Supramolecular Capsules: Strong versus Weak Chalcogen Bonding

Article abstract of DOI:10.1002/anie.201812095

Resorcin[4]arene cavitands containing either 2,1,3-benzotelluradiazole or 2,1,3-benzothiadiazole motifs were dimerized to supramolecular capsules by chalcogen bonding. Their respective behavior varied depending on the interaction strength of the chalcogen bonds with Te forming strong interactions and S weak interactions. The tremendous strength of multiple 2Te–2N square interactions led to formation of a chalcogen-bonded dimeric capsule in all solvents, as shown by X-ray crystal structures with 16 short Te???N distances (≤2.9 ?) and confirmed by native electrospray ionization mass spectrometry (ESI-MS). With the S cavitand, solvent-dependent crystallization resulted in different arrangements: either a shifted 2S–2N square-bonded capsule or an interlocked 1D polymer with an infinite π–π stacking array. The association constant to form the dimeric capsule in [D₈]THF at 283 K, solely based on weak 2S–2N square interactions, was determined as K_a=786 m^?1.

Full text of DOI:10.1002/anie.201812095

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International Edition: DOI: 10.1002/anie.201812095
German Edition: DOI: 10.1002/ange.201812095
Chalcogen Bonding
Hot Paper
Supramolecular Capsules: Strong versus Weak Chalcogen Bonding
Leslie-Joana Riwar, Nils Trapp, Katharina Root, Renato Zenobi, and FranÅois Diederich*
Dedicated to Professor Jean-Marie Lehn on the occasion of his 80th birthday
Abstract: Resorcin[4]arene cavitands containing either 2,1,3-
benzotelluradiazole or 2,1,3-benzothiadiazole motifs were
dimerized to supramolecular capsules by chalcogen bonding.
Their respective behavior varied depending on the interaction
strength of the chalcogen bonds with Te forming strong
interactions and S weak interactions. The tremendous strength
of multiple 2Te–2N square interactions led to formation of
a chalcogen-bonded dimeric capsule in all solvents, as shown
by X-ray crystal structures with 16 short Te···N distances
(ꢀ 2.9 ꢀ) and confirmed by native electrospray ionization
mass spectrometry (ESI-MS). With the S cavitand, solvent-
dependent crystallization resulted in different arrangements:
either a shifted 2S–2N square-bonded capsule or an interlocked
1D polymer with an infinite p–p stacking array. The associ-
ation constant to form the dimeric capsule in [D8]THF at
283 K, solely based on weak 2S–2N square interactions, was
Figure 1. Schematic representation of dimerization with the 2,1,3-
benzochalcogenadiazole motif for small molecules (top) and applied
in a capsular assembly (bottom). Chalcogen-bonding interactions are
indicated by red, dashed lines. In perfect capsules, 16 such interac-
tions (8 2Z–2N squares) are established.
determined as Ka = 786mꢁ1
.
C
halcogen bonding, the equivalent to halogen bonding[1] but
comprising Group VI elements (S, Se, Te) has become
a frequent topic in recent literature.[2–8] For years, noncovalent
contacts with sulfur in biological molecules have been
reported.[9,10] But only recently, widening the scope from
sulfur to other Group VI elements, such as selenium or
tellurium, revealed the application potential of chalcogen
bonding in various fields, such as supramolecular chemis-
try,[3,4] medicinal chemistry,[5] catalysis,[6] crystallography,[7]
and computational studies.[8] In particular, the benzochalco-
genadiazole motif received considerable attention in the last
decades for its tendency to form chalcogen (Z)-bonded 2Z–
2N square assemblies.[7a–d,8d,11] Its ability to dimerize in the
solid state is discussed in numerous publications (Figure 1,
top). Nevertheless, only few experimental studies address the
investigation of intermolecular chalcogen-bonding interac-
tions in solution.[3] In 2015, Taylor and co-workers presented
a quantitative study employing 2,1,3-benzochalcogenadi-
azoles.[3a] They observed strong complexation of 2,1,3-benzo-
telluradiazole derivatives with association constants (Ka) at
298 K up to 96mꢁ1 with neutral Lewis bases and up to
130000mꢁ1 with anionic Lewis bases. However, no association
was observed with the corresponding sulfur and selenium
analogues, showcasing the decreased ability of S and Se to
establish chalcogen bonds.
