Selective Photooxygenation of Dihydroartemisinic Acid in a Reusable Microreactor with Physically Immobilized Photocatalysts

Article abstract of DOI:10.1016/j.materresbull.2021.111540

Photocatalytic production of organic materials including Artemisinin has been hampered in the pharmaceutical industry because of low reusability and selectivity of photocatalysts. In this work, reusable photocatalysts were synthesized through novel physical and electrostatic immobilizations. After four reaction cycles of dihydroartemisinic acid (DHAA) photooxygenation using physically supported photosensitizers, the conversion was slightly reduced from 81 to 78%, indicating their high reusability. This occurred while maintaining the selectivity of the desired product above 85%, which was higher than that of the homogeneous photosensitizers. Then, a continuous-flow microreactor functionalized with these reusable polystyrene-supported photocatalysts was applied toward the photooxygenation of DHAA at ambient temperature and pressure to produce Artemisinin with a high yield confirmed by the ¹H-NMR analysis. Moreover, theoretical evaluations using finite element method simulation showed a 2-μm high local singlet oxygen (¹O₂) concentration around the reusable photocatalysts which agreed very satisfyingly with the data available in the literature.

Full text of DOI:10.1016/j.materresbull.2021.111540

Materials Research Bulletin 145 (2022) 111540
Contents lists available at ScienceDirect
Materials Research Bulletin
journal homepage: www.elsevier.com/locate/matresbu
Research Papers
Selective Photooxygenation of Dihydroartemisinic Acid in a Reusable
Microreactor with Physically Immobilized Photocatalysts
a,
b
a,
*
b
b
Mohsen Tamtaji , Mohammad Kazemeini , Abhishek Tyagi , Alexander Perez Roxas
a
Department of Chemical and Petroleum Engineering, Sharif University of Technology, Azadi Avenue, Tehran 1136594655, Iran
b
Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR
A R T I C L E I N F O
A B S T R A C T
Keywords:
Photocatalytic production of organic materials including Artemisinin has been hampered in the pharmaceutical
industry because of low reusability and selectivity of photocatalysts. In this work, reusable photocatalysts were
synthesized through novel physical and electrostatic immobilizations. After four reaction cycles of dihy-
droartemisinic acid (DHAA) photooxygenation using physically supported photosensitizers, the conversion was
slightly reduced from 81 to 78%, indicating their high reusability. This occurred while maintaining the selec-
tivity of the desired product above 85%, which was higher than that of the homogeneous photosensitizers. Then,
a continuous-flow microreactor functionalized with these reusable polystyrene-supported photocatalysts was
applied toward the photooxygenation of DHAA at ambient temperature and pressure to produce Artemisinin
Artemisinin
COVID-19
Singlet Oxygen
Selective Photooxidation
Heterogeneous Photocatalyst
FEM simulation
with a high yield confirmed by the 1H-NMR analysis. Moreover, theoretical evaluations using finite element
1
method simulation showed a 2-µm high local singlet oxygen ( O
2
) concentration around the reusable photo-
catalysts which agreed very satisfyingly with the data available in the literature.
