Alkyne Functionality Research Articles

Synthetic Approaches towards Peptide‐Conjugates of Pt(II) Compounds with an (O,S) Chelating Moiety

AbstractMetal‐containing peptide (bio−)conjugates have received continuous interest due to their enormous potential for bioinorganic and medicinal research. In many bioconjugates the chemical inertness of the metal‐containing units facilitates synthesis e. g. by copper‐catalyzed alkyne−azide cycloaddition or the formation of peptide bonds. However, when the metal complex contains labile ligands, which are often critical to their biological activity, the synthetic proceeding requires careful planning. Here, we report on the synthesis of a set of peptide bioconjugates with a platinum(II) core, coordinated through widely variable (O,S) chelating β‐hydroxydithiocinnamic ester and two monodentate ligands. We have evaluated the synthetic applicability of metal−peptide bioconjugation techniques between the model peptide Leu5−enkephalin and differently functionalized (O,S)Pt units. Within this, the type and position of anchor used at the β‐hydroxydithiocinnamic unit proved to be crucial for success, but equally important was the synthetic order of conjugation and complexation. In this work, synthetic approaches for the linkage of metal complexes that are coordinated by functionalized ligands towards peptides were explored. Two general methods to link the studied (O,S)Pt pharmacophore to the model peptide, Leu5−enkephalin, have been applied, namely the most prominent “click” reaction, CuAAC, and the linking via amide bonds. Overall, it could be shown that the structural motif of the (O,S)Pt compounds presented here offers multiple possibilities of derivatization, so that bioconjugation towards peptides can be made possible. Depending on the demands made on the resulting metal bioconjugate, both the dithioester and the aromatic unit of β‐hydroxydithiocinnamic esters can be used as anchor for peptides. However, from our results here, it can be concluded that anchoring at the aromatic subsite seems preferable from a synthetic point of view as the spatial distance of the reactive terminal functional group (alkyne or azide) to the metal center may avoid intramolecular reactions. Also, for using azide−alkyne click chemistry as a conjugation strategy, the (O,S) unit should contain the azide function and not the alkyne function, as triple bond hydration may occur. Classical amide‐bond conjugation also proved to be a suitable method in our hands when performed in solution. A coupling of the β‐hydroxydithiocinnamic unit to resin‐bound peptide would not be possible due to the typically harsh cleavage conditions.

"Click" Chemistry for the Functionalization of Graphene Oxide with Phosphorus Dendrons: Synthesis, Characterization and Preliminary Biological Properties.

Two families of phosphorhydrazone dendrons having either an azide or an alkyne linked to the core and diverse types of pyridine derivatives as terminal functions have been synthesized and characterized. These dendrons were grafted via click reaction to graphene oxide (GO) functionalized with either alkyne or azide functions, respectively. The resulting modified-GO and GO-dendrons materials have been characterized by Fourier Transform Infrared (FTIR), Raman spectroscopy (RS), and Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) analyses. In addition, the free dendrons and the dendrons grafted to GO were tested toward cancerous (HCT116) and non-cancerous (RPE1) cell lines.

Physico‐mechanical properties of poly(ethylene glycol)‐based polymer networks

AbstractPoly(ethylene glycol) (PEG) based networks have been used extensively for biomedical applications and as solid state electrolytes. In this work, a series of PEG networks was prepared using bifunctional PEG of molar mass 400, 1000, 2000, 4000, and 6000 g mol−1 and star shaped PEG (Mn = 1000 g mol−1) cross‐linker using copper‐catalyzed Huisgen 1,3‐dipolar cycloaddition or “click” chemistry. The end‐group modification of the bifunctional polymers and the star shaped cross‐linker with alkyne and azide groups, respectively, was confirmed by 1H NMR spectroscopy. The coupling reaction between azide and alkyne functionalities for the network formation was confirmed by Fourier transform infrared (FTIR) spectroscopy. The thermal properties of polymer network were determined by differential scanning calorimetry. Swelling studies of the networks were performed to correlate the network structure with the physical properties. The molar mass between the cross‐links was determined using the Bray‐Merill modified Flory‐Rehner equation. The effect of molar mass between the cross‐linking points on the strength of the networks was compared. Additionally, the effect of the stoichiometry of the precursors on the network strength was also studied. Finally, thickness‐dependent tensile testing was performed to investigate the stress oscillation phenomenon.

