# Taming explosive and highly energetic reactions: scaling up the liquid-phase aerobic oxidation of alcohols and aldehydes in flow

Boris Guicheret, Marco Antonio Dos-Santos, Claude de Bellefon, Laurent

Vanoye, Régis Philippe, Alain Favre-Réguillon

► To cite this version:

Boris Guicheret, Marco Antonio Dos-Santos, Claude de Bellefon, Laurent Vanoye, Régis Philippe, et al. Taming explosive and highly energetic reactions: scaling up the liquid-phase aerobic oxidation of alcohols and aldehydes in flow. Reaction Chemistry & Engineering, 2026, 10.1039/d5re00444f. [hal-05534269](https://hal.science/hal-05534269v1)

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# Taming explosive and highly energetic reactions: scaling up the liquid-phase
aerobic oxidation of alcohols and aldehydes in flow

Boris Guicheret<sup>a</sup>, Marco Antonio Dos-Santos<sup>a,b</sup>, Claude de Bellefon<sup>a</sup>, Laurent Vanoye<sup>a</sup>, Régis
Philippe<sup>a*</sup>, Alain Favre-Reguillon<sup>a,c*</sup>

<sup>a</sup> Catalyse Polymérisation Procédés & Matériaux (CP2M), UMR 5128 CNRS – CPE Lyon – Université Claude Bernard Lyon 1, 43 boulevard du 11 novembre 1918, F-69100 Villeurbanne (France).

<sup>b</sup> Processium, 30 Rue Marguerite, 69100 Villeurbanne (France).

<sup>c</sup> Conservatoire National des Arts et Métiers, EPN 7, Synergie, 10 rue de la procession, 93210 La plaine Saint Denis (France).

E-mail: regis.philippe@lgpc.cpe.fr and alain.favrereguillon@lecnam.net

## Abstract

In an era of growing environmental awareness, pharmaceutical companies, which undergo a significant number of non-optimized transformations during the early stages of synthesizing active pharmaceutical ingredients (APIs), need to evolve. This evolution can be achieved through new processes, protocols, and specific multiphasic continuous-flow reactors. Although this technology has been proven at the laboratory scale, its implementation at the pilot scale remains limited, especially for oxidation reactions using oxygen, a cost-effective and readily available green oxidizing agent. This limitation largely stems from the hazardous nature of these reactions and the challenges related to scaling up the gas-liquid process. Here, we present two examples of the successful, seamless scale-up of the aerobic oxidation of primary alcohols and aliphatic aldehydes in a compact heat exchanger reactor, while preserving the segmented flow characteristics and intensified conditions observed at the laboratory scale. The results crucially demonstrate the potential for implementing milli-structured reactors in pharmaceutical process chemistry.

## Introduction

The liquid-phase oxidation of hydrocarbons using gas-phase oxygen is a critical process for producing commodity chemical intermediates.<sup>1–3</sup> Molecular oxygen (O<sub>2</sub>) is recognized as a cost-effective and readily available green oxidizing agent. Furthermore, oxygen's classification as a non-toxic gas and its ease of removal during workup enhance its utility compared to traditional oxidants.<sup>4</sup> Despite this, oxygen remains underutilized as an oxidant in the fine and pharmaceutical chemical industries.<sup>5</sup> This is primarily due to significant process challenges related to its use, as highlighted in various reviews.<sup>6–9</sup> We would like to emphasize two key issues contributing to its limited application: i) due to the limited solubility of O<sub>2</sub> in water or organic solvents, reactions are often mass transfer-limited. These
constraints can create considerable challenges when scaling up from laboratory experiments to larger manufacturing processes; ii) aerobic oxidations are generally highly exothermic. The combination of energy, flammable organics, and excess O₂ poses a serious risk of fires and explosions, raising safety concerns during the process scale-up.⁸

It has been shown that mass transfer limitations and safety risks can be effectively tackled by using continuous-flow microreactors (CFM).¹⁰⁻¹³ Liquid-phase oxidation reactions are exothermic, and inefficient heat management in reactors leads to low selectivity and yield. Furthermore, intermediates, such as oxygenated compounds (i.e., organic peroxides and peracids), are thermally unstable, and their decomposition may trigger the ignition of explosive mixtures in the headspace of traditional stirred tank reactors. Heat management in CFM is more effective due to the high surface-to-volume ratio. The small volumes of microreactors restrict the reactive volume and, consequently, limit the total inventory of hazardous chemicals. Furthermore, the small channel dimensions help mitigate the risk of explosion and deflagration-to-detonation transition (DDT).¹⁴,¹⁵ The size of detonation cells directly relates to the risk of DDT in chemical reactors.¹⁶,¹⁷ DDT occurs when reactive mixtures exist in volumes larger than several times the detonation cell size, enabling flame acceleration and shock formation that can lead to detonation. The detonation cell size in oxygen-hydrocarbon mixtures varies significantly depending on factors like hydrocarbon type, equivalence ratio, pressure, and dilution. Typically, at 1 atm and 353 K, these cell sizes range from a few millimeters to a few centimeters.¹⁸ Because DDT needs a critical dimension usually several times larger than the detonation cell size, the small size of the microreactor limits the space available for flame acceleration and transition. This containment prevents the conditions necessary for DDT, reducing the chances of sudden, high-pressure detonations. It thus improves safety by lowering explosive hazards, equipment damage, and risks to personnel.

