Unexpected cleavage of the Cpy–Cpy bond in the reaction of 2,2′-bipyridine N,N′-diimines with acetylenes

An unusual cleavage of the C_py–C_py bond in the reaction of 2,2′-bipyridine N,N′-diimine and its C-methyl substituted derivatives with acetylenes is described. The effect of the solvent on the yield of 7,7′-bipyrazolo[1,5-a]pyridine-2,2′,3,3′-tetracarboxylates and the products of cleavage of the C_py–C_py bond has been studied. The mechanism of the cleavage reaction is discussed on the basis of DFT calculations.     

Effect of Various Intercalators on the Fenton‐Type Oxidative Cleavage of Double‐Stranded DNA

The intensity of the linear dichroism (LD) in the absorption region of DNA (about 260 nm) decreased with time in the presence of [Fe(EDTA)]²⁺ (EDTA=ethylenediaminetetraacetic acid), H₂O₂, and ascorbate. The decrease in the LD signal indicated either an increase in flexibility, a shortening of the DNA stem, or both, owing to oxidative cleavage, and was best described by the difference between the two single‐exponential‐decay curves, thereby suggesting the involvement of two sequential first‐order reactions. The fast reaction was assigned to cleavage of one of two DNA strands, which increased the flexibility of the DNA. The slow reaction corresponded to cleavage at or near the first cleavage site, thereby shortening the DNA stem. The presence of an intercalator, including ethidium, propidium, 9‐aminoacridine, and proflavine, inhibited the first step of the cleavage reaction. One of the possible reasons for the observed inhibition might be a change in the DNA conformation near the intercalation site. Intercalation caused an unwinding and elongation of the DNA and resulted in changes in the location of the H atoms of the sugar moiety, which is known to be the main site at which hydroxyl radicals react.     

Nitrile Oxide‐Norbornene Cycloaddition as a Bioorthogonal Crosslinking Reaction for the Preparation of Hydrogels

This communication describes the first application of cycloaddition between an in situ generated nitrile oxide with norbornene leading to a polymer crosslinking reaction for the preparation of poly(ethylene glycol) hydrogels under physiological conditions. Hydrogels with high water content and robust physical strength are readily formed within 2–5 min by a simple two‐solution mixing method which allows 3D encapsulation of neuronal cells. This bioorthogonal crosslinking reaction provides a simple yet highly effective method for preparation of hydrogels to be used in bioengineering.

     

Diradicals Photogeneration from Chloroaryl-Substituted Carboxylic Acids

With the aim of generating new, thermally inaccessible diradicals, potentially able to induce a double-strand DNA cleavage, the photochemistry of a set of chloroaryl-substituted carboxylic acids in polar media was investigated. The photoheterolytic cleavage of the Ar−Cl bond occurred in each case to form the corresponding triplet phenyl cations. Under basic conditions, the photorelease of the chloride anion was accompanied by an intramolecular electron-transfer from the carboxylate group to the aromatic radical cationic site to give a diradical species. This latter intermediate could then undergo CO₂ loss in a structure-dependent fashion, according to the stability of the resulting diradical, or abstract a hydrogen atom from the medium. In aqueous environment at physiological pH (pH=7.3), both a phenyl cation and a diradical chemistry was observed. The mechanistic scenario and the role of the various intermediates (aryl cations and diradicals) involved in the process was supported by computational analysis.     

A DFT Study on the Binuclear Copper(I)-Catalyzed Synthesis Mechanism of 1,2,3-Triazolo[1,5-c]Pyrimidine via Interrupted Click and Ketenimine Rearrangement

In this paper, the mechanism of the full catalytic cycle for binuclear Cu(I)-catalyzed sulfonyl azide-alkyne cycloaddition reaction for the synthesis of triazolopyrimidines was rationalized by density functional theoretical (DFT) calculations. The computed reaction route consists of: (a) formation of dicopper intermediates, including C−H activation of terminal alkyne, 3+2 ring cycloaddition and ring-reducing reaction and transmetalation, (b) interrupted CuAAC reaction, including di-copper catalyzed ring-opening of 2H-azirines and C−C bond formation to generate the copper-triazoles and -ketenimines, (c) two-step C−N cross-coupling and following (d) multi-step hydrogen transfer by the hydrogen bonding chain of water to promote the C−N formation and another C−N cleavage through the removal of p-tolyl sulfonamides. Our DFT results indicate that the multi-step hydrogen transfer process is the rate-determining step along the potential energy surface profile. The explicit water model was used for systematic determination of barrier for C−C cross-coupling, C−N bond formation and cleavage, and p-tolylsulfonamide removal. A critical insight in the interrupted CuAAC reaction was proposed. Further prediction interprets H₂O hydrogen bond chain plays an important role in C−N bond formation and cleavage, and the removal of p-tolylsulfonamide. This may have fundamental guidance on the design of 1, 5-herterocyclic functionalized triazolopyrimidines via interrupted CuAAC rearrangement reaction, as well as hydrogen bond chain of water.     

Production of Alkyl Aryl Sulfides from Aromatic Disulfides and Alkyl Carboxylates via a Disilathiane–Disulfide Interchange Reaction

The results of this study show that disilathiane is an effective mediator in the synthesis of alkyl aryl sulfides with disulfides and alkyl carboxylates. Mechanistic studies suggest that disilathiane promotes cleavage of the sulfur–sulfur bond of disulfides to generate thiosilane as a key intermediate. Diselenides were also applicable to this transformation to produce the corresponding selenides.     

