Boosting the Catalytic Performance of Metal–Organic Frameworks for Steroid Transformations by Confinement within a Mesoporous Scaffold

Article abstract of DOI:10.1002/anie.201706721

Solid-state crystallization achieves selective confinement of metal–organic framework (MOF) nanocrystals within mesoporous materials, thereby rendering active sites more accessible compared to the bulk-MOF and enhancing the chemical and mechanical stability of MOF nanocrystals. (Zr)UiO-66(NH₂)/SiO₂ hybrid materials were tested as efficient and reusable heterogeneous catalysts for the synthesis of steroid derivatives, outperforming the bulk (Zr)UiO-66(NH₂) MOF. A clear correlation between the catalytic activity of the dispersed Zr sites present in the confined MOF, and the loading of the mesoporous SiO₂, is demonstrated for steroid transformations.

Full text of DOI:10.1002/anie.201706721

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Accepted Article
Title: Boosting catalytic performance of MOFs for steroid
transformations by confinement within mesoporous scaffolds
Authors: Francisco G Cirujano, Ignacio Luz, Mustapha Soukri, Cedric
Van Goethem, Ivo Vankelecom, Marty Lail, and Dirk E. De
Vos
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706721
Angew. Chem. 10.1002/ange.201706721
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10.1002/anie.201706721
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Boosting catalytic performance of MOFs for steroid
transformations by confinement within mesoporous scaffolds
[b]
Francisco G. Cirujano*¥ [a], Ignacio Luz¥ [b], Mustapha Soukri* , Cedric Van Goethem [a], Ivo F.J.
Vankelecom [a], Marty Lail [b] and Dirk E. De Vos* [a]
Abstract: Selective confinement of MOF nanocrystals within
mesoporous materials via novel ‘solid state’ crystallization provides
more accessible active sites compared to the bulk MOF counterpart,
enhancing chemical and mechanical stability of MOF nanocrystals.
(Zr)UiO-66(NH2)/SiO2 hybrid materials were tested as efficient and
reusable heterogeneous catalysts for the synthesis of steroid
derivatives, outperforming the bulk (Zr)UiO-66(NH2) MOF. A clear
correlation between catalytic activity of the dispersed Zr sites
present in the confined MOF and the loading of the mesoporous
SiO2 is demonstrated for steroid transformations.
In order to demonstrate these advantages, zirconium
containing MOF nanocrystals have been confined within
mesoporous silica materials. The composite hybrid materials are
employed as active, selective and stable heterogeneous
catalysts for the conversion of large molecules exhibiting low
diffusion coefficients, such as testosterone and epiandrosterone
(see Scheme 1, for recently reported examples).[4] The steroidal
analogues obtained show diverse pharmacological applications
due to their effects on sex hormones, immune response, cell
proliferation and because of their neuroactive properties. Given
the bifunctional nature of the testosterone substrate, both the
esterification of the hydroxyl group at C17 and the selective
reduction of the carbonyl group present at C3 are two important
transformations leading to pharmacologically active testosterone
derivatives.[5] Common to these reactions is the use of Lewis
acid sites for the activation of carbonyl groups in the reactants,
improving the yields of the desired products.[6-8] However,
homogeneously catalyzed transformations of testosterone also
produce dehydration by-products, form soaps which consume
the organic acid reactant and the reuse of the catalyst is not
possible.[9a-d] In this sense, heterogeneous catalysts have been
reported for a few steroid transformations, with the esterification
as the most widely described reaction.[10] These heterogeneous
catalysts are typically active, stable and easily recovered but
their lower selectivity, high temperatures of operation and the
formation of side-products are important drawbacks.
Porous crystalline metal-organic frameworks (MOFs)
composed of inorganic secondary building units (SBUs)
interlinked by organic polytopic ligands have been extensively
explored during the last decade as promising heterogeneous
catalysts.[1] Defective sites in the crystal are considered the
active sites in ‘non-post-modified’ MOF catalysts. Several
synthetic strategies have been recently developed to enhance
the generation of such defect sites in MOFs during their
crystallization.[2] Nevertheless, the concentration of defect sites
incorporated in those materials is usually inherently limited since
the framework stability directly depends on the coordination
number of the SBUs. Therefore, new directions must be
explored to achieve a fair compromise between activity and
stability of MOF catalysts.
