TEMPO-functionalized mesoporous silica particles as heterogeneous oxidation catalysts in flow

Article abstract of DOI:10.1039/c9ta12416k

Organocatalysts immobilized on inorganic porous substrates possess fundamental benefits, e.g., a high catalyst/reactant ratio, easy scalability as well as work-up, and continuous processing. Here we report the development of a heterogeneous (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) catalyst immobilized on mesoporous SiO₂ and demonstrate its feasibility in the oxidation of benzyl alcohol to benzaldehyde. Our catalyst system is based on commercially available mesoporous silica particles that are optimized for flow applications (LiChrospher Si 100 from Merck). The transition from well-known silica materials like MCM-41 and SBA-15 to specialized high-performance materials such as the used LiChrospher particles is of great value for getting closer to industrial applications on large scale. We functionalized the material by applying click-chemistry and employed a packed HPLC column for the investigation of the catalyst performance and stability in continuous flow. The material shows the best performance with low catalyst loadings. The catalytic activity can be improved significantly by conversion of the TEMPO radical to an oxoammonium salt prior to the reaction. The material is well suited for applications in continuous flow syntheses, as the spherical shape of the particles results in low back pressures. The organic catalyst produces yields up to 89% with a flow rate of 0.05 mL min^-1. The mild reaction conditions allow the use of the material in multi-step reactions. This option was demonstrated by combining the TEMPO-functionalized column with an aminopropyl-functionalized column and performing a TEMPO-mediated oxidation followed by a Knoevenagel condensation in a continuous flow setup for the first time. Long-term tests and post-catalytic analysis show a previously neglected decomposition pathway of TEMPO due to the co-catalyst.

Full text of DOI:10.1039/c9ta12416k

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Migenda, M. Becker, S. Schuler, R. C. Wende, B. Smarsly and P. R. Schreiner, J. Mater. Chem. A, 2020,
DOI: 10.1039/C9TA12416K.
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Number 12
March 2018
Pages 4883-5230
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DOI: 10.1039/C9TA12416K
ARTICLE
TEMPO-functionalized mesoporous silica particles as
heterogeneous oxidation catalysts in flow
Julia S. Schulze, Julia Migenda, Maximilian Becker, Sören M. M. Schuler, Raffael C. Wende,b
a
a
a
b,c
Received 00th January 20xx,
Accepted 00th January 20xx
b,
a,
Peter R. Schreiner, * and Bernd M. Smarsly *
DOI: 10.1039/x0xx00000x
Organocatalysts immobilized on inorganic porous substrates possess fundamental benefits, e.g., a high catalyst/reactant
ratio, easy scalability as well as work-up, and continuous processing. Here we report the development of a heterogeneous
(
2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) catalyst immobilized on mesoporous SiO and demonstrate its feasibility in
2
the oxidation of benzyl alcohol to benzaldehyde. Our catalyst system is based on commercially available mesoporous silica
particles that are optimized for flow applications (LiChrospher® Si 100 from Merck). The transition from well-known silica
materials like MCM-41 and SBA-15 to specialized high-performance materials such as the used LiChrospher® particles is of
great value for getting closer to industrial applications on large scale. We functionalized the material by applying click-
chemistry and employed a packed HPLC column for the investigation of the catalyst performance and stability in continuous
flow. The material shows the best performance with low catalyst loadings. The catalytic activity can be improved significantly
by conversion of the TEMPO radical to an oxoammonium salt prior to the reaction. The material is well suited for applications
in continuous flow syntheses, as the spherical shape of the particles results in low back pressures. The organic catalyst
–
1
produces yields up to 89% with a flow rate of 0.05 mL min . The mild reaction conditions allow the use of the material in
multi-step reactions. This option was demonstrated by combining the TEMPO-functionalized column with an aminopropyl-
functionalized column and performing a TEMPO-mediated oxidation followed by a Knoevenagel condensation in a
continuous flow setup for the first time. Long-term tests and post-catalytic analysis show a previously neglected
decomposition pathway of TEMPO due to the co-catalyst.
structures, have also been investigated and used with good
3–8
Introduction
results.
Compared to heterogeneous batch catalysis, reactions in
continuous flow have additional advantages. As main benefits,
catalyst separation and recycling are replaced by a continuous
process, which simplifies work-up. A reaction in continuous flow
is scalable and allows the extension to a continuous multistep
synthesis by adding different reactor columns in one setup. At
the same time, the requirements for the carrier material are
challenging. Immobilized organocatalysts in high throughput
reactors must be equipped with a carrier material that is
suitable for high flow rates and does not produce high pressures
inside the column. Silica particles designed for HPLC
applications provide these properties and should be considered
as alternatives to conventional silica materials.
