Head-to-Tail Dimerization of N-Heterocyclic Diazoolefins.

The head-to-tail dimerization of N-heterocyclic diazoolefins is described. The products of these formal (3+3) cycloaddition reactions are strongly reducing quinoidal tetrazines. Oxidation of the tetrazines occurs in a stepwise fashion, and we were able to isolate a stable radical cation and diamagnetic dications. The latter are also accessible by oxidative dimerization of diazoolefins.

Copper Complexes with Diazoolefin Ligands and their Photochemical Conversion into Alkenylidene Complexes.

Homometallic copper complexes with alkenylidene ligands are discussed as intermediates in catalysis but the isolation of such complexes has remained elusive. Herein, we report the structural characterization of copper complexes with bridging and terminal alkenylidene ligands. The compounds were obtained by irradiation of CuI complexes with N-heterocyclic diazoolefin ligands. The complex with a terminal alkenylidene ligand required isolation in a crystalline matrix, and its structural characterization was enabled by in crystallo photolysis at low temperature.

Vanadium complexes with N-heterocyclic vinylidene ligands.

The preparation and the structural characterization of vanadium complexes with terminal and bridging N-heterocyclic vinylidene ligands is reported. The synthesis of the complexes was enabled by utilization of diazoolefins as ligand precursors. Structural data and theoretical results show that N-heterocyclic vinylidenes can act as 6e- donor ligands, leading to strong metal-carbon interactions.

Synthesis, structural characterization, and coordination chemistry of imidazole-based alkylidene ketenes.

Alkylidene ketenes typically display high intrinsic reactivity, impeding isolation on a preparative scale. Herein, we report the synthesis of alkylidene ketenes by reaction of imidazole-based diazoolefins with carbon monoxide. The good thermal stability of these heterocumulenes allows for characterization by single crystal X-ray diffraction. N-Heterocyclic alkylidene ketenes can be used as C-donor ligands for transition and main group metals, as evidenced by the isolation of complexes with AuCl, RhCl(CO)2, PdCl(C3H5) and GaCl3.

Isolation and characterization of diazoolefins.

Diazoolefins tend to be highly reactive compounds that rapidly lose dinitrogen. So far, most experimental evidence for diazoolefins is indirect, via trapping experiments. Here we show that diazoolefins are observed to form in reactions of N-heterocyclic olefins with nitrous oxide. The products benefit from resonance stabilization, which enables isolation on a preparative scale, and comprehensive characterization, which includes crystallographic analyses. N-heterocyclic diazoolefins show a strong ylidic character, with a high charge density at the carbon atom next to the diazo group. Despite the presence of terminal N2 groups, N-heterocyclic diazoolefins display a good thermal stability, which surpasses that observed for most diazoalkanes. N-heterocyclic diazoolefins can bind transition and main group metal complexes without the liberation of dinitrogen, and spectroscopic data show that they are strong electron donors. They can also undergo reactions that involve the N2 group, as evidenced by cycloaddition reactions.

Synthesis of Organic Super-Electron-Donors by Reaction of Nitrous Oxide with N-Heterocyclic Olefins.

The reaction of nitrous oxide (N2O) with N-heterocyclic olefins (NHOs) results in cleavage of the N-O bond and formation of azo-bridged NHO dimers. The latter represent very electron-rich compounds with a low ionization energy. Cyclic voltammetry studies show that the dimers can be classified as new organic super-electron-donors, with a reducing power similar to what is found for tetraazafulvalene derivatives. Mild oxidants are able to convert the neutral dimers into radical cations, which can be isolated. Further oxidation gives stable dications.

Synthesis of aminyl biradicals by base-induced Csp3-Csp3 coupling of cationic azo dyes.

The synthesis of the industrially important polymer parylene is achieved by polymerization of p-quinodimethane (p-QDM). The polymerization is thought to proceed via a biradical p-QDM dimer, but isolation or characterization of such a biradical has remained elusive. Here, we describe the synthesis of an aza-analogue of this p-QDM dimer. The biradical is formed by base-induced dimerization of an azoimidazolium dye. Due to the presence of sterically shielded aminyl radicals instead of terminal H2C groups, the stability of this dimer is sufficient for analyses by ESR spectroscopy and X-ray crystallography. A similar Csp3-Csp3 coupling was observed for an azotriazolium dye, suggesting that base-induced C-C coupling reactions can be realized for different types of azo dyes.

De Novo Discovery of Nonstandard Macrocyclic Peptides as Noncompetitive Inhibitors of the Zika Virus NS2B-NS3 Protease.

The Zika virus presents a major public health concern due to severe fetal neurological disorders associated with infections in pregnant women. In addition to vaccine development, the discovery of selective antiviral drugs is essential to combat future epidemic Zika virus outbreaks. The Zika virus NS2B-NS3 protease, which performs replication-critical cleavages of the viral polyprotein, is a promising drug target. We report the first macrocyclic peptide-based inhibitors of the NS2B-NS3 protease, discovered de novo through in vitro display screening of a genetically reprogrammed library including noncanonical residues. Six compounds were selected, resynthesized, and isolated, all of which displayed affinities in the low nanomolar concentration range. Five compounds showed significant protease inhibition. Two of these were validated as hits with submicromolar inhibition constants and selectivity toward Zika over the related proteases from dengue and West Nile viruses. The compounds were characterized as noncompetitive inhibitors, suggesting allosteric inhibition.