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The mechanism of N-demethylation of N,N-dimethylanilines (DMAs) by cytochrome P450, a highly debated topic in mechanistic bioinorganic chemistry (Karki, S. B.; Dinnocenczo, J. P.; Jones, J. P.; Korzekwa, K. R. J. Am. Chem. Soc. 1995, 117, 3657), is studied here using DFT calculations of the reactions of the active species of the enzyme, Compound I (Cpd I), with four para-(H, Cl, CN, NO2) substituted DMAs. The calculations resolve mechanistic controversies, offer a consistent mechanistic view, and reveal the following features: (a) the reaction pathways involve C-H hydroxylation by Cpd I followed by a nonenzymatic carbinolamine decomposition. (b) C-H hydroxylation is initiated by a hydrogen atom transfer (HAT) step that possesses a "polar" character. As such, the HAT energy barriers correlate with the energy level of the HOMO of the DMAs. (c) The series exhibits a switch from spin-selective reactivity for DMA and p-Cl-DMA to two-state reactivity, with low- and high-spin states, for p-CN-DMA and p-NO2-DMA. (d) The computed kinetic isotope effect profiles (KIEPs) for these scenarios match the experimentally determined KIEPs. Theory further shows that the KIEs and TS structures vary in a manner predicted by the Melander-Westheimer postulate: as the substituent becomes more electron withdrawing, the TS is shifted to a later position along the H-transfer coordinate and the corresponding KIEs increases. (e) The generated carbinolaniline can readily dissociate from the heme and decomposes in a nonenzymatic environment, which involves water assisted proton shift.

Dopamine can be generated from tyramine via arene hydroxylation catalyzed by a cytochrome P450 enzyme (CYP2D6). Our quantum mechanical/molecular mechanical (QM/MM) results reveal the decisive impact of the protein in selecting the 'best' reaction mechanism. Instead of the traditional Meisenheimer-complex mechanism, the study reveals a mechanism involving an initial hydrogen atom transfer from the phenolic hydroxyl group of the tyramine to the iron-oxo of the compound I (Cpd I), followed by a ring-π radical rebound that eventually leads to dopamine by keto-enol rearrangement. This mechanism is not viable in the gas phase since the O-H bond activation by Cpd I is endothermic and the process does not form a stable intermediate. By contrast, the in-protein reaction has a low barrier and is exothermic. It is shown that the local electric field of the protein environment serves as a template that stabilizes the intermediate of the H-abstraction step and thereby mediates the catalysis of dopamine formation at a lower energy cost. Furthermore, it is shown that external electric fields can either catalyze or inhibit the process depending on their directionality.

High-valent cobalt-oxo intermediates are proposed as reactive intermediates in a number of cobalt complex-mediated oxidation reactions. Herein we report the spectroscopic capture of low-spin (S = 1/2) Co(IV)-oxo species in the presence of redox-inactive metal ions, such as Sc3+, Ce3+, Y3+, and Zn2+ and investigation of their reactivity in C-H bond activation and sulfoxidation reactions. Theoretical calculations predict that the binding of Lewis-acidic metal ions to the cobalt-oxo core increases the electrophilicity of the oxygen atom, resulting in the redox tautomerism of a highly unstable [(TAML)CoIII-(O•)]2− species to a more stable [(TAML)CoIV-(O)(Mn+)] core. The present report supports the proposed role of the redox-inactive metal ions in facilitating formation of high-valent metal-oxo cores as a necessary step for oxygen evolution in chemistry and biology.

The preceding decade has witnessed an immense surge of activity in the bioinorganic chemistry of transition metal enzymes and synthetic analogs that model their operation. The wide range of research covers both experimental and theoretical investigations of structure and reactivity patterns. Theory, and especially density functional theory (DFT), has become a very useful tool, an important partner of experiment in resolving structural and mechanistic issues. This flare of activity has generated a great deal of knowledge on intermediates, transition states, barriers, rate constants, rate-equilibrium relationships, stereoselectivity, and so forth. This abundance of acquired knowledge has created the need for establishing order, namely, the outlining of broad generalizations, as well as the creation of a more-intuitive interface between experimental and theoretical data. The valence bond (VB) diagram model, originally developed for organic reactions, is such a theoretical framework that has the potential to guide the requisite generalizations in the field of bioinorganic chemical reactivity. In this Account, we briefly describe the principles of construction of VB diagrams for bioinorganic reactions, detailing applications in the booming research area of heme enzyme (specifically cytochrome P450) reactivity, and particularly two archetypal reactions of these enzymes, alkane hydroxylation and thioether sulfoxidation. For congruence with the lingua franca of bioinorganic chemistry, the VB model is formulated to create bridges to (i) the molecular orbital (MO) description, (ii) the oxidation state formulation of transition metal complexes, and (iii) widely used concepts such as the Bell-Evans-Polanyi (BEP) principle. The VB diagram model reveals the origins of the barrier, describes the formation of transition states and reaction intermediates, and allows the prediction of barrier heights and structure-reactivity relationships. Thus, from the VB diagram model, we can rationalize the mechanistic selection during alkane hydroxylation compared with thioether sulfoxidation, as well as the different behaviors of the spin states during the reactions with the active species of P450, the high-valent iron oxo species called compound I (Cpd I). Furthermore, the VB model leads to expressions that enable us to estimate barrier heights from easily accessible reactant properties, such as bond energies, ionization potential, and electron affinities. We further show that the model is not limited to these archetypal processes: its applicability is wider and more general. Accordingly, we outline the potential applications of these principles to other reactions of P450 (such as olefin epoxidation and arene hydroxylation) and to similar reactions of nonheme enzymes and synthetic models. The VB diagram model leads to a unified understanding of complex bioinorganic transformations, creates order in the data, and provides an important framework for making useful predictions.

