Calcium carbonate as heterogeneous support for recyclable organocatalysts

Article abstract of DOI:10.1016/j.jcat.2020.11.013

The controlled synthesis of calcium carbonate particles surface-functionalized with azido groups and its subsequent copper-catalyzed alkyne-azide cycloaddition (CuAAC) reactions with organocatalysts bearing alkyne anchors allowed the preparation of novel catalytic materials. A calcium carbonate-supported α,α-diarylprolinol silyl ether prepared in this manner catalyzes Michael addition of aldehydes to trans-β-nitrostyrenes with very high diastereo- and enantioselectivity. The immobilized catalyst can be recovered by simple decantation and reused. In addition, this heterogeneous catalytic system can also be adapted to continuous-flow operation, affording a five-fold productivity increase in comparison with the batch process.

Full text of DOI:10.1016/j.jcat.2020.11.013

Journal Pre-proofs
Calcium Carbonate as Heterogeneous Support for Recyclable Organocatalysts
Carlos Lizandara-Pueyo, Xinyuan Fan, Carles Ayats, Miquel A. Pericàs
PII:
S0021-9517(20)30459-0
https://doi.org/10.1016/j.jcat.2020.11.013
YJCAT 13972
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Journal of Catalysis
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Revised Date:
Accepted Date:
3 October 2020
11 November 2020
12 November 2020
Please cite this article as: C. Lizandara-Pueyo, X. Fan, C. Ayats, M.A. Pericàs, Calcium Carbonate as
Heterogeneous Support for Recyclable Organocatalysts, Journal of Catalysis (2020), doi: https://doi.org/10.1016/
j.jcat.2020.11.013
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Calcium Carbonate as Heterogeneous Support for Recyclable
Organocatalysts
Carlos Lizandara-Pueyo,a,b,* Xinyuan Fan,a,c,f,* Carles Ayats,a,d Miquel A. Pericàs,a,e
a Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of
Science and Technology, Avda. Països Catalans 16, E-43007 Tarragona, Spain.
b BASF SE, Carl-Bosch-Strasse 38, 67056 Ludwigshafen am Rhein, Germany
c Beijing National Laboratory for Molecular Sciences, Synthetic and Functional
Biomolecules Center, Department of Chemical Biology, College of Chemistry and
Molecular Engineering, Peking University, Beijing 100871, China.
d Leitat Technological Center, Carrer de la Innovació 2, 08225 Terrassa, Spain
e Departament de Química Inorgànica i Orgànica, Universitat de Barcelona (UB),
08028 Barcelona, Spain
f State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, 201203 Shanghai, China
KEYWORDS
Solid-supported catalysis, calcium carbonate, surface functionalization, click
chemistry, asymmetric catalysis, catalyst recycling, continuous flow processes.
ABSTRACT
The controlled synthesis of calcium carbonate particles surface-functionalized
with azido groups and its subsequent copper-catalyzed alkyne-azide cycloaddition
(CuAAC) reactions with organocatalysts bearing alkyne anchors allowed the
preparation of novel catalytic materials. A calcium carbonate-supported  -
diarylprolinol silyl ether prepared in this manner catalyzes Michael addition of
aldehydes to trans--nitrostyrenes with very high diastereo- and enantioselectivity.
The immobilized catalyst can be recovered by simple decantation and reused. In
addition, this heterogeneous catalytic system can also be adapted to continuous-flow
operation, affording a five-fold productivity increase in comparison with the batch
process.
1. INTRODUCTION
Asymmetric catalysts have progressively gained a central role in the sustainable
1

production of chiral non-racemic substances [1-3]. Among them, organocatalysts are
especially interesting due to their relatively low prices, moisture tolerance, readily
availability, easy fine-tuning and easy handling. Organocatalysts, however, often
possess similar polarity and solubility behaviors than the molecules they help to
produce, and this translate into solvent, time and energy consuming chromatographic
separations for product purification. To solve this problem, the heterogenization of
homogeneous catalysts onto solid supports has evolved into a prevalent strategy.
Noteworthy, this brings an additional advantage: immobilized not only facilitate
catalyst/product separation, but also allow catalyst recycling and reuse by simple
filtration or magnetic decantation [4-6]. As a further advantage, heterogeneous
organocatalysts have been also proven effective in continuous-flow mode, thus
allowing the integration of reaction and separation into a single operation with
important process intensification [7-41].
The heterogenization of homogeneous organocatalysts has been performed onto
supports of different nature, such as inorganic materials, organic polymers of different
natures and magnetic nanoparticles. Primarily, materials where the degree of
functionalization at the particle surface can be easily adjusted are highly attractive as
solid supports, since a high density of active sites can be achieved. According to that,
relatively low-cost organic and inorganic materials, such as polystyrene (PS) [8-10, 18, 23-
30] and silica (SiO2) [42-44], have been highlighted as excellent solid supports enabling
reusability and operation in flow. Another option for supporting organocatalysts are
magnetic nanomaterials [45]. Solid supports of this class, with sizes of approx. 5 nm
have also received much attention as solid supports due to the high surface areas and
the possibility of simple removal from the reaction mixture by magnetic decantation
[
46-52]. Other solid supports like graphene oxide, clays or potassium fluoride have also
been investigated and reported [53-55]. Excellent reviews about the organocatalytic
supported systems can be found in the literature [17, 56-58].
Herein we report the functionalization of calcium carbonate (CaCO3), which is a
highly tunable carrier, as new solid support for the covalent immobilization of
2

