Mechanistic Study in Click Reactions by Using (N-Heterocyclic

Article Cite This: Organometallics XXXX, XXX, XXX−XXX

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Mechanistic Study in Click Reactions by Using (N‑Heterocyclic carbene)Copper(I) Complexes: Anionic Effects Yi-Chen Lin,† Yen-Jen Chen,† Tzung-Yu Shih,† Yu-Hsieh Chen,† Yi-Chun Lai,† Michael Y. Chiang,†,‡ Gopal Chandru Senadi,§ Hsing-Yin Chen,*,† and Hsuan-Ying Chen*,†,‡,∥ †

Department Department § Department ∥ Department ‡

of of of of

Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, R.O.C. Chemistry, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan, R.O.C. Chemistry, SRM Institute of Science and Technology, Kattankulathur, Chennai - 603203, India Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan, R.O.C.

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S Supporting Information *

ABSTRACT: A series of Cu complexes bearing N-heterocyclic carbene were synthesized, and their application for the copper-catalyzed azide−alkyne cycloaddition reaction was studied. The catalytic results demonstrated that [L2Cu]Br exhibited the most activity, and the trend of the other complexes was I > Br > Cl ∼ BF4 > PF6. The 1H NMR spectrum of the reaction of LCuCl and phenylacetylene demonstrated that the NHC ligand dissociated from the Cu atom and deprotonated phenylacetylene to produce phenylacetylide. The conductivity study also proved this phenomenon. According to the density functional theory calculations, a mechanism was proposed in which acetylide copper halide was formed after NHC ligand dissociation and phenylacetylene deprotonation. Then, the six-membered metallacycle from the cycloadditions of methyl azide with mononuclear copper acetylide reacted with the second copper catalyst, (NHC)CuX, to form the dinuclear intermediate, which in turn underwent a rapid ring contraction to form another more stable dinuclear intermediate. After the protonation by neighboring NHC−H+, triazole was produced, and two (NHC)CuX catalysts were recovered.

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INTRODUCTION Click reactions are useful methods for synthesizing biomaterials for applications in drug development1a,b and biology.1c−g Many metal complexes2 can be used as catalysts in click reactions, and the copper-catalyzed azide−alkyne cycloaddition (CuAAC) reaction3 is commonly used for the aforementioned applications. Although various ligands4 can be used in the CuAAC reaction, N-heterocyclic carbenes (NHCs)5 are familiar and practical, and Nolan5j was the first one to use [Cu(NHC)X] and bis NHC complexes as catalysts for click reactions. For [(NHC)CuX] complexes, their possible catalytic mechanism5i,k,p−r illustrated in Scheme 1 is the metathesis of a halide from copper, which initiates the catalytic cycle to produce a copper acetylide. To prove the correctness of this mechanism in this study, an experiment was attempted to isolate copper acetylide with NHC ligands from the mixture of LCuCl (where L is 1-benzyl-3-methylimidazolin-2-ylidene) and phenylacetylene in CDCl3. However, the 1H NMR spectra depicted in Figure 1 revealed the deprotonation of phenylacetylene and protonation of NHC ligands, and these results differed from those of another study.5q To understand the actual mechanism, a series of LCuX complexes with various anions and [L2Cu]Br were synthesized, and their application in © XXXX American Chemical Society

the CuAAC reaction was studied. In addition, a possible mechanism was discussed according to the density functional theory (DFT) study and the experimental results.

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RESULTS AND DISCUSSION

Synthesis and Characterization of Cu Complexes. A series of imidazolium salts was prepared through the reaction of 1-methylimidazole with various benzyl halides (I, Br, Cl). Imidazolium BF4− and PF6− were synthesized from the substitution of 1-benzyl-3-methylimidazolium bromide with NaBF4 and KPF6, respectively. All [LCuX] complexes were prepared through the reaction of CuX and sodium bis(trimethylsilyl)amide in tetrahydrofuran (THF) for 1 day, after which various imidazolium X− in CH3CN were transferred and reacted for 1 day (Figure 2a). [L2Cu]Br was synthesized through the reaction of 1 equiv of CuBr and 2 equiv of sodium bis(trimethylsilyl)amide in THF for 1 day, and then, 2 equiv of imidazolium Br− in CH3CN was transferred to react for 1 day (Figure 2b). Received: August 7, 2018

A

DOI: 10.1021/acs.organomet.8b00565 Organometallics XXXX, XXX, XXX−XXX

Article

Organometallics Scheme 1. Mechanism of the CuAAC Reaction through [LCuX] Complexes

Figure 1. 1H NMR spectra of (A) phenylacetylene, (B) NHCCuCl, (C) NHC−Cl ligand, and (D) the mixture of phenylacetylene and LCuCl (1:1).

