Development of a Solid-Compatible Continuous Flow Reactor for the Paraformaldehyde Slurry Mediated 𝛼-hydroxymethylation of Methyl Vinyl Ketone

Abstract

The 𝛼-hydroxymethylation reaction hold a significant position within the pharmaceutical industry due to their intriguing nature. Despite numerous reported methods, they often entail prolonged reaction times and moderate yields. Moreover,...

Full text

rsc.li/reaction-engineering
Linking fundamental chemistry and engineering to create scalable, efficient processes
Reaction Chemistry
& Engineering
rsc.li/reaction-engineering
ISSN 2058-9883
PAPER
Timothy Noel et al.
A convenient numbering-up strategy for the scale-up of gas-
liquid photoredox catalysis in flow
Volume 1
Number 1
1 February 2016
Pages 1-120
Linking fundamental chemistry and engineering to create scalable, efficient processes
Reaction Chemistry
& Engineering
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after acceptance,
before technical editing, formatting and proof reading. Using this free
service, authors can make their results available to the community, in
citable form, before we publish the edited article. We will replace this
Accepted Manuscript with the edited and formatted Advance Article as
soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes to the
text and/or graphics, which may alter content. The journal’s standard
Terms & Conditions and the Ethical guidelines still apply. In no event
shall the Royal Society of Chemistry be held responsible for any errors
or omissions in this Accepted Manuscript or any consequences arising
from the use of any information it contains.
Accepted Manuscript
View Article Online
View Journal
This article can be cited before page numbers have been issued, to do this please use: B.
Vandekerckhove, L. Van Coillie, B. Metten, T. Heugebaert and C. V. Stevens, React. Chem. Eng., 2024,
DOI: 10.1039/D4RE00220B.

1
Development of a Solid-Compatible Continuous
Flow Reactor for the Paraformaldehyde Slurry
Mediated 𝛼-hydroxymethylation of Methyl Vinyl
Ketone
Bavo Vandekerckhove,a* Lise Van Coillie,a* Bert Metten,b Thomas S.A. Heugebaert,a Christian V.
Stevensa
a SynBioC Research Group, Department of Green Chemistry and Technology, Faculty of
Bioscience Engineering, Ghent University, Coupure Links 653, B-9000 Ghent, Belgium
b Ajinomoto Bio-Pharma Services, Cooppallaan 91, 9230 Wetteren, Belgium
*Equal first author contribution
E-mail: Chris.Stevens@UGent.be
KEYWORDS
Flow Chemistry – Solids in Flow – Paraformaldehyde Slurry – 𝛼-Hydroxymethylation
ABSTRACT
The 𝛼-hydroxymethylation reaction hold a significant position within the pharmaceutical industry
due to their intriguing nature. Despite numerous reported methods, they often entail prolonged
Page 1 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

2
reaction times and moderate yields. Moreover, the prevalent use of aqueous formaldehyde restricts
the applicability of this chemistry to water-compatible substrates. Gaseous formaldehyde remains
largely avoided due to its toxicity, hazards, and requirement for substantial excess. Within this
context, paraformaldehyde emerges as a promising alternative for the C1 building block, offering
safety and ease of handling. Continuous flow methodology is employed to facilitate the in situ
depolymerization of paraformaldehyde under optimized conditions, enabling direct utilization of
the released formaldehyde gas. This research explores the use of a paraformaldehyde slurry in
continuous flow for 𝛼-hydroxymethylation reactions, with methyl vinyl ketone serving as a proof-
of-concept substrate. A solid-compatible continuous flow reactor was self-constructed and the
hydroxymethylation of methyl vinyl ketone could successfully be optimised, resulting in a STY
of 2040 kg h-1 m-3.
INTRODUCTION
Hydroxymethyl motifs are often found in the core structure of natural products and in various
important active pharmaceutical ingredients (APIs). For example, α-hydroxymethyl ketones are
found in anticholinergic medication (Antropine), antiproliferative agents, antitumor agents
(Olivomycin A and Chromomycin A3), possible anti-cancer substances etc [1,2]. Moreover, the -
CH2OH unit is easily converted into many other functional groups, which contributes to the further
expansion of its synthetic potential. In addition, the introduction of small substituents such as a
hydroxymethyl group, has the capacity to modulate molecular properties such as solubility,
bioavailability, receptor binding affinity and metabolic stability. These modifications have a
pivotal role in optimizing the pharmacological and pharmacokinetic properties [3-7].
Page 2 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

3
The synthesis of α-hydroxymethyl ketones is most often performed with formaldehyde as a C1
source. Under normal circumstances, formaldehyde exists as a colorless gas with flammable
properties, marked by a high reactivity and characterized by a pungent, irritating odor. The levels
at which gaseous formaldehyde is carcinogenic and causes toxic irritations are lower than its odor
threshold, generating a substantial safety hazard. Theoretically, formaldehyde gas could be used
in batch reactors by bubbling it through the reaction mixture. In practice, however, formaldehyde
gas is avoided in industry because of these safety concerns. Therefore, it is mostly used as a
solution in water, known as formalin. However, this limits the substrate scope tremendously since
only water compatible substrates and reactive intermediates can be used [8,9]. In addition, both
aqueous and gaseous formaldehyde most often require very long reaction times or high
stoichiometric excesses, leading to low efficiencies, low atom economy and/or low yields [10-13].
To address the limitations of aqueous and/or gaseous formaldehyde, the solid paraformaldehyde
(PFA) polymer could be an interesting alternative. Due to its polymeric nature, PFA is easily
transported and stored, and can be handled safely. Under appropriate reaction conditions, it enables
a gradual release of monomeric formaldehyde gas. The latter can be used directly to perform the
hydroxymethylation reaction of interest. Several indicators show that continuous flow chemistry
could be advantageous for this type of chemistry [14]. At elevated temperatures and pressures, the
depolymerization efficiency can be increased while maintaining the containment of the
in situ
generated formaldehyde, thus strongly reducing the dangers associated with the use of this
carcinogenic gas. In addition, the reactivity of the monomeric formaldehyde molecules can be
Page 3 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