organocatalysts. This material is interesting in this context for several reasons. Firstly,
the shape and size of CaCO3 can be varied by adjusting the kinetics of crystallization,
allowing a fine control of the support since its crystallization [59, 60]. Secondly, a high
degree of particle surface functionalization can be potentially achieved by using ligands
with functional groups like carboxylic acids, which perfectly fit at the crystal surface
[61]. Furthermore, the low cost of this support, which has made this material highly
attractive as carrier for gas phase catalyzed reactions [62] as well as for the encapsulation
of hydrophobic drugs [63], represents an additional advantage. As representative
examples, diphenylprolinol silyl ethers were chosen as organocatalyst for their broad
applications in catalyzing organic transformations [23, 64], and the performance of these
catalytic systems was tested in the asymmetric Michael reactions of trans--
nitrostyrene with aldehydes, a reaction that was subsequently used for the
implementation of a single-pass, continuous flow process.
2. EXPERIMENTS
All reagents were purchased from Aldrich and used as received. All reactions were
carried out directly under open air unless otherwise noted.
1
13
2.1. Analytical techniques. The H and C NMR spectra were recorded at 400
1
13
MHz and 500 MHz for H, or at 100 MHz and 125 MHz for C, respectively. TMS
1
13
was used as internal standard for H-NMR and CDCl3 for C-NMR. Chemical shifts
are reported in ppm referred to TMS. FT-IR measurements were carried out on a Bruker
Optics FTIR Alpha spectrometer equipped with a DTGS detector. Elemental analyses
were performed on a LECO CHNS 932 micro-analyzer at the Universidad Complutense
de Madrid, Spain. The experiments under microwave irradiation were carried out in a
CEM Discover microwave reactor. High performance liquid chromatography (HPLC)
was performed on Agilent Technologies chromatographs (Series 1100 and 1200), using
Chiralpak columns and guard columns. Racemic standard products were prepared using
racemic catalyst in order to establish HPLC conditions. TEM images were collected
using a JEOL 1011 Transmission Electron Microscope operating at 100 kV and
magnification values of 12–60k. The dried samples were placed onto carbon coated-
3

copper grids. The same equipment was applied to make Selected Area Electron
Diffraction (SAED). SEM images were recorded using a JEOL JSM-6400 scanning
microscope. The same equipment was applied to measure Energy-dispersive X-ray
spectroscopy (EDX). The PXRD samples were prepared by placing the powders
between two foils without background. PXRD data were acquired on a Bruker D8
Advance.
2.2. Synthesis of Supported Catalysts
2.2.1. Synthesis of Support-1. A solution of CaCl2·2H2O (1.46 g, 9.93 mmol)
dissolved in deionized water (5 mL) was added into a solution of azido pentanoic acid
(0.35 g, 2.41 mmol) in 10 g PEG (200Mwt) under vigorous stirring at 40 ºC [65]. Finally, a
solution of Na2CO3 (1.052 g, 9.92 mmol) in deionized water (5 mL) was added
dropwise and stirred for 30 minutes at 40 ºC. The resulting materials were isolated by
centrifugation, washed three times with THF und finally dried under vacuum.
CHN analysis: 10.88 %C, 0.97 %H, 0.96 %N
2.2.2. Synthesis of Support 2. A solution of CaCl2·2H2O (1.46 g, 9.93 mmol) in
deionized water (5 mL) was added into a solution of -azido undecanoic acid (0.50 g,
2.20 mmol) in 10 g PEG (200Mwt) under vigorous stirring at 40 ºC [65]. Finally, a solution
of Na2CO3 (1.05 g, 9.92 mmol) in deionized water (5 mL) was added dropwise and
stirred for 30 minutes at 40 ºC. The resulting materials were isolated by centrifugation,
washed three times with THF and finally dried under vacuum.
CHN analysis: 18.14 %C, 1.68 %H, 2.58 %N
2.2.3. Synthesis of Supports 3 and 4. A solution of CaCl2·2H2O (0.30 g, 2.03
mmol) in deionized water (5 mL) was added into a solution of -azido undecanoic acid
(0.50 g, 2.20 mmol) and co-ligand (2.20 mmol, octanoic acid or palmitic acid) in
THF/PEG(200Mwt) (6/3) (9 mL) under vigorous stirring at 40 ºC [65]. Finally, a solution
of Na2CO3 (0.21 g, 1.99 mmol) in deionized water (5 mL) was added dropwise and
stirred for 30 minutes at 40 ºC. The resulting materials were isolated by centrifugation,
washed three times with THF and finally dried under vacuum.
Support-3, CHN analysis: 26.05 %C, 3.20 %H, 2.72 %N
4

