Honeycomb reactor: a promising device for streamlining aerobic oxidation under continuous-flow conditions

We report on the high potential of a honeycomb reactor for the use in aerobic oxidation under continuous-flow conditions. The honeycomb reactor is made of porous material with narrow channels separated by porous walls allowing for high density accumulation in the reactor. This structure raised the mixing efficiency of a gas–liquid reaction system, and it effectively accelerated the aerobic oxidation of benzyl alcohols to benzaldehydes under continuous-flow conditions. This reactor is a promising device for streamlining aerobic oxidation with high process safety because it is a closed system.


S1
Contents: S2-10: Experimental procedures S11-12: Supplementary experiment: residence time distribution in the honeycomb reactor S13: Supplementary experiment: evaluation of the reaction rate using the honeycomb reactor without BPR S14: Supplementary experiment: evaluation of the transition of reaction rate using the honeycomb reactor S15: HPLC method for aerobic oxidation S16: 1 H NMR and 13 C NMR spectra of 2a S17: Detailed description of the setup for the honeycomb reactor S18: Author contributions S2 Experimental procedures

General information
Solvents and reagents were purchased from commercial sources and used without further purification.
Benzyl alcohols (1a-h) and authentic samples (2a, 3a and 2b-h) were purchased from Tokyo Chemical Industry Co., Ltd. TEMPO was purchased from Tokyo Chemical Industry Co., Ltd. and Fe(NO 3 ) 3 ·9H 2 O was purchased from FUJIFILM Wako Pure Chemical Corporation. High performance liquid chromatographic (HPLC) analysis was carried out using a Shimadzu LC-2010CHT. 1 H NMR and 13 C NMR were recorded on a Bruker AVANCE ΙΙΙ HD 400 MHz. A batch reaction was conducted using EYELA ChemiStation PPS-1511 with a cross-shaped stirring bar unless otherwise noted. The heat of reaction was evaluated using a Mettler Toledo EasyMax 102 (100 mL). IR spectra were measured using Mettler Toledo ReactIR 702L with a TE-MCT detector connected with a flow cell (DS dicomp micro flow cell, internal volume: 50µL). Differential Scanning Calorimetry (DSC) was carried out using a Mettler Toledo Thermal Analysis System DSC 3+.
A standard tube reactor was purchased from Vapourtec Ltd (Vapourtec standard coiled tubular reactor, inner diameter: 1.0 mm, internal volume: 20 mL (10 mL × 2)). A tube reactor equipped with a static mixer was purchased from Vapourtec Ltd (large diameter tubular reactor for rapid mixing, inner diameter: 3.2 mm, internal volume: 20 mL). A T-shape mixer was purchased from EYELA Co., Ltd. (JTF-310, through hole 1.0 mm). A backpressure regulator (BPR) was purchased from DFC Co. Ltd (FC-BPV1-250). The Flow rates were calibrated manually as follows: the weight of the fed amount was measured for 1 min using AcOH and the measured weight was converted to the volume using the density (pump A). The volume of the fed O 2 gas was collected for 1 min over water, and the measured volume was converted to that under standard conditions (273 K, 1 atm) according to Boyle-Charles law (MFC).

S3
Detailed information for the honeycomb reactor (see also The honeycomb reactor was coated with fluorine-based film for leak prevention (cf. WO2022024748, February 3, 2022.) and was contained in a housing made of stainless steel (see also Figure 3c).

[Cleaning method]
After the use of the honeycomb reactor, the reaction solvent was fed under 8 bar until the remaining O 2 gas was not observed. After feeding the reaction solvent, the BPR was eliminated, and the honeycomb reactor was flushed with inert N 2 gas until the reaction solvent was not observed.

