Triangular Regulation of Cucurbit[8]uril 1:1 Complexes

Article abstract of DOI:10.1021/jacs.9b00150

Triangular shapes have inspired scientists over time and are common in nature, such as the flower petals of oxalis triangularis, the triangular faces of tetrahedrite crystals, and the icosahedron faces of virus capsids. Supramolecular chemistry has enabled the construction of triangular assemblies, many of which possess functional features. Among these structures, cucurbiturils have been used to build supramolecular triangles, and we recently reported paramagnetic cucurbit[8]uril (CB[8]) triangles, but the reasons for their formation remain unclear. Several parameters have now been identified to explain their formation. At first sight, the radical nature of the guest was of prime importance in obtaining the triangles, and we focused on extending this concept to biradicals to get supramolecular hexaradicals. Two sodium ions were systematically observed by ESI-MS in trimer structures, and the presence of Na⁺ triggered or strengthened the triangulation of CB[8]/guest 1:1 complexes in solution. X-ray crystallography and molecular modeling have allowed the proposal of two plausible sites of residence for the two sodium cations. We then found that a diamagnetic guest with an H-bond acceptor function is equally good at forming CB[8] triangles. Hence, a guest molecule containing a ketone function has been precisely triangulated thanks to CB[8] and sodium cations as determined by DOSY-NMR and DLS. A binding constant for the triangulation of 1:1 to 3:3 complexes is proposed. This concept has finally been extended to the triangulation of ditopic guests toward network formation by the reticulation of CB[8] triangles using dinitroxide biradicals.

Full text of DOI:10.1021/jacs.9b00150

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Article
Triangular regulation of cucurbit[8]uril 1:1 complexes
Sébastien Combes, Khoa Truong Tran, Mehmet Menaf Ayhan, Hakim Karoui, Antal
Rockenbauer, Alain Tonetto, Valérie Monnier, Laurence Charles, Roselyne Rosas, Stéphane
Viel, Didier Siri, Paul Tordo, Sylvain Clair, Ruibing Wang, David Bardelang, and Olivier Ouari
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b00150 • Publication Date (Web): 26 Feb 2019
Downloaded from http://pubs.acs.org on February 26, 2019
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Triangular regulation of cucurbit[8]uril 1:1 complexes
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†
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†,∆
†
Sébastien Combes, Khoa Truong Tran, Mehmet Menaf Ayhan, Hakim Karoui, Antal
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≡
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†

Rockenbauer, Alain Tonetto, Valérie Monnier, Laurence Charles, Roselyne Rosas, Stéphane
†,≠
†
†
§
ψ*
†*
Viel, Didier Siri, Paul Tordo, Sylvain Clair, Ruibing Wang, David Bardelang, Olivier
†
*
Ouari,
†
∆
Aix Marseille Univ, CNRS, ICR, Marseille, France, Department of Chemistry, Gebze Technical University, P.K.:141,
1400 Gebze, Kocaeli, Turkey, Institute of Materials and Environmental Chemistry, Hungarian Academy of
Sciences, 1519 Budapest, P.O. Box. 286, and Department of Physics, Budapest University of Technology and
Economics 1111 Budapest, Hungary, Aix Marseille Univ, CNRS, Centrale Marseille, FSCM (FR1739), PRATIM, F-13397
Marseille, France, Aix Marseille Univ, CNRS, Centrale Marseille, FSCM, Spectropole, Marseille, France, Institut
Universitaire de France, F-75005 Paris (France), Aix Marseille Univ, Univ Toulon, CNRS, IM2NP, Marseille, France,
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of
Macau, Taipa, Macau, China.
‡
4
≡

≠
§
ψ
ABSTRACT: Triangular shapes have inspired scientists over time and are common in nature, such as the flower petals of
oxalis triangularis, or the triangular faces of tetrahedrite crystals or on the icosahedron faces of virus capsids.
Supramolecular chemistry has enabled the construction of triangular assemblies, many of which possess functional
features. Among these structures, cucurbiturils have been used to build supramolecular triangles and we recently
reported paramagnetic - cucurbit[8]uril (CB[8]) triangles but reasons of their formation remain unclear. Several
parameters have now been identified to explain their formation. At first sight, the radical nature of the guest appeared of
prime importance to get the triangles and we focused on extending this concept to biradicals for obtaining
supramolecular hexaradicals. Two sodium ions were systematically observed by ESI-MS in trimer structures and the
+
presence of Na triggered or strengthened the triangulation of CB[8]:guest 1:1 complexes in solution. X-ray crystallography
and molecular modelling have allowed proposing two plausible sites of residence for the two sodium cations. We then
found that a diamagnetic guest with an H bond acceptor function is equally good at forming CB[8] triangles. Hence, a
guest molecule containing a ketone function has been precisely triangulated thanks to CB[8] and sodium cations as
determined by DOSY-NMR and DLS. A binding constant for the triangulation of 1:1, to 3:3 complexes, is proposed. This
concept has finally been extended to the triangulation of ditopic guests toward network formation by reticulation of
CB[8] triangles using dinitroxide biradicals.
INTRODUCTION
superstructures. On the other hand, cucurbit[n]urils
(CB[n]) have emerged as a unique series of synthetic
macrocycles whose main members (CB[5] to CB[8]) have
demonstrated outstanding recognition properties.
