Carbon-hydrogen Bond Cleavage Research Articles

Identification of heterozygous mutations of ABCC8 gene responsible for maturity-onset diabetes of the young with exome sequencing

Abstract Background Although the MODY12 subtype, caused by ABCC8 mutations, is rare, it is highly sensitive to sulfonylureas. The identification of ABCC8 mutations in patients clinically diagnosed with MODY has the ability to contribute to the precise management of diabetes. Methods Genetic analysis of two families with MODY were conducted using whole-exome sequencing (WES) and Sanger sequencing. The spatial structures of the mutant proteins were constructed using MODELLER and PyMOL software to provide further evidence of pathogenicity. Results The heterozygous missense mutations V357I and R1393H in ABCC8 were found in probands of two unrelated MODY pedigrees, which co-segregated with the hyperglycemic phenotypes in these two pedigrees. Detection of the V357I mutation enabled the proband of family A to successfully transfer from insulin to sulfonylurea (SU). After 3 months of follow-up for the SU trial, the HbA1c level of proband A improved from 12.4% at the initial diagnosis to 7.20%. Proband B was treated with insulin because of pregnancy and poor islet function. In silico analysis indicated that the R1393H mutation resulted in a longer hydrogen bond distance to L1389 and cleavage of carbon-hydrogen bonds to V1395, A1390, and L1389. Conclusions We have described two pathogenic missense mutations in ABCC8 in Chinese families with MODY. Our findings support the heterogeneity in the clinical features of MODY12 caused by ABCC8 mutations.

Programmed alternating current optimization of Cu-catalyzed C-H bond transformations.

Direct current (DC) electrosynthesis, which has undergone optimization over the past century, plays a pivotal role in a variety of industrial processes. Alternating current (AC) electrosynthesis, characterized by polarity reversal and periodic fluctuations, may be advantageous for multiple chemical reactions, but apparatus, principles, and application scenarios remain underdeveloped. In this work, we introduce a protocol for programmed AC (pAC) electrosynthesis that systematically adjusts currents, frequencies, and duty ratios. The application of representative pAC waveforms facilitates copper-catalyzed carbon-hydrogen bond cleavage in cross-coupling and difunctionalization reactions that exhibit suboptimal performance under DC and chemical oxidation conditions. Moreover, observing catalyst dynamic variation under diverse waveform applications provides mechanistic insight.

HYDROGENATION OF SILICON, ALUMINUM AND CHLORINE AS CONSTITUENTS OF TARFAYA OIL SHALE (MOROCCO) AT 550°C AND 750°C

The formation of hydrogen chloride as well as silicon hydrides and aluminum hydrides called silanes and alanes respectively are formed when oil shale are thermally treated with hydrogen. These elements are part of the constituents of this oil shale. This work was carried out by a thermobalance (Red Croft) in the dynamic regime for thermal hydrogenation at 550°C and 750°C. The quantitative identification of the elements was done by X-ray diffraction using a dispersive method, a technique that is coupled to the scanning microscope. This work being the continuation of the one already carried out at a temperature of 550°C (A.Attaoui and M. Hafid: 2022), we have extended this to higher temperatures where we have decompositions in addition to kerogen as well as mineral matter. Studies comparing the thermal decomposition of oil shale and kerogen have shown that the mineral matter in oil shale provides surfaces capable of cracking high molecular weight products by thermal or catalytic mechanisms (A.K. Burnham, A. K and J.A.Happe: 1984). These studies indicate that reactions involving the cleavage of carbon-carbon bonds and carbon-hydrogen bonds on mineral surfaces (R.A.Regtop et al: 1985). These authors demonstrated that the carbonized residue in spent shale can increase the magnitude of secondary reactions.

Photocatalytic property of WO3 modified with noble metal co-catalysts towards selective hydroxylation of benzene to phenol under visible light irradiation

Direct synthesis of phenol from benzene in the presence of water and oxygen were conducted under visible-light irradiation. Effects of several noble metal co-catalyst on the selective hydroxylation of benzene over WO3 photocatalysts have been extensively studied. The photocatalytic activities of WO3 for phenol formation strongly depend on co-catalyst such as Pt, Au, Pd metal species, i.e., phenol formation was as follows: Pt-WO3 > Au-WO3 > Pd-WO3. Furthermore, the WO3 photocatalyst deposited bimetal co-catalysts such as Pd/Pt, Pd/Au and Pt/Au were also investigated. The Pd/Pt-WO3 photocatalyst was found to show the highest photocatalytic activity for phenol formation due to an effective oxygen reduction reaction (ORR) for bimetallic Pd/Pt cocatalyst. From the experimental and theoretical studies, phenol was confirmed to form by the insertion of OH derived from H2O into benzene, and simultaneous cleavage of benzylic carbon-hydrogen bond (Csp2-H) by an assist of co-catalyst surface through the push-pull process.

