Chunsen Li

A Theory for Bioinorganic Chemical Reactivity of Oxometal Complexes and Analogous Oxidants: The Exchange and Orbital-Selection Rules

Over the past decades metalloenzymes and their synthetic models have emerged as an area of increasing research interest. The metalloenzymes and their synthetic models oxidize organic molecules using oxometal complexes (OMCs), especially oxoiron(IV)-based ones. Theoretical studies have helped researchers to characterize the active species and to resolve mechanistic issues. This activity has generated massive amounts of data on the relationship between the reactivity of OMCs and the transition metals identity, oxidation state, ligand sphere, and spin state. Theoretical studies have also produced information on transition state (TS) structures, reaction intermediates, barriers, and rate-equilibrium relationships. For example, the experimental-theoretical interplay has revealed that nonheme enzymes carry out H-abstraction from strong C-H bonds using high-spin (S = 2) oxoiron(IV) species with four unpaired electrons on the iron center. However, other reagents with higher spin states and more unpaired electrons on the metal are not as reactive. Still other reagents carry out these transformations using lower spin states with fewer unpaired electrons on the metal. The TS structures for these reactions exhibit structural selectivity depending on the reactive spin states. The barriers and thermodynamic driving forces of the reactions also depend on the spin state. H-Abstraction is preferred over the thermodynamically more favorable concerted insertion into C-H bonds. Currently, there is no unified theoretical framework that explains the totality of these fascinating trends. This Account aims to unify this rich chemistry and understand the role of unpaired electrons on chemical reactivity. We show that during an oxidative step the d-orbital block of the transition metal is enriched by one electron through proton-coupled electron transfer (PCET). That single electron elicits variable exchange interactions on the metal, which in turn depend critically on the number of unpaired electrons on the metal center. Thus, we introduce the exchange-enhanced reactivity (EER) principle, which predicts the preferred spin state during oxidation reactions, the dependence of the barrier on the number of unpaired electrons in the TS, and the dependence of the deformation energy of the reactants on the spin state. We complement EER with orbital-selection rules, which predict the structure of the preferred TS and provide a handy theory of bioinorganic oxidative reactions. These rules show how EER provides a Hunds Rule for chemical reactivity: EER controls the reactivity landscape for a great variety of transition-metal complexes and substrates. Among many reactivity patterns explained, EER rationalizes the abundance of high-spin oxoiron(IV) complexes in enzymes that carry out bond activation of the strongest bonds. The concepts used in this Account might also be applicable in other areas such as in f-block chemistry and excited-state reactivity of 4d and 5d OMCs.

Oxidation of tertiary amines by cytochrome p450-kinetic isotope effect as a spin-state reactivity probe.

Two types of tertiary amine oxidation processes, namely, N-dealkylation and N-oxygenation, by compound I (Cpd I) of cytochrome P450 are studied theoretically using hybrid DFT calculations. All the calculations show that both N-dealkylation and N-oxygenation of trimethylamine (TMA) proceed preferentially from the low-spin (LS) state of Cpd I. Indeed, the computed kinetic isotope effects (KIEs) for the rate-controlling hydrogen abstraction step of dealkylation show that only the KIE(LS) fits the experimental datum, whereas the corresponding value for the high-spin (HS) process is much higher. These results second those published before for N,N-dimethylaniline (DMA), and as such, they further confirm the conclusion drawn then that KIEs can be a sensitive probe of spin state reactivity. The ferric-carbinolamine of TMA decomposes most likely in a non-enzymatic reaction since the Fe-O bond dissociation energy (BDE) is negative. The computational results reveal that in the reverse reaction of N-oxygenation, the N-oxide of aromatic amine can serve as a better oxygen donor than that of aliphatic amine to generate Cpd I. This capability of the N-oxo derivatives of aromatic amines to transfer oxygen to the heme, and thereby generate Cpd I, is in good accord with experimental data previously reported.

A mononuclear non-heme high-spin iron(III)-hydroperoxo complex as an active oxidant in sulfoxidation reactions.

We report the first direct experimental evidence showing that a high-spin iron(III)-hydroperoxo complex bearing an N-methylated cyclam ligand can oxidize thioanisoles. DFT calculations showed that the reaction pathway involves heterolytic O-O bond cleavage and that the choice of the heterolytic pathway versus the homolytic pathway is dependent on the spin state and the number of electrons in the d(xz) orbital of the Fe(III)-OOH species.

