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CONTEXT: The negative of the Shannon entropy derivative is proposed to account for electron density contraction as the chemical bonds are breaking and forming during a chemical reaction. We called this property the electron density contraction index, EDC, which allows identifying stages in a reaction that are dominated by electron contraction or expansion. Four different reactions were analyzed to show how the EDC index changes along the reaction coordinate. The results indicate that the rate of change of Shannon entropy is directly related to the rate of change of the electron density at the bond critical points between all the atomic pairs in the molecular systems. It is expected that EDC will complement the detailed analysis of reaction mechanisms that can be performed with the theoretical tools available to date. METHODS: Density functional theory calculations at the B3LYP/6-31G(d,p) level of theory were carried out using Gaussian 16 to analyze the reaction mechanisms of the four reactions studied. The reaction paths were obtained via the intrinsic reaction coordinate method, which served as the reaction coordinate to obtain the reaction force and the EDC profiles in each case. Shannon entropy and electron density at the bond critical points were calculated using the Multiwfn 3.7 package.

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In this research work, we examined the decomposition mechanisms of N-substituted diacetamides. We focused on the substituent effect on the nitrogen lone-pair electron delocalization, with electron-withdrawing and electron donor groups. DFT functionals used the following: B1LYP, B3PW91, CAMB3LYP, LC-BLYP, and X3LYP. Dispersion corrections (d3bj) with Becke-Johnson damping were applied when necessary to improve non-covalent interactions in the transition state. Pople basis sets with higher angular moments and def2-TZVP basis sets were also applied and were crucial for obtaining consistent thermodynamic parameters. The proposed mechanism involves a six-membered transition state with the extraction of an α hydrogen. Several conformers of N-diacetamides were used to account for the decrease in entropy in the transition state in the rate-determining state. All calculations, including natural bond orbital (NBO) analyses, were performed using the Gaussian16 computational package and its GaussView 6.0 visualizer, along with VMD and GNUPLOT software. The isosurfaces and IBSIs were calculated using MultiWFN and IGMPlot, respectively.

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Photochemical and photocatalytic oxidation of naproxen (NPX) with UV-A light and commercial TiO2 under constant flow of oxygen have been investigated. Adsorption experiments indicated that 90% of the solute remained in the solution. Combined chemical analysis of samples on the photochemical degradation indicated that NPX in an aqueous solution (20 ppm) is efficiently transformed into other species but only 18% of the reactant is mineralized into CO2 and water after three hours of reaction. Performing the photocatalytic oxidation in the presence of TiO2, more than 80% of the organic compounds are mineralized by reactive oxidation species (ROS) within four hours of reaction. Analysis of reaction mixtures by a combination of analytical techniques indicated that naproxen is transformed into several aromatic naphthalene derivatives. These latter compounds are eventually transformed into polyhydroxylated aromatic compounds that are strongly adsorbed onto the TiO2 surface and are quickly oxidized into low-molecular-weight acids by an electron transfer mechanism. Based on this and previous studies on NPX photocatalytic oxidation, a unified and complete degradation mechanism is presented.

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CONTEXT: The combined use of transition metal-catalyzed C-H activation with aryne annulation reactions has emerged as an important strategy in organic synthesis. In this study, the mechanisms of the palladium(II)-catalyzed annulation reaction of N-methoxy amides and arynes were computationally investigated by density functional theory. The role of methoxy amide as a directing group was elucidated through the calculation of three different pathways for the C-H activation step, showing that the pathway where amide nitrogen acts as a directing group is preferable. At the reductive elimination transition state, an unstable seven-membered ring is formed preventing the lactam formation. A substituent effect study based on an NBO analysis, Hammet, and using a More O'Ferall-Jenks plot indicates that the C-H activation step proceeds via an electrophilic concerted metalation-deprotonation (eCMD) mechanism. The results show that electron-withdrawing groups increase the activation barrier and contribute to an early Pd-C bond formation and a late C-H bond breaking when compared with electron-donating substituents. Our computational results are in agreement with the experimental data provided in the literature. METHODS: All calculations were performed using Gaussian 16 software. Geometry optimizations, frequency analyses at 393.15 K, and IRC calculations were conducted at the M06L/Def2-SVP level of theory. Corrected electronic energies, NBO charges, and Wiberg bond indexes were computed at the M06L/Def2-TZVP//M06L/Def2-SVP level of theory. Implicit solvent effects were considered in all calculations using the SMD model, with acetonitrile employed as the solvent.

