Copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC)

The azide-alkyne Huisgen cycloaddition is a 1,3-dipolar cycloaddition that involves the reaction between an azide and a terminal or internal alkyne, leading to the formation of a 1,2,3-triazole. Rolf Huisgen[1] was a trailblazer in understanding the wide applicability of this organic reaction. Renowned American chemist Karl Barry Sharpless has characterized this cycloaddition as the epitome of click chemistry, referring to it as "the cream of the crop"[2] and "the premier example of a click reaction."[3]

Fig 1.Thermal Huisgen 1,3-dipolar cycloaddition.

In the presented reaction[4], azide 2 effectively undergoes a reaction with alkyne 1, resulting in the formation of the triazole product as a mixture of 1,4-adduct (3a) and 1,5-adduct (3b) after 18 hours at 98°C.

The conventional 1,3-cycloaddition involving an azide as a 1,3-dipole and an alkene as a dipolarophile has been largely overlooked due to limited reactivity, particularly with electron-poor olefins, and the occurrence of concurrent elimination side reactions. While some success has been achieved with non-metal-catalyzed cycloadditions, especially those utilizing electron-poor olefins[5] or alkynes as dipolarophiles.

Despite azides not being the most reactive 1,3-dipole for such reactions, they are preferred for their relative lack of side reactions and stability under typical synthetic conditions.

Copper Catalysis

A notable variation of the Huisgen 1,3-dipolar cycloaddition involves the copper(I)-catalyzed version, which departs from a truly concerted cycloaddition mechanism. In this modified approach, organic azides and terminal alkynes are combined, resulting exclusively in the 1,4-regioisomers of 1,2,3-triazoles, where substitution occurs at positions 1' and 4'. This copper(I)-catalyzed variant, documented in 2002 through independent publications by Morten Meldal[6] at the Carlsberg Laboratory in Denmark and Valery Fokin and K. Barry Sharpless at the Scripps Research Institute, produces triazoles from terminal alkynes and azides. [7] Formally, it doesn't meet the criteria of a 1,3-dipolar cycloaddition. Therefore, it is more accurately referred to as the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC).

Fig.2 A comparison of the Huisgen and the copper-catalyzed Azide-Alkyne cycloadditions

Furthermore, this copper-catalyzed "click" reaction does not necessitate ligands on the metal, although accelerating ligands like tris(triazolyl)methyl amine ligands with various substituents have been reported and proven effective in aqueous solutions.[8] Other ligands such as PPh3 and TBIA can also be employed, although PPh3 is susceptible to Staudinger ligation with the azide substituent. Notably, Cu2O in water at room temperature has been discovered to catalyze the same reaction within 15 minutes, yielding a 91% success rate.[9]

Initially, the proposed mechanism for this reaction involved a single catalytic copper atom.[10-14] However, subsequent studies, including isotope labeling, kinetic analyses, and other investigations, have indicated that a dicopper mechanism may be more pertinent. Despite the efficacy of this reaction under biological conditions, the cytotoxicity of copper within this dosage range poses a challenge. Various solutions have been proposed, such as employing water-soluble ligands on the copper to enhance the catalyst's cell penetration, thereby reducing the required dosage. [15-17]Alternatively, chelating ligands can be utilized to further increase the effective concentration of Cu(I), consequently lowering the actual dosage needed.[18-20]

Fig 3.The two-copper mechanism of the CuAAC catalytic cycle

Although the Cu(I)-catalyzed variant was initially disclosed by Meldal and colleagues for synthesizing peptidotriazoles on solid support, their conditions diverged from the essence of click chemistry and were eventually overshadowed by the more widely recognized contributions of Sharpless. Interestingly, Meldal and co-workers chose not to designate this reaction as "click chemistry," a decision that may have contributed to its limited recognition within the mainstream chemical society. In contrast, Fokin and Sharpless independently characterized it as a dependable catalytic process, offering "an unprecedented level of selectivity, reliability, and scope for those organic synthesis endeavors reliant on establishing covalent links between diverse building blocks."

In 2005, the Jia and Fokin research groups reported a RuAAC reaction analogous to CuAAC, but catalyzed by ruthenium instead of copper. This alternative method enables the selective synthesis of 1,5-isomers.[21]

Reference

1. Huisgen, R. (1961). "Centenary Lecture - 1,3-Dipolar Cycloadditions".Proceedings of the Chemical Society of London: 357. https://doi.org/10.1039/PS9610000357

2. H. C. Kolb; M. G. Finn; K. B. Sharpless (2001). "Click Chemistry: Diverse Chemical Function from a Few Good Reactions". Angewandte Chemie International Edition. 40 (11): 2004–2021. https://doi.org/10.1016/S1359-6446(03)02933-7

3. Kolb, H.C.; Sharpless, B.K. (2003). "The growing impact of click chemistry on drug discovery". Drug Discov Today. 8 (24): 1128–1137. https://doi.org/10.1016/S1359-6446(03)02933-7

