Substitution Of Group Research Articles

Uncommon Phosphonylation of Pyrazine‐2,3‐dicarbonitrile Derivatives via C(sp2)‐CN Bond Cleavage

A direct phosphonylation of the sp2C−CN bond under mild catalytic and non‐catalytic reaction conditions is disclosed. Pyrazine‐2,3‐dicarbonitriles are readily coupled with HPO(OEt)2 to produce the corresponding dialkoxyphosphoryl‐substituted pyrazines. The phosphonylation reaction occurs in the presence of a base (Et3N, Cs2CO3) as nucleophilic substitution of the CN groups. The yield of target diphosphonates depends on the nature of substituents in the 5,6‐positions of the pyrazine ring: it exceeds 90% for di‐5,6‐aryl‐substituted pyrazines and is significantly lower when electron‐donating alkyl (n‐propyl) groups are attached to the 5,6‐positions. It should be noted that for pyrazine‐2,3‐dicarbonitriles bearing vicinal 4‐bromophenyl groups, the nucleophilic phosphonylation leading to C‐‐CN/P‐‐H coupling in the pyrazine ring is predominant over Pd‐catalyzed Hirao’s C‐‐Br/P‐‐H coupling reaction in phenyl rings. Detailed structural characterization, both in solution by means of 1H, 13C and 31P NMR spectroscopy and in the solid state by single crystal X‐ray diffraction, of a series of newly synthesized pyrazine phosphonates is reported.

Synthesis of alkylated carbonyl‐bearing furans via acid‐catalyzed Friedel‐Crafts reaction

Carbonyl‐bearing furans, certain pyrroles, and thiophenes were alkylated using alcohols in an acidic medium. Some 5‐alkylated derivatives of 2‐furoic acid with various adamantyls‐, cycloalkyl‐, other 2°‐ and 3°‐alkyl substituents were synthesized using 2‐furoic acid as a biomass‐derived chemical platform. Side reaction resulted in the substitution of the carboxylic group, leading to the formation of 1,5‐dialkyl furans. In the alkylation of acyl and formyl furan, either mono‐ or di‐alkyl products were obtained, depending on the functional group present in the furan nucleus. Pyrroles (or thiophenes) with related functional groups exclusively (or near‐exclusively) yielded mono‐alkyl products. The resultant 5‐substituted carbonyl furans can be used as building blocks and synthetic equivalents for 1C and 4C synthons, as demonstrated by a series of reactions involving 5‐adamantan‐1‐yl‐2‐furoic acid.

Design, synthesis and antitumor activity of triphenylphosphonium-linked derivatives of quinazolinone

Cancer is the leading cause of human death. Quinazolinone heterocyclic compounds have a variety of biological activities and have been extensively studied in recent years, especially for their potential anticancer activity. The triphenylphosphonium moiety (TPP+) has become a very important lipophilic cation, especially concerning its application the development of anticancer agents. In this work, we designed and synthesised 24 new TPP+ -conjugated quinazolinone derivatives, which have alkylated TPP+ at the N-3 position and different small group substitutions at the C-6 position, and their antiproliferative activity was evaluated in three cancer cell lines (human alveolar adenocarcinoma cells (A549), human hepatoblastoma cells (HepG2) and human breast cancer cells (MCF-7)) and human normal liver cells (QSG-7701). The cytotoxicity screening results showed that some derivatives exhibited effective inhibitory effects in cancer cells. Among them, the compound 5k–o showed better antiproliferative activity than the positive control drug gefitinib on MCF-7 and A549 cells. The most active compounds being 5o, with IC50 values of 6.56, 14.52 and 7.51 µM in MCF-7 cells, HepG2 cells and A549 cells, respectively. Compound 5o may be a promising compound for cancer treatment worthy of further study.

