Base-catalyzed Michael Addition Research Articles

Grafting well-defined polymers onto unsaturated PVDF using thiol-ene reactions

Poly(vinylidene fluoride) (PVDF) is commonly used in membranes, lithium-ion battery binders, and coatings due to its thermal and chemical robustness. Nevertheless, PVDF-based copolymers can broaden the application scope and performance capabilities of pristine PVDF. PVDF has been modified via grafting-from reactions. However, grafting density and graft length, two important properties of graft copolymers, cannot be accurately determined. Herein, we used grafting-onto thiol-ene reactions as a method to modify PVDF. The molar mass of pre-synthesized, thiol-terminated polymers were accurately determined, and grafting densities were calculated. Unsaturated sites were generated through dehydrofluorination and dehydrochlorination in PVDF and P(VDF-co-chlorotrifluoroethylene) (PVDF-CTFE). Various conditions were studied, including the molar mass and chemical structure of grafts, the degree of thiol substitution, and thiol-ene reaction mechanisms. Base-catalyzed Michael addition with secondary thiols performed best, with the highest grafting density calculated to be about 4 chains per PVDF chain. Despite the low grafting density, changes in material properties between the product and starting materials were observed, validating this controlled method for PVDF modification.

Photoswitchable Keto-Enol Tautomerism Driven by Light-Induced Change in Antiaromaticity.

The bidirectional interconversion between ketone and enol structures of 4-cyclopentene-1,3-dione derivatives was realized by photoswitching of fused dithienylethene using UV and visible light. A loss of antiaromaticity offered the driving force for light-triggered enolization and was supported by theoretical studies. Solvent and substituent effects provided additional means for regulating photoswitchable keto-enol tautomerism. Moreover, a significant change of acidity was revealed with light-induced keto-to-enol conversion, enabling control over base-catalyzed Michael addition.

Development of a Flow-free Gradient Generator Using a Self-Adhesive Thiol-acrylate Microfluidic Resin/Hydrogel (TAMR/H) Hybrid System.

Microfluidic gradient generators have been used to study cellular migration, growth, and drug response in numerous biological systems. One type of device combines a hydrogel and polydimethylsiloxane (PDMS) to generate “flow-free” gradients; however, their requirements for either negative flow or external clamps to maintain fluid-tight seals between the two layers have restricted their utility among broader applications. In this work, a two-layer, flow-free microfluidic gradient generator was developed using thiol-ene chemistry. Both rigid thiol-acrylate microfluidic resin (TAMR) and diffusive thiol-acrylate hydrogel (H) layers were synthesized from commercially available monomers at room temperature and pressure using a base-catalyzed Michael addition. The device consisted of three parallel microfluidic channels negatively imprinted in TAMR layered on top of the thiol-acrylate hydrogel to facilitate orthogonal diffusion of chemicals to the direction of flow. Upon contact, these two layers formed fluid-tight channels without any external pressure due to a strong adhesive interaction between the two layers. The diffusion of molecules through the TAMR/H system was confirmed both experimentally (using fluorescent microscopy) and computationally (using COMSOL). The performance of the TAMR/H system was compared to a conventional PDMS/agarose device with a similar geometry by studying the chemorepulsive response of a motile strain of GFP-expressing Escherichia coli. Population-based analysis confirmed a similar migratory response of both wild-type and mutant E. coli in both of the microfluidic devices. This confirmed that the TAMR/H hybrid system is a viable alternative to traditional PDMS-based microfluidic gradient generators and can be used for several different applications.

Controllable Lewis Base Catalyzed Michael Addition of α-Amino­nitriles to Activated Alkenes: Facile Synthesis of Functionalized γ-Amino Acid Esters and γ-Lactams

A novel protocol for the synthesis of functionalized γ-amino acid esters and γ-lactams through a controllable Lewis base catalyzed Michael addition of α-aminonitriles to simple activated alkenes has been developed. The scope, versatility, and efficiency of the process were demonstrated.

Synthesis and characterization of thiol-acrylate hydrogels using a base-catalyzed Michael addition for 3D cell culture applications.

