What factors influence the ratio of C-H hydroxylation versus C=C epoxidation by a nonheme cytochrome P450 biomimetic?

Density functional calculations on a nonheme biomimetic (Fe=O(TMCS+) have been performed and its catalytic properties versus propene investigated. Our studies show that this catalyst is able to chemoselectively hydroxylate C=H bonds even in the presence of C=C double bonds. This phenomenon has been analyzed and found to occur due to Pauli repusions between protons on the TMCS ligand with protons attached to the approaching substrate. The geometries of the rate determining transition states indicate that the steric hindrance is larger in the epoxidation transition states than in the hydroxylation ones with much shorter distances; hence the hydroxylation pathway is favored over the epoxidation. Although, the reactant experiences close lying triplet and quintet spin states, the dominant reaction mechanism takes place on the quintet spin state surface; i.e., Fe=O(TMCS)+ reacts via single-state reactivity. Our calculations show that this spin state selectivity is the result of geometric orientation of the transition state structures, whereby the triplet ones are destabilized by electrostatic repulsions between the substrate and the ligand while the quintet spin transition states are aligned along the ideal axis. The reactivity patterns and geometries are compared with oxoiron species of dioxygenase and monoxygenase enzymes. Thus, Fe=O(TMCS)+ shows some similarities with P450 enzyme reactivity: it chemoselectively hydroxylates C=H bonds even in the presence of a C=C double bond and therefore is an acceptable P450 biomimetic. However, the absolute barriers of substrate oxidation by Fe=O(TMCS)+ are higher than the ones obtained with heme enzymes, but the chemoselectivity is lesser affected by external perturbations such as hydrogen bonding of a methanol molecule toward the thiolate sulfur or a dielectric constant. This is the first oxoiron complex whereby we calculated a chemoselective hydroxylation over epoxidation in the gas phase.     

Tuning the electrochemistry of Re2(6+) species with divergent bicyclic guanidinate ligands and by modification of axial π interactions

Four Re(2)(6+) paddlewheel compounds with equatorial bicyclic guanidinate ligands and two monodentate anions in axial positions show a large change in the metal-metal distance that depends on the bite angle of the ligands and whether there are pi interactions between the dimetal unit and the axial ligands. These processes are accompanied by significant changes in the redox behavior. The two pairs of compounds that have been synthesized are Re(2)(tbn)(4)Cl(2), 1, and Re(2)(tbn)(4)(SO(3)CF(3))(2), 2, as well as Re(2)(tbo)(4)Cl(2), 3, and Re(2)(tbo)(4)(SO(3)CF(3))(2), 4, where tbn is the anion of a bicyclic guanidinate with six- and five-membered rings (1,5,7-triazabicyclo[4.3.0]non-6-ene) and tbo is an analogous species with two five-membered rings (the anion of 1,4,6-triazabicyclo[3.3.0]oct-4-ene). For both 1 and 2 as well as for 3 and 4, the metal-metal distances are shorter for the triflate species than for the chloride analogues because of the π interactions of the Cl with the π bonds of the triply bonded Re(2)(6+) cores compounded by a small but symmetry allowed interaction between the antisymmetric combination of the filled σp orbitals of the chlorine atom and the empty σ* orbital of the metal atoms. In addition there is a significant increase in the Re-Re distance from that in the six/five tbn-membered ring to the five/five-membered tbo species. Electrochemical measurements show two redox processes for each set of compounds corresponding to the uncommon Re(2)(6+) → Re(2)(7+) and Re(2)(7+) → Re(2)(8+) processes, which are strongly affected by the bite angle of the guanidinate ligand as well as the ability of the axial ligands to interact with the π orbitals of the dirhenium unit. For 1 and 3, the first redox couples are at 0.146 and 0.487 V, respectively, while for 2 and 4 these are at 0.430 and 0.698 V, respectively.     

How does product isotope effect prove the operation of a two-state "rebound" mechanism in C-H hydroxylation by cytochrome P450?

C-H hydroxylation is a fundamental process. In Nature it is catalyzed by the enzyme cytochrome P450, in a still-debated mechanism that poses a major intellectual challenge for both experiment and theory; currently, the opinions keep swaying between the original single-state rebound mechanism, a two-oxidant mechanism (where ferric peroxide participates as a second oxidant, in addition to the primary active species, the high-valent iron-oxo species), and two-state reactivity (TSR) mechanism (where two spin states are involved). Recent product isotope effect (PIE) measurements for the trans-2-phenyl-methyl cyclopropane probe (1), led Newcomb and co-workers (Newcomb, M.; Aebisher, D.; Shen, R.; Esala, R.; Chandrasena, P.; Hollenberg, P.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064-6065) to rule out TSR in favor of the two-oxidant scenario, since the direction of the PIE was at odds with the one predicted from calculations on methane hydroxylation. The present report describes a density functional theoretical study of C-H hydroxylation of the Newcomb probe, 1, leading to rearranged (3) and unrearranged (2) products. Our study shows that the reaction occurs via TSR in which the high-spin pathway gives dominant rearranged products, whereas the low-spin pathway favors unrearranged products. The calculated PIE(2/3) values based on TSR are found to be in excellent agreement with the experimental data of Newcomb and co-workers. This match between experiment and theory makes a strong case that the reaction occurs via TSR mechanism.     

