Green production of 5-hydroxymethylfurfural (HMF) in biphasic continuous microreactor using terpenoid-based solvents

• COSMO-RS simulation identifies carvacrol and carvacrol:thymol as the best solvents for HMF extraction. • Continuous flow production of HMF from glucose using carvacrol as extraction solvent achieved a yield of 55 % in a residence time of 12 min. • Terpenoid-based solvents inhibit the humins formation due to the high affinity by HMF compared to conventional solvents. The synthesis of bio-based molecules from biomass offers a sustainable alternative to petrochemical-derived products. This study explores the continuous production of 5-hydroxymethylfurfural (HMF) from glucose using a biphasic microreactor system catalyzed by Lewis (AlCl 3 ) and Brønsted (HCl) acids. Natural solvents with high affinity for HMF were identified using the COSMO-RS method. Where carvacrol and the natural deep eutectic solvent (NADES, mix of carvacrol:thymol) outperform conventional solvents like MIBK and ethyl acetate in extraction efficiency. Under optimized conditions 160 °C, an organic to aqueous (O/A) volume ratio of 2:1, equimolar catalyst concentrations (AlCl 3 /HCl) of 40 mM, and a residence time of 12 min a maximum HMF yield of 55 mol% was achieved with carvacrol and 52 mol% with carvacrol:thymol, compared to 43 mol% obtained with MIBK, all at similar glucose conversions (∼85 mol%). MALDI-TOF MS analysis demonstrated that terpenoid-based solvents inhibit the formation of humin precursors, enabling selective HMF production. The proposed first-order kinetic model further revealed that the use of carvacrol minimizes the formation of by-products such as formic acid and levulinic acid, enhancing the HMF yield to as high as 65 mol% under optimized conditions but increasing the residence time in 12 min compared to the experimental conditions. Additionally, calculated overall liquid–liquid mass transfer coefficient indicates the absence of significant mass transfer limitations within the studied parameters. These findings highlight the effectiveness of combining terpenoid-based solvents with AlCl 3 /HCl catalysts for sustainable and efficient HMF production.