Tuning the Structure and Hydrolysis Stability of Calcium Metal-Organic Frameworks through Integrating Carboxylic/Phosphinic/Phosphonic Groups in Building Blocks

Article abstract of DOI:10.1021/acs.cgd.0c01272

Crystal structure and hydrolysis stability are fundamentally important for the application of metal-organic frameworks (MOFs) in biotechnology. Herein, five novel 3-D MOFs, built up from biocompatible calcium ions and ligands containing carboxylic, phosphinic, or phosphonic coordinating groups, have been solvothermally synthesized, and their crystal structures were determined by single-crystal X-ray diffraction. Their hydrolysis stability study demonstrated that the water stability of these Ca-based MOFs can be tuned by integrating carboxylic/phosphinic/phosphonic coordinating groups in building blocks.

Full text of DOI:10.1021/acs.cgd.0c01272

pubs.acs.org/crystal
Article
Tuning the Structure and Hydrolysis Stability of Calcium Metal−
Organic Frameworks through Integrating Carboxylic/Phosphinic/
Phosphonic Groups in Building Blocks
Jing Sun, Tao Huang, Qi Yin, Lan Li, Tian-Fu Liu, Xin-Song Huang,* and Rong Cao*
Cite This: https://dx.doi.org/10.1021/acs.cgd.0c01272
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Crystal structure and hydrolysis stability are
fundamentally important for the application of metal−organic
frameworks (MOFs) in biotechnology. Herein, five novel 3-D
MOFs, built up from biocompatible calcium ions and ligands
containing carboxylic, phosphinic, or phosphonic coordinating
groups, have been solvothermally synthesized, and their crystal
structures were determined by single-crystal X-ray diffraction.
Their hydrolysis stability study demonstrated that the water
stability of these Ca-based MOFs can be tuned by integrating
carboxylic/phosphinic/phosphonic coordinating groups in build-
ing blocks.
considered to avoid the damage to cells and tissues.25 Owing
to relatively weak coordination bonds, MOFs can be
biodegraded inside the human body.26 The toxicity and
biocompatibility of metals and organic linkers used in MOFs
should be carefully evaluated. Calcium, as one of the most
essential metal elements in the human body with low atomic
weight and low toxicity, is extremely attractive as a candidate in
building bioapplicable MOFs. Meanwhile, Ca-based MOFs are
highly promising to meet simultaneously the requirements of
adjusting the overall stability and reducing the toxicity of metal
ions and organic ligands, which are the main focuses in the
present research on biological toxicity of MOFs.27 For
instance, Ca-MOFs are proved to be effective in flurbiprofen
delivery.28 Miller et al. reported the preparation of a porous
calcium 3,3′,5,5′-azobenzenetetracarboxylate with accessible
metal acid sites toward delivering NO at the biological level.29
Bioactive rodlike Ca-BDC MOFs (BDC = 1,4-benzenedicar-
boxylate anion) particles costabilized CO2-in-water high
internal phase emulsion in the presence of polyvinyl alcohol
was presented by Yang et al., showing promising applications
in bio-tissue engineering.30 George et al. reported a microwave
route of synthesizing Ca-BDC and subsequent adsorption-
1. INTRODUCTION
Over the past 20 years, the development of carriers showing
desired stability and appropriate pharmacokinetics for
controlled drug release has attracted intense research interest.
A variety of synthetic materials have been established as
promising candidates, such as molecular sieves, micelles,
liposomes, and cosmetic polymers,1−3 while few of them can
simultaneously satisfy the high loading amount, controllable
release rate, and good biocompatibility. In 2005 and 2006,
́
Ferey and co-workers first considered and introduced metal−
organic frameworks (MOFs) into drug delivery, reaching a
record ibuprofen loading amount with a complete release
under physiological conditions in days.4,5 Since then, MOFs
have been widely studied as carriers to improve the efficacy of
conventional drug delivery thanks to their regular internal
structures, large specific surface areas, adjustable pore sizes,
and easy functionalization.6−11 By choosing suitable MOFs
according to the sizes and nature of the guest molecules, or
directly using a bioactive molecule as linker or a bioactive
metal as metal node, as well as utilizing some intrinsic ionic
and environment-responsive nature of MOFs, we can further
achieve high drug loading and controlled release.12−17
Therefore, the construction and application of MOFs-based
hybrid material may provide a promising way toward designing
effective and safe drug-delivery systems.18−23
Received: September 15, 2020
Revised: October 22, 2020
As a drug carrier, on the one hand, MOFs with varied
stability (sometimes even “water-unstable”) in different
environments are required in consideration of the diverse
biological situations.24 Meanwhile, the biocompatibility of the
carrier ought to be another important factor that needs to be
https://dx.doi.org/10.1021/acs.cgd.0c01272
Cryst. Growth Des. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

Crystal Growth & Design
pubs.acs.org/crystal
Article
desorption (release) study of curcumin.31 Yaghi et al. reported
that MOF-1201 [Ca14(L-lactate)20(acetate)8(C2H5OH)-
(H2O)] can be used as a carrier for the slow release of
fumigant cis-1,3-dichloropropene.32 Shi et al. prepared three-
dimensional Ca-bearing metal organic frameworks, [Ca-
(H2O)3(HPXBP)] (CaP1), where PXBP = p-xylylenebi-
sphosphonate, and found that CaP1 readily precipitates
bone-precursor phases (octacalcium phosphate and hydrox-
yapatite) in the solutions simulating body fluid.33 It should be
noted that, although many calcium-based MOFs have been
reported,34−46 the research on their stability especially in
water-based systems is relatively rare, and the design of new
Ca-based MOFs with desired stability adapting to different
biological environments is still a challenge.
To tune the robustness of MOFs, choosing organic ligands
with appropriate functional groups is of decisive importance.
