Double-click: unexpected 1:2 stoichiometry in a norbornene–tetrazine Reaction
Double-click: unexpected 1:2 stoichiometry in a norbornene–tetrazine Reaction
We report a new reactivity for the inverse electron demand Diels-Alder (iEDDA) reaction between norbornene and tetrazine. Instead of simple 1:1 condensation between norbornene- and tetrazine-conjugated biomolecules, we observed that dimeric products were preferentially formed. As such, an olefinic intermediate formed after the addition of the first tetrazine unit to norbornene rapidly undergoes a consecutive cycloaddition reaction with a second tetrazine unit to result in a conjugate with 1:2 stoichiometric ratio. This unexpected dimer formation was consistently observed in the reactions of both small-molecule norbornenes and tetrazines, as well as oligonucleotide conjugates. When norbornene was replaced with bicyclononyne to by-pass the formation of this olefinic reaction intermediate, the reactions resulted exclusively in rapid formation of the expected 1:1 stoichiometric conjugates.
5341–5347
Devi, Gitali
dda8d99b-8400-41ab-811f-f90e8d3827d3
Hedger, Adam
236a0ea0-ed4d-4885-8976-95da33c67a47
Whitby, Richard J.
45632236-ab00-4ad0-a02d-6209043e818b
Watts, Jonathan
3c6023dc-c35c-4b99-9832-386cac53c32d
5 May 2023
Devi, Gitali
dda8d99b-8400-41ab-811f-f90e8d3827d3
Hedger, Adam
236a0ea0-ed4d-4885-8976-95da33c67a47
Whitby, Richard J.
45632236-ab00-4ad0-a02d-6209043e818b
Watts, Jonathan
3c6023dc-c35c-4b99-9832-386cac53c32d
Devi, Gitali, Hedger, Adam, Whitby, Richard J. and Watts, Jonathan
(2023)
Double-click: unexpected 1:2 stoichiometry in a norbornene–tetrazine Reaction.
Journal of Organic Chemistry, 88 (9), .
(doi:10.1021/acs.joc.2c02861).
Abstract
We report a new reactivity for the inverse electron demand Diels-Alder (iEDDA) reaction between norbornene and tetrazine. Instead of simple 1:1 condensation between norbornene- and tetrazine-conjugated biomolecules, we observed that dimeric products were preferentially formed. As such, an olefinic intermediate formed after the addition of the first tetrazine unit to norbornene rapidly undergoes a consecutive cycloaddition reaction with a second tetrazine unit to result in a conjugate with 1:2 stoichiometric ratio. This unexpected dimer formation was consistently observed in the reactions of both small-molecule norbornenes and tetrazines, as well as oligonucleotide conjugates. When norbornene was replaced with bicyclononyne to by-pass the formation of this olefinic reaction intermediate, the reactions resulted exclusively in rapid formation of the expected 1:1 stoichiometric conjugates.
More information
Accepted/In Press date: 28 February 2023
e-pub ahead of print date: 14 April 2023
Published date: 5 May 2023
Additional Information:
Funding Information:
The authors thank Scott A. Shaffer, Cameron Groshek, and Yanglan Tan of the UMass Chan Mass Spectrometry Facility for their help. They also thank the IRIDIS High Performance Computing Facility at the University of Southampton. This work was funded by the NIH (R01 NS111990 and UG3/UH3 TR002668-03 to JKW) and the Ono Pharmaceutical Foundation (Breakthrough Science Award to JKW). AKH was supported in part by a predoctoral fellowship from the PhRMA Foundation.
Identifiers
Local EPrints ID: 477151
URI: http://eprints.soton.ac.uk/id/eprint/477151
ISSN: 0022-3263
PURE UUID: 884b1701-50a2-4bc3-af23-2d96cafcf72b
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Date deposited: 30 May 2023 16:40
Last modified: 17 Mar 2024 02:32
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Author:
Gitali Devi
Author:
Adam Hedger
Author:
Jonathan Watts
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