pubs.acs.

org/OPRD Article

Continuous Flow Epoxidation of Alkenes Using a Homogeneous

Manganese Catalyst with Peracetic Acid
Ailbhe A. Ryan, Seán D. Dempsey, Megan Smyth, Karen Fahey, Thomas S. Moody, Scott Wharry,
Paul Dingwall, David W. Rooney, Jillian M. Thompson,* Peter C. Knipe,* and Mark J. Muldoon*
Cite This: https://doi.org/10.1021/acs.oprd.2c00222 Read Online

ACCESS Metrics & More Article Recommendations *

sı Supporting Information
See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

ABSTRACT: Epoxidation of alkenes is a valuable transformation in the synthesis of fine chemicals. Described herein are the design
and development of a continuous flow process for carrying out the epoxidation of alkenes with a homogeneous manganese catalyst at
metal loadings as low as 0.05 mol%. In this process, peracetic acid is generated in situ and telescoped directly into the epoxidation
reaction, thus reducing the risks associated with its handling and storage, which often limit its use at scale. This flow process lessens
Downloaded via 37.68.6.132 on January 15, 2023 at 12:28:54 (UTC).

the safety hazards associated with both the exothermicity of this epoxidation reaction and the use of the highly reactive peracetic
acid. Controlling the speciation of manganese/2-picolinic acid mixtures by varying the ligand:manganese ratio was key to the success
of the reaction. This continuous flow process offers an inexpensive, sustainable, and scalable route to epoxides.
KEYWORDS: flow chemistry, oxidation, catalysis, manganese, epoxidation, continuous processing

■ INTRODUCTION
Epoxides are a valuable class of compounds across the
pharmaceutical and fragrance industries.1,2 They can be
found in medicinal compounds such as carfilzomib (an
anticancer agent) and troleandomycin (a macrolide antibiotic),
though they are more often employed as key building blocks in Figure 1. Alkene epoxidation using manganese triflate, 2-picolinic
acid, and peracetic acid as reported by Stack and co-workers.17 PAAM
the syntheses of fine chemical products.3,4 The reactivity of = 10:3:13 v/v/v 32 wt% PAA/10 wt% KOH(aq)/AcOH.
epoxides toward a broad range of nucleophiles makes them
versatile intermediates.5,6
The oxidation of an alkene is an effective route for the catalytic system facilitated the epoxidation of a broad range of
preparation of epoxides; however, oxidations are often alkenes, including terminal alkenes, at low catalyst loadings
challenging due to the environmental and economic problems (0.4 mol%) and forms the basis of this study under flow
conditions.
associated with traditional, stoichiometric oxidizing agents.6
From an industrial perspective, the use of peracetic acid
For example, the storage, transport, and use of 3-chloroper-
(PAA) is attractive, as it is an inexpensive oxidant which
oxybenzoic acid (mCPBA) on a large scale has been
produces relatively benign byproducts and side products
highlighted as a challenge for some time due to the risk of
(acetic acid, oxygen, and water). Although PAA has been
explosion.7−9 The use of catalysts with environmentally
successfully utilized for very large scale applications such as
sustainable oxidants offers an attractive approach.10 Catalyst
wastewater treatment, its use in fine chemical synthesis is often
development is driven by a number of factors, with important
hindered because of the associated risk of fire and explosion
drivers being substrate scope, product selectivity, and overall
incidents due to the presence of metals or flammable organic
cost. The use of abundant, first-row transition metals is highly
chemicals or the use of heat.18,19 The catalytic method
desirable, and therefore, many research groups interested in reported by Stack and co-workers demonstrated that alkenes
epoxidation reactions have reported catalysts based on could be converted to epoxides with very short reaction times.
manganese and iron.11−13 In the case of homogeneous It was calculated that these epoxidation reactions are
catalysis, it is not only the choice of metal that is important exothermic and exergonic, with ΔHrxn = −40 to −50 kcal
but also the ligand. 2-Picolinic acid (pyridine-2-carboxylic mol−1 and ΔGrxn = −30 to −40 kcal mol−1.20 This suggests
acid) is a ligand that is both inexpensive and commercially
available. Browne and co-workers previously employed 2-
picolinic acid with manganese(II) salts and a hydrogen Received: July 14, 2022
peroxide/butanedione oxidant for alkene, alcohol, and C−H
oxidation reactions.14−16 Complementary work by Stack and
co-workers used a similar catalyst system for alkene
epoxidation but used a base-modified solution of commercial
peracetic acid (PAAM) as the oxidant (Figure 1).17 This
© XXXX The Authors. Published by
American Chemical Society https://doi.org/10.1021/acs.oprd.2c00222
A Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Article

