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The enzymatic biosynthesis of fragrance molecules from lignin fragments is an important reaction in biotechnology for the sustainable production of fine chemicals. In this work we investigated the biosynthesis of vanillin from lignostilbene by a nonheme iron dioxygenase using QM/MM and tested several suggested proposals via either an epoxide or dioxetane intermediate. Binding of dioxygen to the active site of the protein results in the formation of an iron(II)−superoxo species with lignostilbene cation radical. The dioxygenase mechanism starts with electrophilic attack of the terminal oxygen atom of the superoxo group on the central C=C bond of lignostilbene, and the second‐coordination sphere effects in the substrate binding pocket guide the reaction towards dioxetane formation. The computed mechanism is rationalized with thermochemical cycles and valence bond schemes that explain the electron transfer processes during the reaction mechanism. Particularly, the polarity of the protein and the local electric field and dipole moments enable a facile electron transfer and an exergonic dioxetane formation pathway. [ABSTRACT FROM AUTHOR]

The nonheme iron dioxygenase deoxypodophyllotoxin synthase performs an oxidative ring-closure reaction as part of natural product synthesis in plants. How the enzyme enables the oxidative ring-closure reaction of (-)-yatein and avoids substrate hydroxylation remains unknown. To gain insight into the reaction mechanism and understand the details of the pathways leading to products and by-products we performed a comprehensive computational study. The work shows that substrate is bound tightly into the substrate binding pocket with the C7'-H bond closest to the iron(IV)-oxo species. The reaction proceeds through a radical mechanism starting with hydrogen atom abstraction from the C7'-H position followed by ring-closure and a final hydrogen transfer to form iron(II)-water and deoxypodophyllotoxin. Alternative mechanisms including substrate hydroxylation and an electron transfer pathway were explored but found to be higher in energy. The mechanism is guided by electrostatic perturbations of charged residues in the second-coordination sphere that prevent alternative pathways. [ABSTRACT FROM AUTHOR]

CO2 utilization is an important process in the chemical industry with great environmental power. In this work we show how CO2 and H2 can be reacted to form methanol on an iron(II) center and highlight the bottlenecks for the reaction and what structural features of the catalyst are essential for efficient turnover. The calculations predict the reactions to proceed through three successive reaction cycles that start with heterolytic cleavage of H2 followed by sequential hydride and proton transfer processes. The H2 splitting process is an endergonic process and hence high pressures will be needed to overcome this step and trigger the hydrogenation reaction. Moreover, H2 cleavage into a hydride and proton requires a metal to bind hydride and a nearby source to bind the proton, such as an amide or pyrazolyl group, which the scorpionate ligand used here facilitates. As such the computations highlight the non‐innocence of the ligand scaffold through proton shuttle from H2 to substrate as an important step in the reaction mechanism. [ABSTRACT FROM AUTHOR]

High‐valent metal‐oxo species play critical roles in enzymatic catalysis yet their properties are still poorly understood. In this work we report a combined experimental and computational study into biomimetic iron(IV)‐oxo and iron(III)‐oxo complexes with tight second‐coordination sphere environments that restrict substrate access. The work shows that the second‐coordination sphere slows the hydrogen atom abstraction step from toluene dramatically and the kinetics is zeroth order in substrate. However, the iron(II)‐hydroxo that is formed has a low reduction potential and hence cannot do OH rebound favorably. The tolyl radical in solution then reacts further with alternative reaction partners. By contrast, the iron(IV)‐oxo species reacts predominantly through OH rebound to form alcohol products. Our studies show that the oxidation state of the metal influences reactivities and selectivities with substrate dramatically and that enzymes will likely need an iron(IV) center to catalyze C−H hydroxylation reactions. [ABSTRACT FROM AUTHOR]

High‐valent iron(IV)‐oxo intermediates are versatile oxidants in the biotransformation of various substrates by metalloenzymes and catalyze essential reactions for human health as well as in the biodegradation of toxic organic pollutants in the environment. Herein, we report a biomimetic system that efficiently reacts with halophenols through defluorination reactions and characterize various short‐lived intermediates along the reaction mechanism. We study the reactivity pattern of a nonheme iron(IV)‐oxo species with a series of trihalophenols (X=F, Cl, Br). A combined experimental and computational study reveals that the oxidative dehalogenation of 2,4,6‐trifluorophenol is initiated with an H‐atom abstraction from the phenolic group by the iron(IV)‐oxo species resulting in the formation of a phenolate radical and an iron(III)‐hydroxo species. This iron(III)‐hydroxo species forms an adduct with the oxidized substrate with λmax at 558 nm which subsequently decays to give quinones as products. [ABSTRACT FROM AUTHOR]

Bioorthogonal chemistry involves selective biocompatible reactions between functional groups that are not normally present in biology. It has been used to probe biomolecules in living systems, and has advanced biomedical strategies such as diagnostics and therapeutics. In this review, the challenges and opportunities encountered when translating in vitro bioorthogonal approaches to in vivo settings are presented, with a focus on methods to deliver the bioorthogonal reaction components. These methods include metabolic bioengineering, active targeting, passive targeting, and simultaneously used strategies. The suitability of bioorthogonal ligation reactions and bond cleavage reactions for in vivo applications is critically appraised, and practical considerations such as the optimum scheduling regimen in pretargeting approaches are discussed. Finally, we present our own perspectives for this area and identify what, in our view, are the key challenges that must be overcome to maximise the impact of these approaches. [ABSTRACT FROM AUTHOR]

