Synthetic Reactions Research Articles

Versatile Light‐Mediated Synthesis of Degradable Bottlebrush Polymers Using α‐Lipoic Acid

AbstractBottlebrush polymers have a variety of useful properties including a high entanglement molecular weight, low Young's modulus, and rapid kinetics for self‐assembly. However, the translation of bottlebrushes to real‐world applications is limited by complex, multi‐step synthetic pathways and polymerization reactions that rely on air‐sensitive catalysts. Additionally, most bottlebrushes are non‐degradable. Herein, we report an inexpensive, versatile, and simple approach to synthesize degradable bottlebrush polymers under mild reaction conditions. Our approach relies on the “grafting‐through” polymerization of α‐lipoic acid (LA)‐functionalized macromonomers. These macromonomers can be polymerized under mild, catalyst‐free conditions, and due to reversibility of the disulfide bond in LA, the resulting bottlebrush polymers can be depolymerized by cleaving disulfide backbone bonds. Bottlebrushes with various side‐chain chemistries can be prepared through the atom transfer radical polymerization (ATRP) of LA‐functionalized macromonomers, and the backbone length is governed by the macromonomer molecular weight and solvent polarity. We also demonstrate that LA‐functionalized macromonomers can be copolymerized with acrylates to form degradable bottlebrush networks. This work demonstrates the preparation of degradable bottlebrush polymers with a variety of side‐chain chemistries and provides insight into the light‐mediated grafting‐through polymerization of dithiolane‐functionalized macromonomers.

Controlling (E/Z)-Stereoselectivity of -NHC=O Chlorination: Mechanism Principles for Wide Scope Applications.

Organic halogen compounds are cornerstones of applied chemical sciences. Halogen substitution is a smart molecular design strategy adopted to influence reactivity, membrane permeability and receptor interaction. Chiral bioreceptors may restrict the stereochemical requirements in the halo-ligand design. Straightforward (but expensive) catalyzed stereospecific halogenation has been reported. Historically, PCl5 served access to uncatalyzed stereoselective chlorination although the stereochemical outcomes were influenced by steric parameters. Nonetheless, stereochemical investigation of PCl5 reaction mechanism with carbamoyl (RCONHX) compounds has never been addressed. Herein, we provide the first comprehensive stereochemical mechanistic explanation outlining halogenation of carbamoyl compounds with PCl5; the key regioselectivity-limiting nitrilimine intermediate (8-Z.HCl); how substitution pattern influences regioselectivity; why oxadiazole byproduct (P1) is encountered; stereo-electronic factors influencing the hydrazonoyl chloride (P2) production; and discovery of two stereoselectivity-limiting parallel mechanisms (stepwise and concerted) of elimination of HCl and POCl3. DFT calculations, synthetic methodology optimization, X-ray evidence and experimental reaction kinetics study evidence all supported the suggested mechanism proposal (Scheme 2). Finally, we provide mechanism-inspired future recommendations for directing the reaction stereoselectivity toward elusive and stereochemically inaccessible (E)-bis-hydrazonoyl chlorides along with potentially pivotal applications of both (E/Z)-stereoisomers especially in medicinal chemistry and protein modification.

Radical Polarity.

The polarity of a radical intermediate profoundly impacts its reactivity and selectivity. To quantify this influence and predict its effects, the electrophilicity/nucleophilicity of >500 radicals has been calculated. This database of open-shell species entails frequently encountered synthetic intermediates, including radicals centered at sp3, sp2, and sp hybridized carbon atoms or various heteroatoms (O, N, S, P, B, Si, X). Importantly, these computationally determined polarities have been experimentally validated for electronically diverse sets of >50 C-centered radicals, as well as N- and O- centered radicals. High correlations are measured between calculated polarity and quantified reactivity, as well as within parallel sets of competition experiments (across different radical types and reaction classes). These multipronged analyses show a strong relationship between the computed electrophilicity, ω, of a radical and its relative reactivity (krel vs Δω slopes up to 40; showing mere Δω of 0.1 eV affords up to 4-fold rate enhancement). We expect this experimentally validated database will enable reactivity and selectivity prediction (by harnessing polarity-matched rate enhancement) and assist with troubleshooting in synthetic reaction development.