Among them, CB[6] has already been used for the
construction of triangular molecular necklaces, and
triangular structures are periodically described in
honeycomb crystal structures containing CB[6] or CB[8].
Among the many guests that have been included in
CB[n], nitroxides enabled the exploration of unusual
properties mainly by EPR spectroscopy. CB[n] have been
shown to modulate the magnetic exchange interaction
between nitroxides. Their paramagnetic nature has
allowed nitroxides to be used as spin probes coupled to
EPR to investigate allosteric systems,
dynamics and CB[8] host-guest aggregates in the form of
triangular 3:3 complexes (Scheme 1).
1
2
Advanced triangular assemblies have recently been
described at the nanoscale, for example scalene molecular
triangles with all sides of different lengths, or molecular
sierpinsky triangles that possess fractal patterns of
triangular arrangements. Wisely designed DNA strands
1
3-16
1
1
7
2
3
4
18
and proteins have also been triangulated. In chemistry,
5
triangular molecules have been used as templates for
6
7
interlocked structures,
in catalysis or for the
8
,9
19
construction of spin triangles, most being covalent or of
metal-ligand type. However, the supramolecular
triangulation of 1:1 host:guest complexes is surprisingly
rare. Controlling factors exerting their influence beyond
:1 complexation are few,
20
1
0
1
0,11
21
1
and new systems featuring
rotational
22
triangular regulation could represent a significant step
toward precisely organizing 1:1 complexes in discrete
2
3-25
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(
oxazolidinoxyl or pyrrolidinoxyl) with
isoindolinoxyl before cleavage of acetyl protecting groups
Scheme S1).
a protected
(
0
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Figure 1. DFT minimized structures of the Isodoxa•CB[8] 1:1
complexes with the host centred on nitroxide parts I or D
(B3LYP/6-31G(d)
dispersion and CPCM as water continuum).
27
with the D3(BJ) correction for
28
29
Because the height of CB[8] is too small (6.1 Å, 9.1 Å with
van der Waals radii) to make it fully complexing Isodoxa,
CB[8] can bind either the isoindolinoxyl moiety (I part,
Figure 1a) or the doxyl moiety (D part, Figure 1b). The
EPR spectrum of Isodoxa in water at room temperature
has a 15-line pattern with 9 lines in the center, Figure 2a).
Six additional lines (*) are also present due to forbidden
transitions appearing because of the magnitude of the
intramolecular spin exchange interaction J ≈ a as often
1 N
reported for similar compounds.
CB[8], the 9-line pattern in the central region of the
spectrum changes to a 7-line pattern and the satellite
lines are at different positions (Figure 2b, blue spectrum).
This new spectrum indicates that a significant change in
Scheme 1. Structures of cucurbit[8]uril (CB[8]) and of the
guest molecules studied for a) triangulation of a biradical, b)
triangulation of a diamagnetic molecule and c) reticulation
by CB[8] triangulation (D and I stations in a) are for Doxyl
and Isoindolinoxyl fragments respectively).
23-
Several reports have described nitroxide-CB[8] triangles
30,31
In the presence of
25
and the absence of triangles for a nitroxide analogue
N-Me instead of N-O ) suggested that the triangular

25
(
arrangement of CB[8] complexes was limited to nitroxide
radicals. Yet, the occurrence of these triangular
arrangements remains largely unexplained and even if
nitroxides have been used as interesting building-blocks
1
the J interaction of Isodoxa has occurred, due to
inclusion complexation. Superposed spectra at 0.5 equiv
CB[8] (Figure S1) suggest slow exchange between the free
and the included biradical with respect to the EPR
timescale. To estimate the degree of binding, EPR
titrations were performed gradually increasing the host
concentration and monitoring the spectral changes
26
in supramolecular chemistry, it would be interesting to
extend this triangulation concept to the larger palette of
diamagnetic compounds. So, we decided to investigate a
cationic dinitroxide biradical (Isodoxa, Scheme 1a) to
prepare triangular hexaradicals followed by another class
of (diamagnetic) compounds for triangulation (Scheme
1b). We propose that other guest molecules, compatible
with CB[8] and featuring similar H bond acceptors near
the entrance of the cavity can also trigger the formation
of supramolecular triangles. Finally, reticulation thanks to
the CB[8] triangle motif was assessed using a di-TEMPO
biradical connected by a flexible linker (Scheme 1c, 1,3-
bis-TEMPO-2-hydroxy-trimethylenediamine: bTHT).
(
Figure S1). Simulations of this set of spectra thanks to a
32
two-dimensional simulation program
determine a binding constant K
allowed to
5
-1
a
= 2.04 × 10 M assuming
main formation of a 1:1 complex (no further change after
1.5 equiv of host, even if 1:2 complexes cannot completely
be ruled out). CB[8] can, in principle, bind either of the
two moieties of Isodoxa, the I part or the D part, by a
process expected to involve hydrophobic effects and ion-
dipole interactions (cationic charge of the guest). The
spin exchange interaction of Isodoxa in water is J = 2.175
1
mT and is unremarkable for this kind of biradical (de--
e- (X-
ray) = 10.8 Å, Figure S2).
with CB[8] (J
changes in the surrounding of the biradical as a
consequence of its inclusion in CB[8]. DFT calculations of
RESULTS AND DISCUSSION
Hexaradical
characterization of the cationic biradical, Isodoxa
Scheme 1), is described in the supporting information.
triangles.