4
increased and thus reaction times can be shortened. Nevertheless, paraformaldehyde is a solid and
handling suspensions/slurries is known to be detrimental for continuous flow applications [15-17].
Literature showed alternative reaction setups regarding the
ex situ
generation of formaldehyde gas
from paraformaldehyde and its use within a Teflon AF 2400 tube-in-tube design [18]. However,
this setup is often limited as well by difficult heating, relatively low gas loading, insufficient radial
mixing and rather challenging scale-up [19].
Until present, the use of solids or slurries in continuous flow has posed significant challenges,
primarily due to issues such as clogging, accumulation and sedimentation, subsequently leading
to blockage of the setup. A number of studies attempt to address this, but place a predominant
focus on immobilized catalyst chemistry, often in packed bed-type reactors [20-23]. The amount
of studies addressing the use of solid reagents requiring accurate dosing into the flow reactor or
handling formed precipitations are scarce [24,25]. This study presents the efforts to design a novel
continuous flow setup to deal with the conditions required for paraformaldehyde slurry mediated
chemistry.
SCOPE
𝛼-hydroxymethylation of Michael acceptor systems using formaldehyde, embodies a simple, yet
important reaction with respect to the products' vital role in total synthesis and polymer science.
The Morita-Baylis-Hillman (MBH) reaction has been generally described for vinyl ketones using
formaldehyde for the synthesis of hydroxymethyl 𝛼,-unsaturated ketones. Mantel et al. reported
an efficient one-pot MBH-type 𝛼-hydroxymethylation of vinyl ketones followed by the
Page 4 of 27
Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

5
convenient, temperature-controlled etherification using alcohols [26]. Even though this type of
chemistry is generally known in literature, long reaction times are often required, while using toxic
solvents/reagents and a disfavorable atom economy [27-29]. The two-step 𝛼-hydroxymethylation
consist of preliminary paraformaldehyde depolymerization, followed by addition of the vinyl
ketone (Figure 1).
O O
HO
1. Paraformaldehyde (1.4 eq.)
Ethanol (2.9 eq.)
DABCO (0.05 eq.)
85 °C, 20 min
2. additon of methyl vinyl ketone (1 eq.), 3h, rt
Literature yield: 85%
Figure 1. Two-step 𝛼-hydroxymethylation of methyl vinyl ketone in batch according to Mantel
et al [26].
The 𝛼-hydroxymethylation of methyl vinyl ketone (MVK) was chosen as a proof-of-concept
reaction to evaluate paraformaldehyde slurry chemistry in continuous flow (Figure 1). Although
the reported batch reaction time is reasonable (+- 3.5h), there is potential to significantly reduce it
to the minute range. Hence, this reaction is a good model to monitor the efficiency of a
paraformaldehyde slurry mediated continuous flow process. The focus is set on the reduction of
reaction times, yield optimisation and safety improvement of the procedure. If PFA
depolymerization can be performed efficiently in the flow reactor, the applicability of the MBH
reaction can be widened and scale-up of this type of chemistry can be performed safely.
Page 5 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

6
RESULTS AND DISCUSSION
Batch control experiments
Before attempting the paraformaldehyde (PFA) mediated 𝛼-hydroxymethylation reaction in a
continuous flow setup, a short batch optimisation was performed to validate literature reports and
tune the reaction conditions towards a flow compatible process. Therefore, sealed vials were used
in a batch setup to withstand some possible pressure build-up. According to the Arrhenius law,
increasing reaction temperatures can decrease the reaction time. Nevertheless, Mantel et al.
showed that at elevated temperatures, the hydroxyl group undergoes an etherification reaction with
the alcohol that is present (as solvent). Since higher temperatures will be employed in further
optimisation, it may be of interest to avoid alcoholic solvents to minimise the etherification. A
variety of solvents were tested using the reaction conditions outlined by Mantel et al., involving
the two-step process (Table 1). It is apparent that the alcoholic solvents such as EtOH and IPA
exhibited the most favourable reaction performance. Only 1,4-dioxane provided a moderate yield
when employed as a non-alcoholic solvent. Consequently, these will be revisited during the
subsequent reaction time screening phase. Moreover, Robiette et al. already demonstrated the
beneficial impact of protic solvents on the kinetics of the MBH reaction [30].
Entry
Temperature
(°C)
Reaction time
(min)
Solvent
PFA
(Eq.)
NMR yieldc
(%)
1a
85/rt
20/180
EtOH
1.4
71 (68)b
2
85-115/rt
20-60/180
THFd
1.4
2
3
85-115/rt
20-60/180
THF + 5% EtOHd
1.4
37
4
85-115/rt
20-60/180
THF + 10% EtOHd
1.4
49
5
85/rt
20/180
IPA
1.4
71
Page 6 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

