Methylene Bridge Research Articles

Triel Bonds with Methyl Groups as Electron Donors. A Pentacoordinate Carbon Atom.

The triel bond (TrB) formed between Be(CH3)2/Mg(CH3)2 and TrX3 (Tr = B, Al, and Ga; X = H, F, Cl, Br, and I) is investigated via the MP2/aug-cc-pVTZ(PP) quantum chemical protocol. The C atoms of the methyl groups in M(CH3)2 are characterized by a negative electrostatic potential and act as an electron donor in a triel bond with the π-hole above the Tr atom of planar TrX3. The interaction energy spans a wide range between 2 and 69 kcal/mol. Mg(CH3)2 forms a stronger TrB than does Be(CH3)2, which comports with the more negative electrostatic potential on its methyl groups. Some of the complexes involving Mg display a high degree of transfer of the methyl group from Mg to Tr, which is accompanied by an inversion of the bridging methyl and a sizable pyramidalization of the TrX3 unit. The geometries of these complexes have the properties of the long sought pentacoordinate C which has eluded identification and characterization in the past.

Synthesis of π-Extended [1.1]Paracyclophanes, [1.1][n]PCP (n = 2, 3, and 4), and Their Through-space Conjugation.

[1.1][n]Paracyclophanes ([1.1][n]PCPs) (3) with n = 2, 3, and 4, which consist of two[n]paraphenylene units connected by methylene bridges, were synthesized using short synthetic pathways with good overall yields. Single-crystal X-ray diffraction analyses reveal that the paraphenylene unit in 3 is bent, resulting in an elliptic core structure of 3. The facing bridgehead carbons of the paraphenylene units are separated by a distance much shorter than the sum of the van der Waals radii of sp2-carbon atoms. UV-vis absorption spectra, fluorescence spectra, electrochemical measurements, and theoretical calculations were used to demonstrate the presence of through-space (TS) conjugation in 3. Furthermore, host-guest complex formation between 3D (n = 3) and tetracyanoquinodimethane in the solid state was revealed.

Inhibitory Effects of New Epicatechin Oligomers on Nitric Oxide Production.

The primary aim of this research was to identify the structural characteristics of three newly derived procyanidins from cold plasma-treated (-)-epicatechin, known for their anti-inflammatory properties. The newly generated compounds were isolated through column chromatography, and their chemical structures were elucidated through spectroscopic data analyses, including both one-dimensional and two-dimensional nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. Furthermore, their absolute configurations were determined via circular dichroism (CD) spectroscopy. The inhibitory activity of the isolated compounds on nitric oxide (NO) production and expression levels of inducible NO synthase (iNOS) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages was evaluated. Three new procyanidins-methylenetrisepicatechin (2), isomethylenetrisepicatechin (3), and methylenebisepicatechin (4)-along with two reported dimeric flavan-3-ols (5 and 6), were identified from plasma-treated (-)-epicatechin (1). The unique oligomerized products 2 and 3 linked by methylene bridges significantly suppressed both NO production and iNOS expression, demonstrating higher anti-inflammatory activities in LPS-stimulated RAW 264.7 cells compared with the parent compound. The newly oligomerized procyanidins have potential applications in the treatment of inflammatory diseases owing to their significant anti-inflammatory properties.

Copper(II) Complexes of Phenolate‐Bridged Dimeric Cyclam Ligands: Synthesis, Coordination and Electrochemical Study

AbstractBis(macrocyclic) complexes are investigated as artificial analogues of natural dinuclear metalloenzymes. Two ligands containing two cyclam rings connected through a p‐cresol or 4‐nitrophenol spacer were synthesized and their complexing properties were investigated. CuII complexes were prepared and their properties were studied by a combination of spectral, diffraction and electrochemical methods. The phenolate group is not or only weakly coordinated to the central CuII ion and the two macrocycles behave mostly as two independent complexing units. All the determined solid‐state structures showed cyclam adopting trans‐III geometry, however, solution study indicated the presence of more isomers in the solution whose abundance changes with pH. Electrochemical reduction of the complexes is irreversible and results in the reductive decomplexation to amalgamated Cu metal. The amalgamated metal is re‐oxidized to CuII during the anodic scan of CV and the metal ion is re‐coordinated. The ligand containing the nitro group shows an irreversible four‐electron reduction of the nitro group. The ligands and the complexes undergo also a slow degradation when incubated in the aqueous solutions for a prolonged time. The degradation relies on the “retro‐Mannich” cleavage of the methylene bridge connecting the cyclam ring with the phenol moiety.