1
. Introduction
number of strategies were considered to address such industrial chal-
lenges while trying to keep up with the principles of the green chemistry
[15]. Most recently, a key step toward sustainable photooxygenation
reactions was achieved by the development of a solvent-free procedure
Malaria is one of the most widespread and deadliest illnesses,
causing about one million deaths each year [1,2]. Sesquiterpene endo-
peroxide artemisinin is an essential antiviral drug that has been recog-
nized as the first-line and effective treatment for malaria as
recommended by the World Health Organization (WHO) [3–5]. Arte-
misinin is also known as a potent treatment for cancer [6,7] and has
been tested and used as a treatment in several epidemics, such as the
seasonal dengue and influenza and the historic MERS-CoV, SARS-CoV,
and, most recently, SARS-CoV-2 [8–10]. Due to its wide range of ap-
plications, there is a huge demand for artemisinin; however, multi-step
as well as low-yield synthetic processes, large waste production, and
high costs have limited its usability in medicinal applications. Moreover,
it is reiterated that, through a continuous photooxygenation of dihy-
droartemisinic acid (DHAA), in particular, most of the undesired foot-
prints are caused by solvent contamination and photobleaching of
photosensitizers [11–13]. To solve these problems, a high-selective,
single-step, and low-cost production through the photooxygenation of
DHAA [14] toward producing artemisinin is proposed to reduce the
economic burden as well as to improve the reaction yields. For years, a
[16]. Besides, photosensitizers immobilization were repeatedly studied
1
to facilitate singlet oxygen ( O
2
) generation and photooxygenation re-
actions [17–28], a very important component of the modern pharma-
ceutical manufacturing. On the other hand, the continuous flow reactor
technology has also received much attentions towards being used in
photooxygenation reactions, owing to their high irradiation efficiency
and large surface area [29–32]. Nonetheless, despite recent advances in
photochemical reactions towards achieving sustainable chemistry in
pharmaceutical manufacturing, the incorporation of such technology in
the industry has rather been scarce due to several economic and envi-
ronmental concerns. For example, in the well-established photo-
oxygenation reaction of DHAA, a high pressure as well as; low
temperature conditions were usually applied to enhance the solubility of
the dissolved oxygen, which otherwise would lead to a primary ther-
modynamic limitation of the process [33]. However, a previously pub-
lished report showed that about 70% of the total energy budget of the
process was allocated towards maintaining of the sub-ambient
*
Corresponding Author.
E-mail address: kazemini@sharif.edu (M. Kazemeini).
https://doi.org/10.1016/j.materresbull.2021.111540
Received 20 April 2021; Received in revised form 24 August 2021; Accepted 27 August 2021
Available online 31 August 2021
0
025-5408/© 2021 Elsevier Ltd. All rights reserved.

M. Tamtaji et al.
Materials Research Bulletin 145 (2022) 111540
temperatures in the reactor. This indeed would have increased the
so-called environmental footprint for the process [34].
achieved their closest interactions at ~4.7 Å. For an equal-mole mixture
of water and ethanol system, the distance between methylene blue and
the sulfonated PSt increased to ~13 Å, while for pure water, methylene
blue and the sulfonated PSt did not interact and stayed apart at a dis-
tance of 30 Å from one other (Figure S17b). Furthermore, as was indi-
cated through the Figure S17c, the interactions between methylene blue
and the sulfonated PSt was achieved under -0.06 and -3.41 kcal/mol of
energy for water and ethanol, respectively. These all emphasized that,
the ethanol led to a stronger interaction and hence a better immobili-
zation for the understudied system. The collected supernatant was then
analyzed using UV-Vis absorption spectra (see Figure S15 of Supporting
Information) to examine the presence of unattached photosensitizers.
The results revealed that 52% of methylene blue and 66% of TTAPP
remained attached on the MB@PSt and TTAPP@PSt, respectively.
Hereinafter, the photosensitizers immobilized physically by polymer
swelling are referred to as TTAPP-PSt or MB-PSt and those immobilized
through the electrostatic bonding are referred to as TTAPP@PSt or
MB@PSt.
In the current research, a novel method was developed to physically
immobilize the photosensitizers into swelled polystyrene (PSt)
microbeads, which eventually resulted in an efficient loading of several
layers of sensitizers. Their photoactivity and reusability were compared
with those of electrostatically immobilized photosensitizers on sulfo-
nated polystyrene microparticles. These polymer-supported photosen-
sitizers were then embedded on a chip-based continuous flow
microreactor towards a continuous photooxygenation of the DHAA
followed by one acid-catalyzed reaction to produce the Artemisinin.
Eventually, the reusability of photosensitizers without the need for post-
reaction separation and a negligible photobleaching of them were ach-
ieved. Moreover, through the Finite Element Method (FEM) a simulation
1
model was constructed to further investigate the localized O
layer produced around the reusable photosensitizers.
2
[35–38]
2
. Experimental section
2
.1. Chemicals
2.3. Experimental setup for the continuous flow photooxygenation
Absolute ethanol (99.9%, Merck), dichloromethane (≥ 99.9%,
The experimental setup, shown in Figure 5, was composed of a glass
microreactor assembled with a plexiglass holder as shown in Figure S9a.
