Olive-Shaped Organic Cages: Synthesis and Remarkable Promotion of Hydrazone Condensation through Encapsulation in Water

Article abstract of DOI:10.1021/acs.joc.0c02792

Two organic cages have been prepared in situ in water through the 2 + 3 hydrazone coupling of two pyridinium-derived trialdehydes and oxalohydrazide. The highly water-soluble cages encapsulate and solubilize linear neutral molecules. Such encapsulation ha

Full text of DOI:10.1021/acs.joc.0c02792

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Article
Olive-Shaped Organic Cages: Synthesis and Remarkable Promotion
of Hydrazone Condensation through Encapsulation in Water
Yan-Yan Xu, Hong-Kun Liu, Ze-Kun Wang, Bo Song, Dan-Wei Zhang,* Hui Wang, Zhiming Li,*
Xiaopeng Li, and Zhan-Ting Li*
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ABSTRACT: Two organic cages have been prepared in situ in water through the 2 + 3 hydrazone coupling of two pyridinium-
derived trialdehydes and oxalohydrazide. The highly water-soluble cages encapsulate and solubilize linear neutral molecules. Such
encapsulation has been applied for the promotion of both two- or three-component hydrazone condensation in water. For two-
component reactions, the yields of the resulting monohydrazones are increased from 5−10 to 90−96%. For three-component
reactions of hydrazinecarbohydrazide with 11 aromatic aldehydes, in the presence of the organic cages, the bihydrazone products can
be produced in 88−96% yields. In contrast, without the promotion of the organic cages, 9 of the reactions do not afford the
corresponding dihydrazone product.
applications in the fabrication of hollow supramolecular capsules
in organic solvents.2j,3,5,6a We have utilized the pyridinium unit
to provide water solubility for both supramolecular and covalent
organic networks from tetraphenylmethane-based precursors.9
Given that pyridinium-incorporated organic macrocycles and
cages can be generated in water through hydrazone or oxime
condensation,10,11 we envisioned that triphenylmethane-cored
tripyridinium derivatives might be used as precursors for the
construction of new water-soluble organic cages. Herein, we
describe the construction of two olive-like organic cages through
the 2 + 3 condensation of tritopic pyridinium-based trialdehydes
and diacylhydrazines in water. We further demonstrate that the
new water-soluble cages can remarkably promote two- and
three-component hydrazone condensation through efficient
encapsulation of the resulting linear uni- and bihydrazone
products.
INTRODUCTION
■
Molecular cages provide unique microenvironments for the
exploitation of molecular recognition and chemical trans-
formations in a confined space.1 The construction of molecular
cages has been realized mainly in a stepwise synthetic manner
through the formation of relatively strong, irreversible bonds,2
such as amides or C−C bonds, which is often accompanied by a
low yield for the last step of macrocyclization.3 The utilization of
dynamic covalent chemistry (DCC) has allowed for the
generation of molecular cages in higher or even quantitative
yields.4 Nevertheless, most of the reported structures of this
category have been achieved in organic solvents.5 The
development of efficient DCC approaches for the self-assembly
of molecular cages in water, the highly polar medium of biology,
has only gained limited success,6 whereas the potential of water-
compatible organic cages for the enhancement or catalysis of
chemical transformations in water has been rarely explored, even
though macrocycles and cages constructed by the metal−ligand
coordination-driven self-assembly have been extensively inves-
tigated.7
Received: November 21, 2020
Published: February 18, 2021
Quantitative formation of the hydrazone bonds from rigid
tritopic precursors represents an efficient strategy for the
construction of covalent organic frameworks.8 In contrast,
flexible tritopic building blocks have also found important
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Scheme 1. Synthesis of Organic Cages C1 and C2 and the Structure of Guest G1
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1
temperature. H NMR spectra in D2O showed that, at higher
temperature (>50 °C), the solids dissolved slowly to afford the
cage molecules again.
RESULTS AND DISCUSSION
■
Compounds C1 and C2 were designed as water-soluble organic
cages for the encapsulation of molecular guests and possible
further application for the promotion of organic reactions in
water. Their synthetic routes are shown in Scheme 1.