In this sense, the selective growth of MOF nanocrystals
within mesoporous materials (MPMs) via novel ‘solid-state’
crystallization allows for an outstanding loading of the
mesoporous cavities with very small MOF nanocrystals.[3] This
approach addresses key challenges that MOFs are experiencing
as heterogeneous catalysts. On the one hand, the concentration
of coordination vacancies at the outer crystal surface is
maximized by reducing the MOF crystalline domain down to a
few nanometers via confinement within the mesoporous scaffold,
without decreasing their inherent activity. On the other hand, the
matrix protects and confers additional stability, as well as
handling, to the highly active MOF nanocrystals used as
catalysts.
[a]
[b]
[¥]
Dr. F. G. Cirujano, C. Van Goethem, Prof. I.F.J. Vankelecom, Prof.
D. E. De Vos
Centre for Surface Chemistry and Catalysis
KU Leuven Celestijnenlaan 200F, 3001 Leuven (Belgium)
E-mail: francisco.garcia@kuleuven.be; dirk.devos@kuleuven.be
Dr. I. Luz, Dr. M. Soukri, Dr. M. Lail
RTI International
Research Triangle Park, NC 27709-2194 (USA)
E-mail: msoukri@rti.org
Scheme 1. Transformations of testosterone (1st and 2nd) and epiandrosterone
(3rd and 4th) steroids involving the activation of carbonyl groups, together with
the particular stoichiometric[9a],[9k] or catalytic conditions[8b],[9g] employed.
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end
of the document
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The design of highly active, reusable and selective
heterogeneous catalysts is crucial to perform these
transformations under mild and clean conditions, inspired by the
catalytic efficiency of natural enzymes.[11] Here we focus our
attention on hexanuclear Zr(IV) oxoclusters as catalytically
active sites due to their relatively low price and minimum toxicity,
especially when immobilized in a solid support.[12] Thus, (Zr)UiO-
66(NH2) was selected to be grown within the ordered
monodimensional channels of SBA-15 based on the already
reported reaction rate enhancement when using this MOF as
acid-base catalyst.[2b],[13] This is due to the fact that its linker
content is generally lower than that expected for the ideal
stoichiometric MOF (missing linker defects), generating
hydrophilic Zr defect sites with acid character in addition to the
Zr4+-O2- acid-base pairs present in the (Zr)UiO-66(NH2).[7a-f]
The broad XRD peak around 2θ ~7-8º of the resulting
(Zr)UiO-66(NH2)/SBA-15 seems to indicate the presence of UiO
type MOF nanocrystals in the SBA-15 matrix, although it is
difficult to discern the two characteristic peaks of UiO-66 due to
the small size of the crystals (see Figure S1). When the MOF
synthesis was performed under the same conditions but in the
absence of the SBA-15 matrix, slightly larger (15-20 nm,
according to the Scherrer equation) UiO-66-NH2 nanocrystals
were obtained. This supports that the MOF is formed under the
mild conditions proposed here for the (Zr)UiO-66(NH2)/SBA-15
hybrid catalysts (see Figure S2a). TEM images show the
selective loading of the SBA-15 monodimensional channels
(9 nm) with (Zr)UiO-66(NH2) (~5 nm), although a smaller fraction
of MOF crystals (~5-20 nm) were also observed outside the
channels when increasing the MOF loading (see Figures 1a and
S3). In fact, the lower contrast between the brighter channels
and darker walls of SBA-15 and the presence of Zr, N and C
obtained by EDX evidences the MOF formation in the channels
of the SBA-15. Elemental analysis of the (Zr)UiO-66(NH2)/SBA-
15 samples are in agreement with the Zr:N ratio found in
defective (Zr)UiO-66(NH2) samples (see Table S2).[2b]
Figure 1. TEM images (a), FTIR spectra (b), N2 physisorption (c) and EDX
mapping (scale bar = 50 nm) (d), indicating the filling of the SBA-15 channels
with (Zr)UiO-66(NH2).