The
synthesis
and
30,31
However, this value increases
(
1
= 2.937 mT) presumably due to significant
Briefly, the biradical was obtained by a convergent
synthesis involving the reaction of a suitable nitroxide
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Figure 2. EPR spectra of Isodoxa (forbidden transitions: *) (a) before (top) and after (bottom) partial reduction with sodium
ascorbate. Controls have showed that the D part of Isodoxa is reduced. The blue spectrum (b) is that of included Isodoxa in
CB[8] before (top) and after reduction by ascorbic acid (bottom). The I part is included in CB[8] (see text and Figure S3). When
sodium chloride was added (c, pink spectrum, top), the blue spectrum was replaced by a new feature with broader lines. When
ascorbic acid was added (c, bottom), a 7-line pattern assigned to the supramolecular trinitroxide {partly reduced
Isodoxa •CB[8] } was observed (green spectrum) for which the only remaining spin exchange interaction is J (proposed
3 3 2
structures next to EPR spectra, proposed assemblies in (d) and corresponding spin exchange interactions in (e)); superposed
spectra (Isodoxa in 2b and Isodoxa•CB[8] in 2c are shown to clarify comparisons and assess the impact of the added species).
the Isodoxa•CB[8] 1:1 complex considering various host
hydroxylamines22,23,33-35 suppressed J
typical 7-line pattern of nitroxide triangles
bottom, green spectrum assigned to 71% of partly reduced
Isodoxa •CB[8] , a = 0.48 mT plus a 29% contribution of
3-line pattern assigned to partly reduced
Isodoxa •CB[8] , a = 1.52 mT, Figure S5). Indeed, for 3
spins in interaction such that Jij >> a , a 7-line pattern is
expected with a successive intensity ratio of 1:3:6:7:6:3:1
1
and resulted in the
23-25
positions along the guest indicate a clear preference for
(Figure 2c
-1
the I-in complex by at least 6 kcal.mol (Figure 1 left).
With CB[7], EPR spectra are in line with formation of a D-
in complex without ambiguity (see controls, Figure S3)
but the EPR spectrum of the complexed species (Figure
S3) is different from that obtained with CB[8] (Figure 2b,
blue spectrum). This supports complexation of CB[8] by
the other side (I-in complex) as suggested by DFT. In this
geometry, the isoindolinoxyl part is well positioned to
engage in interactions compatible with triangulation (N-
O• bond pointing toward CB[8] entrance, Figure 1a) but
not the other geometry (in the D-in complex, the N-O•
bond points toward the CB[8] cavity walls, Figure 1b).
As sodium cations were reported to improve triangle
3
3
N
a
1
1
N
N
23-25,36
and lines separated by ~a
N
/3.
This shows that, in
reducing conditions, CB[8] triangles are present (Figure
2d and 2e, bottom) and that the only remaining exchange
interaction is J . But to get such a 7-line spectrum,
2
distances between the three nitroxide radicals must
remain between nearly 8 and 9 Å. Without CB[8] (Figures
2a and 2b, bottom), EPR showed that the doxyl radical (D
moiety) is reduced faster than the isoindolinoxyl radical (I
moiety, remaining 3-line spectrum). The I part is included
24,25
formation,
we titrated 1:1 and 1:2 guest•host mixtures
+
with NaCl (example at 1:2 ratio in Figure S4). The Na
cation is typically competitive at high concentration (> 5
mM) with EPR signatures corresponding to those of the
free guest (Figure S4), but when used at 4 or 5 mM in a
mixture containing Isodoxa (1 mM) and CB[8] (2 mM), a
new spectrum was observed (Figure 2c, pink spectrum).
Less sodium gives no change compared to the blue
spectrum while more sodium induces competition (black
spectrum, Figure 2a top). The pink spectrum is different
from the EPR spectrum of free Isodoxa or of
Isodoxa•CB[8] and the EPR lines are broader, in line with
a polyradical (slower tumbling, in agreement with a
higher molecular weight species). If the assumption of
triangle formation is correct (3:3 complex, Figure 2d), a
in CB[8] (a
of the high field line).
= 0.054 mT, typical broadening
EPR spectra using the other half
N reduced Isodoxa
21-25
of the dinitroxide (doxyl mononitroxide, supporting
information, compound 9) showed that the results in
Figure 2 cannot be explained by the inclusion of the D
moiety of Isodoxa in CB[8] (aN free 9 = 1.56 mT and aN 9•CB[8]
= 1.47 mT). Additional controls with compound 9 showed
that no additional EPR lines are observed upon addition
of CB[8] and NaCl, in line with an absence of triangle
+
formation (instead, we have observed Na competition).
While temperature has little effect on the 1:1 complex (see
Variable-Temperature EPR, Figure S7), rising temperature
of a solution of Isodoxa, CB[8] and NaCl to 358 K has
afforded the EPR spectrum of the 1:1 complex (Figure S8)
reflecting a rather weak and reversible (Figure S9) 1:1 →
new intermolecular spin exchange interaction J
should occur (Figure 2e, pink) that is difficult to
disentangle from the intramolecular J (≈ a ) interaction
Figure 2e, blue). The addition of ascorbic acid, well
known to reduce nitroxides into EPR silent
2 N
(>> a )
1
N
3:3:x
association
toward
formation
of
the
(
Isodoxa •CB[8] •Na complex.
