Autocatalytic Cycles in a Copper-Catalyzed Azide–Alkyne Cycloaddition Reaction

Abstract

This work describes the autocatalytic copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between tripropargylamine and 2-azidoethanol in the presence of Cu(II) salts. The product of this reaction, tris-(hydroxyethyltriazolylmethyl)amine (N(CN)), accelerates the cycloaddition reaction (and thus its own production) by two mechanisms: (i) by coordinating Cu(II) and promoting its reduction to Cu(I) and (ii) by enhancing the catalytic reactivity of Cu(I) in the cycloaddition step. Because of the cooperation of these two processes, a rate enhancement of >400× is observed over the course of the reaction. The kinetic profile of the autocatalysis can be controlled by using different azides and alkynes or ligands (e.g., ammonia) for Cu(II). When carried out in a layer of 1% agarose gel, and initiated by ascorbic acid, this autocatalytic reaction generates an autocatalytic front. This system is prototypical of autocatalytic reactions where the formation of a product, which acts as a ligand for a catalytic metal ion, enhances the production and activity of the catalyst.

Autocatalysis: Kinetics, Mechanisms and Design

“…Often, the autocatalytic network does not involve a series of catalysts – only one catalyst and a series of non‐catalytic intermediates (Figure 3c). Semenov and Skorb showed that thioester autocatalysis, [22] some variants of azide‐alkyne autocatalysis [23] and the formaldehyde sulfide reaction [24] all belong to this type of network structure [25] . This network always results in exponential growth after some lag phase where growth is slower than an exponential rate.…”

Copper‐Catalyzed Oxidative C(sp3)−H/N−H Cross‐Coupling of Hydrocarbons with P(O)−NH Compounds: the Accelerating Effect Induced by Carboxylic Acid Coproduct

“…Such a process is quite rare in copper catalysis . A notable exception is the recent success on copper‐catalyzed azide‐alkyne cycloaddition reaction disclosed by Whitesides et al . On the other hand, the improvement by additional acetic acid was observed in a few cases of C−N forming reactions ,.…”

Mathematical Analysis of a Prototypical Autocatalytic Reaction Network

“…Semenov, Whitesides, and coworkers have recently published two autocatalytic reactions that can be reduced to a catalytic cycle, followed by the noncatalytic conversion of one product of this catalytic cycle to the catalyst itself (Figure 1) [37,38].…”

“…In the first example, we can separate a catalytic cycle of cysteamine (CSH), which catalyzed the acylation of cystamine (CSSC) by a thioester; this is followed by converting one of its byproducts, ethanethiol, into CSH (Figure 1a) [37]. In the second example, the catalytic cycle of the copper-catalyzed azide-alkyne cycloaddition reactions is followed by the formation of a catalytically active complex from triazole derivatives (Figure 1b) [38]. Because of the abundance of catalytic reactions in nature, we speculate that these motifs might be among the most common autocatalytic motifs in simple (i.e., non-biological) reaction networks.…”