Supporting Information. Table of Contents. 1) General methods S-2. 2) General method for the synthesis of solvate ionic liquids S-2

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1 Improving the catalytic performance of (S)-proline as organocatalyst in asymmetric aldol reactions in the presence of solvate ionic liquids: involvement of a supramolecular aggregate Arturo Obregón-Zúñiga, a Mario Milán, a and Eusebio Juaristi *a,b a Departamento de Química, Centro de Investigación y de Estudios Avanzados, Av. Instituto Politécnico Nacional 2508, Ciudad de México, México. b El Colegio Nacional, Luis González Obregón 23, Centro Histórico, Ciudad de México, México juaristi@relaq.mx Supporting Information Table of Contents 1) General methods S-2 2) General method for the synthesis of solvate ionic liquids S-2 3) Optimization of cyclohexanone equivalents in the model aldol reaction S-3 4) Evaluation of SIL loading in the model reaction S-3 5) Alternative conditions to confirm the crucial role of the SIL S-4 6) General method for the organocatalyzed aldol reaction S-4 7) 1 H NMR spectra of crude aldol products in the determination of diastereomeric ratios 8) HPLC chromatograms and conditions of aldol products to determine enantiomeric ratios S-5 S-12 9) Figure S1. 7 Li NMR spectra S-39 10) Figure S2. IR spectra S-40 11) Outputs and structures from calculations performed in demon2k S-43 12) Figure S3. Supramolecular cooperative aggregate S-45 13) References S-52 S-1

2 1) General methods 1 H NMR spectra were recorded on a JEOL ECA 500. CDCl 3 signal at 7.26 ppm was used as reference value for 1 H NMR spectra. High resolution mass spectra were recorded on an HPLC 1100 coupled to a MSD-TOF Agilent series HR-MSTOF model 1969 A. Chromatograms were acquired in a Dionex HPLC Ultimate 3000 with a UV/Visible detector, with diode array, at 210 and 254 nm. Reaction progress was routinely monitored by TLC on silica gel 60 (pre-coated F254 Merck plates), and compounds were visualized under a UV lamp (254 nm). Flash chromatography was performed using silica gel ( mesh). All reagents were purchased from Sigma-Aldrich. The aldol products have been already reported, and the spectroscopic data were correlated with those in the literature. 1 In particular, 1 H NMR signals of the crude aldol products and chromatograms peaks were assigned according to those reports, in order to determine diastereomeric and enantiomeric ratios. 2) General method for the synthesis of the solvate ionic liquids The four solvate ionic liquids (SILs) studied in this work were prepared according to previously reported methodologies. 2 The glyme, lithium salt (in an equimolar relation) and a stirring bar were placed in a vial or flask. The reaction container was purged with nitrogen and placed in an oil bath and stirred at 60 C overnight. SILs were obtained in quantitative yield and used without further purification. Representative example: Triglyme (1.78 g, 10 mmol), LiNTf 2 (2.87 g, 10 mmol) and a stirring bar were placed in a vial. The reaction container was purged with nitrogen and placed in an oil bath and stirred at 60 C overnight (12 h). After that, 4.65 g of a colorless viscous liquid was obtained (quantitative yield of G3NTf 2 ). The formation of the SIL was confirmed by MS-TOF, by the observation of the coordinated lithium in positive mode and the anion in negative mode. G3NTf 2, colorless viscous liquid, 4.65 g (10 mmol) (quantitative yield): MS-TOF: calculated for C 8 H 18 LiO , found , calculated for C 2 F 6 NO 4 S , found G3ClO 4, creamy solid, 2.84 g (10 mmol) (quantitative yield): MS-TOF: calculated for C 8 H 18 LiO , found , calculated for ClO , found G4NTf 2, colorless viscous liquid, 5.09 g (10 mmol) (quantitative yield): MS-TOF: calculated for C 10 H 22 LiO , found , calculated for C 2 F 6 NO 4 S , found G4ClO 4, colorless viscous liquid, 3.28 g (10 mmol) (quantitative yield): MS-TOF: calculated for C 10 H 22 LiO , found , calculated for ClO , found S-2

3 3) Optimization of cyclohexanone equivalents in the model aldol reaction essay cyclohexanone equiv yield (%) a dr (anti/syn) b er (anti) c :7 96: :6 98: :6 97: :5 97: :5 98:2 a) Determined after purification by flash chromatography. b) determined by 1 HNMR from the crude reaction. c) determined by HPLC with chiral stationary phase of the pure product. 4) Evaluation of SIL loading in the model reaction essay mol % G3Tf 2 N Yield (%) a dr (anti/syn) b er (anti) c :10 96: :6 98: :8 97:3 a) Determined after purification by flash chromatography. b) determined by 1 HNMR from the crude reaction. c) determined by HPLC with chiral stationary phase of the pure product. S-3