3
3
x
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1500
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1750
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1850
1900
1950
m/z
Figure 3. ESI-MS spectrum of a mixture of Isodoxa (1) and CB[8] highlighting the formation of CB[8]
theoretical patterns in blue, and experimental ones in red).
3 3
•Isodoxa hexaradicals
(
Mass spectrometry has allowed the detection of
supramolecular hexaradicals in the form of 3:3:2
guest•host•Na complexes, observed at the +5 charge state
at m/z 1046.7 (Figure 3). Besides the peak of Isodoxa at
m/z 400.2 (not shown), electrospray ionization mass
spectrometry (ESI-MS) showed less intense peaks at m/z
317.4 and m/z 1328.7 which correspond to the following
3 3 2
canonical composition {Isodoxa •CB[8] •Na } , balanced
by a chloride or bromide anion, respectively (and hence
detected at the +4 charge state). A less abundant species
at m/z 1160.7 can be assigned to a 4:4 complex
H•••O 123°; O•••H 2.1 Å, O-H•••O 133°), in addition to the
preexisting network of intermolecular CH•••O
interactions typical of cucurbituril assemblies.
+
40
3
7
1
5
+
6+
{
Isodoxa
4
•CB[8]
4
•Na
2
}
that could be the signature of a
20,38
Isodoxa•CB[8] square.
Accurate mass measurements
support the elemental composition proposed for these
four ions (Tables S1 to S4) with relative errors below 1.5
ppm. Increasing the cone voltage to enable more
energetic ion transfer has allowed 1:1 complexes to be
observed, as a result of in-source decomposition of the
trimeric assemblies into monomeric complexes. Since we
noted the systematic presence of two sodium cations per
3:3
complex,
we
postulated
that
the
3:3:2
guest•host•sodium stoichiometry was the most favored for
Isodoxa•CB[8]•Na triangles. In the absence of a relevant
crystal structure, we decided to re-investigate the
previously reported crystal structure of the {4-MeO-
+
3
9
2
3
Figure 4. X-ray structure of the previously reported
TEMPO
3
•CB[8]
3
} triangle to find possible binding sites
23
triradical triangle highlighting (a) the presence of two
ordered water molecules in the centre of the triangle (guest
removed for clarity) and (b) nitroxide-CB[8] interactions.
+
for the two Na cations. Two well-resolved water
molecules were found in the central region of the
triangles (Figure 4a and Figure S10 in green) and they are
strongly hydrogen bonded to the three interior CB[8]
carbonyl rims. There are four H bonds (O•••H 1.5 Å, O-
H•••O 146°; O•••H 1.6 Å, O-H•••O 129°; O•••H 1.7 Å, O-
These two places could be the actual sites for the two Na+
cations despite the short distance separating them of ~ 3.5
Å, because the three carbonyl rims provide a cryptand like
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•-O
•
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•
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•-O
•
•-O
•
•
•
O
O
O
1
2
3
2
3
1
9.0 ± 0.8 Å
9.0 ± 0.8 Å
9.0 ± 0.8 Å
O
O
1
2
2
9.0 ± 0.7 Å
9.4 ± 1.0 Å
11.2 ± 0.9 Å
O
1
2
9.6 ± 1.0 Å
11.6 ± 1.0 Å
11.5 ± 1.0 Å
O
O
O
1
2
3
2
3
1
11.3 ± 1.0 Å
11.7 ± 1.0 Å
12.0 ± 1.0 Å
•-O
•-O
•-O
O
•-O
•-O
•
•-O
•-O
3
2
3
3
•-O
•
O
•
O
3
1
1
Figure 5. DFT minimized structures (top) of the I-I-I, I-I-D, I-D-D and D-D-D {Isodoxa
3
•CB[8]
•Na+
} triangles (B3LYP/6-
3 2
27
28
+
3
1G(d) with the D3(BJ) correction for dispersion) highlighting Na •••O=C interactions and host-host interactions (black
arrows, C-H•••O type), and (bottom) averaged distances between nitroxide oxygen atoms near the centre of the triangles from
molecular dynamic trajectories.
environment with the lone pairs of 5 oxygen atoms
preorganized and available for each of them.
