Computational Study on the Attack of .OH Radicals on Aromatic Amino Acids

The attack of hydroxyl radicals on aromatic amino acid side chains, namely phenylalanine, tyrosine, and tryptophan, have been studied by using density functional theory. Two reaction mechanisms were considered: 1) Addition reactions onto the aromatic ring atoms and 2) hydrogen abstraction from all of the possible atoms on the side chains. The thermodynamics and kinetics of the attack of a maximum of two hydroxyl radicals were studied, considering the effect of different protein environments at two different dielectric values (4 and 80). The obtained theoretical results explain how the radical attacks take place and provide new insight into the reasons for the experimentally observed preferential mechanism. These results indicate that, even though the attack of the first ^.OH radical on an aliphatic C atom is energetically favored, the larger delocalization and concomitant stabilization that are obtained by attack on the aromatic side chain prevail. Thus, the obtained theoretical results are in agreement with the experimental evidence that the aromatic side chain is the main target for radical attack and show that the first ^.OH radical is added onto the aromatic ring, whereas a second radical abstracts a hydrogen atom from the same position to obtain the oxidized product. Moreover, the results indicate that the reaction can be favored in the buried region of the protein.     

Radical Polymerization of Vinyl Acetate with Bis(tetramethylheptadionato)cobalt(II): Coexistence of Three Different Mechanisms

Poly(vinyl acetate) by OMRP : Increasing the steric encumbrance of the β‐diketonate R substituents in vinyl acetate (VAc) polymerization mediator [Co{OC(R)CHC(R)O}₂] from Me to tBu sufficiently weakens the Co^III? PVAc bond of the polymer chain to allow it to operate by both associative (degenerative transfer) and dissociative (organometallic radical polymerization, OMRP) mechanisms (see scheme). The Co^III? PVAc species also acts as a transfer agent in the absence of Lewis bases, whereas the Co^II complex shows catalytic chain transfer (CCT) activity.

     

Photolysis of o‐Nitrobenzaldehyde in the Gas Phase: A New OH. Formation Channel

New route to gas‐phase OH^. : UV photolysis of gaseous o‐nitrobenzaldehyde forms OH radicals via the transformation into the ketene or o‐nitrosobenzoic acid intermediate (see figure). The OH^. product is monitored by single‐photon laser‐induced fluorescence (LIF).

     

PPV Polymerization through the Gilch Route: Diradical Character of Monomers

Despite various studies on the polymerization of poly(p‐phenylene vinylene) (PPV) through different precursor routes, detailed mechanistic knowledge on the individual reaction steps and intermediates is still incomplete. The present study aims to gain more insight into the radical polymerization of PPV through the Gilch route. The initial steps of the polymerization involve the formation of a p‐quinodimethane intermediate, which spontaneously self‐initiates through a dimerization process leading to the formation of diradical species; chain propagation ensues on both sides of the diradical or chain termination occurs by the formation of side products, such as [2.2]paracyclophanes. Furthermore, different p‐quinodimethane systems were assessed with respect to the size of their aromatic core as well as the presence of heteroatoms in/on the conjugated system. The nature of the aromatic core and the specific substituents alter the electronic structure of the p‐quinodimethane monomers, affecting the mechanism of polymerization. The diradical character of the monomers has been investigated with several advanced methodologies, such as spin‐projected UHF, CASSCF, CASPT2, and DMRG calculations. It was shown that larger aromatic cores led to a higher diradical character in the monomers, which in turn is proposed to cause rapid initiation.     

A DFT Study of the Nitric Oxide and Tyrosyl Radical Interaction: A Proposed Radical Mechanism

The present study employs a complete theoretical investigation, at the B3LYP/cc‐pVTZ level of theory, of the interactions between the tyrosyl radical and nitric oxide, exploring in detail the nitrotyrosine formation radical mechanism. Tyrosyl radicals play an essential role in catalytic reactions of numerous enzymes and biological systems have regulated appropriate mechanisms for their formation. Nitric oxide reacts with the tyrosyl radical and affords a weak intermediate complex which, through a sequence of non‐ionic water catalyzed and biologically feasible intermediate reactions, yields the iminoxyl radical. The iminoxyl radical further combines with hydroxyl radical, a species present in pathophysiological conditions, to yield nitrotyrosine.     

