Aliphatic Substituents Research Articles

Synthesis of 1,2,3-Triazine Derivatives by Deoxygenation of 1,2,3-Triazine 1-Oxides.

A convenient, efficient, and inexpensive method has been developed for the synthesis of 1,2,3-triazine derivatives via deoxygenation of 1,2,3-triazine 1-oxide using trialkyl phosphites. Triethyl phosphite is more reactive than trimethyl phosphite, and both phosphites form their corresponding phosphates in these reactions. This procedure provides a range of aromatic and aliphatic substituted 1,2,3-triazine-4-carboxylate derivatives cleanly in high yields. Unexpected 1,2,4-triazine derivatives were also obtained as minor products during deoxygenation of 1,2,3-triazine-4-carboxylate 1-oxides having an aliphatic substituent at the 5-position.

Molecular Docking of Monomethine Cyanine Dyes to Lysozyme Amyloid Fibrils

Protein aggregation into highly ordered supramolecular aggregates is the hallmark of many degenerative diseases including the neurological disorders (Parkinson’s, Alzheimer’s, and Huntington’s diseases), type II diabetes, systemic amyloidosis, spongiform encephalopathies, etc. One of the simplest and effective methods for the identification and characterization of amyloid fibrils in vitro and the visualization of amyloid inclusions in vivo is based on the use of probes sensitive to the beta-pleated motifs. In the attempt to design new amyloid-sensing dyes or to optimization the existing molecules, it is crucial to have the sufficient knowledge of the molecular and atomic levels interactions in the binding sites. Among the especially useful methods available to provide the atomic-level insights into the mechanisms of various types of biomolecular interactions is molecular docking technique. In the present study, the molecular docking tool has been employed to investigate the interactions between the monomethine cyanine dyes and the lysozyme amyloid fibrils constructed from the K-peptide of lysozyme, GILQINSRW (residues 54–62 of the wild-type protein). Using the AutoDOCK and the protein-ligand interaction profiler PLIP it was found: i) monomethines interact with the fibril surface (with the aromatic residues on the top of β-sheet or with the edges of the β-sheet); ii) the dye binding is governed by the hydrophobic interactions, salt bridges and the hydrogen bonds between the aliphatic substituents on the nitrogen atom of benzothiazole part of dye molecules and the lysozyme amyloid fibril; iii) the variations in the cyanine structure and in the lysozyme amiloid twisting didn’t insert significant effect on the binding mode of cyanines.

Unraveling the radical chain mechanism in the pyrolysis of β-O-4 linked lignin: The role of aliphatic substituents

Lignin pyrolysis involves complex radical reactions, whereas the radical chain process, especially the influence of aliphatic substituents, has been rarely studied. Herein, the typical β-O-4 lignin dimer, phenethyl phenyl ether (PPE), and three aliphatic substituted derivatives of PPE, namely α-OH substituted, β-CH2OH substituted, and α,β-disubstituted PPE (αPPE, βPPE, and αβPPE) were employed as model compounds. DFT calculations, electronic analyses, and fast pyrolysis experiments were combined to investigate three core steps of the radical chain mechanism in lignin pyrolysis, i.e., homolysis, hydrogen abstraction, and radical decomposition. The pathway involving successive Cβ-O homolysis → α-hydrogen abstraction → Cβ-O breakage of α-dehydrogenated radical is dominated for the pyrolysis of aliphatic substituted β-O-4 linked lignin, with the formation of phenolics. The hydrogen abstraction reactions at the Cα site are obviously superior to those at other sites for PPE derivatives, due to the p-π conjugate stability. Notably, α-hydrogen abstraction can be significantly promoted by the π-electron-dispersing α-OH substitution. The decomposition step of dehydrogenated radicals can be facilitated by the electron-donating β-CH2OH substitution, where the Cβ-O breakage of the α-dehydrogenated radical is dominant. Totally, aliphatic substituents can improve the radical growth stage and change the competitiveness of the hydrogen abstraction and radical decomposition reactions. The fast pyrolysis experiments of PPE and αPPE gave direct proof that the generation of characteristic products from the radical chain process, i.e., benzaldehyde and phenylacetaldehyde, was enhanced by the α-OH substitution. The present work offers the potential to give a comprehensive image of the radical chain mechanism in lignin pyrolysis.

