Benzyl Group Research Articles

Copper-Catalyzed Hydrodifluoroalkylation of N-benzylacrylamides via Intramolecular 1,4-Hydrogen Atom Transfer: Reaction Development and Mechanistic Insights.

A one-pot protocol for Cu(I)-catalyzed hydrodifluoroalkylation of benzyl-protected acrylamides to construct difluoropentanedioate compounds in moderate to excellent yields has been achieved by using the benzyl group as a traceless redox-active hydrogen donor. The mechanistic studies confirmed that the reaction proceeds by adding a difluoroalkyl radical to acrylamide, followed by unexpected intramolecular 1,4-hydrogen atom transfer (HAT) and SET oxidation reaction. DFT calculations demonstrate that the destabilizing steric repulsion is the key factor controlling the chemoselectivity, which switches from 1,4-HAT to 5-exo spirocyclization. This work provides an important basis for the 1,4-HAT reaction in theoretical and practical synthesis applications.

Electrospun Hyaluronan Nanofiber Membrane Immobilizing Aromatic Doxorubicin as Therapeutic and Regenerative Biomaterial.

Lesioned tissue requires synchronous control of disease and regeneration progression after surgery. It is necessary to develop therapeutic and regenerative scaffolds. Here, hyaluronic acid (HA) was esterified with benzyl groups to prepare hyaluronic acid derivative (HA-Bn) nanofibers via electrospinning. Electrospun membranes with average fiber diameters of 407.64 ± 124.8 nm (H400), 642.3 ± 228.76 nm (H600), and 841.09 ± 236.86 nm (H800) were obtained by adjusting the spinning parameters. These fibrous membranes had good biocompatibility, among which the H400 group could promote the proliferation and spread of L929 cells. Using the postoperative treatment of malignant skin melanoma as an example, the anticancer drug doxorubicin (DOX) was encapsulated in nanofibers via hybrid electrospinning. The UV spectroscopy of DOX-loaded nanofibers (HA-DOX) revealed that DOX was successfully encapsulated, and there was a π-π interaction between aromatic DOX and HA-Bn. The drug release profile confirmed the sustained release of about 90%, achieved within 7 days. In vitro cell experiments proved that the HA-DOX nanofiber had a considerable inhibitory effect on B16F10 cells. Therefore, the HA-Bn electrospun membrane could facilitate the potential regeneration of injured skin tissues and be incorporated with drugs to achieve therapeutic effects, offering a powerful approach to developing therapeutic and regenerative biomaterial.

Anomalous deep-red luminescence of perylene black analogues with strong π-π interactions

Perylene bisimide (PBI) dyes are known as red, maroon and black pigments, whose colors depend on the close π−π stacking arrangement. However, contrary to the luminescent monomers, deep-red and black PBI pigments are commonly non- or only weakly fluorescent due to (multiple) quenching pathways. Here, we introduce N-alkoxybenzyl substituted PBIs that contain close π stacking arrangement (exhibiting dπ−π ≈ 3.5 Å, and longitudinal and transversal displacements of 3.1 Å and 1.3 Å); however, they afford deep-red emitters with solid-state fluorescence quantum yields (ΦF) of up to 60%. Systematic photophysical and computational studies in solution and in the solid state reveal a sensitive interconversion of the PBI-centred locally excited state and a charge transfer state, which depends on the dihedral angle (θ) between the benzyl and alkoxy groups. This effectively controls the emission process, and enables high ΦF by circumventing the common quenching pathways commonly observed for perylene black analogues.

Regioselective 2,7-dimethyl-9-phenyl xanthen-9-yl protection and deprotection of nucleosides under mild conditions

A simple and efficient protocol is developed for regioselective protection of primary hydroxyl group of nucleosides using 2,7-dimethylpixyliumtrifluoroacetate, prepared in-situ from 2,7-dimethyl-9-phenylxanthen-9-ol (DMPx-OH) and trifluoroacetic anhydride (TFAA). Furthermore deprotection of DMPx group is accomplished with TFAA in shorter reaction times with excellent yields in DCM:Methanol solvent system. Both procedures are successfully implemented on gram scale for synthesis of natural as well as other modified nucleosides. Various functional groups such as benzoyl, benzyl, tetrahydropyranyl, TBDPS, and formamidine groups are intact during protection with DMPx-group.