In this work, the organocatalyst (2,2,6,6 tetramethylpiperidin-1-
yl)oxyl (TEMPO) is immobilized on mesoporous silica particles
designed for HPLC applications, aiming at high yields, easy
separation of the products, and recycling of the catalyst by
continuous flow catalysis. Packing the material into a stainless
steel HPLC column produces a dense, homogeneous reactor
bed with good flow properties and low pressure build-up and
the possibility for scale-up with longer or parallel column
setups. The oxidation of benzyl alcohol to benzaldehyde with
TEMPO is used as a model reaction to demonstrate that flow-
The immobilization of organocatalysts on solid supports allows
for easy separation and reuse of the catalysts and prevents
product contamination with catalyst traces. Since work-up and
purification as well as synthesis of the organocatalyst itself are
often laborious and expensive, immobilized catalysts are a
desirable goal from an ecological and economic point of view.1,2
Mesoporous silica has several properties making it an excellent
carrier material for immobilized organocatalysts. It is
mechanically stable, inexpensive, does not swell in organic
solvents, and high catalyst loadings are possible through
functionalization of its large surface area. For a good carrier
material, not only the area of the surface is important, but the
pores must also be easily accessible. The structure of
mesoporous silica combines its high surface area with good
accessibility of immobilized catalyst molecules for substrates
and regeneration reagents. Other carrier materials, e.g.,
polymers, magnetic nanoparticles, ionic liquids or carbon
a. Institute of Physical Chemistry, Justus Liebig University Giessen, Heinrich-Buff-
Ring 17, D-35392 Giessen (Germany).
b.
Institute of Organic Chemistry, Justus Liebig University Giessen, Heinrich-Buff-Ring
1
7, D-35392 Giessen (Germany).
c.
Present address: Evotec International GmbH, Marie-Curie-Str. 7, D-37079
Goettingen (Germany).
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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Page 2 of 12
ARTICLE
Journal Name
optimized mesoporous silica particles are well suited as carrier thorough investigation of the functionalization of the silica
View Article Online
DOI: 10.1039/C9TA12416K
materials for immobilized organocatalysts.
particles.
The oxidation of alcohols to aldehydes is an important reaction, We aim to demonstrate the potential of the system by
since a wide range of functionalities can be integrated into a investigating the activity of the material in heterogeneous and
molecule starting from aldehydes. A variety of reagents can be continuous flow oxidation of benzyl alcohol and a two-step
used for the oxidation of alcohols to carbonyl groups. The synthesis of ethyl-2-cyano-3-phenylacrylate in a continuous
preparation of aldehydes requires a careful selection of reaction setup. By choosing a catalyst system with a co-catalyst, we
conditions in order to prevent over-oxidation to carboxylic address the importance of good accessibility of the surface
acids; the key is the meticulous exclusion of water. This is through the mesopores and the long-term effects of the co-
possible with chromate reagents, but they generate toxic and catalyst on the immobilized catalyst. Particular emphasis is put
carcinogenic chromium(VI) waste in stoichiometric quantities. on the comprehensive characterization of the system consisting
Alternative synthesis routes without the use of heavy metals of mesoporous silica and organocatalyst. The successful
include Swern oxidation and oxidation by Dess-Martin immobilization of the organocatalyst was verified by infrared
periodinane.
spectroscopy, thermogravimetric analysis, and elemental
An alternative approach is the use of the persistent radical analysis, while the influence of functionalization on the
TEMPO, either as a stoichiometric oxidant or as a catalyst with mesoporosity was studied with physisorption experiments. The
a co-oxidant, which may allow control of reaction conditions macroscopic structure was monitored with scanning electron
and selectivity. The most widely used experimental procedure microscopy (SEM). By measuring the radical character of the
9
using sodium hypochlorite was developed by Anelli et al. For catalyst with electron paramagnetic resonance (EPR), we
continuous flow applications, a major drawback of the Anelli monitored the effect of catalyst activation. Basic organocatalyst
oxidation is the use of a two phase system. These disadvantages performance parameters were determined, especially the
can be avoided by the use of (diacetoxyiodo)benzene (DAIB), a impact of the catalyst loading on the yield, the dependence on
mild co-catalyst that also tolerates many functional groups like the flow rate, and the stability. Finally, we discuss the
amines, base-labile compounds, and alkenes that usually lead performance of the functionalized particles in relation to a
to side products when using sodium hypochlorite. Due to its heterogeneous batch reaction, in order to scrutinize the
wide substrate scope, DAIB has been used in various potential of organocatalysts applied in continuous flow.
1
0,11,12
homogeneous
oxidations.
and heterogeneous TEMPO-mediated
1
3,14,15
Experimental
Materials
While the oxidation of alcohols using immobilized TEMPO has
already been investigated intensively for discontinuous batch
3,7,16–27
systems,
only few studies investigate continuous flow
Chemicals were purchased from Sigma-Aldrich (benzyl alcohol
experiments with immobilized TEMPO. Bogdan et al. and Okuno
et al. both reported polymer-supported TEMPO and a two-
phase flow system for the Anelli oxidation of various
≥
99%;
N-chlorosuccinimide ≥ 98%, ethyl cyanoacetate ≥ 98%,
-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl ≥ 97%, copper(I)
iodide ≥ 97%, sodium azide ≥ 99%, Amberlite IRA-96), Carl-Roth
N,N-diisopropylethylamine 99.5%, ethylenediaminetetraacetic
acid disodium salt 99%) or Alfa-Aesar (propargyl bromide, 80 w.-
in toluene). Dry solvents were purchased from Acros Organics
water < 50 ppm). Non-water free solvents were purchased
(3-chloropropyl)trimethoxysilane
≥
97%,
4
2
8,29
substrates.
Aellig et al. used a silica-based TEMPO catalyst
and HNO in a
combined with a co-catalyst system based on O
2
3
(
three phase continuous flow reaction under relatively high
pressures (up to 5 bar), but thorough characterization of the
catalyst material was not carried out.30
There are two main approaches to synthesize organo-
functionalized silica: co-condensation to imbed the organic
moieties directly into the silica framework during synthesis of
the porous silica or post-synthetic grafting, whereby the surface
of porous silica materials is functionalized with organosilanes.