Support-4, CHN analysis: 56.04 %C, 8.66 %C, 1.45 %N
2.2.4. Synthesis of (2S,4R)-diphenyl(4-(prop-2-yn-1-yloxy)pyrrolidin-2-
yl)methanol. This compound was synthesized according to our reported procedure [66].
(2S,4R)-tert-butyl 2-(hydroxydiphenylmethyl)-4-(prop-2-yn-1-yloxy)pyrrolidine-1-
carboxylate (2.8 g, 6.9 mmol) was dissolved in 4 M HCl solution of 1,4-dioxane (150
mL) and stirred at room temperature for 40 min. Then, the reaction mixture was cooled
to 0 ºC and pH value was adjusted slowly to pH 8.0 using aqueous NaOH solution (20
wt.%). The mixture was extracted with ethyl acetate (3 x 100 mL) and the combined
organic phase was washed with brine and dried (MgSO4). Solvent removal under
reduced pressure afforded 1.74 g of product (83% yield) that was directly used in the
next step.
2.2.5. Synthesis of (2S,4R)-2-(diphenyl((trimethylsilyl)oxy)methyl)-4-(prop-2-
yn-1-yloxy)pyrrolidine. This compound was synthesized according to our reported
procedure [64]. To a solution of (2S,4R)-diphenyl(4-(prop-2-yn-1-yloxy)pyrrolidin-2-
yl)methanol (460 mg, 1.13 mmol) in DCM (25 mL) at 20 ºC was added triethylamine
(0.31 mL, 2.15 mmol) and trimethylsilyl trifluoromethanesulfonate (0.39 mL, 2.15
mmol). The solution was then allowed to reach 0 ºC and was stirred for 3 h at this
temperature. The reaction was quenched with water and the aqueous layer was extracted
with DCM (3 x 20 mL). The combined organic extracts were dried over Na2 SO4 and
concentrated under reduced pressure. The resulting crude was purified by flash
chromatography on silica gel (cyclohexane:ethyl acetate 1:1) to afford the desired
product as a pale yellow oil (288 mg, 68% yield). 1H NMR (500 MHz, CDCl3): δ =
 0.11 (s, 9H), 1.67-1.70 (m, 2H), 1.74 (br, NH), 2.36 (t, J = 2.4 Hz, 1H), 2.79 (dd, J
= 11.8 and 4.85 Hz, 1H), 2.95 (dd, J = 11.8 and 2.4 Hz, 1H), 3.91-3.95 (m, 1H), 4.05
(dd, J = 2.3 and 1.2 Hz, 2H), 4.32 (t, J = 7.9 Hz, 1H), 7.18-7.47 (m, 10H). 13C NMR
(125 MHz, CDCl3): δ = 2.3, 34.2, 52.8, 56.2, 63.7, 74.1, 79.4, 80.2, 83.0, 127.0-128.6
(CH, Ar), 145.5, 146.8.
2.2.6. Synthesis of (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)diphenylmethyl)-
4-(prop-2-yn-1-yloxy)pyrrolidine. This compound was synthesized according to our
5

