Methyl Substituents Research Articles

Sterically Hindered Derivatives of Pentacene and Octafluoropentacene.

6,13-Diethynylpentacene derivatives with sterically bulky substituents (Tr*, tris(3,5-di-tert-butylphenyl)methyl groups) appended to the ethynyl moieties at the 6- and 13-positions have been synthesized, as well as derivatives with electron-withdrawing fluorine groups on the 1,2,3,4,8,9,10,11-positions. These molecules are designed to investigate relationships between steric and electronic effects on the stability of pentacene toward endoperoxide formation via reaction with photosensitized oxygen in solution under ambient light (i. e., 'laboratory' conditions). It is evident from the study that stabilization through changes to the electronic characteristics of pentacene are more effective than the incorporation of sterically bulky groups at the acetylenic termini. Selected pentacene derivatives have been made into binary, amorphous films with the fullerene derivative PCBM to investigate the stability imparted by substituents against cycloaddition reactions. Overall, the introduction of steric protection through the incorporation of Tr* groups is not an efficient strategy for enhancing the persistence of pentacenes. Stabilization through fluorination proves successful for extending the lifetime of the pentacene derivatives by an order of magnitude in solution. Notably, the persistence of pentacene derivatives in solution can also be enhanced through the use of ethereal solvents stabilized with butylated hydroxy toluene (BHT) and/or an increased number of trialkylsilyl groups as substituents.

Designing ferrocenyl thiophene chalcones as light harvester candidates for dye-sensitized solar cells

In dye-sensitized solar cells (DSSCs), the dye (or photosensitizer) plays a crucial role. It absorbs light and generates electrons, which affects the efficiency of converting sunlight into electricity. While Ru(II)-based dyes are common in DSSCs, their scarcity, susceptibility to degradation, and limited absorption range pose challenges for wider adoption. Three new ferrocenyl-thiophene compounds have been synthesized, all sharing the same core structure, but the distinctive difference is the existence of methyl group (CH3) and bromine (Br) substituents attached to the thiophene ring. Using the structures obtained from spectroscopic and X-ray crystallography analyzes, the chemical reactivity of these compounds is theoretically evaluated. Cyclic voltammetry (CV) analysis and electrochemical impedance spectroscopy (EIS) were employed to investigate the redox properties and electron transport mechanisms of the material. The bromination process demonstrates its efficacy for dye applications, while the methyl attachment to the thiophene ring enhances anchoring toward TiO₂, contributing to improved performance in DSSCs. Overall, the compound featuring bromine exhibited a lower band gap compared to the others, resulting in higher efficiency in solar simulation analysis, nearly double that of the methyl-containing compound, and significantly surpassing the plain thiophene compound. EIS analysis revealed that, among the three ferrocenyl chalcone dyes, the bromine-containing compound exhibited the highest charge recombination resistance and longest electron lifetime.

A UV-Vis method for investigation of gallium(III) complexation kinetics with NOTA and TRAP chelators: advantages, limitations and comparison with radiolabelling.

An easy and cheap method for measurement of GaIII complexation kinetics was developed. The method is based on UV-Vis quantification of non-complexed chelators after the addition of CuII ions at individual time points. The method was evaluated using established ligands, H3nota and H6notPPr, and was utilized to study the kinetics of GaIII complexation with four new symmetric derivatives of 1,4,7-triazacyclononane bearing methylphosphonate/phosphinate pendant arms - TRAP ligands. Chelators bearing ethoxy groups (H3L1) or 2,2,2-trifluoroethyl groups (H3L2) on the phosphorus atoms showed fast formation (t99% = 21 and 10 min, respectively, at pH 2.0) and efficient radiolabelling which were comparable to the previously reported chelators bearing the 2-carboxyethyl group (H6notPPr). Chelators bearing (N,N-dibenzyl-amino)methyl (H3L3) and aminomethyl (H3L4) substituents showed a significantly slower complexation (t99% = 4.4 and 3.6 h, respectively, at pH 2.0) and inefficient radiolabelling, mainly at room temperature or low pH. This was caused by protonation of the amino groups of the pendant arms leading to coulombic repulsion between the GaIII ion and the positively charged protonated amines. The trends in complexation rates determined by the UV-Vis method correlated well with the results of the 68Ga radiolabelling study.