Mechanism-Based Approach to Reagent Selection for Oxidative Carbon-Hydrogen Bond Cleavage Reactions.

Numerous hydride-abstracting agents generate the same cationic intermediate, but substrate features such as intermediate cation stability, oxidation potential, and steric environment can influence reaction rates in an oxidant-dependent manner. This manuscript provides experimental data to illustrate the role that structural features play in the kinetics of hydride abstraction reactions with commonly used quinone-, oxoammonium ion-, and carbocation- based oxidants. Computational studies of the transition state structures and energies explain these results and energy decomposition analysis calculations reveal unique sensitivities to electrostatic attraction and steric repulsions. Rigorous rate studies of select reactions validated the capacity of the calculations to predict reactivity trends. Additionally, kinetics studies demonstrate the potential for product inhibition in DDQ-mediated reactions. These studies provide a clear guide to select the optimal oxidant for structurally disparate substrates and lead to predictions of reactivity that were validated experimentally.

The [3+2] Annulation of CF3-Ketimines by Re Catalysis: Access to CF3-Containing Amino Heterocycles and Polyamides.

SummaryTransition metal catalyzed [3 + 2] annulation of imines with double bonds via directed C-H activation offers a direct access to amino cyclic motifs. However, owing to weak coordination and steric hindrance, trifluoromethylated ketimines have been an unaddressed challenge for TM-catalyzed annulations. Here, a rhenium-catalyzed [3 + 2] annulation of trifluoromethylated ketimines with isocyanates via C(sp2)-H activation has been disclosed. This approach provides an efficient platform for rapid access to a privileged library of CF3-containing iminoisoindolinones and polyamides by utilizing challenging CF3-ketimines as the annulation component. The capability of gram scale synthesis, the post-functionalization of the cyclization adduct, the derivation of complex natural molecules and the facile synthesis of polyamides highlight a diversity of synthetic potential of the current methodology.

Selenocysteine as a Substrate, an Inhibitor and a Mechanistic Probe for Bacterial and Fungal Iron-Dependent Sulfoxide Synthases.

Sulfoxide synthases are non-heme iron enzymes that participate in the biosynthesis of thiohistidines, such as ergothioneine and ovothiol A. The sulfoxide synthase EgtB from Chloracidobacterium thermophilum (CthEgtB) catalyzes oxidative coupling between the side chains of N-α-trimethyl histidine (TMH) and cysteine (Cys) in a reaction that entails complete reduction of molecular oxygen, carbon-sulfur (C-S) and sulfur-oxygen (S-O) bond formation as well as carbon-hydrogen (C-H) bond cleavage. In this report, we show that CthEgtB and other bacterial sulfoxide synthases cannot efficiently accept selenocysteine (SeCys) as a substrate in place of cysteine. In contrast, the sulfoxide synthase from the filamentous fungus Chaetomium thermophilum (CthEgt1) catalyzes C-S and C-Se bond formation at almost equal efficiency. We discuss evidence suggesting that this functional difference between bacterial and fungal sulfoxide synthases emerges from different modes of oxygen activation.

Intrinsic kinetic model for oxidative dehydrogenation of ethane over MoVTeNb mixed metal oxides: A mechanistic approach

An intrinsic kinetic model for the selective production of ethene via oxidative dehydrogenation of ethane over the M1 phase of MoVTeNb mixed metal oxides is presented. Formation of acetic acid, carbon monoxide and carbon dioxide has been incorporated using a holistic reaction mechanism. The proposed model is based on two different oxygen sites, namely, lattice oxygen causing carbon-hydrogen bond cleavage and electrophilic surface oxygen responsible for the formation of carbon-oxygen bonds. It is found that carbon dioxide exclusively originates from decarboxylation of acetate species, while ethene selectively reacts to CO. Consumption and formation of all species are well predicted by the proposed model. Sensitivity analyses demonstrate the strong impact of the initial carbon-hydrogen cleavage on the net ethene production rate. Moreover, regeneration of lattice oxygen sites is found to become rate-determining at oxygen-lean conditions.

Biocatalytic Carbon-Hydrogen and Carbon-Fluorine Bond Cleavage through Hydroxylation Promoted by a Histidyl-Ligated Heme Enzyme.

