Challenges in Elucidating the Free Energy Scheme of the Laccase Catalyzed Reduction of Oxygen

Artificial redox catalysts are typically limited by unfavorable scaling relations of reaction intermediates leading to a significant overpotential in multi‐electron redox reactions such as for example the oxygen reduction reaction (ORR). The multicopper oxidase laccase is able to catalyze the ORR in nature. In particular the high‐potential variants show a remarkably low overpotential for the ORR and apparently do not suffer from such unfavorable scaling relations. Although laccases are intensively studied, it is presently unknown why the overpotential for ORR is so low and a clear description regarding the thermodynamics of the catalytic cycle and the underlying design principles is lacking. In order to understand the laccase catalyzed ORR from an electrochemical perspective, elucidation of the free energy scheme would be of high value. This article reviews the energetics of the proposed laccase catalyzed ORR mechanisms based on experimental and computational studies. However, there are still remaining challenges to overcome to elucidate the free energy scheme of laccase. Obtaining thermodynamic data on intermediates is hard or even impossible with analytical techniques. On the other hand, several computational studies have been performed with significantly different parameters and conditions, thus making a direct comparison difficult. For these reasons, a consensus on a clear free energy scheme is still lacking. We anticipate that ultimately conquering these challenges will result in a better understanding of laccase catalyzed ORR and will allow for the design of low overpotential redox catalysts. Bioinorganic chemistry: High potential variants of the multicopper enzyme laccase have a remarkably low overpotential for the oxygen reduction reaction (ORR). Understanding the precise underlying principles are potentially of great value in light of the energy transition wherein the ORR plays a crucial role. The aim of this work is to review the progress that has been made in elucidating what makes laccases such excellent ORR catalysts, and to identify the remaining challenges in a complete elucidation of the free energy scheme for the ORR mediated by laccases.