Topology selection and tautoleptic aggregation: Formation of an enantiomerically pure supramolecular belt over a helix

Article abstract of DOI:10.1002/anie.201002665

In control: An enantiomerically pure monomer selects the formation of a supramolecular belt (see structure; blue N, red O, gray C, white H) over a helix. Induced tautomerization allows for a three-hydrogen-bond motif to be employed in cyclic homoleptic ag

Full text of DOI:10.1002/anie.201002665

DOI: 10.1002/anie.201002665
Self-Assembly
Topology Selection and Tautoleptic Aggregation: Formation of an
Enantiomerically Pure Supramolecular Belt over a Helix**
Edvinas Orentas, Carl-Johan Wallentin, Karl-Erik Bergquist, Mikael Lund, Eugenijus Butkus,*
and Kenneth Wꢀrnmark*
The understanding of self-assembly processes is one of the
most important areas of todayꢀs science,[1] and the assembly of
monomers to discrete cyclic structures by hydrogen bonding is
one of the major areas of supramolecular chemistry.[2–5]
Despite developments in the field, there are still important
issues to be addressed in the design of supramolecular
structures. One such issue is the self-assembly of cyclic
cavities that have enantiomerically pure skeletons derived
from enantiomerically pure monomers, where the challenge is
to favor cyclic aggregation over helical polymerization. Both
the cyclic and helical topologies can have important applica-
tions. Self-assembled cavity compounds can be used for
applications in catalysis and recognition, and helical aggre-
gates can transport compounds in their interior. For the same
“angle bar” (Figure 1, center), the position of the hydrogen-
bonding motif will influence the likelihood to form a cyclic
structure. Another issue has to do with the economical and
practical aspects of the synthesis of the monomers. For
monomers to be able to form extended stable cyclic aggre-
gates, robust complementary hydrogen-bonding motifs must
be introduced at each terminus. In heteroleptic aggregation,
there are two different monomers, and within each monomer
the termini have the same hydrogen-bonding pattern, which is
complementary to that of the other monomer type (Figure 2,
left). In homoleptic aggregation, there is only one type of
monomer, and the monomers aggregate through a self-
Figure 2. Heteroleptic, homoleptic, and tautoleptic aggregation and
their interconversion.
Figure 1. The properties of the construction elements lead to cyclic or
helical self-assembly depending on the position and orientation of the
hydrogen-bonding motif.
complementary hydrogen-bonding motif, with one half at
each terminus (Figure 2, center). The first approach needs the
synthesis of two different types of symmetric monomers. The
second needs the synthesis of only one type of monomer,
however often with two different but complementary termini.
We now suggest a third approach—namely, tautoleptic
aggregation. This approach is based on the use of one single
symmetric monomer that acquires self-complementarity by
tautomerization. Two cases can be distinguished (Figure 2,
right): In the homo-tautoleptic case, one side of a self-
complementary hydrogen-bonding pattern (for example,
DDA in a three hydrogen-bonding system, where D repre-
sents the H donor and A the acceptor) is located at one
terminus of one single monomer and the other side (AAD) is
located at the other terminus. In the hetero-tautoleptic case,
the same side (DDA) of a self-complementary H-bonding
motif is found at both termini of one monomer and the other
side (AAD) is found at both termini of a second monomer.
Tautoleptic aggregation would require the least synthetic
effort in terms of covalent synthesis of chiral building blocks,
in that only one dissymmetric monomer has to be synthesized.
