Journal of Molecular Graphics and Modelling 34 (2012) 101–107 Contents lists available at SciVerse ScienceDirect Journal of Molecular Graphics and Modelling j ourna l h o me p age: www.elsevier.com/locate/JMGM The mechanism of copper-catalyzed azide–alkyne cycloaddition reaction: A quantum mechanical investigation Cihan Özen, Nurcan S ¸ . Tüzün ∗ Chemistry Department, Istanbul Technical University, Faculty of Science and Letters, Ayazaga Campus, Maslak, Istanbul, Turkey a r t i c l e i n f o Article history: Accepted 30 December 2011 Available online 8 January 2012 Keywords: Copper-catalyst Triazole Copper-acetylide CuAAC DFT Click chemistry a b s t r a c t In this study, the mechanism of CuAAC reaction and the structure of copper acetylides have been investigated with quantum mechanical methods, namely B3LYP/6-311 + G(d,p). A series of possible copper-acetylide species which contain up to four copper atoms and solvent molecules as ligand has been evaluated and a four-copper containing copper-acetylide, M1A, was proposed more likely to form based on its thermodynamic stability. The reaction has been modeled with a representative simple alkyne and a simple azide to concentrate solely on the electronic effects of the mechanism. Later, the devised mechanism has been applied to a real system, namely to the reaction of 2-azido-1,1,1-trifluoroethane and ethynylbenzene in the presence of copper. The copper catalyst transforms the concerted uncatalyzed reaction to a stepwise process and lowers the activation barrier. The pre-reactive complexation of the negatively charged secondary nitrogen of azide and the positively charged copper of copper-acetylide brings the azide and the alkyne to a suitable geometry for cycloaddition to take place. The calculated acti- vation barrier difference between the catalyzed and the uncatalyzed reactions is consistent with faster and the regioselective synthesis of triazole product. © 2012 Elsevier Inc. All rights reserved. 1. Introduction 1,2,3-Triazole derivatives are pharmacologically very important class of compounds and have received considerable attention due to their ability to mimic peptide bonds and work as precursor for a number of important compounds. They are chemically stable, inert to severe hydrolytic, oxidizing and reducing conditions even at high temperatures. Their derivatives show anti-HIV [1,2], anti-bacterial [3], anti-histamine [4–6] and anti-tumor [7–9] activity. Besides their pharmacological features, they are used in agro chemistry, dye industry and anti-corrosion agent [10]. Formerly, 1,2,3-triazoles were synthesized by heat. However; this process required high temperature, showed slow rate and low regioselectivity. In 2001, Sharpless and Meldal independently devised processes in which azide and alkyne have produced tria- zole in the presence of copper catalyst at room temperature (Fig. 1) [11,12]. This methodology provided faster (about 10 7 times) [13] and regioselective (1,4 disubstituted 1,2,3-triazole) synthesis under benign reaction conditions. The reaction can take place in organic solvents or on solid support regardless of the reaction conditions, as long as Cu(I) is present in the medium. ∗ Corresponding author. E-mail address: nurcant@itu.edu.tr (N.S ¸ . Tüzün). The most well-known click reaction, copper catalyzed azide–alkyne cycloaddition reaction (CuAAC), has been the subject of many synthetic and application studies [14–18]. Although the area of click chemistry ranges from the fuel cells to polymers, there are still some uncertain points in the mechanism of CuAAC reaction. Generally copper salts are used as catalyst and the catalytically active form of the copper is known to be +1. The catalytic activity of copper (I) has been explained by its ability to have  and -interactions with the alkynes and to exchange alkyne and other ligands in its coordination sphere, especially in aqueous conditions. In the proposed mechanism of CuAAC (Fig. 2), first, copper coordinates to  electrons of the alkyne compound. After deprotonation by base or solvent, copper-acetylide molecule is formed. Formation of copper-acetylide has been verified by the reaction being possible only by the terminal alkynes. The deprotonation is expected to be very efficient since the reaction takes place even in highly acidic conditions [19]. Experimentally, a decrease in pK a has also been observed as evidence to deproto- nation. Coordination of the azide to copper-acetylide is followed by the cyclization to produce the triazole ring. Finally, protonation releases the free triazole molecule [20]. The first DFT-based mechanistic study was carried out by the Sharpless group [21]. In their study, the mechanism advances with mononuclear copper-acetylide species in step-wise manner. Soon after this study, the kinetic study, done by the same group, showed that the reaction is second order with respect to copper, 1093-3263/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2011.12.012