Multistate Reactivity in Styrene Epoxidation by Compound I of Cytochrome P450: Mechanisms of Products and Side Products Formation

Abstract

Density functional theoretical calculations are used to elucidate the epoxidation mechanism of styrene with a cytochrome P450 model Compound I, and the formation of side products. The reaction features multistate reactivity (MSR) with different spin states (doublet and quartet) and different electromeric situations having carbon radicals and cations, as well as iron(III) and iron(IV) oxidation states. The mechanisms involve state-specific product formation, as follows: a) The low-spin pathways lead to epoxide formation in effectively concerted mechanisms. b) The high-spin pathways have finite barriers for ring-closure and may have a sufficiently long lifetime to undergo rearrangement and lead to side products. c) The high-spin radical intermediate, (4)2(rad)-IV, has a ring closure barrier as small as the C--C rotation barrier. This intermediate will therefore lose stereochemistry and lead to a mixture of cis and trans epoxides. The barriers for the production of aldehyde and suicidal complexes are too high for this intermediate. d) The high-spin radical intermediate, (4)2(rad)-III, has a substantial ring closure barrier and may survive long enough time to lead to suicidal, phenacetaldehyde and 2-hydroxostyrene side products. e) The phenacetaldehyde and 2-hydroxostyrene products both originate from crossover from the (4)2(rad)-III radical intermediate to the cationic state, (4)2(cat,z(2) ). The process involves an N-protonated porphyrin intermediate that re-shuttles the proton back to the substrate to form either phenacetaldehyde or 2-hydroxostyrene products. This resembles the internally mediated NIH-shift observed during benzene hydroxylation.

Biodegradation of Cosmetics Products: A Computational Study of Cytochrome P450 Metabolism of Phthalates

“…Overall, epoxidation is a thermoneutral process and at our level of theory, it is slightly endothermic in the quartet spin state (by 4.3 kcal·mol −1 ), while it is slightly exothermic in the doublet spin state (by 3.9 kcal·mol −1 ). Structures along the epoxidation pathway are similar to those calculated before on alternative substrates [29][30][31][32][72][73][74][75].…”

Transition Metal Complexes and the Activation of Dioxygen

“…Subsequent ring closure yields the epoxide product coordinated to the Fe(III) center of the resting state. Similar to the hydroxylation reactivity for these models, DFT studies also suggest a two-state reactivity scenario for epoxidation, with major differences between the two pathways being the barrier to ring closure, which is almost negligible for the doublet state and slightly higher for the quartet state [112][113][114].…”

Ab initio dynamics of the cytochrome P450 hydroxylation reaction

“…Theoretical investigations of small alkene oxidation have underscored the so-called multistate reactivity hypothesis, in which different spin states of Cpd I preferentially catalyze distinct chemistry. [73][74][75][76][77][78] Within this context, the doublet state has been associated with substrate hydroxylation, while the quartet has been associated with rearranged products, such as epoxides. These explorations nonetheless predict the quartet to be capable of catalyzing hydroxylation as a minority pathway.…”