Molecular engineering of terpyridine-Fe(II) coordination polymers consisting of quinoxaline-based π-spacers toward enhanced electrochromic performance

In this work, four new terpyridine-Fe (Ⅱ) coordination polymers (FeQ1 ∼ FeQ4) consisting of quinoxaline-based π-spacers were developed, and further deposited on ITO substrates via spin-coating process for electrochromic applications. All these Fe (Ⅱ) coordination polymers exhibited fast and reversible electrochromic switching between purple and yellow with high optical contrast as well as high coloration efficiency, and showed good cycle stability. The variation of substituents on the quinoxaline-based π-spacers resulted in tunable electrochromic properties. Remarkably, polymers FeQ3 and FeQ4 with aliphatic substituents on the ligands showed superior optical contrast up to 76.7% and 81.6% around 575 nm, with coloring time around 0.5 s and bleaching time around 2 s, respectively. To the best of our knowledge, FeQ4 gained the highest optical contrast value among the reported electrochromic materials based on Fe-complexes up to date.

Structural and Molecular Packing study of Three New Amidophosphoric Acid Esters and Assessment of Their Inhibiting Activity Against SARS-CoV-2 by Molecular Docking.

Three new compounds of amidophosphoric acid esters with a [OCH2C(CH3)2CH2O]P(O)[X] segment (where X=cyclopentylamido (1), 2‐aminopyridinyl (2) and pyrrolidinyl (3)) were synthesized and studied using FT‐IR and 31P/13C/1H NMR spectroscopies and single‐crystal X‐ray diffraction analysis. The compounds crystallize in the triclinic space groups P 1‾ for 1 and 3 and in the orthorhombic space group Pca21 for 2, where the asymmetric unit consists of three symmetrically‐independent molecules for 1 and one molecule for 2 and 3. The intermolecular interactions and supramolecular assemblies are assessed by Hirshfeld surface analysis and enrichment ratios. The results reveal that the substituent effect plays an important role in directing the supramolecular structures. The presence of the aromatic substituent aminopyridine in 2 providing the C−H…π interactions leads to a larger variety in interactions including H…H, H…O/O…H, H…C/C…H and H…N/N…H contacts, whereas the packings of the compounds 1 and 3 bearing aliphatic substituents only include H…H and H…O/O…H contacts. The enrichment ratios affirm the importance of O…H/H…O contacts reflecting the hydrogen bond N−H…O interactions to be the enriched contacts. Compounds 1–3 were also investigated along with five similar reported structures with a [OCH2C(CH3)2CH2O]P(O) segment for their inhibitory behavior against SARS‐CoV‐2. The molecular docking results illustrate that the presence of the aromatic amido substituent versus the aliphatic type provides a more favorable condition for their biological activities.

Synthesis and Luminescent Properties of s-Tetrazine Derivatives Conjugated with the 4H-1,2,4-Triazole Ring.

New derivatives obtained by the combination of unique 1,2,4,5-tetrazine and 4H-1,2,4-triazole rings have great application potential in many fields. Therefore, two synthetic few-step methodologies, which make use of commercially available 4-cyanobenzoic acid (method A) and ethyl diazoacetate (method B), were applied to produce two groups of the aforementioned heterocyclic conjugates. In both cases, the target compounds were obtained in various combinations, by introducing electron-donating or electron-withdrawing substituents into the terminal rings, together with aromatic or aliphatic substituents on the triazole nitrogen atom. Synthesis of such designed systems made it possible to analyze the influence of individual elements of the structure on the reaction course, as well as the absorption and emission properties. The structure of all products was confirmed by conventional spectroscopic methods, and their luminescent properties were also determined.

Structural studies of halide hexaalkylguanidinium salts

Crystal structure of the series of three hexaalkylguanidinium halides (hexa-n-propylguanidinium tri-n-propylguanidinium diiodide (1), hexa-n-butylguanidinium bromide (2) and hexa-n-pentylguanidinium bromide (3) has been revealed and reported for the first time. Investigated hexalkylguanidinium derivatives belong to the group of compounds which find application as phase transfer catalysts, however due to their different structural features related to the length of the aliphatic substituent and the size of the halide anion, they might be potentially useful also for crystal engineering. Compound 1 represents a first example of a crystalline alkylguanidinium salt containing two chemically distinct cations. Performed analysis allowed for detailed description of the geometry of cationic species within 1−3 and enabled its comparison with structurally-similar systems. Investigated compounds showed essential differences in the supramolecular architecture of ions in their crystals. Adjacent tri-n-propylguanidinium cations and the iodide anions in the crystal network of 1 were interacting via the N−H···I− and C−H···I− hydrogen bonds. In the case of both bromides (2 and 3), no hydrogen bonds have been identified.

Synthesis and Liquid Crystalline Properties of Low Molecular Weight Bis- Chalcone Compounds.

