Continuous Heterogeneous Photocatalysis in Serial Micro-Batch Reactors

Article abstract of DOI:10.1002/anie.201712568

Solid reagents, leaching catalysts, and heterogeneous photocatalysts are commonly employed in batch processes but are ill-suited for continuous-flow chemistry. Heterogeneous catalysts for thermal reactions are typically used in packed-bed reactors, which cannot be penetrated by light and thus are not suitable for photocatalytic reactions involving solids. We demonstrate that serial micro-batch reactors (SMBRs) allow for the continuous utilization of solid materials together with liquids and gases in flow. This technology was utilized to develop selective and efficient fluorination reactions using a modified graphitic carbon nitride heterogeneous catalyst instead of costly homogeneous metal polypyridyl complexes. The merger of this inexpensive, recyclable catalyst and the SMBR approach enables sustainable and scalable photocatalysis.

Full text of DOI:10.1002/anie.201712568

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Accepted Article
Title: Continuous Heterogeneous Photocatalysis in Serial Micro-Batch
Reactors
Authors: Bartholomaeus Pieber, Menny Shalom, Markus Antonietti,
Peter H Seeberger, and Kerry Gilmore
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712568
Angew. Chem. 10.1002/ange.201712568
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10.1002/anie.201712568
Angewandte Chemie International Edition
COMMUNICATION
Continuous Heterogeneous Photocatalysis in Serial Micro-Batch
Reactors
Bartholomäus Pieber[a], Menny Shalom[b]†, Markus Antonietti[b], Peter H. Seeberger*[a], Kerry Gilmore*[a]
Abstract: Solid reagents, leaching catalysts, and heterogeneous
photocatalysts are commonly employed in batch processes but are
ill suited for continuous flow chemistry. Heterogeneous catalysts for
thermal reactions are typically used in packed bed reactors that
cannot be penetrated by light and thus are not suitable for
photocatalytic reactions involving solids. We demonstrate that serial
micro-batch reactors (SMBRs) allow for the continuous utilization of
solid materials together with liquids and gases in flow. This
technology was utilized to develop selective and efficient fluorination
protocols using a modified graphitic carbon nitride heterogeneous
catalyst instead of costly homogeneous metal polypyridyl complexes.
The merger of this inexpensive, recyclable catalyst and the SMBR
approach gives access to sustainable and scalable photo catalysis.
stable and homogeneously distributed wall coatings are difficult
to prepare and different for each heterogeneous catalyst.
Efficient irradiation is ensured by pumping a suspension through
a coil reactor but the solid material settles, leading to a
heterogeneous distribution, irreproducible results, or clogging
(Fig. 1B).
Dosing a catalyst suspension into a segmented gas-
liquid stream should, based on suspension feeding into
segmented flow regimes,[20-22] provide a promising alternative for
heterogeneous photocatalysis. Such triphasic systems resemble
a series of small solid-liquid batch reactors (serial micro-batch
reactors - SMBRs) that are separated by an inert gas spacer
and “stirred” by toroidal currents (Fig. 1C).
Solid-liquid reactions are ubiquitous in chemical synthesis and
are usually straightforward in batch, but they are less trivial in
continuous flow devices.[1-4] Packed bed reactors with
heterogeneous catalysts embedded between filter units[1,5] suffer
from periodic deactivation or loss of catalyst due to leaching.
Photochemistry on the other hand is perfectly suited for
continuous processing as the large surface-to-volume ratio
ensures an increased irradiation efficiency, resulting in
intensified and scalable protocols.[1,6] Visible-light photoredox
catalysis (PRC)[7-8] employs costly ruthenium and iridium
catalysts or organic molecules prone to degradation.[9-10]
Difficulties associated with separation and recycling of these
catalysts render heterogeneous or easily recyclable catalysts
such as modified transition metal catalysts[11-13] and
semiconductors[14-16] highly desirable for PRC. Graphitic carbon
nitrides (g-C3N4), a class of metal-free polymers, are among the
most promising materials for heterogeneous PRC.[17-18]
Combining the advantages of continuous photochemistry and g-
C3N4 catalysis to provide an efficient and sustainable process is
conceptually attractive but challenging practically. Packed bed
reactors are not the method of choice as photons will be
exclusively absorbed at the outer region while the inner particles
are shielded (Fig. 1A). Small diameter packed bed reactors can
overcome the irradiation problem,[19] but packing is tedious and
channeling phenomena, as well as high pressure drops, are
foreseeable drawbacks.[20] Wall-coated reactors were previously
utilized for continuous photocatalytic reactions,[6] however,
Figure 1. Strategies for heterogeneous photocatalysis in flow. (A) Packed bed
reactors are ideal for heterogeneous catalysis but suffer from insufficient light
penetration. (B) Pumping a solid-liquid suspension is troublesome as the
material settles and aggregates. (C)
A triphasic gas-liquid-solid system
combines the advantages of batch and flow processing for heterogeneous
photocatalysis.