Compound 1 first reacted with bromomethyl methyl ether in
the presence of titanium bromide in dichloromethane to afford
tribromide 2 in 51% yield.12 Treatment of 2 with nicotinalde-
hyde 3a or isonicotinaldehyde 3b in DMF produced
trialdehydes M1 and M2 in 50 or 49% yield. Finally, the two
intermediates reacted with highly soluble oxalohydrazide 4
(2:3) in water at 60 °C to generate C1 or C2, respectively. Both
M1 and M2 had a high water-solubility (≥30 mM). 1H NMR in
D2O showed that because of the strong electron-withdrawing
effect of the pyridinium, about 95% of the CHO group of M1
was hydrated to afford CH(OH)2 (Figure 1), which was
Dynamic light scattering (DLS) experiments in water revealed
the formation of only one small entity with a hydrodynamic
diameter (DH) of approximately 1.3 nm for both the samples
even at a very high concentration ([M1] = [M2] = 10 mM)
(Figure 2), whereas M1 and M2 of the same concentration
Figure 2. DLS profiles of the solution of M1, M2, C1, and C2 ([M1] =
[M2] = 10 mM) in water at 25 °C.
afforded even smaller DH values (<0.7 nm). These results were
consistent with the size of the olive-shaped organic cages of C1
and C2 and the selective formation of the proposed cages. Thus,
the complexity of the 1H NMR spectra of C1 and C2 might be
attributed to the existence of different conformers as a result of
the rigidity of the backbones. Heating the solution to 80 °C
notably increased the resolution of the 1H NMR spectra of C1
and C2 (Figures S7 and S8). Even at 80 °C, both spectra did not
exhibit the signal of the CH(OH)2 group. Diluting the solution
from [M1] = [M2] = 5 mM to [M1] = [M2] = 0.5 mM did not
lead to an observable signal of the CH(OH)2 group (Figures S9
and S10), suggesting high stability of the two organic cages in
water.
Figure 1. 1H NMR spectra (400 MHz) of the 2:3 mixture of M1 (10
mM) and 4 (15 mM) in D2O at 60 °C after 0.25, 1, 2, and 3 h, which
illustrates the formation of molecular cage C1 from the condensation of
M1 and 4 after 3 h.
evaluated by comparing the ratio of the integral intensity of the
two signals at 10.1 and 6.2 ppm, respectively, whereas the
hydration of the CHO group was quantitative for M2 (Figure
S1). In contrast, their 1H NMR spectra in DMSO-d6 exhibited
the signals of both CHO and CH(OH)2 units, with the latter
being 11 and 61%, respectively (Figures S2 and S3). At the
concentration of 10 mM, the reactions of M1 and M2 with 4 (15
mM) in D2O were complete after about 3 or 6 h, as revealed by
the 1H NMR spectra which indicated that the diagnostic signals
of the CHO and CH(OH)2 groups of M1 and M2 disappeared
completely. The formation of C1 and C2 was first evidenced by
their 1H NMR spectra (Figures 1 and S1), which exhibited one
set of broad signals. The signals in the downfield area could be
assigned through their 2D 1H COSY spectrum (Figures S4 and
S5). The mass spectra of the two samples exhibited peaks which
were consistent with the cage structures (Figures S6).
Compound C1 displayed strong peaks corresponding to [M −
6Br − 2H]4+ (m/z: 370.15) and [M − 6Br − 3H]3+ (m/z:
493.20), whereas C2 gave rise to peaks that were related to [M −
6Br + MeOH − H]5+ (m/z: 302.75), [M − 6Br + MeOH −
2H]4+ (m/z: 378.18), and [M − 6Br − 3H + H2O]3+ (m/z:
499.57). Upon evaporation of the solvent under reduced
pressure, the resulting solids became insoluble in water at room
To get a deep insight into the conformational isomers of C1
and C2, we further conducted molecular modeling studies for
both cages using the density functional theory method. B3LYP
computations were carried out using Gaussian 09 software
package.13,14 Because of the large size of the structures, small
basis sets 3-21G were used. Truhlar’s SMD solvation model was
employed to consider the solvent effect (water).15 The other
calculation details are provided in the Supporting Information. It
was found that the rigidity of the dihydrazone linkers and the
rotation hindrance of the H2C−N(py) bonds led to the
formation of multiple low-energy cage conformers (Figures 3
and S11 and Table S1). For both the molecules, interconver-
sions between different low-energy conformations do not occur,
which indicate the existence of high energy barriers and may
1
account for the complicated signal patterns of their H NMR
spectra. In both the molecules, the central linkers are almost
perfect planar. The relative energies of the three conformers of
C1 are 0.0, 0.5, and 1.2 kcal/mol. Two of the three linker planes
of the first conformer are nearly parallel to each other, whereas
the remaining one is perpendicular to the two formers. For the
second conformer, the three chains are distorted into S-shape
because of the H2C−N(py) bond rotation, while the plane of the
three linkers of the third one is roughly parallel with the benzyl
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Figure 3. Lowest-energy conformers of (a) C1-1, (b) complex C1 ⊂ 7b-1, (c) C2-1, and (d) complex C2 ⊂ 7b-1. The numbers are the lengths of
hydrogen bonds in Å.