The O₂ mass transfer rate significantly influences the apparent reaction rate and selectivity in fast liquid-phase aerobic oxidation processes. A critical factor in enhancing mass transfer is increasing the interfacial area. Unlike conventional reactors, CFM can provide higher interfacial area and, therefore, higher mass transfer rates for gas/liquid (G/L) reaction processes.¹³,¹⁹ In particular, the Taylor flow regime (or slug flow), a particular flow pattern characterized by regular slugs of liquid separating gas phase bubbles, offers an improved mass transfer performance compared to other G/L flow regimes.⁷,¹³ The internal secondary circulations generated by interfacial friction and the slip velocity of the gas bubble within the liquid promote rapid interface renewal and enhance mass transfer between the two phases.²⁰ This specific G/L flow regime could be easily obtained at the lab scale using single, low-diameter tubing (typically 0.1 – 1 mm range). Furthermore, due to the small characteristic length, a good overall wall heat transfer capacity is obtained at lab-scale thanks to the favourable wall surface-to-reactive volume ratio and the fluid recirculation loops.²¹ This generally contributes to the access to intensive novel process windows, offering higher productivities while remaining selective and safe. Such conditions are usually unattainable in traditional stirred tank vessels.¹⁰ These remarkable properties explain why CFM has received much attention in academia and industry, and, in particular, aerobic oxidation in continuous flow has been comprehensively reviewed.⁸⁻¹³,²²

However, to our knowledge, the scale-up from lab-scale to pilot plant for aerobic oxidation (reactive reactor volumes below 2 mL and above 20 mL, respectively) has been rarely studied in the literature.²³⁻³¹ ²²⁻³⁰,²³⁻³¹ This could be attributed to the hazardous nature of aerobic oxidation
reactions and the challenges of transferring Taylor flow from lab-scale CFM to pilot-scale. Specifically, evenly distributing gas and liquid flow rates across a large number of channels is challenging and could negatively impact the overall performance of the process (yield and selectivity). Even if the sensitivity is linked to the specific reaction network studied, generally, a poor gas liquid distribution may result in large discrepancies from one channel to the other in terms of phase hold up (possible ) and mean flow velocity affecting the overall liquid residence time distribution and the overall mass transfer intensity.

The Kobelco SMCR® (Stacked Multi-Channel Reactor) design aims to tackle this issue and is based on the direct numbering-up of segmented flow in a multi-plate, multi-channel compact heat exchanger setup (Figure 1), with the goal of preserving the characteristics of the Taylor flow pattern. In this paper, we determine the type of flow in the Kobelco SMCR® by analysing the residence time distribution. We demonstrate that two lab-scale aerobic oxidation reactions can be safely and efficiently scaled up using a reactor featuring sixteen parallel reactive channels distributed across four reactive plates.
# Materials and methods

## Chemicals

All chemicals and solvents were purchased from Sigma Aldrich, Fischer, or Acros. 2-ethylhexanal (96%) was purchased in small bottles (250 mL) and stored at 4°C with protection from light. Once the bottles were opened, the aldehyde was used immediately. The solvents were used without further purification; particularly, acetonitrile (99.9%, suitable for HPLC) was not dried.

## KOBELCO SMCR® description and experimental setup

The Kobelco SMCR® (Stacked Multi-Channel Reactor) is a multi-structured continuous compact heat-exchanging reactor made up of a stack of 304L stainless steel plates featuring semi-circular channels (ID = 1 mm, L = 6.85 m).<sup>32,33 31,3232,33</sup> Reactive plates alternate with cross-heat-exchanging plates, ensuring intimate and effective thermal control on the reactive side. Distributors and collectors ensure the split of the inlet flow into sixteen parallel reactive channels distributed across four reactive plates, each with four channels and their recombination into the outlet flow. The total effective reactive volume submitted to G/L flow in this pilot demonstrator is 43 mL. The chamber for liquid distribution across the different plates has a volume of 6.5 mL and must be considered for liquid residence time distribution analysis. Some details of the reactor are shown in Figure 1.

<figure><img src="image_2.png" /><figcaption>Figure 1. Kobelco SMCR®: diagram illustrating the arrangement of the parallel channels, liquid and gas distributors (blue and yellow), and collectors (green) and heat-exchange connectors (striped red); cross-sectional image of its semi-circular channels and diffusion bonded interface (right). Reproduced with permission from<sup>32</sup> and<sup>33</sup>.</figcaption></figure>

The experimental setup is shown in Figure 2. The liquid flow supply and control were ensured by Shimadzu LC-20AP HPLC pumps ① (0-150 mL/min), while the gas flow rate was regulated by a Bronkhorst EL-FLOW mass flow meter ② (0-5 NL<sub>O2</sub>/min). A back pressure regulator ③ (Equilibrar LF Research Series, P<sub>max</sub> = 34 barg) was used to maintain a pulsation-free and stable pressure in the reactor. The gas-liquid flow was separated at the outlet using a Zaiput SEP-10 membrane separator ④ (Q<sub>L,total</sub>, max. = 10 mL/min, P<sub>max</sub. = 2 MPa). Oxygen gas was diluted with nitrogen at the reactor outlet, and liquid collection was continuously purged with nitrogen. A refrigerated circulating bath (GRANT LT Ecocool apparatus) ⑤ with a cooling capacity of 385W at 25°C was used to control the reactor temperature with a water liquid flow rate of 1.865 L/min. The temperatures of the reaction mixture ⑥ and heat exchange fluid ⑦ at the inlet and outlet of the reactor were monitored using thermocouples and recorded using LabVIEW®.
Residence time distribution (RTD) measurements and modeling

In this work, the RTD of the liquid phase for the experimental conditions in which the reaction was
carried out was characterized to verify whether the hydrodynamic performance of the entire reactor
aligns with the expected theoretical segmented flow (quasi-ideal plug flow and nearly no-slip velocity
between the gas and liquid phases). This helps confirm the proper operation of the 16 channels in
segmented flow and assesses whether any mal-distribution or changes in flow patterns are present
in one or more channels. Indeed, it will result in a measurable deviation in the RTD curve (either in
mean residence time or in Péclet number). To achieve this, step injections of a tracer were
performed by switching the liquid inlet flow from pure solvent to a tracer solution with a four-way
valve at the same flow rate. At the reactor outlet, the gas and liquid phases were separated, and the
liquid phase was analyzed synchronously to measure the evolution of the tracer concentration over
time. Tracer concentration was measured online using UV-Vis spectrophotometer (UV5bio from
Mettler-Toledo equipped with a quartz cell QS from Hellma Analytics).

The G/L mixture studied is the acetonitrile/O₂ used during alcohol oxidation in the reactive experiments, and MIBK was used as a tracer. The experimental domain covered by the RTD experiments is as follows: Tₐmb; P=2.5 or 5 bar; 20 < QG < 200 NmL/min; QL = 2.5; 3.7; 7.5 and 15 mL/min.