Other characterization techniques were used to provide
additional evidences of the formation of the MOF within the
mesoporous scaffold. First, the UV-Vis spectra of the (Zr)UiO-
66(NH2)/SBA-15 show the two main peaks around 265 and 365
nm, attributed to the absorption of Zr−O clusters and ligand-
based absorption in this MOF (Figure S4).[13c-d] Second, the
MOF decomposition temperature is similar for both the MOF and
the hybrid material (see TGA in Figure S9). In addition, the FTIR
spectra of the (Zr)UiO-66(NH2)/SBA-15 completely match with
several of the characteristic bands of the (Zr)UiO-66(NH2), such
as the medium N-H bending vibration at 1626 cm-1 and the
strong C-N stretching absorption indicative for aromatic amines
at 1356 cm-1 (Figure 1b).13b Furthermore, N2 physisorption also
indicates the pore filling of the mesoporous SBA-15 channels
since increasing MOF loading leads to a proportional drop in
mesoporosity and pore size but not in microporosity (Figures 1c
S6). Finally, STEM-HAADF confirms the homogeneous
distribution of the MOF within the SBA-15 (Figure 1d). The EDX
analysis qualitatively shows the uniform dispersion of Zr in the
siliceous matrix and moreover quantitatively determines a Zr:Si
ratio of 0.19, which fairly coincides with the Zr:Si ratio of 0.16
determined by XRF.
were tested as catalysts in the testosterone esterification to
produce the testosterone caprylate 1 derivative. For comparison,
the catalyst weight of all the materials was adjusted to use the
same Zr concentration for all the reactions. The highest catalytic
activity in the esterification of testosterone is obtained with the
hybrid material containing the lowest amount of MOF (6.6 wt.%),
with complete conversion to the desired ester 1 after 48 h
(Figures 2 and S12). The advantage of using the mesoporous
silica component is confirmed by the higher TOF obtained with
the hybrid material (0.38 h-1) with respect to those obtained with
the similar MOF sample in the absence of SBA-15, following the
method proposed here (0.19 h-1) or by solvothermal reaction in
DMF (0.16 h-1). In fact, the reaction rate was increased up to
140% by using the catalyst containing 6.6 wt.% of MOF
compared to the one containing 18.6 wt.%, and the rate was
almost 230% higher than with the bulk MOF (see TOF values in
Figure 2, right part).[14] These results demonstrate that Zr
catalytic sites in the well-dispersed MOF nanocrystals confined
within the mesoporous matrix are more active than those
present in the microporous bulk MOF because the latter are less
available to interact with bulky reactants such as testosterone.
The (Zr)UiO-66(NH2)/SBA-15 solids at varying MOF loadings
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wt.% MOF/SBA-15, bulk MOF and Zr-Beta, respectively. The
increased testosterone concentration at the active sites of the
MOF/SBA-15 hybrid solid makes those sites more available to
interact with the bulky testosterone reactant,[1g] enhancing its
catalytic activity with respect to the bulk MOF in the absence of
the mesoporous silica component.
To compare with a traditional ZrO2-SBA-15 material, ZrO2
nanocrystals confined within SBA-15 were obtained by calcining
the 6.6 wt.% (Zr)UiO-66(NH2)/SBA-15 to maintain the same
concentration and dispersion. Remarkably, hexanuclear Zr
oxoclusters located at the nodes of MOF nanocrystals exhibit a
much better performance than the metal oxide nanocrystals
resulting from calcination (TOFs of 0.38 h-1 vs 0.15 h-1,
respectively), demonstrating the advantage of using MOF hybrid
materials as heterogeneous catalysts instead of traditional
supported metal oxide nanoparticles for this specific reaction of
high pharmaceutical interest (Figure S12). Moreover, when the
aim is the large-scale development of MOF/SiO2 hybrid catalysts,
the use of commercially available non-regular mesoporous silica
(Silica(A)) exhibit excellent characteristics to meet some of the
basic requirements for large scale industrial application, meeting
the DOE’s target price of 10 $/Kg MOF.[3],[15] In this way,
comparable catalytic activity was measured for 10.2 wt.% MOF
nanocrystals on Silica(A) with respect to that of 13.2 wt.% MOF
on SBA-15 (0.33 h-1 vs 0.35 h-1, see table S3). Therefore,
although this study mainly focuses on SBA-15 matrix, these
results encourage further research in the use of alternative silica
(or other matrices) to grow catalytically active MOF
nanoparticles. In fact, the 10.2 wt.% (Zr)UiO-66(NH2)/Silica(A)
has been used as a stable and active catalytic packing for the
esterification of octanoic acid with n-heptanol operating in
continuous mode (Figure S26).