Figure 2. Synthesis of (a) LCuX and (b) [L2Cu]Br.

Compound formulas and structures were confirmed through H and 13C NMR spectra and elemental analysis. The X-ray structure of [LCuBr] (CCDC 1855955) obtained in the NMR tube (CDCl3) (Figure 3) illustrated the triangular geometry of the Cu complex with the two bridging Br atoms. The sum of the angles Br−Cu−Br(A) (97.558(13)°), C(1)−Cu−Br

(128.81(8)°), and C(1)−Cu−Br(A) (133.62(8)°) was close to 360°, revealing that C(1), Cu, Br, and Br(A) were coplanar. Catalytic Study of the CuAAC Reaction. The catalytic activity of these Cu complexes was tested for the CuAAC reaction of benzyl azide and phenylacetylene. At room temperature, all complexes with a loading of 6.25 mM were

1

B


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Organometallics

catalyst, the conductivity study was used to identify the product of the reaction of the (NHC)CuX complex and phenylacetylene. The results demonstrated that the conductivity was 0.3 mS/m for phenylacetylene (57.33 mM in acetonitrile) and 15 mS/m for LCuCl (6.67 mM in acetonitrile). After 4 h of the reaction of Cu complexes and phenylacetylene (1:8.6), the conductivity was 80 mS/m for LCuCl with phenylacetylene. These data implied that the NHC of the Cu complex dissociated and attached the proton of phenylacetylene to form (NHCH)+ and phenylacetylide. Then, phenylacetylide bonded to the Cu center to form (NHCH)+[(PhCC−)CuX]−. Mechanism Discussion Based on 1H NMR Study and DFT Calculation. The aforementioned results demonstrated that NHC dissociates from Cu atom and deprotonates phenylacetylene to form (NHCH)+ and phenylacetylide. To confirm whether the anion bonding on the copper atom affected the dissociation of the NHC and further affected the deprotonation of the phenylacetylene, the reactions of phenylacetylene with [L2Cu]Br, LCuI, LCuBr, LCuCl, LCuBF 4 , and LCuPF 6 (LCuX:phenylacetylene = 1:1, [LCuX] = 0.06 M in 5 mL of CDCl3), respectively, were monitored using 1H NMR. After 15 min, 70% of phenylacetylene had transferred to phenylacetylide using [L2Cu]Br, 52% for LCuI, 22% for LCuBr, and 0% for LCuCl, LCuBF4, and LCuPF6. After 45 min, more than 99% of phenylacetylene had transferred to phenylacetylide using [L2Cu]Br and LCuI, 98% to LCuBr, 37% to LCuCl, 12% to LCuBF4, and 0% for LCuPF6. This may explain why LCuPF6 exhibited significantly lower catalytic activityLCuPF6 could not form phenylacetylide. To ascertain the reaction mechanism, the processes involved in the CuAAC reaction of LCuCl, benzyl azide, and phenylacetylene (1:1.5:2, [LCuX] = 0.06 M in 1 mL of CDCl3) in CDCl3 were monitored by using 1H NMR, as shown in Figure 4. Figure 1 depicts the deprotonation of phenylacetylene and protonation of the NHC ligand, and Figure 4 only reveals LCuCl, benzyl azide, phenylacetylene, and the final product, 1-benzyl-4-phenyl-1,2,3-triazole, without NHCH+ and (1-benzyl-4-phenyl-1,2,3-triazol-5-yl)CuCl. It implied that the association of benzyl azide to rgw Cu atom of (NHCH)+[(PhCC−)CuX]−, the cycloaddition formation to (1-benzyl-4-phenyl-1,2,3-triazol-5-yl)CuCl, and the proton exchange between NHCH+ and (1-benzyl-4-phenyl-1,2,3triazol-5-yl)CuCl were fast. DFT calculations were used to clarify the reaction mechanism of CuAAC reactions. The reaction was assumed to be initiated through ligand substitution by phenylacetylene and subsequent deprotonation to form copper acetylide. For the (NHC)CuX catalysts, either NHC or X− could be replaced. We first performed thermodynamics analysis of the ligand exchange process to determine which channel was preferred. The calculated free energy changes of ligand substitutions (Table 2) indicated that, for X = I, Br, and Cl, the dissociation of NHC was thermodynamically more favorable, whereas, for X = BF4 and PF6, the situation was the converse. We then calculated the free energy changes of the formation of copper acetylides through phenylacetylene deprotonation by either dissociated NHC or anions (Table 3). Deprotonation of phenylacetylene by NHC yielded ion-pair complexes of anionic copper acetylides and protonated carbene. [(PhCC)CuX]−·NHCH+ was estimated to be moderately endergonic (5.4−8.1 kcal/mol) and thermodynamically accessible. By contrast, the formation of neutral