1,4-Naphthoquinone thiazoles: Synthesis, crystal structure, anti-proliferative activity, and inverse molecular docking study

In this study, 1,4-naphthoquinone thiazole hybrids were synthesized by reacting 1,4-naphthoquinone thioureas with various α-bromoketones in 78–86 % yields and characterized using 1H NMR, 13C NMR, FT-IR, and HRMS techniques. Furthermore, single crystal x-ray diffraction studies were also performed for 3b and 3c hybrids to determine stereochemistry. Density Functional Theory (DFT) calculations were performed to obtain additional information and to support the x-ray studies. The in vitro anti-proliferative activities of 1,4-naphthoquinone thiazoles were investigated against PC3 human prostate cancer cells. The products 3a–h showed anti-proliferative activity against PC3 cells, and the cell viability studies showed that the IC50 values of compounds 3f and 3e were 20.10 µM and 21.14 µM, respectively, while the other compounds exhibited lesser cytotoxic effects than the former two. Potential target underlying the mechanism of action of the synthesized compounds against prostate cancer was identified using inverse (reverse) docking method. Molecular dynamics simulation was also conducted to confirm the stability of the 3f/enzyme system. It was determined that the solubility in ethanol was better for compounds bearing methyl substituent on X1 location than compounds containing tert‑butyl on the same location. Compounds with F atom on X2 position were more soluble than the others in the corresponding groups.

Herbidomicins, two pairs of polyketide tautomers produced by an actinomycete of the genus Herbidospora.

Herbidospora is one of the underexplored actinomycete genera from which only a limited number of secondary metabolites are reported. In our continuing investigation on less explored actinomycetes, a liquid culture of Herbidospora sp. RD 11066 was found to contain unknown metabolites that had no match in our in-house UV database. Chromatographic separation and following structural analysis using NMR and MS identified these metabolites to be chromanone and chromene derivatives, which were respectively composed of an inseparable mixture of two isomeric forms. The former polyketides, designated to be herbidomicins A1 (1) and A2 (2), are positional isomers in terms of a methyl substituent on an aromatic ring that mutually interconvert by acetal exchange by two phenolic hydroxy groups. The latter pair, herbidomicins B1 (3) and B2 (4), is Z/E-isomers regarding an enol ether double bond. Herbidomicins 1-4 were weakly antifungal against a dermatophytic fungus Trichophyton rubrum and were moderately cytotoxic against murine leukemia P388 cells.

Synthesis and Analysis of (γ,γ',γ''-Trifluoro)neopentyl (TFNP) Aryl Ethers as a Polar Fluoroaliphatic Motif.

A route is developed to (γ,γ',γ'''-trifluoro)neopentyl (TFNP) aryl ethers to extend the methods for the introduction of the tert-butyl group, carrying a fluorine on each of the methyl substituents. The route combines neopentyltosylate 3 with phenols and thiophenols to give efficient substitution reactions to the corresponding TFNP aryl ethers. The three C-F bonds adopt a helical propeller conformation as revealed by computation and single crystal X-ray structure analysis. The LogPs of TFNP ethers are lower (more hydrophilic) than their neopentyl analogues. The metabolism of selected TFNP ethers was explored in the fungus Cunninghamella elegans.

Spirocyclic pyrrolidinyl nitroxides with exo-methylene substituents.

Nitroxides are stable organic radicals with exceptionally long lifetimes, which render them uniquely suitable as observable probes or polarising agents for spectroscopic investigation of biomolecular structure and dynamics. Radical-based probes for biological applications are ideally characterized by both robustness towards reductive degradation and beneficial electron spin relaxation parameters. These properties are largely influenced by the molecular structure of the nitroxide scaffold, and also by the conformations it prefers to adopt. In this study we present the synthesis of the first nitroxides based on a spirocyclic pyrrolidine scaffold with an exocyclic methylene substituent. The conformations adopted by these nitroxides were evaluated by X-ray crystallography, both with single nitroxide crystals and by inclusion of nitroxides in a microporous crystalline sponge. The kinetic and thermodynamic stability of the new nitroxides towards reduction was investigated by electron paramagnetic resonance (EPR) spectroscopy and cyclic voltammetry (CV). In combination with EPR measurements of electron spin relaxation properties, these results suggest that this new family of nitroxides can provide access to multifunctionalized probes and polarising agents suitable for use in biological environments at elevated temperatures.