%
(
from VWR (HPLC grade). The silica material was purchased from
Merck (LiChrospher® Si 100, particle size 5 µm).
Preparation of catalyst
The latter approach allows for the synthesis of a pure and stable Synthesis of propargylether-TEMPO. 0.85 g (21.3 mmol) of
mesoporous silica matrix, which is not impeded by the presence sodium hydride were dispersed in 100 mL dry DMF under argon.
of organic groups. Furthermore, there are no organic molecules The mixture was cooled to 0 °C. 3.00 g (17.4 mmol) 4-Hydroxy-
trapped inside the silica framework, which leads to well-defined TEMPO were added and the solution was stirred for 30 min.
catalyst loading. Organocatalysts can be immobilized 2.5 mL propargyl bromide (22.4 mmol, 80 w.-% in toluene) were
subsequently through functionalization of the organosilane, slowly added and the mixture was stirred for 3 h at room
preferably with low by-product generation, e.g., by click- temperature. 100 mL water were added and the aqueous phase
31–36
was extracted with ethyl acetate. The organic layer was washed
chemistry approaches.
The preservation of activity during
immobilization requires careful selection of the reaction with water. After removing the solvent, the product was
parameters. Additionally, it is a demanding task not to purified via column chromatography (ethylacetate/hexane 1:9).
mechanically damage the material during grafting. Since the 2.38 g (11.3 mmol) of propargylether-TEMPO was obtained as
literature mostly deals with ordered pore systems or an orange solid (65%).
23,25–27,37–39
structurally undefined silica gels,
we performed a
2
| J. Name., 2012, 00, 1-3
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Journal Name
1H NMR (400 MHz, CDCl
ARTICLE
3
): δ = 4.17 (d, J = 2.3 Hz, 2H), 3.89–3.82 When determining the TEMPO loading of the functionalized
View Article Online
DOI: 10.1039/C9TA12416K
(
(
(
2
C
m, 1H), 2.42 (app t, J = 2.3 Hz, 1H), 2.00–1.88 (m, 2H), 1.53 particles by elemental analysis, non-reacted azide groups must
13
app t, J = 12.0 Hz, 2H), 1.25 (s, 6H), 1.19 (s, 6H) ppm; C NMR be included in the calculation. The nitrogen content originating
100 MHz, CDCl ): δ = 80.2, 74.2, 69.8, 59.8, 55.4, 44.3, 32.0, from TEMPO molecules %NTEMPO was calculated from the
0.8 ppm; HRMS (ESI–TOF): [M + Na]+ calculated for measured CHN contents %XEA and the CHN content of the
3
12
H
20NO
2
Na: m/z = 233.1386; found: m/z = 233.1393; EA: preliminary azide stage %Xazide
: C 68.54; H 9.59; N 6.66%; found: C
.
calculated for C12H20NO
2
6
8.72; H 9.66; N 6.64%.
%푁푇퐸ꢀ푃푂 =
(
2)
%
푁퐸퐴 ∙ ꢁ100 − (%푁푎푧푖푑푒 + %퐶푎푧푖푑푒+%퐻푎푧푖푑푒)ꢂ
Synthesis of (3-azidopropyl)trimethoxysilane. 0.806 g
1
00 − (%푁퐸퐴 + %퐶퐸퐴 + %퐻퐸퐴)
(
(
2.18 mmol) tetrabutylammonium iodide and 7.06 g
109 mmol) sodium azide were dried in a desiccator. The solids
%
푁푇퐸ꢀ푃푂 − %푁푎푧푖푑푒
were transferred into a flask and 25 mL of dry acetonitrile were
added under argon. 4.00 mL (21.8 mmol) (3-
chloropropyl)trimethoxysilane were added and the mixture was
푋푇퐸ꢀ푃푂
=
(1)
푁푎푑푑(N) ∙ 푀(N)
X
TEMPO
TEMPO loading
refluxed for 72 h. The solids were filtered off and the solvent N(N)
was evaporated under reduced pressure. The resulting solid
was dissolved in pentane and solid residues were removed by
filtration. 3.103 g (15 mmol, 70%) of a colourless liquid was
number of additional nitrogen atoms from TEMPO
functionalization (1)
obtained. The purity of the product was determined to be 87% Characterization methods
by NMR. The crude product was used without further
The particles were investigated by scanning electron
microscopy (SEM, Zeiss Merlin) at an acceleration voltage of
kV and a current of 90 pA. The samples were sputter-coated
with platinum prior to the analysis. Nitrogen physisorption
experiments were performed at 77 K using a Quadrasorb evo
purification.
1
3
H NMR (400 MHz, CDCl ): δ = 3.57 (s, 9H), 3.26 (t, J = 6.8 Hz,
H), 1.74–1.67 (m, 2H), 0.71–0.68 (m, 2H) ppm; C NMR (100
3
13
2
MHz, CDCl
3
): δ = 52.8, 49.7, 21.6, 5.5 ppm; HRMS (ESI–TOF): [M
Si: m/z = 228.0775; found: m/z =
+
+
2
Na] calculated for C
28.0775.
6
H
15
N
3
O
3
(
Quantachrome Instruments). Surface areas and pore size
distributions were calculated using Brunauer-Emmet-Teller
BET) and Barret-Joyner-Halenda (BJH) models. The particles
(
Functionalization of silica particles with (3-azidopropyl)-
trimethoxysilane. 50 mg of the material (LiChrospher® Si 100,
particle size 5 µm) were heated to 80 °C under argon overnight.
