Supporting information

Supporting information Design and applications of an efficient amphiphilic click Cu I catalyst in water Changlong Wang, a Dong Wang, a Shilin Yu, a Thomas Cornilleau, a Jaime Ruiz, a Lionel Salmon, b and Didier Astruc a * a ISM, UMR CRS º 5255, Univ. Bordeaux, 33405 Talence, France b Laboratoire de Chimie de Coordination, UPR CRS 8241, 31077 Toulouse, France * Corresponding Author: didier.astruc@u-bordeaux.fr Table of content: I. General data.s 2 II. Synthesis of the Cu I catalysts..s 4 III. General procedure for the CuAAC reactions S 5 IV. Comparison of the results of the CuAAC reactions between benzyl azide and phenylacetylene... S 6 V. Recycling of the PEG-tristrz-Cu I catalyst S 7 VI. Procedure for the click dendrimer synthesis.s 9 VII. Spectroscopic characterization of the compounds.s 10 VIII. Spectra of the compounds...s 18 IX. Reference....S 41 1

I. General data --All the solvents and chemicals were used as received, unless otherwise noted. --Degassed water was used for the catalyst synthesis and CuAAC reactions. -- 1 H MR spectra were recorded at 25 C with a Bruker AC 200, or 300 (200 or 300 MHz) spectrometer. All the chemical shifts are reported in parts per million (δ, ppm) with reference to Me 4 Si (TMS) for the 1 H MR spectra. --The UV-vis. absorption spectra were measured with a Perkin-Elmer Lambda 19 UV-vis. spectrometer. --Flash column chromatography was performed using silica gel (300-400 mesh). 2

Ⅱ. Synthesis of the Cu I catalysts The mono-trz-peg, and tris-trz-peg ligands were synthesized according to previous reports. [S1-S2] Synthesis of the PEG-tris-trz-Cu I catalyst: In a dried Schlenk flask, tris-trz-peg ligand (1 equiv., 7.96 mg) solubilized in 1 ml of degassed water and CuSO 4 5H 2 O (0.8 mg, 3.20 10-6 mol) solubilized in 1 ml of water were successively added. 12 ml of degassed water were added into the Schlenk flask, and the solution was stirred at r.t. for 30 min under 2. Sodium ascorbate (aasc, 10 equiv. per Cu 2+ ) solubilized in 2 ml of degassed water was added dropwise to the solution of PEG-tris-trz-Cu 2+. After stirring for another 30 min under 2, the PEG-tris-trz-Cu I solution was ready for use. The synthesis of the PEG-Cu I (B) and PEG-mono-trz-Cu I catalysts (C and D) followed the above mentioned procedure under identical conditions, except that 1 equiv. of PEG2000, 1 equiv. of mono-trz-peg and 3 equiv. of mono-trz-peg were used for B, C and D, respectively, instead of the tris-trz-peg ligand. The synthetic procedure with the PEG-tris-trz-Cu I catalyst was monitored by UV-vis. spectroscopy, as shown in the main text in Figure 1. A similar procedure for the preparation of PEG-tristrz-Cu I catalyst in D 2 O, but more concentrated, was also monitored by 1 H MR, as shown in Figure S1. 3

Figure S1: 1 H MR spectrum (300 MHz) of PEG-tristrz-Cu I catalyst synthesis procedure in D 2 O. (From bottom to up line, PEG-tristrz (black line), l PEG-tristrz-Cu 2+ (red line), and PEG-tristrz-Cu I (blue line)). (aasc was directly added to the D 2 O solution containing the tris-trz-peg ligand and CuSO 4 in the MR tube under 2. The triazole proton signal of tris-trz-peg ligand reappeared at 8.190 ppm, revealing the presence of diamagnetic Cu I species). 4

Ⅲ. Comparison between the yields obtained using various Cu I catalysts for the CuAAC reactions between of benzyl azide and phenylacetylene Figure 2. Comparison studies between Cu I, PEG-Cu I, PEG-mono-trz-Cu I, and PEG-tris-trz-Cu I catalysts in the CuAAC of benzyl azide and phenylacetylene. a ( a This Figure is Figure 2 of the main text that is re-add here for improved clarity concerning the comparisons of the catalytic activity among different catalysts A-E.) 5