There is significant interest in developing new approaches for culturing mammalian cells in a three-dimensional (3D) environment due to the fact that it better recapitulates the in vivo environment. The goal of this work was to develop thiol-acrylate, biodegradable hydrogels that possess highly tunable properties to support in vitro 3D culture. Six different hydrogel formulations were synthesized using two readily available monomers, a trithiol (ETTMP 1300 [ethoxylated trimethylolpropane tri(3-mercaptopropionate) 1300]) and a diacrylate (PEGDA 700 [polyethylene glycol diacrylate 700]), polymerized by a base-catalyzed Michael addition reaction. The resultant hydrogels were homogeneous, hydrophilic, and biodegradable. Different mechanical properties such as gelation time, storage modulus (or the elasticity G'), swelling ratio, and rate of degradation were tuned by varying the weight percentage of polymer, the molar ratio of thiol-to-acrylate groups, and the pH of the solution. Cytocompatibility was assessed using two model breast cancer cell lines by both 2D and 3D cell culturing approaches. The hydrogel formulations with a thiol-to-acrylate molar ratio of 1.05 were found to be optimal for both 2D and 3D cultures with MDA-MB-231 cellular aggregates found to be viable after 17 days of 3D continuous culture. Finally, MCF7 cells were observed to form 3D spheroids up to 600 μm in diameter as proof of principle for the thiol-acrylate hydrogel to function as a scaffold for in vitro 3D cell culture. A comparison of the different mechanical properties of the six hydrogel formulations coupled with in vitro cell culture results and findings from previously published hydrogels conclude that the thiol-acrylate hydrogels have significant potential as a scaffold for 3D cell culture.

KOtBu-Catalyzed Michael Addition Reactions Under Mild and Solvent-Free Conditions.

Designed transition metal complexes predominantly catalyze Michael addition reactions. Inorganic and organic base-catalyzed Michael addition reactions have been reported. However, known base-catalyzed reactions suffer from the requirement of solvents, additives, high pressure and also side-reactions. Herein, we demonstrate a mild and environmentally friendly strategy of readily available KOt Bu-catalyzed Michael addition reactions. This simple inorganic base efficiently catalyzes the Michael addition of underexplored acrylonitriles, esters and amides with (oxa-, aza-, and thia-) heteroatom nucleophiles. This catalytic process proceeds under solvent-free conditions and at room temperature. Notably, this protocol offers an easy operational procedure, broad substrate scope with excellent selectivity, reaction scalability and excellent TON (>9900). Preliminary mechanistic studies revealed that the reaction follows an ionic mechanism. Formal synthesis of promazine is demonstrated using this catalytic protocol.

An investigation on sunlight-induced shape memory behaviors of PCL/TiN composites film

Plasmonic materials possess good optical properties in effectively converting solar energy into heat, here a series of sunlight responsive shape memory composites films based on acrylate-terminated Poly (ε-caprolactone) (PCL) and titanium nitride nanoparticles (TiN NPs) are prepared via base-catalyzed Michael addition. Compared with conventional free radical polymerization or physical blending, this paper constructs a network architecture from view of structural controllability, favoring a subsequent flexible and elastic materials as well as fine dispersion of TiN NPs in the cross-linked networks, the resultant materials show an outstanding mechanical and the incorporated TiN NPs enable rapid temperature increase over the melting temperature of PCL and trigger the shape change of the composite with good shape recovery rate. The effect of light density and TiN NPs concentration on composite film are elucidated and investigated systematically, it is found that the amount of TiN NPs content virtually has a negligible effect on the surface temperature of the films when subjected to a specific illumination, however, light intensity has a remarkable influence on it. Furthermore, an electronics device switch actuated by 160 mw cm−2 simulated sunlight irradiation is demonstrated and envisioned for flexible electronic applications.

Acetoacetate Based Thermosets Prepared by Dual-Michael Addition Reactions.

