Ligand‐Assisted, Copper(II) Acetate‐Accelerated Azide–Alkyne Cycloaddition

Abstract

Polytriazole ligands such as the widely used tris[(1‐benzyl‐1 H‐1,2,3‐triazol‐4‐yl)methyl]amine (TBTA), are shown to assist copper(II) acetate‐mediated azide–alkyne cycloaddition (AAC) reactions that involve nonchelating azides. Tris(2‐{4‐[(dimethylamino)methyl]‐1 H‐1,2,3‐traizol‐1‐yl}ethyl)amine (DTEA) outperforms TBTA in a number of reactions. The satisfactory solubility of DTEA in a wide range of polar and nonpolar solvents, including water and toluene, renders it advantageous under copper(II) acetate‐mediated conditions. The copper(II) acetate‐mediated formation of the three triazolyl groups in a tris(triazolyl)‐based ligand occurs sequentially with an inhibitory effect in the last step. The kinetic investigations of the ligand‐assisted reactions reveal an interesting mechanistic dependence on the relative affinity of azide and alkyne to copper (II). In addition to expanding the scope of the copper(II) acetate‐mediated AAC reactions to include nonchelating azides, this work offers evidence for the mechanistic synergy between the title reaction and the alkyne oxidative homocoupling reaction. The elucidation of the structural details of the polytriazole‐ligand‐bound reactive species in copper(I/II)‐mediated AAC reactions, however, awaits further characterization of the metal coordination chemistry of polytriazole ligands.

Kinetics of bulk photo-initiated copper(i)-catalyzed azide–alkyne cycloaddition (CuAAC) polymerizations

“…Alkynes 3 , 4 , 5 , 6 , and 8 showed a noticeable increase in the average initial polymerization rate, as compared to alkyne 7, during the first 2 minutes of irradiation, mainly due to the higher reactivity of an alkyne functional group next to an ether linkage compared to a hydrocarbon linkage. 32,34 The alkyne reactivity was also confirmed through a study of small molecule model compound reactivity in solution by FTIR, using a 2 M solution in DMF of propargyl alcohol or 5-hexyn-1-ol, difunctional azides 2c , 2% CuCl 2 -[PMDETA], and 4% DMPA, irradiated at ambient temperature (Fig. S1 † ).…”

Inverse electron demand Diels–Alder (iEDDA)-initiated conjugation: a (high) potential click chemistry scheme

“…All click chemistry schemes involving azides have in common that tuning of reaction rates via modification of the azide reaction partner is virtually impossible (albeit aryl azides tend to be less reactive than their alkyl counterparts 25 ). In CuAAC reactions, rates are influenced by employing different solvents, copper species or the use of specific ligands which accelerate CuAAC, for example via stabilisation of copper(I) in aqueous solution.…”

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

“…In many cases, deliberate measures have to be taken to create a reducing, oxygen‐free environment to stabilize copper(I); in other cases, CuAAC reactions do not seem to miss a beat under apparently oxidizing conditions. In our laboratory, we mostly use copper(II) acetate monohydrate (1–5 mol%) in solid form (sometimes in combination with the ligand TBTA)12,43 in t BuOH or EtOH under air at room temperature (20–25°C) maintained by a water bath for CuAAC reactions. Under most circumstances, the reaction mixtures remain homogeneous with a blue/green color, which suggests that copper is mostly in the +2 oxidation state.…”