Chiral Azepines: In silico Potential in Cancer and Neurodegenerative Diseases, a Chemical Analysis

Background: Chiral azepines are synthesized with remarkable diastereoselectivity, but their biological activity has not been investigated. However, benzazepines have demonstrated notable effects, particularly on the central nervous system (CNS) and infections. This characteristic attracts the interest of bioinformatic investigations in this new family, as their structural similarity can confirm their potential based on their kinship or discovering new options for biological potential. Objective: Possible interaction targets of previously synthesized chiral azepines are investigated. This study involves examining the interaction between these targets, conducting molecular docking analysis, ADME (administration, distribution, metabolism, excretion), and toxicology prediction to assess biological potential. Methods: Modeling 3D-optimized structural, virtual screening, molecular docking, ADME, and toxicological studies were performed. Results: Structural analysis demonstrated potential against neurodegenerative diseases and cancer. In Molecular docking against cancer, pathways dependent on MAP2K1 and COX-2 exhibited energetically superior inhibitors than reference drugs, namely azepines 1, 3, and 6. Additionally, azepines 1 and 8 exhibited selective impacts against GSK3 and HMG-CoA-Reductase, respectively. Azepine 6 demonstrated an effect on CNS vs. GSK3 and HMG-CoA-Reductase, as well as potential against Alzheimer's disease; however, with a lower energy level with subunit 33 GABA-receptor. ADMETx investigations indicated satisfactory results for azepines. However, the opening of the cycle results in adverse effects and increased bioaccumulation, indicating the importance of preserving the integrity of azepine to propose its biological effect. Conclusion: Chiral azepines exhibit significant biological potential, particularly azepine 6 with a methyl substituent, which demonstrates multitarget potential. In addition, p-nitro phenyl substituent makes it highly selective towards CNS diseases. These findings indicate a strong relationship between biological activity and the stability of chiral azepines.

η6-Arene Ru(II) Complexes as Modulators of Amyloid Aggregation.

Inorganic medicinal compounds represent a unique and versatile source of potential therapeutics in many diseases and, more recently, in neurodegeneration. Herein we investigated the effects of two η6-arene Ru(II) complexes on the self-aggregation processes of several amyloidogenic peptides endowed with different kinetics and primary sequences. The Ru(II) complexes exhibit, around the metal ion, two chlorides, one NHC = N-heterocyclic carbene, with a glucosyl and a methyl substituent and separately a hexamethylbenzene, which is named Ru1, and one benzene, named Ru2. Both complexes were demonstrated to bind monomeric amyloids suppressing aggregation as evidenced in thioflavin T (ThT) binding assays and autofluorescence experiments. Electrospray ionization mass spectrometry (ESI-MS) indicated the formation of direct adducts between amyloid and metal complexes, which determined the marked conformational variation of peptides and a rescue of cellular viability in SH-SY5Y cells. The complex Ru2 was demonstrated to be a more potent inhibitor of amyloid aggregation compared to Ru1 likely because of the less hindrance of the arene moiety. The presented data strongly support the in vitro ability of η6-arene Ru(II) complexes to suppress amyloid aggregation, providing insights into their potential application as novel therapeutics in neurodegenerative diseases.

Magnesium(II) Porphyrazine with Thiophenylmethylene Groups-Synthesis, Electrochemical Characterization, UV-Visible Titration with Palladium Ions, and Density Functional Theory Calculations.

