Terminal Alkyne Groups Research Articles

Synthesis of 1,4-Bis(diaryl)-1,3-Butadiynes Bearing Two Amino Moieties by Electrochemical Reaction Site Switching and Their Solvatochromic Fluorescence

Recently, π-conjugated compounds have been on focus because they are known to be as key building blocks for pharmaceuticals and potent candidates for electrochemical and optical materials. While the optical and electrochemical properties of π-conjugated compounds highly depends on the structure, it has not been easy to predict these properties. It is the reason why facile and diversity-oriented methodologies to construct π-conjugated structure have been strongly required. From such a point of view, we have investigated electrochemically assisted coupling reactions for constructing π-conjugated compounds, and recently reported sequential coupling reactions which include Pd/Cu-catalyzed electro-oxidative homo-coupling of p-bromophenylacetylene to give 1,4-bis(p-bromophenyl)-1,3-diyne and subsequent Suzuki–Miyaura coupling with arylboronic acids leading to 1,4-bis(diaryl)-1,3-butadiynes.1 Two reaction sites of p-boromophenylacetylene, terminal alkyne and Br group, could be discriminated in a virtually complete manner by on/off application of electricity, and we called the strategy as “Electrochemical Reaction Site Switching (e-RSS)”. Several arylboronic acids could be applied to the reactions, and the reactions proceeded selectively to give 1,4-bis(diaryl)-1,3-butadiynes in good to excellent yields.During the course of the investigation, we unexpectedly found that 1,4-bis(diaryl)-1,3-butadiyne bearing two dimethylamino groups at p-position exhibited solvatochromic fluorescence. To the best of our knowledge, while there have been many reports on the amines which exhibit solvatochromic fluorescence, there have been few reports on the solvatochromic fluorescence of diamines which have small dipole moment. Most of the amines exhibiting solvatochromic fluorescence so far have a strong acceptor moiety. This unexpected result prompted us to get deeper insight into this unusual phenomenon; however the poor solubility of diaminodiynes prevented us from further investigation. We therefore designed novel 1,4-bis(diaryl)-1,3-butadiynes bearing two dialkylamino or diphenylamino groups at p-position of the terminal benzene rings. The butadiynes could be easily synthesized by e-RSS with the corresponding p-aminoarylboronic acids. As expected, thus obtained diynes could be solved into several solvents and they exhibited solvatochromic fluorescence. We will discuss the detail of the synthesis of 1,4-bis(diaryl)-1,3-butadiynes bearing two dialkylamino or diphenylamino groups at p-position, and their unique optical properties. (1) Mitsudo, K.; Kamimoto, N.; Murakami, H.; Mandai, H.; Wakamiya, A.; Murata, Y.; Suga, S. Org Biomol Chem 2012, 10, 9562-9569.

Alkynyl–coumarinyl ethers as MAO-B inhibitors

In this study, alkynyl–coumarinyl ethers were developed as inhibitors of human monoamine oxidase B (MAO-B). A series of 31 new, ether-connected coumarin derivatives was synthesized via hydroxycoumarins, whose phenolic group at position 6, 7 or 8 was converted by means of the Mitsunobu reaction. The majority of the final products were produced from primary alcohols with a terminal alkyne group. The inhibitors were optimized with respect to the structure of the alkynyloxy chain and its position at the fused benzene ring as well as the residue at position 3 of the pyran-2H-one part. A hex-5-ynyloxy chain at position 7 was found to be particular advantageous. Among the 7-hex-5-ynyloxy-coumarins, the 3-methoxycarbonyl derivative 36 was characterized as a dual-acting inhibitor with IC50 values of less than 10nM towards MAO-A and MAO-B, and the 3-(4-methoxy)phenyl derivative 44 was shown to combine strong anti-MAO-B potency (IC50=3.0nM) and selectivity for MAO-B over MAO-A (selectivity >3400-fold).

Synthesis and biological activity of N-substituted-tetrahydro-γ-carbolines containing peptide residues.