Figure 4. Partial 1H NMR of (a) C1, (b) G1 + C1, (c) G1, (d) M1 + G1, (e) M1, (f) C2, (g) C2 + G1, (h) G1, (i) M2 + G1, and (j) M2 ([C1] = [C2]
= [G1] = 1.25 mM, [M1] = [M2] = 2.5 mM) in D2O at 25 °C.
moieties that connect them. In contrast, the difference of the
conformers of C2 is quite small, which is mainly caused by the
relative orientation of the pyridinium units.
The inclusion of C1 and C2 was then investigated with
commercially available, linear G1 (Scheme 1) as a guest. G1 was
soluble in water but also generally hydrophobic. Compared with
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a
Scheme 2. Molecular Cage-Promoted Reactions of 5 with 6a and 6b in Water
a
[C1] = [C2] = [5] = [6a,b] = 1.25 mM. The yield of the products was determined by HPLC.
the corresponding signals of G1, the signals of the H-a−d
protons of G1 in D2O in the 1:1 mixture with C1 shifted upfield
by 0.23, 0.23, 0.18, and 0.18 pm, respectively (Figure 4). In
contrast, all the signals of G1 in the solution of its 1:2 mixture
with M1 underwent much smaller shifting (≤0.08 ppm) (Figure
4). Similar results were also observed for G1 with C2. Thus, we
proposed that both C1 and C2 were capable of encapsulating
G1. The Job plot further supported that the encapsulation of G1
by C1 and C2 was in a 1:1 stoichiometry (Figure S12).6a The
larger upfield shifting of the H-a and H-b signals of G1, as
compared with that of its H-c and H-d signals, also suggested
that the guest adopted an extended conformation inside the cage
of the host, and thus the H-a and H-b protons suffered the
strongest shielding of the triphenylmethyl moiety of the host.
Diffusion-ordered spectroscopic experiments were further
conducted for the solution of C2, G1, and their 1:1 mixture in
D2O. The diffusion coefficient (D) of the two species in their
respective pure solution was determined to be 1.4 × 10−6 and 5.9
× 10−6 cm2/s, while their mixture afforded the identical D of 1.4
× 10−6 cm2/s for both the compounds (Figure S13). The fact
that the D value of G1 was decreased to the level of C2 solidly
concentration, compound 7a could be formed in 90 or 94%
yield, whereas the yield of compound 7b was increased to 94 or
96%. The H NMR spectra of the two 1:1 mixtures in D2O
1
showed that the signals of the mixtures changed considerably
(Figures S17 and S18) compared with the respective spectrum
of C1 and the hydrazones, which supported the fact that
important interactions occurred between the organic cages and
the two hydrazones. In the presence of C1 (1.25 mM), the
reaction of 5 and 6b (1:1) was also conducted at higher
concentrations of the substrates (2.5 and 5.0 mM), which gave
rise to 7b in 93 and 96% yields, respectively, which were
comparable to that obtained at the substrate concentration of
1.25 mM (94%). Thus, the promotion of the hydrazine bond in
the molecular cage did not suffer from product inhibition. As 7b
was formed in higher yield in the presence of C1 or C2,
isothermal titration calorimetric experiments were conducted in
water for evaluating the encapsulation of 7b by C1 and C2
(Figures S19 and S20), which afforded a Ka of 5.8 ( 0.5) × 104
and 4.4 ( 0.7) × 104 M−1 for their 1:1 complexes. The values
were even higher than that of the complex formed by G1 and C1
or C2, which might be attributed to the higher rigidity of 7b as
compared with G1. The corresponding enthalpy changes (ΔH)
of the two complexes were −3.12 ( 0.14) and −4.69 ( 0.43)
kcal/mol, whereas their entropy changes (−TΔS) were −3.37
and −1.63 kcal/mol. Thus, the formation of the first complex
was driven both enthalpically and entropically. For the second
one, the entropy contribution played the major role.