A novel set of dual-curable multiacetoacetate-multiacrylate-divinyl sulfone ternary materials with versatile and manipulable properties are presented. In contrast to common dual-curing systems, the first stage polymer herein consists of a densely crosslinked, high Tg network as a result of base-catalyzed multiacetoacetate-divinyl sulfone Michael addition. A more flexible secondary network forms after base-catalyzed Michael addition of remaining multiacetoacetate to multiacrylate. Curing is truly sequential as the rates of the two Michael additions are significantly different. Curing kinetics were analyzed using differential scanning calorimetry (DSC) and Fourier-transform infrared (FTIR). The materials at each curing stage were characterized using dynamic mechanical analysis (DMA) and SEM. Although some phase separation was observed in certain formulations, the incompatibilities were minimized when the molar percentage of the acetoacetate-divinyl sulfone polymer network was above 75%. Furthermore, the environmental scanning electron microscopy (ESEM) images of these materials show that the more flexible acetoacetate-acrylate phase is dispersed in the form of polymeric spheres within the rigid acetoacetate-divinyl sulfone matrix. This unique dual microstructure can potentially render these materials highly resilient in applications requiring densely crosslinked polymer architectures with enhanced toughness.

Analyses of lysine aldehyde cross-linking in collagen reveal that the mature cross-link histidinohydroxylysinonorleucine is an artifact

Lysyl oxidase-generated intermolecular cross-links are essential for the tensile strength of collagen fibrils. Two cross-linking pathways can be defined, one based on telopeptide lysine aldehydes and another on telopeptide hydroxylysine aldehydes. Since the 1970s it has been accepted that the mature cross-linking structures on the lysine aldehyde pathway, which dominates in skin and cornea, incorporate histidine residues. Here, using a range of MS-based methods, we re-examined this conclusion and found that telopeptide aldol dimerization is the primary mechanism for stable cross-link formation. The C-telopeptide aldol dimers formed labile addition products with glucosylgalactosyl hydroxylysine at α1(I)K87 in adjacent collagen molecules that resisted borohydride reduction and after acid hydrolysis produced histidinohydroxylysinonorleucine (HHL), but only from species with a histidine in their α1(I) C-telopeptide sequence. Peptide MS analyses and the lack of HHL formation in rat and mouse skin, species that lack an α1(I) C-telopeptide histidine, revealed that HHL is a laboratory artifact rather than a natural cross-linking structure. Our experimental results also establish that histidinohydroxymerodesmosine is produced by borohydride reduction of N-telopeptide allysine aldol dimers in aldimine intermolecular linkage to nonglycosylated α1(I) K930. Borohydride reduction of the aldimine promotes an accompanying base-catalyzed Michael addition of α1(I) H932 imidazole to the α,β-unsaturated aldol. These aldehydes are intramolecular at the N terminus but at the C terminus they can be both intramolecular and intermolecular according to present and earlier findings.

Covalently Crosslinked 1,2,3-Triazolium-Containing Polyester Networks: Thermal, Mechanical, and Conductive Properties.

Azide–alkyne “click” cyclization was used to prepare a series of polymerizable acetoacetate monomers containing a 1,2,3-trizolium ionic liquid group. The monomers were subsequently polymerized using base-catalyzed Michael addition chemistry, producing a series of covalently crosslinked 1,2,3-triazolium poly(ionic liquid) (TPIL) networks. Structure–activity relationships were conducted to gauge how synthetic variables, such as counteranion ([Br], [NO3], [BF4], [OTf], and [NTf2]), and crosslink density (acrylate/acetoacetate ratio) effected thermal, mechanical, and conductive properties. TPIL networks were found to exhibit ionic conductivities in the range of 10–6–10–9 S/cm (30 °C, 30% relative humidity), as determined from dielectric relaxation spectroscopy, despite their highly crosslinked nature. Temperature-dependent conductivities demonstrate a dependence on polymer glass transition, with free-ion concentrations impacted by various ions’ Lewis acidity/basicity and ion mobilities impacted by freely mobile anion size.