The synthesis of novel peptide conjugates of N-substituted-tetrahydro-γ-carbolines has been performed using the sequence of the Ugi multicomponent reaction and Cu(I)-catalyzed click chemistry. The effect of obtained γ-carboline–peptide conjugates on the rat liver mitochondria was evaluated. It was found that all compounds in the concentration of 30 µM did onot induce depolarization of mitochondria but possessed some inhibitory effect on the mitochondria permeability transition. The original N-substituted-tetrahydro-γ-carbolines containing an terminal alkyne group demonstrated a high prooxidant activity, whereas their conjugates with peptide fragments slightly inhibited both autooxidation and the t-BHP-induced lipid peroxidation.

Synthesis of well dispersed graphene in conjugated poly(3,4-ethylenedioxythiophene):polystyrene sulfonate via click chemistry

Abstract The well dispersed graphene in poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) composites was achieved by chemical modification via click chemistry under mild condition in order to improve the electrical conductivity of polymer. Graphene sheets were prepared from natural graphite flake by a modified Hummers method followed by reducing with hydrazine. Graphene and PEDOT:PSS were functionalized with alkyne and azide, respectively followed by reacting via click chemistry at room temperature for 48 h using copper sulfate as catalyst. The successful functionalization and click reaction between terminal alkyne groups ( C C) on graphene sheets and terminal azide groups ( N3) of PEDOT:PSS were confirmed by Fourier Transform Infrared (FTIR), Raman and X-ray photoelectron (XPS) spectroscopy. The preliminary test to check the dissimilar dispersibility between graphene oxide and alkyne-modified graphene oxide in mixed water/hexane solvent was performed. Thermogravimetric analysis result exhibited the composites having excellent thermal stabilities due to the incorporation of graphene in PEDOT:PSS; however, clicked composites showed slightly lower thermal stabilities than unclicked ones as a result of cleavages of amide linkages and remaining oxygen-containing functionalities. It was also found that the surface morphologies observed by scanning electron microscope of clicked composites were smoother than those of unclicked composites because of the enhancement of interfacial interaction between graphene sheets and PEDOT:PSS matrix, resulting in a decrease in graphene agglomeration and, in turn, an increase in electrical conductivity.

Hyperbranched polycaprolactone-click-poly(N-vinylcaprolactam) amphiphilic copolymers and their applications as temperature-responsive membranes.

Hyperbranched poly(ε-caprolactone) with peripheral terminal alkyne groups (HPCL) was synthesized via thiol-yne click reaction among the AB2-type α-thiol-ω-alkyne-poly(ε-caprolactone) (CH[triple bond, length as m-dash]C-PCL-SH) linear precursors. Azide-terminated poly(N-vinylcaprolactam) (PVCL-N3), prepared a priori via xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization of N-vinylcaprolactam (VCL), was then linked to HPCL chains through Cu(i)-catalyzed alkyne-azide click reaction. The resultant hyperbranched-linear HPCL-click-PVCL copolymers were cast, by phase inversion in an aqueous medium, into microporous membranes of well-defined and uniform pores. The PVCL content in the HPCL-click-PVCL copolymers could be used to control the pore size and porosity of the resulting membranes. The temperature-responsive characteristics of the HPCL-click-PVCL membranes were illustrated in the swelling behavior and controlled drug transport through the membranes. These stimuli responsive membranes with controllable morphology, improved mechanical properties and negligible cytotoxicity are useful as biomaterials for controlled drug delivery.

A base-catalyzed cycloisomerization of 5-cyano-pentyne derivatives: an efficient synthesis of 3-cyano-4,5-dihydro-1H-pyrroles.

A base-catalyzed cycloisomerization of 5-cyano-pentyne bearing a terminal alkyne group has been developed under metal-free conditions. This reaction involves a tandem process providing efficient access to 3-cyano-4,5-dihydro-1H-pyrroles in good to excellent yields in an atom-economic manner with 1,3-cyano migration as the key transformation.