Unexpectedly Large Structural Variations in Benzyl-Substituted Sila[1]ferrocenophanes.

A set of four planar-chiral sila[1]ferrocenophanes equipped with a benzyl group in the α-position, either on one or both Cp rings, and substituted on the bridging silicon atom, either by methyl or phenyl groups, were prepared. While NMR, UV/Vis, and DSC measurements did not show anything uncommon, single crystal X-ray analyses revealed unexpectedly large variations of the dihedral angles between both Cp rings (α tilt angle). While DFT calculations predicted α between 19.6 and 20.8°, measured values were found between 16.6(2) and 21.45(14)°. However, experimentally determined conformers differ significantly from those calculated for the gas phase. For the sila[1]ferrocenophane with the largest mismatch between the experimental and predicted α angle, it was shown that the orientation of benzyl groups have a significant influence on the ring-tilted structure. Packing of molecules in the crystal lattice forces benzyl groups into unusual orientations, resulting in a significantly reduced α angle through steric repulsions.

Synthesis and structure of 4-hy-droxy-N-iso-propyl-tryptamine (4-HO-NiPT) and its precursors.

The title compound, 4-hy-droxy-N-iso-propyl-tryptamine (4) or 4-HO-NiPT (systematic name: 3-{2-[(propan-2-yl)amino]-eth-yl}-1H-indol-4-ol), C13H18N2O, was synthesized in three steps from 4-benzyl-oxyindole (1) (systematic name: 4-phen-oxy-1H-indole), C15H13NO. (1) was treated with oxalyl chloride and iso-propyl-amine to produce N-isopropyl-4-benz-yloxy-3-indole-glyoxyl-amide (2) {systematic name: 2-[4-(benz-yloxy)-1H-indol-3-yl]-2-oxo-N-(propan-2-yl)acet-amide}, C20H20N2O3. (2) was reduced to generate 4-benz-yloxy-N-iso-propyl-tryptamine (3) or 4-HO-NiPT, which was characterized as its chloride salt 4-benz-yloxy-N-iso-propyl-tryptammonium chloride (3a) (systematic name: {2-[4-(benz-yloxy)-1H-indol-3-yl]eth-yl}(propan-2-yl)aza-nium chloride), C20H25N2O·Cl. Finally the benzyl group of (3) was removed via hydrogenation to generate 4-HO-NiPT. The crystal structures of the title compound and all three synthetic precursors are presented.

Mechanistic DFT Study of 1,3-Dipolar Cycloadditions of Azides with Guanidine

Density functional calculations SMD(chloroform)//B3LYP/6-311+G(2d,p) were employed in the computational study of 1,3-dipolar cycloadditions of azides with guanidine. The formation of two regioisomeric tetrazoles and their rearrangement to cyclic aziridines and open-chain guanidine products were modeled. The results suggest the feasibility of an uncatalyzed reaction under very drastic conditions since the thermodynamically preferred reaction path (a), which involves cycloaddition by binding the carbon atom from guanidine to the terminal azide nitrogen atom, and the guanidine imino nitrogen with the inner N atom from the azide, has an energy barrier higher than 50 kcal mol-1. The formation of the other regioisomeric tetrazole (imino nitrogen interacts with terminal N atom of azide) in direction (b) can be more favorable and proceed under milder conditions if alternative activation of the nitrogen molecule releases (e.g., photochemical activation), or deamination could be achieved because these processes have the highest barrier in the less favorable (b) branch of the mechanism. The introduction of substituents should favorably affect the cycloaddition reactivity of the azides, with the greatest effects expected for the benzyl and perfluorophenyl groups.

