The integration of organometallic and enzymatic catalysis in one pot is often limited by mutual inhibition between metal complexes and enzymes, particularly in NAD(P)⁺-dependent redox cascades that require efficient cofactor regeneration. Here we report a family of IrCp* pyridinium-amidate (PYA) complexes that regenerate NAD(P)H in aqueous media. Systematic tuning of the pyridinium and phenolate substituents identified Ir4 containing an acetamide substituent at the pyridinium unit as the most active catalyst (turnover frequency TOF = 5.6 h^-1), which reduces both NAD⁺ and NADP⁺ alike, making it compatible with both cofactors. The catalyst was successfully paired with ene-reductase mcOYE and ketoreductase cgKR1. While mcOYE proved intrinsically compatible and supported productive cascades under simple monophasic conditions, cgKR1 showed co-aggregation with the iridium catalyst in aqueous buffer. However, switching to Ir2 and a simple biphasic set-up largely overcame mutual inhibition, raising the regeneration TOF threefold (to 17.6 h^-1) and restoring cascade activity. Computational surface analysis across six oxidoreductases showed that the inhibition is not correlated to any single surface descriptor. This work establishes phase separation as a low-effort strategy for combining molecular transition metal catalysts with enzymes when mutual inhibition in water is stronger than their sensitivity to the liquid–liquid interface.

Great collaboration with Martin’s team, and with our shared PhD student Laura!

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