Development of Lab-Scale Continuous Stirred-Tank Reactor as Flow Process Tool for Oxidation Reactions Using Molecular Oxygen

The use of sustainable oxidants is of great interest to the chemical industry, considering the importance of oxidation reactions for the manufacturing of chemicals and society’s growing awareness of its environmental impact. Molecular oxygen (O2), with an almost optimal atom efficiency in oxidation reactions, presents one of the most attractive alternatives to common reagents that are not only toxic in most cases but produce stoichiometric amounts of waste that must be treated. However, fire and explosion safety concerns, especially when used in combination with organic solvents, restrict its easy use. Here, we use state-of-the-art 3D printing and experimental feedback to develop a miniature continuous stirred-tank reactor (mini-CSTR) that enables efficient use of O2 as an oxidant in organic chemistry. Outstanding heat dissipation properties, achieved through integrated jacket cooling and a high surface-to-volume ratio, allow for a safe operation of the exothermic oxidation of 2-ethylhexanal, surpassing previously reported product selectivity. Moving well beyond the proof-of-concept stage, we characterize and illustrate the reactor’s potential in the gas–liquid–solid triphasic synthesis of an endoperoxide precursor of antileishmanial agents. The custom-designed magnetic overhead stirring unit provides improved stirring efficiency, facilitating the handling of suspensions and, in combination with the borosilicate gas dispersion plate, leading to an optimized gas–liquid interface. These results underscore the immense potential that lies within the use of mini-CSTR in sustainable chemistry.

. The calculation of the kLa was done using equation 3 (see SI for experimental protocols).Here,  2 * and CL are the saturation concentration of dissolved oxygen and the concentration of dissolved gas in the liquid phase, respectively.

Reactor design
The reactor is a cylindrical block with a dimension of Ø 60 mm×100 mm (170 mm including the stirrer motor) with an inner diameter of the reactor 18 mm and a total volume of 6.52 mL.A total of five ports were drilled perpendicular to the reaction chamber to allow modular combinations of inlets and outlets.All connection ports have ¼-28 threads that can be attached directly to common IDEX fittings (IDEX Health & Science LLC.) without additional adapters, ideal for use with common laboratory equipment.All threads were hand-made after printing to achieve the desired precision.The stirrer motor can be mounted directly on the reactor top with a corresponding adapter.Since the bearings for the stirrer shaft and the impeller were located inside the container, compatible ceramic slide and roller bearings made of zirconium oxide were used.A commercially available mechanical cross PTFE-coated stirrer (Ø 8 mm) was used for mixing.The reactor middle section with the corresponding cooling system was 3D printed (ECOPARTS AG, Hinwil Switzerland) with stainless steel 316 L, having a non-insulating property and satisfying chemical stability.Polyoxymethylene (POM) was used for the reactor bottom and lid, as it is inexpensive and compatible with most solvents/reagents (except strong acids/bases).For constructing the reactor prototype, 3D sketches were created with the computer-aided design (CAD) of NX Siemens.The reactor base and the reactor lid with the overhead stirring system were manufactured by milling due to the simple geometry.Another major element is the gas dispersion system, achieved by installing a porous borosilicate filter plate on the reactor floor.By applying pressure, gas can be dispersed through the plate into the liquid phase.The flexibility of the design allows the user to remove and clean the plate or replace it with a filter of different porosity.By changing the porosity of the plate the bubble size and thus, the gas-liquid interlayer can be affected as well as the probability of pore plugging is reduced when using insoluble fine powders in the reactors, e.g., solid-supported catalysts.
At the time of writing (2023), the material costs for one module are currently amounting to 3'500 CHF: • 3D printed reactor, made of 316L stainless steel 1'500 CHF • overhead stirring unit with magnetic coupling 750 CHF • Joints, stirrer, frits, fittings 750 CHF • Electric control box for stirrer

Procedure to assess the mini-CSTR mixing properties
The measurement of the residence time distribution (RTD) was carried out using the pulse injection method and the setup shown in Figure S1.Deionized water was introduced as carrier liquid using a peristaltic pump and a 10-second pulse injection of Orange II (max = 485 nm) was performed.The tracer was analyzed by offline UV-Vis spectrometry and mean residence time was interpolated using a custom R script.Different stirring speeds (200, 400, 800, and 1200 rpm) were tested at a volumetric rate of 700 L min -1 , as well as different volumetric rates of 0.05, 0.1, 0.4, 0.7, 0.9, 1.2, and 2.0 mL min -1 at 800 rpm were also examined.Table S3.Results of the residence time distribution investigation by varying flow rate qv,liq.

Figure S1 .
Figure S1.Set up for RTD Determination.

Figure
Figure S8. 1 H NMR Spectrum of a sample for O2-oxidation of 2-ethylhexanal.

Figure S9 .
Figure S9.The continuous-flow set-up for endoperoxide synthesis.The number of modules n used in this study ranges between 1 and 3.

Figure
Figure S10. 1 H NMR Spectrum of a sample for endoperoxide synthesis.
The equation describes a statistical model that combines two components: a Gaussian distribution for stochastic phenomena such as molecular diffusion and mixing, and an exponential decay distribution to account for delays, for example, due to mass transfer or reaction kinetics.In this context,  represents the mean residence time,  is the standard variance,  is the standard deviation, and  is the rate parameter of the exponential decay component.This type of function is often used to model an asymmetric distribution, particularly one with a broadening towards the rear (React.Chem.Eng.2016, 1, 501-507).
, −  , −  , −  , Equation S2.In addition to the mass flow rate, ̇, the corresponding temperatures are included, with Th,IN/OUT, and Tc,IN/OUT referring to the inlet (IN) and outlet (OUT) temperatures of the cold (c) and hot (h) fluids.

Table S1 .
Material used for construction of a mini-CSTR module.

accessories to complete the mini-CSTR setupTable S2 .
Accessories that are used in addition to the reactor in the flow setup.

Table S4 .
kLa and  for different gas flow rates qv,g.qv,liq of 0.7 ml min -1 , qv,j = 10 ml min -1 , ϑr,IN = 22 °C.b at 20 °C and 1.01 bar.c time at which 63% of the overall change in CL is achieved.

Table S5 .
kLa and  for different stirring speeds.