Chitosan derivatives as promising green corrosion inhibitors for carbon steel in acidic environment: Inhibition performance and interfacial adsorption mechanism

Among the biodegradable polysaccharide, chitosan is widely present in the cell membranes of bacteria and algae and in the cell walls of higher plants. As a promising biopolymer, chitosan has great potential as eco-friendly corrosion inhibitor. Herein, two synthetic chitosan derivatives (N-phenylthiourea chitosan (CS-PT), N-phenyl-O-benzylthiourea chitosan (CS-PT-Bn)) were investigated as high-efficient acidic corrosion inhibitors to deal with the corrosion issue of carbon steel. The anti-corrosion property of the chitosan derivatives was explored by electrochemical tests, surface characterization and theoretical calculations. The experimental results indicate that both CS-PT and CS-PT-Bn present high-efficient inhibition performance with the inhibition efficiency of 98.4% and 98.5% at the concentration of 100 mg/L, respectively. Their adsorption mechanism at steel/solution interface is revealed by quantum chemical calculations, molecular dynamics (MD) and GFN-xTB calculations. It is found that CS-PT and CS-PT-Bn adsorb at the steel/solution interface by forming Fe-N and Fe-S bonds. Compared to CS-PT molecule, the introduction of benzyl group endows CS-PT-Bn molecule with stronger electrostatic effect and hydrophobicity, which favors the interfacial adsorption of CS-PT-Bn molecule on carbon steel surface.

Design, Synthesis, and Study of the Anxiolytic Activity of New Pyrrolo[1,2-<i>a</i>]pyrazine-Containing TSPO Ligands

A new group of 1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamides, in which substituents at the amide nitrogen atom are alkyl, benzyl or alkoxyphenylalkyl groups, amino acid residues or their derivatives, has been obtained in this work. The synthesized compounds have high theoretical affinities for the 18 kDa translocator protein (TSPO) and a favorable profile of ADMET characteristics, which makes them promising for drug development. Anxiolytic activity was detected for eight compounds at doses of 0.1–5.0 mg/kg when administered intraperitoneally under conditions of emotional stress in the open field test in Balb/c mice and in the elevated plus maze test in ICR mice. N-Benzhydryl-1-phenylpyrrolo[1,2-a]pyrazine-3-carboxamide was selected as a lead compound for further development as a potential anxiolytic agent, which showed the presence of anti-anxiety activity in a wide range of doses in both tests used.

DFT CALCULATIONS IN MONOMERIC AND DIMERIC FORMS OF N-BENZYLMALEIMIDE (NBM) COMBINED WITH VIBRATIONAL SPECTROSCOPIC PARAMETERS

The structural, vibrational and theoretical analyses of N-benzylmaleimide (NBM) having chemical and biological significances have been made. The four possible conformers and their sixty-six dimeric forms linked by the intermolecular C=O···H hydrogen bonding were investigated for the stability. The conformational and the dimeric structures of NBM in the gas phase were investigated and the population distributions of the conformations and dimers were obtained using the Boltzmann distribution. The experimental IR and Raman spectra of solid phase NBM were recorded, and the bands were compared with the theoretical wavenumber the values of the monomer and the dimer forms for their assignments. The new scale factors (0.9617 for B3LYP/6-31G(d) and 0.9531 for M06-2X/6-31G(d)) obtained for NBM can be used more accurately in vibration calculations of all maleimide derivatives. The Molecular Electrostatic Potential (MEP) map showed that the negative and the positive regions have changed from monomeric to dimeric form changes, while the HOMO-LUMO shapes did not generally change in monomeric and dimeric forms. The nucleophilic and electrophilic Fukui functions and dual descriptors shows that maleimide and benzyl groups are nucleophilic and electrophilic regions, respectively, additionally the dual descriptor values decrease upon dimerization.

Sunlight Stimulated Photochemical Self-Healing Polymers Capable of Re-Bonding Damages up to a Centimeter Below the Surface Even Out of the Reach of the Illumination.

The development of photochemical self-healing polymers faces the the following bottlenecks: i) only the surface cracks can be restored and ii) materials' mechanical properties are lower. To break these bottlenecks, cross-linked poly(urethane-dithiocarbamate)s carrying photo-reversible dithiocarbamate bonds covalently linked to indole chromophores and benzyl groups are designed. The conjugated structure of the chromophore and benzyl enhances the addition reactivity of thiocarbonyl moiety and facilitates photo-cleavage of CS bond, so that transfer of the created radicals among dithiocarbamate linkages is promoted. Accordingly, reshuffling of the reversibly cross-linked networks via dynamic exchange between the activated dithiocarbamates is enabled in both surface layer and the interior upon exposure to the low-intensity ultraviolet (UV) light from the sun. It is found that the damages up to a centimeter below the surface can be effectively recovered in the sunshine, which greatly exceeds the maximum penetration distance of UV light (hundreds of microns). Besides, tensile strength and failure strain of the poly(urethane-dithiocarbamate) are superior to the reported photo-reversible polymers, achieving the record-high 33.8 MPa and 782.0% owing to the wide selectivity of soft/hard blocks, multiple interactions, and appropriate cross-linking architecture. The present work provides a novel paradigm of photo self-healing polymers capable of re-bonding cracks even out of the reach of the illumination.