Lignin-based monophenolic model compounds in L-tyrosine derivative synthesis via tyrosine phenol lyase

Tyrosine phenol lyase (TPL) synthesises L-tyrosine derivatives from monophenols, pyruvate and ammonia. Production of such high-value aromatic chemicals from biomass-derived raw materials is of great interest. In this study, six monophenols (guaiacol, phenol, o-cresol, m-cresol, catechol and syringol) were chosen based on the structure of lignin and were studied as substrates in the enzymatic reaction. Single monophenol reactions (SMR) and binary monophenol reactions (BMR) with guaiacol were carried out. TPL-M379V was found to be selective towards guaiacol (84.5 % conv.). The highest single activity was measured towards phenol (93.9 % conv.). However, the enzyme preferred guaiacol over phenol in the BMRs. Syringol was found to be inert in the reaction, whereas catechol had an inhibitory effect on the enzymatic reaction, in addition to causing degradation of all the substrates in the medium. Doubling the guaiacol concentration in the SMR did not significantly increase the production of 3-O-methyldopa (conv. 45.9 %). However, in the binary reaction systems the total monophenol conversions were higher with guaiacol and phenol (total 62.4 %) or o-cresol (total 57.1 %). This indicates possible substrate/product specific inhibition. The study provides new data on activity, selectivity and inhibitory effects of monophenols in the synthetic reaction catalysed by TPL-M379V, especially in mixed-substrate reactions.

Biopolymers: Histopathologic Case Series of Patients with Permanent Synthetic Fillers Presenting Chronic Granulomatous Reaction and Hypercalcemia

Background: Biopolymers, which are diverse and permanent synthetic fillers, are nonbiocompatible allogeneic materials. Their implantation can result in clinical, radiological, and histopathological manifestations that contribute to our understanding of foreign-body-induced human adjuvant disease. Methods: We conducted a descriptive observational case series involving 20 patients who underwent open biopolymer removal surgery in the buttocks and lumbosacral regions using the Meticulous Approach Safer and Keeper technique, followed by gluteal reconstruction with autologous tissue. Histopathological analysis was performed. This study was conducted in Bogotá, Colombia, from 2020 to 2023. Results: Documented clinical records and histopathological analyses of the 20 patients revealed an inflammatory response that was initially considered healthy. Cytoplasmic vacuolization in reactive adipocytes was observed in all cases, meriting consideration in the differential diagnosis of liposarcoma and suggesting local aggressiveness. One patient showed a positive lymphocytic inflammatory response in the Alcian blue test. Hypercalcemia was present in 30% of the patients, elevated lactate dehydrogenase in 40%, and elevated parathyroid hormone levels in 15%. Conclusions: Surgeons should consider measuring lactate dehydrogenase, serum calcium, and parathyroid hormone levels to assess the severity and guide clinical practice. Secondary prevention through the open surgical removal of biopolymers is recommended.

Sustainable Chemistry in Synthesis of Heterocyclic Systems: [Atom Economy, Yield Economy and Reaction Mass Efficiency As Metrics of Synthetic Reaction Efficiency

Sustainable Chemistry in Synthesis of Heterocyclic Systems: [Atom Economy, Yield Economy and Reaction Mass Efficiency As Metrics of Synthetic Reaction Efficiency

200 Years of The Haloform Reaction: Methods and Applications.

Discovered in 1822, the haloform reaction is one of the oldest synthetic organic reactions. The haloform reaction enables the synthesis of carboxylic acids, esters or amides from methyl ketones. The reaction proceeds via exhaustive a-halogenation and then substitution by a nucleophile to liberate a haloform. The methyl group therefore behaves as a masked leaving group. The reaction methodology has undergone several important developments in the last 200 years, transitioning from a diagnostic test of methyl ketones to a synthetically useful tool for accessing complex esters and amides. The success of the general approach has been exhibited through the use of the reaction in the synthesis of many different complex molecules in fields ranging from natural product synthesis, pharmaceuticals, agrochemicals, fragrants and flavouring. The reaction has not been extensively reviewed since 1934. Therefore, herein we provide details of the history and mechanism of the haloform reaction, as well as an overview of the developments in the methodology and a survey of examples, particularly in natural product synthesis, in which the haloform reaction has been used.

