Lessons from nature: unraveling biological CH bond activation

Abstract

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 pK(a), 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.

Figure 1

A possible mechanism for metal-oxo mediated C—H bond cleavage (A), thermodynamic cycle describing the BDE_OH (B), and the relationship between redox potential and pK_a for a metal-oxo species in the cleavage of a C—H bond in methane with BDE_C-H = 104 kcal/mol (C).

Figure 2

Structure of [Mn^V(TBP₈Cz)(O)] (A) and [Mn^IIIH₃buea(O)]²⁻ (B).

Figure 3

Active site structures of cytochrome C peroxidase (A, 1ZBZ) and human MnSOD (B, 2ADQ) highlighting the H-bonding networks surrounding the metal centers. Gln69 refers to FeSOD.

Figure 4

Example of a modular synthetic system containing varied H-bonding networks.