Given that the injection and sampling lines have a non-negligible volume, which may lead to non-
ideal behavior,²¹ their RTD must also be characterized. This allows further treatment of both RTDs to
effectively isolate the reactor's RTD. To achieve this, a bypass configuration was implemented in the
setup, in which liquid and gas phases passed by the same elements from injection to analysis, except
for the reactor itself. These different features of the experimental setup are illustrated in Figure 2.

<figure><img src="image_3.png" /><figcaption>Figure 2. Experimental setup utilized for both RTD characterizations and running reactions. Dashed lines indicate the bypass configuration used for the RTD method.</figcaption></figure>

The modeling of the RTD signals was carried out by regressing the experimental data using the well-
known axial dispersion model,³⁴ which provides the analytical solution presented in Eq. 1. This two-
parameter model accounts for flow non-idealities that create dispersion in a plug flow, such as
velocity gradients, turbulence, molecular diffusivity, *bends*, etc.³⁵
$$E(t) = \frac{1}{2} \left(\frac{Pe}{\pi\tau t}\right)^{\frac{1}{2}} \exp\left[-\frac{Pe(\tau - t)^2}{4\tau t}\right], \quad Pe = \frac{vL}{D_{ax}} \#(Eq. 1)$$

with Pe, Péclet number; τ, mean residence time; v, average flow velocity; L, reactor length and D<sub>ax</sub>, axial dispersion coefficient.

In order to characterize the system's response to our step injections, cumulative F-curves are required. The F-curve definition is recalled in Eq. 2; it is simply the integration of the E-curve over all the residence times.

$$F(t) = \int_{0}^{t} E(\tau) d\tau \#(Eq. 2)$$

Full setup and bypass signals were fitted through a simple and robust least square regression using Eq. 1. For each signal, two parameters characteristic of the encountered hydrodynamic behavior are obtained: the liquid mean residence time (τ) and the liquid Péclet number (Pe). Then, the true RTD of the isolated reactor and its characteristics mean residence time (τ<sub>r</sub>) and le liquid Péclet number (Pe<sub>r</sub>) were derived according to Eq. 3 and 4 linking both signals, their first order moments (τ) and their variance (σ<sup>2</sup>).

$$\tau_r = \tau_{full-setup} - \tau_{by-pass}, \sigma_r^2 = \sigma_{full-setup}^2 - \sigma_{by-pass}^2 \#(Eq. 3)$$

$$Pe_r = \frac{2\tau_r^2}{\sigma_r^2} \#(Eq. 4)$$

## Preparation of the stock solution for the aerobic oxidation of alcohols in flow (0.4 M in acetonitrile)

Freshly prepared Cu(II) complex, [(bipy)Cu(OH)]<sub>2</sub>(OTf)<sub>2</sub>,<sup>36,37</sup> (3.8 g, 5 mmol), was weighed into a 500 mL volumetric flask. Approximately 300 mL of acetonitrile was added, followed by 2,2'-bipyridine (1.56 g, 10 mmol) and NMI (0.82 g, 10 mmol). After solubilisation of the copper complex, the co-oxidant, i.e., TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl (0.31 g, 2mmol) or ABNO (9-azabicyclo[3.3.1]nonane N-oxyl) (56 mg, 0.4 mmol, 0.2mol%), was added, followed by the alcohol (0.2 mol). The volume of the solution was then adjusted to 500 mL with acetonitrile and homogenized. The solution was transferred to a 1000 mL screw-top Schott Duran bottle, connected to the HPLC pump, and continuously purged with N<sub>2</sub>.

## Preparation of the stock solution for the aerobic oxidation of 2-ethylhexanal in flow (neat, 5.6 M)

Sodium 2-ethylhexanoate (21.6 g, 0.13 mol, 8 mol%), manganese(II) cyclohexanebutyrate (8 mg, 0.2 mmol, 0.0125 mol%), and 2-ethylhexanoic acid (12.0 g, 0.08 mol) were weighed in a 500 mL screw-top Schott Duran bottle and mixed. Next, 250 mL of 2-ethylhexanal (205.5 g, 1.60 mol) was added, and the mixture was stirred under N<sub>2</sub> at 30 °C until a homogeneous solution was obtained (5.6 M). The bottle was then connected to the HPLC pump and continuously purged with N<sub>2</sub>.

## Procedure for the aerobic oxidation in Flow with the Kobelco SMCR® (Figure 2)

The Kobelco SMCR® was equilibrated at the requested temperature using a refrigerated heating circulating bath ⑤ while solvent ⑧ was pumped into the reactor, i.e., acetonitrile or EtOH for
alcohols and 2-ethylhexanal oxidation, respectively. The O₂ flow rate was set ②, and the pure solvent was switched to the organic solution ⑨ at the same flow rate. The liquid and gas flow rates, O₂ pressure, and temperature could be independently adjusted. An excess of O₂ was used in all experiments. The temperature of the reaction mixture ⑥ and heat exchange fluid ⑦ at the inlet and outlet of the reactor were recorded using LabVIEW.

At the outlet of the Kobelco SMCR®, the reaction mixture was collected in a 1000 mL screw-top Schott Duran bottle ⑩ and continuously purged with N₂. Samples were taken continuously and analyzed by GC/FID using a Shimadzu GC2030 equipped with an Agilent DB-heavywax column (20 m x 0.1 mm x 0.1 µm). The products were unequivocally identified by their GC retention times, which matched authentic compounds. Conversion and selectivity toward the products were determined based on the normalized peak areas. For the oxidation of 2-ethylhexanal, samples were diluted with ethanol containing hexanoic acid as an external standard. The concentration of peracid ⑦ was determined using methyl p-tolyl sulfide according to the procedure described in our previous works.<sup>38-40</sup>

Before disposal, all the organic phases are tested with QUANTOFIX strips and, if necessary, washed with an excess of aqueous sodium sulfide solution.