Taurine/α‐ketoglutarate dioxygenase is an important enzyme that takes part in the cysteine catabolism process in the human body and selectively hydroxylates taurine at the C1‐position. Recent computational studies showed that in the gas‐phase the C2−H bond of taurine is substantially weaker than the C1−H bond, yet no evidence exists of 2‐hydroxytaurine products. To this end, a detailed computational study on the selectivity patterns in TauD was performed. The calculations show that the second‐coordination sphere and the protonation states of residues play a major role in guiding the enzyme to the right selectivity. Specifically, a single proton on an active site histidine residue can change the regioselectivity of the reaction through its electrostatic perturbations in the active site and effectively changes the C1−H and C2−H bond strengths of taurine. This is further emphasized by many polar and hydrogen bonding interactions of the protein cage in TauD with the substrate and the oxidant that weaken the pro‐R C1−H bond and triggers a chemoselective reaction process. The large cluster models reproduce the experimental free energy of activation excellently. [ABSTRACT FROM AUTHOR]

Aryloxyalkanoate dioxygenases are unique herbicide biodegrading nonheme iron enzymes found in plants and hence, from environmental and agricultural point of view they are important and valuable. However, they often are substrate specific and little is known on the details of the mechanism and the substrate scope. To this end, we created enzyme models and calculate the mechanism for 2,4‐dichlorophenoxyacetic acid biodegradation and 2‐methyl substituted analogues by density functional theory. The work shows that the substrate binding is tight and positions the aliphatic group close to the metal center to enable a chemoselective reaction mechanism to form the C2‐hydroxy products, whereas the aromatic hydroxylation barriers are well higher in energy. Subsequently, we investigated the metabolism of R‐ and S‐methyl substituted inhibitors and show that these do not react as efficiently as 2,4‐dichlorophenoxyacetic acid substrate due to stereochemical clashes in the active site and particularly for the R‐isomer give high rebound barriers. [ABSTRACT FROM AUTHOR]

Thiol dioxygenases are important enzymes for human health; they are involved in the detoxification and catabolism of toxic thiol‐containing natural products such as cysteine. As such, these enzymes have relevance to the development of Alzheimer's and Parkinson's diseases in the brain. Recent crystal structure coordinates of cysteine and 3‐mercaptopropionate dioxygenase (CDO and MDO) showed major differences in the second‐coordination spheres of the two enzymes. To understand the difference in activity between these two analogous enzymes, we created large, active‐site cluster models. We show that CDO and MDO have different iron(III)‐superoxo‐bound structures due to differences in ligand coordination. Furthermore, our studies show that the differences in the second‐coordination sphere and particularly the position of a positively charged Arg residue results in changes in substrate positioning, mobility and enzymatic turnover. Furthermore, the substrate scope of MDO is explored with cysteinate and 2‐mercaptosuccinic acid and their reactivity is predicted. [ABSTRACT FROM AUTHOR]

This article, titled "Mechanism of CO2 Reduction to Methanol with H2 on an Iron(II)-scorpionate Catalyst," explores the reaction mechanism of a homogeneous catalyst that binds H2 and CO2 on an iron(II)-scorpionate complex. Through calculations, it is determined that the iron complex can cleave H2 into a hydride and proton, which then bind to different sites on the complex. CO2 is subsequently reduced through a series of hydride and proton transfer steps, ultimately resulting in the formation of methanol products. The full research article provides more detailed information on this topic. [Extracted from the article]

While the fascinating chemistry demonstrated by metalated N‐heterocyclic carbene (NHC) complexes highlights the significance of metalated heterocyclic chemistry, the development of other metalated heterocycles is falling behind, presumably because of the sparseness of general synthetic methodologies. In this Concept article, the strategy to prepare metalated heterocyclic complexes by metal‐induced cycloisomerization of heteroatom‐functionalized alkynes is presented. The isolation of and calculations on novel ruthenium complexes bearing chromene, chromone, indole, indoline, indolizine, and indolizinone moieties prepared from reactions between alkynes and ruthenium complexes are discussed, with emphasis on the mechanistic insights into the ruthenium‐induced alkyne transformations and applications in material design and drug discovery. Metalated heterocycles: This Concept article highlights the recent progress of isolating metalated heterocyclic complexes by ruthenium‐mediated activation of heteroatom‐functionalized alkynes, with emphasis on mechanistic insights into the ruthenium‐induced alkyne transformations and applications in material design and drug discovery. [ABSTRACT FROM AUTHOR]

The discovery that traditional silver(I)‐oxide‐promoted glycosidations of glycosyl bromides (Koenigs–Knorr reaction) can be greatly accelerated in the presence of catalytic trimethylsilyl trifluoromethanesulfonate (TMSOTf) is reported. The reaction conditions are very mild that allowed for maintaining a practically neutral pH and, at the same time, providing high rates and excellent glycosylation yields. In addition, unusual reactivity trends among a series of differentially protected glycosyl bromides were documented. In particular, benzoylated α‐bromides were much more reactive than their benzylated counterparts under these conditions. Fast glycosylations! Effective reaction conditions for a rapid Koenigs–Knorr glycosylation catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf) are reported. The glycosylation products were formed in minutes and the neutral activation conditions were compatible with many protecting and leaving groups. An unusual reactivity trend according to which benzoylated α‐bromides are much more reactive than their benzylated counterparts was demonstrated. The reaction mechanism was also investigated. [ABSTRACT FROM AUTHOR]

