Date: 6 August 2024 | Category: News
Multiphase photochemistry in flow mode via an integrated continuous stirred tank reactor (CSTR) approach
Antonella Ilenia Alfano*, Megan Smyth, Scott Wharry, Thomas S. Moody, Manuel Nuño, Chris Butters, and Marcus Baumann*
The Baumann group at University College Dublin have successfully used the Vapourtec photochemical CSTR (continuous stirred tank reactor) to prepare Δ1- and Δ2-pyrazolines through cycloaddition between an alkene and a diazo species generated in situ from a tosylhydrazone, see figure [1, 2]. This method was superior to the batch process, where substantial product degradation through ring contraction to give the cyclopropane was observed.
The use of photochemistry within organic synthesis is a rapidly advancing field, allowing the preparation of molecules that are considered challenging to access using ground state chemistry. Undertaking photochemistry in flow mode rather than batch enables uniform sample irradiation, excellent temperature control, and the opportunity for reaction automation, facilitating rapid scale-up and library generation. However, in some photochemical reactions, such as that in Figure 1, a solid additive is required, which can cause issues in flow mode through solids fouling the reactor.
To overcome this issue, the Baumann group invoked the use of the recently developed photochemical flow CSTR module from Vapourtec. Not only was solid processing facilitated but the researchers could also magnetically stir samples, maintain excellent temperature control, and easily adjust the wattage of the light using the dimmer embedded in the CSTR set-up. Using this approach, a range of tosylhydrazones and acrylates were tolerated with little to no cyclopropane formation observed. At larger scales, a drop in conversion was noted that was attributed to a broadened residence time in the CSTR, which meant that some molecules received much shorter exposure to the light than others. This was easily remedied by connecting another CSTR in series. Scale-up to 10 and 15 mmol scale provided Δ1- and Δ2-pyrazolines in yields of over 95%. Finally, in-line purification through the use of a Zaiput membrane separation [3] ensured that the only downstream processing required was solvent removal.
Dr Baumann said, “The main benefit of the photo-CSTRs is that they are easy to use and are generally applicable, enabling continuous heterogeneous photoreactions that avoid reactor fouling through clogging. Process robustness along with prolonged operation allowed us to access gram-quantities of intricate compounds that are otherwise difficult to obtain. Moreover, the modularity offered by the combination of this CSTR approach with classical continuous flow processing provides an attractive hybrid approach, with many potential applications in both academic and industrial labs.”
[1] Multiphase photochemistry in flow mode via an integrated continuous stirred tank reactor (CSTR) approach (A. I. Alfano, M. Smyth, S. Wharry, T. S. Moody, M. Nuño, C. Butters, and M. Baumann, Chem. Commun., 2024, 60, 7037–7040). https://doi.org/10.1039/d4cc02477j
[2] Photogenerated donor–donor diazo compounds enable facile access to spirocyclopropanes (V. George, and B. König, Chem. Commun., 2023, 59, 11835–11838). https://doi.org/10.1039/D3CC03581F
[3] In-Line Purification: A Key Component to Facilitate Drug Synthesis and Process Development in Medicinal Chemistry (N. Weeranoppanant, and A. Adamo, ACS Med. Chem. Lett., 2020, 11, 1, 9–15). https://doi.org/10.1021/acsmedchemlett.9b00491