# Results and discussion

## Residence time distribution

A typical confrontation of experimental signals, their fittings with the procedure, and the recovery of the true RTD function is given in Figure 3. It illustrates the very good ability of this modelling approach to match the experimental results. The liquid RTD curve E(t) extracted here reflects only the contribution of the reactor.

<figure><img src="image_4.png" /><figcaption>Figure 3. Example of Kobelco SMCR® characterization. Liquid flow rate 2.5 mL/min, gas flow rate 20 NmL/min at 5 bar ($\tau$=530s $Pe$=203)</figcaption></figure>

One characteristic of a regular segmented Taylor flow is its high Péclet number. This is mainly due to the nature of the dispersed bubbles that fill the entire channel cross-section, except for a very thin (and often negligible) lubrication layer of liquid. A high Péclet number ($Pe > 50$) is often assumed as
close to an ideal plug flow. Here, in the selected example, a Péclet number of 203 is obtained, which is consistent with that aspect.

A second characteristic expected with a segmented flow is the quasi-absence of slip velocity between phases. This indicates that both phases have the same theoretical mean residence time in the reactor, and that this can be approximated simply by the ratio of the reactive volume to the sum of the flow rates (Eq. 5).

$$ \tau_{theo} = \frac{V_R}{Q_G + Q_L} \#(Eq. 5) $$

The reactor consists of parallel channels with a known volume ($V_R$), as well as a liquid distributor (Figure 1) with a non-negligible volume ($V_{dis}$). Since the tracer injection was performed upstream of the distributor, the theoretical mean residence time expected in the RTD measurements must account for the additional volume occupied by liquid only. According to this consideration, the no-slip characteristics of segmented flow turn into Eq. 6:

$$ \tau_{theo} = \frac{V_R}{Q_G + Q_L} + \frac{V_{dis}}{Q_L} \#(Eq. 6) $$

The mean liquid residence time $\tau$ of the RTD example illustrated in Figure 3 is 530s. It is close to the theoretical one $\tau_{theo}$ of 532 s obtained thanks to Eq. 6 validating the good agreement of the RTD to the one expected with a regular Taylor flow distributed over 16 channels.

Figure 4a) presents the confrontation of the experimental and theoretical mean residence times obtained in all the RTD experiments. It clearly indicates that the observed mean residence times are those expected for the no-slip velocity hypothesis throughout the tested experimental domain. Figure 4 b) depicts the Péclet numbers obtained in the RTD experiments. Except for one point close to 65, all the Péclet numbers are determined between 100 and 400, indicating little deviation from the ideal plug flow as expected with segmented flows. For a given liquid flow rate, the Péclet number decreases when the gaseous flow rate increases. On the contrary, the Péclet number increases when the liquid flow rate increases for a given gaseous flow rate. These behaviours are expected with segmented flows and are related to the evolution of liquid repartition between wall lubricating film and slugs with flow rates.²⁰

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>
Figure 4. a) Confrontation of experimental mean residence times obtained through RTD measurements with the theoretical ones expected for Taylor flow with the no-slip velocity hypothesis. b) Péclet numbers obtained for the different RTD experiments. Each symbol is related to experiments with the same liquid flow rate and various gaseous flow rates.

Overall, on the whole experimental domain investigated, the RTD experiments teach us that the reactor behaves accordingly to what is expected with segmented flows. If any maldistribution were present, this would have been detected by shortcuts, dead-end, or possibly multimodal RTD curves. Therefore, a very good distribution of the two phases over the 16 reactive channels and work under identical segmented flow conditions in each channel is confirmed, indicating the possibility to scale up by direct numbering up single tube experiments.

## Aerobic oxidation of alcohols

Liquid phase oxidations of alcohols to aldehydes or ketones are useful transformations in organic chemistry.⁵,⁴¹ Well-established techniques like the Swern oxidation⁴² and hypervalent iodide protocols are common for small-scale oxidations.⁴³ However, their applicability diminishes on a larger manufacturing scale due to the necessity of cryogenic conditions and the presence of sensitive intermediates. Even if oxidation is less commonly performed compared to other reactions for the synthesis of active pharmaceutical ingredients (API),⁴⁴,⁴⁵ Parikh-Doering (DMSO-Pyridine-SO₃)⁴⁶ and Anelli-Montanari (TEMPO-NaOCl-CH₂Cl₂)⁴⁷ oxidation protocols provide robust and inexpensive access to these carbonyl compounds. Even if the Anelli-Montanari protocol could be performed with greener solvents⁴⁸,⁴⁹ or in flow,⁴⁸,⁵⁰ efficient green oxidation protocols in flow are needed.⁵

Many attractive protocols have been described for the green liquid phase aerobic oxidation of alcohols.⁵¹⁻⁵⁴ The Cu/nitroxyl-catalyzed protocol developed by Stahl et al.⁵⁵,⁵⁶ was identified as having the best balance between efficiency and sustainability and has been scaled up to 7.4 kg in an 80 L pilot reactor using air bubbling.⁵¹ Total conversion of benzylic primary alcohol was obtained in 32 h using 0.2 eq. of Cu in DMSO at 20°C, resulting in a volumetric productivity of 2.9 g/L<sub>R</sub>/h (Table 1, entry 1). In this case, safety considerations justify this relatively long reaction time. However, the safe implementation of this reaction in flow could enhance productivity. Several protocols for the aerobic oxidation of alcohols in flow have been described.¹¹,⁵¹,²³,²⁴,⁵⁷,⁵⁸ The Stahl protocol has been implemented in flow, and Stahl et al. demonstrated a significant improvement in the reaction time despite using diluted oxygen.²⁴,²⁸ We have shown that this protocol can be safely applied under pressurized O₂ using PFA tubing (i.d. 1.6 mm),³⁷ and we aim to scale up the process with the Kobelco SMCR®. The studies began by comparing the reactivity of primary alcohol, benzyl alcohol, cinnamyl alcohol, and 1-octanol (Figure 5).
<figure><img src="image_7.png" /><figcaption>Figure 5. Aerobic oxidation of primary alcohols to their corresponding aldehydes using the Cu/Bipyridine/NMI/TEMPO catalyst system</figcaption></figure>

Since the mass flow rate of the organic phase (solvent, starting material, and catalytic system) used in the pilot experiments is higher than at the lab scale, reaching up to 10 mL/min compared to 0.16 mL/min,³⁷ the reaction conditions could not be optimized in the Kobelco SMCR® because of excessive reagents and solvent consumption. Thus, the same experimental conditions used at the lab scale were used,³⁷ specifically Cu(II) 5 mol%, bipyridine 10 mol%, NMI 10 mol%, TEMPO 1 mol% in CH₃CN at 25°C and 5 bar of O₂).

