Synthesis of Sterically Shielded Nitroxides Using the Reaction of Nitrones with Alkynylmagnesium Bromides

Dobrynin, Sergey A.; Gulman, Mark M.; Morozov, Denis A.; Zhurko, Irina F.; Taratayko, Andrey I.; Sotnikova, Yulia S.; Glazachev, Yurii I.; Gatilov, Yuri V.; Kirilyuk, Igor A.

doi:10.3390/molecules27217626

Cited by 4 publications

(32 citation statements)

References 36 publications

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“…Since the parameters of the force field for the nitroxide moiety were not available, the parameters for ketones of the same topology were used, whose geometry and electronic properties are very similar. It should be noted that the most favorable conformations found for 1a and 1c coincide with the conformations obtained from the X-ray analysis data. , …”

Section: Results and Discussionsupporting

confidence: 79%

“…The EPR spectra of some of these nitroxides, e.g., structures 1a – c and 2 (Figure ), reveal one or two large additional doublet splittings with a hyperfine coupling (hfc) constant (ca. 0.2–0.33 mT). ,, Similar spectral features were earlier observed for some cyclic nitroxides with a five-membered saturated ring and bulky substituents adjacent to the N–O· group, i.e., oxazolidine 3 , and imidazolidine 4 nitroxides (Figure ). To the best of our knowledge, a large hfc was never observed in the EPR spectra of conventional tetramethyl nitroxides.…”

Section: Introductionsupporting

confidence: 79%

“…Here, we used trimethylsilyl chloride to protect the hydroxymethyl groups in nitrones 8a− d. The resulting crude nitrones 11 without purification were treated with ethynylmagnesium bromide. Subsequent quenching and oxidation with air oxygen in the alkaline solution of methylene blue in analogy to the previously reported procedure 11 afforded nitroxides 10a and 12a−c. The 1 H NMR spectrum of the 10a sample prepared using TMS protection (see Figure S8, Supporting Information) showed no trace of other isomers and corresponded to the previously published data.…”

Section: ■ Results and Discussionmentioning

confidence: 92%

“…0.38−0.40 mT on a hydrogen atom. 11,15 Complicated hyperfine structure and line broadening in the EPR spectra of sterically shielded nitroxides makes them inefficient in EPRI and OMRI applications, where radicals with a minimal number of narrow lines are required for better resolution and enhancement. 16−18 Broadened spectral lines can also hamper analysis of molecular dynamics using spin labeling and EPR.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Recently, another pattern of the hyperfine structure was described for newly synthesized sterically shielded nitroxides 5 and 6 with only one large splitting of ca. 0.38–0.40 mT on a hydrogen atom. , …”

Section: Introductionmentioning

confidence: 99%

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Origin of Long-Range Hyperfine Couplings in the EPR Spectra of 2,2,5,5-Tetraethylpyrrolidine-1-oxyls

Polienko,

Dobrynin,

Lomanovich

et al. 2023

ACS Omega

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Cyclic nitroxides with several bulky alkyl substituents adjacent to the nitroxide group are known to demonstrate a much higher stability to bioreduction than their tetramethyl analogues. Among these so-called “sterically shielded” nitroxides, the pyrrolidine derivatives are the most stable. The EPR spectra of some sterically shielded pyrrolidine-1-oxyls were reported to show one or two large additional doublet splittings with a hyperfine coupling (hfc) constant (ca. 0.2–0.4 mT). To determine the origin of these hfc, a series of 2-R-2,5,5-triethyl-3,4-bis(hydroxymethyl)-pyrrolidine-1-oxyls with methylene groups stereospecifically enriched with deuterium were prepared, and their CW EPR spectra were studied. In addition, these nitroxides were investigated using quantum chemical calculations on the UB3LYP/def2-TZVP level and NBO analysis. The apparent constants were assigned to hfc with γ-hydrogen in the side chain, with the contribution of the NBO orbital βπ*(N–O) to the natural localized molecular orbital βσ(C–H) playing the major role. This interaction is efficient if the ethyl substituent is in the pseudoaxial position of the ring and the CH2–CH3 bond is codirected with (parallel to) N–O. The apparent constant a H increases with the Boltzmann population of this conformation.

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Section: Results and Discussionsupporting

confidence: 79%

Section: Introductionsupporting

confidence: 79%

Section: ■ Results and Discussionmentioning

confidence: 92%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Origin of Long-Range Hyperfine Couplings in the EPR Spectra of 2,2,5,5-Tetraethylpyrrolidine-1-oxyls

Polienko,

Dobrynin,

Lomanovich

et al. 2023

ACS Omega

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A novel method for the sterically shielded pyrrolidine nitroxides synthesis using donor–acceptor cyclopropanes

Taratayko

Trakhinina

Ломанович

et al. 2023

Tetrahedron Letters

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Hydrophilic Reduction-Resistant Spin Labels of Pyrrolidine and Pyrroline Series from 3,4-Bis-hydroxymethyl-2,2,5,5-tetraethylpyrrolidine-1-oxyl

Usatov,

Dobrynin,

Polienko

et al. 2024

IJMS

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Highly resistant to reduction nitroxides open new opportunities for structural studies of biological macromolecules in their native environment inside living cells and for functional imaging of pH and thiols, enzymatic activity and redox status in living animals. 3,4-Disubstituted nitroxides of 2,2,5,5-tetraethylpyrrolidine and pyrroline series with a functional group for binding to biomolecules and a polar moiety for higher solubility in water and for more rigid attachment via additional coordination to polar sites were designed and synthesized. The EPR spectra, lipophilicities, kinetics of the reduction in ascorbate-containing systems and the decay rates in liver homogenates were measured. The EPR spectra of all 3,4-disubstituted pyrrolidine nitroxides showed additional large splitting on methylene hydrogens of the ethyl groups, while the spectra of similar pyrroline nitroxides were represented with a simple triplet with narrow lines and hyperfine structure of the nitrogen manifolds resolved in oxygen-free conditions. Both pyrrolidine and pyrroline nitroxides demonstrated low rates of reduction with ascorbate, pyrrolidines being a bit more stable than similar pyrrolines. The decay of positively charged nitroxides in the rat liver homogenate was faster than that of neutral and negatively charged radicals, with lipophilicity, rate of reduction with ascorbate and the ring type playing minor role. The EPR spectra of N,N-dimethyl-3,4-bis-(aminomethyl)-2,2,5,5-tetraethylpyrrolidine-1-oxyl showed dependence on pH with pKa = 3, ΔaN = 0.055 mT and ΔaH = 0.075 mT.

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Synthesis of Sterically Shielded Nitroxides Using the Reaction of Nitrones with Alkynylmagnesium Bromides

Cited by 4 publications

References 36 publications

Origin of Long-Range Hyperfine Couplings in the EPR Spectra of 2,2,5,5-Tetraethylpyrrolidine-1-oxyls

Origin of Long-Range Hyperfine Couplings in the EPR Spectra of 2,2,5,5-Tetraethylpyrrolidine-1-oxyls

A novel method for the sterically shielded pyrrolidine nitroxides synthesis using donor–acceptor cyclopropanes

Hydrophilic Reduction-Resistant Spin Labels of Pyrrolidine and Pyrroline Series from 3,4-Bis-hydroxymethyl-2,2,5,5-tetraethylpyrrolidine-1-oxyl

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