Mercury Methylation by Cobalt Corrinoids: Relativistic Effects Dictate the Reaction Mechanism

The methylation of Hg^II(SCH₃)₂ by corrinoid‐based methyl donors proceeds in a concerted manner through a single transition state by transfer of a methyl radical, in contrast to previously proposed reaction mechanisms. This reaction mechanism is a consequence of relativistic effects that lower the energies of the mercury 6p_1/2 and 6p_3/2 orbitals, making them energetically accessible for chemical bonding. In the absence of spin–orbit coupling, the predicted reaction mechanism is qualitatively different. This is the first example of relativity being decisive for the nature of an observed enzymatic reaction mechanism.     

Towards the Accurate Thermodynamic Characterization of Enzyme Reaction Mechanisms

We employed QM/MM molecular dynamics (MD) simulations to characterize the rate-limiting step of the glycosylation reaction of pancreatic α-amylase with combined DFT/molecular dynamics methods (PBE/def2-SVP : AMBER). Upon careful choice of four starting active site conformations based on thorough reactivity criteria, Gibbs energy profiles were calculated with umbrella sampling simulations within a statistical convergence of 1–2 kcal ⋅ mol⁻¹. Nevertheless, Gibbs activation barriers and reaction energies still varied from 11.0 to 16.8 kcal ⋅ mol⁻¹ and −6.3 to +3.8 kcal ⋅ mol⁻¹ depending on the starting conformations, showing that despite significant state-of-the-art QM/MM MD sampling (0.5 ns/profile) the result still depends on the starting structure. The results supported the one step dissociative mechanism of Asp197 glycosylation preceded by an acid-base reaction by the Glu233, which are qualitatively similar to those from multi-PES QM/MM studies, and thus support the use of the latter to determine enzyme reaction mechanisms.     

Lowering Energy Barriers in Surface Reactions through Concerted Reaction Mechanisms

Any technologically important chemical reaction typically involves a number of different elementary reaction steps consisting of bond‐breaking and bond‐making processes. Usually, one assumes that such complex chemical reactions occur in a step‐wise fashion where one single bond is made or broken at a time. Using first‐principles calculations based on density functional theory we show that the barriers of rate‐limiting steps for technologically relevant surface reactions are significantly reduced if concerted reaction mechanisms are taken into account.     

Theoretical Study of the Cycloaddition Reaction of a Tungsten‐Containing Carbonyl Ylide

The [3+2] cycloaddition reaction of a tungsten‐containing carbonyl ylide with methyl vinyl ether and the insertion reactions of the nonstabilized carbene complex intermediates produced have been investigated through the use of B3LYP density functional theory. The [3+2] cycloaddition reaction of the tungsten‐containing carbonyl ylide has been proven to proceed concertedly, reversibly, and with high endo selectivity. The intermolecular Si? H insertion reactions of the carbene complex intermediates have been proven to be favored over the intramolecular C? H insertion, in good agreement with experimental results. Moreover, the kinetic endo/exo ratio of the [3+2] cycloaddition reaction has been shown to determine the endo/exo selectivity of the Si? H insertion products. In addition, secondary orbital interactions involving the benzene ring and the carbonyl ligand on the metal center have turned out to strongly influence the high endo selectivity of the [3+2] cycloaddition reaction with methyl vinyl ether.     

On the Reaction of Glycerol Dehydratase with But‐3‐ene‐1,2‐diol

Intriguing inactivation : Calculations suggest that the ability of relatively high‐energy radical intermediates to inactivate glycerol dehydratase (GDH) may reflect a general and hitherto unidentified inactivation mechanism in the reaction of coenzyme B₁₂‐dependent enzymes and 3‐unsaturated 1,2‐diols (see scheme; AdoCbl: adenosylcobalamin or coenzyme B₁₂).

     

DFT Calculations Suggest a New Type of Self‐Protection and Self‐Inhibition Mechanism in the Mammalian Heme Enzyme Myeloperoxidase: Nucleophilic Addition of a Functional Water rather than One‐Electron Reduction