Benzyl alcohol **1** and cinnamyl alcohol **3** were selectively converted into the corresponding aldehydes, i.e., benzaldehyde **2** and cinnamaldehyde **4**, in less than 4 min (Figure 6). No exothermicity was detected at the reactor's outlet. As expected from the literature,⁵⁵,⁵⁷,⁵⁶ the reaction proceeds slowly with 1-octanol **5**, resulting in a conversion of less than 60% after 10 min (Figure 6). Under those conditions, an hourly productivity of 20.6 g/h of benzaldehyde **2** could be obtained (Table 1, entry 1). Cinnamaldehyde **4** was found to be less reactive with a lower productivity of 6.5 g/h.

<figure><img src="image_8.png" /><figcaption>Figure 6. Product yield as a function of residence time for oxidation of primary alcohols using Cu(II)/bpy/NMI/TEMPO catalyst system in the Kobelco SMCR®. Experimental conditions: alcohol (0.4M) in acetonitrile; PO₂: 5 bar; Temp.: 25°C; QL: 0.5-10 ccm; QG: 10-200 Nccm; QG/QL: 4.4; F O₂/F alcohol: 2.2; Cu(II) (5 mol %); 2,2'-Bipyridyl (10 mol %); NMI (5 mol%);</figcaption></figure>
TEMPO (1 mol%). Residence times were determined based on the results obtained in the RTD section. The lines in the Figure serve as a guide for the eye.

Under those conditions, total conversion could not be reached for 1-octanol 5. Conversion was below 60% for residence times of up to 8 minutes (Figure 6). For non-activated alcohols, the Taylor flow regime limit has been reached. Total conversion could not be achieved because the Taylor flow regime could not be maintained at lower liquid flow rates, i.e., longer residence time. Next, we attempted to enhance the chemical rate of aerobic oxidation of 1-octanol 5 by increasing the oxygen pressure and temperature (Figure 7). The apparent activation energy, Ea, is determined from the Arrhenius plots within the temperature range of 287–333 K. The least-squares analysis provides an Ea value below 17 kJ/mol, with a minimal effect from the O₂ pressure.

<figure><img src="image_9.png" /><figcaption>Figure 7. Arrhenius plots for the aerobic oxidation of 1-octanol 5 at different O₂ pressures. Experimental conditions: 1-octanol (0.4M) in acetonitrile; Cu(II) (5 mol %); 2,2'-Bipyridyl (10 mol %); NMI (5 mol %); TEMPO (1 mol %); PO₂: 2.5-4-6-7.5 bar; Temp.: 14, 25, 39, and 59.5°C; Q_L: 0.3 ccm; Q_G: 5-20 Nccm; F O₂/F₁-octanol: 2-7.5; Conversion of 1-octanol 5 was below 40% to ensure reliable results; Residence time (τ) ~ 30s; Ln(K_app) = [Ald] / τ</figcaption></figure>

At 60°C, the yield of octanal 6 increased (Figure 8) compared to 25°C (Figure 6), rising from 55% to 95% for a residence time of 6.5 min at 25°C and 60°C, respectively. To obtain a complete conversion, the use of ABNO instead of TEMPO was investigated. As expected from the literature,⁵⁹,⁶⁰ the use of ABNO significantly enhanced the oxidation rate of 1-octanol (Figure 8). With just 0.2 mol% of ABNO, the total conversion of 1-octanol 5 was achieved in 6.5 min at 60°C. Under these conditions, the selectivity towards the corresponding aldehyde, i.e., octanal 6, exceeded 98% with an hourly productivity of 10.3 g/h of octanal 6 (Table 1, entry 11).
<figure><img src="image_10.png" /><figcaption>Figure 8. Octanal 6 yield as a function of time and N-oxide. Experimental conditions: 1-octanol 5 (0.4M) in acetonitrile; PO₂: 5 bar; Temp.: 60°C; Cu(II) (5 mol %); 2,2'-Bipyridyl (10 mol %); NMI (5 mol %); TEMPO (1 mol %) or ABNO (0.2 mol %). Residence times were determined based on the results obtained in the RTD section. The lines in the Figure serve as a guide for the eye.</figcaption></figure>

From these experiments, a comparison can be made between the previously described aerobic oxidation of benzyl alcohol experiments, as shown in Table 1. Since experimental conditions and characterization details of the experimental setup are not directly comparable across publications, we chose to calculate the volumetric productivity, which is the mass of aldehydes produced (kg) per reactor reactive volume ($L_R$) per hour (See Table S1). Such a value can be more informative than yield or residence time and can clearly demonstrate the scalability of the experimental setup.

In our conditions, a volumetric productivity of 0.48 kg/L<sub>R</sub>/h was calculated for benzyl alcohol 1 (Table 1, entry 1). As expected, the volumetric productivity was higher than that in a pilot batch reactor (Table 1, entry 2)⁵¹ and also exceeded the values from lab-scale CFM²⁴,³⁷ (Table 1, entries 3 and 4). This difference cannot be explained and would require further study, particularly regarding the reactivity and stability of the copper (II) complex. Ongoing investigations into copper salts are currently in progress. A higher volumetric productivity could be calculated using the same catalytic system (Table 1, entry 5),²⁸ but at a higher temperature (Figure 7) and with a higher TEMPO loading, which could explain the observed improvement. Other different catalytic systems were compared (Table 1, entries 6 and 7), but yield lower volumetric productivities.²³,²⁹

