Direct Asymmetric Aldol Reaction in Continuous Flow Using Gel-Bound Organocatalysts

Article abstract of DOI:10.1002/ejoc.202100268

Continuous flow catalysis using a microfluidic reactor with gel-bound proline organocatalysts is an attractive approach in organic synthesis due to interesting advantages such as the permanent production of catalyst-free products and the easy product isol

Full text of DOI:10.1002/ejoc.202100268

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Direct Asymmetric Aldol Reaction in Continuous Flow
Using Gel-Bound Organocatalysts
[a]
[a]
[a]
Carsten J. Schmiegel, Rene Baier, and Dirk Kuckling*
Continuous flow catalysis using a microfluidic reactor with gel-
bound proline organocatalysts is an attractive approach in
organic synthesis due to interesting advantages such as the
permanent production of catalyst-free products and the easy
product isolation by evaporation. Further advantages are the
online detection of reactions and an adjustment of reaction
parameters while the reaction is already running. Herein the
formation of differently substituted aldol products within
minutes at mild conditions in good to almost quantitative yields
is described. The effects of different solvent mixtures and
temperatures on the conversion and selectivity are analyzed in
detail by NMR as well as the relationship between the height of
the polymer structures and the conversion behavior of the
asymmetric aldol reaction of 4-nitrobenzaldehyde and cyclo-
hexanone. The applicability of this system is demonstrated for a
wide range of differently substituted nitrobenzaldehydes. It is
shown that the described reactor setup delivers high con-
version and good selectivity over up to 144 hours and that a
highly reusable system was established.
Introduction
selected as the initial example (Figure 1). Organocatalysts, and
L-Proline in particular, have become important catalysts for CÀ C
[7]
A useful tool for continuous product synthesis in modern
chemistry and especially in organic synthesis are flow reactors.
Advantages of flow reactors in general and microfluidic reactors
linking reactions with directed enantioselectivity. Using L-
proline-based catalysts offers a great advantage for the
asymmetric aldol reaction in particular. Namely, the ketones
used do not have to be converted into an enol in order to be
[
1]
(MFRs) in particular are the continuous operation, a possible
[2]
[8]
online detection, and the opportunity of an adjustment of
made accessible for the aldol addition. L-proline is a natural
[3]
reaction parameters during an ongoing reaction. Particular
advantages of microfluidic reactors are an outstanding heat
transfer which, together with a laminar flow, leads to good
control of the reaction conditions such as heating, cooling, and
mixing behavior of educts. These advantages combined with
the small amount of chemicals required for an MFR lead to a
more economic and in particular safer reaction. On the basis
of the previously mentioned advantages, using MFRs is
especially beneficial for a fast screening of reactions. The
combination of MFRs with highly active and selective organo-
catalysts such as proline appears to be a promising goal of
modern synthesis methods. Proline and especially supported
derivatives of L-proline are versatile organocatalysts for various
amino acid and therefore carries chiral information with it so
that the aldol addition is performed as an asymmetric reaction.
Li et al. showed that the chiral information can be transferred
well to the product and the products can be isolated with good
[9]
enantioselectivities. The aldol reaction is known to be
accelerated by L-proline in the presence of water, which also
[4]
[10]
leads to improved enantioselectivity. There are many exam-
ples of polymer-supported L-Proline moieties catalyzing aldol
reactions. L-proline moieties are immobilized on the surface of
[
11]
[12]
solid particles,
single-chain nanoparticles,
or as part of
[13,14]
block copolymers in micellar catalysis.
Especially for organo-
catalysts a high catalyst loading and an efficient recovery, as
well as recycling, is essential for satisfactory results due to
[5]
[13]
reactions in organic chemistry. In particular, they can be used
for Aldol and Michael addition as well as for aldol
rather low turnover numbers of the catalysts.
To prevent a loss of the catalytically active species and to
enlarge the catalytic activity inside flow reactors, catalysts can
be integrated within crosslinked polymer networks. Such
immobilized catalysts combine the physical properties of the
carrier material with the catalytic activity of catalysts to improve
[6]
condensations. In this way, L-proline and its derivatives offer
the possibility of examining their catalytic ability on the basis of
many different reactions. In this work, the aldol addition was
[13,15]
[13]
[16]
the reusability
and long-term activity of the catalysts.
[
a] C. J. Schmiegel, R. Baier, Prof. Dr. D. Kuckling
Department of Chemistry, Faculty of Science, Paderborn University
Warburger Str. 100, 33098 Paderborn, Germany
E-mail: dirk.kuckling@uni-paderborn.de
https://chemie.uni-paderborn.de/arbeitskreise/organische-chemie/kuck-
ling
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100268
©
2021 The Authors. European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited.
Figure 1. Reactionscheme for an asymmetric aldol reaction.
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An immobilization within crosslinked polymer networks enables
reactions inside of swollen, three-dimensional textures, which in
contrast to solid particles, increases the amount of immobilized
[16,17]
and accessible catalyst from surface area to bulk volume.
The general applicability of surface-bound gels with a high
crosslinker content as carriers of catalysts and enzymes in MFRs,
[18–20]
has already been shown recently.
In all three cases,
hexagonally ordered gel arrays, immobilized on glass slides,
were obtained via photolithography, and used for various
reactions within MFRs. Thus immobilization of tertiary amines
as catalysts in surface-bound gels is also possible and offers
access to a wide range of Knoevenagel reactions under
[19]
continuous flow conditions. In addition, the immobilization of
proline derivatives is also possible, which opens up access to
rather unusual adducts such as aromatic azoxy compounds
[20]
under mild reaction conditions.
Results and Discussion
Figure 2. Synthesis route for the bifunctional prolineamide 3.
