Tertiary Amine Function Research Articles

Controlling the pH-response of branched copolymer nanoprecipitates synthesised by transfer-dominated branching radical telomerisation (TBRT) through telogen chemistry and spatial distribution of tertiary amine functionality.

Amine functionality offers the modification of polymer properties to enable stimuli-responsive behaviour, and this feature has been utilised in numerous studies of self-assembly and disassembly. The ability to place amines as pendant groups along linear polymer backbones within distinct blocks, at chain ends or as statistical mixtures with other functionalities, has allowed fine tuning of responses to pH. Here we study and compare the placement of amines within the backbones or as pendant groups within polyesters synthesised by the newly reported transfer-dominated branching radical telomerisation (TBRT). Branched polymers with backbone amines are clearly shown to undergo dissolution that is determined by pH and telogen selection; they undergo nanoprecipitation only when hydrophilic telogens are present within their structure and provide nanoprecipitates that are highly sensitive to the addition of acid. In contrast, TBRT polymers with pendant amines form uniform nanoparticles with remarkable stability to pH changes, under identical nanoprecipitation conditions. The behaviour differences shown here open new avenues of synthetic flexibility for pH-responsive polymer design using TBRT.

Biopatterned Reorganization of Alkaloids Enabled by Ring-Opening Functionalization of Tertiary Amines.

Biosynthetic processes often involve reorganization of one family of natural products to another. Chemical emulation of nature's rearrangement-based structural diversification strategy would enable the conversion of readily available natural products to other value-added secondary metabolites. However, the development of a chemical method that can be universally applied to structurally diverse natural products is nontrivial. Key to the successful reorganization of complex molecules is a versatile and mild bond-cleaving method that correctly places desired functionality, facilitating the target synthesis. Here, we report a ring-opening functionalization of a tertiary amine that can introduce desired functionalities in the context of alkaloids reorganization. The semistability of the difluoromethylated ammonium salt, accessed by the reaction of tertiary amine and in situ generated difluorocarbene, enabled the attack at the α-position by various external nucleophiles. The utility and generality of the method is highlighted by its applications in the transformation of securinega, iboga, and sarpagine alkaloids to neosecurinega, chippiine/dippinine, and vobasine-type bisindole alkaloids, respectively. During the course of these biosynthetically inspired reorganizations, we could explore chemical reactivities of biogenetically relevant precursors.

Synthesis and in vitro evaluation of chlorogenic acid amides as potential hypoglycemic agents and their synergistic effect with acarbose

Type 2 Diabetes mellitus is a chronic disease considered one of the most severe global health emergencies. Chlorogenic acid (1) has been shown to delay intestinal glucose absorption by inhibiting the activity of α-glucosidase (α-Glu) and α-amylase (α-Amy). In the present work, eleven chlorogenic acid amides have been synthesized and evaluated for their antioxidant properties (as DPPH and ORAC) and inhibition activity towards the two enzymes and, with the aim to obtain dual-action antidiabetic agents. The two most promising hypoglycemic compounds, bearing a tertiary amine function on an alkyl chain (8) and a benzothiazole scaffold (11), showed IC50 values lower than that of (1) (45.5 µM α-Glu; 105.2 µM α-Amy). Amides 8 and 11 were by far more potent α-Glu inhibitors than the antidiabetic drug acarbose (IC50 = 268.4 µM) and about twice less active toward α-Amy than acarbose (IC50 = 34.4 µM). Kinetics experiments on amides 8 and 11 indicated these compounds as mixed-type inhibitors of α-Glu with Kʹi values of 13.3 and 6.3 µM, respectively. The amylase inhibition occurred with a competitive mechanism in the presence of 8 (Ki = 79.7 µM) and with a mixed-type mechanism with 11 (Ki = 19.1 µM; Kʹi = 93.6 µM). Molecular docking analyses supported these results, highlighting the presence of additional binding sites in both enzymes. Fluorescence experiments confirmed the grater affinity of amides 8 and 11 towards the two enzymes respect to (1). Moreover, a significant enhancement in acarbose efficacy was observed when inhibition assays were performed adding acarbose and amide 11. The above outcomes pinpointed the benzothiazole-based amide 11 as a promising candidate for further studies on type 2 diabetes treatment, both alone or combined with acarbose.

