3D Hydrazone-Functionalized Covalent Organic Frameworks as pH-Triggered Rotary Switches

Article abstract of DOI:10.1002/smll.202102630

The property expansion of 3D functionalized covalent organic frameworks (COFs) is important for developing their potential applications. Herein, the first case of 3D hydrazone-decorated COFs as pH-triggered molecular switches is reported, and their applic

Full text of DOI:10.1002/smll.202102630

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3D Hydrazone-Functionalized Covalent Organic
Frameworks as pH-Triggered Rotary Switches
Wenjuan Zhao, Chengyang Yu, Jie Zhao, Fengqian Chen, Xinyu Guan, Hui Li, Bin Tang,*
Guangtao Yu, Valentin Valtchev, Yushan Yan, Shilun Qiu, and Qianrong Fang*
heterogeneous catalysis,[4] and others.[5]
At present, most of the discovered COFs
The property expansion of 3D functionalized covalent organic frameworks
(COFs) is important for developing their potential applications. Herein,
the first case of 3D hydrazone-decorated COFs as pH-triggered molecular
switches is reported, and their application in the stimuli-responsive drug
delivery system is explored. These functionalized COFs with hydrazone
groups on the channel walls are obtained via a multi-component bottom–up
synthesis strategy. They exhibit a reversible E/Z isomerization at various pH
values, confirmed by UV–vis absorption spectroscopy and proton conduction.
Remarkably, after loading cytarabine (Ara-C) as a model drug molecule, these
pH-responsive COFs show an excellent and intelligent sustained-release
effect with an almost fourfold increase in the Ara-C release at pH = 4.8 than
at pH = 7.4, which will effectively improve drug-targeting. Thus, these results
open a way toward designing 3D stimuli-responsive functionalized COF
materials and promote their potential application as drug carriers in the field
of disease treatment.
are still 2D frameworks with eclipsed
stacking structures because of their
simpler synthesis and easier function-
alization. Compared with 2D analogues,
3D functionalized COFs have recently
attracted more and more attention due to
their unique pore structures and higher
specific surface areas.[6] For example, we
have acquired a series of 3D functional-
ized COFs,[7] for example, 3D tetrathiaful-
valene-based COFs for tunable electrical
conductivity, 3D carboxy-functionalized
COF for selective ion adsorption, and 3D
Salphen-based COFs as catalytic antioxi-
dants. Despite the aforementioned efforts
in the in-situ synthesis and post-synthesis
modifications, the functionalization of 3D
COFs still remains largely undeveloped up
to now, especially 3D architectures with
stimuli-responsive functions,[8] due to the lacking of building
units, the difficulty of directional synthesis, and the sophisti-
cated procedure for introducing functional groups into the
framework.
1. Introduction
Covalent organic frameworks (COFs) are a new class of crys-
talline porous polymers that allow crystallographically precise
integration of building blocks into periodic structures.[1] The
potential applications of COFs are in various fields, including
gas adsorption and separation,[2] organic electronics,[3]
It is well-known that hydrazone and its derivatives are signif-

icant synthons for numerous transformations, and their C N
groups can undergo efficiently reversible structures between
W. Zhao, C. Yu, F. Chen, X. Guan, H. Li, S. Qiu, Q. Fang
State Key Laboratory of Inorganic Synthesis and Preparative Chemistry
Jilin University
V. Valtchev
Qingdao Institute of Bioenergy and Bioprocess Technology
Chinese Academy of Sciences
Changchun 130012, P. R. China
189 Songling Road, Laoshan District, Qingdao, Shandong 266101, P. R. China
E-mail: qrfang@jlu.edu.cn
J. Zhao
SINOPEC Research Institute of Petroleum Processing
Beijing 100083, P. R. China
B. Tang
Institute for Frontier Materials
Deakin University
Geelong, Victoria 3216, Australia
E-mail: bin.tang@deakin.edu.au
V. Valtchev
Normandie Univ
ENSICAEN
UNICAEN
CNRS
Laboratoire Catalyse et Spectrochimie
6 Marechal Juin, Caen 14050, France
Y. Yan
Department of Chemical and Biomolecular Engineering
Center for Catalytic Science and Technology
University of Delaware
G. Yu
College of Chemistry and Materials Science
Fujian Normal University
Fuzhou 350007, P. R. China
Newark, DE 19716, USA
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/10.1002/smll.202102630.
