Modeling the Mononuclear, Dinuclear, and Trinuclear Copper(I) Reaction Centers of Copper Proteins Using Pyridylalkylamine Ligands Connected to 1,3,5-Triethylbenzene Spacer

The structure and O2-reactivity of copper(I) complexes supported by novel ligands, Pye2 (1,3,5-triethyl-2,4-bis((N-benzyl-N-(2-(pyridin-2-yl)ethyl)-)aminomethyl)benzene), Pye3 (1,3,5-triethyl-2,4,6-tris((N-benzyl-N-(2-(pyridin-2-yl)ethyl))aminomethyl)benzene), MePym2 (1,3,5-triethyl-2,4-bis((N-benzyl-N-(6-methylpyridin-2-ylmethyl))aminomethyl)benzene), and MePym3 (1,3,5-triethyl-2,4,6-tris((N-benzyl-N-(6-methylpyridin-2-ylmethyl))aminomethyl)benzene) have
been examined. The ligands are designed to construct mono-, di-, and trinuclear copper(I) complexes by connecting
two or three pyridylalkylamine metal-binding sites to a 1,3,5-triethylbenzene spacer. Thus, the reaction of the ligands
with [CuI(CH3CN)4]X (X = PF6, CF3SO3) or CuICl gave the expected mononuclear copper(I) complexes [CuI(Pye2)(CF3SO3)] (1) and [CuI(Pye3)](CF3SO3) (2), dinuclear copper(I) complex [CuI2(MePym2)(Cl)]CuICl2 (3), and trinuclear
copper(I) complex [CuI3(MePym3)(CH3CN)3](CF3SO3)3 (4), the structures of which were determined by X-ray
crystallographic analysis. The mononuclear copper(I) complexes, 1 and 2, exhibit a distorted three-coordinate T-shape
structure and a trigonal planar structure, respectively, which are very close to the coordination geometry of the
CuA site of PHM (peptidylglycine α-hydroxylating monooxygenase) and the CuB site of CcO (cytochrome c oxidase).
Notably, 1 and 2 showed a significantly high oxidation potential (990 mV vs SCE), thus showing virtually no reactivity
toward O2. On the other hand, the metal centers of the dinuclear and trinuclear copper(I) complexes, 3 and 4,
exhibit a distorted trigonal planar geometry and a trigonal pyramidal geometry, respectively. In contrast to the
mononuclear copper(I) complexes, these dinuclear and trinuclear copper(I) complexes reacted with O2 to induce
an aromatic ligand hydroxylation reaction involving an NIH-shift of one of the ethyl substituents on the benzene
spacer. The NIH-shift of the alkyl substituent on the aromatic ring is strong evidence of the electrophilic aromatic
substitution mechanism, although the active oxygen intermediate could not be directly detected during the course
of the reaction. The biological relevance of the copper(I) complexes is also discussed on the basis of structure and
O2-reactivity.