that they could be challenging to scale-up safely using batch The thermal properties of this reaction were investigated by
reactors, as oxidations are known to pose a risk of thermal calorimetric studies (see the Supporting Information (SI) for
runaway and possible explosion.21,22 Utilization of a con- further details), which indicated that for the reaction to be
tinuous flow process is regarded as the safest for the safely scaled in semibatch conditions, the addition of peracetic
development of scalable oxidation protocols.23−25 The acid would have to be at a low and controlled rate. This slow
increased safety associated with flow systems is due to the addition is required to ensure that the reaction is controllable
smaller reactor volumes, which reduces the risks when using at scale and to avoid a potential adiabatic temperature rise of
hazardous reagents.26,27 A smaller reactor volume is inherently 60.5 °C. Therefore, a flow approach could allow for the
safer, as it allows for greater control over the reaction development of a more efficient and safer process. The
conditions. Smaller reactor volumes also ensure that only a reactivity of epoxides, which renders them valuable inter-
small fraction of the starting material or product is at risk (due mediates, also makes their preparation challenging due to the
to equipment failure or human error) at any one time, limiting formation of other products, including the corresponding diol,
the scale of any potential adverse event. Such process keto alcohol, and aldehyde.31,32 Nonetheless, the selectivity for
intensification not only means smaller reaction volumes but the desired products for this catalytic method compares well to
also superior heat transfer, something particularly important those for alternative systems.12,33,34 Analysis of these reaction
for this exothermic epoxidation. Exploiting continuous flow mixtures was carried out to determine whether there were any
further, PAA can be prepared in situ and subsequently used for major byproducts which could be identified. In the case of
the desired reaction, which is an attractive option for accessing styrene, one major byproduct, phenylacetaldehyde (formed via
epoxidation.28−30 Meinwald rearrangement of the epoxide35) was formed in 15%
The design and development of a Mn(II)/2-picolinic acid yield (confirmed by 1H NMR and GC-MS), in agreement with
catalyst system is described herein. results reported by Stack and co-workers.17 This brings the

■ RESULTS AND DISCUSSION

Initial Batch Investigations. Model substrates to
mass balance for this reaction to 95%. As mentioned, a range of
products can be formed in oxidation systems, and in this case,
benzaldehyde was observed (by 1H NMR and GC-MS
represent aromatic, cyclic aliphatic, and terminal linear analysis). In the case of the aliphatic substrates, 1-octene and
aliphatic alkenes were selected, with studies initiated to cyclooctene, there was no one significant byproduct that could
successfully reproduce literature conditions17 followed by be observed, with no GC peaks with area greater than 1% of
examination of aspects of the methodology that could be the epoxide product (see the SI for GC traces). Difficulty in
varied to make it more amenable to an industrial process. identifying all byproducts is common in such catalytic
Previous reports (Figure 1) used a Mn(OTf)2 catalyst with epoxidation studies.34,36−39
PAAM (15 wt%) as the oxidant, but this work demonstrates the Peracetic Acid Synthesis in Flow. An acidic polymer
application of the less expensive Mn(OAc)2 (Table 1) and resin was utilized for the catalytic synthesis of PAA, as this is a
proven method and is well-suited to flow systems.28,40 A
Table 1. Batch Studies of the Epoxidation of Alkene number of different commercially available polymeric sulfonic
Substrates with PAAR and Mn(OAc)2a acid resins were tested, and all were found to produce peracetic
acid solutions of similar concentration (Table 2); there was

Table 2. Variation of Resin in Peracetic Acid Synthesis

entry resin wt% PAAc yield (%)d

1a Amberlite IR120 (H+ form) 16 95
2a Amberlyst 16 (H+ form) 16 95
3a Amberlyst 15 (H+ form) 15 90
a
Reactions were carried out at a 1 mmol (substrate) scale in 2 mL of a 4a Amberlyst 36 (H+ form) 16 95
10 mM solution of 2-picolinic acid in acetonitrile with 0.2 mL of a 20 5b Amberlyst 36 (H+ form) 15 76
a
mM solution of Mn(OAc)2 in methanol. PAAR (15 wt%) synthesized Using 85:15 v/v AcOH/H2O2 (aq. 50 wt%) as the feed solution with
in flow (0.55 mL) was added at a rate of 50 μL/10 s at 0 °C. a flow rate of 0.5 mL/min. bUsing 7:3 v/v AcOH/H2O2 (aq. 30 wt%)
b
Conversions and yields were determined by GC-FID using as the feed solution with a flow rate of 0.15 mL/min. cDetermined by
benzonitrile as an internal standard. cSelectivity is defined as the titration with potassium permanganate followed by an iodometric
percentage of reacted starting material converted to the corresponding titration as outlined in the SI. dYield with respect to H2O2.
epoxide.

also little variation in results for the epoxidation reaction

MnCl2 (Table S1) along with a resin-synthesized peracetic acid compared to the base-modified solution employed by Stack
(PAAR) (15 wt%) for epoxidation of the model substrates.17 and co-workers17 (Table 3). Amberlyst 36, a macroporous
Table 1 shows the conditions developed in batch, with sulfonic acid resin, was selected for further study. The
methanol required when preparing stock solutions of Mn- experimental setup employed (Table 2) consisted of a packed
(OAc)2 due to the poor solubility of Mn(OAc)2 in acetonitrile. bed of acidic polymer resin within an Omnifit borosilicate glass
Initial studies found that the reactions were indeed very fast, column (Omnifit SolventPlus chromatography column with
proceeding to >80% conversion in under 5 min, and therefore one fixed and one adjustable endpiece, 10 mm × 400 mm),
well-suited to the development of a continuous flow system. and a mixture of acetic acid and hydrogen peroxide was
B https://doi.org/10.1021/acs.oprd.2c00222
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Article