LmbB2 is a peroxygenase-like enzyme that hydroxylates L-tyrosine to L-3,4-dihydroxyphenylalanine (DOPA) in the presence of hydrogen peroxide. However, its heme cofactor is ligated by a proximal histidine, not cysteine. We show that LmbB2 can oxidize L-tyrosine analogs with ring-deactivated substituents such as 3-nitro-, fluoro-, chloro-, iodo-L-tyrosine. We also found that the 4-hydroxyl group of the substrate is essential for reacting with the heme-based oxidant and activating the aromatic C-H bond. The most interesting observation of this study was obtained with 3-fluoro-L-tyrosine as a substrate and mechanistic probe. The LmbB2-mediated catalytic reaction yielded two hydroxylated products with comparable populations, i.e., oxidative C-H bond cleavage at C5 to generate 3-fluoro-5-hydroxyl-L-tyrosine and oxygenation at C3 concomitant with a carbon-fluorine bond cleavage to yield DOPA and fluoride. An iron protein-mediated hydroxylation on both C-H and C-F bonds with multiple turnovers is unprecedented. Thus, this finding reveals a significant potential of biocatalysis in C-H/C-X bond (X = halogen) cleavage. Further 18O-labeling results suggest that the source of oxygen for hydroxylation is a peroxide, and that a commonly expected oxidation by a high-valent iron intermediate followed by hydrolysis is not supported for the C-F bond cleavage. Instead, the C-F bond cleavage is proposed to be initiated by a nucleophilic aromatic substitution mediated by the iron-hydroperoxo species. Based on the experimental results, two mechanisms are proposed to explain how LmbB2 hydroxylates the substrate and cleaves C-H/C-F bond. This study broadens the understanding of heme enzyme catalysis and sheds light on enzymatic applications in medicinal and environmental fields.

Total Synthesis of Divergolides E and H

AbstractThis manuscript describes the first total syntheses of divergolides E and H. The route employs a telescoped hetero‐Diels–Alder and oxidative carbon–hydrogen bond cleavage as an entry into the central bridged bicyclic acetal unit. Additional key steps of the highly convergent route include a desymmetrizing epoxidation, a chelation‐controlled alkenylzinc addition, an amide formation between a hindered aniline and an acylating agent that is prone to ketene formation, and a challenging macrolactonization.

Total Synthesis of Divergolides E and H.

This manuscript describes the first total syntheses of divergolides E and H. The route employs a telescoped hetero-Diels-Alder and oxidative carbon-hydrogen bond cleavage as an entry into the central bridged bicyclic acetal unit. Additional key steps of the highly convergent route include a desymmetrizing epoxidation, a chelation-controlled alkenylzinc addition, an amide formation between a hindered aniline and an acylating agent that is prone to ketene formation, and a challenging macrolactonization.

Generating carbyne equivalents with photoredox catalysis.

Carbon has the unique ability to bind four atoms and form stable tetravalent structures that are prevalent in nature. The lack of one or two valences leads to a set of species-carbocations, carbanions, radicals and carbenes-that is fundamental to our understanding of chemical reactivity. In contrast, the carbyne-a monovalent carbon with three non-bonded electrons-is a relatively unexplored reactive intermediate; the design of reactions involving a carbyne is limited by challenges associated with controlling its extreme reactivity and the lack of efficient sources. Given the innate ability of carbynes to form three new covalent bonds sequentially, we anticipated that a catalytic method of generating carbynes or related stabilized species would allow what we term an 'assembly point' disconnection approach for the construction of chiral centres. Here we describe a catalytic strategy that generates diazomethyl radicals as direct equivalents of carbyne species using visible-light photoredox catalysis. The ability of these carbyne equivalents to induce site-selective carbon-hydrogen bond cleavage in aromatic rings enables a useful diazomethylation reaction, which underpins sequencing control for the late-stage assembly-point functionalization of medically relevant agents. Our strategy provides an efficient route to libraries of potentially bioactive molecules through the installation of tailored chiral centres at carbon-hydrogen bonds, while complementing current translational late-stage functionalization processes. Furthermore, we exploit the dual radical and carbene character of the generated carbyne equivalent in the direct transformation of abundant chemical feedstocks into valuable chiral molecules.

13C kinetic isotope effects on the reaction of a flavin amine oxidase determined from whole molecule isotope effects

A large number of flavoproteins catalyze the oxidation of amines. Because of the importance of these enzymes in metabolism, their mechanisms have previously been studied using deuterium, nitrogen, and solvent isotope effects. While these results have been valuable for computational studies to distinguish among proposed mechanisms, a measure of the change at the reacting carbon has been lacking. We describe here the measurement of a 13C kinetic isotope effect for a representative amine oxidase, polyamine oxidase. The isotope effect was determined by analysis of the isotopic composition of the unlabeled substrate, N, N’-dibenzyl-1,4-diaminopropane, to obtain a pH-independent value of 1.025. The availability of a 13C isotope effect for flavoprotein-catalyzed amine oxidation provides the first measure of the change in bond order at the carbon involved in this carbon-hydrogen bond cleavage and will be of value to understanding the transition state structure for this class of enzymes.