The glass microreactor was fabricated with two glass slides, one as a
cover- and the other as a substrate, through several consecutive steps,
with details provided in the section S3 of Supporting Information. In
short, we started with the engraving of the microreactor pattern,
depicted in Figure S10 (composed of one T-shaped microbubble gener-
Merck), toluene (99.5%, Rci Labscan Co.) and anthracene (≥ 99.0%,
Fluka Co.) were all used as received. Dihydroartemisinic acid (DHAA,
9
9
8%) was purchased from the Xi’an Quanao Biotech Co. Butyl acetate (≥
9.5%), 2-propanol (100.0%), sulfuric acid (95%), triphenylphosphine
(
99%), methylene blue (MB, ≥ 82%), tetra(4-trimethylammoniophenyl)
porphyrin (TTAPP, 99%), Styrene (99%), divinylbenzene (80%), po-
tassium persulfate (≥ 99.0%), methacrylic acid (99%), acrylic acid
ator and one reaction zone), into a substrate glass slide using a CO laser.
2
(
99%), and (3-aminopropyl) triethoxysilane (APTES, 97%) were all
We then drilled the inlet and outlet fluidic access holes on the cover glass
obtained from the Sigma Co. All abovementioned chemicals were used
as received.
slide and performed the thermal bonding of glass slides in a muffle type
furnace [42]. The cross-sectional shape and top-view microscopic image
of a typical microchannel are presented in Figures S9b and S9c. As
shown in Figure 5, a 20 W white LED lamp was used for illumination. A
common LED lamp to make the process as simple as possible was used as
well [43]. Oxygen was stored in a balloon that was connected through a
2
.2. Synthesis of polystyrene-supported photosensitizers
The subsequent procedure demonstrates the novel swelling method
through which the photosensitizers were immobilized physically into
polystyrene (PSt) microbeads [39]. Crosslinked monodisperse PSt
microbeads with carboxyl functional groups on their surface were syn-
thesized using a typical delayed emulsion polymerization method, with
details provided in the section S1 of Supporting Information of this
paper. The produced microbeads (100 mg) were well-dispersed into
toluene (10 ml) under sonication and stirred for 5 hours. Then, as shown
in Figure S3, the photosensitizer (1 mg, methylene blue or TTAPP) was
dissolved in a mixture of dichloromethane and ethanol (1 ml, 1:1 v/v)
and vigorously stirred at room temperature for 12 hours. The solution
PTFE tubing and a peristaltic pump to the inlet designated as Q
syringe pump and a glass syringe were used to inject liquid solution
through into Q
1
, while a
2
.
2.4. Photooxygenation of DHAA in a continuous microreactor
To prepare the reaction mixture, the polystyrene-supported photo-
sensitizers (0.192 mg of MB@PSt, 0.152 mg TTAPP@PSt, 0.1 mg MB-
PSt, and 0.1 mg TTAPP-PSt, in order to keep the same weight of pho-
tosensitizers methylene blue and TTAPP) were added to DHAA (1 mg)
dissolved in dichloromethane (2 ml). Oxygen gas and the reaction
mixture were separately pumped through inlets 1 (at 1.6 ml/h) and 2 (at
1.6 ml/h), respectively, into the fabricated continuous microreactor
irradiated with a 20 W white LED lamp. (see MovieS1 from Supporting
Information for more details on a typical flow regime that occurs inside
the fabricated microreactor). The reactor effluent collected through the
outlet was centrifuged at 15000 rpm for 10 min in order to analyze the
supernatant using HPLC and to recover the immobilized photosensi-
tizers for further use. The procedure was repeated three more times
using the same photosensitizers to investigate the reusability of the
polystyrene-supported photosensitizers.
◦
was then heated to 50 C to remove the solvents. Afterwards, the
microbeads were washed 10 times with 50 ml of a mixture of
dichloromethane and ethanol (3:7 v/v). The collected supernatant was
finally analyzed using the UV-Vis absorption spectra (see Figure S15 of
Supporting Information) to examine the presence of unattached photo-
sensitizers. Results demonstrated that about 98% and 100% of methy-
lene blue and TTAPP were attached onto the MB-PSt and TTAPP-PSt,
respectively.