The presented studies aimed to evaluate the peripheral coordinating properties of a novel porphyrinoid family representative preceded by its synthesis for potential sensing purposes. Two synthetic pathways were employed to a obtain maleonitrile derivative, further used as a starting material in the cyclotetramerization reaction. In the first one, DAMN was used in sequential double-reductive alkylation with 2-thiophene-carboxyaldehyde and sodium borohydride. In the second, DAMN was used in a one-pot reaction with 2-thiophene-carboxyaldehyde in the presence of a 5-ethyl-2-methylpyridine borane complex in methanol and acetic acid. Following the Linstead approach, the cyclization reaction led to a novel symmetrical magnesium(II) octaaminoporphyrazine with methyl(2-thiophenylmethylene) substituents. The macrocycle's electrochemical properties were assessed by cyclic and differential pulse voltammetries revealing one reduction and two oxidation peak potentials. The additional spectroelectrochemical measurements showed formation of a cationic form of the macrocycle at an applied potential of 0.6 V. The coordinating properties due to the palladium ion of novel porphyrazines were measured with the use of titration combined with UV-vis spectrometry. The titration of Pd2+ revealed the good sensing activity of porphyrazine in the range of 0.1 to 5 palladium molar equivalents. In addition, Pd2+ ions coordination was also assessed by electrochemical studies, indicating the peak potential shift of 0.1 V in the presence of metal cations. DFT calculations showed the good agreement between theoretical and experimental data in the UV-vis and 1H NMR studies.

Pyridyl-Substituted Nitronyl Nitroxides: Comprehensive Magnetochemical and Quantum Chemical Study.

A series of pyridyl-substituted nitronyl nitroxides was synthesized and structurally characterized. A comprehensive magnetochemical and quantum chemical study of extended raw of the nitroxides with different substituents R in the pyridine fragment was performed. It was shown, that temperature-dependent magnetic properties are determined by the short contacts between nitroxide groups of adjacent molecules as well as between nitroxide group and methyl substituents in the pseudo axial positions of imidazoline fragments. Quantum chemistry allows to select the appropriate model of exchange cluster for analysis of experimental magnetic data and evaluation of the exchange interaction parameters. For NN-PyCl the "order-disorder" transition was detected by means of low temperature XRD. The difference in the experimental and calculated exchange interaction energies may serve as an indicator of temperature-induced structural rearrangements. For instance, for methyl substituted nitronyl nitroxide NN-PyMe structural transformations and significant changes in exchange interaction energies were observed.

Selective Synthesis of Deuterated cis- and trans-Isohumulones and trans-Isohumulinones

AbstractDeuterated isohumulones can be prepared directly from humulones by an acyloin ring contraction under either magnesium-catalyzed basic conditions or by photochemical-induced reactions in deuterated solvents. Reactions of humulones with biphasic methylene chloride/aqueous NaOD and MgSO4 in D2O leads to stereoselective formation of cis-d 3-isohumulones (cis/trans ratio of 82:18) as the magnesium salts in yields of 71–83%. Greater than 95% incorporation of three deuterons is observed at the C5 position of the pentenone ring and the methylene position of the C4 acyl group. Photochemical isomerization with a 400 nm blue LED source enables stereospecific formation of deuterated trans-isohumulones in 36–82% yield with greater than 95% incorporation of deuterium at the C5 ring position. Oxidation of humulones with cumene hydroperoxide in basic D2O gives isohumulinones with partial 55–73% incorporation of deuterium due to keto–enol isomerization of the methylene substituent of the C4 acyl group. The structural identities of the deuterated products are determined by a combination of negative-mode electrospray mass spectrometry (MS-ESI–) and 2D heteronuclear proton–carbon HMQC NMR analysis.

How Do the Position and Number of Methyl Substituents Affect the Photochemical Process of Criegee Intermediate? Trajectory Surface-Hopping Dynamics of Four-Carbon CIs.

