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1 Dual-Cavity Baskets Promote Encapsulation in Water in an Allosteric Fashion Shigui Chen, Makoto Yamasaki, Shane Polen, Judith Gallucci, Christopher M. Hadad and Jovica D. Badjić* Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, OH SUPPORTING INFORMATION

2 Content General Methods...S2 Volume Determination...S2 Synthetic Procedures...S4 1 H NMR spectra of basket 1 at variable concentrations...s7 1 H NMR spectra of basket 1 with guest 4...S7 ITC data of basket 1 with guest 4...S8 1 H NMR spectra of basket 1 with guest 6...S8 ITC data of basket 1 with guest 6...S9 UV-Vis spectra...s9 1 H NMR spectra of guest 6 with basket 1...S10 Crystallographic Data... S11 Electronic Structure Methods...S13-S126 References... S126 S1

3 General methods: All solvents were dried before use following standard procedures. Unless indicated otherwise, all starting materials were obtained from commercial suppliers and used without additional purification. Analytical thin-layer chromatography (TLC) was performed on silica-gel plates w/uv H NMR and 13 C NMR spectra were recorded on 400, 500 or 600 MHz spectrophotometers. Chemical shifts are expressed in parts per million (δ, ppm) using residual solvent protons as internal standard ( 1 H NMR δ (ppm) for CDCl 3 = 7.24, DMSO-d 6 = 2.50 and D 2 O = 4.79; 13 C NMR δ (ppm) for CDCl 3 = and DMSO-d 6 = 39.52). Isothermal Titration Calorimetry (ITC) data was recorded with Nano ITC (TA instruments). UV-vis spectra were measured using Shimadzu UV-2401PC spectrophotometer. The reported binding constants were, from 1 H NMR titration data (Figures 2 and 4), obtained by nonlinear least-square fitting procedures using theoretical models described in (a) Schneider, H. J.; Duerr, H.; Editors Frontiers in Supramolecular Organic Chemistry and Photochemistry, 1991 (1:1 complexation, Figure 2) and (b) Thordarson, P. Chem. Soc. Rev. 2011, 40, (1:2 complexation, Figure 4). The method of continuous variation (the Job plot, Figures 2 and 4) was implemented following a theoretical model described in Hirose, K. Anal. Methods Supramol. Chem. 2007, Volume determination of basket 1: As suggested in the original study (3V: cavity, channel and cleft volume calculator and extractor' Nucleic Acids Res. 2010; 38, W555 W562 by Neil R. Voss and Mark Gerstein), we used the following website to compute the volume of two "channels" within dual-cavity 1. See our earlier report (Yian Ruan, Wang Bao-Yu, Erb M. Jeremy, Shigui Chen, Hadad M. Christopher and Badjić D. Jovica, On the Role of Guests in Enforcing the Mechanism of Action of Gated Baskets, Organic & Biomolecular Chemistry 2013, 11, 77667), describing the choice for the radii of the small and large rolling probes. Additional details are given below. S2

4 S3

5 Synthetic Procedures: Scheme S1 depicts the procedure for obtaining dual-cavity basket 1. Note that compound 7 was prepared following a methodology that was already optimized and reported earlier (see J. Org. Chem. 2013, 78, 2984) by our research group. Compound 2: Compound 7 (88.2 mg, mmol) was suspended in anhydrous toluene (4.0 ml). (S)-alanine benzyl ester (75.8 mg, mmol; as a hydrochloride salt) was added to this suspension, which was then stirred for 10 min. Upon the addition of 0.4 ml of pyridine, the reaction mixture was refluxed for 12 h. The solvents were removed under reduced pressure and the residual crude product purified by silica chromatography (CH 2 Cl 2 /CH 3 OH = 20:1) to give 74.8 mg (52 %) of compound 2 as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 7.83 (s, 4H), (m, 10H), 5.56 (s, 2H), 5.16 (dd, J=27.6, 12.4, 4H), 4.97 (q, J=7.3, 2H), 1.68 (d, J=7.4, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ (ppm) = , , , , , , , , 128,21, , 67.66, 61.35, 48.01, HR-MS (ESI): calculated (M+Na) + = , found Compound 8: Compound 2 (31.6 mg, mmol) was dissolved in anhydrous dioxane under an atmosphere of argon, followed by the addition of: Pd(OAc) 2 (0.9 mg), PPh 3 (2.0 mg), n-bu 4 NBr (25 mg), K 2 CO 3 (53 mg) and 4 Å molecular sieves (25 mg). The solution was brought to reflux and stirred for 48 h. The reaction mixture was quenched with a dilute aqueous solution of HCl (5 ml, 5%) and then extracted with ethyl acetate (3 10 ml). The organic layer was dried over sodium sulfate followed by the removal of organic solvent in vacuum. The crude product was washed with methanol (10 ml), to remove the excess of PPh 3, and then purified with preparative TLC (CH 2 Cl 2 /CH 3 OH = 100:1) to yield 7.8 mg (31 %) of dual-cavity 8 as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ (ppm) = 7.89 (s, 12H), (m, 30H), (m, 6H), (m, 12H), (m, 6H), 1.63 (d, J=7.3, 18H). 13 C NMR (100 MHz, CDCl 3 ): δ (ppm) = , , , , , , , , , , 67.68, 50.61, 48.03, HRMS (ESI): calculated (M+Na) + = , found Compound 9: Compound 8 (4.0 mg, mmol) was suspended in CH 3 OH (2.0 ml), and solid Pd/C catalyst (0.4 mg) was added. The suspension was stirred for 9 h under an atmosphere of hydrogen at elevated 50-psi pressure. The crude mixture was filtered with celite to remove solid Pd/C. Upon the removal of methanol in vacuum, we obtained 2.3 mg (83 %) of dual-cavity basket 9 as a white solid. 1 H NMR (400 MHz, CD 3 OD): δ (ppm) = (m, 12H), (m, 6H), (m, 6H), (m, 18H). 13 C NMR (150 MHz, CD 3 OD): δ (ppm) = , , , , , , 57.49, 51.16, HRMS (ESI): calculated (M-3H) 3- = , found Basket 1: To prepare a standard D 2 O solution of hexaanionic basket 1 (1.0 mm), compound 9 (3.7 mg) was suspended in D 2 O (2.4 ml) followed by the addition of 100 mm solution of NaOH (0.15 ml, mmol). S4

