Computational modeling of substituent effects on phenol toxicity

Area of Science:

• Computational chemistry
• Toxicology
• Structure-activity relationships

Background:

• Quantitative structure-activity relationship (QSAR) models predict phenol cytotoxicity using descriptors like log P and bond dissociation enthalpy (BDE).
• Toxicity is often linked to phenoxyl radical production, with electron-donating groups (EDG) and electron-withdrawing groups (EWG) hypothesized to act via different mechanisms.

Purpose of the Study:

• To investigate the rate constant for phenoxyl radical production in substituted phenols.
• To evaluate the influence of EDG and EWG on toxicity mechanisms.
• To develop a generalized approach for analyzing toxicity data.

Main Methods:

• Utilized the Evans-Polanyi principle to calculate activation energies for X-phenol reactions with peroxyl radicals.
• Determined rate constants as a function of DeltaBDE for both EDG and EWG sets.
• Applied the method to different target radicals and parent compounds.

Main Results:

• A plot of log k (phenoxyl formation) versus DeltaBDE revealed distinct linear relationships for EDG and EWG, supporting their separate analysis without mechanism change.
• The methodology proved effective for various radicals and compound sets, indicating a generalizable approach.
• Predicted regions of constant toxicity were identified across all tested scenarios.

Conclusions:

• The established method provides a unified framework for analyzing phenol toxicity data, justifying the conventional separation of EDG and EWG.
• Competing parallel mechanisms are suggested as dominant for EWG-substituted phenols.
• This approach offers a valuable tool for predicting and understanding chemical toxicity.