O2 Reduction Reaction by Biologically Relevant Anionic Ligand Bound Iron Porphyrin Complexes

Iron porphyrin complex with a covalently attached thiolate ligand and another with a covalently attached phenolate ligand has been synthesized. The thiolate bound complex shows spectroscopic features characteristic of P450, including the hallmark absorption spectrum of the CO adduct. Electrocatalytic O2 reduction by this complex, which bears a terminal alkyne group, is investigated by both physiabsorbing on graphite surfaces (fast electron transfer rates) and covalent attachment to azide terminated self-assembled monolayer (physiologically relevant electron transfer rates) using the terminal alkyne group. Analysis of the steady state electrochemical kinetics reveals that this catalyst can selectively reduce O2 to H2O with a second-order k(cat.) ~10(7) M(-1 )s(-1) at pH 7. The analogous phenolate bound iron porphyrin complex reduces O2 with a second-order rate constant of 10(5) M(-1) s(-1) under the same conditions. The anionic ligand bound iron porphyrin complexes catalyze oxygen reduction reactions faster than any known synthetic heme porphyrin analogues. The kinetic parameters of O2 reduction of the synthetic thiolate bound complex, which is devoid of any second sphere effects present in protein active sites, provide fundamental insight into the role of the protein environment in tuning the reactivity of thiolate bound iron porphyrin containing metalloenzymes.

Nano-size ZnS: A novel, efficient and recyclable catalyst for A3-coupling reaction of propargylamines

Nano-size ZnS was prepared by a simple, economic and elegant chemical bath deposition technique and characterized by using SEM, TEM, XRD, and EDAX techniques. Prepared nano-size ZnS was found to be highly efficient novel heterogeneous catalyst for A3-coupling reaction of Propargylamines (4a–4l) using various aldehydes, amines and terminal alkyne groups through CH activation. The catalyst was recycled more than eight consecutive cycles and reused in the subsequent reactions without any loss in its activity. The developed protocol offers efficient synthesis of diverse propargylamines without using co-catalyst and any other activator, high catalytic activity and short reaction times were obtained when compared to other metal ion and/or metal oxide catalysts.

Long-Wavelength, Photostable, Two-Photon Excitable BODIPY Fluorophores Readily Modifiable for Molecular Probes

Near-infrared (NIR) fluorescent probes are increasingly popular in biological imaging and sensing, as long-wavelength (650-900 nm) excitation and emission have the advantages of minimum photodamage, deep tissue penetration, and minimum interference from autofluorescence in living systems. Here, a series of long-wavelength BODIPY dyes SPC, DC-SPC, DPC, and DC-DPC are synthesized conveniently and efficiently. They exhibit excellent photophysical properties in far red to near-infrared region, including large extinction coefficients, high fluorescence quantum yields, good photostability, and reasonable two-photon absorption cross section. Comparison of single-molecular imaging confirms that DPC is a much more efficient and more photostable NIR fluorophore than the commonly used Cy5. Also importantly, two kinds of convenient functionalization sites have been reserved: the aryl iodide for organometallic couplings and the terminal alkyne groups for click reactions. Further derivatives DC-SPC-PPh3 exhibit specificity to localize in mitochondria. The introduction of triphenylphosphonium (TPP) moieties mediates its hydrophilic-lipophilic balance and makes DC-SPC-PPh3 appropriate for cell labeling. Their long-wavelength emission at ∼650 nm can efficiently avoid the spectral crosstalk with other probes emitting in the visible light region. Superior photostability, low cytotoxicity, and two-photon excitable properties demonstrate its utility as a standard colocalizing agent to estimate the other probes' local distribution.

ChemInform Abstract: Palladium‐Catalyzed Sonogashira Reaction for the Synthesis of Arylalkynecarboxylic Acids from Aryl Bromides at Low Temperature.

A variety of aryl bromides were coupled with propiolic acid in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and catalyst Pd(PPh3)4 to afford the corresponding arylalkynecarboxylic acids in good yields at low temperature. This method showed good tolerance toward functional groups such as alkoxy, ketone, ester, aldehyde, cyano, nitro, and hydroxy. Under these conditions, propiolic acid showed higher reactivity than any other compound containing terminal alkyne groups. According to the mechanistic studies, the key reaction step for the high reactivity of propiolic acid might be ligand exchange between the acetylide and bromide at palladium, and/or reductive elimination, but not the oxidative addition step.

A novel click-chemistry approach to flame retardant polyurethanes

The low thermo-oxidative properties of PU foams somewhat limits their practical application, particularly as heat sensitive materials. The introduction of a covalently linked flame retardant organophosphonate ester into the PU foam was achieved using the CuAAC ‘click’ reaction of an alkyne-polyol and azidoalkylmonophosphonate. These functionalised materials were prepared in four steps: first, a number of azidoalkyl monophosphonate compounds were formed via nucleophilic substitution of bromoalkylphosphonates with NaN3; next, polyols bearing terminal alkyne groups were prepared by anionic ring opening copolymerization between propylene oxide and glycidyl propargyl ether; followed by ‘clicking’ the azidoalkylphosphonate to the polyol and finally, synthesis of the PU foam with 2.4wt% of “click-polyol”. The functionalised PU foam demonstrated a well-formed polyhedral cell structure and an increase in the fire resistance, according to the SEM and thermogravimetric analysis, respectively. Even after thermal treatment at 400°C, the new PU foam material displayed enhanced flame resistant properties by forming a char layer on the surface of the polymer, whilst maintaining its polyhedral structure.

Efficient synthesis of solid-emissive Boron–Fluorine derivatives

A highly solid-emissive Boron–Fluorine scaffold with two conjugated alkyne groups (BOPIM-S) is facilely synthesized, which shows enhanced fluorescent intensity compared to the BOPIM dye without alkyne units. According to X-ray single crystal analysis, the terminal alkyne groups interact with atoms B, F, C and N on neighbouring molecules, producing a rigid rectangular structure, which helps to avoid energy loss via non-irradiative decay. Furthermore, BOPIM-S can undergo copper catalysed alkyne–azide-cycloaddition (CuAAC) chemistry with aromatic azides to produce conjugated molecules with high yields. According to absorption and fluorescent measurements, all these compounds synthesized by CuAAC emit large Stokes shift (over 100 nm) both in solution and in solid state. But the electronic environments of terminal aromatic rings slightly affect their photophysical properties.

Enhanced Chemical Stability of AdoMet Analogues for Improved Methyltransferase-Directed Labeling of DNA

Methyltransferases catalyze specific transfers of methyl groups from the ubiquitous cofactor S-adenosyl-l-methionine (AdoMet) to various nucleophilic positions in biopolymers like DNA, RNA, and proteins. We had previously described synthesis and application of AdoMet analogues carrying sulfonium-bound 4-substituted but-2-ynyl side chains for transfer by methyltransferases. Although useful in certain applications, these cofactor analogues exhibited short lifetimes in physiological buffers. Examination of the reaction kinetics and products showed that their fast inactivation followed a different pathway than observed for AdoMet and rather involved a pH-dependent addition of a water molecule to the side chain. This side reaction was eradicated by synthesis of a series of cofactor analogues in which the separation between an electronegative group and the triple bond was increased from one to three carbon units. The designed hex-2-ynyl moiety-based cofactor analogues with terminal amino, azide, or alkyne groups showed a markedly improved enzymatic transalkylation activity and proved well suitable for methyltransferase-directed sequence-specific labeling of DNA in vitro and in bacterial cell lysates.

