Michael Addition Research Articles

ZnCl2-Based Deep Eutectic Solvent as Solvent-Catalyst in the Michael Addition Reaction of Pyrrole to Maleimide

The use of deep eutectic solvents (DESs) as catalysts presents indisputable advantages, for example, their simplicity of preparation, high biodegradability, and recyclability, as well as zero toxicity and their effectiveness as environmentally friendly reaction media. However, aspects related to their reactivity and catalytic activity are still unclear. In this work, we explore the versatility of ChCl/ZnCl2 DES in the formation of C-C bonds through the Michael-type addition of pyrrole to maleimide, where ChCl/ZnCl2 DES leads to catalysis and chelation of the substrates, thus describing a recommended method for the construction of C-C bonds with high atomic economy. We describe experimental and theoretical aspects that explain the ability of ChCl/ZnCl2 DES in the presence of water to act as a catalyst in the formation of C-C bonds between pyrrole and maleimide. The potential energy surface showed that the ChCl and the zinc-zincate species 2ZnCl2·3H2O, formed by the interaction between zinc chloride and water, decrease the relative free Gibbs energy values for all the species involved in the reaction mechanism (TSs, intermediates, product), favoring the kinetics and thermodynamics of the Michael addition.

Gem-Difluorovinyl and trifluorovinyl Michael acceptors in the synthesis of α,β-unsaturated fluorinated and nonfluorinated amides

The incorporation of fluorine atoms within the structure of organic compounds is known to exert a significant impact on their electronic properties, thereby modulating their reactivity in diverse chemical transformations. In the context of our investigation, we observed a striking illustration of this phenomenon. A Michael addition involving gem-difluorovinyl and trifluorovinyl acceptors was successfully achieved, demonstrating high stereoselectivity. This selectivity was further elucidated through theoretical calculations. Using this methodology, a series of new α,β-unsaturated amides, both fluorinated and nonfluorinated, were synthesized.

Fine-Tuned "Click" Functionalization of PAMAM Dendrimers with a Linear Fluorinated Guanidino Linker: Synthesis, Characterization, and Applications.

This study presents the synthesis, characterization, and application of multifunctional PAMAM G2 and G4 dendrimers decorated with a linear fluorinated guanidino linker designed to improve gene delivery efficiency while minimizing cytotoxicity. For the first time, we were able to fine-tune the degree of grafting (DG) during the functionalization process through efficient "click" Michael addition, achieving the synthesis of a collection of six PAMAM conjugates that showed a significant enhancement in transfection efficiency (TE), surpassing the performance of traditional nonviral vectors. The incorporation of fluorinated moieties not only facilitated better deoxyribonucleic acid (DNA) condensation and TE but also introduced potential applications in 19F magnetic resonance imaging thanks to the sharp and intense fluorine nuclear magnetic resonance signals and favorable relaxation parameters. The new dendrimer conjugates demonstrated a promising balance between low cytotoxicity and high TE, with the low-generation PAMAM G2 with lower DG being the best-performing conjugate, making them strong candidates for further development in gene therapy. These findings highlight the potential of these multifunctional PAMAM dendrimers as efficient, nontoxic, and trackable gene delivery vectors.

Switch of Five Contiguous Chiral Centers in the Synthesis of Both Enantiomers of Hajos-Parrish Ketone Analogs via Diphenylprolinol Silyl Ether-Mediated Domino Reaction.

Both enantiomers of functionalized Hajos-Parrish ketone (HPK) analogs were prepared with excellent diastereoselectivities and enantioselectivities using the same chiral catalyst under two slightly different conditions. In condition A, dioxane was used as the solvent with 3 equivalents of water. In condition B, acetonitrile was used as the solvent with 30 equivalents of water, followed by epimerization with a base in a one-pot. The reaction consisted of a domino reaction including a diphenylprolinol silyl ether-mediated asymmetric Michael reaction and an intramolecular Henry reaction. In the Michael reaction, depending on the solvent and water amounts, syn- and anti-isomers were selectively synthesized with excellent enantioselectivity, in which the absolute configuration at C5 (indanone numbering) was opposite. The subsequent Henry reaction was diastereoselective, in which the C5 substituent controlled the three chiral centers in a highly diastereoselective manner. The final base treatment in condition B caused epimerization, changing the stereochemistry at C6. Switching more than two chiral centers with high enantioselectivity is extremely difficult using the same chiral catalyst; the present reaction is a very rare enantiodivergent reaction that switches five continuous chiral centers with high enantioselectivity.

