Free Primary Amine Research Articles

Catalytic Installation of Primary Amines Onto Polyolefins for Oligomer Valorization.

Polymerization of primary amine-containing monomers is challenging because the amine inhibits polymerization catalyst activity. An alternative approach to access primary amine functionalized polymers is postpolymerization modification. To this end, the hydroaminoalkylation of vinyl-terminated polyolefins with N-(trimethylsilyl)benzylamine is used to prepare primary amine-terminated polyolefins, with the free primary amine substituent being revealed upon hydrolytic work up. These materials are spectroscopically characterized, and an investigation of thermal properties by differential scanning calorimetry and thermogravimetric analysis is completed. These results show that the primary amine substituent increases the glass transition temperature and improves thermal stability. The reactive primary amine functionality is used in the photo-oxidative dimerization of polyolefins to demonstrate how this elusive functionality can be applied in oligomer valorization.

Native Amino Group Directed Meta-Selective C-H Arylation of Primary Amines Via Pd/Norbornene Catalysis.

The selective functionalization of remote C-H bonds in free primary amines holds significant promise for the late-stage diversification of pharmaceuticals. However, to date, the direct functionalization of the meta position of amine substrates lacking additional directing groups remains underexplored. In this Letter, we present a successful meta-C-H arylation of free primary amine derivatives using aryl iodides, resulting in synthetically valuable yields. This meta-selective C-H functionalization is achieved through a sequence involving native amino-directed Pd-catalyzed seven-membered cyclometalation, followed by the utilization of a norbornene-type transient mediator.

Anthraquinone-metal complex fluorescence sensing platform for monitoring PPi mediated by Al3+ and bioimaging

Anions are widely found in humans and the environment. The analysis of its content and distribution shows great potential in the fields of life science, environmental science and biochemical reactions. Herein, a new anthraquinone derivative appended fluorescent probe (HBD) was developed as a reversible fluorescent probe for the detection pyrophosphate (PPi) in methanol/urotropine buffer medium (1:1, v/v, pH 4.5). The probe displayed fluorescence “turn-on” response towards Al3+ with high specificity. Due to the cleaving of the -CN bond and subsequent creation of complex caused by coordination with Al3+, the chelation-enhanced fluorescence (CHEF) effect was activated, resulting in a significantly enhancement fluorescence response. Further, 1H NMR titration and HRMS analysis revealed that the Al3+ induced hydrolysis occurs on one side of the Schiff base and led to the formation of free primary amine compound. Moreover, the binding mechanism was also recognized density functional theory (DFT) studies. Due to the strong binding ability of PPi and Al3+, PPi could remove Al3+ from the complex, causing fluorescence quenching. The specific determination of Al3+ and PPi with the detecting limit of 31.6 nM and 56.8 nM. Due to its good biocompatibility, the sensor was successfully applied to fluorescence imaging of Al3+ and PPi in HeLa cells and zebrafish. The results show that HBD has broad application prospects in environmental and biological analysis.

Practical Synthesis of Polyamine Succinamides and Branched Polyamines.

Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram‐positive and Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4‐Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo‐ and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram‐negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo‐ and hetero‐dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram‐positive or Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16–32 μg mL−1.

Development of chitosan towards the self-healing and mechanically stronger biocompatible hydrogel

Nontoxic, self-healing and biocompatible Chitosan grafted poly (maleic anhydride) based hydrogel (CSHG) have been developed by using Chitosan (CS) and maleic anhydride (MAH) having reasonable mechanical strength with biocompatibility. The self-healing arises due to the presence of free primary amine group and carboxyl group in grafted chitosan either dynamic imine covalent interaction or non-covalent (H-bonding) interactions. In addition to this, the hydrogel showed tremendous swelling at various pH values viz. - 2, 7 and 9, and morphological study reveals the porous nature of the synthesized CSHG hydrogel. The cell viability (MTT) of CS and CSHG was performed on MCF-7 (breast cancer cell line), and phase contrast (cell imaging) of CS and CSHG was taken at 1:5, 1:10, 1:50 and 1:100 ratios in both cases which do not induce any significant changes in cellular morphology thus makes it biocompatible and can be used as biological applications.

Kinetic Resolution of 1,2‐Diaminesvia Organocatalyzed Asymmetric Electrophilic Aminations of Anilines

Comprehensive SummaryAn efficient kinetic resolution (KR) protocol for 1,2‐diamines has been developed through asymmetric electrophilic aminations of anilines enabled by chiral phosphoric acid catalysis. A wide array of substituted 1,2‐diamines were compatible with this method, generating both the recovered staring materials and the amination products with high enantioselectivities (withs‐factor up to 218). Notably, this method is amenable to the kinetic resolution of 1,2‐diamines bearing α‐tertiary amine moieties, which represents the first KR of this type of 1,2‐diamines. Facile removal of the introduced hydrazine group and oxidative cleavage of theN‐aryl group to release the free primary amine demonstrate the value of this method.

