Search Results (15)

In this study, we investigated the [3+2] cycloaddition reaction of CF₃CN (TFAN) with nitrilimine (NI) to produce 1,2,4-triazole and compared the resulting isomers. We determined the preferred reaction pathway by examining the electrophilic and nucleophilic properties of the reaction substrates, performing thermodynamic calculations for the individual pathways, and comparing them with the experimental results. Full article

In this paper, we report a highly regioselective 1,3-dipolar cycloaddition (1,3-DC) reaction of nitrilimines with thioaurone derivatives that afforded the hitherto unreported spiropyrazolines. Spectroscopic and spectrometric data were utilized to confirm the structure of all products and elucidate the reaction’s regiochemistry. A mechanistic study was performed within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311G(d,p) computational level to explain the regioselectivity observed. The electron localization function (ELF) topological analysis confirms the carbenoid-type (cb-type) mechanism of the cycloaddition reactions between nitrilimines and thioaurones. The intermolecular interactions between reagents in this reaction account for the regioselectivity observed experimentally. Full article

The cycloaddition of nitrile oxides and nitrilimines to one or both of the C=C double bonds of caryophyllene is described. The possibility of introducing five-membered fused and spiro-linked heterocycles into the structure of sesquiterpenes by the 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrilimines to caryophyllene was demonstrated. As a result of these reactions, pharmacophore fragments of isoxazoline and pyrazoline are introduced into the structure of caryophyllene, which leads to an increase in the conformational rigidity of the molecule. A complete stereochemical assignment of 1,3-dipolar cycloaddition adducts to caryophyllene was carried out. The study of antiviral and cytotoxic activity for some heterocyclic derivatives synthesized in this work revealed relatively high biological activity of previously little-studied cycloaddition adducts at the exocyclic C=CH₂ bond of caryophyllene. The effect of substituents in the synthesized heterocycles on biological activity was demonstrated. Compounds with a good inhibitory effect on the H1N1 influenza virus were revealed. The activity of the compound was demonstrated up to 6 h post infection, and this could be due to slight inhibiting activity against viral neuraminidase, necessary at the stage of progeny virion budding. Full article

The intriguing ability of C-phenyl-nitrilimine to co-exist as allenic and propargylic bond-shift isomers motivated us to investigate how substituents in the phenyl ring influence this behavior. Building on our previous work on the meta- and para-OH substitution, here we extended this investigation to explore the effect of the NH₂ substitution. For this purpose, C-(4-aminophenyl)- and C-(3-aminophenyl)-nitrilimines were photogenerated in an argon matrix at 15 K by narrowband UV-light irradiation (λ = 230 nm) of 5-(4-aminophenyl)- and 5-(3-aminophenyl)-tetrazole, respectively. The produced nitrilimines were further photoisomerized to carbodiimides via 1H-diazirines by irradiations at longer wavelengths (λ = 380 or 330 nm). Combining IR spectroscopic measurements and DFT calculations, it was found that the para-NH₂-substituted nitrilimine exists as a single isomeric structure with a predominant allenic character. In contrast, the meta-NH₂-substituted nitrilimine co-exists as two bond-shift isomers characterized by propargylic and allenic structures. To gain further understanding of the effects of phenyl substitution on the bond-shift isomerism of the nitrilimine fragment, we compared geometric and charge distribution data derived from theoretical calculations performed for C-phenyl-nitrilimine with those performed for the derivatives resulting from NH₂ (electron-donating group) and NO₂ (electron-withdrawing group) phenyl substitutions. Full article

