Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Triazolinediones enable ultrafast and reversible click chemistry for the design of dynamic polymer systems

An Erratum to this article was published on 22 September 2014

This article has been updated


With its focus on synthetic reactions that are highly specific and reliable, ‘click’ chemistry has become a valuable tool for many scientific research areas and applications. Combining the modular, covalently bonded nature of click-chemistry linkages with an ability to reverse these linkages and reuse the constituent reactants in another click reaction, however, is a feature that is not found in most click reactions. Here we show that triazolinedione compounds can be used in click-chemistry applications. We present examples of simple and ultrafast macromolecular functionalization, polymer–polymer linking and polymer crosslinking under ambient conditions without the need for a catalyst. Moreover, when triazolinediones are combined with indole reaction partners, the reverse reaction can also be induced at elevated temperatures, and the triazolinedione reacted with a different reaction partner, reversibly or irreversibly dependent on its exact nature. We have used this ‘transclick’ reaction to introduce thermoreversible links into polyurethane and polymethacrylate materials, which allows dynamic polymer-network healing, reshaping and recycling.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Summary of applied TAD chemistry for click and transclick reactions.
Figure 2: Model reactions and synthesis of indole components.
Figure 3: Transclick study and theoretical rationalization of TAD reactions.
Figure 4: Irreversible polymer conjugation.
Figure 5: Reversible polymer conjugation.
Figure 6: Dynamic properties of TAD-based materials.

Similar content being viewed by others

Change history

  • 11 August 2014

    Technical issues with our online publication processes resulted in this Article being published the day after that referred to in the print version. The official date of publication is 11 August 2014.


  1. Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001).

  2. Moses, J. E. & Moorhouse, A. D. The growing applications of click chemistry. Chem. Soc. Rev. 36, 1249–1262 (2007).

    Article  CAS  Google Scholar 

  3. Xi, W., Scott, T. F., Kloxin, C. J. & Bowman, C. N. Click chemistry in materials science. Adv. Funct. Mater. 24, 2572–2590 (2014).

    Article  CAS  Google Scholar 

  4. Golas, P. L. & Matyjaszewski, K. Marrying click chemistry with polymerization: expanding the scope of polymeric materials. Chem. Soc. Rev. 39, 1338–1354 (2010).

    Article  CAS  Google Scholar 

  5. Tasdelen, M. A. & Yagci, Y. Light-induced click reactions. Angew. Chem. Int. Ed. 52, 5930–5938 (2013).

    Article  CAS  Google Scholar 

  6. Pauloehrl, T. et al. Adding spatial control to click chemistry: phototriggered Diels–Alder surface (bio)functionalization at ambient temperature. Angew. Chem. Int. Ed. 51, 1071–1074 (2012).

    Article  CAS  Google Scholar 

  7. Barner-Kowollik, C. et al. ‘Clicking' polymers or just efficient linking: what is the difference? Angew. Chem. Int. Ed. 50, 60–62 (2011).

    Article  CAS  Google Scholar 

  8. Tasdelen, M. A. Diels–Alder ‘click' reactions: recent applications in polymer and material science. Polym. Chem. 2, 2133–2145 (2011).

    Article  CAS  Google Scholar 

  9. Mather, B. D., Viswanathan, K., Miller, K. M. & Long, T. E. Michael addition reactions in macromolecular design for emerging technologies. Prog. Polym. Sci. 31, 487–531 (2006).

    Article  CAS  Google Scholar 

  10. Cookson, R. C., Gilani, S. S. H. & Stevens, I. D. R. 4-Phenyl-1,2,4-triazolin-3,5-dione: a powerful dienophile. Tetrahedron Lett. 3, 615–618 (1962).

    Article  Google Scholar 

  11. Radl S. in Advances in Heterocyclic Chemistry Vol. 67 (ed. Katritzky, A. R.) 119–208 (Elsevier, 1997).

  12. Funel, J-A. & Abele, S. Industrial applications of the Diels–Alder reaction. Angew. Chem. Int. Ed. 52, 3822–3863 (2013).

    Article  CAS  Google Scholar 

  13. Nicolaou, K. C., Snyder, S. A., Montagnon, T. & Vassilikogiannakis, G. The Diels–Alder reaction in total synthesis. Angew. Chem. Int. Ed. 41, 1668–1698 (2002).

    Article  CAS  Google Scholar 

  14. Novikov, R. A., Korolev, V. A. & Tomilov, Y. V. Reactions of 4-phenyl-1,2,4-triazoline-3,5-dione with 2-pyrazolines. Russ. Chem. Bull. 60, 1685–1693 (2011).

    Article  CAS  Google Scholar 

  15. Gillis B. T. & Hagarty J. D. The reaction of 4-phenyl-1,2,4-triazoline-3,5-dione with conjugated dienes. J. Org. Chem. 32, 330–333 (1966).

    Article  Google Scholar 

  16. Syrgiannis, Z., Koutsianopoulos, F., Muir, K. W. & Elemes, Y. Reaction of a triazolinedione with simple alkenes. Isolation and characterization of hydration products. Tetrahedron Lett. 50, 277–280 (2009).

    Article  CAS  Google Scholar 

  17. Korobitsyna, I. K., Khalikova, A. V., Rodina, L. L. & Shusherina, N. P. 4-Phenyl-1,2,4-triazoline-3,5-dione in organic synthesis (review). Chem. Heterocycl. Compd 19, 117–136 (1983).

    Article  Google Scholar 

  18. Jensen, F. & Foote, C. S. Reaction of 4-phenyl-1,2,4-triazoline-3,5-dione with substituted butadienes. A nonconcerted Diels–Alder reaction. J. Am. Chem. Soc. 109, 6376–6385 (1987).