DOI: 10.1002/smll.202102630
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E and Z configurations in the presence of acid or base.[9] Con-
sequently, pH-triggered hydrazone-based switches are widely
incorporated into various materials,[10,11] including supramolec-
ular systems, liquid crystals, polymer gels, and some 2D COFs
to achieve such unique properties. However, although the com-
bination of building blocks with hydrazone as side chains and
the interconnected channels of 3D structures will be greatly
beneficial for the development of stimuli-responsive materials,
no hydrazone has been integrated into 3D COF materials so
far because of the difficulties of crystallization and structural
determination.
Herein, we report the synthesis of 3D hydrazone-equipped
COFs and study their application as pH-triggered rotary
switches in the stimuli-controlled release of the drug molecule.
Different from previous reports, the hydrazone groups, in this
case, were decorated on the channel walls of COFs using a
multi-component bottom–up synthesis strategy. The obtained
structures showed well-behaved invertibility of E/Z isomeri-
zation at different pH values, which was confirmed by proton
conduction and UV–vis absorption analysis. More importantly,
after loading drug molecule (cytarabine, Ara-C), these stimuli-
responsive COFs demonstrated exceptional release effects for
Ara-C with an almost fourfold amplification at pH = 4.8 than
at pH = 7.4. This is the first example of 3D hydrazone-func-
tionalized COFs and their application for pH-responsive drug
delivery to the best of our knowledge.
(E) to DABP integrated into JUC-556-[HZ]X (E) were identical
to those employed for their reactions (Section S1, Supporting
Information).[13] The structural characterization of JUC-556-
[HZ]X (E) was executed combining complementary methods.
Scanning electron microscopy indicated that JUC-556-[HZ]X
(E) showed rod-shaped crystals (Figures S1–S4, Supporting
Information). In Fourier transform infrared spectra of JUC-

556-[HZ]X (E), the peaks assigned to C N stretching vibration
appeared at about 1615 cm−1, demonstrating the formation of
imine linkage (Figures S5–S8, Supporting Information). The
solid-state 13C cross-polarization magic-angle-spinning (CP/
MAS) NMR spectra further confirmed the presence of imine

linkage in the light of the distinguishing C N signals at about
152 ppm for JUC-556-[HZ]X (E) (Figures S9–S12, Supporting
Information). According to the thermogravimetric analysis,
JUC-556-[HZ]X (E) began to lose weight at 250 °C due to the
decomposition of the HZ (E) monomer while the overall skel-
eton was stable up to about 500 °C in the nitrogen atmosphere
(Figures S13–S17, Supporting Information). Furthermore, the
crystalline structures of JUC-556-[HZ]X (E) could be maintained
in a variety of organic solvents and aqueous solutions with a
series of pH values, especially in triethylamine, hydrochloric
acid, and trifluoroacetic acid (TFA), verifying their remarkable
stability (Figures S18–S21, Supporting Information).
The crystalline structures of JUC-556-[HZ]X (E) were revealed
by powder X-ray diffraction (PXRD) analysis (Figure 1). Herein
we took JUC-556-[HZ]0.25 (E) as an example to analyze their struc-
tures (Figure 1a). The unit cell parameters of JUC-556-[HZ]0.25
(E) were resolved by the PXRD pattern in conjunction with
structural simulation. After a geometrical energy minimization
by using the Materials Studio software package[14] based on a
twofold interpenetrated dia net and disordered HZ (E), the unit
cell parameters of JUC-556-[HZ]0.25 (E) were obtained (a = b =
28.2591 Å, c = 34.7253 Å, and α = β = γ = 90°). The simulated
PXRD pattern was in good agreement with the experimental
one (Figure 1a). Furthermore, the full profile pattern matching
(Pawley) refinement was performed from the experimental
PXRD pattern. The strong PXRD peaks at 4.03°, 5.11°, 6.25°,
8.27°, 9.20°, 11.10°, 12.18°, 16.42°, and 18.98° 2θ can be assigned
to the (101), (110), (200), (103), (221), (114), (303), (414), and (514)
Bragg peaks of a tetragonal space group P42/n (No. 86). The
refinement results revealed that unit cell parameters were nearly
equivalent to the predicted ones with excellent agreement fac-
tors (a = b = 28.3520 Å, c = 34.8160 Å, α = β = γ = 90°, ωRp =
5.77%, and Rp = 4.29%). In addition, we also examined alterna-
tive structures, such as non-interpenetrated dia network. How-
ever, there were significant differences between the simulated
and experimental PXRDs (Figures S22–S24, Supporting Infor-
mation). As the HZ (E) content increases, the crystallinity of
JUC-556-[HZ]X (E) decreases slightly due to disordered HZ (E)
units on the channel walls; however, these materials also exhibit
similar diffraction patterns, indicating that they have the same
structures (Figure 1b–d). Based on the above results, it is pro-
posed that JUC-556-[HZ]X (E) have the expected architectures
with twofold interpenetrated dia nets, and microporous cavities
with a diameter of about 1.70 nm (Scheme 1f).
