Amine Nitrosation via NO Reduction of the Polyamine Copper(II) Complex Cu(DAC)²⁺

Abstract

The reaction of the fluorescent macrocyclic ligand 1,8-bis(anthracen-9-ylmethyl)-1,4,8,11-tetraazacyclotetradecane with copper(II) salts leads to formation of the Cu(DAC)2+ cation (I), which is not luminescent. However, when aqueous methanol solutions of I are allowed to react with NO, fluorescence again develops, owing to the formation of the strongly luminescent N-nitrosated ligand DAC-NO (II), which is released from the copper center. This reaction is relatively slow in neutral media, and kinetics studies show it to be first order in the concentrations of NO and base. In these contexts, it is proposed that the amine nitrosation occurs via NO attack at a coordinated amine that has been deprotonated and that this step occurs with concomitant reduction of the Cu(II) to Cu(I). DFT computations at the BP/LACVP* level support these mechanistic arguments. It is further proposed that such nitrosation of electron-rich ligands coordinated to redox-active metal centers is a mechanistic pathway that may find greater generality in the biochemical formation of nitrosothiols and nitrosoamines.

Mechanisms of Nitric Oxide Reactions Mediated by Biologically Relevant Metal Centers

“…A somewhat different mechanism has prove necessary to interpret the reaction of NO with the Cu(II) complex Cu(DAC) 2+ (DAC ¼ 1,8-bis (9-anthracylmethyl)(1,4,8,11-tetraaza-cyclotetradecane or bis(9-anthracylmethyl)-cyclam) [136,137] The rate of the reaction depicted in (19) is relatively slow in neutral aqueous media but is accelerated by base. Kinetic studies show it to be first order in the concentrations of Cu(DAC) 2+ , NO, and OH - [137]. Based on these observations, two mechanisms have been discussed.…”

“…This step would lead directly to amine nitrosation and concomitant reduction of Cu(II) to Cu(I) (Scheme 8). This latter pathway is analogous to electron transfer between metal centers involving a bridging ligand, and DFT calculations suggest that this is the more favorable pathway [137].…”

“…, where L is a bidentate ligand such as dansyl ethylenediamine or dansyl aminomethylpyridine [145], or Cu [137], and an inner sphere mechanism in analogy to Scheme 8 was proposed [147].…”

Reactivity of Inorganic Radicals in Aqueous Solution

“…Reductive nitrosation of coordinated amines to form nitrosamines occurs through the conjugate base of the amine, and this process has been reported for reactions of NO with [Ni(tacn) 2 ] 3 þ , 198 with methylamine coordinated to a macrocyclic Ni(III) complex, 199 with triglycyl complexes of Fe(III), Ni(III), and Cu(III), 200 and with Cu(II) macrocyclic complexes. 201 Reductive nitrosation of [Ru(NH 3 ) 6 ] 3 þ produces [Ru(NH 3 ) 5 N 2 ] 2 þ with base-catalyzed kinetics; the coordinated N 2 is produced by hydrolysis after the nitrosation step. 170 Reductive nitrosylation occurs for several Fe III porphyrins, 145,147,159 where the net reaction is LFe III ðH 2 OÞ þ 2NO !…”

64Cu-Labeled PEGylated Polyethylenimine for Cell Trafficking and Tumor Imaging

“…First, in comparison with other short-lived positron emission tomography (PET) isotopes, 64 Cu-labeled PEI allows longer tracking periods due to its 12.7 h half-life. Second, like other polyamine structures [5,6], PEI forms a stable complex with Cu 2+ and simplifies the labeling procedure. Third, the bioreductive mechanisms responsible for trapping endogenous copper can also be used to retain the 64 Cu-PEI complex in the organ or tissue of interest.…”