Svante Augustus Arrhenius (1859, Vik ‐ 1927, Stockholm) received the Nobel Prize for Chemistry in 1903 "in recognition of the extraordinary services he rendered to the advancement of chemistry by his electrolytic theory of dissociation". Arrhenius was a physicist, and he received his PhD from the University of Uppsala, where he later became a professor for phyiscal chemistry, the first in the country for this subject. He was offered several positions as professor abroad, but decided to remain in Sweden and to build a Nobel Institute for physical chemistry using the Nobel funds. He remained director of the Institute until his death. There are powerful lessons to take from Svante August Arrhenius' journey leading to a Nobel laureate as there are from his tremendous contributions to chemistry and science in general, including climate science, immunochemistry and cosmology. The theory of electrolytic dissociation for which Arrhenius received the 1903 Nobel Prize in Chemistry has had a profound impact on our understanding of the chemistry of solutions, chemical reactivity, mechanisms underlying chemical transformations as well as physiological processes. As a tribute to Arrhenius, we present a brief historical perspective and present status of the theory of electrolytic dissociation, its relevance and role to the development of electrochemistry, as well as some perspectives on the possible role of the theory to future advancements in electroanalysis, electrocatalysis and electrochemical energy storage. The review briefly highlights Arrhenius' contribution to climate science owing to his studies on the potential effects of increased anthropogenic CO2 emissions on the global climate. These studies were far ahead of their time and revealed a daunting global dilemma, global warming, that we are faced with today. Efforts to abate or reverse CO2 accumulation constitute one of the most pressing scientific problems of our time, "man's urgent strive to save self from the adverse effects of his self‐orchestrated change on the climate". Finally, we review the application of the Arrhenius equation that correlates reaction rate constants (k) and temperature (T); k=Ae(-Ea/RT), in determining reaction barriers in catalysis with a particular focus on recent modifications of the equation to account for reactions exhibiting non‐linear Arrhenius behavior with concave curvature due to prevalence of quantum mechanical tunneling, as well as infrequent convexity of Arrhenius plots due to decrease of the microcanonical rate coefficient with energy as observed for some enzyme catalyzed reactions. Svante Augustus Arrhenius was awarded the 1903 Nobel Prize in Chemistry for his theory of electrolytic dissociation. This minireview presents a brief historical perspective and present status of the theory, and its impact on our understanding of the chemistry of solutions. In addition, application of the Arrhenius equation in the study of chemical kinetics is also reviewed because of its importance in (electro)catalysis. [ABSTRACT FROM AUTHOR]

Converting renewable biomass and their derivatives into chemicals and fuels has received much attention to reduce the dependence on fossil resources. Photocatalytic ethanol dehydrogenation–acetalization to prepare value‐added 1,1‐diethoxyethane and H2 was achieved over non‐precious metal CdS/Ni‐MoS2 catalyst under visible light. The system displays an excellent production rate and high selectivity of 1,1‐diethoxyethane, 52.1 mmol g−1 h−1 and 99.2 %, respectively. In‐situ electron spin resonance, photoluminescence spectroscopy and transient photocurrent responses were conducted to investigate the mechanism. This study provides a promising strategy for a green application of bioethanol. Remove hydrogen and acetalize: Photocatalytic ethanol dehydrogenation–acetalization to prepare value‐added 1,1‐diethoxyethane and H2 was achieved over non‐precious metal CdS/Ni‐MoS2 catalyst under visible light. This work provides a promising strategy for a green atom‐economic application of bioethanol. [ABSTRACT FROM AUTHOR]

A simple synthesis strategy afforded a family of hydrogen‐bonded azines and Schiff‐bases. Although in dilute solution these dyes are faint light emitters, all exhibit bright luminescence upon aggregation. Changing the peripheral substituents from electron donating to electron withdrawing allows emission fine‐tuning in a range from bluish‐green to orange‐red. The crystal structures of the materials reveal that the restriction of intramolecular rotations is the main mechanism for the aggregation‐induced emission enhancement properties. A rainbow of AIEEgens: Hydrogen‐bonded azines and Schiff bases are non‐emissive in dilute solutions, but exhibit bright luminescence upon aggregation, in a range from bluish‐green to orange‐red. [ABSTRACT FROM AUTHOR]

Abstract: The reaction mechanism in an active site is of the utmost importance when trying to understand the role that an enzyme plays in biological processes. In a recently published paper [Theor. Chem. Acc. 2017, 136, 86], we formalised the Relative Energy Gradient (REG) method for automating an Interacting Quantum Atoms (IQA) analysis. Here, the REG method is utilised to determine the mechanism of peptide hydrolysis in the aspartic active site of the enzyme HIV‐1 Protease. Using the REG method along with the IQA approach we determine the mechanism of peptide hydrolysis without employing any arbitrary parameters and with remarkable ease (albeit at large computational cost: the system contains 133 atoms, which means that there are 17 689 individual IQA terms to be calculated). When REG and IQA work together it is possible to determine a reaction mechanism at atomistic resolution from data directly derived from quantum calculations, without arbitrary parameters. Moreover, the mechanism determined by this novel method gives concrete insight into how the active site residues catalyse peptide hydrolysis. [ABSTRACT FROM AUTHOR]

Abstract: The formation and extractive desulfurization (EDS) mechanisms of aromatic acid based deep eutectic solvents (DESs) were studied experimentally and through quantum chemistry calculations. Hydrogen bonding and van der Waals forces were investigated as the driving forces for the formation of aromatic acid based DESs by means of 1H NMR and FTIR spectroscopy, and DFT calculations. The driving forces of EDS were also studied. The results showed that van der Waals forces and other weak interactions were the main diving forces for EDS, and the structures of the aromatic acid based DESs did not change after EDS. The interaction energy between the aromatic acid based DESs and thiophene (TH), benzothiophene (BT), and dibenzothiophene (DBT) were calculated by DFT to understand the EDS order: TH