3 3 2
likely, four options for the {Isodoxa •CB[8] •Na } triangles
can be envisioned considering which moiety points to the
heart of the triangle: the (i) I-I-I, (ii) I-I-D, (iii) I-D-D and
(iv) D-D-D triangles (Figure 5). For I-I-I, guest rotation
around their main axis would not change much the
orientation of the I nitroxides, pointing toward the heart
Recent reports have shown the possibility for rubidium
cations to be placed at the proposed water molecules sites
of the {4-MeO-TEMPO
CB[8] triangles. In another example, two Ag cations are
3
•CB[8]
3
}, within networks of
4
0
+
•
•
of the triangles and keeping inner triangle, O •••O
also placed in the water molecules sites in a CB[7]
interspin distances about constant (in line with the green
spectrum of Figure 2). Conversely, for D-D-D, such a
rotation is associated with a time fluctuation of the
4
1
triangular assembly. So beside the well-known role of
4
2
cations to (i) lid cucurbiturils cavities, (ii) decrease guest
4
3
44
●
affinities, (iii) seal cucurbituril capsules, or (iv) behave
position of the three doxyl N-O bonds inside the three
4
5
+
•
•
as supramolecular lubricants for guest slippage, Na
CB[8], associated with an increase of the O •••O interspin
cations can also (v) trigger the triangular arrangement of
relevant guest•CB[8] 1:1 complexes into 3:3 complexes as
for Isodoxa, or tighten previously existing CB[8]
distances and a time fluctuation of these distances (i. e. of
the J coupling). The four possible arrangements (I-I-I, I-
2
21
I-D, I-D-D, D-D-D) were investigated by DFT calculations
and molecular dynamic (MD) simulations in water
25
+
+
triangles. Several studies have shown that Na or K
cations can be used as atomic glue to maintain several
+
placing the two Na cations at the water molecules sites of
4
6
23
subcomponents into well-defined structures. Another
aspect of the {4-MeO-TEMPO •CB[8] } structure is that
3 3
the {4-MeO-TEMPO •CB[8] } crystal structure.
3
3
Structure minimization showed that the four triangles
maintain their compact, triangular shape and among
them, the I-I-I version is the most stable by at least 16
the three nitroxide functions point to the exterior of a
neighboring CB[8]. Distance measurements between the
aminoxyl oxygen atoms and CB[8] hydrogen atoms
-1
kcal.mol . The guests are positioned to maximize the
●
indicate that there are five weak N-O •••H-C interactions
three ion-dipole interactions of the ammoniums toward
the outside directed carbonyl rims. The two sodium
cations are nearly ideally placed at the heart of the
●
●
(
2.52 ≤ d O •••H-C ≤ 2.88 Å, 96.2° ≤  O •••H-C ≤ 102.0°,
●
Figure 4b) and three orthogonal N-O •••C=O interactions
distances of 2.8, 2.8 and, 3.0 Å, angles of 102°, 105°, and,
11° respectively). Orthogonal C=O•••C=O interactions are
well documented in the literature and analogous N-
O •••C=O interactions are significant in this case (sum of
(
1
triangle in a cryptand like surrounding (distances Na
O=C (singly engaged): 2.38, 2.40, 2.44 Å, (bifurcated):
2.49, 2.50, 2.52 Å and Na -O=C (singly engaged): 2.36,
1
-
47
2
●
2.44, 2.44 Å, (bifurcated) 2.48, 2.52, 2.52 Å). The inner
triangle nitroxides are engaged in multiple weak guest-
van der Waals radii of oxygen and carbon atoms equal 3.2
4
8
●
Å).
To get a deeper view of the {Isodoxa
host N-O •••H-C interactions, six for I-I-I (2.33, 2.45, 2.50,
3 3
•CB[8] •Na
2
}
2.52, 2.62, 2.63 Å), four for I-I-D (2.35, 2.51, 2.62, 2.67 Å),
two for I-D-D (2.50 and 2.76 Å) and none for D-D-D.
triangular architecture, we performed DFT calculations
and molecular dynamics simulations. Even if a triangle in
which three I-parts engaged in CB[8] seems the most
●
●
However, O •••O distances at the heart of the other
triangles cannot be estimated by DFT mainly due to guest
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Figure 6. Excerpts (4 – 0 ppm) of the 500 MHz H DOSY NMR spectra obtained at 300 K for a 1 mM 4AK D
2
O solution in the
1
presence of 1 mM CB[8]: a) without, and b) with NaCl at 5 mM. The horizontal and vertical axes show H chemical shifts and
diffusion coefficients (logarithmic scale) respectively. In a), the H DOSY spectrum corresponding to free 4AK (i.e. in the
absence of CB[8]) is also showed as a superimposed grey trace to ease the comparison. The dashed horizontal lines emphasize
the D values of 4.6, 2.1, and 1.5 10 m s , which correspond to the diffusion coefficients of free 4AK, 1:1 4AK•CB[8] complexes,
1
-10
2
-1
+
and 3:3 4AK•CB[8] (Na ) triangular complexes, respectively (see text). i denotes an unassigned impurity.
rotation around the CB[8] C
8
axis and rotation of the
function by a carbonyl group and synthesized the amine
ketone 4AK (Figure 6) in which the tetramethylcyclohexyl
skeleton was kept similar to that of TEMPO (see
●
doxyl N-O bonds facing the walls of CB[8], introducing
temporal variation of these distances. We thus used MD
simulations to get statistical data.
Supporting
Information
for
synthesis
and
characterization). We also introduced a protonable amine
site in position 4 to anchor the guest inside CB[8] and
favor CB[8] solubilization. Upon addition of 1 mM CB[8],
+
MD calculations first showed that Na cations positioned
near the center of the complexes are essential to maintain
the trimer arrangement in the triangular shape and, in
these conditions, the four kinds of triangles are stables
over 100 ns. The averaged O •••O interspin distances are
given for the three nitroxides at the center of the triangles
1
all the H NMR resonances of 4AK were shifted upfield (≈
–0.7 ppm), except for the singlet due to the amine methyl
●
●
21,25
group (Figure 6 and Figure S11).