Hydride Ligands Make the Difference: Density Functional Study of the Mechanism of the Murai Reaction Catalyzed by [Ru(H)2(H2)2(PR3)2] (R=cyclohexyl)

The catalytic cycle for the Murai reaction at room temperature between ethylene and acetophenone catalyzed by [Ru(H)₂(H₂)₂(PMe₃)₂] has been studied computationally at the B3PW91 level. The active species is the ruthenium dihydride complex [Ru(H)₂(PMe₃)₂]. Coordination of the ketone group to Ru induces very easy C H bond cleavage. Coordination of ethylene after ketone de-coordination, followed by ethylene insertion into a Ru H bond, creates the Ru ethyl bond. Isomerization of the complex to a Ru^IV intermediate creates the geometry adapted to C C bond formation. Re-coordination of the ketone before the C C coupling lowers the energy of the corresponding TS. The highest point on the potential energy surface (PES) is the TS for the isomerization to the Ru^IV intermediate, which prepares the catalyst geometry for the C C coupling step. Inclusion of dispersion corrections significantly lowers the height of the overall activation barrier. The actual bond cleavage and bond forming processes are associated to low activation barriers because of the presence of hydrogen atoms around the Ru center. They act as redox buffers through formation and breaking of H H bonds in the coordination sphere. This flexibility allows optimal repartition of the various ligands according to the change in stereoelectronic demands along the catalytic cycle.     

Reaction mechanism of apocarotenoid oxygenase (ACO): a DFT study

The mechanism of the oxidative cleavage catalyzed by apocarotenoid oxygenase (ACO) was studied by using a quantum chemical (DFT: B3 LYP) method. Based on the available crystal structure, relatively large models of the unusual active-site region, in which a ferrous ion is coordinated by four histidines and no negatively charged ligand, were selected and used in the computational investigation of the reaction mechanism. The results suggest that binding of dioxygen to the ferrous ion in the active site promotes one-electron oxidation of carotenoid leading to a substrate radical cation and a Fe-bound superoxide radical. Recombination of the two radicals, which can be realized in at least two different ways, yields a reactive peroxo species that subsequently evolves into either a dioxetane or an epoxide intermediate. The former easily decays into the final aldehyde products, whereas the oxidation of the epoxide to the proper products of the reaction requires involvement of a water molecule. The calculated activation barriers favor the dioxetane mechanism, yet the mechanism involving the epoxide intermediate cannot be ruled out.     

Radical-Pair Formation in Hydrocarbon (Aut)Oxidation

The reaction profiles for the uni- and bimolecular decomposition of benzyl hydroperoxide have been studied in the context of initiation reactions for the (aut)oxidation of hydrocarbons. The unimolecular dissociation of benzyl hydroperoxide was found to proceed through the formation of a hydrogen-bonded radical-pair minimum located +181 kJ mol⁻¹ above the hydroperoxide substrate and around 15 kJ mol⁻¹ below the separated radical products. The reaction of toluene with benzyl hydroperoxide proceeds such that O−O bond homolysis is coupled with a C−H bond abstraction event in a single kinetic step. The enthalpic barrier of this molecule-induced radical formation (MIRF) process is significantly lower than that of the unimolecular O−O bond cleavage. The same type of reaction is also possible in the self-reaction between two benzyl hydroperoxide molecules forming benzyloxyl and hydroxyl radical pairs along with benzaldehyde and water as co-products. In the product complexes formed in these MIRF reactions, both radicals connect to a centrally placed water molecule through hydrogen-bonding interactions.     

