Mechanism of Radical Initiation in the Radical SAM Enzyme Superfamily.

Radical S-adenosylmethionine (SAM) enzymes use a site-differentiated [4Fe-4S] cluster and SAM to initiate radical reactions through liberation of the 5'-deoxyadenosyl (5'-dAdo•) radical. They form the largest enzyme superfamily, with more than 700,000 unique sequences currently, and their numbers continue to grow as a result of ongoing bioinformatics efforts. The range of extremely diverse, highly regio- and stereo-specific reactions known to be catalyzed by radical SAM superfamily members is remarkable. The common mechanism of radical initiation in the radical SAM superfamily is the focus of this review. Most surprising is the presence of an organometallic intermediate, Ω, exhibiting an Fe-C5'-adenosyl bond. Regioselective reductive cleavage of the SAM S-C5' bond produces 5'-dAdo• to form Ω, with the regioselectivity originating in the Jahn-Teller effect. Ω liberates the free 5'-dAdo• as the catalytically active intermediate through homolysis of the Fe-C5' bond, in analogy to Co-C5' bond homolysis in B12, which was once viewed as biology's choice of radical generator.

Enantioseparation of organometallic compounds by electromigration techniques.

Over time, chiral organometallic compounds have attracted great interest in several fields, with applications going across several disciplines of chemical, biological, medical, and material sciences. In the last decades, due to advancements in molecular design and computational modeling, the chemistry of chiral transition metal complexes had a remarkable flowering, with the development of new structures for applications in asymmetric synthesis, bioinorganic chemistry, and molecular recognition. In these fields, fast chiral analysis to determine the enantiomeric purity of organometallic structures prepared by asymmetric synthesis, and for high-throughput screening of analytes, catalysts, and reactions, is very important. Capillary electrophoresis and related techniques proved to be extremely versatile for chiral analysis, showing unsurpassed advantages compared to chromatography like low consumption of materials, production of limited amounts of waste, fast equilibration, and possibility to replace easily type and concentration of the chiral selector, among others. Furthermore, electromigration techniques may be useful to gain details about the stereochemistry of the enantiomers of new compounds and to study analyte-selector noncovalent interactions at molecular level. On this basis, this short review aims to provide the reader with a comprehensive view on the enantioseparation of organometallic compounds by electromigration techniques, examining the topic from the historical perspective and showing what was made in this field so far, an essential know-how for developing new and advanced applications in the next future.

Prediction of Covalent Metal-Metal Bonding in Cp-M-M'-Nacnac Complexes of Group 2 and 12 Metals (Be, Mg, Ca, Zn, Cd, Hg).

Bimetallic CpMM'Nacnac molecules with group 2 and 12 metals (M = Be, Mg, Ca, Zn, Cd, Hg) that contain novel metal-metal bonding have been investigated in a theoretical study of their molecular and electronic structure, thermodynamic stability, and metal-metal bonding. In all cases the metal-metal bonds are characterized as electron-sharing covalent single bonds from natural bond orbital (NBO) and energy-decomposition analysis with natural orbitals of chemical valence (EDA-NOCV) analysis. The sum of [MM'] charges is relatively constant, with all complexes exhibiting a [MM']2+ core. Quantum theory of atoms in molecules (QTAIM) analysis indicates the presence of non-nuclear attractors (NNA) in the metal-metal bonds of the BeBe, MgMg, and CaCa complexes. There is substantial electron density (0.75-1.33 e) associated with the NNAs, which indicates that these metal-metal bonds, while classified as covalent electron-sharing bonds, retain significant metallic character that can be associated with reducing reactivity of the complex. The predicted stability of these complexes, combined with their novel covalent metal-metal bonding and potential as reducing agents, make them appealing targets for the synthesis of new metal-metal bonds.

Control of Iron(II)-Tris(2,2'-Bipyridine) Light-Induced Excited-State Trapping via External Electromagnetic Fields.