Study on the electrochemical oxidation mechanism of sulfamethoxazole using three-dimensional boron-doped diamond

In this study, we prepared a novel three-dimensional boron-doped diamond (BDD) electrode. Subsequently, we systematically conducted an electrochemical oxidation reaction on sulfamethoxazole (SMX) using a BDD anode and a platinum plate (Pt) cathode. The effects of initial concentration, current density, initial pH, and carrier electrolyte on SMX degradation were investigated. The SMX was completely removed after 4 h of electrolysis at a current density of 30 mA/cm2, 0.1 mol sodium sulphate as the supporting electrolyte, and a pH of 7. Additionally, the COD removal rate was 65.6 %, while the energy consumption was 40.1 %. Compared with two-dimensional BDD electrode degradation, the energy saving was 54 %. Density functional theory (DFT) and high-performance liquid chromatography (HPLC) were used to analyse the SMX degradation mechanism. Three possible degradation pathways were proposed: ·OH substitution of the amino group in the aromatic ring, oxidation of the amino group to nitrogen dioxide, and addition of ·OH to the isoxazole ring. The active sites detected in the reaction corresponded closely with the calculated results using DFT. Moreover, ECOSAR toxicity analysis was applied to evaluate the toxicity of the intermediates produced during electrolysis. We discovered that the toxicity of SMX and its intermediates decreased significantly during electrolysis.

Model catalytic studies on the thermal dehydrogenation of the benzaldehyde/cyclohexylmethanol LOHC system on Pt(111).

We investigated the dehydrogenation reaction and the thermal robustness of the liquid organic hydrogen carrier (LOHC) couple benzaldehyde/cyclohexylmethanol on a Pt(111) model catalyst in situ in synchrotron radiation photoelectron spectroscopy- and complementary temperature-programmed desorption experiments. The system stores hydrogen in a cyclohexyl group and a primary alcohol functionality and achieves an attractive hydrogen storage capacity of 7.0 mass%. We observed a stepwise dehydrogenation mechanism, characterized by a low temperature dehydrogenation of the alcohol group at 235 K. However, stability limitations challenge the system's applicability as reversible hydrogen storage solution, as the resultant aldehyde was found to decompose during the dehydrogenation of its cyclohexyl group (between 250 and 350 K). A comparison of cyclohexylmethanol with the structurally related secondary alcohol (1-cyclo-hexylethanol; 6.3 mass% hydrogen) revealed a parallel stepwise dehydrogenation pattern for both compounds, but a technically relevant superior thermal robustness of the latter. This demonstrates the influence of the alcohol group's substitution degree on the dehydrogenation characteristics of alcohol-functionalized LOHC compounds. Density functional theory calculations are in good agreement with the experimentally observed stability trend.

Unlocking Terpenoid Transformations: C–H Bond Functionalization for Methyl Group Substitution, Elimination, and Integration

Unlocking Terpenoid Transformations: C–H Bond Functionalization for Methyl Group Substitution, Elimination, and Integration

Fast, Regioselective Aminolysis of Tetrasubstituted Cyclic Carbonates and Application to Recyclable Thermoplastics and Thermosets.

Herein, the long-standing challenge of the ring-opening aminolysis of CO2-derived tetrasubstituted cyclic carbonates at room temperature (r.T) is overcome under catalyst-free conditions. Molecular design of the cyclic carbonate by substitution of an alkyl group by a thioether unlocks quantitative conversion at r.T and ensures total regioselectivity toward highly substituted oxazolidone scaffolds. An in-depth rationalization of the high reactivity of these cyclic carbonate structures and of the aminolysis reaction mechanism is provided by a computational study supporting experimental observations. The high efficiency of the reaction is then translated to the deconstruction of high-performance thermoplastics containing tetrasubstituted cyclic carbonate linkages to deliver building blocks that are reused for designing recyclable thermosets bearing dynamic N,S-acetal linkages.

