Selective Formation of S4-and T-Symmetric Supramolecular Tetrahedral Cages and Helicates in Polar Media Assembled via Cooperative Action of Coordination and Hydrogen Bonds

Article abstract of DOI:10.1021/jacs.0c00722

We report on the synthesis and self-assembly study of novel supramolecular monomers encompassing quadruple hydrogen-bonding motifs and metal-coordinating 2,2′-bipyridine units. When mixed with metal ions such as Fe²⁺ or Zn²⁺, the tetrahedron cage complexes are formed in quantitative yields and full diastereoselectivity, even in highly polar acetonitrile or methanol solvents. The symmetry of the complexes obtained has been shown to depend critically on the flexibility of the ligand. Restriction of the rotation of the hydrogen-bonding unit with respect to the metal-coordinating site results in a T-symmetric cage, whereas introducing flexibility either through a methylene linker or rotating benzene ring allows the formation of S₄-symmetric cages with self-filled interior. In addition, the possibility to select between tetrahedral cages or helicates and to control the dimensions of the aggregate has been demonstrated with a three-component assembly using external hydrogen-bonding molecular inserts or by varying the radius of the metal ion (Hg²⁺ vs Fe²⁺). Self-sorting studies of individual Fe²⁺ complexes with ligands of different sizes revealed their inertness toward ligand scrambling.

Full text of DOI:10.1021/jacs.0c00722

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Article
Selective Formation of S4- and T-Symmetric Supramolecular
Tetrahedral Cages and Helicates in Polar Media Assembled
via Cooperative Action of Coordination and Hydrogen-Bonds
Qixun Shi, Xiaohong Zhou, Wei Yuan, Xiaoshi Su, Algirdas Neniškis, Xin Wei, Lukas Taujenis,
Gustautas Snarskis, Jas S Ward, Kari Rissanen, Javier de Mendoza, and Edvinas Orentas
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c00722 • Publication Date (Web): 26 Jan 2020
Downloaded from pubs.acs.org on January 26, 2020
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Selective Formation of S4- and T-Symmetric Supramolecular
Tetrahedral Cages and Helicates in Polar Media Assembled via
Cooperative Action of Coordination and Hydrogen-Bonds
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Qixun Shi†*, Xiaohong Zhou†, Wei Yuan†, Xiaoshi Su†, Algirdas Neniškis⊥, Xin Wei†, Lukas
Taujenis¶, Gustautas Snarskis⊥, Jas S. Ward#, Kari Rissanen#, Javier de Mendoza‡ and Edvinas Orentas⊥
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation
Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China
⊥
Department of Organic Chemistry, Vilnius University, Naugarduko 24, LT-03225 Vilnius, Lithuania
¶
Thermo Fisher Scientific Baltics, V. A. Graičiūno 8, LT-02241, Vilnius, Lithuania
University of Jyvaskyla, Department of Chemistry, P.O. Box 35, 40014 Jyväskylä, Finland
‡Institute of Chemical Research of Catalonia (ICIQ), AV. Països Catalans, 16, 43007 Tarragona, Spain

State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China
ABSTRACT: We report on the synthesis and self-assembly study of novel supramolecular monomers encompassing quadruple
hydrogen-bonding motifs and metal coordinating 2,2’-bipyridine
units. When mixed with metal ions such as Fe2+ or Zn2+, the
tetrahedron cage complexes are formed in quantitative yields and full
diastereoselectivity, even in highly polar acetonitrile or methanol
solvents. The symmetry of the complexes obtained has been shown
to depend critically on the flexibility of the ligand. Restriction of the
rotation of the hydrogen-bonding unit with respect to the metal
coordinating site results in a T-symmetric cage, whereas by
introducing flexibility either through a methylene linker or rotating
benzene ring allows the formation of S4-symmetric cages with self-
filled interior. In addition, the possibility to select between
tetrahedral cages or helicates, and to control the dimensions of the
aggregate, has been demonstrated with three component assembly using external hydrogen-bonding molecular inserts or by varying
the radius of the metal ion (Hg2+ vs Fe2+). Self-sorting studies of individual Fe2+ complexes of with ligands of different sizes revealed
their inertness toward ligand scrambling.
INTRODUCTION
complexes built upon the octahedral arrangement of bidentate
ligands. The latter class of cage complexes enjoys the diversity
of molecular topologies (tetrahedron, cube, triple stranded
helicate, prism), the use of non-toxic and inexpensive metals
(Fe, Zn, Ga etc.), and well-established synthetic methods to
decorate the metal binding unit (2,2’-bipyridine or related
compounds).8 The selection of a particular shape has been
shown to be possible by structural modification of ligands or by
a templation effect of the guest.9 Some of these structures are
inherently chiral with asymmetry stemming either from chiral
ligands or the metal center itself, and thus provide a platform
for enantioselective binding.10,11 In addition, the reversible
nature of coordination bonds enables the building of more
sophisticated molecular networks consisting of several ligands
and metal ions to explore emerging complexity.12
The introduction of the concept of coordination driven self-
assembly of simple ligands and metal ions into non-covalent
cage structures resulted in the enormous progress of the field of
supramolecular chemistry.1 One-step reliable generation of
sophisticated capsule structures from simple precursors enabled
researchers to access nanoscopic molecular vessels to
experimentally interrogate various molecular phenomena of
fundamental importance. Beyond molecular recognition,2
further developments include enzyme-like modulation of
chemical reactivity,3 stabilization of highly reactive elusive
intermediates,4 selective extraction,5 sensing6 and X-ray
characterization of analytes by providing ordered solid-state
environment for otherwise non-crystalline compounds.7
Two families of coordinative molecular cages are currently
dominating the field: cavity architectures combining the square
geometry of Pd2+ with monodentate ligands and metal
In a classical approach, the coordination cage is built using
covalent ligands, synthesized prior to the self-assembly step
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(Fig. 1a). To simplify the synthesis and to incorporate the Supporting Information). UPy motif was chosen for its well-
known ability to form very stable dimers (up to Ka = 108 M-1 in
toluene) whereas Bipy is a ligand of choice for octahedral metal
coordination ultimately leading to tetrahedral arrangement of
the ligands in the complex. The use of semi-flexible -CH2-
linker to bridge two orthogonal sites was essential for several
reasons. First, it provides necessary conformational freedom for
the Bipy units to adjust around the metal ion coordination center
for optimal binding. Second, by providing limited flexibility
and relatively short distances between metal centers, a
competing aggregation mode to dinuclear triple-stranded
helicate is inhibited due to the steric clash between three bulky
UPy2 dimeric units located close to a helicate axis (Fig. 2b).
