Ligand-Accelerated Cu-Catalyzed Azide−Alkyne Cycloaddition:  A Mechanistic Report

Abstract

The experimental rate law for the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction was found to vary in complex ways with concentration, the presence of chloride ion, and the presence of accelerating ligands. Several examples of discontinuous ("threshold behavior") kinetics were observed, along with a decidedly nonlinear correlation of electronic substituent parameter with the rate of CuAAC reaction with p-substituted arylazides. The previously observed tendency of the CuAAC reaction to provide ditriazoles from a conformationally constrained 1,3-diazide was found to be affected by a class of polybenzimidazole ligands introduced in the accompanying article. Various lines of evidence suggest that the standard tris(triazolylmethyl)amine ligand binds less strongly to Cu(I) than its benzimidazole analogues. On the basis of these observations, it is proposed that (a) a central nitrogen donor provides electron density at Cu(I) that assists the cycloaddition reaction, (b) the three-armed motif bearing relatively weakly coordinating heterocyclic ligands serves to bind the metal with sufficient strength while providing access to necessary coordination site(s), (c) at least two active catalysts or mechanisms are operative under the conditions studied, and (d) pendant acid or ester arms in the proper position can assist the reaction by speeding the protiolysis step that cleaves the Cu-C bond of a Cu.triazolyl intermediate.

Bioorthogonale Chemie – oder: in einem Meer aus Funktionalität nach Selektivität fischen

“…Die Kupfer(I)-katalysierte Cycloaddition verläuft um annä-hernd sieben Größenordnungen schneller als die unkatalysierte [166] und kann durch Verwendung spezieller Liganden für Kupfer(I) weiter beschleunigt werden. [170,171] Die CuAAC hat alle Eigenschaften einer Klickreaktion (einschließlich Effizienz, Einfachheit und Selektivität), wie von Sharpless et al definiert. [172] Tatsächlich ist sie zum Inbegriff der Klickreaktion geworden und wird oft einfach als "Klickchemie" bezeichnet.…”

Copper(I) Complexes of Normal and Abnormal Carbenes and Their Use as Catalysts for the Huisgen [3+2] Cycloaddition between Azides and Alkynes

“…[12][13][14][15][16][17][18][19][20][21][22][23][24] After the initial discovery of the use of tris[(1-benzyl-1H-1,2,3-triazole-4-yl)methyl]amine (tbta) as an additional component of the catalytic mixture, which leads to acceleration of reactions and improvement of yields, [25] efforts have been made to use other such ligands for improving this method. [26][27][28][29] In this regard, the use of copper(I) complexes of N-heterocyclic carbene (NHC) ligands as catalysts for the click reaction as pioneered by Nolan and Diéz-Gonzaléz [30][31][32][33] has turned…”

Stereo‐ and Regioselective Azide/Alkyne Cycloadditions in Carbonic Anhydrase II via Tethering, Monitored by Crystallography and Mass Spectrometry

“…After cyclization and protonation, the catalyst releases the 1,2,3-triazole product. [6][7][8][9] The isolation of a crystalline Cu I triazolide strongly supports the existence of such click intermediates. [10] With respect to pharmaceutical research, click chemistry provides novel opportunities, for example, for polymeric micelles, nanoscale delivery systems, and DNA labeling.…”