Self-Assembly of a Purely Covalent Cage with Homochirality by Imine Formation in Water

Article abstract of DOI:10.1002/anie.202106428

Self-assembly of host molecules in aqueous media via metal–ligand coordination is well developed. However, the preparation of purely covalent counterparts in water has remained a formidable task. An anionic tetrahedron cage was successfully self-assembled

Full text of DOI:10.1002/anie.202106428

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Accepted Article
Title: Self-assembly of a purely covalent cage with homochirality via
imine formation in water
Authors: Yixin Chen, Guangcheng Wu, Binbin Chen, Hang Qu, Tianyu
Jiao, Yintao Li, Chenqi Ge, Chi Zhang, Lixin Liang, Xiuqiong
Zeng, Xiaoyu Cao, Qi Wang, and Hao Li
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10.1002/anie.202106428
Angewandte Chemie International Edition
RESEARCH ARTICLE
Self-Assembly of a Purely Covalent Cage with Homochirality by
Imine Formation in Water
Yixin Chen, [a] Guangcheng Wu, *[a] Binbin Chen, [a] Hang Qu, [b] Tianyu Jiao, [a] Yintao Li, [a] Chenqi Ge,
[a] Chi Zhang, [a] Lixin Liang, [a] Xiuqiong Zeng, [a] Xiaoyu Cao, [b] Qi Wang, [a] Hao Li *[a]
[a]
Y. Chen, G. Wu, B. Chen, T. Jiao, Y. Li, C. Ge, C. Zhang, L. Liang, Prof. X. Zeng, Prof. Q. Wang, Prof. H. Li
Department of Chemistry
Zhejiang University
Hangzhou 310027, China
E-mail: 11637033@zju.edu.cn; lihao2015@zju.edu.cn
[b]
H. Qu, Prof. X. Cao
State Key Laboratory of Physical Chemistry of Solid Surfaces, iChEM and College of Chemistry and Chemical Engineering
Xiamen University
Xiamen 361005, China
Supporting information for this article is given via a link at the end of the document.
Abstract: Self-assembly of host molecules in aqueous media via
metal-ligand coordination is well developed. However, the preparation
of purely covalent counterparts in water has remained a formidable
task. Here, an anionic tetrahedron cage was successfully self-
assembled in a [4+4] manner by condensing a trisamine and a
trisformyl in water. Even although each individual imine bond is rather
labile and apt to hydrolyze in water, the tetrahedron is remarkably
stable or inert due to multivalence. The tetrahedral cages, as well as
its neutral counterparts dissolved in organic solvent, have
homochirality, namely that their four propeller-shaped trisformyl
residues adopt the same rotational conformation. The cage is able to
take advantage of hydrophobic effect to accommodate a variety of
guest in water. When a chiral guest was recognized, the formation of
one enantiomer of the cage becomes more favored relative to the
other. As a consequence, the cage could be produced in an
enantioselective manner. The tetrahedrons are able to maintain its
chirality after removing the chiral guest, probably on account of the
cooperative occurrence of intramolecular forces that restrict the
intramolecular flipping of phenyl units in the cage framework.
addition, because water is the life medium, realizing their
supramolecular functions in aqueous media would be of
importance, if these self-assembled molecules are designed for
biological purposes. A variety of dynamic covalent[7] approaches
were also developed, for the sake of purely covalent molecules.
Such dynamic reactions include formation of imine,[8] and boronic
ester,[9] as well as metathesis of olefin[10] and alkyne.[11] These
approaches, however, are much less successful in water. For
example, imine and boronic ester are apt to undergo hydrolyze in
aqueous media. Using more robust dynamic bond such as
disulfide[12] and hydrazone[13] might solve this problem. However,
unlike the relatively rigid coordinative systems whose ligands are
well-organized in a specific orientation manner around a transition
metal center, purely covalent molecules generally have more
flexible framework. In water where hydrophobic effect is present,
the building blocks of the latter molecules prefer to undergo
aggregation, yielding to either cavity collapse[14] or catenation.[13a,
15]
As a consequence, forming purely covalent molecules with
guest recognition ability in water is still a formidable task.