Earlier solid feeding systems suffer from complex
setups[20-21] or costly equipment[22] and are generally not suitable
for continuous operation.[4] To ensure straightforward access for
the general community, SMBR generation was designed to be
operationally simple and readily assembled from inexpensive,
commercially available parts. The residence time and catalyst
stoichiometry should be adjustable to enable detailed studies of
all reaction parameters.
[a]
Dr. B. Pieber, Dr. K. Gilmore, Prof. Dr. P. H. Seeberger
Department of Biomolecular Systems
Max Planck Institute of Colloids and Interfaces
Am Mühlenberg 1, 14476 Potsdam, Germany
E-mail: peter.seeberger@mpikg.mpg.de;
kerry.gilmore@mpikg.mpg.de
Dr. M. Shalom, Prof. Dr. M. Antonietti
Department of Colloid Chemistry
A flow setup for transformations on small scales meeting
all requirements is a dosing system comprised of two parts. First,
a stable gas-liquid segmented flow pattern is generated from the
reaction solvent and nitrogen gas in a fluorinated ethylene
propylene tube using a Y-shaped mixer (Fig. 2A). Subsequently,
the catalyst suspension is added from below via a mixing Tee
and a vertically mounted syringe pump that incorporates a
magnetic stir bar. The resulting SMBRs can be fed into an
irradiated coil reactor that is submerged in a thermostatic bath.
The residence time is adapted by changing the gas and/or liquid
flow rate or the reactor volume while the catalyst stoichiometry
[b]
Max Planck Institute of Colloids and Interfaces
Am Mühlenberg 1, 14476 Potsdam, Germany
†
Current address: Chemistry Department, Ben Gurion University of
the Negev, Beersheba 009728, Israel
Supporting information for this article is given via a link at the end of the
document.
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10.1002/anie.201712568
Angewandte Chemie International Edition
COMMUNICATION
acids using Selectfluor under PRC conditions[24] served as the
model transformation, as the triphasic SMBR system is perfectly
suited for reactions involving gaseous reagents and/or
byproducts. Batch experiments revealed that CMB-C3N4 can
2+
substitute Ru(bpy)3
in the decarboxylative fluorination of
phenoxyacetic acid (1) and can be reused several times without
losing its catalytic activity (Supporting information). Stirring is of
utmost importance for an efficient, reproducible batch process,
and the reaction rate drops on larger scales.
Under SMBR conditions, the drawbacks associated
with stirring can be elegantly addressed while the high irradiation
efficiency inherent of the small dimensions simultaneously
enhances the catalytic process. Monofluorinated compound 2 is
almost quantitatively formed within only 14 minutes (Fig. 3A).
The generated CO2 can immediately diffuse out of the liquid
phase, to form expanded gas slugs and increase the overall flow
rate without disturbing the integrity of the solid-liquid SMBRs
(Fig. 3B). Following the reaction, a three-step extraction protocol
provides the desired organofluorine compound without
chromatography and allows for both the catalyst and suspension
solvent ([Bmim]BF4) to be fully recovered (Fig. 3C).
Figure 2. Continuous generation of serial micro-batch reactors (SMBRs). (A)
Schematic representation of the solid dosing system. MFC = mass flow
controller. (B) On the fly adjustment of reaction parameters. (C) Internal mixing
results in a uniform, efficiently irradiated suspension (segments were irradiated
with 420 nm LEDs and the picture was taken through a blue light filter). See
Supplementary Information for experimental details.
can be varied by changing the rate of suspension dosing
(Supporting Information). The system continuously produces
identical SMBRs while all parameters can be changed during
operation. The installation of a second catalyst addition unit
enables a fully continuous operation by mimicking a dual syringe
pump (Supporting Information).
A modified carbon nitride (CMB-C3N4) that is highly
efficient for the photocatalytic production of hydrogen from water,
served as heterogeneous photocatalyst for initial tests.[23] This
bench-stable semiconductor can be prepared in large quantities
via a supramolecular approach from bulk chemicals and absorbs
in the visible region.[23] CMB-C3N4 shows minimal settling in
viscous solvents such as ethylene glycol and 1-butyl-3-
methylimidazolium tetrafluoroborate ([Bmim]BF4) a basis for the
reliable preparation of a stable suspension for the accurate
dosing of solid materials. Active mixing of the suspended
catalyst feed via mechanical stirring improves reproducible
additions, as negligible fluctuations over the course of addition
were observed. The internal mixing phenomena caused by
interior vortices inherent to the SMBRs result in a homogeneous
and uniformly irradiated suspension of the semiconductor
(Supporting Information).
Figure 3. Heterogeneous photoredox catalysis with CMB-C3N4 in SMBRs. (A)
Decarboxylative fluorination of phenoxyacetic acid. MFC
= mass flow
controller. NMR yields were determined by 19F-NMR using 2,2,2-
trifluoroethanol as internal standard. (B) CO2 byproduct expands the gas slugs
while keeping the solid-liquid SMBR intact. (C) Separation strategy for product
isolation and recovery of the catalyst and [Bmim]BF4. See Supporting
Information for experimental details.
