Selective functionalization of C–H bonds is achievable mainly through transition-metal catalysis, often guided by directing groups to control site-specific activation under mild conditions. However, universal activation of any C–H bond anywhere in a molecule without limitations is not yet realized due to challenges in selectivity and substrate complexity.

Dear Abdelhak Maghchiche, thank you for your answer.

I agree that transition-metal catalysis with directing groups has enabled many selective C–H activations. However, the central challenge goes beyond substrate complexity: most C–H bonds are intrinsically similar, making universal selectivity extremely difficult. While directing groups remain key, new strategies such as photoredox/electrochemical methods, enzymatic systems, transient directing groups, and even machine-learning models are expanding the scope. The open frontier is whether we can ever achieve a general, position-independent, and mild method for C–H functionalization — a breakthrough that would transform organic synthesis.

That’s one of the most profound and still unresolved questions in synthetic chemistry. While selective C–H activation under mild conditions has seen major advances, especially with transition metal catalysis, single-atom catalysts, and directing groups, we’re far from being able to functionalize any C–H bond anywhere in a molecule with full control