The Effect of a Complexed Lithium Cation on a Norcarane‐Based Radical Clock

Abstract

Density-functional theory (DFT) and ab initio calculations have been used to investigate the effect of a complexed lithium cation on the radical-clock rearrangement of the 2-norcaranyl radical to the 3-cyclohexenylmethyl radical. As found earlier for ring-closing radical clocks, complexation with a metal ion leads to a significant lowering of the barrier to rearrangement. DFT calculations on a model for the norcaranyl clock in cytochrome P450 confirm the two-state reactivity proposal of Shaik et al. and indicate that the porphyrin exerts little or no electrostatic effect on the rearrangement barrier.

Rearrangement-Free Hydroxylation of Methylcubanes by a Cytochrome P450: The Case for Dynamical Coupling of C–H Abstraction and Rebound

“…However, this appears unlikely for 18 – 20 , since CYP101B1 is able to specifically bind and efficiently oxidize larger substrates such as 2-adamantyl isobutyrate and cyclododecyl acetate, suggesting a sterically undemanding active site. , Newcomb et al explored similar ideas with a range of ultrafast probes; their findings with probes that underwent little molecular motion upon rearrangement, and with probes that underwent isotopically induced metabolic branching, led to the conclusion that the rearrangements were not slowed in the enzyme . Furthermore, calculations suggest that the weak interaction of the radical with the (HO)Fe moiety in the active site does not have a significant effect on the rearrangement barrier for either cubylmethyl- or cyclopropylmethyl-type radicals.…”

Reaction mechanisms : Part (i) Radical and radical ion reactions

“…Molecular orbital calculations reported by Clark and coworkers suggest that through electrostatic catalysis, a complexed lithium ion will significantly increase the rate of this rearrangement. 73 Borden et al proposed that tunneling is important in the cyclopropylcarbinylhomoallyl radical rearrangement (12 -13), and further predicted that large inverse H/D isotope effects will be observed for this classic radical rearrangement at low temperatures. Oxidative ring-opening of cyclopropyl silyl ethers using (p-BrC 6 H 4 ) 3 N + and other oxidants was reported by Hasegawa et al to yield ring-expanded ketones.…”

Radical Stabilization Energies for Enzyme Engineering: Tackling the Substrate Scope of the Radical Enzyme QueE

“…Intermediate 3 and its analogues also represent a class of structures known as radical clocks, 24 which undergo quick unimolecular rearrangements and have been described extensively by experiment and theory. [25][26][27][28][29][30][31][32] We recently demonstrated that it is necessary to hold the substrate radical 2 in an energetically unfavorable configuration to overcome the rearrangement barrier for the ring conversion. This conformation is achieved by binding the substrate already in this conformation (which represents for the substrate a local energy minimum only slightly higher in energy than the unbound conformer) and hold this conformation after hydrogen abstraction through electrostatic fixation by a Mg 2+ ion in the active site of the enzyme.…”

“…The rearrangement of 6-carboxytetrahydropterin (CPH 4 ) proceeds after initial hydrogen abstraction from the C6 position through a cyclic azacyclopropylcarbinyl intermediate ( 3 ), before hydrogen reabstraction from AdoH and deamination to form the final product ( 6 ). Intermediate 3 and its analogues also represent a class of structures known as radical clocks, which undergo quick unimolecular rearrangements and have been described extensively by experiment and theory. − …”