    Article  CAS  Google Scholar 

  19. Higashi, T., Shibayama, Y., Fuji, M. & Shimada, K. Liquid chromatography–tandem mass spectrometric method for the determination of salivary 25-hydroxyvitamin D3: a noninvasive tool for the assessment of vitamin D status. Anal. Bioanal. Chem. 391, 229–238 (2008).

    Article  CAS  Google Scholar 

  20. Aronov, P. A., Hall, L. M., Dettmer, K., Stephensen, C. B. & Hammock, B. D. Metabolic profiling of major vitamin D metabolites using Diels–Alder derivatization and ultra-performance liquid chromatography–tandem mass spectrometry. Anal. Bioanal. Chem. 391, 1917–1930 (2008).

    Article  CAS  Google Scholar 

  21. Hoogewijs, K., Buyst, D., Winne, J. M., Martins, J. C. & Madder, A. Exploiting furan's versatile reactivity in reversible and irreversible orthogonal peptide labeling. Chem. Commun. 49, 2927–2929 (2013).

    Article  CAS  Google Scholar 

  22. Ban, H., Gavrilyuk, J. & Barbas, C. F. Tyrosine bioconjugation through aqueous ene-type reactions: a click-like reaction for tyrosine. J. Am. Chem. Soc. 132, 1523–1525 (2010).

    Article  CAS  Google Scholar 

  23. Ban, H. et al. Facile and stabile linkages through tyrosine: bioconjugation strategies with the tyrosine-click reaction. Bioconjugate Chem. 24, 520–532 (2013).

    Article  CAS  Google Scholar 

  24. Pieken, W. et al. Method for solution phase synthesis of oligonucleotides. World patent WO98/47910 (1998).

  25. Chen, T. C. S. & Butler, G. B. Chemical reactions on polymers. 111. Modification of diene polymers via the ene reaction with 4-substituted-1,2,4-triazoline-3,5-diones. J. Macromol. Sci. Pure Appl. Chem. 16, 757–768 (1981).

    Article  Google Scholar 

  26. Butler, G. B. Triazolinedione modified polydienes. Ind. Eng. Chem. Prod. Res. Dev. 19, 512–528 (1980).

    Article  CAS  Google Scholar 

  27. Kaufmann, T. et al. ‘Sandwich' microcontact printing as a mild route towards monodisperse Janus particles with tailored bifunctionality. Adv. Mater. 23, 79–83 (2011).

    Article  CAS  Google Scholar 

  28. Espeel, P. et al. Multifunctionalized sequence-defined oligomers from a single building block. Angew. Chem. Int. Ed. 125, 13503–13506 (2013).

    Article  Google Scholar 

  29. Stamenovic, M. M. et al. Straightforward synthesis of functionalized cyclic polymers in high yield via RAFT and thiolactone–disulfide chemistry. Polym. Chem. 4, 184–193 (2013).

    Article  CAS  Google Scholar 

  30. Hansell, C. F. et al. Additive-free clicking for polymer functionalization and coupling by tetrazine–norbornene chemistry. J. Am. Chem. Soc. 133, 13828–13831 (2011).

    Article  CAS  Google Scholar 

  31. Kricheldorf H. R. & Denchev Z. in Transreactions in Condensation Polymers (ed. Favirov, S.) Ch. 8, 319–389 (Wiley-VCH, 1999).

  32. Collins, K. D. & Glorius, F. A robustness screen for the rapid assessment of chemical reactions. Nature Chem. 5, 597–601 (2013).

    Article  CAS  Google Scholar 

  33. Rickborn, B. The retro-Diels–Alder reaction Part II. Dienophiles with one or more heteroatom (Organic Reactions 53, John Wiley, 2004).

  34. Baran, P. S., Guerrero, C. A. & Corey, E. J. The first method for protection-deprotection of the indole 2,3-π bond. Org. Lett. 5, 1999–2001 (2003).

    Article  CAS  Google Scholar 

  35. Zweifel H., Maier R. D. & Schiller M. Plastics Additives Handbook (Hanser, 2009).

  36. Inglis, A. J., Paulöhrl, T. & Barner-Kowollik, C. Ambient temperature synthesis of a versatile macromolecular building block: cyclopentadienyl-capped polymers. Macromolecules 43, 33–36 (2009).

    Article  Google Scholar 

Download references


B. De Meyer is acknowledged for the measurements of the LC-SEC samples. S.B. and F.D. thank the Agency for Innovation by Science and Technology in Flanders for PhD scholarships. K.D.B. thanks the Research Foundation-Flanders (FWO) for the funding of his fellowship. H.G., F.D.P. and V.V.S. acknowledge the FWO (Vlaanderen), the Research Board of Ghent University and the Belgian Science Policy Office Interuniversity Attraction Poles (IAP) programme in the frame of IAP 7/05 for financial support. Computational resources and services used in this work were provided by Ghent University (Stevin Supercomputer Infrastructure).

Author information

Authors and Affiliations



S.B, K.D.B., F.D. and H.G. performed the experiments. S.B., K.D.B., J.M.W. and F.D.P. conceived and designed the experiments. H.G. and V.V.S. were responsible for the theoretical calculations. S.B., J.M.W. and F.D.P wrote the paper. K.D.B prepared all the figures. All the authors discussed the results and commented on the manuscript at all stages.

Corresponding authors

Correspondence to Johan M. Winne or Filip E. Du Prez.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 17324 kb)

Supplementary movie 1

Supplementary movie 1 (MP4 5325 kb)

Supplementary movie 2

Supplementary movie 2 (MP4 7789 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Billiet, S., De Bruycker, K., Driessen, F. et al. Triazolinediones enable ultrafast and reversible click chemistry for the design of dynamic polymer systems. Nature Chem 6, 815–821 (2014).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing