ChemInform Abstract: On the Mechanism of Copper(I)‐Catalyzed Azide‐Alkyne Cycloaddition

Zhu, Lei; Brassard, Christopher J.; Zhang, Xiaoguang; Guha, Pampa M.; Clark, Ronald J.

doi:10.1002/chin.201633225

Cited by 1 publication

(4 citation statements)

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“…On the basis of the data from ESI-MS, Cu(I) oxidation, 36, 84–86 and our previously proposed mechanism involving a di- or tri-Cu(I)-acetylide stabilized by tris(triazoylmethyl)amine ligands, 87 we proposed the mechanism of CuAAC and O 2 oxidation for Cu(I)-ligand I (Scheme 3). Due to the positive correlation between the CuAAC activity and Cu(I) oxidation (Fig.…”

Section: Resultsmentioning

confidence: 90%

“…3 and Table S1, ESI†), the alkyne and O 2 coordination are the competing processes. 87 In the CuAAC pathway, the alkyne interacts with I in both σ- and π-coordination modes, resulting in IIc 1 or IIc 2 (see ESI-MS of ligand 1 with the tri-Cu(I) complex in Fig. 5).…”

Section: Resultsmentioning

confidence: 99%

“…IIIc 1 and IVc 2 goes through the transition state metallacycle TSc 1 and TSc 2 , leading to the triazolide IVc 1 and Vc 2 . 87 Protonation of the triazolide IVc 1 and Vc 2 by proximal alkyne or protonic solvent generates the triazole product and regenerates the catalyst IIc 1 and IIc 2 . 87 On the other hand, in the Cu(I) oxidation pathway, dioxygen is competing with alkyne in coordination with I .…”

Section: Resultsmentioning

confidence: 99%

“…87 Protonation of the triazolide IVc 1 and Vc 2 by proximal alkyne or protonic solvent generates the triazole product and regenerates the catalyst IIc 1 and IIc 2 . 87 On the other hand, in the Cu(I) oxidation pathway, dioxygen is competing with alkyne in coordination with I . The oxygen coordinates with I in a σ-coordination mode to form intermediate IIo .…”

Section: Resultsmentioning

confidence: 99%

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Tripodal amine ligands for accelerating Cu-catalyzed azide–alkyne cycloaddition: efficiency and stability against oxidation and dissociation

Zhu

Chen

Yang

et al. 2017

Catal. Sci. Technol.

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Ancillary ligands, especially the tripodal ligands such as tris(triazolylmethyl)amines, have been widely used to accelerate the Cu-catalyzed azide-alkyne cycloaddition (CuAAC, a “click” reaction). However, the relationship between the activity of these Cu(I) complexes and their stability against air oxidation and ligand dissociation/exchange was seldom studied, which is critical for the applications of CuAAC in many biological systems. In this work, we synthesized twenty-one Cu(I) tripodal ligands varying in chelate arm length (five to seven atoms), donor groups (triazolyl, pyridyl and phenyl), and steric hindrance. The effects of these variables on the CuAAC reaction, air oxidation, and ligand dissociation were evaluated. Reducing the chelate arm length to five atoms, decreasing steric hindrance, or using a relatively weakly-binding ligand can significantly increase the CuAAC reactivity of the Cu(I) complexes, but the concomitant higher degree of oxidation cannot be avoided, which leads to rapid degradation of a histidine-containing peptide as a model of proteins. The oxidation of the peptide can be reduced by attaching oligo(ethylene glycol) chains to the ligands as sacrificing reagents. Using electrospray ionization mass spectrometry (ESI-MS), we directly observed the tri- and di-copper(I)-acetylide complexes in CuAAC reaction in the [5,5,5] ligand system and a small amount of di-Cu(I)-acetylide in the [5,5,6] ligand system. Only the mono-Cu(I) ligand adducts were observed in the [6,6,6] and [5,6,6] ligand systems.

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