Chimeras Derived from a P2Y14 Receptor Antagonist and UDP-Sugar Agonists for Potential Treatment of Inflammation.

Tethered glycoconjugates of a naphthalene- and piperidine-containing antagonist of the P2Y14 receptor (PPTN) were synthesized, and their nM receptor binding affinity was determined using a fluorescent tracer in hP2Y14R-expressing whole CHO cells. The rationale for preparing mono- and disaccharide conjugates of the antagonists was to explore the receptor binding site, which we know recognizes a glucose moiety on the native agonist (UDP-glucose), as well as enhance aqueous solubility and pharmacokinetics, including kidney excretion to potentially counteract sterile inflammation. Glycoconjugates with varied linker length, including PEG chains, were compared in hP2Y14R binding, suggesting that an optimal affinity (IC50, nM) in the piperidine series was achieved for triazolyl N-linked glucose conjugates having one (8a, MRS4872, 3.21) or two (7a, MRS4865, 2.40) methylene spacers. In comparison of different carbohydrate conjugates lacking a piperidine moiety but containing triazole spacers, optimal hP2Y14R affinity (IC50, nM) was achieved with N-linked glycosides of fucose 10f (6.19) and lactose 10h (1.88), and C-linked glucose 11a (5.30). Selected compounds were examined in mouse models of conditions known to be ameliorated by P2Y14R antagonists. Two glycoconjugates that lacked a piperidine moiety, N-linked glucose derivative 10a and the isomeric C-linked glucose derivative 11a, were protective in a mouse model of allergic asthma. Piperidine-containing glucose conjugate 7a of intermediate linker length and corresponding glucuronide 7b (MRS4866) protected against neuropathic pain. Thus, glycoconjugation of a known antagonist scaffold has produced less hydrophobic P2Y14R antagonists having substantial in vitro and in vivo activity.

Nitrogen-Oxidized Tröger's Base Macrocyclic Arenes: Unprecedented Enantioselective Recognition in Water.

Achieving high enantioselectivity with synthetic receptors, particularly in water, remains a significant challenge despite the success seen in natural biological systems. In this study, we introduce a facile synthesis of Tröger's base (TB)-containing macrocyclic arenes (TBn), where TB units are linked via methylene bridges, providing the macrocycles with a rigid framework. Oxidation of enantiopure TBn yields corresponding chiral nitrogen oxides (TBnNO) with excellent water solubility, attributed to the high polarity of the N-O bond, surpassing the pH limitations of traditional ion-functionalized approaches. Remarkably, TBnNO exhibits exceptional enantioselective recognition toward a wide range of chiral guests in aqueous solution, achieving enantioselectivities as high as 41.0. The underlying mechanism involves a combination of hydrophobic interactions and steric effects caused by rigid chiral cavities. These findings highlight the potential of nitrogen-oxidized macrocycles as a transformative tool for supramolecular application in water.

Nitrogen‐Oxidized Tröger's Base Macrocyclic Arenes: Unprecedented Enantioselective Recognition in Water

Achieving high enantioselectivity with synthetic receptors, particularly in water, remains a significant challenge despite the success seen in natural biological systems. In this study, we introduce a facile synthesis of Tröger's base (TB)‐containing macrocyclic arenes (TBn), where TB units are linked via methylene bridges, providing the macrocycles with a rigid framework. Oxidation of enantiopure TBn yields corresponding chiral nitrogen oxides (TBnNO) with excellent water solubility, attributed to the high polarity of the N‐O bond, surpassing the pH limitations of traditional ion‐functionalized approaches. Remarkably, TBnNO exhibits exceptional enantioselective recognition toward a wide range of chiral guests in aqueous solution, achieving enantioselectivities as high as 41.0. The underlying mechanism involves a combination of hydrophobic interactions and steric effects caused by rigid chiral cavities. These findings highlight the potential of nitrogen‐oxidized macrocycles as a transformative tool for supramolecular application in water.

Amine Exchange of Aminoalkylated Phenols as Dynamic Reaction in Benzoxazine/Amine-Based Vitrimers.

Bisfunctional benzoxazine and polyether diamine-based polymers show Arrhenius-like stress-relaxation varying with stoichiometry and polymerization temperatures proving vitrimeric behavior. Molecular structural investigations reveal the presence of different aminoalkylated phenols occurring at varying ratios depending on polymer composition and polymerization conditions. The vitrimeric mechanism is found to involve an amine exchange reaction of aminoalkylated phenols in an equilibrium reaction like a nucleophilic substitution reaction. As determined by molecular studies and dissolution experiments in reactive solvents, aliphatic and aromatic primary as well as aliphatic secondary amines in the polybenzoxazine structure can act as nucleophiles in reaction with electrophilic methylene bridges. Thus, aminoalkylated phenols proved to be a relevant structural motif resulting in a vitrimeric polybenzoxazine due to amine exchange reaction.