Table 3. Variation of Peracetic Acid Solution Used in Batch Using the setup shown in Figure 2, a precipitate was found
Epoxidation of 1-Octene to develop over time in the feed solution (channel 1), and this
led to a blockage in the reactor tubing. This precipitate
originated from Mn(OAc)2, as it occurred in the absence of
substrate and was not an issue when Mn(OTf)2 was used. It is
known that the acetate ion can act as a bridging ligand to form
PAA used conversion (%)d yield (%)d
Mn(II) coordination polymers, which is a plausible explanation
a
for this insoluble manganese species.43 When reactions are
PAAM 100 80
carried out in flow, the handling and formation of solids are
PAAR50a,b 100 81
well-known challenges, and researchers have tackled this via
PAAR30a,b 99 78
sonication, increased temperature, periodic washes, or
PAAR30b,c 80 60
a
dilution.44,45 Flushing the reactor system with water success-
PAA added at 50 μL/10 s. bPAAR50 = PAAR synthesized using 50 wt fully cleared the tube blockages, but intermittent washing was
% H2O2; PAAR30 = PAAR synthesized using 30 wt% H2O2. cPAA was not a feasible option in this case due to the frequency of
added in one aliquot. dConversions and yields were determined by
clogging. The addition of water to the solvent system was
GC-FID using benzonitrile as an internal standard.
investigated, but a 4:1 v/v acetonitrile:water ratio was required
pumped through. The column was packed with acidic resin, to prevent precipitation, and this led to a reduced yield of
adjusting the column to a volume of 25.5 mL, and the void epoxide (Table S2). To address this solubility issue, a five-
volume was calculated to be 2.85 mL based on a residence pump setup was used, in which the Mn(OAc)2, 2-picolinic
time of 19 min for a 0.15 mL/min flow rate (calculated from acid, substrate, and peracetic acid were introduced as different
the time taken for a solution to pass through a column of dry feeds. (Table 4). The precipitating species takes time to
resin).
The residence time required to produce the desired 15 wt% Table 4. Flow Setup with In Situ Metal Ligation and
peracetic acid concentration is dependent on the concentration Variation of the Conditions
of hydrogen peroxide used, and shorter residence times can be
used if 50 wt% H2O2(aq) is employed rather than 30 wt%
(Table 2). To further enhance the process safety, the more
dilute solution was chosen for development work. These
reactions were conducted at room temperature; as shown by
other studies, higher temperatures would enable shorter
residence times.28,41,42
Catalytic Flow Studies. Initially, a system with three
pumps was employed: one pump introduced PAAR (pre-
prepared), a second pump delivered a stock solution of
substrate and catalyst, and a third pump was used to
continuously add an aqueous solution of sodium thiosulfate T (°C) residence time (s) equiv of PAA conv. (%)a yield (%)a
as a quench stream (Figure 2). The equipment used included b
0 30 1.1 84 63
17 30b 1.1 85 60
0 60c 1.1 85 59
0 25d 2.2 100 53
a
Conversions and yields were determined by GC-FID using
benzonitrile as an internal standard. bThe flow rates of pumps 1, 2,
3, and 4 were 0.1, 0.5, 0.5, and 0.275 mL/min, respectively. cThe flow
rates of pumps 1, 2, 3, and 4 were 0.05, 0.25, 0.25, and 0.138 mL/min,
respectively. dThe flow rates of pumps 1, 2, 3, and 4 were 0.1, 0.5, 0.5,
and 0.550 mL/min, respectively.

Figure 2. Initial setup for flow reactions with Mn(OAc)2.

accumulate; by performing the metal ligation in flow,

precipitation is prevented because the metal complex is
SF10 Vaportec peristaltic pumps with blue peristaltic tubing formed in situ and quickly enters the reactor coil, where it
(which demonstrated the best compatibility with the reaction then contacts the PAA solution, and there is no observed
components) and PTFE tubing (1/16″ o.d., 0.5 mm i.d.) for precipitation.
the reactor coil and additional loops for precooling/premixing. This setup was successful in eliminating the issue of reactor
It was important to use a metal-free setup in order to avoid fouling, allowing for run times of 8 h without any back-pressure
metal-catalyzed decomposition of the peracid. As indicated in increase or precipitation observed. Under these conditions,
the schematics, the precooling loop and reactor tubing were 85% conversion of 1-octene with a 63% yield of 1,2-
cooled in an IPA/water bath using a Huber immersion chiller, epoxyoctane could be achieved. This yield was lower than
whereas all of the other components were at ambient had been obtained in initial batch studies (Table 1).
temperature. When using the flow system with in situ PAA Development studies were carried out with the aim of
synthesis a back-pressure regulator (Zaiput Flow Technologies, achieving results comparable to those observed in batch.
cat. no. BPR-10) was used. However, varying the residence time and the temperature had
C https://doi.org/10.1021/acs.oprd.2c00222
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Article