Herein, we incorporate the well-established 2,1,3-benzo-
telluradiazole and 2,1,3-benzothiadiazole motifs in top-rim-
functionalized resorcin[4]arene based cavitands,[12] and uti-
lized their ability to self-assemble by forming supramolecular
capsules (Figure 1, bottom).[13] Employing the 2,1,3-benzotel-
luradiazole cavitand (Te cavitand) 1 and its sulfur-containing
analogue (S cavitand) 2, we report for the first time multi-
dentate dimeric capsular assemblies solely based on chalc-
ogen-bonding interactions. We contrast strong Te···N in 1 and
weak S···N interactions in 2 and highlight the differences in
behavior in the solid state and in solution dependent on the
association strength.
The synthesis of target cavitands 1 and 2 is shown in
Scheme 1. As precursor, octanitro cavitand 3 was prepared
following reported procedures (see Section S1 in the Sup-
porting Information for details).[14] Tin-mediated reduction of
3 gave an air-sensitive octamino cavitand, which was directly
treated with TeCl4 or N-thionylaniline (PhNSO) to give 2,1,3-
benzotelluradiazole cavitand 1 or 2,1,3-benzothiadiazole
cavitand 2, respectively (see Section S1.3). Longer side
chains (C11) were installed for increased solubility in solution
studies, while shorter side chains (C6) were intended for
improving the crystallization process.
[*] Dr. L.-J. Riwar, Dr. N. Trapp, Dr. K. Root, Prof. Dr. R. Zenobi,
Prof. Dr. F. Diederich
Laboratorium fꢀr Organische Chemie
ETH Zurich
Vladimir-Prelog-Weg 3, 8093 Zurich (Switzerland)
E-mail: diederich@org.chem.ethz.ch
Supporting information and the ORCID identification numbers for
the authors of this article can be found under:
https://doi.org/10.1002/anie.201812095.
Suitable crystals for X-ray analysis were obtained from
various solvents for both the Te cavitand 1C6 and the S
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Scheme 1. Synthesis of cavitands 1, 1C6, 2, and 2C6. Reagents and
conditions: i) SnCl2·H2O, EtOH/conc. HCl (3:1), 958C, 16 h; ii) TeCl4,
NEt3, toluene, 228C, 16 h (1 24% over 2 steps, 1C6 17% over 2 steps);
iii) N-thionylaniline, NEt3, toluene, 1008C, 16 h (2 43% over 2 steps,
2C6 47% over 2 steps).
cavitands 2 and 2C6 (Section S4).[15] The vast difference in
association strength between Te···N and S···N interactions
caused remarkable differences in the solid-state structures.
The crystal structures obtained from a solution of Te
cavitand 1C6 in benzene revealed a perfect linear capsular
assembly 1C6···1C6 (Figure 2, left). Two head-to-head arranged
cavitands form a circular array of 16 strong Te···N interactions
in eight 2Te–2N squares with short distances between 2.9 and
2.6 ꢀ (20–28% below the sum of the van der Waals radii,[16]
Figures 2a,b, left). Each hemisphere encapsulates a benzene
molecule deep inside the cavity which establishes moderately
strong aromatic interactions with the cavitand walls (Fig-
ure 2c, left). Flexibility and rotation of the bound guest
resulted in disorder in the crystal structure. Analysis of the
crystal packing showed several additional solvent molecules
outside the capsule complying with the necessary high
packing density in crystals. It was found that the crystals
lose the outer solvent molecules after being exposed to air for
several days, though maintaining the capsular assembly (see
Section S4.3). Notably, an analogous structure displaying
a chalcogen-bonded dimeric capsule 1C6···1C6 was obtained
from a solution in CHCl3, though solvent molecules within the
cavity were unresolvable owing to fast rotation or small
energetic discrimination of different orientations during the
crystallization process (Section S4.4).
