Copper-Catalyzed Azide–Alkyne Cycloaddition (CuAAC) by Functionalized NHC-Based Polynuclear Catalysts: Scope and Mechanistic Insights

Abstract

Copper(I) [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 L)] n (L = OMe, NEt 2 , NH t Bu) compounds supported by flexible functionalized NHC-based polydentate ligands have been prepared in a one-pot procedure by reacting the corresponding imidazolium salt with an excess of copper powder and Ag 2 O. An X-ray diffraction analysis has revealed that [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 NEt 2 )] n is a linear coordination polymer formed by bimetallic [Cu(μ-Br)] 2 units linked by the lutidine-based NHC-py-NEt 2 ligand, which acts as a heteroditopic ligand with a 1κC-2κ 2 N,N′ coordination mode. We propose that the polymeric compounds break down in the solution into more compact tetranuclear [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 L)] 2 compounds with a coordination mode identical to the functionalized NHC ligands. These compounds have been found to exhibit high catalytic activity in the Cu-catalyzed azide−alkyne cycloaddition (CuAAC) reaction. In particular, [Cu 2 (μ-Br) 2 ( t BuImCH 2 pyCH 2 NEt 2 )] 2 efficiently catalyzes the click reaction of a range of azides and alkynes, under an inert atmosphere at room temperature in neat conditions at a very low catalyst loading, to quantitatively afford the corresponding 1,4-disubstituted 1,2,3-triazole derivatives in a few minutes. The cycloaddition reaction of benzyl azide to phenylacetylene can be performed at 25−50 ppm catalyst loading by increasing the reaction time and/or temperature. Reactivity studies have shown that the activation of the polynuclear catalyst precursor involves the alkyne deprotonation by the NHC moiety of the polydentate ligand to afford a copper(I)-alkynyl species bearing a functionalized imidazolium ligand. DFT calculations support the participation of the dinuclear species [(CuBr) 2 (μ-t BuImCH 2 pyCH 2 NEt 2 )], resulting from the fragmentation of the tetranuclear compound, as the catalytically active species. The proposed reaction pathway proceeds through zwitterionic dinuclear intermediates and entails the active participation of both copper atoms, as well as the NHC moiety as an internal base, which activates the reacting alkyne via deprotonation.

Tetracopper(i) thiolate- and amido-(SNS) complexes and copper-catalyzed azide–alkyne cycloaddition in water

“…15 Further support for mechanism was provided by the isolation and characterization of dicopper σ,π-alkynyl intermediates. 15,16 We have recently been comparing 'soft' thiolate-(L 1 ) and 'hard' amido-(L 2 ) SNS ligands (Schemes 2 and 3) in ligandassisted catalysis. 17,18 Working with base metals from Mn to Zn we demonstrated several different bifunctional mechanisms for catalysed hydroboration [19][20][21][22][23] and hydrosilylation 24 of carbonyls, nitriles 25,26 and N-heterocycles.…”

A molecular dynamics perspective on the cyclization efficiency for poly(2-oxazoline)s and poly(2-oxazine)s

“…Recently, the coordination of several CuAAC catalysts to small molecule substrates has been evaluated using density functional theory. 44–46 Overall, and surprisingly independent of the catalyst used, the studies agreed that the coordination distance of the azide moiety to the pre-formed alkyne-catalyst complex is just above 0.2 nm. This was used as a guideline for the current study, in which we assumed that distances between the polymer termini of below 1 nm would favour intra-molecular CuAAC reaction.…”

New copper(i) complexes of bulky 5-substituted-2-iminopyrrolyl ligands as catalysts for azide–alkyne cycloaddition

“…Such species are proposed in catalytic dinuclear models for the CuAAC reactions, previously established in the literature as one of the possible pathways. 24…”

“…22 As a representative example of the development of nitrogen-based ligands toward CuAAC reactions, Tilley and co-workers, isolated a series of dinuclear copper( i ) intermediates using the dinucleating ligand 2,7-bis(fluoro-di(2-pyridyl)-methyl)-1,8-naphthyridine (Chart 1, D ), 23 which supported the propensity of catalytic dinuclear species in CuAAC reactions, with cooperation between the two copper centers. 24 When considering neutral dinuclear copper( i ) complexes, several examples of their preparation and structural characterization are to be noted, the vast majority utilizing monoanionic ligand systems such as amidinates (X = CR) or guanidinates (X = N) (Chart 1, E ). 25…”