The mammalian heme enzyme myeloperoxidase (MPO) catalyzes the reaction of Cl^? to the antimicrobial‐effective molecule HOCl. During the catalytic cycle, a reactive intermediate “Compound I” (Cpd I) is generated. Cpd I has the ability to destroy the enzyme. Indeed, in the absence of any substrate, Cpd I decays with a half‐life of 100 ms to an intermediate called Compound II (Cpd II), which is typically the one‐electron reduced Cpd I. However, the nature of Cpd II, its spectroscopic properties, and the source of the additional electron are only poorly understood. On the basis of DFT and time‐dependent (TD)‐DFT quantum chemical calculations at the PBE0/6‐31G* level, we propose an extended mechanism involving a new intermediate, which allows MPO to protect itself from self‐oxidation or self‐destruction during the catalytic cycle. Because of its similarity in electronic structure to Cpd II, we named this intermediate Cpd II′. However, the suggested mechanism and our proposed functional structure of Cpd II′ are based on the hypothesis that the heme is reduced by charge separation caused by reaction with a water molecule, and not, as is normally assumed, by the transfer of an electron. In the course of this investigation, we found a second intermediate, the reduced enzyme, towards which the new mechanism is equally transferable. In analogy to Cpd II′, we named it Fe^II′. The proposed new intermediates Cpd II′ and Fe^II′ allow the experimental findings, which have been well documented in the literature for decades but not so far understood, to be explained for the first time. These encompass a) the spontaneous decay of Cpd I, b) the unusual (chlorin‐like) UV/Vis, circular dichroism (CD), and resonance Raman spectra, c) the inability of reduced MPO to bind CO, d) the fact that MPO‐Cpd II reduces SCN^? but not Cl^?, and e) the experimentally observed auto‐oxidation/auto‐reduction features of the enzyme. Our new mechanism is also transferable to cytochromes, and could well be viable for heme enzymes in general.     

Concerted and Stepwise Mechanisms in Metal‐Free and Metal‐Assisted [4+3] Cycloadditions Involving Allyl Cations

The thermal [4+3] cycloaddition reaction between allenes and tethered dienes (1,3‐butadiene and furan) assisted by transition metals (Au^I, Au^III, Pd^II, and Pt^II) was studied computationally within the density functional theory framework and compared to the analogous non‐organometallic process in terms of activation barriers, synchronicity and aromaticity of the corresponding transition states. It was found that the metal‐mediated cycloaddition reaction is concerted and takes place via transition structures that can be even more synchronous and more aromatic than their non‐organometallic analogues. However, the processes exhibit slightly to moderately higher activation barriers than the parent cycloaddition involving the hydroxyallylic cation. The bond polarization induced by the metal moiety is clearly related to the interaction of the transition metal with the allylic π* molecular orbital, which constitutes the LUMO of the initial reactant. Finally, replacement of the 1,3‐butadiene by furan caused the transformation to occur stepwise in both the non‐organometallic and metal‐assisted processes.     

Synthesis of Cyclooctatetraenes through a Palladium‐Catalyzed Cascade Reaction

Reported is a cascade reaction leading to fully substituted cyclooctatetraenes. This unexpected transformation likely proceeds through a unique 8π electrocyclization reaction of a ene triyne. DFT computations provide the mechanistic basis of this surprizing reaction.     

Mechanistic Insights into the Rhenium‐Catalyzed Alcohol‐To‐Olefin Dehydration Reaction

Rhenium‐based complexes are powerful catalysts for the dehydration of various alcohols to the corresponding olefins. Here, we report on both experimental and theoretical (DFT) studies into the mechanism of the rhenium‐catalyzed dehydration of alcohols to olefins in general, and the methyltrioxorhenium‐catalyzed dehydration of 1‐phenylethanol to styrene in particular. The experimental and theoretical studies are in good agreement, both showing the involvement of several proton transfers, and of a carbenium ion intermediate in the catalytic cycle.     

Quantum‐Chemical Study of the FeNCN Conversion‐Reaction Mechanism in Lithium‐ and Sodium‐Ion Batteries

We report a computational study on 3d transition‐metal (Cr, Mn, Fe, and Co) carbodiimides in Li‐ and Na‐ion batteries. The obtained cell voltages semi‐quantitatively fit the experiments, highlighting the practicality of PBE+U as an approach for modeling the conversion‐reaction mechanism of the FeNCN archetype with lithium and sodium. Also, the calculated voltage profiles agree satisfactorily with experiment both for full (Li‐ion battery) and partial (Na‐ion battery) discharge, even though experimental atomistic knowledge is missing up to now. Moreover, we rationalize the structural preference of intermediate ternaries and their characteristic lowering in the voltage profile using chemical‐bonding and Mulliken‐charge analysis. The formation of such ternary intermediates for the lithiation of FeNCN and the contribution of at least one ternary intermediate is also confirmed experimentally. This theoretical approach, aided by experimental findings, supports the atomistic exploration of electrode materials governed by conversion reactions.     