Mixed Monolayer Organic Films via Sequential Electrografting from Aryldiazonium Ion and Arylhydrazine Solutions

Sequential electrografting at glassy carbon from aryldiazonium salt solutions, or an aryldiazonium salt followed by an arylhydrazine, leads to the formation of covalently attached monolayer films incorporating two modifiers. In the first step, a 4-((triisopropylsilyl)ethynyl)phenyl film is electrografted to the surface, followed by removal of the triisopropylsilyl group to give a submonolayer of phenylethynylene groups. Two general strategies can then be applied to "fill in" the sparse monolayer with a second modifier. In the first route, nitrophenyl groups are grafted to the phenylethynylene-modified surface by the oxidation of 4-nitrophenylhydrazine. Ferrocene can be coupled to the terminal alkyne groups on the surface via a click reaction with azidomethylferrocene; an electrochemical measurement of the amount of immobilized ferrocene demonstrates that the phenylethynylene layer retains close to full reactivity after the second grafting step. In the alternative strategy, ferrocene is coupled to the phenylethynylene layer prior to grafting nitrophenyl groups by the reduction of the 4-nitrobenzenediazonium ion or by the oxidation of 4-nitrophenylhydrazine. For all approaches, the optimization of the grafting conditions gives surface concentrations of ferrocene and nitrophenyl groups that are consistent with those of a mixed monolayer. The stepwise generation of mixed monolayers is also monitored by film thickness measurements by depth profiling using the atomic force microscope. Thickness values are consistent with the proposed film structure in each preparation step.

Palladium‐Catalyzed Sonogashira Reaction for the Synthesis of Arylalkynecarboxylic Acids from Aryl Bromides at Low Temperature

AbstractA variety of aryl bromides were coupled with propiolic acid in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) and catalyst Pd(PPh3)4 to afford the corresponding arylalkynecarboxylic acids in good yields at low temperature. This method showed good tolerance toward functional groups such as alkoxy, ketone, ester, aldehyde, cyano, nitro, and hydroxy. Under these conditions, propiolic acid showed higher reactivity than any other compound containing terminal alkyne groups. According to the mechanistic studies, the key reaction step for the high reactivity of propiolic acid might be ligand exchange between the acetylide and bromide at palladium, and/or reductive elimination, but not the oxidative addition step.

Demonstration of a sucrose-derived contrast agent for magnetic resonance imaging of the GI tract

A scaffold bearing eight terminal alkyne groups was synthesized from sucrose, and copies of an azide-terminated Gd–DOTA complex were attached via copper(I)-catalyzed azide-alkyne cycloaddition. The resulting contrast agent (CA) was administered by gavage to C3H mice. Passage of the CA through the gastrointestinal (GI) tract was followed by T1-weighted magnetic resonance imaging (MRI) over a period of 47h, by which time the CA had exited the GI tract. No evidence for leakage of the CA from the GI tract was observed. Thus, a new, orally administered CA for MRI of the GI tract has been developed and successfully demonstrated.

Cross-linking of discotic tetraazaporphyrin dyes in 2 and 3 dimensions by “click” chemistry

An intrinsic shortcoming of self-organizing materials is their susceptibility to structural changes by mechanical forces and exposure to chemicals and radiation. Cross-linking of the molecules in the desired supramolecular structure is a generally applicable pathway to structurally more stable materials but is difficult to apply to self-organizing materials because the introduction of cross-linkable groups affects their self-organization and the process of cross-linking may alter the supramolecular structure of the preceding phase. Reported here are the synthesis, thermal properties, and cross-linking of octaalkylthio substituted tetraazaporphyrins that contain either eight terminal azide groups or eight terminal acetylene groups. Synthesis of these compounds requires the preparation of the azide and alkyne containing side-chains and their reaction with 1,2-dicyanoethylene-1,2-dithiolate to the corresponding maleodinitrile intermediates. All maleodinitriles are successfully converted to tetraazaporphyrins by the established Mg templated cyclotetramerization in typical yields of 60–70%. Thermal properties of the metal-free and copper(II) metallated tetraazaporphyrins were studied by thermal gravimetric analysis, polarized optical microscopy, differential scanning calorimetry, and variable temperature powder X-ray diffraction measurements. Azide substituted tetraazaporphyrins with trimethylene and hexamethylene spacers as well as acetylene derivatives with trimethylene spacers unexpectedly display columnar mesophases over ranges of temperature from 30 °C to 110 °C. A thermally activated cross-linking of a hexagonal columnar mesophase by cycloaddition at 65 °C is demonstrated for a 1 : 1 mixture of azide and acetylene derivatives. At this temperature the reaction progresses for up to 48 hours but renders the mesophase insoluble and stable to above 200 °C. The structure of the mesophase is surprisingly little affected by the cross-coupling process that reaches a conversion of 60% of all azide and acetylene groups based on IR measurements. Conversion of up to 80% of azide and acetylene groups is reached by copper catalysed cross-linking of a 1 : 1 mixture in solution to generate insoluble polymers. A similar degree of conversion is achieved by copper catalysed cross-linking of a 1 : 1 mixture as Langmuir film after 3 hours. However, transfer of intact cross-linked Langmuir films onto substrates was not successful.

