The mechanism of acetate-assisted transmetalation of tetrapyrroles was investigated in a model system consisting of chlorophyll a and copper(II) acetate in organic solvents by using a spectroscopic and kinetic approach. Surprisingly, acetate ions bind to the central Mg in chlorophyll much more strongly than do acetonitrile, methanol and even pyridine, one of the best ligands in chlorophyllic systems. This exceptionally strong non-symmetrical axial ligation of the central Mg by acetate causes its out-of-plane displacement and deformation of the tetrapyrrole ring, thus facilitating the interaction with an incoming CuII complex. This mechanism is controlled by a keto–enol tautomerism of the chlorophyll isocyclic ring. Additionally, depending on solvent, acetate activates the incoming metal ions. These new insights allow to suggest a mechanism for the acetate method of metal exchange in tetrapyrrolic macrocycles, which resembles biological insertion of metal ions into porphyrins. It also provides a guideline for the design of more efficient methods for the metalation of porphyrins and related macrocycles.