One-Pot Depolymerization, Demethylation, and Phenolation of Lignin for Bioactive Polyphenol Production

Lignin is an abundant, renewable biopolymer, but its structural complexity and low reactivity have hindered its effective valorization. Herein, we report an integrated strategy combining depolymerization, demethylation, and phenolation of lignin in an acidic lithium bromide molten salt hydrate system. Spectroscopic analyses (FTIR, ¹H NMR, and 2D-HSQC NMR) confirmed efficient cleavage of major ether linkages, yielding structurally simplified lignin derivatives with enhanced functionalities. Demethylation increased phenolic hydroxyl (Ar-OH) content by 1.36-2.49 mmol/g, while subsequent phenolation further elevated Ar-OH levels to 6.77-7.71 mmol/g, more than doubling those of native lignin. These structural changes translated into enhanced bioactivity: The modified lignins exhibited strong antioxidant activity (>90% DPPH⋅ scavenging), high antimicrobial efficacy (>87% bacterial inhibition), and favorable safety profiles (IC₅₀  > 80 mg/L). In vivo feeding trials demonstrated that the modified lignins significantly improved growth performance and provided robust antiviral protection in mice. Overall, this integrated strategy enables efficient conversion of technical lignin into high-value bioactive polyphenols with performance comparable to or exceeding commercial tannins, while retaining clear economic advantages, highlighting their potential for sustainable applications in feed additives, cosmeceuticals, and nutraceuticals.