Photochemistry and photoredox catalysis have witnessed a remarkable comeback in the last decade. Flow chemistry has been of pivotal importance to alleviate some of the classical obstacles associated with photochemistry. Herein, we analyze some of the most exciting features provided by photo flow chemistry as well as future challenges for the field.
Authors:Evi Habraken, Pieter Haspeslagh, Maarten Vliegen, and Timothy Noël
Deuterated compounds are important in drug discovery and development, e.g., to prepare the so-called stable isotopically labeled internal standards. However, their preparation can be challenging, and its scalability could be difficult with regard to safety aspects. Herein, we report the first continuous-flow iridium(I)-catalyzed ortho-directed hydrogen–deuterium exchange reaction in microreactors. An immobilized iridium(I) catalyst was loaded in continuous-flow microreactors, such as continuous stirred tank reactors and packed-bed reactors. Best results were obtained in a packed-bed reactor allowing deuterium labeling up to M +7.
Authors:Elnaz Shahbazali, Timothy Noël, and Volker Hessel
We converted diverse commercial meta-substituted phenols to the allyl-substituted precursors via nucleophilic substitution using batch technology to allow processing these in microflow by means of the photo-Claisen rearrangement. The latter process is researched on its own, as detailed below, and also prepares the ground for a fully continuous two-step microflow synthesis, as outlined above. It is known that batch processing of electronically deactivated phenols (e.g., bearing a cyano or nitro group) has several orders of magnitude lower reactivity than their parental counterparts . Thus, we here explore if the high quantum yield of microflow, yet at very short residence time, is sufficient to activate the deactivated molecules. In addition, the realization of a true orthogonal two-step flow synthesis can open the door to a large synthetic scope of our approach and possibly overcome limitations due to missing orthogonality of our previously reported thermal approach of combined nucleophilic substitution-Claisen rearrangement in microflow. Consequently, we make for our photo microflow approach an orthogonality check, as previously reported for the thermal approach, and compare both.
To get a broader picture, we have investigated some major parametric sensitivities such as the irradiation intensity, the choice of solvent, the reactant concentration, and, most notably, the influence of the substitution pattern. The irradiation intensity was varied by increasing distance between a lamp and the microflow capillary. In addition, the normal photo-Claisen microflow process (at room temperature) is compared to a high-temperature photo-Claisen microflow process, to check the potential of such novel process window . This is difficult to realize in batch, as the combination of strong ultraviolet (UV) irradiation and high temperature causes a high hazard potential. Yet, under microflow, this can be safely handled.
Authors:Natan Straathof, Dannie Osch, Arian Schouten, Xiao Wang, Jaap Schouten, Volker Hessel, and Timothy Noël
A visible light photocatalytic metal-free perfluoroalkylation method for the functionalization of heteroarenes in continuous flow was developed. Eosin Y was the most efficient photocatalyst with regard to substrate scope, reaction time and cost prize. Faster reaction times were observed in continuous flow compared to batch due to an improved irradiation of the reaction mixture on a microscale. Several pyrroles and indoles were perfluoroalkylated within 30 min residence time (six examples). The trifluoromethylation of pyrroles and indoles was achieved by using a gas–liquid flow with CF3I as a cheap CF3 source (three examples).