After cooling to room temperature, 2 mL dry toluene and the
chosen amounts of water (e.g., 10 µL, 20 w.-%) and (3-
azidopropyl)trimethoxysilane (e.g., 18 µL, 0.098 mmol) were
added. The mixture was heated to 80 °C overnight in a shaking
water bath. The solvent was removed via centrifugation. The
material was washed with dichloromethane, methanol,
methanol:water 1:1 and dried at 40 °C under reduced pressure.
The azide loading of the functionalized material was calculated
from the nitrogen content obtained by elemental analysis.
were degassed for 12 h at 80 °C before the measurement.
Elemental analysis (EA) was performed with the CHN-analyzer
Flash EA-1112 (Thermo Scientific, microbalance Mettler Toledo
UMX2). For quantitative infrared-spectroscopy (IR) pressed KBr
pellets made of 2.5 mg sample substance and 197.5 mg KBr
were analyzed (Alpha FT-IR, Bruker Optics). The IR spectra were
–
1
recorded in a measuring range of 400–4000 cm with a
–
1
resolution of 2 cm . Thermogravimetric analysis was done with
a continuous heating rate of 5 °C min– with a measuring range
of 25–800 °C (STA 409 PC Luxx, Netzsch). EPR was performed at
room temperature with a microwave frequency of 9.78 GHz and
microwave power of 200 mW (Bruker ESP 300). For the
determination of the spin concentration, an amorphous carbon
1
%
푁
푋푎푧푖푑푒
=
(1)
1
13
sample was used for calibration. H and C nuclear magnetic
resonance (NMR) spectra were recorded in CDCl on a Bruker
푁(N) ∙ 푀(N)
3
X
azide azide loading
Advance II 400 MHz at 298 K. Chemical shifts (δ) are given in
ppm relative to tetramethylsilane (TMS, δ = 0.00 ppm) as the
internal standard. Data are reported as follows: chemical shift
%
N
nitrogen content
N(N) number of nitrogen atoms in immobilized azide (3)
M(N) molar mass of nitrogen
(
multiplicity, coupling constants (Hz), integration). HRMS
measurements were carried out with a Bruker Daltonics
MicroTOF II. Catalytic reactions were monitored via gas
chromatography with a flame ionization detector (HP 5890
Series II with capillary column DB-Wax 17, Agilent
Technologies). Continuous flow experiments were carried out
using an HPLC pump (Hitachi L-600, Merck) and a column oven
Functionalization of silica-azide with propargylether-TEMPO.
5
3
0 mg of azide functionalized silica particles were suspended in
mL toluene. 0.92 mg copper iodide (4.85 µmol), 98.9 µL N,N-
diisopropylethylamine
(582 µmol)
and
18.36 mg
propargylether-TEMPO (87.3 µmol) were added and the
mixture was heated to 50 °C in a shaking water bath for 72 h.
The solvent was removed via centrifugation. The material was
(
Hitachi Column Oven L-7300, Merck).
2
washed with acetonitrile, methanol, Na EDTA (5 w.-%), water
and dried at 40 °C under reduced pressure.
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
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DOI: 10.1039/C9TA12416K
4
3
2
1
0
0
0
0
0
0
1
2
3
4
5
elemental analysis (nitrogen) / w.-%
Fig. 1 SEM images of the mesoporous silica particles used as solid support for the
organocatalyst (a and b) and particles damaged by stirring too vigorously (c).
Fig. 3 Correlation of azide band intensity and elemental analysis data.
catalyst material was added and the mixture was shaken gently
for 15 min. After the reagents were removed by centrifugation
the material was washed with dichloromethane and left to air
dry.
Catalytic tests
Heterogeneous
catalysis.
0.266 g
(0.825 mmol)
(
diacetoxyiodo)benzene were dissolved in 3.67 mL acetonitrile
using an ultrasonic bath. 78 µL (0.75 mmol) benzyl alcohol were
added. After addition of the heterogeneous catalyst, the
suspension was stirred at room temperature/40 °C for 5 h
Yield determination of benzaldehyde. Aliquots of 150 µL were
taken at 15, 30, 60, 120, and 300 min reaction time. The aliquot
was diluted with 450 µL tert-butyl methyl ether and 10 µL
hexadecane were added. The mixture was analyzed via gas
chromatography. Yields were determined with a calibration
series of benzaldehyde using hexadecane as internal standard.
(
350 rpm). To extract an aliquot, the suspension was
centrifuged for 2 min at 7500 rpm. After taking the aliquot the
mixture was re-suspended. For recycling tests, the material was
washed with acetonitrile and dried at 40 °C under reduced
pressure.
Heterogeneous catalysis in continuous flow. The catalyst
material was packed into stainless steel HPLC columns
Results and Discussion
(
diameter 0.46 cm, length 5.0 cm). The column was heated in a Preparation and characterization
column oven and the reaction mixture was pumped through
with an HPLC pump.
