Single Bond Cleavage Research Articles

Enantioselective cyanation via radical-mediated C\u2013C single bond cleavage for synthesis of chiral dinitriles

Ring-opening reaction via selective cleavage of C–C bond is known as a powerful strategy for construction of complex molecules. Complementary to the ionic process focusing on mostly small ring systems, radical-mediated C–C bond cleavage offers a solution for further diverse enantioselective functionalization benefited from its mild conditions, whereas such asymmetric transformations are still limited to three-membered rings so far. Herein, we describe radical-mediated ring-opening and enantioselective cyanation of four- and five-membered cycloketone oxime esters to access chiral 1,5- and 1,6-dinitriles. Employment of dual photoredox/copper catalysis is essential for the asymmetric ring-opening cyanation of cyclopentanone oxime esters. Both reactions proceed under mild conditions giving chiral dinitriles in high yields and enantioselectivity with low catalyst loading and broad substrate scope. The products dinitriles can be converted to valuable optically active diamides and diamines. Mechanistic studies indicate that the benzylic radical generated via C–C single bond cleavage is involved in the catalytic cycle.

Rh(III)-Catalyzed [3 + 3] Annulation Reaction of Cyclopropenones and Sulfoxonium Ylides toward Trisubstituted 2-Pyrones.

A new Rh(III)-catalyzed [3 + 3] annulation reaction between cyclopropenones and β-ketosulfoxonium ylides has been reported, enabling metal carbene insertion to access a wide range of trisubstituted 2-pyrones with moderate to excellent yields via C-C single-bond cleavage, in which sulfoxonium ylides serve as potential safe precursors of metal carbenes. This reaction occurred under redox-neutral conditions with a broad substrate scope.

An Unusual Cu(II) Mediated C–N Single Bond Cleavage of Pentacoordinating N4S Ligands: Control of Copper Coordination Geometry by Modified Ligand Structure

Complexation of copper(II) with penta-coordinated N4S ligands in alcohols proceeded through unusual reaction paths involving C-N bond cleavage process. The products are square planar compound with a modified ligand structure that includes an alkoxy group provided by the solvent. The complexes are characterized by single crystal XRD, elemental analyses, IR, UV-visible and EPR spectroscopic techniques. Cyclic voltammetry shows Cu(II)/Cu(I) reduction becomes more difficult with the increase in donor strength of alkoxy group.

Triggering Depolymerization: Progress and Opportunities for Self-Immolative Polymers

Polymers that depolymerize end-to-end upon cleavage of their backbones or end-caps, often termed “self-immolative” polymers (SIPs), have garnered significant interest in recent years. They can be distinguished from other degradable and stimuli-responsive polymers by their ability to provide amplified responses to stimuli, as a single bond cleavage event is translated into the release of many small molecules through a cascade of reactions. Here, the synthesis and properties of the major classes of SIPs including poly(benzyl carbamate)s, poly(benzyl carbonate)s, poly(benzyl ether)s polyphthalaldehydes, polyglyoxylates, polyglyoxylamides, and poly(olefin sulfone)s are presented. In addition, their advantages and limitations as well as their recent applications in areas including sensors, drug delivery, micro- and nanopatterning, transient devices and composites, coatings, antibacterial, and recyclable plastics are described. Finally, the challenges associated with the development of new SIP backbones and their translation into commercial products are discussed.

Reactions in the Radiosensitizer Misonidazole Induced by Low-Energy (0-10 eV) Electrons.

Misonidazole (MISO) was considered as radiosensitizer for the treatment of hypoxic tumors. A prerequisite for entering a hypoxic cell is reduction of the drug, which may occur in the early physical-chemical stage of radiation damage. Here we study electron attachment to MISO and find that it very effectively captures low energy electrons to form the non-decomposed molecular anion. This associative attachment (AA) process is exclusively operative within a very narrow resonance right at threshold (zero electron energy). In addition, a variety of negatively charged fragments are observed in the electron energy range 0–10 eV arising from dissociative electron attachment (DEA) processes. The observed DEA reactions include single bond cleavages (formation of NO2−), multiple bond cleavages (excision of CN−) as well as complex reactions associated with rearrangement in the transitory anion and formation of new molecules (loss of a neutral H2O unit). While any of these AA and DEA processes represent a reduction of the MISO molecule, the radicals formed in the course of the DEA reactions may play an important role in the action of MISO as radiosensitizer inside the hypoxic cell. The present results may thus reveal details of the molecular description of the action of MISO in hypoxic cells.

