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Here, an exhaustive exploration of the reaction mechanism toward the chlorination process carried out by SalL, a chlorinase enzyme that catalyzes the conversion of SAM into 5′‐chloro‐5′‐deoxyadenosine through an SN2 reaction, is presented. To this end, molecular dynamics simulations and quantum mechanical/molecular mechanics calculations are performed, and 14 density functionals are benchmarked. Among the tested functionals, TPSSh(BJ) provides the closest energy barrier to experimental value. Three configurations of interaction between chloride and the halogen pocket are found, where the best model exhibits a barrier height of 20.1 kcal mol−1, close to the 19.9 kcal mol−1 experimentally obtained. This model is characterized by the chloride interacting with the backbone‐amide of Gly131 and Tyr130. The reaction pathway is calculated through the intrinsic reaction coordinate approach, and it is characterized using reaction force analysis and the activation‐strain model with energy decomposition analysis to obtain chemical insights into the inner working of this enzyme. According to the main findings, the overstabilization of the halogen binding on the active site increases the barrier height, explaining the lack of activity against fluoride, while the interaction energy between nucleophile−electrophile is responsible of reducing the barrier height, with the orbital interaction energy as the main stabilizing factor during the chlorination process. Chlorinase (SalL) is an enzyme involved in the biosynthesis pathway of Salinosporamide A. Here, the reaction mechanism of SAM chlorination and fluorination in SalL using QM/MM calculations is studied. The analysis indicates that the configuration of interaction between the halide and the halogen pocket contributes to the reduced barrier height, favoring the charge transfer process during the reaction.

We have quantum chemically investigated the catalytic effect of hydrogen bonding organocatalysts, (H2N)2C=X (X=O, S, Se, NH, PH, AsH, CH2, SiH2 GeH2), such as urea, on the classic Diels‐Alder reaction. All studied hydrogen bond donor catalysts enhance the Diels‐Alder reaction between acrolein and 1,3‐butadiene to a similar extent. Our activation strain and Kohn‐Sham molecular orbital analyses show that these organocatalysts lower the reaction barrier by polarizing the π‐orbitals away from the reactive carbon atoms of acrolein, reducing the Pauli repulsion between the reactants. Interestingly, this catalytic mechanism is not limited to >C=X moieties with relatively electronegative X (e. g., O, S, NH) but extends to situations like >C=CH2 and even >C=SiH2. Quantum chemical activation strain analyses show that urea‐derived hydrogen‐bond organocatalysts, including unconventional alternatives to the C=O group (e. g., C=C and C=Si), lower the Diels‐Alder reaction barrier between butadiene and acrolein by Pauli lowering catalysis.

The influence of transition-state aromaticity on the barrier heights of concerted pericyclic reactions is summarized herein. To this end, selected representative examples ranging from fundamental processes such as Diels–Alder or Alder–ene reactions to double-group transfer reactions or 1,3-dipolar cycloadditions involving metal complexes are presented. It is found that while more synchronous processes tend to exhibit greater aromatic character in their transition states, this increased aromaticity does not necessarily correlate with lower activation barriers. State-of-the-art computational methods on reactivity, such as the combined activation strain model (ASM)–energy decomposition analysis (EDA) method, reveal that factors other than aromaticity govern the barrier heights of these pericyclic reactions.

A density functional theory (DFT) study combined with the steric maps of buried volume (%VBur) as molecular descriptors and an energy decomposition analysis through the ASM (activation strain model)–NEDA (natural energy decomposition analysis) approach were applied to investigate the origins of stereoselectivity for propene polymerization promoted by pyridylamido-type nonmetallocene systems. The relationships between the fine tuning of the ligand and the propene stereoregularity were rationalized (e.g., the metallacycle size, chemical nature of the bridge, and substituents at the ortho-position on the aniline moieties). The DFT calculations and %VBur steric maps reproduced the experimental trend: substituents on the bridge and on the ortho-positions of aniline fragments enhance the stereoselectivity. The ASM–NEDA analysis enabled the separation of the steric and electronic effects and revealed how subtle ligand modification may affect the stereoselectivity of the process.

The Front Cover shows two lorries along the road directed to ‘H2O2 reduction’ destination. The selenol (SeH) lorry is in front, being faster than the thiol (SH) lorry. This cartoon represents the situation of glutathione peroxidase, in which the presence of selenium rather than sulfur warrants a significantly faster hydroperoxide reduction along the same mechanistic path. This can be explained on the basis of the chemistry of the two chalcogens as illustrated in our paper. More information can be found in the Full Paper by L. Orian and co‐workers.

The so‐called peroxidatic cysteines and selenocysteines in proteins reduce hydroperoxides through a dual attack to the peroxide bond in a two‐step mechanism. First, a proton dislocation from the thiol/selenol to a close residue of the enzymatic pocket occurs. Then, a nucleophilic attack of the anionic cysteine/selenocysteine to one O atom takes place, while the proton is shuttled back to the second O atom, promoting the formation of a water molecule. In this computational study, we use a molecular model of GPx to demonstrate that the enzymatic environment significantly lowers the barrier of the latter SN2 step. Particularly, in our Se‐based model the energy barriers for the two steps are 29.82 and 2.83 kcal mol−1, both higher than the corresponding barriers computed in the enzymatic cluster, i. e., 21.60 and null, respectively. Our results, obtained at SMD‐B3LYP‐D3(BJ)/6‐311+G(d,p), cc‐pVTZ//B3LYP‐D3(BJ)/6‐311G(d,p), cc‐pVTZ level of theory, show that the mechanistic details can be well reproduced using an oversimplified model, but the energetics is definitively more favorable in the GPx active site. In addition, we pinpoint the role of the chalcogen in the peroxide reduction process, rooting the advantages of the presence of selenium in its acidic and nucleophilic properties. Be fast or be last! The reaction rate is a highly critical factor when considering enzymatic hydroperoxide reduction by GPx in order to relieve harmful conditions such as oxidative stress. Selenoprotein was squeezed into an oversimplified QM treatable cluster to precisely pinpoint how an enhanced reactivity is observed in the presence of a single Se atom instead of an S atom.