Injectable Hydrogels for Programmable Nanoparticle Release

AbstractInjectable hydrogels represent a promising strategy for the extended release of biological molecules, thereby reducing the frequency of injections. This study introduces a novel system based on Michael addition of dextran and polyethylene glycol (PEG) polymers functionalized with oxanorbornadiene (OND) and thiol groups, respectively. Reliable control over gelation speed allows administration by injection using a simple syringe‐to‐syringe mixing protocol that entrains more than 95% of virus‐like particle (VLP) cargo. A combination of retro‐Diels‐Alder and hydrolytic ester bond cleavage gives rise to programmable release of the VLPs. Different release profiles, including burst, linear, and delayed release over a two‐week period, are engineered using different OND linkages, and rheological characterization shows the hydrogels to be well within the desired range of stiffness for subcutaneous use. The modular nature of this system offers a generalizable platform for developing degradable materials aimed at sustained release biomedical applications.

Hydrogen-Bonded Supramolecular Network Enabled Gentle Reprogramming of Liquid Crystal Elastomer toward Evolutionary Robot.

In nature, many organisms augment chances of survival by reprogramming their structures to evolving environment, among which sea squirts being a prime example. Such reprogramming has been demonstrated in liquid crystal elastomer (LCE) actuator assembled with heat assistance. However, the required temperature being higher than the actuation temperature limits its application. Here, we reported a hydrogen-bonded supramolecular network LCE to construct soft modular and reprogrammable actuator by assembling with a gentle heat treatment. Leveraging the Michael addition reaction, we introduced hydrogen bonding to the LCE matrix with functionalized pyridine monomers. Experimental and molecular dynamics modeling proved the efficient dynamic hydrogen bond exchange at 60 °C, significantly lower than the actuating temperature of the LCE. This gave rise to the reversible and robust adhesion of the same collection of LCE modules capable of being built into different bilayers and performing various morphing upon a short thermal stimulation. Therefore, we demonstrated that these comparatively weak cross-links enabled reconfiguration of the LCE actuator. With the developed hydrogen-bonding LCEs, we built proof-of-concept modular reprogrammable robot, performing crawling, sailing, and microcircuit repair tasks. This bioinspired and efficient method for evolutionary LCE robot offers a viable path for further development of intelligent actuators sustainable in complex environments.

Hydrogen‐Bonded Supramolecular Network Enabled Gentle Reprogramming of Liquid Crystal Elastomer toward Evolutionary Robot

AbstractIn nature, many organisms augment chances of survival by reprogramming their structures to evolving environment, among which sea squirts being a prime example. Such reprogramming has been demonstrated in liquid crystal elastomer (LCE) actuator assembled with heat assistance. However, the required temperature being higher than the actuation temperature limits its application. Here, we reported a hydrogen‐bonded supramolecular network LCE to construct soft modular and reprogrammable actuator by assembling with a gentle heat treatment. Leveraging the Michael addition reaction, we introduced hydrogen bonding to the LCE matrix with functionalized pyridine monomers. Experimental and molecular dynamics modeling proved the efficient dynamic hydrogen bond exchange at 60 °C, significantly lower than the actuating temperature of the LCE. This gave rise to the reversible and robust adhesion of the same collection of LCE modules capable of being built into different bilayers and performing various morphing upon a short thermal stimulation. Therefore, we demonstrated that these comparatively weak cross‐links enabled reconfiguration of the LCE actuator. With the developed hydrogen‐bonding LCEs, we built proof‐of‐concept modular reprogrammable robot, performing crawling, sailing, and microcircuit repair tasks. This bioinspired and efficient method for evolutionary LCE robot offers a viable path for further development of intelligent actuators sustainable in complex environments.