In this paper, we report on the synthesis and liquid crystalline properties of some low molecular weight bis-chalcone compounds derived from acetone, cyclopentanone and cyclohexanone mesogenic cores. Structurally bis-chalcones belong to a broader family of chalcone compounds. Chalcone is a compound that consists of two aromatic rings linked by an unsaturated α, β-ketone. Liquid crystalline chalcones are prepared by aliphatic chain substituents on two aromatic rings. Chalcones are well studied for their mesomorphic properties. Compared to a large number of chalcone based LCs reported, only a few articles have been published on the mesomorphic properties of bis-chalcone compounds. The target compounds of the present study varied not only in their central core but also in number and position of terminal aliphatic chain substitution-a key structural unit in deciding the liquid crystalline properties of a compound. All target compounds were synthesized in good yield by base catalyzed Claisen-Schmidt condensation reaction. Molecular structures were confirmed by FT-IR, 1H NMR, 13C NMR, and mass spectroscopic methods. Liquid crystalline property of these compounds was evaluated using polarizing optical microscopy and differential scanning calorimetry. Although none of the acetone based compounds exhibited mesomorphism, cyclopentanone and cyclohexanone based compounds with octyloxy chain at para position on either side of the dibenzylidine ring stabilized liquid crystalline smectic (SmA and SmC) and nematic (N) phases. The observed structure-liquid crystalline property relationship was explained by structural analysis of molecules using DFT calculations. Considering the inherent photoluminescence nature of the chalcone moiety, a preliminary study was carried out on a selected compound to reveal its fluorescence property. Our study brings about an important structure-liquid crystalline property relationship in a relatively unexplored class of bis-chalcone liquid crystals.

A Straightforward Approach to Fluorinated Pyrimido[1,2-b]indazole Derivatives via Metal/Additive-Free Annulation with Enaminones, 3-Aminoindazoles, and Selectfluor.

A novel and efficient three-component reaction with two C-N bonds and one C-F bond formation has been reported, which provides a straightforward route to a variety of fluorinated pyrimido[1,2-b]indazole derivatives. This transformation has the advantage of excellent functional group compatibility, including aliphatic and aromatic substituents enaminones. Moreover, metal and additives are not necessary for this reaction, which is of great significance for the synthesis and application of fluorinated heterocycles.

Front Cover: Fluorine‐Containing sp3‐Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents (Eur. J. Org. Chem. 15/2022)

The Front Cover shows examples of fluoro-substituted pyrazoles and pyrimidines with saturated heterocyclic substituents – advanced building blocks for organic and medicinal chemistry synthesized by a group of chemists from Kyiv, Ukraine. An efficient approach to the multigram preparation of sp3-enriched fluorinated building blocks bearing protected azetidine, pyrrolidine, piperidine, or cyclohexanone moieties and transformations of these useful intermediates into the nitrogen heterocycles mentioned above are described. The authors thank Mr. Andriy Yakymenko for the photo of rapeseed fields used as a background, Mr. Bohdan Vaschenko and Ms. Vladyslava Prykhodko for their help with picture preparation. More information can be found in the Research Article by O. O. Grygorenko et al.

Oxidative Cyclization of 4‐(2‐Mercaptophenyl)‐Substituted 4H‐1,2,4‐Triazolium Species to Tricyclic Benzothiazolium Salts

AbstractHerein we report a generally applicable method for the preparation of N‐substituted benzo[4,5]thiazolo[2,3‐c][1,2,4]triazol‐1‐ium salts from air stable precursors. This transformation features selective deprotection of a para‐methoxybenzyl protected thiol followed by C−H functionalization of the linked 1,2,4‐triazolium salts under oxidative conditions. Using this procedure, we synthesized a variety of tricyclic thiazolium salts which contain both electron‐withdrawing and electron‐donating aromatic substituents as well as aliphatic substituents. Our approach also tolerates many functional groups including alkynes, alcohols, diols, amides, and polyethers.

Redox Chemistry of tris(β-diketonate)cobalt(III) Complexes: A Molecular View

Reduction of low spin S = 0 tris(β-diketonate)cobalt(III) complexes leads to an intermediate spin S = 3/2 anion. This electron rearrangement upon reduction could be the reason why a large peak potential difference between the reduction and re-oxidation peaks was observed during electrochemical analysis, using cyclic voltammetry. It is shown that experimental redox potentials obtained from the following methods, namely (i) polarography, (ii) cyclic voltammetry on a hanging Hg electrode, as well as (iii) cyclic voltammetry on a carbon fibre surface, related linearly to various empirical (Gordy scale group electronegativities, Hammett meta-substituent constants, pK a and the Lever electronic parameters) and density functional theory (DFT) calculated (LUMO energy, adiabatic electron affinity, chemical potential, global electrophilicity index and molecular electrostatic potential on Co) reactivity parameters. Deviations from these linear trends were due to a resonance effect of aromatic substituent groups. The linear relationships obtained for complexes containing aliphatic substituent groups can be used to predict redox potential and the electrophilic reactivity of related tris(β-diketonate)cobalt(III) complexes.