For comparison purposes, electrostatically immobilized photosensi-
tizers were also synthesized in the following manner. The PSt
microbeads (100 mg) were first sulfonated in a 95% sulfuric acid solu-
tion for 1 day before being washed and added into a mixture of 1 mg of
methylene blue or 1 mg of TTAPP in 5 ml of ethanol, which was then
stirred for another 24 hours. The microbeads were washed 10 times with
In another setup, the surface of the microreactor channels was
chemically functionalized (with details provided in the Supporting In-
formation) and bonded with the polystyrene microparticles and then
TTAPP was directly immobilized inside the flow reactor. This demon-
strated the best potential for reusability in order to avoid post-reaction
separation of sensitizers. The same conditions for the reaction mixture
and oxygen were employed except that the photosensitizers were fixed
within the microchannels. Afterwards, photooxygenation reactions of
triphenylphosphine and anthracene (Scheme 1) were likewise carried
5
0 ml ethanol to remove unattached sensitizers. Based upon these re-
searchers’ findings from the Molecular Dynamics (MD) simulations
which were carried out in the NAMD2.13 [40,41], ethanol rather than
water was used as a solvent in this step (see section S8 of the Supporting
Information section for more details). In other words, in the case of
absolute ethanol as a solvent, methylene blue and the sulfonated PSt
2

M. Tamtaji et al.
Materials Research Bulletin 145 (2022) 111540
Scheme 1. Photooxygenation of dihydroartemisinic acid (DHAA), triphenylphosphine, and anthracene.
1
out to show the capability of proposed microreactor and micro-
photosensitizers for the photooxygenation of a wide range of organic
materials.
( O
2
) [26,48–52]. Scheme 2 describes the reaction kinetics generally
described by: i) the formation of singlet and triplet excited-state pho-
tosensitizers upon the absorption of light; ii) the subsequent formation
1
1
of O
2
; iii) the oxidation of the reactant by O
2
; and iv) the formation of
3
triplet oxygen ( O
2
) [53,54].
2
.5. Simulation of the DHAA photooxygenation by Finite Element Method
The properties and photocatalytic performances of TTAPP-PSt, MB-
PSt, TTAPP@PSt, and MB@PSt were investigated and subsequently
compared. The as-synthesized photocatalysts were characterized via the
Scanning Electron Microscopy (SEM) as well as Transmission Electron
Microscopy (TEM) (see Figures S1 and S2 of Supporting Information)
displaying the high degree of monodispersity with respect to particle’s
shape and size (423 nm ± 2%). Figure S4 shows the Fourier-transforms
infrared spectroscopy (FTIR) of the functionalized beads. The func-
tionalization of the beads was confirmed upon the detection of C-N
(
FEM)
The photooxygenation inside a continuous flow reactor was inves-
tigated through a simulation using the COMSOL 5.1 [44–46]. Moreover,
utilizing dimensions measured from the obtained SEM image
(
Figure 2b), the geometry of the microchannel was replicated and shown
through Figure S14b. The laminar flow module was applied following
Equation 1 [47]:
[
ꢀ
)]
ꢀ 1
+
ꢀ 1
T
peaks at 1330 and 1387 cm and C=N peak at 1699 cm , all of which
ρ
(u⋅∇)u = ∇⋅ ꢀ pI +
μ
∇u + (∇u)
and
ρ
∇⋅(u) = 0
(1)
were practically absent in the spectra of the pure microbead. Interest-
+
ingly, TTAPP-PSt had the strongest C=N peak, indicating the presence
where
ρ
, p, µ, and u are the density, pressure, viscosity, and velocity of
of more photosensitizer on the surface. The effect of the immobilization
method on the crystal size was likewise inferred by examining the X-ray
powder diffraction (XRD) peak at 22.8o (see Figure S5 of Supporting
Information). Following the Scherrer’s equation [55], a peak position
the fluid, respectively. The transport of dilute species module was
similarly used according to Equation 2 [47]:
∇
⋅(ꢀ D
i
∇c
i
) + u⋅∇c
i
= R
i
(2)
◦
shift of about -1.6 for the physically embedded beads (MB-PSt and
where D
i
, R
i
, and c
i
are the diffusion coefficient, reaction rate, and
TTAPP-PSt) suggested that the photosensitizer loading through swelling
resulted in a reduction of the crystal size. In contrast, the electrostati-
cally immobilized beads (MB@PSt and TTAPP@PSt) showed negligible
peak position changes. From the UV-Vis absorption spectra (see
Figure S6 of Supporting Information), the peak of methylene blue
remained unchanged, whereas the peak of TTAPP shifted from 423 nm
towards 414 nm for TTAPP-PSt, demonstrating the effects of porphyrin
rings stacking and J- and H-type aggregate formation [56–58]. In
addition, the peak of TTAPP shifted from 423 nm towards 442 nm for
TTAPP@PSt, which revealed the protonation of porphyrin rings of
TTAPP [28]. Figure S7 shows the difference in color amongst MB-PSt
th
1
2
concentration of the i species ( O , DHAA, or hydroperoxide 3),
respectively. More details are presented in the Supporting Information
section of this paper.
