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A study of selected water-soluble hydrazyl free radicals



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Numerous diseases that afflict living organisms have been linked to cellular/biomolecular damage caused by reactive nitrogenic and oxygenic species (RNS/ROS). Many RNS/ROS are free radicals. In response, a stable water-soluble free radical able to react with other free radicals could, in theory, act as a free-radical scavenger in vivo and detect, decrease or eliminate harmful free-radical activity. Salts of water-soluble analogs of the well-known free radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl were synthesized as were their progenitor molecules, the corresponding hydrazines. The analogs were produced by replacement of either an ortho or para nitro group (NO₂•) with a sulfo group (SO₃¯), in the trinitrophenyl ring. The compounds have been characterized by ultraviolet-visible light spectroscopy, elemental analysis, nuclear magnetic resonance spectroscopy (the hydrazines), x-ray diffraction studies (the hydrazines), and by electron paramagnetic resonance spectroscopy (the hydrazyls). As well, the compounds were evaluated for neurotoxicity in mice and rats, for anticonvulsant activity (an assessment of the compounds' ability to penetrate the central nervous system), and for antineoplastic activity. Potassium salts of both the ortho and para sulfa-substituted hydrazines and hydrazyls were synthesized. Surprisingly, a para-substituted diphenyl hydrazinium salt was obtained where the protonated (H⁺) form had been the goal. All the synthesized sulfohydrazines were successfully purified, and yielded crystals suitable for examination by x-ray diffraction. The crystal structures of the three sulfo-hydrazine salts are included herein. The salts are all water-soluble; the sulfohydrazyls seem to be somewhat more "water-loving" than the sulfohydrazines. They all are stable in their solid form in air at room temperature. Properly stored in a desiccator and away from light, the solids do not decompose over time. Solutions of the sulfohydrazyl salts dissolved in various solvents, including water, are stable at room temperature for at least two days, as followed by EPR. With few exceptions, the solutions are intensely coloured and range from a red-purple (plum) to a black-purple (violet). In solution, the sulfohydrazyls do not seem to be particularly sensitive to the presence of dioxygen (•O―O•). Interesting pH-dependent reactions of the sulfohydrazyl salts have been seen. Addition of dilute HClO₄ or HNO₃ to aqueous solutions of either the ortho- or para- sulfohydrazyl anion eliminated the EPR absorption. Upon neutralization of the acidic solution by dilute aqueous NaOH, the characteristic EPA absorption of the respective sulfohydrazyl reappeared. On the other hand, addition of dilute NaOH to the sulfohydrazyls in H₂O brought about a similar quenching of the EPR signal but subsequent neutralization of the alkaline solution with acid did not result in the reappearance of the EPR absorption. However, oxidation of the neutralized solution (by MnO₂ and dioxane) did result in an EPR spectrum similar to that observed for the "precursor' sulfohydrazyl in a dioxane/water binary-solvent system. Attempts were made to correlate the solvatochromic Kamlet-Taft β parameter to the effect of water and a series of organic solvents on ¹H NMR parameters of the sulfohydrazine salts and on EPR parameters of the sulfohydrazyl salts. In general, both EPR (i.e., A[¹⁴N]) and NMR (i.e., chemical shift of the hydrazinic proton) parameters studied were relatively insensitive to the H-bonding characteristics of the solvent.





Master of Science (M.Sc.)






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