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Disclosure of some obscure mechanistic aspects of the copper-catalyzed click reactions involving N2 elimination promoted by the use of electron-deficient azides from a DFT perspective

journal contribution
posted on 2023-05-20, 06:19 authored by Roohzadeh, R, Nasiri, B, Chipman, A, Brian YatesBrian Yates, Alireza AriafardAlireza Ariafard
We have used density functional theory to explore the copper(I)-catalyzed reaction between a mesyl azide and a terminal alkyne that leads to a ketenimine whose interaction with nucleophilic water produces an amide. It is well reported in the literature that a cuprated triazole intermediate is formed during the course of such a catalytic cycle. In this contribution, we investigated the stability of this key intermediate by varying the R substituent on the azide and found that electron-withdrawing R substituents make this intermediate more reactive toward ring opening/N2 elimination; an electron-withdrawing R substituent facilitates this process by weakening the N–N bond being cleaved. We also rationalized why the cycloaddition step in this class of click reactions is required to proceed via a binuclear mechanism. The copper(I) acetylide intermediate formed during the catalysis gains extra stability upon scavenging a second Cu complex, resulting in the cycloaddition step occurring with a lower activation barrier. We also noticed that, similar to the ring closure step, inclusion of a second Cu complex may accelerate the ring opening/N2 elimination process. It was shown that the ketenimine needs to coordinate to a copper center via its nitrogen atom in order to be activated toward hydrolysis.


Australian Research Council

University of Wollongong


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School of Natural Sciences


Amer Chemical Soc

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