To accomplish the desired difluoromethylation reaction, three inlets for substrate, nBuLi and CHF3 are required (Fig. 2 and 3). The reaction commences with a rapid deprotonation of the substrate with nBuLi at sub-ambient temperatures. Mikami and co-workers performed the first reaction step in a batch vessel on a scale of 0.5 mmol at a reaction temperature of −78 °C.18 The reaction time for the deprotonation step was reported to be 5 min.18 Preliminary experiments from our laboratories suggested that the deprotonation step is completed after a reaction time of only 1 min. After the deprotonation step, the reaction mixture needs to be combined with gaseous CHF3. The reaction time for the reaction with CHF3 was also reported to be around one minute at −78 °C.18 Finally, we decided to have a forth inlet for a quench solution near the outlet of the reactor (Fig. 2 and 3). The quench solution (MeOH) stops the reaction and destroys any excess of base before the reaction stream exits the reactor for collection and analysis. Furthermore, batch experiments demonstrated that small amounts of a precipitate are formed during the reaction (probably LiF). The quench solution is also used to re-dissolve the precipitate at the end of the reactor to avoid accumulation at and eventually blockage of the back pressure regulator. Initial test-prints of cylindrical channels with 10 mm length and internal diameters ranging from 0.5 mm to 2.4 mm demonstrated that the SLM process reliably reproduces channels of around 0.6 mm diameter from the initial CAD model (see Fig. S1 and S2 in the ESI†). We opted for channels with an inner diameter of 0.8 mm (outer diameter of 2.4 mm) to facilitate drainage of the remaining powder from the channels after printing and, furthermore, to reduce risks of blockage during difluoromethylation reactions. The reaction channel was designed with a slightly oval cross section. This geometry yields better surface quality on the top surface of the reaction channel by reducing the printing area that overhangs into the metal powder (see Fig. S1 and S2 in the ESI†). With an envisaged throughput of 0.5 mmol min−1 at a concentration of ∼0.5 M and a reaction time of 1 min for each reaction step, channels of 2 meter length at a diameter of 0.8 mm are required for both reaction zones. The reactor was designed with meandering channels, giving a curvature-based mixing geometry (Fig. 3a). Similar two dimensional meandering channels are widely used in commercial microreactors.13,19The zig-zag nature of the channels has been demonstrated to enhance advective mixing by stretching and folding of the flow stream.13 For the reactor presented herein, the meandering channels are drawn onto the cooling element, thus producing the 3-dimensional channel geometry shown in Fig. 3b. The direct attachment of the reaction channel onto the cooling element reduces heat transport distances and facilitates cooling. The cooling element was designed as a single tube in serpentine form with an inner diameter of 7 mm (outer diameter of 9 mm). Standard hose connectors were attached on both ends of the cooling tube to allow simple connection with a circulation cryostat (Fig. 3c and d). The two reaction channels for the substrate (inlet A) and the nBuLi feed (inlet B) are first guided like threads around the tube of the cooling element (pre-cooling zone), before they are brought together in a T-junction. The T-junction is followed by a reaction channel of 0.9 mL volume. A second T-junction then combines the reaction channel with the third inlet channel (inlet C for CHF3). After a second reaction channel of 1 mL residence volume, a third T-junction is integrated to allow the introduction of the quench solution (inlet D). A support structure was incorporated at the bottom of the build (Fig. 3c). The support structure ensures adhesion of the printed components to the build platform and minimizes curling and distortion due to residual welding stresses.
Fig. 3 CAD drawings of the flow reactor. (a) Top view on the reaction channels; the total length of the channel is ∼4 m (1.89 mL reaction volume). (b) Perspective view on the reaction channels. (c and d) the reaction channels are directly attached onto the cooling element. (c) View from below: a support structure was incorporated at the bottom of the build. (d) View from above.
An especially attractive feature of rapid prototyping techniques is that the initial CAD file can be easily shared and digitally inspected by experts in remote locations. The file can form the basis of finite-volume simulations to examine expected mechanical properties or mixing performance. We used computational fluid dynamics (CFD) simulation to evaluate the mixing geometry. The set of governing equations (i.e.Navier–Stokes equations) was solved using the Ansys-CFX software package. Boundary conditions were set to match the anticipated experimental conditions. Thus, for inlet A a flow rate of 0.8 mL min−1 and for inlet B a flow rate of 0.36 mL min−1 was considered (Fig. 4). The simulation was performed as steady-state simulation. Fig. 4shows the contour plots for the flow vorticity (top) and flow streamlines (bottom) at different cut planes along the flow path. From the streamline results, it is seen that the flow is represented by several vortices on each plane, which causes good mixing perpendicular to the main stream direction along the reaction channel. Fig. 4 also presents contour plots of flow vorticity (top) on different cut planes. The vorticity field exhibit two “poles” of opposite oriented vorticity fields. The opposing rotations of fluid in a given cross-section are expected to contribute to the mixing performance.