Mechanism of Copper(I)-Catalyzed 5-Iodo-1,2,3-triazole Formation from Azide and Terminal Alkyne

Abstract

5-Iodo-1,2,3-triazole (iodotriazole) can be prepared from a copper(I)-catalyzed reaction between azide and terminal alkyne in the presence of an iodinating agent, with 5-protio-1,2,3-triazole (protiotriazole) as the side product. The increasing utilities of iodotriazoles in synthetic and supramolecular chemistry drive the efforts in improving their selective syntheses based on a sound mechanistic understanding. A routinely proposed mechanism takes the cue from the copper(I)-catalyzed azide-alkyne cycloaddition, which includes copper(I) acetylide and triazolide as the early and the late intermediates, respectively. Instead of being protonated to afford protiotriazole, an iodinating agent presumably intercepts the copper(I) triazolide to give iodotriazole. The current work shows that copper(I) triazolide can be iodinated to afford iodotriazoles. However, when the reaction starts from a terminal alkyne as under the practical circumstances, 1-iodoalkyne (iodoalkyne) is an intermediate while copper(I) triazolide is bypassed on the reaction coordinate. The production of protiotriazole commences after almost all of the iodoalkyne is consumed. Using (1)H NMR to follow a homogeneous iodotriazole forming reaction, the rapid formation of an iodoalkyne is shown to dictate the selectivity of an iodotriazole over a protiotriazole. To ensure the exclusive production of iodotriazole, the complete conversion of an alkyne to an iodoalkyne has to, and can be, achieved at the early stage of the reaction.

Mechanochemistry as an emerging tool for molecular synthesis: what can it offer?

“… 39 Under solvent-based conditions, Cu–NHC complexes can be synthesized by the reaction of metallic Cu(0) with imidazolium salts, although these reactions require a large excess of insoluble Cu(0) and long reaction times. 40 Recently, Lamaty and co-workers reported that Cu–NHC complexes ( 2 ) could be synthesized from imidazolium salts ( 1 ) and metallic copper using a planetary ball mill ( Scheme 2 ). 41 The rate of reactions was enhanced due to the high concentration of reagents and the highly efficient mixing under mechanochemical conditions.…”

Exploiting the versatile alkyne-based chemistry for expanding the applications of a stable triphenylmethyl organic radical on surfaces

“…For the synthesis of the target radical PTM-Fc dyad (3-Rad) a copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry strategy was envisaged. [53][54][55] The standard conditions for the click reaction that generates in situ the copper(I) catalyst by reduction of CuSO 4 using ascorbic acid or ascorbate 56 could not be used here because the ascorbic acid reduces the radical to the anion that in turn is irreversibly protonated to the aH form. 57 Therefore, as mentioned above, before performing the reaction on the surface, the synthetic procedure was optimized in solution.…”

On the Mechanism of Copper(I)-Catalyzed Azide-Alkyne Cycloaddition

“…Therefore, the mechanistic understanding of internal alkyne CuAAC reactions is influenced by evolving insights into terminal alkyne CuAAC reactions. The mechanisms of reactions involving iodoalkyne and gold(I) acetylide have been studied in more detail than others 60. At this point, it is reasonable to say that most of these reactions, if not all, adopt similar catalytic cycles to that shown in Scheme , with the internal alkyne substrate R–C≡C–X replacing the copper acetylide (R–C≡C–Cu); hence with X replacing one of the copper centers in the dinuclear model.…”