Gold(I)-catalyzed [4 + 1]/[4 + 3] annulations of diazo esters with hexahydro-1,3,5-triazines: Theoretical study of mechanism and regioselectivity

Hexahydro-1,3,5-triazines are often used as formaldimine precursors. The recent success of Sun et al. (Angew. Chem. Int. Ed., 2016, 55, 11867) in achieving gold-catalyzed [4 + 1]/[4 + 3] annulations of hexahydro-1,3,5-triazines with diazo esters, in which the hexahydro-1,3,5-triazine is directly used as the 1,4-dipole in the annulation, represents a breakthrough in mechanistic studies. In the present work, density functional theory (DFT) calculations were used for detailed investigation of possible catalytic mechanisms. The proposed catalytic cycle involves five major stages: dinitrogen elimination to form a gold–carbene intermediate; diazoacetate–hexahydro-1,3,5-triazine C–C coupling to give an ammonium ylide; ring opening of the hexahydro-1,3,5-triazine via C–N single-bond cleavage; a second C–N single-bond cleavage; and C–C-bond-forming reductive elimination. The regioselectivities of the cycloaddition of hexahydro-1,3,5-triazines with enol diazoacetates differ from those of cycloadditions with vinyl diazoacetates. The calculations also clarified the origins of the substrate-controlled regioselectivity.

Theoretical Studies of the Gas-Phase Reactions of S-Methyl Methanesulfinothioate (Dimethyl Thiosulfinate) with OH and Cl Radicals: Reaction Mechanisms, Energetics, and Kinetics.

The mechanisms, energetics, and kinetics of the gas-phase reactions of terrestrial plant-derived dimethyl thiosulfinate (DMTS) with the atmospheric oxidants OH and Cl radicals were investigated using high-level ab initio calculations. The results show that the addition of OH and Cl radicals to the sulfinyl [-S(═O)] of DMTS, followed by S(═O)-S single bond cleavage to form methanesulfinic acid + CH3S• and methanesulfinyl chloride + CH3S•, respectively, are the more dominant reactions. The barrier heights for the reactions with OH and Cl radicals were found to be -5.6 and -12.7 kcal/mol relative to the energies of the starting reactants, respectively, when computed at the CCSD(T)/aug-cc-pVTZ//M06-2X/6-311++G(3df,3pd) level of theory. The rate constants for all possible pathways of DMTS + •OH/•Cl reactions were investigated using the MESMER kinetics code over the temperature range between 200 and 300 K. The calculated global rate constants for the DMTS + •OH and DMTS + •Cl reactions at 300 K were found to be 1.42 × 10-11 and 3.72 × 10-11 cm3 molecule-1 s-1, respectively. In addition, the thermochemistry of all possible paths and branching ratios was determined. The atmospheric chemistry implications of the DMTS + •OH/•Cl reactions are discussed.

Selective Bond Excision in Nitroimidazoles by Electron Transfer Experiments.

We have performed comprehensive charge-transfer experiments yielding negative ion formation in collisions of fast neutral potassium atoms with nitroimidazole and methylated derivative molecules. The anionic pattern reveals that in the unimolecular decomposition of the precursor parent anion, single and multiple bond cleavages are attained. Selective excision of hydrogen atoms from the N1 position in 4-nitroimidazole (4NI) is completely blocked upon methylation in 1-methyl-4-nitroimidazole (1m4NI) and 1-methyl-5-nitroimidazole (1m5NI). Additionally, only 4NI and 2-nitroimidazole (2NI) are efficient in selectively producing neutral •OH and NO• radicals in contrast to 1m4NI and 1m5NI. These findings present a novel experimental evidence of selective chemical bond breaking by just tuning the proper collision energy in atom-molecule collision experiments. The present work contributes to the current need of pinpointing a class of charge-transfer collisions that exhibit selective reactivity of the kind demonstrated here, extending to tailored chemical control for different applications such as tumor radiation therapy through nitroimidazole-based radiosensitization.

Palladium-Catalyzed C–N Bond Cleavage of 2H-Azirines for the Synthesis of Functionalized α-Amido Ketones

A Pd-catalyzed ring-opening reaction of 2 H-azirines with carboxylic acids was developed. This reaction undergoes nucleophilic addition between 2,3-diaryl-2 H-azirines and carboxylic acids followed by C-N single-bond cleavage and a subsequent thermal rearrangement. This method enables the rapid construction of valuable α-amido ketone derivatives with high atomic efficiency and superb functional group tolerance.

Iron-catalyzed oxidative C-C(vinyl) σ-bond cleavage of allylarenes to aryl aldehydes at room temperature with ambient air.

A general and selective iron-catalyzed allylic C-C(vinyl) σ-bond cleavage of allylarenes without the assistance of heteroatoms to give aryl aldehydes is reported. The unstrained carbon-carbon single bond cleavage reaction uses ambient air as the sole oxidant, proceeds efficiently at room temperature, and allows for exceptional functional-group tolerance, which addresses the long-standing challenges of current C-C bond cleavage/functionalization. Notably, the method enables rapid late-stage oxidation of complex bioactive molecules and can be used to expedite syntheses of natural products (vanillin and glucovanillin) from readily available chemical feedstocks.