Table S1: Comparison between the crude yields (%) obtained with the Cu I, PEG-Cu I, PEG-mono-trz-Cu I, and PEG-tris-trz-Cu I catalysts in the CuAAC reaction between benzyl azide and phenylacetylene. Amount 2000 ppm 200 ppm 100 ppm 50 ppm Catalysts Cu I 34.9 12.3 5 0 PEG-Cu I 40 12.5 5.6 2.9 1 PEG-mono-trz-Cu I 70.7 41 26.5 13.8 3 PEG-mono-trz-Cu I 91.4 79.4 66.7 34 PEG-tris-trz-Cu I 100 100 100 100 Ⅳ. General procedure for the CuAAC reactions: A glass vessel equipped with a magnetic stirring bar was charged with 0.1 mmol of organic azide and 0.105 mmol of alkyne under a nitrogen atmosphere. Catalytic amounts of catalyst were added into the vessel under 2, and degassed water was added in order to obtain 1 ml as the total volume of water. The reaction mixture was stirred during 20 h at 35 C under 2. After the reaction, the mixture was filtered and then extracted using CH 2 Cl 2 (3 x 10 ml). The organic layer was dried over a 2 SO 4 and filtered, and the solvent was removed in vacuo to give the corresponding 1,2,3-triazoles. The product was then purified by silica chromatography when necessary. 6

Ⅴ. Recycling of the PEG-tris-trz-Cu I catalyst The amphiphilic tris-trz-peg ligand is insoluble in cold diethyl ether. After the CuAAC reaction, extraction of the click products from the aqueous solution was conducted using cold diethyl ether (2 5 ml) while keeping the catalyst in the water phase. After charging another run of substrates, the water phase was directly injected by a syringe under 2. External addition of aasc (10 equiv) was necessary to ensure keeping the catalytic Cu I species active during catalysis. After the sixth runs, the water phase was collected and extracted by CH 2 Cl 2, the CH 2 Cl 2 solution was then dried over a 2 SO 4 and filtered, and the solvent was removed in vacuo in order to check the 1 H MR spectrum. Table S2: Product yield upon recycling the catalyst under the condition of entry 4. Recycling 1 st 2 nd 3 rd 4 th 5 th 6 th number Yield 95% 90% 83% 81% 75% 53% 7

Figure S2. 1 H MR spectrum of the tris-trz-peg ligand before catalysis (black line), and after the fifth recycling of the catalyst (green line). 8

Ⅵ. Procedure for the click dendrimer synthesis: 9-ferrocenyltriazole dendrimer 5 and 9-pyridyltriazole dendrimer 6 were synthesized as follows: Taking the synthesis of 9-ferrocenyltriazole dendrimer 5 as the example: A glass vessel equipped with a magnetic stirring bar was charged with nona-azido precursor (16.69 mg, 1 equiv.) and ethynylferrocene (22.1 mg, 1.05 equiv. per azido group) under argon atmosphere. The PEG-tris-trz-Cu I catalyst (100 ppm per azido group) was added into the vessel under argon, and degassed water was added in order to obtain 1 ml as the total volume of water. The reaction mixture was stirred during 24 h at 40 C, the light yellow solid formed sticked on the wall of the glass vessel and magnetic stirring bar. After the reaction, the glass vessel was washed twice with water and pentane respectively, and filtered. CH 2 Cl 2 (30 ml) was then added to solubilize the dendrimer, the CH 2 Cl 2 solution was then dried over a 2 SO 4 and filtered, and the solvent was removed in vacuo to yield the dendrimer. 9

Ⅶ. Characterization of the click products by 1 H MR spectroscopy (1) 1-benzyl-4-phenyl-1H-[1,2,3]triazole was isolated as a white solid (Isolated yield: 90%). 1 H MR (200 MHz, CDCl 3 ) δ ppm : 7.82-7.84 (m, 2H), 7.80 (s, 1H), 7.27-7.46 (m, 7H), 5.59 (s, 2H). (2) 1-benzyl-4-(trimethylsilyl)-1H-[1,2,3]triazole was isolated as a yellow liquid (Isolated yield: 90%). 1 H MR (200 MHz, CDCl 3 ) δ ppm : 7.36 (s, 1H), 7.30-7.31 (m, 3H), 7.21 (d, 2H), 5.55 (s, 2H), 0.24 (s, 9H). (3) 2-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-pyridine was isolated as a yellowish solid (Isolated yield: 93%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 8.49-8.52 (m, 1H), 8.15 (d, 1H), 8.02 (s, 1H), 7.70-7.76 (m, 1H), 7.38-7.41 (m, 5H), 7.30 (m, 1H), 5.63 (s, 2H). (4) 3-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-pyridine was isolated as a yellowish solid (Isolated yield: 94%).. 10