Abstract: Squalene‐hopene cyclase (SHC) catalyzes the conversion of squalene 1 into 6,6,6,6,5‐fused pentacyclic hopene 2 and hopanol 3. To elucidate the binding sites for the terminal positions of 1, four analogs, having the larger ethyl (Et) and the hydrophilic CH2OH groups at the 23E or 23Z positions of 1, were incubated with SHC. The analog with the Et group at the 23E position (23E‐Et‐1) yielded two tetra‐ and three pentacyclic products; however, the analog possessing the Et group at the 23Z position (23Z‐Et‐1) gave two hopene homologs and the neohopane skeleton, but no hopanol homologs. Hopene homolog (C31) was generated from 23E‐Et‐1 by deprotonation from 23Z‐Me (normal cyclization cascade). Intriguingly, the same homolog was also generated from the geometrical isomer 23Z‐Et‐1, indicating C−C bond rotation about the C‐21−C‐22 axis of the hopanyl cation and the more compact nature of the binding domain at 23Z compared with 23E. On the other hand, analogs with the CH2OH group gave novel hopane skeletons having 1‐formylethyl and 1‐hydroxyprop‐2‐en‐2‐yl residues at C‐21. Products bearing an aldehyde group were generated in higher yield from 23Z‐CH2OH‐1 (89 %), than from 23E‐CH2OH‐1 (26 %). The significant yield (26 %) of the aldehyde products from 23E‐CH2OH‐1 indicated that C−C bond rotation had occurred owing to the absence of hydrophobic interactions between the hydrophilic 23E‐CH2OH and its binding site. The polycyclization mechanisms of the four different analogs are discussed. [ABSTRACT FROM AUTHOR]

Abstract: A catalyst‐free self‐catalyzed [3+2] cycloaddition reaction of isatin‐derived α‐(trifluoromethyl)imines with vinylpyridines is reported. The reaction offers a straightforward and atom‐economical procedure for the preparation of a series of 5′‐trifluoromethyl‐spiro[pyrrolidin‐3,2′‐oxindoles] in excellent yields and diastereoselectivities. The reaction mechanism has been investigated by control experiments, DFT calculation of pKa values and the kinetic profiles, revealing that this reaction featured the mutual activation between isatin‐derived α‐(trifluoromethyl)imines and vinylpyridine to generate the reactive species. [ABSTRACT FROM AUTHOR]

Abstract: The luciferin/luciferase system of the firefly has been used in bioluminescent imaging to monitor biological processes. In order to enhance the efficiency and expand the application range, some efforts have been made to tune the light emission, especially the effort to obtain NIR light. However, those case‐by‐case studies have not together revealed the nature and mechanism of the color tuning. In this paper, we theoretically investigated the fluorescence of all kinds of typical oxyluciferin analogues. The present systematical modifications of both oxyluciferin and luciferase indicate that the essential factor affecting the emission color is the charge distribution (or the electric dipole moment) on the oxyluciferin, which impacts on the charge transfer to form the light emitter and, subsequently, influence the strength and wavelength of the emission light. More negative charge distributed on the “thiazolone moiety” of the oxyluciferin or its analogues leads to a redshift. Based on this conclusion, we theoretically designed optimal pairs of luciferin analogue and luciferase for emitting NIR light, which could inspire new synthetic procedures and practical applications. [ABSTRACT FROM AUTHOR]

Abstract: Molecular iodine has been used for more than 100 years as a remarkable catalyst for many organic transformations such as cycloadditions, Michael and aldol reactions, or esterifications. Different explanations for the origin of its catalytic effect have been proposed in the last decades including a “hidden” Brønsted acid catalysis by HI, a Lewis‐acid (or halogen‐bond) activation, or catalysis by an iodonium(I) species. Recently, iodine catalysis again gained more interest due to the latest developments in halogen‐bond catalysis. In this Minireview, we first summarize the experimental basis for the proposed modes of activation. Subsequently, we analyze typical iodine‐catalyzed reactions to gain more insights into the underlying reaction mechanisms. [ABSTRACT FROM AUTHOR]

Abstract: The reaction mechanism of the carbonic anhydrase‐mediated hydrolysis of sulfocoumarins to sulfonic acids has been investigated on an enzyme cluster model using the B3LYP hybrid density functional theory (DFT) and the QST procedure for the Transition State (TS) search. A multistep process was highlighted, with the rate‐determining step identified in the initial dual nucleophilic/acidic attack of the zinc‐bound hydroxide ion to the sulfocoumarin sulfur atom and to the C3=C4 double bond. The reported multi‐step process, combined to SAR analysis on a new set of derivatives, highlighted unprecedented mechanistic aspects of the CA‐mediated prodrug activation, which in turn possess relevant consequences to the isoforms‐selective inhibition profiles reported by such a class of compounds. [ABSTRACT FROM AUTHOR]

A new synthetic route to highly fluorescent benzofuranylmethylidenebenzoxasiloles through cationic rhodium(I)/binap complex‐catalyzed cascade cycloisomerization of bis(2‐ethynylphenol)silanes has been developed involving 1,2‐silicon and 1,3‐carbon (alkyne) migrations followed by oxycyclization. The present synthesis requires only three steps, starting from commercially available dichlorodiisopropylsilane, which is markedly shorter than our previous synthesis (eight steps starting from commercially available chlorodiisopropylsilane). Theoretical calculations elucidated the mechanism of the above cascade cycloisomerization. This reaction is initiated by the formation of a rhodium vinylidene not through direct 1,2‐silicon migration but rather through an unprecedented stepwise 1,5‐silicon migration followed by C−Si bond‐forming cyclization from a dearomatized allenylrhodium complex. Subsequent 1,3‐carbon (alkyne) migration leading to a η3‐allenyl/propargyl‐rhodium complex followed by oxycyclization through π‐bond (alkyne) activation with the cationic rhodium(I) complex affords the benzofuranylmethylidenebenzoxasilole product. The structure–fluorescence property relationships of the thus obtained benzofuranylmethylidenebenzoxasiloles were investigated, which revealed that good fluorescence quantum yields were generated in the solution state (φF=69–87 %) by introduction of electron‐donating alkyl and phenyl groups on two phenoxy groups. In the powder state, 4‐methyl‐ and 4‐methoxy‐phenoxy derivatives exhibited efficient blue fluorescence (φF=52 % and 46 %, respectively). Especially, the 4‐methylphenoxy derivative was thermally stable, and exhibited strong narrow‐band fluorescence in the film state (blue, φF=95 %) and redshifted strong narrow‐band fluorescence (green, φF=90 %) in the crystalline state as a result of the formation of an offset π‐stacked dimer; the latter was confirmed by X‐ray crystallographic analysis and by theoretical calculations. [ABSTRACT FROM AUTHOR]