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Considering the stereochemical outcome of the M4L12 assembly
process, there are three possible diastereomers for the most
commonly occurring all-fac coordination mode, belonging to
the symmetry point groups T, C3 or S4. It is very common that
either the pure homochiral (racemic mixture of  and
 enantiomers) T-isomer or the mixture of all
stereoisomers is obtained. However, it has also been shown that
the extent of stereochemical communication between metal
centers, and thus the ratio of the isomers, is sensitive to the
structure of the ligand.18 With regard to isomerism, in the
bifunctional ligand 1 containing UPy moieties, the tetrahedral
assemblies might also form via dimerization of self-
complementary enolic forms of the UPy unit (Fig. 2b). In this
case, the isocytosine side chains will change the position with
respect to the edges of the so-formed tetrahedron moving from
equatorial in keto-dimer to parallel arrangement in enol-dimer.
Although the formation of tetrahedral complexes is possible for
both tautomers, larger substituents might favor the formation of
the enol-cage as side chains experience less steric interaction in
this aggregation mode.
Figure 1. Coordination driven self-assembly exemplified with
tetrahedron cages. (a) classical approach with covalent ligands; (b)
subcomponent self-assembly combining dynamic covalent and
coordinative bonds; (c) newly proposed subcomponent self-assembly
employing H-bonded dimers as ligands.
into the system, subcomponent self-assembly, combining both
covalent (e.g. imine bonds) and coordinative bonds, has been
introduced and extensively developed by Nitschke and co-
workers as a powerful strategy to construct stimuli responsive
dynamic libraries of various supramolecular constructs (Fig.
1b).13 We speculated that the further extension of
subcomponent self-assembly would be possible by
incorporating hydrogen-bonding (H-bonding) motifs within the
ligand structure, in between the metal coordinating units (Fig.
1c). This would not only allow for an easier synthesis, but also
add an orthogonal input channel for external structure
modulation. The strong directionality, high sensitivity to
polarity of the solvent and temperature, and the possibility for
tautomerization14 define other attractive features of this non-
covalent interaction. Despite obvious advantages, the
combination of metal and H-bonds as integral elements has not
been successfully applied to obtain metal-organic polyhedra
and to date, the known examples are limited to planar polygons
in non-polar chlorinated solvents only.15,16 Here we provide the
first experimental demonstration of a new class of tetrahedron
molecular cages and helicates held together by the cooperative
action of coordination and H-bonds in acetonitrile or even
methanol and disclose some of their properties.
In order to prove the concept and probe the impact of the
bulkiness of the UPy2 dimer on the diastereoselectivity of the
cage formation, five different substituents R (H, Me, n-Bu, n-
C11H23 and 3,4,5-tridodedecyloxyphenyl) were attached to UPy.
The complex formation was then accomplished by simply
mixing the monomer 1 and Fe(OTf)2 in a 3:1 ratio in d3-
acetonitrile under ambient atmosphere. The formation of the
complexes was evident from the appearance of deep red color
and the dissolution of otherwise insoluble ligands. To our
delight, in case of monomers 1a (R = H) and 1b (R = Me), well-
defined 1H NMR spectra were obtained consisting of three sets
of resonances of equal integral intensities (Fig. 2c). Based on
symmetry arguments, it was assigned to the exclusive formation
of the S4-symmetric M4L12 cage.19 The downfield chemical
shifts of the N-H resonances clearly indicate the establishment
of quadruple H-bonds. In addition, DOSY NMR analysis was
also in agreement with the presence of a single species. Namely,
all resonances in the spectrum correlated to a single diffusion
coefficient of D = 5.00  10-10 m2s-1 (1a) and D = 4.83  10-10
m2s-1 (1b), which translate into hydrodynamic radii RH = 1.10
nm and RH = 1.14 nm, respectively. The values obtained agree
well with the radius of circumscribed sphere calculated for the
molecular model of the S4-Fe4(1b)12 tetrahedron (see Fig. S91).
Electrospray ionization mass spectrometry (ESI-MS) also
confirmed the formation of tetrahedron assemblies (Fig. 2e and
Fig. S94-95, S97).
RESULTS AND DISCUSSION
First generation ligands: design, self-assembly and
characterization. Our design of the monomer 1 is outlined in
Figure 2a. This compound was synthesized in two steps from
reported simple starting materials and features Meijer’s
ureidopyrimidinone (UPy)17 as quadruple H-bonding unit
together with the metal binding 2,2’-bipyridyl (Bipy) unit,
connected through single methylene bridge (for synthesis see
In order to fully characterize the supramolecular aggregates in
solution, detailed NMR studies were undertaken. As shown in
Figure 2d, the keto and enol tautomeric forms and their dimers
can be distinguished based on the expected specific through-
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bond and through-space interaction map as outlined in Figure
2d using dimer (1b)2 as an example. Based on the ROESY
correlation observed between the protons at 12.58 ppm, 12.56
ppm
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Figure 2. (a) Design of the first-generation ligand 1; (b) Two possible Fe4112 tetrahedral complexes based on keto and enol tautomers of UPy; (c) 1H
NMR spectra of S4-symmetric tetrahedral complexes with DOSY trace. The resonances of the minor species and their quantities are indicated; (d)
Characteristic through-bond and through-space interaction maps for keto and enol UPy dimers for ligand 1b (left) together with obtained ROESY
and COSY spectra (right); (e) An example of experimental and simulated ESI-HRMS isotopic patterns for S4-Fe4(1b)12.
features are also observed for complexes obtained using ligands
1a, 1c and 1d or by exchanging Fe2+ to Zn2+ (Fig. 2c, bottom,
see the Supporting Information).
and 12.37 ppm (labeled in blue in Fig. 2c) with isocytosine
methyl group protons d, the former was assigned as N-H
protons a, and thus confirm the involvement of the keto form in
quadruple H-bonding. Likewise, the COSY and ROESY cross-
peaks of N-H proton resonances at 10.52 ppm, 10.32 ppm and
10.30 ppm (labeled in green in Fig. 2c) with CH2 resonance e
allows unambiguous assignment of these protons as c.