4 5) Alternative conditions to confirm the crucial role of the SIL dr essay cat. Yield er (%) a (anti/syn) b (anti) c 1 LiOH+(S)-Proline 80 41:59 53:47 2 d LiOH+(S)-Proline 84 56:44 53:47 3 LiNTf a) Determined after purification by flash chromatography. b) determined by 1 HNMR from the crude reaction. c) determined by HPLC with chiral stationary phase of the pure product. d) Triglyme was added in 3 mol %. 6) General method for the organocatalyzed aldol reaction In a small vial was placed 7.0 mg (15 µmol) of the SIL G3NTf 2, 1.7 mg (15 µmol) of (S)-proline, 75.5 mg (0.5 mmol) of p-nitrobenzalaldehyde, 0.21 ml (2.0 mmol) of cyclohexanone, and 9 µl (0.5 mmol) of water. The reaction was stirred at room temperature for 14 hours, until TLC showed complete consumption of the aldehyde. The crude reaction product was subjected to flash chromatography using silica gel as stationary phase and hexane/etoac 9:1 1:1 as mobile phase to afford the pure aldol product. S-4

5 7) 1 H NMR spectra of crude aldol products in the determination of diastereomeric ratios S-5

6 S-6

7 S-7

8 S-8

9 S-9

10 S-10

11 S-11

12 8) Chromatograms and HPLC conditions of aldol products to determine the enantiomeric ratios O OH NO 2 (2S,1 R)-1a Column: Chiralpak AD-H, Eluent: Hexane/IPA 90:10, Flow: 1.0 ml/min S-12

13 O OH NO 2 (2R,1 S)-1a [Prepared from (R)-proline] S-13

14 O OH NO 2 rac-1a S-14

15 O OH CN (2S,1 R)-1b Column: Chiralpak AD-H, Eluent: Hexane/IPA 90:10, Flow: 0.5 ml/min S-15

16 O OH CN rac-1b S-16

17 O OH NO 2 (2S,1 R)-1c Column: Chiralpak AD-H, Eluent: Hexane/IPA 95:5, Flow: 0.8 ml/min S-17

18 O OH NO 2 rac-1c S-18

19 O OH Cl (2S,1 R)-1d Column: Chiralpak AD-H, Eluent: Hexane/IPA 95:5, Flow: 0.5 ml/min S-19

20 O OH Cl rac-1d S-20

21 O OH Br (2S,1 R)-1e Column: Chiralpak AD-H, Eluent: Hexane/IPA 90:10, Flow: 0.5 ml/min S-21

22 O OH Br rac-1e S-22

23 O OH CF 3 (2S,1 R)-1f Column: Chiralpak AD-H, Eluent: Hexane/IPA 90:10, Flow: 0.5 ml/min S-23

24 O OH CF 3 rac-1f S-24

25 O OH OMe (2S,1 R)-1g Column: Chiralpak AD-H, Eluent: Hexane/IPA 95:5, Flow: 0.5 ml/min S-25

26 O OH OMe rac-1g S-26

27 O OH (2S,1 R)-1h Column: Chiralpak OD-H, Eluent: Hexane/IPA 95:5, Flow: 0.5 ml/min S-27

28 O OH rac-1h S-28

29 O OH (2S,1 R)-1i Column: Chiralpak OD-H, Eluent: Hexane/IPA 97:3, Flow: 1.0 ml/min S-29

30 O OH rac-1i S-30

31 O OH (2S,1 R)-1j Column: Chiralpak AD-H, Eluent: Hexane/IPA 90:10, Flow: 1.0 ml/min S-31

32 O OH rac-1j S-32

33 O OH Ph (2S,1 R)-1k Column: Chiralpak AD-H, Eluent: Hexane/IPA 90:10, Flow: 1.0 ml/min S-33

34 O OH Ph rac-1k S-34

35 O OH NO 2 (2S,1 S)-1l Column: Chiralpak AD-H, Eluent: Hexane/IPA 95:5, Flow: 0.5 ml/min S-35

36 O OH NO 2 rac-1l S-36

37 O OH NO 2 (R)-1m Column: Chiralpak AD-H, Eluent: Hexane/IPA 95:5, Flow: 0.5 ml/min S-37

38 O OH NO 2 rac-1m S-38

39 9) 7 Li NMR spectra. Fig. S1. 7 Li NMR spectra, a) pure SIL. b) SIL with (S)-proline, 1:1 ratio. c) SIL, (S)-proline and water in 1:1:1 ratio. d) SIL in the presence of (S)-proline, water and cyclohexanone in equimolar ratios. S-39

40 7 Li NMR of aldol reaction 10) IR spectra Fig. S2. Infrared spectra, a) pure (S)-proline. b) (S)-Proline with SIL in a 1:1 ratio. c) (S)- Proline in presence of SIL and water in an equimolar ration. d) After addition of 1 equivalent of concentrated HCl. S-40

41 S-41

42 S-42

43 11) Outputs of the calculations and structures performed in demon2k 3 Coordinates of the optimized structure of the catalyst (Fig. 4) NO. ATOM X Y Z Z-ATOM MASS TYPE 1 S QM 2 O QM 3 O QM 4 N QM 5 S QM 6 O QM 7 O QM 8 C QM 9 F QM 10 F QM 11 F QM 12 C QM 13 F QM 14 F QM 15 F QM 16 H QM 17 N QM 18 C QM 19 H QM 20 C QM 21 C QM 22 C QM 23 C QM 24 O QM 25 O QM S-43