Nucleophilic Substitution at Phosphorus Centers (SN2@P)

We have studied the characteristics of archetypal model systems for bimolecular nucleophilic substitution at phosphorus (S_N2@P) and, for comparison, at carbon (S_N2@C) and silicon (S_N2@Si) centers. In our studies, we applied the generalized gradient approximation (GGA) of density functional theory (DFT) at the OLYP/TZ2P level. Our model systems cover nucleophilic substitution at carbon in X^?+CH₃Y (S_N2@C), at silicon in X^?+SiH₃Y (S_N2@Si), at tricoordinate phosphorus in X^?+PH₂Y (S_N2@P3), and at tetracoordinate phosphorus in X^?+POH₂Y (S_N2@P4). The main feature of going from S_N2@C to S_N2@P is the loss of the characteristic double‐well potential energy surface (PES) involving a transition state [X? CH₃? Y]^? and the occurrence of a single‐well PES with a stable transition complex, namely, [X? PH₂? Y]^? or [X? POH₂? Y]^?. The differences between S_N2@P3 and S_N2@P4 are relatively small. We explored both the symmetric and asymmetric (i.e. X, Y=Cl, OH) S_N2 reactions in our model systems, the competition between backside and frontside pathways, and the dependence of the reactions on the conformation of the reactants. Furthermore, we studied the effect, on the symmetric and asymmetric S_N2@P3 and S_N2@P4 reactions, of replacing hydrogen substituents at the phosphorus centers by chlorine and fluorine in the model systems X^?+PR₂Y and X^?+POR₂Y, with R=Cl, F. An interesting phenomenon is the occurrence of a triple‐well PES not only in the symmetric, but also in the asymmetric S_N2@P4 reactions of X^?+POCl₂? Y.     

A Stable and Crystalline Triarylgermyl Radical: Structure and EPR Spectra

A radical thing : After being obtained unexpectedly in low yields, the synthesis of the first stable triarylgermyl radical ^.Ge[3,5‐tBu₂‐2,6‐(EtO)₂C₆H]₃ ( 1 ; C gray, O blue) was considerably optimized, and the product was investigated by X‐ray analysis and EPR spectroscopy. The results were compared with DFT‐MO studies for the model compound ^.Ge[2,6‐(MeO)₂C₆H₃].

     

Depolymerization of Free‐Radical Polymers with Spin Migrations

The mechanism of depolymerization is one of the most essential issues in chemical engineering and materials science. In this work, we investigate the depolymerization reactions of three typical free‐radical poly(alpha‐methylstyrene) tetramers by using first‐principles density functional theory. The calculated results show that these reactions all need to overcome the energy barriers in the range of 0.58 to 0.77 eV, and that breaking the C?C bond at the chain end leads to the dissociation of alpha‐methylstyrene monomers from the polymers. Electronic‐structure analysis indicates that the reactions occur easily at the CR₃ unsaturated end, and that the frontier molecular orbitals that participate in the reactions are mainly localized at the unsaturated ends. Meanwhile, spin population analysis presents the unique net spin‐transfer process in free‐radical depolymerization reactions. We hope the current findings can contribute to understanding the free‐radical depolymerization mechanism and help guide future experiments.     

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.     

Ethylene biosynthesis by 1-aminocyclopropane-1-carboxylic acid oxidase: a DFT study

The reaction catalyzed by the plant enzyme 1-aminocyclopropane-1-carboxylic acid oxidase (ACCO) was investigated by using hybrid density functional theory. ACCO belongs to the non-heme iron(II) enzyme superfamily and carries out the bicarbonate-dependent two-electron oxidation of its substrate ACC (1-aminocyclopropane-1-carboxylic acid) concomitant with the reduction of dioxygen and oxidation of a reducing agent probably ascorbate. The reaction gives ethylene, CO(2), cyanide and two water molecules. A model including the mononuclear iron complex with ACC in the first coordination sphere was used to study the details of O-O bond cleavage and cyclopropane ring opening. Calculations imply that this unusual and complex reaction is triggered by a hydrogen atom abstraction step generating a radical on the amino nitrogen of ACC. Subsequently, cyclopropane ring opening followed by O-O bond heterolysis leads to a very reactive iron(IV)-oxo intermediate, which decomposes to ethylene and cyanoformate with very low energy barriers. The reaction is assisted by bicarbonate located in the second coordination sphere of the metal.     

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.     

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.     

