Scalable Chemoenzymatic Iodination of Waste‐Derived Phenolic Acids Using Pyranose 2‐Oxidase for In Situ H ₂ O ₂ Generation

Sustainable valorization of biomass-derived aromatics is essential for green chemical manufacturing. Palm oil mill effluent (POME), a major agro-industrial wastewater, contains phenolic acids such as p-hydroxybenzoic acid (p-HBA) that inhibit anaerobic digestion but represent valuable chemical feedstocks. Here, we demonstrate a scalable chemoenzymatic platform for selective iodination of p-HBA, vanillic acid (VA), and ferulic acid (FA) using pyranose 2-oxidase (P2O) to generate hydrogen peroxide in situ under mild aqueous conditions. Buffer screening revealed that tris(hydroxymethyl)aminomethane hydrochloride, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, and sodium phosphate best promoted monoodination of p-HBA, VA, and FA, respectively. Compared to direct H₂O₂ addition, P2O-mediated oxidant supply improved selectivity for 3-iodo-p-HBA (3-IHBA) (15% vs. 21%), suppressed di-iodination, and prevented oxidative coupling of FA. Liter-scale reactions retained small-scale efficiency, achieving >99% conversion and 93% yield for VA, and 89% conversion with 88% yield for FA. Moreover, direct conversion of POME-derived p-HBA yielded 3-IHBA (19%), confirming compatibility with real wastewater matrices. This work establishes P2O-driven iodination as a mild, selective, and scalable route for synthesizing iodinated aromatics from waste-derived phenolics, providing a green alternative to conventional halogenation and advancing sustainable biorefinery development.