3
. Results and discussion
Scheme 1 displays the already established reaction mechanisms for
the photooxygenation of DHAA, triphenylphosphine, and anthracene
illustrating a high reactivity and selectivity of traceless singlet oxygen
(
(
navy blue), TTAPP-PSt (brown), MB@PSt (sky blue), and TTAPP@PSt
green).
Figure 1 demonstrates the performance of the immobilized photo-
sensitizers in terms of DHAA conversion for four consecutive cycles. In
this setup, the microbeads were dispersed throughout the mixture for a
continuous-flow reaction along the microchannels of the microreactor
(
see Figures S8 and S9 of Supporting Information). The reaction was
repeated for four cycles to investigate the stability of the sensitizers.
After four cycles, the DHAA conversions of TTAPP@PSt and MB@PSt
fell drastically (Figure 1a), but those of TTAPP-PSt and MB-PSt dropped
only by 3% and 4%, respectively, implying the superior catalytic sta-
bility of the photosensitizers when physically loaded by our novel
Scheme 2. Kinetic description of the photooxygenation of dihydroartemisinic
1
3
1
acid (DHAA) to hydroperoxides 3, 4, and 5. In this scheme, S, S, S,
O
2
, and
are the photosensitizer, singlet excited-state photosensitizer, triplet excited-
state photosensitizer, singlet oxygen, and triplet oxygen, respectively.
3
O
2
3

M. Tamtaji et al.
Materials Research Bulletin 145 (2022) 111540
Figure 1. Drop in conversion after four cycles of reactions. (a) The dihydroartemisinic acid (DHAA) conversion when tetra(4-trimethylammoniophenyl)
porphyrin (TTAPP) and methylene blue (MB) electrostatically functionalized on polystyrene microbeads (PSt) were reused. (b) The DHAA conversion when the
photosensitizers were loaded by the swelling method. The flow rates of oxygen and the solution were retained at Q
1
and Q
2
=1.6 ml/h, the initial concentration of the
DHAA was set 0.5 mg/ml, and the concentration of the functionalized PSt microbeads was maintained at 0.05 mg/ml.
