We introduce a representative database of 22α,β-toβ,γ-enecarbonyl isomerisation energies (to be known as the EIE22 data-set). Accurate reaction energies are obtained at the complete basis-set limit CCSD(T) level by means of the high-level W1-F12thermochemical protocol. The isomerisation reactions involve a migration of one double bond that breaks the conjugatedπ-system. The considered enecarbonyls involve a range of common functional groups (e.g., Me, NH2,OMe,F,andCN). Apart from π-conjugation effects, the chemical environments are largely conserved on the two sides of the reactions and therefore the EIE22 data-set allows us to assess the performance of a variety of density functional theory (DFT) procedures for the calculation ofπ-conjugation stabilisation energies in enecarbonyls. We find that, with few exceptions (M05-2X, M06-2X,BMK, and BH&HLYP), all the conventional DFT procedures attain root mean square deviations (RMSDs) between 5.0 and 11.7 kJ mol⁻¹. The range-separated and double-hybrid DFT procedures, on the other hand, show good performance with RMSDs below the 'chemical accuracy' threshold. We also examine the performance of composite and standard ab initio procedures. Of these, SCS-MP2 offers the best performance-to-computational cost ratio with an RMSD of 0.8 kJ mol⁻¹.

Cholesterol oxidase (ChOx), a member of the glucose-methanol-choline (GMC) family, catalyzes the oxidation of the substrate via a hydride transfer mechanism and concomitant reduction of the FAD cofactor. Unlike other GMC enzymes, the conserved His447 is not the catalytic base that deprotonates the substrate in ChOx. Our QM/MM MD simulations indicate that the Glu361 residue acts as a catalytic base facilitating the hydride transfer from the substrate to the cofactor. We find that two rationally chosen point mutations (His447Gln and His447Asn) cause notable decreases in the catalytic activity. The binding free energy calculations show that the Glu361 and His447 residues are important in substrate binding. We also performed high-level double-hybrid density functional theory simulations using small model systems, which support the QM/MM MD results. Our work provides a basis for unraveling the substrate oxidation mechanism in GMC enzymes in which the conserved histidine does not act as a base.

The protein microenvironment surrounding the flavin cofactor in flavoenzymes is key to the efficiency and diversity of reactions catalysed by this class of enzymes. X-ray diffraction structures of oxidoreductase flavoenzymes have revealed recurrent features which facilitate catalysis, such as a hydrogen bond between a main chain nitrogen atom and the flavin redox center (N5). A neutron diffraction study of cholesterol oxidase has revealed an unusual elongated main chain nitrogen to hydrogen bond distance positioning the hydrogen atom towards the flavin N5 reactive center. Investigation of the structural features which could cause such an unusual occurrence revealed a positively charged lysine side chain, conserved in other flavin mediated oxidoreductases, in a second shell away from the FAD cofactor acting to polarize the peptide bond through interaction with the carbonyl oxygen atom. Double-hybrid density functional theory calculations confirm that this electrostatic arrangement affects the N-H bond length in the region of the flavin reactive center. We propose a novel second-order partial-charge interaction network which enables the correct orientation of the hydride receiving orbital of N5. The implications of these observations for flavin mediated redox chemistry are discussed.

The relatively weak London dispersion forces are the only interactions that could cause aggregation between simple aromatic molecules. The use of molecular dynamics and high-level ab initio computer simulations has been used to describe the aggregation and interactions between molecular systems containing benzene, naphthalene and anthracene. Mixtures containing one type of molecule (homogenous) and more than one type of molecule (heterogenous) were considered. Our results indicate that as molecular weight increases so does the temperature at which aggregation will occur. In all simulations, the mechanism of aggregation is through small clusters coalescing into larger clusters. The structural analysis of the molecules within the clusters reveals that benzene will orient itself in T-shaped and parallel displaced configurations. Molecules of anthracene prefer to orient themselves in a similar manner to a bulk crystal with no T-shaped configuration observed. The aggregation of these aromatic molecules is discussed in the context of astrochemistry with particular reference to the dust formation region around stars.

We examine the reaction of ethanol with glyoxal to form hemiacetal by means of the high-level G4(MP2) procedure. In this reaction, an intermolecular proton transfer is coupled with the formation of a covalent C-O bond between the two molecules. We find a novel catalytic reaction mechanism in which an H₂SO₄ catalyst reduces the barrier height from ΔH^‡₂₉₈ = 140.2 to 16.3 kJ mol^-1. It is well established that H₂SO₄ can effectively catalyse intramolecular proton transfers. This letter shows that H₂SO₄ can catalyse an intermolecular proton transfer that is coupled with a covalent bond formation.

Water contamination is generally considered to be detrimental to the performance of aprotic lithium-air batteries, whereas this view is challenged by recent contrasting observations. This has provoked a range of discussions on the role of water and its impact on batteries. In this work, a distinct battery chemistry that prevails in water-contaminated aprotic lithium-oxygen batteries is revealed. Both lithium ions and protons are found to be involved in the oxygen reduction and evolution reactions, and lithium hydroperoxide and lithium hydroxide are identified as predominant discharge products. The crystallographic and spectroscopic characteristics of lithium hydroperoxide monohydrate are scrutinized both experimentally and theoretically. Intriguingly, the reaction of lithium hydroperoxide with triiodide exhibits a faster kinetics, which enables a considerably lower overpotential during the charging process. The battery chemistry unveiled in this mechanistic study could provide important insights into the understanding of nominally aprotic lithium-oxygen batteries and help to tackle the critical issues confronted.

During a respiratory burst the enzyme myeloperoxidase generates significant amounts of hypohalous acids (HOX, X = Cl and Br) in order to inflict oxidative damage upon invading pathogens. However, excessive production of these potent oxidants is associated with numerous inflammatory diseases. It has been suggested that the endogenous antioxidant carnosine is an effective HOCl scavenger. Recent computational and experimental studies suggested that an intramolecular Cl⁺ transfer from the imidazole ring to the terminal amine might play an important role in the antioxidant activity of carnosine. Based on high-level ab initio calculations, we propose a similar reaction mechanism for the intramolecular Br⁺ transfer in carnosine. These results suggest that carnosine may be an effective HOBr scavenger. On the basis of the proposed reaction mechanism, we proceed to design systems that share similar structural features to carnosine but with enhanced HOX scavenging capabilities for X = Cl and Br. We find that (i) elongating the β-alanyl-glycyl side chain by one carbon reduces the reaction barriers by up to 44%, and (ii) substituting the imidazole ring with strong electron-donating groups reduces the reaction barriers by similar amounts. We also show that the above structural and electronic effects are largely additive. In an antioxidant candidate that involves both of these effects the reaction barriers are reduced by 71%.

We introduce a database of 20 accurate cycloreversion barrier heights of 5-membered heterocyclic rings (to be known as the CRBH20 database). In these reactions, dioxazole and oxathiazole rings are fragmented to form isocyanates, isothiocyanates, and carbonyls. The reference reaction barrier heights are obtained by means of the high-level, ab initio W1-F12 and W1w thermochemical protocols. We evaluate the performance of 65 contemporary density functional theory (DFT) and double-hybrid DFT (DHDFT) procedures. The CRBH20 database represents an extremely challenging test for these methods. Most of the conventional DFT functionals (74%) result in root-mean-square deviations (RMSDs) between 10 and 81 kJ mol^-1. The rest of the DFT functionals attain RMSDs = 5-10 kJ mol^-1. Of the 12 tested DHDFT functionals, only five result in RMSDs < 10 kJ mol^-1. The CRBH20 dataset also proves to be a surprisingly challenging target for composite and standard ab initio procedures.

Levoglucosenone (LGO) is an important anhydrosugar product of fast pyrolysis of cellulose and biomass. We use the high-level G4(MP2) thermochemical protocol to study the reaction mechanism for the formation of LGO from the 1,4:3,6-dianhydro-a-D-glucopyranose (DGP) pyrolysis intermediate. We find that the DGP-to-LGO conversion proceeds via a multistep reaction mechanism, which involves ring-opening, ring-closing, enol-to-keto tautomerization, hydration, and dehydration reactions. The rate-determining step for the uncatalyzed process is the enol-to-keto tautomerization (ΔG^‡₂₉₈ = 68.6 kcal mol^-1). We find that a water molecule can catalyze five of the seven steps in the reaction pathway. In the water-catalyzed process, the barrier for the enol-to-keto tautomerization is reduced by as much as 15.1 kcal mol^-1, and the hydration step becomes the rate-determining step with an activation energy of ΔG^‡₂₉₈ = 58.1 kcal mol^-1.

We evaluate the performance of standard and modified MPn procedures for a wide set of thermochemical and kinetic properties, including atomization energies, structural isomerization energies, conformational energies, and reaction barrier heights. The reference data are obtained at the CCSD(T)/CBS level by means of the Wn thermochemical protocols. We find that none of the MPn-based procedures show acceptable performance for the challenging W4-11 and BH76 databases. For the other thermochemical/kinetic databases, the MP2.5 and MP3.5 procedures provide the most attractive accuracy-to-computational cost ratios. The MP2.5 procedure results in a weighted-total-root-mean-square deviation (WTRMSD) of 3.4 kJ/mol, whilst the computationally more expensive MP3.5 procedure results in a WTRMSD of 1.9 kJ/mol (the same WTRMSD obtained for the CCSD(T) method in conjunction with a triple-zeta basis set). We also assess the performance of the computationally economical CCSD(T)/CBS(MP2) method, which provides the best overall performance for all the considered databases, including W4-11 and BH76.