Difference between revisions of "Acetaminophen Radicals"
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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. | 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== | ==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. | + | 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== | ||
Web MO/Gaussian is a software containing various basis sets that allow for various levels of computational chemistry. | Web MO/Gaussian is a software containing various basis sets that allow for various levels of computational chemistry. | ||
| + | |||
===B3YLP/6-311+G(2d,p)=== | ===B3YLP/6-311+G(2d,p)=== | ||
| − | [[File:Pchem_APAP_WINSIM.png|400px | + | After running a calculation on Web MO/Gaussian, the following results were reported. |
| + | {| | ||
| + | |[[File:Screen Shot 2021-04-15 at 3.30.26 PM.png|400px|thumb|left|Results of a geometry optimization of the radicalized acetaminophen ran using B3YLP/6-311+G(2d,p) basis set]] | ||
| + | |- | ||
| + | |[[File:APAP_Rad.png|400px|thumb|left|This molecule is an acetaminophen radical. The hydrogen bond was eliminated off of the phenoxy.]] | ||
| + | |- | ||
| + | |[[File:WEBMO_electronDensity.png|400px|thumb|left|Electron Density map: the green/blue areas are the electron dense areas; the electrons spend the most time here]] | ||
| + | |- | ||
| + | |[[File:Pchem_APAP_WINSIM.png|400px|WINSIM ESR Simulation|thumb|left|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." | ||
| + | |||
| + | {| class="wikitable" | ||
| + | |- | ||
| + | ! 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. | ||
| + | |||
| + | [[File:Screen Shot 2021-04-15 at 4.11.10 PM.png|400px]] | ||
| + | |||
| + | 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<sub>f</sub> Calculations=== | ||
| + | Below are the calculations of the ΔH<sub>f</sub> 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<sub>rxn</sub> = ΔH<sub>f</sub>(Products) - ΔH<sub>f</sub>(Reactants) | ||
| + | :ΔH<sub>rxn</sub> = ΔH<sub>f</sub>[(-OH•) + (H+)]- H<sub>f</sub>(-OH) | ||
| + | :ΔH<sub>rxn</sub> = (-515.01158420 + -0.08303 Hartree) - (-515.480291398 Hartree) | ||
| + | :ΔH<sub>rxn</sub> = 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 | ||
Latest revision as of 15:35, 16 April 2021
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.
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.
ΔHf Calculations
Below are the calculations of the ΔHf 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.
- ΔHrxn = ΔHf(Products) - ΔHf(Reactants)
- ΔHrxn = ΔHf[(-OH•) + (H+)]- Hf(-OH)
- ΔHrxn = (-515.01158420 + -0.08303 Hartree) - (-515.480291398 Hartree)
- ΔHrxn = 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