Compared to the widely studied carboxylate-based ligands,
using phosphinate- or phosphonate-containing ligands for
MOF synthesis is relatively rare, although metal phosphinate/
phosphonate bonds have high thermal, hydrolytic, and
chemical stability.47−53 Meanwhile, natural organophospho-
nates are found to be involved in many biochemical
pathways.50 Specifically, robust Ca-MOFs can be prepared
utilizing bisphosphonates as ligands, which is stable in
simulated body fluid for at least 14 days.33 However, as
reported by Alvarez et al., BioMIL-4 built from calcium and
alendronate (a second-generation bisphosphonate) was inert in
contact with biological simulated fluid without showing any
bioactive effect because the material is too stable to be
degraded in biological medium.54 Hence, the combination of
various functional groups with different coordinating strength
may be an alternative way to get Ca-MOFs with appropriate
stability. In this work, a series of carboxylic/phosphinic/
phosphonic ligands were chosen to fabricate new Ca-based
MOFs. The obtained MOFs display versatile structure with
different coordination geometry and porosity. These MOFs
exhibit different stability in water, and it can be clearly found
that the hydrolysis stability of these Ca-MOFs can be tuned
through incorporating different carboxylic/phosphinic/phos-
phonic groups in organic building blocks.
water (0.7 mL) in ethanol (15 mL) is refluxed for 4 h, and then
ethanol is removed by rotary evaporation. The resulting precipitation
is diluted with water (50 mL). Subsequently, the aqueous solution is
washed with toluene for three times and acidified with hydrochloric
acid. And then, the total medium product (6.6 mmol) is solved with
pyridine (12 mL), and KMnO4 (265.7 mmol) is added portionwise.
Then the brown precipitate is removed by filtering, and the remaining
solution is rotary evaporated until the odor of pyridine is no longer
evident. Finally, the mixture is acidified with hydrochloric acid and
filtered to get the white target product.
2.3. Preparation of Six Ca-Based MOFs. PFC-36. BPDA (30
mg) was dissolved in a mixture of distilled water (0.5 mL) and DMF
(2.5 mL) at room temperature. Calcium nitrate tetrahydrate (30 mg)
was then added to the solution; the reaction mixture was then sealed
in a 20 mL glassware, and kept at 90 °C for 2 days. Once cooled to
room temperature, the resulting colorless rodlike crystals were
collected. FTIR (KBr): = 3441 (w), 1712 (vs), 1576 (s), 1247 (s),
1020 (vs), 701 (s) cm−1. Anal. Calcd (%) for PFC-36: C, 48.32; H,
2.03; N, 9.39%. Found: C, 46.68; H, 3.17; N, 8.26%.
PFC-37. TATB (15 mg) was dissolved in DMA (3 mL), and
calcium nitrate tetrahydrate (15 mg) was then added to the solution,
followed by 20% HNO3 (200 μL). The reaction mixture was then
sealed in a 20 mL glassware, and kept at 120 °C for 3 days. Once
cooled to room temperature, the resulting colorless block crystals
were collected. FTIR (KBr): = 3407 (w), 1622 (vs), 1613 (s), 1558
(s), 1254 (s), 1017 (vs), 702 (s) cm−1. Anal. Calcd (%) for PFC-37:
C, 57.0; H, 3.67; N, 9.49%. Found: C, 49.1; H, 4.48; N, 9.08%.
PFC-38. When the synthesis conditions of PFC-37 were slightly
changed, a mixture of PFC-37 and PFC-38 was obtained. TATB (5
mg) was dissolved in DMA (3 mL), and calcium nitrate tetrahydrate
(15 mg) was then added to the solution, followed by 20% HNO3 (200
μL). The reaction mixture was then sealed in a 20 mL glassware, and
kept at 90 °C for 3 days. Once cooled to room temperature, the
resulting colorless block of PFC-37 and colorless flake of PFC-38
crystals were collected, and PFC-38 was selected from the mixture
manually for single-crystal X-ray diffraction.
PFC-39. TCPA (20 mg) was dissolved in a mixture of distilled
water (1 mL), DMA (1 mL), and EtOH (1 mL) at room temperature,
and calcium nitrate tetrahydrate (80 mg) was then added to the
solution. The reaction mixture was then sealed in a 20 mL glassware,
and kept at 90 °C for 2 days. Once cooled to room temperature, the
resulting colorless flake crystals were collected. FTIR (KBr): = 3624
(vs), 3418 (w), 1706 (s), 1631 (s), 1422 (vs), 1255 (s), 1120 (s), 688
(s), 566 (s), 518 (s) cm−1. Anal. Calcd (%) for PFC-39: C, 40.53; H,
1.70%. Found: C, 41.94; H, 3.9; N, 4.17%.
PFC-40. When the synthesis conditions of PFC-39 were slightly
changed, a mixture of PFC-39 and PFC-40 was obtained. TCPA (5
mg) was dissolved in a mixture of distilled water (1 mL), and DMA (1
mL), calcium nitrate tetrahydrate (10 mg) was then added to the
solution. The reaction mixture was then sealed in a 20 mL glassware,
and kept at 90 °C for 3 days. Once cooled to room temperature, the
resulting colorless flake of PFC-39 and colorless strip of PFC-40
crystals were collected, and PFC-40 was selected from the mixture
manually for single-crystal X-ray diffraction.
PFC-41. COOH-PO3 (5 mg) was dissolved in a mixture of distilled
water (1 mL) and DMA (1 mL), and calcium nitrate tetrahydrate (10
mg) was then added to the solution. The reaction mixture was then
sealed in a 20 mL glassware, and kept at 90 °C for 3 days. Once
cooled to room temperature, the resulting colorless fine needle
crystals were collected. FTIR (KBr): = 3602 (vs), 3087 (w), 1824 (s),
1562 (s), 1427 (vs), 1281 (s), 1144 (s), 702 (s), 561 (s), 544 (s)
cm−1. Anal. Calcd (%) for PFC-41: C, 32.82; H, 1.97%. Found: C,
33.52; H, 3.68; N, 1.76%.