2. Results and Discussion
2.1. Synthesis and Characterization
Our strategy for constructing 3D stimuli-responsive COFs is
based on a hydrazone derivative with E/Z interconversion, (E)-
ethyl-2-(2-(4,4″-diaminobiphenyl)
hydrazono)-2-(pyridin-2-yl)
acetate (HZ (E), Scheme 1a). To maximize the functionalization
of materials while maintaining their crystallinity and porosity,
we have employed a multi-component condensation system
to synthesize a series of 3D COFs. As shown in Scheme 1b,
4,4″-diaminobiphenyl (DABP) and HZ (E) were chosen as
linear linkers, while 1,3,5,7-tetrakis(4-formylphenyl) adaman-
tane (TFPA) was designed as an ideal tetrahedral building unit.
The condensation of TFPA with HZ (E) and DABP produced
3D COFs with different amounts of HZ (E), JUC-556-[HZ]X (E),
where X is the proportion of HZ (E) (X = [HZ (E)]/([DABP] +
[HZ (E)])); X = 0.25, 0.50, 0.75, or 1.00; Scheme 1c). Similar
to HZ (E) building unit, JUC-556-[HZ]X (E) also displayed the
excellent acid/base controlled E/Z isomerization (Scheme 1d).
Composed from linear and tetrahedral building blocks and sub-
jected to the large steric effect of HZ (E) groups, these COFs
are expected to exhibit a twofold interpenetrated diamondoid
(dia) network (Scheme 1e).[12]
Typically, JUC-556-[HZ]X (E) were synthesized by suspending
DABP and/or HZ (E) with TFPA in the mixed solvent of
dioxane and mesitylene in the presence of acetic acid followed
by heating at 120 °C for 3 days. These condensation reactions
exhibited similar isolated yields (≈80%), indicating that the
reactivities of DABP and HZ (E) were similar. Similar to pre-
vious reports, elemental analysis revealed that the ratios of HZ
The porosity and specific surface areas of JUC-556-[HZ]X (E)
were analyzed by nitrogen gas adsorption measurements at 77 K
(Figure 2). A sharp increase in gas uptake at low pressure
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Scheme 1. Schematic representation of the strategy for preparing JUC-556-[HZ]X with E/Z isomerization. a) Acid/base controlled E/Z isomerization
of free HZ molecule. b) Molecular structures of TFPA as a tetrahedral building unit as well as HZ (E) and DABP as linear linkers. c) JUC-556-[HZ]X
constructed by the condensation reaction of TFPA with HZ (E) and DABP (X = 0.25, 0.5, 0.75, and 1.00). d) Acid/base controlled E/Z isomerization in
JUC-556-[HZ]X. e) Twofold interpenetrated dia network in JUC-556-[HZ]X (E). f) Structural representation of JUC-556-[HZ]X (E).
(below 0.1 P/P0) demonstrated the microporous nature of
JUC-556-[HZ]X (E). An inclination of the isotherm and slight
desorption hysteresis were observed, implying the presence
of textural mesopores caused by the agglomeration of COF
crystals.[7d] Their surface areas exhibited a decreasing ten-
dency with the increase of HZ (E) content. The Brunauer–
Emmett–Teller (BET) surface areas were 634 m2 g−1 for JUC-
556-[HZ]0.25 (E), 527 m2 g−1 for JUC-556-[HZ]0.50 (E), 467 m2 g−1
for JUC-556-[HZ]0.75 (E), and 430 m2 g−1 for JUC-556-[HZ]1.00
(E), respectively (Figures S25–S28, Supporting Information).