Figure 2. Testosterone esterification with caprylic acid catalyzed by (Zr)UiO-
66(NH2)/SBA containing varying MOF loadings (6.6, 13.2 and 18.6 wt.%)
compared to bare SBA-15 and bulk MOF (100 wt.%). Yields of testosterone
caprylate obtained by esterification of testosterone (left) and TOF values
calculated for all the catalysts employed (right). Reaction conditions: 75 ºC, 5
wt.% Zr with respect to testosterone, testosterone:caprylic acid molar ratio
1:20
It is noteworthy that the catalytic activity of the 6.6 wt.%
(Zr)UiO-66(NH2)/SBA-15 is practically the same after a second
reaction cycle (92% yield), although some gradual decay is
observed in subsequent runs (77% yield after seven reaction
cycles). Less than 1% leaching of Zr from the solid catalyst was
detected by ICP analysis of the liquid reaction medium after 24 h.
Moreover, a hot filtration test of the solid catalyst slows down the
reaction to a similar rate as the blank (autocatalytic) reaction,
showing conversions similar to those measured for the blank
reaction, thus demonstrating that the catalytic process is
heterogeneous (Figure S13).
The benefits of using the (Zr)UiO-66(NH2)/SBA-15 hybrid
composite as catalyst with respect to bulk microporous inorganic
or metal-organic solids are clear when large substrates such as
testosterone are involved. To prove this, the esterification of a
smaller substrate, such as 4-methylcyclohexanol, with octanoic
acid was carried out by using the same reaction conditions and
in the presence of 6.6 wt.% (Zr)UiO-66(NH2)/SBA-15, bulk MOF
and Zr-Beta zeolite, which exhibit similar pore dimensions as the
MOF (6-7 Å). The ratio between the rate constant for
esterification of testosterone and 4-methylcyclohexanol (Ø =
ktestosterone/kcyclohexanol) reveals a drop in the esterification rate for
bulky substrates when the reaction is catalyzed by microporous
catalysts, that is, bulk MOF (Ø = 0.6) and Zr-Beta (Ø = 0.2),
compared to the hybrid material (Ø = 1.2), which exhibits the
same or even a slightly higher catalytic activity for the bulky
substrate, as shown in Figure S15 and Table S4. These ratios
quantitatively demonstrate that the esterification of testosterone
is catalyzed by those sites located at the outer surface of the
cystal, which activity is notably boosted when the MOF is growth
within SBA-15. Adsorption of testosterone was performed on all
of the porous catalysts included in this work (see supporting
information), resulting in 67 wt.%, 57 wt.%, 32 wt.% and 8 wt.%
of testosterone uptakes for the same mass of SBA-15, 18.6
At this point, we also wanted to extend the scope of steroid
transformations to further confirm the enhanced catalytic
performance for the (Zr)UiO-66(NH2)/SiO2 hybrid catalysts with
respect to the bulk MOF. A resume of this scope is shown in
Figure 3 and Scheme S1. As demonstrated for testosterone
esterification, superior catalytic performance and good stability
were found for MOF hybrids in all cases (see details in Figures
S16-S25). Hence, we also carried out the selective reduction of
testosterone into androst-4-ene-3,17-diol 2. The most widely
Figure 3. Resume of the catalytic performance, yield and (TOF) for the bulk
MOF compared to 6.6 wt.% (Zr)UiO-66(NH2)/SBA-15 in the synthesis of 1, 2, 3
and 4.The reactions were carried out at 75 °C during 48 h for 1 and 24 h for 3
and 4, while the synthesis of 2 was performed at room temperature for 0.75 h.
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10.1002/anie.201706721
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temperature. Afterwards, a metal salt precursor solution of ZrOCl2·8H2O
in water was used to impregnate the [H2BDC(NH2)/SBA-15] mesoporous
silica. The [ZrOCl2/H2BDC(NH2)/SBA-15] solid was finally dried at 50 °C
under vacuum in a rotavapor for 2 h and heated in an oven at 120 °C for
2 h. Finally it was washed with water and MeOH and dried overnight at
120 ºC under vacuum (see supporting information for details).
applied procedure is based on the use of NaBH4 as reducing
agent in the presence of stoichiometric amounts of Lewis acid,
as in the Luche reduction conditions, to obtain a high selectivity
for the allylic alcohol rather than for the saturated ketone or
alcohol.[9c-d,16] Herein we substitute the use of homogeneous
catalysts by our heterogeneous hybrid catalysts, employing for
the first time Zr as a Lewis acid in catalytic amounts (only 5 wt.%
of Zr with respect to testosterone) for this particular reaction.