2. EXPERIMENTAL SECTION
2.1. Synthesis of 4,4′,4″-s-Triazine-2,4,6-triyl-tribenzoic
Acid (TATB). The synthesis was carried out following the procedure
published by Stock et al.55 2.9 mL of p-tolunitrile was added slowly
under stirring to 5.85 mL of trifluoromethanesulfonic acid, and the
mixture was stirred overnight. Ice cold water was added and
neutralized with 25% aqueous ammonia solution. The precipitate
was filtered off and subsequently washed with water and acetone.
Recrystallization from toluene yielded 2,4,6-tri-p-tolyl-s-triazine as
white needle-shaped crystals. A 500 mL three-neck flask was charged
with 72.64 g of acetic acid, 4.4 mL of H2SO4, and 2.783 g of 4,4′,4″-s-
triazine-2,4,6-tri-p-tolyl. Then 7.2 g of chromium oxide and 4.8 mL of
acetic anhydride were added with stirring, carefully keeping the
temperature below 50 °C. The resulting black-brown slurry was
stirred overnight, poured into 300 mL of cold water, well mixed, and
filtered. The solid was washed with water and dissolved in 200 mL of
2N NaOH solution. After the unreacted starting material was
removed by filtration, the solution was acidified with HCl to give
crude product. Recrystallization from DMF gave pure product as a
white solid.
3. RESULTS AND DISCUSSION
A linear ligand BPDA was first chosen to get a Ca-BPDA MOF
(named as PFC-36), whose structure was shown in Figure 1.
The compound crystallizes in the monoclinic space group P21/
c; the asymmetric unit comprises one calcium atom, one BPDA
2.2. Synthesis of 5,5′-(Hydroxyphosphoryl)diisophthalic
Acid (TCPA). The synthesis was carried out following the procedure
published by Li et al.56 A mixture of bis(3,5-dimethylphenyl)-
phosphine oxide (7.8 mmol), potassium hydroxide (12.5 mmol), and
B
https://dx.doi.org/10.1021/acs.cgd.0c01272
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
Figure 2. (a) The scheme of TATB ligand, (b) the PXRD patterns of
as-synthesized PFC-37 and after water treatment, (c) the crystal
structure of PFC-37 seen from the c-axis direction, and (d) three-
dimensional structure with parallelogram-like channels of PFC-38.
state (Figure S4), suggesting that the framework of PFC-37
underwent decomposition in the N2 adsorption test. The
results of elemental analysis for PFC-37 showed that the
measured value for carbon was quite smaller than the
calculated value. We speculated that PFC-37 partially
decomposed in air during the storage in the test center and
part of the carbon escaped in the form of CO2 during the
process.
When the synthesis conditions were slightly changed, a
mixture of PFC-37 (colorless block) and PFC-38 (colorless
flake) was obtained, and PFC-38 was selected from the
mixture. For PFC-38, the compound crystallizes in the triclinic
Figure 1. (a) The scheme of BPDA ligand, (b) the PXRD patterns of
as-synthesized PFC-36 and after water treatment, and the crystal
structures of PFC-36 seen from b-axis (c) and c-axis (d) directions.
ligand, and one coordinated H2O molecule. The CaO7
pentagonal bipyramids25 share their edges to create chain-
like building blocks (Figure S1), which are further connected
by organic linkers to form a three-dimensional structure
(Figure 1c,d). By regarding the calcium atom and BPDA
ligands as a 6-c net, the PFC-36 has a Shubnikov plane net
topology. The obtained PXRD patterns matched well with the
simulated one, which verifies the purity of PFC-36. We also
studied the water stability of PFC-36 by soaking it in water for
12 h, and it can be observed that PFC-36 almost lost its
crystallinity after water treatment (Figure 1b). The N2
adsorption of PFC-36 had been tested at 77 K, and no
obvious adsorption behavior was found, due to the almost
nonporous structure of PFC-36 (Figure S2).
Compared with the BPDA ligand, a larger triangular ligand
TATB was applied to get PFC-37, whose structure was the
same as the reported one,57 and the PXRD patterns are shown
in Figure 2b. The compound of PFC-37 crystallizes in the
monoclinic space group P21; the asymmetric unit comprises six
calcium atoms and four TATB ligands. The CaO6 octahedron
and CaO8 snub disphenoid polyhedrons37 share their edges to
create 6-nuclear CaO6-CaO8-CaO6-CaO6-CaO8-CaO6 rodlike
building blocks (Figure S3), which are further connected by
organic linkers to form a three-dimensional structure with
hexagonal-like channels of 12.7 × 17.7 Å2 seen from the c-axis
direction as shown in Figure 2c, and the theoretical porosity of
PFC-37 is 31.9%. The water stability of PFC-37 has been
tested by soaking it in water for 12 and 24 h; the PXRD test of
PFC-37 is shown in Figure 2 after water treatment. We can
observe that there was no crystalline state, suggesting that the
framework of PFC-37 is not robust and underwent
decomposition (Figure 2b). The N2 adsorption of PFC-37
had been tested at 77 K; however, no obvious adsorption
behavior was found. The PXRD test of PFC-37 was performed
after adsorption, and it was found that there was no crystalline
̅
space group P1; the asymmetric unit comprises three calcium
atoms, two TATB ligands, two coordinated DMA molecules,
and one isolated dimethylamine molecule. The CaO6
octahedron, CaO7 pentagonal bipyramid, and CaO8 snub
disphenoid polyhedrons share their edges to create 5-nuclear
CaO7-CaO8-CaO6-CaO8-CaO7 rodlike building blocks (Figure
S5), which are further connected by organic linkers to form a
three-dimensional structure with parallelogram-like channels of
5.6 × 9.0 Å2, as shown in Figure 2d.
According to the theory of Hard-Soft-Acid-Base, the
coordination bond between Ca2+ (hard acid) and −COOH
(soft base) is weak, which results in the instability of Ca-
COOH MOFs. The human body is a water-rich system, so the
Ca-based MOFs as drug carriers would inevitably have contact
with water, and the stability of Ca-based MOFs is a noteworthy
aspect when it is applied to living organisms. Compared with
−COOH ligands, the −PO3 group has a stronger coordinating
ability with metals. Taking this into account, the −PO3 groups
were introduced into the ligands as coordination sites to
enhance the stability of Ca-based MOFs.