Unprecedented aromatic homolytic substitutions and cyclization of amide-iminyl radicals: experimental and theoretical study

Amide-iminyl radicals are versatile and efficient intermediates in cascade radical cyclizations of N-acylcyanamides. They are easily trapped by alkenes or (hetero-)aromatic rings and cyclize into a series of new heterocyclic compounds which bear a pyrroloquinazoline moiety. As an illustration of the synthetic importance of these compounds, the total synthesis of the natural antitumor compound luotonin A was achieved through a tin-free radical cascade cyclization process. Not only do amide-iminyl radicals lead to new tetracyclic heterocycles but these nitrogen-centered radical species also react in aromatic homolytic substitutions. Indeed, the amide-iminyl radical moiety unprecedentedly displaces methyl, methoxy, and fluorine radicals from an aromatic carbon atom. This seminal reaction in the field of radical chemistry has been developed experimentally and its mechanism has additionally been investigated by a theoretical study.     

Kinetics and Mechanisms for the Reactions of Phenyl Radical with Ketene and its Deuterated Isotopomer: An Experimental and Theoretical Study

Kinetics and mechanism for the reaction of phenyl radical (C₆H₅) with ketene (H₂C_β?C_α?O) were studied by the cavity ring‐down spectrometric (CRDS) technique and hybrid DFT and ab initio molecular orbital calculations. The C₆H₅ transition at 504.8 nm was used to detect the consumption of the phenyl radical in the reaction. The absolute overall rate constants measured, including those for the reaction with CD₂CO, can be expressed by the Arrhenius equation k=(5.9±1.8)×10¹¹ exp[?(1160±100)/T] cm³ mol^?1 s^?1 over a temperature range of 301–474 K. The absence of a kinetic isotope effect suggests that direct hydrogen abstraction forming benzene and ketenyl radical is kinetically less favorable, in good agreement with the results of quantum chemical calculations at the G2MS//B3LYP6‐31G(d) level of theory for all accessible product channels, including the above abstraction and additions to the C_α, C_β, and O sites. For application to combustion, the rate constants were extrapolated over the temperature range of 298–2500 K under atmospheric pressure by using the predicted transition‐state parameters and the adjusted entrance reaction barriers E_α=E_β=1.2 kcal mol^?1; they can be represented by the following expression in units of cm³ mol^?1 s^?1: k_α=6.2×10¹⁹ T^?2.3 exp[?7590/T] and k_β=3.2×10⁴ T^2.4 exp[?246/T].     

Revisiting the Molecular Roots of a Ubiquitously Successful Synthesis: Nickel(0) Nanoparticles by Reduction of [Ni(acetylacetonate)2]

The widely used preparation of Ni⁰ nanoparticles from [Ni(acac)₂] (acac=acetylacetonate) and oleylamine, often considered to be a thermolysis or a radical reaction, was analyzed anew by using a combination of DFT modeling and designed mechanistic experiments. Firstly, the reaction was followed up by using TGA to evaluate the energy barrier of the limiting step. Secondly, all the byproducts were identified using NMR spectroscopy, mass spectrometry, FTIR, and X‐ray crystallography. These methods allowed us to depict both main and side‐reaction pathways. Lastly, DFT modeling was utilized to assess the validity of this new scheme by identifying the limiting steps and evaluating the corresponding energy barriers. The oleylamine was shown to reduce the [Ni(acac)₂] complex not through a one‐electron radical mechanism, as often stated, but as an hydride donor through a two‐electron chemical reduction route. This finding has strong consequences not only for the design of further nanoparticles syntheses that use long‐chain amine as a reactant, but also for advanced understanding of catalytic reactions for which these nanoparticles can be employed.     

Evolutionary Algorithm-Based Crystal Structure Prediction for Copper(I) Fluoride

Despite numerous experimental studies since 1824, the binary copper(I) fluoride remains unknown. A crystal structure prediction has been carried out for CuF using the USPEX evolutionary algorithm and a dispersion-corrected hybrid density functional method. In total about 5000 hypothetical structures were investigated. The energetics of the predicted structures were also counter-checked with local second-order Møller–Plesset perturbation theory. Herein 39 new hypothetical copper(I) fluoride structures are reported that are lower in energy compared to the previously predicted cinnabar-type structure. Cuprophilic Cu−Cu interactions are present in all the low-energy structures, leading to ordered Cu substructures such as helical or zig-zag-type Cu−Cu motifs. The lowest-energy structure adopts a trigonal crystal structure with space group P3₁21. From an electronic point of view, the predicted CuF modification is a semiconductor with an indirect band gap of 2.3 eV.