Microwave-Assisted Synthesis of Bis-(Hydroxybenzylidene)-Cycloalkanones via Acid Catalyzed Claisen-Schmidt Condensation

In the present study, bis-(hydroxybenzylidene)cycloalkanone derivatives were synthesized by Claisen-Schmidt condensation using cycloalkanones and arylaldehydes in the presence of HCl as an acid catalyst. The synthetic reaction was carried out under microwave irradiation. The structure of the synthesized compounds was determined by UV, IR, 1H NMR spectroscopic methods. The obtained reaction yields were not optimal due to the self-polymerization of p-hydroxybenzaldehyde in an acid solution.

Synthetic Approaches Toward Imidazo‐Fused Heterocycles: A Comprehensive Review

ABSTRACTImidazole moiety when fused with other heterocyclic system form numerous compounds with different types of pharmacological and biological activities. In this review, we discussed a comprehensive analysis of the synthetic methodologies and reaction mechanisms for imidazo‐fused heterocyclic molecules. These molecules represent a crucial class of compounds due to their significant applications and versatile chemical reactivity. This article meticulously examined various synthetic routes for the construction of imidazo‐fused heterocycles, ranging from traditional methods to modern approaches such as microwave‐assisted reactions, NPs‐catalyzed reactions, light‐mediated synthesis, electrochemical reactions, and transition metal‐free synthesis routes. By consolidating the current knowledge and highlighting future directions, this review aims to serve as a treasure for research community in the fields of organic chemistry, medicinal chemistry, and material science.

Synthesis, DFT investigation, antioxidant, molecular docking and ADME-T properties of N′-(1-benzylpiperidin-4-ylidene) furan-2-carbohydrazide derivatives against SARS-CoV-2 spike proteins

ABSTRACT A novel synthetic reaction was used to produce a piperidine derivative, specifically N′-(1-benzylpiperidin-4-ylidene)furan-2-carbohydrazide (BPFC). The structure of the synthesised compound was confirmed through FT-IR, 1H-NMR and 13C-NMR spectral analysis. DFT calculations were performed to optimise structural parameters and investigate Natural Bond Orbital (NBO) analysis, Frontier Molecular Orbitals (FMOs), Molecular Electrostatic Potentials, Mulliken Charge Analysis, and Non-linear Optical properties. The predicted chemical shift values align well with the expected results. The antioxidant properties of the newly synthesised compound were assessed using DPPH, ABTS, and H2O2 radical scavenging assays. Molecular docking studies were also carried out to explore the binding mechanism of the compound with COVID-19-related proteins, particularly 6WCF and 6LU7. Additionally, the synthesised compound was assessed for drug-likeness and ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties, revealing favourable pharmacokinetic profiles without any signs of toxicity.

Recent Advances in the Application of 2-Aminobenzothiazole to the Multicomponent Synthesis of Heterocycles.

Heterocycles are a vital class of compounds in numerous fields, including drug discovery, agriculture, and materials science. Efficient methods for the synthesis of heterocycles remain critical for meeting the demands of these industries. Recent advances in multicomponent reactions (MCRs) utilizing 2-aminobenzothiazole (ABT) have shown promising results for the formation of heterocycles. The versatility of 2-aminobenzothiazole in this context has enabled the rapid and efficient construction of diverse heterocyclic structures. Various synthetic methodologies and reactions involving 2-aminobenzothiazole are discussed, highlighting its importance as a valuable building block in the synthesis of complex heterocycles. The potential applications of these heterocycles in drug discovery and material science are also explored. Overall, this review provides a comprehensive overview of the current state of research in the field and offers insights into the future directions of this promising area of study. We highlight the potential of ABT as a versatile and sustainable starting material in heterocyclic synthesis via MCRs, with significant implications for the chemical industry.

Metal‐Supported Heterogeneous Catalysts for the Synthesis of Nitrogen‐Containing Heterocycles: A Comprehensive Review