Moreover, molecular systems that are inherently non-self-
complementary, such as three-hydrogen-bond motifs, can now
[*] Dr. E. Orentas, Prof. E. Butkus
Department of Organic Chemistry, Vilnius University
Naugarduko 24, 03225 Vilnius (Lithuania)
Fax: (+370)5-233-0987
E-mail: eugenijus.butkus@chf.vu.lt
Dr. C.-J. Wallentin, Dr. K.-E. Bergquist, Prof. K. Wꢀrnmark
Organic Chemistry, Department of Chemistry, Lund University
P. O. Box 124, 221 00 Lund (Sweden)
Fax: (+46)46–222-8209
E-mail: kenneth.warnmark@organic.lu.se
Dr. M. Lund
Theoretical Chemistry
Department of Chemistry, Lund University (Sweden)
[**] We thank the Swedish Foundation for Strategic Research, the
Crafoord Foundation, the Swedish Research Council, the Royal
Physiographic Society, and NordForsk for financial support. We
thank Franꢁois Paoloni and Mark Ingratta for GPC measurements
and Anders Sundin and Robert Vꢂcha for discussions concerning
computational aspects of this project.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201002665.
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2071

Communications
become self-complementary and can thereby aggregate using
one type of monomer.
1H NMR spectrum of 2 in CDCl3 shows a doubling of all
resonances in a 1:1 ratio, thus indicating the presence of either
a 1:1 mixture of two different C2-symmetric monomers in a
DDA–DDA—AAD–AAD hetero-tautoleptic aggregate
(Figure 3b) or of one monomer with C1 symmetry in a
DDA–AAD homo-tautoleptic aggregate (Figure 3c). By
using NOESY spectra, it is evident from NOE interactions
of the centrally positioned protons that the doubling of all
resonances detected in the 1H NMR spectra is due to only one
monomer of C1 symmetry. Thus, H-13a gives a NOESY
crosspeak with only one of the benzylic protons H-31b,
whereas H-13b interacts with another benzylic proton H-14b.
However, both H-13a and H-13b give NOESY crosspeaks
with H-12 as well as with H-6 (Figure S30 and Figure 3c). This
evidence shows that all the mentioned resonances originate
from protons belonging to one and the same molecule and
thus that the structure of 2 in the aggregate is the DDA–AAD
tautomer as depicted in Figure 3c. This finding is supported
by the fact that the resonances of H-13a and H-13b exhibit a
typical AB quartet pattern (Figure 4), showing that there is
We now report on the first selective assembly by
tautoleptic aggregation of an enantiomerically pure cavity,
that is, a supramolecular belt, from one enantiomerically pure
monomer containing one inherently non-self-complementary
motif. We also show that the positioning of the hydrogen-
bonding motif is important for the topological selectivity in
the assembly of a cyclic structure over a helical one using
enantiomerically pure C2-symmetric monomers.
Our starting point was that isocytosine and some deriv-
atives thereof form dimers in CHCl3 by tautomerization,
resulting in self-complementary DDA–AAD hydrogen-bond-
ing systems.[6–11] Accordingly, we have designed a monomer 1
containing one isocytosine unit at each end of an enantio-
merically pure C2-symmetric angle bar, the bicyclo-
[3.3.1]nonane system (Figure 1, bottom left). Molecular
modeling at the semi-empirical level (see the Supporting
Information) indicated that a cyclic tetramer 14 is favored and
that its quadratic cavity would have a width of approximately
13 ꢁ from face to face in hetero- and homotautoleptic
aggregation (Figure 3). The calculations also suggested the
possible formation of a stable cyclic pentamer but excluded a
trimer or a hexamer as stable species.
Figure 4. 1H NMR spectra of 2 in CDCl3 and [D6]DMSO/CDCl3 (5:1).
only one monomer and that one is of C1 symmetry, since
H-13a and H-13b are obviously not chemically equivalent. In
contrast, if 2 would assemble by hetero-tautoleptic aggrega-
tion (Figure 3b), the two different monomers would be of C2
symmetry, and H-13a and H-13b would then be chemically
equivalent. In fact, in [D6]DMSO/CDCl3 (5:1), monomer 2 is
of C2 symmetry, and the H-13a and H-13b resonances are
chemically equivalent (Figure 4 and Figure S31 in the Sup-
porting Information). Moreover, the 13C NMR spectrum of 2
in CDCl3 shows a doubling of all carbon resonance frequen-
cies in the bicyclo[3.3.1]nonane framework except for the
centrally positioned C-13 (all of the same intensity and line
width), which gives one resonance peak only (Figure S22 in
the Supporting Information), thus supporting homo-tauto-
leptic aggregation. In contrast, in the case of hetero-tauto-
leptic aggregation of monomer 2, two resonances for C-13
would have been expected, one for each of the two different
monomers (Figure 3b).
