Type I Photosensitized Oxidation of Methionine†

Methionine (Met) is an essential sulfur‐containing amino acid, sensitive to oxidation. The oxidation of Met can occur by numerous pathways, including enzymatic modifications and oxidative stress, being able to cause relevant alterations in protein functionality. Under UV radiation, Met may be oxidized by direct absorption (below 250 nm) or by photosensitized reactions. Herein, kinetics of the reaction and identification of products during photosensitized oxidation were analyzed to elucidate the mechanism for the degradation of Met under UV‐A irradiation using pterins, pterin (Ptr) and 6‐methylpterin (Mep), as sensitizers. The process begins with an electron transfer from Met to the triplet‐excited state of the photosensitizer (Ptr or Mep), to yield the corresponding pair of radicals, Met radical cation (Met^?+) and the radical anion of the sensitizer (Sens^??). In air‐equilibrated solutions, Met^?+ incorporates one or two atoms of oxygen to yield methionine sulfoxide (MetO) and methionine sulfone (MetO₂), whereas Sens^?? reacts with O₂ to recover the photosensitizer and generate superoxide anion (O₂^??). In anaerobic conditions, further free‐radical reactions lead to the formation of the corresponding dihydropterin derivatives (H₂Ptr or H₂Mep).     

Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes

Oxidative stress (OS) is a metabolic dysfunction mediated by the imbalance between the biochemical processes leading to elevated production of reactive oxygen species (ROS) and the antioxidant defense system of the body. It has a ubiquitous role in the development of numerous noncommunicable maladies including cardiovascular diseases, cancers, neurodegenerative diseases, aging and respiratory diseases. Diseases associated with metabolic dysfunction may be influenced by changes in the redox balance. Lately, there has been increasing awareness and evidence that diabetes mellitus (DM), particularly type 2 diabetes, is significantly modulated by oxidative stress. DM is a state of impaired metabolism characterized by hyperglycemia, resulting from defects in insulin secretion or action, or both. ROS such as hydrogen peroxide and the superoxide anion introduce chemical changes virtually in all cellular components, causing deleterious effects on the islets of β-cells, in turn affecting insulin production. Under hyperglycemic conditions, various signaling pathways such as nuclear factor-κβ (NF-κβ) and protein kinase C (PKC) are also activated by ROS. All of these can be linked to a hindrance in insulin signaling pathways, leading to insulin resistance. Hyperglycemia-induced oxidative stress plays a substantial role in complications including diabetic nephropathy. DM patients are more prone to microvascular as well as atherosclerotic macrovascular diseases. This systemic disease affects most countries around the world, owing to population explosion, aging, urbanization, obesity, lifestyle, etc. However, some modulators, with their free radical scavenging properties, can play a prospective role in overcoming the debilitating effects of OS. This review is a modest approach to summarizing the basics and interlinkages of oxidative stress, its modulators and diabetes mellitus. It may add to the understanding of and insight into the pathophysiology of diabetes and the crucial role of antioxidants to weaken the complications and morbidity resulting from this chronic disease.     

亚铜催化的碳杂偶联反应机理*

近年来,亚铜催化的碳杂偶联反应以其高效、低成本和易制备等优点被广泛研究并应用于工业生产,有机合成及生物活性分子的制备中。目前对于这些碳杂偶联反应机理的探究仍然处于探索性阶段。本文主要评述了近年来亚铜催化的碳杂偶联反应机理的研究进展。重点综述近年来研究相对较多,对机理认识较为完善的碳-氮偶联(特别是酰胺类化合物的芳基化过程),碳氧偶联以及碳硼偶联(不饱和有机化合物的硼化、二硼化反应)机理等方面的进展。最后,基于目前这些机理研究工作的现状,展望了未来机理探究的主要方向。     

Mechanistic Pathways and Identification of the Electrochemically Generated Oxidation Products of Flavonoid Eriodictyol in the Presence of Glutathione

