Practical conversion of waste heat into electricity via thermoelectrochemical cells requires high Seebeck coefficient (α) to increase cycle efficiency. The complexation of Cu2+ species with dissolved multidentate ligands, such as ethylenediaminetetraacetic acid, and the control of dimerization equilibria with bridging ligands, such as 1,6-diaminohexane or 1,2-diaminoethane, dramatically improve, by up to ∼185%, the magnitude of the α of Cu/Cu2+ thermoelectrochemical cells. This results in the highest α for any Cu/Cu2+ redox system yet reported. The coefficient α is directly proportional to the change in entropy (ΔS). It was experimentally measured and correlated with ΔS obtained from quantum-chemical methods. This offers a deeper insight about a molecule-based interpretation of the macroscopic response. The agreement between the theoretically estimated and experimentally observed α is remarkable. Hence, we believe that this synergistic approach allows us to systematically scan different systems to obtain efficient thermoelectrochemical cells with enhanced Seebeck coefficient.