For 1-octanol 5, a similar improvement in volumetric productivity is observed (Table 1, entries 8 to 10). Increasing the temperature (25 to 60°C) significantly improves conversion (Figure 6 and Figure 8). However, the most significant productivity improvement is achieved by replacing TEMPO with ABNO (Table 1, entry 11). Using ABNO (Figure 8), impressive volumetric productivity can be achieved for this non-activated alcohol up to 10.3 g/h. From these experiments, hourly productivities of 20.6 g/h and 10.3 g/h, for benzaldehyde 2 (Table 1, entry 1) for octanal 6 (Table 1, entry 11), respectively, could be reached under safe conditions using a continuous-flow methodology with MSCR technology.
<table><caption>Table 1. Comparison of the productivity for batch and continuous flow aerobic oxidation of alcohols</caption><thead><tr><th>Entry</th><th>Alcohol</th><th>Catalytic system</th><th>Temp. (°C)</th><th>O<sub>2</sub> (bar)</th><th>Vol. prod. (kg/L<sub>R</sub>/h)<sup>a)</sup></th><th>Ref</th></tr></thead><tbody><tr><td>1</td><td>0.4 M benzyl alcohol 1 in CH<sub>3</sub>CN</td><td>Cu<sup>II</sup> 5 mol% / TEMPO 1 mol%</td><td>25</td><td>5</td><td>0.48</td><td>This work</td></tr><tr><td>2</td><td>1 M heteroarylmethyl alcohol<sup>b)</sup> in DMSO</td><td>Cu 10 mol%/TEMPO 10 mol%</td><td>50</td><td>0.2</td><td>0.002<sup>b) c)</sup></td><td><sup>51</sup></td></tr><tr><td>3</td><td>0.4 M benzyl alcohol 1 in CH<sub>3</sub>CN</td><td>Cu<sup>I</sup> 5 mol% / TEMPO 5 mol%</td><td>100</td><td>3.2<sup>d)</sup></td><td>0.06</td><td><sup>24</sup></td></tr><tr><td>4</td><td>0.4 M benzyl alcohol 1 in CH<sub>3</sub>CN</td><td>Cu<sup>II</sup> 5 mol% / TEMPO 5 mol%</td><td>r.t.</td><td>5</td><td>0.08</td><td><sup>37</sup></td></tr><tr><td>5</td><td>0.4 M benzyl alcohol 1 in CH<sub>3</sub>CN</td><td>Cu<sup>I</sup> 5 mol% / TEMPO 5 mol%</td><td>40</td><td>3.2<sup>d)</sup></td><td>0.87</td><td><sup>28</sup></td></tr><tr><td>6</td><td>0.3 M benzyl alcohol 1 in toluene</td><td>Pd<sup>II</sup> 5 mol % / Pyridine 20 mol%</td><td>100</td><td>1.9<sup>d)</sup></td><td>0.016</td><td><sup>23</sup></td></tr><tr><td>7</td><td>0.06 M benzyl alcohol 1 in AcOH</td><td>Fe<sup>III</sup> 2 mol% / TEMPO 2 mol%</td><td>80</td><td>8</td><td>0.008</td><td><sup>29</sup></td></tr><tr><td>8</td><td>0.4 M 1-octanol in 5 CH<sub>3</sub>CN</td><td>Cu<sup>II</sup> 5 mol% / TEMPO 1 mol%</td><td>60</td><td>5</td><td>0.12</td><td>This work</td></tr><tr><td>9</td><td>0.3 M 1-octanol in 5 CH<sub>3</sub>CN</td><td>Cu<sup>I</sup> 5 mol% / TEMPO 5 mol%</td><td>65</td><td>3.2<sup>d)</sup></td><td>0.03</td><td><sup>28</sup></td></tr><tr><td>10</td><td>0.2 M 1-octanol in 5 CH<sub>3</sub>CN</td><td>Cu<sup>I</sup> 5 mol% / TEMPO 5 mol%</td><td>100</td><td>3.2<sup>d)</sup></td><td>0.0007</td><td><sup>24</sup></td></tr><tr><td>11</td><td>0.4 M 1-octanol in 5 CH<sub>3</sub>CN</td><td>Cu<sup>II</sup> 5 mol% / ABNO 0.2 mol%</td><td>60</td><td>5</td><td>0.24</td><td>This work</td></tr></tbody></table>

<footnote>a) All data were extracted from the publications can be found in the supporting information. b) A heteroarylmethyl alcohol was studied, i.e., 4-fluorobenzothiophen-2-yl)methanol; c) reaction performed in batch; d) calculated O₂ pressure, i.e., air or diluted O₂ in N₂ was used.</footnote>
## Aerobic oxidation of neat aldehyde: a challenging, demanding reaction

Aliphatic carboxylic acids ranging from $C_3$ to $C_{13}$ are industrially obtained by autoxidation (oxidation by air via free radical intermediates) of the corresponding aldehydes. These aldehydes are typically produced from olefins through hydroformylation (oxo-aldehydes).<sup>1,61</sup> Carboxylic acids are typically produced in air-sparged stirred tanks or gas lift bubble column reactors. The oxidation of 2-ethylhexanal **7** to 2-ethylhexanoic acid **8**, one of the acids with the highest production capacity worldwide<sup>61,62</sup> could serve as a test (Figure 9). The neat aerobic oxidation of **7** is highly exothermic ($Δ_rH = -287$ kJ/mol) with an adiabatic temperature rise of 1065 K for neat **7**. Under industrial conditions, gas lift bubble column reactors are preferred over stirred tank reactors because they can be packed with heat transfer tubes, providing a higher heat transfer surface area-to-volume ratio than stirred tank reactors with cooling coils.<sup>63,64</sup> Air, enriched air, or oxygen is introduced at the bottom of the reactors through gas spargers, creating a dispersion of gas bubbles. These reactors face limitations in mass transfer due to the relatively low solubility of $O_2$ in the liquid phase. This situation can be somewhat improved by increasing the overall system pressure, which raises the oxygen partial pressure, or by enhancing mixing, thereby increasing the interfacial area.<sup>65,31</sup> However, these alternatives are generally quite expensive, and regardless of the reactors used, the oxygen partial pressure in the reactor headspace must be maintained below a practical safety limit of 5% to prevent the formation of flammable gas mixtures.<sup>6</sup>

We have successfully demonstrated that the aerobic oxidation of aliphatic acids can be efficiently and safely produced in flow under the Taylor flow regime<sup>66,67</sup> Neat oxidation of 2-ethylhexanal **7** under 7.5 bar of $O_2$ and 10 ppm of Mn(II) as catalyst could be performed with a PFA tubing (Ø 1.65 mm).<sup>67</sup> Under these conditions, a volumetric productivity of 4.1 kg/L<sub>R</sub>/h could be achieved (Table 2, entry 1).

