An ab initio study of the interaction of O2, the most abundant radical and oxidant species in the atmosphere, with a Cu5 cluster, a new generation atomic metal catalyst, is presented. The open-shell nature of the reactant species is properly accounted for by using the multireference perturbation theory, allowing the experimentally confirmed resistivity of Cu5 clusters toward oxidation to be investigated. Approximate reaction pathways for the transition from physisorption to chemisorption are calculated for the interaction of O2 with quasi-iso-energetic trapezoidal planar and trigonal bipyramidal structures. Within the multireference approach, the transition barrier for O2 activation can be interpreted as an avoided crossing between adiabatic states (neutral and ionic), which provides new insights into the charge-transfer process and gives better estimates for this hard to localize and therefore often neglected first intermediate state. For Cu5 arranged in a bipyramidal structure, the O–O bond cleavage is confirmed as the rate-determining step. However, for planar Cu5, the high energy barrier for O2 activation, related to a very pronounced avoided crossing when going from physisorption to chemisorption, determines the reactivity in this case.