aza-Michael Addition Reaction Research Articles

Deciphering the Microdroplet Acceleration Factors of Aza-Michael Addition Reactions.

Microdroplet chemistry is emerging as a great tool for accelerating reactions by several orders of magnitude. Several unique properties such as extreme pHs, interfacial electric fields (IEFs), and partial solvation have been reported to be responsible for the acceleration; however, which factor plays the key role remains elusive. Here, we performed quantum chemical calculations to explore the underlying mechanisms of an aza-Michael addition reaction between methylamine and acrylamide. We showed that the acceleration in methanol microdroplets results from the cumulative effects of several factors. The acidic surface of the microdroplet plays a dominating role, leading to a decrease of ∼9 kcal/mol in the activation barrier. We speculated that the dissociation of both methanol and trace water contributes to the surface acidity. An IEF of 0.1 V/Å can further decrease the barrier by ∼2 kcal/mol. Partial solvation has a negligible effect on lowering the activation barrier in microdroplets but can increase the collision frequency between reactants. With acidity revealed to be the major accelerating factor for methanol droplets, reactions on water microdroplets should have even higher rates because water is more acidic. Both theoretically and experimentally, we confirmed that water microdroplets significantly accelerate the aza-Michael reaction, achieving an acceleration factor that exceeds 107. This work elucidates the multifactorial influences on the microdroplet acceleration mechanism, and with such detailed mechanistic investigations, we anticipate that microdroplet chemistry will be an avenue rich in opportunities in the realm of green synthesis.

Fabrication of gelatin-polyester based biocomposite scaffold via one-step functionalization of melt electrowritten polymer blends in aqueous phase

The rapid manufacturing of biocomposite scaffold made of saturated-Poly(ε-caprolactone) (PCL) and unsaturated Polyester (PE) blends with gelatin and modified gelatin (NCO-Gel) is demonstrated. Polyester blend-based scaffold are fabricated with and without applying potential in the melt electrowriting system. Notably, the applied potential induces phase separation between PCL and PE and drives the formation of PE rich spots at the interface of electrowritten fibers. The objective of the current study is to control the phase separation between saturated and unsaturated polyesters occurring in the melt electro-writing process and utilization of this phenomenon to improve efficiency of biofunctionalization at the interface of scaffold via Aza-Michael addition reaction. Electron-deficient triple bonds of PE spots on the fibers exhibit good potential for the biofunctionalization via the aza-Michael addition reaction. PE spots are found to be pronounced in which blend compositions are PCL-PE as 90:10 and 75:25 %. The biofunctionalization of scaffold is monitored through CN bond formation appeared at 400 eV via X-ray photoelectron spectroscopy (XPS) and XPS chemical mapping. The described biofunctionalization methodology suggest avoiding use of multi-step chemical modification on additive manufacturing products and thereby rapid prototyping of functional polymer blend based scaffolds with enhanced biocompatibility and preserved mechanical properties. Additionally one-step additive manufacturing method eliminates side effects of toxic solvents and long modification steps during scaffold fabrication.

Stimuli-directed selective detection of Cu2+ and Cr2O72- ions using a pH-responsive chitosan-poly(aminoamide) fluorescent microgel in aqueous media.

In this work, the preparation of a pH-responsive fluorescent microgel, (NANO-PAMAM-CHT), is presented for the selective detection of Cu2+ and Cr2O72- ions. The NANO-PAMAM-CHT (nanosized polyaminoamide-chitosan microgel) is synthesized via aza-Michael addition reactions in a controlled and stepwise manner in water, using easily affordable starting materials like 1,4-diaminobutane, N,N'-methylene-bis-acrylamide, NIPAM and chitosan. NANO-PAMAM-CHT shows pH-responsive fluorescent properties, whereas the fluorescence intensity shows a pH-responsive change. Due to the selective fluorescence quenching, the microgel can detect both Cu2+ ions and Cr2O72- ions selectively at ambient pH in aqueous medium. Moreover, it can selectively differentiate between Cu2+ ion and Cr2O72- ions at pH ∼3 in water. The limits of detection for Cu2+ ions and Cr2O72- ions are reported as 16.9 μM and 2.62 μM, respectively (lower than the minimum allowed level in drinking water) at pH ∼7. Mechanistic study further reveals the dynamic quenching phenomenon in the presence of Cu2+ ions and static quenching in the presence of Cr2O72- ions.

