A Visible-Light-Powered Polymerization Method for the Immobilization of Enantioselective Organocatalysts into Microreactors

Article abstract of DOI:10.1002/chem.202002063

A versatile one-step photopolymerization approach for the immobilization of enantioselective organocatalysts is presented. Chiral organocatalyst-containing monoliths based on polystyrene divinylbenzene copolymer were generated inside channels of microfluidic chips. Exemplary performance tests were performed for the monolithic Hayashi–J?rgensen catalyst in continuous flow, which showed good results for the Michael addition of aldehydes to nitroalkenes in terms of stereoselectivity and catalyst stability with minimal consumption of reagents and solvents.

Full text of DOI:10.1002/chem.202002063

Accepted Article
Accepted Article
Title: A visible-light-powered polymerization method for the
immobilization of enantioselective organocatalysts into
microreactors
Authors: Rico Warias, Daniele Ragno, Alessandro Massi, and Detlev
Belder
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202002063
Link to VoR: https://doi.org/10.1002/chem.202002063
01/2020

10.1002/chem.202002063
Chemistry - A European Journal
COMMUNICATION
A visible-light-powered polymerization method for the
immobilization of enantioselective organocatalysts into
microreactors
Rico Warias,[a] Daniele Ragno,[b] Alessandro Massi,[b] and Detlev Belder*[a]
Abstract: A versatile one-step photopolymerization approach for the
immobilization of enantioselective organocatalysts is presented.
Chiral organocatalyst-containing monoliths based on polystyrene
divinylbenzene copolymer were generated inside channels of
microfluidic chips. Exemplary performance tests were performed for
the monolithic Hayashi-Jørgensen catalyst in continuous flow, which
showed good results for the Michael addition of aldehydes to
nitroalkenes in terms of stereoselectivity and catalyst stability with
minimal consumption of reagents and solvents.
the other hand, one drawback of using a particulate packed bed
lies in the troublesome processes packing and anchoring the
catalyst beads which are becoming more difficult within minimized
reactor volumes. The implementation of monoliths into a micro-
flow regime is a well-studied topic. Main advantages of these
porous networks are their excellent mass transfer properties, low
pressure drop, and ease of preparation.[20-22]
A variety of porous materials have been investigated for this
purpose,[23] such as inorganic materials,[24] metal-organic
frameworks (MOFs),[25,26] and covalent-organic frameworks
(COFs).[27] For the immobilization of organic catalysts, porous
organic polymers (POPs) are preferred as support material.
These materials are well studied and have been used for a variety
of applications such as stationary phases in separation
science[28,29] and as reagent supports in continuous flow
Flow synthesis has gained much attention in recent years as a
powerful alternative over conventional batch approaches due to
superior process control, hazard reduction, and the avenue of
exploring novel process windows.[1-5] Especially the use of
continuous flow microreactors has become a popular means of
quickly mapping synthetic parameters, and process
intensification.[6-8] Using such miniaturized approaches can help
to minimize reagent and catalyst consumption, as well as
reducing waste production, with an overall higher reaction
efficiency.[9,10] These benefits were already exploited in academia
and industry for the production of fine chemicals and API (active
pharmaceutical ingredient) precursors and flow chemistry itself
has been seen as sustainable technology.[11-14] Further, the
integration of heterogeneous catalysts inside micro-flow reactors
provides another “green” approach. Its benefits, like no demand
for separation of the catalytic species from the resulting reaction
mixture, a reduction of catalysts mechanical degradation and
deactivation (limited contact with air and moisture) and
continuous production with catalyst TON increase, are often
improving the system’s overall productivity.[5,15-17]
synthesis.[30-34]
Various
polymerization
processes
and
modification protocols have been reported.[35-38] For polystyrene-
based monoliths, most common preparation methods involve
radical-initiated (thermal or photochemical) copolymerization of
monomers in the presence of porogens inside the reactor.[39-41]
Photochemical strategies for catalyst immobilization profit from
shorter reaction times mild temperatures which extends the range
of possible monomers that can be used. When light transparent
glass microreactors are used, a site-specific localization of the
catalyst material can be achieved. This is appealing when
microfluidic lab-on-a-chip devices with complex channel networks
and integrated functionalities are used, such as micromixers,[42]
further reaction units,[43] or even subsequent analytics.[44-46] Light
transparent glass microreactors are also attractive for
photochemical or photocatalytic reactions in micro-flow.[47-50]
While thermally initiated polymerization is well established,[22,51,52]
respective methods for photo-initiated polymerization of catalyst
supports are rare. To the best of our knowledge, there is just a
single example focusing on photo-initiated polymerization of an
organic monolith with an application in organocatalysis.[53] There,
Three main strategies for catalyst immobilization inside
microreactors are described in the literature, namely the wall-
coated, the packed bed, and the monolithic approach.[15,18]
Despite the very good mass transfer and the minimal pressure
drop, wall coated flow reactors lack in the loading of the desired
catalyst, whereas packed bed reactors seem to be superior.[19] On
a
DMAP functionalized polystyrene-based monolith was
synthesized inside an Omnifit glass column (10.0  6.6 mm)
through a photo-induced two-step protocol (fabrication of the
monolith with an activated ester followed by catalyst
displacement) and finally applied for acylation reactions.