Synthesis of bifunctional proline-amid catalyst
The basic approach of this work was to extend the successful
results of the Knoevenagel reaction in microfluidic reactor
[19]
systems to the more complex asymmetric aldol reaction.
Furthermore, a simple and inexpensive to manufacture organo-
catalyst should be immobilized within an MFR, which works
reliably at room temperature without additives and selectively
catalyzes the asymmetric aldol reaction between different
ketones and aldehydes. To achieve this goal, a reliable synthesis
route for the desired catalyst structure 3 had to be established.
The proposed synthesis route for the bifunctional prolineamide
Figure 3. Components of polymergel. Gel building component: methyl
methacrylate (MMA), crosslinker: ethylene glycol dimethacrylate (EGDMA),
catalyst structure (3).
[14]
3
is based on previous work. and involves the creation of an
amide bond between the carboxylic acid functionality of the N-
Boc-protected L-proline and the primary amine functionality of
L-leucinol in the first step as shown in Figure 2.
Based on prolineamide 1, subsequent Steglich esterification
of the alcohol function of 1 and the carboxylic acid of mono-2-
reactor design was adapted to the specific requirements of the
asymmetric aldol reaction. Namely, longer reaction times were
necessary to achieve high conversions. The reactor used had a
volume of 100 μl and a height of the reaction chamber of
140 μm. 662 catalytically active polymer dots were imple-
mented in this hardware setup. An illustration of the course of
photopolymerization as well as an illustration of the reactor
setup is shown in Figure 4 and Figure S2.
For continuously operated flow reactors, the size of the
reaction chamber available for the reaction is invariable. Hence,
it is important to make the best possible use of the available
reactor volume. Consequently, the flexible, swelling network
structures need to be adapted to the reactor geometry as best
as possible (Figure 5).
(methacryloyloxy)ethyl succinate finally yielded 2. Deprotection
of the N-Boc-prolineamide 2 with 4 N HCl in dioxane yielded
the HCl salt of the desired catalyst structure 3.
To implement the MFR and the catalytic concept, the
corresponding catalyst structure 3 then had to be immobilized
(see Figure 3). Prolineamide 3 was incorporated via photo-
polymerization using methyl methacrylate (MMA) as gel build-
ing component and ethylene glycol dimethacrylate (EGDMA) as
crosslinker (Figure 3).
In the run-up to the photopolymerization and in order to
ensure a covalent connection of the polymer network to the
object slides, the slides were modified with 3-(trichlorosilyl)
propylmethacrylate. This modification provides free methacry-
late functionalities on the surface of the slide, which serve as
anchor functionalities during the photopolymerization. Due to
the hydrophobic effect, a successful modification can be
verified by means of contact angle measurement (Figure S1).
The general reactor setup has already been described in a
In order to achieve this, the degree of swelling of macro-
scopic polymer workpieces was analyzed and the height
swelling of surface-bound polymers was adjusted based on the
[21]
[22]
work of Rühe
and Dostalek.
Images of the resulting
macroscopic polymer workpieces are presented in Figure S3.
Using confocal microscopy, the height of the attached
structures was determined to 106 (�19) μm as can be seen in
Figures S4 and Figure 6. In Figure S4, the original data obtained
from the confocal microscopy measurements are shown.
[19]
previous report. In the work presented here, however, the
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Figure 6. Average polymer height for different light exposure times in dry
state determined by confocal microscopy (blue bars). Calculated polymer
height in swollen state (green bars). Polymer composition: 90% catalyst, 5%
crosslinker, 5% methyl methacrylate.
Figure 4. Schematic illustration of the general structure of the diamond-
shaped reactor with 662 polymerdots (a). The mask used for polymerization
(
(
b) together with a typical example of the polymer structure after workup
c).
polymer composition, leading to a calculated height extension
of 1.57 for connected polymers.
On the basis of these results, the height of the polymer dots
was analyzed for different light irradiation times in order to
estimate an optimal use of the reactor chamber in the swollen
state. As shown in Figure 6, the height of the hexagonally
ordered gel structures increased from 23 (�6) μm after 6 sec of
irradiation and 73 (�11) μm after 9 sec to 106 (�19) μm after
1
1
2 seconds of irradiation. A further increase of the irradiation to
5 seconds led to a height of 122 (�12) μm and could not be
Figure 5. Schematic illustration of construction design of the glass surface/
PTFE stack.
increased by further extension of irradiation time. Using a
polymer composition containing 90 mol% catalyst, 5 mol%
crosslinker, and 5 mol% gel-forming component and an
irradiation time of 12 sec led to polymers with a calculated
height of 166 μm in swollen state and thus exceeds the height
of the reactor cell, which leads to more robust polymer-dot
arrays. Hence, this composition was selected for further analysis,
since this polymer composition showed the most pronounced
feedback in terms of conversion and diastereoselectivity using
4-nitrobenzaldehyde and cyclohexanone as a model reaction
for the optimization of the aldol reaction inside the MFR.
To calculate the increase in height of the attached gels,
macroscopic polymer samples similar to surface-bound gels
were prepared (monomer concentration of 3.34 M, an irradi-
ation time of 12 sec, and an intensity of 428 mW with 8 cm
distance between sample and UV-lamp). To release the proline
moiety from the HCl salt, a procedure established by Kristensen
[23]
was used.