Here, we successfully self-assembled a tetrahedral cage in
water, by condensing an anionic trisbenzaldehyde and a trisamine
in a [4+4] manner. Control experiments demonstrated that the
self-assembly of this cage is in fact nontrivial. First, the success
of self-assembly in water results from multivalence, otherwise
water would lead to imine hydrolysis. Second, the tetrahedral
cage, as well as its organic-soluble counterparts, only form when
their substitution units are located in the meta position with
respect to the formyl units. X-ray crystallography and theoretical
results indicate that in the tetrahedron framework, intramolecular
CH∙∙∙π and hydrogen bonding interactions occur to the ortho
protons with respect to the formyl units. These intramolecular
forces are disturbed when one of the ortho protons in the
benaldehyde units are replaced with substitutional groups. As a
consequence, the trisbenzaldehydes with ortho substitution units
would produce triangular prisms instead. In each tetrahedron, the
Introduction
Self-assembly represents a more advanced technique
compared to traditional synthesis relying on irreversible reaction,
especially in the preparation of molecules with complex structures
and topology, in whose formation multiple bonds are formed
simultaneously. Metal-ligand coordination has been developed for
self-assembly, by many groups led by Fujita,[1] Raymond,[2]
Stang,[3] Leigh,[4] Nitschke[5] and other authors.[6] Some of these
self-assembled molecules often have pre-organized cavities or
pockets to accommodate guests, where properties of the latter
are modulated. Water is often used as the solvent, where
hydrophobic effect is available to drive host-guest recognition. In
1
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10.1002/anie.202106428
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RESEARCH ARTICLE
four propeller-shaped trisbenzaldehyde residues adopt the same
rotational conformation, namely either P or M, endowing the
cages homochirality. The cage self-assembled in water is able to
take advantage of hydrophobic effect to encapsulate guests with
complementary sizes, which act as template for the cage
formation. The self-assembly of the cage becomes
enantioselective in the presence of chiral template. Once self-
assembled, the homo-chirality of the cages bearing ester or
carboxylate units is rather stable. No racemization was observed
after removing solvent or guest template.
water, so that the cage is able to employ hydrophobic effect to
drive host-guest recognition.
Our trials began by synthesizing
a set of triangular
trisbenzaldehydes 1a-1f, each of which contains three
functionalized benzaldehyde functional groups grafted on a
central phenyl unit. In 1a, 1b and 1d, the substitutional units,
namely OMe, COOMe and COOH, are located in the meta
position with respect to each of the formyl units. In the case of 1c,
1e, 1f and 1g, the corresponding substitutional groups are placed
in the ortho positions. 1a, 1b, 1c, 1f and 1g are soluble in organic
solvent including CDCl3 and DMSO-d6. 1d and 1e undergoes
deprotonation in the presence of base, forming water-soluble
anions namely 1d3− and 1e3−.
Results and Discussion
Our group[16] and others[17] have demonstrated that a
tetrahedral cage could be self-assembled in high or close to
quantitative yields, by condensing a trisamine namely tris(2-
aminoethyl)amine (TREN) and a rigid triangular trisbenzaldehyde
compounds, which constitute the vertex and face parts of the
tetrahedron, respectively. Because the self-assembly was
performed in organic solvent, a solvent molecule occupies the
cage cavity as a competitive guest, as a consequence of which,
these tetrahedrons often have little or no guest binding ability. One
of the often used approaches to favor host-guest recognition is to
use water where hydrophobic effect is present. However,
molecules containing imine bonds are often considered
incompatible with water, except a few exceptions.[18] More recently,
it was found by us[19] that multivalence can help avoid imine
hydrolysis, namely that a self-assembled molecule whose
components have multiple connections to the parent cage would
be rather inert or stable in aqueous solution, even though each
individual imine bond is apt to undergo hydrolysis in the presence
of water. We thus envision that a tetrahedral cage comprising
trisamino and trisformyl building blocks might also be stable in
Figure 1. a) Triangular trisformyl units exhibits two rotational modes, namely
P or M conformations; Single-crystal structures of b) (4P)-2a (left), (4M)-2a
(right), as well as c) (4P)-2b (left) and (4M)-2b (right). Disordered solvent
molecules and part of hydrogen atoms that are not involved in intramolecular
interactions are omitted for the sake of clarity. Carbon, grey; hydrogen,
white; nitrogen, blue; oxygen, red. View of the packing of the cages d) 2a
and e) 2b along b-axis by spacefill model. The cages with (4P) and (4M)
configurations are colored orange and blue, respectively.