Highly stereoselective synthesis of heparin tri- and tetra-saccharide derivatives

<p indent="0mm">Heparin, a naturally highly sulfated glycosaminoglycan, mediates various physiologic and pathophysiologic processes, and is mainly used for the prevention and treatment of venous thrombosis in clinic. Here we report an efficient synthesis of heparin oligosaccharides with different degrees of 6-<italic>O</italic>-sulfonation modification, employing orthogonal protective group strategy. <italic>tert</italic>-Butyldiphenylsilyl (TBDPS) group is used as the protective group of 6-OH of the 2-azide-glucose donors, and highly α-selective construction of the key GlcN-(1→4)-GlcUA glycosidic bond was achieved with the corresponding <italic>N</italic>-phenyl trifluoroacetimidate donors. Thus, tri- and tetra-saccharides are synthesized by the convergent [1 + 2] and [2 + 2] glycosylation. The fully elaborated oligosaccharides have then been successfully transformed into the target heparin oligosaccharides <bold>28</bold>–<bold>34</bold> <italic>via</italic> an optimal sequence of manipulation of the protecting groups. The post-assembly manipulations include desilylation with HF·Py (for removal of TBDPS group), delevulinoylation with hydrazine hydrate (for removal of levulinoyl group), saponification under Zemplén conditions (for removal of methyl ester and benzoyl group), <italic>O</italic>-sulfonation with sulfur trioxide pyridine complex (for hydroxyl groups), reduction and <italic>N</italic>-sulfonation (for azido group), and atmospheric pressure hydrogenation (for removal of benzyl and Cbz groups). The availability of these heparin oligosaccharide derivatives which bear amino linker shall facilitate the preparation of glycan chips for studies on the interaction between heparin oligosaccharides with proteins, such as the heparanase.

Strategies for improving extraction capacity through preorganization structure: A novel 5,6-bicyclicmalonamide extractant (THPPD)

Rational design of extractant structure to improve the extraction and separation capacity of rare earth elements (REEs) is a long-standing challenge. Herein, a new strategy was proposed to improve the stability of the chelating structure formed by malonamide and REEs. The stability of the chelating structure is greatly improved by using a double-ring framework structure which makes the two carbonyl groups of malonamide unable to rotate freely and both of them point to the metal ion position. Three benzyl groups were used to construct the hydrophobicity of the extractant and the organic shell of the extracted species. Tribenzylhexahydro-pyrrolo-pyridine-dione (THPPD) was designed and synthesized. The structure reduces the energy consumed by rotating carbonyl group in the coordination with metal ions and then improves the extraction ability of extractant. The crystal structure was preorganized as expected, with the two carbonyls pointing in a favorable coordination direction to the structural complement of the metal ion. The extraction behaviors of REEs with THPPD in a nitric acid medium were studied. Compared with N,N′-dibenzyl-N,N′-dimethylmalonamide (DBDM-MA) with a chain structure, the extraction capacity of THPPD is 360 times higher than that of DBDM-MA at 5.0 mol/L sodium nitrate. Furthermore, the binding energy and Gibbs free energy were investigated by density functional theory (DFT) in conjunction with the B3LYP. The theoretical results show that THPPD has more effective interaction with Pr(NO3)3 than DBDM-MA. The construction of chelating groups conformation is a worthy direction to improve the coordination ability and even selectivity of extractant.