7
6
85-115/rt
20-60/180
EtOAcd
1.4
0
7
85/rt
20/180
H2O
1.4
14
8
85-115/rt
20-60/180
Toluened
1.4
6
9
85-115/rt
20-60/180
ACNd
1.4
7
10
85/rt
20/180
1,4-Dioxane
1.4
57
11
85/rt
20/180
DME
1.4
50
aLiterature conditions by Mantel et al.
bIsolated yield after column chromatography.
cNMR yield calculated relative to internal standard (trimethoxybenzene).
dDepolymerisation time and temperature were increased to ensure complete depolymerisation
of PFA.
Table 1. Solvent screening of the 𝛼-hydroxymethylation of methyl vinyl ketone in batch (2
steps, catalyst = DABCO (0.05 eq.)).
Following the solvent screening, it becomes crucial to decrease the reaction time to maintain
an acceptable material throughput using continuous flow. Initially, ethanol was used to start the
reaction time optimisation. As a first improvement, depolymerisation of paraformaldehyde and
the subsequent reaction could be combined in a single step (Table 2). A short optimisation
resulted in a decrease of the reaction time from 3.5h to 8 minutes at 100 °C, giving similar NMR
spectra and isolated yields to those obtained using the literature conditions. It was expected that
less etherification side product would be formed when using isopropanol, however a lower yield
was obtained under these conditions. Furthermore, alternative degradation mechanisms took
precedence when 1,4-dioxane was utilized as a solvent, leading to a substantially lower yield.
Entry
Temperature
(°C)
Reaction time
(min)
Solvent
PFA
(Eq.)
NMR yieldc
(%)
1a
85/25
20/180
EtOH
1.4
71 (68)b
Page 7 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

8
2
60
180
EtOH
1.4
71
3
60
60
EtOH
1.4
56
4
60
50
EtOH
1.4
51
5
60
40
EtOH
1.4
65
6
60
30
EtOH
1.4
66
7
60
20
EtOH
1.4
60
8
80
10
EtOH
1.4
68
9
80
20
EtOH
1.4
39
10
100
10
EtOH
1.4
53
11
100
8
EtOH
1.4
74 (70)b
12
100
8
IPA
1.4
65
13
100
8
1,4-Dioxane
1.4
27
14
100
5
EtOH
1.4
65
15
120
5
EtOH
1.4
59
16
120
3
EtOH
1.4
66
17
120
1
EtOH
1.4
57
18
100
8
EtOH
1.0
66
aLiterature conditions by Mantel et al.
bIsolated yield after column chromatography.
cNMR yield calculated relative to internal standard (trimethoxybenzene).
Table 2. Temperature/reaction time screening of the 𝛼-hydroxymethylation of methyl vinyl
ketone in batch (catalyst = DABCO (0.05 eq.)).
Experimental setup
As mentioned earlier, solids or slurries are acknowledged to pose challenges within continuous
flow systems. This research utilizes a paraformaldehyde slurry, thus requiring a flow reactor design
compatible with such a slurry. This has the potential to expand the scope of continuous flow
chemistry, encompassing solids as reagents, catalysts, or products.
Page 8 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

9
Initially, tests were performed with a high pressure Teledyne ISCO 500d module with a Büchi
mixer, a semi-continuous syringe pump with internal mixing to prevent solid sedimentation.
However, it quickly became evident that this pump was underperforming with a significant portion
of the solids remaining in the syringe, leading to a notably low paraformaldehyde output. Hence,
a peristaltic pump (Vapourtec, SF-10) was employed as an alternative to accurately dose
suspensions into the flow reactor. Conversely, this restricts the process window to pressures up to
10 bar. To avoid sedimentation of solids and eventually clogging of the flow setup, several
alternative techniques have been reported: pulsatile flow, sonication, mechanical agitation,
segmented flow etc [31-34]. Within our reactor design, an oscillatory flow was used to keep solid
particles suspended. Therefore, the Lewa Ecosmart diaphragm metring pump was selected and
subsequently, its valves were removed to enable its operation as a pulsator (Figure 2) [35]. This
device is capable of handling system pressures up to 80 bar and the stroke amplitude of the
oscillating flow can be manually adjusted. A frequency controller was installed and connected to
the Lewa Ecosmart pump to allow adjustments of the stroke frequency of the oscillation as well,
enabling complete control of the parameters governing the oscillatory flow.
Page 9 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

10
Figure 2. Lewa Ecosmart diaphragm metring pump.
The stainless steel Uniqsis Hotcoil, a standalone heated reactor module with an internal volume
of 40 mL was used as reactor, allowing reaction temperatures up to 300 °C and maximum pressures
up to 100 bar [36]. To interconnect all components, 1/8” stainless steel tubing and Swagelok
connections were used to comply with the demands of the process window. Back pressure
regulators (BPR), such as dome pressurized (Equilibar, Zaiput) and spring loaded cartridges, prove
problematic when dealing with solids. Therefore, a blockage-resistant BPR was constructed, based
on the research of Deadman et al [37]. The design consists of a pressurised collection vessel with
a tube-in-tube design (Figure 3). To permit freely flowing chemical slurries, the flow paths had
to be sufficiently wide-bore without restrictions to prevent blockages from occurring. At the
bottom of the pressure chamber, a large-bore quarter-turn valve allows the contents of the chamber
to be expelled whilst maintaining back pressure in the flow system. Inert nitrogen gas is employed
for vessel pressurization, while Swagelok connections guarantee a system pressure capped at 100
bar [35].
Page 10 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