Synthesis and Anti-Inflammatory and Analgesic Potentials of Ethyl 2-(2,5-Dioxo-1-Phenylpyrrolidin-3-yl)-2-Methylpropanoate

Background/Objectives: Inflammation and analgesia are two prominent symptoms and often lead to chronic medical conditions. To control inflammation and analgesia, many marketed drugs are in practice but the majority of them have severe side effects. Methods: This study involved the synthesis of a pivalate-based Michael product and evaluated it for in vitro COX-1, COX-2, and 5-LOX inhibitory potentials using specific assays. Molecular docking studies were also assessed. Based on the in vitro results, the compound was also subjected to in vivo anti-inflammatory and antinociceptive studies. Results: The pivalate-based Michael product (MAK01) was synthesized by an organocatalytic asymmetric Michael addition of ethyl isobutyrate to N-phenylmaleimide with an isolated yield of 96%. The structure of the compound was confirmed through 1H and 13C NMR analyses. The observed IC50 values for COX-1, COX-2, and 5-LOX were 314, 130, and 105 μg/mL, respectively. The molecular docking studies on the synthesized compound showed binding interactions with the minimized pockets of the respective enzymes. In a carrageenan model, a percent reduction in edema when administered at 10 mg/kg (a reduction of 33.3 ± 0.77% at the second hour), 20 mg/kg (a reduction of 34.7 ± 0.74% at the second hour), and 30 mg/kg (a reduction of 40.58% ± 0.84% after the fifth hour) was observed. The compound showed a significant response at concentrations of 50, 100, and 150 mg/kg with latency times of 10.32 ± 0.82, 12.16 ± 0.51, and 12.93 ± 0.45 s, respectively. Conclusion: In this study, we synthesized a pivalate-based Michael product for the first time. Moreover, based on its rationality and potency, it was found to be an effective future medicine for the management of analgesia and inflammation.

Synthesis of Amorphous Cellulose Derivatives via Michael Addition to Hydroxyalkyl Acrylates for Thermoplastic Film Applications

The aim of this study is to prepare new cellulose derivatives that show good feasibility and processability. Accordingly, in this study, we demonstrate Michael addition to hydroxyalkyl acrylates, that is, 2-hydroxyethyl and 4-hydroxybutyl acrylates (HEA and HBA, respectively), to synthesize amorphous cellulose derivatives under alkaline conditions. The reactions were carried out in the presence of LiOH in ionic liquid (1-butyl-2,3-dimethylimidazolium chloride)/N,N-dimethylformamide (DMF) solvents at room temperature or 50 °C for 1 h. The Fourier transform infrared and 1H nuclear magnetic resonance (NMR) measurements of the products supported the progress of Michael addition; however, the degrees of substitution (DS) were not high (0.3–0.6 for HEA and 0.6 for HBA). The powder X-ray diffraction analysis of the products indicated their amorphous nature. The cellulosic Michael adduct from HEA with DS = 0.6 was swollen with high polar organic liquids, such as DMF. In addition to swelling with these liquids, the cellulosic Michael adduct from HBA was soluble in dimethyl sulfoxide (DMSO), leading to its 1H NMR analysis in DMSO-d6. This adduct was found to form a cast film with flexible properties from its DMSO solutions. Furthermore, films containing an ionic liquid, 1-butyl-3-methylimidazolium chloride, showed thermoplasticity. The Michael addition approach to hydroxyalkyl acrylates is quite effective to totally reduce crystallinity, leading to good feasibility and processability in cellulosic materials, even with low DS. In addition, the present thermoplastic films will be applied in practical, bio-based, and eco-friendly fields.

