Catalysis of Methyl Transfer Reactions by Oriented External Electric Fields: Are Gold–Thiolate Linkers Innocent?

Oriented external electric fields (OEEFs) are potent effectors of chemical change and control. We show that the Menshutkin reaction, between substituted pyridines and methyl iodide, can be catalyzed/inhibited at will, by just flipping the orientation of the EEF (<i>F</i>_<i>Z</i>) along the “reaction axis” (<i>Z</i>), N---C---I. A theoretical analysis shows that catalysis/inhibition obey the Bell–Evans–Polanyi principle. Significant catalysis is predicted also for EEFs oriented off the reaction axis. Hence, the observation of catalysis can be scaled up and may not require orienting the reactants vis-à-vis the field. It is further predicted that EEFs can also catalyze the front-side nucleophilic displacement reaction, thus violating the Walden-inversion paradigm. Finally, we considered the impact of gold–thiolate linkers, used experimentally to deliver the EEF stimuli, on the Menshutkin reaction. A few linkers were tested and proved not to be innocent. In the presence of <i>F</i>_<i>Z</i>, the linkers participate in the electronic reorganization of the molecular system. In so doing, these linkers induce local electric fields, which map the effects of the EEF and induce catalysis/inhibition at will, as in the pristine reaction. However, as the EEF becomes more negative than −0.1 V/Å, an excited charge transfer state (CTS), which involves one-electron transfer from the 5p lone pair of iodine to an antibonding orbital of the gold cluster, crosses below the closed-shell state of the Menshutkin reaction and causes a mechanistic crossover. This CTS catalyzes nucleophilic displacement of iodine radical from the CH₃I^•+ radical cation. The above predictions and others discussed in the text are testable

Emergence of Function in P450-Proteins: A Combined Quantum Mechanical/Molecular Mechanical and Molecular Dynamics Study of the Reactive Species in the H₂O₂‑Dependent Cytochrome P450_SPα and Its Regio- and Enantioselective Hydroxylation of Fatty Acids

This work uses combined quantum mechanical/molecular mechanical and molecular dynamics simulations to investigate the mechanism and selectivity of H₂O₂-dependent hydroxylation of fatty acids by the P450_SPα class of enzymes. H₂O₂ is found to serve as the surrogate oxidant for generating the principal oxidant, Compound I (Cpd I), in a mechanism that involves homolytic O–O bond cleavage followed by H-abstraction from the Fe–OH moiety. Our results rule out a substrate-assisted heterolytic cleavage of H₂O₂ en route to Cpd I. We show, however, that substrate binding stabilizes the resultant Fe–H₂O₂ complex, which is crucial for the formation of Cpd I in the homolytic pathway. <i>A network of hydrogen bonds locks the HO· radical</i>, formed by the O–O homolysis, thus directing it to exclusively abstract the hydrogen atom from Fe–OH, thereby forming Cpd I, while preventing the autoxoidative reaction, with the porphyrin ligand, and the substrate oxidation. The so formed Cpd I subsequently hydroxylates fatty acids at their α-position with <i>S</i>-enantioselectivity. These selectivity patterns are controlled by the active site: substrate’s binding by Arg241 determines the α-regioselectivity, while the Pro242 residue locks the prochiral α-CH₂, thereby leading to hydroxylation of the <i>pro</i>-<i>S</i> C–H bond. Our study of the mutant Pro242Ala sheds light on potential modifications of the enzyme’s active site in order to modify reaction selectivity. Comparisons of P450_SPα to P450_BM3 and to P450_BSβ reveal that <i>function</i> has evolved <i>in these related metalloenzymes by strategically placing very few residues in the active site</i>