Based on nonlocal density functional theory, JUC-556-[HZ]X
(E) showed similar microporous diameters of 1.62–1.80 nm
(Figures S29–S32, Supporting Information), which were in
good agreement with the pore sizes predicted from their crystal
structures (1.70 nm).
2.2. pH-Triggered E/Z Isomerization
Inspired by the abundant presence of HZ dangling groups,
we studied the pH-triggered rotary switching effect of JUC-
556-[HZ]X under different pH conditions (Figures S33–S62,
Supporting Information). The acid/base induced E/Z isomeri-
zation of dissociative HZ units was inspected by UV–vis
1
absorption spectroscopy and H NMR, and the results clearly
showed that the pH-triggered switching process was revers-
ible (Figures S33–S44, Supporting Information). Similar to
free HZ, JUC-556-[HZ]X also exhibited good pH-responsive
switching behaviors. The color of the as-synthesized JUC-556-
[HZ]X (E) evolved gradually from yellow to red upon acid treat-
ment, and then went back to yellow when the base was added
(Figure 3e; Figure S45, Supporting Information). Furthermore,
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Figure 1. PXRD patterns of a) JUC-556-[HZ]0.25 (E), b) JUC-556-[HZ]0.50 (E), c) JUC-556-[HZ]0.75 (E), and d) JUC-556-[HZ]1.00 (E).
the evolution of UV–vis absorption spectra verified the E/Z con-
figurational changes. JUC-556-[HZ]0.50 (E) was selected as an
example to illustrate the acid–base isomerization. When JUC-
556-[HZ]0.50 (E) was titrated with TFA (Figure 3a; Figure S46,
Supporting Information), the intensity of the absorption band
at 283 nm decreased whereas that at 249 nm increased as the
amount of the added acid increased. The spectral conversion
clearly indicated that the HZ groups of the JUC-556-[HZ]0.50
(E) underwent the configurational changes from E to Z. Upon
the addition of triethylamine (Et3N) to the sample of JUC-
556-[HZ]0.50 (Z) (Figure 3b; Figure S47, Supporting Informa-
tion), the absorption band of 283 nm restored, accompanying
with the declining of the absorption band at 249 nm. JUC-
556-[HZ]0.50 (E) also showed good pH-triggered switching pro-
cesses upon the addition of TFA/Et3N with low concentrations
and remarkable reversibility (Figure 3c,d). Notably, one isos-
bestic point at around 263 nm was observed, which clearly indi-
cated the interconversion of two species of JUC-556-[HZ]X upon
the variation of pH values. In addition, the transformation of
colors and UV–vis absorption spectra of JUC-556-[HZ]X were
slightly different from those of free HZ, which could be caused
by steric hindrance and confinement effects of COF channels as
well as potential inductive effects of atoms around HZ units.[15]
Furthermore, the spectral conversion of JUC-556-[HZ]0.50 (E)
occurred with other acids, such as HCl (Figure 3f; Figure S48,
Supporting Information). As for other JUC-556-[HZ]X (E),
similar acid/base dependent changes of UV–vis absorption
spectra were observed, and their E/Z configurations were also
reversible under acidic/basic conditions (Figures S49–S62, Sup-
porting Information).