Figure 3. Molecular structure of complex LCuBr represented as 20% ellipsoids (all of the hydrogen atoms were omitted for clarity).

examined in CDCl3 (3 mL), and the results indicated that the activity was closely related to the catalyst’s anions (Table 1). In Table 1. Catalyst Screening for the Preparation of [1,2,3]Triazolea

entry

Cu salt

time (min)

conv (%)

1 2 3 4 5 6 7

CuI LCuI LCuBr LCuCl LCuBF4 LCuPF6 [L2Cu]Br

60 10/60 10/60 10/60 10/60 10/60 10/60

0 47/75 18/69 14/55 10/50 3/15 72/93

a

[Cat] = 6.25 mM, [phenylacetylene] = 62.5 mM, [azide] = 62.5 mM, CDCl3 3 mL.

Table 1, copper(I) iodide exhibited no activity under this condition (entry 1). [L2Cu]Br exhibited the most activity, and the trend for other complexes was I > Br > Cl ∼ BF4 > PF6. The results were attributable to the substitution of phenylacetylene for the anion,5i and the trend of bond strength between Cu and anion was I > Br > Cl. However, the 1H NMR spectrum (Figure 1) of the mixture of LCuCl and phenylacetylene in CDCl3 exhibited the deprotonation of phenylacetylene and protonation of the NHC ligand. The reactive order was consistent with the rank of the trans effect.6 The results presented in Table 1 and the phenomenon of the NMR study implied the X of LCuX controlled the rate of the L (NHC) dissociation and further influenced the deprotonation of phenylacetylene and the association of phenyl acetylide. The X of LCuX with a higher trans effect increased the L (NHC) dissociation and then increased the traction rate of the CuAAC reaction. Conductivity Study. If a halide dissociation occurs after the reaction of the (NHC)CuX complex and phenylacetylene, the neutral complex of (NHC)Cu(PhCC −) results. Conversely, if NHC dissociates and is protonated by phenylacetylene after the reaction of (NHC)CuX complex and phenylacetylene, the ionic compound (NHC H)+[(PhCC−)CuX]− is the product. To understand the mechanism of the CuAAC reaction using (NHC)CuX as a C


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Organometallics

Figure 4. 1H NMR spectra of the reaction of LCuCl, benzyl azide, and phenylacetylene (1:1:1) in CDCl3.

and conductivity studies that the NHC acted as a base to deprotonate phenylacetylene rather than anions. One could possibly be misled by the data displayed in Table 3 to conclude that the formation of anionic copper acetylide [(PhC C)CuX]− was feasible for X = BF4 and PF6 (6.4 and 5.4 kcal/ mol). However, one must be aware that for these systems the free NHC was not available because the dissociation of weakly bonded BF4 and PF6 was predominant (Table 2). The BF4 and PF6 were bases too weak to deprotonate and transform the phenylacetylene to copper acetylide (25.6 and 29.0 kcal/mol in Table 3). The thermodynamic data also explained why the (NHC)Cu(PF6) exhibited a significantly lower reactivity. For this catalyst, the dissociation of PF6 was dominant (Table 2), and this base was too weak to deprotonate and transform the phenylacetylene to copper acetylide (Table 3). The theoretical prediction was verified by the aforementioned NMR study. Furthermore, the tendency toward the generation of anionic copper acetylide [(PhCC)CuX]− was I (7.0 kcal/mol) > Br (7.5 kcal/mol) > Cl (8.1 kcal/mol), which paralleled the trend of catalytic activity exhibited in LCuX catalysts (Tables 1 and 3). The subsequent cycloadditions of methyl azide with mononuclear copper acetylide [(PhCC)CuX]− to form six-membered metallacycle were calculated for X = Cl and I. However, the activation energy of mononuclear cycloaddition

Table 2. Free Energy Changes (kcal/mol) of Ligand Substations (NHC)CuX + PhCCH → (PhCCH)CuX + NHC X=I