A Sequential Transition Metal and Organocatalytic Approach to the Enantioselective Synthesis of C2-Spiroindoline Systems.

We report herein an organocatalyzed enantioselective spirocyclization strategy to access valuable C2-spiroindoline scaffolds bearing a quaternary stereocenter via an aza-Michael addition reaction, wherein the acid additive plays the role of dual functionality. The substrates for this key step were put together by an exo-selective, Pd-catalyzed γ-arylation of silyldienol ethers of the corresponding cyclohexenones. A close alliance between a low catalyst loading and a slow reaction rate yields C2-spiroindolines with good enantioselectivity.

Digital light 3D printed fast- and controlled degradation of covalent hydrogel networks

Digital light processing (DLP)-based 3D printing of hydrogels with sophisticated structures has been widely used in myriads of fields. However, the inherent covalently crosslinked network of hydrogels limits their further applications, such as working as sacrificial molds. In this work, a photocurable hydrogel system with labile covalent bonds suitable for DLP based printing to fabricate 3D complex hydrogel structures with fast- and controlled degradation ability is reported. The hydrogel precursor is composed of polyethylene glycol 400 (PEG400), a water soluble photoinitiator, and PEGDA575-Do, a degradable photocurable diacrylate monomer that can be degraded in aqueous condition via reversable aza-Michael addition reaction. The mechanical properties of formed hydrogels can be regulated by changing the PEG content and water content, and the degradation rate can be regulated by changing parameters such as PEG400 content, water content and the treating temperature. Moreover, the DLP printed degradable hydrogels networks can be used as sacrificial molds to fabricate structures from materials that cannot be directly used for DLP 3D printing (e.g. thermoplastic polycaprolactone (PCL), epoxy-based resin, and chocolate). As proofs-of-concept, a microfluidic chip is fabricated by using the biocompatible 3D printed hydrogel as a sacrificial template. Similarly, a flexible RFID tag and a flexible self-powered device are also prepared, demonstrating the potential applications in the field of flexible electronics.

Programmable liquid crystal elastomers with dynamic covalent siloxane bonds based on a dual self-catalytic strategy

The exchange reaction of preparing the siloxane-based liquid crystal elastomers (Si-LCEs) always require the acid or base catalysts, which will increase the complexity of the operation and reduces the stability of the Si-LCE materials. In this paper, a novel and simple dual self-catalytic strategy for producing Si-LCEs with dynamic covalent siloxane bonds was proposed. A readily available compound-1,3-bis (aminopropyl) tetramethyldisiloxane (BATS) acts as chain extender and crosslinker for elastomers and provides dynamic covalent bonds (DCBs) as well. More importantly, amino groups of BATS play the role of dual self-catalyst, not only accelerating the thiol Michael addition reaction and aza Michael addition reaction simultaneously during producing Si-LCEs, but also promoting dynamic covalent siloxane bonds exchange reaction at an elevated temperature after the formation of the cross-linked network. With this ingenious design, the obtained fully cured polydomain Si-LCEs possess excellent self-healing and processing abilities enabled by DCBs and outstanding mechanical properties facilitated by hydrogen bond, which can be easily aligned, programmed and recycled. By exploiting these dynamic features, a series of multi-functional soft actuators were realized by simple welding, showing a local fast response and precise control by light and heat. Furthermore, soft robots fabricated with a bilayer structure of Si-LCEs can perform crawling and coiling actuation controlled by near-infrared (NIR) light facilely. These results manifest that the self-catalytic dynamic covalent siloxane bonds strategy is a facile and effective approach for preparing Si-LCEs and provides a new solution for the exploitation of multi-functional liquid crystal elastomers with fast response to various stimulus.