Furthermore, the E/Z isomerization of JUC-556-[HZ]X was
demonstrated by proton conduction at room temperature
(Figure 4; Figures S63–S66, Supporting Information). As HZ
(E) has rich nitrogen atoms, it can combine with HCl to form
hydrogen bonds,[16] and therefore the as-synthesized JUC-556-
[HZ]X (E) possessed the ability to accept protons. Typically, JUC-
556-[HZ]X (E) were compressed into cylindrical pellets with a
diameter of 6.0 mm and a thickness of 1.0 mm. The proton con-
ductivities of the original JUC-556-[HZ]X (E) were 2.73 × 10−6 S m−1
for JUC-556-[HZ]0.25 (E), 3.70 × 10−7 S m−1 for JUC-556-[HZ]0.50 (E),
1.32 × 10−6 S m−1 for JUC-556-[HZ]0.75 (E), and 3.91 × 10−7 S m−1 for
JUC-556-[HZ]1.00 (E), respectively. Remarkably, upon protonation
with HCl vapor, the proton conductivities of activated JUC-556-
[HZ]X (Z) increased up to 4.41 × 10−4 S m−1 for JUC-556-[HZ]0.25
(Z), 7.04 × 10−4 S m−1 for JUC-556-[HZ]0.50 (Z), 2.17 × 10−4 S m−1 for
JUC-556-[HZ]0.75 (Z), and 3.30 × 10−4 S m−1 for JUC-556-[HZ]1.00
(Z), which are 162-fold, 1903-fold, 164-fold, and 844-fold improve-
ment than those of the original ones, respectively. In addition, the
proton conductivity dropped when the JUC-556-[HZ]X (Z) were
treated with Et3N vapor, indicating that the pH switching process
was reversible. The proton conductivity could be maintained after
three cycles (Figure S67, Supporting Information).
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Figure 2. N2 adsorption-desorption isotherms for a) JUC-556-[HZ]0.25 (E), b) JUC-556-[HZ]0.50 (E), c) JUC-556-[HZ]0.75 (E), and d) JUC-556-[HZ]1.00 (E)
at 77 K.
2.3. pH-Responsive Drug Release
sustained-release effects in two buffer solutions (Figure 5b;
Figures S77–S79, Supporting Information). Among them, JUC-
556-[HZ]0.50 displayed the best performance in the release of
drug, and the release rate reached 74.56% in the pH = 4.8 buffer
within 72 h (Z isomerization), but only 18.59% in the pH = 7.4
buffer (E isomerization, Figure 5b). The release rate of drug
molecule under acidic condition was nearly fourfold higher
than that under neutral condition, greatly improving the drug
targeting delivery and reducing its side effects. Furthermore,
JUC-556-[HZ]0.50 with E or Z isomerization exhibited reproduc-
ible identical effect for the capture and release of Ara-C even
after five cycles (Figure 5c).
As for the drug release mechanism, it is suggested that the
HZ unit as a pH-responsive rotary switch in JUC-556-[HZ]X
plays a key role, which can form a variety of hydrogen bonds
with drug molecules.[19] When the solution is neutral or basic,
the hydrogen bonds between Ara-C and HZ (E) units promote
the loading of Ara-C onto JUC-556-[HZ]X (E). Meanwhile, the
channels of JUC-556-[HZ]X (E) provide the platforms for encap-
sulating Ara-C. On the contrary, when the surrounding is
acidic, JUC-556-[HZ]X (E) transforms to Z-type configuration
through the protonation of pyridine subunits, and simultane-
ously Ara-C was also protonated. The repulsive effect between
JUC-556-[HZ]X (Z) and Ara-C can drive the high-efficiency
release of Ara-C at the acidic condition (Figure 5a).