reported procedure [64]. (2S,4R)-diphenyl(4-(prop-2-yn-1-yloxy)pyrrolidin-2-
yl)methanol (0.92 g, 3 mmol) was dissolved in dry DCM (15 mL), and the solution was
cooled to 0 ºC with an ice-water bath. Then, 2,6-lutidine (24 mmol) and TBSOTf (12
mmol) were added. The reaction mixture was maintained in the bath and allowed to
warm to room temperature. After the reaction was completed (8 h), saturated aqueous
NH4Cl solution (20 mL) was added and the product was extracted with DCM (2 x 20
mL). The combined organic phase was washed with brine (10 mL), dried (MgSO4) and
concentrated under reduced pressure. The crude product was purified by fast flash
chromatography on silica gel, eluting with cyclohexane/ethyl acetate (4/1), to afford
0.86 g of pure product (68% yield). 1H NMR (500 MHz, CDCl3):  = 0.48 (s, 3H),
0.21 (s, 3H), 0.95 (s, 9H), 1.68-1.78 (m, 3H), 2.35 (t, J = 2.4 Hz, 1H), 2.65 (dd, J =
12.1 and 4.9 Hz, 1H), 2.90 (ddd, J = 12.1, 2.5 and 1.2 Hz, 1H), 3.88-3.78 (m, 1H), 4.03
(dd, J = 2.4 and 1.3 Hz, 3H), 4.30 (dd, J = 8.8 and 7.0 Hz, 1H), 7.21-7.29 (m, 6H), 7.30-
13
7.36 (m, 2H), 7.51-7.55 (m, 2H); C NMR (125 MHz, CDCl3):  = 146.3, 145.0,
129.3, 128.5, 127.8, 127.3, 127.2, 127.1, 82.9, 80.2, 79.5, 77.4, 77.2, 76.9, 74.1, 63.9,
56.2, 52.8, 34.6, 26.5, 19.2, 2.5 3.2.
2.2.7. Synthesis of (2S,4R)-2-(diphenyl((triisopropylsilyl)oxy)methyl)-4-
(prop-2-yn-1-yloxy)pyrrolidine. This compound was synthesized using the same
procedure as synthesizing TBS protected monomer [64]. 61% yield was obtained from
1
(2S,4R)-diphenyl(4-(prop-2-yn-1-yloxy)pyrrolidin-2-yl)methanol and TIPSOTf. H
NMR (500 MHz, CDCl3):  = 0.82 (m, 3H), 0.93 (t, J = 7.5 Hz, 18H), 1.71-1.74 (m,
1H), 1.96 (dd, J = 14.1 and 7.3 Hz, 1H), 2.35 (t, J = 2.4 Hz, 1H), 2.39 (dd, J = 12.0 and
4.5 Hz, 1H), 2.84 (ddd, J = 12.0, 2.3 and 1.6 Hz, 1H), 3.73 (dq, J = 4.4 and 2.3 Hz, 1H),
4.03 (d, J = 2.4 Hz, 2H), 4.41 (t, J = 7.8 Hz, 1H), 7.20-7.30 (m, 6H), 7.35-7.42 (m, 2H),
7.48-7.55 (m, 2H); 13C NMR (125 MHz, CDCl3):  = 146.0, 144.6, 129.4, 129.3, 127.6,
127.5, 127.1, 83.5, 80.3, 79.7, 77.4, 77.2, 76.9, 74.0, 64.1, 56.2, 52.4, 34.6, 18.7, 18.6,
13.9.
2.2.8. Synthesis of catalysts CXS-1-6. Azide functionalized solid supports (1
equiv, 0.22-0.75 mmol) were functionalized with silyl protected organocatalysts (1.5
6

equiv, 0.33-1.125 mmol) using CuI (1.05 equiv), DIPEA (0.2 equiv) and a mixture of
THF/DMF=1/1 (3.5 mL) in microwave conditions, 80 °C, for 2.5 hours. The supported
catalyst was separated by centrifugation, washed several times with THF, and dried
under vacuum.
CXS-1, CHN analysis: 13.75 %C, 0.68 %H, 1.17 %N
CXS-2, CHN analysis: 18.08 %C, 1.25 %H, 1.52 %N
CXS-3, CHN analysis: 27.78 %C, 3.13 %H, 1.93 %N
CXS-4, CHN analysis: 41.76 %C, 6.18 %H, 1.63 %N
CXS-5, CHN analysis: 18.03 %C, 1.59 %H, 1.44 %N
CXS-6, CHN analysis: 18.33 %C, 1.45 %H, 1.39 %N
2.3. Catalysts test.
Immobilized catalyst (10 mol%, 40 mg) and trans--nitrostyrene (1.0 equiv, 0.1
mmol) were mixed in a 1 mL vial with DCM (0.5 mL). Then, propanal (1.5 equiv or
5.0 equiv) was added and this mixture was shaken at room temperature. The reaction
was stopped at a given time by removing the catalyst by centrifugation, and the solvent
was removed under reduced pressure. The dr values and conversions were determined
by 1H NMR with crude product. The ee was determined by HPLC with chiral column.
2.4. Recycling experiments with catalyst CXS-5.
Immobilized catalyst CXS-5 (10 or 20 mol%, 40 or 80 mg) and trans--
nitrostyrene (1.0 equiv, 0.1 mmol) were mixed in a 1 mL vial with DCM (0.5 mL).
Then, propanal (1.5 equiv or 5.0 equiv) was added and this mixture was shaken (at
room temperature or 0 ºC). The reaction was stopped at a given time by removing the
catalyst by centrifugation, and the solvent was removed under reduced pressure. The dr
values and conversions were determined by 1H NMR with crude product. The ee was
determined by HPLC with chiral column.
2.5. Continuous-flow process. The packed-bed reactor consisted of a vertical
mounted and fritted low-pressure Omnifit glass chromatography column (10 mm
diameter, 10 mm pore size and up to maximal 70 mm of adjustable bed height) loaded
with the catalyst CXS-5 (500 mg, 0.1 mmol, f ≈ 0.2 mmol·g-1, 8 mm bed height), 2
7

