Electrophilic aromatic substitution reactions of compounds with Craig-Möbius aromaticity

Electrophilic aromatic substitution (EAS) reactions are widely regarded as characteristic reactions of aromatic species, but no comparable reaction has been reported for molecules with Craig-Möbius aromaticity. Here, we demonstrate successful EAS reactions of Craig-Möbius aromatics, osmapentalenes, and fused osmapentalenes. The highly reactive nature of osmapentalene makes it susceptible to electrophilic attack by halogens, thus osmapentalene, osmafuran-fused osmapentalene, and osmabenzene-fused osmapentalene can undergo typical EAS reactions. In addition, the selective formation of a series of halogen substituted metalla-aromatics via EAS reactions has revealed an unprecedented approach to otherwise elusive compounds such as the unsaturated cyclic chlorirenium ions. Density functional theory calculations were conducted to study the electronic effect on the regioselectivity of the EAS reactions.

Acidic Stabilization of the Dual-Aromatic Heterocyclic Anions

Recently, we discovered that the delocalization of nitrogen lone-pair electrons (NLPEs) in five-membered nitrogen heterocycles created a second σ-aromaticity in addition to the prototypical π-aromaticity. Such dual-aromatic compounds, such as the pentazole anion, were proved to have distinct chemistry in comparison to traditional π-aromatics, such as benzene, and were surprisingly unstable, susceptible to electrophilic attack, and relatively difficult to obtain. The dual-aromatics are basic in nature, but prefer not to be protonated when confronting more than three hydronium/ammonium ions, which violates common sense understanding of acid−base neutralization for a reason that is unclear. Here, we carried out 63 test simulations to explore the stability and reactivity of three basic heterocycle anions (pentazole anion N5¯, tetrazole anion N4C1H1¯, and 1,2,4-triazole anion N3C2H2¯) in four types of solvents (acidic ions, H3O+ and NH4+, polar organics, THF, and neutral organics, benzene) with different acidities and concentrations. By quantum mechanical calculations of the electron density, atomistic structure, interatomic interactions, molecular orbital, magnetic shielding, and energetics, we confirmed the presence of dual aromaticity in the heterocyclic anions, and discovered their reactivity to be a competition between their basicity and dual aromaticity. Interestingly, when the acidic ions H3O+/NH4+ are three times more in number than the basic heterocyclic anions, the anions turn to violate acid−base neutralization and remain unprotonated, and the surrounding acidic ions start to show a significant stabilization effect on the studied heterocyclic anions. This work brings new knowledge to nitrogen aromatics and the finding is expected to be adaptable for other pnictogen five-membered ring systems.

Molecular Mechanism of Thymidylate Synthase Inhibition by N4-Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies

Novel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N4-hydroxy-dCMP (N4-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N4-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N4-OH-dCMP and N5,10-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode Trichinella spiralis, both co-crystallized with N4-OH-dCMP and N5,10-methylenetetrahdrofolate. The crystal structure of the mouse TS-N4-OH-dCMP complex soaked with N5,10-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer.

Electron-Enriched Pd Nanoparticles for Selective Hydrogenation of Halonitrobenzenes to Haloanilines

Selective hydrogenation of halonitrobenzenes into haloanilines represents a green process to replace the environmentally unfriendly non-catalytic chemical reduction process in industry. However, this transformation often suffers from serious dehalogenation due to the easy break of carbon-halogen bonds on metal surfaces. Modulations of the electronic structure of the supported Pd nanoparticles on Lewis-basic layered double hydroxides have been demonstrated to promote catalytic activity and selectivity for hydrogenation of halonitrobenzenes into haloanilines. Mechanism studies suggest that Pd with the enhanced electron density not only improves the capability for hydrogen activation, but also generates the partially negative-charged hydrogen species to suppress the electrophilic attack on the carbon-halogen bond and avoid the dehalogenation.

Strong electron affinity PDI supramolecules form anion radical for organic pollutants degradation via directly electrophilic attack

Pharmaceutical and personal care products (PPCPs) are the most common hazardous environmental pollutants. PDIs anion radical is the promising photocatalyst to transform PPCPs into non-toxic CO2 and H2O for clean...

Iodocyclisation of Electronically Resistant Alkynes: Synthesis of 2-Carboxy (and sulfoxy)-3-iodobenzo[b]thiophenes

The iodocyclisation of alkynes bearing tethered nucleophiles is a highly effective method for the construction and diversification of heterocycles. A key limitation to this methodology is the 5-endo-dig iodocyclisation of alkynes that have an unfavourable electronic bias for electrophilic cyclisation. These tend to direct electrophilic attack of the iodonium atom to the wrong carbon for cyclisation, thus favouring competing addition reactions. Using our previously determined reaction conditions for the 5-endo-dig iodocyclisations of electronically resistant alkynes, we have achieved efficient synthetic access to 2-carboxy (and sulfoxy)-3-iodobenzo[b]thiophenes. The corresponding benzo[b]furans and indoles were not accessible under these conditions. This difference may arise due to the availability of a radical mechanism in the case of iodobenzo[b]thiophenes. The 2-carboxy functionality of the iodocyclised products can be further employed in iterative alkyne-coupling iodocyclisation reactions, where the carboxy group or an imine (Schiff base) partakes in a second iodocyclisation to generate a lactone or pyridine ring.

