Mononuclear nickel(ii)–flavonolate complexes of tetradentate tripodal 4N ligands as structural and functional models for quercetin 2,4-dioxygenase: structures, spectra, redox and dioxygenase activity

Abstract

Three new nickel(II)-flavonolate complexes of the type [Ni(L)(fla)](ClO₄) 1–3, where L is the tripodal 4N ligand tris(pyrid-2-ylmethyl)amine (tpa, L1) or (pyrid-2-ylmethyl)bis(6-methylpyrid-2-ylmethyl)amine (6-Me₂-tpa, L2) or tris(N-Et-benzimidazol-2-ylmethyl)amine (Et-ntb, L3), have been isolated as functional models for Ni(II)-containing quercetin 2,4-dioxygenase. Single crystal X-ray structures of 1 and 3 reveal that Ni(II) is involved in π-back bonding with flavonolate (fla⁻), as evident from enhancement in CO bond length upon coordination [H(fla), 1.232(3); 1, 1.245(7); 3, 1.262(8) Å]. More asymmetric chelation of fla⁻ in 3 than in 1 [Δd = (Ni–O_carbonyl − Ni–O_enolate): 1, 0.126; 3, 0.182 Å] corresponds to lower π-delocalization in 3 with electron-releasing N-Et substituent. The optimized structures of 1–3 and their geometrical isomers have been computed by DFT methods. The HOMO and LUMO, both localized on Ni(II)-bound fla⁻, are highly conjugated bonding π- and antibonding π*-orbitals respectively. They are located higher in energy than the Ni(II)-based MOs (HOMO–1, d_x²–y²; HOMO–2/6, d_z²), revealing that the Ni(II)-bound fla⁻ rather than Ni(II) would undergo oxidation upon exposure to dioxygen. The results of computational studies, in combination with spectral and electrochemical studies, support the involvement of redox-inactive Ni(II) in π-back bonding with fla⁻, tuning the π-delocalization in fla⁻ and hence its activation. Upon exposure to dioxygen, all the flavonolate adducts in DMF solution decompose to produce CO and depside, which then is hydrolyzed to give the corresponding acids at 70 °C. The highest rate of dioxygenase reactivity of 3 (k_O2: 3 (29.10 ± 0.16) > 1 (16.67 ± 0.70) > 2 (1.81 ± 0.04 × 10⁻¹ M⁻¹ s⁻¹)), determined by monitoring the disappearance of the LMCT band in the range 440–450 nm, is ascribed to the electron-releasing N-Et substituent on bzim ring, which decreases the π-delocalization in fla⁻ and enhances its activation.