beds of CPG 75C porous SiO2 (5 mm bed height each in order reduce the pressure
inside the column) and a bed of Merrifield resin (4 mm bed height, at the end of the
column in order to prevent the catalyst leaching through the column). At the start, DCM
was pumped at a flow rate of 250 µL·min-1 using an Asia syringe pump by Syrris for
an hour. After that, the solvent channel was switched to a solution of trans--
nitrostyrene (6.3 mmol, 1.3 g) and propanal (3.1 mL, 43 mmol) in 44 mL of DCM was
flushed a flow rate of 250 µL·min-1 through the system until the solution filled the
column. Then, the flow rate was reduced to 25 µL·min-1 and the system was run for 21
h. The reactor outlet was connected to a receiving flask where the product was
collected. Samples were collected from 2h (when the experiment was stabilized) to 7 h
(showing both constant conversion and stereoselectivity) of periodically collected
samples. The solvent from the collected samples were removed under reduced pressure
to give a yellow oil which was submitted to flash chromatography on silica gel, eluting
with cyclohexane/ethyl acetate (5/1), to give pure Michael adduct (0.081 g, 0.39 mmol)
as a yellow oil. Productivity: 0.65 mmol product·(mmol catalyst)-1·h-1; theoretical yield
during 6 h = 1.8 mmol.
3. RESULTS AND DISCUSSION
Two strategies were devised in order to synthesize the target catalytic system. In
2-
both, precipitation of CaCO3 was induced using Ca2+ and CO3 sources, and the
catalytic monomer was immobilized onto the solid support via a triazole linker, which
was formed using a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction as
the click strategy [67, 68]. The main difference between the catalytic materials (CXS) lies
in the synthetic pathway used for the formation of the solid support. On the one hand,
the post-functionalization strategy (Figure 1, upper route) in which, CaCO3 particles
are first formed and then treated with azide-substituted long-chain carboxylic acids to
deliver ready-to-click materials. The advantage of this method for the preparation of
solid supports is that the size and the crystal structure of CaCO3 can be easily adjusted
by changing the crystallization kinetics before surface functionalization (see Figure
S1). In each case, the amount of azide groups present in the resulting powder, was
8

determined by nitrogen elemental analysis (EA), since the only source of nitrogen in
the samples is the azido group present in the organic ligand [69].
The surface functionalization achieved in the structures with more surface area,
those with vaterite structure [70-75], was relatively low (up to 0,14 mmol/g) (see Table
S1). On the other hand, the biomineralization strategy targeted the formation of CaCO3
using azide containing long-chained carboxylic acids as crystal-mimicking ligands
during the crystallization (Figure 1, bottom route).
Post-functionalization strategy
CaCO3
O2C
1. Precipitation
2. Surface Functionalization
O
O
N3
Ph
Ph
OR
n
N3
2-
O
Ca2++CO3
CaCO3
N
n
+
H
Solid support
Catalytic Monomer
Biomineralization strategy
CuAAC reaction
1. Co-Precipitation
N
N
N
O
n
O
O
CaCO3
Ph
Ph
OR
N
H
Catalytic system "CXS"
Figure 1. Synthesis of catalytic materials
Interestingly, the use of these ligands during the crystallization process directs
crystal growth in specific directions because of the good fit between these carboxylate
anions and certain crystal lattices of the emerging inorganic surfaces [63]. These
approaches has been widely used during the past decades, and are still being used for
the formation of new materials, particularly in the formation of anisotropic materials
[
76-80]. A nice illustration of this use can be found in the work by Mahapatra et al, who
triggered the formation of CaCO3 particles with lauric acid and successfully tested the
resulting CaCO3 materials depicting non-polar surfaces as oil absorbent materials [81].
Different supports have been synthesized using this approach. The
characterization of Support-1 can be seen in Figure 2. Support-1 has been synthesized
9

using 5-azido-pentanoic acid as ligand in the co-precipitation route. The SEM image of
Support-1 is shown in Figure 2a, here particles with both spherical and ill-defined shape
can be seen.
Figure 2. a) SEM image of Support-a, b) Powder X-ray diffraction (PXRD) of
Support-a, c) TEM image of Support-a, d) N2 adsorption/desorption isotherm of
Support-a.
The PXRD showed in Figure 2b confirmed the formation of CaCO3 with vaterite
structure. As observed in Figure 2c, the spherical particles are composed by smaller
nanocrystals and, therefore, they are polycrystalline. Moreover, the degree of
functionalization of the resulting materials calculated from EA was found to be much
higher in this case (Table 1) with values ranging from 0.23 to 0.65 mmol/g depending
on the nature of the ligand and the co-ligand used in the formation of the particles.
Finally, it is noticeable that N2 adsorption desorption isotherm indicated a specific
surface area of 52 m2/g. From a practical perspective, the resulting materials can be
well-dispersed in most of the organic solvents like tetrahydrofuran (THF),
10

dichloromethane (DCM), chloroform or toluene due to their non-polar surfaces, and
this facilitates further chemical modification. To complete the preparation of the
immobilized catalysts, the azide functionalized particles were reacted with the
propargyloxy-modified Jørgensen-Hayashi catalyst (1) using a CuAAC reaction as a
“click” method [67] to combine the two fragments (Figure 1).
Table 1. Different prepared supports
Functionalization
Support
Ligand
Co-Ligand
(mmol/g)
0.228
Support-1
Support-2
Support-3
Support-4
5-azido-pentanoic acid
-azido-undecanoic acid
-azido-undecanoic acid
-azido-undecanoic acid
-

