Rapid Catalyst Screening for Sonogashira Coupling Using H-Cube® Continuous Flow Reactor

ThalesNano’s H-Cube^® can be used to perform reactions other than hydrogenation by utilizing “No H2” mode. In “No H2” mode, the H-Cube^® reactor can perform reactions at temperatures and pressures up to 100 °C and 100 bar, respectively in the absence of a reagent gas. In this application note we will be focusing on Sonogashira chemistry.

Pd-catalyzed Sonogashira coupling is currently the most practical method for synthesizing aryl-(vinyl) acetylenes from the corresponding terminal alkynes and arylhalides. Copper-free modification suppresses the dimerization of the alkynes (Figure 1). Several homogeneous, as well as immobilized catalysts, were developed over the years. Selecting the most appropriate catalyst for a particular coupling reaction often requires time and resources. With their ability to change reaction conditions “on the fly”, continuous flow devices provide a convenient tool for rapid catalyst and parameter screening.

To facilitate the reaction, we applied immobilized catalysts in a fixed-bed flow reactor, the H-Cube®. The H-Cube®system can be utilized for many heterogeneous catalytic reactions including cross-coupling using immobilized transition metal catalysts in prepacked-columns „catalyst cartridges” (CatCarts^®). For mg to g scale operation, 70 mm standard catalyst cartridges are typically applied and we have chosen this size for our current study. The void volume for the 70 mm cartridges is between 0.5-0.8 mL (for 10% Pd/C: 0.669 mL), therefore the estimated residence time at a 0.1 mL/min flow rate is between 5-8 min. We tested 3 polymer-bound catalysts and in addition 10% Pd/C (Table 1.).