Abstract: A family of doubly isonitrile‐stabilized terphenyl borylenes could be obtained by addition of three equivalents of isonitrile to the corresponding Cr and W terminal terphenyl‐borylene complexes. The mechanism of isonitrile‐ and carbon‐monoxide‐induced borylene liberation was investigated computationally and found to be significantly exergonic in both cases. Furthermore, addition of a small N‐heterocyclic carbene (NHC) to a terminal Cr borylene complex results in release of an NHC‐stabilized borylene carbonyl species, whereas the analogous reaction with bulkier phosphines results in metal‐centered substitution. [ABSTRACT FROM AUTHOR]

Abstract: Exchange of X (F, Cl, OMe) and a substituted enolate chain between SiMe3 and various CuI complexes was examined. Reaction mechanisms pass through a cyclic transition state in which the reaction coordinate is associated with rotation of the SiMe3 moiety. The dependence of the thermodynamic and kinetic features on the nature of the active and ancillary ligands was examined. Formation of copper enolate is shown to be favored when stabilized enolates are used. Replacement of F by Cl reverses the preference of the reaction. This is associated with the small difference between the Cu−Cl and Si−Cl bond energies, in contrast to other Si−X bonds, which are systematically stronger than their Cu−X analogues. [ABSTRACT FROM AUTHOR]

Abstract: Treatment of dodecatrienyne derivatives with [RhCl(CO)2]2 in refluxing toluene effected the cycloisomerization to produce tricyclo[6.4.0.02,6]dodecadienes. The one‐carbon shortened undecatrienyne derivatives, however, afforded bicyclo[6.3.0]undecatriene derivatives instead of tricyclic compounds, the latter of which are well known as a basic skeleton of naturally occurring octanoids. On the basis of two experiments with deuterated substrates, a plausible reaction mechanism for the construction of these products was proposed. [ABSTRACT FROM AUTHOR]

Abstract: Imatinib is a synthetic tyrosinase inhibitor that is employed for the treatment of some kinds of human cancer. This drug has a low phototoxicity towards DNA, but its pyridylpyrimidine (1) fragment by itself exhibits significant phototoxicitiy. The intrinsic mechanism that leads to the enhanced photosafety of Imatinib is not yet known. Here, the properties of the excited state and interchromophoric interactions of Imatinib have been explored by using ultrafast laser flash photolysis and agarose electrophoresis studies. An intramolecular charge separation was directly observed for the irradiated Imatinib, which accounts for the relaxation of its excited state. An anionic form of pyridylpyrimidine (1) was deduced from the results of time‐resolved resonance Raman spectra and by quenching experimental studies on compound 1 and diaminotoluene. In contrast, compound 1 efficiently transformed into triplet excited states with a long lifetime, which explained the phototoxicity associated with this fragment. This work provides insight into how to design drugs with lower phototoxicitiy or improved photostability by using interchromophoric interactions. [ABSTRACT FROM AUTHOR]

The functions of metal-containing proteins (metalloproteins) are determined by the reactivities of transition metal ions at their active sites. Because protein macromolecular structures have several molecular degrees of freedom, global structural flexibility may also regulate the properties of metalloproteins. However, the influence of this factor has not been fully delineated in mechanistic studies of metalloproteins. Accordingly, we have investigated the relationship between global protein flexibility and the characteristics of a transition metal ion in the protein core using thiol-subtilisin (tSTL) with a Cys-coordinated Cu2+ ion as a model system. Although tSTL has two Ca2+-binding sites, the Ca2+-binding status hardly affects its secondary structure. Nevertheless, guanidinium-induced denaturation and amide H/D exchange indicated the increase in the structural flexibility of tSTL by the removal of bound Ca2+ ions. Electron paramagnetic resonance and absorption spectral changes have revealed that the protein flexibility determines the characteristics of a Cu2+ ion in tSTL. Therefore, global protein flexibility should be recognized as an important factor that regulates the properties of metalloproteins. [ABSTRACT FROM AUTHOR]

A randomized library is constructed based on pET30a-CYP119-T214V plasmid. This library of random mutants of CYP119-T214V was screened by means of the reduced CO difference spectra and epoxidation of styrene. By using directed evolution, a new CYP119 quadruple mutant S148P/I161T/K199E/T214V is constructed, expressed, and purified. This quadruple mutant significantly increases the turnover rate and conversion for the asymmetric epoxidation of styrene and its derivatives. The kcat. value of cis-β-methylstyrene epoxidation catalyzed by the quadruple mutant exhibits an approximately 10-fold increase, relative to the previously reported T213M mutant under the same conditions. This is the first engineered CYP119 peroxygenase for the epoxidation of cis-β-methylstyrene with a high turnover rate. The proposed mechanism, on the basis of a molecular docking study, for the asymmetric epoxidation suggests that the introduction of an acidic amino acid side chain into the active site and a hydrophobic amino acid into the substrate channels of CYP119 peroxygenase might result in high efficiency for the formation of compound I, and its subsequent peroxygenation by reconstructing the hydrogen-bonding interaction and increasing the substrate affinity and access. [ABSTRACT FROM AUTHOR]

This study aims at extending the understanding of the toxicity mechanism of ionic liquids (ILs) using various analytical methods and cytotoxicity assays. The cytotoxicity of eight ILs and one zwitterionic compound was determined using mammalian and bacterial cells. The time dependency of the IL toxicity was assessed using human corneal epithelial cells. Hemolysis was performed using human red blood cells and the results were compared with destabilization data of synthetic liposomes upon addition of ILs. The effect of the ILs on the size and zeta potential of liposomes revealed information on changes in the lipid bilayer. Differential scanning calorimetry was used to study the penetration of the ILs into the lipid bilayer. Pulsed field gradient nuclear magnetic resonance spectroscopy was used to determine whether the ILs occurred as unimers, micelles, or if they were bound to liposomes. The results show that the investigated ILs can be divided into three groups based on the cytotoxicity mechanism: cell wall disrupting ILs, ILs exerting toxicity through both cell wall penetration and metabolic alteration, and ILs affecting solely on cell metabolism. [ABSTRACT FROM AUTHOR]