<figure><img src="image_11.png" /><figcaption>Figure 9. Aerobic oxidation of 2-ethylhexanal **7** and the reactive intermediates formed during the reaction. Compounds **3**, **4**, and **7** have been identified, while compounds **5**, **6**, and **8** have been proposed to explain the formation of **2** and by-products as a function of time. See ref.<sup>39,40</sup></figcaption></figure>

The reactor volumetric productivity was shown to be limited by PFA's relatively low heat transfer coefficient. Notably, total vaporization of the liquid phase was observed at high catalyst loadings.<sup>67</sup>
We believe that this rapid and highly exothermic reaction, with the formation of highly reactive intermediates (Figure 9, compounds **9** to **11**), provides a good assessment of the heat and mass transfer capacities of the Kobelco SMCR®. Furthermore, the reaction proceeds through thermally unstable oxygenated compounds (Figure 9, compounds **12** to **14**).³⁹,⁶⁸ We have shown that the uncontrolled decomposition of the latter strongly influenced the selectivity of the reaction,³⁸,⁴⁰ and a large amount of peracids at the reactor outlet can lead to safety problems. In the absence of solvent, a high concentration of aldehyde **7** (5.6 M) is injected into the reactor, thus requiring at least half an equivalent of O₂. Therefore, this reaction can be regarded as a challenging and demanding process (i.e., highly exothermic, high O₂ consumption, fast kinetics, and formation of unstable intermediates and by-products) for evaluating a pilot-scale SMCR.

Again, minimal modifications of the experimental conditions used with the PFA tubing⁶⁷ have been made. A higher concentration of sodium 2-ethylhexanoate, 9 mol% vs. 2 mol%, was used to ensure the lowest concentration of peracid **13** at the reactor outlet.⁴⁰ The handling of a liquid phase, saturated by O₂ and potentially containing significant concentrations of peracid **13** is not recommended from a safety perspective. On the other hand, the amount of catalyst increased from 10 ppm to 125 ppm (0.0125 mol%) due to the higher heat transfer capacity of the SMCR (better conductivity of the wall material and slightly lower hydrodynamic diameter of Kobelco SMCR® channels), which allows better control of the temperature of the reaction medium. The thermal conductivities of PFA and stainless steel are 0.2 and 16 W m⁻¹ K⁻¹, respectively.

The temperature of the heat exchange fluid was set to 30°C. We have already confirmed that, at a lower temperature, the reaction was sluggish.⁶⁷ The organic mixture was injected into the Kobelco SMCR® with O₂, and the temperatures of the different fluids at the inlet and outlet of the reactor were recorded as a function of time (Figure 10).
<figure><img src="image_12.png" /><figcaption>Figure 10. Evolution of the temperature of the different fluids at the inlet and outlet of the Kobelco SMCR® as a function of time on stream. Conditions: 2-ethylhexanal 1 neat (5.6 M); sodium 2-ethylhexanoate 9 mol%; Mn(II): 125 ppm; Q<sub>L</sub>: 12.5 mL/min, Q<sub>G</sub>: 1 NL/min, F<sub>G</sub>/F<sub>L</sub>: 0.58, initial P O<sub>2</sub>: 10 bar, Q<sub>G</sub>/Q<sub>L</sub>: 8.6. Numbers ⑥ and ⑦ refer to Figure 2.</figcaption></figure>

During the first minutes, no exothermicity could be noticed (Figure 10). Post-run analysis of liquid samples confirmed that a low conversion of the aldehyde was obtained. This period corresponds to the typical initiation period of a free radical mechanism. Then, the temperature of the heat exchange fluid at the reactor outlet increases, indicating that aerobic oxidation has begun. The oxidation of neat 2-ethylhexanal **7** to 2-ethylhexanoic acid **8** generates ~370 W at 12.5 mL/min. The maximum temperature of the organic mixture (34°C) at the reactor outlet was reached after 4 min and then stabilized at 32-33°C, demonstrating the high heat dissipation capability of the Kobelco SMCR®. From 3 minutes onwards, a complete conversion of the aldehyde **7** could be determined by GC under those conditions. The selectivity toward carboxylic acid **8** was higher than 98% (Table 2, entry 3), and as expected from the higher concentration of carboxylate, no peracid **13** could be detected.

Under these conditions, a volumetric productivity of 16.1 kg/L<sub>R</sub>/h was achieved using the Kobelco SMCR® and compared with the productivity obtained with the lab-scale PFA tubing (Table 2, entries 1 and 2). Such higher volumetric productivity could be attributed to the higher conductivity of channel materials, which allows a higher catalyst loading compared to PFA tubing,<sup>67</sup> while maintaining selectivity at up to 98%. An hourly productivity of 692 g/h for 2-ethylhexanoic acid **8**, with a selectivity exceeding 98%, could be achieved (Table 2, entry 2). Compared to the oxidation of primary alcohols, this reaction has been less studied. Recently, the aerobic oxidation of **7** has been used to evaluate a lab-scale continuous stirred-tank reactor (CSTR).<sup>28</sup> Using 3 CSTRs in series, a volumetric productivity of 0.28 kg/L<sub>R</sub>/h was achieved (Table 2, entry 3), which is lower than the results obtained in a CFM (Table 2, entry 1),<sup>67</sup> highlighting the challenge of this highly demanding reaction.
<figure><img src="image_13.png" /><figcaption>Table 2. Comparison of the productivity for the continuous flow aerobic oxidation of 2-ethylhexanal</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Catalyst</th><th>Concentration</th><th>Reactive reactor volume (mL)</th><th>Residence time</th><th>Conv./Selec.</th><th>Volumetric productivity</th><th>Ref</th></tr></thead><tbody><tr><td>1</td><td>0.0005 mol% <sup>a)</sup></td><td>5.6 M (neat)</td><td>15</td><td>~ 2 min</td><td>> 99% / 97%</td><td>4.1 kg/L<sub>R</sub>/h</td><td><sup>67</sup></td></tr><tr><td>2</td><td>0.0125 mol% <sup>c)</sup></td><td>5.6 M (neat)</td><td>43</td><td>30 s</td><td>> 99% / 98%</td><td>14.0 kg/L<sub>R</sub>/h</td><td>This work</td></tr><tr><td>3</td><td>0.0001 mol% <sup>d)</sup></td><td>1.5 M</td><td>20 (3 x 6.52)</td><td>13.4 min</td><td>90% / 96%</td><td>0.28 kg/L<sub>R</sub>/h</td><td><sup>31</sup></td></tr></tbody></table>

