Unexpected stable dimerisation of an anionic imidopyrrolecarboxylate in polar solution

Article abstract of DOI:10.1039/c1cc13446a

The imidopyrrolecarboxylate 3^- unexpectedly forms stable dimers (K_ass = 130 M^-1 in CHCl₃/DMSO, 1:1, v/v) despite the fact that two anions have to interact. The dimer is more stable than an analogous neutral amid

Full text of DOI:10.1039/c1cc13446a

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COMMUNICATION
Unexpected stable dimerisation of an anionic imidopyrrolecarboxylate in
polar solutionw
Carolin Rether, Elisabeth Verheggen and Carsten Schmuck*
Received 10th June 2011, Accepted 1st July 2011
DOI: 10.1039/c1cc13446a
The imidopyrrolecarboxylate 3À unexpectedly forms stable
dimers (Kass = 130 MÀ1 in CHCl3/DMSO, 1 : 1, v/v) despite
the fact that two anions have to interact. The dimer is more
stable than an analogous neutral amidopyrrolecarboxylic acid
dimer (Kass o 10 MÀ1) underlining the importance of charged
H-bonds compared to neutral ones.
For example, whereas the guanidiniocarbonyl pyrrole carboxylate
1 forms extremely stable dimers with an estimated stability of
Kass 4 108 MÀ1 in DMSO the neutral analogue 2 which has
the same H-bond pattern but lacks the charges is present only
as monomers under the same conditions (Kass o 10 MÀ1 in
5% DMSO in CHCl3, v/v). Efficient dimerization only occurs
in pure chloroform.
The anion 3À forms surprisingly stable dimers even in
chloroform/DMSO mixtures, despite the fact that the dimer
does have even one H-bond less than 2Á2 and requires two
anions to interact. Most likely this is due to the fact that within
3ÀÁ3À charged H-bonds occur in contrast to the neutral
H-bonds within 2Á2. The imidopyrrole carboxylic acid 3 was
synthesized as shown in Scheme 1, starting from pyrrole-2,5-
dicarboxylic acid monobenzyl ester 4. The acid 4 was reacted
with acetamidine hydrochloride 5 after activation of the acid
with oxalyl chloride. The resulting product mixture consisted
of ca. 40% of the imide 7, 30% of the amide 8 and ca. 5% of the
double substitution product 9. The reaction mixture could be
separated using flash chromatography. Interestingly, obviously
the initial product, the acetamidine 6, is not stable under the
reaction conditions and is hydrolyzed first to the imide 7 and
then to the amide 8 or further reacts to 9. After deprotection of
Self-assembly has become an increasing area of interest in the
last decade as it allows for rather facile formation of large and
complex nanostructures from small and simple building
blocks.1 However, to achieve stable self-assembly in polar
solvents is still challenging especially when purely H-bonded
systems are used.2 Due to the competitive solvation of donor
and acceptor sites in polar solvents, H-bonded systems
are most often only stable in nonpolar organic solvents such
as chloroform or acetonitrile and dissociate in more polar
solvents such as DMSO, alcohols or water.3 We have therefore
been studying self-complementary zwitterions for the last
few years in which H-bonds are combined with charge inter-
actions leading to very stable self-assembly even in polar and
protic solvents.4 Detailed experimental and theoretical studies
using knock-out analogues have revealed the importance of
charge interactions for stable dimerization in polar solution.5
University of Duisburg-Essen, Faculty of Chemistry,
Universitaetsstrasse 7, 45141 Essen, Germany.
E-mail: carsten.schmuck@uni-due.de; Fax: +49 2211834256;
Tel: +49 2211833097
w Electronic supplementary information (ESI) available: Synthesis of
3 and its alkali metal salts, NMR dilution study of the Cs-salt. See
DOI: 10.1039/c1cc13446a
Scheme 1 Synthesis of imidopyrrole carboxylic acid 3 and its salt 3À.
c
9078 Chem. Commun., 2011, 47, 9078–9079
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Fig. 2 Calculated lowest energy structure of dimer 3ÀÁ3À as obtained
from a force field calculation (Macromodel V 8.0, amber* force field,
GBSA solvation model).
X-ray crystal analyses reveal completely planar dimers at least
in the solid state, the dimer 3ÀÁ3À is slightly tilted. This could
however also be an artefact of the calculation as force field
calculations tend to overestimate stacking interactions. The
most likely explanation for the surprisingly high stability of
dimer 3ÀÁ3À is the fact that charged H-bonds are more stable
than neutral ones.8 Whereas within dimer 2Á2 all H-bonds are
formed between neutral H-bond donors and acceptors, within
3ÀÁ3À the H-bond acceptor (the carboxylate) is charged and
the two donors (the imido and the pyrrole NH, respectively)
are neutral. Of course even more stable dimers result when
also the H-bond donors are charged as in 1Á1. However, the