The mechanism of H2 activation by recently reported N/Sn Lewis pairs is unravelled using the representative iPr3SnOTf/DABCO combination. Computations provide evidence for weak intermolecular associations between Lewis acid and Lewis base (LA/LB) in which the counteranion to cationic LA fragment plays a critical role. Two frustrated Lewis pairs (FLPs) are observed; an unprecedented counteranion-mediated noncovalent LA/LB association is characterised along with the usual FLP structure. Both the FLPs are shown to be capable of H2 activation through cooperative electron transfer processes involving the LA/LB centres. Overall, computed results are in good agreement with the experimental findings and account for the observed reactivity. Insights obtained in this study are fundamentally important for the rational design of Sn-based alternative FLP LAs. The present findings could also provide a general mechanistic framework for H2 activation by FLPs having an ion pair LA component. [ABSTRACT FROM AUTHOR]

Abstract: Organic synthesis boasts a wide array of reactions involving either radical species or ionic intermediates. The combination of radical and polar species, however, has not been explored to a comparable extent. Herein we present the hydrative aminoxylation of ynamides, a reaction which can proceed by either a polar‐radical crossover mechanism or through a rare cationic activation. Common to both processes is the versatility of the persistent radical TEMPO and its oxidised oxoammonium derivative TEMPO+. The unique mechanisms of these processes are elucidated experimentally and by in‐depth DFT‐calculations. [ABSTRACT FROM AUTHOR]

Abstract: An NHC‐catalyzed formal [3+4] annulation of α,β‐unsaturated acylazoliums with protecting‐group‐free aryl 1,2‐diamines was developed for a direct and highly enantioselective synthesis of 4‐aryl N−H‐free 1,5‐benzodiazepin‐2‐ones. This methodology offers an efficient and rapid access to a wide range of enantioenriched target compounds from easily accessible starting materials. The protocol is also scalable and the desired products can easily undergo subsequent N‐functionalization to afford diverse N‐substituted derivatives. Additionally, a mechanism was proposed to explain the high enantioselectivity in this process. [ABSTRACT FROM AUTHOR]

Abstract: Oxidative addition of iodoarenes (ArI) to Pd0 ligated by 1‐methyl‐1H‐imidazole (mim) in polar solvents leads to cationic arylpalladium(II) complexes [ArPd(mim)3]+. Kinetic analyses evidence that this reaction is second order with respect to the concentration of Pd0, and a mechanism involving the cooperative intervention of two Pd0 centers has been postulated to explain this finding. This unusual behavior is also observed with other nitrogen‐containing ligands and it is general for iodobenzenes substituted with electron‐donating or weakly electron‐withdrawing groups. In contrast, bromoarenes and electron‐poor iodoarenes display first‐order kinetics with respect to Pd0. Theoretical calculations performed at the density functional theory (DFT) level suggest the existence of mim‐ligated ArI‐Pd0 complexes, in which the iodoarene is bound to the metal in a halogen‐bond‐like fashion. Coordination weakens the C−I bond and facilitates the oxidative insertion of another Pd0 center across this C−I bond. This conceptually novel mechanism, involving the cooperative participation of two distinct metal centers, allows a full explanation of the experimentally observed kinetics. [ABSTRACT FROM AUTHOR]

Abstract: In this Concept article, we will scrutinize different approaches devoted to the mechanistic understanding of catalytic processes, paying special attention to the successful use of triazamacrocyclic aryl‐halide or arene‐containing substrates used for Cu‐, Ag‐, Au‐, Co‐ and Ni‐catalysis. The importance of designing model substrate platforms to unravel mechanistic details at a molecular level of C−C or C‐heteroatom bond‐forming processes catalyzed by transition metals will be highlighted. This fundamental mechanistic knowledge will serve as a foundation for the catalyst design for a desired transformation. [ABSTRACT FROM AUTHOR]

The reaction specificity of lipoxygenases is of physiological relevance since the various oxygenation products exhibit different biological activities. Among mammalian ALOX15 orthologs there are arachidonic acid 12- and 15- lipoxygenating enzymes and recent studies suggested an evolutionary switch in that reaction specificity during late primate development. Previous reports showed that 12-lipoxygenating ALOX15 orthologs can be converted to 15-lipoxygenating enzymes by site-directed mutagenesis of some sequence determinants. Unfortunately, the molecular basis for those alterations are not well understood. Here, the arachidonic acid 12-lipoxygenating N-terminal truncation variant of pig ALOX15, for which a crystal structure is available, was used to explore the catalytic mechanism of the specificity switch induced by mutagenesis of Val418 and Val419 sequence determinants. We found that Val418Ile+ Val419Met double mutant is dominantly 15-lipoxygenating. Docking and MD simulations, and quantum mechanics/molecular mechanics calculations indicated that the wildtype energy barrier for arachidonic acid 15-lipoxygenation is 3.4 kcalmol@1 higher than for 12-lipoxygenation. In contrast, for the Val418Ile+Val419Met double mutant the energy barrier for 12-lipoxygenation is 6.0 kcalmol@1 higher than for 15-lipoxygenation. Our data suggest that enzyme-substrate complex geometries determine the value of these energy barriers and, as a consequence, the reaction specificity of ALOX15 orthologs. [ABSTRACT FROM AUTHOR]

