Frontier molecular orbital (FMO) theory coupled with density functional calculations has been applied to investigate the chemical reactivity of three key bioinorganic Cu n -O 2 complexes, the mononuclear end-on hydroperoxo-Cu(II), the side-on bridged μ-η 2 :η 2 -O 2 2 - Cu(II) 2 dimer and the bis-μ-oxo Cu(III) 2 dimer. Two acceptor orbitals (σ* and π*) of each complex and two types of donating substrates (σ-substrate, phosphine; π-substrate, alkylbenzene) are considered in the electrophilic attack mechanism. The angular dependences of different reaction pathways are determined using FMO theory and the angular overlap model. Including steric effects, the σ*/σ and π*/π pathways are found more reactive than the corresponding cross σ*/π and π*/σ pathways which have poor donor-acceptor orbital overlaps in the sterically constrained substrate access region.