Combining TREN and either 1a or 1b yielded tetrahedrons 2a
and 2b respectively in a [4+4] manner (Scheme 1), whose yields
were determined to be 96% and 88%, by using an internal
standard in the corresponding 1H NMR samples (Figure S113 and
S114). In contrast, condensing 1c, 1f, 1g and TREN did not afford
the corresponding tetrahedron. Instead, a triangular prism 3c, 3f,
3g was self-assembled in a 95%, 69% and 50% yield in a [2+3]
Scheme 1. Structural formulas of tetrahedrons 2a, 2b, 2d12−, as well as
triangular prisms 3c, 3e6−, 3f, 3g self-assembled via condensing a trisamine
namely tris(2-aminoethyl)amine (TREN) and each of the triformyl
precursors 1a, 1b, 1d3−, 1c, 1e3−,1f, 1g. The solvents used here include
CDCl3 (2a, 2b, 3c and 3f), D2O (2d12− and 3e6−) and DMSO-d6 (3g).
2
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10.1002/anie.202106428
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RESEARCH ARTICLE
manner, which contains three unreacted amino groups in the
TREN residues (Figure S115,127 and 128).
example, the resonance of one of the ortho protons pointing
inward undergoes remarkable upfield shift, on account of the
occurrence of CH∙∙∙π interactions, an observation in reminiscence
of those of 2a and 2b. In the mass spectrum, prominent peaks
corresponding to [2d12-+ aH+ + bK+]5− (a + b = 7) and [2d12-+aH+ +
bK+]4− (a + b = 8) were clearly observed. In the absence of CHCl3,
self-assembly only afforded a library of mixture containing both
the tetrahedral cage 2d12- and other oligomeric byproducts (Figure
S140), indicating that CHCl3 plays an important role of template.
In order to unravel the mechanism of structurally similar
trisbenzaldehyde compounds going to totally different self-
assembly pathways, diffraction-grade single crystal of 2a and 2b
were obtained by vapor diffusion of isopropyl ether into the
corresponding CHCl3 solutions. In solid-state structures of both
2a and 2b (Figure 1), the phenyl protons in the ortho positions
with respect to the imine are observed to undergo intramolecular
forces within the cage frameworks. On the one hand, the distance
between one of the ortho protons pointing inward to the cage
cavity and the adjacent phenyl moiety is approximately 2.8 Å
(Figure 1b, right), indicating the occurrence of CH∙∙∙π interactions.
The occurrence of such intramolecular interactions is also
convinced by the corresponding 1H NMR spectra of both 2a and
2b (Figure S68 and S75), i.e., the corresponding resonances
undergo remarkable upfield shifts (i.e., approximate 2 ppm),
indicating these ortho protons undergo shielded magnetic
chemical environment within the cage framework. According to
DFT calculation, the CH∙∙∙π interaction between a phenyl proton
and its adjacent phenyl moiety is favored by -2.75 kcal/mol (Table
S1 and S2). On the other hand, each of the ortho protons pointing
outward undergoes CH∙∙∙N hydrogen bonding with the imine
nitrogen atoms, i.e., the H∙∙∙N distances are around 2.6 Å (Figure
1b, right). MD simulation indicated that such CH∙∙N interaction is
favored by -17.96 kJ/mol (Figure 2). In the case of 1c, one of
whose ortho positions are occupied by a OMe unit, either the
hydrogen bonding or CH∙∙∙π interactions would be disturbed. As
a consequence, 1c produces the prism 3c, whose formation is
mainly driven by π∙∙∙π interactions between two 1c residues.[16b]
Such π∙∙∙π interactions was disfavored in both 1a and 1b, which
are less planar compared to 1c, because their substitution units
in meta positions introduce phenyl-phenyl steric hindrance.