Figure 2. a) X-ray crystal structure 1C6···1C6 (left, CCDC: 1873512)
obtained from a benzene solution revealing a linear capsule and X-ray
crystal structure 2C6···2C6 (right, CCDC: 1873519) obtained from
a toluene solution revealing a shifted capsule. b) Schematic represen-
tation of the capsular assembly 1C6···1C6 with a circular array of
16 Te···N interactions (left) and 2C6···2C6 with two lines of 6 S···N
interactions each (right). Black and gray dots indicate benzochalcoge-
nadiazole moieties. Chalcogen bonds are shown as red dashed lines.
c) Top view of 1C6 (left) encapsulating a benzene molecule and of
2C6 (right) encapsulating a toluene molecule. Gray Ccavitand, green Csolvent
,
blue N, red O, orange Te, yellow S. Distances are given in ꢁ. Hydrogen
atoms are omitted for clarity.[15]
In contrast to the consistent capsular packing of 1C6,
crystallization of S cavitands 2C6 proved to be solvent-
dependent and resulted in two distinct structures.
Crystallization from aromatic solvents, such as benzene or
toluene, yielded a shifted capsular assembly 2C6···2C6, bound
together by only 12 S···N contacts in 6 2S–2N squares (3.0–
3.5 ꢀ, 90–105% of the sum of the van der Waals radii, shown
for toluene in Figure 2a, right). Compared to 1C6···1C6, the
chalcogen-bonding interactions are not arranged in a circular
array but rather in two lines on the elongated sides of the
rectangularly shaped capsule (Figure 2b). As observed for
1C6···1C6, a solvent molecule is encapsulated in each hemi-
sphere (Figure 2c). However, the rectangular structure of the
2C6···2C6 cavity binds the guest more tightly reducing the
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flexibility and establishing more favorable aromatic interac-
tions inside the deep resorcin[4]arene framework.
Intriguingly, crystal structures of obtained from
2
dichloromethane do not display a capsular assembly nor
chalcogen-bonding interactions.[17] Instead, they reveal an
interlocked one-dimensional (1D) supramolecular polymeric
arrangement with a linear p–p stacking array, where two
cavitand walls are incorporated into the cavity of a third
hemisphere (Figure 3). To our knowledge, this structure
presents the first example in which one resorcin[4]arene-
based cavitand encapsulates two aromatic guests in the solid
state.[18] This exception entails a widening of the cavity which
is stabilized by the encapsulated 2,1,3-benzothiadiazole
moieties undergoing antiparallel p–p stacking with two
opposite lying walls (3.4 ꢀ) and edge-to-face interactions
with the remaining two walls (center-to-center distances
between 4.7–5.3 ꢀ, Figures 3a,b). The crystal packing reveals
a membrane-like structure where a hydrophobic layer of
intertwining alkyl legs is alternated with an infinite arrange-
ment of interlocked cavitands (Figure 3c).[19] The alkyl chains
pack very tightly, leaving no space for solvent inclusion.
Investigations in solution showed a solvent-dependent
conformational switching of 2,1,3-benzothiadiazole cavitand
2, consistent with other resorcin[4]arene-based cavitands in
the literature.[20] In chlorinated solvents (such as CH2Cl2, see
Figure S9a), the flat kite conformation with equatorially
oriented walls dominates, indicated by an upfield shifted
methine resonance frequency at 4.2 ppm. The deep vase
conformation with axially standing walls on the other hand is
stabilized by small aprotic solvent molecules with the ability
to solvate the inner cavity (e.g. THF and benzene in
Figures S9b,c). There, the methine protons encounter
deshielding from the axially oriented walls, resulting in
a chemical shift above 5.5 ppm. Note that exclusively the
vase conformation was observed for 2,1,3-benzotelluradiazole
cavitand 1 and 1C6 in all solvents screened, indicated by
1
a methine H chemical shift in the downfield region above
5.5 ppm (Figure S10).
These observations support our findings in the solid state.