0.613
Octanoic Acid
Palmitic Acid
0.647
0.344
The progress of the CuAAC reaction leading to the preparation of the catalytic
systems (CXS-1-4) was monitored by IR spectroscopy using the azide stretching band
at ca. 2100 cm-1 as a diagnostic tool (Figure 3). It can be observed in Figure 3a that
this signal had disappeared from all supports when the reactions were completed. In
that moment, all nitrogen present in the samples is due to the generated 1,2,3-triazole
moieties (see Figure 1, Catalytic Systems CXS), so that nitrogen elemental analysis
continues to be the method of choice for the determination of the functionalization of
the catalytic materials.
Figure 3. a) IR of the catalytic systems (CXS-1-4) and the support materials
11

(Support-1-4) and b) TEM image of the catalytic material (CXS-1)
Table 2. Functionalization of the catalytic systems (CXS1-4)
Catalyst
CXS-1
Support-1
0,208
CXS-2
Support-2
0,278
CXS-3
Support-3
0,343
CXS-4
Support-4
0,291
Support
Functionalization (mmol/g)
Therefore, we assumed that the -diphenyl prolinol trimethyl silyl ether
catalytic units were successfully immobilized at the particle surfaces (with catalyst
loading between 0.21 and 0.34 mmol/g, Table 2). The TEM image of CXS-1 was taken
as a confirmation that the supports remained stable after the CuAAC reaction (Figure
3b). With the first family of organocatalysts immobilized onto CaCO3 in hand (CXS-
1-4), their ability to catalyze enantioselective Michael additions was tested in the
reaction of propanal (Y) with trans--nitrostyrene (Z), which is one of the most
successful applications of the Jørgensen-Hayashi-type organocatalysts (Table 3) [23, 64].
As previously mentioned, the supported-organocatalyst allowed us to recover the
catalyst from the reaction products for reuse by simple decantation of the supernatant
and washing of the precipitate.
Table 3. Reaction condition optimization in Michael additions catalyzed by CXS
immobilized catalysts
CXS
(7 mol%),
solvent, R.T.
O
NO2
O
+
NO2
2a
3a
4a
N
N
Ph
Ph
OR
O
O
N
n
O
CaCO3
NH
1
CXS
(n = 2 or 8; R = TMS, TBS or TIPS)
conv.
(%)a
ee
dr (%)a
Support
Entry
Catalyst
R
Solvent
t (h)
(%)b
1
2
Support-2
Support-2
CXS-2
CXS-2
TMS
TMS
Toluene
THF
24
24
42
4
91/9
n.d.
64
n.d.
12

3
4
Support -2
Support -1
Support-2
Support-3
Support-4
Support-2
Support-2
Support-2
CXS-2
CXS-1
CXS-2
CXS-3
CXS-4
CXS-2
CXS-5
CXS-6
TMS
TMS
TMS
TMS
TMS
TMS
TBS
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
24
24
24
24
120
24
48
48
n.c.
95
-
-
93/7
89/11
91/9
-
74
75
76
-
5
89
6
83
7
n.c.
89
8
93/7
97/3
91/9
75
98
95
9
82
10
TIPS
35
1
a) Determined by H NMR spectroscopy of the crude mixture. b) Determined by
HPLC using a chiral stationary phase. n.c. = no conversion, n.d. = not determined.
After the screening of different solvents, we observed that the best conversions,
diastereo- and enantioselectivities were achieved in DCM. Interestingly, noticeable
differences between the four catalytic systems were observed depending on the
chemical composition of the surface of the supports [82]. We thus noticed that no
reaction was taking place if the co-ligands (C16) involve longer chains than the ligands
(C11) used for catalyst immobilization (Table 3, entry 7) [65], possibly due to the
inaccessibility of the catalyst to the reactants. To our delight, excellent
diastereoselectivities (93/7) and moderate enantioselevitivies (up to 76%) were
observed with other CaCO3 supported catalysts.
In order to improve the stereoselectivity of the process, the catalytic site was fine-
tuned by modifying the nature of the silyl ether group nearby. In this respect, we have
already reported that modification of this group involving increased bulkiness leads to
increased robustness of the catalyst as well as to much better control of
enantioselectivity [64].
Accordingly, more sterically demanding silyl group could result in a better control
of enantioselectivity of the reaction. In our case, when we changed the trimethyl silyl
ether group (TMS) by tert-butyldimethylsilyl group (TBS) and triisopropylsilyl group
(TIPS) in the catalytic sites, a remarkable increase in enantioselectivity was observed
(Table 3， entries 8-10). Thus, CXS-5 containing a TBS protecting group, led to
13