We have quantum chemically analyzed the structure and stability of archetypal chalcogen‐bonded model complexes D2Ch⋅⋅⋅A− (Ch = O, S, Se, Te; D, A = F, Cl, Br) using relativistic density functional theory at ZORA‐M06/QZ4P. Our purpose is twofold: (i) to compute accurate trends in chalcogen‐bond strength based on a set of consistent data; and (ii) to rationalize these trends in terms of detailed analyses of the bonding mechanism based on quantitative Kohn‐Sham molecular orbital (KS‐MO) theory in combination with a canonical energy decomposition analysis (EDA). At odds with the commonly accepted view of chalcogen bonding as a predominantly electrostatic phenomenon, we find that chalcogen bonds, just as hydrogen and halogen bonds, have a significant covalent character stemming from strong HOMO−LUMO interactions. Besides providing significantly to the bond strength, these orbital interactions are also manifested by the structural distortions they induce as well as the associated charge transfer from A− to D2Ch. Covalency strikes back! Our quantitative molecular orbital analyses show that chalcogen bonds have a considerable covalent component and are far from being purely electrostatic phenomena. They closely resemble halogen bonds and have similarity with hydrogen bonds.

Sulfoxides and selenoxides oxidize thiols to disulfides while being reduced back to sulfides and selenides. While the reduction mechanism of sulfoxides to sulfides has been thoroughly explored experimentally as well as computationally, less attention has been devoted to the heavier selenoxides. In this work, we explore the reductive mechanism of dimethyl selenoxide, as an archetypal selenoxide and, for the sake of comparison, the reductive mechanism of dimethyl sulfoxide to gain insight into the role of the chalcogen on the reaction substrate. Particular attention is devoted to the key role of sulfurane and selenurane intermediates. Moreover, the capacity of these system to oxidize selenols rather than thiols, leading to the formation of selenyl sulfide bridges, is explored in silico. Notably, this analysis provides molecular insight into the role of selenocysteine in methionine sulfoxide reductase selenoenzyme. The activation strain model of chemical reactivity is employed in the studied reactions as an intuitive tool to bridge the computationally predicted effect of the chalcogen on the chalcogenoxide as well as on the chalcogenol.

In the current literature, many non-covalent interaction (NCI) donors have been proposed that can potentially catalyze Diels-Alder (DA) reactions. In this study, a detailed analysis of the governing factors in Lewis acid and non-covalent catalysis of three types of DA reactions was carried out, for which we selected a set of hydrogen-, halogen-, chalcogen-, and pnictogen-bond donors. We found that the more stable the NCI donor–dienophile complex, the larger the reduction in DA activation energy. We also showed that for active catalysts, a significant part of the stabilization was caused by orbital interactions, though electrostatic interactions dominated. Traditionally, DA catalysis was attributed to improved orbital interactions between the diene and dienophile. Recently, Vermeeren and co-workers applied the activation strain model (ASM) of reactivity, combined with the Ziegler-Rauk-type energy decomposition analysis (EDA), to catalyzed DA reactions in which energy contributions for the uncatalyzed and catalyzed reaction were compared at a consistent geometry. They concluded that reduced Pauli repulsion energy, and not enhanced orbital interaction energy, was responsible for the catalysis. However, when the degree of asynchronicity of the reaction is altered to a large extent, as is the case for our studied hetero-DA reactions, the ASM should be employed with caution. We therefore proposed an alternative and complementary approach, in which EDA values for the catalyzed transition-state geometry, with the catalyst present or deleted, can be compared one to one, directly measuring the effect of the catalyst on the physical factors governing the DA catalysis. We discovered that enhanced orbital interactions are often the main driver for catalysis and that Pauli repulsion plays a varying role.

Context Quantum chemical modeling (DFT-PBE0/cc-pVTZ) of the [4 + 2]-cycloaddition reaction of 1,3-cyclopentadiene (CPD) to (exo/endo)-dicyclopentadiene (DCPD) was carried out, resulting in 14 products—CPD trimers. According to calculations, exo-addition of CPD to the norbornene (NB) fragment of DCPD and trans-addition of CPD to the cyclopentene (CP) fragment of DCPD are kinetically preferred. Ring strain energies E RS were calculated for all trimers using the homodesmotic reaction approach. The least strained trimers are formed by exo-addition of CPD to the NB fragment of exo-DCPD, while the most strained ones are formed by endo-addition of CPD to the NB fragment of endo-DCPD. E RS values are in good agreement with thermodynamic stability of trimers. Analysis of activation energy using the activation strain model showed steric effects causing deformation of the DCPD molecule upon reaching the transition state to be the leading factor of the magnitude of the cycloaddition reaction activation barrier. Deformation of the DCPD molecule mostly occurs in two dihedral angles—the angle of escape of H atoms from the plane of the double bond involved in cycloaddition and the angle between the NB and CP fragments. The sum of deviations of these angles in the transition states (or products) structures is in good agreement with Gibbs activation energies of cycloaddition reactions of CPD to DCPD. Methods Quantum chemical calculations were carried out using density functional theory in Gaussian 09 software. Hybrid exchange–correlation PBE0 functional was used with cc-pVTZ basis set.