Moreover, characteristic long-range W-type COSY coupling of
N-H protons a to C(sp2)-H proton f of the isocytosine ring as
well as ROESY interaction between protons b and c fully
corroborates the above assignments (Fig. 2d). The same spectral
Interestingly, increasing the size of UPy substituents in 1c and
1d gives rise to an additional three sets of resonances of lower
intensities (Fig. 2c). Initially thought to belong to the enolic
form of the UPy, these minor resonances were shown to be part
of the keto tautomer, giving the same characteristic 1H-1H cross-
peaks as described above. Careful inspection of the ROESY
spectra, however, revealed some subtle differences in the
surroundings of proton c (see Fig. S35, S38). Most likely, the
minor species observed are due to different arrangement of the
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Figure 3. (a) Molecular model of S4-Fe4(1b)12; (b) Surface of S4-
UPy dimers caused by bulkier butyl and undecyl chains in 1c
and 1d, respectively, resulting in slowly equilibrating
conformers. The DOSY spectra indicate similar hydrodynamic
radii of the minor and major species (Fig. S36, S39). Increasing
the size of the isocytosine substituent even further as in
monomer 1e, eventually prevents the formation of a tetrahedron
cage leading to a broad undefined 1H NMR spectrum, and only
ions of smaller complexes Fen(1e)m are detected in the ESI-MS
spectrum (Fig. S96). Dilution of the solution of S4-Fe4(1b)12 in
acetonitrile with diethyl ether provided a red precipitate. The
Fe4(1b)12 (left) and cavity (middle) compared with cavity of
hypothetical T-Fe4(1b)12 (right); (c) Extended section of 1H NMR
spectrum (400 MHz, CD3CN) of S4-Fe4(1b)12; (d) Selected parts of
ROESY spectrum of S4-Fe4(1b)12; (e) Closeup view of molecular
model showing spatial arrangement of protons c, f and C-HAr.
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computationally obtained model is perhaps not fully accurate, it
provides some important clues regarding the data obtained from
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the H and ROESY NMR spectra. The most downfield proton
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of the c subset is unique as it gives no cross-peak with the Bipy
C-HAr protons (Fig. 2d and 3d) indicating that it assumes a
conformation with rather large distance between these protons.
Moreover, in contrast to the downfield protons f, the most
upfield proton f at 4.01 ppm gives a cross-peak with C-HAr,
indicating their proximity. As seen from the molecular model,
proton f of the isocytosine ring is located inside the tetrahedron
and nearby the Bipy ring, experiencing significant shielding
(Fig 3c-e). In addition, a weak cross-peak between protons c
and f is also in accord with the calculated structure (Fig. S26).
recorded H NMR spectrum of the freshly dissolved crystals
showed only the major conformer, which gradually returned to
an equilibrium mixture.
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1
The H NMR spectra of the tetrahedral complexes S4-Fe4(1a-
c)12 show that the chemical shifts of some proton resonances
greatly differ from those of the other two of the same type,
indicating their unique chemical environment. For instance, the
resonances of vinyl proton f at 4.01 ppm in S4-Fe4(1b)12 is
shifted upfield ( = 1.40 ppm), whereas resonance c at 10.52
ppm is shifted downfield compared to the other two c
resonances (Fig. 2c, Fig. 3c and Fig. S20, S25, S34, S37). The
molecular models for S4-Fe4(1b)12 obtained using semi-
empirical PM7R8 method show a highly deformed tetrahedron
with negligible internal cavity (Fig. 3a-b). Compared to the
structure of the hypothetical T-Fe4(1b)12 complex, the former
features a geometry where all UPy2 dimers within the ligand
(1b)2 are forced to move into the cavity as a result of the
connecting CH2 groups, which dictates the ligands’ bent shape.
Although the
The small cavity within the S4-symmetric cage suggests that the
formation of the cage complex most likely requires no anion
-
templation. The exchange of a triflate counterion with BF4 ,
-
-
-
BPh4 , SbF6 , Br- or C12H25OSO3 did not affect the symmetry
and resulted in no change of the 1H NMR spectrum (Fig. S29-
S33).
Second generation ligands: effect of the linker and
conformational rigidity. In order to gain more insight into the
importance of the flexibility and length of the ligand on the
symmetry of the complexes, two new rigid monomers 2 and 3,
lacking methylene linkers, were synthesized. In monomer 2, the
Bipy unit is connected to UPy directly through the urea
functionality, whereas monomer 3 features an additional
benzene ring spacer (Fig. 4a-b). The 1H NMR spectra of
complexes obtained using Fe(OTf)2 and Zn(OTf)2 as metal ion
sources in
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Figure 4. (a-b) Chemical structures of ligands 2-3 and selected parts of
1H NMR and DOSY spectra of T-Fe4212, T-Zn4212, S4-Fe4312 and S4-
Zn4312. Broad resonances are labelled with *; (c) Molecular model of
T-Fe4212. Experimentally determined and calculated Fe2+ ions are
labelled in green and orange, respectively; (d) Molecular model of S4-
Fe4312. Insert shows the surface of the cage.
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CD3CN indicate the quantitative formation of a T-symmetric
(one set of resonances) cage for monomer 2 and a S4-symmetric
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Figure 5. Selected 1H NMR spectra of titration experiments of S4-Fe4(1b)12 (a-b), T-Fe4212 (c-d) and S4-Fe4312 (e-f) CD3CN solution with d6-DMSO
(top) and D2O (bottom). The content of the competing solvent was calculated as [V(solvent)/(V(solvent)+V(CD3CN))]*100%, V = volume.