The above promotion of organic cages C1 and C2 for
hydrazone condensation was further applied for the three-
component reactions of 6a−k with 8 in water (Scheme 3),
which afforded dihydrazones 9a−k and hydrazones 10a−k. In
the absence of C1 or C2, the reactions of 6a−k with 8 afforded
hydrazone derivatives 10a−k as the major products, all in low
yields (4−19%) (Table 1). Moreover, except for the reactions of
6c and 6d, which produced dihydrazone 9c or 9d both in 6%
yield, all the other reactions did not give rise to the
corresponding dihydrazone product in an observable yield.
However, in the presence of C1 or C2, all the reactions gave rise
to the dihydrazone product in high to excellent yields (88−96%)
(Table 1). Consistently, the yield of the monohydrazone
derivatives decreased to 2−9%. It is reasonable to assume that
the hydrazone bond of the same series of mono- and
dicondensation products were comparable. Thus, the formation
1
supported that it was encapsulated by C2. H NMR titration
experiments were then conducted (Figures S14 and S15). By
using a nonlinear regression fitting, the 1:1 binding pattern with
the change of the chemical shifting of H-d (CH2) of G1 as the
probe, we determined the association constant (Ka) of the 1:1
complexes formed between G1 and the two cages to be 2.2
( 0.4) × 103 and 1.6 ( 0.3) × 103 M−1. As the encapsulation for
the neutral G1 occurred in water, the main driving force should
come from hydrophobicity.16 Through the titration experiments
(Figures S14 and S15), the H-d of G1 displayed a signal of high
resolution, which also supported that the host and guest were in
fast exchange.
Given the efficient encapsulation of C1 and C2 for linear guest
G1, we envisioned that the new cages C1 and C2 might stabilize
the molecules of similar size and length in water through efficient
encapsulation. To test this hypothesis, we first investigated the
reactions between acylhydrazine 5 and aldehydes 6a and 6b. At
the concentration of 1.25 mM for all the substrates, the two
reactions gave rise to hydrazones 7a and 7b only in 5 and 10%
yields in water that contained 7.5 mM of KBr which had the
identical ion concentration as the systems of C1 and C2
(Scheme 2). However, in the presence of C1 and C2 of the same
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Finally, the effect of C1 and C2 on the solubility of all the
linear hydrazone derivatives in water was investigated (Table
S2). It was found that both C1 and C2 were able to enhance the
solubility of all the hydrazones. The water solubility of the
hydrazones was quite different depending on the polarity of the
aromatic units. However, at [C1] = [C2] = 1.25 mM, their
solubility increased to 1.1−1.2 mM, which may be attributed to
the formation of the 1:1 encapsulation complexes.
Scheme 3. Molecular Cage-Promoted Reactions of 6a−k with
a
8 in Water
CONCLUSIONS
■
We have demonstrated that organic cages can be constructed in
situ in water through the formation of multiple hydrazone bonds
from rationally designed molecular precursors. The new organic
cages can efficiently encapsulate the linear molecular guests
driven by hydrophobicity and enhance their water solubility
through encapsulation. The encapsulation remarkably improves
the formation of linear products from two- or three-component
reactions of aldehyde and acylhydrazine precursors in water,
with the yield being increased from zero to 88−96%. The results
described herein well illustrate the importance of the structural
matching for host−guest systems in water. By introducing chiral
linkers, new chiral organic cages may be constructed, which will
allow for the investigation of the stereoselectivity of the reactions
of the chiral substrates. Large molecular cages are expected to
encapsulate long, folded linear molecules in water, which may be
utilized to promote intramolecular reactions to produce giant
macrocycles.
a
[C1] = [C2] = [8] = 1.25 mM. [6a−k] = 2.5 mM. The yield of the
products was determined by HPLC.
of the dihydrazones in high yields in the presence of C1 or C2
should be attributed to the efficient encapsulation of the organic
cages for the linear dihydrazones. The lower yield of 10a−k in
the presence of the two molecular cages also suggested that these
shorter molecules were not efficiently encapsulated probably
owing to structural mismatching. It is noteworthy that, although
both the organic cages and the guests were hydrazone
derivatives, the fact that the linear mono- and dihydrazones
could be generated inside the organic cages suggests that the two
species possessed good orthogonality.
Molecular modeling studies for the encapsulation of 7b by C1
and C2 also revealed multiple low-energy conformations of the
1:1 complexes, with the guest being orientated in the cavity of
the two hosts (Figures 3 and S11). The computed complexes
also showed the existence of intermolecular hydrogen bonds,
which should combine with the hydrophobicity, mainly
occurring between the triphenylmethane moieties of the cage
and the aromatic units of the guest, to stabilize the encapsulation
complexes.