Spherical, porous silica particles (that are commercially used in
HPLC) with a particle diameter of 5 to 7 μm and a pore diameter
of approx. 100 Å were chosen as the support for the
heterogeneous catalyst. An overview of the particles and their
porous interior is shown in Fig. 1 a and b. The specific BET
Catalyst activation. Example for 39 mg of 1.0 mmol g–1 Silica-
TEMPO: 30 mg (0.2 mmol) N-chlorosuccinimide and 47 µL HCl in
dioxane (4 M) were dissolved in 4 mL dichloromethane. The
2
–1
surface area was determined to be 400 m g by a nitrogen
Fig. 2 Grafting of azide groups onto the mesoporous silica particles (a) and copper(I)- physisorption measurement.
catalyzed cycloaddition between the azide-functionalized support and propargylether-
The uniformity and spherical shape of the particles is of great
TEMPO (b).
value because it allows dense and homogeneous packing,
40
leading to low back pressures in continuous flow. Therefore,
-
1
Fig. 4 Thermogravimetric analysis of silica-TEMPO (1.0 mmol g ).
1
00
0.0
9
9
8
8
7
7
5
0
5
0
5
0
-0.2
-0.4
-0.6
-0.8
25% weight loss
1
00
200
300
400
500
600
700
800
T / °C
4
| J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
0.5 equiv Az-PTMS
View Article Online
DOI: 10.1039/C9TA12416K
2
0 w.-% H O
2
1
0 w.-% H O
2
azide loading:
1.0 mmol/g
0
.6 mmol/g
.3 mmol/g
0
water-free
synthesis
after reaction
with TEMPO
2000
2100
2200
2300
500
1000
1500
2000
2500
3000
3500
4000
wavenumber / cm-1
wavenumber / cm-1
Fig. 5 Influence of water on azide loading with same amounts of Az-PTMS (left) and correlation between azide loading and intensity of the azide band in IR spectra (right). After
functionalization with TEMPO the azide band disappears.
it is important not to destroy the particles during under inert conditions. Since a completely water-free reaction
functionalization. SEM images reveal damaged particles after a resulted in materials with negligibly small azide loading, defined
functionalization experiment using a magnetic stirring bar (Fig. amounts of water were added to the reaction. Elemental
1
c). To avoid damaging of the particles, functionalization analysis, IR spectroscopy, and nitrogen physisorption
experiments were carried out in a shaking water bath. experiments show the influence of different amounts of water
A click-chemistry approach was used to functionalize the silica on the loading, with higher water content resulting in higher
material with TEMPO (Fig. 2).33,41 The copper-catalyzed loading of azide groups (Table 1, Fig. 3). The azide loading of the
cycloaddition between an azide group and an alkyne group functionalized material was calculated from the nitrogen
produces high yields under mild reaction conditions with content obtained by elemental and thermogravimetric analysis
negligible by-product formation.
The first functionalization step is a grafting reaction with of the azide band from IR spectroscopy (Fig. 5, left).
3-azidopropyl)trimethoxysilane (Az-PTMS). The equivalents of In the second functionalization step, propargyl ether-TEMPO
Az-PTMS used refer to the number of hydroxyl groups on the was immobilized on the silica-azide particles. The progress of
(Fig. 4). The EA data reveal good agreement with the integration
(
–
2
silica particles (a surface concentration of 8 µmol m was the reaction can be easily followed by the vanishing of the azide
42
assumed). The amount of water present in the reaction band in IR spectroscopy (Fig. 5, right). Thermogravimetric data
mixture plays a major role in the resulting loading of the show the decomposition of immobilized TEMPO at
material. Water promotes the condensation reaction between temperatures of 170–470 °C. The catalyst loading calculated
the organosilanol and the silica surface hydroxy groups, but also from the mass loss is in good agreement with the results
leads to increased homocondensation between silanols. This
reduces the reactivity towards the surface, and no uniform
monolayer forms.
Fig. 6 Effect of normalization to silica content for TEMPO functionalized silica material
(
4
3–46
1.0 mmol g-1).
To control the amount of water present in the reaction, the
silica was heated under reduced pressure and functionalized
1000
silica
silica-TEMPO as measured
silica-TEMPO normalized
Table 1 Summary of experiments with various amounts of Az-PTMS and water, and
resulting material loading. Amount of Az-PTMS relative to amount of silica hydroxyl
800
amount
of
Az-PTMS
equiv
H
w.-%
2
O
N
(EA)
w.-%
loading
mmol g
BET
surface
loading
µmol m
6
00
–
1
m2 g
–1
–
2
400
0
0
0
0
0
0
0
.5
.5
.5
.2
.2
.1
.1
0
0.7
4.5
5.9
2.4
3.1
1.9
1.7
0.1
0.9
1.1
0.4
0.6
0.3
0.4
380
330
340
380
340
400
360
0.3
2.3
2.8
1.1
1.5
0.7
1.0
10
20
10
20
10
20
2
00
0
0.0
0.2
0.4
0.6
0.8
1.0
relative pressure p/p0
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DOI: 10.1039/C9TA12416K
1
000
1000
1000
800
600
400
200
0
silica
silica
silica-azide
silica-TEMPO
silica
water-free synthesis
1.0 mmol/g
0.6 mmol/g
0.3 mmol/g
10w.-% H O
8
6
4
2
00
00
00
00
0
2
800
600
400
200
0
20w.-% H O
2
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
0.0
0.2
0.4
0.6
0.8
1.0
relative pressure p/p0
relative pressure p/p0
relative pressure p/p0
1
.4
.2
.0
.8
.6
.4
.2
.0
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
pore size shift
pore size shift
pore size shift
0
.20
0.20
0.15
0.10
0.05
0.00
0.20
0.15
0.10
0.05
0.00
1
1
0
0
0
0
0
0.15
0
.10
.05
silica
water-free
10w.-% H O
0
silica
silica
silica-azide
silica-TEMPO
1.0 mmol/g
0.6 mmol/g
0.3 mmol/g
2
20w.-% H O
2
0.00
5
10
15
20
25
30
35
5
10
15
20
25
30
35
5
10
15
20
25
30
35
pore size / nm
pore size / nm
pore size / nm
2
Fig. 7 N -physisorption isotherms (top) and BJH pore size distributions (bottom) of functionalized particles with various amounts of water (left), before and after two-step
functionalization (middle) and various amounts of immobilized TEMPO catalyst (right).
obtained from elemental analysis, showing a complete higher decrease in the pore size distributions than small pores
functionalization of azide groups with TEMPO moieties.
