Mechanistic Basis of the Cu(OAc)2 Catalyzed Azide-Ynamine (3 + 2) Cycloaddition Reaction.

The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is used as a ligation tool throughout chemical and biological sciences. Despite the pervasiveness of CuAAC, there is a need to develop more efficient methods to form 1,4-triazole ligated products with low loadings of Cu. In this paper, we disclose a mechanistic model for the ynamine-azide (3 + 2) cycloadditions catalyzed by copper(II) acetate. Using multinuclear nuclear magnetic resonance spectroscopy, electron paramagnetic resonance spectroscopy, and high-performance liquid chromatography analyses, a dual catalytic cycle is identified. First, the formation of a diyne species via Glaser-Hay coupling of a terminal ynamine forms a Cu(I) species competent to catalyze an ynamine-azide (3 + 2) cycloaddition. Second, the benzimidazole unit of the ynamine structure has multiple roles: assisting C-H activation, Cu coordination, and the formation of a postreaction resting state Cu complex after completion of the (3 + 2) cycloaddition. Finally, reactivation of the Cu resting state complex is shown by the addition of isotopically labeled ynamine and azide substrates to form a labeled 1,4-triazole product. This work provides a mechanistic basis for the use of mixed valency binuclear catalytic Cu species in conjunction with Cu-coordinating alkynes to afford superior reactivity in CuAAC reactions. Additionally, these data show how the CuAAC reaction kinetics can be modulated by changes to the alkyne substrate, which then has a predictable effect on the reaction mechanism.

Ligand-Enabled Copper-Mediated Radioiodination of Arenes.

The discovery of a copper precatalyst that facilitates the key mechanistic steps of arene halodeboronation has allowed a step change in the synthesis of radioiodine-containing arenes. The active precatalyst [Cu(OAc)(phen)2]OAc was shown to perform room temperature radio-iododeboronation of aryl boronic acids with 1-2 mol % loadings and 10 min reaction times. These mild conditions enable particularly clean reactions, as demonstrated with the efficient preparation of the radiopharmaceutical and SPECT tracer, meta-iodobenzylguanidine (MIBG).

Glutathione Mediates Control of Dual Differential Bio-orthogonal Labelling of Biomolecules.

Traditional approaches to bio-orthogonal reaction discovery have focused on developing reagent pairs that react with each other faster than they are metabolically degraded. Glutathione (GSH) is typically responsible for the deactivation of most bio-orthogonal reagents. Here we demonstrate that GSH promotes a Cu-catalysed (3+2) cycloaddition reaction between an ynamine and an azide. We show that GSH acts as a redox modulator to control the Cu oxidation state in these cycloadditions. Rate enhancement of this reaction is specific for ynamine substrates and is tuneable by the Cu:GSH ratio. This unique GSH-mediated reactivity gradient is then utilised in the dual sequential bio-orthogonal labelling of peptides and oligonucleotides via two distinct chemoselective (3+2) cycloadditions.

Mechanism of Cu-Catalyzed Iododeboronation: A Description of Ligand-Enabled Transmetalation, Disproportionation, and Turnover in Cu-Mediated Oxidative Coupling Reactions.

We report a combined experimental and computational study of the mechanism of the Cu-catalyzed arylboronic acid iododeboronation reaction. A combination of structural and density functional theory (DFT) analyses has allowed determination of the identity of the reaction precatalyst with insight into each step of the catalytic cycle. Key findings include a rationale for ligand (phen) stoichiometry related to key turnover events-the ligand facilitates transmetalation via H-bonding to an organoboron boronate generated in situ and phen loss/gain is integral to the key oxidative events. These data provide a framework for understanding ligand effects on these key mechanistic processes, which underpin several classes of Cu-mediated oxidative coupling reactions.

Glutathione Mediates Control of Dual Differential Bio-orthogonal Labelling of Biomolecules.

Traditional approaches to bio-orthogonal reaction discovery have focused on developing reagent pairs that react with each other faster than they are metabolically degraded. Glutathione (GSH) is typically responsible for the deactivation of most bio-orthogonal reagents. Here we demonstrate that GSH promotes a Cu-catalysed (3+2) cycloaddition reaction between an ynamine and an azide. We show that GSH acts as a redox modulator to control the Cu oxidation state in these cycloadditions. Rate enhancement of this reaction is specific for ynamine substrates and is tuneable by the Cu:GSH ratio. This unique GSH-mediated reactivity gradient is then utilised in the dual sequential bio-orthogonal labelling of peptides and oligonucleotides via two distinct chemoselective (3+2) cycloadditions.

Gas-Phase Conversion of 1,3-Dithiolane-2-Thione Into 1,3-Dithiolan-2-One Over Molybdenum Trioxide.

Gas-phase reaction of 1,3-dithiolane-2-thione over molybdenum trioxide supported on pumice stone results in efficient conversion into 1,3-dithiolan-2-one. The solid reagent is regenerated on exposure to air and thus acts as a catalyst for the overall conversion of the thione and oxygen from the air into the ketone and sulfur dioxide. The process can be carried out under either dynamic vacuum or atmospheric pressure flow conditions and using a solid reagent prepared either by physical mixing of MoO3 with the support or by solution impregnation, with an isolated yield of up to 67% obtained.