Since the desired Aldol reaction takes place
essentially in DMSO, the degree of swelling was also analyzed
in DMSO. To ensure sufficient mechanical stability of the
polymer structures even with longer continuous operation, the
gel composition was set at 5% gelling agent, 5% crosslinker,
and 90% catalyst, also addressing the low turnover efficiency
compared to metal-based catalysts. The degree of swelling
investigated in DMSO for unattached gel samples was trans-
ferred to attached ones using equations (1) and (2) (see the
determination of the degree of swelling in the Experimental
The organocatalyzed asymmetric aldol reaction was ana-
lyzed regarding different parameters, such as solvent composi-
tion and temperature. As an initial investigation, different
solvent compositions of DMSO and water were screened
regarding conversion and selectivity. As can be seen in the
summarized results in Table 1, neither pure DMSO nor larger
proportions of water yield good conversion and selectivity at
room temperature (~23°C) (Table 1, entries 1 and 4). While all
of the reaction conditions analyzed led to sufficient conversions
with moderate selectivity, the solvent composition DMSO: water
(9:1) with 95% conversion and an anti-selectivity of 67:33 gave
the best results at room temperature (Table 1, entry 2). At a
[21]
Section) along with results from free swelling (Figure S3).
A
degree of swelling of 2.28 was obtained for the described
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cantly in both cases. After a polymerization time of 12 seconds
Table 1. Optimization of reaction conditions for the asymmetric aldol
reaction of p-nitrobenzaldehyde and cyclohexanone.
and a polymer height of 106 (�19) μm, the polymer structures
deliver an almost constant conversion of 97% after 6 hours and
9
2% after 24 hours of reaction time. In contrast to this, no
further increase in conversion can be achieved by further
extending the polymerization time. A further increase in
irradiation time leads to an increasingly unselective polymer-
ization and thus to the formation of larger polymer domains
without a fine structure. Consequently, efficient diffusion of the
reactants into the gel is made more difficult by the smaller
surface area. However, applying 15 seconds of irradiation,
leading to polymer structures of 122 (�12) μm, the reactor
delivers 87% conversion after 6 hours and 82% after 24 hours.
The importance of diffusion into the gel becomes clear when
gels with a higher crosslinker content are produced. A doubling
of the crosslinker content led on the one hand to more difficult
diffusion processes of the educts into the gel structure and on
the other hand to a more difficult release of the product formed
from the gel. As a result of these effects, after 12 seconds of
light exposure, significantly lower conversions of slightly above
70% can be observed.
For the evaluation of the substrate generality of this
organocatalyzed asymmetric aldol reaction inside the MFR, the
reaction of various aromatic aldehydes with different ketones
was investigated applying the optimized conditions. As can be
seen in Table 2, different aromatic aldehydes and ketones can
effectively be transformed to the corresponding aldol products
inside the MFR.
Entry
DMSO-water
ratio
Temperature
[°C]
Conversion
[%]
Diastereomeric
ratio
[a]
(
v:v)
syn/anti
[a]
[
%]
1
2
3
4
5
6
7
10:0
9:1
8:2
7:3
9:1
8:2
7:3
rt
rt
rt
rt
40°C
40°C
40°C
26
95
58
80
78
73
82
36/64
33/67
35/65
41/59
41/59
43/57
41/59
1
[
a] Determined by H-NMR after 24 h of sample collection. Using 0,034 M of
aldehyde respective 0,167 M of ketone.
reaction temperature of 40°C, all solvent compositions showed
weaker results for conversion or selectivity than their counter-
parts at room temperature.
Using the optimized reaction conditions, and for a more in-
depth analysis of the relationship between conversion behavior
and polymer structure height, reactor surfaces with attached
gel structures of different heights were prepared. The corre-
sponding results are summarized in Figure 7. The surfaces with
polymer structures prepared with 6 and 9 seconds of UV-light
irradiation and heights of 23 (�6) μm and 73 (�11) μm,
respectively, provide a similar conversion of 54 and 56 % after a
reaction time of 6 hours. After reaction times of 12 and
Using a mixture of DMSO:water (9:1 v:v) as the solvent, the
feasibility of different cyclic and acyclic ketones as donors for
the asymmetric aldol reaction was examined. As shown in
Table 2 when cyclohexanone serves as donor part of the aldol
reaction, good yields ranging from 75–93% with moderate to
good ee values (57–87%) for the anti-isomer were received. In
contrast, however, the diastereomeric ratios obtained were
1
8 hours, both polymer structures showed an almost constant
conversion behavior with a conversion of around 30 and 45%
respectively. After 24 hours the conversion dropped signifi-
6
7:33, 68:32 and 71:29, respectively, for the three different
aldehydes investigated. With the use of cyclopentanone,
moderate to good yields of 63–86%, but attenuated enantiose-
lectivities with 18–76% ee, could be obtained in this case for
[
24]
the syn product, which is in line with previous findings. When
using cyclopentanone, the diastereomeric ratio was between
2
1:79 and 26:74. Furthermore, acetone, a non-cyclic ketone,
was also investigated as a donor in the aldol reaction within the
MFR. The reaction of acetone with 4-nitrobenzaldehyde also
provides a good yield of 80%, but again attenuated ee
[
25]
selectivity of only 19% was obtained. Tang et al.
also
investigated the basic structure of proline amide 3 without
immobilization for the asymmetric aldol reaction of acetone
with various aldehydes. The comparison between the immobi-
lized catalyst and the low molecular weight catalyst shows a
comparable yield, which suggests that the catalyst is equally
active, even in immobilized form. However, a difference can be
seen when comparing the ee values. In the case of the free
catalyst, these are slightly higher at 33% than in the case of the
immobilized catalyst. A possible explanation could be seen in
the mechanism of the proline-catalyzed aldol reaction and the
conformations that are necessary for high selectivity. The
Figure 7. Relationship between the height of the polymer structures and the
conversion behavior of the asymmetric aldol reaction of 4-nitrobenzalde-
1
hyde and cyclohexanone, analyzed by H-NMR over a total reaction time of
2
4 hours with a residence time of 3.34 hours. Using 0.034 M of aldehyde
respective 0.167 M of ketone in a 9:1 DMSO:water mixture.
