The Application of Peroxide for Organic Synthesis in Continuous Flow Chemistry

Abstract Peroxides, as high-efficiency oxidants, are widely used in various areas of industry, such as chemical, pharmaceutical, environmental protection, etc. However, their applications in batches are limited due to their explosive and unstable nature. Continuous flow reactions have the advantages of a large area-to-surface ratio, high mixing efficiency, high mass and heat transfer performance, accurate control of process parameters, and high security. These are beneficial for the improvement of the product yield and the reduction of the reaction time and risk. Thus, in the reaction involving peroxide, continuous flow technology can effectively improve the operational safety and enhance the reaction efficiency of peroxides. This review summarized the applications of peroxides in various organic syntheses in continuous-flow chemistry. These examples illustrated the promising prospects of peroxides in green organic synthesis.


Introduction
Hydrogen peroxide (H 2 O 2 ) can be regarded as a green oxidant in the chemical industry. 1,2H 2 O 2 is the simplest form of peroxides and is mainly prepared by the anthraquinone (AO) process. 3,4H 2 O 2 has a unique advantage compared with inorganic metal oxidants because its only by-product is water. 5,6However, H 2 O 2 usually needs to combine with other reagents as a terminal oxidant to participate in a wide variety of reactions (►Fig. 1). 3,7n organic synthesis, peroxides are widely used to oxidize alcohols, aldehydes, olefins, etc., however, the potential hazards associated with peroxides and organic compounds limit their practical development, for example, the thermal runaway process of the mixture of H 2 O 2 and 1,3,5-trimethylbenzene, demonstrated by Qian et al through a method combining reactive molecular dynamics (ReaxFF MD) and density function theory. 8They elucidated the mechanism of the explosion hazard.They also emphasized that controlling H 2 O 2 and substrate concentrations outside the explosive range can effectively reduce the activity of the explosive system.In traditional industrial production, batch or tandem batch is used for peroxidation reaction, yet it tends to cause localized heat accumulation in the reactor that may even lead to an explosion.In the scale-up, the thermal control of the peroxide reaction is usually achieved by a "de-intensification" in the batch mode, whereby avoiding high concentrations of peroxide, lowering the reaction temperature, and preventing the concentration of the peroxide solution. 9,10Therefore, the safe use of peroxides has always been of great concern, both in the laboratory and chemical industry.
2][13] It can be used to address safety issues of peroxide in large-scale reactions.Flow reactors have a large area-to-surface ratio that provides excellent heat exchange and prevents localized hot pots.Continuous flow technology allows for continuous operation where peroxides can be transported to the reaction site for continuous consumption rather than accumulating in one unit of the reactor.Flow reactors also allow for precise control of reaction parameters, thus, enhancing the safety and efficiency of the whole process.However, the transition from batch reaction to continuous flow reaction still faces challenges, e.g., pipe blockage and the advances in online analytical techniques, and international coordination of continuous flow technology needs to be improved to reduce barriers to technology implementation and regulation.Peroxides play an important role in organic synthesis. 2,14,15This article attempts to summarize the successful applications of peroxides in continuous-flow reactors and supplement the safe use of the compounds in the synthesis process.

