Hybrid quantum-mechanistic insights into β-O-4 ether cleavage in lignin-carbohydrate complexes using a choline...

Lignin-carbohydrate complexes (LCCs) contribute to biomass recalcitrance, making β-O-4 ether linkages important targets for selective lignin depolymerization. β-O-4 cleavage in a representative LCC was studied using a hybrid quantum-mechanical/semiempirical (QM/xTB) approach, an explicit choline chloride/lactic acid (ChCl : LA) cluster, and M06-2X/6-31+G(2d,2p) refinement. Vacuum calculations were compared with C-PCM water (ε = 78), which was used as a high-polarity reference and upper-bound estimate of dielectric stabilization rather than as a representation of bulk deep eutectic solvent microstructure. Frontier-orbital, Fukui-function, and Hirshfeld-charge analyses identify C43 as the electrophilic center for chloride attack and O28 as the leaving-group atom, while revealing progressive electron-density loss from chloride. The optimized transition state (TS) supports a concerted S_N2-like mechanism in which chloride attacks C43 as the O28-C43 bond elongates from 1.43 to 2.25 Å. Thermochemically corrected stationary-point calculations at 298.15 K give Gibbs activation energies of 93.2 kJ mol^-1 for the isolated explicit cluster and 75.8 kJ mol^-1 with a C-PCM water dielectric, indicating a 17.5 kJ mol^-1 sensitivity to high-dielectric screening. Decomposition of these barriers yielded optimized electronic activation energies of 121.0 and 119.7 kJ mol^-1 for the isolated and dielectric-embedded clusters, whereas thermochemical corrections accounted for most of the predicted reduction and highlighted the substantial contribution of thermal and entropic terms to the model-dependent free-energy estimates. This study provides a descriptor-based mechanistic rationale for β-O-4 cleavage in an explicit ChCl interaction model and clarifies how local chloride coordination and lactic-acid hydrogen-bonding contacts can promote β-O-4 bond activation, providing a mechanistic framework for designing greener solvents for selective biomass fractionation.