When taken together, it can be noted that the supramolecular
ligands 1-3 show a preference for S4-symmetry wherever the
(three sets of resonances) cage for monomer 3. The DOSY
flexibility of the ligand allows it. Owing to the many available
spectra confirm the formation of a single species in all cases.
conformations of 12 and distances between Bipy units due to
The molecular ions corresponding to a tetrahedral (Fe-Zn)4(2-
unrestricted rotation around the -CH2- linker, a deformed S4-
3)12 cage were observed in the ESI-MS spectra and agree well
with simulated isotopic patterns. In the case of Fe4312, a trace
amount of cubic Fe8324 was also detected by ESI-MS (Fig. S99).
Some of the resonances in the N-H region and one of the
symmetric cage is formed easily and is stabilized by multiple
non-covalent inter-ligand interactions (internal solvation)
inside the cavity. Ligand 22 is completely flat because of the
conjugation of the urea nitrogen lone pair with the Bipy
aromatic system. Although a syn ligand geometry is still
possible, the capability of the system to adjust for optimum
packing is limited, and therefore the most symmetric T-
geometry is adopted with all UPy2 dimers located at the
maximum distance from each other, tangential to the
tetrahedron surface. Finally, in the case of ligand 32, the Bipy
and urea moieties are twisted almost perpendicular with respect
to the benzene ring linker for the anti-configuration, whereas
such a twist angle for the syn-configuration is much smaller.18
In contrast to the fully covalent rigid ligands reported in the
literature, the distance between Bipy units, and thus between the
metal ions, can also be modulated by distorting the quadruple
H-bonding motifs from coplanarity. As demonstrated
previously with other supramolecular systems, quadruple H-
bonds can tolerate bending up to ca. 20 and 10 with respect to
the center or the plane of the H-bonding interface,
repectively.14e,f The molecular model shows that within the
shortest edge comprising anti-conformer of ligand 32, the UPy
units are unidirectionally twisted along the line of quadruple H-
bonding interface resulting in a distorted V-shaped geometry
and reduced distance between metal centres. The preferential
formation of the S4-symmetric cage is most likely governed by
partial accommodation of the UPy2 dimers inside the cavity of
the cage owing to a significantly larger cavity size as compared
to T-Fe4212. Indeed, the void volume of S4-Fe4312 is not
resonances in the C(sp2)-H region in the spectrum of S4-Fe4312
were not fully resolved due to broadening, however, they were
clearly visible in the spectrum of S4-Zn4312. Vapor diffusion of
chloroform into an acetonitrile solution of T-Fe4212 allowed the
isolation of single crystals. However, the crystals were found to
be very weakly diffracting, even with extremely prolonged
exposure times using Cu radiation. This is routinely observed
for supramolecular species, especially when they are comprised
of predominantly light atoms, as is the case for the cages
described herein. As expected for supramolecular complexes
with a high void volume, the data collected for this structure
suffered from rapid fall-off of reflection intensity at high
diffraction angles, and this had a negative impact on the quality
of the high angle reflections collected, with some not being
observed. Fortunately, the positions of the heaviest atoms
present (Fe) could be located with high certainty. The perfectly
tetrahedral arrangement of four Fe2+ ions, separated by 16.1 Å,
was found, supporting the formation of the T-symmetric cage
Fe4212. Overlay of experimentally determined coordinates of
Fe2+ ions with the computationally obtained structure resulted
in good agreement (<0.6 Å error) (Fig. 4c). The X-ray quality
crystals of S4-Fe4312 could not be obtained and the molecular
model of the cage is shown in Figure 4d. The hydrodynamic
radii for T-Fe4212 and S4-Fe4312 extracted from DOSY spectra
also agree well with the ones obtained from the above models
(Fig. S91).
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significant and the assembly resembles more a molecular bowl of one particular pair of quadruple H-bonds or their reduced
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with open cavity rather than a cage (Fig. 4d).
solvent accessibility (Fig. 5f).
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Stability studies: effect of solvent polarity and competing
agents. The quantitative formation of tetrahedron cages in
acetonitrile indicates the high stability of quadruple H-bonds
even in such polar solvents. To further probe the strength of H-
bonding in these assemblies, we conducted more detailed
Intrigued by the remarkable stability of these aggregates in
polar solvents, we then characterized them in pure d4-MeOD. In
contrast to water, methanol provided sufficient solubility of
complexes S4-Fe4(1b)12 and T-Fe4212 for 1H NMR experiments
(Fig. 6a-b).
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The evaluation of the size of the complexes was made by using
DOSY together with control ligands 4 and 5 containing a Bipy
unit and non-H-bonding 1,3-dimethyl benzene isostere as the
isocytosine ring (Fig. 6c). These controls can form only
monomeric octahedron complexes Fe(4-5)32+ and thus provided
a reliable reference for the size of a single vertex of the
tetrahedral assembly. The data obtained shows the formation of
S4-Fe4(1b)12 in d3-MeOD based on both DOSY (single species),
1H NMR (three sets of resonances) and ESI-MS experiments.
DOSY measurements also indicate the formation of single
species in the case of T-Fe4212. Compared to diffusion
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coefficients obtained for controls Fe43 and Fe532+, the so
2+
formed aggregates are much larger, in agreement with the
formation of cage complexes. Moreover, the hydrodynamic
radii of cage complexes are very close to the ones obtained in a
CD3CN solution. Unfortunately, the low solubility of the
complex S4-Fe4312 in d3-MeOD impeded the analogous
experiments; however, the titration of a CD3CN solution of the
latter with an excess of d3-MeOD also confirms the formation
of the tetrahedron complex (Fig. S65, S104).
The stability of H-bonds in UPy2 dimers in complexes S4-
Fe4(1b)12, T-Fe4212 and S4-Fe4312 is exceptional and exceeds
greatly the stability of cyclic tetrameric aggregates based on
UPy aggregation, previously reported by us.14e
titration experiments by gradually increasing the polarity of the
media with addition of DMSO or water into an acetonitrile
solution of S4-Fe4(1b)12, T-Fe4212 and S4-Fe4312. As shown in
Figure 5a, the cage S4-Fe4(1b)12 is exceptionally stable; traces
of the cage were still detected in solvent mixtures containing up
to 31% (v/v) d6-DMSO and 64% D2O (v/v). Full H to D
exchange of N-H protons was achieved at ca. 16% (v/v) content
of D2O. Cage T-Fe4212 displays similar stability, surviving in as
much as 22% (v/v) d6-DMSO in CD3CN (Fig. 5c). The addition
of D2O resulted in full H to D exchange at ca.