Photoinduced Reactions of Diruthenium Tetrahydride Complexes: Carbon–Hydrogen Bond Cleavage of Tetrahydrofuran Leading to Bridging Cyclic Fischer-Type Carbene Complexes

Photochemical reactions of diruthenium tetrahydride complexes containing cyclopentadienyls as auxiliary ligands, CpsRu(μ-H)4RuCps (1) (a: Cps = C5Me5 (Cp*), b: C5EtMe4 (CpEt), and c: 1,2,4-C5(t-Bu)3H2 (Cp‡)), with tetrahydrofuran were studied for elucidation of the reaction mode of dinuclear complexes containing multiple bridging hydrides. Complexes 1a–c reacted with tetrahydrofuran under UV irradiation (365 nm) to produce bridging cyclic Fischer-type carbene complexes, {CpsRu(μ-H)}2(μ-cyclo-CCH2CH2CH2O−)(μ-H)2 (5), via consecutive C–H bond cleavage at the α-position of the oxygen atom. The characteristic cyclic structures of the bridging carbene ligands were unambiguously confirmed by X-ray diffraction studies. Line-shape analysis of the variable-temperature 1H NMR spectra of 5c demonstrated the rotation of the bridging carbene ligand.

Palladium(ii)-catalyzed synthesis of dibenzothiophene derivatives via the cleavage of carbon-sulfur and carbon-hydrogen bonds.

A new process has been developed for the palladium(ii)-catalyzed synthesis of dibenzothiophene derivatives via the cleavage of C-H and C-S bonds. In contrast to the existing methods for the synthesis of this scaffold by C-H functionalization, this new catalytic C-H/C-S coupling method does not require the presence of an external stoichiometric oxidant or reactive functionalities such as C-X or S-H, allowing its application to the synthesis of elaborate π-systems. Notably, the product-forming step of this reaction lies in an oxidative addition step rather than a reductive elimination step, making this reaction mechanistically uncommon.

Convergent One-Pot Oxidative [n + 1] Approaches to Spiroacetal Synthesis.

Two one-pot oxidative annulative approaches to spiroacetal synthesis are described. One approach uses a Lewis acid mediated Ferrier reaction in the fragment-coupling stage followed by DDQ-promoted oxidative carbon-hydrogen bond cleavage and cyclization. An alternative approach employs a Heck reaction for fragment coupling followed by DDQ-mediated enone formation and cyclization. These strategies provide convergent routes to common subunits in natural products, medicinal agents, and chemical libraries under mild reaction conditions.

ChemInform Abstract: Spiroacetal Formation Through Telescoped Cycloaddition and Carbon‐Hydrogen Bond Functionalization: Total Synthesis of Bistramide A.

Spiroacetals can be formed through a one-pot sequence of a hetero-Diels–Alder reaction, an oxidative carbon–hydrogen bond cleavage, and an acid treatment. This convergent approach expedites access to a complex molecular subunit which is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin-binding cytotoxin bistramide A.

Spiroacetal formation through telescoped cycloaddition and carbon-hydrogen bond functionalization: total synthesis of bistramide A.

Spiroacetals can be formed through a one-pot sequence of a hetero-Diels-Alder reaction, an oxidative carbon-hydrogen bond cleavage, and an acid treatment. This convergent approach expedites access to a complex molecular subunit which is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin-binding cytotoxin bistramide A.

Spiroacetal Formation through Telescoped Cycloaddition and Carbon–Hydrogen Bond Functionalization: Total Synthesis of Bistramide A

AbstractSpiroacetals can be formed through a one‐pot sequence of a hetero‐Diels–Alder reaction, an oxidative carbon–hydrogen bond cleavage, and an acid treatment. This convergent approach expedites access to a complex molecular subunit which is present in numerous biologically active structures. The utility of the protocol is demonstrated through its application to a brief synthesis of the actin‐binding cytotoxin bistramide A.

ChemInform Abstract: Bimolecular Coupling Reactions Through Oxidatively Generated Aromatic Cations: Scope and Stereocontrol.

Chromenes, isochromenes, and benzoxathioles react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form stable aromatic cations that react with a range of nucleophiles. These oxidative fragment coupling reactions provide rapid access to structurally diverse heterocycles. Conducting the reactions in the presence of a chiral Bronsted acid results in the formation of an asymmetric ion pair that can provide enantiomerically enriched products in a rare example of a stereoselective process resulting from the generation of a chiral electrophile through oxidative carbon–hydrogen bond cleavage.