excellent diastereoselectivity (97/3) and enantioselectivity in the major product (98%
ee), as it can be seen by comparison of the results in entries 1 and 2, while CXS-6
containing the more stable, but more difficult to introduce TIPS group led to slightly
less optimal results (entry 10).
It has to be mentioned that CXS-5 and CXS-6, involving more sterically
demanding silyl groups are affected by a slight decrease in catalytic activity with
respect to those involving TMS groups. In any case, full conversion is recorded with
catalyst CXS-5 after 48 h reaction (vs. 24 h with CXS-1 to CXS-3).
Next, we focused on studying the scope of the reaction catalyzed by CXS-5. As it
is shown in Table 4, trans--nitrostyrenes (3a-e) bearing electron-donating and
electron-withdrawing groups in different positions of the ring were tested in Michael
reactions with aldehydes 2a-b as donors.
Table 4. Scope of the Michael addition catalyzed by the CaCO3 immobilized
organocatalyst CXS-5.a
R2
O
NO2
CXS-5
(10 mol%),
DCM, R.T.
O
+
NO2
R1
R2
R1
2
3
4
4 (yield, %) b
dr (%) b
92/8
ee (%) c
98
Entry
2
3
1
2
3
4
5
6
2a (R1=Me)
2a (R1=Me)
2a (R1=Me)
2a (R1=Me)
2a (R1=Me)
3a (R2=H)
99
90
80
84
91
45
3b (R2=2-F)
3c (R2=3-Cl)
3d (R2=4-Br)
3e (R2=4-Me)
3a (R2=H)
94/6
96
92/8
95
91/9
92
92/8
96
2b (R1=n-Pent)
82/18
93
a) The reaction was carried out for 24 h. b) Determined by 1H NMR spectroscopy of the crude mixture. c) Determined
by HPLC using a chiral stationary phase.
When propanal was used under the previously optimized conditions, the addition
products were obtained in high yields (80-99%), with diastereo- and enantioselectivities
(Table 4, entries 1–5). However, it must be noted that when structural changes in the
Michael donor were introduced, the stereoselectivity remained constant (ee = 93%), but
14

decrease of yield (45%) and diastereoselectivity (dr = 82/18) was observed possibly
due to the steric hindrance effect of the longer alkyl chain [66] and the catalyst
architecture [83] respectively (Table 4, entry 6).
After demonstrating the behaviour of the catalytic systems and its recoverability,
we focused our efforts on the recyclability for CXS-5 in the reaction between propanal
and trans--nitrostyrene. Firstly, we attempted the recycling of CXS-5 by submitting
the reaction mixture to centrifugation (2000 rpm, 10 min), then separating the solution,
and repeating the whole process before the next use. However, using this workflow, we
observed a decrease in conversion between cycles, although stereoselectivities
remained constant (see Table 5).
Table 5. Recycling experiment of the CaCO3 immobilized organocatalyst CXS-5.
Particles centrifuged in DCM
Catalyst
Conversion syn/anti
Cycle
ee (%)b
97
(%)a
(%)a
1
2
3
87
91/9
CXS-5
41
18
85/15
80/20
97
97
a) Determined by 1H NMR spectroscopy of the crude mixture. b)
Determined by HPLC using a chiral stationary phase.
The elemental analysis of a sample of catalyst CXS-5 used in three reaction cycles
with this protocol showed a significant decrease in functionalization (a drop of 60%
was observed), providing clear indication on the origin of catalyst deactivation (Table
6).
Table 6. Functionalization of the catalytic systems before and after recycling.
Catalyst – CXS-5
Cycle 1
Functionalization (mmol/g)
0,343
0,136
Cycle 3
At this moment, we reasoned that the very high dispersibility of the catalytic
15

materials in DCM could be the reason for the loss of catalytic sites between cycles.
Taking into account that the primarily observed spherically-shaped CaCO3 particles are
in fact agglomerates of smaller particles, it is logical to expect that, after centrifugation,
the smallest CaCO3 particles, which are those with higher surface area and, therefore,
those bearing higher functionalization, could remain in solution as colloids, and would
be lost with the solution in the inter-cycle treatments. Under this assumption, we
modified the recycling protocol in the following manner: Once the reaction was
complete, DCM was evaporated and the semi-solid residue was treated with n-pentane,
where the particles are not so well-dispersed, but the reaction product is very soluble.
Finally, we centrifuged and washed the particles with n-pentane to recover the
catalyst before reuse. Table 7 shows the results of the catalytic performance of the
recycled CXS-5. Using this approach (centrifugation in n-Pentane), we were able to run
two cycles at different temperature (0 and 25 ºC) and loading of catalyst (10 and 20
mol%) obtaining constant conversions and excellent stereoselectivities. However, we
observed that after every cycle, longer times of reaction were needed and that after the
third cycle, the conversion started to drop, even under the best conditions (20 mol%
catalyst at 25 ºC, Table 7).
Table 7. Recycling experiment of the CaCO3 immobilized organocatalyst CXS-5.
Particles centrifuged in DCM
Catalys Cycl
syn/anti
(%)a
96/4
93/7
96/4
ee
(%)b
94
93
93
T (ºC)
Time (h) %mol Conversion (%)a
t
e
1
2
3
1
2
3
0
0
0
47
68
68
24
36
72
10
10
10
20
20
20
62
66
17
CXS-5
25
25
25
>99
>99
72
91/9
90/10
92/8
94
95
93
CXS-5
a) Determined by 1H NMR spectroscopy of the crude mixture. b) Determined by
HPLC using a chiral stationary phase.
As the ultimate test for sustainable use, catalyst CXS-5 was tested in continuous
flow [66] for the Michel addition of propanal (2a) to trans--nitrostyrene (3a) process
in order to have clear evidence that the reaction was occurring at the interface of the
16