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We have studied the reduction reactions of two cytosolic human peroxiredoxins (Prx) in their disulfide form by three thioredoxins (Trx; two human and one bacterial), with the aim of better understanding the rate and mechanism of those reactions, and their relevance in the context of the catalytic cycle of Prx. We have developed a new methodology based on stopped-flow and intrinsic fluorescence to study the bimolecular reactions, and found rate constants in the range of 105 -106 m-1 s-1 in all cases, showing that there is no marked kinetic preference for the expected Trx partner. By combining experimental findings and molecular dynamics studies, we found that the reactivity of the nucleophilic cysteine (CN ) in the Trx is greatly affected by the formation of the Prx-Trx complex. The protein-protein interaction forces the CN thiolate into an unfavorable hydrophobic microenvironment that reduces its hydration and results in a remarkable acceleration of the thiol-disulfide exchange reactions by more than three orders of magnitude and also produces a measurable shift in the pKa of the CN . This mechanism of activation of the thiol disulfide exchange may help understand the reduction of Prx by alternative reductants involved in redox signaling.

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A non-segregated kinetic model is proposed to describe a fermentation process of agro-industrial residues derived via cocoa (mucilage juice) by Pichia kudriavzevii. The novel proposed hybrid model is based on a multiple coupling reaction mechanisms (structured) to describe the kinetics of substrate consumption, biomass, carbon dioxide, and ethanol, coupled to an unstructured model for the activity enzyme. The parameters of the kinetic model are estimated by non-linear least-squares curve fitting using the Marquardt-Levenberg algorithm. In addition, numerical simulations were compared with the experimental data via residual graphs. The effectiveness of the model was statistically evaluated using dimensionless efficiency coefficients under different initial conditions. A global sensitivity analysis was applied (Fisher's information matrix). The experimental results of the batch reactor showed a maximum ethanol concentration of 29 g/L, with a yield of 0.48 g-ethanol/g-glucose and a productivity of 0.30 g/L h. The method determined that the cell formation coefficient and the specific substrate consumption rate (θ1 and θ2) directly influence most of the states of our system. The proposed scheme is particularly suitable to assist in the rational design of cell factory properties or fermentation processes because it can represent the complex biochemistry in more detail and under different initial experimental conditions; the above reveals that the generated model is robust and can be considered for control and optimization purposes.

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Proteins equipped with flavin adenine dinucleotides (FAD) or flavin mononucleotides (FMN) are named flavoproteins and constitute about 1% of all existing proteins. They catalyze redox, acid-base and photochemical reactions in a variety of biochemical phenomena that goes from energy metabolism to DNA repair and light sensing. The versatility observed in flavoproteins is ultimately a balance of flavin intrinsic properties modulated by a protein environment. This thesis aims to investigate how flavoproteins work by systematic evaluating flavin properties and reactivity. In particular, the mechanism of fumarate reduction by the flavoenzyme fumarate reductase Fcc3 was determined. Electronic-structure calculations were used for this task based on rigorous calibration with experimental data and error assessment. Flavin properties at chemical accuracy were obtained with single reference coupled-cluster CCSD(T) calculations at the complete basis set limit. Density functional theory was demonstrated an excellent alternative with lower computational costs and slightly less accuracy. Flavin protonation and tautomerism were shown to be important modulators of flavin properties and reactivity, with the possibility of various tautomers existing at neutral pH. Regarding flavin redox properties, an analysis based on multiconfigurational wave function weights was proposed for categorizing flavin redox reactions as hydride or hydrogen-atom transfers. This analysis is an upgrade over traditional partial charges methods and can be applied not only to flavin reactions but to any protoncoupled electron transfer. In the investigation of the enzymatic mechanism of fumarate reduction, the reaction was determined as a nucleophilic addition by hydride transfer with carbanion formation. Fumarate reductase employs electrostatic catalysis in contrast to previous proposals of substrate straining and general-acid catalysis. Also, hydride transfer was shown to be vibronically adiabatic with low tunneling contribution. These findings give new insights into the mechanisms of fumarate reductases and provide a framework for future computational studies of flavoproteins in general. The analyses and benchmark studies presented can be used to build better models of properties and reactivity of flavins and flavoproteins

