Benchmarking CuₙO (n = 1, 2) complexes via ab initio methods: structural, electronic, and thermodynamic insights with biochemical relevance.

CONTEXT: Copper is an essential trace element that plays a central role in redox chemistry and electron transfer processes in biological systems. To gain a deeper understanding of the electronic behavior of copper species, we carried out a comparative evaluation of the Cu2 and CuO molecules, focusing on key properties such as ionization energy, electron affinity, vibrational frequencies, bond lengths, and dissociation energies. Cu2 serves as a model for dinuclear copper sites present in metalloproteins like tyrosinase and hemocyanin, while CuO captures the essential features of copper-oxygen bonding relevant to copper-dependent oxidases and oxygen-activating enzymes. By systematically benchmarking density functional approximations (DFAs) against high-level CCSD(T) reference calculations or experimental data, we identify the methodologies that best reproduce the electronic and structural properties of these prototypical copper systems. The functional PBE, in particular, demonstrates the most consistent performance across both species. Insights obtained from Cu2 and CuO serve as a foundation for understanding more complex copper coordination environments. In this context, we extend our analysis to the Cu(II)/indomethacin complex, illustrating how the lessons learned from the fundamental systems can be applied to biologically relevant copper-ligand interactions. Overall, this study provides a systematic assessment of the accuracy of different DFAs for describing copper-containing species, establishing a solid framework for future investigations of bioinorganic copper chemistry and copper-based drug candidates.

METHODS: This study employed density functional theory (DFT) alongside thermodynamic cycles to assess the stability of Cu(Indo)₂ and Cu₂(Indo)₄ complexes in ethanol solution. To select suitable computational methods, a benchmark was conducted using Cu(II)/acetate complexes as reference systems. A total of fifteen DFT functionals-BPW91, PBE, B97D, revTPSS, M06-L, M11-L, B3LYP, BHandHLYP, PBE0, ωB97XD, APDF, M06, M06-2X, M06-HF, and TPSSh-were tested in combination with four basis sets: Def2-SVP, Def2-TZVP, 6-31 + G(d,p), and 6-311 + G(d,p). The most reliable functional-basis set combinations were then applied to the copper-indomethacin complexes. In addition, electronic and structural properties of Cu₂ and CuO-such as ionization potentials, electron affinities, vibrational frequencies, equilibrium bond lengths, and spin or magnetic coupling constants-were calculated. Computational results were validated through comparison with available experimental data.