In-depth unveiling the interfacial adsorption mechanism of triazine derivatives as corrosion inhibitors for carbon steel in carbon dioxide saturated oilfield produced water

In this work, two triazine derivatives (BTT-1 and BTT-2) were synthesized by the simple one-step condensation of three components and used as high-efficient corrosion inhibitors to deal with the corrosion issue of carbon steel (CS) in petroleum industry. Electrochemical tests indicate that both BTT-1 and BTT-2 present superior inhibition performance with the inhibition efficiency of 97.9 % and 98.4 % at a low concentration of 0.18 mM, respectively. Quantum chemical calculations reveal that compared to BTT-1 molecule with a butyl chain, the introduction of benzyl group endows BTT-2 molecule with more adsorption sites, which favors the adsorption of BTT-2 molecule on CS surface. Furthermore, the GFN-xTB calculations demonstrate that BTT-1 and BTT-2 could adsorb on CS surface through the formation of Fe−N and Fe−S bonds. Compared to BTT-1, BTT-2 exhibits stronger adsorption on CS surface by forming more and shorter bonds with a more negative adsorption energy, which accounts for the better inhibitive performance of BTT-2.

Efficient Kilogram-Scale Synthesis of a Novel Oxazolidinone Antibacterial Candidate YG-056SP

The development of an improved kilogram-scale synthesis of a novel oxazolidinone antibacterial candidate YG-056SP for the treatment of multidrug-resistant Gram-positive bacterial infection is described. The new process is highlighted by a step economical construction of the chiral N-methyloxazolidone, employing an asymmetric reduction of the carbonyl and methylamine substitution, followed by the cyclization with N,N′-carbonyldiimidazole. Another highlight is the safe construction of the fused ring with high optical purity. Epoxy intermediates were obtained by intramolecular ring closure, and reacted with phenol fragments, followed by reduction, protection, and an intramolecular tandem reaction to afford the fused ring. The endgame process features the completion of the Miyaura reaction and the Suzuki coupling reaction in one pot and tert-butyldimethylsilyl deprotection to make dibenzyl phosphate. Finally, cheap hydrochloric acid was used to deprotect the benzyl group, which delivered YG-056SP with a defined particle-size distribution suitable for preclinical studies after crystal transformation. Compared with the initial synthetic route, the overall yield of this optimized process increased significantly from 2.3 to 29.6%.

A New Thermal Stable and Salt Tolerant Alkyl Polyether Benzyl Sulfonate Surfactant with Ultralow Interfacial Tensions for Enhanced Oil Recovery

A large variety of surfactants have been widely used in enhanced oil recovery, yet there is still a challenge for the application of surfactants in oil reservoirs with high salinity and high temperatures. Herein we report a new alkyl polyether benzyl sulfonate anionic surfactant named sodium iso-tridecanol polyoxyethylene ether benzyl sulfonate with ultralow interfacial tensions at high salinity and high temperatures synthesized through a strategy connecting the alkyl polyether with a benzyl group. Its structure was confirmed by 1H NMR. Effects of the temperature, salinity, divalent ion, and surfactant concentration on interfacial tensions and phase behaviors were investigated. The alkyl polyether benzyl sulfonate surfactant demonstrated a strong interfacial activity and excellent phase behavior with high solubilization parameters at salinities up to 18.0 wt % NaCl and temperatures up to 120 °C, which suggest that the new alkyl polyether benzyl sulfonate surfactant has good temperature resistance and salt tolerance and is promising for applications in enhanced oil recovery in high temperature and high salinity oil reservoirs.