particles. The system consisted of a low-pressure chromatography column with two
adjustable endpieces, which was loaded with the catalyst CXS-5 and connected to a
single pump used to feed the reactor with the reagents. The reaction was conducted at
room temperature, and preliminary experiments showed that a flow rate of 25 L·min-1
was the best option to produce the product with very good stereoselectivity and
moderate conversion. Thus, 0.1 mmol of catalyst CXS-5 (500 mg, f ≈ 0.2 mmol·g-1)
was loaded onto the column and the reaction was performed using trans--nitrostyrene
(6.3 mmol) and propanal (43 mmol) in DCM (44 mL), so that the concentrations of the
reactants was 0.143 M.
NO2
O
O
catalyst (500 mg)
+
NO2
Flow = 25 L·min-1
Residence time: 25 min.
syn/anti = 91/9
97% ee
Figure 4. Synthesis of the Michael adduct 4a using catalyst CXS-5 in continuous
flow
The flow experiment showed both constant conversion and stereoselectivity for a
7 h run (Figure 4). Notably, the process produced 4a with high diasteremeric purity
17

(syn/anti = 91/9) and higher enantiopurity (97% ee) than the batch process (the average
ee after three cycles in batch was 94%, see Table 7). In addition, the flow process was
characterized by a productivity of 0.65 mmol 4a·(mmol catalyst)-1·h-1, which represents
a five-fold increase in productivity compared to the batch process (the accumulated
productivity in batch after 3 reaction cycles was 0.13 mmol 4a·(mmol catalyst)-1·h-1,
see Table 7).
4. CONCLUSIONS
Calcium carbonate has been used for the first time as a competent support for the
immobilization of organocalaysts. A Jørgensen-Hayashi catalyst immobilized onto this
support has been used in the highly enantioselective Michael addition of aldehydes to
trans--nitrostyrene derivatives. By adjusting the crystallization of CaCO3 through the
addition of long-chain carboxylic acids functionalized at the terminal position with
azido groups yielded low-cost, azide-functionalized supports suitable for universal
CuAAC reactions with terminal alkynes. Interestingly, the resulting supports were
polycrystalline in nature, and the preparative approach used allowed a fine control of
the particle surfaces. The azide-functionalized CaCO3 supports were successfully
loaded with different propargyloxy-functionalized -diphenylprolinol silyl ether
containing increasingly demanding silyl groups. The possibility of adjusting the
chemical composition with respect to ligand/co-ligand at the particle surface has served
to rationalize the effect of the relative chain length of these species on the catalytic
performance of the system. The recoverability and recyclability of the optimal
heterogenenized organocatalyst (CXS-5) has been tested under batch processes and
then successfully transferred to a continuous-flow operation, which has allowed the
preparation of a Michael product with significant improvements in terms of
productivity referred to batch process. According to these findings, calcium carbonate
can be considered as a suitable support for the further heterogenization of more
organocatalysts working under non-acidic conditions. Finally, this contribution
provides indication that control of the crystalline nature of inorganic supports during
its formation can allow the fine-tuning of their catalytic activity. According to this,
18

research aiming at the controlled formation of supports using co-precipitation
approaches offers important potential in view of the introduction of new supports,
complementary to those already existing, for the immobilization of catalytic species.
ASSOCIATED CONTENT
Supporting Information. Experimental details are provided in the Supporting
Information.
AUTHOR INFORMATION
Corresponding Authors
* Email: xinyuanfan@pku.edu.cn and carlos.lizandara@basf.com
Author Contributions
The manuscript was written through contributions of all authors. All authors have
given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was funded by MINECO (Grants CTQ2008-00947/ BQU and
CTQ2012-38594-C02-01) and ICIQ Foundation. X.F thanks the National Key R&D
Program of China (2019YFA0904201), the National Natural Science Foundation of
China (21708020, 91957101, 22077004) and the State Key Laboratory of Drug
Research for foundation support.
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Graphical abstract
25

Highlights:
--The CaCO3 particles are evaluated in the heterogenization of homogeneous
asymmetric catalysts for the first time.
--The CaCO3-supported Jørgensen-Hayashi catalysts are developed for asymmetric
Michael additions.
--Recycling of CaCO3 heterogeneous catalysts are achieved by condition
optimization.
--CaCO3 heterogeneous catalysts are adapted in catalytic continuous flow processes.
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