Density Functional Theory Bond Dissociation Energies of Model Compounds Relevant to LDL Oxidation: Bis-Allylic C–H, Phenolic O–H and Hydroperoxide O–H Bonds
Year: 2026
Type: preprint
Abstract: Background : Oxidative modification of low-density lipoprotein (LDL) contributes to atherogenesis, with polyunsaturated fatty acids (PUFAs) as its main chemical target. Vitamin E is an effective chainbreaking antioxidant in vitro, yet large clinical trials showed no cardiovascular benefit. We calculated bond dissociation energies (BDEs) of model compounds to quantify the underlying thermodynamics. Methods : Density functional theory calculations (PySCF; B3LYP/6-311+G(d,p)//B3LYP/6-31G*, scaled zero-point energy, 0K) were performed for butane, 1,4-pentadiene, phenol, catechol and methyl hydroperoxide. Vitamin E was not calculated at the relaxed level; published values were used. A truncated tocopherol model (5,7,8-trimethylchroman-6-ol) was run at screening level only (B3LYP/6-31+G*, unrelaxed geometries, no zero-point correction), with phenol at the same level. Results : The bis-allylic C–H bond of 1,4-pentadiene (68.2 kcal/mol) was 28.3 below that of butane (96.5). Catechol O–H (73.4) was 8.4 below phenol (81.8). The hydroperoxide model (79.6) fell 2.2 below phenol, opposite to the approximate literature order; the cause was not investigated. In screening calculations the tocopherol model was 9.0 below phenol. Published values place α-tocopherol O–H at about 77 to 78 kcal/mol, about 10 below phenol, the same direction as our screening gap. Computed values were 1.7 to 8.6 kcal/mol below approximate literature values, so gaps and ordering, not absolute values, are interpreted. Conclusions : The calculations quantify the thermodynamic basis for PUFA vulnerability and for the stronger hydrogen donation of polyphenol-type O–H bonds. They do not by themselves show donation to peroxyl radicals. Bond energies cannot explain the clinical trial results; kinetics, LDL localization and tocopherol-mediated peroxidation must be considered. No clinical outcomes or biomarkers were computed.
Source: ChemRxiv
Author: Yadlapalli Anirudh
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7221526033