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[
a]
of 0.5 μl/min, a total volume of 1.44 ml results for the educt
solution. Based on the volume of educt solution conveyed, a
catalyst concentration of 6.02 μmol/ml was used. In order to
achieve a comparable catalyst concentration, around 0.6 mol%
of catalyst, based on the educt, must be used in a batch reactor
Table 2. Direct asymmetric aldol reaction inside the MFR.
À 2
[a]
[b]
with an educt concentration of 3.4·10 mmol/ml.
Entry
1
Product
Yield
%]
Dr
Ee
[
[anti:syn]
[%]
After a reaction time of 200 minutes, which corresponds to
the residence time in the reactor, no conversion was detected
for the batch experiment (Figure S12). These findings appear
reasonable, as the lower turnover efficiency of organocatalysts
typically makes larger amounts necessary. In the case of the
prolineamide already mentioned, for instance, 20 mol% were
78
67:33
87
[25]
2
3
93
75
68:32
71:29
57
72
used.
Opposingly this is compensated by the high local catalyst
concentration inside the microfluidic reactor chamber. While in
case of the batch reaction the catalyst concentration is
6
.02 μmol/ml, the low volume of the reactor chamber of 100 μl
À 2
corresponds with a catalyst concentration of 8.6·10 mmol/ml
in the case of the MFR concept. This provides an approximately
4
5
6
86
63
82
26:74
25:75
21:79
18
67
76
1
5-fold higher catalyst concentration within the microfluidic
reactor chamber compared to the corresponding batch experi-
ment.
In order to serve as an efficient catalyst system in a
continuous process, a catalyst system must be robust, versatile,
and deliver high conversions and good selectivity over a long
period of time. Using a 9:1 mixture of DMSO and water as a
solvent, the reusability and robustness of the MFR system were
analyzed in a recycling study. To investigate the corresponding
behavior of the polymer gel produced, different ketones were
alternately reacted with 4-nitrobenzaldehyde. After a reaction
time of 24 hours in each case, the reactor system was flushed
with pure DMSO and then the other ketone was injected. The
corresponding conversions and diastereoselectivities were ana-
7
80
–
19
1
[a] Determined by H-NMR after 48 h of sample collection. Using 0,034 M of
aldehyde respective 0,167 M of ketone at dwell times of 3.34 h. The
original H-NMR spectra are provided in Figures S5–S11. [b] Determined by
1
1
lyzed using H-NMR and are summarized in Figure 8. After
chiral HPLC analysis (IA, IC columns). HPLC data for each compound is
provided in the SI.
immobilization could inhibit the formation of only one con-
formation and thus reduce the selectivity. Oppositely the
reaction time is dramatically decreased. The reaction of the free
catalyst takes place within 12 hours, whereas the residence time
within the MFR is only 3.34 hours and consequently significantly
shorter reaction times are needed in the case of the MFR
concept. A further comparison was made between a reaction in
the MFR and a classic batch reaction using the model reaction
of cyclohexanone and 4-nitrobenzaldehyde. The first step was
to calculate the appropriate amount of catalyst for the batch
reaction. Therefore, a density of 0.28 (�0.1) g/ml was deter-
mined for the gels based on catalyst structure 3. Since the
substance concentration of the monomers used is known
during the polymerization, an amount of substance within the
irradiated volume can be calculated using equation (3).
As a result, the amounts of substance of the immobilized
gel constituents were obtained. An amount of 8.68 μmol results
for catalyst structure 3. Since the corresponding flow experi-
ments were analyzed over 48 hours and operated at a flow rate
Figure 8. Reusability of MFR with different ketones at dwell times of 3.34 h
in DMSO/water (9:1 v:v). Reaction of 0.167 M of the ketone and 0.033 M of
4-nitrobenzaldehyde.
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performing the first reaction with cyclohexanone and 4-nitro-
corresponding in-depth analysis shows the general and exten-
sive applicability of the MFR concept with immobilized organo-
catalyst 3 for carrying out the asymmetric aldol reaction with
various substrates. In particular, a direct relationship between
the height of the gel matrix and the conversion behavior of the
MFR could be verified. Furthermore, with cyclohexanone and
cyclopentanone as well as acetone, various ketones could be
successfully converted as donors in the aldol reaction with
various substituted aldehydes in relatively short reaction times.
The yields and selectivities obtained are satisfactory to good.
Based on this, the reusability of the reactor over several cycles
with different ketones could also be demonstrated. Based on
this good reusability, investigations over 144 hours were carried
out, which showed good long-term stability using the model
substrates cyclohexanone and 4-nitrobenzaldehyde.
benzaldehyde (mixture A), a conversion of 93% with an anti-
selectivity of 66% was achieved. After rinsing with pure DMSO
for 24 hours, the second educt solution of cyclopentanone and
4
-nitrobenzaldehyde (mixture B) was injected, which could be
converted to the desired product in 94% with a syn-selectivity
of 74%. The second reaction run with A delivered a conversion
of 64% and an anti-selectivity of 74% over further 24 hours of
reaction time. After rinsing again for 24 hours with pure DMSO,
conversions of 85% and syn-selectivities of 72% could still be
obtained in a second reaction with B. Even after a total reaction
time of 168 h, the presented reactor system still delivers good
conversions with acceptable selectivities and can thus serve as
a solid foundation for further investigations.
For a satisfactory, long-term, continuous process, it is
necessary to achieve consistently high conversions over long
periods of time with good selectivities at the same time. As
shown in Figure 9 and Figure S13, the behavior of the reactor Experimental Section
was analyzed over a period of 144 hours (6 days). Even after
General remarks: All reagents used are commercial products.
Column purifications were carried out using silica gel unless
otherwise noted.