4. Development and Applications of Click Chemistry Gregory C. Patton November 8, 2004

5. David Amantini; Francesco Fringuelli; Oriana Piermatti; Ferdinando Pizzo; Ennio Zunino & Luigi Vaccaro (2005). "Synthesis of 4-Aryl-1H-1,2,3-triazoles through TBAF-Catalyzed [3+2] Cycloaddition of 2-Aryl-1-nitroethenes with TMSN3 under Solvent-Free Conditions". The Journal of Organic Chemistry. 70 (16): 6526–6529.https://doi.org/10.1021/jo0507845

6. Christian W. Tornøe; Caspar Christensen & Morten Meldal (2002). "Peptidotriazoles on Solid Phase: [1,2,3]-Triazoles by Regiospecific Copper(I)-Catalyzed 1,3-Dipolar Cycloadditions of Terminal Alkynes to Azides". Journal of Organic Chemistry. 67 (9): 3057–3064. https://doi.org/10.1021/jo011148j

7. Vsevolod V. Rostovtsev; Luke G. Green; Valery V. Fokin; K. Barry Sharpless (2002). "A Stepwise Huisgen Cycloaddition Process: Copper(I)-Catalyzed Regioselective Ligation of Azides and Terminal Alkynes". Angewandte Chemie International Edition. 41 (14): 2596–2599. https://doi.org/10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4

8. L. Liang and D. Astruc: "The copper(I)-catalysed alkyne-azide cycloaddition (CuAAC) "click" reaction and its applications. An overview", 2011; 255, 23–24, 2933–2045, p. 2934

9. K. Wang, X. Bi, S. Xing, P. Liao, Z. Fang, X. Meng, Q. Zhang, Q. Liu, Y. Ji Green Chem., 13 (2011), p. 562

10. B. T. Worrell, J. A. Malik, V. V. Fokin 2013, 340, 457–459 ; J.E. Hein, V.V. Fokin, Chem. Soc. Rev. 39 (2010) 1302.

11. Rodionov, Valentin O.; Fokin, Valery V.; Finn, M. G. (2005-04-08). "Mechanism of the Ligand-Free CuI-Catalyzed Azide–Alkyne Cycloaddition Reaction". Angewandte Chemie International Edition. 44 (15): 2210–2215. https://doi.org/10.1002/anie.200461496

12. Iacobucci, Claudio; Reale, Samantha; Gal, Jean-François; De Angelis, Francesco (2015-03-02). "Dinuclear Copper Intermediates in Copper(I)-Catalyzed Azide–Alkyne Cycloaddition Directly Observed by Electrospray Ionization Mass Spectrometry". Angewandte Chemie International Edition. 54 (10): 3065–3068. https://doi.org/10.1002/anie.201410301

13. Özkılıç, Yılmaz; Tüzün, Nurcan Ş. (2016-08-22). "A DFT Study on the Binuclear CuAAC Reaction: Mechanism in Light of New Experiments". Organometallics. 35 (16): 2589–2599. https://doi.org/10.1021/acs.organomet.6b00279

14. Ziegler, Micah S.; Lakshmi, K. V.; Tilley, T. Don (2017-04-19). "Dicopper Cu(I)Cu(I) and Cu(I)Cu(II) Complexes in Copper-Catalyzed Azide–Alkyne Cycloaddition" (PDF). Journal of the American Chemical Society. 139 (15): 5378–5386. https://doi.org/10.1021/jacs.6b13261

15. Brotherton, W. S.; Michaels, H. A.; Simmons, J. T.; Clark, R.J.; Dalal, N. S.; Zhu, L. Org. Lett. 2009, 11, 4954.

16. Kuang, G.-C.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Zhu, L" J. Org. Chem. 2010; 75, 6540.

17. Uttamapinant, C.; Tangpeerachaikul, A.; Grecian, S.; Clarke, S.; Singh, U.; Slade, P.; Gee, K. R.; Ting, A. Y" Angew. Chem. Int. Ed. 2012; 51, 5852

18. Alder, K.; Stein, G.; Finzenhagen, H. Justus Liebigs Ann.Chem 1931, 485, 211.

19. Alder, K.; Stein, G. Justus Liebigs Ann. Chem. 1933, 501, 1.

20. Wittig, G.; Krebs, A. Chem. Ber. 1961, 94, 3260.

21. Zhang, Li; Chen, Xinguo; Xue, Peng; Sun, Herman H. Y.; Williams, Ian D.; Sharpless, K. Barry; Fokin, Valery V.; Jia, Guochen (November 2005). "Ruthenium-Catalyzed Cycloaddition of Alkynes and Organic Azides". Journal of the American Chemical Society. 127 (46): 15998–15999. https://doi.org/10.1021/ja054114s