(<7 nm), which remain constant in their contribution to the
Maintaining the mesoporosity is important for good volume. This leads to a slight decrease in the mean pore size
accessibility of the catalyst molecules for substrates and with higher content of immobilized species (Fig. 7).
regeneration reagents. To study changes of the mesoporous
space after the functionalization steps, nitrogen physisorption Heterogeneous catalysis
experiments were carried out. For meaningful comparison, the
Benzyl alcohol was chosen to test the performance of the
data for the functionalized particles must be corrected for the
immobilized TEMPO catalyst in oxidation reactions (Fig. 8).
mass increase through functionalization so that all samples are
Importantly, benzaldehyde formed in the oxidation reaction is
sensitive to over-oxidation to benzoic acid, but the GC-spectrum
normalized to the same silica content (Fig. 6).
푉푚푒푎푠푢푟푒푑
of a test reaction with benzyl alcohol (Fig. 9) does not show
benzoic acid formation, meaning that the immobilized TEMPO
푉푛표푟푚푎푙푖푧푒푑
=
(3)
1
− ꢁ푋 ∙ 푀(TEMPO)ꢂ
X
catalyst loading of the material
Fig. 9 Typical GC signals of a reaction mixture aliquot.
M(TEMPO) molar mass of immobilized species
The BJH method was used to determine the pore size
distribution since a DFT kernel for SiO could not depict the
change in polarity of the surface after functionalization.
The physisorption data confirm the results from IR spectroscopy
and elemental analysis. Higher loading of organic molecules
reduces the BET surface area and the pore volume. Larger pores
2
3
2
1
x105
x105
(
bigger than 10 nm) are preferably functionalized and show
x105
Fig. 8 Oxidation of benzyl alcohol with co-catalyst DAIB as a test reaction for the
heterogeneous catalyst.
0
0
5
10
15
20
25
30
t / min
6
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Due to the reaction conditions during functionalization, the
View Article Online
DOI: 10.1039/C9TA12416K
catalyst is initially present mostly as the inactive hydroxyl
species. It is possible to use the catalyst as synthesized, but the
conversion to the active species by the co-catalyst takes some
time, thus slowing the reaction. The treatment of the material
with N-chlorosuccinimide (NCS) and HCl in dioxane ensures
rapid transformation of the material into the active species.47
This change can be traced by the color change from white to
orange (Fig. 11).
To quantify the effect of the activation on the catalyst, an
electron paramagnetic resonance (EPR) spectrum was
recorded. The EPR signal of TEMPO consists of three lines (due
to the unpaired electron interactions with the nitrogen nucleus)
that merge into a broad single line at high concentrations. For
the catalyst material, a partially resolved EPR structure was
26,48–51
observed.
after activation was calculated (Table 2), enabling an estimation
catalyst has retained its ability to oxidize substrates to the what proportion of the immobilized TEMPO is present as a
corresponding aldehydes.
radical.
The spin content of the material before and
Fig. 10 Regeneration of TEMPO with the secondary oxidation agent DAIB.
Since TEMPO was not intended to be used stoichiometrically, a In the untreated material, about one third of the TEMPO
co-catalyst was needed to regenerate TEMPO during the molecules is present in radical form, which means that two-
reaction. Diacetoxyiodobenzene (DAIB) was chosen as a mild thirds exist in the hydroxyl form. After activation, the measured
secondary oxidation agent. Fig. 10 summarizes the reaction spin content is about 1% of the maximum spin content. This
cycle of TEMPO during the oxidation.
suggests that virtually all molecules are converted into the
oxoammonium species through activation. After activation, the
material needs to be washed thoroughly because NCS residues
can disturb the reaction by converting benzyl alcohol to benzoic
acid.
Fig. 11 The EPR spectrum of silica-TEMPO shows a partially resolved structure (top).The
conversion of the hydroxylamine species to the oxoammonium of TEMPO is
accompanied by a color change (bottom).
6
4
2
00
00
00
0
Fig. 12 shows the catalyst performance (batch mode) after
activation for three different TEMPO loadings (0.3, 0.6, and
-
1
1
.0 mmol g ). At 40 °C with 5 mol% catalyst high yields are
Fig. 12 Performance of the heterogeneous TEMPO catalyst for the oxidation of benzyl
alcohol to benzaldehyde (top) and recycling tests carried out with 0.6 mmol g–1 silica-
TEMPO (bottom).
-200
-400
-600
3
1
00
7
5
2
5
0
5
0
350
3400
3450
3500
3550
3600
3650
H / Gauss
5 mol% cat., 40 °C, MeCN, activated
homogeneous
0.6 mmol/g
1.0 mmol/g
0.3 mmol/g
0
50
100
150
t / min
200
250
300
3
1
6
3
00 min
20 min
0 min
100
0 min
7
5
0
15 min
Table 2 Calculated spin content for the immobilized TEMPO catalyst before and after
activation with NCS/HCl.