Herein we present a new method for the immobilization of
enantioselective organocatalysts into microreactors using visible
light-initiated polymerization. The formation of an organic
monolith based on polystyrene is achieved straightforwardly
without any need for further chemical modification steps. These
new functionalized microreactors were tested in organocatalytic
flow processes evaluating their chemical efficiency and stability
over time.
[a]
[b]
R. Warias, Prof. D. Belder
Institute of Analytical Chemistry
Leipzig University
Linnéstraße 3, 04103 Leipzig, Germany
E-mail: belder@uni-leipzig.de
Dr. D. Ragno, Prof. A. Massi
Department of Chemical and Pharmaceutical Sciences
University of Ferrara
Via L. Borsari 46, I-44121 Ferrara, Italy
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.202002063
Chemistry - A European Journal
Figure 1. A) General reaction scheme: pre-polymer mixture containing photoinitiators (S-camphorquinone (CQ, 1.6 µmol), ethyl-N-dimethylbenzoate (EDAB,
6.7 µmol)N-methoxy-phenyl-pyridinium tetrafluoroborate (NMPPT, 6.9 µmol)), monomers (monomer-HJ (0.019 mmol), styrene (STY, 0.121 mmol), divinylbenzene
(DVB, 0.051 mmol)), and porogens (1-decanol (24 µL) 2-propanol (20 µL) in CH3CN (10 µL)). Irradiation with 470 nm LED source (2x LED array, 70 mm x 20 mm, 2x
126 lm) for 2 h, followed by THF flush (0.5 µL·min-1) inside the chip for 2 h. B) Assembly for photopolymerization with LED array as used for microreactor preparation.
C) Targeted photopolymerized structure by using an inverted epifluorescence microscope equipped with a 473 nm laser (Cobolt, Sweden). D) Photograph of the chip
after polymerization procedure. Light microscopic pictures showing the retaining elements (porous acrylate-based polymers). E) SEM images of the chips cross section
showing the monoliths macroporous structure.
The approach described here is based on previous work which 0.051 mmol), and porogens (1-decanol, 24 µL; 2-propanol, 20 µL)
focused on the fabrication of polystyrene monolithic microreactors with residue solvent (acetonitrile, 10 µL) from the photoinitiator
functionalized with the Ley-Arvidsson-Yamamoto (S)-5-(pyrrolidin- stock solution (Fig. 1A, see SI for further details).
2-yl)-1H-tetrazole organocatalyst[54] as well as on the TMS- This resulting pre-polymer solution was vortexed, duly degassed by
protected Hayashi-Jørgensen (HJ) catalyst immobilized on silica a gentle N2 stream for 10 min, and finally sonicated for 20 min. The
and its application in chip devices with multiple functionalities.[55] solution was transferred by pipetting it into the glass microreactor.