Radical clock substrates, their C-H hydroxylation mechanism by cytochrome P450, and other reactivity patterns: what does theory reveal about the clocks' behavior?

There is an ongoing and tantalizing controversy regarding the mechanism of a key process in nature, C-H hydroxylation, by the enzyme cytochrome P450 (Auclaire, K.; Hu, Z.; Little, D. M.; Ortiz de Montellano, P. R.; Groves, J. T. J. Am. Chem. Soc. 2002, 124, 6020-6027. Newcomb, M.; Aebisher, D.; Shen, R.; Esala, R.; Chandrasena, P.; Hollenberg, P. F.; Coon, M. J. J. Am. Chem. Soc. 2003, 125, 6064-6065). To definitely resolve this controversy, theory must first address the actual systems that have been used by experiment, and that generated the controversy. This is done in the present paper, which constitutes the first extensive theoretical study of such two experimental systems, trans-2-phenylmethyl-cyclopropane (1) and trans-2-phenyl-iso-propylcyclopropane (4). The theoretical study of these substrates reveals that the only low energy pathway for C-H hydroxylation is the two-state rebound mechanism described originally for methane hydroxylation (Ogliaro, F.; Harris, N.; Cohen, S.; Filatov, M.; de Visser, S. P.; Shaik, S. J. Am. Chem. Soc. 2000, 122, 8977-8989). The paper shows that the scenario of a two-state rebound mechanism accommodates much of the experimental data. The computational results provide a good match to experimental results concerning the very different extents of rearrangement for 1 (20-30%) vs 4 (virtually none), lead to product isotope effect for the reaction of 1, in the direction of the experimental result, and predict as well the observed metabolic switching from methyl to phenyl hydroxylation, which occurs upon deuteration of the methyl group. Furthermore, the study reveals that an intimate ion pair species involving an alkyl carbocation derived from 4 gives no rearranged products, again in accord with experiment. This coherent match between theory and experiment cannot be merely accidental; it comes close to being aproof that the actual mechanism of C-H hydroxylation involves the two-state reactivity revealed by theory. Analysis of the rearrangement modes of the carbocations derived from 1 and 4 excludes the participation of free carbocations during the hydroxylation of these substrates. Finally, the mechanistic significance of product isotope effect (different isotope effects for the rearranged and unrearranged alcohol products) is analyzed. It is shown to be a sensitive probe of two-state reactivity; the size of the intrinsic product isotope effect and its direction reveal the structural differences of the hydrogen abstraction transition states in the low-spin vs high-spin reaction manifolds.     

Infrared spectra of aluminogermanate- and aluminate-sodalites and a re-examination of the relationship between TO bond length,TOT angle and the position of the main i.r. absorption band for compounds with framework structures

Cell parameters and i.r. data are presented for 6 aluminogermanate-sodalites, 11 aluminate-sodalites and for Na₈(Ga₆Ge₆O₂₄)Br₂ and Na₈(Ga₈Si₆O₂₄)Br₂. Apart from the borate-sodalites the framework absorption bands of the sodalite family can be grouped into three sets: ν_as TOT between 800 and 1000 cm⁻¹, ν_s TOT between 500 and 800 cm⁻¹ and δ OTO between 300 and 500 cm⁻¹ (T =tetrahedral framework cation). The aluminogermanate-sodalites have one ν_as TOT mode and two v_s TOT and δ OTO modes. Cubic aluminate-sodalites with ∼ 9 Å cells are similar but with only one δ OTO mode; aluminate-sodalites without cubic ∼9 Å cells showed broadening of the v_as TOT mode, which has several maxima and additional v_s TOT bands. Compounds with framework structures having AlO, (Al, Ge)O, (Al, Si)O, (Ga, Ge)O, GeO and SiO framework bonds, when grouped into those with TOT angles close to either 125° or 145°, show good correlations between the wave numbers of their main absorption bands and their mean TO distances.     

Alkyl,aryl and cis-dihydride complexes of iridium with the tripodal phosphine P(CH2CH2PPh2)3 as excellent precursors of active systems for the activation of hydrocarbon CH bonds

The CH bonds of tetrahydrofuran, acetone and benzene are activated by the fragment [(PP₃)Ir]⁺ (PP₃ = P(CH₂CH₂PPh₂)₃) generated either by photolytic dehydrogenation of the cis-dihydride [(PP₃)IrH₂](SO₃CF₃) or by thermal decomposition of the cis-organyl)hydrides [(PP)₃)IrH(R)](SO₃CF₃) (R = Me, Ph). The latter compounds are obtained by protonation of the σ-organyl complexes (PP₃)IrR.