Synthesis of Highly Substituted 1,2,4-Triazole-Based 3-Nitrochromanes through Aza-Michael Addition Reaction under Catalyst- and Base-Free Conditions

AbstractA simple and efficient aza-Michael addition reaction of 1,2,4-triazoles to functionalized 2-aryl-3-nitro-2H-chromenes has been demonstrated under catalyst- and base-free conditions. In this transformation, one intermolecular C–N bond formation is achieved at room temperature. A series of highly substituted 1,2,4-triazole-based 3-nitrochromanes were produced in good to excellent yields, up to 86%. The relative configuration of the Michael adducts was confirmed by X-ray crystallographic analysis. High yield, easy accessibility and a wide variety of functional group tolerance are the key features of this aza-Michael­ addition reaction.

Solution polymerization mechanisms and kinetics of bismaleimide with trithiocyanuric acid

Solution polymerization mechanisms and kinetics of 4,4′-bismaleimidodiphenylmethane (BMI) with trithiocyanuric acid (TCA) in n-methyl-2-pyrrolidone (NMP) were investigated. A competition between the aza-Michael addition reaction and free radical polymerization occurred, and the reaction system competed with the predominant aza-Michael addition reaction. Model-free in differential form method was used to determine activation energy along fractional conversion. In addition, the model-fitting approach was adopted to assess compensation effect parameters for the activation energy and pre-exponential factor. Then, triplet kinetic parameters were achieved. The average activation energy and frequency factor were approx. 94 kJ mol−1 and 1.45 × 1012 min−1, respectively, in the fractional conversion (α) range 0.1–0.9, and the reaction-order model, f(α) = (1 − α)0.81, was of choice. Importantly, these triplet kinetic parameters could effectively predict kinetic curves for the isothermal reaction BMI and TCA.

Branched hydrophobic tails in lipid nanoparticles enhance mRNA delivery for cancer immunotherapy

Efficient and safe delivery of vulnerable mRNA is a long-standing challenge for the broad application of the emerging mRNA-based therapeutics. Herein, a combinatorial library containing 119 novel lipids was constructed via sequential aza-Michael addition reactions of arylates and varying amines to tackle the ongoing challenge in mRNA delivery. Through in vitro screening of the lipid library on IGROV 1 cells, we identified several synthetic lipids with superior mRNA delivery efficacy. The delivery capability of these lipids was verified by the potent expression of luciferase in BALB/c mice upon intravenous administration of luciferase-encoding mRNA lipid nanoparticles (LNPs). Further investigations on the structure-activity relationship revealed that lipids with branched hydrophobic tails were better at delivering mRNA than those containing linear tails at the similar total number of carbons. In comparison to linear tails, the branched tails endowed LNPs with less inner hydrophobicity, fewer surface charges, and proper stability, which benefits the cellular uptake of LNPs and the intracellular trafficking of mRNA, thus improves the delivery efficacy of mRNA. The therapeutical potential of the lead LNPs was evaluated by delivering ovalbumin (OVA)-encoding mRNA to mice bearing B16-OVA melanoma tumors. The results demonstrated that the administration of OVA mRNA LNPs significantly activated CD8+ T cells in tumor microenvironment and substantially prohibited the growth of the aggressive B16-OVA tumors. The robust antitumor efficacy highlights the great potential of these LNPs in cancer immunotherapy.

Protonated-amino-functionalized bamboo hydrochar for efficient removal of hexavalent chromium and methyl orange

Hydrochar has great potential for wastewater treatment and the functional modification can significantly improve the ability of hydrochar to remove pollutants. Herein, a novel protonated amino-modified bamboo hydrochar (PAHC) was synthesized by the reaction of bamboo hydrochar first with acryloyl chloride, then with amine and finally with hydrochloric acid, and employed to adsorb methyl orange (MO) and Cr(VI). The PAHC was observed by BET, SEM-EDX, FTIR, elemental analysis, and zeta potential to monitor its textural properties before and after adsorption. The amino groups were effectively grafted onto the hydrochar by the Aza-Michael addition reaction through characterization. Adsorption results showed the PAHC possessed high MO/Cr(VI) adsorption amounts (515.35/523.57 ​mg ​g−1 ​at 298 ​K) because the introduction of protonated amine was pivotal in eliminating anionic pollutants by electrostatic interaction. The Langmuir/Freundlich model can well describe MO/Cr(VI) adsorption, which proves the removal process belongs to MO monolayer/Cr(VI) multilayer adsorption. The PAHC also exhibited a good regeneration performance. These results indicate the PAHC is a green and efficient adsorbent with potential application in wastewater treatment.