11
Figure 3. Design of the blockage-resistant back pressure regulator based on the research of
Deadman et al [37].
The integration of the aforementioned systems results in a slurry-compatible continuous flow
reactor. Despite the initial focus of the reactor design being on high temperature/pressure
chemistry (300 °C, 100 bar), the current process window is restricted to 10 bar due to the absence
of a slurry-compatible high-pressure pump (TBoil, EtOH = 144 °C @ 10 bar). The applicability and
efficiency of this self-constructed CØPE reactor1 (C = Celsius (temperature), Ø = particle size
(slurry), P = pressure, E = extreme) will be monitored with the paraformaldehyde slurry mediated
𝛼-hydroxymethylation of methyl vinyl ketone.
In a continuous flow system, residence time distribution (RTD) is introduced as an important
parameter to describe the plug flow character. Narrow RTDs decrease the probability of side
Page 11 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

12
reactions or incomplete conversion to occur. With the addition of a pulsator to prevent solid
particle sedimentation, the amplitude and frequency of pulsations emerge as new process
parameters significantly impacting the RTD. Symmetrical oscillations will be applied generating
vortices (eddies), leading to improved radial mixing, whilst aiming to maintain a plug flow
character (minimal axial mixing). Therefore, mixing is decoupled from the net flow rate and
mainly depends on the oscillation conditions. Axial dispersion previously proved to be very
sensitive to oscillatory conditions at low net flow rates [38]. As such, the RTD of our assembly
was measured for different pulsator amplitudes and frequencies to gain insights in the mixing
behaviour (Table 3, Figure 4).
Entry
Oscillation frequency (Hz)
Oscillation amplitudea (%)
ReOsc
Bo
1
3
15
542
51
2
3
30
1134
63
3
3
50
1874
59
4
3
70
2614
69
5
3
95
3551
68
6
1
15
181
54
7
1
30
378
57
8
1
50
625
51
9
1
70
871
43
10
1
95
1184
49
aPulsator amplitude is expressed in percentage of the maximum stroke volume of 0.76 mL.
Table 3. Oscillating Reynolds number and Bodenstein numbers for different pulsator settings
(flow rate = 5 mL/min, mean residence time = 8 min).
Page 12 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

13
1This system was constructed as a down-scaled model of the CØPE reactor of Ajinomoto Bio-Pharma Services,
Belgium.
Figure 4. Residence time distribution for different pulsator settings within the CØPE reactor
with a pulsator frequency of 3 Hz (a) and 1 Hz (b).
For all pulsator amplitudes, the Bodenstein number (Bo) exhibits consistency for every
frequency, with a slightly elevated Bo number observed at a 3 Hz frequency. Although all RTD
a)
b)
Page 13 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

14
curves are nearly symmetrical, the Bo number indicates that no fully ideal plug flow behaviour is
observed (Bo<100) within this tubular system (Figure 4).
Continuous Flow Optimisation
Equipped with these optimised batch conditions and the self-constructed slurry-compatible flow
reactor, the transition towards a continuous flow process in the CØPE reactor was initiated.
Originally, all reagents were mixed in a continuously stirred feed vessel and used as such within
setup A (Figure 5).
Paraformaldehyde + DABCO + MVK + EtOH
Coil reactor
40 mL
Pulsator
Peristaltic pump
N2inlet
N2outlet
Figure 5. Schematic overview of continuous flow setup A.
Although the residence time distribution was measured for different pulsator settings, it seems
valuable to study their effect on the conversion of methyl vinyl ketone. However, Table 4 shows
similar NMR derived yields for all pulsator settings. All experiments were conducted using a large
premixed feed vessel (2L), leading to possible preliminary reaction/degradation before entering
Page 14 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

15
the flow reactor. Particularly, considering the literature's specified conditions of a 3.5-hour reaction
time at room temperature, pre-mixing all reagents in a feed vessel could cloud the interpretation
of these obtained yields. NMR analysis indeed confirmed a partial preliminary conversion (55%)
after 2 hours within the feed vessel, indicating that only a fraction of the MVK remained available
for the reaction within the flow reactor. To increase controllability of the process and reliability of
the results, the setup was adapted to a two-stream flow process (Figure 6). This setup modification
significantly enhanced the obtained yields, achieving results similar to or slightly better than those
obtained in the high temperature batch experiments. With conversions ranging from 89% to 92%,
it is evident that the reactions are much cleaner, with a significant reduction in side products. It is
important to highlight that even when low yields are obtained, all paraformaldehyde undergoes
depolymerization and dissolution at these elevated temperatures. Based on Table 4, an oscillation
frequency of 3 Hz and an amplitude of 50% were determined to be the most suitable for further
experiments.
Entry
Oscillation
frequency (Hz)
Oscillation
amplitudea (%)
NMR yieldb (%)
Setup A
NMR yieldb (%)
Setup B
1
3
15
36
80
2
3
30
34
70
3
3
50
52
84
4
3
70
62
76
5
3
95
47
86c
6
1
15
43
56
7
1
30
44
80
8
1
50
48
83
9
1
70
47
82c
10
1
95
44
82c
Page 15 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