Remdesivir triphosphate is a valid substrate to initiate synthesis of DNA primers by human PrimPol

Remdesivir is a broad-spectrum antiviral drug which has been approved to treat COVID-19. Remdesivir is in fact a prodrug, which is metabolized in vivo into the active form remdesivir triphosphate (RTP), an analogue of adenosine triphosphate (ATP) with a cyano group substitution in the carbon 1’ of the ribose (1’-CN). RTP is a substrate for RNA synthesis and can be easily incorporated by viral RNA-dependent RNA polymerases (RdRp). Importantly, once remdesivir is incorporated (now monophosphate), it will act as a delayed chain terminator, thus blocking viral RNA synthesis. It has been reported that mitochondrial Polγ is also blocked in vitro by RTP, but the low impact in vivo on mitochondrial DNA replication stalling is likely due to repriming by the human DNA-directed DNA Primase/Polymerase (HsPrimPol), which also operates in mitochondria. In this work, we have tested if RTP is a valid substrate for both DNA primase and DNA polymerase activities of HsPrimPol, and its impact in the production of mature DNA primers. RTP resulted to be an invalid substrate for elongation, but it can be used to initiate primers at the 5´site, competing with ATP. Nevertheless, RTP-initiated primers are abortive, ocassionally reaching a maximal length of 4–5 nucleotides, and do not support elongation mediated by primer/template distortions. However, considering that the concentration of ATP, the natural substrate, is much higher than the intracellular concentration of RTP, it is unlikely that HsPrimPol would use RTP for primer synthesis during a remdesivir treatment in real patients.

Optimization of synthesis of cationic starches for wastewater sludge and microalgae separation

The implementation of stricter water protection legislation requires the development of novel environmentally friendly water treatment materials. A new method for the preparation of water soluble cationic starch flocculants using potato starch, 3-chloro-2-hydroxypropyltrimethylammonium chloride and CaO additive was developed and surface response methodology was successfully utilized for the optimization of degree of substitution in the cationization of potato starch with and without CaO additive. Based on the results of destabilization studies of model kaolin, wastewater sludge, and microalgae dispersion systems, optimized conditions ware proposed for obtaining an efficient, soluble, and biodegradable cationic starch flocculant with optimal structure. The duration of starch etherification reaction was reduced to <12 h to obtain soluble cationic starch derivatives with a degree of substitution of quaternary ammonium groups of 0.25, which retained the granular structure during synthesis. An efficient flocculation technology using anionic polymer and high content of biodegradable cationic flocculant was proposed. The highly efficient flocculation of microalgae suspensions using developed cationic starch derivative with the degree of substitution of cationic groups of 0.25 has been also achieved. The developed environmentally friendly cationic starches with tailored flocculation properties proofed to have a great potential in various water cleaning and separation technologies with prospects in wastewater treatment, agriculture or energy sectors.

Synthesis and Redox Activity of Polyenaminones for Sustainable Energy Storage Applications

In the search for novel polymeric molecules that could be used as electroactive materials, seven novel polyenaminones were prepared in high yields by the transaminative polymerization of resorcinol-derived bis-enaminones with m- and p-phenylenediamine and with 2,5-diaminohydroquinone. The obtained polymers show very low solubility in organic solvents and absorb UV light and visible light at wavelengths below 500 nm. All the obtained polymeric products were tested for redox activity in a Li battery setup. The 2,5-diaminohydroquinone-derived compound showed the best redox activity, with a maximum capacity of 86 mAh/g and relatively good capacity retention, thus confirming the hydroquinone group as the primary redox-active group. Other potential redox-active groups, such as resorcinol and conjugated carbonyls, showed limited activity, while variations in the phenylene groups and the substitution of phenolic groups in the resorcinol residue did not impact the electrochemical activity of the polymers. Their electrochemical properties, together with their previously established chemical recyclability, make polyenaminones promising scaffolds for the development of materials for sustainable energy storage applications.