On the Influence of a Camphor‐based 1,3‐Diamine Fragment in a Proline‐Based Organocatalyst

AbstractMultifunctional C1‐symmetric organocatalysts were prepared incorporating a camphor‐ and a proline‐based moiety. The new catalysts were evaluated in an asymmetric aldol reaction of acetone and aromatic aldehydes. A significant increase in the catalytic activity was found for the new proline analogue with the camphor‐based 1,3‐diamine unit. This new organocatalyst has one free primary amine group next to the secondary amine group of the proline unit. High yields of up to 97 % with good enantioselectivities (83 % ee) were obtained in the aldol reaction between various aromatic aldehydes and acetone in a shorter reaction time compared with (S)‐proline. A camphor‐based prolineamide analogue with a thiourea group was an efficient multifunctional organocatalyst for the aldol reaction of p‐nitrobenzaldehyde and cyclohexanone with 86 % yield and up to 73 % ee. Moreover, matched‐mismatched studies with opposite stereocenters in the camphor‐based 1,3‐diamine fragment revealed a significant influence of this unit on the overall performance of the new organocatalyst.

Elucidating the structure and cytochrome P450-mediated mechanism for novel metabolites of GDC-0575 in rats

1. GDC-0575 is an ATP-competitive small-molecule inhibitor of ChK1 that is being developed by Genentech for the treatment of various human malignancies. 2. In a radiolabeled mass balance study of GDC-0575 in rats, two novel metabolites, named M12 (-71 Da,) and M17 (+288 Da), were detected as abundant circulating metabolites. 3. Subsequent mass spectrometry and nuclear magnetic resonance analysis showed that M12 was a cyclized metabolite of GDC-0575, whereas M17 was its heterodimer to the parent. We further determined that M12 was mainly generated by cytochrome P450 (Cyp) 2d2. 4. We proposed the potential mechanism was initiated by the oxidation on the pyrrole ring and subsequent cyclisation of the free primary amine onto C-3 of the pyrrole ring. This was followed by expulsion of cyclopropylcarboxamide and a loss of water to form intermediate I, which can be further oxidised to form M12, or dimerise with another molecule of GDC-0575 as nucleophile to form M17. 5. To verify this hypothesis, we attempted to trap the intermediate I with glutathione (GSH) trapping assay and the GSH conjugate on the pyrrole ring was identified. This suggests the oxidation on the pyrrole led to reactive metabolite formation and supported this proposed mechanism.

A sensitive and less cytotoxic assay for identification of proliferating T cells based on bioorthogonally-functionalized uridine analogue

Quantitative detection of T cell proliferation is an important readout in immunology research, as it is one of the hallmarks of T cell activation. Fluorescence-based methods for T cell proliferation mostly rely on the usage of probes that non-specifically conjugate to free primary amine groups in cells. Each cell division then results in a two-fold dilution of the probes which is detectable with flow cytometry. However, questions have been raised about cytotoxicity of these dilution-based T cell proliferation probes and they potentially affect T cell activation. An alternative assay relies on the incorporation of the uridine analog BrdU in the DNA of dividing T cells that can be detected with an antibody, but this requires harsh fixation and denaturation conditions. Recently, a new assay for detection of cell proliferation has been developed, based on the incorporation of the bioorthogonally-functionalized uridine analog 5-ethynyl-2′-deoxyuridine (EdU). Goal of this study was to compare the sensitivity and cytotoxicity of the EdU assay with a widely-used dilution-based T cell proliferation probe, CellTrace Far Red. We found that, compared to the dilution-based probe, the EdU-based assay better preserves T cell viability, is more sensitive for detecting T cell proliferation, and allows for better discernable interferon gamma responses.

Microbial transglutaminase-mediated formation of erythropoietin-polyester conjugates

Erythropoietin (EPO) is a glycoprotein hormone that has been used to treat anemia in patients with chronic kidney disease and in cancer patients who are receiving chemotherapy. Here, we investigated the accessibility of the glutamine (Gln, Q) residues of recombinant human erythropoietin (rHuEPO) towards a thermoresistant variant microbial transglutaminase (mTGase), TG16 with the aim of developing novel rHuEPO conjugates that may potentially enhance its biological efficacy. As a model bioconjugation, we studied the reactivity of rHuEPO towards TG16 with a low molar mass amine group containing substrate, monodansyl cadaverine (MDC). The reactions were carried out at a Tm of 54.3 °C, the transition temperature of rHuEPO. Characterization by SDS-PAGE and mass spectrometry confirmed the conjugates formation. Then, we examined the conjugation of rHuEPO with a biodegradable and biocompatible polyester, poly(D-sorbitol adipate) (PDSA). To achieve this, PDSA was enzymatically synthesized using lipase B from Candida antartica (CAL-B), chemically modified with side chains having free primary amine (NH2) groups that can be acyl acceptor substrate of TG16, thoroughly characterized by 1H NMR spectroscopy, and then applied for the TG16-mediated conjugation reaction with rHuEPO. rHuEPO conjugates generated by this approach were identified by SDS-PAGE proving that the amine-grafted PDSA is accepted as a substrate for TG16. The successful conjugation was further verified by the detection of high molar mass fluorescent bands after labelling of amine-grafted PDSA with rhodamine B-isothiocyanate. Overall, this enzymatic procedure is considered as an effective approach to prepare biodegradable rHuEPO-polymer conjugates even in the presence of N- and O-glycans.