Excited-state hydrogen transfer (ESHT) is responsible for various photochemical processes of aromatics, including photoprotection of nuclear basis. Its mechanism is explained by internal conversion from the aromatic pp* to ps* states via conical intersection. This means that the electron is transferred to a diffuse Rydberg-like s* orbital apart from proton migration. This picture means the electron and the proton do not move together and the dynamics are different in principle. Here, we have applied picosecond time-resolved near-infrared (NIR) and infrared (IR) spectroscopy to the phenol-(NH3)5 cluster, the benchmark system of ESHT, and monitored the electron transfer and proton motion independently. The electron transfer monitored by the NIR transition rises within 3 ps, while the overall H transfer detected by the IR absorption of NH vibration appears with a lifetime of about 20 ps. This clearly proves that the electron motion and proton migration are decoupled. Such a difference of the time-evolutions between the NIR absorption and the IR transition has not been detected in a cluster with three ammonia molecules. We will report our full observation together with theoretical calculations of the potential energy surfaces of the pp* and ps* states, and will discuss the ESHT mechanism and its cluster size-dependence between n=3 and 5. It is suggested that the presence and absence of a barrier in the proton transfer coordinate cause the different dynamics. [ABSTRACT FROM AUTHOR]

Treatment of a pyrazine (pz)-impregnated CuI metal-organic framework (MOF) ([1⊃pz]) with HCl vapor renders an interstitial pyrazinium chloride salt-hybridized MOF ([1⊃pz∙6 HCl]) that exhibits proton conductivity over 10-2 Scm-1 both in anhydrous and under humid conditions. Framework [1⊃pz∙6 HCl] features the highest anhydrous proton conductivity among the lesser-known examples of MOF-based materials exhibiting proton conductivity under both anhydrous and humid conditions. Moreover, [1⊃pz] and corresponding pyrazinium sulfate- and pyrazinium phosphate- hybridized MOFs also exhibit superprotonic conductivity over 10-2 Scm-1 under humid conditions. The impregnated pyrazinium ions play a crucial role in protonic conductivity, which occurs through a Grotthuss mechanism. [ABSTRACT FROM AUTHOR]

Abstract: While thiophosgene finds widespread usage on a multi‐ton scale, its fluorinated counterpart S=CF2 is essentially unexplored in synthesis. Using experimental reactivity tests, ReactIR and computational techniques, we herein showcase that the solid (Me4N)SCF3 functions as a safe reservoir for S=CF2. A key feature is that the reactive electrophile is not simply released over time, but instead is liberated under activation with a protic nucleophile. The reactivity of S=CF2 is mild, allowing large‐scale and late‐stage synthetic applications without special reaction control. The mechanism was fully elucidated, including a rationalization of the role of the Me4N cation and the origins of selectivity. [ABSTRACT FROM AUTHOR]

Abstract: The self‐assembly process of a Pd2L4 cage complex consisting of rigid ditopic ligands, in which two 3‐pyridyl groups are connected to a benzene ring through acetylene bonds and PdII ions was revealed by a recently developed quantitative analysis of self‐assembly process (QASAP), with which the self‐assembly process of coordination assemblies can be investigated by monitoring the evolution with time of the average composition of all the intermediates. QASAP revealed that the rate‐determining steps of the cage formation are the intramolecular ligand exchanges in the final stage of the self‐assembly: [Pd2L4Py*2]4+→[Pd2L4Py*1]4++Py* and [Pd2L4Py*1]4+→[Pd2L4]4++Py* (Py*: 3‐chloropyridine, which was used as a leaving ligand on the metal source). The energy barriers for the two reactions were determined to be 22.3 and 21.9 kcal mol−1, respectively. DFT calculations of the transition‐state (TS) structures for the two steps indicated that the distortion of the trigonal‐bipyramidal PdII center at the TS geometries increases the activation free energy of the two steps. [ABSTRACT FROM AUTHOR]

The control of stereoselectivity in a glycosylation reaction remains one of the most challenging aspects of oligosaccharide synthesis. Especially the synthesis of 1,2- cis-glycosides is challenging and generally applicable methodology to prepare this linkage is needed to standardize oligosaccharide synthesis. This review highlights the recent development of an elegant strategy employing a C-2 auxiliary to control the anomeric stereoselectivity in glycosylations. The various auxiliaries developed to date, their compatibility with protecting groups and monosaccharide types as well as mechanistic aspects are summarized. Furthermore, the application, advantages and limitations of C-2 auxiliaries in oligosaccharide synthesis are discussed. [ABSTRACT FROM AUTHOR]

Recent experimental reports of heme carbene C−H insertions show promising results for sustainable chemistry due to good yield and selectivity, low cost of iron, and low/no toxicity of hemes. But mechanistic details are mostly unknown. Despite structural similarity and isoelectronic nature between heme carbene and the FeIV=O intermediate, our quantum chemical studies with detailed geometric and electronic information for the first time reveal an FeII-based, concerted, hydride-transfer mechanism, which is different from the FeIV-based stepwise hydrogen atom transfer mechanism for C−H functionalization by native heme enzymes. A trend of broad range experimental C−H insertion yields (0-88 %) of five different C−H bonds, including mostly non-functionalized moieties, was well reproduced. Results suggest that the substrate selectivity originates from the hydride formation capability. The predicted kinetic isotope effects were also in excellent agreement with experiment. Useful geometry, charge, and energy parameters well correlated with barriers were reported. These results provide the first theoretical evidence that carbene formation is the overall rate-limiting step, and suggest a key role of the formation of strong electrophilic heme carbene in developing heme-based C−H insertion catalysts and biocatalysts. [ABSTRACT FROM AUTHOR]