On the Prebiotic Synthesis of D‐Sugars Catalyzed by L‐Peptides: Assessments from First‐Principles Calculations

What accounts for a particular chiral selection in the case of a few sugars of prebiotic relevance, thereby mirroring the asymmetry observed in nature? By using first‐principles calculations, the generation of pentoses from glycolaldehyde (the initial product of the autocatalytic formose reaction), which has been detected in outer space), has been modeled by using L ‐Val‐L ‐Val as a primeval catalyst. Our theoretical study provides insight into the mechanism of this reaction and satisfactorily explains a few key molecular events. Our rationale agrees with the reported experimental data and shows that the D ‐configuration is only favored for ribose. L ‐pentoses are usually favored in the presence of L ‐configured dipeptides, as observed experimentally, although no chiral selection could be observed in the case of xylose. These results confirm that a prebiotic sugar soup could be fine‐tuned in the presence of shorter peptides as catalysts and that D ‐ribose would have also resulted in an advantageous imbalance for further amplification and chemical evolution.     

Enantioselective Arylation of N‐Tosylimines by Phenylboronic Acid Catalysed by a Rhodium/Diene Complex: Reaction Mechanism from Density Functional Theory

A DFT study of the reaction mechanism of the rhodium‐catalysed enantioselective arylation of (E)‐N‐propylidene‐4‐methyl‐benzenesulfonamide by phenylboronic acid [Lin et al J. Am. Chem. Soc.­ 2011 , 133, 12394] is reported. The catalyst ([{Rh(OH)(diene)}₂]) includes a chiral diene ligand and the reaction is conducted in 1,4‐dioxane in the presence of drying agents (4 Å molecular sieves). Because phenylboronic acid is in equilibrium with phenylboroxin and water under the reaction conditions, three catalytic cycles are proposed that differ in the way the transmetallation and the release of the product are brought about, depending on the availability of phenylboronic acid, water and boroxin in the reaction medium. Based on computations, a new mechanism for the title reaction is proposed, in which phenylboronic acid plays the double role of “aryl source” and proton donor. This path does not require the presence of adventitious water molecules, in keeping with a reaction conducted in a dry medium. Comparisons with the generally accepted mechanism for arylation of enones proposed by Hayashi and co‐workers (J. Am. Chem. Soc.­ 2002 , 124, 5052) show that the latter mechanism is less favourable and is not expected to operate in the case of the N‐tosylimine substrate considered herein. Finally, the possibility that phenylboroxin is the aryl source has also been investigated, but is not found to be competitive.     

Mechanism of the Tyrosine Ammonia Lyase Reaction—Tandem Nucleophilic and Electrophilic Enhancement by a Proton Transfer

Quantum mechanics/molecular mechanics calculations in tyrosine ammonia lyase (TAL) ruled out the hypothetical Friedel–Crafts (FC) route for ammonia elimination from L ‐tyrosine due to the high energy of FC intermediates. The calculated pathway from the zwitterionic L ‐tyrosine‐binding state (0.0 kcal mol^?1) to the product‐binding state ((E)‐coumarate+H₂N? MIO; ?24.0 kcal mol^?1; MIO=3,5‐dihydro‐5‐methylidene‐4H‐imidazol‐4‐one) involves an intermediate (IS, ?19.9 kcal mol^?1), which has a covalent bond between the N atom of the substrate and MIO, as well as two transition states (TS1 and TS2). TS1 (14.4 kcal mol^?1) corresponds to a proton transfer from the substrate to the N1 atom of MIO by Tyr300? OH. Thus, a tandem nucleophilic activation of the substrate and electrophilic activation of MIO happens. TS2 (5.2 kcal mol^?1) indicates a concerted C? N bond breaking of the N‐MIO intermediate and deprotonation of the pro‐S β position by Tyr60. Calculations elucidate the role of enzymic bases (Tyr60 and Tyr300) and other catalytically relevant residues (Asn203, Arg303, and Asn333, Asn435), which are fully conserved in the amino acid sequences and in 3D structures of all known MIO‐containing ammonia lyases and 2,3‐aminomutases.     

Mechanistic Origin of Cross‐Coupling Selectivity in Ni‐Catalysed Tishchenko Reactions

Mechanistic studies have been performed for the recently developed, Ni‐catalysed selective cross‐coupling reaction between aryl and alkyl aldehydes. A mono‐carbonyl activation (MCA) mechanism (in which one of the carbonyl groups is activated by oxidative addition) was found to be the most favourable pathway, and the rate‐determining step is oxidative addition. Analysing the origin of the observed cross‐coupling selectivity, we found the most favourable carbonyl activation step requires both coordination of the aryl aldehyde and oxidative addition of the alkyl aldehyde. Therefore, the stronger π‐accepting ability of the aryl aldehyde (relative to alkyl aldehyde) and the ease of oxidative addition of the alkyl aldehyde (relative to aryl aldehyde) are responsible for the cross‐coupling selectivity.     

