The Impact of Secondary Coordination Sphere Nucleophiles on Methane Activation: A Computational Study

Density functional theory and ab initio calculations indicate that nucleophiles can significantly reduce enthalpic barriers to methane C–H bond activation. Different pieces of evidence point to an electrostatic origin for the nucleophile effect such as the sensitivity of the C–H activation barriers to the external nucleophile and to continuum solvent polarity. The data further imply a transition state with significant charge build-up on the active hydrogen of the hydrocarbon substrate. From the present modeling studies, one may propose proteins with hydrophobic active sites, available nucleophiles, and hydrogen bond donors as attractive targets for the engineering of novel methane functionalizing enzymes.