Visible photocatalysis of novel oxime phosphonates: synthesis of β-aminophosphonates.

A novel type of oxime phosphonate was synthesized and used in the intermolecular cascade radical addition reaction of alkenes to access β-aminophosphonates via visible-light-driven N-centered iminyl radical-mediated and redox-neutral selective C-P single-bond cleavage in an active phosphorus radical route. The procedure is characterized by its ability to achieve the construction of Csp3-P and Csp3-N bonds without the requirement for oxidants and bases.

Superbase-promoted selective carbon-carbon bond cleavage driven by aromatization.

A novel selective carbon-carbon single bond cleavage has been disclosed through the copper-catalyzed reaction of 1-alkyl-3-alkylindolin-2-imine hydrochlorides with substituted 1-(bromomethyl)-2-iodobenzenes leading to fused N-heterocycles. Mechanistic studies showed that the intrinsic drive of aromatization and the action of the superbase derived from sodium tert-butoxide and dimethylsulfoxide were the key factors leading to the carbon-carbon single bond cleavage. Furthermore, the obtained N-heterocycles are indoloquinoline derivatives with wide biological activities.

Characterization of Protein Disulfide Linkages by MS In-Source Dissociation Comparing to CID and ETD Tandem MS.

Direct characterization of disulfide linkages in proteins by mass spectrometry has been challenging. Here, we report analysis of disulfide linkages in insulin variant, endothelin 3, and relaxin 2 by in-source dissociation (ISD) during LC-MS. A duplet insulin peptide from Glu-C digestion that contains peptides p1 and p2 (from chains A and B, respectively) was selected as a model peptide. This duplet peptide has an inter-chain disulfide bond between p1 and p2, and an intra-chain disulfide bond in p1. To compare the gas-phase fragmentation, it was subjected to ISD MS and MS/MS methods, including collision-induced dissociation (CID) and electron transfer dissociation (ETD). The pattern and efficiency of peptide backbone and disulfide cleavage varied with these dissociation methods. ETD, CID, and ISD were able to generate single backbone, double backbone, and triple (double backbone and single disulfide bond) cleavages in this model peptide, respectively. Specifically, CID did not cleave disulfide bonds and ETD was able to only cleave the inter-chain disulfide bond at low efficiency, limiting their usage in this disulfide analysis. In contrast, ISD was able to cleave the intra-chain disulfide bond in addition to peptide backbone, creating multiple fragment ions that allow accurate assignment of both intra- and inter-chain disulfide linkages. ISD was also successfully applied to determine double disulfide linkages in endothelin 3 and relaxin 2 peptides. This study contributes to the fundamental understanding of disulfide bond cleavages in different gas-phase fragmentations and provides an efficient cleavage strategy for identification of disulfide bonds in proteins by ISD ESI-MS. Graphical Abstract.

Deconstructive diversification of cyclic amines.

Deconstructive functionalization involves C–C bond cleavage followed by bond construction on one or more of the constituent carbons. For example, ozonolysis1 and olefin metathesis2, 3 have allowed each carbon in C–C double bonds to be viewed as a functional group. Despite the significant advances in deconstructive functionalizations involving scission of C–C double bonds, there are very few methods that achieve C(sp3)–C(sp3) single bond cleavage/functionalization, especially in relatively unstrained cyclic systems. Here, we report a deconstructive strategy to transform saturated nitrogen heterocycles such as piperidines and pyrrolidines, important moities in bioactive molecules, into halogen-containing acyclic amine derivatives through sequential C(sp3)–N/C(sp3)–C(sp3) single bond cleavage followed by C(sp3)–halogen bond formation. The resulting acyclic haloamines serve as versatile intermediates that are transformed into a variety of structural motifs through substitution reactions. In this way, skeletal remodeling of cyclic amines, which constitutes a scaffold hop, can be achieved. The value of this deconstructive strategy has been demonstrated through the late-stage diversification of proline-containing peptides.

Copper-Catalyzed Unstrained C-C Single Bond Cleavage of Acyclic Oxime Acetates Using Air: An Internal Oxidant-Triggered Strategy toward Nitriles and Ketones.

A copper-catalyzed aerobic oxidative C-C single bond cleavage of acyclic unstrained oxime acetates is reported, providing various aryl nitriles and ketones in good yields. Mechanistic studies indicate a radical procedure is involved in this transformation, and the oxygen atom in the ketone products is originated from O2 in the air. Oxime acetates as an internal oxidant have been proved to be an initiator, which may promote the discovery of novel protocol for C-C bond cleavage and dioxygen activation.

