Acetaminophen Radicals

The Ab-initio computation of the acetaminophen radical. The goal of this project is to elucidate where electrons are located on the molecule when a radicalization occurs.

Background

Acetaminophen(APAP) is an active ingredient in many over-the-counter and prescription painkillers, such as Tylenol and Oxycodone. APAP is also responsible for approximately 50% of the cases of acute liver-failure in the United States and Great Britain. Treatments for acetaminophen-induced liver injury(AILI) are limited. The current mechanism for AILI is the production of hepatotoxic NAPQI as a metabolite in an enzymatic, two-electron oxidation. However, evidence also supports a one electron oxidation.

Web MO/Gaussian

Web MO/Gaussian is a software containing various basis sets that allow for various levels of computational chemistry.

B3YLP/6-311+G(2d,p)

After running a calculation on Web MO/Gaussian, the following results were reported.

Results of a geometry optimization of the radicalized acetaminophen ran using B3YLP/6-311+G(2d,p) basis set

This molecule is an acetaminophen radical. The hydrogen bond was eliminated off of the phenoxy.

Electron Density map: the green/blue areas are the electron dense areas; the electrons spend the most time here

WINSIM ESR simulation showing the evidence of a radical on the molecule

Analysis

Radical Location

As seen on the electron density map above, the radical spends a lot of time at the ortho positions. To aid with this, the possible resonance structures are shown below.

Knowing this information is important because it helps with predicting which dimer products will form. Certain dimers may be biologically active, which could play a role in hepatotoxicity.

ΔH_f Calculations

Below are the calculations of the ΔH_f for the formation of a radical of the phenoxyl in acetaminophen. The values listed in Hartree were found doing geometry optimizations using B3LYP/6-311+G(2d,p) basis sets.

ΔH_rxn = ΔH_f(Products) - ΔH_f(Reactants)

ΔH_rxn = ΔH_f(-OH•) - H_f(-OH)

ΔH_rxn = (-515.01158420 Hartree) - (-515.480291398 Hartree)

ΔH_rxn = 0.468707198 Hartree = 1230.59084209 kJ/mol

Cites

https://ehp.niehs.nih.gov/doi/pdf/10.1289/ehp.8564127