Synthesis of acetylenic alcohols with calcium carbide as the acetylene source

Propargyl alcohols containing a terminal alkyne group are highly important and versatile intermediates. Here, we report the synthesis of these compounds from an inexpensive and renewable resource, calcium carbide (CaC2). No metal catalysts are required in this new protocol and the reactions take place under very mild conditions.

Surface-functionalizable membranes of polycaprolactone-click-hyperbranched polyglycerol copolymers from combined atom transfer radical polymerization, ring-opening polymerization and click chemistry.

Hyperbranched polyglycerols containing terminal alkyne and alkyl bromide groups (CH[triple bond, length as m-dash]C-HPG-Br) were first synthesized via propargyl alcohol-initiated ring-opening polymerization (ROP) of glycidol, followed by reaction of 2-bromoisobutyryl bromide (BIBB) with the hydroxyl groups to introduce the atom transfer radical polymerization (ATRP) initiators on HPG. Hydrophobic azido-terminated poly(ε-caprolactone) (PCL-N3), prepared a priori via 2-azidoethanol-initiated ROP of ε-caprolactone, was then coupled to the CH[triple bond, length as m-dash]C-HPG-Br polymer through a Cu(i)-catalyzed alkyne-azide click reaction. The resultant linear-hyperbranched PCL-click-HPG copolymers were cast by phase inversion in an aqueous medium into microporous membranes of well-defined and uniform pores. Not only could the HPG contents in the PCL-click-HPG copolymers be used to control the pore size and porosity of the resulting membranes, but also the alkyl halide chain-ends of HPG allowed the subsequent functionalization of membrane and pore surfaces. The PCL-click-HPG-b-PMPC membrane was prepared via surface-initiated ATRP of zwitterionic 2-methacryloyloxyethyl phosphorylcholine (MPC) from the PCL-click-HPG membrane and pore surfaces. The PCL-click-HPG-b-PMPC membranes exhibit good antifouling and antibacterial adhesion properties with negligible cytotoxicity effects, making the membranes potentially useful for biomaterials and biomedical applications.

Enhanced copper-catalyzed “click” reaction between homopolymers with terminal azide and alkyne groups in the presence of water

AbstractWe report here that the efficiency of the click chemistry between the terminal azide and alkyne groups of different polymer chains could be drastically increased with the addition of an optimum amount of water into a reaction system. That is, the efficiency was only slightly promoted by the addition of a small amount of water into the reaction mixture. However, the reaction efficiency was increased dramatically near the water volume fraction to lead the reaction mixture into nanosized phase separation. Further increasing in water content caused the polymer(s) to undergo macroscopic phase separation and the click reaction efficiency was decreased once again. The enhanced efficiency of click coupling reaction including conversion and rate was also demonstrated via in-situ 1H-NMR. The reaction kinetics as well as reaction rate constant for these reaction system with typical water content were also evaluated. This finding on enhanced click reaction is of practical value, because click reactions in polymer synthesis are generally more difficult to be carried out and proceed relative slowly at low yield in most case because of the strong steric hindrance effect from “large and long” polymer chains, as compared to “click” reactions which are employed for preparation of the low molecular weight organic compounds.