EXPERIMENTAL SECTION
■
General Methods. All reagents and solvents were purchased from
commercial sources and used without further purification. All the
reactions were conducted under the N2 atmosphere. Nuclear magnetic
resonance (NMR) spectra were recorded using Bruker AVANCE III
400 spectrometers, with working frequencies of 400 and 100 MHz for
1H and 13C, respectively. Chemical shifts are reported in ppm relative to
the residual internal nondeuterated solvent signals (D2O: δ = 4.79
ppm). High-resolution mass spectra (HRMS) were recorded on
Fourier transform ion cyclotron resonance mass spectrometry. DLS
experiments were conducted on a Malvern Zetasizer Nano ZS90 using a
monochromatic coherent He−Ne laser (633 nm) as the light source
and detector that detected the scattered light at an angle of 90°. The
thermodynamic parameters and association constants were determined
by titration calorimetry with a MicroCal PEAQ-ITC instrument.
Compound 1 and 2 were prepared according to the reported
method.17,18
High-performance liquid chromatography (HPLC) was conducted
on an Agilent 1260 using a Platisilph-C18 column (4.6 mm × 150 mm
a
Table 1. Yields of Hydrazone Products 9a−k and 10a−k
b
c
d
b
c
d
entry
product
yield (%)
yield (%)
yield (%)
product
yield (%)
yield (%)
yield (%)
1
2
3
4
5
6
7
8
9a
9b
9c
9d
9e
9f
9g
9h
9i
94
90
92
93
90
92
91
88
94
94
93
89
92
93
91
92
94
89
91
96
93
92
0
0
6
6
0
0
0
0
0
0
0
10a
10b
10c
10d
10e
10f
10g
10h
10i
3
8
4
6
8
6
6
6
2
3
4
6
5
6
7
5
3
9
4
3
2
6
19
8
10
12
14
12
12
5
4
5
15
9
10
11
9j
9k
10j
10k
a
b
c
The yields were determined by HPLC using anisole as an internal standard. In the presence of C1 (1.25 mM). In the presence of C2 (1.25
d
mM). Containing KBr (7.5 mM).
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1
× 5 μm). The yields of products were determined by HPLC using
anisole as the internal standard. The mobile phase was MeOH and H2O
and the flow rate was 1.0 μL/min. The radio (v/v) of H2O and MeOH
was 35:65 for 9a, 9e, 9f, 9g, 9i, 9j, and 9k; 40:60 for 9h; 45:55 for 7a and
7b; and 60:40 for 9b, 9c, and 9d.
Compound 9b. mp 207−209 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.94 (s, 2H), 8.62 (d, 4H, J = 2.0 Hz), 7.18
(s, 2H), 7.70 (d, 4H, J = 2.0 Hz).21
1
Compound 9c. mp 201−202 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 11.12 (s, 2H), 8.91 (s, 2H), 8.57−8.59 (m,
2H), 8.17−8.24 (m, 4H), 7.45−7.49 (m, 4H).21
Compound M1. To a round-bottom flask were added N,N-
dimethylformamide (10 mM) and then compounds 2 (0.20 g, 0.37
mmol) and 3-pyridinecarboxaldehyde 3a (0.24 g, 2.3 mmol). The
mixture was stirred at 86 °C in an oil bath for 12 h and then
concentrated under reduced pressure. The resulting slurry was then
triturated in acetonitrile (10 mL) and sonicated for 5 min and later
filtered. The solid was washed with acetonitrile (5 mL × 3) and then
dried to give compound M1 as a pale amorphous solid (0.16 g, 50%).
mp >300 °C. 1H NMR (D2O, 400 MHz): δ 8.99 (s, 3H), 8.86 (d, 3H, J
= 6.0 Hz), 8.62 (d, 3H, J = 8.4 Hz), 8.04−8.08 (m, 3H), 7.36 (d, 6H, J =
8.0 Hz), 7.21 (d, 6H, J = 8.0 Hz), 6.19 (s, 3H), 5.80 (s, 6H), 2.11 (s,
3H). 13C{1H} NMR (D2O, 100 MHz): δ 149.9, 144.0, 143.7, 143.3,
142.3, 130.9, 129.6, 128.8, 128.3, 86.7, 64.2, 52.1, 29.4.