little impact, and the yields remained significantly lower than Table 6. Batch Control Experiments for Ligand Variation
those obtained in batch (Table 4). with Single Aliquot PAA Addition
In the batch procedure, PAA is slowly added over 2 min, as
Mn(OAc)2 loading mode of PAA conv. yield
addition of a single aliquot negatively affects results (Table 3). entry (mol %) ligand:Mn addition (%)a (%)a
This highlights the impact of the oxidant concentration. A
1 0.4 5:1 one aliquot 80 60
competing metal-catalyzed decomposition of PAA that reduces
2 0.4 5:1 over 2 min 98 80
the amount of oxidant available to carry out the epoxidation is
3 0.05 20:1 one aliquot 95 80
a possible explanation. Titration of a control reaction mixture
4 0.05 20:1 over 2 min 98 78
(Mn(OAc)2 and 2-picolinic acid) with no substrate found that a
80% of the PAA had decomposed after 5 min. Simply Conversions and yields were determined by GC-FID using
benzonitrile as an internal standard.
increasing the amount of PAA achieves full conversion for 1-
octene, but this is detrimental to the epoxide selectivity. This is
mitigates the impact of higher PAA concentrations. Addition of
likely due to subsequent reaction of the epoxide.31,32
PAA in one aliquot when using a 5:1 ligand:metal ratio results
To replicate the gradual addition of PAA used in batch, the
in an 18% decrease in conversion (see entry 1 vs entry 2 in
effect of introducing PAA via three separate streams was
Table 6), while using a 20:1 ligand to metal ratio allows for
assessed, as shown in Table 5. In this case, Mn(OTf)2 was
PAA addition in a single aliquot without a negative effect on
the results (see entry 3 vs entry 4 in Table 6).
Table 5. Results from PAA Split Addition A range of ligand:metal ratios were assessed to improve
performance under continuous flow conditions. As shown in
Table 7, the influence of the ligand:metal ratio was assessed, as

Table 7. Screening of Ligand:Mn Ratios and Temperatures

equiv of PAA split ratio conv. (%)a yield (%)a

1.2 no splitb 85 63
1.2 1:1:1b 83 61
1.2 2:1:1b 80 60 Mn(OTf)2
loading T residence conv. yield
1.2 4:1:1b 83 61 entry (mol %) ligand:Mn (°C) time (min) (%)a (%)a
2 no splitc 99 53
1 0.05 10:1 0 7b 79 68
2 1:1:1c 99 55
a b
2 0.05 10:1 −10 7b 82 73
Determined by GC with an internal standard (benzonitrile). The 3 0.05 20:1 0 5c 100 78
sum of flow rates 2, 3, and 4 was 0.176 mL/min. cThe sum of flow 4 0.05 20:1 −10 7b 82 73
rates 2, 3, and 4 was 0.293 mL/min.
5 0.1 10:1 0 3c 95 73
6 0.1 10:1 −10 7b 98 72
used, as this allowed the use of a catalyst/substrate stock 7 0.1 20:1 0 3c 98 83
solution without the problems of precipitation. The addition of 8 0.1 20:1 −10 7b 100 72
PAAR across numerous points in the reaction tubing was 9 0.01 10:1 0 1d 16 14
studied, but the epoxide yield did not improve (Table 5). 10 0.05 30:1 0 1d 86 74
As can be seen in Table 5, 1-octene undergoes 83% 11 0.4 10:1 0 1d 95 73
conversion with 61% epoxide yield when the PAA is split a
Determined by GC with an internal standard (benzonitrile).
across three different points of the reactor. Although the yields b
Reactor volume of 4.7 mL. cReactor volume of 2 mL. dReactor
obtained remained lower than previously observed in batch, volume of 0.74 mL.
this is potentially due to high local concentrations as a
consequence of the rate of addition of peracetic acid.
Following these results, it was decided to explore catalyst were the effects of temperature and residence time. To
speciation, as this can also have a significant impact on the eliminate any potential effect of precipitation on the
performance of the reaction. stoichiometry, Mn(OTf)2 was selected for this study. It was
Increasing the Ligand:Mn Ratio. In solution, an demonstrated that a Mn(OTf)2 loading of just 0.05 mol% with
equilibrium between several Mn(II)/2-picolinic acid species a 20:1 ligand:Mn ratio at 0 °C could match the performance
is expected, and it was previously predicted that a Mn(OTf)2 previously achieved in batch studies (see Table 1). These
to 2-picolinic acid ratio of 1:5 would maximize the results further illustrate the importance of the PAA to Mn and
concentration of bisligated species (see the SI of ref 18). ligand ratios. The conditions outlined in entry 3 were found to
The ratios of PAA to Mn and ligand are important and clearly be the most attractive, with lower temperatures and longer
have an impact on catalyst speciation, which is key not only for residence times adding little benefit.
the epoxidation pathway but also in controlling PAA Having demonstrated performance comparable to batch
decomposition.46−48 Control reactions carried out in batch results by varying the ligand:metal ratio, the continuous flow
(Table 6) demonstrated that increasing the ligand:metal ratio Mn(OAc)2-catalyzed epoxidation with in situ synthesis of PAA
D https://doi.org/10.1021/acs.oprd.2c00222
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Article

Table 8. Flow System Developed for Alkene Epoxidation with Mn(OAc)2

substrate Mn(OAc)2 loading (mol%) 2-picolinic acid loading (mol%) conv. (%)a yield (%)a
b
cyclooctene 0.05 1 100 83 (76d)
1-octeneb 0.05 1 100 78e
styreneb 0.05 1 32 26
styrenec 0.2 4 93 63
a
Determined by GC with an internal standard (benzonitrile, which is in the substrate feed). b5.5 mM Mn(OAc)2 solution in MeOH and 11 mM 2-
picolinic acid solution in MeCN. c22 mM Mn(OAc)2 solution in MeOH and 44 mM 2-picolinic acid solution in MeCN. dIsolated yield.
e
Consistently obtained over 8 h of operation.