Incorporation of β-Alanine in Cu(II) ATCUN Peptide Complexes Increases ROS Levels,DNA Cleavage and Antiproliferative Activity**

Redox-active Cu(II) complexes are able to form reactive oxygen species (ROS) in the presence of oxygen and reducing agents. Recently, Faller et al. reported that ROS generation by Cu(II) ATCUN complexes is not as high as assumed for decades. High complex stability results in silencing of the Cu(II)/Cu(I) redox cycle and therefore leads to low ROS generation. In this work, we demonstrate that an exchange of the α-amino acid Gly with the β-amino acid β-Ala at position 2 (Gly2→β-Ala2) of the ATCUN motif reinstates ROS production (^•OH and H₂O₂). Potentiometry, cyclic voltammetry, EPR spectroscopy and DFT simulations were utilized to explain the increased ROS generation of these β-Ala2-containing ATCUN complexes. We also observed enhanced oxidative cleavage activity towards plasmid DNA for β-Ala2 compared to the Gly2 complexes. Modifications with positively charged Lys residues increased the DNA affinity through electrostatic interactions as determined by UV/VIS, fluorescence, and CD spectroscopy, and consequently led to a further increase in nuclease activity. A similar trend was observed regarding the cytotoxic activity of the complexes against several human cancer cell lines where β-Ala2 peptide complexes had lower IC₅₀ values compared to Gly2. The higher cytotoxicity could be attributed to an increased cellular uptake as determined by ICP-MS measurements.     

Palladium‐Catalyzed One‐Pot Three‐ or Four‐Component Coupling of Aryl Iodides,Alkynes, and Amines through CN Bond Cleavage: Efficient Synthesis of Indole Derivatives

An efficient synthesis of N‐substituted indole derivatives was realized by combining the Pd‐catalyzed one‐pot multicomponent coupling approach with cleavage of the C(sp³)?N bonds. Three or four components of aryl iodides, alkynes, and amines were involved in this coupling process. The cyclopentadiene–phosphine ligand showed high efficiency. A variety of aryl iodides, including cyclic and acyclic tertiary amino aryl iodides, and substituted 1‐bromo‐2‐iodobenzene derivatives could be used. Both symmetric and unsymmetric alkynes substituted with alkyl, aryl, or trimethylsilyl groups could be applied. Cyclic secondary amines such as piperidine, morpholine, 4‐methylpiperidine, 1‐methylpiperazine, 2‐methylpiperidine, and acyclic amines including secondary and primary amines all showed good reactivity. Further application of the resulting indole derivatives was demonstrated by the synthesis of benzosilolo[2,3‐b]indole.     

Comparative Studies of Thermally Induced Homolytic CarbonCarbon Bond Cleavage Reactions of Strained Dicarba[2]ferrocenophanes and Their Ring‐Opened Oligomers and Polymers

Reactivity studies of dicarba[2]ferrocenophanes and also their corresponding ring‐opened oligomers and polymers have been conducted in order to provide mechanistic insight into the processes that occur under the conditions of their thermal ring‐opening polymerisation (ROP) (300 °C). Thermolysis of dicarba[2]ferrocenophane rac‐[Fe(η⁵‐C₅H₄)₂(CHPh)₂] (rac‐ 14 ; 300 °C, 1 h) does not lead to thermal ROP. To investigate this system further, rac‐ 14 was heated in the presence of an excess of cyclopentadienyl anion, to mimic the postulated propagating sites for thermally polymerisable analogues. This afforded acyclic [(η⁵‐C₅H₅)Fe(η⁵‐C₅H₄)‐CH₂Ph] ( 17 ) through cleavage of both a Fe?Cp bond and also the C?C bond derived from the dicarba bridge. Evidence supporting a potential homolytic C?C bond cleavage pathway that occurs in the absence of ring‐strain was provided through thermolysis of an acyclic analogue of rac‐ 14 , namely [(η⁵‐C₅H₅)Fe(η⁵‐C₅H₄)(CHPh)₂‐C₅H₅] ( 15 ; 300 °C, 1 h), which also afforded ferrocene derivative 17 . This reactivity pathway appears general for post‐ROP species bearing phenyl substituents on adjacent carbons, and consequently was also observed during the thermolysis of linear polyferrocenylethylene [Fe(η⁵‐C₅H₄)₂(CHPh)₂]_n ( 16 ; 300 °C, 1 h), which was prepared by photocontrolled ROP of rac‐ 14 at 5 °C. This afforded ferrocene derivative [Fe(η⁵‐C₅H₄CH₂Ph)₂] ( 23 ) through selective cleavage of the ?H(Ph)C?C(Ph)H? bonds in the dicarba linkers. These processes appear to be facilitated by the presence of bulky, radical‐stabilising phenyl substituents on each carbon of the linker, as demonstrated through the contrasting thermal properties of unsubstituted linear trimer [(η⁵‐C₅H₅)Fe(η⁵‐C₅H₄)(CH₂)₂(η⁵‐C₅H₄)Fe(η⁵‐C₅H₄)(CH₂)₂(η⁵‐C₅H₄)Fe(η⁵‐C₅H₅)] ( 29 ) with a ?H₂C?CH₂? spacer, which proved significantly more stable under analogous conditions. Evidence for the radical intermediates formed through C?C bond cleavage was detected through high‐resolution mass spectrometric analysis of co‐thermolysis reactions involving rac‐ 14 and 15 (300 °C, 1 h), which indicated the presence of higher molecular weight species, postulated to be formed through cross‐coupling of these intermediates.