Requirements in structure for chiral recognition of chitosan derivatives

In order to investigate the influence of a minor variation in structure of N-acyl chitosan derivatives on enantioseparation, chiral selectors (CSs) of chitosan 3,6-bis(phenylcarbamate)-2-(phenylacetamide)s and chitosan 3,6-bis(phenylcarbamate)-2-(cyclohexylacetamide)s were synthesized. The corresponding chiral stationary phases (N-PhAc CSPs and N-cHeAc CSPs) were also prepared, respectively, with the two series of CSs. Enantioseparation results revealed that the N-PhAc CSPs were better than the N-cHeAc ones in enantioseparation. Thus, benzyl group (Bn) at C2 should be more preferable to enantioseparation than cyclohexylmethyl (cyclohexyl–CH2–) at the same position. Because N-PhAc CSPs exhibited higher enantioseparation capability than chitosan 3,6-bis(phenylcarbamate)-2-(benzamide) based CSPs (N-Bz CSPs), the Bn should also be more beneficial to enantioseparation than phenyl group (Ph) at C2 in N-Bz CSPs. In addition, it was found that, the cyclohexyl group at C2 in chitosan 3,6-bis(phenylcarbamate)-2-(cyclohexylformamide) CSPs was better than cyclohexyl–CH2– in N-cHeAc CSPs to enantioseparation. In a word, a minor variation at C2 of chitosan derivatives significantly affected enantioseparation. After the prepared CSPs were stood for six months, their enantioseparation capabilities were changed obviously, and the changes were probably related to nature, position and number of a substituent on Ph connected to carbamates at C3 and C6 of the CSs.

Site- and enantioselective cross-coupling of saturated N-heterocycles with carboxylic acids by cooperative Ni/photoredox catalysis

Site- and enantioselective cross-coupling of saturated N-heterocycles and carboxylic acids—two of the most abundant and versatile functionalities—to form pharmaceutically relevant α-acylated amine derivatives remains a major challenge in organic synthesis. Here, we report a general strategy for the highly site- and enantioselective α-acylation of saturated N-heterocycles with in situ-activated carboxylic acids. This modular approach exploits the hydrogen-atom-transfer reactivity of photocatalytically generated chlorine radicals in combination with asymmetric nickel catalysis to selectively functionalize cyclic α-amino C−H bonds in the presence of benzylic, allylic, acyclic α-amino, and α-oxy methylene groups. The mild and scalable protocol requires no organometallic reagents, displays excellent chemo-, site- and enantioselectivity, and is amenable to late-stage diversification, including a modular synthesis of previously inaccessible Taxol derivatives. Mechanistic studies highlight the exceptional versatility of the chiral nickel catalyst in orchestrating (i) catalytic chlorine elimination, (ii) alkyl radical capture, (iii) cross-coupling, and (iv) asymmetric induction.

Benzoxazolone-5-Urea Derivatives as Human Soluble Epoxide Hydrolase (sEH) Inhibitors.

Inhibition of soluble epoxide hydrolase (sEH) is indicated as a new therapeutic modality against a variety of inflammatory diseases, including metabolic, renal, and cardiovascular disorders. In our ongoing research on sEH inhibitors, we synthesized novel benzoxazolone-5-urea analogues with highly potent sEH inhibitory properties inspired by the crystallographic fragment scaffolds incorporating a single H-bond donor/acceptor pair. The tractable SAR results indicated that the aryl or benzyl fragments flanking the benzoxazolone-urea scaffold conferred potent sEH inhibition, and compounds 31-39 inhibited the sEH activity with IC50 values in the range of 0.39-570 nM. Docking studies and molecular dynamics simulations with the most potent analogue 33 provided valuable insights into potential binding interactions of the inhibitor in the sEH binding region. In conclusion, benzoxazolone-5-ureas furnished with benzyl groups on the urea function can be regarded as novel lead structures, which allow the development of advanced analogues with enhanced properties against sEH.

Study of the Antioxidant Activity of Synthetic 3-hydroxyflavone Derivatives by DPPH and Hydrogen Peroxide Methods

Flavonoids have good efficacy as antioxidants due to their ability to scavenge free radicals within cells. In our previous study, synthetic flavonoid derivatives (A2-A13) were prepared in vitro through condensation, oxidative cyclization, alkylation and esterification reactions. The antioxidant activity of the alkyl and esterified derivatives of the flavonoid compound (A2) 3-hydroxy-2-(4-[dimethylamino]phenyl) benzo-4-pyrone was studied by two methods: 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical inhibition method and inhibition of hydrogen peroxide (H2O2) and compared to the activity of standard antioxidant compounds, ascorbic acid and quercetin. The flavonoids (prepared samples) A2, A5, and A7 showed high activity approaching that of ascorbic acid and quercetin as well-known antioxidants. As for the compounds (A3, A6, A8, A9, A10, A11, A12, A13), which contain an -OH enol group, a benzyl group, and a chlorine group and the acetate group, its effectiveness has decreased significantly.