Unveiling How Stereoelectronic Factors Affect Kinetics and Thermodynamics of Protonation Regiochemistry in [FeFe] Hydrogenase Synthetic Models: A DFT Investigation

The DFT investigation of protonation regiochemistry for a series of [Fe(l)](2)(edt)(PR)(x)(CO)((6-x))] complexes differing for steric and electronic properties of ligands has allowed the disclosure of several key relations between the structure of the complexes and reactivity toward acids, from both a thermodynamics and kinetics perspective. The phosphine/CO ratio strongly affects both the thermodynamics and kinetics of protonation. In particular, with the exception of dppv complexes, in which steric factors become more important, the presence of phosphines, which are better electron donors than CO ligands, leads to lower reaction barriers. The presence of bulky phosphine ligands, which severely hinder the accessibility to the Fe-Fe bond, is a crucial factor responsible for kinetic preference of terminal- versus mu-protonation in symmetric complexes. The investigation of asymmetric models allowed us to rationalize why protonation takes place preferentially on the less electron-rich iron atom, i. e., the iron atom coordinated by the largest number of CO ligands. Importantly, the presence of at least one electron-donor ligand on the protonating Fe atom is fundamental to allow facile terminal protonation, suggesting that one of the reasons for the presence of CN- ligands in the enzyme might be related to the facile formation of catalytically relevant terminally protonated species. Finally, it was found that poorly reacting mu-H Fe(II)Fe(II) species are always thermodynamically more stable than corresponding terminal-hydride forms, indicating that one of the main challenges for the development of efficient synthetic catalysts inspired to the [FeFe] hydrogenase active site will be the design of complexes that undergo terminal protonation but cannot interconvert to the corresponding mu-H forms.