X = Br

X = Cl

X = BF4

X = PF6

27.0 27.2 28.2 29.0 29.0 (NHC)CuX + PhCCH → [(NHC)Cu(PhCCH)]+ + X− X=I

X = Br

X = Cl

X = BF4

X = PF6

33.4

35.7

42.2

11.4

5.6

Table 3. Free Energy Changes (kcal/mol) of the Formation of Copper Acetylides (NHC)CuX + PhCCH → [(PhCC)CuX]−·NHCH+ X=I

X = Br

X = Cl

X = BF4

X = PF6

7.0 7.5 8.1 6.4 5.4 (NHC)CuX + PhCCH → [(NHC)Cu(CCPh)] + HX X=I

X = Br

X = Cl

X = BF4

X = PF6

27.8

27.5

25.9

25.6

29.0

copper acetylide [(NHC)Cu(CCPh)] and HX through phenylacetylene deprotonation by anions was very unlikely because these processes were highly endergonic, exceeding 25 kcal/mol. This result supported the observation in the NMR D


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Organometallics

Figure 5. Free energy profile for the binuclear CuAAC reaction (kcal/mol).

Figure 6. Selected bond lengths (in Å) and charge distribution for the transition state TS1 of cycloaddition in mononuclear and binuclear (NHC)CuCl models.

was estimated to be 30.3 kcal/mol for Cl and 28.9 kcal/mol for I, which seemed too high to rationalize the demonstrated efficiency of CuAAC reactions. We thus investigated the possibility of involving the second copper catalyst (NHC)CuX in the cycloaddition reaction. In fact, the binuclear mechanism was proposed in other CuAAC systems.7 The calculated free energy profile for the binuclear CuAAC reaction is presented in Figure 5, and the optimized transition state structures TS1 of the cycloaddition step in mononuclear and binuclear models are depicted in Figure 6. It was evident that the activation energies of the cycloadditions of methyl azide with bicopper acetylide were significantly reduced to 21.8 and 21.4 kcal/mol for X = Cl and I, respectively. The reduction of the

cycloaddition barrier can be attributed to the delocalization of negative charge induced by the presence of a second copper catalyst. Charge distribution analysis of TS1 (Figure 6) indicated that when going from mononuclear to binuclear the negative charge on the methyl azide and phenylethynyl group decreased from −0.194 to −0.128 and from −0.511 to −0.504, respectively, and the positive charge on Cuα increased from 0.381 to 0.429; overall, approximately 0.12 |e| was transferred from the [(PhCC)CuCl]−MeN3 moiety to the (NHC)CuCl moiety. The resultant six-membered metallacycle (3) was kinetically and thermodynamically unstable, but it then underwent a rapid ring contraction to form the more stable [(NHC)CuX][(1-methyl-4-phenyl-1,2,3-triazol-5-yl)E


Article

Organometallics CuX]− complex (4). In the final step, the intermediate (4) was protonated by neighboring NHCH+ to produce a triazole product, which then recovered two (NHC)CuX catalysts (5); this process was determined to be more exergonic by approximately 20 kcal/mol. According to the experimental NMR study, the transformation of 4 to 5 was expected to be relatively fast because the intermediate (4) was not detected. The overall activation energy of the cycloaddition reaction was almost the same for X = Cl and I (21.8 vs 21.4 kcal/mol) and thus could not account for the exhibited difference in activity between these two catalysts. In addition, we also calculated the cycloaddition reaction for X = PF6, although this catalyst has been demonstrated to be extremely inefficient at producing copper acetylides. Interestingly, we discovered that, if copper acetylides were formed in the X = PF6 catalytic system, the following cycloaddition reaction would be even somewhat faster (activation energy was 20.6 kcal/mol) than that for X = Cl and I. The present DFT calculations yielded a key conclusion that for the series of (NHC)CuX catalysts the type of anion had a minor effect on the cycloaddition step, and the efficiency of the CuAAC reaction mainly depended on the extent of copper acetylide formation. These theoretical findings inspired us to design and synthesize the three-coordinate catalyst (NHC)2CuBr. The logic behind this strategy was simple: increasing the coordination number was expected to attenuate the ligand bonding, which in turn would promote the NHC dissociation and the copper acetylide formation. Indeed, this catalyst was determined to possess the most reactivity (Table 1). DFT calculations indicated that the presence of a second NHC ligand indeed significantly weakened the coordination of NHC in (NHC)2CuBr; the bonding energy was only −9.6 kcal/mol, which was substantially lower than −50.2 kcal/mol for the twocoordinate (NHC)CuBr catalyst. Therefore, when (NHC)2CuBr was dissolved in a solvent, partial dissociation occurred and the free NHC base was readily available in the environment. We also calculated the free energy change of the formation of copper acetylide, (NHC)2CuBr + PhCC H → (NHC)Cu(CCPh) + NHCH+Br−, and determined that this reaction was less endergonic (6.2 kcal/mol) than the copper acetylide formation in (NHC)CuX catalysts (Table 3, X = Cl, Br, I). These computational results explain why the three-coordinate catalyst (NHC)2CuBr exhibited the highest catalytic reactivity.

