Lab Documentation. General methods

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1 Lab Documentation Just Click It: Undergraduate Procedures for the Copper (I) Catalyzed Formation of 1,2,3-Triazoles from Azides and Terminal Acetylenes General methods Commercial reagents were obtained from Aldrich, Acros, Frinton, and GFS chemicals and were used without further purification. Deuterated solvents were purchased from Cambridge Isotope Laboratories, Inc. Analytical TLC was performed on commercial Merck Plates coated with silica gel GF254 (0.24 mm thick). MR ( 1 H) spectra were recorded either on a Bruker AMX-400, AMX-500 or AMX-600 MHz spectrometer. Coupling constants (J) are reported in hertz, and chemical shifts are reported in parts per million (δ) relative to CHCl 3 (7.26 ppm) or DMS (2.50 ppm) as internal reference. Chemicals required and Hazards Benzyl azide (CAS o ; toxic if swallowed. Risk of explosion by shock, friction or fire above 100 C) Phenyl propargyl ether (CAS o ) DL-2-Phenyl-3-butyn-2-ol (CAS o ; harmful if swallowed) 1,3-Diethynylbenzene (CAS o ) -(Propargyloxy)phthalimide (CAS o ) Phenyl acetylene (CAS o ; harmful if swallowed, inhaled, or absorbed through skin. Vapor or mist is irritating to the eyes, mucous membranes and upper respiratory tract) Sodium azide (CAS o ; very toxic if swallowed, contacts with acids liberating hydrazoic acid, a highly toxic and explosive gas) 1

2 2-Bromoacetophenone (CAS o ; irritating to eyes, respiratory system and skin) 4-Hydroxyacetophenone (CAS o ; irritating) 4-itrophenol (CAS o ; toxic and irritant, possible mutagen, readily absorbed through skin) Propargyl bromide (CAS o ; highly flammable, toxic if swallowed, causes burns) Potassium carbonate, anhydrous (CAS o ) Cupric sulfate pentahydrate (CAS o ; harmful if swallowed, dust or mist are mucous membrane irritants and a skin sensitizer) Sodium ascorbate (CAS o ) Sodium sulfate, anhydrous (CAS o ) General procedure A: triazole formation from benzyl azide 133 mg (1 mmol) of benzyl azide and 1 mmol of acetylene were stirred in 2-3 ml of t BuH/water (1:1) solution in a 20 ml-screw-top scintillation vial mg (10 mol%) sodium ascorbate and 50 µl (5 mol%) of 1M aq. copper (II) sulfate pentahydrate were added sequentially and the mixture was stirred at 60 o C for 1-2 hrs until completion, monitored by TLC (hexane/ethyl acetate 2/1). Reaction mixture was diluted with 10 ml ice water, followed by the addition of 2 ml of 10 % aqueous ammonia. After stirring for another 5 min, the solid precipitate was collected with a Buchner filter and air-dried overnight. General procedure B: one-pot triazole formation 2-Bromoacetophenone 399 mg (2 mmol), acetylene (2 mmol) and sodium azide mg (2.1 mmol) were mixed with 6 ml of t BuH/water (1:1) solution in a 20 mlscrew-top scintillation vial mg (10 mol%) sodium ascorbate and 100 µl (5 mol%) 1M aq. copper (II) sulfate pentahydrate were added sequentially and the reaction mixture was stirred at 60 o C for 2-3 hrs, until completion, monitored by TLC. The reaction 2