Peroxide Preparation
The continuous flow technology has expanded our capabilities for the preparation of peroxides.In addition to the AO process, •h. 16Furthermore, a simple kinetic model is proposed to guide the synthesis of H 2 O 2 , and it showed that it is the decomposition reaction, rather than the hydrogenation reaction, that has the greatest effect on the amount of H 2 O 2 generated.The gas composition should be kept below the lower explosive limit of H 2 , which is 5% in air at room temperature.
Maralla and Sonawane synthesized performic acid (PFA) in a polytetrafluoroethylene spiral capillary microreactor using formic acid as a reactant. 17The preferred reaction parameters were 30°C, a feed flow rate of 10 mL/h, and 30% H 2 O 2 , and the maximum PFA (5.175 mol/L) was obtained in 6 minutes.The reaction device could provide a reference for the preparation of similar peroxides (►Fig. 2).Gaikwad et al synthesized PFA in Corning advanced-flow reactors using formic acid and H 2 O 2 as reactants and sulfuric acid as a homogeneous catalyst. 18The preferred reaction parameters were 30°C, a flow rate of 80 mL/h, and 1 w/w% H 2 SO 4 , and the maximum PFA was obtained within 1 minute.Katuri et al produced PFA in a T-junction spiral capillary microreactor system using formic acid and H 2 O 2 as substrates and Amberlite IR 120 Na as a catalyst. 19As a heterogeneous catalyst, Amberlite IR 120 Na is preferred because of its ability to reduce reactor corrosion and solve product separation problems compared with homogeneous catalysts.Under the parameters of 30°C and 6 wt % catalyst, the maximum PFA (2.8 mol/L) was obtained in 10 minutes.Peroxyacetic acid (PAA) is unstable due to its rapid thermal decomposition; therefore, safety concerns need to be taken into account when producing and using PAA.Jolhe et al synthesized PAA in a continuous flow micro-structured reactor in the presence of ultrasonic irradiations innovatively. 20The results showed that the concentration of PAA reached 3.375 mol/L in 60 minutes in a batch reaction while 5.12 mol/L within 10 minutes in a continuous flow.Maralla and Sonawane also proposed a safe and efficient synthesis of PAA under a continuous flow condition. 21They verified the kinetics in detail and investigated the effect of three different flow reactors on the efficiency of PAA production.The results showed that a spiral capillary reactor produced PAA with the best efficiency.The preferred reaction conditions were 50°C, a feed flow rate of 6.7 mL/h, and acetic acid/ H 2 O 2 (1:1, a molar ratio), and the maximum PAA (3.751 mol/L) was obtained in 9 minutes.
Li et al synthesized anhydrous tert-butyl hydroperoxide (TBHP) in the presence of membrane pervaporation. 22The pervaporation skid was included, and the pervaporation system is shown in ►Fig.3A.The process ran for more than 96 hours and successfully obtained a target of 0.15 wt % water.The advantage of this process was that TBHP could be produced on demand at low temperatures, avoiding the need to store large quantities of reaction solution under batch conditions.TBPH obtained was directly used to oxidize γ-butyrolactam substrate to prepare key pharmaceutical intermediates (►Fig.3B).

Oxidation of Hydroxyl Compounds
Hydroxyl compounds can be oxidized by several conventional oxidants, including inorganic metal oxidants, high-valued iodine oxidants, and TEMPO (2,2,6,6-tetramethylpiperidin-1-oxyl). 23However, these oxidants are costly and environmentally unfriendly and may pose challenges in terms of functional group compatibility.
In 2021, Kon et al performed a selective oxidation of cinnamyl alcohol to cinnamaldehyde in a continuous flow reactor in the presence of H 2 O 2 . 24This can be achieved by optimizing the concentration of Pt black and the contact time of the substrate with Pt and H 2 O 2 .H 2 O 2 decomposition was also prevented.The aldehydes obtained can be directly used in subsequent organic transformations.In 2022, the same group selectively oxidized alcohols to aldehydes and carboxylic acids in flow reactors in the presence of Pt catalyst and H 2 O 2 for the first time (►Fig.4). 25 Carboxylic acids were obtained at 90°C and a flow rate of 0.1 mL/min, with a yield of 94%.Lowering the temperature to 40°C and increasing the flow rate to 0.425 mL/min contributed to the production of aldehydes in a yield of 98%.Interestingly, the catalytic activity of Pt increases as the temperature increases from 40 to 90°C.Liu et al oxidized alcohols to carbonyl compounds using H 2 O 2 in combination with catalytic amounts of bromide ions (Br À ) and acid. 26A possible mechanism is proposed in ►Scheme 1.The mechanism is  important in the selective oxidation of compounds containing two or more hydroxyl groups because of the higher reactivity selectivity of secondary alcohols compared with that of primary alcohols.
Derikvand et al screened silver oxide (Ag 2 O) as a heterogeneous catalyst, combined with H 2 O 2 as a green oxidant to oxidize hydroquinones to benzoquinones, with a product yield of up to 95%. 27Ag 2 O can be recycled at least five times and can be filled in continuous flow reactors to perform the same oxidation reaction with a similar experimental result.Using TBHP, Li et al synthesized 2,3,5-trimethylbenzoquinone (TMBQ) from 2,3,6trimethylphenol in a continuous flow. 28The optimal reaction temperature was 40°C, the residence time was 12 minutes, and the inner diameter of the microreactor can be negligible.The two-injection strategy of TBHP resulted in a higher space-time yield of 0.36 kg/(L Â h) compared with the batch reactor and the one-injection strategy (►Table 1).