Delivery of N-heterocyclic drugs, acids, phenols, and thiols via Tailor−made Self−immolative linkers

Heterocyclic drugs display diverse pharmacological activities and metabolic stability. However, their poor solubility and pharmacokinetic properties often compromise bioavailability and clinical outcomes. Nevertheless, the prodrug approach provides a viable strategy to overcome unwanted attributes of drug candidates. In this proof-of-concept study, we report the synthesis and biological evaluation of glycol methylene-bridged phosphate (GMBP) prodrugs developed for heterocyclic drug delivery. Through methylene bridging, the heterocyclic nitrogen was directly attached to the phosphate, whereas the glycol moiety enabled drug release via cyclization, as confirmed by 31P NMR spectroscopy. Additional prodrugs of carboxylic acids, phenols, and thiols confirmed the broad application scope of our GMPB approach. Heterocyclic GMBP prodrugs were stable in aqueous buffers and activated by phospholipase CAL-B in vitro. Select prodrugs, including zidovudine prodrug 33, were even more potent (3 nM on HIV-1) than the parent compound. These findings demonstrate that our GMBP approach is not only feasible but also highly versatile.

Highly crosslinked resin prepares hard carbon anode for enhanced sodium storage performance and reduced cost

Resins have shown significant potential as a precursor for hard carbons (HCs) in sodium-ion batteries (SIBs) due to their high purity and adjustability. However, the high cost and low Na+ storage capacity limit their industrialization. Herein, the highly crosslinked resin is developed by linear phenolic resin crosslinking with inexpensive hexamethylenetetramine (HMTA) via the C-N and methylene bridges between phenolic rings, which can effectively reduce the resin consumption ratio by over 44% per unit mass and regulate the sodium storage performance of the prepared HC with a high reversible capacity of 323.9 mAh g-1 and an initial coulombic efficiency (ICE) of 90.7% at 15 mA g−1, where a high plateau capacity of 286.8 mAh g-1 is proved to be a coupled storage mechanism of intercalation and pore-filling behavior. Meanwhile, defects associated with hydrogen content, rather than nitrogen defects, are verified to be directly linked to slope capacity. Furthermore, the 18650 cylindrical-type batteries assembled with this HC anode coupled with NaFe1/3Ni1/3Mn1/3O2 cathode achieve a high energy density of about 280.9 Wh kg−1 and excellent capacity retention of 86.4% over 2500 cycles, providing a promising prospect for the practical application of the resin-based HC for SIBs.

Hydrogen Bond‐Assisted Macrocyclic Synthesis: An Extended Application For 4‐Hydroxybenzylamine Derivatives

AbstractThis work involved synthesizing three N‐benzyl‐4‐hydroxybenzylamines using indirect reductive amination of aromatic aldehydes and 4‐hydroxybenzylamine. Such benzylamines’ reaction with formaldehyde produced tricyclic azacyclophanes formed by two benzylamine units joined by methylene bridges. Computational calculations established that macrocyclization was promoted by template formation stabilized by hydrogen bonds and π‐stacking.

Recent Advances in Synthesis and Applications of Calixarene Derivatives Endowed with Anticancer Activity.

Calix[n]arenes, macrocycles constituted of 4-8 phenol moieties linked through methylene bridges, are stable molecules that can be selectively functionalised at the upper or lower rim. It has already been demonstrated that calixarene derivatives can be biologically or pharmacologically active compounds. More recently, suitably functionalised calixarenes and calixarene analogues (dihomooxacalixarenes, thiacalixarenes, calix[4]resorcinols, azacalixarenes, calixpyrroles, and pillarenes) were found to act as anticancer agents, at least in in vitro assays. We are reporting on the latest progress in this research field.

Applying pH Modulation to Improve the Thermal Stability of Melamine-Formaldehyde Microcapsules Containing Butyl Stearate as a Phase-Change Material.