For the latter approach, one challenge was the rather elaborate For initial experiments, an in-house manufactured device with a
multi-step process for the creation of packed bed reactors inside straight channel design of the microreactor and adjacent packing
microfluidic chips including the synthesis of the catalyst particles channel was chosen (76  26  2 mm in size, empty reactor volume
and the slurry packing process. Herein, a one-step photo-initiated ca. 300 nL). Once the chip was filled, the openings were sealed
immobilization strategy for the TMS-protected HJ catalyst on with adhesive tape and the microreactor was placed in front (2 cm
monolithic poly(styrene-co-divinylbenzene) is presented and its distance) of a 470 nm LED source with similar size of the chip (2 
activity tested in enantioselective C-N- and C-C-bond forming flow LED array, 70 mm  20 mm, 2  126 lm). The polymerization could
reactions.
be followed visually by the increasing opaqueness. After 30
A starting point for the development of a photo-curable porous minutes, the polymerized material was recognizable. To assure a
polymer-supported organocatalyst was the work of Levkin and co- complete polymerization the chip was flipped every half an hour for
workers who presented the first visible-light photopolymerization of a total illumination time of 2 hours. To prevent movement of the
a poly(styrene-co-divinylbenzene)- monolith,[56] as well as the work solution by thermal convection, the microreactor and LED array
of Ismail et al. presenting its application on a microfluidic platform were cooled by a fan and temperature kept at 25-30 °C (Fig. 1B).
for radiochemistry studies.[57] Accordingly, first part of our study After the polymerization was completed, the microreactor was
consisted in the synthesis of the HJ styrenyl derivative (Monomer- flushed with THF for approximately 2 hours to remove the monolith
HJ, Fig. 1A) through the Cu(I)-catalyzed azide-alkyne 1,3-dipolar porogens and non-reacted monomers. During this process, 1H-
cycloaddition (CuAAC) of a propargyl HJ derivative and 1- NMR measurements of the effluent assured for complete removal.
(azidomethyl)-4-vinylbenzene (see the SI for details). With the The last step of the reactor preparation was closing the packing
Monomer-HJ in our hands, we developed a suitable polymerization channel via targeted photopolymerization of acrylates.[54] In Fig. 1D,
protocol. To this end, a solution was prepared containing a resulting microfluidic device can be seen with additional
photoinitiators (S-camphorquinone, CQ, 1.6 µmol; ethyl-N- microscopic images of the microreactor channels. Scanning
dimethylbenzoate, EDAB, 6.7 µmol; N-methoxy-phenyl-pyridinium electron microscopy (SEM) measurements showed the
tetrafluoroborate, NMPPT, 6.9 µmol), monomers (Monomer-HJ, characteristic monolithic structure with a pore size in the range of
0.019 mmol; styrene, STY, 0.121 mmol; divinylbenzene, DVB, macropores (>50 nm, Fig. 1E).
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COMMUNICATION
Table 1. Evaluation of catalyst performance under continuous flow conditions[a]
Scheme 1. Asymmetric α-amination reaction. Reaction mixture: 1 (6.25 mmol·L-
1), 2 (1.25 mmol·L-1) and CH3COOH (0.62 mmol·L-1) as co-catalyst in pure CH3CN
Entry
R1
R2
Product
d.r.[b]
e.r.[c]
The comparison between two different microreactors confirmed the
good reproducibility of the polymerization process, as shown in the
SEM in Fig. 1E (see SI for further details). In addition to the
presented method for illuminating the entire chip, it is also possible
to create polymer structures of smaller dimensions free of their
positional selection through targeted laser irradiation (Fig. 1C).
For the determination of catalyst loading of Monolith-HJ, the
polymerization procedure was performed under batch conditions
applying the same parameters as for the full-chip irradiation (details
in SI). Elemental analysis of the resulting polymer particles
revealed an average loading of 0.63 mmol g-1.
To investigate organocatalytic flow reactions and results on the
catalytic performance of Monolith-HJ, the chip was integrated
inside an on-line HPLC/MS system (detailed description in the SI).
This allowed the transfer of little portions of the reactors effluent for
an on-line analysis in real-time.
Initially, the flow-through behavior of the fabricated device was
evaluated using the asymmetric α-amination of aliphatic aldehyde
1 with dibenzyl azodicarboxylate (DBAD) 2 as the benchmark
(Scheme 1). This model reaction was performed under the
conditions previously employed with the silica-supported
counterpart for a direct comparison.[54] This on-line HPLC/MS
analysis revealed the formation of adduct 3 with a much higher
enantiomeric excess (50% vs. 6% ee). Furthermore, the low
pressure drop of just 1 bar at the applied flow rate of 0.2 µL·min-1
allows operating the setup with economic low pressure pumps.
