Nickel(ii)–flavonolate complexes of tetradentate 4N donor ligands as enzyme–substrate models of quercetin-2,4-dioxygenase: the effect of ligand steric and electronic properties on dioxygenolysis

Abstract

Four new flavonolate-bound nickel(II) complexes of piperidine appended tetradentate 4N donor ligands of the type [Ni(L^H–L^Br)(fla)]ClO₄ 1–4, where L^H = 2-(piperidin-1-yl)-N,N-bis(pyridin-2-ylmethyl)ethan-1-amine, L^Me = N,N-bis((6-methylpyridin-2-yl)methyl)-2-(piperidin-1-yl)ethan-1-amine, L^OMe = N,N-bis((6-methoxypyridin-2-yl)methyl)-2-(piperidin-1-yl)ethan-1-amine, and L^Br = N,N-bis((6-bromopyridin-2-yl)methyl)-2-(piperidin-1-yl)ethan-1-amine, have been isolated as synthetic enzyme–substrate analogues of nickel(II)-containing quercetin 2,4-dioxygenases (Ni-2,4-QDOs). The complexes were characterized by spectral, electrochemical, and thermal methods. Single-crystal X-ray diffraction analyses of adducts 1, 2 and 4 reveal distorted octahedral coordination geometries around the nickel(II) centres, consistent with the solution-state features deduced from electronic absorption and ESI-MS spectral data. The oxidation potential (E_pa) of the fla⁻/fla˙ couple of 1–4 appears in the range +0.821 to +1.052 V (vs. SCE) in DMF. Infra-red spectral results support the existence of synergistic π-backbonding from the Ni(II)-to-OC bond of the fla^– ring. All the adducts undergo oxidative decomposition of the coordinated flavonolate moiety in O₂ saturated DMF at 70 °C with a moderate rate (k_obs: 1.07–7.26 × 10⁻⁴ s⁻¹) and the reactivity is highly influenced by the steric and electronic nature of the primary ligand architecture, mimicking the function of 2,4-QDOs. The stronger Ni–N_py bonds of the unsubstituted pyridyl donors in adduct 1 enhance the π-back donation ability of the nickel(II) centre to the flavonolate ring, thereby weakening the C3C4 bond, lowering the E_pa value of the fla⁻/fla˙ couple, and exhibiting superior 2,4-QDO reactivity. The generation of the radical intermediates fla˙ and fla-O₂˙⁻ during the reaction was indirectly confirmed with the aid of TEMPO and NBT²⁺ radical scavenging experiments.