Evaluation of the heat of reaction (Figure 2)
TEMPO (180.9 mg, 1.16 mmol, 0.02 equiv), Fe(NO 3 ) 3 ·9H 2 O (468.0 mg, 1.16 mmol, 0.02 equiv) and AcOH (24.18 g) were mixed in EasyMax 102 (100 mL). The catalyst solution was heated to 80 °C under an O 2 balloon. 4-Methoxybenzyl alcohol (1a) (8.00 g, 57.90 mmol) was added to the catalyst solution for 3 min, and the vessel of 1a was washed with AcOH (1.00 g) (total amount of AcOH: 25.18 g, 24 mL, 3 mL/g), which was added to the reaction solution. The reaction solution was vigorously stirred at 80°C under the O 2 balloon until the exotherm was not detected in EasyMax. After the exotherm was not detected, the reaction solution (10 µL) was sampled and diluted in MeCN/H 2 O (80/20 (v/v), 1 mL). The diluted sample was further diluted 4 times with MeCN/H 2 O (80/20 (v/v)) and analyzed by HPLC, which confirmed the completion of reaction.
The time course of T r -T j was shown in Figure S1, and ΔH R and ΔT ad were calculated from the following formulae. ΔH R was calculated to be 161 kJ/mol, and ΔT ad was calculated to be 138 K (= 161 × 0.05790 / (0.03383 × 2.0)). DSC analysis of the reaction solution did not show any exotherms (Table S1).
The equivalent of O 2 gas was calculated to be 12 equiv (excess amount).
The reaction solution and O 2 gas were mixed by a T-shape mixer (through hole: 1.0 mm), and the slug flow was passed through the standard tube reactor (internal volume: 20 mL) at 80°C for jacket temperature under 8 bar (atmospheric pressure: 1 bar).
After running for 30 min, the obtained reaction solution (100 µL Flow rate of the reaction solution was set as 1.50 mL/min, that of O 2 gas was set as 24.0 mL/min. The equivalent of O 2 gas in each cycle was calculated to be 12 equiv (excess amount).
The reaction solution and O 2 gas were mixed by a T-shape mixer (through hole: 1.0 mm), and the slug flow was passed through the standard tube reactor (internal volume: 20 mL) at 80 °C for jacket temperature under 8 bar (atmospheric pressure: 1 bar).
The obtained reaction solution was stored at 15 °C for 30 min (running time: 10-40 min) (the first cycle).
The stored reaction solution was fed in the similar manner to the first cycle (the second cycle). The obtained reaction solution was stored at 15 °C for 20 min (running time: 10-30 min).
The stored reaction solution was fed in the similar manner to the second cycle (the third cycle). After running 10 min, the obtained reaction solution (100 µL) was sampled and diluted in MeCN/H 2 O (80/20 (v/v), 0.9 mL). The diluted sample was analyzed by HPLC.

(Entry 3)
Entry 3 was conducted using the tube reactor with static mixer (internal volume: 20 mL) in the similar manner to entry 1 using the standard tube reactor.
After running for 50 min, the obtained reaction solution (100 µL (v/v), 0.9 mL). The diluted sample was analyzed by HPLC.
(Entries 5 and 6) Entries 5 and 6 were conducted using the honeycomb reactor (internal volume: 25 mL) in the similar manner to entry 1 using the standard tube reactor.
After running for 90 min, the obtained reaction solution (100 µL) was sampled and diluted in MeCN/H 2 O (80/20 (v/v), 0.9 mL). The diluted sample was analyzed by HPLC.

(Entry 7)
Entry 7 was conducted using the honeycomb reactor (internal volume: 25 mL) in the similar manner to entry 2 using the standard tube reactor.
The obtained reaction solution was stored at 15°C for 70 min (running time: 30-100 min) (the first cycle).
The stored reaction solution was fed in the similar manner to the first cycle (the second cycle
(Standard tube reactor) Flow rate of the reaction solution was set as 0.50 mL/min, that of O 2 gas was set as 8.0 mL/min.
The reaction solution and O 2 gas were mixed by a T-shape mixer (through hole: 1.0 mm), and the slug flow was passed through the standard tube reactor (internal volume: 20 mL) at 80 °C for jacket temperature under 8 bar (atmospheric pressure: 1 bar).
After running for 30 min, the obtained reaction solution (200 mg In the IR measurements, the peak height at 1602 cm −1 (height to two-point baseline: 1636 to 1538 cm -1 ) was measured. The peak height of AcOH at 1602 cm −1 was subtracted from the measured peak height of 2a for the zero-point adjustment. The measured curves obtained from the real time monitoring using ReactIR show the residence time distribution during the flow experiments. These curves were compared to the theoretical one in Figure S2. When the honeycomb reactor was set vertically under 8 bar, the measured curve shifted to the far right in Figure S2 ( Figure S2c), which indicated that this setup could make the most of the internal volume in the honeycomb reactor.
Scheme S1. Flow setup for investigating the residence time distribution. Note that unexpected inclusion of air in the flow cell temporarily disturbed the IR measurement in (b), which was included in the reactor when the flow channel was switched from AcOH to solution of 2a.

S13
Supplementary experiment: evaluation of the reaction rate using the honeycomb reactor without BPR Scheme S2. Flow setup for evaluation of the reaction rate using the honeycomb reactor without BPR. Without BPR, the residence time was shortened due to the increase of the observed volume of O 2 and the solubility of O 2 decreased, leading to the low conversion (Table S2).

S14
Supplementary experiment: evaluation of the transition of reaction rate using the honeycomb reactor Scheme S3. Flow setup for evaluation of the transition of reaction rate using the honeycomb reactor. No reduction in the conversion was observed for 120 min (Table S3). The relative sensitivity coefficients at 254 nm were determined to calculate Conv (%) and summarized in Table S4.

Author contributions
This study was conceptualized and designed by Masahiro Hosoya. The design and assembly for the honeycomb reactor were performed by Yusuke Saito and Yousuke Horiuchi. Data collection and analysis were mainly performed by Masahiro Hosoya. The first draft of the manuscript was written by Masahiro Hosoya, and all the authors commented on the previous versions of the manuscript. All authors read and approved the final manuscript.