Exploring Spectral and Electrochemical Behavior of Hydroxy‐N‐Benzylideneanilines by Integrated Theoretical and Experimental Approaches

ABSTRACTThe present work explored the effect of –OH group substitution (o/p) on the spectral and electrochemical behavior of N‐benzylideneaniline. The geometry optimization of unsubstituted and (o/p)‐OH‐substituted analogs revealed the coplanarity of the molecules. The vibrational spectra of the compounds were computed using density functional theory (DFT) and compared with the experimental data. The observed bands were assigned based on total energy distribution (TED). Predicted electronic absorption spectra from time‐dependent density functional theory (TD‐DFT) calculation were compared with the UV–visible spectra of the molecules. The analysis of the lowest spin‐allowed (singlet‐singlet) excited states divulged possible electronic transition. The o‐substituted benzylideneaniline possessed the lowest highest occupied molecular orbital (HOMO)–lowest unoccupied molecular orbital (LUMO) energy gap among the substituted and unsubstituted analogs. The intramolecular contacts were interpreted using natural bond orbital and localized molecular orbital analysis. The –CH=N– linkage was investigated as a bridge for the electron delocalization from the donor to acceptor moieties. The manifestation of a reduction peak in the cyclic voltammetric studies confirmed the electrochemical behavior in the –OH‐substituted molecule, which was diffusion‐controlled. The discrepancy in the electrochemical property concerning the position of the –OH substituent of the candidate molecules was put forward.

2-(1,1-Dicyanomethylene)rhodanine-Functionalized Oligothiophenes: A Structure-Property Investigation of Z/E Photoisomerization Behavior.

A series of oligothiophenes singly and doubly functionalized with dicyanorhodanine (RCN) units have been investigated to understand their Z/E photoisomerization behavior upon structural modulation. Monotopic RCN target molecules (1-Z-9-Z) were designed to observe the consequences of π-conjugation, solubilizing group substitution, and formylation of the thiophene units. In all cases, the Z isomer is obtained from synthesis as the thermodynamically stable isomer, whereas the E isomer is achieved through selective irradiation (including red light, λirr = 628 nm) as a Z/E mixture in solution. For the quarterthiophene entries, photoisomerization is inhibited, with photoirradiation resulting only in degradation. The result comports with concentration-dependent studies, which show that increasing π-conjugation results in greater aggregation and muted Z/E photoisomerization. Ditopic RCN targets (10-ZZ-12-ZZ), mimicking acceptor-donor-acceptor (A-D-A) oligomers relevant to OPV materials, also show evidence of photoisomerization in solution, with formation of Z,Z/Z,E mixtures at the photostationary state (PSS). Complementary ground- and excited-state DFT calculations show excellent agreement with the experimental findings. This comprehensive structure-property analysis is expected to both guide and caution the functional materials community with respect to the usage of photoisomerizable RCN-oligothiophenes for optoelectronic applications.

Degradation of enestroburin in the water-sediment system: kinetics, transformation products identification and toxicity assessment to aquatic organisms

ABSTRACT Pesticides inevitably enter the water environment in the process of use. However, the degradation and its transformation products (TPs) of enestroburin in water-sediment systems are not yet known. This study systematically investigated the degradation behaviour of enestroburin through indoor simulation experiments. The study demonstrated that the different organic content of sediments and oxygen conditions had a little effect on the degradation. The study also analysed transformation products by UPLC-QTOF-MS and MetabolitePilot software. A total of 3 TPs of enestroburin were identified, and one product (M-381) was confirmed and quantified. Based on these transformation products, the pathways of enestroburin were supposed, namely hydrolysis of chlorobenzene, hydrolysis of ester group and electrophilic substitution of benzene ring. Finally, ECOSAR software was utilised to predict the potential toxicity of the proposed TPs towards fish, daphnids, and green algae. The toxicity of TPs to aquatic organisms is lower than the parent compound, but they are still toxic. The study results provide data to support the safe use of enestroburin and provide a reference for the degradation and transformation of other strobilurin fungicides.