Proline-Catalyzed Diastereoselective Synthesis of Dihydroquinolinyl-Spirooxindole via Aza-Michael/Aldol Reaction

AbstractAn efficient diastereoselective synthesis of 1′,4′-dihydro-2′H-spiro[indoline-3,3′-quinolin]-2-one derivatives was achieved using catalytic amount of l-proline. The key reactions involved in the present tandem reaction are aza-Michael addition and aldol reaction. This atom economic reaction proceeded under mild conditions with a broad substrate scope and excellent diastereoselectivity in good to excellent yields.

Amino-Ene Click Reaction of Electron-Deficient π-Conjugated Molecules with Negative Activation Enthalpies.

An amino-ene click reaction is a type of aza-Michael addition reaction that is congruent with click chemistry in terms of its reaction efficiency and rate under mild conditions. The amino-ene click reaction is increasingly recognized as a prominent synthetic tool to form C-N bonds in the context of organic materials chemistry and polymer chemistry. Herein, an unconventional amino-ene click reaction with negative activation enthalpies, in which an electron-deficient π-conjugated molecule, such as a naphthalenediimide, reacts with an amine faster at lower temperatures is reported. The detailed study of the reaction mechanism reveals that the amino-ene click reaction proceeds via a pre-equilibrium reaction, the key to which is the formation of a stable reaction intermediate due to the solvation and charge delocalization on the π-core. By optimizing the reaction conditions, it was demonstrated that the amino-ene click reaction proceeded faster at 273 K than at 347 K, which was easily observed visually.

Synthesis, Biological Activity Evaluation and Molecular Docking of Imidazole Derivatives Possessing Hydrazone Moiety.

In an attempt to identify potential active anticancer agents with low cytotoxic properties and CA inhibitors, a new series of hybrid compounds incorporating imidazole ring and hydrazone moiety as part of their structure were synthesized by aza-Michael addition reaction followed by intramolecular cyclization. The structure of synthesized compounds was elucidated using various spectral techniques. Synthesized compounds were evaluated for their in vitro anticancer (prostate cell lines; PC3) and CA inhibitory (hCA I and hCA II) activity. Among them, some compound displayed remarkable anticancer activity and CA inhibitory activity with Ki values in range of 17.53±7.19-150.50±68.87 nM against cytosolic hCA I isoform associated with epilepsy, and 28.82±14.26-153.27±55.80 nM against dominant cytosolic hCA II isoforms associated with glaucoma. Furthermore, the theoretical parameters of the bioactive molecules were calculated to establish their drug-likeness qualities. The proteins used for the calculations are prostate cancer protein (PDB ID: 3RUK and 6XXP). ADME/T analysis was carried out to examine the drug properties of the studied molecules.

Cinchona Alkaloid-derived Polymer Catalysts for Asymmetric Aza-Michael Addition of Aniline to Chalcone

Chiral cinchona alkaloid-derived polymers having cinchona squaramide repeating units showed excellent catalytic performance in the asymmetric aza-Michael reaction between aniline and chalcone. By the use of the polymer organocatalyst, chiral β-amino ketones were yielded in a highly enantioselective manner (up to >99% ee) under solvent-free conditions. The insolubility of the polymer catalyst facilitated the separation of the catalyst from the reaction mixture. The recovered polymer was reused several times without any loss of its catalytic performance. The cinchona alkaloid-derived polymers reported in this paper catalyzed an aza-Michael addition reaction more effectively than already-reported catalysts. The reaction was excellent when the squaramide-linked polymer was used under solvent-free conditions. The polymer catalyst was recoverable by an easy separation from the reaction solution and reused without loss of the catalytic performance.