An in-depth computational probe of the copper-mediated formal aminoboration of β-alkylstyrenes with bis(pinacolato)diboron B2pin2 and an archetype hydroxylamine ester by a dppbz-ligated {P^P}CuI boryl catalyst (dppbz≡{P^P}≡1,2-bis(diphenylphosphino)benzene) is presented. This first comprehensive computational study of the copper-mediated formal aminoboration utilising an electrophilic strategy has identified the most accessible pathway for productive catalysis. The mechanistic picture derived from smooth energy profiles acquired by employing a reliable computational protocol applied to a realistic catalyst model conforms to all available experimental data. The high degree of regio- and stereoselectivity achieved in syn-borylcupration and Umpolung electrophilic amination is instrumental to the exclusive generation of the ( syn)-β-aminoalkylborane product. On the one hand, syn-borylcupration furnishes exclusively β-borylalkylcopper nucleophile upon boryl addition onto the vinylarene β-carbon. Its subsequent approach by the hydroxylamine electrophile to deliver the product with the release of {P^P}CuI benzoate favours a stepwise stereoretentive SN2-type oxidative addition/N−C bond-forming reductive elimination sequence. The copper benzoate species represents the catalyst resting state, and its transformation into the catalytically active borylcopper species upon salt metathesis with Li(O tBu) base and transmetallation with B2pin2 is turnover limiting. Electronically modified β-alkylstyrenes featuring a para-CF3 substituted phenyl ring render the borylcupration faster, and more electron-rich hydroxylamine agents decelerate the electrophilic amination. [ABSTRACT FROM AUTHOR]

The reaction mechanism associated with the synthesis of phosphorus-based heteropolyaromatic architectures was investigated by DFT calculations at the B3LYP-D3/6-311+G(D) level of theory. The aim of this study is to provide essential information for the future development of improved polycyclic organophosphorus materials. To that end, the impact of the structure of the initial reactant and/or the intermediates structure on the mechanistic features and energetic profiles of the phosphorus cyclization process was studied. Moreover, the reactivity parameters were analyzed in detail in a conceptual DFT framework and the underlying reactivity trends were extracted. Thus, these findings provide important insights for a rational design of polycyclic phosphorus compounds. [ABSTRACT FROM AUTHOR]

Novel pyrrolidine-based multivalent iminosugars, synthesized by a CuAAC approach, have shown remarkable multivalent effects towards jack bean α-mannosidase and a Golgi α-mannosidase from Drosophila melanogaster, as well as a good selectivity with respect to a lysosomal α-mannosidase, which is important for anticancer applications. STD NMR and molecular modeling studies supported a multivalent mechanism with specific interactions of the bioactive iminosugars with Jack bean α-mannosidase. TEM studies suggested a binding mode that involves the formation of aggregates, which result from the intermolecular cross-linked network of interactions between the multivalent inhibitors and two or more dimers of JBMan heterodimeric subunits. [ABSTRACT FROM AUTHOR]

A selection of NIR-optically responsive neuron probes was produced comprising of a donor julolidyl group connected to a BODIPY core and several different styryl and vinylpyridinyl derived acceptor moieties. The strength of the donor-acceptor interaction was systematically modulated by altering the electron withdrawing nature of the aryl unit. The fluorescence quantum yield was observed to decrease as the electron withdrawing effect of the aryl subunit increased in line with changes of the Hammett parameter. The effectiveness of these fluorophores as optically responsive dyes for neuronal imaging was assessed by measuring the toxicity and signal-to-noise ratio (SNR) of each dye. A great improvement of SNR was obtained when compared to the first-generation BODIPY-based voltage sensitive dyes with concomitant toxicity decrease. The mechanism for the optical response is disparate from conventional cyanine-based dyes, opening up a new way to produce effective voltage sensitive dyes that respond well into the NIR region. [ABSTRACT FROM AUTHOR]

Lewis base-borane complexes are shown to be potent hydrogen atom donors in radical chain reduction reactions. Results obtained in 1H, 11B, and 13C NMR measurements and kinetic experiments support a complex reaction mechanism involving the parent borane as well as its initial reaction products as active hydrogen atom donors. Efficient reduction reactions of iodides, bromides, and xanthates in apolar solvents rely on initiator systems generating oxygen-centered radicals under thermal conditions and pyridine-borane complexes carrying solubilizing substituents. In contrast to tin hydride reagents, the pyridine-boranes reduce xanthates faster than the corresponding iodides. [ABSTRACT FROM AUTHOR]

Comparative investigation of copper-assisted oxidative and reductive amination showed that the latter was preferable for the synthesis of bulky diarylamines. DFT estimation of the mechanism of copper(I)-assisted reductive amination of boronic acids with aryl nitroso compounds was performed and possible active species were identified. DFT estimation of the steric penalty revealed that the barrier for the transmetalation step for the hindered nitroso compound was almost the same as that for the unsubstituted one, whereas a bulky group in the boronic acid increased the activation energy. A DFT study of the influence of the electronic properties of the substituents in both reactants on the activation energy revealed that the optimal combination for the synthesis of unsymmetrical diarylamines to provide better yields was an electron-rich aryl boronic acid and an electron-deficient nitroso compound. By using these helpful guidelines, a series of new bulky diarylamines were obtained and fully characterized. [ABSTRACT FROM AUTHOR]

Sustainable, cobalt-catalyst enabled, synthetically significant C−F/C−H functionalizations were achieved with an ample substrate scope at an ambient temperature of 25 °C, thereby delivering perfluoroallylated heteroarenes. Detailed experimental and computational mechanistic studies on the C−F/C−H functionalizations provided strong support for a facile C−F cleavage. [ABSTRACT FROM AUTHOR]

A detailed mechanistic investigation identified the stepwise nature of the 1,3-aryl shift, which enables our recently disclosed Al3+-catalyzed insertion of unactivated alkynes into the sp2-sp3 C−C bond of benzyl alcohols. The selectivity for the rearranged product was found to be induced by the continued coordination of the aluminum catalyst to the rearranging species, which is encouraged by a reversible background reaction. This participation of the catalyst beyond the ionization step is unique in the realm of carbocation driven reactions and opens up the possibility of a catalyst-induced chiral induction in the future. Furthermore, the study represents a rare example of detailed mechanistic analysis of a reaction with a product selectivity that changes with increasing conversion. [ABSTRACT FROM AUTHOR]