44 26 LI QM 27 H QM 28 H QM 29 H QM 30 H QM 31 H QM 32 H QM 33 H QM 34 O QM 35 C QM 36 C QM 37 C QM 38 O QM 39 C QM 40 C QM 41 O QM 42 C QM 43 C QM 44 O QM 45 C QM 46 H QM 47 H QM 48 H QM 49 H QM 50 H QM 51 H QM 52 H QM 53 H QM 54 H QM S-44

45 55 H QM 56 H QM 57 H QM 58 H QM 59 H QM 60 H QM 61 H QM 62 H QM 63 H QM TOTAL ENERGY = ZPE = ) Figure S3. Supramolecular cooperative aggregate. NO. ATOM X Y Z Z-ATOM MASS TYPE 1 C QM 2 O QM 3 O QM 4 LI QM S-45

46 5 C QM 6 N QM 7 C QM 8 C QM 9 C QM 10 C QM 11 C QM 12 C QM 13 C QM 14 C QM 15 C QM 16 H QM 17 H QM 18 H QM 19 H QM 20 H QM 21 H QM 22 H QM 23 H QM 24 H QM 25 H QM 26 H QM 27 H QM 28 H QM 29 H QM 30 H QM 31 H QM 32 O QM 33 C QM S-46

47 34 C QM 35 C QM 36 O QM 37 C QM 38 C QM 39 O QM 40 C QM 41 C QM 42 O QM 43 C QM 44 H QM 45 H QM 46 H QM 47 H QM 48 H QM 49 H QM 50 H QM 51 H QM 52 H QM 53 H QM 54 H QM 55 H QM 56 H QM 57 H QM 58 H QM 59 H QM 60 H QM 61 H QM 62 H QM S-47

48 63 O QM 64 H QM 65 O QM 66 C QM 67 C QM 68 C QM 69 C QM 70 C QM 71 C QM 72 C QM 73 H QM 74 H QM 75 H QM 76 H QM 77 H QM 78 H QM TOTAL ENERGY = ZPE = S-48

49 Coordinates of the intermediate iminium before the hydrolysis of the proline. The water molecule is shown still bonded via a hydrogen bond to the carboxylate group and the alcoxy group of the aldol NO. ATOM X Y Z Z-ATOM MASS TYPE 1 C QM 2 O QM 3 O QM 4 LI QM 5 C QM 6 C QM 7 C QM 8 C QM 9 N QM 10 C QM 11 C QM 12 C QM S-49

50 13 C QM 14 C QM 15 C QM 16 H QM 17 H QM 18 H QM 19 H QM 20 H QM 21 H QM 22 H QM 23 H QM 24 H QM 25 H QM 26 H QM 27 H QM 28 H QM 29 H QM 30 H QM 31 H QM 32 C QM 33 O QM 34 C QM 35 C QM 36 C QM 37 C QM 38 C QM 39 C QM 40 H QM 41 H QM S-50

51 42 H QM 43 H QM 44 H QM 45 H QM 46 O QM 47 C QM 48 C QM 49 C QM 50 O QM 51 C QM 52 C QM 53 O QM 54 C QM 55 C QM 56 O QM 57 C QM 58 H QM 59 H QM 60 H QM 61 H QM 62 H QM 63 H QM 64 H QM 65 H QM 66 H QM 67 H QM 68 H QM 69 H QM 70 H QM S-51

52 71 H QM 72 H QM 73 H QM 74 H QM 75 H QM 76 H QM 77 O QM 78 H QM TOTAL ENERGY = ZPE = ) References (1) (a) Hernández, J.G.; Juaristi, E. Tetrahedron. 2011, 67, J.G. (b) Hernández, J.G.; Juaristi, E. J. Org. Chem. 2011, 76, (2) (a) Eyckens, D.J.; Champion, M.E.; Fox, B.L.; Yoganantharajah, P.; Gibert, Y.; Welton, T.; Henderson, L.C. Eur. J. Org. Chem. 2016, 913. (b) Ueno, K.; Yoshida, K.; Tsuchiya, M.; Tachikawa, N.; Dokko, K.; Watanabe, M. J. Phys. Chem. B. 2012, 116, (c) Yoshida, K.; Tsuchiya, M.; Tachikawa, N.; Dokko, K.; Watanabe, M. J. Phys. Chem. C. 2011, 115, (3) Koster, A.M.; Geudtner, G.; Calaminici, P.; Casida, M.E.; Dominguez, V.D.; Flores-Moreno, R.; Gamboa, G.U.; Goursot, A.; Heine, T.; Ipatov, A.; Janetzko, F.; del Campo, J.M.; Reveles, J. U.; Vela, A.; Zuniga-Gutierrez, B.; Salahub, D.R. demon2k (Version 3), The demon developers, Cinvestav, Mexico City, S-52