Total Synthesis of Phenanthropiperidine Alkaloids by Sequential Alkylation of N,N‐Dibenzylaminoacetonitrile

AbstractTwo representative members of the phenanthropiperidine alkaloid family, tylophorine (1) and cryptopleurine (2), were synthesized by a bidirectional alkylation strategy employing dibenzylaminoacetonitrile as a substrate. This approach relies on the unprecedented condensation of metallated α‐aminonitriles with bromomethylphenanthrenes to provide fully substituted α‐aminonitriles, which are subjected to a NaBH4‐mediated reductive decyanation process to form homobenzylic amines. From these intermediates, a terminal leaving group was introduced by simple chemical manipulation, and its displacement by a free primary amine under two favorable cyclization processes led to the formation of the future E‐ring of both alkaloids in high yields. Finally, a late Pictet‐Spengler cyclization ensured the formation of a D‐ring for the alkaloids 1 and 2.

Native Amine-Directed ortho-C–H Halogenation and Acetoxylation /Condensation of Benzylamines

AbstractFree or unfunctionalized benzylamines are well known to participate in C–H activation in the presence of palladium salts. Despite the ease with which these complexes can be activated, subsequent functionalization of the dimeric cyclometalates can be challenging. We demonstrate herein a free primary amine based C–H activation/functionalization protocol that allows for the ortho-C–H chlorination and bromination of unprotected benzylamines. We also demonstrate how use of fluorine-based oxidants gives rise to a unique acetoxylation/­cyclization owing to the nucleophilicity of the free primary amine directing group.

Life-Inspired Endogenous Dynamic Behavior of Lipid Droplet-like Microcompartments in Artificial Adipocyte-like Structures

Chemical systems that can replicate cellular behaviors are gaining increasing attention and are being used to study various biological processes. Here, a protein- or amylose-based assembly at an oi...

Chemical composition as an indicator for evaluating heated whey protein isolate (WPI) and sugar beet pectin (SBP) systems to stabilize O/W emulsions.

We investigated changes in the chemical composition of WPI as a result of heating (60°C, 72h) with SBP in solution (pH 6.75). The concentration of WPI was kept at a constant (3%), whereas the level of SBP was varied at 1, 1.5, and 3%. The reaction products were examined using the Ellman's reagent, ninhydrin assay, and gel electrophoresis. The results demonstrated that the losses of the free sulfhydryl (-SH) and primary amine (-NH2) contents in WPI were less severe compared to those occurring in the dry-state at similar conditions (mass ratio, temperature, and reaction duration). The mixtures were used as emulsifiers in an O/W emulsion system at pH 3.20 and 6.75 and showed an improved ability to stabilize the average size of the droplets than WPI alone at acidic pH. The mixtures at higher levels of SBP, ≥ 1.5%, however, adversely affected the emulsion stability at neutral pH.

Integration of silica with benzoxazine to improve particle dispersion and thermal performance of composites

The concentration gradient and non-uniform dispersion of the most commonly used filler (silica) in the polymer matrix is one of the main reason for the inferior performance of the polymer composite. The present work utilizes surface chemistry to integrate the surface of silica particles with benzoxazine moieties in order to improve the dispersion of silica particles in bio-based benzoxazine resin with a generic aim to develop polybenzoxazine composites with improved thermal performance. In view of the same, co-condensation of tetraethoxysilane (TEOS) and 3-aminopropylltriethoxysilane (APTES) at room temperature has been performed, resulting in amine functionalized silica (AFS) particles. The feed concentration of the reactants has been optimised to prepare least agglomerated particles. The organic functionalization on silica particles has been evidenced using Fourier transform infrared (FTIR), 13C solid state NMR, X-ray photoelectron (XPS) spectroscopies and thermogravimetric analysis (TGA). The free primary amine groups of amine functionalized silica (AFS) particles has been utilized as amine co-reactants which undergoes Mannich like condensation with various bio-based phenols to integrate oxazine functionality on the surface of silica particles. The presence of oxazine moieties on the surface of silica particles has been confirmed using various thermal techniques including differential scanning calorimetry (DSC) and TGA. The improved dispersion of benzoxazine functionalized silica (BFS) particles in a bio-based benzoxazine resin based on cardanol-aniline (C-a) as well as the polybenzoxazine thermoset has been demonstrated using digital and SEM images. Thermogravimetric results shows the influence of improved dispersion in terms of relatively higher thermal stability of the polybenzoxazine composite prepared using modified silica particles.