An efficient, eco-compatible, and very cheap method for the construction of fully substituted pyrazoles (Pzs) via eliminative nitrilimine-alkene 1,3-dipolar cycloaddition (ENAC) reaction was developed in excellent yield and high regioselectivity. Enaminones and nitrilimines generated in situ were selected as dipolarophiles and dipoles, respectively. A deep screening of the employed base, solvent, and temperature was carried out to optimize reaction conditions. Recycling tests of ionic liquid were performed, furnishing efficient performance until six cycles. Finally, a plausible mechanism of cycloaddition was proposed. Then, the effect of three different structures of Pzs was evaluated on the F₁F_O-ATPase activity and mitochondrial permeability transition pore (mPTP) opening. The Pz derivatives’ titration curves of 6a, 6h, and 6o on the F₁F_O-ATPase showed a reduced activity of 86%, 35%, and 31%, respectively. Enzyme inhibition analysis depicted an uncompetitive mechanism with the typical formation of the tertiary complex enzyme-substrate-inhibitor (ESI). The dissociation constant of the ESI complex (K_i’) in the presence of the 6a had a lower order of magnitude than other Pzs. The pyrazole core might set the specific mechanism of inhibition with the F₁F_O-ATPase, whereas specific functional groups of Pzs might modulate the binding affinity. The mPTP opening decreased in Pz-treated mitochondria and the Pzs’ inhibitory effect on the mPTP was concentration-dependent with 6a and 6o. Indeed, the mPTP was more efficiently blocked with 0.1 mM 6a than with 1 mM 6a. On the contrary, 1 mM 6o had stronger desensitization of mPTP formation than 0.1 mM 6o. The F₁F_O-ATPase is a target of Pzs blocking mPTP formation. Full article

Sulfur vulcanization is the most used method for curing of natural and synthetic rubbers. The crosslinking degree achieved is usually controlled by adding proper quantities of accelerants, activators, co-activators, retardants, and inhibitors, and influences the hardness, elasticity, hysteresis of elastomers and, consequently, the properties and behavior of the materials that incorporate them. Despite the fine tuning pursued over the years, sulfur crosslinking is still difficult to control both in terms of degree and homogeneity of cross-link. Addition of thermally activable bifunctional reagents able to crosslink the polymer matrix through covalent bonds could be a strategy to modulate and control finely the reticulation grade of elastomers. Tetrazoles can form highly reactive nitrilimines by thermal treatment at appropriate temperature, which can react with the vinyl double bonds present in the rubber. In this work a set of bis-tetrazoles were synthesized and those with the right activation temperatures were used for the curing of styrene-butadiene rubber, acting both as single crosslinkers and together with classic sulfur-based ones. The addition of bistetrazoles simplified and made more efficient the compounding process, allowing to prolong the mixing until optimum dispersion and homogeneity were obtained. Moreover, they led to an improvement in the hysteretic properties of the compound and to the reduction of the non-linearity of the dynamic behavior (Payne effect). Full article

We investigated the reactivity of different substituted nitrylimine-type three atom components (TACs) in [3+2] cycloaddition (32CAs) reactions with electrophilically activated nitroethenes within molecular electron density theory (MEDT). In parallel research, the molecular mechanism of the considered transformation was examined through analysis of all possible reaction channels and full optimization of all critical structures. In particular, the existence of zwitterionic intermediates on reaction paths was verified. On the basis of the bonding evolution theory (BET), the mechanism of the 32CA reaction between C,N-diphenylnitrylimine and (E)-2-phenyl-1-cyano-1-nitroethene should be treated as a one-step two-stage mechanism. Full article

Gelatin is a costless polypeptide material of natural origin, able to form hydrogels that are potentially useful in biomaterial scaffold design for drug delivery, cell cultures, and tissue engineering. However, gelatin hydrogels are unstable at physiological conditions, losing their features only after a few minutes at 37 °C. Accordingly, treatments to address this issue are of great interest. In the present work, we propose for the first time the use of bi- and trifunctional tetrazoles, most of them unknown to date, for photoinduced gelatin cross-linking towards the production of physiologically stable hydrogels. Indeed, after UV-B irradiation, aryl tetrazoles generate a nitrilimine intermediate that is reactive towards different functionalities, some of them constitutively present in the amino acid side chains of gelatin. The efficacy of the treatment strictly depends on the structure of the cross-linking agent used, and substantial improved stability was observed by switching from bifunctional to trifunctional cross-linkers. Full article