Dissociation of methyl formate (HCOOCH3) molecules upon low-energy electron attachment

Context. The methyl formate molecule (HCOOCH3) is considered to be a key molecule in astrochemistry. The abundance of this molecule in space depends on the stability upon irradiation with particles like low-energy electrons. Aims. We have investigated the decomposition of the molecule upon electron capture in the electron energy range from about 0 eV up to 15 eV. All experimentally obtained fragmentation channels of the molecular anion were investigated by quantum chemical calculations. Methods. A high resolution electron monochromator coupled with quadrupole mass spectrometer was used for the present laboratory experiment. Quantum chemical calculations of the electron affinities of the generated fragments, the thermodynamic thresholds and the activation barriers for the associated reaction channels were carried out to complement the experimental studies. Results. Electron attachment is shown to be a purely dissociative process for this molecule and proceeds within two electron energy regions of about 1 eV to 4 eV and from 5 eV to 14 eV. In our experiment five anionic fragments with m/z (and possible stoichiometric structure) 59 (C2H3O2−), 58 (C2H2O2−), 45 (CHO2−) 31 (CH3O−), and 29 (CHO−) were detected. The most abundant anion fragments that are formed through dissociative electron attachment to methyl formate are the complementary anions CH3O− and CHO−, associated with the same single bond cleavage and different survival probability. Conclusions. The low-energy electron induced dissociation of methyl formate differs from its isomers acetic acid and glycolaldehyde, which leads to possible chemical selectivity in the chemical evolution.

Ketone C–C Bond Activation Meets the Suzuki-Miyaura Cross-coupling

In a recent issue of the Journal of the American Chemical Society, Dong and coworkers report that ketones can participate as electrophiles in the Suzuki-Miyaura cross-coupling reaction under Rh(I) catalysis. They show that activation of C–C bonds of unstrained ketones is a versatile process that can engage in cross-coupling reaction with aryl boronates.

Metal-Free Multiple Carbon-Carbon and Carbon-Hydrogen Bond Activations via Charge-Switching Mechanism in Unstrained Diindolylmethanes.

A transformation of the unstrained phenol substituted 3,3'-diindolylmethanes (DIPMs) to 2,3'-diindolylketones (DIKs) by double C-C single bond cleavage with associated rearrangements, triggered by phenyliodine(III) diacetate (PIDA), is reported. Density functional theory studies reveal a mechanism involving multiple "charge-switching" steps by synergistic involvement of the two indole units with overall low activation energy. The indole 'charge-switching' mechanism in DIPMs was further extended toward synthesis of a natural product motif cyclohepta[b]indole from biaryl appended DIBM.

Iridium(III) and Rhodium(III) compounds of dipyridyl-N-alkylimine and dipyridyl-NH-ketimine: Spectral characterization and crystal structure

Pentamethylcyclopentadienyl iridium(III) and rhodium(III) complexes of formulation [(η 5-C 5Me 5)M{(C 5 H 4N) 2 C=NR)}Cl]PF 6 were prepared by the reaction of [MCl 2(η 5-C 5Me 5)] 2(M = Ir or Rh) with dipyridyl-N-alkylimine ligands, (C 5 H 4N) 2 C=NR (R = Me or Et) in the presence of NH 4 PF 6 at room temperature. The reaction also produced an unexpected dipyridyl-NH-ketimine organometallic compound [(η 5-C 5Me 5)M {(C 5 H 4N) 2 C=NH}Cl]PF 6 as minor product when the reaction was performed under refluxing acetonitrile. The NH-ketimine compounds were formed via N-C single bond cleavage of imine ligand resulting in coordination of the transformed ligand, (C 5 H 4N) 2 C=NH to the metal centre. Complexes were obtained as their hexafluorophosphate salts and characterized based on IR, NMR and ESI-MS spectroscopic data. Authenticity of NH-ketimine organometallic compound was established by single crystal X-ray analysis of a representative compound, which crystallized in orthorhombic space group Pbcn and has a pseudo-octahedral geometry around the metal ion. Pentamethylcyclopentadienyl iridium(III) and rhodium(III) complexes containing dipyridyl-N-alkylimine and dipyridyl-NH-ketimine ligands of formulation [(η 5-C5Me5)M{(C5H4N)2C=NR}Cl]PF6 and [(η 5-C5Me5)M{(C5H4N)2C=NH}Cl]PF6 were synthesized and characterized on the basis of spectroscopic data. Solid state structure of one representative NH-ketimine compound [6]PF 6 has been determined by X-ray crystallography

Recent Methodologies That Exploit C-C Single-Bond Cleavage of Strained Ring Systems by Transition Metal Complexes.

In this review, synthetic and mechanistic aspects of key methodologies that exploit C-C single-bond cleavage of strained ring systems are highlighted. The focus is on transition-metal-catalyzed processes that are triggered by C-C bond activation and β-carbon elimination, with the review concentrating on developments from mid-2009 to mid-2016.