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 (1). 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 (1). However, evidence also supports a one electron oxidation (2).

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

Hyperfine Coupling Constants

These were the constants used to generate the simulated ESR data above in WINSIM. These were found in the raw data output from the geometry optimization of the acetaminophen radical under "Isotropic Fermi Contact Couplings."

Phenoxy (G)
2.04
6.11
5.73
1.71
1.73
1.36

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+)]- H_f(-OH)

ΔH_rxn = (-515.01158420 + -0.08303 Hartree) - (-515.480291398 Hartree)

ΔH_rxn = 0.385677198 Hartree = 1012.59556048 kJ/mol

Citation

1.) Hinson, Jack A., Dean W. Roberts, and Laura P. James. "Mechanisms of Acetaminophen-Induced Liver Necrosis." Handbook of Experimental Pharmacology Adverse Drug Reactions (2009): 369-405. Web.

2.) Potter, David W., Dwight W. Miller, and Jack A. Hinson. "Identification of Acetaminophen Polymerization Products Catalyzed by Horseradish Peroxidase." Journal of Biological Chemistry 260.22 (1985): 12174-2180. Print

This paper has ESR data on the acetaminophen radical

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