Light-induced excited spin-state trapping reactions in iron pyridinic complexes allow the iron's low-to-high spin transition in a sub-picosecond timescale. Employing a recently developed model for [Fe(2,2'-bipyridine)3]2+ photochemical spin-crossover reaction in conjunction with quantum wavepacket dynamics, we explore the possibility of controlling the reaction through external electromagnetic fields, aiming at stabilizing the initial metal-to-ligand charge transfer states. We show that simple Gaussian-shaped electromagnetic fields have a minor effect on the population kinetics. However, introducing vibrationally excited initial wavepacket representations allows for maintaining the population trapped in the metal-to-ligand charge transfer states. Using optimal control theory, we propose an electromagnetic field shape that increases the lifetime of metal-to-ligand charge transfer states. These results open the route for controlling the iron photochemistry through the action of external electric fields.

Exploring antimalarial potential: Conjugating organometallic moieties with organic fragments for enhanced efficacy.

In the search for novel ligands with efficacy against various diseases, particularly parasitic diseases, molecular hybridization of organometallic units into biologically active scaffolds has been hailed as an appealing strategy in medicinal chemistry. The conjugation to organometallic fragments can be achieved by an appropriate linker or by directly coordinating the existing drugs to a metal. The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. We present the evolution of organometallic antimalarial agents over the last decade, focusing on the parent moiety's class and the type of organometallics involved. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases.

Synthesis, Spectroscopic Properties, and Metalation of 3-Alkoxybenziporphyrins.

A series of 5-alkoxy-1,3-benzenedicarbaldehydes and related dimers were prepared in three steps from dimethyl 5-hydroxyisophthalate. Acid catalyzed condensation of the dialdehydes with a tripyrrane dicarboxylic acid, followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, afforded good yields of 3-alkoxybenziporphyrins, although dimeric tetraaldehydes failed to give isolatable porphyrinoid products. Proton NMR spectroscopy gave no indication of an aromatic ring current, but addition of trifluoroacetic acid resulted in the formation of dications that exhibited weakly diatropic characteristics. Spectroscopic titration with TFA demonstrated that stepwise protonation took place, generating monocationic and dicationic species. 3-Alkoxybenziporphyrins reacted with nickel(II) or palladium(II) acetate to give the related nickel(II) or palladium(II) complexes. These stable organometallic derivatives showed increased diatropic properties that were most pronounced for the palladium(II) complexes. These unique porphyrinoids provide further insights into the properties of benziporphyrins.

Infrared Matrix-Isolation and Theoretical Studies of the Reactions of Bis(benzene)chromium with Ozone.

Reactions of bis(benzene)chromium (Bz2Cr) and ozone (O3) were studied using low-temperature argon matrix-isolation infrared spectroscopy with supporting DFT calculations. When Bz2Cr and O3 were co-deposited, they reacted upon matrix deposition to produce two new prominent peaks in the infrared spectrum at 431 cm-1 and 792 cm-1. These peaks increased upon annealing the matrix to 35 K and decreased upon UV irradiation at λ = 254 nm. The oxygen-18 and mixed oxygen-16,18 isotopic shift pattern of the peak at 792 cm-1 is consistent with the antisymmetric stretch of a symmetric ozonide species. DFT calculations of many possible ozonide products of this reaction were made. The formation of a hydrogen ozonide (H2O3) best fits the original peaks and the oxygen-18 isotope shift pattern. Energy considerations lead to the conclusion that the chromium-containing product of this reaction is the coupled product benzene-chromium-biphenyl-chromium-benzene (BzCrBPCrBz). 2Bz2Cr+O3→H2O3+BzCrBPCrBz, ∆Ecalc=-52.13kcal/mol.

Review on the Applications of Selected Metal-Based Complexes on Infectious Diseases.

Fatalities caused by infectious diseases (i.e., diseases caused by parasite, bacteria, and viruses) have become reinstated as a major public health threat globally. Factors such as antimicrobial resistance and viral complications are the key contributors to the death numbers. As a result, new compounds with structural diversity classes are critical for controlling the virulence of pathogens that are multi-drug resistant. Derivatization of bio-active organic molecules with organometallic synthons is a promising strategy for modifying the inherent and enhanced properties of biomolecules. Due to their redox chemistry, bioactivity, and structural diversity, organometallic moieties make excellent candidates for lead structures in drug development. Furthermore, organometallic compounds open an array of potential in therapy that existing organic molecules lack, i.e., their ability to fulfill drug availability and resolve the frequent succumbing of organic molecules to drug resistance. Additionally, metal complexes have the potential towards metal-specific modes of action, preventing bacteria from developing resistance mechanisms. This review's main contribution is to provide a thorough account of the biological efficacy (in vitro and in vitro) of metal-based complexes against infectious diseases. This resource can also be utilized in conjunction with corresponding journals on metal-based complexes investigated against infectious diseases.

Modular Synthesis of Heterobenzylic Amines via Carbonyl Azinylative Amination.

Transformations enabling the synthesis of α-alkyl, α'-2-azinyl amines by addition of 2-heteroaryl-based nucleophiles to in situ-generated and non-activated alkyl-substituted iminium ions are extremely rare. Approaches involving classical 2-azinyl organometallics, such as the corresponding Grignard reagents, often fail to produce the desired products. Here, we report an operationally straightforward solution to this problem through the development of a multicomponent coupling process wherein a soft 2-azinyl indium nucleophile, generated in situ from the corresponding 2-iodo heteroarene and indium powder, adds to an iminium ion that is also formed directly in the reaction. This modular carbonyl azinylative amination (CAzA) displays a broad scope and only a metal reductant is needed to generate a reactive 2-azinyl nucleophile. Beyond the addition to iminium ions, the 2-azinyl addition to polyfluoromethyl ketones forms the corresponding tertiary alcohols. Together, the products of these reactions possess a high degree of functionality, are typically challenging to synthesize by other methods, and contain motifs recognized as privileged in the context of pharmaceuticals and agrochemicals.

New Frontiers in Organosodium Chemistry as Sustainable Alternatives to Organolithium Reagents.

With their highly reactive respective C-Na and N-Na bonds, organosodium and sodium amide reagents could be viewed as obvious replacements or even superior reagents to the popular, widely utilised organolithiums. However, they have seen very limited applications in synthesis due mainly to poor solubility in common solvents and their limited stability. That notwithstanding in recent years there has been a surge of interest in bringing these sustainable metal reagents into the forefront of organometallics in synthesis. Showcasing the growth in utilisation of organosodium complexes within several areas of synthetic chemistry, this Minireview discusses promising new methods that have been recently reported with the goal of taming these powerful reagents. Special emphasis is placed on coordination and aggregation effects in these reagents which can impart profound changes in their solubility and reactivity. Differences in observed reactivity between more nucleophilic aryl and alkyl sodium reagents and the less nucleophilic but highly basic sodium amides are discussed along with current mechanistic understanding of their reactivities. Overall, this review aims to inspire growth in this exciting field of research to allow for the integration of organosodium complexes within common important synthetic transformations.

Cobalt-Catalyzed Electroreductive Alkylation of Unactivated Alkyl Chlorides with Conjugated Olefins.

Reactions of unactivated alkyl chlorides under mild and sustainable conditions are rare compared to those of alkyl bromides or iodides. As a result, synthetic methods capable of modifying the vast chemical space of chloroalkane reagents, wastes, and materials are limited. We report the cobalt-catalyzed reductive addition of unactivated alkyl chlorides to conjugated alkenes. Co-catalyzed activation of alkyl chlorides is performed under electroreductive conditions, and the resulting reactions constitute formal alkyl-alkyl bond formation. In addition to developing an operationally simple methodology, detailed mechanistic studies provide insights into the elementary steps of a proposed catalytic cycle. In particular, we propose a switch in the mechanism of C-Cl bond activation from nucleophilic substitution to halogen atom abstraction, which is critical for efficiently generating alkyl radicals. These mechanistic insights were leveraged in designing ligands that enable couplings of primary, secondary, and tertiary alkyl chlorides.

Synthesis, Isolation, and Reactivity Studies of 'Naked' Acyclic Gallyl and Indyl Anions.

By exploiting the electronic capabilities of the N-heterocyclic boryloxy (NHBO) ligand, we have synthesized "naked" acyclic gallyl [Ga{OB(NDippCH)2}2]- and indyl [In{OB(NDippCH)2}2]- anions (as their [K(2.2.2-crypt)]+ salts) through K+ abstraction from [KGa{OB(NDippCH)2}2] and [KIn{OB(NDippCH)2}2] using 2.2.2-crypt. These systems represent the first O-ligated gallyl/indyl systems, are ultimately accessed from cyclopentadienyl GaI/InI precursors by substitution chemistry, and display nucleophilic reactivity which is strongly influenced by the presence (or otherwise) of the K+ counterion.

Formation of a Decanuclear Organometallic Dysprosium Complex via a Radical-Radical Cross-Coupling Reaction.

Over the years, polynuclear cyclic or torus complexes have attracted increasing interest due to their unique metal topologies and properties. However, the isolation of polynuclear cyclic organometallic complexes is extremely challenging due to their inherent reactivity, which stems from the labile and reactive metal-carbon bonds. In this study, the pyrazine ligand undergoes a radical-radical cross-coupling reaction leading to the formation of a decanuclear [(Cp*)20Dy10(L1)10]·12(C7H8) (1; where L1 = anion of 2-prop-2-enyl-2H-pyrazine) complex, where all DyIII metal centers are bridged by the anionic L1 ligand. Amongst the family of polynuclear Ln organometallic complexes bearing CpR2Lnx units, 1 features the highest nuclearity obtained to date. In-depth computational studies were conducted to elucidate the proposed reaction mechanism and formation of L1, while probing of the magnetic properties of 1, revealed slow magnetic relaxation upon application of a static dc field.

Metal-Mediated Synthesis of a Mixed Arduengo-Fischer Carbodicarbene Ligand.

Carbodicarbenes are strong C-donor ligands, which have found numerous applications in organometallic and main group element chemistry. Herein, we report a structurally distinct carbodicarbene ligand, which is formed by dinitrogenative coupling of a Fischer carbene complex with an N-heterocyclic diazoolefin. The resulting carbonyl complex serves as a stable source for the mixed Arduengo-Fischer carbodicarbene ligand. Facile ligand transfer reactions were demonstrated to occur with gold(I), copper(I), palladium(II), and rhodium(I) complexes.

Molecular Dynamic Simulations of Aqueous Micellar Organometallic Catalysis: Methane Functionalization as a Case Study.

Molecular Dynamics (MD) simulations constitute a powerful tool that provides a 3D perspective of the dynamical behavior of chemical systems. Herein the first MD study of the dynamics of a catalytic organometallic system, in micellar media, is presented. The challenging methane catalytic functionalization into ethyl propionate through a silver-catalyzed process has been targeted as the case study. The intimate nature of the micelles formed with the surfactants sodium dodecylsulfate (SDS) and potassium perfluorooctane sulfonate (PFOS) has been ascertained, as well as the relative distribution of the main actors in this transformation, namely methane, the diazo reagent and the silver catalyst, the latter in two different forms: the initial compound and a silver-carbene intermediate. Catalyst deactivation occurs with halide containing surfactants dodecyltrimethylammonium chloride (DTAC) and Triton X-100. Computed simulations allow explaining the experimental results, indicating that micelles behave differently regarding the degree of accumulation and the local distribution of the reactants and their effect in the molecular collisions leading to net reaction.

Boost the Circularly Polarized Phosphorescence of Chiral Organometallic Platinum Complexes by Hierarchical Assembly into Fibrillar Networks.

Circularly polarized luminescence (CPL)-active molecular materials have drawn increasing attention due to their promising applications for next-generation display and optoelectronic technologies. Currently, it is challenging to obtain CPL materials with both large luminescence dissymmetry factor (glum) and high quantum yield (Φ). A pair of enantiomeric N N C-type Pt(II) complexes (L/D)-1 modified with chiral Leucine methyl ester are presented herein. Though the solutions of these complexes are CPL-inactive, the spin-coated thin films of (L/D)-1 exhibit giantly-amplified circularly polarized phosphorescences with |glum| of 0.53 at 560 nm and Φair of ~50 %, as well as appealing circular dichroism (CD) signals with the maximum absorption dissymmetry factor |gabs| of 0.37-0.43 at 480 nm. This superior CPL performance benefits from the hierarchical formation of crystalline fibrillar networks upon spin coating. Comparative studies of another pair of chiral Pt(II) complexes (L/D)-2 with a symmetric N C N coordination mode suggest that the asymmetric N N C coordination of (L/D)-1 are favorable for the efficient exciton delocalization to amplify the CPL performance. Optical applications of the thin films of (L/D)-1 in CPL-contrast imaging and inducing CP light generation from achiral emitters and common light-emitting diode lamps have been successfully realized.

Guest-Shuttling in a Nanosized Metallobox.

An iridium-conjoined long and narrow metallorectangle was obtained by combining a quinoxalinophenanthrophenazine-connected Janus-di-imidazolylidene ligand and pyrazine. The size and shape of this assembly together with the fused polyaromatic nature of its panels provides it with properties that are uncommon for other metallosupramolecular assemblies. For example, this nanosized 'slit-like' metallobox is able show very large binding affinities with planar organic molecules in such a way, that the cavity is asymmetrically occupied by the guest molecule. This unsymmetrical conformation leads to the existence of a large amplitude motion of these guests, which slide between the two sides of the cavity of the host, thus constituting rare examples of molecular shuttles.

A Gold(I)-Acetylene Complex Synthesised using Single-Crystal Reactivity.

Using single-crystal to single-crystal solid/gas reactivity the gold(I) acetylene complex [Au(L1)(η2-HC≡CH)][BArF 4] is cleanly synthesized by addition of acetylene gas to single crystals of [Au(L1)(CO)][BArF 4] [L1=tris-2-(4,4'-di-tert-butylbiphenyl)phosphine, ArF=3,5-(CF3)2C6H3]. This simplest gold-alkyne complex has been characterized by single crystal X-ray diffraction, solution and solid-state NMR spectroscopy and periodic DFT. Bonding of HC≡CH with [Au(L1)]+ comprises both σ-donation and π-backdonation with additional dispersion interactions within the cavity-shaped phosphine.

Carbonylative synthesis and functionalization of indoles.

Carbonylation processes have become widely recognized as a versatile, convenient, and low-cost method for the synthesis of high-value compounds. Given the great importance of heterocyclic compounds, the carbonylative approach has become increasingly important for their synthesis. In this mini-review, as a class of benzo-fused nitrogen-containing heterocyclic compounds, we summarized and discussed the recent achievements on the synthesis and functionalization of indole derivatives via carbonylative approaches.

Targeting cancer lactate metabolism with synergistic combinations of synthetic catalysts and monocarboxylate transporter inhibitors.

Synthetic anticancer catalysts offer potential for low-dose therapy and the targeting of biochemical pathways in novel ways. Chiral organo-osmium complexes, for example, can catalyse the asymmetric transfer hydrogenation of pyruvate, a key substrate for energy generation, in cells. However, small-molecule synthetic catalysts are readily poisoned and there is a need to optimise their activity before this occurs, or to avoid this occurring. We show that the activity of the synthetic organometallic redox catalyst [Os(p-cymene)(TsDPEN)] (1), which can reduce pyruvate to un-natural D-lactate in MCF7 breast cancer cells using formate as a hydride source, is significantly increased in combination with the monocarboxylate transporter (MCT) inhibitor AZD3965. AZD3965, a drug currently in clinical trials, also significantly lowers the intracellular level of glutathione and increases mitochondrial metabolism. These synergistic mechanisms of reductive stress induced by 1, blockade of lactate efflux, and oxidative stress induced by AZD3965 provide a strategy for low-dose combination therapy with novel mechanisms of action.