Nickel(II)-Flavonolate Complexes of Tetradentate 4N Donor Ligands as Enzyme-Substrate Models of Quercetin-2,4-Dioxygenase: Role 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(LH–LBr)(fla)]ClO4 1–4, where LH = 2-(piperidin-1-yl)-N,N-bis(pyridin-2-ylmethyl)ethan-1-amine, LMe = N,N-bis((6-methylpyridin-2-yl)methyl)-2-(piperidin-1-yl)ethan-1-amine, LOMe = N,N-bis((6-methoxypyridin-2-yl)methyl)-2-(piperidin-1-yl)ethan-1-amine, LBr = 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-QDO). The complexes were characterized by spectral, electrochemical, and thermal methods. Single-crystal X-ray diffraction analyses of the 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 (Epa) of fla–/fla• couple of 1–4 appears in the range +0.821 – +1.052 V (vs SCE) in DMF. Infra-red spectral results support the existence of synergistic π-backbonding from Ni(II)-to-O=C bond of fla– ring. All the adducts undergo oxidative decomposition of the coordinated flavonolate moiety in O2 saturated DMF at 70 °C with moderate rate (kobs: 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–Npy bonds of the unsubstituted pyridyl donors in adduct 1 enhances π-back donation ability of the nickel(II) centre to the flavonolate ring, thereby weakens the C3=C4 bond, lowers the Epa value of the fla⁻/fla• couple, and exhibit 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. Keywords: Pyridinyl and piperidinyl donors, tetradentate ligands, nickel(II)-flavonolate adducts, crystal structures, quercetin-2,4-dioxygenase activity.