The TCPA ligand56 was selected to synthesize PFC-39, in
which the −PO2 group contained two additional coordination
sites (Figure 3a). The compound of PFC-39 crystallizes in the
̅
triclinic space group P1; the asymmetric unit comprises two
calcium atoms, one TCPA ligand, and one coordinated DMA
molecule. The binuclear CaO7-CaO7 pentagonal bipyramids
share their edges to create bulk-like building blocks (Figure
C
https://dx.doi.org/10.1021/acs.cgd.0c01272
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
̅
group P1; the asymmetric unit comprises five calcium atoms,
two TCPA ligands, one coordinated DMA molecule, one
isolated DMA molecule, eight coordinated water molecules,
and two isolated water molecules. The CaO6 octahedron,
CaO7 pentagonal bipyramid, and CaO8 snub disphenoid
polyhedrons simultaneously exist in PFC-40. The mono-
nuclear CaO6 octahedron and tetranuclear CaO7-CaO6-CaO8-
CaO7 rodlike building blocks (Figure S8) are further
connected by organic linkers to form two 3-D rectangle-like
channels of 9.6 × 9.9 Å2 and 9.6 × 15.2 Å2 seen from the a-axis
direction, as shown in Figure 3c, and the bigger channel were
blocked by small DMA molecules. The simulated PXRD of
PFC-40 is shown in Figure 3d, whose chief peaks can hardly
match with that of the PFC-39 water-treated for 12 h.
Therefore, PFC-40 is a new crystalline phase that may not be
obtained by the transformation of PFC-39 in water.
Further optimizing the ligand, we selected a COOH-PO3
ligand (Figure 4a), in which the −PO3 group contained one
more coordination site than the TCPA ligand, and a new
structure was gotten and named as PFC-41. The compound
crystallizes in the monoclinic space group Pn; the asymmetric
unit comprises four calcium atoms and four COOH-PO3
ligands. The −CaO7-CaO8-CaO7-CaO8− chain formed a
planar Ca-SBU by a dislocation stacking method in PFC-41
(Figure S9). Both sides of the plane were coordinated with the
phosphonic acid group, so that the carboxylic acid group in the
para position of the organic ligand is exposed and does not
coordinate with Ca clusters. Instead, the face-to-face carboxylic
acid groups are connected by hydrogen bonds. The O−H···O
distance and angle are 2.608 Å and 151.7°, respectively, falling
into the strong hydrogen bond range according to the
literature (2.49−3.15 Å).58 A parallelogram 1-D channel is
formed between the planar Ca-SBUs and the perpendicular
organic ligands, forming channels with a size of 4.2 × 14.0 Å2
along the a-axis direction (Figure 4b), and the theoretical
porosity of PFC-41 is 27.3%. The PXRD patterns of PFC-41,
shown in Figure 4c, confirmed its purity. The CO2 adsorption
of PFC-41 had been tested at 298 K, and a 10 cm3/g volume
of adsorption was observed (Figure S10). However, no
obvious N2 adsorption behavior was found. The hydrolysis
stability of PFC-41 had also been studied, and it is stable in
water for at least 5 days, which is sufficiently long for drug
release applications. Because all the oxygen atoms of the PO3
group participate in the coordination, the formed 1-D calcium
chain greatly improves the hydrolysis stability of the calcium-
based MOFs. Inspired by the hydrolysis stability of PFC-41,
we tried to explore its potential in bioapplications. Loading 5-
fluorouracil and cisplatin had been carried out in PFC-41, but
no loading was found since the pore of PFC-41 is too small for
Figure 3. (a) The scheme of TCPA ligand, (b) the crystal structure of
PFC-39 seen from the a-axis direction, (c) 3-D rectangle-like
channels of PFC-40, and (d) the PXRD patterns of PFC-39 treated
with water in different conditions.
S6), which are further connected by phosphinic and carboxylic
acid groups from organic linkers to form a 3-D structure. A
rectangle-like channel of 8.8 × 9.2 Å2 can be found between
two clusters seen from the a-axis direction, as shown in Figure
3b, and the theoretical porosity of PFC-39 is 13.1%. There is a
disorder of the aromatic ring in the structure of PFC-39, but it
has no effect on the overall structure. The PXRD patterns of
PFC-39 are shown in Figure 3d, which confirmed the purity of
PFC-39. The CO2 adsorption of PFC-39 had been tested at
298 K, and a 11.2 cm3/g volume of adsorption was observed.
However, no obvious N2 adsorption behavior was found
(Figure S7). We speculate that, compared with CO2, the N2
molecule is too large to enter the pores of PFC-39. We also
studied the water stability of PFC-39 by soaking it in water for
12 h. Although the peaks of PXRD still existed, they did not
match with the as-synthesized PFC-39. After 24 h treated with
water, the sample exhibited no peaks at all (Figure 3d). PFC-
39 first transformed into another crystalline phase after water-
treated for 12 h, which then slowly lost its crystallinity during
the next 12 h in water. Such distinctive hydrolysis of PFC-39
among the Ca-MOFs in this work indicates that PFC-39 might
be highly important for bioapplications requiring metastable
carriers.
A mixture of PFC-39 (colorless flake) and PFC-40
(colorless strip) was gained when the synthesis conditions
were changed, and PFC-40 was separated from the mixture.
For PFC-40, the compound crystallizes in the triclinic space
Figure 4. (a) The scheme of COOH-PO3 ligand, (b) the crystal structure of PFC-41 seen from the a-axis direction, and (c) the PXRD patterns of
PFC-41 treated with water in different conditions.