1
44 hours of continuous operation, a conversion of 75 (�5) %
can still be achieved with an anti-selectivity of 71 (�4) %. The
maximum conversion could be reached after an operating time
of 24 hours with 94 (�5) %. Subsequently, the conversion
decreases slightly, whereby the decrease seems to gradually
slow down with increasing reaction time, as indicated by the
third-order polynomial fit. After about 140 hours an almost
constant conversion level can be assumed. In contrast, the anti-
selectivity increases slightly with increasing reaction time. After
Analysis Methods: Confocal Microscopy: The confocal microscope
Keyence “VK-9700” was used for height determination of polymer
dots. Images were taken with the software “VK Viewer 2.4.0.1” and
the analysis of polymer height was done with the software “VK
Analyzer 3.4.0.1”.
1
Nuclear magnetic resonance spectroscopy: The H-NMR spectra
for conversion determination were measured on a Bruker “Ascent
700” spectrometer. Product spectra of synthesized products were
2
4 hours an anti-selectivity of 65 (�3) % was obtained whereas
1
13
measured on a Bruker “Avance 500” ( H, 500.1 MHz; C, 125.8 MHz;
it slightly increased to 71 (�4) % after 144 hours.
3
1
1
13
P, 202.0 MHz) and “Ascent 700” ( H, 700.1 MHz; C, 176.0 MHz)
spectrometer, using different solvents purchased by Deutero. The
NMR signals were referenced to residual solvents measured relative
to TMS as internal standard.
Conclusion
Electron impact mass spectrometry: The EI-MS measurements
In conclusion, the results obtained from the study of the
asymmetric aldol reaction using an immobilized proline based
amid in DMSO:water mixtures as solvent represent a further
application of the recently established MFR concept. The
were done with
a high-resolution sector field “DFS” mass
spectrometer from Thermo Scientific.
Electro spray ionization mass spectrometry: The ESI-MS measure-
ments were done with a “Synapt-G2 HDMS” mass spectrometer
from Waters. The spectrometer is used in combination with a time-
of-flight analyser.
Contact angle measurement: The contact angle measurements
were performed using a “Drop Shape Analyzer-DSA25” from Krüss.
Using Diiodomethane ReagentPlus (99%) from Sigma-Aldrich and
Water Rotisolv HPLC Gradient Grade from Roth.
HPLC analysis: For analytical HPLC a chiral stationary phase for the
determination of enantiomeric excess (ee) a VARIAN 920-LC was
used with the following capillary columns: CHIRALCEL IA and IC.
Surface Modification: The surface modification of the slides was
[19]
carried out as described previously.
Photopolymerization: The photopolymerization was carried out via
an “Omnicure® S1500” UV-Lamp, from Lumen Dynamics. UV
irradiation for photopolymerization was done with an intensity of
4
8
28 mW (intensity=20%) at the end of the lighting cable, with
cm distance of light source to substrate. 15 mmol of monomers
Figure 9. Long-term conversion and diastereomeric share of the aldol
reaction of 4-nitrobenzaldehyde and cyclohexanone at dwell times of 3.34 h
in DMSO/water (9:1 v:v). Reaction of 0.167 M of the ketone and 0.033 M of
aldehyde.
was mixed in the desired ratios and were dissolved in 1.7 mL
ethanol with an initiator concentration of 33.25 mg/mL. 820 μL of
monomer solution were transferred into an incubation chamber
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gasket, made from dark grey polyoxymethylene to minimize
calculated according to the following equation (1):
scattered radiation. The incubation chamber gasket was covered by
a modified microscopy slide and the photopolymerization mask
(diamond-shaped position of 662 dots) on the backside (Figure S2).
This stack was half-covered with an opaque cover and the
uncovered side was centered below UV light for 12 s, followed by
the other half. Afterward, the incubation chamber was removed,
and the polymer structures were washed with water, followed by
CH Cl for 1 h. To remove the HCl-salt washing with a mixture of
methanol and triethylamine (9:1) as well as with tetrahydrofuran
and triethylamine (9:1) followed by pure tetrahydrofuran and pure
methanol as the last purification step was applied (1 h for each
step). The substrates were dried in air and stored at room
temperature till usage.
2
2
[21]
Approximation formula of Toomey, Freidank and Rühe (2):
Reactor Setup: The flow system was set up according to the
following schematic illustration (Figure S3). The flow rate was
generated by a “Legato 200” syringe pump, from KDScientific. As
reservoir one “Hamilton 1000 series” syringe was used. All tubes
were PTFE capillary tubes with iD=0.2 mm, from Fisher Scientific.
The reactor itself is a self-made alumina holder (Figure S2, right
side) to connect imprinted PTFE layer with the flow system. The
Approximation formula for the comparison between batch and
flow experiments (3):
[
18]
reactor design is described by Simon et al.
Polymer dots on
microscopy slides were inserted into the reactor by covering the
polymer structure with an imprinted PTFE layer. The channel height
of the imprinted cover was approximately 140 μm. This stack was
inserted into the alumina holder (Figure 5) and fixed by screws with
a torque of 8 cN/m. The PTFE layer was connected to the alumina
holder with special screw threads and with drill holes to capillary
tubes.
Initiator Synthesis: The initiator (LAP) was synthesized according to
[26,19] 1
Majima et al.
H NMR (500 MHz, D O): δ=7.73 (dd, J=7.3 Hz;
2
J=11.4 Hz, 2H), 7.49 (t, J=7.8 Hz, 1H), 7.42 (dt, J=7.7 Hz, J=3.1 Hz,
1
3
2H), 6,80 (s, 2H), 2.16 (s, 3H), 2.01 (s, 6H). C NMR (125 MHz, D
δ=238.8 (C), 138.3 (C), 138.0 (C), 133.7 (C), 133.5 (C), 132.5, 132.3/
O):
2
3
1
132.4, 132.1, 128.4/128.5, 128.1, 20.3, 18.5. P-NMR (202 MHz, D
O):
δ=12.31 (s).MS (ESI): m/z calculated for C16O PH16Na 311.0808;
3
2
+
found 311.0795.
