Single Electron Transfer Agents Research Articles

Minocycline mitigates Aβ and TAU pathology, neuronal dysfunction, and death in the PSEN1 E280A cholinergic-like neurons model of familial Alzheimer’s disease

Familial Alzheimer’s disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aβ), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 μM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aβ by −69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by −33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by −25%, (iv) diminishes oxidized DJ-1 at Cys106-SO3 by −29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by −33, −86, and −78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca2+ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aβ (Vina Score −6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca2+ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

Sulfoxylate Anion Radical-Induced Aryl Radical Generation and Intramolecular Arylation for the Synthesis of Biarylsultams.

Aryl radical generation from the corresponding aryl halides using an electron donor and subsequent intramolecular cyclization with arenes could be an important advancement in contemporary biaryl synthesis. A green and practically useful synthetic protocol to access diverse six- and seven-membered biarylsultams especially with a free NH group including demonstration of a gram-scale synthesis is reported herein. The sulfoxylate anion radical (SO2-•), generated in situ from the reagents rongalite or sodium dithionite (Na2S2O4), was found to be the key single electron transfer agent forming aryl radicals from aryl halides, which upon intramolecular arylation gives biarylsultams with good to excellent yields. The approach features generation of aryl radicals that remained underexplored, use of a cheap and readily available industrial reagents, and transition metal-free, mild, and green reaction conditions.

Controlled Single-Electron Transfer via Metal-Ligand Cooperativity Drives Divergent Nickel-Electrocatalyzed Radical Pathways.

Electrocatalysis enables the construction of C-C bonds under mild conditions via controlled formation of carbon-centered radicals. For sequences initiated by alkyl halide reduction, coordinatively unsaturated Ni complexes commonly serve as single-electron transfer agents, giving rise to the foundational question of whether outer- or inner-sphere electron transfer oxidative addition prevails in redox mediation. Indeed, rational design of electrochemical processes requires the discrimination of these two electron transfer pathways, as they can have outsized effects on the rate of substrate bond activation and thus impact radical generation rates and downstream product selectivities. We present results from combined synthetic, electroanalytical, and computational studies that examine the mechanistic differences of single electron transfer to alkyl halides imparted by Ni metal-ligand cooperativity. Electrogenerated reduced Ni species, stabilized by delocalized spin density onto a redox-active tpyPY2Me polypyridyl ligand, activates alkyl iodides via outer-sphere electron transfer, allowing for the selective activation of alkyl iodide substrates over halogen atom donors and the controlled generation and sequestration of electrogenerated radicals. In contrast, the Ni complex possessing a redox-innocent pentapyridine congener activates the substrates in an inner-sphere fashion owning to a purely metal-localized spin, thereby activating both substrates and halogen atom donors in an indiscriminate fashion, generating a high concentration of radicals and leading to unproductive dimerization. Our data establish that controlled electron transfer via Ni-ligand cooperativity can be used to limit undesired radical recombination products and promote selective radical processes in electrochemical environments, providing a generalizable framework for designing redox mediators with distinct rate and potential requirements.

The Proven Versatility of Cp2TiCl.

In the last two decades, titanocene monochloride has been postulated as a monoelectronic transfer reagent capable of catalyzing an important variety of chemical transformations. In this Perspective, our contributions to this growing field of research are summarized and analyzed. Especially known have been our contributions in C-C bond formation reactions, hydrogen-atom transfer from water to radicals, and isomerization reactions, as well as the development of a catalytic cycle that has subsequently allowed the preparation of a great variety of natural terpenes. It is also worth mentioning our contribution in the postulation of this single-electron transfer agent (SET) as a new green catalyst with a broad range of applications in organic and organometallic chemistry. The most significant catalytic processes developed by other research groups are also briefly described, with special emphasis on the reaction mechanisms involved. Finally, a reflection is made on the future trends in the research of this SET, aimed at consolidating this chemical as a new green reagent that will be widely used in fine chemistry, green chemistry, and industrial chemical processes.

