Reductive cross-coupling/cross-electrophile coupling reactions are powerful synthetic tools which have gained significant attention with the development of Ni-catalysed processes (Fig. 1a). Many of these happens through single electron transfers (SETs) and radical intermediates, which enable access to different reactivity to those of traditional Pd-catalysed coupling reactions, e.g. coupling with sp3 partners with retention of stereochemistry. Their main drawback, which restricts scaled-up processes, is the need for stoichiometric reductant, e.g. Zn and Mn, and subsequent problems associated with cost and waste. Organic reductants, such as PPh3, tetra(dimethylamino)ethylene (TDAE) and HNiPr2, have been shown to work on lab-scale, although their recycling has not been explored in the literature. Scaling up reactions using Zn or zinc reagents remains difficult.

Electrochemical methods present a possible solution to this problem. The reductant with finely tuned redox potential may be electrochemical recycled in situ, changing its role to a redox mediator. Alternatively, Ni-intermediates may undergo SET directly at the electrodes, bypassing the reductant altogether. A sacrificial reductant is still needed on the opposite electrode, but these allow significant flexibility in its redox potential. Some early successes with organic reductants have been reported, but process understanding and development in this area has yet to be taken up by the wider community.

In this project, we aim to develop electrochemical flow processes to enable Ni-catalysed reductive coupling reactions and to generate the required process understanding for their further development. This will be achieved through the following objectives:
O1: Development of electrochemical recycling processes for inorganic and organic reductants, e.g. TDEA.
O2: Exploration of sacrificial reductant on anode and flow reactor designs.
O3: Development of Ni-catalysed reductive decarboxylative cross coupling with electrochemical flow reactors (EFRs).

O1 and O2 will directly address the various aspects of process development of Ni-catalysed reductive cross coupling and enable the use of redox mediators, which have been successfully employed in oxidative electrochemical processes by Stahl and co-workers. O3 is aimed at applying the process understanding gained in O1 and O2 to completely circumvent the need for a reductant by substituting it with the readily available carboxylate coupling partner. This is currently feasible with photochemistry, but a flow electrochemical process will be easier to control and more energy efficient.

The project will take advantage of the expertise in EFRs (Bao Nguyen - BN, Charlotte Willans - CEW, Nikil Kapur - NK), catalysis (BN, CEW), electrochemical activation of zinc (BN), alternating polarity (AP) developed in the iPRD (NK), and the self-optimised electrochemical flow platform (CEW, NK) at Leeds. It will deliver the following: (i) in-depth understanding of the redox chemistry and recycling possibility of a wide range of reductants for reductive cross-coupling; (ii) EFRs and process designs for Ni-catalysed reductive coupling reactions; (iii) electrode kinetics and understanding of the influence of electrode material, solvent, voltage and current density, and (iv) electrochemical flow decarboxylative coupling reactions with Ni-catalysts.