Oxidation of Carbonyl Compounds
Oxidation of carbonyl compounds is a common method for the preparation of various carboxylic acids.Prieschl et al conducted an oxidation of aldehyde in continuous flow in the presence of PFA. 29 The hazards of potentially explosive reagents were safely eliminated.They dissolved the substrate directly in formic acid and obtained carboxylic acid in 86% yield in 20 minutes under 90°C and 1 equiv.H 2 O 2 ; however, the poor solubility of the raw material had the risk of clogging the pipeline.They solved the problem by dissolving the substrate in ethyl acetate and obtained the target with 99% yield in 20 minutes (►Fig.5).Flow processes are rarely used in the synthesis of chiral drugs.γ-Nitrobutyric acids are key intermediates of the GABA analogues baclofen, phenibut, and fluorophenibut.In 2020, Ötvös et al asymmetrically synthesized chiral γ-nitrobutyric acids via a two-step telescoped continuous flow process. 30α,β-Unsaturated aldehydes were first converted to γ-nitroaldehydes via enantioselective Michael-type addition, then, the γ-nitroaldehydes obtained were oxidized to γ-nitrobutyric acids by in situ-generated PFA (►Fig. 6).

Olefin Oxidation
Epoxidation reactions play an important role in organic synthesis.Epoxides are useful in the establishment of chiral centers.Limnios and Kokotos introduced the epoxidation reaction of various styrenes using 2,2,2-trifluoroacetophenone as an organocatalyst and H 2 O 2 as a green oxidant. 31owever, due to poor mixing properties and exothermic decomposition of H 2 O 2 , the process took an hour to scale up.Yuan et al performed the reaction in a commercial fluidic reactor. 32This process takes 3.17 minutes with a substrate conversion of 96.7% and a product yield of 91.8%, which greatly reduced the reaction time and ensured the safety and continuity of operation (►Fig.(4-VCH) using Ps•AMP•Mo (polystyrene 2-(aminomethyl) pyridine-supported molybdenum (VI) complex) as a catalyst, and TBHP as an oxidant. 33The data showed that the reaction time in the FlowSyn reactor (5 minutes) was significantly reduced in comparison to that in the batch reactor (40 minutes).The conversion of TBHP and the yield of 4-VCH The hydroboration/oxidation of olefins can be used to prepare primary alcohols and is commonly used to insert hydroxyl groups in the total synthesis of natural products or drugs. 35Due to the rapid exothermic nature of the reaction, Souto et al used a flow-through process to accelerate heat dissipation and implemented online purification techniques to produce alcohols efficiently. 36When the reaction temperature is 25°C, the reaction time was reduced from 4 hours (in a batch) to 50 minutes, and the yield of alcohol was 92%.Innovative continuous extraction and collection of organic solvents was achieved with a customized glass extraction unit (►Fig.9).
H 2 O 2 also participated in the direct oxidation of olefins to various carboxylic acids.Wen et al conducted a clean production of adipic acid (AA) using H 2 O 2 as an oxidant and H 2 WO 4 , H 2 SO 4 , and H 3 PO 4 as catalysts, which can be recycled 20 times. 37AA was produced in a laboratory continuous flow   Application of Peroxide for Organic Synthesis in Continuous Flow Chemistry Zhu et al. e247 system in 94.1% yield using cyclohexene as a reactant.The pilot plant scaled up 10,000-fold for continuous operation, and AA was achieved in 94.7% yield (►Fig. 10).Shang et al used Na 2 WO 4 •2H 2 O as a catalyst, [CH 3 (n-C 8 H 17 ) 3 N]HSO 4 as a phase transfer catalyst, and H 2 O 2 as a benign oxidant to oxidize cyclohexene to AA in a solvent-free continuous flow. 38In this work, AA was achieved with a yield of 50% within 20 minutes, which obtained a higher space-time yield of 0.57 kg L -1 h -1 compared with the batch (►Table 2).

