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Angewandte Highlights

Click Chemistry

DOI: 10.1002/anie.201108044

Unlocking the 1,2,3-Triazole Ring Using Mechanical Force**

Yuan Lin and Qian Wang*
click chemistry copper heterocycles mechanophore ultrasound

The 1,2,3-triazole ring is a highly stable functional group,

which is readily accessed through the 1,3-dipolar cycloaddition of an azide and an alkyne. This reaction was extensively studied by Rolf Huisgen and co-workers from the 1950s to the 1970s.[1] In the early 1990s, Sharpless and co-workers revisited this reaction and used it as a typical reaction to demonstrate the click chemistry concept.[2] In particular, the introduction of CuI as a catalyst can lead to an enormous rate acceleration of 107 to 108 compared to the uncatalyzed reaction.[3, 4] The socalled CuAAC, CuI-catalyzed alkyneazide cycloaddition, reaction has become the cream of the crop for click chemistry, and has been broadly used in organic synthesis, drug discovery, biology, and materials science.[5, 6] This cycloaddition process is strongly favored thermodynamically (DH = 45 to 55 kcal mol1), an essential feature of click reactions.[7] As a result, the triazole product is stable toward most thermal and chemical treatments and is inert in aqueous or biologically relevant environments. In addition, the 1,2,3-triazole motif can tolerate high-temperature treatment and normal-light irradiation. Although the stability of the triazole ring is an advantage in many applications, it limits the potential of this reaction when a reversible process is demanded. Therefore, it is a great challenge for synthetic chemists to find a robust and clean approach to unlock the 1,2,3-triazole ring and regenerate the parent alkyne and azide. Such a process will be extremely useful for polymer and materials synthesis, as well as controlled bioconjugation applications.

Recently, Bielawski and co-workers developed an elegant strategy to unclick the triazole ring.[8] Instead of using known chemical transformations, they hypothesized that triazoles might not retain their structural integrity under the appropriate mechanical stress. The triazole ring was incorporated into long polymer chains of poly(methyl acrylate) through the controlled radical polymerization of methyl acrylate in the presence of a bifunctional triazole initiator. When the polymer was subjected to ultrasonication in a Suslick cell at 0 8C,[9] the formation of bubbles in solution (i.e. cavitation processes) resulted in solvodynamic sheer forces that were directed to the triazole rings through the appended polymer chains. Within only 2 hours of ultrasonication, these forces resulted in the cleavage of the triazole ring (Scheme 1). Control experiments have been performed, and ruled out the possibility of a thermally induced retro-cycloaddition reaction. Furthermore, a variety of spectroscopic and chemicallabeling techniques were employed to confirm that the triazole ring was cleanly reverted to the azide and alkyne moieties. Moreover, the uncoupled components could be reclicked either with each other or with other counterpart reagents using the typical CuI catalysis condition.

[*] Prof. Q. Wang Department of Chemistry & Biochemistry University of South Carolina Columbia, SC 29208 (USA) E-mail: wang@mail.chem.sc.edu Dr. Y. Lin State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences Changchun, 130022 (P. R. China) [**] Q.W. is grateful to a guest professorship from CIAC and the Robert L. Sumwalt Prof. endowment at USC. Y.L. gratefully acknowledges the financial support from the State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, the Chinese Academy of Sciences, and the National Natural Science Foundation of China (Programs 21128002 and 21104080). Scheme 1. The application of mechanical forces (ultrasonication) can result in a formal retro-[3+2] cycloaddition reaction between an azide and alkyne. The regenerated azide and alkyne moieties can be rejoined under CuI catalysis.