Proteínas equipadas com dinucleotídeos de flavina-adenina (FAD) e mononucleotídeos de flavina (FMN) são chamadas flavoproteínas e constituem cerca de 1% de todas as proteínas existentes. Elas catalisam reações redox, ácido-base e fotoquímicas numa variedade de fenômenos bioquímicos que vão desde o metabolismo energético até reparo de DNA e captação de luz. A versatilidade observada em flavoproteínas é em última instância um balanço das propriedades intrínsecas de flavinas moduladas por um ambiente proteico. Esta tese busca investigar como flavoproteínas funcionam através de avaliações sistemáticas de propriedades e reatividade de flavinas. Em particular, o mecanismo de redução de fumarato pela flavoenzima fumarato redutase Fcc3 foi determinado. Cálculos de estrutura eletrônica foram usados para esta tarefa com base em rigorosa calibração com dados experimentais e avaliação de erros. As propriedades de flavinas foram determinadas com acurácia química com cálculos monoconfiguracionais de coupled-cluster CCSD(T) no limite de conjunto base completo. A teoria do funcional da densidade mostrou-se uma alternativa excelente com menor custo computacional e um pouco menos de acurácia. Protonação e tautomerismo de flavinas mostraram-se moduladores importantes de suas propriedades e reatividade, com a possibilidade de vários tautômeros existirem em pH neutro. Em relação às propriedades redox de flavinas, uma análise baseada nos pesos de funções de onda multiconfiguracionais foi proposta para categorizar as reações redox de flavinas como transferências de hidreto ou hidrogênio. Esta análise é uma melhoria em relação aos métodos tradicionais de cargas parciais e pode ser aplicada não apenas para reações de flavinas mas para qualquer transferência de próton acoplada a elétrons. Na investigação do mecanismo enzimático de redução de fumarato, a reação foi designada como uma adição nucleofílica por transferência de hidreto e formação de carbânion. A fumarato redutase usa catálise eletrostática diferentemente de prospostas anteriores envolvendo distorção do substrato e catálise ácida geral. Além disso, a transferência de hidreto mostrou-se vibronicamente adiabática com pouca contribuição de tunelamento. Estas descobertas abrem novas perspectivas sobre os mecanismos de fumarato redutases e fornecem uma base para estudos computacionais futuros sobre flavoproteínas em geral. As análises e estudos comparativos apresentados podem ser usados para construir melhores modelos para propriedades e reatividade de flavinas e flavoproteínas

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Few kinetic parameters, or reaction rates, are known up to date in detail about 1-chloro and 1-fluoro-2,4-dinitrobenzene (ClDNB and FDNB, respectively) with a series of biothiols in aqueous media. These biological nucleophiles with thiol groups have been widely used as a reference in nucleophile reactivity assays due to their prevalence and cellular abundance. The main aim of this study was to elucidate the reaction mechanism based on Brönsted-type plots and reactivity patterns of the electrophile/nucleophile pairs. A complete kinetic study was performed in terms of the comparison of Brönsted-type slope parameters (ß nuc) for the reactions and was used for assigning the mechanism and the rate-determining step associated with the reaction route. A mass spectrometry analysis demonstrated that the nucleophilic center of the biothiols is the -SH group and there is only one kinetic product. The kinetic study suggests that the reaction mechanism might be the borderline between concerted and stepwise pathways. An amine-enol equilibrium for the most reactive nucleophiles appears to be the main determining factor controlling the nucleophilic attack in the nucleophilic aromatic substitution reactions investigated, highlighting the anionic form for these nucleophiles. This amine-enol equilibrium involves a hydrogen bond which stabilizes the intermediate species in the reaction pathway. Thus, intramolecular bonds are formed and enhance the nucleophilic strength through the contribution of the solvent surrounding the electrophile/nucleophile pairs. Finally, we highlight the importance of the formation of electrophile/nucleophile adducts that could modify structures and/or functions of biological systems with potential toxic effects. Therefore, it is essential to know all these kinetic and reactivity patterns and their incidence on other studies.

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A complete mechanism for the •OH-initiated atmospheric decomposition of the pesticides chlorpyrifos and chlorpyrifos-methyl is proposed, incorporating additional studies on the competing reaction with singlet oxygen. The computational study is based on density functional theory (DFT) at the double-hybrid functional level to treat static correlation in the calculations of energy barriers. Reaction of the P-bonded intermediate with 1O2 has a small energy barrier of ~ 2 kcal mol-1, generating the Oxone compound and the HOSO• radical, with a reaction free energy of - 49.8 kcal/mol for the chlorpyrifos reaction pathway. Direct reaction of the pesticides with singlet oxygen is unlikely to happen due to the exceedingly high energy barrier of ~ 52 kcal/mol. However, in aqueous solution, the activation energy reduces dramatically and changes the reaction thermodynamics, making it kinetically accessible and thermodynamically viable.