The crystal structure obtained for Te cavitand 1C6···1C6 shows
a supramolecular dimeric capsule with 16 short Te···N con-
tacts suggesting exceptionally strong interactions. In all
solvents, regardless of solvation of the deep cavity, strong
Te···N interactions favor the supramolecular capsule with
both hemispheres in the vase conformation. Crystallized in
aromatic solvents, S cavitand 2C6 in the vase conformation
forms a shifted dimeric capsule assembled by S···N chalcogen
bonds. It can be reasoned that these weak S···N interactions in
solution allow for a dynamic process of forming and breaking
the contacts between two hemispheres, resulting in a shifted
capsular assembly in the solid state, additionally stabilized by
packing effects. In dichloromethane, the kite conformation of
2 and 2C6 dominates owing to the lack of proper solvation of
the deep cavity. To enable a high packing density upon
crystallization, the cavitands are forced into a vase confor-
mation with adjacent cavitand walls stabilizing the thereby
formed cavity. Furthermore, the absence of S···N chalcogen-
bonding interaction in this crystal structure demonstrate the
significance of preorganization. Only if ideal geometric
Figure 3. a) X-ray crystal structure 2 obtained from a dichloromethane
solution revealing a polymeric arrangement with an infinite p–p
stacking array between cavitand walls (CCDC: 1873516). b) Top view
of 2: encapsulation of two 2,1,3-benzothiadiazole scaffolds leads to
widening of the cavity. c) Crystal packing shows membrane-like layers
of entangled alkyl legs (ca. 13–14 ꢁ width) and stacked cavitands,
indicated by gray dashed lines. Gray C, blue N, red O, yellow S.
Distances are given in ꢁ. Hydrogen atoms are omitted for clarity.[15]
requirements for capsule formation in solution are provided
by prevalence of the vase conformation, the system is able to
establish weak S···N contacts between two hemispheres.
Consequently, we decided to use [D8]THF in quantitative
1H NMR studies to provide the necessary geometrical
requirements to form a supramolecular capsule while ensur-
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ing sufficient solubility. Dimerization of cavitands 1 and 2 was
investigated by a 1H NMR dilution study at 283 K (see
Section S3.2). A highly concentrated solution of 2 at 16.2 mm
was diluted stepwise to 0.1 mm. At high concentration,
dimerization forces both hemispheres into a more rigid
structure. Upon dilution, the capsular assembly dissociates
resulting in a more flexible vase conformation, indicated by
a clear upfield shift of the methine resonance frequency and
all aromatic signals. The association constant could be
determined by non-linear curve fitting of the dimerization-
induced chemical shift as a function of concentration. The
multitude of weak S···N interactions forming a dimeric
capsule 2···2 resulted in an association constant of Ka =
786mꢁ1 [21,22]
Dimerization of 2 was further confirmed by
.
1
determination of the diffusion coefficient through H diffu-
sion ordered spectroscopy (DOSY).[23] With increasing con-
centration the diffusion coefficient decreased, indicating
a doubling of volume and thus, corroborating dimerization
of S cavitand 2 to a chalcogen-bonded capsule 2···2 (see
Section S3.4.1).
Figure 4. Variable temperature (VT) study of 1C6 in [D8]toluene
(10 mm, 1H NMR, 500 MHz). The region of the methine and aromatic
signals is displayed. Signals corresponding to species (1C6···1C6)a are
indicated in red, to species (1C6···1C6)b in blue. The equilibrium is
shifted upon heating from 20 to 858C in less than one hour.
1
As expected, the H NMR spectra of Te cavitand 1 in
[D8]THF did not display a change in chemical shift upon
dilution (Figure S12). We concluded that strong chalcogen-
bonding interactions favor formation of a supramolecular
structure at all concentrations measured. Hence, a dimeric
assembly 1···1 could be detected exclusively within the NMR
detection limit, never the monomeric cavitand 1.
both species (Dð1ꢂꢂꢂ1Þ = 2.99 ꢁ 10ꢁ10 m2 sꢁ1, Dð1ꢂꢂꢂ1Þ = 2.83 ꢁ
a
b
10ꢁ10 m2 sꢁ1, see Section S3.4.2), suggesting a comparable
volume of (1···1)a and (1···1)b. Furthermore, mass spectrom-
etry showed signals of the singly charged homodimer and
monomer but not of oligomeric assemblies (Section S5).
Therefore, we propose for initial species (1···1)a a dimeric
assembly, similar to the crystal structure obtained for 2C6···2C6
(Figure 2a, right) displaying a shifted supramolecular capsule
based on chalcogen bonding.[25] In a shifted capsule, fewer
Te···N interactions than the maximum of 16 in a linear capsule
with 8 2Te–2N squares would make this structure more easily
accessible but less stable.