The metabolic oxidation pathways of dietary flavonoid eriodictyol (Er) are not very well‐probed. In the present work, the electrochemical oxidation behavior of Er was studied in aqueous Britton‐Robinson (B‐R) buffer solution using cyclic voltammetry (CV), chronoamperometry (CA), and bulk‐electrolysis (BE). The oxidation products and reaction pathways of Er in the absence and the presence of glutathione (GSH) were proposed and identified in view of the results obtained by ultra‐high‐performance liquid chromatography coupled with mass spectrometry (UPLC‐MS). In the absence of GSH, eriodictyol shows one quasi‐reversible oxidation process at E_1/2=0.305 V, followed by a totally irreversible anodic peak at a more positive potential (E_p^a=1.05 V vs. Ag/AgCl, 3 M KCl). Putatively, the first process corresponds to the oxidation of the catechol moiety on the B ring of Er while the second one is attributed to the oxidation of the resorcinol moiety on the A ring. In the presence of GSH, however, the anodic oxidation of Er was proposed to be an ECEC‐type mechanism. The Er molecule first underwent a two‐electron oxidation coupled with loss of two‐proton to generate the corresponding quinone, which was either reduced to the original Er molecule by GSH, or further interacted with GSH to produce mono‐ and bi‐ glutathione conjugates of Er. The proposed mechanism was confirmed by digital simulation of the cyclic voltammograms.     

Kinetics and Mechanism of the Photosensitized Oxidation of Furosemide*

Detection of O2(1δg) phosphorescence emission, γmax = 1270 nm, following laser excitation and steady-state competitive methods was employed to measure total rate constants, kT, for the reactions of the diuretic furosemide, 2-methylfurane and furfurylamine with singlet oxygen in several solvents. Correlation of kT values with solvent parameters and product identification shows that the reaction mechanism is strongly solvent dependent. In aliphatic alcohols, the dependence of kT on solvent parameters is similar to the one observed for triethylamine, suggesting a reaction mechanism involving partial charge transfer from the amino group to the singlet oxygen. In nonprotic solvents, the dependence of kT on solvent parameters resembles the behavior found for 2-methylfur-ane and furfurylamine, implying that mostly a 2 + 4 cy-cloaddition mechanism of singlet oxygen to furane ring of furosemide occurs in these solvents. These mechanistic differences are explained in terms of hydrogen-bonding interactions between the carboxylic group in the aromatic ring and the amino group of furosemide. Furthermore, direct generation of C2(1δg) by furosemide was detected. Quantum yields of 0.047 ± 0.003 and 0.078 ± 0.004 were determined in acetonitrile and benzene, respectively. This last result may be related, at least partially, to the photodynamic effects of this diuretic drug.     

Ruthenium(IV) and Osmium(II) Tetraphenylporphine Complexes: Synthesis and Oxidation Reactions

The Ru(IV) and Os(II) complexes (PhO)₂RuTPP and OsTPP were synthesized from tetraphenylporphine (H₂TPP) and K₂RuO₄ or K₂OsO₄ (taken in the molar ratio of 1 : 30) in boiling phenol. The kinetics of oxidation reactions of these complexes in solutions of HOAc (acetic), H₂SO₄, and HOAc–H₂SO₄ acids was studied. It was found that in the aerated HOAc–H₂SO₄ mixture heated above 340 K, these complexes are oxidized with participation of different reaction sites: the Ru(IV) complex is oxidized at macrocycle to give the -radical-cation (PhO)₂RuPP⁺, while in the Os(II) complex, the metal atom is oxidized to form the Os(III) complex. In the first case, the reaction follows the activation mechanism, whereas in the second case, the activation energy of the reaction is zero.     

Acylation Reactions of Dibenzo-7-phosphanorbornadiene: DFT Mechanistic Insights

Extensive DFT calculations provide deep mechanistic insights into the acylation reactions of tert-butyl dibenzo-7-phosphanobornadiene with PhCOX (X=Cl, Br, I, OTf) in CH₂Cl₂ solution. Such reactions are initialized by the nucleophilic P⋅⋅⋅C attack to the carbonyl group to form the acylphosphonium intermediate A⁺ together with X⁻ anion, followed either by nucleophilic X⁻⋅⋅⋅P attack (X=Cl, Br, and I) toward A⁺ to eliminate anthracene or by slow rearrangement or decomposition of A⁺ (X=OTf). In contrast to the first case (X=Cl) that is rate-limited by the initial P⋅⋅⋅C attack, other reactions are rate-limited by the second X⁻⋅⋅⋅P attack for X=Br and I and even thermodynamically prevented for X=OTf, leading to isolable phosphonium salts. The rearrangement of phosphonium A⁺ is initiated by a P-C bond cleavage, followed either by sequential proton-shifts to form anthracenyl acylphosphonium or by deprotonation with additional base Et₃N to form neutral anthracenyl acylphosphine. Our DFT results strongly support the separated acylphosphonium A⁺ as the key reaction intermediate that may be useful for the transfer of acylphosphenium in general.     