Pyrene‐based fluorescent supramolecular hydrogel: scaffold for nanoparticle synthesis

AbstractThe present work illustrates the design and development of pyrene‐based fluorescent supramolecular hydrogel consisting of l‐phenylalanine residue as the linker and ethyleneoxy unit with free primary amine at C‐terminal. The gelator efficiently immobilized aqueous media, and the critical gelation concentration (CGC) was found at 2.8 mM of the compound. Interestingly, the presence of pyrene moiety in the structure made the hydrogel intrinsically fluorescent. The self‐aggregation properties of the thermo‐reversible hydrogel were investigated using different microscopic and spectroscopic techniques such as high‐resolution transmission electron microscopy (HRTEM), Fourier transform infrared (FTIR) spectroscopy, fluorescence spectroscopy, and X‐ray diffraction (XRD) spectroscopy. A balanced participation of noncovalent interactions like hydrogen bonding, π‐π stacking, and van der Waals interaction was identified as the driving force for gelation. Rheological experiments were performed to confirm the viscoelastic nature of the prepared hydrogel. Furthermore, primary amine (─NH2) group of hydrogelator was utilized for the in situ synthesis of silver nanoparticles (AgNPs) within the soft material under sunlight in the absence of any external reducing and stabilizing agent.

Confining Photoacidity

Confining Photoacidity

Synthesis and Characterization of Controlled Nitric Oxide Release from S-Nitroso-N-Acetyl-d-Penicillamine Covalently Linked to Polyvinyl Chloride (SNAP-PVC).

Polyvinyl chloride (PVC) is one of the most widely used polymers in medicine but has very poor biocompatibility when in contact with tissue or blood. To increase biocompatibility, controlled release of nitric oxide (NO) can be utilized to mitigate and reduce the inflammatory response. A synthetic route is described where PVC is aminated to a specified degree and then further modified by covalently linking S-nitroso-N-acetyl-d-penicillamine (SNAP) groups to the free primary amine sites to create a nitric oxide releasing polymer (SNAP-PVC). Controllable release of NO from SNAP-PVC is described using photoinitiation from light emitting diodes (LEDs). Ion-mediated NO release is also demonstrated as another pathway to provide a passive mechanism for NO delivery. The large range of NO fluxes obtained from the SNAP-PVC films indicate many potential uses in mediating unwanted inflammatory response in blood- and tissue-contacting devices and as a tool for delivering precise amounts of NO in vitro.

Synthesis and characterization of Schiff base 4,4-diaminodiphenyl ether-vanillin possessed of free primary amine

The synthesis and characterization of Schiff base 4,4 diaminodiphenyl ether-vanillin possesed of free primary amine has been done. The aims of this research were synthesis Schiff base 4,4 diaminodiphenyl ether-vanillin possesed of free primary amine from reaction between 1 mol of 4,4 diaminodiphenyl ether and 1 mol of vanillin which affected by temperature of synthesis (30-90°C) and its characterization using FTIR spectroscopy and X Ray diffraction analysis. The result showed that the functional group of all product of Schiff base 4,4 diaminodiphenyl ether-vanillin possesed of free primary amine was not affected by temperature of synthesis. The functional group of –C=N in this Schiff base compound appeared at wave number 1597 cm−1 and its consequences, the aldehyde group (C=O) was not detected at 1666 (stretching) and 632 cm−1 (bending vibration). The wave number between 3387-3441 cm−1 was stretching vibration of primary amine (N-H) and stretching vibration of –C-N from aromatic amine (NH2-aromatic) can be found at wave number between 1280-1288 cm−1. Diffractogram of 4,4 diaminodiphenyl ether, vanillin and Schiff base 4,4 diaminodiphenyl ether-vanillin were 11.91° - 50.39°, 13.13° and 39.99° and 10.13° - 50.6° respectively.

Efficient Synthesis of Multifunctional Chelating Agents Based on Tetraazacycloalkanes

An efficient route has been developed for the synthesis of multifunctional tetraazacycloalkanes (in particular 1,4,7,10‐tetraazacyclotridecane) incorporating an aminomethyl pendant arm on the carbon skeleton. Starting from the appropriate C‐functionalized bisaminal‐protected intermediate, the target macrocycles were easily obtained by means of a step‐by‐step introduction of the desired functional groups onto the free primary amine group, followed by deprotection of the bisaminal intermediates. This straightforward and versatile synthetic approach paves the way for the design of a new family of multifunctional chelators.