D
https://dx.doi.org/10.1021/acs.cgd.0c01272
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
those drugs (Figures S11 and S12). A smaller molecule, urea,
which is of interest for cosmetics,59 was further tried to study
the loading capacity of PFC-41. The content of urea into PFC-
41 was quantified by thermogravimetric analysis (TGA), and
the integrity of the loaded samples was examined by PXRD
(Figures S13 and S14). Urea can be loaded into PFC-41 at the
content of 57.2 wt % without damages to the crystallinity,
which is comparable to the reported data for MIL-100 (69.2 wt
%) and MIL-53 (63.5 wt %).59
Thermogravimetric analysis (TGA) of PFC-36, PFC-37,
PFC-39, and PFC-41 is revealed in Figure S15. PFC-36 causes
a mass loss at about 160 °C, assigned to solvent (DMF), with
no further mass loss occurring until 540 °C, PFC-37 causes a
mass loss at about 100 °C, assigned to solvent (DMA), with no
further mass loss occurring until 500 °C, PFC-39 with no
further mass loss occurring until 610 °C, and PFC-41 causes a
mass loss at about 170 °C, assigned to solvent (DMA), with no
further mass loss occurring until 460 °C. Fourier transform
infrared (FT-IR) analysis was also carried out as shown in
Figure S16.
From the above results, we found that assembly of the linear
BPDA ligand and Ca2+ gave rise to a nonporous structure. To
acquire a porous structure, a larger triangular TATB ligand,
instead of the BPDA ligand, was used to build a new Ca-based
MOF named PFC-37. However, the structure displayed poor
stability in water and cannot maintain permanent porosity
during N2 adsorption. On the basis of the above experimental
study and the guidance of Hard-Soft-Acid-Base theory, a
TCPA ligand, containing a −PO2 group that can strongly
coordinate with Ca2+, was selected to build a porous structure
of PFC-39. Unfortunately, PFC-39 still underwent decom-
position upon N2 adsorption. Considering that the TCPA
ligand has only two coordination sites on −PO2, a COOH-PO3
ligand containing three phosphonic coordination sites was
selected to get the PFC-41. As expected, we found that the
water stability has been significantly improved for PFC-41,
which can maintain crystallinity in water for at least 5 days.
determination, thermogravimetric analysis, and IR
spectra (PDF)
Accession Codes
CCDC 2003104−2003108 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
Xin-Song Huang − State Key Laboratory of Structural
Chemistry, Fujian Institute of Research on the Structure of
Matter, Chinese Academy of Sciences, Fuzhou 350002, People’s
Republic of China; Email: xshuang@fjirsm.ac.cn
Rong Cao − State Key Laboratory of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, People’s Republic of
China; School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, People’s Republic
of China; University of Chinese Academy of Sciences, Beijing
100049, People’s Republic of China; orcid.org/0000-0002-
2398-399X; Email: rcao@fjirsm.ac.cn
Authors
Jing Sun − State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, People’s Republic of
China; School of Physical Science and Technology,
ShanghaiTech University, Shanghai 201210, People’s Republic
of China
Tao Huang − State Key Laboratory of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, People’s Republic of
China
Qi Yin − State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, People’s Republic of
China
Lan Li − State Key Laboratory of Structural Chemistry, Fujian
Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, People’s Republic of
China; University of Chinese Academy of Sciences, Beijing
100049, People’s Republic of China; orcid.org/0000-0002-
7933-8869
4. CONCLUSION
In this work, we successfully synthesized a series of new Ca-
based MOFs based on various carboxylic/phosphinic/
phosphonic ligands and studied their crystal structures and
water stability. The obtained Ca-MOFs show diverse structures
with different coordination geometry and porosity. We further
disclosed that the stability of the Ca-based MOF can be
significantly improved by introducing a phosphonic acid group
in the ligand, which presents a universal method to tune the
hydrolytic stability of Ca-based MOFs. PFC-41 with much
improved stability was finally successfully obtained, which can
maintain the structural integrity in water for at least 5 days.
The work presented here provides useful information about
the hydrolysis stability of calcium MOFs, which would benefit
further studies on the design of biocompatible drug carriers for
biological and medical applications.
Tian-Fu Liu − State Key Laboratory of Structural Chemistry,
Fujian Institute of Research on the Structure of Matter, Chinese
Academy of Sciences, Fuzhou 350002, People’s Republic of
China; University of Chinese Academy of Sciences, Beijing
100049, People’s Republic of China; orcid.org/0000-0001-
9096-6981
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.0c01272
ASSOCIATED CONTENT
Notes
■
The authors declare no competing financial interest.
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.0c01272.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the financial support from the
National Key Research and Development Program of China
(grant no. 2018YFA0208600), National Natural Science
Material and instruments, crystallographic details, nitro-
gen and carbon dioxide isotherms, drug loading
E
https://dx.doi.org/10.1021/acs.cgd.0c01272
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
Different External Stimuli: A Way toward Smart Drug Delivery
System. Mol. Pharmaceutics 2015, 12, 3158−3166.
(18) Tan, L.-L.; Song, N.; Zhang, S. X.-A.; Li, H.; Wang, B.; Yang,
Y.-W. Ca2+, pH and thermo triple-responsive mechanized Zr-based
MOFs for on-command drug release in bone diseases. J. Mater. Chem.
B 2016, 4, 135−140.
(19) Wang, Z.; Tang, X.; Wang, X.; Yang, D.; Yang, C.; Lou, Y.;
Chen, J.; He, N. Near-infrared light-induced dissociation of zeolitic
imidazole framework-8 (ZIF-8) with encapsulated CuS nanoparticles
and their application as a therapeutic nanoplatform. Chem. Commun.
2016, 52, 12210−12213.
(20) Ke, F.; Yuan, Y.-P.; Qiu, L.-G.; Shen, Y.-H.; Xie, A.-J.; Zhu, J.-
F.; Tian, X.-Y.; Zhang, L.-D. Facile fabrication of magnetic metal-
organic framework nanocomposites for potential targeted drug
delivery. J. Mater. Chem. 2011, 21, 3843−3848.
(21) Parveen, S.; Misra, R.; Sahoo, S. K. Nanoparticles: a boon to
drug delivery, therapeutics, diagnostics and imaging. Nanomedicine
2012, 8, 147−166.