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Five new spiro[indoline-3,3'-indolizine]s have been synthesized with high regio- and stereospecificity in one-pot three-component reactions between a substituted indole-2,3-dione, (S)-pipecolic acid and trans-3-benzoylacrylic acid, and subsequently characterized using a combination of elemental analysis, IR and 1H and 13C NMR spectroscopy, mass spectrometry and crystal structure analysis. (1'SR,2'SR,3RS,8a'RS)-2'-Benzoyl-5-fluoro-2-oxo-1',5',6',7',8',8a'-hexahydro-2'H-spiro[indoline-3,3'-indolizine]-1'-carboxylic acid, C23H21FN2O4, (I), and (1'SR,2'SR,3RS,8a'RS)-2'-benzoyl-5-methyl-2-oxo-1',5',6',7',8',8a'-hexahydro-2'H-spiro[indoline-3,3'-indolizine]-1'-carboxylic acid, C24H24N2O4, (II), are isomorphous, as are (1'SR,2'SR,3RS,8a'RS)-2'-benzoyl-1-methyl-2-oxo-1',5',6',7',8',8a'-hexahydro-2'H-spiro[indoline-3,3'-indolizine]-1'-carboxylic acid, C24H24N2O4, (III), and (1'SR,2'SR,3RS,8a'RS)-2'-benzoyl-5-chloro-1-methyl-2-oxo-1',5',6',7',8',8a'-hexahydro-2'H-spiro[indoline-3,3'-indolizine]-1'-carboxylic acid, C24H23ClN2O4, (IV). Within each isomorphous pair, the spiro ring systems show some conformational differences. In each of (I) and (II), the molecules are linked into complex sheets by a combination of four types of hydrogen bond, and in each of (III) and (IV), a combination of O-H...O and C-H...π(arene) hydrogen bonds links the molecules to form a chain of centrosymmetric rings. In (1'SR,2'SR,3RS,8a'RS)-2'-benzoyl-1-hexyl-2-oxo-1',5',6',7',8',8a'-hexahydro-2'H-spiro[indoline-3,3'-indolizine]-1'-carboxylic acid, C29H34N2O4, (V), a combination of five hydrogen bonds links the molecules into sheets of alternating R22(16) and R66(46) rings. A mechanism is proposed for the formation of compounds (I)-(V) and some comparisons with related structures are made.

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The analysis of the reaction force and its topology has provided a wide range of fruitful concepts in the theory of chemical reactivity over the years, allowing to identify chemically relevant regions along a reaction profile. The reaction force (RF), a projection of the Hellmann-Feynman forces acting on the nuclei of a molecular system onto a suitable reaction coordinate, is partitioned using the interacting quantum atoms approach (IQA). The exact IQA molecular energy decomposition is now shown to open a unique window to identify and quantify the chemical entities that drive or retard a chemical reaction. The RF/IQA coupling offers an extraordinarily detailed view of the type and number of elementary processes that take reactants into products, as tested on two sets of simple reactions.

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In the present work, the fast amide bond cleavage of [3-((1R,5S,7s)-3-azabicyclo[3.3.1]nonane-7-carbonyl)-3-azabicyclo[3.3.1]nonane-7-carboxylic acid (bi-ATDO)], through an intramolecular nucleophilic attack of an amine group is evaluated. First, six possible peptide bond cleavage mechanisms, two of them including a water molecule, are described at the ωB97XD/6-311 + G(d,p)//MP2/6-311 + G(d,p) level of theory. The reaction consisting of an intramolecular nitrogen nucleophilic attack followed by a proton transfer and the amide bond cleavage is determined as the most favorable mechanism. The activation free energy computed for the latter is 20.5 kcal mol-1 , which agrees with the reported experimental result of 24.8 kcal mol-1 . Inclusion of a water molecule to assist the first step of the reaction results in an activation free energy increase of about 17 kcal mol-1 . All the steps in the most favorable mechanism are studied more in detail employing intrinsic reaction coordinate as well as the reaction force and reaction electronic flux analysis.

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The dynamic equilibria of organomagnesium reagents are known to be very complex, and the relative reactivity of their components is poorly understood. Herein, a combination of DFT calculations and kinetic experiments is employed to investigate the detailed reaction mechanism of the Pummerer coupling between sulfoxides and turbo-organomagnesium amides. Among the various aggregates studied, unprecedented heterometallic open cubane structures are demonstrated to yield favorable barriers through a concerted anion-anion coupling/ S-O cleavage step. Beyond a structural curiosity, these results introduce open cubane organometallics as key reactive intermediates in turbo-organomagnesium amide mixtures.