Modified POSS nano-structures as novel co-initiator-crosslinker: Synthesis and characterization

ObjectiveTo synthesize an amine-modified polyhedral oligomeric silsesquioxane (POSS) nano-structure as a novel co-initiator-crosslinker (co-Ini-Linker) and to determine the effect of the co-Ini-linker on the physical and mechanical behavior of an experimental dental composite. MethodsThe amine-methacrylate POSS nano-structures (AMA-POSS) were chemically synthesized by anchoring a tertiary amine functionality on the methacrylate POSS (MA-POSS) branches. Three types of AMA-POSS, having different amine branches in their structures, were synthesized through the Aza Michael reaction. The chemical structure of AMA-POSSs were evaluated by1H-NMR spectroscopy. Afterward, the AMA-POSS was incorporated into a dental resin system composed of Bis-GMA, TEGDMA, and photo-initiator. Three resin systems with different AMA-POSS types were then prepared, and their properties were compared with a resin containing DMAEMA as a conventional co-initiator. The degree of conversion evaluated by FTIR spectroscopy and the shrinkage kinetics of the resins were determined through the bonded-disk technique. The flexural properties of the photopolymerized resins were also investigated. The distribution of nano-structures in the matrix resin was analyzed using EDX analysis. ResultsThe modified POSS structure and the number of amine branches were confirmed with1H-NMR spectroscopy. The resin containing 8 amine branches (P8) showed the same degree of conversion (DC%) as the resin containing DMAEMA (P > 0.05). Decreasing the amine branches in the POSS structure, however, revealed an increasing trend in DC%. The resin containing P8 showed the lowest shrinkage strain. By incorporating AMA-POSS into the resin system, the water sorption significantly decreased (P < 0.05). The flexural strength and modulus increased by adding P3 into the resin system (P < 0.05). EDX Si-map revealed that the co-Ini-linker was well dispersed in the resin matrix. SignificanceThe synthesized novel amine-methacrylate POSS nanostructures not only act as an amine co-initiator but also work as a reinforcing filler and a cross-linking agent.

Amphiphilic antifouling membranes by polydopamine mediated molecular grafting for water purification and oil/water separation

A polydopamine mediated amphiphilic molecular grafting approach was designed by combining hydrophilic and hydrophobic segments into the same moiety for creating amphiphilic surfaces with enhanced antifouling properties. Polydopamine (PDA) coating was performed on microporous polysulfone (PSF) membranes to form an active mediating layer. After that N,N-dimethyl ethylenediamine (DMEDA) was grafted on the PDA layer via Michael addition reaction and the tertiary amine functionality of DMEDA was reacted with 1-Iodo-1H,1H,2H, 2H-perfluorodecane to obtain amphiphilic molecular functionalization. All modification steps were confirmed by characterizations using X-ray photoelectron spectroscopy, scanning electron microscopy, capillary flow porometry, and surface wetting using a dynamic contact angle method. The antifouling study by protein adsorption shows that the hydrophilic-hydrophobic molecular layers in proximity effectively prevent nonspecific protein adsorption compared to the virgin PSF membrane. The antifouling property was further evaluated by real-time cyclic filtration with a 5 mg ml−1 bovine serum albumin (BSA) solution. The final modified amphiphilic surface has shown reduced irreversible protein bounded properties on and inside the membrane surfaces along with high flux recovery. Furthermore, the oil-in-water emulsion filtration shows excellent oil rejection at a high flux rate with nearly complete flux recovery. These findings indicate a promising and smart membrane surface modification technique that can be readily tailored for water filtration and separation applications.

α-C–H functionalization of tertiary amines catalyzed/promoted by molecular iodine/derivatives

A recent review on the α-C–H functionalization of tertiary amines using low-cost and benign I2 or its derivatives.

CuO-NiO-TiO2 bimetallic nanocomposites for catalytic applications

CuO-NiO-TiO2 nanocomposites with of 0.01–5.0 wt.% of Cu:Ni (1:1) supported on TiO2 were prepared by a decomposition method. The catalysts structure and chemical composition were studied by means of XRD, SEM, EDX, TEM, FT-IR, UV–DRS, BET-analysis and compared for direct sunlight photo-degradation of methylene blue with commercial P25 catalyst. These studies revealed that the catalyst efficiency solely depends on the percentage of Cu-Ni dopants. The catalyst with low metal dopants displayed better photocatalytic activity. The optimum doping concentration for photo-degradation was 0.05 wt.%. The nanocomposite with higher metal loading (5.0 wt.%) was effectively employed as heterogenous catalyst for selective reduction of nitro benzene to aniline using sodium borohydride and for air oxidation of tertiary amine functionality to a tertiary amide. The synergistic effect of the metals was confirmed by comparing the catalytic activity with individual metal dopings.

Activated charcoal grafted with phenyl imidazole groups for Knœvenagel condensation of furfural with malononitrile

Commercial activated charcoal Darco® KB-G with large specific area (1345 m2 g−1) was found to be an excellent carbonaceous support for chemical surface functionalization. Its covalent grafting with phenyl imidazole groups via diazonium chemistry was carried out under mild conditions (25 °C, Patm) by reacting 4-(1H-imidazol-1-yl)aniline with Darco in the presence of isopentyle nitrite as diazotization initiator. The success of the surface functionalization was evidenced by experimental XPS spectra and DFT calculations. The functionalized solid Darco-0.5IM with tertiary amine functions was well characterized and its catalytic activity was evaluated in the Knœvenagel condensation of furfural with malononitrile.

Stereodivergent Synthesis of Camphor-Derived Diamines and Their Application as Thiourea Organocatalysts.

A series of 18 regio- and stereo-chemically diverse chiral non-racemic 1,2-, 1,3-, and 1,4-diamines have been synthesized from commercial (1S)-(+)-ketopinic acid and (1S)-(+)-10-camphorsulfonic acid. The structures of the diamines are all based on the d-(+)-camphor scaffold and feature isomeric diversity in terms of regioisomeric attachment of the primary and the tertiary amine function and the exo/endo-isomerism. Diamines were transformed into the corresponding noncovalent bifunctional thiourea organocatalysts, which have been evaluated for catalytic activity in the conjugative addition of 1,3-dicarbonyl nucleophiles (dimethyl malonate, acetylacetone, and dibenzoylmethane) to trans-β-nitrostyrene. The highest enantioselectivity was achieved in the reaction with acetylacetone as nucleophile using endo-1,3-diamine derived catalyst 52 (91.5:8.5 er). All new organocatalysts 48–63 have been fully characterized. The structures and the absolute configurations of eight intermediates and thiourea derivative 52 were also determined by X-ray diffraction.

Toward Rational Understandings of α-C-H Functionalization: Energetic Studies of Representative Tertiary Amines.

SummaryFunctionalization of α-C–H bonds of tertiary amines to build various α-C–X bonds has become a mainstream in synthetic chemistry nowadays. However, due to lack of fundamental knowledge on α-C–H bond strength as an energetic guideline, rational exploration of new synthetic methodologies remains a far-reaching anticipation. Herein, we report a unique hydricity-based approach to establish the first integrated energetic scale covering both the homolytic and heterolytic energies of α-C–H bonds for 45 representative tertiary amines and their radical cations. As showcased from the studies on tetrahydroisoquinolines (THIQs) by virtue of their thermodynamic criteria, the feasibility and mechanisms of THIQ oxidation were deduced, which, indeed, were found to correspond well with experimental observations. This integrated scale provides a good example to relate bond energetics with mechanisms and thermodynamic reactivity of amine α-C–H functionalization and hence, may be referenced for analyzing similar structure-property problems for various substrates.

Multifunctional monomer acts as co-initiator and crosslinker to provide autonomous strengthening with enhanced hydrolytic stability in dental adhesives

ObjectiveThe purpose of this study was to evaluate a new synthesized multifunctional monomer, aminosilane functionalized methacrylate (ASMA), containing polymerizable methacrylate, tertiary amine, and methoxysilane functionalities in dental adhesive formulations, and to investigate the polymerization kinetics, leachates, thermal and mechanical properties of copolymers. MethodsAdhesive contained HEMA/BisGMA (45/55, w/w) was used as a control, and mixtures based on HEMA/BisGMA/ASMA at the mass ratio of 45/(55-x)/x were used as experimental adhesive. Adhesives were characterized with regard to water miscibility, photo-polymerization behavior (Fourier transform infrared spectroscopy, FTIR), leached co-monomers (high performance liquid chromatography, HPLC), thermal properties (modulated differential scanning calorimeter, MDSC), and mechanical properties (dynamic mechanical analyzer, DMA). Stress relaxation times and the corresponding moduli, obtained from stress relaxation tests, are used in a simulated linear loading case. ResultsAs compared to the control, ASMA-containing adhesives showed higher water miscibility, lower viscosity, improved monomer-to-polymer conversion, significantly greater Tg and rubbery modulus. HPLC results indicated a substantial reduction of leached HEMA (up to 85wt%) and BisGMA (up to 55wt%) in ethanol. The simulation reveals that the ASMA-containing adhesive becomes substantially stiffer than the control. SignificanceASMA monomer plays multiple roles, i.e. it serves as both a co-initiator and crosslinker while also providing autonomous strengthening and enhanced hydrolytic stability in the adhesive formulations. This multifunctional monomer offers significant promise for improving the durability of the adhesive at the composite/tooth interface.