(22) Chen, Q.; Xu, M.; Zheng, W.; Xu, T.; Deng, H.; Liu, J. Se/Ru-
Decorated Porous Metal-Organic Framework Nanoparticles for The
Delivery of Pooled siRNAs to Reversing Multidrug Resistance in
Taxol-Resistant Breast Cancer Cells. ACS Appl. Mater. Interfaces 2017,
9, 6712−6724.
(23) Nazari, M.; Rubio-Martinez, M.; Tobias, G.; Barrio, J. P.;
Babarao, R.; Nazari, F.; Konstas, K.; Muir, B. W.; Collins, S. F.; Hill,
A. J.; Duke, M. C.; Hill, M. R. Metal-Organic-Framework-Coated
Optical Fibers as Light-Triggered Drug Delivery Vehicles. Adv. Funct.
Mater. 2016, 26, 3244−3249.
(24) Canivet, J.; Fateeva, A.; Guo, Y.; Coasne, B.; Farrusseng, D.
Water adsorption in MOFs: fundamentals and applications. Chem.
Soc. Rev. 2014, 43, 5594−5617.
(25) Hidalgo, T.; Cooper, L.; Gorman, M.; Lozano-Fernandez, T.;
Simon-Vazquez, R.; Mouchaham, G.; Marrot, J.; Guillou, N.; Serre,
C.; Fertey, P.; Gonzalez-Fernandez, A.; Devic, T.; Horcajada, P.
Crystal structure dependent in vitro antioxidant activity of
biocompatible calcium gallate MOFs. J. Mater. Chem. B 2017, 5,
2813−2822.
(26) Gao, M. L.; Qi, M. H.; Liu, L.; Han, Z. B. An exceptionally
stable core-shell MOF/COF bifunctional catalyst for a highly efficient
cascade deacetalization-Knoevenagel condensation reaction. Chem.
Commun. 2019, 55, 6377−6380.
(27) Sun, C. Y.; Qin, C.; Wang, X. L.; Su, Z. M. Metal-organic
frameworks as potential drug delivery systems. Expert Opin. Drug
Delivery 2013, 10, 89−101.
(28) Al Haydar, M.; Abid, H. R.; Sunderland, B.; Wang, S. Metal
organic frameworks as a drug delivery system for flurbiprofen. Drug
Des., Dev. Ther. 2017, 11, 2685−2695.
Foundation of China (grant nos. 21871267 and 2152-
0102001), and Strategic Priority Research Program of the
Chinese Academy of Sciences (grant no. XDB20000000).
REFERENCES
■
(1) Cheng, Y.; Wang, J.; Rao, T.; He, X.; Xu, T. Pharmaceutical
applications of dendrimers: promising nanocarriers for drug delivery.
Front. Biosci., Landmark Ed. 2008, 13, 1447−1471.
(2) Liu, R.; Li, D.; He, B.; Xu, X.; Sheng, M.; Lai, Y.; Wang, G.; Gu,
Z. Anti-tumor drug delivery of pH-sensitive poly(ethylene glycol)-
poly(L-histidine-)-poly(L-lactide) nanoparticles. J. Controlled Release
2011, 152, 49−56.
(3) Zhang, J.; Wang, L. Q.; Wang, H.; Tu, K. Micellization
phenomena of amphiphilic block copolymers based on methoxy
poly(ethylene glycol) and either crystalline or amorphous poly-
(caprolactone-b-lactide). Biomacromolecules 2006, 7, 2492−2500.
(4) Ferey, G.; Mellot-Draznieks, C.; Serre, C.; Millange, F.; Dutour,
J.; Surble, S.; Margiolaki, I. A chromium terephthalate-based solid
with unusually large pore volumes and surface area. Science 2005, 309,
2040−2042.
(5) Horcajada, P.; Serre, C.; Vallet-Regi, M.; Sebban, M.; Taulelle,
F.; Ferey, G. Metal-organic frameworks as efficient materials for drug
delivery. Angew. Chem., Int. Ed. 2006, 45, 5974−5978.
(6) Wu, M. X.; Yang, Y. W. Metal-Organic Framework (MOF)-
Based Drug/Cargo Delivery and Cancer Therapy. Adv. Mater. 2017,
29, 1606134−1606154.
(7) Horcajada, P.; Chalati, T.; Serre, C.; Gillet, B.; Sebrie, C.; Baati,
T.; Eubank, J. F.; Heurtaux, D.; Clayette, P.; Kreuz, C.; Chang, J.-S.;
́
Hwang, Y. K.; Marsaud, V.; Bories, P.-N.; Cynober, L.; Gil, S.; Ferey,
G.; Couvreur, P.; Gref, R. Porous metal−organic-framework nano-
scale carriers as a potential platform for drug delivery and imaging.
Nat. Mater. 2010, 9, 172−178.
(8) Huang, G.; Wang, Y.; Liu, T. A low-temperature synthesis-
induced defect formation strategy for stable hierarchical porous
metal−organic frameworks. Chin. Chem. Lett. 2019, 30, 2309−2312.
(9) Zhang, Y.; Wang, Y.; Liu, L.; Wei, N.; Gao, M. L.; Zhao, D.;
Han, Z. B. Robust Bifunctional Lanthanide Cluster Based Metal-
Organic Frameworks (MOFs) for Tandem Deacetalization-Knoeve-
nagel Reaction. Inorg. Chem. 2018, 57, 2193−2198.
(10) Li, L.; Yi, J.-D.; Fang, Z.-B.; Wang, X.-S.; Liu, N.; Chen, Y.-N.;
Liu, T.-F.; Cao, R. Creating Giant Secondary Building Layers via
Alkali-Etching Exfoliation for Precise Synthesis of Metal−Organic
Frameworks. Chem. Mater. 2019, 31, 7584−7589.
(11) Chen, W.; Wu, C. Synthesis, functionalization, and applications
of metal-organic frameworks in biomedicine. Dalton Trans. 2018, 47,
2114−2133.