BRET Nano Q-Body: A Nanobody-Based Ratiometric Bioluminescent Immunosensor for Point-of-Care Testing.

We developed a nanobody-based homogeneous bioluminescent immunosensor to achieve a one-pot detection for point-of-care testing (POCT). This immunosensor was named BRET nano Q-body as its emission color changes via bioluminescence resonance energy transfer (BRET) upon antigen addition. NanoLuc luciferase and a cysteine-containing tag were fused to the N-terminus of the nanobody, which was labeled with a fluorescent dye via thiol-maleimide Michael addition. The nanobody employed in this proof-of-principle experiment recognizes methotrexate (MTX), a chemotherapeutic agent. After optimizing the fluorescent dye and linker, the BRET nano Q-body dose-dependently exhibited a greater than 7-fold increase in emission ratio (TAMRA/NanoLuc). Moreover, we found its superior thermostability endurance in organic solvents, reducing agents, and detergents due to the robust structure of nanobody, as well as accommodation in biological fluids, such as milk, serum, and whole blood without dilution, with limits of detection of 0.50, 1.6, and 3.7 nM, respectively. Furthermore, the BRET nano Q-body was subjected to lyophilization and fabricated into a paper device, which markedly improved its portability and enabled more than one month of storage at 25 °C. The paper device also performed appropriate functions in the biological fluids without any dilution and can be used for on-site therapeutic drug monitoring of MTX. Altogether, we developed a powerful tool, the BRET nano Q-body, for POCT, and demonstrated its applicability in several biological fluids. In addition, we confirmed the feasibility of paper devices, which are expected to be transformative for in situ detection in therapeutic, diagnostic, and environmental applications.

Organocatalytic Asymmetric Synthesis of C-N Atropisomers with Pyrrole, Oxindole and Succinimide Scaffold.

An asymmetric synthesis of C-N atropisomers with pyrrole, oxindole and succinimide moities was developed via organocatalytic desymmetric Michael addition of 3-pyrrolyloxindole with prochiral N-aryl maleimides. The C-N atropisomers were obtained in acceptable yields with high diastero- and enantioselectivities (>20:1 dr, up to >99% ee). C-N Rotational energy barrier has also been determined.

Multicomponent Cyanation of 2‐Amino‐3‐cyano‐4H‐chromenes in Aqueous Media

AbstractChromenes represent a pivotal molecular structure found in a diverse range of biologically active compounds. Specifically, derivatives of 2‐amino‐3‐cyano‐4H‐chromene have demonstrated pharmacological applications, displaying potential antioxidant and anticancer activities. This has heightened interest in the exploration of new and more efficient methods for their synthesis. In recent years, few examples have emerged, focusing on the organocatalytic and enantioselective synthesis of 2‐amino‐3‐cyano‐4H‐chromene derivatives, although the overall number of works to date is limited. In this study, we present the results of the synthesis of 2‐amino‐4H‐chromen‐3,4‐dicarbonitriles through a Michael addition of cyanide to 2‐iminochromenes. To achieve this, we utilized a mild source of cyanide (acetone cyanohydrin), green solvents and catalytic conditions at room temperature, via a multicomponent approach. Furthermore, we initiated the enantioselective study of this process using chiral organocatalysts obtaining promising preliminary results.

A Photochemical Strategy towards Michael Addition Reactions of Cyclopropenes.

The development of Michael addition reactions to conjugated cyclopropenes is a challenge in organic synthesis due to the fleeting and reactive nature of such strained Michael acceptor systems. Herein, the development of a photochemical approach towards such conjugated cyclopropenes is reported that serves as a strategic entry point to densely functionalized cyclopropanes in a diastereoselective fashion. The process involves the light-mediated generation of transient cyclopropenyl α,β-unsaturated esters from vinyl diazo esters, followed by an organic base catalyzed nucleophilic addition of N-heterocycles to directly access β-N-heterocyclic cyclopropanoic esters. With this synergistic approach, various trisubstituted cyclopropanes bearing N-heteroaryl and N-heterocyclic rings such as indole, pyrrole, benzimidazole, isatin, pyridinone and quinolinone were accessed efficiently in good yield and decent to good diastereoselectivities. Further, β-indolyl cyclopropanoic acids have been synthesized and were successfully evaluated as FABP-4 inhibitors. Theoretical calculations have been performed to elucidate the mechanism which was further supported by experimental findings.