Because of the broad application of the CuAAC reaction,[57] it is not hard to expect this unlocking strategy will soon be embraced by materials chemists in designing novel, smart materials, and by biochemists in chemical biology
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applications.[10, 11] More importantly, this research highlights a new paradigm in synthesis, that is, using mechanical force as either an orthogonal or alternative tool (other than chemical, thermal, and photochemical strategies) to manipulate molecules; this approach will have much boarder impact. It has been known for decades that mechanical force can promote chemical reactions, a field known as mechanochemistry.[12] However, Bielawskis work is a rare example of a chemical reaction that can only be accessed through mechanical activation. Another attractive feature of this unlocking process is the possibility of spatial control. As indicated in the paper, cycloreversion is only observed if the triazole ring is centrally located in the polymer chain, because tensile forces generated along the polymer backbone are maximized at the center of the chain.[12] Therefore, in theory, one can envision that similar reactions can be manipulated, or even programmed sequentially, by locating the mechanophore (i.e. the triazole ring in this case) at different positions along a polymer chain. Furthermore, the length and chemical nature of the polymer arms should also significantly affect the activation process. Thus, in combination with some more precise methods to focus mechanical force, it may be possible to achieve singlemolecule manipulation with great spatial control. Clearly, this work has opened many new possibilities in organic synthesis. A natural extension of this work will be to explore other chemical transformations, especially other pericyclic reactions including the DielsAlder reaction[13] and variations of 1,3-dipolar cycloaddition reactions. In addition, it will be important to find out how to achieve better control of reactivity, as well as the directionality of a reversible process, by mechanical manipulation. It would be interesting to learn if a mechanical-force gradient can selectively decouple (or couple) different covalent bonds, thus providing a force-selective process. Finally, many practical questions are yet to be answered. For example, how can we design a biologically orthogonal mechanoprocess for applications in chemical biology? How can we use mechanoprocesses in large-scale manufacturing? Clearly, a better understanding of the mechanochemical process in different reaction systems, the design of novel mechanochemical apparatus, and a multidisciplinary research endeavor are needed to fully harness mechanical forces for applications in synthetic chemistry.
Received: November 15, 2011 Published online: && &&, &&&&

Chemie

[1] R. Huisgen in 1,3-Dipolar Cycloaddition Chemistry, Vol. A (Ed.: A. Padwa), Wiley, New York, 1984, pp. 1 176. [2] H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113, 2056 2075; Angew. Chem. Int. Ed. 2001, 40, 2004 2021. [3] V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem. 2002, 114, 2708 2711; Angew. Chem. Int. Ed. 2002, 41, 2596 2599. [4] C. W. Torne, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057 3064. [5] M. G. Finn, V. V. Fokin, Chem. Soc. Rev. 2010, 39, 1231 1232. [6] Q. Wang, C. Hawker, Chem. Asian J. 2011, 6, 2568 2569. [7] Q. Wang, S. Chittaboina, H. Barnhill, Lett. Org. Chem. 2005, 2, 293 301. [8] J. N. Brantley, K. M. Wiggins, C. W. Bielawski, Science 2011, 333, 1606 1609. [9] K. S. Suslick, J. W. Goodale, P. F. Schubert, H. H. Wang, J. Am. Chem. Soc. 1983, 105, 5781 5785. [10] C. J. Hawker, K. L. Wooley, Science 2005, 309, 1200 1205. [11] C. R. Bertozzi, Acc. Chem. Res. 2011, 44, 651 653. [12] M. M. Caruso, D. A. Davis, Q. Shen, S. A. Odom, N. R. Sottos, S. R. White, J. S. Moore, Chem. Rev. 2009, 109, 5755 5798. [13] K. M. Wiggins, J. A. Syrett, D. M. Haddleton, C. W. Bielawski, J. Am. Chem. Soc. 2011, 133, 7180 7189.

Angew. Chem. Int. Ed. 2012, 51, 2 4

 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Highlights

Highlights
Click Chemistry Y. Lin, Q. Wang* &&& &&&

Unlocking the 1,2,3-Triazole Ring Using Mechanical Force K(l)ick it into reverse: Mechanical force (ultrasound) may be employed to promote a retrocycloaddition reaction of a 1,2,3-triazole to regenerate the parent azide and alkyne, a reaction that cannot be achieved by other means.

www.angewandte.org

 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2012, 51, 2 4

These are not the final page numbers!