Hypervalent Iodine‐Mediated Alkyne Functionalization: Facile Access to Trifluoromethyl‐ and Pentafluoroethyl‐Substituted Thiazoles

AbstractThe use of hypervalent iodine with Lewis acid provided alkyne trifluoromethylation and pentafluoroethylation to access trifluoro‐and pentafluoro‐substituted thiazoles. This simple and efficient method is compatible with a broad range of aryl‐ and alkyl‐substituted thiourea starting materials. Additionally, a gram‐scale reaction proves the practicality of this transformation.

Exploring the Divergent Reactivity of Vinyl Radicals Emanating from Alkynes and Thiols via Photoredox Catalysis.

Organic chemistry has seen a surge in visible-light-driven transformations, which offer unique reaction pathways and access to new synthetic possibilities. We aim to provide a comprehensive understanding of state-of-the-art photo-mediated alkyne functionalization, with a focus on the reactive behavior of vinyl radicals. This review outlines our contributions to the field, including developing new methods for forming carbon-carbon and carbon-heteroatom bonds.

Synthesis of N-Propargyl Pyrrolylamides and Theoretical Study of Pyrrolylimide Reduction by NaBH4

AbstractThis study is divided into two parts: experimental and theoretical. In the experimental part, N-propargyl-substituted pyrrolylamide derivatives are synthesized in five steps starting from pyrrole. The main features of this procedure are (i) the synthesis of 2- and 3-nitropyrrole, (ii) the introduction of a propargyl group on the nitrogen atom of the pyrrole, (iii) coupling of various substituents with the alkyne functionality by the Sonogashira reaction, (iv) synthesis of pyrrolylimides by a tin-catalyzed reaction with phthalic anhydride, and, finally, (v) reduction of pyrrolylimides with sodium borohydride (NaBH4) in the presence of water. The theoretical part concerns the reduction mechanism of the pyrrolylimide by NaBH4. The hybrid functional B3LYP in density functional theory is used to determine and discuss the energetics of the compounds.

Controlled Partial Linker Thermolysis in Metal‐Organic Framework UiO‐66‐NH2 to Give a Single‐Site Copper Photocatalyst for the Functionalization of Terminal Alkynes

AbstractMetal–organic frameworks (MOFs) with expanding porosity and tailored pore environments are intriguing for catalytic applications. We report herein a straightforward method of controlled partial linker thermolysis to introduce desirable mesopores into mono‐ligand MOFs, which is different from the classical thermolyzing method that starts from mixed‐linker MOFs. UiO‐66‐NH2, after partial ligand thermolysis, exhibits significant mesoporosity, retained crystal structure, improved charge photogeneration and abundant anchoring sites, which is ideal to explore single‐site photocatalysis. Atomically dispersed Cu is then accommodated in the tailored pore. The resulting single‐site Cu catalyst exhibits excellent performance for photocatalytic alkylation and oxidation coupling for the functionalization of terminal alkynes. The study highlights the advantage of controlled partial linker thermolysis to synthesize hierarchical MOFs to achieve the advanced single‐site photocatalysis.

Controlled Partial Linker Thermolysis in Metal-Organic Framework UiO-66-NH2 to Give a Single-Site Copper Photocatalyst for the Functionalization of Terminal Alkynes.

Metal-organic frameworks (MOFs) with expanding porosity and tailored pore environments are intriguing for catalytic applications. We report herein a straightforward method of controlled partial linker thermolysis to introduce desirable mesopores into mono-ligand MOFs, which is different from the classical thermolyzing method that starts from mixed-linker MOFs. UiO-66-NH2 , after partial ligand thermolysis, exhibits significant mesoporosity, retained crystal structure, improved charge photogeneration and abundant anchoring sites, which is ideal to explore single-site photocatalysis. Atomically dispersed Cu is then accommodated in the tailored pore. The resulting single-site Cu catalyst exhibits excellent performance for photocatalytic alkylation and oxidation coupling for the functionalization of terminal alkynes. The study highlights the advantage of controlled partial linker thermolysis to synthesize hierarchical MOFs to achieve the advanced single-site photocatalysis.

Microwave Spectrum and Novel Molecular Structure of (Z)-1-Chloro-3,3,3-trifluoropropene-Acetylene.

The gas-phase heterodimer formed between (Z)-1-chloro-3,3,3-trifluoropropene and acetylene is investigated using quantum chemistry calculations and observed via chirped-pulse Fourier transform microwave (FTMW) spectroscopy. Subsequent analysis of higher resolution spectra, including those using a sample enriched in H13C13CH, obtained with a Balle-Flygare FTMW spectrometer reveals a novel structure, as predicted by theory, for the complex, in which the acetylene functions as the gas-phase (Lewis) base and the halopropene as the acid. In the equilibrium structure, the acetylene molecule is located perpendicular to the symmetry plane of (Z)-1-chloro-3,3,3-trifluoropropene with the triple bond interacting with the two olefinic hydrogens. Mapped electrostatic potential surfaces suggest that this structure results from a reduction in the nucleophilicity of the halogen atoms as compared to previously studied acetylene halo-olefin complexes and a concomitant increase in the electrophilicity of the hydrogen atoms.

Iron-Mediated C-H Functionalization of Unactivated Alkynes for the Synthesis of Derivatized Dihydropyrrolones: Regioselectivity Under Thermodynamic Control.

Cyclopentadienyliron dicarbonyl-based complexes present opportunities for underexplored disconnections in synthesis. Access to challenging dihydropyrrolone products is achieved by propargylic C-H functionalization of alkynes for the formation of cyclic organoiron species. Excellent regioselectivity for unsymmetrical alkynes is observed in many cases. Notably, regioselectivity under these stoichiometric conditions diverges from those observed previously under catalysis, occurring at the more-substituted terminus of the alkyne, allowing for methine functionalization and the formation of quaternary centers. Divergent demetallation of the intermediate organoiron complexes gives access to chemically diverse products which are amenable to further functionalization.

Total Synthesis and Structural Studies of Zwitterionic Bacteroides fragilis Polysaccharide A1 Fragments.

Zwitterionic polysaccharides (ZPSs) are exceptional carbohydrates, carrying both positively charged amine groups and negatively charged carboxylates, that can be loaded onto MHC-II molecules to activate T cells. It remains enigmatic, however, how these polysaccharides bind to these receptors, and to understand the structural features responsible for this "peptide-like" behavior, well-defined ZPS fragments are required in sufficient quantity and quality. We here present the first total synthesis of Bacteroides fragilis PS A1 fragments encompassing up to 12 monosaccharides, representing three repeating units. Key to our successful syntheses has been the incorporation of a C-3,C-6-silylidene-bridged "ring-inverted" galactosamine building block that was designed to act as an apt nucleophile as well as a stereoselective glycosyl donor. Our stereoselective synthesis route is further characterized by a unique protecting group strategy, built on base-labile protecting groups, which has allowed the incorporation of an orthogonal alkyne functionalization handle. Detailed structural studies have revealed that the assembled oligosaccharides take up a bent structure, which translates into a left-handed helix for larger PS A1 polysaccharides, presenting the key positively charged amino groups to the outside of the helix. The availability of the fragments and the insight into their secondary structure will enable detailed interaction studies with binding proteins to unravel the mode of action of these unique oligosaccharides at the atomic level.

Polylactic-Containing Hyperbranched Polymers through the CuAAC Polymerization of Aromatic AB2 Monomers.

We report on the synthesis and characterization of a novel class of hyperbranched polymers, in which a copper(I)-catalyzed alkyne azide cycloaddition (CuAAC) reaction (the prototypical "click" reaction) is used as the polymerization step. The AB2 monomers bear two azide functionalities and one alkyne functionality, which have been installed onto a 1,3,5 trisubstituted benzene aromatic skeleton. This synthesis has been optimized in terms of its purification strategies, with an eye on its scalability for the potential industrial applications of hyperbranched polymers as viscosity modifiers. By taking advantage of the modularity of the synthesis, we have been able to install short polylactic acid fragments as the spacing units between the complementary reactive azide and alkyne functionalities, aiming to introduce elements of biodegradability into the final products. The hyperbranched polymers have been obtained with good molecular weights and degrees of polymerization and branching, testifying to the effectiveness of the synthetic design. Simple experiments on glass surfaces have highlighted the possibility of conducting the polymerizations and the formation of the hyperbranched polymers directly in thin films at room temperature.