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In this study, we have investigated the enzyme shikimate 5-dehydrogenase from the causative agent of tuberculosis, Mycobacterium tuberculosis. We have employed a mixture of computational techniques, including molecular dynamics, hybrid quantum chemical/molecular mechanical potentials, relaxed surface scans, quantum chemical descriptors and free-energy simulations, to elucidate the enzyme's reaction pathway. Overall, we find a two-step mechanism, with a single transition state, that proceeds by an energetically uphill hydride transfer, followed by an energetically downhill proton transfer. Our mechanism and calculated free energy barrier for the reaction, 64.9 kJ mol- 1, are in good agreement with those predicted from experiment. An analysis of quantum chemical descriptors along the reaction pathway indicated a possibly important, yet currently unreported, role of the active site threonine residue, Thr65.

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The mechanism of SNAr reactions between 2-chloro-5-nitropyrimidine with primary and secondary alicyclic amines, respectively, have been studied by kinetic measurements. The kinetic data obtained in aqueous media opens a controversial discussion based on Brönsted-type plots analysis. The first approach based on the kinetic data reveals a non-catalyzed pathway. Then, the subtlety of the mathematical treatment of the kinetic data is discussed over a concerted or stepwise mechanism, respectively.

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Malolactic fermentation (MLF) is responsible for the decarboxylation of l-malic into lactic acid in most red wines and some white wines. It reduces the acidity of wine, improves flavor complexity and microbiological stability. Despite its industrial interest, the MLF mechanism is not fully understood. The objective of this study was to provide new insights into the role of pH on the binding of malic acid to the malolactic enzyme (MLE) of Oenococcus oeni. To this end, sequence similarity networks and phylogenetic analysis were used to generate an MLE homology model, which was further refined by molecular dynamics simulations. The resulting model, together with quantum polarized ligand docking (QPLD), was used to describe the MLE binding pocket and pose of l-malic acid (MAL) and its l-malate (-1) and (-2) protonation states (MAL- and MAL2-, respectively). MAL2- has the lowest ∆Gbinding, followed by MAL- and MAL, with values of -23.8, -19.6, and -14.6 kJ/mol, respectively, consistent with those obtained by isothermal calorimetry thermodynamic (ITC) assays. Furthermore, molecular dynamics and MM/GBSA results suggest that only MAL2- displays an extended open conformation at the binding pocket, satisfying the geometrical requirements for Mn2+ coordination, a critical component of MLE activity. These results are consistent with the intracellular pH conditions of O. oeni cells-ranging from pH 5.8 to 6.1-where the enzymatic decarboxylation of malate occurs.

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ß-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of ß-lactamases, enzymes that hydrolyze the amide bond present in all ß-lactam compounds. There are several inhibitors against serine-ß-lactamases (SBLs). Metallo-ß-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most ß-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.

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Intrinsic reaction coordinate (IRC) data regarding the interactions of water with a carbene-like active site located at the edge of a polyaromatic hydrocarbon [1-3] has been obtained using density functional theory (DFT) and the 6-31g(d) basis set as implemented in the Gaussian 16 software [4]. The data is presented as two videos (frontal and lateral mechanism views) combining four consecutive IRC calculations corresponding to the four different transition states presented on "https://doi.org/10.1016/j.carbon.2020.01.011" [3] (Figure 6, side approach). These videos provide powerful insights on two key aspects: a) the rotational process that occurs during water adsorption and b) the hydrogen gas desorption process during water gasification of carbons.

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Reactive oxygen and nitrogen species have been implicated in many biological processes and diseases, including immune responses, cardiovascular dysfunction, neurodegeneration, and cancer. These chemical species are short-lived in biological settings, and detecting them in these conditions and diseases requires the use of molecular probes that form stable, easily detectable, products. The chemical mechanisms and limitations of many of the currently used probes are not well-understood, hampering their effective applications. Boronates have emerged as a class of probes for the detection of nucleophilic two-electron oxidants. Here, we report the results of an oxygen-18-labeling MS study to identify the origin of oxygen atoms in the oxidation products of phenylboronate targeted to mitochondria. We demonstrate that boronate oxidation by hydrogen peroxide, peroxymonocarbonate, hypochlorite, or peroxynitrite involves the incorporation of oxygen atoms from these oxidants. We therefore conclude that boronates can be used as probes to track isotopically labeled oxidants. This suggests that the detection of specific products formed from these redox probes could enable precise identification of oxidants formed in biological systems. We discuss the implications of these results for understanding the mechanism of conversion of the boronate-based redox probes to oxidant-specific products.

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