5
Spin content % of maximum spin content
–
1
25
0
g
before activation
after activation
1.1∙1020
2.6∙1018
30
1
1
2
3
4
5
recycling #
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Fig. 14 Schematic illustration of the continuous flow experiment.
Fig. 13 Photograph of a stainless steel column filled with the immobilized catalyst.
at room temperature. To test this hypothesis, the reaction
conditions were simulated by stirring a solution of TEMPO and
acetic acid with appropriate concentrations for two days.
Analysis with ESI-MS showed an intense m/z signal not present
in the reference measurement. The signal indicates the
presence of TEMPH (m/z 142.1590 [M+H ], found: 142.1592).
From this, we conclude that the immobilized TEMPO
decomposes on the silica surface in a similar way.
achieved with the heterogeneous catalyst system. Surprisingly,
the material with the highest loading shows the worst
performance in catalytic tests, presumably because of diffusion
limitation due to the narrowing of the pore entrances, or steric
impairment of the individual TEMPO functionalities.
Furthermore, it cannot be guaranteed that the functionalization
is largely immobilized in form of a monolayer on the particle.
Inner layers of a multilayer contribute to loading calculations in
characterization methods such as elemental analysis, but do not
+
Flow catalysis
participate in the oxidation reaction. The effective particle The silica particles used in this paper are designed to withstand
loadings can therefore be much lower than the calculated HPLC applications with high pressures and high flow rates. To
–
1
loading of 1 mmol g . The material with a medium catalyst take advantage of these benefits, we chose to use a classic
loading of 0.6 mmol g– shows the best performance and is a stainless steel column for continuous flow experiments. The
good compromise between activity and material consumption. particles can be packed into the column with high pressure,
As expected, the control experiment with homogeneous creating a dense and homogeneous bed with good flow
TEMPO proceeds faster: the two-phase system of solvent and characteristics. The material loaded with 0.6 mmol g–1 catalyst
immobilized solid catalyst limits the contact area compared to was packed in HPLC columns (Fig. 13). Before packing, the
1
a homogeneous mixture.
material was treated with the activation reagent. 310 mg of
Since the immobilized catalyst was envisaged to be used in a material was used for a column with a diameter of 0.4 cm and a
continuous flow setup, recycling experiments were performed length of 5 cm (volume = 0.63 mL). Alcohols such as methanol
first. For this, the material was centrifuged, washed, and reused or isopropanol are typically used as packing solvents; in order to
five times after the initial test reaction. The activation reaction avoid oxidation with the immobilized TEMPO, the columns were
with NCS and HCl does not need to be repeated after the first packed using acetone as solvent. For catalyst tests in continuous
time. The first three cylces show no decrease in yield. In the flow, the same concentrations and temperatures as in
fourth and fifth reuse, the performance of the catalyst declines heterogeneous batch catalysis were used. The reaction solution
from 97% to 77% and 65%, respectively.
containing the substrate benzyl alcohol and the co-catalyst DAIB
Various post-catalytic measurements were performed to was pumped through the column with an HPLC pump. Fig. 14
determine why the activity of the material decreases. Leaching shows a schematic illustration of the experiment.
of the catalyst can be excluded by EA and physisorption analysis The oxidation of benzyl alcohol was carried out in continuous
of the used material, hence a change in the catalyst at the flow at different flow rates and the conversion of the reaction
molecular level is more likely to occur. Ciriano et al. investigated product was determined by GC (Fig. 15, Table 3). The turnover
the stability of TEMPO and its derivatives.52 According to their frequency (TOF) was calculated based on the concentration of
research,
TEMPO
can
decompose
to
2,2,6,6- the product cproduct, the flow rate F, and the amount of catalyst
tetramethylpiperidine (TEMPH) via hydroxylamine at ncat.
temperatures above 105 °C. Acids such as ascorbic acid catalyze
this reaction. It is plausible that prolonged contact with acetic
acid formed during the reaction causes similar decomposition
ꢅ푝푟표푑푢푐푡
ꢇ푝푟표푑푢푐푡 ∙ 퐹
ꢃꢄ퐹 =
=
(4)
ꢅ푐푎푡 ∙ ꢆ푟푒푎푐푡푖표푛
ꢅ푐푎푡
Table 3 Key data of the continuous flow experiments with calculated turnover At the lowest flow rate of 0.05 mL min–1 (and therefore a
frequency.
residence time of approximately twelve minutes) the highest
conversion of 89% was obtained. As the flow rate increases, the
flow rate residence time back pressure yield TOF
conversion of benzaldehyde decreases, while the TOF increases.
The benzaldehyde formed was not oxidized to benzoic acid as
evident in the gas chromatogram.
mL min–1
.05
s
bar
1
2
%
h
–1
0
816
408
82
89
73
48
3.2
5.3
17.5
0
0
.1
.5
7
8
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1
7
6
0
0
8
6
4
2
0
0
0
0
0
6
5
4
3
2
1
0
5
40
30
20
10
0
DAIB only
0.05
0.1
0.5
1
2
3
4
5
t / h
6
7
8
9
-
1
flow rate / mL min
Fig. 15 Yield of benzaldehyde for continuous flow oxidation with different flow rates and corresponding pressure built-up (left); long-term catalytic test of a second column filled
with silica-TEMPO (right, flow rate 0.05 mL min–1).