was demonstrated (Table 8). To incorporate the peracetic acid when considering carrying out the epoxidation of alkenes on a
synthesis, the peracetic acid output from the packed column larger scale. The protocol reported herein avoids the
was fed directly to the reactor tube, mixing with the substrate precipitation of solids, allowing long-term operation. Future
and catalyst at a T-piece. work on the scale-up of such a flow process could be achieved
These conditions were also applied to cyclooctene and by using established approaches, for example, scale-out using a
styrene, and the results are shown in Table 8. Styrene required numbering-up strategy with multiple reactors or scale-up by
a higher catalyst loading to achieve yields comparable to those increasing the size of the reactor50,51 Numbering-up maintains
obtained in batch under these conditions, but the loading is the benefits of using small-diameter tubing, whereas larger
still comparatively low. To demonstrate the scalability and reactor tubing would likely require the use of mixing elements
robustness of this flow procedure, the process was run for 8 h to maintain the efficiency of mixing and heat exchange.52
with 1-octene. The reaction proceeded for 8 h without any
blockages, and sampling at 30 min intervals showed that 100%
conversion with 78% epoxide yield was maintained through-
■
*
ASSOCIATED CONTENT
sı Supporting Information
out, delivering 16.32 g of 1,2-epoxyoctane at a rate of 2.04 g/h. The Supporting Information is available free of charge at
Control experiments further demonstrated the effectiveness https://pubs.acs.org/doi/10.1021/acs.oprd.2c00222.
of this catalytic method. Rutjes and co-workers previously
reported a study on the continuous flow dihydroxylation of Greater detail on the equipment used, including a photo
cyclohexene (via epoxidation).49 In that study it was reported of the flow setup; formulae used to calculate reagent
that oxidation with peracetic acid could be carried out without stoichiometry, conversion, and yield; additional reaction
a catalyst at elevated temperatures (e.g., 60 °C). The results of data related to the effect of varying the Mn(II) salt, the
this study found that good yields of epoxide could be obtained solvent mix, and the ligand:Mn ratio; calorimetry data;
by heating without the Mn catalyst for cyclooctene (Table S4), full experimental detail and characterization data for the
but this thermal approach was not applicable for styrene and 1- isolation of cyclooctene oxide; and sample GC spectra
octene (Table S5). The Mn(II)/2-picolinic acid method is for reactions (PDF)
attractive for synthesis because it has previously been shown to
have a wide substrate scope,17 and this work has demonstrated
that it can be operated continuously in a scalable manner.
■ AUTHOR INFORMATION
Corresponding Authors

■ CONCLUSIONS
A continuous flow method for the epoxidation of alkenes has
Jillian M. Thompson − Queen’s University Belfast, Belfast
BT9 5AG, United Kingdom; orcid.org/0000-0002-8165-
2494; Email: [email protected]
been developed using a Mn(II)/2-picolinic acid catalyst with Peter C. Knipe − Queen’s University Belfast, Belfast BT9
peracetic acid as the oxidant. In flow, varying the ligand:metal 5AG, United Kingdom; orcid.org/0000-0001-9728-
ratio proved to be beneficial. Epoxide yields of up to 83% could 2339; Email: [email protected]
be obtained with loadings of Mn(OAc)2 as low as 0.05 mol% Mark J. Muldoon − Queen’s University Belfast, Belfast BT9
and 2-picolinic acid at 1 mol%. This continuous flow system is 5AG, United Kingdom; orcid.org/0000-0002-9286-
an alternative for process chemists to have in their toolbox 9672; Email: [email protected]
E https://doi.org/10.1021/acs.oprd.2c00222
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Article

Authors Pharmaceuticals Containing Oxygen Heterocycles. J. Med. Chem.