swelling method (Figure 1b). The drop in the DHAA conversion can be
attributed to an either leaching or photobleaching of photosensitizers. In
order to determine the quantity of leached sensitizer for the TTAPP-PSt,
Figure 3 shows the microreactor setup utilized in this research for a
photooxygenation reaction. It consisted of the microreactor, one warm
white LED (20 W) lamp, one oxygen balloon connected to a peristaltic
pump along with PTFE tubing to inject oxygen into the microreactor
a solution that passed through the reactor coated with TTAPP-PSt was
1
irradiated in the presence of triphenylphosphine as a O
2
trap and the
through the inlet Q
with the PTFE tubing to inject the solution into the microreactor through
an inlet designated as Q . We used the warm white LED lamp to make
1
, and one syringe pump and one glass syringe along
triphenylphosphine oxide formed was quantitated. Based upon the ob-
tained results, very small amount of triphenylphosphine oxide was
synthesized under this situation (i.e.; about 2.4% conversion) which
emphasized that, there was no leached-out TTAPP. These results were in
a good agreement with the UV-vis spectra presented in the section S7
which showed that, there was no leached-out sensitizer (i.e.; of MB or
TTAPP types) after washing of physically immobilized micro-
photosensitizers. Therefore, it was concluded that, because there were
no leached-out sensitizers, drop in the DHAA conversion was due to the
photobleaching [59,60. Selectivity of the hydroperoxide 3 was deter-
mined to be 82, 87, 88, 85, and 84% for homogeneous TTAPP, MB@PSt,
TTAPP@PSt, MB-PSt, and TTAPP-PSt; respectively (Table 1). These re-
sults emphasized that immobilization of photosensitizer could affect the
selectivity; a long-standing goal in singlet oxygen chemistry [61]. The
selectivity of electrostatically immobilized photocatalysts are higher
than physically embedded photocatalysts. In addition, the turnover
frequencies (TOF) of MB@PSt, TTAPP@PSt, MB-PSt, and TTAPP-PSt
2
the process as simple as possible.
Figure 4 demonstrates the photoconversion of the DHAA as a func-
tion of the residence time through the (TTAPP-PSt)-coated microreactor
at 298 K and 1 bar. In addition, the trifluoroacetic acid (TFA) was used
for the acid catalyzed reaction towards a one-pot production of the
Artemisinin species under the aforementioned ambient conditions. The
1
pertinent results were shown in Figure 5 through the H-NMR analysis.
1
Moreover, based upon the H-NMR analysis, it is emphasized that, the
Artemisinin yield is rather satisfyingly high. Furthermore, the conver-
sion for the photooxygenation of triphenylphosphine and anthracene
were also determined using the same reactor as well as operating con-
ditions and revealed in Figure 4. Then a zeroth-order reaction rate law
(the details of which were presented in the section S5 of the Supporting
Information of this work), was revealed to be consistent with the
available data in the open literature for photooxygenation of the DHAA
and unsaturated hydrocarbon polymers [53,63].
ꢀ 1
were determined to be 1.6, 4.4, 1.2, and 3.9 s , respectively, for the
first cycle and the turnover numbers (TON) of abovementioned photo-
catalysts were determined to be 1259, 3446, 934, and 3067, respectively
To further probe the proposed process, a simulation of the photo-
oxygenation along the functionalized microchannels was constructed in
1
(
Table 1).
Figure 2 shows the immobilization of microbeads on the micro-
COMSOL Multiphysics, monitoring the local concentrations of the O
2
,
reactants, and products (the details of which are shown in Table S2 of
reactor wall. The microchannel surface was functionalized with the
physically embedded photosensitizers by coupling the carboxylic groups
with the surface [62], which was pre-aminated using APTES (Figure 2a).
A 16% surface coverage was estimated from the SEM image of the
functionalized channels (Figures 2b and S11). A schematic of the pho-
tooxygenation using TTAPP-PSt is illustrated in Figure 2c, following the
reaction path shown in Schemes 1 and 2.
Supporting Information section of this paper). Figure 6a demonstrates
1
the concentration of the O
2
on the surface of microchannels and around
the microphotosensitizers (the geometry of which is based upon the
1
Figure 2b). Moreover, Figure 6b plots the O
2
concentration profile near
the surface of microbeads. From the onset of Figure 6b, one may observe
1
about 2-µm penetration length of O
2
, which is in accordance with the
data available in literature amounting to about 1.5 µm for dichloro-
methane [64] (see the equation S3 of the Supporting Information).
Difference between the simulation and experimental data, results from
the presence of mixing on the surface of microchannels. This further led
to increase the singlet oxygen diffusion length through the theoretical in
comparison with that of the experimental data. Furthermore, Figures 6c
Table 1
The selectivity of hydroperoxide 3, the turnover frequencies (TOF), and the
turnover numbers (TON) for MB@PSt, TTAPP@PSt, MB-PSt, and TTAPP-PSt.