Use of 6.6 wt.% (Zr)UiO-66(NH2)/SBA-15 catalysts leads to the
desired androst-4-ene-3,17-diol in quantitative yield and
excellent chemoselectivity (95%) after just one hour of reaction
at room temperature (see Figure S16 and Table S6).
Beside esterification and NaBH4 reduction of testosterone,
we explored the hydrogen transfer and aldol condensation
reactions using epiandrosterone (5α-androstan-3β-ol-17-one) as
a substrate. Different promotors or catalysts have been used to
successfully carry out these two transformations (3rd and 4th
transformations in Scheme S1).[8,9g-l] On the one hand, using the
6.6 wt.% MOF loaded SBA-15, the catalytic hydrogen transfer
from isopropanol to the carbonyl group of epiandrosterone
produces the androstanediol 3 in 70% yield after 24 h (Figure
S21) while only 45% was measured for bulk MOF. On the other
hand, we tested the activity of the hybrid MOF/MPM in the
Catalytic tests for steroid transformations
The specific amount of catalyst was added to a vial containing the
reactants and n-tetradecane as the internal standard (see supporting
information for details of each specific reaction). The suspension was
stirred at the required temperature and sample aliquots were taken from
the supernatant at different reaction times. The supernatant solution was
analyzed with GC-FID.
Acknowledgements
Marie-Curie Individual Fellowship (MSCA-IF 750391-SINMOF)
program, Flemish government (Methusalem CASAS2), FWO,
Belspo (IAP-PAI 7/05) and Flemish Agency for Innovation
through Science and Technology (IWT) are acknowledged for
financial support. Funding for the TEM through Hercules project
AKUL/13/19 is kindly acknowledged.
synthesis of 16-(E)-benzylidene-androsterone
4
by aldol
condensation with benzaldehyde, which is an intermediate in the
synthesis of (spiro) heterocyclic steroids (see Scheme S3). In
fact, the alteration of the chemical and biological properties of
epiandrosterone by insertion of carbon atoms makes compound
4 a versatile intermediate or even a final product in the synthesis
of novel anticancer drugs.[9h-l] Thus, using the 6.6 wt.% loaded
catalyst, the aldol condensation between epiandrosterone and
benzaldehyde produces 83% yield of 4 with respect to the 41%
obtained in the presence of the bulk MOF after 24 h (Figure
S23). The hybrid material also preserves the major part of its
activity in further reuses, obtaining 73% yield of 4 after five
reaction runs (Figure S24)
In conclusion, we have demonstrated the superior catalytic
performance of the MOF/MPM materials with respect to bulk
microporous solids for the transformation of steroids, generating
pharmaceutically interesting compounds. The use of such novel
heterogeneous catalysts containing catalytically active MOF
nanocrystals on mesoporous supports, will encourage the
adoption of this approach for other applications. The increased
catalytic activity and mechanical stability of this hybrid MOF
nanocatalysts confined in the mesoporous scaffolds allows for
multiple reuse of the catalyst without significant leaching of the
active sites in batch and in continuous mode, important for its
commercial use in industrial processes.
Keywords: mesoporous silica • nanoMOF • steroid chemistry •
active site confinement • MOF composite
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Experimental Section
[5]
Procedure for solid state crystallization of (Zr)UiO-66(NH2) within
SBA-15
First, a ligand salt precursor solution (TEA)2BDC(NH2) was used to
impregnate the evacuated SBA-15. After drying at 50 °C under vacuum
for 2 h, the resulting [(TEA)2BDC(NH2)/SBA-15] was treated with a
nitrogen flow saturated with concentrated HCl (37%) for 2 hours at room
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10.1002/anie.201706721
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Layout 1: MOF/SBA-15 for the synthesis of bioactive steroid derivatives
COMMUNICATION
Confined Zr-MOF
nanocrystals
Author(s),
Corresponding
Author(s)*
enhances the
catalytic activity
and stability of
bulk MOF for
different
Page No. – Page
No.
Title
transformations of
bulky steroids
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