Electronic-structure calculations combined with nonadiabatic trajectory surface-hopping (TSH) dynamic simulations were carried out on two alkenyl-substituted Criegee intermediates (CIs), i.e., propenyl-substituted CI (PCI) and 1-methyl-propenyl substituted CI (MPCI), in order to investigate the influence of the position and number of substituents on the photochemical process of CI in S1 states. It is found that they play critical roles in the reactivity, dominant product channel, and mechanism of the CIs. More specifically, introducing a methyl group on either C1 (α-C) or C3 (γ-C) position of a vinyl-substituted CI (VCI) skeleton facilitates the rotation of the C1═O1 bond and leads to the formation of a three-membered dioxirane ring; meanwhile, it evidently enhances the reactively of the S1-state molecule. Meanwhile, methyl substitution on the vinyl moiety [i.e., C2 (β-C) and C3 (γ-C) positions] is beneficial for the rotation of the C2═C3 bond and thus facilitates the formation of the five-membered 1,2-dioxole ring, and the substitution on C2 site decreases the reactivity. The cosubstitution of C2 and C3 atoms by methyl groups well balances the features of VCI in the sense of high reactivity, consistently predominant channel, and possible dioxole side-product. The findings here not only deepen the knowledge on the photochemical processes of the CI but also inspire the rethinking of the "old" concept of substitution effect.

Innovative application of CRISPR for eliminating Ustiloxin in Cordyceps militaris: Enhancing food safety and quality

Cordyceps militaris (L.) Fr. Has long been recognized as a valuable functional food consumed in numerous countries. However, biosynthetic gene clusters of this species and safety regarding mycotoxin production remain largely unexplored. In this study, a ribosomally synthesized and post-translationally modified peptide (RiPP) cluster responsible for the production of cyclopeptide mycotoxins in Cordyceps was unveiled via genome mining. Ustiloxin B and a novel, predominant and Cordyceps specific ustiloxin I were confirmed by extraction and structural analysis. The difference between Ustiloxins I and B lied in the side chain at C19, where an additional methyl substituent in Ustiloxin I resulted in an alanine moiety substitution for glycine of Ustiloxin B. The simultaneous deletion of the two adjacent core genes, CmustYb and CmustYa, using a single guide RNA designed in the intergenic region, and subsequent in-situ complementation via AMA-mediated CRISPR/Cas9 system confirmed the RiPP cluster's responsibility for ustiloxin production. The cultivation of the edited strain yielded ustiloxin-free fruiting bodies without affecting agronomic characters. PCR and genome resequencing confirmed the absence of any off-target events or foreign sequence remnants. This study marks a significant advancement in utilizing CRISPR technology to control ustiloxins in food, underscoring its broader implications for food safety and quality improvement.

Synthesis of four-ring unsymmetrical bent-core mesogens and cybotactic cluster formation in their nematic phase

The synthesis and characterization of novel achiral unsymmetrical four-ring bent-core molecules resembling a hockey-stick shape are described. The present compounds bearing a methyl substituent in the central phenyl ring exhibit the skewed cybotactic nematic (NcybC), smectic C (SmC) and additional tilted smectic phase with tilted molecular arrangement. The skewed cybotactic nematic phase is formed by the bent-core molecules with long range orientational ordered clusters possessing local smectic C type order and within a cluster of tilted molecular assembly. The previously reported four-ring compounds without the methyl moiety did not exhibit nematic phase but show polarization modulated B1revtilt phase. The x-ray diffraction pattern clearly indicated the existence of SmC-type cybotactic clusters over a wide N temperature range; the layer reflection peak is weak at a higher temperature region and becomes more conspicuous with decreasing temperature. The lower temperature phase is distinctly the SmC phase, and in addition another tilted smectic phase emerges below SmC.

Effect of substituents at the C3´, C3´N, C10 and C2-meta-benzoate positions of taxane derivatives on their activity against resistant cancer cells