Probably this is another explanation that 1a and 1b form the
tetrahedrons selectively. Combining TREN with either 1f or 1g
also produced the corresponding triangular prism, instead of a
tetrahedron. Both 1f and 1g bear substitutional groups in the ortho
positions, which further supports our hypothesis that tetrahedrons
only form when the intramolecular interactions are not disturbed.
Figure 3. a) Structural formula of the cage 2d12− by condensing 1d3− and
TREN in water in the presence of a hydrophobic template; b) 1H NMR
spectra (400 MHz, D2O 298 K) of 2d12− encapsulating a template CHCl3.
The resonances corresponding to CHCl3 both inside and outside the cage
were observed; c) ESI-HRMS of 2d12−. The signals labelled in the
spectrum correspond to molecular ions of 2d12− taking five and four
negative charges by gaining seven or eight counter-cations including
either H+ or K+.
The yield of 2d12− in the presence of CHCl3 was calculated to be
84% by using an internal standard in the NMR sample (Figure
S118). It seems that a variety of other guests with complementary
sizes could also template the cage formation, including CH2Cl2,
CCl4, THF, cyclohexane, pyridine, isopropanol, tert-butanol, as
well as S- or R-propylene oxide (Figure S141-162). The self-
assembly of 2d12− was less successful when the templates used
are either not size complementary to fit within the cage cavity, or
too hydrophilic to take advantage of hydrophobic effect (Figure
S163). The framework of the cage 2d12− seemed to be remarkably
inert, i.e., removal of the template and solvent via evaporation did
not lead to cage degradation (Figure S164). Such inertness
Figure 2. a) The energy released due to the interactions between N36 atom
and H226 atom, including electrostatic interactions (red trace), van der
Waals interactions (blue trace), and overall interactions (black trace). b) The
optimized structure of 2b obtained by using Licorice models. Insert: a
fragment containing N36 and H226 by using CPK models.
Combining 1d, TREN, KHCO3 in a 1:1:5 ratio in D2O (0.6 mL)
in the presence of CHCl3 (10 µL), a tetrahedral cage 2d12− with K+
counter-cations was observed to be produced as the predominant
product, whose formation was supported by both 1H NMR
spectroscopy and mass spectrometry (Figure 3b and 3c). For
3
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10.1002/anie.202106428
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RESEARCH ARTICLE
results from multivalence. That is, each of the residues including
both TREN and 1d3− was connected with the cage framework by
three imine bonds. It is relatively energy demanding to cleave
three imine linkages simultaneously, even though each individual
imine bond is labile. Such hypothesis is supported by a control
experiment that, combining 3-formylbenzoic acid, TREN, KHCO3
in a 3:1:5 ratio in D2O (0.6 mL) only yielded a mixture containing
mostly the formyl reactant and small amount of imine (Figure
S139). In addition, combining 1e, TREN, NaOH in a 2:3:6 ratio in
D2O (0.6 mL) produced 3e6− as the predominant product (Figure
S95), an observation further confirms our aforementioned results
that tetrahedron only forms when both hydrogen bonding and
CH∙∙∙π interaction are available.
second one with negative signal corresponds to (4P)-2b (Figure
S173). Upon purification, the chirality of both (4P)-2b and (4M)-
2b was observed to be rather stable, i.e., no remarkable CD signal
attenuation was observed to either of these two enantiomers at
room temperature for no less than two weeks. In the case of 2a,
however, only one peak was observed in the chiral HPLC trace
after several trials of separation. The possible explanations
include that i) the two enantiomers (4P)-2a and (4M)-2a have the
same retention time in HPLC purification; ii) the two enantiomers
undergo fast racemization at room temperature.
