Lessons from nature: unraveling biological CH bond activation

The cleavage of unactivated CH bonds is one of the most challenging reactions in chemical biology. Metalloenzymes have evolved that efficiently perform these transformations with exquisite control of selectivity; however, a proposed requirement is the generation of highly reactive intermediates that could be lethal. A thermodynamic argument involving the putative reactive species is outlined, whereby the interplay between two tunable parameters, redox potential and pKa, may be the key to sustainable function. In addition, factors that control these parameters are also described, including hydrogen-bonding networks found within protein active sites. Synthetic examples are used to corroborate these ideas.