Probing the dynamic and rehealing behavior of crosslinked polyester networks containing thermoreversible thiol-Michael bonds

A thermoreversible thiol-Michael bond was incorporated into a series of covalently crosslinked polyester networks using base-catalyzed Michael addition polymerization. Variations in acrylate:acetoacetate ratio (crosslink density), thiol-Michael bond content and cure temperature were employed in order to gauge dynamic and rehealing properties. All of the networks investigated in this study were found to display rehealing behavior after being cut at 100 °C within 48 h. Increasing the curing temperature to 120 °C led to a decrease in time to reheal (≤8 h), however the network which employed the highest thiol-Michael bond content, coupled with the lower acrylate:acetoacetate monomer ratio, did not recuperate the original crosslink density upon cooling as evidenced by strain recovery values in excess of 100% and a steady decrease in DSC Tg and TGA weight % as a functional of exposure time.

Michael addition at neutral pH: a facile synthesis of 1,3-dinitroalkanes

Base-catalyzed Michael addition of nitroalkane to conjugated nitroalkene suffers serious practical difficulties due to the formation of oligomeric byproduct. Given its importance for synthesis of pharmacologically relevant organic compounds, a scalable synthesis of 1,3-dinitroalkane is developed by addition of nitroalkane to nitroalkene in aqueous phosphate buffer at pH 7.0 with no added traditional base catalyst.

DBU-catalyzed synthesis of novel 2-amino-3-nitrile-4H-chromenes

Abstract A simple method via the base-catalyzed Michael addition of nitroalkanes to 2-iminochromenes was developed, which leads to the production of highly functionalized 2-amino-3-nitrile-4H-chromenes in good yields.

Synthesis and crystal structures of three new benzotriazolylpropanamides.

The base-catalyzed Michael addition of 2-methyl-acryl-amide to benzotriazole afforded 3-(1H-benzotriazol-1-yl)-2-methyl-propanamide, C10H12N4O (1), in 32% yield in addition to small amounts of isomeric 3-(2H-benzotriazol-2-yl)-2-methyl-propanamide, C10H12N4O (2). In a similar manner, 3-(1H-benzotriazol-1-yl)-N,N-di-methyl-propanamide, C11H14N4O (3), was prepared from benzotriazole and N,N-di-methyl-acryl-amide. All three products have been structurally characterized by single-crystal X-ray diffraction. The crystal structures of 1 and 2 comprise infinite arrays formed by N-H⋯O and N-H⋯N bridges, as well as π-π inter-actions, while the mol-ecules of 3 are aggregated to simple π-dimers in the crystal.

Synthesis and Characterization of Injectable Sulfonate-Containing Hydrogels.

Sulfonate-containing hydrogels are of particular interest because of their tunable mechanical and swelling properties, as well as their biological effects. Polysulfonate copolymers were synthesized by reacting 2-acrylamido-2-methylpropanesulfonic acid (AMPS), acrylamide (AM), and acrylic acid (AA). We found that the incorporation rate of sulfonate-containing monomer and the molecular weight of the copolymer were significantly enhanced by increasing the ionic strength of the solution. We introduced thiol groups by modifying the pendant carboxylates or copolymerizing along with a disulfide-containing monomer. The thiol-containing copolymers were reacted with a 4-arm acrylamide-terminated poly(ethylene glycol) via a thiol-ene click reaction, which was mediated by a photoinitiator, a redox initiator, or a base-catalyzed Michael-Addition. We were able to tailor the storage modulus (33-1800 Pa) and swelling capacity (1-91 wt %) of the hydrogel by varying the concentration of the copolymers. We determined that the injectable sulfonate-containing hydrogels were biocompatible up to 20 mg/mL, as observed by an electric cell-substrate impedance sensing (ECIS) technique, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay using three different cell lines: human retinal pigment epithelial cells (ARPE-19), fibroblasts (NIH 3T3), and Chinese hamster ovary cells (CHO).

Temporal Control of Gelation and Polymerization Fronts Driven by an Autocatalytic Enzyme Reaction.