Figure 6. 1H NMR spectra and DOSY trace of S4-Fe4(1b)12 (a) and T-
Fe4212 (b) in d3-MeOD; (c) Chemical structures and hydrodynamic radii
of control compounds 4 and 5.
14% D2O and caused only slight shift of resonances assigned to
aromatic and vinylic protons. Cage S4-Fe4312 was detected at d6-
DMSO and D2O contents of up to 52% and 29%, respectively.
In the case of S4-Fe4(1b)12 and T-Fe4212, the H/D exchange rate
of N-H protons with D2O correlates with their pKa values and
inversely with the strength of the H-bonds they form. In both
cases, the least acidic N-H proton c exchanged at the slowest
rate. Surprisingly, these protons exchanged even slower than
the N-H protons a, involved in intramolecular H-bonding. This
observation cannot be explained by solvent accessibility alone
since all N-H protons of the UPy2 dimer in complex T-Fe4212
are residing on the surface, and thus are equally accessible to
D2O. Contrarily, in cage S4-Fe4312, one full set of protons
exchanged slower suggesting either markedly different stability
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is only weakly aggregating in solution. On the other hand, it
forms a very stable ADDA-DAAD heterocomplex with UPy
(Ka = 107 M-1 in CDCl3), and even though the value of Ka is
comparable to those of the UPy dimerization (enol and keto
forms), the heterocomplex is favored because of the increase of
the total number of H-bonds in the system. Even highly stable
cyclic supramolecular constructs assembled using cooperative
UPy dimerization is fully disintegrated by the action of DAN.14e
Figure 7. (a) Scheme depicting the disassembly of cage S4-Fe4(1b)12 upon
2
3
4
5
addition of phenanthroline (reaction 1) and the establishment of equilibrium
of various species after introducing Zn2+ ions (reaction 2). Conversion of
cage S4-Zn4(1b)12 into cage S4-Fe4(1b)12 is also indicated. (b) The 1H NMR
spectra are shown for reactions 1 and 2; (c) Formation of heterocomplex
1b-6 and its transformation to cage S4-Fe4(1b)12 upon addition of Fe2+ ions.
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To further evaluate the robustness of the complexes, we next
performed experiments with external competitors for metal ion
and H-bonds. First, a stoichiometric amount of phenanthroline
(Phen) was added to the CD3CN solution of S4-Fe4(1b)12 (Fig.
7a, reaction 1). Owing to much stronger complexing properties
of Phen compared to Bipy, the cage was fully converted into
In our hands, treating the complex S4-Fe4(1b)12 with an excess
of DAN derivative 6 resulted in no changes in 1H NMR
spectrum. Moreover, the pre-formed heterodimer 1b-6 is also
transformed into cage S4-Fe4(1b)12 and free DAN upon addition
of Fe(OTf)2, indicating the remarkable stability of the H-bonds
of the UPy2 dimers in S4-Fe4(1b)12. In fact, to our knowledge
this is the first example of UPy2 dimers that resists DAN. This
can be explained by the cooperative action of the network of
coordination and H-bonds within the cage structure.
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2+
homoleptic Fe(Phen)3 and the free ligand 1b. Addition of an
equimolar amount of Zn(OTf)2 to the above mixture resulted in
a complex mixture with an unexpected speciation of species
(Fig. 7a,b reaction 2). Instead of simple scavenging of the
liberated 1b by Zn2+ ions, the redistribution of metal ions
between various species took place. In an equilibrated mixture,
Finally, the assembly and disassembly of S4-Fe4(1b)12 can also
be controlled by the action of acid and base. The cage was fully
destroyed by adding an excess of trifluoroacetic acid, and then
regenerated to some extent by neutralizing with triethylamine
(Fig. S74).
2+
2+
Zn(Phen)3 and Fe(Phen)3 were found in the molar ratio
~1.26, together with homoleptic cages S4-Fe4(1b)12/S4-
Zn4(1b)12 (~2.5:1) and mixed cages FenZn4-n(1b)12 (Fig. S66-
S67).20 Independently, we also showed that cage S4-Fe4(1b)12 is
much more stable than S4-Zn4(1b)12 (Fig. 7a, Fig. S71).
Interestingly, the distribution of Fe2+ and Zn2+ within
M(Phen)32+ (M = metal) complexes favors otherwise less stable
Self-sorting studies: effect of ligand structure. Having
complexes S4-Fe4(1)12, T-Fe4212 and S4-Fe4312 in hand we
became interested in whether the length or rigidity of the
ligands can have any influence on the fidelity of the assembly
process. The precise control of the assembly process within a
mixture with multiple species present is one of the main goals
of systems chemistry towards creation of adaptive molecular
networks.12,25
2+
Zn(Phen)32+. Based on lgK3 values, the Fe(Phen)3 is more
stable than Zn(Phen)32+ by four orders of magnitude,21 and the
control experiment with Fe(Phen)32+ and added Zn(OTf)2 shows
that Fe(Phen)32+ remains in the mixture as the dominant species
together with concomitant formation of Zn(Phen)2+ and
Zn(Phen)22+, and no Zn(Phen)32+ (Fig. S70). Moreover, the same
species as in reaction 2 are also formed in the control
experiment in which equimolar amounts of S4-Fe4(1b)12 and S4-
Zn4(1b)12 were mixed, thus ruling out the presence of mixed
species of the type Mn(1b)m(Phen)l (M = metal) (Fig. S68).