16
aPulsator amplitude is expressed in percentage of the maximum stroke volume of 0.76 mL.
bNMR yield calculated relative to internal standard (trimethoxybenzene).
cNMR yield of multiple samples vary, creating a non-representative average.
Table 4. Pulsator frequency and amplitude influence on the NMR-yield of methyl vinyl ketone
(100 °C, 8 min, 5 bar).
Paraformaldehyde + DABCO + EtOH
Methyl vinyl ketone Coil reactor
40 mL
Pulsator
Peristaltic pump
N2inlet
N2outlet
Peristaltic pump
Figure 6. Schematic overview of continuous flow setup B.
Since full conversion was not obtained in the two-feed approach yet, the residence time and
temperature were varied to push the reaction towards completion and maximize the yield (Table
5). However, prolonging the residence time at 100 °C led to a higher conversion rate but a
significant drop in NMR yield, accompanied by increased formation of side products (see
further) [39]. Similar patterns were noted when the residence time was reduced at higher
temperatures (110 °C). These trends were consistently observed during the batch screening phase
as well (Table 2). Reducing the paraformaldehyde equivalents to stoichiometric amounts resulted
in a decrease of the NMR yield. Thus, a residence time of 8 minutes at 100 °C resulted in the
Page 16 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

17
most optimal yield for the 𝛼-hydroxymethylation of methyl vinyl ketone in continuous flow.
While parallel trends are visible in both batch and flow screening, reactions conducted in flow
tend to exhibit less side product formation and a higher yield compared to batch processes.
Entry
Temperature
(°C)
Residence time
(min)
PFA
(eq.)
Conversion
(%)
NMR yielda
(%)
1
100
8
1.4
89
84 (80)b
2
100
10
1.4
96
62
3
100
12
1.4
97
62
4
110
5
1.4
90
61
5
110
4
1.4
88
49
6
100
8
1.0
93
60
aNMR yield calculated relative to internal standard (trimethoxybenzene).
bIsolated yield after column chromatography.
Table 5. Residence time and temperature screening on the conversion of methyl vinyl ketone
(pulsator amplitude = 50%, pulsator frequency = 3 Hz, 5 bar).
As outlined above, both elevated temperatures and extended residence times led to a reduction
in yield, albeit with an increase in conversion. Analysis via 1H-NMR and GC-MS revealed the
formation of three significant side products under these conditions. As anticipated, further
etherification with ethanol (B1) was evident. As mentioned earlier, a solvent switch to
isopropanol to suppress this side reaction did not lead to an improved yield. Additionally, B3
resulted from the introduction of a second formaldehyde unit, followed by etherification. Also
the free hemiacetal was detected by NMR (B2). Lastly, the Diels-Alder type dimer of methyl
Page 17 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

18
vinyl ketone was observed (B4, Figure 7). Post-treatment with acidic water failed to convert B1,
B2 and B3 into the desired product.
O
O
O
OO O
O
B1 B3 B4
O
OHO
B2
Figure 7. Side products formed during the 𝛼-hydroxymethylation of methyl vinyl ketone at
suboptimal reaction conditions.
Productivity comparison
Mantel et al. performed the hydroxymethylation of MVK only on a milligram scale (166 mg)
within a batch setup. With a reaction time of 200 minutes and an isolated yield of 85%, the
reaction's productivity was calculated to be 0.06 g/h. Similarly, this calculation was applied to the
developed flow process under optimal conditions (8 min, 100 °C, flow rate = 5 mL/min, isolated
yield = 80%), yielding a productivity of 81.6 g/h (Equation 1). This represents a significant
increase in productivity compared to previously reported literature, with > 3 orders of magnitude
improvement.
𝑃𝑟𝑜𝑑𝑢𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝑀𝑎𝑛𝑡𝑒𝑙 𝑒𝑡 𝑎𝑙.
(
𝑏𝑎𝑡𝑐ℎ
)
=
0.201 𝑔 𝑝𝑟𝑜𝑑𝑢𝑐𝑡 𝑓𝑜𝑟𝑚𝑒𝑑
200 𝑚𝑖𝑛
=
0.001
𝑔
𝑚𝑖𝑛
=
0.06 𝑔
/
ℎ
𝑃𝑟𝑜𝑑𝑢𝑐𝑡𝑖𝑣𝑖𝑡𝑦 𝑡ℎ𝑖𝑠 𝑟𝑒𝑠𝑒𝑎𝑟𝑐ℎ (𝑓𝑙𝑜𝑤)
=
0.0034
𝑚𝑜𝑙 𝑀𝑉𝐾
𝑚𝐿
∗
5
𝑚𝐿
𝑚𝑖𝑛
∗
80% 𝑦𝑖𝑒𝑙𝑑
∗
100.12
𝑔
𝑚𝑜𝑙
=
1.36
𝑔
𝑚𝑖𝑛
=
81.6 𝑔
/
ℎ
Equation 1. Productivity calculation of both batch and flow processes.
Page 18 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

