This study provides atomistic insights into the interface between a single-site catalyst and a transition metal chalcogenide support and illustrates how their cooperativity can be harnessed to modulate catalytic activity. A molecular platform MCo6Se8(PEt3)4(L)2 (1-M, M = Cr, Mn, Fe, Co, Cu, Zn) was designed in which the active site (M)/support (Co6Se8) interactions are interrogated by sys-tematically probing the electronic and structural changes that occur as the identity of the metal varies. All 3d transition metal 1-M clusters display remarkable catalytic activity for coupling tosyl azide and tert-butyl isocyanide, with Mn and Co derivatives show-ing the fastest turnover in the series. Detailed structural, electronic, and magnetic characterization of the clusters was performed using single crystal X-ray diffraction, 1H and 31P nuclear magnetic resonance spectroscopy, electronic absorption spectroscopy, cyclic voltammetry, and computational methods. Distinct metal/support redox regimes can be accessed in 1-M based on the energy of the edge metal’s frontier orbitals with respect to those of the cluster support. As the degree of electronic interaction between the edge and the support increases, a cooperative regime is reached wherein the support can deliver electrons to the catalytic site, in-creasing the reactivity of key metal-nitrenoid intermediates.