Flow reaction: Initially the polymer dots were pre-swollen with
DMSO for at least 2 h. Therefore, the “Legato 200 Syringe” pump
was loaded with one syringe (Braun 20 mL syringe with iD=
Tert-butyl-(2S)-2-((1-hydroxy-4-methylpentan-2-yl)-carbamoyl)
pyrrolidin-1-carboxylate (1): The synthesis was performed as
[
14]
1
2
0.1 mm), filled up with pure solvent and the flow rate were set to
previously described. Yield 11.49 g (38.5 mmol, 82%); H NMR
3
2.0 μL/min. Afterward, the syringe pump was loaded with the
(700 MHz, DMSO): δ=0.86 (m, 6H), 1.30 (dd, JHH =7.16 Hz, 2H), 1.36
reactant syringe (Hamilton 1000 series). The flow rate was adjusted
to 0.5 μL/min. The product solution was collected for 48 h in case
of the screening and diluted by saturated NaCl-solution. This
solution was then extracted with EtOAc or CH Cl , the phases were
(s, br.,), 1.57–1.66 (m, 1H), 1.68–2.13 (m, 4H), 3.18–3.27 (m, 2H),
3
3.29–3.40 (m, 2H), 3.74–3.81 (m, 1H), 4.04 (d, JHH =4.27 Hz, 1H), 4.55
3
13
(m, 1H), 7.41 (d, JHH =8.69 Hz, 1H) ppm. C NMR (176 MHz, DMSO):
δ=21.7, 23.5, 24.1, 28.0, 29.9, 31.4, 40.0, 46.5, 46.7, 48.6, 59.7, 78.3,
2
2
+
separated using a hydrophobic filter, the solvent was removed, and
the crude product was obtained. Purification by flash chromatog-
raphy afforded the corresponding pure products.
153.4, 172.1 ppm. MS (ESI): m/z calculated for C16
337.2103; found 337.2114.
H N ONa
30 2
(
R)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-carbox-amido)-4-
Determination of conversion and diastereomeric ratio: The
conversion was determined by NMR spectroscopy. NMR spectro-
scopy enables an offline determination of conversion and fast
screening of different reactions. For NMR spectroscopy the outlet
methylpentyl-(2-(methacryloyloxy)ethyl)succinate
(2):
7.25 g
(24.1 mmol) of the proline amide
1 together with 9.96 g
(48.2 mmol) DCC and 130 mg (1.1 mmol) DMAP in 150 ml DCM
were placed in a 250 ml round bottom flask. To the mixture, 5.75 g
(25.0 mmol) of O- (2-methacryloyloxyethyl) succinic acid was added.
The mixture was stirred for 48 hours under an argon atmosphere at
room temperature. The precipitated white solid was filtered off,
washed with DCM and then discarded. The solvent was then
removed. For further work-up, the crude product was purified by
column chromatography with neutral aluminum oxide as the
stationary phase. A solvent gradient from n-hexane: ethyl acetate
flow was collected into a vial with 400 μL DMSO-d and was frozen
6
immediately after the desired time of sample collection with liquid
nitrogen. The sample was warmed up just before the tube was
inserted into the NMR spectrometer.
Determination of degree of swelling: The degree of swelling was
determined by measuring length and diameter of prepared
polymer samples. Therefore, 0.5 mL the monomer mixture in the
desired ration was inserted into 1 mL plastic pipette. The solution
was irradiated with UV light for 12 sec applying an intensity of
(
10: 1) to n-hexane: ethyl acetate (1: 9) was used. Rf=0.93 in the
mobile phase n-hexane: ethyl acetate (1: 9). The product was then
purified again by column chromatography with silica as the
stationary phase. The same mobile phase was used as in the
4
0%. Afterward, the plastic pipette was cut into pieces to extract
the cylindric polymer gel. The sample was cut into smaller pieces
followed by the same workup as described in “Photopolymeriza-
tion”. In the end, the samples were dried at 40°C for several days
previous column chromatography. Yield 11.30 g (21.4 mmol,
1
8
9.0%); viscous, slightly yellowish oil. H NMR (700 MHz, DMSO):
δ=0.71–0.93 (m, 6H), 1.29–1.46 (m, 9H), 1.51–1.63 (m, 2H), 1.70–
until a constant mass was observed. The length and diameter of
the samples were measured using a light microscope and micro-
scopic ruler. Subsequently, the samples were swollen in the desired
solvent overnight. In the end, the swollen samples were again
measured using a light microscope and microscopic ruler. With the
volume in the dry and swollen state the degree of swelling was
1
3
.81 (m, 3H, CH ), 1.87 (s, 3H), 2.05–2.15 (m, 1H), 2.51–2.60 (m, 4H),
.22–3.28 (m, 1H), 3.34–3.41 (m, 1H), 3.78–3.85 (m, 1H), 3.87–3.98
2
(
1
2
m, 1H), 3.99–4.06 (m, 2H), 4.23–4.31 (m, 4H), 5.69 (s, 1H), 6.03 (s,
H), 7.65 (m, 1H) ppm. C NMR (176 MHz, DMSO): δ=17.9, 21.4,
13
2.8, 23.2, 24.0, 28.0, 28.5, 28.6, 31.3, 34.5, 45.5, 46.4, 59.6, 62.0, 62.4,
Eur. J. Org. Chem. 2021, 2578–2586
www.eurjoc.org
2584
© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH

Full Papers
doi.org/10.1002/ejoc.202100268
[
24,27–30]
6
6.2, 78.3, 126.1, 135.6, 153.4, 166.4, 168.3, 171.7, 172.1 ppm. MS
(2S,10R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclopentan-1-one
+
(ESI): m/z calculated for C H N O Na 549.2890; found 549.2774.