These results show that the combination of Fe/Zn/Phen and
Fe/Zn/1b subsets, where the resulting equilibrium manifold
becomes overwhelmed by the equilibrium between cage
complexes resulting in the formation of S4-Fe4(1b)12 as the
dominant complex. Surprisingly, the metal exchange between
cages is very fast, observed shortly after mixing the
components.22,23 The importance of the formation of cage
complexes to the outcome of species distribution was also
corroborated by another control experiment. Namely, repeating
the same experiment (reactions 1 and 2) and replacing the cage
forming ligand 1b with simple Bipy, the homoleptic complexes
2+
2+
Fe(Phen)3 and Zn(Bipy)3 were found to be the major
products, whereas scrambled complexes formed only to a small
extent (Fig. S72). The driving force for metal scrambling within
cages is most likely of both enthalpic and entropic origin.
Borrowing Fe2+ from S4-Fe4(1b)12 to form the mixed cage
FenZn4-n(1b)12 results in an increase of cage stability compared
Figure 8. Self-sorting of molecular cages composed of the same type
of ligands 1b and 1d having substituents of different size (a) and self-
sorting of preformed cages having different types of ligands (b).
to S4-Zn4(1b)12, at the same time preserving
a large
concentration of the most stable species, S4-Fe4(1b)12, and
increasing the entropy of the system. The example described
herein thus provides a simple system from which a complicated
reaction network can be built that is relevant to systems
chemistry.
As shown in the previous mixing experiments (Fig.7a), two
cages of the same type built from two different metals of similar
size (Fe2+/Zn2+) resulted in scrambling of the metal ions to
produce a significant amount of mixed-metal cages. We next
probed the possibility for self-sorting based on the variation of
the ligand. First, two 1st generation ligands 1b and 1d having
CH3- and C11H23- substituents in the isocytosine ring were
The stability of UPy2 dimer within cage S4-Fe4(1b)12 was also
probed by using the powerful competing agent for ADDA H-
bonding array - 2,7-diamido-1,8-naphthyridine (DAN) (Fig.
7c).24 DAN is a non-self-complementary H-bonding motif that
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mixed together in 1:1 ratio followed by addition of a
resonances in the 1H NMR might result from the overlap of the
1
2
3
4
5
6
7
8
stoichiometric amount of Fe(OTf)2. The formation of a complex
mixture with no dominant species was noted (Fig. 8a). To avoid
kinetic trapping of intermediates along the assembly pathway,
a control experiment was performed with separately prepared
individual cages S4-Fe4(1b)12 and S4-Fe4(1d)12. Exchange of the
ligands was observed shortly after mixing, resulting in the same
complex spectral pattern (Fig. S75). DOSY experiments
showed that all equilibrating species are of similar size and
therefore represent isomeric cage complexes (Fig. S76). The
mixing process is most likely driven by the increase of the
entropy, and also by the release of steric crowding in S4-
Fe4(1d)12. Unfortunately, it was not possible to prove whether
the mixing process involved exchange of free ligands (or their
dimers) via monomer dissociation or exchange of intact vertices
via selective H-bond cleavage. Self-sorting experiments with
pairs of preformed complexes Fe4(1b)12/Fe4212, Fe4(1b)12/Fe4312
and Fe4212/Fe4312 comprised of different ligands revealed full
narcissistic self-sorting even after sonicating the solution at
50ºC overnight (Fig. 8b). Mixing of the free ligands with
Fe(OTf)2, however, resulted in a kinetically trapped state
consisting of various aggregates (Fig. S80-S81). In stark
contrast, the more labile Zn cages afforded a mixture of
scrambled aggregates even at room temperature reaching
equilibrium after 15 minutes (Fig. 8b, Fig. S82-S84).
resonances of three non-equivalent UPy2 dimers having similar
chemical shifts. Another possibility is the fast (on the NMR
timescale) interconversion of H-bonding networks between
three - stacked dimers giving rise to averaged signals.
The comparison of the relative stabilities of Hg2(1b)6 and S4-
Fe4(1b)12 was made by adding a stoichiometric amount of
Fe(OTf)2 into the solution of the helicate. Formation of S4-
Fe4(1b)12 was noted together with new species having one set
of resonances (Fig. 9b). The latter was shown by ESI-MS and
independent synthesis to be rod-shaped Hg2(1b)2(OTf)4 (Fig.
S107-S108). Surprisingly, the equilibrium was not affected
even in the presence of a large excess of Fe2+. The exceptionally
stable Hg2(1b)2(OTf)4 might thus be useful in more complicated
systems chemistry setups providing a reservoir for ligand 1b
other than Fe2+ or by building heterometallic architectures.
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Modulation of self-assembly by H-bonding molecular
inserts. The H-bonded nature of the edges in the cages
described herein render them amenable for structural
modifications and stimuli-responsiveness using external H-
bonding molecular blocks that have a high affinity for UPy. As
discussed above (Fig. 7c), the addition of DAN to ligand 1b
indeed provided the corresponding heterodimer in quantitative
yield. Although mono-DAN derivative 6 (Fig. 7c) is readily
expelled from the heterodimer in the presence of Fe2+, we
speculated that the bis-DAN derivative could be in principle
inserted into the tetrahedron edge leading to either a change in
topology or dimensions of the aggregate. For the proof-of-
principle, bis-DAN insert 7 containing a flexible adipic acid
linker was synthesized. The attempt to insert 7 directly into
preformed cage S4-Fe4(1b)12 in CD3CN, however, was not
successful (Fig. 10a, reaction 2). Mixing 1b, 7 and Fe(OTf)2
components together gave the same result, most likely due to
solubility issues (Fig. 10a, reaction 1). Compound 7 is
completely insoluble in acetonitrile, whereas
Influence of the radius of metal ion. So far, using Fe2+ (r(2+)
=
61 pm) or Zn2+ (r(2+) = 74 pm) ions as metal nodes resulted in
formation of tetrahedral cages as the sole products. We next
posed the question whether larger metal ions would provide
enough space for UPy2 to deliver different molecular
architectures such as helicates or cubic cages. For this purpose,
we decided to explore Hg2+ as a suitable candidate having one
of the largest ionic radii (r(2+) = 116 pm) among the transition
metals. Surprisingly, supramolecular chemistry of homoleptic
mercury complexes HgL32+ with Bipy or Phen ligands is almost
2+
unexplored and only few examples of Hg(Bipy)3 or
Hg(Phen)32+ have been reported.26 These complexes can only be
obtained from mercury salts with weakly coordinating
counterions,
such
as
triflates,
perchlorates
or
hexafluorosilicates; otherwise, formation of complexes
Hg(Phen/Bipy)n=1,2X2 (X = halogen, rodanide, etc.) is preferred
as a result of the soft character of Hg2+ and the hard nature of
the Phen/Bipy ligands.27 Because of the lack of ligand field
stabilization energy (5d10 electronic configuration) in their
coordination compounds, there is no particular coordination
geometry preferred by Hg2+ ions. Intrigued by the possible
outcome, we prepared the corresponding complex by mixing 1b
1
and Hg(OTf)2 in 3:1 ratio in CD3CN. The H NMR spectrum
indicated the formation of the complex by displaying one set of
rather broadened resonances (Fig. 9b). ESI-MS data supported
the binuclear species, i.e. complexes Hg2(1b)6 (Fig. 9a, Fig.