Oxidation of Sulfur Compounds
Sulfone and sulfoxide are usually prepared from thioethers and the most important concern is the selectivity of the oxidation.Maggi et al performed a highly selective oxidation of sulfides to sulfoxides in a continuous flow reactor under mild conditions and no metal catalysts. 39The reaction parameters were 22°C, a stoichiometric amount of 30% H 2 O 2 (aq), and a residence time of 25 minutes.Sulfoxide was obtained in 94% yield and 99% selectivity.Then, diluted H 2 O 2 was tried, and encouragingly, the oxidation of thioanisole still proceeded successfully, which was the first example (►Fig. 11).Mangiavacchi et al achieved a switchable synthesis of sulfones and sulfoxides from sulfides in flow reactors with the catalyst perselenic acid, which was in situ generated by the oxidation of selenium oxide in H 2 O 2 (aq). 40he reaction was conducted at a feed flow rate of 0.1 mL/min and 2 equiv. of H 2 O 2 , and obtained sulfoxides in a yield of 85% and a chemoselectivity of 100%.When the amount of H 2 O 2 was increased from 2 to 10 equiv., there was only a single product, sulfone.The mechanism for the catalytic cycle was proposed as shown in ►Scheme 2.
Doherty et al utilized the peroxometalate-based polymerimmobilized ionic liquid phase catalyst [PO 4 {WO(O 2 ) 2 } 4] @PIILP as a heterogeneous catalyst, and H 2 O 2 (aq) as the oxidant for the oxidation of sulfides to the corresponding sulfones and sulfoxides in a continuous flow. 41Solvent has an important effect on the reaction; when methanol was used as a solvent, the conversion rate of sulfide was 83% with a sulfoxide selectivity of 98% in 4 minutes, when acetonitrile was used as a solvent, the  conversion rate of sulfide was 100% with a sulfone selectivity of 96% in 15 minutes.The immobilized catalyst maintained its activity for 8 hours under a continuous flow condition.Zhang et al reported a simple and efficient oxidation of thioether into 2,3-dimethyl-4-methylsulfonylbromobenzene under flow conditions using PAA as an oxidant, which was in situ generated from the oxidation of acetic acid (CH 3 COOH) in diluted H 2 O 2 (aq). 42The three-stream micromixing process improved the efficiency and safety of the reaction significantly and greatly reduced the reaction time (6 minutes) compared with the batch reactor (75 minutes) (►Table 3).continuous flow using H 2 O 2 as an oxidant (►Fig.12). 43The reliability of the process was confirmed by the successfully obtained 5-amino-3-nitro-1,2,4-triazole and 1-methyl-3,4,5-trinitropyrazole with a high efficiency.

Oxidation of Nitrogen Compounds
Gu et al used TBHP as an oxidant and conducted a metalfree oxidative amination of aromatic alcohols in a two-step continuous flow. 44The reaction time in continuous flow (15 minutes) was significantly shortened in comparison to a batch reaction (3 hours).The targets were produced with a yield of 86 to 96%.The mechanism is described in ►Scheme 3.Then, the group used H 2 O 2 as an oxidant to further achieve a continuous-flow process of the oxidative amination of aromatic aldehydes and alcohols. 45The process was metal-free catalysis.The continuous reaction was performed at 80°C with a feed flow rate of 0.1 mL/min, and produced 96% yield of the product at 25 minutes, which was significantly higher than a batch reaction (64% yield).

C-H Oxidation
C-H bond activation is a convenient method for constructing carbon-carbon bonds and carbon-heteroatom bonds with high atomic economy.Chaudhari has explored the C(sp 3 )-H peroxidation of 2-oxindole and barbituric acid derivatives in ethyl acetate, an eco-friendly solvent. 46They used TBHP as an oxidant and Fe(OH) 3 @Fe 3 O 4 as the catalyst to conduct a batch reaction with a yield of 81% of the product in 4 hours.To avoid the risk of explosions of organic peroxide and a long reaction time, a continuous flow process was performed, and the product successfully obtained in 75% yield in 7.9 minutes (►Fig. 13).The catalyst could be reused up to ten times.The group also explored iron-catalyzed dehydrogenative crosscoupling of carbonyl in a continuous flow. 47The substrate (0.1 mol/L) passed through a continuous flow reactor at a flow rate of 0.2 mL/min at 35°C to give the target product an 88% yield.This method is applied to a wide range of substrates (2-oxindole, barbituric acid, and coumarin substrates) and can be used for gram-scale synthesis.
Zhang et al presented a continuous flow technology to achieve Cu-catalyzed trifluoromethylation of coumarins under mild conditions, using inexpensive Langlois reagent (CF 3 SO 2 Na) and its partner tert-butyl hydroperoxide. 48At 60°C, the reaction time was shortened from 6 hours to 50 minutes by converting the batch to a continuous flow.7-diethylamino-4-methyl coumarin can be used as the substrate to participate in the reaction with the output of the product at 305 mg/h, suggesting the stability of the process.Furthermore, a possible mechanism is provided in ►Scheme 4.

