Synthesis and spin-trapping properties of a trifluoromethyl analogue of DMPO: 5-methyl-5-trifluoromethyl-1-pyrroline N-oxide (5-TFDMPO).

The 5-diethoxyphosphonyl-5-methyl-1-pyrroline N-oxide superoxide spin adduct (DEPMPO-OOH) is much more persistent (about 15 times) than the 5,5-dimethyl-1-pyrroline N-oxide superoxide spin adduct (DMPO-OOH). The diethoxyphosphonyl group is bulkier than the methyl group and its electron-withdrawing effect is much stronger. These two factors could play a role in explaining the different half-lifetimes of DMPO-OOH and DEPMPO-OOH. The trifluoromethyl and the diethoxyphosphonyl groups show similar electron-withdrawing effects but have different sizes. We have thus synthesized and studied 5-methyl-5-trifluoromethyl-1-pyrroline N-oxide (5-TFDMPO), a new trifluoromethyl analogue of DMPO, to compare its spin-trapping performance with those of DMPO and DEPMPO. 5-TFDMPO was prepared in a five-step sequence by means of the Zn/AcOH reductive cyclization of 5,5,5-trifluoro-4-methyl-4-nitropentanal, and the geometry of the molecule was estimated by using DFT calculations. The spin-trapping properties were investigated both in toluene and in aqueous buffer solutions for oxygen-, sulfur-, and carbon-centered radicals. All the spin adducts exhibit slightly different fluorine hyperfine coupling constants, thereby suggesting a hindered rotation of the trifluoromethyl group, which was confirmed by variable-temperature EPR studies and DFT calculations. In phosphate buffer at pH 7.4, the half-life of 5-TFDMPOOOH is about three times shorter than for DEPMPO-OOH and five times longer than for DMPO-OOH. Our results suggest that the stabilization of the superoxide adducts comes from a delicate balance between steric, electronic, and hydrogen-bonding effects that involve the ß group, the hydroperoxyl moiety, and the nitroxide.

Synthesis of a New Spin Trap: 2-(Diethoxyphosphoryl)-2-phenyl-3,4-dihydro-2H-pyrrole 1-Oxide.

Recently, the synthesis of a new phosphorylated nitrone, 2-(diethoxyphosphoryl)-2-methyl-3,4-dihydro-2H-pyrrole 1-oxide (DEPMPO) (2) was described. The presence of the phosphorylated group strongly stabilized the DEPMPO-superoxide spin adduct. To understand the role of the diethoxyphosphoryl group in this stabilization, a new phosphorylated nitrone, 2-(diethoxyphosphoryl)-2-phenyl-3,4-dihydro-2H-pyrrole 1-oxide (DEPPPO) (7), was prepared through a four-step synthetic pathway, and its ability to trap free radicals was investigated. Data obtained from spin trapping experiments of a wide variety of free radicals generated in situ showed the formation of two diastereoisomers spin adducts with different phosphorus and hydrogen coupling constants. Superoxide trapping by DEPPPO gave a persistent nitroxide spin adduct, and its half-time life was measured and compared to that of the DEPMPO analogue.