A Photochemical Strategy towards Michael Addition Reactions of Cyclopropenes

A Photochemical Strategy towards Michael Addition Reactions of Cyclopropenes

Regio-, Enantio-Controlled Cascade Oxa-Michael Addition of Hydroxyl Amine: Synthesis of Dihydro-1,2-Oxazines.

Herein, we disclose a cinchona-alkaloid-based squaramide-catalyzed intermolecular oxa-Michael cascade addition cyclization of N-protected hydroxyl amine to formyl-tethered Michael acceptors toward the synthesis of enantioenriched 1,2-oxazine scaffolds. Generally, good yield (up to 78%), good to excellent enantiomeric ratio (up to 98:2 er), and excellent regioselectivity (>19:1) were observed. Furthermore, the scalability of this methodology and a successful demonstration of postsynthetic transformations have been accomplished.

Diverse reactivity of maleimides in polymer science and beyond

AbstractMaleimides are remarkably versatile functional groups, capable of participating in homo‐ and copolymerizations, Diels–Alder and (photo)cycloadditions, Michael additions, and other reactions. Their reactivity has afforded materials ranging from polyimides with high upper service temperatures to hydrogels for regenerative medicine applications. Moreover, maleimides have proven to be an enabling chemistry for pharmaceutical development and bioconjugation via straightforward modification of cysteine residues. To exert spatiotemporal control over reactions with maleimides, multiple approaches have been developed to photocage nucleophiles, dienes, and dipoles. Additionally, further substitution of the maleimide alkene (e.g. monohalo‐, dihalo‐, thio‐, amino‐ and methyl‐maleimides, among other substituents) confers tunable reactivity and dynamicity, as well as responsive mechanical and optical properties. In this mini‐review, we highlight the diverse functionality of maleimides, underscoring their notable impact in polymer science. This moiety and related heterocycles will play an important role in future innovations in chemistry, biomedical, and materials research. © 2024 The Author(s). Polymer International published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Synergistic catecholamine and coordination chemistry for enhanced bioactivity and secondary grafting activity of zirconia dental implants

The inherent bioinertness of zirconia (ZrO2) hinders its early bone integration, presenting a significant obstacle to its widespread use in dental implant technologies. Addressing this, we developed a surface coating leveraging the synergistic effects of catecholamine and coordination chemistry inspired by the mussel byssus cuticle. This coating, named PDPA@Sr, is enriched with strontium ions and amine groups, resulting from a simple immersion of polydopamine (PD)-coated ZrO2 in an alkaline strontium chloride and poly(allylamine) (PA) solution. Compared to conventional mussel-inspired PD coatings, PDPA@Sr demonstrates enhanced aesthetic properties and mechanical stability. The continuous release of strontium ions from the coating significantly enhances osteogenesis, while the abundant surface amine groups offer notable antibacterial effects. More importantly, these amine groups also enable a variety of chemical modifications, including electrostatic adsorption, carbodiimide chemistry, Michael addition, Schiff base formation, and click chemistry, thus providing a multifaceted platform for the advanced surface modification of ZrO2 implants.