Biocatalytic Oxidation Reactions: A Chemist's Perspective

Oxidation chemistry using enzymes is approaching maturity and practical applicability in organic synthesis. Oxidoreductases (enzymes catalysing redox reactions) enable chemists to perform highly selective and efficient transformations ranging from simple alcohol oxidations to stereoselective halogenations of non‐activated C?H bonds. For many of these reactions, no “classical” chemical counterpart is known. Hence oxidoreductases open up shorter synthesis routes based on a more direct access to the target products. The generally very mild reaction conditions may also reduce the environmental impact of biocatalytic reactions compared to classical counterparts. In this Review, we critically summarise the most important recent developments in the field of biocatalytic oxidation chemistry and identify the most pressing bottlenecks as well as promising solutions.     

Visible‐Light‐Photosensitized Aryl and Alkyl Decarboxylative Functionalization Reactions

Despite significant progress in aliphatic decarboxylation, an efficient and general protocol for radical aromatic decarboxylation has lagged far behind. Herein, we describe a general strategy for rapid access to both aryl and alkyl radicals by photosensitized decarboxylation of the corresponding carboxylic acids esters followed by their successive use in divergent carbon–heteroatom and carbon–carbon bond‐forming reactions. Identification of a suitable activator for carboxylic acids is the key to bypass a competing single‐electron‐transfer mechanism and “switch on” an energy‐transfer‐mediated homolysis of unsymmetrical σ‐bonds for a concerted fragmentation/decarboxylation process.     

Silver(I)-promoted Oxidation and Ring-enlargement Reactions of Unstrained Hydrocarbons, Polyphenyl-cyclopentadiene

The activation of carbon-carbon bonds by soluble transitional metal complexes has been one of the most prominent challenges in recent years1-3. Despite the inertness of carbon-carbon bonds, some possible ways to cleave carbon-carbon bonds have been devised, such as relieving ring energy4, inducing aromatic stabilization5, forming stable metallocyclic complexes6, etc. Silver salts, such as silver perchlorate and silver trifluoroacetate, play an important role in carbon-carbon bond activation,…     

Terminal Alkyne Coupling Reactions through a Ring: Mechanistic Insights and Regiochemical Switching

The mechanism and selectivity of terminal alkyne coupling reactions promoted by rhodium(I) complexes of NHC‐based CNC pincer ligands have been investigated. Synthetic and kinetic experiments support E‐ and gem‐enyne formation through a common reaction sequence involving hydrometallation and rate‐determining C?C bond reductive elimination. The latter is significantly affected by the ligand topology: Employment of a macrocyclic variant enforced exclusive head‐to‐head coupling, contrasting the high selectivity for head‐to‐tail coupling observed for the corresponding acyclic pincer ligand.     

Rh(I)-Catalyzed Asymmetric Hydrosilylation and Hydroboration/Oxidation Reactions Using Berens Ligand

The Berens ligand 2 was used in a number of Rh(I)-catalyzed asymmetric hydrosilylations of acetophenones under standard conditions, affording the corresponding 1-arylalcohols in ees up to 65%. Some novel Rh catalysts were generated in situ from the neutral precatalyst [Rh(µ-Cl)(COD)]₂ and screened in the catalytic asymmetric hydroboration/oxidation of styrenes, gave enantioselectivities of up to 62%.     

Bridge‐Splitting Reactions of Platinum(II) Complexes with Parametalated Pyridine Spacer Groups: A Kinetic and Mechanistic Study