(29) Miller, S. R.; Alvarez, E.; Fradcourt, L.; Devic, T.; Wuttke, S.;
Wheatley, P. S.; Steunou, N.; Bonhomme, C.; Gervais, C.; Laurencin,
D.; Morris, R. E.; Vimont, A.; Daturi, M.; Horcajada, P.; Serre, C. A
rare example of a porous Ca-MOF for the controlled release of
biologically active NO. Chem. Commun. 2013, 49, 7773−7775.
(30) Yang, X.; Hao, Y.; Cao, L. Bio-Compatible Ca-BDC/Polymer
Monolithic Composites Templated from Bio-Active Ca-BDC Co-
Stabilized CO2-in-Water High Internal Phase Emulsions. Polymers
2020, 12, 931−953.
(31) George, P.; Das, R. K.; Chowdhury, P. Facile microwave
synthesis of Ca-BDC metal organic framework for adsorption and
controlled release of Curcumin. Microporous Mesoporous Mater. 2019,
281, 161−171.
(32) Yang, J.; Trickett, C. A.; Alahmadi, S. B.; Alshammari, A. S.;
Yaghi, O. M. Calcium L-Lactate Frameworks as Naturally Degradable
Carriers for Pesticides. J. Am. Chem. Soc. 2017, 139, 8118−8121.
(33) Shi, F. N.; Almeida, J. C.; Helguero, L. A.; Fernandes, M. H. V.;
Knowles, J. C.; Rocha, J. Calcium Phosphonate Frameworks for
Treating Bone Tissue Disorders. Inorg. Chem. 2015, 54, 9929−9935.
(34) Kojima, D.; Sanada, T.; Wada, N.; Kojima, K. Synthesis,
structure, and fluorescence properties of a calcium-based metal-
organic framework. RSC Adv. 2018, 8, 31588−31593.
(12) He, C.; Lu, K.; Liu, D.; Lin, W. Nanoscale metal-organic
frameworks for the co-delivery of cisplatin and pooled siRNAs to
enhance therapeutic efficacy in drug-resistant ovarian cancer cells. J.
Am. Chem. Soc. 2014, 136, 5181−5184.
(13) McKinlay, A. C.; Morris, R. E.; Horcajada, P.; Ferey, G.; Gref,
R.; Couvreur, P.; Serre, C. BioMOFs: Metal-Organic Frameworks for
Biological and Medical Applications. Angew. Chem., Int. Ed. 2010, 49,
6260−6266.
(14) An, J.; Geib, S. J.; Rosi, N. L. Cation-Triggered Drug Release
from a Porous Zinc-Adeninate Metal-Organic Framework. J. Am.
Chem. Soc. 2009, 131, 8376−8377.
(15) Yang, Y.; Hu, Q.; Zhang, Q.; Jiang, K.; Lin, W.; Yang, Y.; Cui,
Y.; Qian, G. A Large Capacity Cationic Metal-Organic Framework
Nanocarrier for Physiological pH Responsive Drug Delivery. Mol.
Pharmaceutics 2016, 13, 2782−2786.
(16) Sun, C.-Y.; Qin, C.; Wang, C.-G.; Su, Z.-M.; Wang, S.; Wang,
X.-L.; Yang, G.-S.; Shao, K.-Z.; Lan, Y.-Q.; Wang, E.-B. Chiral
Nanoporous Metal-Organic Frameworks with High Porosity as
Materials for Drug Delivery. Adv. Mater. 2011, 23, 5629−5632.
(17) Adhikari, C.; Das, A.; Chakraborty, A. Zeolitic Imidazole
Framework (ZIF) Nanospheres for Easy Encapsulation and
Controlled Release of an Anticancer Drug Doxorubicin under
F
https://dx.doi.org/10.1021/acs.cgd.0c01272
Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design
pubs.acs.org/crystal
Article
(35) Mazaj, M.; Zabukovec Logar, N. Phase Formation Study of Ca-
Terephthalate MOF-Type Materials. Cryst. Growth Des. 2015, 15,
617−624.
(36) Li, L.; Guo, L.; Pu, S.; Wang, J.; Yang, Q.; Zhang, Z.; Yang, Y.;
Ren, Q.; Alnemrat, S.; Bao, Z. A calcium-based microporous metal-
organic framework for efficient adsorption separation of light
hydrocarbons. Chem. Eng. J. 2019, 358, 446−455.
(37) Sun, S.; Henke, S.; Wharmby, M. T.; Yeung, H. H.; Li, W.;
Cheetham, A. K. Mechanical Properties of a Calcium Dietary
Supplement, Calcium Fumarate Trihydrate. Inorg. Chem. 2015, 54,
11186−11192.
(38) Darkhijav, B.; Suo, Q.-L.; Gao, Y.-Y.; Hai, E.-H.; Xie, R.-J.; Zhu,
N.; Han, L.-M. Synthesis and Crystal Structure of a Novel Ca(II)
Coordination Polymer Containing Dipyridine Dicarboxylic Ligand.
Chin. J. Struct. Chem. 2014, 33, 585−590.
(39) Wang, X.; San, L. K.; Nguyen, H.; Shafer, N. M.; Hernandez,
M. T.; Chen, Z. Alkaline earth metal-organic frameworks supported
by ditopic carboxylates. J. Coord. Chem. 2013, 66, 826−835.
(40) Liang, P.-C.; Liu, H.-K.; Yeh, C.-T.; Lin, C.-H.; Zima, V. t. z.
Supramolecular Assembly of Calcium Metal−Organic Frameworks
with Structural Transformations. Cryst. Growth Des. 2011, 11, 699−
708.
(41) Alavijeh, R. K.; Akhbari, K.; White, J. Solid-Liquid Conversion
and Carbon Dioxide Storage in a Calcium-Based Metal-Organic
Framework with Micro- and Nanoporous Channels. Cryst. Growth
Des. 2019, 19, 7290−7297.
(52) Tholen, P.; Zorlu, Y.; Beckmann, J.; Yucesan, G. Probing
Isoreticular Expansions in Phosphonate MOFs and their Applications.
Eur. J. Inorg. Chem. 2020, 2020, 1542−1554.