Figure 3. a) Molecular modeling at the semi-empirical level of two
possible types of tetrameric aggregates 14 of monomer 1: Two different
monomers AAD–AAD and DDA–DDA, respectively (left, hetero-tauto-
leptic aggregation), and one monomer DDA–AAD (right, homo-tauto-
leptic aggregation). b,c) The targeted monomer 2 and its numbering
for hetero- (b) and homo-tautoleptic (c) aggregation.
To obtain the necessary solubility for 1 in CHCl3, we
added branched 3,5-didecyloxybenzyl groups to 1. The
resulting compound 2 is shown in Figure 1, bottom left, and
its synthesis and full characterization are given in the
Supporting Information.
The characterization of 2 and its self-aggregation in
CHCl3 was performed partly by NMR spectroscopy. The
The hydrogen-bonding motif in 2 in CDCl3 is partly
characterized by the properties of the NH proton resonances
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in the NMR spectrum (see Figure 4, bottom). The 15N-1H
HMQC spectrum shows the bonding from H-c at d =
14.33 ppm to one nitrogen atom displaying a chemical shift
of d = 150.2 ppm and from H-f at d = 12.23 ppm to the
nitrogen atom with a resonance at d = 146.3 ppm, whereas
the signal from the two protons H-d and H-e, which have the
same chemical shift d = 4.83 ppm at 300 K, correlates to one
nitrogen chemical shift at d = 65.7 ppm (Figure S29 in the
Supporting Information). The H-a/H-b resonance at d =
7.58 ppm has a line width that is too large to give correlations
to nitrogen shifts in the HMQC spectra. A change of the
sample temperature from 300 to 200 K resulted in splitting of
the chemical shifts for each of the NH2 groups into individual
resonances for each proton (Figure S41 in the Supporting
Information). The chemical shifts of H-c and H-f as well as the
temperature dependence of the chemical shifts for NH2 H-a/
H-b and H-d/H-e pairs are consistent with previous evalua-
tions of hydrogen-bonding motifs in an isocytosine dimer in
CDCl3.[9,11] By comparing the spectra at different temper-
atures it is also evident that the strength of the hydrogen
bonds differs between the two amino groups in the DDA–
AAD tautomers, with a stronger bond for the NH2-b than for
the NH2-d proton. Thus, the NH2-a/b protons are frozen out
into two individual chemical shifts at higher temperature than
the NH2-d/e protons, and their chemical shifts are more
strongly separated (Figure S41 in the Supporting Informa-
tion). This difference in hydrogen-bonding strength can be
either a result of different electron distribution in the two
tautomers, which would change donor and acceptor proper-
ties of the hydrogen bond, or be due to a distorted geometry
of the hydrogen-bonding motif, a geometry that is required
for the formation of the cyclic aggregate.
tration range (Figure S43 in the Supporting Information),
thus supporting the formation of a tetrameric aggregate.[14]
Further insight into the aggregation of 2 was given by
diffusion NMR spectroscopy[15–18] using the bipolar longitu-
dinal eddy delay (BPLED) technique (see the Supporting
Information).[19] The value of the diffusion coefficient D was
estimated in CDCl3 at three different concentrations (10, 20,
and 30 mm) and by monitoring four different proton reso-
nances: H-c, H-f, and the combined H-d/e and H-21/38
resonances. It was found that D is inversely proportional to
the viscosity (h; Figure S49 in the Supporting Information),
thus strongly supporting a static system on the time scale of
NMR spectroscopy and allowing for the determination of a
highly accurate value of the hydrodynamic Stokesꢀ radius Rs
from D0 after extrapolation of D to infinite dilution to give
D0 = 2.71 ꢂ 10À10 m2 sÀ1 in CHCl3. Using the Stokes–Einstein
equation D0 = kbT/(6ph0Rs)[20] gave Rs = 13.2 ꢁ (kb is the
Boltzmann constant, and T is the temperature). The DOSY
spectra showed that all proton resonances only gave corre-
lation with one and the same value of D, a significant
indication of one type of aggregate.