ꢀ
1
3
Selectivity of hydroperoxide 3
TOF (s
)
TON
and 6d show the concentrations (mol/m ) of the DHAA and hydroper-
oxide 3 on the surface of microchannels, respectively. From the con-
MB@PSt
87 %
88 %
85 %
84 %
1.6
4.4
1.2
3.9
1259
3446
934
TTAPP@PSt
MB-PSt
centration distribution of the DHAA, these researchers verified that, the
photooxygenation reaction occurred inside a thin and highly concen-
TTAPP-PSt
3067
1
trated O
2
region around each microbead. Figure S14b represents the
4

M. Tamtaji et al.
Materials Research Bulletin 145 (2022) 111540
Figure 2. Immobilization of the microbeads on the microreactor wall. (a) Schematic of the coating of the PSt beads on the surface of the microchannels. (b) SEM
image of the distribution of the PSt beads coated on the surface of the microchannels. (c) The scheme of the photooxygenation reaction inside a microreactor coated
with TTAPP-PSt.
Figure 4. Reaction kinetics. The conversion of dihydroartemisinic acid
(
DHAA, ●), anthracene (■), and triphenylphosphine (▴) vs the residence time
using a microreactor functionalized with TTAPP-PSt. For these experiments, the
flow rate of oxygen is set at Q ) was
=1.6 ml/h, the flow rate of the solution (Q
varied between 0.5 and 1.6 ml/h, and the initial concentration of the reagent
DHAA, triphenylphosphine, or anthracene) was set at 0.1 mg/ml. Zero-order
reaction was fitted to the experimental data (solid lines), leading to rate con-
1
2
(
Figure 3. Microreactor setup utilized in this research for a photooxygenation
reaction. It consisted of the microreactor, one warm white LED (20 W) lamp,
one oxygen balloon connected to a peristaltic pump along with PTFE tubing to
2
2
stants 0.395±0.072 (R =0.993), 0.411±0.023 (R =0.999), and 0.477±0.092
2
(R =0.991) mg/ml•min for DHAA, anthracene, and triphenylphosphine,
inject oxygen into the microreactor through the inlet Q
and one glass syringe along with the PTFE tubing to inject the solution into the
microreactor through the inlet designated as Q . We used the warm white LED
1
, and one syringe pump
respectively.
2
applied triangular mesh upon the geometry of the microchannel surface
emphasizing the finer mesh near the surface of the microbeads. More-
over, as evident in the obtained velocity field (see Figures S14c and S14d
lamp to make the process as simple as possible. (For interpretation of the ref-
erences to colour in this figure legend, the reader is referred to the web version
of this article.)
5

M. Tamtaji et al.
Materials Research Bulletin 145 (2022) 111540
1
Figure 5. Artemisinin production. H-NMR spectroscopy of synthesized Artemisinin. 10 µl trifluoroacetic acid (TFA) was used for the acid catalyzed reaction for
the production of Artemisinin in dichloromethane as solvent. Other reaction conditions are explained through section “Photooxygenation of DHAA in a continuous
microreactor”. The peaks are assigned based upon the data available in the open literature [2,28,33].
1
Figure 6. Finite Element Method (FEM) simulation. (a) The concentration of O
2
on the surface of microchannels and around the microphotosensitizers (geometry
1
obtained from Figure 2b). (b) The length of penetration of
2
O around one microphotosensitizer. (c) The concentration of dihydroartemisinic acid (DHAA) and (d)
3
hydroperoxide 3 on the surface of the microchannels (mol/m ).
of the Supporting Information), the presence of microbeads on the
microchannel surface enhanced the mixing of the reaction medium.
Altogether, the photocatalytic performance of TTAPP-PSt microbead
revealed to be superior amongst the reported materials for continuous
flow photooxygenation of the DHAA. The method presented in this
paper eliminated the typical reaction requirement of a low-temperature
6

M. Tamtaji et al.
Materials Research Bulletin 145 (2022) 111540
and high-pressure operating conditions previously needed for this re-
action. Furthermore, considering the advantages of continuous flow
microreactors, this process could be easily scaled-out for industrial ap-
plications through utilizing several such microfluidic devices in parallel
[2] L. Feng, Y. Wang, S. Yuan, K.Y. Wang, J.L. Li, G.S. Day, D. Qiu, L. Cheng, W.