Metal-based surface active ionic liquids: Self-assembling characteristics and C[sbnd]C bond functionalization of tertiary amines with TMSCN in aqueous micellar solutions

Metal-based surface active ionic liquids (MSAILs), 1-alkyl-3-methyl imidazoliumtetrachloromanganate [Cnmim][MnCl4]2− (n= 8,10,12) have been synthesized and characterized for self-assembling behavior in aqueous solution using tensiometry, fluorescence, conductivity, dynamic light scattering (DLS) and transmission electron microscopy (TEM) techniques. MSAILs have exhibited 4 to 5 fold higher surface activity as compared to the non-metal based surface active ionic liquids. MSAILs micellar solutions have been successfully used for C(sp3)-H functionalized oxidative cyanation of the tertiary amines. Oxidative Strecker reaction was carried out with different concentrations of the MSAILs, cyanide source (TMSCN) and substrate, and moderate to very high yields (up to 95%) could be achieved in 3–4 h. Usually, cyanation of tertiary amines is carried out in organic solvents under harsh conditions without recycling of the catalyst. Herein aqueous MSAILs micellar solutions have been used as a solvent, catalyst as well as template with a good recycling ability, thus making the approach simpler, greener, and sustainable.

Integrated soluble polymer and mesoporous silica as a double–type support to immobilize tertiary amine–Ru/diamine–bifunctionality for aza–addition/reduction cascade reaction

Exploiting advantages of a double–type support to create an active site–isolated heterobifunctional catalyst is beneficial to an efficiently sequential organic transformation. Herein, an integrated soluble polymer and mesoporous silica as a double–type support to immobilize the tertiary amine–Ru/diamine–bifunctionality for the construction of an active site–isolated catalyst is developed, where the tertiary amine–functionality is tethered in the outer soluble polymer and chiral ruthenium/diamine–functionality is anchored within the inner mesoporous silica. Electron microscopy images, together with analyses of solid–state NMR spectra, disclose that catalyst possesses the uniformly distributive morphology with well–defined single–site ruthenium/diamine active centers. As envisaged, the heterobifunctional catalyst performs a highly efficient aza–Michael addition/asymmetric transfer hydrogenation enantioselective cascade reaction, where the outer tertiary amine–functionality enables a high reactivity to afford β–secondary amino ketones via an aza–Michael addition reaction of enones and amines, and the inner chiral ruthenium/diamine–functionality guarantees a high enantioselectivity to chiral γ–secondary amino alcohols via an asymmetric transfer hydrogenation of β–secondary amino ketones. Furthermore, this catalyst can also be recovered easily and recycled for six runs, showing a practical preparation of aryl–substituted γ–secondary amino alcohols.

Palladium(II)-Catalyzed Remote meta-C-H Functionalization of Aromatic Tertiary Amines.

Pd(II)-catalyzed remote C-H olefination of aromatic tertiary amines was achieved with high meta selectivity. With the assistance of an elaborated template, C-H functionalization of unreactive aryl tertiary amines, hindered by the p-π conjugation between the lone-pair electrons of the nitrogen atom and the phenyl ring, was realized with high meta regioselectivity via a quaternary ammonium salt assembly. The results demonstrate that apart from the distance and geometry of the template, the conformation of the arene substrate also plays a crucial role in the templated-assisted remote C-H functionalization.