We tested the effect of substituents at the (1) C3´, C3´N, (2) C10, and (3) C2-meta-benzoate positions of taxane derivatives on their activity against sensitive versus counterpart paclitaxel-resistant breast (MCF-7) and ovarian (SK-OV-3) cancer cells. We found that (1) non-aromatic groups at both C3´ and C3´N positions, when compared with phenyl groups at the same positions of a taxane derivative, significantly reduced the resistance of ABCB1 expressing MCF-7/PacR and SK-OV-3/PacR cancer cells. This is, at least in the case of the SB-T-1216 series, accompanied by an ineffective decrease of intracellular levels in MCF-7/PacR cells. The low binding affinity of SB-T-1216 in the ABCB1 binding cavity can elucidate these effects. (2) Cyclopropanecarbonyl group at the C10 position, when compared with the H atom, seems to increase the potency and capability of the derivative in overcoming paclitaxel resistance in both models. (3) Derivatives with fluorine and methyl substituents at the C2-meta-benzoate position were variously potent against sensitive and resistant cancer cells. All C2 derivatives were less capable of overcoming acquired resistance to paclitaxel in vitro than non-substituted analogs. Notably, fluorine derivatives SB-T-121205 and 121,206 were more potent against sensitive and resistant SK-OV-3 cells, and derivatives SB-T-121405 and 121,406 were more potent against sensitive and resistant MCF-7 cells. (4) The various structure-activity relationships of SB-T derivatives observed in two cell line models known to express ABCB1 favor their complex interaction not based solely on ABCB1.

Enhancing color brilliance and fastness of polyester dyeing with antipyrine-derived disperse dyes

Disperse azo dyes are important colorants for dyeing polyester fabrics, but developing optimized disperse azo dyes remains a challenge. This work details the synthesis of seven new disperse azo dyes 3a-g derived from the coupling reaction of 4-aminoantipyrine diazonium salt with various phenolic precursors including phenol (3a), salicylic acid (3b), salicylaldehyde (3c), cresols (3d-f), and resorcinol (3g). The dyes were characterized by spectroscopic techniques. Their UV–visible absorption spectra were studied, revealing bathochromic shifts for 3d-g containing electron-donating methyl and hydroxyl substituents compared to parent dye 3a while dyes 3b-c showed hypsochromic shifts. The impact of acid and base on the absorption spectra indicates azo-hydrazone tautomerism for 3f-g but predominant azo form for 3a-e. The dyes showed excellent dyeing on polyester fabrics with up to 97.86 % dye exhaustion. High wash, light and perspiration fastness was exhibited while fastness to respiration varied. The strongest color yield on polyester was achieved with 3g derived from resorcinol coupler. Density functional theory calculations were performed to elucidate relationships between substituent effects and spectral attributes. Lower energy gaps were computed for 3f-g, consistent with enhanced reactivity. This work expands disperse azo dye precursors while offering fundamental structure-performance insight to guide future design. The potent polyester coloration and good fastness properties warrant ongoing investigation of these dyes.

Isomer‐Dependent Melting Behavior of Low Molar Mass Azobenzene Derivatives: Observation of a Higher Melting Z‐Isomer

AbstractAzobenzene compounds are putative solar thermal fuels (STF) due to the excellent photostability and structural control of isomerization rates. Azobenzenes, in which both Z‐ and E‐isomers are liquid at room temperature, are promising candidates for STF flow technology. A literature survey of melting points led to the synthesis and isomer separation of ortho‐ and meta‐monosubstituted azobenzenes with fluoro, methyl, ethyl, trifluoromethyl and methoxy substituents and several dimethyl substituted azobenzenes. Four of the compounds are liquid azobenzenes with higher specific energy than literature work with higher molar mass, liquid compounds. Eight of the compounds unexpectedly displayed a higher melting point for the Z‐isomer which is rarely observed. Intermolecular close contacts in the crystal lattice of the Z‐isomer are the main factor responsible for the higher melting temperatures.

Sterically Crowded Gold Germylene Compounds with Methyl and Hydride Substituents

AbstractThis work explores the combination of sterically crowded low‐valent germanium compounds bearing one or two terphenyl (C6H3‐2,6‐Ar2) substituents with gold fragments, the latter stabilized by crowded phosphines also containing a terphenyl moiety. The steric protection of these motifs has allowed to examine a series of unusual gold‐germylene compounds featuring small hydride and methyl substituents at the germanium site. A gold‐germylene dicationic structure is also reported. The bonding in this series is investigated by computational means, providing understanding for the two‐way transfer of electrons from germanium to gold and vice versa.

Experimental Study for the Influence of Methyl Substituent's Position on Quinoline for Inhibition of Aluminium Corrosion in Hydrochloric Acid

Experimental Study for the Influence of Methyl Substituent's Position on Quinoline for Inhibition of Aluminium Corrosion in Hydrochloric Acid