Given the high porosity and stability of JUC-556-[HZ]X (E) as
well as favorable pH-responsive HZ units, we explored their
potential application in the stimuli-responsive drug delivery
system. Ara-C with a molecular size of about 0.9 nm was
chosen as a model molecule because it is a traditional drug for
cancer therapy, especially for pancreatic cancer, acute myelog-
enous leukemia, and chronic lymphoma.[17] Typically, the JUC-
556-[HZ]X (E) were immersed in Ara-C aqueous solution for 9
h under stirring at 200 rpm, and Ara-C-loaded JUC-556-[HZ]X
(E) were confirmed by UV–vis absorption spectra (Figure S68,
Supporting Information). Then, the mixtures were filtered and
washed. The resultant PXRD peaks were coincided with those
of starting materials, confirming the structural integrity after
loading Ara-C (Figures S69–S72, Supporting Information). As
can be seen from nitrogen adsorption isotherms, the relevant
porosity data after loading Ara-C showed significantly reduced
BET surface areas (Figures S73–S76, Supporting Informa-
tion). Each Ara-C-loaded JUC-556-[HZ]X (E) was transferred
to two ampoules containing 5.0 mL releasing buffer solution
separately, and the maximum UV–vis absorption intensity at
272 nm was chosen to indicate the drug concentration during
the drug-releasing process. It is known that the cancer tis-
sues generally exist in acidic extracellular environments with
pH = 4 to 6. Therefore, we chose acetic acid buffer with pH
= 4.8 as simulated cancer fluid to release the drug. The pH
value in the normal physiological environment is almost neu-
tral, and so a phosphate buffer (pH = 7.4) was used to simulate
normal body fluid.[18] All JUC-556-[HZ]X showed smart drug
To further verify the mechanism of JUC-556-[HZ]X for
the drug adsorption and release, we generated electrostatic
potential (ESP) mapped van der Waals surfaces using Multiwfn
software (Figure S80, Supporting Information)[20] and per-
formed DFT calculations using Gaussian09 program packages
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Figure 3. a) Absorption spectra of JUC-556-[HZ]0.50 (E) upon protonation in TFA solution with increasing concentrations. b) Absorption spectra of JUC-
556-[HZ]0.50 (Z) upon deprotonation in Et3N solution with increasing concentrations. c) Absorption spectra of JUC-556-[HZ]0.50 (E) upon protonation in
TFA solution under low concentrations. d) Absorption spectra of JUC-556-[HZ]0.50 (Z) upon deprotonation in Et3N solution under low concentrations.
e) Reversible change of JUC-556-[HZ]0.50 (E) in the acid/base solution. Inset: the color change of JUC-556-[HZ]0.50 (E). f) Absorption spectra of JUC-
556-[HZ]0.50 (E) upon protonation in HCl solution with increasing concentrations.
(Figures S81–S83, Supporting Information).[21] As shown in
Figure S80, Supporting Information, the hydrogen bond could
be formed between the hydrogen atom of amino group of
drug molecule and the oxygen atom of ester carbonyl group
of E configuration fragment. Furthermore, the DFT calcula-
tion results showed that the interaction energy between drug
molecule and E configuration fragment was −18.16 kcal mol−1.
The distance between the hydrogen atom of amino group and
the oxygen atom of ester carbonyl group was 2.1 Å, indicating
a strong hydrogen bond interaction between these two mole-
cules. These results clearly indicate that JUC-556-[HZ]X (E) is a
closed form for the drug adsorption. However, after being pro-
tonated, the ESP of oxygen atom of ester carbonyl group turned
to be positive, which means the Z configuration fragment
could not produce hydrogen bond with the drug (Figure S80,
Supporting Information). According to the DFT calculation,
the complex showed a strong electrostatic repulsive force,
and thus the interaction energy between drug molecule and Z
configuration fragment extremely dropped to 16.4 kcal mol−1,
which demonstrates that JUC-556-[HZ]X (Z) is an open form
for drug release.
3. Conclusion
We have synthesized a series of novel 3D hydrazone-decorated
COFs, JUC-556-[HZ]X (E), as pH-triggered rotary switches via
the bottom–up multi-component approach. JUC-556-[HZ]X (E)
showed high crystallinity, good chemical stability, and revers-
ible E/Z isomerization at various pH values, verified by UV–vis
absorption spectroscopy and proton conduction. Furthermore,
these functionalized COF materials were applied to intelligent
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Figure 4. a) Proton conductivity of activated JUC-556-[HZ]0.25 (E) in contact with HCl vapor. b) Proton conductivity of JUC-556-[HZ]0.25 (Z) in contact
with Et3N vapor. c) Proton conductivity of activated JUC-556-[HZ]0.50 (E) in contact with HCl vapor. d) Proton conductivity of JUC-556-[HZ]0.50 (Z) in
contact with Et3N vapor.
pH-responsive Ara-C delivery and exhibited a nearly fourfold
increase in the drug release at pH = 4.8 than at pH = 7.4, which
will effectively improve drug-targeting and reduce drug side
effects. This study thus develops the design and synthesis of 3D
stimuli-responsive COFs, and promotes the potential applica-
tion of COF materials for disease theragnostic.