<footnote>a) PFA tubing; Mn(II) catalyst; sodium 2-ethylhexanoate 2 mol%; reactive reactor volume: 15 mL; Q<sub>L</sub>: 1.25 ccm; Q<sub>G</sub>: 100 Nccm, F<sub>G</sub>/F<sub>L</sub>: 0.58, P O<sub>2</sub>: 7.5 bar, Q<sub>G</sub>/Q<sub>L</sub>: 8.6. b) Kobelco SMRC®; Mn(II) catalyst; sodium 2-ethylhexanoate 9 mol%; reactive reactor volume: 43 mL; Q<sub>L</sub>: 12.5 ccm; Q<sub>G</sub>: 1000 Nccm, F<sub>G</sub>/F<sub>L</sub>: 0.58, P O<sub>2</sub>: 10 bar, Q<sub>G</sub>/Q<sub>L</sub>: 8.6. c) Continuous stirred-tank reactor; Mn(II) catalyst; sodium 2-ethylhexanoate 2 mol%; reactive reactor volume: 20 mL (3 x 6.52); Q<sub>L</sub>: 0.5 ccm; Q<sub>G</sub>: 4.8 Nccm, P O<sub>2</sub>: 1.38 bar.</footnote>
## Conclusion

These experiments demonstrate the capability of continuous flow Stacked Multi-Chanel Reactor (SMCR) technology (total volume of 43 mL, overall footprint of half the size of a standard laboratory fume hood) to perform continuous reactions under explosive conditions safely. Two reactions using O₂ as a cost-effective and readily available green oxidizing agent have been studied. We have demonstrated that the Cu/nitroxyl-catalyzed protocol developed by Stahl³⁷,³⁸ could be safely implemented in a pilot-scale SMCR using pressurized O₂. Benzyl alcohol and 1-octanol (0.4 M in acetonitrile) are quantitatively transformed into the corresponding aldehyde using TEMPO or ABNO, respectively. Under these conditions, hourly productivities of 20.6 g/h and 10.3 g/h for benzaldehyde **2** and octanal **6**, respectively, could be achieved under safe conditions using a continuous-flow methodology with MSCR technology.

The SMCR has also been used for a challenging, demanding reaction, i.e., the neat aerobic oxidation of aliphatic aldehyde into the corresponding carboxylic acid. The reaction is strongly exothermic and generates unstable reactive intermediates that could influence the selectivity. A significant improvement in hourly productivity was demonstrated in lab-scale experiments (CFM⁶⁷ or CSTR³¹). An hourly productivity of 692 g/h for 2-ethylhexanoic acid **8**, with a selectivity exceeding 98%, could be achieved.

In summary, we have successfully implemented aerobic oxidation reactions in a commercially available, milli-structured intensified pilot-scale reactor, taking a step towards reliable, continuous pilot production of liquid-phase oxidation with pure oxygen.

## Safety

Aerobic oxidation could be performed at higher temperatures and concentrations but requires specific experimental setups and skills. It is worth mentioning that in the case of oxidation reactions, fuel, oxidant, and energy are present simultaneously; thus, the safety of the process should receive explicit attention, particularly in the training of personnel working on this type of reaction.⁵⁸,⁵⁹ Liquid-phase aerobic oxidation innately poses the risk of fire and the formation of explosive vapor space, particularly when flammable organic solvents are used.⁶ As such, intensification of this reaction by increasing the reaction volume, the concentration of reactant(s) and catalyst, and the temperature **should not be considered with classical stirred tank reactors.** Furthermore, the formation of peroxides is expected during aerobic oxidations. The bond dissociation energy of the peroxy bond of peroxides is low (ca. 50 kcal mol⁻¹).⁶⁹ As a consequence, peroxides can decompose spontaneously and explosively under thermal or mechanical stress (shock, sparks, ...). All liquid wastes must also be treated with an excess aqueous sodium sulfide solution.

## Author contributions

C. de B., L. V., R. P., and A. F.-R. conceived the study and designed the experiments. B. G. and M. A. D-S performed the experiments and analysed the data. R. P. and A. F.-R. wrote the first draft of the manuscript, and L. V., R. P. and A. F.-R. performed the final editing of the manuscript. The manuscript was written through contributions from all the authors.
**Conflicts of interest**

There are no conflicts to declare.

**Data availability**

The experimental setup details and data supporting this article have been included as part of the SI.

**Acknowledgments**

The authors acknowledge Kobelco for the loan of the Kobelco SMCR®. Frédéric Bornette is recognized for his contributions to the experimental setup and the implementation of safety procedures. Experiments have been conducted in the Flow Chem and Process Intensification CP2M facility located at Axel'One Campus-LyonTech la Doua. (https://axel-one.com/en/service-offering/hosting/axelone-campus/).

This work was supported by the French National Research Agency (ANR) as part of the IRSIS project "Intensified Reactor Structures for Intrinsically Secure processes" (ANR-16-CE07-0008) and "France Relance Program" (ANR-21-PRRD-0064-01). The authors would like to thank the "France Relance Program" (ANR-21-PRRD-0064-01) and Processium for funding Marco Antonio Dos Santos 's PhD thesis.

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