additional benefit of at least one charged H-bond not only
overcomes the mutual repulsion of the two anions but also
leads to significantly more stable self-assembly than in a
completely neutral H-bonded system. Long ranging charge
repulsion between the two interaction anions is most likely
also attenuated by the rather polar solvent.
Fig. 1 NMR dilution study of 3À (Na+-salt) in CDCl3/[d6]DMSO
1 : 1 (v/v). Shown is the shift change of the pyrrole NH along with the
non linear curve fit (red) which provides an association constant for
dimerisation of Kass = 145 MÀ1
.
the benzyl ester (H2/Pd/C in MeOH) in 7 the imidopyrrole
carboxylic acid 3 was obtained.
Similar to the previously studied knock-out analogue 2,4
the imidopyrrole carboxylic acid 3 did not show any signs of
self-assembly in pure DMSO solution (as judged by the
absence of any concentration dependent NMR shift changes).
Unfortunately, 3 is not soluble enough to study its self-
assembly in less polar solvents (e.g. CHCl3/DMSO mixtures).
However, the sodium salt of 3 is well soluble in a 1 : 1-mixture
of CHCl3/DMSO (v/v) and forms surprisingly stable dimers.
Dimerization was studied by following the 1H NMR shift
changes of either the methyl group CH3 protons or the pyrrole
NH proton upon dilution in the concentration range between
18 and 0.05 mM.6 Identical binding isotherms were obtained
which can be analyzed using non-linear regression. A dimeri-
zation constant of either Kass = 115 MÀ1 (CH3) or 145 MÀ1
(pyrrole NH) was obtained (Fig. 1), respectively (estimated
error in each K-value is ca. Æ20%). Hence, an average dimer
stability of ca. 130 MÀ1 results from the 1H NMR dilution
studies. To assure that the countercation does not affect the
dimerization, we also prepared the cesium salt of 3 and
performed the same dilution experiment (see ESIw). The shifts
are identical to those of the sodium salt and an identical
dimerization constant of Kass = 115 MÀ1 is obtained. Hence,
the presence of close ion pairs in these solvent mixtures or a
significant impact of the countercation on the dimerization
process are rather unlikely.
In conclusion we have shown here that the use of charge
assisted H-bonds is superior to neutral H-bonds to obtain
stable self-assembly in polar solution. Hence, for the design of
new self-complementary binding motifs not only the number
of H-bonds but even more importantly their nature (ion
paired, charged, neutral) should be taken into consideration.
Notes and references
1 (a) H.-J. Schneider and A. Yatsimirsky, Principles and Methods in
Supramolecular Chemistry, VCH, Weinheim, 2000; (b) J. W. Steed
and J. L. Atwood, Supramolecular Chemistry, Wiley, Chichester,
2000; (c) J.-M. Lehn, Supramolecular Chemistry: Concepts and
Perspectives, VCH, Weinheim, 1995.
2 (a) T. Rehm and C. Schmuck, Chem. Commun., 2008, 801–813;
(b) T. Rehm and C. Schmuck, Chem. Soc. Rev., 2010, 39,
3597–3611.
The dimer of anion 3À is therefore significantly more stable
than that of the neutral analogue 2 which in the same solvent is
at least one order of magnitude less stable (Kass o 10 MÀ1
already in 5% DMSO in CHCl3). This is quite surprising at the
first glance as the dimer 2Á2 is held together by a network of six
H-bonds whereas within dimer 3ÀÁ3À only four H-bonds are
possible. Furthermore, dimerization requires the interaction of
two anions. Nevertheless, the latter dimer is definitely more stable
than the former. Empirical force field calculations (Macromodel
V 8.0,7 amber* force field, water GBSA/solvation model)
confirm the possibility for anion 3À to form a dimer held
together by four H-bonds. The energy minimized structure is
shown in Fig. 2. In contrast to dimer 1Á1 or 2Á2, for which
3 Two recent reviews on the challenge of bringing supramolecular
chemistry into water can be found in: (a) G. V. Oshovsky,
D. N. Reinhoudt and W. Verboom, Angew. Chem., Int. Ed., 2007,
46, 2366–2393; (b) S. Kubik, C. Reyheller and S. Stuewe, J. Inclusion
Phenom. Macrocyclic Chem., 2005, 52, 137–187.
4 C. Schmuck and W. Wienand, J. Am. Chem. Soc., 2003, 125,
452–459.
5 (a) S. Schlund, C. Schmuck and B. Engels, J. Am. Chem. Soc., 2008,
127, 11115–11124; (b) C. Rether, W. Sicking, R. Boese and
C. Schmuck, Beilstein J. Org. Chem., 2010, 6, No. 3.
6 K. A. Connors, Binding Constants, John Wiley & Sons, 1987.
7 F. Mohamadi, N. G. J. Richards, W. C. Guida, R. Liskamp,
M. Lipton, C. Caufiled, G. Chang, T. Hendrickson and
W. C. Still, J. Comput. Chem., 1990, 11, 440–467.
8 (a) M. Meot-Ner, Chem. Rev., 2005, 105, 213–284;
(b) H.-J. Schneider, Angew. Chem., Int. Ed., 2009, 48, 3924–3977.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 9078–9079 9079