Multicomponent Synthesis of Biologically Relevant S‐Diarylmethane Dithiocarbamates Using p‐Quinone Methides

AbstractA metal and base‐free, operationally simple, and scalable multicomponent approach towards the synthesis of S‐diarylmethane dithiocarbamates is reported. A range of structurally and electronically diverse p‐quinone methides are shown to react with a variety of amines, and carbon disulfide to furnish corresponding dithiocarbamates in good to excellent yields under mild conditions. Furthermore, p‐QMs embedded with aliphatic substituents are well accommodated. Importantly, these readily accessible compounds demonstrated promising anti‐proliferative activity in the low micromolar ranges in lung adenocarcinoma cells, reiterating the importance of the developed methodology.magnified image

Fluorine‐Containing sp3‐Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents

AbstractEfficient approaches to the gram‐scale synthesis of fluorinated pyrazoles and pyrimidines bearing saturated (hetero)cyclic substituents are described. The methods rely on the heterocyclizations of sp3‐enriched β‐bromo‐α,α‐difluoroketones and fluorinated enaminones (in turn prepared from saturated heterocyclic α‐fluoroketones), respectively; these compounds themselves are useful synthetic intermediates that have been prepared on multigram scale for the first time. LogP and aqueous solubility measurements, as well as lead‐likeness assessment using the Nelson's LLAMA tool show that the 19 synthesized sp3‐enriched fluorinated building blocks meet the lead‐oriented synthesis criteria.

Energetic Materials Based on N-substituted 4(5)-nitro-1,2,3-triazoles.

The regularities and synthetic potentialities of the alkylation of 4(5)-nitro-1,2,3-triazole in basic media were explored, and new energetic ionic and nitrotriazole-based coordination compounds were synthesized in this study. The reaction had a general nature and ended with the formation of N1-, N2-, and N3-alkylation products, regardless of the conditions and reagent nature (alkyl- or aryl halides, alkyl nitrates, dialkyl sulfates). This reaction offers broad opportunities for expanding the variability of substituents on the nitrotriazole ring in the series of primary and secondary aliphatic, alicyclic, and aromatic substituents, which is undoubtedly crucial for solving the problems related to both high-energy materials development and medicinal chemistry when searching for new efficient bioactive compounds. An efficient methodology for the separation of regioisomeric N-alkyl(aryl)nitrotriazoles has been devised and relies on the difference in their basicity and reactivity during quaternization and complexation reactions. Based on the inaccessible N3-substitution products that exhibit a combination of properties of practical importance, a series of energy-rich ionic systems and coordination compounds were synthesized that are gaining ever-increasing interest for the chemistry of energy-efficient materials, coordination chemistry, and chemistry of ionic liquids.

Characterization Techniques Coupled with Mathematical Tools for Deepening Asphaltene Structure

Asphaltenes are the heavy fraction of fossil fuels, whose characterization remains a very difficult and challenging issue due to the still-persisting uncertainties about their structure and/or composition and molecular weight. Asphaltene components are highly condensed aromatic molecules having some heteroatoms and aliphatic functionalities. Their molecular weights distribution spans in a wide range, from hundreds to millions of mass units, depending on the diagnostic used, which is mainly due to the occurrence of self-aggregation. In the present work, mass spectrometry along with size exclusion chromatography and X-ray diffraction analysis have been applied to asphaltenes for giving some further insights into their molecular weight distribution and structural characteristics. Relatively small polycyclic aromatic hydrocarbons (PAHs) with a significant degree of aliphaticity were individuated by applying fast Fourier transform (FFT) and double bond equivalent (DBE) number analysis to the mass spectra. X-ray diffraction (XRD) confirmed some aliphaticity, showing peaks specific of aliphatic functionalities. Size exclusion chromatography indicated higher molecular weight, probably due to the aliphatic substituents. Mass spectrometry at high laser power enabled observing a downward shift of molecular masses corresponding to the loss of about 10 carbon atoms, suggesting the occurrence of aryl-linked core structures assumed to feature asphaltenes along with island and archipelago structures.

