The Mechanical Bond Reveals Hidden Interrupted Click Reactions
6 affiliations
- 1Department of Chemistry, Teknikringen 30, Stockholm, Sweden, 10044
- 2Department of Chemistry, University of Warwick, Gibbet Hill Rd, Coventry, UK, CV4 7AL
- 3School of Chemistry
- 4University of Birmingham
- 5Department of Chemistry
- 6Stockholm University
Abstract
The Cu I -triazolide intermediate of the Cu-mediated alkyne-azide cycloaddition (CuAAC) typically undergoes rapid proto-demetallation but can be intercepted by suitable coupling partners to give 5-substituted triazole products. However, the scope of such “interrupted click” reactions is restricted because some partners react too slowly to outcompete proto-demetallation or even actively promote the decomposition of the Cu I -triazolide in preference to the desired coupling. Here we show that mechanical stabilisation of a Cu I -triazolide within a [2]rotaxane can allow otherwise unproductive “hidden” interrupted click reactions to proceed; the triazolide intermediate of the active template CuAAC reaction couples with cyanide and primary amines under oxidative conditions to install these groups at the triazole 5-position in up to 99% yield. In contrast, the interlocked triazolide reacts slowly with some typical interrupted electrophiles that intercept non-interlocked Cu I -triazolides. Based on these reactivity trends, we propose that the mechanical bond prevents direct attack of electrophiles on the Cu-C bond, instead enforcing inner-sphere reactivity at the Cu I centre with a Cu I /Cu III /Cu I redox cycle. The C-5 substituent leads to a new source of mechanical positional isomerism and a suitably designed macrocycle can be removed after the coupling, allowing the interlocked architecture to serve as an auxiliary for products of otherwise inaccessible interrupted click reactions.
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BibTeX
@misc{ramstrom2026mechanical,
title = {{The Mechanical Bond Reveals Hidden Interrupted Click Reactions}},
author = {Anja Ramström and Qilong Sun and Daisy R. S. Pooler and A. Ken Inge and Stephen M. Goldup and Fredrik Schaufelberger},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010334/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010334/v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - The Mechanical Bond Reveals Hidden Interrupted Click Reactions
AU - Anja Ramström
AU - Qilong Sun
AU - Daisy R. S. Pooler
AU - A. Ken Inge
AU - Stephen M. Goldup
AU - Fredrik Schaufelberger
PY - 2026
DA - 2026/10/13
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010334/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010334/v1
AB - The Cu I -triazolide intermediate of the Cu-mediated alkyne-azide cycloaddition (CuAAC) typically undergoes rapid proto-demetallation but can be intercepted by suitable coupling partners to give 5-substituted triazole products. However, the scope of such “interrupted click” reactions is restricted because some partners react too slowly to outcompete proto-demetallation or even actively promote the decomposition of the Cu I -triazolide in preference to the desired coupling. Here we show that mechanical stabilisation of a Cu I -triazolide within a [2]rotaxane can allow otherwise unproductive “hidden” interrupted click reactions to proceed; the triazolide intermediate of the active template CuAAC reaction couples with cyanide and primary amines under oxidative conditions to install these groups at the triazole 5-position in up to 99% yield. In contrast, the interlocked triazolide reacts slowly with some typical interrupted electrophiles that intercept non-interlocked Cu I -triazolides. Based on these reactivity trends, we propose that the mechanical bond prevents direct attack of electrophiles on the Cu-C bond, instead enforcing inner-sphere reactivity at the Cu I centre with a Cu I /Cu III /Cu I redox cycle. The C-5 substituent leads to a new source of mechanical positional isomerism and a suitably designed macrocycle can be removed after the coupling, allowing the interlocked architecture to serve as an auxiliary for products of otherwise inaccessible interrupted click reactions.
ER -