Molecularly Defined Nanostructures Based on a Novel AAA-DDD Triple Hydrogen-Bonding Motif

Article abstract of DOI:10.1002/anie.201510423

A facile and flexible method for the synthesis of a new AAA-DDD triple hydrogen-bonding motif is described. Polytopic supramolecular building blocks with precisely oriented AAA and DDD groups are thus accessible in few steps. These building blocks were used for the assembly of large macrocycles featuring four AAA-DDD interactions and a macrobicyclic complex with a total of six AAA-DDD interactions.

Full text of DOI:10.1002/anie.201510423

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International Edition: DOI: 10.1002/anie.201510423
German Edition: DOI: 10.1002/ange.201510423
Hydrogen Bonds
Molecularly Defined Nanostructures Based on a Novel AAA–DDD
Triple Hydrogen-Bonding Motif
Marcus Papmeyer, ClØment A. Vuilleumier, Giovanni M. Pavan, Konstantin O. Zhurov, and
Kay Severin*
Abstract: A facile and flexible method for the synthesis of
a new AAA–DDD triple hydrogen-bonding motif is described.
Polytopic supramolecular building blocks with precisely
oriented AAA and DDD groups are thus accessible in few
steps. These building blocks were used for the assembly of large
macrocycles featuring four AAA–DDD interactions and
a macrobicyclic complex with a total of six AAA–DDD
interactions.
blocks with precisely oriented AAA and DDD groups in few
steps. The utility of such building blocks is demonstrated by
the formation of large macrocycles. Furthermore, we report
the synthesis of a macrobicyclic complex resulting from the
self-assembly of five components by six AAA–DDD inter-
actions.
A practical route for the synthesis of useful supramolec-
ular building blocks with AAA/DDD motifs should 1) enable
facile synthesis and purification, 2) provide the desired
compounds in high yields, 3) provide access to building
blocks with different geometry and solubility, and 4) enable
the preparation of polytopic building blocks with multiple
AAA/DDD units.
In our attempt to realize a synthetic method with these
characteristics, we chose aromatic aldehydes for commencing
the synthesis. Following a procedure developed by Meyer and
co-workers,[4] we first synthesized diamino-substituted dihy-
dropyridines by the reaction of benzaldehyde with methyl- or
ethyl 3,3-diaminoacrylate hydrochloride in the presence of
K2CO3. Analogous dihydropyridines have been used by
Zimmerman and Murray as DDD units,[1k] but they were
susceptible to tautomerization.[1e, 4,5] We therefore decided to
directly add an oxidation step with DDQ, which gave the
diaminopyridines 1a and 1b in good overall yields
T
he combination of a triple hydrogen-bond acceptor AAA
with a triple hydrogen-bond donor DDD is known to give
a highly stable complex in apolar organic solvents.[1] A first
AAA–DDD complex was described in 1992 by Zimmerman
and Murray,[1k] and several other AAA–DDD motifs[1] and
two AAAA–DDDD pairs[2] have been reported since. The
association constants of AAA–DDD complexes in apolar
organic solvents such as chloroform typically exceed 105 mÀ1
.
The extraordinary strength of these complexes is a result of
the presence of multiple favorable secondary interactions.[3]
For a system with a positively charged DDD donor, a re-
markable value of Ka = 3 ” 1010 mÀ1 has been measured.[1d]
Given the high stability of AAA–DDD complexes, such
a triple hydrogen-bonding motif is an ideal, yet largely
unexplored, candidate for structural supramolecular chemis-
try. Molecularly defined nanostructures based on multiple
AAA–DDD interactions are unknown, and a first example of
a supramolecular polymer was only recently described.[1a] The
difficulty of employing the AAA–DDD motif for the
construction of more elaborate structures stems from the
fact that polytopic building blocks with two or more AAA/
DDD groups are difficult to access with the synthetic routes
described thus far. Typical syntheses involve low-yielding
steps, especially for the construction of the AAA part, and do
not allow straightforward functionalization of the backbone.
Below, we describe the synthesis and characterization of
a new and easily accessible AAA–DDD motif. Importantly,
our method enables the preparation of polytopic building
[*] Dr. M. Papmeyer, C. A. Vuilleumier, Dr. K. O. Zhurov, Prof. K. Severin
Institut des Sciences et IngØnierie Chimiques
École Polytechnique FØdØrale de Lausanne (EPFL, Switzerland)
E-mail: kay.severin@epfl.ch
Dr. G. M. Pavan
Department of Innovative Technologies
University of Applied Sciences and Arts of Southern Switzerland
Galleria 2, 6928 Manno (Switzerland)
Supporting information and ORCID(s) from the author(s) for this
article are available on the WWW under http://dx.doi.org/10.1002/
anie.201510423.
Scheme 1. Synthesis of triply hydrogen-bond acceptor 2 and triple
donor 3.
