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. 2006 Sep 15;71(19):7268-79.
doi: 10.1021/jo0610560.

Reactivity of molecular oxygen with ethoxycarbonyl derivatives of tetrathiatriarylmethyl radicals

Shijing Xia  1 , Frederick A Villamena, Christopher M Hadad, Periannan Kuppusamy, Yunbo Li, Hong Zhu, Jay L Zweier
Affiliations

Reactivity of molecular oxygen with ethoxycarbonyl derivatives of tetrathiatriarylmethyl radicals

Shijing Xia et al. J Org Chem. .

Abstract

Tetrathiatriarylmethyl (TAM) radicals are commonly used as oximetry probes for electron paramagnetic resonance imaging applications. In this study, the electronic properties and the thermodynamic preferences for O2 addition to various TAM-type triarylmethyl (trityl) radicals were theoretically investigated. The radicals' stability in the presence of O2 and biological milieu was also experimentally assessed using EPR spectroscopy. Results show that H substitution on the aromatic ring affects the trityl radical's stability (tricarboxylate salt 1-CO2Na > triester 1-CO2Et > diester 2-CO2Et > monoester 3-CO2Et) and may lead to substitution reactions in cellular systems. We propose that this degradation process involves an arylperoxyl radical that can further decompose to alcohol or quinone products. This study demonstrates how computational chemistry can be used as a tool to rationalize radical stability in the redox environment of biological systems and aid in the future design of more biostable trityl radicals.

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Figures

Figure 1
Figure 1
CW X-band EPR spectra of various trityl radicals in DMSO under anaerobic condition. (a) 1-CO2Et; (b) 1-CO2Na (in H2O); (c) 2-CO2Et; (d) 3-CO2Et. See Experimental Section for the EPR parameters.
Figure 2
Figure 2
Spin populations (α−β) and atomic charges (in parentheses) of various trityl radicals at the B3LYP/6-311+G**//B3LYP/6-31G* level in the gas phase using the natural population analysis partitioning scheme.
Figure 3
Figure 3
Product ESI mass spectra of (a) 3-CO2Et and (b) 1-CO2Et; and MALDI-ToF mass fingerprint of (c) 1-CO2Na upon exposure to O2.
Figure 4
Figure 4
Product ESI mass spectra of M residues (trityl cation or anion) of (a) 2-CO2Et and (b) 3-CO2Et decomposition products.
Figure 5
Figure 5
EPR signal intensity of 1-CO2Na (○) and 1-CO2Et (●) in rat H9C2 cardiomyocytes after 1, 2, 3, 4 and 5 hours of incubation and washing using phenol-red-free DMEM medium. (The 2-CO2Et and 3-CO2Et trityl radicals did not show an EPR signal after 1 hr of incubation and washing.)
Scheme 1
Scheme 1. Molecular Oxygen Reaction with Trityl Radicals by Addition to the Center Carbon Atom of the Trityl Radical (A) or by Addition to the Aromatic Ring of the Trityl Radical (B)
Scheme 2
Scheme 2. Proposed mechanism for decomposition of an Unsubstituted Trityl Radical. (a) radical, (b) charged molecule pathways
See this image and copyright information in PMC

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