A Horseradish Peroxidase-Mediator System for Benzylic C-H Activation

Enzyme-mediator systems generate radical inter-mediates that abstract hydrogen atoms under mild conditions. These systems have been employed extensively for alcohol oxidation, primarily in biomass degradation, but they are underexplored for direct activation of C(sp3)-H bonds in alkyl groups. Here, we combine horseradish peroxidase (HRP), H2O2, and redox mediator N-hydroxyphthalimide (NHPI) for C(sp3)-H functionalization of alkylbenzene-type substrates. The HRP- NHPI system is >10-fold more active than existing enzyme- mediator systems in converting alkylbenzenes to ketones and aldehydes under air, and it operates from 0-50 degrees C and in numerous aqueous-organic solvent mixtures. The benzylic substrate radical can be trapped through a reaction with NHPI, demonstrating the formation of benzylic products beyond ketones. Furthermore, we demonstrate a one-pot, two-step enzymatic cascade for converting alkylbenzenes to benzylic amines. Overall, the HRP-NHPI system enables the selective benzylic C-H functionalization of diverse substrates under mild conditions using a straightforward procedure.

Automated summary

Enzyme-mediator systems, such as the horseradish peroxidase (HRP), H2O2, and N-hydroxyphthalimide (NHPI) system, are effective for the functionalization of alkylbenzenes. The HRP-NHPI system shows superior activity compared to existing enzyme-mediator systems, converting alkylbenzenes to ketones and aldehydes. This system operates under mild conditions and can be used in aqueous-organic solvent mixtures. It also enables the conversion of alkylbenzenes to benzylic amines in a one-pot, two-step enzymatic cascade.