S86). To our delight, the presence of heavy atoms allowed us to
unambiguously confirm its structure by using X-ray diffraction
of the crystals grown by using vapor diffusion of chloroform
into an acetonitrile solution. The data revealed the
unprecedented molecular structure of the helicate (Fig. 9c, Page
S57). Namely, three UPy2 dimers in their keto tautomeric form
are perfectly - stacked along the helicate axis with distance
between aromatic planes of isocytosines d = 3.4 Å. The
- stacking of the UPy2 dimers provides an energetically
favorable way to avoid steric clash between them, however, this
requires larger separation of the Bipy units at the metal nodes.
For this reason, the helicate of this type is obtained only with
the large Hg2+ ions, and not with Fe2+. The broad N-H
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Fe2+ ions; (b) H NMR spectra of Hg2(1b)6 and the reaction mixture
shown in (a); (c) X-ray structure of helicate Hg2(1b)6.
Figure 9. (a) Schematic representation of helicate Hg2(1b)6 and its
conversion to cage S4-Fe4(1b)12 and Hg2(1b)2(OTf)4 upon addition of
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Figure 10. (a) Reaction 1: unsuccessful attempt to produce an extended cage Fe4[7(1b)2]6 using three component reaction between Fe2+, 1b and 7.
Reaction 2: unsuccessful attempt to insert bis-DAN derivative 7 into preformed cage S4-Fe4(1b)12. Reaction 3: formation of heterocomplex 1b-7-1b.
Reaction 4: reaction of 1b-7-1b with Fe2+ to produce mesocate Fe2[7(1b)2]3; (b) 1H NMR spectra of heterocomplex 1b-7-1b (bottom) and mesocate
Fe2[7(1b)2]3 (top).
selectivity towards a mesocate observed in our case stems from
the bulkiness of the UPy-DAN unit. The formation of a helicate
aggregate using S-shaped conformation of 1b-7-1b would
result in steric clash between UPy-DAN heterodimers, which
on the other hand can be relieved in a mesocate formed from
the pseudo-C conformation of 1b-7-1b, as argued previously by
Wu.9b
the also poorly soluble 1b is gradually and selectively brought
into solution during complexation. Hence, the formation of
heterocomplex 1b-7-1b is not possible. Finally, after switching
to a mixed solvent CD3CN:CDCl3-1:3 system, the 1:2 mixture
1
of 7 and 1b afforded a clean H NMR spectrum assigned to
heterocomplex 1b-7-1b (Fig. 10a, reaction 3). After addition of
Fe(OTf)2, a new spectrum consisting of a set of 10 resonances
was obtained (Fig. 10b). The resonances corresponding to two
protons at 12.07 ppm, 11.46 ppm and 9.99 ppm were not fully
resolved due to similar values of chemical shifts. The spectrum
is thus suggestive of two non-equivalent UPy-DAN
heterodimers within the assembly. ESI-MS analysis indicated
the formation of dinuclear species Fe2[7(1b)2]3, and not the
extended cage Fe4[7(1b)2]6 (Fig. S109). The obtained results
can be rationalized by assuming the formation of a triple-
stranded structure with opposite  and  chirality at each six-
coordinated metal center, i.e. a mesocate.28 Based on the fact
that the most stable conformation for alkyl chain is a zigzag,
Albrecht et al. has proposed that a carbon chain linker
comprised of an even number would favour a helicate, while a
chain with an odd number of carbon atoms would result in a
mesocate.29 Our results contradict this rule. In fact, Raymond et
al. and others30,9b have shown that formulating any general
selection rule might be impossible due to stabilization of one of
the aggregates by the formation of a host-guest complex with
solvent molecules or counter anions. We assume that the
Host-guest chemistry. Tetrahedron cages are well documented
to display rich host-guest chemistry having implications to
catalysis, separation, or modulation of chemical reactivity of the
complexed chemical entities.2 To demonstrate the encapsulat
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Supporting Information
1
2
3
Figure 11. Molecular model of host-guest complex C60@ S4-Fe4312 (a)
Experimental procedures and spectroscopic data (PDF)
X-ray diffraction data files (cif)
and 1H NMR spectra of cage S4-Fe4312 (top) and C60@ S4-Fe4312
(bottom) (b).
The Supporting Information is available free of charge on the ACS
Publications website.
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ion ability of the hybrid cages described herein, we have chosen
S4-Fe4312 as a model system because of its largest metal-metal
distance. Fullerene C60 was selected as representative guest due
to its high symmetry, its importance to material science and
growing interest in the application of supramolecular cages for
site selective functionalization.31 Although the calculated cavity
in S4-Fe4312 is too small for encapsulation of C60, molecular
modelling studies suggested that S4-Fe4312 can accommodate
C60 after rotation of the CAr-Nurea bond without a change in the
overall symmetry. Heating the mixture of an excess of C60 and
S4-Fe4312 in CD3CN resulted in the formation of the
corresponding inclusion complex C60@S4-Fe4312, which was of
AUTHOR INFORMATION
Corresponding Author
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* ias_qxshi@njtech.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Q. S. acknowledges the financial support from the Natural Science
Foundation of Jiangsu Province (BK20181375), Nanjing Tech
University (Start-up Grant 39837129) and the State Key
Laboratory of Fine Chemicals (KF1707). Q. S. is indebted to
SICAM Fellowship from Jiangsu National Synergetic Innovation
Center for Advanced Materials for financial support. A. N.
acknowledges the PhD scholarship from Research Council of
Lithuania. The authors thank Dr Rong Zhang for the initial attempt
of HRMS.