AbstractThe use of metals in the preparation of heterocycles has become increasingly popular due to several key advantages of metals as catalysts. These include recycling capability, eco‐friendliness, simplicity of catalyst preparation and separation, longer lifespan, abundance, and higher yields. As a result of their novel applications in organic, inorganic, medicinal, industrial, polymer chemistry, material sciences, nanotechnology, and biological processes, the utilization of nitrogen‐containing heterocycles has rapidly increased in recent years. Various nitrogen‐containing organic moieties are used in therapeutic processes to enhance effectiveness against several bacterial and viral diseases. This review covers the preparation of imidazoles, triazoles, tetrazoles, pyridine derivatives, azo compounds, pyrimidines, quinoxalines, and quinolines using metals as heterogeneous catalysts. It provides an overview of current methodologies for metal‐assisted heterogeneous catalytic reactions, including product yield, operating temperature, and solvents, among other factors. Heterogeneous catalyst‐mediated organic synthetic reactions offer several advantages, particularly in medicinal chemistry, pharmaceuticals, and industrial applications, by reducing time and energy consumption. This review emphasizes recent advancements in the fabrication of nitrogen heterocycles utilizing heterogeneous catalysts, taking into account various economic, eco‐friendly, and user‐friendly considerations. Additionally, it discusses the benefits, reaction conditions, and yields reported in the literature over the past six years.

A Decade of Advancement in Ruthenium (II)-Catalyzed Direct C-H Activation and Consequent C-C/C-N Bond Formation Using Microwave Heating

: Transition-metal catalysed activation of unreactive C-H bonds and subsequent C-C bond formation has emerged as a principal and essential tool in the field of synthetic organic chemistry. On the other hand, the microwave heating technique has been intensively used to carry out organic transformation of almost all kinds and has become a promising non-conventional technique for performing synthetic reactions. Direct C-H activation for C-C bond-forming reactions using ruthe-nium as a catalyst is currently a hot topic and represents a cost-effective synthetic pathway in or-ganic chemistry which is accompanied by the advantages of MW irradiation resulting in shorter reaction time and greener 3 as well as sustainable accomplishments.

Decoding the Promiscuous Activity of Bile Salt Hydrolase

The recently identified bile salt hydrolase (BSH) from gastrointestinal bacteria catalyzes the formation of bacterial bile acid amidates (BBAAs), significantly impacting host metabolism. While this activity was characterized as promiscuous, the underlying mechanism was not explored. This commentary proposes that BSH exhibits condition promiscuity, where typical hydrolytic enzymes catalyze synthetic reactions under specific conditions. Drawing parallels with micellar enzymology, we suggest that bile salts, acting as both substrates and micelle-forming agents, create an environment conducive for BSH to catalyze amidation. This represents a potential first in vivo demonstration of such a mechanism. Future investigations should explore BSH-catalyzed reactions with bile salts below critical micelle concentrations and alternative surfactants to validate this hypothesis.

Solution Synthesis and Diffusion-Mediated Formation Pathway of NbTe4 Particles.

NbTe4 is an important material because of its fundamental low-temperature electronic behavior and its potential interest for thermoelectric, catalytic, and phase-change applications, especially as nano- and microscale particles. As a tellurium-rich group V transition metal telluride, bulk NbTe4 is typically synthesized through high-temperature solid-state or metal flux reactions and NbTe4 films can be made by sputtering and annealing, but NbTe4 is generally not amenable to the lower-temperature solution-based syntheses that yield small particles. Here, we demonstrate a solvothermal route to NbTe4 particles that is based on mainstream colloidal nanoparticle synthesis. We find that the reaction proceeds in situ through a multistep pathway that begins by first forming elemental tellurium needles. NbTe4 then deposits on the surface of the tellurium needles through a diffusion-based process. Time-point studies throughout the reaction reveal that crystallographic relationships between Te and NbTe4 define how the diffusion-based reaction proceeds and help to rationalize the morphology of the resulting NbTe4 particles. As synthesized, NbTe4 particles exhibit a surface consisting of predominantly Nb-Te and reduced NbOx species, but after storage, surface oxidation transforms these species to primarily Nb2O5 and TeO2, while the NbTe4 remains unchanged. These synthetic capabilities and reaction pathway insights for NbTe4, made using a solvothermal method, will help to advance future studies on the properties and applications of this and related tellurides.

Versatile Light-Mediated Synthesis of Degradable Bottlebrush Polymers Using α-Lipoic Acid.