This paper presents a two-stage microencapsulation process that uses pH modulation to enhance the thermal stability of microcapsules that consist of a melamine-formaldehyde (MF) shell and a butyl stearate core. In the first stage, the pH value was modulated between 6.0 and 8.0. Rising the pH value to 8.0 slowed the polycondensation rate, allowing the MF resin with a lower degree of polymerization to migrate to the capsule surface and form a smooth shell. Lowering the pH value to 6.0 accelerated polycondensation. In the second stage, a relatively fast, continuous reduction in the pH value to 5.0 led to further MF polycondensation, hardening the shell. Post-curing at 100 °C prevented shell damage caused by the liquid-gas phase transition of the core material during the process. The microcapsules produced by increasing the pH value to 8.0 twice demonstrated improved thermal stability, with only a minimal overall weight loss of 5% at 300 °C. Significant weight loss was observed between 350 and 400 °C, temperatures at which the methylene bridges in the MF shell undergo thermal degradation. The results from differential scanning calorimetry, electron microscopy, and thermogravimetry analyses confirmed a successful optimization of the microencapsulation, showing that these microcapsules are promising for thermal energy storage and other applications that require high thermal stability.

The Preparation and Crystal Structures of Octaoxoketocalix[8]arene Derivatives: The Ketocalixarene Counterparts of the Largest "Major" Calixarene.

The purpose of this study was to synthesize and structurally characterize ketocalixarenes (i.e., calixarenes where the bridging methylene bridges are replaced by carbonyl groups) derived from the largest "major" calixarene, namely p-tert-butylcalix[8]arene 3a. Ketocalix[8]arenes were synthesized by the oxidation of protected p-tert-butylcalix[8]arene derivatives. Octamethoxy-p-tert-butylketocalix[8]arene 6b was prepared by the photochemical reaction of the calixarene 3b with NBS in a CHCl3/H2O mixture. The oxidation of the methylene groups of octaacetoxy-p-tert-butylcalix[8]arene 3c was conducted by a reaction with CrO3 in Ac2O/AcOH. The basic hydrolysis of the acetate groups of the oxidation product yielded octahydroxy-p-tert-butylketocalix[8]arene 6a. In the crystal, the molecule adopts a saddle-like conformation of crystallographic C2 and idealized S4 symmetry. Strikingly, the array of OH/OH intramolecular hydrogen bonds present in the parent 3a is completely disrupted in 6a.

Derivatives of (5-Oxooxazolidin-4-yl)acetic acids in aspartic acid α-carboxyl protection: a word of caution

Isomeric products could be isolated in a reaction of pentafluorophenyl ester of (S)-2-(3-((benzyloxy)-carbonyl)-5-oxooxazolidin-4-yl)acetic acid with aminoacid esters. One product is an expected dipeptide, the isomeric one is an N-hydroxymethylamino succinimide – a product of methylene bridge cleavavge. Steric bulkness of aminoacid esters favors the formation of a peptide, however the reaction selectivity is quite unpredicatable. Moreover, the precise structure assignement requires high-temperature NMR experiments.

Synthesis of spinnable isotropic pitch from low-softening-point coal tar pitch via Blanc bromomethylation-dehydrobromination towards carbon fibers with enhanced mechanical properties

Blanc bromomethylation-dehydrobromination is proposed to synthesize isotropic pitches with superior spinnability, utilizing refined coal tar pitch as the feedstock. This strategy involves introducing bromomethyl functional groups into pitch molecules through the Blanc bromomethylation reaction. In the subsequent process of dehydrobromination, methylene bridges generate between neighboring aromatic molecules. The pitch precursor prepared by this method not only displays an increased level of oligomerization and pitch yield, but also exhibits a more linear molecular structure compared with that produced through purely thermal polycondensation. The enhanced linear molecular configuration contributes to the improved spinnability of the pitch precursor and the oxidation reactivity of its derived fiber. Furthermore, the tensile strength of the resulting carbon fibers rises with an elevation in the amount of polyoxymethylene, and it exhibits the trend of an initial growth followed by a subsequent decrease as the stabilization temperature escalates. The carbon fibers obtained from the pitch prepared through thermal polycondensation present a low Young’s modulus of 24 GPa and a low tensile strength measuring of 456 MPa. In contrast, carbon fibers derived from the pitch synthesized via Blanc bromomethylation-dehydrobromination exhibit superior mechanical performance, offering Young’s modulus and tensile strength of 58 GPa and 1210 MPa, separately.