Samarium Iodide Showcase: Unraveling the Mechanistic Puzzle

ConspectusSmI2 was introduced to organic chemistry as a single electron transfer agent in 1977. After ca. 15 years of latency, the scientific community has realized the high potential of this reagent, and its chemistry has started blooming. This versatile reagent has mediated a myriad of new bond formations, cyclizations, and other reactions. Its popularity stems largely from the fact that three different intermediates, radical anions, radicals, and anions, depending on the ligand or additive used, could be obtained. Each of these intermediates could in principle lead to a different product. While these options vastly enrich the repertoire of SmI2, they necessitate a thorough mechanistic understanding, especially concerning how appropriate ligands direct the SmI2 to the desired intermediate. Our first paper on this subject dealt with the reduction of an activated double bond. The results were puzzling, especially the H/D isotope effect, which depended on the order of the reagents addition. This seminal paper was fundamental to an understanding of how the SmI2 works and enabled us to later explain various phenomena. For example, it was found that in a given reaction, when MeOH is used as a proton source, a spiro compound is obtained, while a bicyclic product is obtained when t-BuOH is used. Our contribution culminated in formulating guidelines for the rational use of proton donors in SmI2 reactions.The need to understand the complexity of the effect of additives on various processes is nicely demonstrated in photoinduced reactions. For example, hexamethylphosphoramide (HMPA) enhances the reduction of anthracene while hampering the reaction of benzyl chloride. The mechanistic understanding gained enabled us also to broaden the scope of photostimulated reactions from substrates reacting by a dissociative electron transfer mechanism to normal reductions, which are difficult to accomplish at the ground state. Harnessing the classical knowledge of proton transfer mechanisms to our SmI2 research enabled us to decipher an old conundrum: why does the combination of water and amine have such an enhancing effect on the reactivity of SmI2, which is not typical of these two when used separately. In our studies on the affinity of ligands to SmI2, we discovered that, in contradistinction to the accepted dogma, SmI2 is much more azaphilic than it is oxophilic. On the basis of the size difference between Sm3+ and Sm2+, we developed a simple diagnostic tool for the nature of the steps following the electron transfer. The reduction of imines showed that substrate affinity to SmI2 plays also a crucial role. In these reactions, new features such as autocatalysis and catalysis by quantum dots were discovered. Several studies of the ligand effect lead to a clear formulation of when an inner sphere or outer sphere electron transfer should be expected. In addition, several reactions where proton-coupled electron transfer (PCET) is the dominant mechanism were identified. Finally, the surprisingly old tool of NMR “shift reagents” was rediscovered and used to directly derive essential information on the binding constants of ligands and substrates to SmI2.

Carbonyl-Photoredox/Metal Dual Catalysis: Applications in Organic Synthesis

Photoredox/metal dual catalysis is a versatile tandem methodology to construct carbon–carbon and carbon–heteroatom bonds. The focus of this short review is the application of this technology to C(sp3)–C(sp3), C(sp3)–C(sp2), C(sp2)–C(sp2), C(sp2)–O, and C(sp3)–O bond formation induced by readily available and inexpensive carbonyl complexes as single electron transfer agents, photosensitizers, or hydrogen atom transfer agents.1 Introduction2 Homocoupling of Aryl Halides3 Functionalization of C(sp3)–H Bonds3.1 Dehydrogenation of Alkanes3.2 Arylation/Alkylation3.3 Carboxylation3.4 Acylation3.5 Hydroalkylation of Olefins3.6 Hydroalkylation of Imines4 Benzoylation of Aryl Bromides5 Aryl Esterification6 Oxidation of β-Keto Esters7 Conclusions and Future Outlook

Selective Photocatalytic C-F Borylation of Polyfluoroarenes by Rh/Ni Dual Catalysis Providing Valuable Fluorinated Arylboronate Esters.

A highly selective and general photocatalytic C-F borylation protocol that employs a rhodium biphenyl complex as a triplet sensitizer and the nickel catalyst [Ni(IMes)2] (IMes = 1,3-dimesitylimidazoline-2-ylidene) for the C-F bond activation and defluoroborylation process is reported. This tandem catalyst system operates with visible (blue, 400 nm) light and achieves borylation of a wide range of fluoroarenes with B2pin2 at room temperature in excellent yields and with high selectivity. Direct irradiation of the intermediary C-F bond oxidative addition product trans-[NiF(ArF)(IMes)2] leads to very fast decomposition when B2pin2 is present. This destructive pathway can be bypassed by indirect excitation of the triplet states of the nickel(II) complex via the photoexcited rhodium biphenyl complex. Mechanistic studies suggest that the exceptionally long-lived triplet excited state of the Rh biphenyl complex used as the photosensitizer allows for efficient triplet energy transfer to trans-[NiF(ArF)(IMes)2], which leads to dissociation of one of the NHC ligands. This contrasts with the majority of current photocatalytic transformations, which employ transition metals as excited state single electron transfer agents. We have previously reported that C(arene)-F bond activation with [Ni(IMes)2] is facile at room temperature, but that the transmetalation step with B2pin2 is associated with a high energy barrier. Thus, this triplet energy transfer ultimately leads to a greatly enhanced rate constant for the transmetalation step and thus for the whole borylation process. While addition of a fluoride source such as CsF enhances the yield, it is not absolutely required. We attribute this yield-enhancing effect to (i) formation of an anionic adduct of B2pin2, i.e., FB2pin2-, as an efficient, much more nucleophilic {Bpin-} transfer reagent for the borylation/transmetalation process, and/or (ii) trapping of the Lewis acidic side product FBpin by formation of [F2Bpin]- to avoid the formation of a significant amount of NHC-FBpin and consequently decomposition of {Ni(NHC)2} species in the reaction mixture.

Critical Review—Electrochemical Properties of 13 Vitamins: A Critical Review and Assessment

Review of the literature on the currently recognized, thirteen vitamins yields an overview of the electrochemical properties that include estimates of the formal potentials at physiological pH and identification of the general classes of redox mechanisms. All vitamins are electroactive and map a range of formal potentials over a 3 V window. The vitamins are grouped as lipid soluble (vitamins A, D, E, and K) and water soluble (B vitamins and vitamin C). Mechanisms are grouped as single electron transfer agents (B3, B7, B2, C, and D), vitamins that can be both oxidized and reduced (B1, B5, B6, B9, and E), and vitamins that undergo two successive, distinct reductions (B12 and K). Vitamin A voltammetry is uniquely complex. Plot of the formal potentials on a potential axis allows assessment of mechanistic paths to vitamin recycling, antioxidant behavior, pH dependence, electrochemical stability in air, acid, and water, electrochemical instability of vitamin pairs, and cooperative interactions between vitamins in medicine. The potential axis is shown as an effective tool for mapping thermodynamically complex interactions. The voltammetry literature for each vitamin is critically assessed.

Preparation of visible-light-activated metal complexes and their use in photoredox/nickel dual catalysis.

Visible-light-activated photoredox catalysts provide synthetic chemists with the unprecedented capability to harness reactive radicals through discrete, single-electron transfer (SET) events. This protocol describes the synthesis of two transition metal complexes, [Ir{dF(CF3)2ppy}2(bpy)]PF6 (1a) and [Ru(bpy)3](PF6)2 (2a), that are activated by visible light. These photoredox catalysts are SET agents that can be used to facilitate transformations ranging from proton-coupled electron-transfer-mediated cyclizations to C-C bond constructions, dehalogenations, and H-atom abstractions. These photocatalysts have been used in the synthesis of medicinally relevant compounds for drug discovery, as well as the degradation of biological polymers to access fine chemicals. These catalysts are prepared from IrCl3 and RuCl3, respectively, in three chemical steps. These steps can be described as a series of two ligand modifications followed by an anion metathesis. Using the cost-effective, scalable procedures described here, the ruthenium-based photocatalyst 2a can be synthesized in a 78% overall yield (∼8.1 g), and the iridium-based photocatalyst 1a can be prepared in a 56% overall yield (∼4.4 g). The total time necessary for the complete protocols ranges from ∼2 d for 2a to 5-7 d for 1a. Procedures for applying each catalyst in representative photoredox/Ni cross-coupling to form Csp3-Csp2 bonds using the appropriate radical precursor-organotrifluoroborates with 1a and bis(catecholato)alkylsilicates with 2a-are described. In addition, more traditional photoredox-mediated transformations are included as diagnostic tests for catalytic activity.

ChemInform Abstract: Highly Regioselective Indoline Synthesis under Nickel/Photoredox Dual Catalysis.

Nickel/photoredox catalysis is used to synthesize indolines in one step from iodoacetanilides and alkenes. Very high regioselectivity for 3-substituted indoline products is obtained for both aliphatic and styrenyl olefins. Mechanistic investigations indicate that oxidation to Ni(III) is necessary to perform the difficult C–N bond-forming reductive elimination, producing a Ni(I) complex, which in turn is reduced to Ni(0). This process serves to further demonstrate the utility of photoredox catalysts as controlled single electron transfer agents in multioxidation state nickel catalysis.

Highly Regioselective Indoline Synthesis under Nickel/Photoredox Dual Catalysis.

Nickel/photoredox catalysis is used to synthesize indolines in one step from iodoacetanilides and alkenes. Very high regioselectivity for 3-substituted indoline products is obtained for both aliphatic and styrenyl olefins. Mechanistic investigations indicate that oxidation to Ni(III) is necessary to perform the difficult C-N bond-forming reductive elimination, producing a Ni(I) complex, which in turn is reduced to Ni(0). This process serves to further demonstrate the utility of photoredox catalysts as controlled single electron transfer agents in multioxidation state nickel catalysis.

Contrasting reactivity of thioglucoside and selenoglucoside donors towards promoters: implications for glycosylation stereocontrol

The stereochemical outcome of glycosylation reactions with model thioglycosides and selenoglycosides proved to be dependent on the source of promoter iodonium ion, with iodine giving different results to N-iodosuccinimide (NIS) alone or N-iodosuccinimide/trimethylsilyltrifluoromethanesulfonate (NIS/TMSOTf). In contrast to armed thioglycosides, which anomerise, and disarmed thioglycosides, which do not react, both armed and disarmed selenoglycosides give rise to the corresponding glycosyl iodides when reacted with iodine. Further, whilst the single electron transfer agent DDQ alone is an ineffective promoter, in combination with iodine it produces better acetonitrile-assisted β-stereoselectivity with both thioglycosides and selenoglycosides than does tris(4-bromophenyl)aminium hexachloroantimonate (BAHA).

Removal of benzotriazole moiety from 2-[2-aryl-2-(benzotriazol-1-yl)ethyl]tetrahydro-2 H-pyrans and 2-[2-aryl-2-(benzotriazol-1-yl)ethyl]-5-(methyl)tetrahydrofurans using lithium naphthalene radical anion

In order to see the effects of non-bonding electrons in oxygen atoms on the cleavage of a bond between N-1 of the benzotriazole moiety and the α-carbon atom bonded to N-1 by lithium ( 6a) and sodium naphthalenides ( 6b), 2-[2-aryl-2-(benzotriazol-1-yl)ethyl]tetrahydro-2 H-pyrans ( 4), and 2-[2-aryl-2-(benzotriazol-1-yl)ethyl]-5-(methyl)tetrahydrofurans ( 5), and 1-(benzotriazol-1-yl)-1,2-diphenylethane ( 7) were prepared. The reactions of 4 with 6a in THF at room temperature gave 2-(2-arylethyl)tetrahydro-2 H-pyrans ( 12) in 45 to 62 % yields along with benzotriazole and naphthalene. In addition, 2-(benzoylethyl)tetrahydro-2 H-pyran ( 15) (12 %) was obtained only from the reaction of 2-[2-(benzotriazol-1-yl)-2-(phenyl)ethyl]tetrahydro-2 H-pyran. Similarly, the reactions of 5 with 6a under the same conditions afforded 2-(2-arylethyl)-5-(methyl)tetrahydrofurans ( 30) in 59 to 77 % yields along with the foregoing byproducts. Interestingly, the reaction of 7 with 6a under the same conditions gave deoxybenzoin ( 24) in 41 % yield along with the foregoing byproducts. The results suggest that 6a acts as a single electron-transfer agent in the reactions of 4 and 5, and a base in the reaction of 7. It is envisaged that for the former, Li + participates in the formation of a six-membered cyclic intermediate so that cleavage of α-CN-1 bond is facilitated to give eventually 12 and 22, whereas for the latter, 6a abstracts a proton from α-C bonded to N-1 to generate a carbanion 19, which extrudes a nitrogen molecule to generate a new phenyl carbanion 20. Protonation leading to mono iminobenzoin 21, followed by hydrolysis gives 15. The formation of 24 can be explained based on the same mechanism as for the latter reaction.