Ailbhe A. Ryan − Almac Group, Craigavon BT63 5QD, 2018, 61 (24), 10996−11020.
United Kingdom; Arran Chemical Company, Roscommon (4) Moschona, F.; Savvopoulou, I.; Tsitopoulou, M.; Tataraki, D.;
N37 DN24, Ireland; Queen’s University Belfast, Belfast BT9 Rassias, G. Epoxide Syntheses and Ring-Opening Reactions in Drug
5AG, United Kingdom; orcid.org/0000-0002-9616-3677 Development. Catalysts 2020, 10 (10), 1117.
(5) Thirumalaikumar, M. Ring Opening Reactions of Epoxides. A
Seán D. Dempsey − Almac Group, Craigavon BT63 5QD,
Review. Org. Prep. Proced. Int. 2022, 54 (1), 1−39.
United Kingdom; Arran Chemical Company, Roscommon (6) Sienel, G.; Rieth, R.; Rowbottom, K. T. Epoxides. In Ullmann’s
N37 DN24, Ireland; Queen’s University Belfast, Belfast BT9 Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim,
5AG, United Kingdom; orcid.org/0000-0001-8071-609X Germany, 2000; pp 139−152. DOI: 10.1002/14356007.a09_531.
Megan Smyth − Almac Group, Craigavon BT63 5QD, United (7) Heaney, H. Novel Organic Peroxygen Reagents for Use in
Kingdom; orcid.org/0000-0002-2771-0382 Organic Synthesis. Top. Curr. Chem. 1993, 164, 1−19.
Karen Fahey − Arran Chemical Company, Roscommon N37 (8) Ho, T.-L.; Fieser, M.; Fieser, L. m-Chloroperoxybenzoic Acid
DN24, Ireland (MCPBA). In Fieser and Fieser’s Reagents for Organic Synthesis; John
Thomas S. Moody − Almac Group, Craigavon BT63 5QD, Wiley & Sons: Hoboken, NJ, 2011; pp 203−204. DOI: 10.1002/
United Kingdom; Arran Chemical Company, Roscommon 9780471264194.fos02600.pub4.
N37 DN24, Ireland; orcid.org/0000-0002-8266-0269 (9) Zhang, X.; Hu, A.; Pan, C.; Zhao, Q.; Wang, X.; Lu, J. Safer
Scott Wharry − Almac Group, Craigavon BT63 5QD, United Preparation of m-CPBA/DMF Solution in Pilot Plant. Org. Process
Kingdom Res. Dev. 2013, 17 (12), 1591−1596.
(10) Adolfsson, H. Transition Metal-Catalyzed Epoxidation of
Paul Dingwall − Queen’s University Belfast, Belfast BT9 5AG,
Alkenes. In Modern Oxidation Methods; Bäckvall, J. E., Ed.; Wiley-
United Kingdom; orcid.org/0000-0002-6961-7995 VCH: Weinheim, Germany, 2010; pp 37−84.
David W. Rooney − Queen’s University Belfast, Belfast BT9 (11) Costas, M. Green Oxidative Synthesis of Epoxides. In Green
5AG, United Kingdom Oxidation in Organic Synthesis; John Wiley & Sons, 2019; pp 123−
Complete contact information is available at: 157. DOI: 10.1002/9781119304197.ch7.
https://pubs.acs.org/10.1021/acs.oprd.2c00222 (12) Saisaha, P.; de Boer, J. W.; Browne, W. R. Mechanisms in
Manganese Catalysed Oxidation of Alkenes with H2O2. Chem. Soc.
Author Contributions Rev. 2013, 42 (5), 2059−2074.
(13) Philip, R. M.; Radhika, S.; Abdulla, C. M. A.; Anilkumar, G.
The manuscript was written through the contributions of all
Recent Trends and Prospects in Homogeneous Manganese-Catalysed
authors. All of the authors approved the final version of the Epoxidation. Adv. Synth. Catal. 2021, 363 (5), 1272−1289.
manuscript. (14) Dong, J. J.; Unjaroen, D.; Mecozzi, F.; Harvey, E. C.; Saisaha,
Funding P.; Pijper, D.; de Boer, J. W.; Alsters, P.; Feringa, B. L.; Browne, W. R.
This project received funding from the European Union’s Manganese Catalyzed Selective Oxidation of Aliphatic C-H Groups
Horizon 2020 Research and Innovation Programme under and Secondary Alcohols to Ketones with Hydrogen Peroxide.
Marie Skłodowska-Curie Grant Agreement 813394. This ChemSusChem 2013, 6 (9), 1774−1778.
publication contains the views of the authors, and the (15) Dong, J. J.; Saisaha, P.; Meinds, T. G.; Alsters, P. L.; Ijpeij, E.
European Commission is not responsible for any use that G.; van Summeren, R. P.; Mao, B.; Fañanás-Mastral, M.; de Boer, J.
W.; Hage, R.; et al. Oxidation of Alkenes with H2O2 by an in-Situ
may be made of the information it contains.
Prepared Mn(II)/Pyridine-2-Carboxylic Acid Catalyst and the Role of
Notes Ketones in Activating H2O2. ACS Catal. 2012, 2 (6), 1087−1096.
The authors declare no competing financial interest. (16) Saisaha, P.; Dong, J. J.; Meinds, T. G.; de Boer, J. W.; Hage, R.;

■ ACKNOWLEDGMENTS
The authors thank Lara J. Nolan (QUB) and the Almac
Mecozzi, F.; Kasper, J. B.; Browne, W. R. Mechanism of Alkene,
Alkane, and Alcohol Oxidation with H2O2 by an in Situ Prepared Mn
II /Pyridine-2-Carboxylic Acid Catalyst. ACS Catal. 2016, 6 (6),
3486−3495.
Sciences Hazard Evaluation Team for their contributions to (17) Moretti, R. A.; Du Bois, J.; Stack, T. D. P. Manganese(II)/
this article. Picolinic Acid Catalyst System for Epoxidation of Olefins. Org. Lett.

■ ABBREVIATIONS
AcOH, acetic acid; BPR, back-pressure regulator; EtOAc, ethyl
2016, 18 (11), 2528−2531.
(18) Bettenhausen, C. A. How Peracetic Acid Is Changing
Wastewater Treatment. Chemical & Engineering News, Vol. 98, No.
acetate; GC-FID, gas chromatography with flame ionization 15, April 19, 2020. https://cen.acs.org/magazine/98/09815.html.
detector; HDPE, high-density polyethylene; MeCN, acetoni- (19) Kim, J.; Huang, C.-H. Reactivity of Peracetic Acid with Organic
Compounds: A Critical Review. ACS ES&T Water 2021, 1 (1), 15−
trile; MeOH, methanol; PAA, peracetic acid; PAAM, base-
33.
modified commercial peracetic acid (10:3:13 v/v/v 32% PAA/ (20) Moretti, R. A. Bioinspired Manganese/Picolinic Acid Catalyst
10% KOH(aq)/AcOH); PAAR, resin-synthesized peracetic System for Organic Oxidations. Ph.D. Thesis, Stanford University,
acid Stanford, CA, 2017.