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(Scheme 1). The triple donor 2 was then obtained by
protonation of 1b with HCl and ion exchange with sodium
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBArF).
To synthesize the triple acceptor 3, we adopted a cycliza-
tion method originally introduced by Besson et al. for the
preparation of pyrimidin-4(3H)-ones starting from anthra-
nilic acid derivatives.[6] Treatment of 1b[7] with N,N-dimethyl-
formamide dimethyl acetal and subsequent heating with
butylamine in acetic acid under microwave conditions yielded
a mixture of the desired dipyrimidine-4,6(3H,7H)-dione 3 and
a monocyclized pyrimidone intermediate. The latter could be
converted into the product by repeating the two steps for
a second time to give 3 in an overall yield of 81% (Scheme 1).
The syntheses of 2 and 3 are easily scalable and can be
performed on multigram scale.
With this straightforward synthesis in hand, we inves-
tigated the binding of the AAA–DDD couple 2 and 3 in
1
dichloromethane. H NMR titration experiments in CD2Cl2
gave binding isotherms that were linear until a 1:1 molar ratio
was reached, followed by an abrupt change (see the Support-
ing Information, Figure S1). Such a behavior is expected for
Scheme 2. Self-assembly of different AAA/DDD building blocks to
discrete [2+2] macrocycles.
an association constant higher than 104 mÀ1 [8]
To obtain
.
a numerical value for the binding constant, isothermal
titration calorimetry (ITC) was then carried out (288 K,
CH2Cl2). Interestingly, the titration data were best fitted
assuming a 2:1 binding model involving a ternary complex
(2·3)·3 aside from the expected dimer 2·3 (Figures S3 and S4).
The association constant for dimer formation was Ka1 =
1.1(Æ 0.2) ” 107 mÀ1. Whereas this value is in the expected
range for an AAA–DDD system, it is lower than the strongest
interaction reported in the literature (3 ” 1010 mÀ1).[1d] Pre-
sumably, the weaker binding is due to the diminished basicity
of the pyrimidone nitrogen atoms in acceptor 3 compared to
the 2,3-fused pyridine rings employed by Leigh and co-
workers. For the complexation of the second AAA unit 3, an
association constant of Ka2 = 1.8(Æ 0.2) ” 105 mÀ1 was deter-
mined. It is worth noting that the formation of a 2:1 complex
with a weaker second binding constant has also been observed
for an AAAA–DDDD system.[2a] Unfortunately, it was not
possible to investigate the association of 2 and 3 by
fluorescence spectroscopy as both compounds are non-
fluorescent.
To utilize AAA–DDD interactions for the construction of
more complex supramolecular assemblies, it is necessary to
incorporate multiple AAA and/or DDD units in a single
molecular building block. Here, the advantage of our new
method becomes evident. By applying our synthetic proce-
dure to aromatic dialdehydes (isoterephthaldehyde and
naphthalene-2,7-dicarbaldehyde), we were able to access the
corresponding DDD-DDD building blocks 4 (85% yield) and
5 (63%), as well as the AAA-AAA building blocks 6 (43%)
and 7 (61%; all yields were calculated starting from the
corresponding aromatic dialdehyde; Scheme 2). The yields of
43–85% are considerably higher than those recently reported
by Song and co-workers for the only other synthesis of ditopic
AAA-AAA and DDD-DDD units.[1a]
macrocyclic assemblies to occur upon mixing of equimolar
amounts of donors and acceptors. Considering the angle
between the donor and acceptor sites (ca. 1208), the formation
of [3+3] macrocycles was expected. However, it is known that
AAA–DDD systems can tolerate a deviation from the ideal
1808 bond angle.[1d] Therefore, the formation of [2+2] macro-
cycles seemed possible as well. The entropically favored
formation of simple [1+1] dimers appeared unlikely because
such assemblies would display more strongly bent AAA–
DDD units.
Analysis of a CD2Cl2 solution containing equimolar
amounts of 4 and 6 (5.0 mm) by 1H NMR spectroscopy
(298 K, 400 MHz) revealed upfield shifts of the signals of Ha
and HA, which point into the macrocycle (see Scheme 2), as
well as significant downfield shifts and broadening of the NHB
signals of 4 (Figure 1a). This shift was expected as the NH
bonds become more polarized upon complex formation.
Interestingly, a small upfield shift of 0.06 ppm was also
observed for the signals of the BArFÀ anion, indicating a weak
interaction between the cationic macrocycle and the “non-
coordinating” anion. A similar shift was not observed for the
simple dimer 2·3.
Analysis of solutions containing 4 and 6 by high-resolution
mass spectrometry with nanoelectrospray ionization gave
a clean mass spectrum, with the two most prominent peaks
corresponding to the ions [4262(BArF)]3+ and [4262(BArF)2]2+
(Figure 1b). Peaks corresponding to the [1+1] or [3+3]
macrocycles were not detected at all.