Site- and Stereoselective Synthesis of Alkenyl Chlorides by Dual Functionalization of Internal Alkynes via Photoredox/Nickel Catalysis

Herein, we report a redox-neutral and atom-economical protocol to synthesize valuable alkenyl chlorides from unactivated internal alkynes and abundant organochlorides via photoredox and nickel catalysis. This protocol enables the site- and stereoselective addition of organochlorides to alkynes via chlorine photoelimination-initiated sequential hydrochlorination/remote C-H functionalization. The protocol is compatible with a wide range of medicinally relevant heteroaryl, aryl, acid, and alkyl chlorides for efficiently producing γ-functionalized alkenyl chlorides, exhibiting excellent regioselectivities and stereoselectivities. Late-stage modifications and synthetic manipulations of the products and preliminary mechanistic studies are also presented.

Polarity and functionality tailored conjugated microporous polymer coatings on silica microspheres for enhanced pollutant adsorption

Many sources of pollution that are generated by modern society are not addressable by conventional methods. Especially organic compounds, like pharmaceutics, are particularly hard to remove from waterbodies. Herein, a new approach is presented using conjugated microporous polymers (CMPs) to coat silica microparticles yielding specifically tailored adsorbents. The CMPs are generated with three different monomers: 2,6-dibromonaphthalene (DBN), 2,5-dibromoaniline (DBA) and 2,5-dibromopyridine (DBPN) respectively coupled to 1,3,5-triethynylbenzene (TEB) via Sonogashira coupling. By optimizing the polarity of the silica surface, all three CMPs were converted into microparticle coatings. The resulting hybrid materials feature the advantages of being adjustable in polarity and functionality, as well as morphology. Sedimentation allows facile removal of the coated microparticles after the adsorption. Further, the expansion of the CMP to a thin coating increases the accessible surface area compared to the bulk material. These effects were demonstrated by the adsorption of the model drug diclofenac. Thereby, the aniline-based CMP proved to be most advantageous due to a secondary crosslinking mechanism of amino and alkyne functionalities. An outstanding adsorption capacity of 228 mg diclofenac per gram of the aniline CMP within the hybrid material was achieved. This represents a five-fold increase compared to the value obtained by the pure CMP material underlining the advantages of the hybrid material.

Synthesis of Skipped Trienes via Ni-Catalyzed Bis-Allylation of Alkynes

Key words nickel catalysis - allylation - alkyne functionalization

Brønsted acid-catalyzed asymmetric dearomatization for synthesis of chiral fused polycyclic enone and indoline scaffolds.

In the past two decades, substantial advances have been made on the asymmetric alkyne functionalization by the activation of inert alkynes. However, these asymmetric transformations have so far been mostly limited to transition metal catalysis, and chiral Brønsted acid-catalyzed examples are rarely explored. Here, we report a chiral Brønsted acid-catalyzed dearomatization reaction of phenol- and indole-tethered homopropargyl amines, allowing the practical and atom-economical synthesis of a diverse array of valuable fused polycyclic enones and indolines bearing a chiral quaternary carbon stereocenter and two contiguous stereogenic centers in moderate to good yields with excellent diastereoselectivities and generally excellent enantioselectivities (up to >99% enantiomeric excess). This protocol demonstrates Brønsted acid-catalyzed asymmetric dearomatizations via vinylidene-quinone methides.

