An organic chemist's guide to the best Mediator for Laccase-catalyzed Oxidations

Abstract

Laccases are a potent class of enzymes, increasingly applied as green oxidation-biocatalysts within the organic synthesis community and are evaluated for their use in several industrial applications. A major advantage of their use is that dioxygen is the stoichiometric oxidant with water as sole byproduct, making it a very green oxidation reaction. However, one limitation is their narrow substrate scope, which is usually tackled by using mediators: small molecules that can be oxidized by the laccase and, in turn, can oxidize the target substrate. With TEMPO being the go-to solution, literature is rich in other alternative mediators, however, lacks consistent and comparable data for their performance. This knowledge gap represents a burden for the organic chemist to use this type of biocatalysts. Herein, we want establish a robust entry point for organic chemists to employ laccase-mediator systems for their intended transformations. We started by screening all literature known mediators under identical conditions and chose anis alcohol which proved to be a superior substrate over the widely used benzyl alcohol. Time-resolved measurements delivered a detailed picture of the differences in the mediators’ performance. We also included several commercial laccases, evaluated different mediator oxidation states and reaction conditions with selected mediators within our study. Building up on the upper results, we set out to synthesize several novel TEMPO derivatives and determined their LogP values and their electrochemical properties via cyclic voltammetry measurements yielding both the mediators' redox potential and redox stability. Finally, we tested their performance as mediators in the aforementioned anis alcohol oxidation assay. Thus, we found several novel mediators that gave better performance than TEMPO and could also substantiate a correlation between their electrochemical and physical properties and their performance in the laccase-catalyzed oxidation.