1 H MR (300 MHz, CDCl 3 ) δ ppm : 8.99 (s, 1H), 8.59-8.60 (d, 1H), 8.19-8.24 (m, 1H), 7.78 (s, 1H), 7.30-7.43 (m, 6H), 5.64 (s, 2H). (5) 4-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-benzaldehyde was isolated as a white solid (Isolated yield: 91%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 9.93 (s, 1H), 7.86-7.92 (m, 4H), 7.71 (s, 1H), 7.28-7.34 (m, 5H), 5.53 (s, 2H). (6) 1-benzyl-4-(4-bromophenyl)-1H-[1,2,3]triazole was isolated as a white solid (Isolated yield: 95%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 7.63-7.71 (m, 3H), 7.51-7.55 (m, 2H), 7.26-7.41 (m, 5H), 5.55 (s, 2H). (7) 1-Benzyl-4-ferrocenyl-1H-[1,2,3]triazole was isolated as a golden yellow solid (Isolated yield: 93%). Fe 1 H MR (300 MHz, CDCl 3 ) δ ppm : 7.33-7.38 (m, 4H), 7.24-7.27 (m, 2H), 5.52 (s, 2H), 11

4.65-4.67 (t, 2H), 4.24-4.26 (t, 2H), 4.03 (s, 5H). (8) 1,4-diphenyl-1H-[1,2,3]triazole was isolated as a light yellow solid (Isolated yield: 92%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 8.24 (s, 1H), 7.94-7.97 (m, 2H), 7.82-7.86 (m, 2H), 7.56-7.62 (m, 2H), 7.47-7.53 (m, 3H), 7.38-7.44 (m, 1H). (9) 2-[1-(4-Bromophenyl)-1H-1,2,3-triazol-4-yl]pyridine was isolated as a yellowish solid (Isolated yield: 93%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 8.62-8.66 (m, 2H), 8.26-8.29 (d, 1H), 7.69-7.88 (m, 5H), 7.28-7.33 (m, 1H). (10) 1-Hexyl-4-phenyl-1H-[1,2,3]triazole was isolated as a white solid (Isolated yield: 93%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 7.86-7.88 (m, 2H), 7.78 (s, 1H), 7.34-7.43 (m, 3H), 4.40-45 (t, 2H), 1.93-2.00 (m, 2H), 1.27-1.39 (m, 6H), 0.90 (t, 3H). (11) 1-Benzyl-4-butyl-1H-[1,2,3]triazole was isolated as a white solid (Isolated yield: 88%). 12

1 H MR (300 MHz, CDCl 3 ): δ H 7.24-7.39 (m, 5H), 7.21 (s, 1H), 5.49 (s, 2H), 2.70 (t, J = 7.8 Hz, 2H), 1.58-1.66 (m, 2H), 1.33-1.41 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H). (12) 1-(4-bromo-benzyl)-4-phenyl-1H-[1,2,3]triazole was isolated as a white solid (Isolated yield: 87%). 1 H MR (200 MHz, CDCl 3 ) δ ppm : 7.78-7.83 (m, 2H), 7.68 (s, 1H), 7.50-7.55 (m, 2H), 7.34-7.46 (m, 3H), 7.17-7.21 (d, 2H), 5.54 (s, 2H). (13) 4-(4-phenyl-[1,2,3]triazol-1-ylmethyl)-benzonitrile was isolated as a white solid (Isolated yield: 90%). 1 H MR (200 MHz, CDCl 3 ) δ ppm : 7.80-7.84 (m, 2H), 7.74 (s, 1H), 7.66-7.70 (m, 2H), 7.35-7.43 (m, 5H), 5.66 (s, 2H). (14) (1-benzyl-1H-[1,2,3]triazol-4-yl)-coumarin was isolated as a white solid (Isolated yield: 89%). 1 H MR (300 MHz, DMSO) δ ppm : 8.38 (s, 1H), 8.01-7.98 (d, 1H), 7.65-7.63 (d, 1H), 7.38-7.31 (m, 5H), 7.15-7.14 (s, 1H), 7.03-7.00 (d, 1H), 6.33-6.30 (d, 1H), 5.62 (s, 2H), 5.28 (s, 2H), 4.90 (s, 1H). 13