Bottlebrush polymers have a variety of useful properties including a high entanglement molecular weight, low Young's modulus, and rapid kinetics for self-assembly. However, the translation of bottlebrushes to real-world applications is limited by complex, multi-step synthetic pathways and polymerization reactions that rely on air-sensitive catalysts. Additionally, most bottlebrushes are non-degradable. Herein, we report an inexpensive, versatile, and simple approach to synthesize degradable bottlebrush polymers under mild reaction conditions. Our approach relies on the "grafting-through" polymerization of α-lipoic acid (LA)-functionalized macromonomers. These macromonomers can be polymerized under mild, catalyst-free conditions, and due to reversibility of the disulfide bond in LA, the resulting bottlebrush polymers can be depolymerized by cleaving disulfide backbone bonds. Bottlebrushes with various side-chain chemistries can be prepared through the atom transfer radical polymerization (ATRP) of LA-functionalized macromonomers, and the backbone length is governed by the macromonomer molecular weight and solvent polarity. We also demonstrate that LA-functionalized macromonomers can be copolymerized with acrylates to form degradable bottlebrush networks. This work demonstrates the preparation of degradable bottlebrush polymers with a variety of side-chain chemistries and provides insight into the light-mediated grafting-through polymerization of dithiolane-functionalized macromonomers.

Copper-Catalyzed P-H Bond Functionalization to Construct Biaryl Phosphafluorene Oxides.

In this study, in the presence of a certain amount of cuprous chloride catalyst and the synergistic action of ligand and base, the P-H bond activation of secondary biarylphosphine oxides and the attack on the β-site of orthoaryl groups were investigated. Phosphafluorene oxide was synthesized by C-H bond activation and an intramolecular dehydrogenation coupling reaction to construct a C-P bond. Subsequently, we conducted a control experiment and made reasonable speculations about its mechanism. In addition, the use of phosphafluorene as a ligand in some synthetic catalytic reactions has shown excellent results, demonstrating its excellent catalytic properties.

Recent Progress in Synthesis of Alkyl Fluorinated Compounds with Multiple Contiguous Stereogenic Centers.

Organic fluorides are widely used in pharmaceuticals, agrochemicals, material sciences, and other fields due to the special physical and chemical properties of fluorine atoms. The synthesis of alkyl fluorinated compounds bearing multiple contiguous stereogenic centers is the most challenging research area in synthetic chemistry and has received extensive attention from chemists. This review summarized the important research progress in the field over the past decade, including asymmetric electrophilic fluorination and the asymmetric elaboration of fluorinated substrates (such as allylic alkylation reactions, hydrofunctionalization reactions, Mannich addition reactions, Michael addition reactions, aldol addition reactions, and miscellaneous reactions), with an emphasis on synthetic methodologies, substrate scopes, and reaction mechanisms.

Non-carrier immobilization of yeast cells by genipin crosslinking for the synthesis of prebiotic galactooligosaccharides from plant-derived galactose

Galactooligosaccharides (GOS), as mimics of human milk oligosaccharides, are important prebiotics for modulating the ecological balance of intestinal microbiota. A novel carrier-free cell immobilization method was established using genipin to cross-link Kluyveromyces lactis CGMCC 2.1494, which produced β-galactosidase, an enzyme essential for GOS synthesis. The resulting immobilized cells were characterized as stable by thermogravimetric analysis and confirmed to be crosslinked through scanning electron microscopy analysis (SEM) and Fourier transform infrared spectroscopy (FTIR). The Km and Vmax values of β-galactosidase in immobilized cells towards o-nitrophenyl β-D-galactoside were determined to be 3.446 mM and 2210 μmol min−1 g−1, respectively. The enzyme in the immobilized showed higher thermal and organic solvent tolerance compared to that in free cells. The immobilized cells were subsequently employed for GOS synthesis using plant-derived galactose as the substrate. The synthetic reaction conditions were optimized through both single-factor experiments and response surface methodology, resulting in a high yield of 49.1 %. Moreover, the immobilized cells showed good reusability and could be reused for at least 20 batches of GOS synthesis, with the enzyme activity remaining above 70 % at 35 °C.

Recent Advances in the Transition Metal (Cu, Ni, Fe, Co) Catalyzed OrganicReaction: A Mini-Review

: Transition metals have a useful and significant role in catalysis. They are considered essential chemical tools in various organic transformations. Transition Metal catalysts are extensively used in the research laboratory and industrial/manufacturing processes. Indeed, it is hard to find a complex synthetic reaction or an industrial process that does not, at some stage, require a metal catalyst. They have a paramount impact on organic transformations and have been considered the core part of catalysis in chemistry. This article reports the catalyst reaction by transition metals (Cu, Ni, Fe, and Co).