Figure 5. a) Schematic representation of the release of Ara-C from the channels of JUC-556-[HZ]X in acidic solution. b) Drug release profiles and c) revers-
ibility of Ara-C-loaded JUC-556-[HZ]0.50 in simulated cancer fluid (pH = 4.8 buffer solution) and in simulated normal body fluid (pH = 7.4 buffer solution).
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4. Experimental Section
Supporting Information
Synthesis
of
HZ
(E):
(E)-ethyl-2-(2-(4,4″-4,4″-dinitro-2-
Supporting Information is available from the Wiley Online Library or
from the author.
biphenylamine) hydrazono)-2-(pyridin-2-yl)acetate (HZ-NO2, 1.5 g,
3.45 mmol, equivalent to NO2 6.90 mmol), active carbon (0.225 g),
hexahydrate ferric chloride (0.05 g, 0.185 mmol), and tetrahydrofuran
(THF, 10.0 mL) were added into 100 mL three-necked round-bottomed
flask with a magnetic stir-bar. Under a dried argon-flowing, the mixture
was stirred rapidly and heated to 60 °C. Then, 80% hydrazine hydrate
(0.875 mL, 14.35 mmol) was slowly added dropwise to the mixture
and the resulting mixture was heated reflux for 8 h at 60 °C. The
precipitation was washed in batches with 30.0 mL THF and added
40.0 mL ethyl acetate to the filtrate. The combined organic phases
were washed four times with 40.0 mL saturated salt water, once with
deionized water, and dried with NaSO4. The solution was poured into
200.0 mL hexane, filtered, and removed solvent by rotary evaporation.
The resulted red solid was purified by column chromatography
Acknowledgements
This work was supported by the National Natural Science Foundation
of China (22025504, 21621001, and 21390394), “111” project (BP0719036
and B17020), China Postdoctoral Science Foundation (2020TQ0118
and 2020M681034), and the program for JLU Science and Technology
Innovative Research Team. V.V., Q.F., and S.Q. acknowledge the
collaboration in the framework of China-French joint laboratory
“Zeolites.”
1
(SiO2: CH2Cl2/ ethyl acetate 8:1) to give HZ (0.90 g, 69%). H NMR
(400 MHz, DMSO): δ (ppm) 14.52 (s, 1 H), 8.06 (d, 1 H), 7.98 (d, 1 H),
7.89 (m, 1 H), 7.00 (d, 2 H), 6.96 (d, 1 H), 6.61 (d, 1 H), 6.69 (d, 2 H),
4.30 (q, 2 H), 1.35 (t, 3 H).
Conflict of Interest
The authors declare no conflict of interest.
Synthesis of TFPA: 1,3,5,7-Tetraphenyladamantane (3.80 g, 8.6 mmol,
1 eq.) and dichloromethane (DCM, 150 mL) was added to a 250 mL
three-necked round-bottomed flask with a magnetic stir-bar. Under
a dried argon-flowing, the mixture was stirred rapidly and cooled
to −10 °C with an ice/salt bath. Titanium tetrachloride (19.0 mL,
172.4 mmol, 20 eq.) was then added slowly to the mixture and stirred
at −10 °C for 30 min. α, α-Dichloromethyl methyl ether (12.5 mL,
137.9 mmol, 16 eq.) was subsequently added dropwise to the mixture,
which turned pale yellow during the addition. The reaction was held
at −10 °C for 3 h and then allowed to warm to room temperature with
stirring overnight. The mixture was poured into 300.0 mL ice-water,
and 100.0 mL of 1 m HCl was added. Then, the resulting mixture was
stirred for 30 min. During this time, the red/black organic phase
turned bright yellow and some white precipitate was observed.
The two-phase mixture was separated, and the aqueous phase was
washed twice with 100.0 mL DCM. The combined organic phases
were washed once with 100.0 mL of 1 m HCl, twice with deionized
water, once with saturated aqueous NaHCO3, once with saturated
aqueous NaCl, and dried with MgSO4. The solution was filtered and
removed solvent by rotary evaporation. The resulted yellow solid was
purified by column chromatography and then recrystallized from
Data Availability Statement
The data that support the findings of this study are available within the
manuscript and the supporting information.
Keywords
covalent organic frameworks, drug release, functionalization, stimuli-
responsive materials
Received: May 5, 2021
Revised: July 4, 2021
Published online:
1
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