less as laboratory curiosities for a long time. How-
ever, this situation changed dramatically with the emer-
gence of supramolecular chemistry about 30 years ago.2
Since then and in particular over the last decade
chemists all over the world have shown an increasing
interest in these compounds due to their unique proper-
ties in molecular recognition studies, leading to ever
more sophisticated receptor molecules of this class of
compounds.3 Especially molecular container molecules,
also called carcerands and hemicarcerands, have been
studied extensively in this context.3d–f,j,m
ture upon complexation of another guest species. Most
notably 2,2%-bipyridines have been demonstrated to be
particularly effective for this purpose and a number of
examples of positive allosterism have been reported
where the formation of the bipyridine transition metal
ion complex induced a conformational change that
enables further binding sites to complex another guest.4
Thus, we designed bipyridine bridged bis(resorcinare-
nes) 1 by using MMFF-force field molecular modelling,5
where the co-ordination induced conformational
change upon addition and binding of a suitable transi-
tion metal ion, e.g. Ag+, should orientate the two
resorcinarenes in a position that assembles a hemi-
carcerand (Fig. 1).
We were interested in the design and the synthesis of an
allosteric analogon of these fascinating compounds
which incorporates another binding site that switches
the conformation of a molecule bearing two resor-
cinarene moieties towards a hemicarcerand-like struc-
The synthesis (Scheme 1) of the bipyridine building
block 3 started from 4,4%-dimethyl-2,2%-bipyridine 2,
which was first oxidised using CrO3/H2SO4 to afford
+
Figure 1. 2,2%-Bipyridine bridged bis(resorcinarene) 1 and its Ag(I) complex Ag12 (side chains omitted for viewing clarity).
Keywords: resorcinarenes; hemicarcerands; bipyridines; molecular recognition; allosteric receptors.
* Corresponding author. Tel.: +49 441 798 3706; fax: +49 441 798 3329; e-mail: arne.luetzen@uni-oldenburg.de
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00086-2

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A. Lu¨tzen et al. / Tetrahedron Letters 43 (2002) 1807–1811
Scheme 1. Synthesis of 1 (yields are given for the resorcinarenes having R=n-C5H11). (i) CrO3, conc. H2SO4, 87%; (ii) MeOH,
conc. H2SO4, 85%; (iii) NaOH, MeOH, 98%; (iv) SOCl2; (v) 1 equiv. n-BuLi, 1 equiv. B(OMe)3, THF; (vi) 3 equiv. n-BuLi, 3
equiv. MeOH, 1 equiv. H2O2, THF, 63% over two steps; (vii) 1 equiv. 3, 2.5 equiv. 5b, Et3N, CHCl3, 19%. 1a was prepared in
analogous fashion from 5a in 75% yield.
the dicarboxylic acid. This could in principle be con-
verted directly to the corresponding diacid chloride 3.
However, as reported earlier the slightly longer way
including the formation, purification, and saponifica-
tion of the corresponding dimethylester followed by the
reaction with thionyl chloride proved to be the more
practical way to get the desired intermediate 3, which
was directly reacted with 5 after removal of excess
thionyl chloride without further purification.6
were fully characterised by NMR spectroscopic and
mass spectrometric means.10,11
Addition of previously prepared and thoroughly dried
Ag(CH3CN)2BF4 dissolved in acetonitrile-d3 to a solu-
tion of 1 (two equivalents) in deuterated benzene
+
afforded the desired metal complex Ag12 , as indicated
1
by significant shifts in the H (Fig. 2) and 13C NMR
spectra. The stoichiometry of this complex could be
+
proven by ESI MS of metal complex Ag1b2 (Fig. 3).
Tetrabromocavitands 4 were prepared in three steps
from resorcinol following published procedures, which
were subsequently transformed into monosubstituted
resorcinarenes 5.7–9 The new compounds 1a and 1b
With the complexes in hand the next task was to study
the solution-phase recognition behaviour of 1 and its
silver(I) complex towards non-polar organic molecules
Figure 2. 1H NMR spectra (500.1 MHz, 300 K, C6D6/CD3CN (50/1), [1a]0=4 mM) of (a) 1a and (b) Ag(CH3CN)2BF4+2 equiv.
1a.

A. Lu¨tzen et al. / Tetrahedron Letters 43 (2002) 1807–1811
1809
a better guest than aromatic compounds because the
recognition experiments were performed in solutions
with a large content of benzene which should favour
the formation of complexes with 6 but not with
aromatics.
With respect to the huge mass difference we decided
to use a large excess of guest rather than vice versa to
get qualitative information about the recognition
behaviour from NMR investigations in order to avoid
solubility problems and other unspecific aggregation
effects of the host. Thus, our experiments were set up to
observe a maximum effect for the signals of the bis-
(resorcinarene) host, whereas effects for the guest were
only expected in case of a slow guest exchange
behaviour on the NMR time scale.
Figure 3. ESI MS of a 0.75 mM solution of (Ag1b2)BF4 in
benzene/acetonitrile.
Addition of a 10-fold excess of 6 to 1 did not give any
1
noticable shifts in the H NMR spectrum, indicating
that no intra- or intermolecular binding event occurs.
However, addition of Ag(CH3CN)2BF4 to this solution
changes the situation dramatically (Fig. 5b). Virtually
the same spectrum was obtained when we added a
10-fold excess of 6 to preformed silver complex Ag1+.
In both cases we saw significant shifts and sharpening
of the signals of the hemicarcerand unit compared to
the pure silver complex (Fig. 5c), indicating successful
binding to the bis(adamantyl), although fast guest
exchange on the NMR time-scale seems to occur since
we could not see different sets of signals for the com-
plexed guest, which were expected far upfield,13 and the
free guest under these conditions and even if we per-
formed NMR experiments at 278 K.
to reveal the allosteric potential. We decided to use
adamantanecarboxylic acid adamantylester 6 as guest
molecule (Fig. 4).12 Compound 6 was chosen because
resorcinarenes and cavitands in particular have already
been demonstrated to be very efficient hosts for the
recognition of adamantyl derivatives as well as aro-
matic compounds.3c–e,k,13 However, 6 was thought to be
Figure 4. Bis(adamantyl) 6.
Figure 5. 1H NMR spectra (500.1 MHz, 300 K, C6D6/CD3CN (20/1)) of (a) 1b (1.5 mM); (b) 1b (1.5 mM)+6 (15 mM)+
+
Ag(CH3CN)2BF4 (0.75 mM), and (c) Ag1b2 (0.75 mM).

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A. Lu¨tzen et al. / Tetrahedron Letters 43 (2002) 1807–1811
These results clearly indicate that the new bis(resor-
cinarene) 1 indeed shows heterotropic positive co-oper-
ative allosteric behaviour and we are currently
exploring its binding properties towards other non-
polar substrates like biphenyls.
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Acknowledgements
We are indebted to Professor Dr. Peter Ko¨ll for provid-
ing us with excellent working conditions. We thank
Professor Dr. Ju¨rgen O. Metzger for the opportunity to
perform the ESI MS experiments. Additional financial
support from the Fonds der Chemischen Industrie is
gratefully acknowledged.
5. Molecular modelling was performed using commercially
available PC Spartan Pro software package from
Wavefunction.
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acid and 1-hydroxyadamantane following Garelli’s pro-
cedure (see Ref. 6).

A. Lu¨tzen et al. / Tetrahedron Letters 43 (2002) 1807–1811
1811
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