Multifunctional metallochaperone modifications for targeting subsite cavities in mutant p53-Y220C

The p53 protein, known as the ‘guardian of the genome’, plays an important role in cancer prevention. Unfortunately, p53 mutations result in compromised activity with over 50% of cancers resulting from point mutations to p53. There is considerable interest in mutant p53 reactivation, with the development of small-molecule reactivators showing promise. We have focused our efforts on the common p53 mutation Y220C, which causes protein unfolding, aggregation, and can result in the loss of a structural Zn from the DNA-binding domain. In addition, the Y220C mutant creates a surface pocket that can be stabilized using small molecules. We previously reported the bifunctional ligand L5 as a Zn metallochaperone and reactivator of the p53-Y220C mutant. Herein we report two new ligands L5-P and L5-O that are designed to act as Zn metallochaperones and non-covalent binders in the Y220C mutant pocket. For L5-P the distance between the Zn-binding di-(2-picolyl)amine function and the pocket-binding diiodophenol was extended in comparison to L5, while for L5-O we extended the pocket-binding moiety via attachment of an alkyne function. While both new ligands displayed similar Zn-binding affinity to L5, neither acted as efficient Zn-metallochaperones. However, the new ligands exhibited significant cytotoxicity in the NCI-60 cell line screen as well as in the NUGC3 Y220C mutant cell line. We identified that the primary mode of cytotoxicity is likely reactive oxygen species (ROS) generation for L5-P and L5-O, in comparison to mutant p53 reactivation for L5, demonstrating that subtle changes to the ligand scaffold can change the toxicity pathway.

Divergent Functionalization of Alkynes Enabled by Organic Photoredox Catalysis.

Direct functionalization of alkynes under oxidative conditions is challenging, as alkynes are usually recalcitrant towards typical oxidants. Herein, we communicate a strategy for the divergent functionalization of alkynes with photoexcited acridinium organic dyes, presumably via the formation of vinyl cation radicals as key intermediates. Based on the nature of the nucleophiles, different types of difunctionalized products were obtained in moderate to good yields. Addition of lithium Lewis acids resulted in a surprising reversal of diastereocontrol.

Ag-NHC Complexes in the π-Activation of Alkynes.

Silver-NHC (NHC = N-heterocyclic carbene) complexes play a special role in the field of transition-metal complexes due to (1) their prominent biological activity, and (2) their critical role as transfer reagents for the synthesis of metal-NHC complexes by transmetalation. However, the application of silver-NHCs in catalysis is underdeveloped, particularly when compared to their group 11 counterparts, gold-NHCs (Au-NHC) and copper-NHCs (Cu-NHC). In this Special Issue on Featured Reviews in Organometallic Chemistry, we present a comprehensive overview of the application of silver-NHC complexes in the p-activation of alkynes. The functionalization of alkynes is one of the most important processes in chemistry, and it is at the bedrock of organic synthesis. Recent studies show the significant promise of silver-NHC complexes as unique and highly selective catalysts in this class of reactions. The review covers p-activation reactions catalyzed by Ag-NHCs since 2005 (the first example of p-activation in catalysis by Ag-NHCs) through December 2022. The review focuses on the structure of NHC ligands and p-functionalization methods, covering the following broadly defined topics: (1) intramolecular cyclizations; (2) CO2 fixation; and (3) hydrofunctionalization reactions. By discussing the role of Ag-NHC complexes in the p-functionalization of alkynes, the reader is provided with an overview of this important area of research and the role of Ag-NHCs to promote reactions that are beyond other group 11 metal-NHC complexes.

Efficient Synthesis of High-Performance Anion Exchange Membranes by Applying Clickable Tetrakis(dialkylamino)phosphonium Cations.

Tetrakis(dialkylamino)phosphonium (TKDAAP) compounds exhibit extraordinary base resistance, a prerequisite feature for high-performance anion exchange membranes (AEMs). It is, however, challenging to synthesize a TKDAAP compound with reactive functionality that can be used to link the cation to a polymer backbone. In this study, two TKDAAP compounds with alkyne functionality were synthesized and incorporated into an azide-modified SBS triblock copolymer backbone via Cu(I)-catalyzed alkyne-azide cycloaddition (CuAAC) "click" chemistry. The properties of the resulting AEMs were characterized. It was found that (1) the triazole linker between the cation and the polymer backbone was stable under alkaline conditions; (2) varying the substituents of TKDAAP compounds could dramatically alter the stability; and (3) increasing the hydrophilicity of the AEM was an efficient way to enhance its ionic conductivity. Using clickable TKDAAP compounds makes it easy to combine various cations into polymer backbones with adjustable cation content, thus potentially leading to an efficient way to screen a wide variety of polyelectrolyte structures to identify the most promising candidates for high-performance AEMs.