Chemical changes in thermally modified, acetylated and melamine formaldehyde resin impregnated beech wood

Abstract Wood modification (by thermal or chemical treatment) helps to improve the dimensional stability of wood and enhance its resistance to biological agents. Beech wood is non-durable and exposure in exterior settings dramatically shortens its service life. To determine the full potential of beech wood for advanced applications, a better understanding of the chemical changes induced by modification is needed. Two chemical treatments (acetylation and melamine formaldehyde resin impregnation) and three thermal treatments (heating to 180, 200 and 220 °C) were performed on beech wood. The modification effect was examined based on (i) molecular changes in functional groups by Fourier-transform infrared spectroscopy (ATR-FTIR); (ii) extractive content; and (iii) pH changes. Moreover, the explanation of these changes was supported by the FTIR-analysis of isolated main wood components (cellulose, holocellulose and lignin) from the modified wood. The high temperatures applied to samples during thermal modification promoted the deacetylation and degradation of hemicelluloses. Hemicelluloses were targeted also by acetic anhydride and melamine resin, the bonding of which was confirmed by FTIR analysis. The formation of fewer methylene bridges affected the properties of the melamine network. This observation suggests the need to determine optimal curing conditions in future research, to reduce melamine-wood hydrophilicity.

Synthesis of Novel Benazepril-Derived Trizole Compounds Assisted by Ultrasound: In Vitro and In Silico Analysis for Potential Anticancer Properties.

Benazepril-based novel trizole derivatives are being explored as potential anticancer agents, designed with an N-substituted 1,2,3-triazole moiety linked to Benazepril's N-1 position via a methylene bridge. An ultrasound irradiated CuAAC method was used to prepare all these compounds and evaluated their anti-proliferative activities against cancer and drug-resistant cell lines. While some of these compounds demonstrated anti-proliferative activity towards leukemic cancer cell line K562, two of them displayed complete inhibitory activity. Interestingly, the compounds 5n and 5o showed potent activity against imatinib-resistant cell lines suggesting their promise to overcome cancer drug resistance. Furthermore, molecular docking analysis revealed that compounds 5n and 5o have higher predicted sensitivity towards ACE protein when compared to benazepril and lisinopril indicating their value as potential drug lead molecules. This research introduces a distinctive approach by employing ultrasound to facilitate CuAAC reactions in medicinal chemistry.

Insights into the production and evolution of lantibiotics from a computational analysis of peptides associated with the lanthipeptide cyclase domain.

Lanthipeptides are a large group of ribosomally encoded peptides cyclized by thioether and methylene bridges, which include the lantibiotics, lanthipeptides with antimicrobial activity. There are over 100 experimentally characterized lanthipeptides, with at least 25 distinct cyclization bridging patterns. We set out to understand the evolutionary dynamics and diversity of lanthipeptides. We identified 977 peptides in 2785 bacterial genomes from short open-reading frames encoding lanthipeptide modifiable amino acids (C, S and T) that lay chromosomally adjacent to genes encoding proteins containing the cyclase domain. These appeared to be synthesized by both known and novel enzymatic combinations. Our predictor of bridging topology suggested 36 novel-predicted topologies, including a single-cysteine topology seen in 179 lanthionine or labionin containing peptides, which were enriched for histidine. Evidence that supported the relevance of the single-cysteine containing lanthipeptide precursors included the presence of the labionin motif among single cysteine peptides that clustered with labionin-associated synthetase domains, and the leader features of experimentally defined lanthipeptides that were shared with single cysteine predictions. Evolutionary rate variation among peptide subfamilies suggests that selection pressures for functional change differ among subfamilies. Lanthipeptides that have recently evolved specific novel features may represent a richer source of potential novel antimicrobials, since their target species may have had less time to evolve resistance.

Optimizing light and heavy aromatic ratios in fluid catalytic cracking slurry oil for mesophase pitch with wide-area optically anisotropic texture

Aromatics are the preponderant component of fluid catalytic cracking (FCC) slurry oil, with notable differences in molecular structure between the light and heavy aromatics. The effect of these differences on the formation and optically anisotropic texture of mesophase remains elusive, impeding the preparation of high-quality mesophase pitch. This paper aims to regulate the ratio of light to heavy aromatics in the FCC slurry oil for optimizing the optically anisotropic texture of mesophase pitch. The results show that the heavy aromatics possess higher aromaticity, longer alkane side chains, larger molecular size and more reactive structures (methylene bridges, n-alkane structures) compared with the light aromatics. As an “accelerator”, heavy aromatics can form mesophase quickly. Light aromatics not only served as a “diluent,” but also assumed the function of a “lubricant”, which facilitated the orderly arrangement of aromatic molecular lamellar. The system exhibits moderate reactivity that inhibits excessive condensation and modifies the structural orientation of pyrolysis products with the 2/5 ratio of light to heavy aromatics. Under these conditions, a high-quality mesophase pitch (d002 = 3.485 Å, Lc = 19.832 Å) with wide-area optically anisotropic texture, suitable softening point (262 °C) and short polymerization time (t = 5.5 h) was obtained. This work provides theoretical support for the preparation of high-quality mesophase pitch by regulating the components of slurry oil.