Rate of a Click Chemistry reaction under catalysis by trace‐amounts of copper as evaluated by NMR spectroscopy

Since its introduction, click chemistry revolutionized many fields of synthetic chemistry such as material science and molecular biology. It is considered the ‘cream of the crop’ of synthesis because of its speed and success rate. This notwithstanding, many kinetic and thermodynamic aspects of the typical Cu-catalysed [3 + 2] azide–alkyne cycloaddition (CuAAC) remain vaguely characterized at the present time. There are a number of studies focusing also on the kinetics of typical CuAAC reactions, showing how these follow first-order or, in some chain reaction mechanisms, secondorder kinetics, and no regioselectivity is observed. In the absence of any Cu catalyst, it was established that a cycloaddition reaction between azide and alkyne groups may only occur by using high temperatures (>70 °C) which are capable of overcoming the relatively high-energy activation barrier by increasing the collision energy between these groups. In such instances, second-order kinetics are observed. Conversely, owing to the introduction of a Cu catalyst, the cycloaddition step follows a different mechanism which requires a lower activation energy. Specifically, the Cu catalyst binds with the alkyne group in the initial step and facilitates conjugation of the azido group to the Cu–alkyne complex in the subsequent step. This alternative mechanism operates at milder temperatures (~40 °C) and follows first-order kinetics. Furthermore, the reaction implies a preferential orientation of the ligands of the azide and the alkyne to minimize steric hindrance, thereby yielding a regioselective product. One of the most critical disadvantages deriving from a nocatalyst approach is represented by the costs of heating required to improve the rate of cycloaddition and the loss of regioselectivity. Conversely, the catalytic approach brings the advantage of milder reaction temperatures, albeit with the requirement of a costly and time consuming Cu removal step, which is necessary in most cases. This conundrum, however, may be overcome by a method using very low amounts of catalyst, only for those applications where traces of Cu in the final product are acceptable. Therefore, we hereby report the reaction rate, monitored through NMR spectroscopy, of a [3+ 2] cycloaddition reaction between a watersoluble alkynol and a poly(ethylene glycol) oligomer, capped with an azido and an amine group at each end of the chain, and catalysed by trace amounts of copper (Scheme 1). Here, we aimed to demonstrate that despite the relevantly low amount of catalyst, the cycloaddition reaction may be carried out maintaining regioselectivity and at acceptable rates under the same mild temperature conditions as ordinarily used for click chemistry.