With the robust dosing system in place, the SMBR
concept was illustrated for heterogeneous photocatalysis. The
well documented decarboxylative fluorination of phenoxyacetic
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10.1002/anie.201712568
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COMMUNICATION
The process can be easily scaled for the gram scale synthesis of
2 using a setup with two catalyst addition units (Supporting
Information). Control experiments in the absence of either the
semiconducting material or light did not result in an observable
gas formation and only trace amounts of 2 were identified by
NMR spectroscopy (Fig. 4A). Even when the reaction mixture
was not degassed, the SMBR approach still produced 2 in
excellent yield, whereas no reaction occurred in batch under
similar conditions. Using compressed air instead of nitrogen for
segment generation resulted in a 36% NMR yield and only pure
oxygen completely inhibited the photocatalytic cycle. The “in situ
degassing” of the SMBR system may occur via diffusion of
Homogeneous PRC fail for continuous chemistry on larger
scale due to irreproducible reaction parameters and the high risk
of clogging. The SMBR fluorodecarboxylation produced a range
of phenoxyacetic acid derivatives (Fig. 4B). The hydrophobic
nature of most products necessitated an acetone:water solvent
mixture to avoid the generation of an “organic film” on the
surface of the FEP coil (Supporting Information). Higher catalyst
loading in combination with longer reaction times (up to 48 min)
ensured sufficient conversions and yields similar to those
obtained by the original protocol,[24] as well as the uncatalyzed
version using UV light.[25]
The catalytic system was amenable to other
fluorinations (Fig. 4C). The decarboxylative fluorination of 4-
biphenylacetic acid (3) relied previously on a strongly oxidizing
2+
dissolved oxygen into the gas segments. When Ru(bpy)3 was
used instead of CMB-C3N4 employing a segmented flow pattern
without prior degassing of the solution product was formed, but
the homogeneous catalyst suffered from significantly lower
conversion than the heterogeneous PRC. Moreover, reactor
fouling with the ruthenium PRC resulted in a random flow profile
over time (Supporting Information).
iridium(III)
photocatalyst
(Ir[dF(CF3)ppy]2(dtbbpy)PF6)
in
presence of a base.[26] Under SMBR conditions, 3 was converted
to 4 (73% yield) within 40 min at 50 °C without additional
reagents.
Figure 4. Application of SMBR to heterogeneous photoredox catalysis. (A) Control experiments indicate an “in situ degassing” effect of the triphasic
reaction system. (B) Scope of the decarboxylative fluorination of phenoxyacetic acid derivatives. (C) Decarboxylative fluorination of 4-biphenylacetic
acid and direct monofluorination of ethylbenzene and ibuprofen methyl ester. (D) Selectivity studies for the fluorination of ibuprofen. aNMR yields are
given in parenthesis. b2,6-lutidine was added to dissolve the starting material. cIsolated yield in parenthesis. See Supporting Information for
experimental details.
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10.1002/anie.201712568
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[9]
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(5) was achieved using the heterogeneous photocatalyst and
Selectfluor (5, Fig. 4D), a transformation usually carried out
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the reaction without any additive was significantly increased by
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methyl ester (7) was carried out under water-free conditions to
avoid ester hydrolysis.
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decarboxylative fluorination product 10 and benzylic C-H
fluorination product 11 were identified by NMR analysis. In
presence of a base, only 10 was selectively obtained in
moderate yield. Without water as cosolvent under acidic
conditions, the decarboxylative fluorination pathway was
suppressed, to produce mainly 9 (Supporting Information).
In summary, we have developed a flow chemistry
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for heterogeneous materials with the benefits of flow
photochemistry. The simple and efficient continuous utilization of
heterogeneous photocatalysts serves as example and can be
extended to many solid catalysts and reagents where packed
bed reactors are non-ideal. The system is well suited for
reactions involving gases. Three different fluorination protocols
utilizing a heterogeneous organic semiconductor - which holds
numerous advantages over standard metal catalysts - were
developed and the methodology proved efficient, flexible, and
robust on various scales and allowed for the site-selective, late-
stage fluorination of ibuprofen. The SMBR concept, in
combination with graphitic carbon nitride photocatalysis, will
contribute to the development of more sustainable and
industrially relevant photoredox processes in the future.
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Acknowledgements
We gratefully acknowledge the Max-Planck Society for generous
financial support. We gratefully acknowledge our colleagues
Günter Haseloff, Jesús Barrio Hermida, Ines Cazin, Xuan Pham,
and Dr. Daniel Varón Silva for technical, synthetic, and analytical
support and Dr. Matthew B. Plutschack, Dr. Jiawei Rong, and Dr.
Martina Delbianco for fruitful discussions.
Keywords: flow chemistry • heterogeneous photocatalysis •
carbon nitride • fluorination
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COMMUNICATION
COMMUNICATION
Bartholomäus Pieber, Menny Shalom,
Markus Antonietti, Peter H. Seeberger*,
Kerry Gilmore*
((Insert TOC Graphic here))
Page No. – Page No.
Continuous Heterogeneous
Photocatalysis in Serial Micro-Batch
Reactors
A flow system for processing solids enables the efficient and scalable utilization of
heterogeneous photocatalysts for selective fluorinations.
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