Experience with Scale-Up of Low-Temperature Organometallic Reactions in Continuous Flow

Continuous lithiation of fluoroaromatics has been successfully performed in a microreactor demonstration unit. Since microreactors enable superior temperature control, it was possible to operate at higher temperatures, thus allowing higher space–time yields to be achieved compared to those from batch systems. Selectivities and yields were comparable to those obtained in standard laboratory flow equipment. For stable operation of the lithiation reaction, though, temperature control has been shown to be critical—isothermal operation conditions are not always guaranteed even when using highly effective microreactors, with run-away being observed as a result of a reactor overload, for example. For selection of optimal reaction conditions, various tests and optimizations were performed. The most difficult challenge for organometallic reactions certainly resides in the precipitation of salts. This has to be countered by selection of suitable hardware, careful purification of reactants, and choice of an appropriate operating window.