3 mixture was then poured into ml ice water, followed by the addition of 5 ml of 10% aqueous ammonia. After stirring for another 5 min, the solid precipitate was collected with a Buchner filter and air-dried overnight. General procedure C: phenol propargylation As a representative example: To a 100 ml-erlenmeyer flask was added 4- hydroxyacetophenone 2.72g (20 mmol) followed by 15 ml DMF. The mixture was stirred at room temperature for 1 min followed by the addition of propargyl bromide (80% weight solution in toluene) 3 ml (27.8 mmol) and potassium carbonate 3.84g (27.8 mmol). The resulting mixture was stirred at room temperature for 5 hrs (or overnight) until TLC analysis indicated the completion of the reaction (R f of the product: 0.4, R f of the starting material: 0.1; eluent: ethyl acetate/hexane = 1:3). The reaction mixture was diluted with 20 ml of water and extracted with 100 ml of ether. The organic phase was washed 5 times with 15 ml of brine, then dried over anhydrous sodium sulfate. Evaporating the solvent gave the corresponding propargyl ether. Yield: 2.85 g (82%). 1 H MR (CDCl 3, 400MHz): δ =2.56 (br, CH3C, 3H and C CH, 1H), 4.75 (d, J = 1.1 Hz, CH 2 C CH, 2H), 7.01 (d, J= 8.5 Hz, Ar-H, 2H), 7.94 (d, J=8.5 Hz, Ar-H, 2H). Further information on one-pot reaction procedure at 60 C The one pot reaction using para-nitro phenyl propargyl ether is slower than other one pot reactions. In case the reaction does not finish within 3hrs, the trace amounts of starting acetylene can be removed easily by recrystallizing the crude reaction product in ether. Further information on reaction procedure at room temperature All reactions outlined for procedures 1 and 2 can be carried out at room temperature. The reactions usually finish overnight. As a representative example: 133 mg of benzyl azide (1 mmol) and 146 mg of DL-2-Phenyl-3-butyn-2-ol (1 mmol) were 3

4 mixed with 3 ml of t BuH/water (1:1) solution in a 20 ml-screw-top scintillation vial. 19 mg sodium ascorbate (10 mol%) and 50 µl 1M aq. copper (II) sulfate solution (5 mol%) were added sequentially and the reaction mixture was stirred at room temperature overnight. Reaction mixture diluted with 10 ml ice water, followed by the addition of 2 ml of 10% aqueous ammonia. After stirring for another 5 min, the solid precipitate was collected with a Buchner filter and air-dried (or dried under high vacuum). Yield: 259 mg (93%). The one-pot triazole formation can be easily extended to other systems, several examples are shown in Scheme % isolated yield Mp o C 2 2 S H 81% isolated yield Mp 190 o C (dec.) 2 S H S Br + a % isolated yield Mp o C S 89 % isolated yield Mp o C Scheme 6. ne-pot triazole formation from ethyl bromoacetate at room temperature 4

5 MR Specra of the triazole products (1) H (1) The peak at 3.3 ppm in all triazole products 1 H MR spectra is water; the peak at 2.5 ppm is the solvent residue of DMS. 5

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13 Instructor otes: The experiment is suitable for undergraduate-level organic chemistry laboratory courses (second or third year students). It illustrates several important topics in organic chemistry, including heterocyclic chemistry, cycloaddition, etc. Moreover, it is very easy to carry out, can be performed by a relatively large group of students (ca. 50), and offers students unprecedented opportunities to develop building blocks of their own. The examples given are meant to demonstrate the basic concepts of click chemistry, not meant to delineate a specific procedure that future students must follow. The experiment presents a number of important chemistry topics to students: - rganic chemistry in water - Metal-catalyzed reactions - Heterocyclic chemistry - Concepts of click chemistry - Interpretation of 1 H MR spectra - Investigation of several organic functionalities - ne-pot processes For recent applications of copper(i)-catalyzed 1,3-dipolar cycloaddtion of azide and acetylene in materials science and chemical biology, see: (a) Wu, P.; Feldman, A. K.; ugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, L.; Fréchet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem. Int. Ed. 2004, 43, 3863; (b) Collman, J. P.; Deveraj,. K.; Chidsey, C. E. D. Langmuir 2004, 20, 1051; (c) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125, 3192; (d) Anderson, J. C.; Schultz, P. G. J. Am. Chem. Soc. 2003, 125, 11782; (e) Link, A. J.; Tirell, D. A. J. Am. Chem. Soc. 2003, 125, 11164; (f) Speers, A. E., Adam, G. C.; Cravatt, B. F. J. Am. Chem. Soc. 2003, 125, For one-pot catalysis, see: Ajamian, A; Gleason, J. L.; Angew. Chem. Int. Ed. 2004, 43,