19
The space-time yield (STY) was calculated as well to provide valuable insights into reactor
performance of the CØPE reactor (Equation 2). The achieved STY significantly surpasses that of
the batch procedure (STY batch = 3
𝑘𝑔
ℎ
∗
𝑚³
).
𝑆𝑇𝑌
=
𝑘𝑔
ℎ
∗
𝑚
3
=
0.0816 𝑘𝑔
1
ℎ
∗
40
∗
10
―
6
𝑚
3
=
2040 𝑘𝑔
ℎ
―
1
𝑚
―
3
Equation 2. Calculation of the Space-time yield within the CØPE reactor.
CONCLUSIONS
This research introduces a novel approach to reactor design, employing a solid-compatible
continuous flow reactor utilizing pulsatile flow to maintain solid suspension and featuring a self-
constructed blockage-resistant back pressure regulator. The efficacy of this innovative setup was
evaluated through the hydroxymethylation reaction of methyl vinyl ketone using a
paraformaldehyde slurry. Initially, significant improvements of the reaction conditions were
achieved in a batch setting. The reaction was streamlined into a single step, eliminating the need
for a separate depolymerization stage, while reducing the reaction time from hours to minutes.
Subsequently, optimisation of the reaction was successfully performed in continuous flow,
resulting in even cleaner reactions and a higher yield compared to the optimised batch conditions.
Furthermore, hydroxymethylation reactions were performed through in situ depolymerization of a
paraformaldehyde slurry, allowing direct use of the formed formaldehyde. This approach allows a
continuous and safe operation of formaldehyde chemistry with a remarkable increase in
productivity of 3 orders of magnitude.
SUPPORTING INFORMATION
Page 19 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

20
A detailed description of the experimental work is provided in the supporting information.
AUTHOR INFORMATION
Corresponding Author
Christian V. Stevens – University of Ghent (Belgium), Faculty of Bioscience Engineering,
Department of Sustainable Organic Chemistry and Technology, Coupure links 653, B-9000 Ghent;
Email: Chris.Stevens@UGent.be
Author Contributions
Bavo Vandekerckhove – University of Ghent (Belgium), Faculty of Bioscience Engineering,
Department of Sustainable Organic Chemistry and Technology, Coupure links 653, B-9000 –
designed the project, reactor assembly, conducted wet lab experiments, analysis and calculations,
writing of the manuscript.
Lise Van Coillie – University of Ghent (Belgium), Faculty of Bioscience Engineering,
Department of Green Chemistry and Technology, Coupure links 653, B-9000 Ghent - conducted
wet lab experiments, analysis and calculations.
Bert Metten – Ajinomoto Bio-Pharma Services Belgium, Cooppallaan 97, 9230 Wetteren,
Belgium – designed and supervised the project, technical input.
Thomas S. A. Heugebaert – University of Ghent (Belgium), Faculty of Bioscience Engineering,
Department of Green Chemistry and Technology, Coupure links 653, B-9000 Ghent – designed
and supervised the project, contributed to the implementation of the research, to the analysis of the
results, to the writing of the manuscript.
Page 20 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

21
Christian V. Stevens – University of Ghent (Belgium), Faculty of Bioscience Engineering,
Department of Green Chemistry and Technology, Coupure links 653, B-9000 Ghent – designed
and supervised the project, contributed to the implementation of the research, to the analysis of the
results, to the writing of the manuscript.
Funding Sources
The authors are indebted to VLAIO – Belgium (Baekeland HBC.2021.0198) for financial
support.
REFERENCES
1) L. K. Kohn, C. H. Pavam, D. Veronese, F. Coelho, J. E. De Carvalho, W. P. Almeida,
Antiproliferative effect of Baylis-Hillman adducts and a new phthalide derivative on
human tumor cell lines, Eur. J. Med. Chem., 2006, 41(6), 738-44,
https://doi.org/10.1016/j.ejmech.2006.03.006.
2) L. N. Solano, G. L. Nelson, C. T. Ronayne, E. A. Lueth, M. A. Foxley, S. K. Jonnalagadda,
S. Gurrapu, V. R. Mereddy, Synthesis, in vitro, and in vivo evaluation of novel
functionalized quaternary ammonium curcuminoids as potential anti-cancer agents,
Bioorg. Med. Chem. Lett., 2015, 25(24), 5777-80,
https://doi.org/10.1016/j.bmcl.2015.10.061.
3) E. Papadaki, L. Delaude, V. Magrioti, Microwave-Assisted Synthesis of Hydroxymethyl
Ketones Using Azolium-2- Carboxylate Zwitterions as Catalyst Precursors, Tetrahedron
2017, 73 (52), 7295–7300, https://doi.org/10.1016/j.tet.2017.11.024
Page 21 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