This indicated that the
guest was included in the CB[8] cavity, except for the
protruding amine methyl group. Closer inspection of this
spectrum revealed the presence of 2 series of resonances
for each chemical site (~ 70:30 molar ratio, signal 4 of
Figure 6). At these concentrations, no signal of free guest
was observed indicating that the binding constant for
(
Figure 5) and indicate that, for I-I-I, the three distances
between the aminoxyl oxygen atoms are equal to 9.0 ± 0.8
Å. This structure is compatible with the pink EPR
spectrum of Figure 2.
The I-I-D triangle has two core O •••O distances at the
right value (9.0 ± 0.7 Å and 9.4 ± 1.0 Å) but one above
these values (11.2 ± 0.9 Å). For the I-D-D triangle, core
O •••O distances become equal to 9.6 ± 1.0, 11.5 ± 1.0 and
1.6 ±1.0 Å; for the D-D-D triangle, they are 11.3 ± 1.0, 11.7 ±
.0 and 12.0 ± 1.0 Å, as a result of Isodoxa inversion inside
●
●
5
-1
4AK toward CB[8] is Ka 1:1 > 5 × 10 M (assuming NMR is
precise within a limit of ~5%, confirmed by ITC, Figure
●
●
49
nd
S12). The 2 series of resonances could be assigned to a
CB[8] triangle. Indeed, after adding 5 mM NaCl to the 1:1
4AK/CB[8] mixture, only one of these forms remained. In
the presence of CB[8], all the signals due to both sets of
4AK resonances were characterized by a lower molecular
1
1
CB[8] and reflect gradually weaker spin exchange in the
center of the triangles. Other measurements between spin
centers have revealed distances above 14 Å (except for the
-10
2
-1
translational diffusion coefficient D (≈ 2.1 × 10 m s )
than that measured for 4AK in the absence of CB[8] (4.6 ×
1
initial intramolecular J coupling (11.0 ± 1.0 Å).
-10
2
-1
Diamagnetic triangles. We have shown that a relevant
dinitroxide (reduced or not) can also trigger the
triangulation of CB[8] but diamagnetic compounds would
broaden the scope of CB[8] triangulation. Even though
the reported diamagnetic, nitroxide analogue does not
form trimers in the presence of CB[8], this compound
carried an N-methyl amine with a H bond donor
character, instead of the H bond acceptor character of the
aminoxyl function, and may not be relevant for CB[8]
triangulation. We decided to replace the nitroxide
10 m s ), as evidenced by the superimposed grey trace
in Figure 6a. This confirmed the increase in molecular
size resulting from the encapsulation of 4AK by CB[8].
The correlation peaks due to the 4AK and CB[8]
resonances in the DOSY spectrum were aligned on the
same horizontal line, suggesting that they belonged to the
same hydrodynamic species (i.e. the 4AK•CB[8] complex).
The two forms observed for the 4AK resonances were
characterized by two significantly distinct D values: 2.1
25
-10
2
-1
and 1.5 × 10 m s (e.g. see the singlet signals due to the
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+
+
amine methyl group at 2.7 and 2.8 ppm, respectively),
Na and K ions although other ions are probably also
bound inside but less efficiently. Moroxydine
2
3
4
5
6
7
8
9
1
1
1
1
1
1
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1
2
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4
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4
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which suggested the presence in solution of two distinct
assemblies of different size. Using the Stokes-Einstein
equation
51
hydrochloride, cholic acid, estrone, -estradiol, cortisol,
52
(with
the
spherical
approximation),
cortisone, nandrolone, progesterone,
and other
hydrodynamic diameters of 19.9 and 27.9 Å, respectively
could be derived. These values are in agreement with the
sizes derived from the X-ray data of {4-MeO-
compounds (Scheme S3), potential guests of CB[8]
featuring H bonds acceptor groups, were assessed for
triangulation but showed no sign of trimer formation by
NMR, without or with NaCl. A proper guest design is
necessary to induce CB[8] triangulation, often with the
3 3
TEMPO •CB[8] }, for the 1:1 complexes and the 3:3
triangular assemblies (17.3 and 25.4 Å, respectively),
suggesting that both were present in solution in the
absence of NaCl (each giving rise to one of the above-
mentioned set of resonances). In contrast, upon NaCl
addition (Figure 6b), only the signals characterized by a
+
0
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2
3
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8
9
0
assistance of Na ions. We observed no evidence for
higher symmetry complexes in solution (i. e.
supramolecular squares or pentagons) presumably due to
+
less favorable Na •••O=C rim interactions. The possibility
-10
2
-1
diffusion coefficient of 1.5 × 10 m s (i.e. those due to
the 3:3 complexes) could be observed in the spectrum.
This unambiguously confirmed the pivotal role played by
sodium cations in promoting the assembly of 1:1
complexes into triangles. Control experiments for CB[8]
to use diamagnetic compounds to obtain triangular 3:3
complexes adds to the palette of advanced (informed)
building-blocks able to induce hierarchically controlled,
successive supramolecular events.
Reticulation by CB[8] triangulation. Efforts to prove
the usefulness of the “CB[8] triangle” supramolecular
motif converged toward connecting two TEMPO type
nitroxides by a linker prior to the addition of CB[8] and
sodium ions. The biradical bTHT (Scheme 1c and Figure
7c) was thus used with CB[8] and NaCl and water
solutions of this mixture yielded near round-shape
particles of sizes 200 ± 100 nm as observed by SEM
(Figure 7a,b). AFM showed structures, 20 to 150 nm wide,
after spin coating deposition on freshly cleaved mica
(Figure 7d,e).