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[
65,66]. In addition, the safety of the photooxygenation process is
confidently believed to be satisfied within such microfluidic systems
67,68]. The catalytic stability of the material combined with the
[
method used to embed the microbeads onto the microchannel surface
both allowed the reusability of the photosensitizers without a necessary
post-reaction separation process.
4
. Conclusion
In this research, a procedure to increase the selectivity and reus-
[
ability of photooxygenation of the DHAA towards Artemisinin produc-
tion was developed. In addition, minimization of waste resulted from the
integrated strategies of reduced photobleaching, ambient reaction con-
ditions, and solvent as well as photosensitizer reusability without a
necessary separation stage. The inherent issue of the photobleaching of
homogeneous photocatalysts was addressed when the high photo-
activity of the physically embedded TTAPP-PSt photocatalysts was
almost retained after four reaction cycles amounting to a small decrease
from 81 to 78% in reaction conversion between the first and fourth
repetition. To the best of these authors’ knowledge, this is the best
selectivity and reusability for the photocatalysts applied in the Artemi-
sinin production. In addition, the electrostatically functionalized
TTAPP@PSt resulted in a higher selectivity of 88% for hydroperoxide 3,
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[
[
ꢀ
1
higher turnover frequency of 4.4 s amongst all other photocatalysts
understudied. Moreover, the functionalization of the microchannels
with TTAPP-PSt induced the flow channel roughness thus, enhanced the
mixing of the reaction medium. This approach also enabled the reutili-
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5
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required expansion of financial resources as well as might have perhaps
1
led into environmental problems. Ultimately, a high local O
2
concen-
tration around the photosensitizers was concluded from a FEM simula-
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literature data.
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Credit Toxonomy
Mohsen Tamtaji: Conceptualization, Data Curation, Visualization,
Software, Methodology, Validation, Formal analysis, Investigation,
Writing - Original Draft, Writing - Review & Editing. Mohammad
Kazemeini: Conceptualization, Methodology, Validation, Formal anal-
ysis, Investigation, Writing - Original Draft, Writing - Review & Editing,
Supervision, Funding acquisition. Abhishek Tyagi: Conceptualization,
Data Curation, Visualization, Software, Writing - Original Draft, Writing
[
[
-
Review & Editing. Alexander Perez Roxas: Formal analysis, Investi-
19] F.S. Rocha, A.J. Gomes, C.N. Lunardi, Graphene oxide–metallophthalocyanine
hybrids with enhanced singlet oxygen generation, Mater. Res. Bull. 114 (2019)
gation, Writing - Original Draft, Writing - Review & Editing.
4
5–51, https://doi.org/10.1016/j.materresbull.2019.02.018, https://doi.org/.
Declaration of Competing Interest
[20] M. Wojtoniszak, D. Rogi n´ ska, B. Machali n´ ski, M. Drozdzik, E. Mijowska, Graphene
oxide functionalized with methylene blue and its performance in singlet oxygen
generation, Mater. Res. Bull. 48 (2013) 2636–2639, https://doi.org/10.1016/j.
materresbull.2013.03.040, https://doi.org/.
These authors respectfully declare that there are no conflicts of in-
terest to acknowledge for this research.
[21] J.M. Tobin, T.J.D. McCabe, A.W. Prentice, S. Holzer, G.O. Lloyd, M.J. Paterson,
V. Arrighi, P.A.G. Cormack, F. Vilela, Polymer-Supported Photosensitizers for
Oxidative Organic Transformations in Flow and under Visible Light Irradiation,
ACS Catal 7 (2017) 4602–4612, https://doi.org/10.1021/acscatal.7b00888,
https://doi.org/.
Supplementary materials
[
[
[
22] Y. Liu, C.T. Buru, A.J. Howarth, J.J. Mahle, J.H. Buchanan, J.B. Decoste, J.T. Hupp,
O.K. Farha, Efficient and selective oxidation of sulfur mustard using singlet oxygen
generated by a pyrene-based metal-organic framework, J. Mater. Chem. A. 4
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.materresbull.2021.111540.
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2016) 13809–13813, https://doi.org/10.1039/c6ta05903a, https://doi.org/.
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