22
4) P. Hoyos, J. V. Sinisterra, F. Molinari, A. R. Alcántara, P. D. De María, Biocatalytic
Strategies for the Asymmetric Synthesis of α-Hydroxy Ketones, Acc Chem Res, 2010, 43
(2), 288–299, https://doi.org/10.1021/ar900196n.
5) S. S. Santos, R. V. Gonzaga, C. B. Scarim, J. Giarolla, M. C. Primi, C. M. Chin, E. I.
Ferreira, Drug/Lead Compound Hydroxymethylation as a Simple Approach to Enhance
Pharmacodynamic and Pharmacokinetic Properties, Frontiers in Chemistry, Frontiers
Media S.A., 2022, https://doi.org/10.3389/fchem.2021.734983.
6) L. Guillemard, N. Kaplaneris, L. Ackermann, M. J. Johansson, Late-Stage C–H
Functionalization Offers New Opportunities in Drug Discovery, Nature Reviews
Chemistry, 2021, 522–545, https://doi.org/10.1038/s41570-021-00300-6
7) L. Caiger, C. Sinton, T. Constantin, J. J. Douglas, N. S. Sheikh, F. Juliá, D. Leonori,
Radical Hydroxymethylation of Alkyl Iodides Using Formaldehyde as a C1 Synthon,
Chem Sci, 2021, 12 (31), 10448–10454, https://doi.org/10.1039/d1sc03083c.
8) A. Duong, C. Steinmaus, C. M. McHale, C. P. Vaughan, L. Zhang, Reproductive and
Developmental Toxicity of Formaldehyde: A Systematic Review, Mutation Research -
Reviews in Mutation Research, 2011, 118–138,
https://doi.org/10.1016/j.mrrev.2011.07.003.
9) Formaldehyde General Description, Chapter 5.8, 2001, WHO Regional Office for Europe.
Page 22 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

23
10) R. K. Boeckmann, J. R. Miller, Direct Enantioselective Organocatalytic
Hydroxymethylation of Aldehydes Catalyzed by a,a Diphenylprolinol Trimethylsilyl
Ether, Org. Lett., 2009, 4544-4547, http://doi.org/10.1055/s-0029-1218409
11) S. Nishimura, A. Shibata, Hydroxymethylation of Furfural to HMF with Aqueous
Formaldehyde over Zeolite Beta Catalyst, Catalysts, 2019, 9, 314.
https://doi.org/10.3390/catal9040314
12) S. Nishimura, A. Shibata, K Ebitani, Direct Hydroxymethylation of Furaldehydes with
Aqueous Formaldehyde over a Reusable Sulfuric Functionalized Resin Catalyst, ACS
Omega, 2018, 3 (6), 5988-5993, http://doi.org/10.1021/acsomega.8b00120
13) J. Cong-Bin, L. Yun-Lin, C. Zhong-Yan, Z. Yi-Yu, Z. Jian, Hydroxymethylation of α-
substituted nitroacetates, Tetrahedron Letters, 2011, 6118-6121,
https://doi.org/10.1016/j.tetlet.2011.09.020
14) M. Movsisyan, E. I. P. Delbeke, J. K. E. Berton, C. Battilocchio, S. Ley, C. V. Stevens,
Taming Hazardous Chemistry by Continuous Flow Technology, Chem. Soc. Rev., 2016,
4892-4928, https://doi.org/10.1039/C5CS00902B
15) W. Li, X. F. Wu, The Applications of (Para)Formaldehyde in Metal-Catalyzed Organic
Synthesis, Advanced Synthesis and Catalysis, 2015, 3393–3418,
https://doi.org/10.1002/adsc.201500753
Page 23 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

24
16) World Health Organization, IARC Working Group on the Evaluation of Carcinogenic
Risks to Humans, International Agency for Research on Cancer, Formaldehyde, 2-
Butoxyethanol and 1-Tert-Butoxypropan-2-Ol. International Agency for Research on
Cancer, 2006
17) X. L. Liu, Y. H. Liao, Z. J. Wu, L. F. Cun, X. M. Zhang, W. C. Yuan, Organocatalytic
Enantioselective Hydroxymethylation of Oxindoles with Paraformaldehyde as C1 Unit,
Journal of Organic Chemistry, 2010, 4872–4875, https://doi.org/10.1021/jo100769n.
18) A.E. Buba, S. Koch, H. Kunz, H. Löwe, Fluorenylmethoxycarbonyl-N-methylamino Acids
Synthesized in a Flow Tube-in-Tube Reactor with a Liquid–Liquid Semipermeable
Membrane, Eur. J. Org. Chem., 2013, 4509-4513, https://doi.org/10.1002/ejoc.201300705
19) L. Yang, K. F. Jensen, Mass Transport and Reactions in the Tube-in-Tube Reactor, Organic
Process Research & Development, 2013, 17 (6), 927-933,
https://doi.org/10.1021/op400085a
20) A. Simoens, T. Scattolin, T. Cauwenbergh, G. Pisanò, C. S. J. Cazin, C. V. Stevens, S. P.
Nolan, Continuous Flow Synthesis of Metal–NHC Complexes, Chem. Eur. J. 2021, 27,
5653, https://doi.org/10.1002/chem.202100190
21) L. Huck, A. de la Hoz, A. Díaz-Ortiz, J. Alcázar, Grignard Reagents on a Tab: Direct
Magnesium Insertion under Flow Conditions, Org Lett., 2017, 19(14):3747-3750,
https://doi: 10.1021/acs.orglett.7b01590.
Page 24 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