The [3+2] cycloaddition (32CA) reactions of diphenyl nitrilimine and phenyl nitrile oxide with (R)-carvone have been studied within the Molecular Electron Density Theory (MEDT). Electron localisation function (ELF) analysis of these three-atom-components (TACs) permits its characterisation as carbenoid and zwitterionic TACs, thus having a different reactivity. The analysis of the conceptual Density Functional Theory (DFT) indices accounts for the very low polar character of these 32CA reactions, while analysis of the DFT energies accounts for the opposite chemoselectivity experimentally observed. Topological analysis of the ELF along the single bond formation makes it possible to characterise the mechanisms of these 32CA reactions as cb- and zw-type. The present MEDT study supports the proposed classification of 32CA reactions into pdr-, pmr-, cb- and zw-type, thus asserting MEDT as the theory able to explain chemical reactivity in Organic Chemistry. Full article

The reaction of diphenyl nitrilimine (NI) with methyl 1-methyl-allenoate yielding a spirobipyrazoline has been studied within molecular electron density theory (MEDT) at the MPWB1K/6-311G(d) computational level in dichloromethane. This reaction is a domino process that comprises two consecutive 32CA reactions with the formation of a pyrazoline intermediate. Analysis of the relative Gibbs free energies indicates that both 32CA reactions are highly regioselective, the first one being also completely chemoselective, in agreement with the experimental outcomes. The geometries of the TSs indicate that they are associated to asynchronous bond formation processes in which the shorter distance involves the C1 carbon of diphenyl NI. Despite the zwitterionic structure of diphenyl NI, the appearance of a pseudoradical structure at the beginning of the reaction path, with a very low energy cost, suggests that the 32CA reaction between diphenyl NI, a strong nucleophile, and the allenoate, a moderate electrophile, should be mechanistically considered on the borderline between pmr-type and cb-type 32CA reactions, somewhat closer to the latter. Full article

Conventional frontier molecular orbital theory is not able to satisfactorily explain the regioselectivity outcome of the nitrilimine–alkene cycloaddition. We considered that conceptual density functional theory (DFT) could be an effective theoretical framework to rationalize the regioselectivity of the title reaction. Several nitrilimine–alkene cycloadditions were analyzed, for which we could find regioselectivity data in the literature. We computed DFT reactivity indices at the B3LYP/6-311G(2d,p)//B3LYP/6-31G(d,p) and employed the grand potential stabilization criterion to calculate the preferred regioisomer. Experimental and calculated regioselectivity agree in the vast majority of cases. It was concluded that predominance of a single regioisomer can be obtained by maximizing (i) the chemical potential difference between nitrilimine and alkene and (ii) the local softness difference between the reactive atomic sites within each reactant. Such maximization can be achieved by carefully selecting the substituents on both reactants. Full article

Nitrilimine generated by photolysis of diaryltetrazole in aqueous phase under mild conditions was trapped by nucleophiles including amines and thioalcohols. The representative products were characterized, while products with all 20 natural amino acids and a peptide were observed by MALDI-TOF mass spectroscopy. Competitive studies showed that this reaction also occurred in the presence of acrylamide. These results provided new information for understanding the potential side reactions when tetrazole-alkene pairs were used as a bioorthogonal reaction in labeling proteins and related studies in buffered systems. Full article

The reaction of nitrilimine 6a with ethyl pyridine-2-acetate (7) gave thecorresponding pyrrolo[1,2-a]pyridine 8, while the reaction of 6b containing an estermoiety afforded the acyclic adduct 9. The reaction of 6a with 2-aminopyrimidine (10)gave the novel unexpected pyrimido[2,1-d]1,2,3,5-tetrazine 11. Acyclic adducts 16 and17 were obtained from the reaction of 6b with 2-cyanomethylbenzimidazole (14) and 2-aminobenzimidazole (15), respectively. Full article

This review article discusses the reaction of nitrilimines and nitrile oxides with hydrazines, hydrazones, and oximes. Three reaction modes were observed. The article mainly covers our work published over the last fifteen years, in which interesting heterocyles such as oxadiazoles, triazoles, and tetrazines were synthesized and fully characterized. Full article