One-Pot Construction of β-Selective Quinolines with γ-Quaternary Carbon from Vinylquinolines with Active Ylides via Pd/Sc/Brønsted Acid Co-Catalysis

Vinyl-substituted N-heterocycles, as more challenging inert olefins with more stable reactivity, have brought about widespread attention in the reaction of aza-Michael addition or reduction coupling reaction. Here, we report a [Pd(η3-C3H5)Cl]2/Sc(OTf)3-catalyzed catalytic process accelerated by Brønsted acids with a β-selective aza-Michael addition to yield a γ-quaternary carbon from vinyl-substituted quinolines, diazos, and anilines/alcohols in one pot. The generation of anhydride analogues from Brønsted acid and the counter anion (OTf–) of Lewis acid promotes the activation of the corresponding Lewis acid and the nearly quantitative transformation. Both π-cation and coordination interactions play pivotal roles in the activation of the vinyl-quinoline substrates by the activated Lewis acid Sc(OTf)3. The control mechanistic evidence and DFT calculations presented a Pd/Sc/Brønsted acid co-catalyzed addition mechanism. The triple co-catalytic system provides a strategy for the activation of vinyl-quinolines with a linear selectivity containing γ-quaternary carbon, and the developed method shows a broad substrate scope varying from alkyl/aryl alcohols and amines which provides a general and rapid strategy for the quinoline-based diverse library construction.

Acrylonitrile adducts: design, synthesis and biological evaluation as antimicrobial, haemolytic and thrombolytic agent

In this work, five acrylonitrile adducts were screened for antibacterial activity against Gram-positive Bacillus subtilis, Microbial Type Culture Collection and Gene Bank (MTCC 1305) and Gram-negative Escherichia coli (MTCC 443). Synthesis was followed by aza-Michael addition reaction, where the acrylonitrile accepts an electron pair from the respective amines and results in the formation of n-alkyliminobis-propionitrile and n-alkyliminopropionitrile under microwave irradiation. Characterization of the compounds were performed using Fourier Transform Infrared (FTIR), Proton Nuclear Magnetic Resonance (1H NMR) and Electrospray Ionisation Mass Spectrometry (ESI–MS). The particle size characterization was done by Dynamic Light Scattering (DLS) technique. The antibacterial study showed higher inhibition rate for both Gram-positive and Gram-negative bacteria. The antibacterial ability was found to be dose dependent. The minimum inhibitory concentration against both bacteria were found to be 1, 3, 0.4, 1, 3 µl/ml for E. coli and 6, 6, 0.9, 0.5, 5 µl/ml for B. subtilis. Time-kill kinetics evaluation showed that the adducts possess bacteriostatic action. Further it was evaluated for high-throughput in vitro assays to determine the compatibility of the adducts for drug delivery. The haemolytic and thrombolytic activity was analysed against normal mouse erythrocytes. The haemolytic activity showed prominent results, and thereby projecting this acrylonitrile adducts as potent antimicrobial and haemolytic agent.

Divergent Protocol for the Synthesis of Isoquinolino[1,2-b]quinazolinone and Isoquinolino[2,1-a]quinazolinone Derivatives.

The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities. In this context, the development of an efficient strategy for their access is needed. Herein, we report a divergent metal-free operation to access a diverse collection of C6-substituted pyrrolo[4',3',2':4,5]isoquinolino[1,2-b]quinazolin-8(6H)-one and pyrrolo[4',3',2':4,5]isoquinolino[2,1-a]quinazolin-12(6H)-one architectures. The described cascade unites Friedel-Crafts and aza-Michael addition reactions. This operationally simple protocol enables a rapid access to these scaffolds and is compatible with a wide scope of starting materials. In addition, the cascade features a promising approach for the design of unique compound libraries for drug design and discovery programs.

3D printed multi-growth factor delivery patches fabricated using dual-crosslinked decellularized extracellular matrix-based hybrid inks to promote cerebral angiogenesis.