Particularly remarkable are the low back pressures of the Multi-step reaction in continuous flow
system. At low flow rates, nearly no pressure build-up is
The wide substrate scope of oxidations catalyzed by
immobilized TEMPO has been well established, so we decided
measurable. When switching to higher flow rates, the pressure
only rises slightly, which means longer columns (that will
produce even higher yields due to higher contact times) could
be used without running into pressure limitations.
The flow rate tests were followed by a long-term test with a
second column (Fig. 15, right). The activity of the column
material remains constant for 6 h, after which the yield of
benzaldehyde decreases.
53
to focus on the possibilities of continuous flow catalysis instead.
In order to take advantage of the continuous flow synthesis, a
second reaction step was added to the reactor setup. The two-
step synthesis of ethyl-2-cyano-3-phenylacrylate from benzyl
alcohol was carried out in continuous flow (Fig. 16). The TEMPO-
functionalized silica column was combined with an amino-
functionalized silica column that was synthesized using (3-
aminopropyl)trimethoxysilane. This second column had a
Comparison to the homogeneous reaction
–1
catalyst loading of 1.1 mmol g . It can catalyze the Knoevenagel
The direct comparison of heterogeneous catalysis in continuous condensation of an aldehyde with an active hydrogen
flow with the homogeneous reaction can be problematic and is compound bearing an electron withdrawing functional
therefore usually not discussed. One method is to scale the group.54,55 The amino-functionalized silica column achieved a
homogeneous reaction so that it uses the same amount of yield of 90% when tested separately in the condensation
–
1
catalyst as the heterogeneous column reactor. This leads to a reaction of benzaldehyde with ethyl cyanoacetate (0.2 mol L ,
–
1
homogeneous reaction using 0.186 mmol TEMPO to oxidize 0.05 mL min ).
.7 mmol benzyl alcohol. In order to carry out the oxidation with TEMPO and the
3
The two highest flow rates produce more benzaldehyde than Knoevenagel reaction in one continuous setup, an acid
the homogeneous experiment at the end of the batch scavenger column needed to be inserted between the two
experiment (5 h), and the TOF of the highest flow rate is catalyst columns. Amberlite® IRA-96 was used to trap acetic
comparable to the homogeneous reaction.
acid formed from DAIB, as the acid interferes with Knoevenagel
To take into account how much substrate is used for a given
Table 4: Comparison of homogeneous batch and heterogeneous flow catalysis. The
amount of product, it is useful to consider the reactions under batch experiment was scaled to the same amount of catalyst the flow experiment used
normalization to the amount of benzyl alcohol used. The (0.186 mmol). The reaction was carried out with 0.2 mmol mL–1 substrate and 5 mol%
catalyst.
homogeneous reaction thereby determines the amount of
flow rate yield
product
amount at
end of batch
TOF
h
t for
3.7 mmol
BnOH use
min
product
amount
mmol
reactant for the comparison. The time it takes this amount of
benzyl alcohol to flow through the column is calculated for the
three flow rates. With high flow rates, the reaction time is
shorter, but the product quantity is smaller due to incomplete
conversion. These approaches can only give a rough overview
of the performance of the catalyst column in comparison to
homogeneous catalysis; further studies need to take into
account additional aspects like operating costs and different
column lengths.
−
1
–1
mL min
%
(
5 h)
mmol
3.7
batch
99
89
73
48
19.7
3.2
300
372
186
37
3.7
3.3
2.7
1.8
0
.05
0.1
.5
2.7
4.4
5.3
0
14.4
17.5
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Fig. 16 Schematic illustration of the multi-step synthesis step.
condensation by deactivating the catalyst. The scavenger can be
regenerated by treatment with sodium hydroxide in ethanol
and be reused without loss of capacity.
Notes and references
The yield over both steps for a substrate concentration of 1.
0
combination of three columns, the back pressures remain at
low levels while the yield of the reaction is comparable to the 3.
total yield of the individual steps.
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Conclusions
A heterogeneous organocatalyst was prepared by immobilizing
TEMPO on mesoporous silica particles, which are optimized for
HPLC applications. With IR, elemental, and nitrogen
physisorption analysis, we show that the amount of water
during functionalization has significant influence on the
resulting catalyst loading and performance. The material was
investigated with EPR spectroscopy, suggesting performance
enhancement by activation with NCS. In catalytic tests, the
silica-TEMPO catalyst showed good conversion of benzyl
alcohol to benzaldehyde. Long-term tests and post-catalytic
analyses reveal that the co-catalyst DAIB leads to catalyst
decomposition over time, therefore other co-catalysts should
be considered for long-term use. In flow experiments only little
pressure build-up in the column was detected. With the highest
6
2
2
2
1
V. Chiroli, M. Benaglia, A. Puglisi, R. Porta, R. P. Jumde, A.
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1
1
flow rate, about 0.3 g h– benzaldehyde is produced by one
1
column. A novel two-step continuous flow synthesis with the 13. H. A. Beejapur, V. Campisciano, F. Giacalone and M.
immobilized catalysts TEMPO and aminopropyl delivered ethyl-
Gruttadauria, Adv. Synth. Catal., 2015, 357(1), 51.
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2
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There are no conflicts to declare.
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Journal of Materials Chemistry A
Page 12 of 12
View Article Online
DOI: 10.1039/C9TA12416K
TEMPO was immobilized on continuous-flow-optimized mesoporous silica particles and a
TEMPO/DAIB mediated oxidation followed by Knoevenagel condensation was investigated.