The tetrahedral frameworks including 2a, 2b and 2d12− are
chiral, as inferred from the corresponding 1H NMR spectra of
these three cages that, the two protons in each of the methylene
units in the TREN residues become diastereotopic (Figure 3b,
S68 and S75). X-ray crystallography demonstrates that, in each
of the cage framework of either 2a or 2b, the four tetraphenyl units
namely either 1a or 1b residues adopt the same rotational
conformation, namely either P or M. Each cage framework thus
has homochirality, namely 4P or 4M. Such homochirality is
attributed to the intermolecular CH∙∙∙π interactions, which drive
the three phenyl units in each of the tetrahedron vertices to
orientate in the direction of either clockwise or counter-clockwise.
Only the cage framework with homochirality is able to maximize
such intramolecular forces, as a consequence of which, they are
self-assembled as the more thermodynamically favored products
compared to their diastereomers including PPPM, PMMM, as well
as PPMM. Solid state structures indicate that the cages with 4P
and 4M conformations are associated with clockwise and counter-
clockwise conformations in the TREN residues, respectively. In
solid state, each cage undergoes packing with its enantiomer
(Figure 1d and 1e), probably because such mix-and-match
packing manner favors more efficient intermolecular interactions
than the homo-homo packing mode. Several trials to obtain the
single crystal of 2d12− from its water solution were unsuccessful.
In the case of 2d12−, the occurrence of CH∙∙∙π interactions is in
assistance of hydrophobic effect. We thus reasonably predicate
that 2d12− is also homochiral as 2a and 2b.
Figure 5. CD spectra of 2d12− (0.1 mM, H2O) templated by S-PPO (black
trace) or R-PPO (red trace) and CHCl3 (green trace), indicating that the
cage formation is enantioselective upon addition of chiral guests. After
replacing the chiral guests with CHCl3, CD signals of 2d12− templated by S-
PPO (blue trace), or R-PPO (pink trace) do not undergo attenuation.
The water compatibility of 2d12− inspired us to develop guest-
induced chirality. When the chiral guests, namely the S- or R-
propylene oxide (PPO), were used as the template, the cage 2d12−
was generated in an enantioselective manner (Figure 5). For
example, 2d12− produced in the presence of 5 equiv. (relative to
the cage) of R-propylene oxide, exhibits negative CD signal at =
277 nm, indicating (4P)-2d12− is more favored than (4M)-2d12−
upon encapsulating R-propylene oxide. S-propylene oxide
provided the opposite results. The relationship between CD signal
of 2d12− and the ratio of S-propylene oxide and 2d12− was shown
in figure S170. The ee values were calculated to be 10% based
on an assumption that a pure enantiomer of 2d12− in water
provides the CD signal with the same intensity as that of a pure
enantiomer of 2b in chloroform. 1H NMR spectrum indicated that
the chiral guests within the cage cavity could be replaced by
addition of excess amount of chloroform (Figure S168). After
guest exchange, no remarkable CD signal attenuation was
observed for no less than seven days (Figure 5), indicating that
the chirality of 2d12− was rather stable in water. Possible
explanations include, i) the carboxylate units form hydrogen
bonds with the protons in the central phenyl units of the 1d3−
residues, ii) a water molecule bridges two adjacent carboxylate
anions in 1d3− residues. Such hydrogen bonds raise the energy
Figure 4. a) Chiral HPLC spectrum exhibits two peaks corresponding to
(4M)-2b (red) and (4P)-2b (blue) in a 1:1 ratio; b) Experimental and
TDDFT-predicted (the insert) CD spectra of the isolated chiral tetrahedral
cages ((4M)-2b, red trace; (4P)-2b, navy trace).