bromide, copper chloride, and benzyl azide were purchased from Aldrich. 1H and 13C NMR spectra were recorded on Varian Gemini2000-200 (200 MHz for 1H and 50 MHz for 13C) spectrometers with chemical shifts given in ppm from the internal TMS or center line of CDCl3. Conductivity study was recorded on a COND-6021 Pen Type Waterproof Conductivity Meter. 1-Benzyl-3methylimidazolium chloride,8a 1-benzyl-3-methylimidazolium bromide,8b 1-benzyl-3-methylimidazolium iodide,8c 1-benzyl-3-methylimidazolium tetrafluoroborate,8d 1-benzyl-3-methylimidazolium hexafluorophosphate,8d LCuBr,8e LCuPF6,8e and CuBF48f were synthesized following the literature. Synthesis of LCuCl. The mixture of CuCl (0.99 g, 0.01 mol) and sodium bis(trimethylsilyl)amide (1.83g, 0.01 mol) in THF (15 mL) was stirred for 1 day at room temperature. 1-Benzyl-3-methylimidazolium chloride (2.087 g, 0.01 mol) in CH2Cl2 (10 mL) was transferred into the solution to stir for 1 day. Filtration through Celite and concentration under a vacuum to about 5 mL followed by hexane (20 mL) addition provided the brown powder. Yield: 2.176 g (80%). 1 H NMR (CDCl3, 200 MHz) δ 7.35−7.26 (5H, m, Ar), 6.90, 6.85 (2H, d, J = 1.8 Hz, NCHCHN), 5.30 (2H, s, CH2Ph), 3.85 (3H, s, CH3N). 13C NMR (CDCl3, 50 MHz) δ 178.12 (NCN), 135.57 (CH2C (Ar)), 129.06 (Ar-o), 128.59 (Ar-m), 127.97 (Ar-p), 122.12, 120.55 (NCCN), 55.13 (NCH2Ph), 38.20 (NCH3). Elemental Anal. Calcd (found) for C11H12ClCuN2: N, 10.33 (10.46); C, 48.71 (48.53); H, 4.46 (4.84) %. Mp: 103 °C. Synthesis of LCuI. A method similar to that used for LCuCl was used for the synthesis of LCuI, except 1-benzyl-3-methylimidazolium iodide was used in place of 1-benzyl-3-methylimidazolium chloride and CuI was used in place of CuCl. Yield: 2.73 g (75%). 1H NMR (CDCl3, 200 MHz) δ 7.29−7.28 (5H, m, Ar), 6.80, 6.72 (2H, br, NCHCHN), 5.39 (2H, s, CH2Ph), 3.84 (3H, s, CH3N). 13C NMR (CDCl3, 50 MHz) δ 181.06 (NCN), 136.47 (CH2C (Ar)), 128.93 (Ar-o), 128.68 (Ar-m), 127.99 (Ar-p), 121.63, 119.80 (NCCN), 54.38 (NCH2Ph), 38.12 (NCH3). Elemental Anal. Calcd (found) for C11H12CuIN2: N, 7.72 (7.66); C, 36.43 (36.60); H, 3.34 (3.60) %. Mp: 90 °C. Synthesis of LCuBF4. A method similar to that used for LCuCl was used for the synthesis of LCuBF4, except 1-benzyl-3methylimidazolium tetrafluoroborate was used in place of 1-benzyl3-methylimidazolium chloride and CuBF48f was used in place of CuCl. Yield: 1.88 g (71%). 1H NMR (CDCl3, 200 MHz) δ 7.38−7.26 (5H, m, Ar), 6.90, 6.86 (2H, br, NCHCHN), 5.31 (2H, s, CH2Ph), 3.79 (3H, s, CH3N). 13C NMR (CDCl3, 50 MHz) δ 177.97 (NCN), 135.60 (CH2C (Ar)), 128.96 (Ar-o), 128.49 (Ar-m), 127.94 (Ar-p), 122.11, 120.52, (NCCN), 55.01 (NCH2Ph), 38.15 (NCH3). Elemental Anal. Calcd (found) for C11H12BCuF4N2: N, 8.68 (8.95); C, 40.96 (49.95); H, 3.75 (3.56) %. Mp: 130 °C. Synthesis of [L2Cu]Br. The mixture of CuBr (1.41 g, 0.01 mol) and sodium bis(trimethylsilyl)amide (3.66 g, 0.02 mol) in THF (25 mL) was stirred for 1 day at room temperature. 1-Benzyl-3methylimidazolium bromide (5.04 g, 0.02 mol) in CH2Cl2 (10 mL) was transferred into the solution to stir for 1 day. Filtration through Celite and concentration under a vacuum to about 5 mL followed by hexane (20 mL) addition provided the brown powder. Yield: 2.58 g (53%). 1H NMR (CDCl3, 200 MHz) δ 7.28−7.24 (5H, m, Ar), 6.91, 6.85 (2H, br, NCHCHN), 5.31 (2H, s, CH2Ph), 3.76 (3H, s, CH3 N). 13C NMR (CDCl3, 50 MHz) δ 180.22 (NCN), 136.21 (CH2C (Ar)), 128.43 (Ar-o), 127.73 (Ar-m), 127.48 (Ar-p), 121.51, 120.08 (NCCN), 54.12 (NCH2Ph), 37.71 (NCH3). Elemental Anal. Calcd (found) for C22H24BrCuN4: N, 11.48 (11.39); C, 54.16 (54.42); H, 4.96 (4.92) %. Mp: 151 °C. General Procedure for CuAAC Reaction. A typical CuAAC reaction was exemplified by the synthesis of entry 2 (Table 1) using LCuI complex (0.01875 mmol), benzyl azide (0.1875 mmol), and phenylacetylene (0.1875 mmol) in CDCl3 (3 mL) under N2 at room temperature under stirring. At appropriate time intervals, 0.1 mL aliquots were removed from the NMR tube and CDCl3 (0.7 mL) was added into the NMR tube. The CDCl3 solution was analyzed by 1H NMR.

