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
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 chain-breaking 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, 0 K) were performed for butane (secondary C–H), 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 the secondary C–H bond 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, whereas experimental values place the two within about 1 kcal/mol, comparable to their uncertainties, so phenol is a weak test of the order; catechol was 6.2 below the hydroperoxide, as expected. 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. For the four bonds with experimental references, computed values were 1.7 to 8.6 kcal/mol below them; no direct experimental value exists for the bis-allylic C–H. Gaps and ordering, not absolute values, are therefore 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.
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BibTeX
@misc{anirudh2026density,
title = {{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}},
author = {Yadlapalli Anirudh and Anirudh yadlapalli},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010181/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010181/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - 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
AU - Yadlapalli Anirudh
AU - Anirudh yadlapalli
PY - 2026
DA - 2026/10/09
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010181/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010181/v1
AB - 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 chain-breaking 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, 0 K) were performed for butane (secondary C–H), 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 the secondary C–H bond 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, whereas experimental values place the two within about 1 kcal/mol, comparable to their uncertainties, so phenol is a weak test of the order; catechol was 6.2 below the hydroperoxide, as expected. 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. For the four bonds with experimental references, computed values were 1.7 to 8.6 kcal/mol below them; no direct experimental value exists for the bis-allylic C–H. Gaps and ordering, not absolute values, are therefore 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.
ER -