Owing to the presence of many flexible alkyl chains in the
aggregate of 2, an estimation of Rs based on the size of the
aggregate is difficult, as also noted by others for other
aggregates.[17,18] We therefore argued that more accurate
results would be obtained using molecular dynamics (MD)
simulations. Hence, in order to have some correlation
between the value of Rs obtained from the DOSY experiment
and from size estimation, we performed MD simulations in
the isothermal–isobaric ensemble for the tetramer and
pentamer solvated in fully atomistic chloroform using the
Gromacs 4 package[21] and the proven Gromos forcefield (see
the Supporting Information). For the tetramer and pentamer,
Rs was found to be 14.0 and 14.8 ꢁ, respectively (see the
Supporting Information for details on how Rs was calcu-
lated.). Thus the experimental value of Rs from the DOSY
experiments, 13.2 ꢁ, corresponds better to the formation of a
tetramer than a pentamer.
In the ROESY spectra in CDCl3 (Figure S27 in the
Supporting Information), a strong cross peak between the
resonances of protons H-c and H-f was observed, despite the
À
rather long H H distance (4.8 ꢁ), thus clearly demonstrating
intermolecular interactions between monomers of 2. How-
ever, the NH hydrogen atoms that take part in the hydrogen
bonding most probably undergo chemical exchange with each
other in a tautomerization–dissociation–association mecha-
nism, in analogy with the similar guanidine–cytosine hydro-
gen-bonding pair.[12,13] The aforementioned spectral features
are absent in hydrogen-bond-competing solvents like DMSO,
in which compound 2 exists as the monomeric C2-symmetric
species DDA–DDA or AAD–AAD or a mixture thereof, as
evaluated on the basis of the symmetry of the 1H and
13C NMR spectra in [D6]DMSO/CDCl3 (5:1; Figure 4 and
Figure S32 in the Supporting Information).
Gel permeation chromatography (GPC) was performed
using a set of O-acylated b- and g-cyclodextrins as standard
compounds. These standard compounds are particularly
suitable for our purposes in that they not only have the
same mass range as the tetramer and the pentamer but they
also have the same shape as the self-assembled cyclic
structure. GPC confirmed the results obtained from the
diffusion NMR spectroscopy studies that the aggregate of 2 is
monodisperse, having Mw/Mn = 1.08 (Mw is the weight-aver-
age molecular weight and Mn the number-average molecular
weight). Moreover, the molecular mass of the aggregate was
determined to be 4130. This result is consistent with the
formation of a tetramer (Mw = 4366) and is inconsistent with a
pentamer (Mw = 5457), thus clearly supporting tetrameric
aggregation.
The absorption (UV/Vis) spectrum of 2 (Figure S45 in the
Supporting Information) is composed of two bands, one at
232 nm and another at 285 nm in CHCl3.[7] The intensity of the
long-wavelength band is dominated by the DDA tautomer,
whereas the short-wavelength band is dominated by the AAD
tautomer, on the basis of the comparison with the assignment
of isocytosine itself in various solvents.[8]
To acquire information about the size and size distribution
of aggregates, monomer 2 was subjected to vapor pressure
osmometry (VPO) in CHCl3 at 378C, 11–53 mm. It showed a
constant degree of association of 4.4 Æ 0.1 over this concen-
In summary, we have shown an example of the topological
selection of an enantiomerically pure cyclic structure over a
helical one upon aggregation of an enantiomerically pure
monomer 2 containing a self-complementary hydrogen-bond-
ing motif. In fact, when the same chiral angle bar, the
bicyclo[3.3.1]nonane framework, was used and a hydrogen-
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Communications
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Received: May 3, 2010
Revised: October 27, 2010
Published online: January 24, 2011
Keywords: H-bonding · molecular belts · self-assembly ·
.
tautomerization · topological selectivity
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