The two enantiomers of the cage 2b were resolved by using
chiral HPLC (Figure 4). CD spectra of these two fractions were
independently recorded, exhibiting mirror-like CD signal, which
further convinced that each of two fractions is corresponding to
each one of the two enantiomers of the cage 2b. By using TDDFT
calculations, the first fraction from HPLC exhibiting positive
Cotton effect at = 277 nm corresponds to (4M)-2b, while the
4
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10.1002/anie.202106428
Angewandte Chemie International Edition
RESEARCH ARTICLE
barrier of flipping the phenyl units, preventing racemization of
2d12−. Such strategy of guest-induced chirality was also employed
by other groups.[20]
(No. 21532005 and No. 21772173), and the Natural Science
Foundation of Zhejiang Province (No. LR18B020001). We thank
Dr. Zhong Chen from the Instrumentation and Service Center for
Molecular Sciences at Westlake University for the efficient circular
dichroism measurement.
Conclusion
Keywords: enantioselectivity • imine • host-guest chemistry •
multivalence • homochirality
In summary, a set of structurally similar tetrahedrons were
self-assembled by condensing
a trisamino linker and a
trisbenzaldehyde precursor bearing substitutional units in the
meta positions with respect to the formyl groups. The formation of
tetrahedrons is attributed to the two ortho protons that are
involved in either CH∙∙∙π interactions or hydrogen bonds within the
cage framework. At least one of these supramolecular forces
would be disturbed, when the substitutional functional groups are
moved to the ortho positions. As a consequence, a triangular
prism was obtained instead of a tetrahedron. Our fundamental
understanding of tuning the self-assembly products by slightly
modulating the constitutions of the precursors, is thus improved.
The intramolecular CH∙∙∙π interactions endow the tetrahedral
cages homochirality. When water-soluble functional groups
namely carboxylate units are introduced onto the trisformyl
precursor, self-assembly of a tetrahedron was successful in water
in the presence of hydrophobic guest templates with
complementary sizes. When the template is chiral, the tetrahedral
cage could be obtained in an enantioselective manner, i.e., ee
values up to 10% when 5 equiv. (relative to the cage) S-propylene
oxide was used as the guest template. Due to multivalence, the
cage is rather kinetic inert upon either removal of the guests or
evaporation of the solvent. The cage is also able to reserve its
chirality in water after the chiral template was replaced with an
achiral one. To the best of our knowledge, this report is the first
example of using imine condensation in water to self-assemble
chiral cages containing only achiral building blocks. Future
research might include self-assembly of larger cages which could
function as molecular flasks and reaction vessels. Such trials are
ongoing in our lab.
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Experimental Section
2d12−: To a D2O (0.6 mL) solution containing 1d (6 mg, 0.011 mmol,
1 equiv.), TREN (1.61 mg, 0.011 mmol, 1 equiv.), KHCO3 (5.51
mg, 0.055 mmol, 5 equiv.), 0.01 mL of CHCl3 was added. The
mixture was stirred at room temperature for 8 h to obtain 2d12− as
the major observable product without further purification. 1H NMR
(400 MHz, D2O) δ 7.95 (s, 12H), 7.71 (s, 12H), 7.34 (s, 12H), 6.69
(d, J = 7.9 Hz, 12H), 5.92 (d, J = 7.7 Hz, 12H), 3.67 (d, J = 11.3
Hz, 12H), 3.24 (t, J = 12.4 Hz, 12H), 3.03 (t, J = 7.0 Hz, 12H), 2.84
(t, J = 6.4 Hz, 12H). 13C NMR (100 MHz, D2O) δ 179.40, 165.23,
144.36, 143.44, 142.87, 136.69, 133.39, 132.27, 129.32, 125.51,
63.61, 56.47. ESI-HRMS: m/z calcd for [2d12-+9H]3−
C144H117N16O243−, 818.2732; found 818.2711.
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Acknowledgements
This work was supported by the Chinese “Thousand Youth
Talents Plan”, the National Natural Science Foundation of China
5
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Table of Contents
A chiral tetrahedral cage could be self-assembled in water in enantioselectively, templated by a chiral guest.
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