The formation of a single aggregate was confirmed by
diffusion-ordered NMR spectroscopy (DOSY; CD2Cl2,
298 K, 400 MHz, 1.0 mm), which confirmed the presence of
a defined assembly with a diffusion coefficient of D = 3.98 ”
10À6 cm2 sÀ1. Taken together, the data are good evidence for
the hypothesis that the combination of 4 and 6 exclusively
gives the [2+2] macrocycle 42·62.
Building blocks 4–6 are relatively rigid, and the two AAA/
DDD units are oriented in a divergent fashion. Owing to the
large degree of preorganization, we expected the formation of
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unfavorable columbic interactions (!slow exchange with
excess 4), whereas the neutral acceptor 6 can readily associate
and exchange with complex 42·62 (!fast exchange with excess
6). This assumption is corroborated by the ITC data described
above, which showed that one donor can coordinate to two
acceptor units. The exchange between 4 and 42·62 was also
studied by exchange spectroscopy (EXSY) in CD2Cl2. We
were able to derive an exchange rate constant of k = 0.40 sÀ1,
which confirmed the slow exchange between the dicationic
building block and the tetracationic macrocycle.
To complement our experimental studies, we employed
all-atom molecular dynamics (MD) simulations, which have
proven to be an effective technique for studying supramolec-
ular systems.[14] The entire simulation work was carried out
with AMBER 12.[15] Initially, 160 monomers 4 and 6 (80 + 80)
were dispersed in a simulation box containing CH2Cl2
molecules and 160 BArFÀ counterions (for computational
details, see the Supporting Information). This system under-
went 400 ns of MD simulations in NPT periodic boundary
conditions at 258C and 1 atm of pressure. During the MD
simulation, spontaneous self-assembly of the monomers
occurred. Two [2+2] macrocycles were formed, one of
which is depicted in Figure 2. Some short oligomeric species
Figure 1. a) 1H NMR spectra (CD2Cl2, 298 K, 400 MHz) of acceptor 6
(5 mm, top), an equimolar mixture of 4 and 6 (5 mm each, middle),
and donor 4 (5 mm, bottom). For the proton assignment, see
Scheme 2. b) ESI mass spectrum of a solution containing 4 and 6
showing peaks corresponding to the tetramer 42·62.
Similar results were obtained for solutions containing the
donor–acceptor combinations 4 + 7, 5 + 6, and 5 + 7. In all
cases, we were able to observe dominant peaks for the [2+2]
macrocycles by mass spectrometry (Figures S28–S33). DOSY
spectra revealed the presence of a single large species with
diffusion coefficients of 3.74 ” 10À6 (42·72), 3.56 ” 10À6 (52·62),
and 3.40 ” 10À6 cm2 sÀ1 (52·72). These values indicate that the
relative size of the macrocycles follows the order 42·62 <
42·72 ꢀ 52·62 < 52·72, which is in agreement with the size
increase for assemblies based on the larger naphthyl-derived
monomers 5 and 7 compared to the phenyl-based building
blocks 4 and 6.
The assemblies described above are first examples of
macrocycles based on AAA–DDD interactions. Until now,
the synthesis of H-bonded cyclic tetramers has relied on AD–
DA,[9] AAD–DDA,[10] or self-complimentary AADD inter-
actions.[11] H-bonded tetramers are also found in G quartets
and their synthetic analogues.[12,13]
To obtain information on the kinetic stability of macro-
cycle 42·62, we recorded 1H NMR spectra of solutions
containing a constant amount of acceptor 6 (2.5 mm) and
a variable amount of donor 4 (Figures S5–S8). When the
amount of 6 was in excess compared to 4, the exchange
between free 6 and macrocycle 42·62 was found to be fast on
the NMR time scale. However, slow exchange between
monomer and macrocycle was observed when the concen-
tration of donor 4 was larger than that of acceptor 6. These
data suggest that exchange reactions proceed by an associa-
tive mechanism. The cationic nature of macrocycle 42·62
inhibits the association of doubly charged 4 owing to
Figure 2. Structure of a [2+2] macrocycle formed from building blocks
4 and 6 during MD simulation viewed from the top (left) and from the
side (right).
and six [1+1] macrocycles were also observed (see the
Supporting Information). As the MD run is limited to
a short time window (400 ns), this result should be regarded
as a snapshot of the assembly process, rather than as the full
equilibration of the self-assembling system. Nevertheless, this
explorative MD simulation demonstrates that self-assembly
of [2+2] macrocycles may occur very rapidly in solution. MD
simulations of [1+1], [2+2], and [3+3] macrocycles, as well as
of the single monomers 4 and 6, in explicit CH2Cl2 solvent
with BArFÀ counterions were employed to calculate the free
energy of formation for macrocycles with different sizes.[16,17]
The self-assembly energies confirm the preferential formation
of [2+2] macrocycles in solution over smaller [1+1] or larger
[3+3] macrocycles (see the Supporting Information).