Substitution reactions of three dinuclear Pt(II) complexes connected by a pyridine‐bridging ligand of variable length, namely [ cis‐{PtOH₂(NH₃)₂}₂–μ–L]⁴⁺, where L = 4,4′‐bis(pyridine)sulfide ( Pt1 ), 4,4′‐bis(pyridine)disulfide ( Pt2 ), and 1,2‐bis(4‐pyridyl)ethane ( Pt3 ) with S‐donor nucleophiles (thiourea, 1,3‐dimethyl‐2‐thiourea, and 1,1,3,3‐tetramethyl‐2‐thiourea) and anionic nucleophiles (SCN^?, I^?, and Br^?) were investigated. The substitutions were followed under pseudo–first‐order conditions as a function of the nucleophile concentration and temperature, using stopped‐flow and UV–visible spectrophotometric methods. The observed pK_a values were, respectively, Pt1 (pK_a1: 4.86; pK_a2: 5.53), Pt2 (pK_a1: 5.19; pK_a2: 6.42), and Pt3 (pK_a1: 5.04; pK_a2: 5.45). The second‐order rate constants for the lability of aqua ligands in the first step decreased in the order Pt2 > Pt3 > Pt1 , whereas for the second step it is Pt1 > Pt2 > Pt3 . The obtained results indicate that introduction of a spacer atom(s) on the structure of the bridging ligand influences the substitution reactivity as well as acidity of the investigated dinuclear Pt(II) complexes. Also nonplanarity of the bridging ligand of Pt1 complex significantly slows down the rate of substitution due to steric hindrance, whereas release of the strain enhances the dissociation of the bridging ligand. The release of the bridging ligand in the second step was confirmed by the ¹H NMR of Pt1‐Cl with thiourea in DMF‐d₇. The temperature dependence of the second–order rate constants and the negative values of entropies of activation (ΔS^#) support an associative mode of the substitution mechanism.     

Catalytic Reactions of Titanium Alkoxides with Grignard Reagents and Imines: A Mechanistic Study

The reactivity of Grignard reagents towards imines in the presence of catalytic and stoichiometric amounts of titanium alkoxides is reported. Alkylation, reduction, and coupling of imines take place. Whereas reductive coupling is the major reaction in stoichiometric reactions, alkylation is favored in catalytic reactions. Mechanistic studies clearly indicate that intermediates involved in the two reactions are different. Catalytic reactions involve a metal–alkyl complex. This has been confirmed by reactions of deuterium‐labeled substrates and different alkylating agents. Under the stoichiometric conditions, however, titanium olefin complexes are formed through reductive elimination, probably through a multinuclear intermediate.     

Natural anthraquinones probed as Type I and Type II photosensitizers: singlet oxygen and superoxide anion production

The photosensitizing properties of six anthraquinones (AQs): soranjidiol (1), soranjidiol-1-methyl ether (2), rubiadin (3), rubiadin-1-methyl ether (4), damnacanthal (5) and damnacanthol (6), isolated from leaves and stems of Heterophyllaea pustulata Hook. f. (Rubiaceae) were studied. By means of photobiological and photophysical methods in vitro, the type of photosensitization that these metabolites are capable of producing was determined. Whereas the photosensitized generation of superoxide anion radical (O(2)(-)) (Type I) was evaluated in leukocyte suspensions, singlet molecular oxygen ((1)O(2)) production (Type II) was examined in organic solution. In addition, the quantum yield of (1)O(2) (Phi) in chloroform was measured for those AQs that generate it. It was established that 4 behaves exclusively as a Type I photosensitizer. By contrast, the others AQs act by both types of mechanisms, among which 5 showed the largest Phi of (1)O(2).     

Reactions of Cationic Gold(I) with Allenoates: Synthesis of Stable Organogold(I) Complexes and Mechanistic Investigations on Gold‐Catalyzed Cyclizations

The reaction of allenoates with cationic gold(I)—generated in situ from a phosphine gold chloride and a silver salt—formed unusual, room temperature stable vinyl gold(I) lactones under very mild conditions. The scope and limitations for the synthesis of this novel organogold complex was investigated. DFT calculations on the highest occupied molecular orbitals (HOMOs) of allenoates and the natural bond orbital (NBO) charge densities provided an explanation for the limitations. A plausible mechanism for its formation was proposed based on in situ ¹H and ³¹P NMR spectroscopic analyses. Controlled experiments for the cleavage of the gold–carbon bond by electrophiles indicated that this vinyl gold(I) complex is the likely intermediate in the gold‐catalyzed reaction of carbon–carbon multiple bonds.     

Mechanistic Study of Oxidation of Palladium(II) by Cerium(IV) in Aqueous Acid

The kinetics of oxidation of Pd^II by Ce^IV have been studied spectrophotometrically in HClO₄ media at 40 °C. The reaction is first order each in [Ce^IV] and [Pd^II] at constant [H⁺]. Increasing [H⁺] accelerates the reaction rate with fractional order in [H⁺]. The initially added products, palladium(IV) and cerium(III) do not have any significant effect on the reaction rate. At constant acidity, increasing the added chloride concentration enhances the rate of reaction. H₃Ce(SO₄)₄⁻ and PdCl₄²⁻ are the active species of oxidant and reductant respectively. The possible mechanisms are proposed and the reaction constants involved have been determined.