Mutations Selectively Evolving Peroxidase Activity Among Alternative Catalytic Functions of Human Glutathione Transferase P1-1

Glutathione transferases are detoxication enzymes with broad catalytic diversity, and small alterations to the protein’s primary structure can have considerable effects on the enzyme’s substrate selectivity profile. We demonstrate that two point mutations in glutathione transferase P1-1 suffice to generate 20-fold enhanced non-selenium-dependent peroxidase activity indicating a facile evolutionary trajectory. Designed mutant libraries of the enzyme were screened for catalytic activities with alternative substrates representing four divergent chemistries. The chemical reactions comprised aromatic substitution, Michael addition, thiocarbamoylation, and hydroperoxide reduction. Two mutants, R1 (Y109H) and an R1-based mutant V2 (Q40M-E41Q-A46S-Y109H-V200L), were discovered with 16.3- and 30-foldincreased peroxidase activity with cumene hydroperoxide (CuOOH) compared to the wildtype enzyme, respectively. The basis of the improved peroxidase activity of the mutant V2 was elucidated by constructing double-point mutants. The mutants V501 (Q40M-Y109H) and V503 (E41Q-Y109H) were found to have 20- and 21-fold improvements in peroxidase activity relative to the wildtype enzyme, respectively. The steady-state kinetic profiles of mutants R1 and V2 in the reduction of CuOOH were compared to the wildtype parameters. The kcat values for R1 and V2 were 34- and 57-fold higher, respectively, than that of the wildtype enzyme, whereas the mutant Km values were increased approximately 3-fold. A 10-fold increased catalytic efficiency (kcat/Km) in CuOOH reduction is accomplished by the Tyr109His point mutation in R1. The 23-fold increase of the efficiency obtained in V2 was caused by adding further mutations primarily enhancing kcat. In all mutants with elevated peroxidase activity, His109 played a pivotal role.

Synthetic studies on fusicoccin A: Enantioselective synthesis of the C-ring fragment

The enantioselective synthesis of the C-ring fragment of fusicoccin A is described. The TBS ether of hydroxyketone prepared by baker’s yeast reduction was converted to the α-ethylidene ketone by aldol condensation with propionaldehyde, followed by Michael reaction with divinylcopper reagent and conversion to enol triflate to afford a single diastereomer. X-ray crystallographic analysis of the crystalline derivative of the single diastereomer showed that the asymmetric carbon formed by the Michael reaction was consistent with the configuration of the C15 asymmetric carbon of fusicoccin A. The vinyl group of the enol triflate was converted to a hydroxymethyl group by selective dihydroxylation with a bulky ligand, oxidative cleavage of the resultant 1,2-diol with lead tetraacetate, and DIBAL-H reduction. The hydroxymethyl group was subsequently converted to TBS ether, followed by the hydrogenolysis of the benzyl group and Dess–Martin oxidation, accomplishing the enantioselective synthesis of the desired C-ring fragment of fusicoccin A.

High performance loose-structured membrane enabled by rapid co-deposition of dopamine and polyamide-amine for dye separation

Textile wastewater poses a significant environmental challenge that demands effective treatment. Membrane separation offers a promising solution, with high-flux tight ultrafiltration membranes recognized as an effective technology for dye separation. Polyamide amine (PAMAM), a dendritic macromolecule renowned for its regular structure, high monodispersity, excellent solubility, and tunable molecular weight, has emerged as a promising material for membrane fabrication. This study introduces a novel, eco-friendly, and time-efficient method for preparing polymer composite membranes through one-step co-deposition of dopamine (DA) and PAMAM, predominantly utilizing Michael addition and Schiff base reactions. The incorporation of ammine-rich PAMAM imparts ultra-high hydrophilicity to the membranes (contact angle of 38°), facilitating strong adhesion of water molecules to the membrane surface. The effects of co-deposition time and concentrations of DA and PAMAM on the separation performance of the resulting membranes were systematically investigated. Notably, the optimal membrane demonstrated a high water flux (126.1 L m-2h−1 bar−1), primarily due to the incorporation of PAMAM, which resulted in a looser selective separation layer. Furthermore, the membrane demonstrated excellent rejection of methyl blue (MB) at 98.9 % and low rejection os methyl orange (MO) at 13.2 %, making it well-suited for the selective separation of mixed dyes. Our approach offers a sustainable and technologically advanced solution for addressing resource recovery from textile wastewater.