Catalytic 1,3‐H Atom Shift of a Terminal Benzylic Alkyne by Iron and Alkali Metal Silylamides – Switching between Allene and Internal Alkyne

Herein the examination of the transformation of alkynes by low-coordinate iron silylamides is presented. An anionic linear iron(I) silylamides ([Fe(N{Dipp}SiR3)2]−; Dipp=2,6-di-iso-propylphenyl, R=Me) acts as precatalyst for the cyclotrimerization of diphenyl acetylene but is unable to transform internal alkynes with aliphatic substituents or terminal alkynes accordingly. For a benzylic, terminal alkyne, however, the 1,3-H-shift to the internal alkyne is observed and proceeds via phenyl allene. Using 10 mol% of the iron complex, the terminal alkene is selectively transformed to phenyl allene within minutes, and further fully transformed to the internal alkyne within 24 h. The transformation is retraced on a stoichiometric level and leads to the isolation of a π-alkyne complex with a shifted triple bond. Further, the anionic, trigonal iron(II) silylamide [Fe(NR2)3]− also mediates the catalytic conversion of the terminal alkyne but is restricted to allene formation. Overall, a deprotonation/reprotonation mechanism is assumed for these transformations. This was ultimately proven by using potassium hexamethyldisilazanide KNR2, which is an even more active catalyst for the complete triple bond shift.

Rapid access to t-butylalkylated olefins enabled by Ni-catalyzed intermolecular regio- and trans-selective cross-electrophile t-butylalkylation of alkynes.

Among the carbo-difunctionalization of alkynes, the stereoselective dialkylation of alkynes is the most challenging transformation due to associated competitive side reactions and thus remains underdeveloped. Herein, we report the first Ni-catalyzed regio- and trans-selective cross-dialkylation of alkynes with two distinct alkyl bromides to afford olefins with two aliphatic substituents. The reductive conditions circumvent the use of organometallic reagents, enabling the cross-dialkylation process to occur at room temperature from two different alkyl bromides. This operationally simple protocol provides a straightforward and practical access to a wide range of stereodefined dialkylated olefins with broad functional group tolerance from easily available starting materials.

2-Substituted perimidines: Zwitterionic tauterism in solid state, substituent effect on their crystal packing and biological activity

Structural and electronic properties of five 2-substituted 1H-perimidines: 3-(1H-perimidin-2-yl)propanoic acid (SPm), (Z)-3-(1H-perimidin-2-yl)acrylic acid) (MPm), (Z)-3-(1H-perimidin-2-yl)but-2-enoic acid (CPm-1), (Z)-2-methyl-3-(1H-perimidin-2-yl)acrylic acid (CPm-2) and 2-((1H-perimidin-2-yl)methyl)acrylic acid (IPm) have been studied. All perimidines bear aliphatic acidic substituents at 2-position andare distinguished by a carbon-carbon double bond in the substituents. The crystallographic X-ray diffraction analysis revealed that they exist in the solid state as zwitterions. Primary screening of 2-substituted 1H-perimidines against different cancer cell lines were also realized. The results obtained are discussed in terms of the structure-property relationships and compared with density functional theory calculations. Additionally, the effect of inclusion of water molecules in the crystal lattice on the molecular packing is analyzed.

Postdiagenetic Bacterial Transformation of Nickel and Vanadyl Sedimentary Porphyrins of Organic-Rich Shale Rock (Fore-Sudetic Monocline, Poland).

Nickel and vanadyl porphyrins belong to the so-called fossil geo- or sedimentary porphyrins. They occur in different types of organic matter-rich sediments but mostly occur in crude oils and their source rocks, oil shales, coals, and oil sands. In this study, we aimed to understand the process of bacterial transformation of geoporphyrins occurring in the subsurface shale rock (Fore-Sudetic Monocline, SW Poland). We studied these transformations in rock samples directly obtained from the field; in rock samples treated with bacterial strain isolated from shale rock (strain LM27) in the laboratory; and using synthetic nickel and vanadyl porphyrins treated with LM27. Our results demonstrate the following: (i) cleavage and/or degradation of aliphatic and aromatic substituents of porphyrins; (ii) degradation of porphyrin (tetrapyrrole) ring; (iii) formation of organic compounds containing 1, 2, or 3 pyrrole rings; (iv) formation of nickel- or vanadium-containing organic compounds; and (v) mobilization of nickel and vanadium. Our results also showed that the described bacterial processes change the composition and content of geoporphyrins, composition of extractable organic matter, as well as nickel and vanadium content in shale rock.