1
Compound 9d. mp 191−192 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 11.04 (s, 2H), 8.57−8.59 (m, 2H), 8.23 (d,
2H, J = 2.0 Hz), 8.11 (d, 4H, J = 2.0 Hz), 7.84−7.89 (m, 2H), 7.36−
7.39 (m, 2H).20
1
Compound 9e. mp 230−232 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.58 (s, 2H), 8.13 (s, 2H), 7.62 (d, 4H, J =
4.0 Hz), 7.23 (d, 4H, J = 4.0 Hz), 2.33 (s, 6H).20
1
Compound 9f. mp 206−207 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.6 (s, 2H), 7.98−8.13 (m, 3H), 7.54 (s,
2H), 7.47 (d, 2H, J = 4.0 Hz), 7.23−7.27 (m, 2H), 7.14 (d, 2H, J = 4.0
Hz), 2.33 (s, 6H).22
1
Compound 9g. mp 229−230 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.64 (s, 2H), 8.46 (s, 2H), 7.94 (d, 2H, J = 2
HRMS (ESI) m/z: [M − 3Br + 2H2O]3+ calcd for C41H40N3O5,
218.0989; found, 218.1006.
Hz), 7.21−7.29 (m, 6H), 2.41 (s, 6H).22
1
Compound 9h. mp 193−195 °C (amorphous solid). H NMR
Compound M2. Compound M2 was prepared from the reaction of
compounds 2 and 3b in 49% yield as a pale amorphous solid according
to the procedure described above for the preparation of M1 (0.15 g,
49%). mp >300 °C (amorphous solid). 1H NMR (D2O, 400 MHz): δ
8.78 (d, 6H, J = 4.0 Hz), 8.02 (d, 6H, J = 8.0 Hz), 7.28 (d, 6H, J = 8.0
Hz), 7.14 (d, 6H, J = 8.0 Hz), 6.09 (s, 3H), 5.68 (s, 6H), 2.03 (s, 3H).
13C{1H} NMR (D2O, 100 MHz): δ 160.2, 149.9, 144.5, 130.9, 129.6,
128.9, 125.5, 87.5, 63.7, 52.2, 29.4.
(DMSO-d6, 400 MHz): δ 10.69 (s, 2H), 8.49 (s, 2H), 8.01 (s, 2H),
7.34−7.39 (m, 2H), 7.06−7.08 (m, 2H), 6.98−7.01 (m, 2H), 3.84 (s,
6H).23
1
Compound 9i. mp 236−237 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 11.05 (s, 2H), 8.58 (s, 2H), 8.16 (s, 2H),
7.48−7.52 (m, 4H), 7.38−7.44 (m, 4H).20
1
Compound 9j. mp 221−223 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.91 (s, 2H), 8.14 (s, 2H), 8.01 (s, 2H), 7.69
HRMS (ESI) m/z: [M − 3Br + 3H2O]3+ calcd for C41H42N3O6,
224.1025; found, 224.1041.
(d, 2H, J = 4.0 Hz), 7.56−7.58 (m, 2H), 7.37−7.41 (m, 2 Hz).20
1
Compound 9k. mp 234−235 °C (amorphous solid). H NMR
Cage C1. Compounds M1 (8.6 mg, 10 μmol) and 4 (1.8 mg, 15
μmol) were added to D2O (1 mL). The mixture was heated under
stirring at 60 °C in an oil bath for 3 h to afford compound C1. It was
found that, once evaporation took place, the resulting product became
insoluble. Thus, C1 was prepared in situ and characterized in solution.
1H NMR (D2O, 400 MHz): δ 9.33−9.36 (m, 6H), 8.94−9.01 (m, 6H),
8.86−8.88 (m, 6H), 8.52−8.58 (m, 6H), 8.13 (s, 6H), 7.42 (d, 12H, J =
4.0 Hz), 7.25 (d, 12H, J = 4.0 Hz), 5.85 (s, 12H), 2.12 (s, 6H). MS
(ESI) m/z: [M − 3H]3+ calcd for C88H75N18O6, 493.20; found, 493.20.
[M − 2H+]4+ calcd for C88H76N18O6, 370.15; found, 370.15.
