Nitrite-Phenol-NO Crosstalk: Phenol Oxidation and NO Generation from Nitrite at Copper(II) Sites

Abstract

Nitrite is involved in a plethora of biological phenomena that includes tyrosine nitration associated with neurodegenerative disorders and gastric phenol metabolism. Reaction of the b-diketiminato model complex [Cl<sub>2</sub>NN<sub>F6</sub>]Cu(k<sup>2</sup>-O<sub>2</sub>N) with phenols outlines the coupled generation of NO with phenol oxidation by nitrite at copper(II). Kinetic studies support nucleophilic attack of the hydroxyl group of phenols ArOH on the bound nitrite in [Cu<sup>II</sup>](k<sup>2</sup>-O<sub>2</sub>N) to give the copper(II) hydroxide [Cu<sup>II</sup>]-OH along with the <i>O-</i>nitrosated phenol ArONO that ultimately leads to the corresponding biphenol or <i>o</i>-nitrophenol. The especially electron-rich antioxidant a-tocapherol (vitamin E) quickly generates NO upon interaction with [Cu<sup>II</sup>](k<sup>2</sup>-O<sub>2</sub>N). X-ray analysis of the oxidation products of the a-tocapherol analogue PMC reveal formation of an elusive <i>O</i>-quinone methide bound to [Cu<sup>I</sup>], revealing two electron oxidation of PMC by [Cu<sup>II</sup>](k<sup>2</sup>-O<sub>2</sub>N). These studies illustrate anaerobic pathways that generate NO from nitrite at copper(II) sites that result in phenol oxidation.

A Copper(II)‐Nitrite Complex Hydrogen‐Bonded to a Protonated Amine in the Second‐Coordination‐Sphere

“…As illustrated by the DFT calculations, however, the protonation of nitrite anion by a weakly acidic 3° ammonium (p K a ∼9.8) can be ruled out under our reaction conditions. Alternatively, a nucleophilic attack of phenol on the nitrite in {[ oC H]Cu II ( κ 1 ‐ONO)} 2+ ( 2H‐NO 2 ) may provide nitrophenol through the intermediacy of an O ‐nitrite derivative of phenol [38,42,70] . Yet another route, as proposed in the previous report, [42] the complex with protonated second‐coordination‐sphere may facilitate a primary electron‐transfer (ET) from phenol (ArOH) to yield a transient [ArOH] .+ intermediate, which undergoes nucleophilic attack by nitrite anion to yield nitrophenol in addition to a competitive decomposition of [ArOH] .+ leading to the oxidative coupling of phenol.…”

NO Generation from the Cross-Talks between Ene-diol Antioxidants and Nitrite at Metal Sites

“…49 Notably, an analogous nucleophilic pathway has been previously considered for the NO releasing reactions of Cu II -nitrite complexes with substituted phenols. 27 However, complexes 1, 2, and 4 do not react with 2,4-di-tert-butyl phenol under our reaction conditions which may be attributed to lower nucleophilicity of phenol as compared to catechol.…”

“…Oxygen-atom-transfer-mediated transformation of cobalt-nitrite to cobalt-nitrosyl has been depicted recently in the presence of strong oxophilic VCl 3 . The previous illustrations of chemical reductions of nitrite typically employ exogenous reducing agents such as thiols, phosphines, H 2 S, phenols, and catechol. − However, the insights into ene-diol-mediated nitrite reduction remain in its infancy. − Herein, this report employs mononuclear cobalt­(III)- and cobalt­(II)-nitrite complexes ( 1 and 2 ) of a tripodal ligand Bz 3 Tren to illustrate NO generation from the cross-talks between nitrite and ene-diols such as l -ascorbic acid (AH 2 ), gallic acid (GAH 2 ), and 3,5-di- tert -butylcatechol (DTBC) (Scheme ). Notably, AH 2 -mediated 1e – /2H + transformation of NO 2 – to NO at the [Co III ] site (in 1 ) results in DHA.…”

Involvement of a Formally Copper(III) Nitrite Complex in Proton-Coupled Electron Transfer and Nitration of Phenols

“…The O-nitrosated DTBP would then release NO and the phenoxyl radical of DTBP, which could then combine to form 2,4-di-tert-butyl-6-nitrophenol. 71 The stoichiometry experiments do not support this nitration mechanism because it does not use more than 1 equiv of LCuNO 2 to nitrate the phenol. However, we cannot rule out nucleophilic attack of the phenol on LCuNO 2 to form the phenoxyl radical of DTBP, which then could react with another 1 equiv of LCuNO 2 via the "rebound" mechanism.…”

“…LCuNO 2 could be involved in generation of the phenoxyl radical of DTBP via a nucleophilic attack of the phenol on the nitrite ligand of LCuNO 2 , as previously seen for a Cu II -NO 2 compound (Scheme S2). 66,71 The products of the nucleophilic attack would be O-nitrosated DTBP and LCu III OH, which would react with another 1 equiv of DTBP to form bisphenol. The O-nitrosated DTBP would then release NO and the phenoxyl radical of DTBP, which could then combine to form 2,4-di-tert-butyl-6-nitrophenol.…”