1
the same symmetry as the free host based on H NMR results
(Fig. 11). Full conversion to the inclusion complex was
confirmed by a control experiment using only 0.5 equivalent of
C60. The spectrum consisted of two sets of resonances
corresponding to free and complexed host in slow equilibrium
(Fig. S89-S90). Similar diffusion coefficients were found for
both species indicating that the host undergoes no significant
structural changes upon complexation. The ESI-MS spectrum
shows the ions derived from C60@S4-Fe4312, and no signals of
the cubic Fe8324 or C60@Fe8324 impurities were detected.
Although we were not able to accurately determine the
association constant Ka using UV-vis spectroscopy, the lower
limit of Ka  106 M-1 can be estimated from 1H NMR
experiments (see Page S61).
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CONCLUSIONS
In conclusion, we have demonstrated the fully
diastereoselective assembly of supramolecular tetrahedral
cages by using the cooperative action of coordination and
quadruple H-bonds. The dynamic H-bonds embedded into the
edges of a tetrahedron scaffold open up new ways for structural
and functional modulation of these assemblies and might also
facilitate the ingress of relevant species into the cavity. In
addition, the enhanced stability of H-bonds allowed the
formation of tetrahedral complexes even in highly competitive
protic media which renders them prospective cavitands for non-
polar or anion (in)organic guests. We have realized for the first
time the selection of a mesocate over a tetrahedral cage motif
by modifying the rigidity of the ligand via insertion of flexible
non-covalent wedge. The use of the large Hg2+ ion provided yet
another approach to direct the assembly process towards
dinuclear triple-stranded architectures. The Fe2+ tetrahedron
cages obtained from ligands of different lengths showed no
ligand scrambling when mixed together. These findings pave
the way for simultaneous use of several cages for host-guest
applications or synthetic cascades. Moreover, the possibility to
exchange metal ions within the cage was demonstrated. The
herein introduced molecular tetrahedron cages are potentially
useful as receptors for guests as large as C60. Further studies
aiming to employ the host-guest chemistry of these cages in
catalysis are undergoing.
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Hydrophobic Dimers of cis-Azobenzene and -Stilbene Derivatives in a
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Ozeki, T.; Fujita, M. Sequence-Selective Recognition of Peptides
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Cage. J. Am. Chem. Soc. 2005, 127, 4546-4547. (c) Ronson, T. K.;
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Kaphan, D. M.; Toste, F. D.; Bergman, R. G.; Raymond, K. N.
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Chem. Soc. 2015, 137, 9202-9205. (c) Yoshizawa, M.; Tamura, M.;
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ASSOCIATED CONTENT
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H. Self-Assembled Nanospheres with Multiple Endohedral Binding
Substitution in M4L6 Cages. Angew. Chem. Int. Ed. 2012, 51, 1464-
Sites Pre-Organize Catalysts and Substrates for Highly Efficient
Reactions. Nat. Chem. 2016, 8, 225-230.
1468. (c) Sun, B.; Nurttila, S. S.; Reek, J. N. H. Synthesis and
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Characterization of Self‐Assembled Chiral FeII L3 Cages. Chem. Eur.
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intensity of resonances at 10.84 ppm and 10.89 ppm and their 1:1 ratio
are indicative of the dominance of one particular species. The control
experiments with different Fe2+/Zn2+ ratio support this assumption. See
Fig. S68.
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Structure
of
Tris(1,10-phenanthroline)mercury
(II)
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Complexes,
[Hg(phen)2(SCN)2],
[Hg(2,2′-bipy)2(SCN)2]
and
[Hg(phen)2(NO3)2], Thermal and Fluorescence Studies. J. Coord.
Chem. 2008, 61, 789-795.
28. To ensure sufficient solubility, unsymmetrically branched DAN
derivative 7 was used in our study. The stereogenic center at branching
carbon renders this compound chiral. As prepared, compound 7 is a
mixture of (S,S), (R,R) and (R/S) stereoisomers and in principle, might
influence the stereochemical outcome of the assembly of 7-1b-7.
However, in our related studies using 7 and chiral UPy derivatives, we
never observed any impact of the chiral side chain, perhaps due to its
peripheral location. The exact 1:1 relationship of all integrals in the
spectrum of Fe2[7(1b)2]3 suggests that the chirality of the side chain
plays no role for directing the self-assembly.
29. (a) Albrecht, M.; Kotila, S. Formation of a “meso‐Helicate” by
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Capsule with Enhanced Catalytic C-C Bond Formation Activity upon
C60 Binding. Angew. Chem. Int. Ed. 2019, 58, 9073-9077. (b) Brenner,
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Metal-Organic Cages with Cube-Like Cavities for Selective
Encapsulation of Fullerene Guests and Their Spin-Crossover
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Agramunt, V.; Eder, T.; Darmandeh, H.; Guisado-Barrios, G.; Peris, E.
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Fuertes-Espinosa, C.; García-Simón, C.; Castro, E.; Costas, M.;
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Echegoyen, L.; Ribas, X.
A
Copper-Based Supramolecular
Nanocapsule that Enables Straightforward Purification of Sc3N-Based
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Juanhuix, J.; Maspoch, D.; Poblet, J. M.; Echegoyen, L.; Ribas, X.
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Purification of Uranium-Based Endohedral Metallofullerenes (EMFs)
Nat. Commun. 2014, 5, 5557 (l) Sánchez-Molina, I.; Grimm, B.;
Calderon, R. M. K.; Claessens, C. G.; Guldi, D. M.; Torres, T. Self-
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Ribas, X. Sponge-Like Molecular Cage for Purification of Fullerenes.
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