(15) 4-(1-Benzyl-1H-[1,2,3]triazol-4-yl)-phenylamine was isolated as a yellowish solid (Isolated yield: 93%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 7.61-7.64 (m, 2H), 7.56 (s, 1H), 7.32-7.42 (m, 5H), 6.73-6.76 (m, 2H), 5.59 (s, 2H). (16) 1-[(3-methylphenyl)methyl]-4-phenyl-1H-[1,2,3]triazole was isolated as a white solid (Isolated yield: 91%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 7.83-7.86 (m, 2H), 7.69 (s, 1H), 7.03-7.47 (m, 7H), 5.57 (s, 2H), 2.39 (s, 3H). (17) 2-[1-(6-O-monotosyl-β-CD)-1H-1,2,3-triazol-4-yl]pyridine was isolated as a white product (Isolated yield: 85%). 1 H MR (300 MHz, DMSO-d 6 ): δ ppm : 8.58 (d, 1H), 8.56 (s, 1H), 7.85-7.79 (t, 1H), 7.58-7.55 (d, 1H), 7.42 (t, 1H), 5.84-5.64 (m, 14H), 4.94-4.79 (m, 7H), 4.57-4.48 (m, 6H), 3.84-3.56 (m, 28H), 3.46-3.26 (m, overlaps peaks). (18) p-bis(ferrocenyl-1,2,3-triazolylmethyl) benzene was isolated as an orange powder (Isolated yield: 83%). 14

1 H MR (300 MHz, DMSO-d 6 ): δ ppm : 8.25 (2H, CH of triazole ),7.41-7.32 (4H, CH of Ar ), 5.62 (4H, Ar-CH 2 ), 4.73, 4.44, 4.31, 4.03 (18H, CH of Cp). (19) The 9-ferrocenyltriazole dendrimer was isolated as light yellow waxy solid (Isolated yield: 93%). Fe Fe Si Si Si Fe Si Fe Fe Si Fe Si Si Si Si Fe Fe Fe 1 H MR (300 MHz, CDCl 3 ) δ ppm : 7.41 (s, 9H, triazole CH), 6.96 (s, 3H, A r core), 4.75, 4.32 and 4.09 (s, 81H, Cp), 3.87 (s, 18H, SiCH 2 ), 1.63 (s, 18H, CH 2 CH 2 CH 2 Si), 1.09 (s, 18H, CH 2 CH 2 CH 2 Si), 0.65 (s, 18H, CH 2 CH 2 CH 2 Si), 0.10 (s, 54H, Si(CH 3 ) 2 ). (20) The 9-pyridyltriazole dendrimer was isolated as a light yellow waxy solid 15

(Isolated yield: 90%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 8.54 (d, 9H, CH of pyridyl), 8.15-8.11 (d, 9H, CH of pyridyl), 8.04 (s, 9H, CH of triazole), 7.73 (t, 9H, CH of pyridyl), 7.18 (s, 9H) 6.96 (s, 3H, CH of Ar), 3.94 (s, 18H, SiCH 2 -triazole), 1.62 (s, 18H, CH 2 CH 2 CH 2 Si), 1.10 (s, 18H, CH 2 CH 2 CH 2 Si), 0.63 (t, 18H, CH 2 CH 2 CH 2 Si), 0.074 (s, 54H, Si(CH 3 ) 2 ). (21) 3'-Desoxy-3'-[4-((5-(hydroxymethyl)-4-iodo-2-methylphenoxy)methyl)-1H-1,2,3- triazole-1-yl]- thymidine 6 was isolated as a white solid (Isolated yield: 89%). 16

1 H MR (400 MHz, MeOD/CDCl 3 ) δ ppm : 8.21 (s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 7.20 (s, 1H), 6.50-6.43 (t, 1H), 5.45-5.42 (m, 1H), 5.19 (s, 2H), 4.51 (s, 2H), 4.37-4.36 (m, 1H), 3.87 (dd, J= 12.3Hz, J= 2.9Hz, 1H), 3.79 (dd, J= 12.3Hz, J= 2.9Hz, 1H), 2.97-2.85 (m, 1H), 2.79-2.64 (m, 1H), 2.10 (s, 3H), 1.89 (s, 3H). (22) (1-benzyl-1H-[1,2,3]triazol-4-yl)-cyclohexylmethanol was isolated as a white solid (Isolated yield: 93%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 7.43-7.28 (m, 6H), 5.54 (s, 2H), 2.43 (s, 1H), 2.03-1.22 (m, 10H). (23) 17α-(1-Benzyl-1H-1,2,3-triazol-4-yl) estradiol was isolated as a white solid (Isolated yield: 93%). 1 H MR (300 MHz, CDCl 3 ) δ ppm : 0.50-0.56 (m, 3H), 1.24 (s, 3H), 1.27-1.37 (m, 2H), 1.54-1.64 (m, 2H), 1.65-1.70 (m, 1H), 1.82-1.97 (m, 3H), 2.09-2.14 (m, 2H), 2.32-2.42 (m, 1H), 2.68-2.91 (m, 3H), 3.26 (s, 3H), 3.97 (s, 1H), 5.55 (s, 2H), 6.53-6.54 (d, 1H), 6.59-6.63 (m, 1H), 6.88-6.92 (m, 1H), 7.26-7.30 (m, 3H), 7.37-7.41 (m, 4H). 17

