Molecular Dynamics of Iron Porphyrin-Catalyzed C–H Hydroxylation of Ethylbenzene

Abstract

Quasi-classical molecular dynamics (MD) simulations were carried out to study the mechanism of iron porphyrin-catalyzed hydroxylation of ethylbenzene. The hydrogen atom abstraction from ethylbenzene by iron-oxo species is the rate-determining step, which generates the radical pair of iron-hydroxo species and the benzylic radical. In the subsequent radical rebound step, the iron-hydroxo species and benzylic radical recombine to form the hydroxylated product, which is barrierless on the doublet energy surface. In the gas-phase quasi-classical MD study on the doublet energy surface, 45% of the reactive trajectories lead directly to the hydroxylated product, and this increases to 56% in implicit solvent model simulations. The percentage of reactive trajectories leading to the separated radical pair is 98–100% on high-spin (quartet/sextet) energy surfaces. The low-spin state reactivity dominates in the hydroxylation of ethylbenzene, which is dynamically both concerted and stepwise, since the time gap between C–H bond cleavage and C–O bond formation ranges from 41 to 619 fs. By contrast, the high-spin state catalysis is an energetically stepwise process, which has a negligible contribution to the formation of hydroxylation products.

Dynamical Origin of Rebound versus Dissociation Selectivity during Fe-Oxo-Mediated C–H Functionalization Reactions

“…As such, rebound should occur even in the gas phase trajectories. 17,18 Taken together, these findings confirm the dynamical nature of the rebound processes and are consistent with the observations of Srnec, 30 Soler, 48 and Sarkar 15 that post-HAT rebound is indeed a dynamically controlled nonsynchronous concerted process, and HAT transition state and the post-HAT reactivity are dynamically coupled. 17,30 The dynamic coupling between the HAT transition state and the rebound product pathway can be rationalized based on the concept of dynamic matching, originally proposed by Carpenter 21,22 and popularized by Houk, Singleton, Doubleday, Hase, Tantillo, and others.…”

“…Based on a static transition-state reactive mode kinetic energy distribution model for synthetic heme and nonheme Fe-oxo complexes, Srnec has suggested that the HAT-initiated rebound versus dissociation corresponds to a nonequilibrium ballistic process . More recently, our direct dynamics simulations, and later trajectories by Houk, have established that most of the rebound reactions are dynamically concerted with HAT transition-state motion, albeit with some nonsynchronous/lagging motion.…”

“…24−28 This method/basis set combination was shown to perform well for Fe-oxo spin-state energies and barrier heights, 29,30 and this method performed well in ours and Houk's trajectories to replicate the experimental chemoselectivity. 17,18 For fully optimized structures, solvation effects were incorporated using the CPCM solvation model for acetonitrile. 31,32 Frequency calculations and intrinsic reaction coordinate (IRC) analysis were used to confirm the transitionstate structure connections.…”

“…12−14 There are also literature precedents for the existence of radical-pair species of intermediate lifetimes (few picoseconds). 15,16 Recent direct dynamics studies from our group, 17 and later by Houk, 18 have established that the radical-pair intermediates in some of these Fe-oxo C−H functionalization reactions are best described as nonstatistical and they do not undergo complete intramolecular vibrational energy redistribution (IVR) before entering rebound or dissociation pathways. 19,20 Importantly, our simulations demonstrated that rebound trajectories are nearly concerted although asynchronous.…”

Influence of Cage Effects in Directing the Outcome of C–X Bond Forming Reactions

“…Recently, Houk and co-workers carried out a detailed molecular dynamics (MD) simulation to better understand the hydrogen abstraction and radical rebound steps in iron porphyrin catalyzed C–H bond hydroxylation of ethylbenzene . On the doublet energy surface, 45% of reactive trajectories led directly to the hydroxylated product when quasi-classical MD was carried out in the gas phase, while 56% led directly to the alcohol with an implicit DCM solvent model.…”