Background Since SARS‐CoV‐2 infection was first identified in December 2019, the novel coronavirus‐induced pneumonia COVID‐19 spread rapidly and triggered a global pandemic. Recent bioinformatics evidence suggests that angiotensin converting enzyme 2—the main cell entry target of SARS‐CoV‐2—is predominantly enriched in spermatogonia, Leydig and Sertoli cells, which suggests the potential vulnerability of the male reproductive system to SARS‐CoV‐2 infection. Objectives To identify SARS‐CoV‐2 RNA in seminal plasma and to determine semen characteristics from male patients in the acute and recovery phases of infection. Methods From February 26 to April 2, 2020, 23 male patients with COVID‐19 were recruited. The clinical characteristics, laboratory findings and chest computed tomography scans of all patients were recorded in detail. We also investigated semen characteristics and the viral RNA load in semen from these patients in the acute and recovery phases of SARS‐CoV‐2 infection using approved methods. Results The age range of the 23 patients was 20–62 years. All patients tested negative for SARS‐CoV‐2 RNA in semen specimens. Among them, the virus had been cleared in 11 patients, as they tested negative. The remaining 12 patients tested negative for SARS‐CoV‐2 RNA in semen samples, but were positive in sputum and fecal specimens. The median interval from diagnosis to providing semen samples was 32 days, when total sperm counts, total motile sperm counts and sperm morphology of the patients were within normal ranges. Discussion and Conclusion In this cohort of patients with a recent infection or recovering from COVID‐19, there was no SARS‐CoV‐2 RNA detected in semen samples, which indicates the unlikely possibility of sexual transmission through semen at about 1 month after first detection.

It is shown that H-abstraction reactivity by oxoiron(IV) complexes with a quintet ground state is highly enhanced due to exchange-stabilization endowed by the increased number of the exchange Correspondence to: Lawrence Que, Jr, larryque@umn.edu; Sason Shaik, sason@yfaat.ch.huji.ac.il. One of us, [6] has recently prepared two such S=2 reagents and compared their H-abstraction activities to those of the synthetic complexes that possess the more common S=1 ground state. These results generated however, a bag full of surprises, which are addressed herein by means of DFT calculations. Shown in Figure 1 are DFT calculated iron(IV)-oxo complexes along with their key geometric features, and spin state information. The isolated complex with an S=2 ground state is TMG 3 trenFe(IV)O 2+ (1),[6a] which possesses a trigonal bipyramidal iron coordination, typified by two-below-two-below-one d-orbital block, [3b] and hence a quintet ground state, well below the S=1 state. Surprisingly, however, 1 exhibited a rather sluggish H-abstraction reactivity even towards the weak C-H bonds of 1,4-cyclohexadiene (CHD). Thus, 1 was slightly less reactive than N4PyFe(IV)O 2+ 2 and five times more reactive than TMC(AN)Fe(IV)O 2+ , 3;[6b] both of which are thought to react via TSR. NIH Public Access[4] To add to the puzzle, the putative Tp(OBz)Fe(IV)O, 4, which was proposed to form upon oxygenation of Tp(benzoylformate)Fe(II) as a model for TauD, was found to be highly reactive and capable of activating even the strong C-H bond of cyclopentane (BDE = 96.3 kcal mol −1 ).[6b] Note that in the S=2 state, 5 4, Fe loses one of the benzoate arms and becomes a pentacoordinated square pyramid with a basal Fe(IV)-oxo moiety (Fig. 1). Thus, it is this weaker ligand field that stabilizes S=2 relative to the hexacoordinated S=1. Indeed, as can be seen from Figure 1, 4 is computed to involve degenerate S=1 and S=2 states.[7] So, in 4 a competition is expected between the two spin states to effect C-H activation; which state dominates? In summation, the experimental relative reactivities of the four Fe=O reagents order in a puzzling sequence:What is the origin of this reactivity pattern, and what are the electronic and steric factors that shape this trend? Answering this question is important for establishing rules of design of effective catalysts for C-H activation.To answer these questions we studied the reactivities of 1-4 towards H-abstraction from CHD. The geometries of all the critical species along the H-abstraction paths of 1-3, which are di-positively charged, were optimized at the B3LYP/B1(CH 3 CN) (B1 is LACVP) level at the reaction solvent, to minimize self-interaction errors which cause artificial electron transfer in some of these systems.[8] For 4, which is neutral and hence less subject to these particular errors, [8] we used B3LYP/B1. All energies were subsequently estimated using a NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript larger basis set, B2 (B2 is LACV3P+*), and solvent corrections, using th...

Synthetically useful hydrocarbon oxidations are catalysed by bio-inspired non-heme iron complexes using hydrogen peroxide as oxidant, and carboxylic acid addition enhances their selectivity and catalytic efficiency. Talsi has identified a low-intensity g ¼ 2.7 electron paramagnetic resonance signal in such catalytic systems and attributed it to an oxoiron(V)-carboxylate oxidant. Herein we report the use of Fe II (TPA*) (TPA* ¼ tris (3,5-dimethyl-4-methoxypyridyl-2-methyl)amine) to generate this intermediate in 50% yield, and have characterized it by ultraviolet-visible, resonance Raman, Mössbauer and electrospray ionization mass spectrometric methods as a low-spin acylperoxoiron(III) species. Kinetic studies show that this intermediate is not itself the oxidant but decays via a unimolecular rate-determining step to unmask a powerful oxidant. The latter is shown by density functional theory calculations to be an oxoiron(V) species that oxidises substrate without a barrier. This study provides a mechanistic scenario for understanding catalyst reactivity and selectivity as well as a basis for improving catalyst design.