Ⅷ. Spectra of the click products Figure S3: 1 H MR spectrum of 1-benzyl-4-phenyl-1H-[1,2,3]triazole. 18

Figure S4: 1 H MR spectrum of 1-benzyl-(trimethylsilyl)-1H-[1,2,3]triazole. 19

Figure S5: 1 H MR spectrum of 2-(1-benzyl-1H-[1,2,3]triazol-4-yl)-pyridine. 20

Figure S6: 1 H MR spectrum of 3-(1-benzyl-1H-[1,2,3]triazol-4-yl)-pyridine. 21

Figure S7: 1 H MR spectrum of 4-(1-benzyl-1H-[1,2,3]triazol-4-yl)-benzaldehyde. 22

Figure S8: 1 H MR spectrum of 1-benzyl-4-(4-bromophenyl)-1H-[1,2,3]triazole. 23

Figure S9: 1 H MR spectrum of 1-benzyl-4-ferrocenyl-1H-[1,2,3]triazole. 24

Figure S10: 1 H MR spectrum of 1,4-diphenyl-1H-[1,2,3]triazole. 25

Figure S11: 1 H MR spectrum of 2-[1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl]pyridine. 26

Figure S12: 1 H MR spectrum of 1-hexyl-4-phenyl-1H-[1,2,3]triazole. 27

Figure S13: 1 H MR spectrum of 1-Benzyl-4-butyl-1H-[1,2,3]triazole. 28

Figure S14: 1 H MR spectrum of 1-(4-bromo-benzyl)-4-phenyl-1H-[1,2,3]triazole. 29

Figure S15: 1 H MR spectrum of 4-(4-phenyl-[1,2,3]triazol-1-ylmethyl)-benzonitrile. 30

Figure S16: 1 H MR spectrum of (1-benzyl-1H-[1,2,3]triazol-4-yl)-coumarin. 31

Figure S17: 1 H MR spectrum of 4-(1-benzyl-1H-[1,2,3]triazol-4-yl)-phenylamine. 32

Figure S18: 1 H MR spectrum of 1-[(3-methylphenyl)methyl]-4-phenyl-1H-[1,2,3]triazole. 33

Figure S19: Partial 1 H MR spectrum of 2-[1-(6-O-monotosyl-β-CD)-1H-1,2,3-triazol-4-yl]pyridine. 34

Figure S20: 1 H MR spectrum of 9-ferrocenyltriazole dendrimer. 35

Figure S21: 1 H MR spectrum of 9-pyridyltriazole dendrimer. 36

Figure S22: 1 H MR spectrum of p-bis (ferrocenyl-1,2,3-triazolylmethyl) benzene. 37

Figure S23: 1 H MR spectrum of 3'-desoxy-3'-[4-((5-(hydroxymethyl)-4-iodo-2-methylphenoxy)methyl)-1H-1,2,3-t riazole-1-yl]- thymidine 6. 38

Figure S24: 1 H MR spectrum of (1-benzyl-1H-[1,2,3]triazol-4-yl)-cyclohexylmethanol. 39

Figure S25: 1 H MR spectrum of compound 7. 40

Ⅸ. Reference S1. Wang, C.; Ciganda, R.; Salmon, L.; Gregurec, D.; Irigoyen, J.; Moya, S.; Ruiz, J.; Astruc, D. Angew. Chem. Int. Ed. 2016, 55, 3091-3095. S2. Zhao, P.; Li,.; Salmon, L.; Liu,.; Ruiz, J.; Astruc, D. Chem. Commun. 2013, 49, 3218-3220. 41