The Te capsule 1···1 (and analogously 1C6···1C6) displayed
a time-dependent transformation in solution from an initial
species (1···1)a to a second species (1···1)b, noticeable by
a doubling and shifting of NMR signals (see Section S3.3).
The pace of this transformation was dependent on solvent and
concentration ranging from full conversion within one day
(e.g. in CDCl3, 1 mm) to more than one week (e.g. in
[D8]toluene, 10 mm). The equilibrium could be shifted in
favor of the second species by heating to 858C in [D8]toluene,
as shown for 1C6···1C6 in Figure 4. The transformation proves
irreversible upon cooling as the second species (1C6···1C6)b
continues to prevail. Considering that crystals of the Te
capsule 1C6···1C6 were grown over several days, the second
species formed is more likely to crystallize. Indeed,
Finally, a native electrospray ionization mass spectrome-
try (ESI-MS)[26] titration was performed to determine the
association constant of the dimerization of Te cavitand 1 to
a supramolecular capsule (Section S5). To ensure the pres-
ence of the vase conformation of 1 at low concentration while
maintaining an environment suitable for ESI experiments,
a solvent mixture of DMSO/toluene/MeOH 10:6:1 (v/v/v)
was used. Comprising DMSO and protic MeOH, this solvent
system allows competitive interactions to chalcogen bonding,
possibly weakening the association. Furthermore, the opti-
mized conditions resulted in precipitation after one day,
which is why presumably only the association of species
(1···1)a could be determined. Figure 5 shows an increasing
intensity for the singly charged dimer at concentrations going
from 9.5 mm to 380 mm while the singly charged monomer
signal substantially decreases. This concentration-dependent
change in intensity allowed determination of a high associ-
1
a H NMR investigation of the redissolved crystals verified
the sole presence of the second species (1C6···1C6)b. The
tremendous strength of 16 Te···N interactions in 8 2Te–2N
squares leads to the kinetically inert, thermodynamically most
stable capsule (1C6···1C6)b. This perfect capsule with 16 Te···N
interactions forms very slowly from an initial less symmet-
rical, less stable capsular assembly with a lower number of
Te···N interactions. Fujita and co-workers reported a similar
observation for the self-assembly of PdII- or PtII-linked
macrocycles with 4,4’-bipyridine (bpy).[24] While the thermo-
dynamically most stable cyclic tetramer was immediately
formed with weak Pd···N interactions, strong Pt···N interac-
tions led first to formation of a mixture of oligomers which
eventually, after heating to 1008C for several weeks, resulted
in the thermodynamically stable cyclic tetramer after all.
However, in the case of our Te cavitand 1, oligomerization
could be excluded on taking into account that 1H DOSY
experiments in C6D6 gave an equal diffusion coefficient for
ation constant of Ka,ð1ꢂꢂꢂ1Þ = 2.9 ꢃ 0.4 ꢁ 107 mꢁ1, caused by the
a
cooperativity of several strong Te···N interactions. For the
thermodynamic species (1···1)b under optimal conditions,
without competitive solvent effects and a linear arrangement
with 16 Te···N interactions in 8 2Te–2N squares, an even much
larger association constant can be expected.
4
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making precursor compounds available. We thank Patrik
Willi for synthetic contributions and Dr. Bruno Bernet and
Dr. Johannes Boshkow for correcting the manuscript.
Conflict of interest
The authors declare no conflict of interest.
Keywords: chalcogen bonding · mass spectrometry ·
self-assembly · supramolecular capsules · X-ray diffraction
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Figure 5. ESI-MS titration of Te cavitand 1 in DMSO/toluene/MeOH
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In summary, we present the first purely chalcogen-bonded
supramolecular capsules formed by dimerization of either
2,1,3-benzotelluradiazole or 2,1,3-benzothiadiazole cavitands.
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sphere. In solution, the kinetic inertness of multiple strong
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a
cavitand 2, solvents stabilizing the vase conformation of
hemisphere 2 enabled dimerization to a supramolecular
capsule 2···2 based on 12 weaker S···N interactions (Ka =
786mꢁ1 in [D8]THF).[27] In solvents favoring the kite con-
formation however, no capsular assembly was observed.