Chemical systems that remain kinetically dormant until activated have numerous applications in materials science. Herein we present a method for the control of gelation that exploits an inbuilt switch: the increase in pH after an induction period in the urease‐catalyzed hydrolysis of urea was used to trigger the base‐catalyzed Michael addition of a water‐soluble trithiol to a polyethylene glycol diacrylate. The time to gelation (minutes to hours) was either preset through the initial concentrations or the reaction was initiated locally by a base, thus resulting in polymerization fronts that converted the mixture from a liquid into a gel (ca. 0.1 mm min−1). The rate of hydrolytic degradation of the hydrogel depended on the initial concentrations, thus resulting in a gel lifetime of hours to months. In this way, temporal programming of gelation was possible under mild conditions by using the output of an autocatalytic enzyme reaction to drive both the polymerization and subsequent degradation of a hydrogel.

Well-Defined Shape-Memory Networks with High Elastic Energy Capacity

Controlling network architecture and chain connectivity is critical to understanding elastic energy storage and improving performance of shape-memory polymers. Acrylate-terminated poly(caprolactones) were converted into thermoset networks by three different reactions: conventional free radical polymerization, radical-induced coupling with multifunctional thiols, and base-catalyzed Michael addition with multifunctional thiols. The highly efficient thiol–acrylate coupling reaction ensures that the molecular weight between cross-links is uniform, resulting in tougher, more elastic materials with a high degree of crystallinity and outstanding shape-memory properties. Elastomers can be cold drawn to achieve several hundred percent of strain, and upon heating, nearly complete shape recovery is observed. Shape fixity upon cold drawing is correlated to the degree of strain-induced crystallization which is influenced by the draw rate and stress treatment immediately following cold drawing. Slow unloading of samples drawn to 400% elongation indicates the material is capable of storing greater than 1.5 MJ/m3 of elastic energy.

A Mechanism Study of a Novel Acid-Activatable Michael-Type Fluorescent Probe for Thiols

A Michael addition is usually taken as a base-catalysed reaction. However, our synthesized 2-(quinolin-2-ylmethylene) malonic acid (QMA) as a Michael-type thiol fluorescent probe is acid-active in its sensing reaction. In this work, based on theoretic calculation and experimental study on 7-hydroxy-2-(quinolin-2-ylmethylene) malonic acid, we demonstrated that QMA as a Michael acceptor is acid-activatable, i.e., it works only in solutions at pH<7, and the lower the pH of solutions is, the higher reactivity QMA has. In alkaline solution, the malonate QMA[-2H+]2− cannot react with both RS− and RSH. In contrast, 2-(quinolin-2-ylmethylene) malonic ester (QME), the ester of QMA, reveal a contrary pH effect on its sensing reaction, that is, it can sense thiols in alkaline solutions but not in acidic solutions, like a normal base-catalysed Michael addition. The values of activation enthalpies from theoretic calculation support the above sensing behavior of two probes under different pH conditions. In acidic solutions, the protonated QMA is more highly reactive towards electrophilic attack over its other ionized states in neutral and alkaline solutions, and so can react with lowly reactive RSH. In contrast, there is a big energy barrier in the interaction of QME with RSH (acidic solutions), and the reaction of QME with the highly reactive nucleophile RS− is a low activation energy process (in alkaline solutions). Theoretic calculation reveals that the sensing reaction of QMA undergoes a 1,4-addition process with neutral thiols (RSH), and a 1,2-addition pathway for the sensing reaction of QME with RS−. Therefore, the sensing reaction of QMA is an acid-catalysed Michael addition via a 1,4-addition, and a normal base-catalysed Michael addition via a 1,2-addition.

Regioselective Synthesis of α-Perfluoroalkylated Ketals via Double Michael Addition of Alcohols to Activated Alkynes

An efficient method was developed for the synthesis of alkyl 3,3-dialkoxy-3-(perfluoroalkyl)propanoates from ethyl 3-(perfluoroalkyl)propynoates and alcohols using a base-catalyzed double Michael addition reaction (which was accompanied by transesterification in the case of MeOH, EtOH, PrOH, and BuOH). This method provides easy access to the product α-perfluoroalkyl ketals with reasonable to good yields with total regioselectivity. This procedure does not require the use of expensive supplementary additives for the preparation of α-perfluoroalkyl ketals which are very sensitive to acidic conditions.

Lewis Acid/Brønsted Base Catalyzed Michael Addition to Thioamides

Lewis Acid/Brønsted Base Catalyzed Michael Addition to Thioamides