3D-printed devices for continuous-flow organic chemistry

Abstract

We present a study in which the versatility of 3D-printing is combined with the processing advantages of flow chemistry for the synthesis of organic compounds. Robust and inexpensive 3D-printed reactionware devices are easily connected using standard fittings resulting in complex, custom-made flow systems, including multiple reactors in a series with in-line, real-time analysis using an ATR-IR flow cell. As a proof of concept, we utilized two types of organic reactions, imine syntheses and imine reductions, to show how different reactor configurations and substrates give different products.

Keywords: 3D printing; flow IR; flow chemistry; imine reduction; imine synthesis; in-line analysis; millifluidics; reactionware.

Figure 1

Schematic representation of the 3D-printed reactionware devices employed in this work showing the internal channels. Both have two inputs (A and B) and one output (C). The main difference consists in the length of the inlets/outlets: the dimension of the inlets/outlets in R1 is 3 mm and in R2 it is 6 mm where the latter is designed to match the size of standard check-valves.

Figure 2

Flow system setup, where a R1 is connected to the syringe pumps and the ATR-IR flow cell with standard connectors.

Figure 3

Carbonyl compounds and primary amines used in the syntheses reported in this work. Carbonyl compounds: benzaldehyde (1a); R-(−)-myrtenal (1b); 3-pentanone (1c). Aniline derivatives: aniline (2a); 3-(trifluoromethyl)aniline (2b); 3-chloroaniline (2c); 3,5-dimethylaniline (2d).

Figure 4

ATR-IR spectra of the synthesis of compounds 3b (on the left) and 3d (on the right). The spectrum on the left shows the reaction that does not go to completion due to the EWG substituent on the meta-position of the primary amine 2b (see Supporting Information File 1).

Figure 5

(a) IR spectra of benzaldehyde at different concentrations. The solvent peak at 1022 cm⁻¹ remains constant while the aldehyde peak at 1704 cm⁻¹ increases with the concentration of benzaldehyde. (b) Calibration curve of the different molar concentrations of benzaldehyde is shown. Equation 1: [benzaldehyde] = −0.432 + 21.56 × A₁₇₀₄ / (A₁₀₂₂ + A₁₇₀₄) and the R² = 0.993.

Figure 6

Comparison of the IR spectra of imine 3a, derived from benzaldehyde (1a) and aniline (2a), synthesized at different flow rates. The conversion of 3a at different flow rates was calculated using the equation of the calibration curve (see Figure 4), and for a flow rate of 0.25 mL min⁻¹ was 97% and at a flow rate of 1.5 mL min⁻¹, 94%.

Figure 7

Representation of the setup for the two-step flow reaction employed in this work. The first reactor (R2’) is used to synthesize the imines under previously optimized conditions. The product is then directly introduced into the next reactor (R2”) and mixed with the reducing agent to produce the secondary amine.

Figure 8

Example of an ATR-IR graph in which an imine spectrum is compared with the reduced imine spectrum.