Enhancing CO2 electrolysis through synergistic control of non-stoichiometry and doping to tune cathode surface structures

Sustainable future energy scenarios require significant efficiency improvements in both electricity generation and storage. High-temperature solid oxide cells, and in particular carbon dioxide electrolysers, afford chemical storage of available electricity that can both stabilize and extend the utilization of renewables. Here we present a double doping strategy to facilitate CO2 reduction at perovskite titanate cathode surfaces, promoting adsorption/activation by making use of redox active dopants such as Mn linked to oxygen vacancies and dopants such as Ni that afford metal nanoparticle exsolution. Combined experimental characterization and first-principle calculations reveal that the adsorbed and activated CO2 adopts an intermediate chemical state between a carbon dioxide molecule and a carbonate ion. The dual doping strategy provides optimal performance with no degradation being observed after 100 h of high-temperature operation and 10 redox cycles, suggesting a reliable cathode material for CO2 electrolysis.

Theory uncovers an unusual mechanism of DNA repair of a lesioned adenine by AlkB enzymes.

DNA-base lesions cause cancer and propagate into the genome. We use in-protein QM/MM calculations to study the repair of etheno-bridged adenine (εA) by the iron(IV)-oxo species of AlkB enzymes. Recent experimental investigations, using mass-spectrometry and in crystallo isolation, suggested that εA was repaired by formation of an epoxide (εA-ep) that further transforms to a glycol (εA-gl), ending finally in adenine and glyoxal. Theory reproduces the experimentally observed barrier for the rate-determining step and its pH dependence. However, as we show, the mass-spectrometrically identified species are side-byproducts unassociated with the repair mechanism. The repair is mediated by a zwitterionic species, of the same molecular mass as the epoxide, which transforms to an intermediate that matches the in crystallo trapped species in structure and mass, but is NOT the assumed εA-gl iron-glycol complex. Verifiable/falsifiable predictions, regarding the key protein residues, follow. The paper underscores the indispensable role of theory by providing atomistic descriptions of this vital mechanism, and guiding further experimental investigations.

Blended hydrogen atom abstraction and proton-coupled electron transfer mechanisms of closed-shell molecules

The paper addresses the surging topic of H-abstractions by closed-shell molecules, such as MnO4−, α-methylstyrene, ketones, metal-oxo reagents, etc. It is found that in the normal hydrogen atom transfer (HAT) regime, closed-shell abstractors require high barriers for H-abstraction. Under certain conditions a closed-shell abstractor can bypass this penalty via a proton-coupled electron transfer (PCET) mechanism. This occurs mainly in the identity reactions, e.g. MnO4− abstracting a hydrogen atom from MnO4H−·, but not in the corresponding non-identity reactions with alkanes. The usage of the valence bond (VB) diagram model allows us to characterize the HAT/PCET mechanistic relationship and bridge their reactivity patterns. It is thus shown that in the normal HAT regime, high barriers for closed-shell abstractors occur due to the additional promotion energy that is required in order to create a radical center and “prepare” the abstractor for H-abstraction. Mixing of the PCET states into the HAT states mitigates however these high barriers. The variable HAT/PCET mixing in a reaction series is discussed and its consequences for reactivity are outlined. It is shown that non-identity reactions sample PCET characters that depend, among other factors, on the C–H bond strength of the alkane, and hence may cause the Marcus analysis to produce different identity barriers for the same identity reaction.

How do perfluorinated alkanoic acids elicit cytochrome P450 to catalyze methane hydroxylation? An MD and QM/MM study