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CONCLUSION In this study, a series of NHCCuX complexes were synthesized. This demonstrated that the activities of Cu complexes for the CuAAC reaction were closely related to X− and consistent with the rank of the trans effect. From the 1H NMR and conductivity studies, we determined that the neutral NHC ligand dissociated and was protonated by phenylacetylene to form cationic NHCH+ and [PhCC CuX]−. The DFT calculation also proved that NHC dissociation should occur at the first step rather than at X− dissociation.

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EXPERIMENTAL SECTION

Sodium tetrafluorobrate, sodium bis(trimethylsilyl)amide, and benzyl azide were purchased from Acros. Triphenylphosphine, 1-methylimidazole, benzyl bromide, benzyl chloride, and phenylacetylene were purchased from Alfa. Potassium hexafluorophosphate and potassium iodide were purchased from SHOWA. Copper iodide, copper F


Article

Organometallics Computational Method. The present DFT calculations were accomplished by the Gaussian 09 program.9 Solution phase (in chloroform) geometry optimization and vibrational frequency analysis were carried out at the M06/Def2-SVP level. To obtain more accurate energies, single point energy calculations with a larger Def2-TZVP basis set were performed. The solution environment was simulated by the CPCM polarizable conductor model. The Gibbs free energy corrections were made under the conditions of 298.15 K and 1 M (i.e., 24.5 atm). Natural population analysis was applied to obtain the information of charge distribution. Numerical integrations were performed with the setting of an ultrafine grid.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.8b00565. Compound characterization data, including NMR spectra, and details of the kinetic study (PDF) Accession Codes

CCDC 1855955 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (Hsuan-Ying Chen). ORCID

Gopal Chandru Senadi: 0000-0003-0149-5423 Hsing-Yin Chen: 0000-0003-3948-8915 Hsuan-Ying Chen: 0000-0003-1424-3540 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the Ministry of Science and Technology of Taiwan (Grant MOST 107-2113-M-037-001) and Kaohsiung Medical University “NSYSU-KMU JOINT RESEARCH PROJECT” (NSYSUKMU 107-P010). We thank the Center for Research Resources and Development at Kaohsiung Medical University for instrumentation and equipment support.

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Mechanistic Study in Click Reactions by Using (N-Heterocyclic

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