Role of extended conjugation on Electronic, Electrochemical, and antimicrobial properties of FeN4-Macrocyclic complexes

Developing novel transition metal complexes with unique structures and properties has garnered significant attention in coordination chemistry. In this work, we prepared two Fe-macrocyclic complexes, A and B, with similar macrocyclic core but differing in the number of phenyl group substitutions via the template approach. The complexes were characterized using several analytical tools. The data were found to be in good agreement with the proposed structure of these complexes. Further electrochemical studies indicated a slight anodic shift in Fe(II) reduction, which can be attributed to the phenyl group effect. The theoretical investigations demonstrated that phenyl groups on the macrocyclic core of complex A significantly reduced the charge density on the Fe center due to extended conjugation, as compared to complex B, making the conversion of Fe(II) to Fe(I) easy. Additionally, the prepared complexes were studied for their antimicrobial activity against various pathogens, and it was found that complex A is more effective against E. coli compared to the standard drug Gentamycin.

Efficient palladium ion adsorption and catalyst preparation from pharmaceutical wastewater using amino-functionalized Ti3C2

This paper reports the recovery and reuse of Pd ions from pharmaceutical wastewater using amino-modified Ti3C2. Ti3C2–NH2 was synthesized by modifying (3-aminopropyl)triethoxysilane and the successful substitution of some surface functional groups of Ti3C2; the decrease in material thickness was verified by characterization. This study revealed that the presence of amino groups significantly enhanced the Pd(II) adsorption capacity of Ti3C2. The effects of the adsorbent material, adsorbent dosage, pH, initial concentration of Pd ions, presence of competing cations, and contact time on the adsorption performance were investigated. The maximum adsorption capacity of 20 mg of Ti3C2–NH2 was 986.65 mg/g in 100 ml of a Pd-ion solution with an initial concentration of 200 mg/l at pH 3. A pseudo-second-order kinetic model fitted well with the experimentally obtained rate data, indicating that the main mode of Pd-ion removal by Ti3C2–NH2 was via chemical reduction. Finally, the catalyst exhibited excellent performances during the photocatalytic and Suzuki coupling reactions with yields of 81 % and 95 %, respectively. The results demonstrated that Ti3C2–NH2 is an excellent material for adsorbing Pd ions and can effectively recycle these ions from pharmaceutical wastewater.

Impact of Methylated Cyclodextrin KLEPTOSE® CRYSMEB on Inflammatory Responses in Human In Vitro Models.

KLEPTOSE® CRYSMEB methylated cyclodextrin derivative displays less methylated group substitution than randomly methylated cyclodextrin. It has demonstrated an impact on atherosclerosis and neurological diseases, linked in part to cholesterol complexation and immune response, however, its impact on inflammatory cascade pathways is not clear. Thus, the impact of KLEPTOSE® CRYSMEB on various pharmacological targets was assessed using human umbilical vein endothelial cells under physiological and inflammatory conditions, followed by screening against twelve human primary cell-based systems designed to model complex human tissue and disease biology of the vasculature, skin, lung, and inflammatory tissues using the BioMAP® Diversity PLUS® panel. Finally, its anti-inflammatory mechanism was investigated on peripheral blood mononuclear cells to evaluate anti-inflammatory or pro-resolving properties. The results showed that KLEPTOSE® CRYSMEB can modulate the immune system in vitro and potentially manage vascular issues by stimulating the expression of molecules involved in the crosstalk between immune cells and other cell types. It showed anti-inflammatory effects that were driven by the inhibition of pro-inflammatory cytokine secretion and could have different impacts on different tissue types. Moreover, this cyclodextrin showed no clear impact on pro-resolving lipid mediators. Additionally, it appeared that the mechanism of action of KLEPTOSE® CRYSMEB seems to not be shared by other well-known anti-inflammatory molecules. Finally, KLEPTOSE® CRYSMEB may have an anti-inflammatory impact, which could be due to its effect on receptors such as TLR or direct complexation with LPS or PGE2, and conversely, this methylated cyclodextrin could stimulate a pro-inflammatory response involving lipid mediators and on proteins involved in communication with immune cells, probably via interaction with membrane cholesterol.