Recent experimental studies show that usage of perfluoro decanoic acid (PFDA), as a dummy substrate, can elicit P450BM3 to perform hydroxylation of small alkanes, such as methane (ref. 17) and propane (ref. 17 and ref. 18). To comprehend the mechanism whereby PFDA operates to potentiate P450BM3 to catalyze the hydroxylation of small alkanes, we used molecular dynamics (MD) and hybrid quantum mechanical / molecular mechanical (QM/MM) calculations. The MD results show that without the PFDA, methane escapes the active site, while the presence of PFDA can potentially induce a productive Cpd I-Methane juxtaposition for rapid oxidation. Nevertheless, when only a single methane molecule is present near the PFDA, it still escapes the pocket within less than a nanosecond. However, when three methane molecules are present in the pocket, they alternate quasi-periodically such that at all times (within 10 ns), a molecule of methane is always present in the proximity of Cpd I in a reactive conformation. Our results further demonstrate that the PFDA does not exert any electrostatic catalysis, whether the PFDA is in the protonated or deprotonated forms. Taken together, we conclude that methane hydroxylation requires, in addition to PFDA, a high partial pressure of methane that will cause a high methane concentration in the active site. Further study of ethane and propane hydroxylations demonstrates that higher alkane concentration is helpful for all the three small alkanes. Thus for the smallest alkane, methane, at least three molecules are necessary whereas for the larger ethane, two molecules are needed to force one ethane to be closer to Cpd I. Finally, for propane a second molecule is helpful but not absolutely necessary; for this molecule the PFDA may well be sufficient to keep propane close to Cpd I for efficient oxidation. We therefore propose that high alkane pressure should assist small alkane hydroxylation by P450 in a manner inversely proportional to the size of the alkanes.

Palladium‐Catalyzed Intermolecular Acylation of Aryl Diazoesters with ortho‐Bromobenzaldehydes

In this work, we describe a palladium-catalyzed intermolecular O acylation of α-diazoesters with ortho-bromobenzaldehydes. The C(sp2 )-H bond activation of the aldehyde is enabled by migratory insertion of a palladium carbene intermediate. The diazoesters act as modular three-atom units to build up key seven-membered palladacycles, which are transformed into a variety of isocoumarin derivatives upon reductive elimination. Mechanistic experiments and DFT calculations provide insight into the reaction pathway.

Synthesis, crystal structure and MMCT of new cyanide-bridged complexes cis-MII(dppm)2(CN)2(FeIIIX3)2 (M = Ru, Os)

The syntheses, crystal structures, IR and electronic absorption spectroscopy of two cyanide precursors cis-MII(dppm)2(CN)2 (M = Ru, 1; Os, 2) (dppm = bis(diphenylphosphino)methane) and four new cyanide-bridged complexes cis-MII(dppm)2(CN)2(FeIIIX3)2 (M = Ru, X = Cl, 3; M = Ru, X = Br, 4; M = Os, X = Cl, 5; M = Os, X = Br, 6) are reported. The crystal structural data, IR and the MMCT (metal-to-metal charge transfer) in the electronic absorption spectroscopy indicate the existence of some electron delocalization along FeIII–NC–MII arrays in complexes 3–6. The presence of a newer MMCT band of the Os-based complexes (5 and 6) than the Ru-based complexes (3 and 4) should result from the larger spin–orbit coupling (SOC) of OsII. Also the theoretical calculated values of the crystal structural data and IR spectra are consistent with the experimental values. Temperature-dependent magnetic properties of complexes 3–6 reveal the presence of the very weak metal–metal interaction between distant FeIII ions.

B-Heterocyclic Carbene Arising from Charge Shift: A Computational Verification

1-Borabicyclo[1.1.0]but-2(3)-ene (1BB) is a singlet biradical with two single electrons that can form an ionic resonance structure through a charge shift. The ionic resonance structure is a B-heterocyclic carbene (BHC), which can act as a carbene, Lewis base, or L- and Z-type ligand, to give adducts and complexes. Through a range of quantum methods, four types of stable compounds (A-D) derived from 1BB have been designed. These compounds retain the unique features of 1BB. As a consequence, the structures, stability, and Wiberg bond indices of the Lewis adducts of A-D with Lewis acids (BePh2 , BH3 , AlH3 , AlCl3 , C5 BH5 , and C13 BH9 ) and CuI , AgI , and AuI complexes have been investigated. Results show that A-D can indeed react as carbenes. Interestingly, compounds A-D, as L-type ligands, can attach to BePh2 , BH3 , AlH3 , AlCl3 , C5 BH5 , C13 BH9 , and CuCl and form compounds with planar tetracoordinate carbon (ptC), whereas Z-type ligands A-D can bind to AgCl and AuCl to provide complexes with planar tetracoordinate boron (ptB). In addition, the binuclear complexes of ClX(1BB)CuCl (X=Ag, Au) have been studied and A-D behave as both L- and Z-type ligands, in which these complexes contain both ptC and ptB. Thus, a novel method for designing compounds with ptC and ptB is presented. These rationally designed compounds involve the elements of carbene, ptC, ptB, and L- and Z-type ligands, and are expected to be unique and useful in experimental chemistry once they are synthesized.