Covalently hooked EOSIN-Y in a Zr(IV) framework as visible-light mediated, heterogeneous photocatalyst for efficient C[sbnd]H functionalization of tertiary amines

Herein, we report the synthesis of a novel heterogeneous photo-catalyst by utilizing post-synthetic modification of an amine functionalized Zr(IV) metal-organic framework (UiO-66-NH2) through covalent hooking of EOSIN-Y via dehydrating coupling. The characterization of the catalyst was accomplished by FT-IR, XRD, BET surface analysis, TGA, as well as TEM, SEM, XPS, DRS-UV–visible, and NMR spectroscopy, confirming successful covalent linking of EOSIN-Y with the pendent NH2 functionality in the framework. That post-modified EY@UiO-66-NH2 acts as simple and green visible light mediated photo-catalyst for the CH activation of tertiary amines with excellent yields. Importantly, the activity of dye incorporated heterogeneous photo-catalyst is found superior to that for the homogeneous photo-catalyst EOSIN-Y. Thus, separation difficulty of homogeneous catalysis, as well as the environmental adverse effects of toxic EOSIN-Y can be excluded by developing such photo-catalyst. Moreover, EY@UiO-66-NH2 catalyst could be consistently recycled up to 10 cycles, without any significant loss in activity. Based on literature report and experimental findings, we also propose a plausible mechanism for the reaction.

Visible-light-mediated α-phosphorylation of N-aryl tertiary amines through the formation of electron-donor–acceptor complexes: synthetic and mechanistic studies

A visible light-mediated photocatalyst-free approach for the oxidative α-CH functionalization of N-aryl tertiary amines with secondary phosphine oxides has been developed.

Development of an Efficient Synthesis of rac‐3‐Demethoxyerythratidinone via a Titanium(III) Catalyzed Imine‐Nitrile Coupling

We herein describe the evolution of a rapid, high‐yielding synthesis of the erythrina alkaloid 3‐demethoxyerythratidinone. The natural product is assembled in six steps from commercial precursors in 30–35 % overall yield and with only two chromatographical purification operations. The key step is a titanium(III) catalyzed umpolung reaction in form of a reductive imine–nitrile coupling that can be combined with a subsequent cyclization reaction on a 50 mmol scale. Furthermore, optimized Wacker oxidation conditions enable the selective alkene oxidation in the presence of a tertiary amine functionality, which has been a problem in previous syntheses of erythrina alkaloids. The racemic route can be used to prepare the natural product on gram scale and the results may be useful for the synthesis of related alkaloids.

A robust strategy for the synthesis of miktoarm star copolymers by combination of ROP and photoinitiated free radical polymerization

A novel approach for the synthesis of miktoarm star copolymers by the combination of ring opening polymerization (ROP) and Type II photopolymerization is described. The method pertains to the use of a multifunctional initiator, bearing primary hydroxyl and tertiary amine functionalities, for the sequential or simultaneous polymerization of vinyl and lactone monomers under mild conditions. In the first step, phosphazene base (P2-t-Bu) catalyzed ROP of ε-caprolactone is accomplished. Subsequently, thus obtained poly(ε-caprolactone) with amine end groups was used as co-initiator for the polymerization of methyl methacrylate by utilizing conventional Type II photoinitiators. The structures, molecular weight characteristics and thermal properties of the polymers are analyzed by NMR, gel permeation chromatography (GPC) and differential scanning calorimetry (DSC) measurements, respectively.

PIDA/I2-Mediated α- and β-C(sp3)-H Bond Dual Functionalization of Tertiary Amines.

The α,β-C(sp3)-H bond dual functionalization of tertiary amines is still a challenging task for both organic and medicinal chemists. Herein a direct, mild, metal-free, and site-specific method mediated by PIDA/I2 was developed for α,β-C(sp3)-H bond dual functionalization of tertiary amines, and this method can provide facile access to α-keto lactams or rarely studied α,α-diiodo lactams. Moreover, this method was used for the effective syntheses of three natural products [obscurumine C (13), obscurumine O (17), and strychnocarpine (18)] and direct preparation of mimics of the in vivo metabolites of two FDA-approved drugs (imatinib and donepezil) in 36-60% overall yield. The method represents a promising protocol for the late-stage α,β-C(sp3)-H bond oxidative dual functionalization of tertiary amine-containing drugs and complex natural products.

Manganese-catalysed benzylic C(sp3)–H amination for late-stage functionalization

Reactions that directly install nitrogen into C–H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C–H amination reactions are known, achieving high levels of reactivity, while maintaining excellent site-selectivity and functional-group tolerance, remains a challenge for intermolecular C–H amination. Herein, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C–H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site-selectivity. In the presence of Brønsted or Lewis acid, the [MnIII(ClPc)]-catalyzed C–H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C–H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C–H cleavage is the rate-determining step of the reaction. Collectively these mechanistic features contrast previous base-metal catalyzed C–H aminations and provide new opportunities for tunable selectivities.