Cage C2. Compounds M2 (8.6 mg, 10 μmol) and 4 (1.8 mg mM, 15
μmol) were added to D2O (1 mL). The mixture was heated at 60 °C for
6 h to afford compound C2. 1H NMR (D2O, 400 MHz): δ 8.83−8.92
(m, 12H), 8.49−8.53 (m, 6H), 8.20−8.34 (m, 12H), 7.21−7.38 (m,
24H), 5.76 (s, 12H), 2.09 (s, 6H). MS (ESI) m/z: [M + MeOH − H]5+
calcd for C89H81N18O7, 302.73; found, 302.75. [M + 2MeOH + 3H2O
− H]5+ calcd for C90H91N18O11, 319.94; found, 319.95. [M + MeOH −
2H+]4+ calcd for C89H80N18O7, 378.16; found, 378.18. [M − H+]5+
calcd for C88H77N18O6, 296.32; found, 296.34; [M − 3H+ + H2O]3+
calcd for C88H77N18O7, 499.54; found, 499.57.
(DMSO-d6, 400 MHz): δ 11.18 (s, 2H), 8.58 (s, 2H), 8.26 (d, 2H, J =
2.0 Hz), 8.03−8.05 (m, 2H), 7.78−7.82 (m, 2H), 7.61−7.66 (m,
2H).24
1
Compound 10a. mp 184−186 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.38 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.73
(d, 4H, J = 2.0 Hz), 7.30−7.38 (m, 3H), 4.10 (s, 2H).25
1
Compound 10b. mp 192−193 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.70 (s, 1H), 8.53 (d, 2H, J = 4.0 Hz), 8.27
(s, 1H), 7.80 (s, 1H), 7.71 (d, 2H, J = 2.0 Hz), 4.08 (s, 2H).26
1
Compound 10c. mp 192−193 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.58 (s, 1H), 8.86 (s, 1H), 8.51 (d, 1H, J =
2.0 Hz), 8.21−8.23 (m, 2H), 7.87 (s, 1H), 7.38−7.42 (m, 1H), 4.08 (s,
2H).26
1
Compound 10d. mp 175−176 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.63 (s, 1H), 8.50 (d, 1H, J = 2.0 Hz), 8.19−
8.20 (m, 2H), 7.87 (s, 1H), 7.76−7.80 (m, 1H), 7.29−7.32 (m, 1H),
4.08 (s, 2H).26
1
Compound 10e. mp 180−182 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.30 (s, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.62
(d, 2H, J = 4.0 Hz), 7.19 (d, 2H, J = 4.0 Hz), 4.05 (s, 2H), 2.32 (s,
3H).25
Compounds 5, 7a, 7b, 9a−9k, and 10a−10k have been reported in
1
Compound 10f. mp 185−187 °C (amorphous solid). H NMR
1
the literature. Their H NMR data are fully consistent with those
(DMSO-d6, 400 MHz): δ 10.35 (s, 1H), 8.00 (s, 1H), 7.81 (s, 1H), 7.61
(s, 1H), 7.48 (d, 1H, J = 4.0 Hz), 7.26 (t, 1H, J = 4.0 Hz), 7.15 (d, 1H, J
= 2.0 Hz), 4.07 (s, 2H), 2.32 (s, 3H).25
reported.
Compound 5. mp 162−163 °C (amorphous solid). 1H NMR
(DMSO-d6, 400 MHz): δ 11.11−10.99 (m, 1H), 10.42 (s, 2H), 9.00−
8.95 (m, 1H), 7.90−7.87 (m, 2H), 7.57−7.53 (m, 1H), 7.50−7.46 (m,
2H), 3.99−3.97 (m, 2H).19
1
Compound 10g. mp 184−185 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.32 (s, 1H), 8.14 (s, 1H), 7.95 (d, 1H, J =
4.0 Hz), 7.89 (s, 1H), 7.16−7.24 (m, 3H), 4.07 (s, 2H), 2.35 (s, 3H).25
1
1
Compound 7a. mp 183−184 °C (amorphous solid). H NMR
Compound 10h. mp 186−187 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 11.51 (s, 1H), 8.89−8.67 (m, 1H), 8.23−8.0
(m, 1H), 7.90−7.88 (m, 2H), 7.71−7.69 (m, 2H), 7.55−7.42 (m, 6H),
4.42−3.96 (m, 2H).19
(DMSO-d6, 400 MHz): δ 10.36 (s, 1H), 8.16 (s, 1H), 8.01−8.04 (m,
1H), 7.96 (s, 1H), 7.29−7.33 (m, 1H), 7.02 (d, 1H, J = 4.0 Hz), 6.93 (t,
1H, J = 4.0 Hz), 4.04 (s, 2H), 3.80 (s, 3H).25
1
1
Compound 7b. mp 193−194 °C (amorphous solid). H NMR
Compound 10i. mp 182−184 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 11.86−11.80 (m, 1H), 8.92−8.72 (m, 1H),
8.63 (d, 2H, J = 2.0 Hz), 8.23−7.92 (m, 1H), 7.89 (d, 2H, J = 4.0 Hz),
7.67−7.62 (m, 2H), 7.54−7.48 (m, 3H), 4.44−3.99 (m, 2H).19
(DMSO-d6, 400 MHz): δ 10.62 (s, 1H), 8.22−8.25 (m, 2H), 8.16 (s,
1H), 8.43−8.45 (m, 1H), 7.31−7.37 (m, 2H), 4.07 (s, 2H).25
1
Compound 10j. mp 187−189 °C (amorphous solid). H NMR
1