■ REFERENCES
(1) Lin, Z.; Huang, B.; Ouyang, L.; Zheng, L. Synthesis of Cyclic
(21) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D.
H. B. Large-Scale Oxidations in the Pharmaceutical Industry. Chem.
Rev. 2006, 106 (7), 2943−2989.
Fragrances via Transformations of Alkenes, Alkynes and Enynes: (22) Shilcrat, S. Process Safety Evaluation of a Tungsten-Catalyzed
Strategies and Recent Progress. Molecules 2022, 27 (11), 3576. Hydrogen Peroxide Epoxidation Resulting in a Runaway Laboratory
(2) Gomes, A. R.; Varela, C. L.; Tavares-da-Silva, E. J.; Roleira, F. M. Reaction. Org. Process Res. Dev. 2011, 15 (6), 1464−1469.
F. Epoxide Containing Molecules: A Good or a Bad Drug Design (23) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-Flow
Approach. Eur. J. Med. Chem. 2020, 201, 112327. Technology-A Tool for the Safe Manufacturing of Active
(3) Delost, M. D.; Smith, D. T.; Anderson, B. J.; Njardarson, J. T. Pharmaceutical Ingredients. Angew. Chemie Int. Ed. 2015, 54 (23),
From Oxiranes to Oligomers: Architectures of U.S. FDA Approved 6688−6728.

F https://doi.org/10.1021/acs.oprd.2c00222
Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development pubs.acs.org/OPRD Article