Generally, brain angiogenesis is a tightly regulated process, which scarcely occurred in the absence of specific pathological conditions. Delivery of exogenous angiogenic factors enables the induction of desired angiogenesis by stimulating neovasculature formation. However, effective strategies of mimicking the angiogenesis process with exogenous factors have not yet been fully explored. Herein, we develop a 3D printed spatiotemporally compartmentalized cerebral angiogenesis inducing (SCAI) hydrogel patch, releasing dual angiogenic growth factors (GFs), using extracellular matrix-based hybrid inks. We introduce a new hybrid biomaterial-based ink for printing patches through dual crosslinking mechanisms: Chemical crosslinking with aza-Michael addition reaction with combining methacrylated hyaluronic acid (HAMA) and vascular-tissue-derived decellularized extracellular matrix (VdECM), and thermal crosslinking of VdECM. 3D printing technology, a useful approach with fabrication versatility with customizable systems and multiple biomaterials, is adopted to print three-layered hydrogel patch with spatially separated dual GFs as outer- and inner-layers that provide tunable release profiles of multiple GFs and fabrication versatility. Consequently, these layers of the patch spatiotemporally separated with dual GFs induce excellent neovascularization in the brain area, monitored by label-free photoacoustic microscopy in vivo. The developed multi-GFs releasing patch may offer a promising therapeutic approach of spatiotemporal drugs releasing such as cerebral ischemia, ischemic heart diseases, diabetes, and even use as vaccines. STATEMENT OF SIGNIFICANCE: Effective strategies of mimicking the angiogenesis process with exogenous factors have not yet been fully explored. In this study, we develop a 3D printed spatiotemporally compartmentalized cerebral angiogenesis inducing (SCAI) hydrogel patch, releasing dual angiogenic growth factors (GFs) using extracellular matrix-based hybrid inks. We introduce a new hybrid biomaterial-based ink through dual crosslinking mechanisms: Chemical crosslinking with aza-Michael addition, and thermal crosslinking. 3D printing technology is adopted to print three-layered hydrogel patch with spatially separated dual GFs as outer- and inner-layers that provide tunable release profiles of multiple GFs and fabrication versatility. Consequently, these layers of the patch spatiotemporally separated with dual GFs induce excellent neovascularization in the brain area, monitored by photoacoustic microscopy in vivo.

One-Step Synthesis of New Amphiphilic Nonionic Surfactants Based on Alkylamine and Poly(ethylene glycol) Dimethacrylate for Demulsification of Arabian Heavy Crude Oil Emulsions.

New non-ionic surfactants based on alkylamine and poly(ethylene glycol) dimethacrylate were synthesized by one-step Aza-Michael addition reaction. The surfactants' chemical compositions, surface and interfacial activities, micellization, and zeta potential were characterized. Their surface and interfacial activities recommended the application as demulsifiers for water in Arabian heavy oil emulsions (w/o). The demulsification of this type of emulsion has attracted researchers' attention because of its high stability with water droplets in the microscale. The outcome of using the prepared surfactants showed high performance as emulsion breakers, as the demulsification efficiency reached 100% for w/o emulsions with different water to oil ratios (50:50, 30:70, and 10:90).

Stereodivergent Desymmetrization of Phenols En Route to Modular Access to Densely Functionalized Quinazoline and Oxazine Scaffolds

The de novo assembly of stereochemically and skeletally diverse scaffolds is a powerful tool for the discovery of novel chemotypes. Hence, the development of modular, step- and atom-economic synthetic methods to access stereochemically and skeletally diverse compound collection is particularly important. Herein, we show a metal-free, stereodivergent build/couple/pair strategy that allows access to a unique collection of benzo[5,6][1,4]oxazino[4,3-a]quinazoline, quinolino[1,2-a]quinazoline and benzo[b]benzo [4,5]imidazo[1,2-d][1,4]oxazine scaffolds with complete diastereocontrol and wide distribution of molecular architectures. This metal-free process proceeds via desymmetrization of phenol derivatives. The cascade unites Mannich with aza-Michael addition reactions, providing expeditious entries to diverse classes of molecular shapes in a single operation.