Compound 9a. mp 200−201 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.48 (s, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 8.78
(s, 1H), 7.62 (d, 1H, J = 4.0 Hz), 7.48−7.51 (m, 1H), 7.29−7.33 (m,
1H), 4.05 (s, 2H).25
(DMSO-d6, 400 MHz): δ 10.69 (s, 2H), 8.18 (s, 2H), 7.74 (d, 2H, J =
4.0 Hz), 7.37−7.45 (m, 6H).20
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J. Org. Chem. 2021, 86, 3943−3951

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Article
1
Compound 10k. mp 212−214 °C (amorphous solid). H NMR
(DMSO-d6, 400 MHz): δ 10.75 (s, 1H), 8.40 (d, 1H, J = 4.0 Hz), 8.23
(s, 1H), 8.17 (s, 1H), 7.97 (d, 1H, J = 4.0 Hz), 7.70 (t, 1H, J = 4.0 Hz),
7.54−7.58 (m, 1H), 4.09 (s, 2H).25
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02792.
Experimental details, 1H and 13C spectra, mass spectra, 1H
NMR and ITC titration results, solubility data, HPLC,
and calculation methods (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Dan-Wei Zhang − Department of Chemistry, Shanghai Key
Laboratory of Molecular Catalysis and Innovative Materials,
Fudan University, Shanghai 200438, China; orcid.org/
0000-0003-1244-1850; Email: zhangdw@fudan.edu.cn
Zhiming Li − Department of Chemistry, Shanghai Key
Laboratory of Molecular Catalysis and Innovative Materials,
Fudan University, Shanghai 200438, China; Email: zmli@
fudan.edu.cn
Zhan-Ting Li − Department of Chemistry, Shanghai Key
Laboratory of Molecular Catalysis and Innovative Materials,
Fudan University, Shanghai 200438, China; orcid.org/
0000-0003-3954-0015; Email: ztli@fudan.edu.cn
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Sanders, J. K. M.; Otto, S. Dynamic Combinatorial Chemistry. Chem.
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Authors
Yan-Yan Xu − Department of Chemistry, Shanghai Key
Laboratory of Molecular Catalysis and Innovative Materials,
Fudan University, Shanghai 200438, China
Hong-Kun Liu − Department of Chemistry, Shanghai Key
Laboratory of Molecular Catalysis and Innovative Materials,
Fudan University, Shanghai 200438, China
Ze-Kun Wang − Department of Chemistry, Shanghai Key
Laboratory of Molecular Catalysis and Innovative Materials,
Fudan University, Shanghai 200438, China
Bo Song − Department of Chemistry, Northwestern University,
Evanston, Illinois 60208, United States; orcid.org/0000-
0002-4337-848X
Hui Wang − Department of Chemistry, Shanghai Key
Laboratory of Molecular Catalysis and Innovative Materials,
Fudan University, Shanghai 200438, China
Xiaopeng Li − College of Chemistry and Environmental
Engineering, Shenzhen University, Shenzhen, Guangdong
518055, China; orcid.org/0000-0001-9655-9551
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̈
coordination cages: Synthesis and potential applications. Coord. Chem.
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macrocycles and cages. Coord. Chem. Rev. 2015, 293−294, 139−157.
(c) Ward, M. D.; Hunter, C. A.; Williams, N. H. Guest binding and
catalysis in the cavity of a cubic coordination cage. Chem. Lett. 2017, 46,
2−9. (d) Bloch, W. M.; Clever, G. H. Integrative self-sorting of
coordination cages based on “naked” metal ions. Chem. Commun. 2017,
53, 8506−8516. (e) Ward, M. D.; Hunter, C. A.; Williams, N. H.
Coordination Cages Based on Bis(pyrazolylpyridine) Ligands:
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Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02792
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was financially supported by National Natural Science
Foundation of China (nos: 21890732, 21890730 and
21921003).
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