Insights into the Mechanism of the Reaction between Tetrachloro‐p‐Benzoquinone and Hydrogen Peroxide and their Implications in the Catalytic Role of Water Molecules in Producing the Hydroxyl Radial

Detailed mechanisms for the formation of hydroxyl or alkoxyl radicals in the reactions between tetrachloro‐p‐benzoquinone (TCBQ) and organic hydroperoxides are crucial for better understanding the potential carcinogenicity of polyhalogenated quinones. Herein, the mechanism of the reaction between TCBQ and H₂O₂ has been systematically investigated at the B3LYP/6‐311++G** level of theory in the presence of different numbers of water molecules. We report that the whole reaction can easily take place with the assistance of explicit water molecules. Namely, an initial intermediate is formed first. After that, a nucleophilic attack of H₂O₂ onto TCBQ occurs, which results in the formation of a second intermediate that contains an OOH group. Subsequently, this second intermediate decomposes homolytically through cleavage of the O? O bond to produce a hydroxyl radical. Energy analyses suggest that the nucleophilic attack is the rate‐determining step in the whole reaction. The participation of explicit water molecules promotes the reaction significantly, which can be used to explain the experimental phenomena. In addition, the effects of F, Br, and CH₃ substituents on this reaction have also been studied.     

Structure and Mechanism Leading to Formation of the Cysteine Sulfinate Product Complex of a Biomimetic Cysteine Dioxygenase Model

Cysteine dioxygenase is a unique nonheme iron enzyme that is involved in the metabolism of cysteine in the body. It contains an iron active site with an unusual 3‐His ligation to the protein, which contrasts with the structural features of common nonheme iron dioxygenases. Recently, some of us reported a truly biomimetic model for this enzyme, namely a trispyrazolylborato iron(II) cysteinato complex, which not only has a structure very similar to the enzyme–substrate complex but also represents a functional model: Treatment of the model with dioxygen leads to cysteine dioxygenation, as shown by isolating the cysteine part of the product in the course of the work‐up. However, little is known on the conversion mechanism and, so far, not even the structure of the actual product complex had been characterised, which is also unknown in case of the enzyme. In a multidisciplinary approach including density functional theory calculations and X‐ray absorption spectroscopy, we have now determined the structure of the actual sulfinato complex for the first time. The Cys‐SO₂^? functional group was found to be bound in an η²‐O,O‐coordination mode, which, based on the excellent resemblance between model and enzyme, also provides the first support for a corresponding binding mode within the enzymatic product complex. Indeed, this is again confirmed by theory, which had predicted a η²‐O,O‐binding mode for synthetic as well as the natural enzyme.     

The Computational Road to Better Catalysts

Computational studies, especially those that use density functional theory (DFT), have become pervasive in the characterization, mechanistic study, and optimization of homogeneous organometallic catalysts, and the “rational” design of such catalysts seems within reach once more. But how advanced, user‐friendly, and reliable are the computational tools that are currently available? Here we summarize the current state of the art for predictive computational organometallic chemistry in reference to the different stages of catalyst development by considering characterization, mechanistic studies, fine‐tuning/optimization, and evaluation of novel designs. We also assess critically where the strengths and weaknesses of computational studies lie and hence map out the road ahead for the design and discovery of novel catalysts in silico and in combination with targeted experimental studies.     

Reaction of Amino Acids,Di‐ and Tripeptides with the Environmental Oxidant NO3.: A Laser Flash Photolysis and Computational Study

Absolute rate coefficients for the reaction between the important environmental free radical oxidant NO₃^. and a series of N‐ and C‐protected amino acids, di‐ and tripeptides were determined using 355 nm laser flash photolysis of cerium(IV) ammonium nitrate in the presence of the respective substrates in acetonitrile at 298±1 K. Through combination with computational studies it was revealed that the reaction with acyclic aliphatic amino acids proceeds through hydrogen abstraction from the α‐carbon, which is associated with a rate coefficient of about 1.8×10⁶ m ^?1 s^?1 per abstractable hydrogen atom. The considerably faster reaction with phenylalanine [k=(1.1±0.1)×10⁷ m ^?1 s^?1] is indicative for a mechanism involving electron transfer. An unprecedented amplification of the rate coefficient by a factor of 7–20 was found with di‐ and tripeptides that contain more than one phenylalanine residue. This suggests a synergistic effect between two aromatic rings in close vicinity, which makes such peptide sequences highly vulnerable to oxidative damage by this major environmental pollutant.