After this explorative study, the catalytic efficiency of Monolith-HJ
was further evaluated performing the Michael addition of aldehydes
on activated alkenes as a more efficient transformation for the
TMS-protected HJ catalyst.[58,59] Hence, the reaction mixture
consisting of an aliphatic aldehyde 4 (0.3 mmol·L-1), a nitro-styrene
derivative 5 (0.03 mmol·L-1) and benzoic acid (0.013 mmol·L-1) in
acetonitrile was pumped through the catalytic microreactor with a
flow rate of 0.1 µL·min-1 (Table 1). The addition products 6 were
obtained with excellent diastereomeric and enantiomeric ratios,
thus proving the effectiveness of the approach.
1
2
3
4
5
6
Me
Et
Ph
6a
6b
6c
6d
6e
6f
83:17
84:16
91:9
83:17
89:11
90:10
90:10
94:6
Ph
Me
Et
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
89:11
85:15
90:10
Me
Et
95:5
[a]Conditions: aldehyde
4 5
(0.30 mmol·L-1), nitro-styrene (0.03 mmol·L-1),
PhCOOH (0.013 mmol·L-1) in pure CH3CN. Flow rate of 0.1 µL·min-1, room
temperature and a residence time of about 10 min (detailed description in the SI).
For on-line analysis, 2 µL of the reactors effluent were injected onto the HPLC-
MS setup using a two-position switching valve. [b]d.r. was determined by
integration of the corresponding peak areas of the extracted ion chromatogram
(EIC) of the product from sampling after a run time of approx. 2 h. [c]e.r. was
determined by HPLC on chiral stationary phase. HPLC: Chiralpak IG-3, 250 mm,
4.6 mm i.d. Mobile phase: 1 mL·min-1, CH3CN/H2O (60/40 vol% with 0.1 mM
sodium formate).
The catalytic performance of Monolith-HJ was tested within the
commercial device using the Michael reaction leading to adduct 6f
(Table 1, entry 6). In addition to the information about catalyst
diastereo- and enantioselectivity, a statement about catalyst
stability over time should be made. Thus, a total volume of 300 µL
of reactant solution was pumped into the microreactor, allowing the
reaction to be monitored over time up to 50 hours at a flow rate of
0.1 µL·min-1. As shown in Fig. 2B, a steady-state yield of about
25-30% for 6f together with an average de of 60% and ee of 88%
were maintained constant throughout this long-term stability
experiment.
Furthermore, we found out that complete removal of the monolithic
material could be achieved by heating the chip at 550 °C for over
24 hours without affecting the integrity of the channels (slow
heating and cooling procedure required, more details in the SI).
Possible residues could also be removed by flushing the chip with
piranha solution. Overall, by this protocol microreactors could be
restored and used again. This is especially appealing for method
development in academic research.
In our initial experiments, homemade glass chips were used. To
prove this technology being widely applicable, we extend our study
to commercially available microfluidic glass chips. For this purpose,
a microreactor chip (Micronit) with an internal volume of about
18 µL was used (photograph in Fig. 2A). We were able to
straightforwardly transfer the procedure described above. By
omitting the polymeric retaining elements, the microreactors
preparation protocol was simplified significantly (see the SI).
In summary, we have presented a novel method for the
immobilization of the Hayashi-Jørgensen catalyst inside glass chip-
microreactors. This catalyst was incorporated by visible-light
photoinduced polymerization inside a polystyrene monolith with
macroporous structure. Continuous flow Michael addition of
aldehydes to nitroalkenes was successfully performed observing
good values of stereocontrol and catalyst stability over time.
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10.1002/chem.202002063
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
Let the light do the work!
A universal protocol for the
immobilization of enantioselective organocatalysts in glass
microreactors was developed. By using the power of visible light,
a Hayashi-Jørgensen catalyst was exemplarily incorporated into
a
polystyrene-based monolithic structure and used for
asymmetric transformations in flow.
This article is protected by copyright. All rights reserved.

10.1002/chem.202002063
Chemistry - A European Journal
COMMUNICATION
This article is protected by copyright. All rights reserved.