Synthesis of 3-arylisoxazoles and their sulfamide derivatives

Great interest in binuclear aromatic systems containing an isoxazole ring and a sulfamide group is due to the effect of two pharmacophore groups at once on the biological activity of these compounds. This article is devoted to the development of a method for the synthesis of 3-arylisoxazole-containing compounds and their sulfamide derivatives from simple and accessible products of organic synthesis. The target products of the developed multistage schemes are derivatives of various bicyclic systems containing an isoxazole ring and a second aromatic ring associated with a sulfofragment. The synthesis of 3-aryl-5-acylaminoisoxazoles was carried out by sequential conversion of methyl esters of aromatic carboxylic acids into the corresponding nitriles by reaction with acetonitrile in the presence of sodium hydride in dioxane. At the next stage, the nitriles reacted with hydroxylamine in an aqueous solution of sodium hydroxide to form the corresponding bicyclic amines, which were then acylated in acetonitrile with acetic acid chloride in the presence of pyridine. The total yields of 3-aryl-5-N-acylaminoisoxazoles were at least 60%. It was found that the sulfonylchlorination of 3-aryl-5-N-acylamino derivatives of isoxazole, depending on the experimental conditions and the structure of the starting substrates, forms both mono- and disulfochlorides. The regioselectivity of the sulfochlorination reaction of the synthesized bicyclic systems was proved by 1H NMR spectroscopy. The influence of various factors on the course of the sulfochlorination reaction of the synthesized bicyclic systems was studied. The dependence of the direction of the electrophilic attack on the structure of the compounds and on the conditions of the experiment was established. As a result of the performed research, both mono and disulfochlorination products were obtained. With an increase in the reaction time, the disulfonylchlorination product accumulates and the deacylation reaction proceeds in parallel. Convincing proof of the structure of all synthesized compounds has been carried out using a complex of modern methods of physical and chemical analysis.

Visible-Light Photoredox-Catalyzed C–O Bond Cleavage of Diaryl Ethers by Acridinium Photocatalysts at Room Temperature

We have developed visible-light photoredox-catalyzed C–O bond cleavage of diaryl ethers by an acidolysis with an aryl car-boxylic acid and a following one-pot hydrolysis. Two phenols are obtained from a diaryl ether at room temperature. The aryl carboxylic acid used for the acidolysis can be recovered. The key to success of the acidolysis is merging visible-light photore-dox catalysis with a new acridinium photocatalyst and Lewic acid catalysis with Cu(TMHD)2. Preliminary mechanistic studies indicate that the catalytic cycle occurs via a rare selective electrophilic attack of the generated aryl carboxylic radical on the electron-rich aryl ring of diphenyl ether. This transformation is applied to a gram-scale reaction and the model of 4-O-5 lignin linkages.

A Leopard Cannot Change Its Spots: Unexpected Products from the Vilsmeier Reaction on 5,10,15-Tritolylcorrole

The reaction of 5,10,15-tritolylcorrole with 3-dimethylaminoacrolein (3-DMA) and POCl3 gives a further example of the rebel reactivity of this contracted macrocycle. While no evidence was obtained for the formation of the expected β-acrolein corrole, the inner core substituted N21,N22-3-formylpropylcorrole and the 10-acrolein isocorrole were the reaction products. By increasing the temperature or the amount of the Vilsmeier reagent, the 10-isocorrole became the unique reaction product. The formation of the isocorrole by electrophilic attack of the Vilsmeier reagent to the 10-position of the corrole is unprecedented in the porphyrinoids field and it could pave the way for a novel route to the preparation of stable isocorroles.

Acid-Mediated Denitrogenation/Rearrangement/Coupling of ­Benzyl Azides with Triazolyl-Substituted Cycloalkanones

Organic molecules containing α-triazolyl or β-amino cyclic ketone fragments have been individually proven to show good bioactivities and to be useful in asymmetric and pharmaceutical syntheses. A triflic acid-promoted simple and efficient method for the synthesis of unsymmetrical α-triazolyl-α′-(aminomethyl)cycloalkanones from benzyl azides and α-triazolylcycloalkanones has been developed. A series of unsymmetrical α,α′-disubstituted cycloalkanones were obtained with high syn-diastereoselectivity and up to 82% yield. Examination of the reaction mechanism showed that the benzyl azides undergo protonation, nitrogen elimination, rearrangement, and electrophilic attack by the enol forms of the cyclic ketones.