Aside from molecularly defined macrocyclic assemblies,
we have examined the formation of a macrobicyclic complex
based on AAA–DDD interactions. Multipoint hydrogen
bonding has been employed extensively for the construction
of hydrogen-bonded cages.[18] However, to the best of our
knowledge, there is no example of a cage-like assembly
relying on AAA–DDD interactions.
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then relaxed in the presence of explicit CH2Cl2 solvent
molecules and BArFÀ counterions. An MD simulation
(400 ns) conducted under the same conditions as described
for the macrocycles demonstrated that the 83·92 assembly is
stable (Figure 3b). At equilibrium, the MD simulation shows
a side-on binding mode of donor 8, with the AAA units of 9
being nearly perpendicular to the central aryl ring of 9. The
free energy of formation per AAA–DDD interaction was to
be found negative (DG = À2.1 kcalmolÀ1), but less favorable
than that of the [2+2] assembly 42·62 (DG = À7.9 kcalmolÀ1).
This difference is due to the increased conformational
flexibility of the building blocks 8 and 9 compared to 4 and
6, which results in a less favorable entropy term. In fact, the
enthalpic contributions per AAA–DDD interaction were
found to be similar for the macrocycle (À15.3 kcalmolÀ1) and
the macrobicycle (À12.9 kcalmolÀ1).
In summary, we have developed a facile and flexible
method for the synthesis of supramolecular building blocks
containing triple hydrogen-bond donor or acceptor groups. A
key advantage of our process is the possibility to access
polytopic building blocks with precisely oriented AAA/DDD
groups in few steps. This finding paves the way for the
utilization of the highly stable AAA–DDD interaction in
structural supramolecular chemistry. As representative exam-
ples, we have prepared tetrameric macrocycles from bent,
ditopic building blocks, and a macrobicyclic complex from
five components, including a tritopic acceptor. It is likely that
our method can be extended to a wide variety of polytopic
compounds, as well as to Janus-type building blocks contain-
ing AAA and DDD groups. These compounds should enable
the formation of novel cage structures, crystalline molecular
networks, and novel supramolecular polymers. Studies in this
direction are ongoing in our laboratory.
Figure 3. a) Structure of anthracene donor 8 and triple acceptor 9.
b) Equilibrated structure of the macrobicyclic complex 83·92 obtained
in the MD simulations.
Starting from literature-known 1,8-bis(pinacolboryl)an-
thracene and the corresponding 4-bromophenylpyridine unit,
we synthesized the clip-shaped donor 8 (Figure 3a) by
employing standard Suzuki coupling conditions. The tritopic
acceptor 9 was obtained from the corresponding trialdehyde
in a similar fashion as described above. Sextuple donor 8 was
isolated in 62%, and 9 was obtained in 75% overall yield over
two steps. The good yields demonstrate once more the utility
of our new synthetic strategy for the preparation of polytopic
building blocks.
Acknowledgements
This work was supported by the Ecole Polytechnique
FØdØrale de Lausanne (EPFL), the Swiss National Science
Foundation, and an EPFL Fellowship co-funded by Marie
Curie FP7 Grant agreement 291771 (M.P.).
Based on simple geometric considerations, we reasoned
that the building blocks 8 and 9 would aggregate to give the
macrobicyclic complex 83·92. The NMR data were in full
accordance with this hypothesis. When increasing amounts of
8 were added to a solution containing 9, we observed
Keywords: hydrogen bonding · macrocycles · self-assembly ·
supramolecular cages · supramolecular chemistry
1
differences for the chemical shifts of some H NMR signals
up to a ratio of 8/9 = 3:2 (Figure S11). The addition of more 8
led to the appearance of a second set of signals corresponding
to free 8. These results indicate the formation of a kinetically
rather inert complex of the stoichiometry 83·92, which is in
slow exchange with excess 8. DOSY measurements (CD2Cl2,
298 K, 400 MHz, 1.0 mm) revealed the formation of a single,
defined aggregate with a diffusion coefficient of D = 1.57 ”
10À6 cm2 sÀ1. This value is significantly smaller than the
diffusion coefficient of the biggest macrocycle 52·72 (3.40 ”
10À6 cm2 sÀ1), which is in line with the expected size of
complex 83·92. The challenging direct detection of 83·92 by
mass spectrometry (Mw = 5.7 kDa) was unfortunately not
successful as only smaller fragments were observed.
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Received: November 10, 2015
Published online: December 22, 2015
Angew. Chem. Int. Ed. 2016, 55, 1685 –1689
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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