Pyridine-Anchored Small Molecule Interlayer Enables Defect Passivation and Enhanced Carrier Transport for Perovskite Solar Cells.

Engineering of the interface between the perovskite and hole transport layer (HTL) has been crucial to achieving high performance. In this study, two interfacial materials, MN-CZ and CN-CZ, are designed by systematically regulating the group substitution site to study the relationship between spatial conformation and the passivation effect. The passivation groups of CN-CZ molecules exhibit a stronger "vector addition" effect, resulting in larger molecular dipoles and enhanced defect passivation and energy level regulation effects. Consequently, the CN-CZ-based perovskite solar cell (PSC) shows a high efficiency of 23.8%, which is much higher than that of the reference device. Meanwhile, the humidity and thermal stability of the unencapsulated device have been significantly improved.

Exploring the binding interaction of Bis-benzimidazoles with BSA and relocation of bound drug from BSA to DNA

In recent years Bis-benzimidazole derivatives have gained much research interest due to their regulatory role in biological reactions to control diseases. Therefore, probing the interaction of the bioactive derivatives with biomolecules is crucial for both physiological and pharmacological aspects. Consequently, we studied the interaction between Bis-benzimidazoles and bovine serum albumin (BSA) as model transport protein by multi-spectroscopic techniques. It was also evident that substitutions of the phenolic OH group of Hoechst-33258 by -OMe and -NEt2 group have negligible impact on the binding phenomenon with BSA. Additionally, we have shown that the bound derivatives can be successfully relocated from serum albumin to calf-thymus DNA (ct-DNA). The observed higher binding affinity of the Hoechst-33258 to ct-DNA than BSA was responsible for the relocation of dyes from BSA to DNA. The competitive displacement assay with known site markers revealed that the probable binding location of the Hoechst-33258 within the serum protein was site IB. Molecular docking study was also performed to support the experimental findings and to obtain the possible interaction of drug molecule in the protein environment. Our findings might be helpful in overcoming the challenges associated with the delivery of bis-benzimidazole derivatives.

Pomotrelvir and Nirmatrelvir Binding and Reactivity with SARS‐CoV‐2 Main Protease: Implications for Resistance Mechanisms from Computations

AbstractWe investigate the inhibition mechanism between pomotrelvir and the SARS‐CoV‐2 main protease using molecular mechanics and quantum mechanics/molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ‐lactam ring is preferred at position P1, a δ‐lactam ring is a good alternative for the design of inhibitors for variants presenting mutations at position 166. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at the P2 position can disrupt the preorganization of the active site, favouring the exploration of non‐reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents a better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of the SARS‐CoV‐2 virus.

Pomotrelvir and Nirmatrelvir Binding and Reactivity with SARS-CoV-2 Main Protease: Implications for Resistance Mechanisms from Computations.

We investigate the inhibition mechanism between pomotrelvir and the SARS-CoV-2 main protease using molecular mechanics and quantum mechanics/molecular mechanics simulations. Alchemical transformations where each Pi group of pomotrelvir was transformed into its counterpart in nirmatrelvir were performed to unravel the individual contribution of each group to the binding and reaction processes. We have shown that while a γ-lactam ring is preferred at position P1, a δ-lactam ring is a good alternative for the design of inhibitors for variants presenting mutations at position 166. For the P2 position, tertiary amines are preferred with respect to secondary amines. Flexible side chains at the P2 position can disrupt the preorganization of the active site, favouring the exploration of non-reactive conformations. The substitution of the P2 group of pomotrelvir by that of nirmatrelvir resulted in a compound, named as C2, that presents a better binding free energy and a higher population of reactive conformations in the Michaelis complex. Analysis of the chemical reaction to form the covalent complex has shown a similar reaction mechanism and activation free energies for pomotrelvir, nirmatrelvir and C2. We hope that these findings could be useful to design better inhibitors to fight present and future variants of the SARS-CoV-2 virus.