(53) Siemensmeyer, K.; Peeples, C. A.; Tholen, P.; Schmitt, F. J.;
Cosut, B.; Hanna, G.; Yucesan, G. Phosphonate Metal-Organic
Frameworks: A Novel Family of Semiconductors. Adv. Mater. 2020,
32, 2000474−2000481.
(54) Alvarez, E.; Marquez, A. G.; Devic, T.; Steunou, N.; Serre, C.;
Bonhomme, C.; Gervais, C.; Izquierdo-Barba, I.; Vallet-Regi, M.;
Laurencin, D.; Mauri, F.; Horcajada, P. A biocompatible calcium
bisphosphonate coordination polymer: towards a metal-linker
synergistic therapeutic effect? CrystEngComm 2013, 15, 9899−9905.
(55) Kruger, M.; Reinsch, H.; Inge, A. K.; Stock, N. Effect of partial
̈
linker fluorination and linker extension on structure and properties of
the Al-MOF CAU-10. Microporous Mesoporous Mater. 2017, 249,
128−136.
(56) Li, L.; Wang, X. S.; Liang, J.; Huang, Y. B.; Li, H. F.; Lin, Z. J.;
Cao, R. Water-Stable Anionic Metal-Organic Framework for Highly
Selective Separation of Methane from Natural Gas and Pyrolysis Gas.
ACS Appl. Mater. Interfaces 2016, 8, 9777−9781.
(57) Marri, S. R.; Chauhan, N.; Tiwari, R. K.; Kumar, J.; Behera, J.
N. Two novel 3D-MOFs (Ca-TATB and Co-HKUST): Synthesis,
structure and characterization. Inorg. Chim. Acta 2018, 478, 8−14.
(58) Desiraju, G. R.; Steiner, T. The Weak Hydrogen Bond in
Structural Chemistry and Biology; Oxford University Press, 1999.
(59) Horcajada, P.; Chalati, T.; Serre, C.; Gillet, B.; Sebrie, C.; Baati,
T.; Eubank, J. F.; Heurtaux, D.; Clayette, P.; Kreuz, C.; Chang, J. S.;
Hwang, Y. K.; Marsaud, V.; Bories, P. N.; Cynober, L.; Gil, S.; Ferey,
G.; Couvreur, P.; Gref, R. Porous metal-organic-framework nanoscale
carriers as a potential platform for drug delivery and imaging. Nat.
Mater. 2010, 9, 172−178.
(42) Li, L.; Guo, L.; Zheng, F.; Zhang, Z.; Yang, Q.; Yang, Y.; Ren,
Q.; Bao, Z. Calcium-Based Metal-Organic Framework for Simulta-
neous Capture of Trace Propyne and Propadiene from Propylene.
ACS Appl. Mater. Interfaces 2020, 12, 17147−17154.
(43) Bazaga-Garcia, M.; Colodrero, R. M. P.; Papadaki, M.;
Garczarek, P.; Zon, J.; Olivera-Pastor, P.; Losilla, E. R.; Leon-Reina,
L.; Aranda, M. A. G.; Choquesillo-Lazarte, D.; Demadis, K. D.;
Cabeza, A. Guest Molecule-Responsive Functional Calcium Phos-
phonate Frameworks for Tuned Proton Conductivity. J. Am. Chem.
Soc. 2014, 136, 5731−5739.
(44) Sun, Y.; Sun, Y.; Zheng, H.; Wang, H.; Han, Y.; Yang, Y.; Wang,
L. Four calcium(II) coordination polymers based on 2,5-dibromoter-
ephthalic acid and different N-donor organic species: syntheses,
structures, topologies, and luminescence properties. CrystEngComm
2016, 18, 8664−8671.
(45) Kim, M. K.; Bae, K.-L.; Ok, K. M. From Pincers to Steps:
Synthesis, Structure, Characterization, and Transformation of a New
Helical Calcium-Organic Framework, CaNC5H3(CO2)2(H2O)1.5
.
Cryst. Growth Des. 2011, 11, 930−932.
(46) Zhang, J.-C.; Wang, J.-J.; Zeng, S.-L.; Wang, Z.-M.; Liu, Y.;
Zhang, D.-J.; Zhang, R.-C.; Fan, Y. Syntheses, characterization, and
luminescent properties of Ca-based metal-organic frameworks based
on 1, 4-naphthalene dicarboxylate. Inorg. Chem. Commun. 2018, 97,
69−73.
(47) Hynek, J.; Brazda, P.; Rohlicek, J.; Londesborough, M. G. S.;
Demel, J. Phosphinic Acid Based Linkers: New Building Block in
MOF Chemistry. Angew. Chem., Int. Ed. 2018, 57, 5016−5019.
(48) Shearan, S. J. I.; Stock, N.; Emmerling, F.; Demel, J.; Wright, P.
A.; Demadis, K. D.; Vassaki, M.; Costantino, F.; Vivani, R.; Sallard, S.;
Ruiz Salcedo, I.; Cabeza, A.; Taddei, M. New Directions in Metal
Phosphonate and Phosphinate Chemistry. Crystals 2019, 9, 270−306.
̈
(49) Yucesan, G.; Zorlu, Y.; Stricker, M.; Beckmann, J. Metal-
organic solids derived from arylphosphonic acids. Coord. Chem. Rev.
2018, 369, 105−122.
(50) Maares, M.; Ayhan, M. M.; Yu, K. B.; Yazaydin, A. O.;
Harmandar, K.; Haase, H.; Beckmann, J.; Zorlu, Y.; Yucesan, G. Alkali
Phosphonate Metal-Organic Frameworks. Chem. - Eur. J. 2019, 25,
11214−11217.
(51) Bao, S.-S.; Shimizu, G. K. H.; Zheng, L.-M. Proton conductive
metal phosphonate frameworks. Coord. Chem. Rev. 2019, 378, 577−
594.
G
https://dx.doi.org/10.1021/acs.cgd.0c01272
Cryst. Growth Des. XXXX, XXX, XXX−XXX