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polymeric arrangement of interlocked cavitands 2. Only
vase hemispheres, stabilized by solvent inclusion, provide
the crucial preorganization to establish weak S···N interac-
tions in a capsular assembly.
Acknowledgements
This study was supported by the Swiss National Science
Foundation (SNF 200020_159802 to FD and 200020_178765
to RZ). We thank Michael Solar (ETH Zurich) for recording
X-ray crystal structures and the NMR service of the LOC
(ETH Zurich) for assistance with NMR spectroscopy. We are
grateful to Dr. Oliver Dumele for useful discussions and for
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Communications
Chemie
[9] R. E. Rosenfield, Jr., R. Parthasarathy, J. D. Dunitz, J. Am.
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like arrangement in the packing where the C6 or C11 alkyl
residues form a hydrophobic layer. More details are presented in
Section S4.
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[20] For detailed information on the conformational behavior and
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[21] The given value Ka = 786mꢁ1 is an average of two independent
measurements. The estimated uncertainty in Ka is ꢃ 20%.
Details are described in Section S3.2.
[12] For a recent Review, see: C. Gropp, B. L. Quigley, F. Diederich,
J. Am. Chem. Soc. 2018, 140, 2705 – 2717.
[13] For other examples of supramolecular capsule formation by self-
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[14] S. Mosca, Y. Yu, J. Rebek, Jr., Nat. Prot. 2016, 11, 1371 – 1387.
[15] CCDC 1873512, 1873513, 1873514, 1873515, 1873516, 1873517,
1873518, 1873519, 1873520 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
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[17] Similar crystal structures were obtained from a dichloromethane
solution for 2C6 and even for 2 which has long undecyl legs.
Details are shown in Sections S4.5 and S4.6.
[18] More examples of single self-inclusion of resorcin[4]arene
cavitands are in the literature: a) C. von dem Bussche-Hꢃnne-
feld, R. C. Helgeson, D. Bꢃhring, C. B. Knobler, D. J. Cram,
Croat. Chem. Acta 1996, 69, 447 – 458; b) A. R. Renslo, F. C.
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[22] From the literature it is known that suitably sized heteroalicycles
form very stable complexes with resorcin[4]arene cavitands
based on polar interactions in addition to dispersion interac-
tions: J. Hornung, D. Fankhauser, L. D. Shirtcliff, A. Praetorius,
W. B. Schweizer, F. Diederich, Chem. Eur. J. 2011, 17, 12362 –
12371. Indeed, performing a dilution study with S cavitand 2 in
a solvent mixture of [D8]THF/C6D6 6:4 resulted in a decreased
association constant (Ka = 146 ꢃ 3mꢁ1).
[23] Y. Cohen, L. Avram, L. Frish, Angew. Chem. Int. Ed. 2005, 44,
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[25] If the initial species (1···1)a undergoes dynamic motion in
solution, a shifted capsular assembly similar to the crystal
structure of 2C6···2C6 (in Figure 2a, right) can tentatively be
assumed.
[26] a) R. H. H. van den Heuvel, A. J. R. Heck, Curr. Opin. Chem.
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[27] The self-assembly of 2,1,3-benzothiadiazoles in the solid state
has been comprehensively studied, see: M. R. Ams, N. Trapp, A.
´
Schwab, J. V. Milic, F. Diederich, Chem. Eur. J. 10.1002/
chem.201804261.
Manuscript received: October 22, 2018
Version of record online: && &&, &&&&
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Angew. Chem. Int. Ed. 2018, 57, 1 – 7
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Angewandte
Communications
Chemie
Communications
Chalcogen Bonding
Strengths and weaknesses: Dimeric
chalcogen-bonding capsules display
a distinct behavior depending on the
association strength, as shown by X-ray
structures and confirmed by NMR spec-
troscopy solution studies. While capsules
based on weak S···N interactions rely on
solvation and the associated hemisphere
preorganization, capsular assemblies
formed by strong Te···N interactions are
beyond external influences.
L.-J. Riwar, N. Trapp, K. Root, R. Zenobi,
F. Diederich*
&&&& — &&&&
Supramolecular Capsules: Strong versus
Weak Chalcogen Bonding
Angew. Chem. Int. Ed. 2018, 57, 1 – 7
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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