(24) Gemoets, H. P. L.; Su, Y.; Shang, M.; Hessel, V.; Luque, R.; (44) Tom, J. K.; Achmatowicz, M. M.; Beaver, M. G.; Colyer, J.;
Noël, T. Liquid Phase Oxidation Chemistry in Continuous-Flow Ericson, A.; Hwang, T.-L.; Jiao, N.; Langille, N. F.; Liu, M.; Lovette,
Microreactors. Chem. Soc. Rev. 2016, 45 (1), 83−117. M. A.; et al. Implementing Continuous Manufacturing for the Final
(25) Wan, L.; Jiang, M.; Cheng, D.; Liu, M.-J.; Chen, F.-E. Methylation Step in the AMG 397 Process to Deliver Key Quality
Continuous Flow Technology�A Tool for Safer Oxidation Attributes. Org. Process Res. Dev. 2021, 25 (3), 486−499.
Chemistry. React. Chem. Eng. 2022, 7, 490−550. (45) Brasholz, M.; Johnson, B. A.; Macdonald, J. M.; Polyzos, A.;
(26) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Tsanaktsidis, J.; Saubern, S.; Holmes, A. B.; Ryan, J. H. Flow Synthesis
Hitchhiker’s Guide to Flow Chemistry. Chem. Rev. 2017, 117 (18), of Tricyclic Spiropiperidines as Building Blocks for the Histrionico-
11796−11893. toxin Family of Alkaloids. Tetrahedron 2010, 66 (33), 6445−6449.
(27) Guidi, M.; Seeberger, P. H.; Gilmore, K. How to Approach (46) Popov, E.; Eloranta, J.; Hietapelto, V.; Vuorenpalo, V. M.;
Flow Chemistry. Chem. Soc. Rev. 2020, 49 (24), 8910−8932. Aksela, R.; Jäkärä, J. Mechanism of Decomposition of Peracetic Acid
(28) Tsukanov, S. V.; Johnson, M. D.; May, S. A.; Kolis, S. P.; Yates, by Manganese Ions and Diethylenetriaminepentaacetic Acid (DTPA).
M. H.; Johnston, J. N. Continuous Platform to Generate Nitroalkanes Holzforschung 2005, 59 (5), 507−513.
On-Demand (in Situ) Using Peracetic Acid-Mediated Oxidation in a (47) Yuan, Z.; Ni, Y.; Van Heiningen, A. R. P. Kinetics of the
PFA Pipes-in-Series Reactor. Org. Process Res. Dev. 2018, 22 (8), Peracetic Acid Decomposition Part II: PH Effect and Alkaline
971−977. Hydrolysis. Can. J. Chem. Eng. 1997, 75 (1), 42−47.
(29) Martin, B.; Sedelmeier, J.; Bouisseau, A.; Fernandez-Rodriguez, (48) Rothbart, S.; Ember, E. E.; van Eldik, R. Mechanistic Studies on
P.; Haber, J.; Kleinbeck, F.; Kamptmann, S.; Susanne, F.; Hoehn, P.; the Oxidative Degradation of Orange II by Peracetic Acid Catalyzed
Lanz, M.; et al. Toolbox Study for Application of Hydrogen Peroxide by Simple Manganese(II) Salts. Tuning the Lifetime of the Catalyst.
New J. Chem. 2012, 36 (3), 732−748.
as a Versatile, Safe and Industrially-Relevant Green Oxidant in
(49) Van Den Broek, B. A. M. W.; Becker, R.; Kössl, F.; Delville, M.
Continuous Flow Mode. Green Chem. 2017, 19 (6), 1439−1448.
M. E.; Nieuwland, P. J.; Koch, K.; Rutjes, F. P. J. T. Prilezhaev
(30) Zhou, S.; Xin, Y.; Wang, J.; Wu, C.; Sun, T. Application of
Dihydroxylation of Olefins in a Continuous Flow Process.
Continuous Flow in Tazobactam Synthesis. Org. Process Res. Dev.
ChemSusChem 2012, 5 (2), 289−292.
2021, 25 (7), 1648−1657. (50) Berton, M.; de Souza, J. M.; Abdiaj, I.; McQuade, D. T.; Snead,
(31) Saisaha, P.; Pijper, D.; Van Summeren, R. P.; Hoen, R.; Smit, D. R. Scaling Continuous API Synthesis from Milligram to Kilogram:
C.; De Boer, J. W.; Hage, R.; Alsters, P. L.; Feringa, B. L.; Browne, W. Extending the Enabling Benefits of Micro to the Plant. J. Flow Chem.
R. Manganese Catalyzed Cis-Dihydroxylation of Electron Deficient 2020, 10 (1), 73−92.
Alkenes with H2O2. Org. Biomol. Chem. 2010, 8 (19), 4444−4450. (51) Hu, C. Reactor Design and Selection for Effective Continuous
(32) Nodzewska, A.; Watkinson, M. Remarkable Increase in the Rate Manufacturing of Pharmaceuticals. J. Flow Chem. 2021, 11 (3), 243−
of the Catalytic Epoxidation of Electron Deficient Styrenes through 263.
the Addition of Sc(OTf)3 to the MnTMTACN Catalyst. Chem. (52) Duan, S.; Feng, X.; Gonzalez, M.; Bader, S.; Hayward, C.;
Commun. 2018, 54 (12), 1461−1464. Ljubicic, T.; Lu, J.; Mustakis, J.; Maloney, M.; Rainville, J.; et al.
(33) Lane, B. S.; Burgess, K. Metal-Catalyzed Epoxidations of Developing a Multistep Continuous Manufacturing Process for
Alkenes with Hydrogen Peroxide. Chem. Rev. 2003, 103 (7), 2457− (1R,2R)-2-Amino-1-methylcyclopentan-1-ol. Org. Process Res. Dev.
2473. 2020, 24 (11), 2734−2744.
(34) Mao, S.; Budweg, S.; Spannenberg, A.; Wen, X.; Yang, Y.; Li,
Y.-W.; Junge, K.; Beller, M. Iron-Catalyzed Epoxidation of Linear α-
Olefins with Hydrogen Peroxide. ChemCatChem 2022, 14 (4),
e202101668.
(35) Wang, Z. Meinwald Rearrangement. In Comprehensive Organic
Name Reactions and Reagents; John Wiley & Sons: Hoboken, NJ,
2010. DOI: 10.1002/9780470638859.conrr422.
(36) White, M. C.; Doyle, A. G.; Jacobsen, E. N. A Synthetically
Useful, Self-Assembling MMO Mimic System for Catalytic Alkene
Epoxidation with Aqueous H2O2. J. Am. Chem. Soc. 2001, 123 (29),
7194−7195.
(37) Fujita, M.; Que, L. In Situ Formation of Peracetic Acid in Iron-
Catalyzed Epoxidations by Hydrogen Peroxide in the Presence of
Acetic Acid. Adv. Synth. Catal. 2004, 346 (23), 190−194.
(38) Hasan, K.; Brown, N.; Kozak, C. M. Iron-Catalyzed
Epoxidation of Olefins Using Hydrogen Peroxide. Green Chem.
2011, 13 (5), 1230−1237.
(39) Verspeek, D.; Ahrens, S.; Spannenberg, A.; Wen, X.; Yang, Y.;
Li, Y.-W.; Junge, K.; Beller, M. Manganese N,N,N-Pincer Complex-
Catalyzed Epoxidation of Unactivated Aliphatic Olefins. Catal. Sci.
Technol. 2022, 12 (24), 7341−7348.
(40) Murphy, A.; Pace, A.; Stack, T. D. P. Ligand and pH Influence
on Manganese-Mediated Peracetic Acid Epoxidation of Terminal
Olefins. Org. Lett. 2004, 6 (18), 3119−3122.
(41) Ebrahimi, F.; Kolehmainen, E.; Turunen, I. Safety Advantages
of On-Site Microprocesses. Org. Process Res. Dev. 2009, 13 (5), 965−
969.
(42) Jolhe, P. D.; Bhanvase, B. A.; Patil, V. S.; Sonawane, S. H.
Sonochemical Synthesis of Peracetic Acid in a Continuous Flow
Micro-Structured Reactor. Chem. Eng. J. 2015, 276, 91−96.
(43) Lynch, W.; Lynch, G.; Sheriff, K.; Padgett, C. Structures of
Substituted Pyridine N-Oxide with Manganese(II) Acetate. Acta
Crystallogr., Sect. E: Crystallogr. Commun. 2018, 74 (Ii), 1405−1410.

G https://doi.org/10.1021/acs.oprd.2c00222
Org. Process Res. Dev. XXXX, XXX, XXX−XXX