25
22) M. P. Thompson, I. Peñafiel, S. C. Cosgrove, N. J. Turner, Biocatalysis Using Immobilized
Enzymes in Continuous Flow for the Synthesis of Fine Chemicals, Organic Process
Research & Development, 2019, 23 (1), 9-18, https://doi:10.1021/acs.oprd.8b00305.
23) C. Len, S. Bruniaux, F. Delbecq, V. S. Parmar, Palladium-Catalyzed Suzuki–Miyaura
Cross-Coupling in Continuous Flow, Catalysts, 2017, 7, 146.
https://doi.org/10.3390/catal7050146
24) K. Matcha, A. Huygaerts, L. Moens, M. Peeters, D. Gala, D. Depré, Exploratory Process
Development of a High-Temperature Thermal (3 + 2) Cycloaddition in Continuous Flow
for the Synthesis of Seltorexant, Organic Process Research & Development, 2023,
https://doi:10.1021/acs.oprd.3c00113.
25) B. Vandekerckhove, B. Ruttens, B. Metten, C. V. Stevens, T. S.A. Heugebaert, Merging
Inline Crystallization and Pulsed Flow Operation to enable Enantiospecific Solid State
Photodecarbonylation, React. Chem. Eng., 2024, DOI
https://doi.org/10.1039/D4RE00058G.
26) M. Mantel, M. Guder, J. Pietruszka, Simple organocatalysts in multi-step reactions: An
efficient one-pot Morita-Baylis-Hillman-type α-hydroxymethylation of vinyl ketones
followed by the convenient, temperature-controlled one-pot etherification using alcohols,
Tetrahedron, 2018, 5442-5450, https://doi.org/10.1016/j.tet.2018.05.026.
27) B. Schwartz, A. Porzelle, K. Jack, J. Faber, I. Gentle, C. Williams, Cyclic Enones as
Substrates in the Morita–Baylis–Hillman Reaction: Surfactant Interactions, Scope and
Page 25 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

26
Scalability with an Emphasis on Formaldehyde. Adv. Synth. Catal., 2009, 1148-1154,
https://doi.org/10.1002/adsc.200800739
28) J. Gu, B.-X. Xiao, Q. Ouyang, W. Du, Y.-C. Chen, Phosphine-Catalyzed Interrupted
Morita–Baylis–Hillman Reaction and Switchable Domino Reactions of α-Substituted
Activated Olefins with Formaldehyde and Mechanism Elucidation, Chin. J. Chem., 2019,
155-160, https://doi.org/10.1002/cjoc.201800466
29) Y. Furukawa, M. Ogura, A Unique Heterogeneous Nucleophilic Catalyst Comprising
Methylated Nitrogen-Substituted Porous Silica Provides High Product Selectivity for the
Morita–Baylis–Hillman Reaction, Journal of the American Chemical Society, 2014, 136
(1), 119-121, https://doi.org/10.1021/ja410781z
30) R. Robiette, V. K. Aggarwal, J. N. Harvey, Mechanism of the Morita−Baylis−Hillman
Reaction: A Computational Investigation, Journal of the American Chemical Society,
2007, 129 (50), 15513-15525, https://doi:10.1021/ja0717865
31) J. Claes, A. Vancleef, M. Segers, B. Brabants, M. E. Leblebici, S. Kuhn, L. Moens, L. C.J.
Thomassen, Synthesis of amines: From a microwave batch reactor to a continuous
milliflow reactor with heterogeneous feed and product, Chemical Engineering and
Processing - Process Intensification, 2023, https://doi.org/10.1016/j.cep.2022.109252.
32) Z. Dong, S. D.A. Zondag, M. Schmid, Z. Wen, T. Noël, A meso-scale ultrasonic milli-
reactor enables gas–liquid-solid photocatalytic reactions in flow, Chemical Engineering
Journal, 2022, 1385-8947, https://doi.org/10.1016/j.cej.2021.130968
Page 26 of 27Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B

27
33) D. L. Browne, B. J. Deadman, R. Ashe, I. R. Baxendale, S. V. Ley, Continuous Flow
Processing of Slurries: Evaluation of an Agitated Cell Reactor, Organic Process Research
& Development, 2011, 693-697, http://doi.org/10.1021/op2000223
34) Z. Peng, G. Wang, B. Moghtaderi, E. Doroodchi, A review of microreactors based on slurry
Taylor (segmented) flow, Chemical Engineering Science, 2022, 0009-2509,
https://doi.org/10.1016/j.ces.2021.117040.
35) Lewa group, accessed 23 February 2024, https://www.lewa.com/en/pumps/metering-
pumps/lewa-ecoflow-diaphragm-metering-pump
36) Uniqsis accessible flow chemistry, accessed 23 February 2024,
https://www.uniqsis.com/paProductsDetail.aspx?ID=HotCoil
37) B. J. Deadman, D. L. Browne, I. R. Baxendale, S. V. Ley, Back Pressure Regulation of
Slurry-Forming Reactions in Continuous Flow, Chemical Engineering and Technology,
2015, 259-264, http://doi.org/10.1002/ceat.201400445
38) P. Bianchi, J. Williams, C. O. Kappe, Oscillatory flow reactors for synthetic chemistry
applications, J Flow Chem, 2020, 475–490, https://doi.org/10.1007/s41981-020-00105-6
39) I. M. Mándity, S. B. Ötvös, F. Fülöp, Strategic Application of Residence-Time Control in
Continuous-Flow Reactors, ChemistryOpen, 2015, 4, 212-223,
https://doi.org/10.1002/open.201500018
Page 27 of 27 Reaction Chemistry & Engineering
Reaction Chemistry & Engineering Accepted Manuscript
Open Access Article. Published on 29 May 2024. Downloaded on 5/30/2024 2:12:13 PM.
This article is licensed under a
Creative Commons Attribution-NonCommercial 3.0 Unported Licence.
View Article Online
DOI: 10.1039/D4RE00220B