-
10
2
alone have given a diffusion coefficient of ≈ 2.95 × 10
s
m
-1
corresponding to an hydrodynamic diameter of ≈ 14 Å
which is consistent with the CB[8] size. If we assume that
formation of 1:1 complexes precedes the occurrence of 3:3
complexes (no free CB[8] trimer observed), and that 1:1
complexes are almost quantitatively formed upon mixing
at 1 mM host and guest (no NMR signal of free 4AK), then
it is possible to estimate a triangulation binding constant
5
-2
K
a 11→3:3 ≈ 8.75 × 10 M based on the integrals of signals
corresponding to the 1:1 and 3:3 species (Figure 6a,
5
0 1
without sodium ions). H NMR spectra of a 1:1 mixture of
AK with CB[8] recorded at several temperatures (Figure
4
S13) didn’t show coalescence but instead, a (reversible)
decrease of the peaks assigned to the 3:3 complexes. At
8
0°C, resonances corresponding to the 1:1 complexes only
could be observed. Surprisingly, the addition of NaCl to
this mixture showed the signals of the trimeric assemblies
with no change upon temperature increase (Figure S14)
highlighting the stability of these triangular assemblies
+
with Na . We believe that tuning of the guest structure
may broaden the scope of triangulation affinities in the
future. Dynamic Light Scattering (DLS) data of solutions
containing 4AK (1 mM) with successive addition of CB[8]
(1 mM) and NaCl (5 mM) qualitatively reproduce the
trend observed by DOSY-NMR with particle sizes
evolving from ~1.0 nm for 4AK to ~ 1.6 nm for 4AK•CB[8]
and 2.5 nm for 4AK•CB[8]•NaCl (Figure S15). We
postulate a slightly different guest position in CB[8]
between the 1:1 and the 3:3 complexes to explain the
occurrence of two distinct chemical shifts for the
included, pendant methyl group on the amine site. The
methyl amine group thus behaves as a local probe of
triangulation. Potassium was assessed instead of sodium
with 4AK and CB[8] and NMR results are similar (i. e.
triangulation, Figure S16). Lithium and calcium ions are
less favorable for triangulation presumably due to the
Figure 7. SEM (a, b), proposed assembly (c), and AFM (d, e)
of mixtures of bTHT, CB[8] and NaCl. (f) Line profile
corresponding to the blue line in (e). X-band EPR spectra of
(g) bTHT, (h) bTHT/CB[8] (spectrum of bTHT alone in grey
for comparison) and (i) bTHT/CB[8]/NaCl in water.
+
2+
DLS data are in line with these results with two sets of
particles detected, measuring ≈ 200 ± 100 nm and 1000 ±
smaller size of Li and the double charge of Ca (Figure
S14). No triangulation was observed using CB[7] with 4AK
3
00 nm (Figure S18). The limited size of the reticulated
(
Figure S17). The cryptand-like environment of the triple-
structures (bTHT precursor) as observed by SEM and
AFM is probably due to the flexibility of the central part
crown of the interior’s CB[8] triangle seems selective for
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of bTHT. This parameter may be responsible for the
absence of extended ordered structures on surfaces
AFM). Similar images were obtained in the absence of
The use of the biradical Isodoxa has allowed to extend
the possibilities of CB[8] triangulation by producing a
new supramolecular hexaradical based on the
trimerization of Isodoxa•CB[8] 1:1 complexes. EPR and
mass spectrometry have confirmed the role of sodium
cations in promoting CB[8] triangulation while X-ray
crystallography and modelling allowed to propose (i) a
plausible location of two sodium cations near the
barycenter of the triangles, and (ii) propose a rationale for
other families of guest compounds amenable for
(
NaCl (i. e. for mixtures of bTHT and CB[8]), however
with smaller size features (Figure S19) reflecting probable
formation of smaller networks without sodium. EPR
spectroscopy of bTHT (Figure 7g) showed a typical 3-line
spectrum with line deviation from an isotropic pattern
(weak intramolecular J interaction). However, when CB[8]
was added (Figure 7h), and beside the broadening of the
high-field line typical of TEMPO inclusion, a broad
component was detected (red arrows) before the
spectrum becomes very large as a result of NaCl addition
(Figure 7i) in line with formation of polyradicals with
slow tumbling.
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triangulation.
A
diamagnetic analogue was then
proposed, synthesized and assessed successfully for
triangulation, before using the “CB[8] triangle” motif for
supramolecular reticulation.
Besides the construction of more paramagnetic and
diamagnetic triangular species, the use of these carefully
designed compounds allowed to precise two conditions to
favor the occurrence of CB[8] triangles:
Discussion. Although not common, the Cambridge
crystallographic database display increasing reports of
2
3,40,53
cucurbituril triangles, reticulated or not.
