Pioneering Enzymatic Halogenation + ChemoCatalysed Cross-Coupling in Flow

The selective formation of carbon halogen bonds (C-Cl, C-Br, C-I, referred to here as a C-X bond) is of great importance to the pharmaceutical and agrochemical industries. The introduction of a halogen into a molecule can be used to modulate bioactivity, bioavailability and metabolic stability. Even more significantly, the carbon halogen bond provides a chemically orthogonal and reactive handle for molecule building. For these reasons, analyses of the top 200 pharmaceuticals reveals that over 90% rely upon chlorine chemistry1 and C-Cl/Br/I formation is estimated as being worth $250B per annum2
A significant manufacturing challenge is that synthetic chemical approaches to halogenation employ highly reactive and toxic reagents: chlorine gas and bromine liquid. Elemental Cl2 are predominantly prepared through high energy processes in China, India, US and Germany 3 while leading Br2 producers are Israel, Jordan and China 4 The halides and often reactive halogenated chemical building blocks are not only hard to handle but subject to fragile and geopolitically challenged supply chains, there would be significant benefit to the UK from an alternative, more robust supply. Furthermore, the use of elemental halides for halogenation of aromatic compounds lacks regioselectivity, mixtures of compounds are generated that require challenging separations. Conversely, biosynthetic (enzymatic) halogenation is mild, highly selective and utilises readily available salts such as NaCl or NH4Br as the source of halide.

Here we will work toward demonstrating enzymatic halogenation in flow in an industry relevant manner.