Spatiotemporal Dual-Catalysis Driving Sustained Radical Evolution for Tetramethylpyrazine Synthesis Under Mild Conditions

Abstract Efficient synthesis of tetramethylpyrazine (TMP) under mild conditions remains a challenge in green catalytic engineering. Herein, a ternary synergistic catalytic system is constructed to achieve highly efficient TMP production. The system achieves sustained generation of hydroxyl radicals (·OH) via epigallocatechin gallate (EGCG)-mediated Fe(III)/Fe(II) redox cycling and the weakly acidic condition provided by slightly acidic electrolyzed water (SAEW). Notably, tert-butanol (TBA) quenching inhibited TMP production by 85.49% at 10 min, confirming ·OH as the dominant reactive species initially. Density functional theory (DFT) calculations show that ·OH-driven acetoin oxidation proceeds with an exceptionally low activation barrier, predominantly yielding 2,3-butanedione via hydrogen abstraction. Multispectroscopic analyses suggested that ·OH-mediated radical pathways involved not only acetoin oxidation but potentially also the key dehydrogenation step during TMP formation from dihydropyrazine. In summary, the ternary system not only achieved a TMP yield of 16.97 g/L (240 min) but also improved the crystal morphology. This work establishes a radical-regulated oxidation–condensation coupling mechanism, which provides a green and efficient catalytic strategy for the synthesis of high-value N-heterocycles under mild conditions and shows considerable potential for scalable chemical manufacturing.