For CB[8]
SO
hydrate, HCl hydrate, acetic acid hydrate, or DMF
in its most elementary crystalline forms (i. e. H
2
4
1) CB[8] guests which are size-complementary, positively
charged, and possess a H-bond acceptor group that can
be positioned near the entrance of the CB[8] cavity, and
5
4
55
18b
5
6
57
hydrate; with few exceptions: nitrate hydrate, and
5
8
+
+
bromide hydrate),
the macrocycles are arranged
2) cations such as Na or K to help to detect (gas phase)
or strengthen (liquid phase) CB[8]:guest triangles.
5
5
according to a cross motif, such as two of the three
CB[8] are nearly ideally placed to form triangles (Figure 8
left). The third one is slightly tilted by an angle of ≈ 50°,
with respect to the ideal triangular geometry (Figure 8
right).
We believe that the explanation of this strange
triangulation lies in the multiplicity of stabilizing
interactions, (multiple CH•••O interactions between
CB[8], guest:host ion-dipole interactions, guest:host N-
●
●
O •••H-C, C=O•••H-C or N-O •••C=O interactions, and
+
Na •••O=C interactions), combined to favor these
assemblies. This strategy adds to the restricted palette of
methods enabling the hierarchical self-assembly of large
molecular objects in a general context for which
structural control at the nanoscale is highly sought after.
Given the strong tendency of CB[8] triangles to form in
certain conditions, we think that more compounds can be
triangulated using these design rules and we anticipate
that new families of CB[8]-based paramagnetic and
diamagnetic triangular assemblies will be reported in the
future. Beside the possibility shown here to triangulate
more species than before (biradicals, diamagnetic
analogues, or build network type assemblies), recent
reports suggest that CB[7] triangles could also orientate
Figure 8. Solid-state structure derived pictures of CB[8]
5
5
assemblies, left in hydrochloride hydrate crystals and right,
in crystals of the host-guest complex with 4-methoxy-
23
TEMPO. Appropriate guests and/or suitable cations bias
the self-assembly of CB[8] molecules which tend to arrange
in a manner already close to the triangular geometry.
5
9
protein aggregation toward hierarchical structures, or
60
influence guest fluorescence properties.
Therefore,
cucurbituril triangles could find new applications in
biotechnology and in materials science in the near future.
So the explanation for the occurrence of these triangles
could be a combination of several factors: (i) the rigid
structure of CB[8] and its tendency to self-assemble in a
partial self-closing fashion close to the triangular
ASSOCIATED CONTENT
55
geometry to maximize multiple CH•••O interactions, (ii)
Supporting Information. Details of chemical syntheses,
characterizations, MS and EPR spectra, NMR spectra, AFM
images, DLS and details of theoretical calculations. “This
material is available free of charge via the Internet at
http://pubs.acs.org.”
the addition of suitable guests with appropriate geometry
and binding features, and/or (iii) appropriate cations, that
slightly bias the self-assembly of CB[8] to produce the
triangles. This last set of cation-dipole interactions would
result in additional multiple weak interactions
strengthening the heart of the assembly.
AUTHOR INFORMATION
Corresponding Author
CONCLUSION
*
Emails: david.bardelang@univ-amu.fr
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*
*
Emails: olivier.ouari@univ-amu.fr
Emails: rwang@um.edu.mo
12949.
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(8) (a) Nalluri, S. K. M. ; Liu, Z. ; Wu, Y. ; Hermann, K. R. ; Samanta,
A.; Kim, D. J.; Krzyaniak, M. D.; Wasielewski, M. R.; Stoddart, J.
F. Chiral Redox-Active Isosceles Triangles. J. Am. Chem. Soc.
Author Contributions
2
016, 138, 5968–5977. (b) Wu, Y.; Krzyaniak, M. D.; Stoddart, J.
The manuscript was written through contributions of all
authors. All authors have given approval to the final version
of the manuscript.
F.; Wasielewski, M. R. Spin Frustration in the Triradical Trianion
of a Naphthalenediimide Molecular Triangle. J. Am. Chem. Soc.
2017, 139, 2948–2951. (c) Schneebeli, S. T.; Frasconi, M.; Liu, Z.;
Wu, Y.; Gardner, D. M. ; Strutt, N. L.; Cheng, C.; Carmieli, R.;
Wasielewski, M. R.; Stoddart, J. F. Electron Sharing and Anion–π
Recognition in Molecular Triangular Prisms. Angew. Chem., Int. Ed.
ACKNOWLEDGMENT
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The CNRS and the Aix-Marseille Université are
acknowledged for financial support. We thank Dr. Micaël
Hardy and Dr. Gilles Casano for HPLC/MS analyses. We are
also grateful to Région PACA for financial support: grant
2
013, 52, 13100−13104.
(
9) Mizuno, A.; Shuku, Y.; Suizu, R.; Matsushita, M. M.; Tsuchiizu,
M.; Maneru, D. R.; Illas, F.; Robert, V.; Awaga, K. Discovery of
the K4 Structure Formed by a Triangular π Radical Anion. J. Am.
Chem. Soc. 2015, 137, 7612–7615.
(10) (a) Kerckhoffs, J. M. C. A.; van Leeuwen, F. W. B.; Spek, A. L.;
Kooijman, H.; Crego-Calama, M.; Reinhoudt, D. N. Regulatory
Strategies in the Complexation and Release of a Noncovalent Guest
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“
Masked Spins”. We also acknowledge the support of the
Hungarian National Research, Development and Innovation
Office (NKFTH) Grant (K119442).
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