(Table 2 entry 5): Yield 7.0 mg (0.029 mmol, 63%); anti/syn=25/75,
enantiomeric excess: 67% (syn diastereomer) determined by HPLC
Daicel Chiralpak IA column; iPrOH/heptane=5:95; 0.5 mL/min;
26
42
2
9
2
-(methacryloyloxy)ethyl
((R)-4-methyl-2-((S)-pyrrolidine-2-
(
1
carboxamido)pentyl) succinate (3): 11.30 g (21.5 mmol) of 2 were
placed in a 500 ml round-bottom flask and dissolved in 100 ml
DCM. 100 ml of 4 molar HCl in 1,4-dioxane were added to the
mixture with vigorous stirring. The mixture was then stirred at
room temperature overnight. After removal of the solvent and
subsequent drying 3 was obtained. Yield 9.60 g (20.9 mmol, quant.);
1
5°C; λ=254 nm, t =42.7 min, t =48.8 min). H NMR (700 MHz,
R1
R2
CDCl ): δ=1.49–1.60 (m, 1H), 1.67–1.79 (m, 2H), 1.93–2.07 (m, 1H),
3
2
1
1
1
.09–2.43 (m, 2H), 2.47–2.53 (m, 1H), 4.78 (s, br. 1H), 5.39–5.45 (m,
H), 7.49–7.55 (m, 1H), 7.65–7.72 (m, 1H), 8.02–8.18 (m, 1H), 8.23 (s,
H) ppm. C NMR (176 MHz, CDCl ): δ=20.5, 22.7, 39.2, 56.3, 70.5,
20.8, 122.5, 129.6, 131.8, 145.2, 148.6, 219.7 ppm. MS (ESI): m/z
13
3
1
highly viscous yellowish oil. H NMR (700 MHz, DMSO): δ=0.81–
+
calculated for C H NO Na 258.0845; found 258.0744.
1
2
13
4
0
2
1
.92 (m, 6H), 1.58–1.63 (m, 1H), 1.70–1.82 (m, 3H), 1.83–1.90 (m, 6H),
.52–2.58 (m, 5H), 3.13–3.27 (m, 3H), 3.80–3.88 (m, 1H), 4.0–4.17 (m,
H), 4.23–4.30 (m, 4H), 5.69 (s, 1H), 6.03 (s, 1H), 8.44–8.61 (m, 2H,
[
24,27–30]
(2S,10S)-2-[Hydroxy(2-nitrophenyl)methyl]cyclopentan-1-one
(Table 2 entry 6): Yield 9.2 mg (0.039 mmol, 82%); anti/syn=21/79,
enantiomeric excess: 76% (syn diastereomer) determined by HPLC
(Daicel Chiralpak IA column; iPrOH/heptane=5:95; 0.5 mL/min;
13
br.), 9.89–10.11 (s, 1H, br.) ppm. C NMR (176 MHz, DMSO): δ=17.9,
2
6
1.6, 22.8, 23.0, 23.5, 24.0, 28.4, 28.5, 29.8, 45.5, 46.3, 58.7, 60.0, 62.0,
1
2.4, 126.1, 135.6, 153.4, 166.4, 168.1, 171.7, 171.8 ppm. MS (ESI):
15°C; λ=254 nm, t =38.1 min, t =39.9 min). H NMR (700 MHz,
R1
R2
+
m/z calculated for C H N O 427.2366; found 427.2479.
CDCl ): δ=1.60–1.82 (m, 3H), 1.97–2.09 (m, 1H), 2.10–2.47 (m, 2H);
3
21
35
2
7
2
.68–2.79 (m, 1H), 5.88–5.94 (m, 1H), 7.41–7.46 (m, 1H), 7.62–7.69
[24,27–30]
(
2S,10R)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one
Table 2 entry 1): Yield 9.2 mg (0.037 mmol, 78%); anti/syn=67/33,
enantiomeric excess: 87% (anti diastereomer) determined by HPLC
Daicel Chiralpak IA column; iPrOH/heptane=15:85; 0.8 mL/min;
3
1
3
(
m, 1H), 7.88 (d, J =7.9 Hz, 1H), 7.96–8.01 (m, 1H) ppm. C NMR
HH
(
(
176 MHz, CDCl ): δ=20.4, 23.2, 38.8, 55.0, 66.9, 124.8, 128.3, 128.8,
33.6, 138.6, 147.3, 218.9 ppm. MS (ESI): m/z calculated for
3
1
(
+
C H NO Na 258.0845; found 258.0738.
1
12 13
4
1
5°C; λ=254 nm; t =26.5 min, t =36.1 min). H NMR (700 MHz,
R1
R2
[24,27–30]
DMSO): δ=1.12–1.24 (m, 1H, CH ), 1.46–1.87 (m, 5H), 2.22–2.39 (m,
(4R)-4-(4-Nitroophenyl)-4-hydroxy-4butan-2-one
(Table 2 en-
2
3
3
2
H), 2.62–2.76 (m, 1H), 5.08 (t,
J
=4.54 Hz, 1H), 5.50 (d,
J
HH
=
try 7): Yield 8.05 mg (0.038 mmol, 80%); enantiomeric excess: 19%
(R-isomer) determined by HPLC (Daicel Chiralpak IC column; iPrOH/
heptane=10:90; 0.7 mL/min; 15°C; λ=254 nm, t =23.9 min, t =
HH
3
3
4
.8 Hz, 1H), 7.61 (d; J =9.7 Hz, 2H), 8.18 (d, J =8.8 Hz, 2H) ppm.