Peroxides in Other Organic Reactions
Traditionally, nitrile is hydrolyzed to primary amide using strong acids or bases, which may lead to excessive hydrolysis.However, Zhan et al used H 2 O 2 as an oxidant for the first time to hydrolyze nitrile to primary amide in a continuous flow. 49he conversion rate of raw materials reached 99% in 150 seconds when the reaction was performed at 2°C in a solution of phenylacetonitrile/NaOH/H 2 O 2 (1:0375:1.2).This method has a wide substrate range and good to excellent yield.The electron-rich phenylacetonitrile has a good yield of 81 to 99% while the electron-deficiency phenylacetonitrile required a longer reaction time to achieve a high yield of 75 to 98%.4-(4-Methyl-piperazine-1-yl-methyl)-benzamide, an intermediate for imatinib, was synthesized in 81% yield in the scale-up experiment (►Fig. 14).
Shi et al studied a free radical reaction for the formation of amide compounds through a two-step series continuous flow reaction, using methyl aromatic, catalyst tetrabutylammonium iodide, and TBHP as raw materials. 50Through the optimization of conditions, the two-step reaction temperature was 50°C (T1) and 80°C (T2), the residence time was 30 minutes (T1) and 33.3 minutes (T2), and the yield reached 66 to 84%.Encouragingly, under the reaction conditions, N-acetylprocainamide, an antiarrhythmic agent, can be obtained in 57% yield in a scale-up experiment using commercially available 4-methylacetanilide as the starting material (►Fig. 15).
Al-Megren et al proposed a direct hydroxylation of benzene to phenol in the presence of H 2 O 2 in a continuous membrane reactor for the first time. 51A hydrophilic membrane was used with a total feed flow rate of 2 mL/min and a stripping flow rate

Conclusion
The peroxides, as green and atom-economy oxidants, are attractive alternatives to some toxic inorganic oxidants in a series of oxidation reactions.However, they tend to be explosive.The problem can be solved well in a continuous flow chemistry with the advantages of safe operation and ensuring the efficiency of the reaction.This article reviews the application of peroxides in oxidizing olefins, alcohols, aldehydes, sulfides, etc. in continuous-flow chemistry.However, the transformation of peroxideinvolved reactions from batch to continuous flow still faces thorny challenges in terms of pipe blockage, advances in online analytical techniques, lack of harmonized standards, and suitable reactors.Most of the applications of peroxides in continuous flow technology remain in the laboratory stage, and the extension of continuous flow technology to production scale needs to be further explored by researchers.With the IUPAC ranking continuous flow chemistry as one of the top 10 emerging technologies in chemistry, and chemists' growing concern about the safe use of peroxides in the laboratory and chemical industry, the application of peroxides in continuous flows will be greatly explored in the future.

Fig. 2
Fig. 2 Schematics of experimental set-up for performic acid synthesis.

Fig. 3 (
Fig. 3 (A) Pervaporation system at the kilo laboratory facility.(B) Synthesis of a key lactam intermediate.

Fig. 4
Fig. 4 Selective oxidation of alcohols in a continuous flow.
Fig. 5 Oxidation of aldehydes in a continuous flow.

Fig. 7
Fig. 7 Flow chart of operating mode of organocatalyzed epoxidation reaction of styrene.

Fig. 8
Fig. 8 Epoxidation of limonene in a continuous flow.

Fig. 10
Fig. 10 Simplified process flow diagram for the oxidation of cyclohexene to adipic acid.

Table 2 Scheme 2
Scheme 2 Proposed mechanism of the oxidation of thioethers to the corresponding sulfone and sulfoxide.

Fig. 11
Fig. 11 Highly selective oxidation of thioethersulphides with H 2 O 2 in a continuous flow.

Fig. 12
Fig. 12 Oxidation of amines in continuous flow setups.

Fig. 13
Fig. 13 Schematic representation of the continuous flow of a C(sp3)-H peroxidation reaction.

Fig. 14 A
Fig.14A sample set-up for the flow platform for hydrolyzing nitrile to a primary amide using hydrogen peroxide as a green oxidant.
of 1 mL/min, resulting in a phenol recovery of 25% and a selectivity of 94%.The mechanism is provided in ►Scheme 5.

Fig. 15 AScheme 5
Fig. 15 A sample set-up for flow platform for the synthesis of N-acetylprocainamide.
Freakley et al demonstrated a direct synthesis of H 2 O 2 from O 2 and H 2 using Au-Pd as catalysts, and the reaction conditions in a continuous flow system were: 10 bar, 2°C, total gas flow rate of 42 N mL/min, H 2 /O 2 ¼ 1, 66% MeOH and 34% H 2 O as a solvent, solvent flow rate of 0.2 mL/min and 120 mg catalyst, the net synthesis rate of H 2 O 2 is 2.2 mol•kg cat À1

Table 3
Comparison of three processes for the oxidation of thioether to the corresponding sulfones