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

“…Alternatively, a nucleophilic attack of phenol on the nitrite in {[oCH]Cu II (k 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-coordinationsphere 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. Curiously, GCMS and HRMS analyses on a reaction mixture of 1,2,4-trimethoxybenzene (1,2,4-TMB) with {[oCH]Cu II (k 1 -ONO)}(ClO 4 ) 2 (2H-NO 2 ) at room temperature show the corresponding nitroderivative (7) and oxidatively coupled product (8) of 1,2,4-TMB in detectable but poor yields (Figure 8, Figure S35, and Figure S36).…”

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

“…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). , 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 .…”

“… , 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 . 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.…”

Nitrite and Nitric Oxide Interconversion at Mononuclear Copper(II): Insight into the Role of the Red Copper Site in Denitrification

“…[12,13,16] A majority of the previous studies employing copper(I)nitrite complexes provide insights into the various mechanistic aspects of T2Cu nitrite reductases. [17][18][19][20] Moreover, reduction of nitrite-to-NO at copper(II) model complexes has been illustrated in the presence of various reductants such as thiol, [21,22] phosphine, [23][24][25] phenol, [26][27][28] catechol, [28] ascorbic acid, [29] and hydrazine. [30] In addition, reduction of a formal copper(III)-nitrite by phenol has been reported to follow proton-coupled electron-transfer (PCET) route.…”