HH
HH
13
C NMR (176 MHz, DMSO): δ=23.2, 27.3, 29.5, 41.2, 57.3, 70.4,
R1
R2
1
1
23.0, 128.1, 146.5, 151.6, 210.7 ppm. MS (ESI): m/z calculated for
25.4 min). H NMR (700 MHz, CDCl ): δ=δ (ppm)=2.22 (s, 3H),
3
+
C H NO Na 272.0899; found 272.0883.
2.79–2.91 (m, 2H), 3.40–3.52 (m, 1H), 5.23–5.29 (m, 1H), 7.54 (d,
1
3
15
4
3
3
13
JHH =8.5 Hz, 2H), 8.21 (d, J =8.7 Hz, 2H) ppm. C NMR (176 MHz,
DMSO): δ=31.0, 52.9, 68.7, 123.9, 127.6, 147.1, 153.8, 206.9 ppm.
MS (ESI): m/z calculated for C H NO 209.0688; found 209.0691.
[24,27–30]
HH
(
2S,10R)-2-[Hydroxy(3-nitrophenyl)methyl]cyclohexan-1-one
Table 2 entry 2): Yield 11.0 mg (0.044 mmol, 93%); anti/syn=68/32,
enantiomeric excess: 57% (anti diastereomer) determined by HPLC
Daicel Chiralpak IA column; iPrOH/heptane=5:95; 0.8 mL/min;
(
+
1
0
11
4
(
1
1
5°C; λ=254 nm, t =29.9 min, t =38.8 min). H NMR (700 MHz,
R1
R2
CDCl ): δ=1.33–1.45 (m, 1H), 1.51–1.62 (m, 3H), 1.79–1.86 (m, 1H),
3
Acknowledgements
2
.06–2.17 (m, 1H), 2.32–2.42 (m, 1H), 2.47–2.53 (m, 1H), 2.59–2.66
3
3
(m, 1H), 3.98–4.25 (s, 1H), 4.89 (d, J =8.48 Hz, 1H), 7.53 (t, J =
HH HH
7
.52 Hz, 1H), 7.65–7.69 (m, 1H), 8.15–8.18 (m, 1H), 8.19–8.23 (m, 1H)
The Kunststofftechnik Paderborn (KTP) is acknowledged for the
Confocal Laser Microscope. Open access funding enabled and
organized by Projekt DEAL.
13
ppm. C NMR (176 MHz, CDCl ): δ=24.8, 27.8, 30.9, 42.8, 57.3, 74.2,
3
122.2, 123.1, 129.5, 133.3, 143.4, 148.4, 215.0 ppm. MS (ESI): m/z
+
calculated for C H NO Na 272.0899; found 272.0893.
13
15
4
[
24,27–30]
(
(
2S,10R)-2-[Hydroxy(2-nitrophenyl)methyl]cyclohexan-1-one
Table 2 entry 3): Yield 8.8 mg (0.035 mmol, 75%); anti/syn=71/29,
enantiomeric excess: 72% (anti diastereomer) determined by HPLC
Daicel Chiralpak IA column; iPrOH/heptane=5:95; 0.8 mL/min;
Conflict of Interest
(
1
1
The authors declare no conflict of interest.
5°C; λ=254 nm, t =28.9 min, t =31.4 min). H NMR (700 MHz,
R1
R2
CDCl ): δ=1.52–1.90 (m, 5H), 2.05–2.15 (m, 1H), 2.29–2.50 (m, 2H),
3
3
2
.71–2.82 (m, 1H), 3.98–4.42 (s, 1H), 5.45 (d, JHH=6.94 Hz, 1H),
Keywords: Asymmetric synthesis · Continuous flow · Gel-bound
catalysts · Microfluidic reactor · Organocatalysis
7
.39–7.45 (m, 1H), 7.60–7.65 (m, 1H), 7.75–7.79 (m, 1H), 7.82–7.87
13
(m, 1H) ppm. C NMR (176 MHz, CDCl ): δ=25.1, 27.9, 31.2, 42.9,
3
5
7.4, 69.9, 124.2, 128.5, 129.1, 133.4,136.7, 148.8, 215.1 ppm. MS
+
(ESI): m/z calculated for C H NO Na 272.0899; found 272.0869.
13 15 4
[24,27–30]
(
2S,10S)-2-[Hydroxy(4-nitrophenyl)methyl]cyclopentan-1-one
[
[
1] G. Jas, A. Kirschning, Chemistry (Weinheim an der Bergstrasse, Germany)
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(
Table 2 entry 4): Yield 9.3 mg (0.041 mmol, 86%); anti/syn=26/74,
enantiomeric excess: 18% (syn diastereomer) determined by HPLC
Daicel Chiralpak IA column; iPrOH/heptane=5:95; 0.8 mL/min;
2
(
1
1
5°C; λ=254 nm, t =61.9 min, t =66.2 min). H NMR (700 MHz,
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R1
R2
CDCl ): δ=1.48–1.64 (m, 1H), 1.69–1.75 (m, 1H), 1.90–2.19 (m, 3H),
3
3
2
8
.33–2.51 (m, 2H), 4.73 (s, br. 1H), 5.40–5.45 (m, 1H), 7.51 (d, J
.6 Hz, 2H), 8.21 (d, JHH =8.8 Hz, 2H) ppm. C NMR (176 MHz,
=
HH
3
13
CDCl ): δ=20.5, 22.6, 39.1, 56.2, 70.8, 123.8, 126.5, 147.4, 150.2,
2
found 258.0735.
3
+
19.5 ppm. MS (ESI): m/z calculated for C H NO Na 258.0845;
12 13 4
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Manuscript received: March 4, 2021
Revised manuscript received: April 12, 2021
Accepted manuscript online: April 13, 2021
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Eur. J. Org. Chem. 2021, 2578–2586
www.eurjoc.org
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© 2021 The Authors. European Journal of Organic Chemistry published
by Wiley-VCH GmbH