6 Figure S1. 1 H NMR spectrum (400 MHz, CDCl 3 ) of dual-cavity 8 at 298 K. Figure S2. 1 H NMR spectrum (400 MHz, CD 3 OD) of dual-cavity 9 at 298 K; we reason that a poor solubility (and aggregation) of hexacid 9 in CD 3 OD contributed to the broadening of the signals. S5

7 Scheme S1 Synthesis of baskets R = CO 2 CH 3 R R R R R R O O O O Pd(OAc) 2, PPh 3, n-bu Br O 4 NBr, K 2 CO 3 Br O Molecular sieves, dioxane reflux, 48 h, 77% O O see J. Org. Chem. 2013, 78, 2984 R R R R R R 1) LiOH, THF/H 2 O see J. Org. Chem. 2013, 78, ) TFAA, THF 3 86% O O O Br Br O O O see J. Org. Chem. 2013, 78, BnOOC NH 2 HCl Toluene/Py, reflux, 12 h 72% BnOOC O N O Br 2 Br O O N COOBn Pd(OAc) 2, PPh 3, n-bu 4 NBr, K 2 CO 3 Molecular sieves, dioxane reflux, 48 h, 31% BnOOC O N O O N COOBn O O N COOBn O HOOC O N O O N COOH O O N COOH O NaOOC O N O O N COONa O O N COONa O H 2 (50 Psi), Pd/C aq. NaOH MeOH, r.t. 9 h, 83% BnOOC O N O O N O N O O COOBn COOBn 8 HOOC O N O O N O N O COOHO COOH 9 NaOOC O N O O N O N O O COONa COONa 1 Guests 4 and 6: For the preparation of guests 4 and 6, we used methods described in Scheme S2 (see Chem. Heterocycl. Compd. 1987, 23, 675 and Czech. Chem. Commun. 1981, 46, 584). 1 H NMR spectra of 4, 6 are in agreement with those previously reported in the literature (see Chem. Heterocycl. Compd. 1987, 23, 675 and Czech. Chem. Commun. 1981, 46, 584). For compound 4: 1 H NMR (600 MHz, CDCl 3 ) δ (ppm) = 9.68 (d, J=5.9, 2H), (m, 1H), 8.29 (t, J=7.1, 2H), 2.45 (s, 9H), 1.88 (d, J=12.3, 3H), 1.82 (d, J=12.3, 3H). For compound 6: 1 H NMR (600 MHz, CDCl 3 ) δ (ppm) = (m, 2H), (m, 1H), (m, 2H), (m, 2H), 7.62 (s, 3H). S6

8 Figure S3. Sections of 1 H NMR spectra (600 MHz, K) of basket 1 at different concentrations ( mm) in D 2 O. Figure S4. 1 H NMR spectra (600 MHz, K) of a solution of basket 1 (0.61 mm in D 2 O) obtained upon an incremental addition of compound 4 ( molar eq., 60.0 mm) in D 2 O. S7

Figure S5. The experimental (top) and integrated (bottom) ITC data corresponding to the titration of a standard H 2 O solution of 4 (2.0 µl per injection of its 40.

The nonlinear least-square analysis (bottom) of the binding data was completed with the assistance of single site-binding model (with the stoichiometric coefficient n fixed to

9 Figure S5. The experimental (top) and integrated (bottom) ITC data corresponding to the titration of a standard H 2 O solution of 4 (2.0 µl per injection of its 40.0 mm solution) to basket 1 (0.2 mm) in µl of H 2 O (in the instrument's cell) at K. The nonlinear least-square analysis (bottom) of the binding data was completed with the assistance of single site-binding model (with the stoichiometric coefficient n fixed to 1) to give K a = 1.45 ± M -1 and ΔHº = ± 0.20 kcal/mol (R 2 = 0.95). Figure S6. 1 H NMR spectra (600 MHz, K) of a solution of basket 1 (0.5 mm in D 2 O) obtained upon an incremental addition of compound 6 ( molar eq., 31.0 mm) in D 2 O. S8

Figure S7. The experimental (top) and integrated (bottom) ITC data corresponding to the titration of a standard H 2 O solution of 6 (2.0 µl per injection of its 6.

20 Basket 1 (2 µm) Basket 1 (2 µm) + G uest 6 (30 µm) 0.15 Abs 0.10 0.05 0.00 200 225 250 275 300 325 350 Wavelength (nm) Figure S8. UV-vis spectra of basket 1 (2.

10 Figure S7. The experimental (top) and integrated (bottom) ITC data corresponding to the titration of a standard H 2 O solution of 6 (2.0 µl per injection of its 6.0 mm solution) to basket 1 (0.2 mm) in µl of H 2 O (in the instrument's cell) at K, giving scattered data points due to a small heat of complexation Basket 1 (2 µm) Basket 1 (2 µm) + G uest 6 (30 µm) 0.15 Abs Wavelength (nm) Figure S8. UV-vis spectra of basket 1 (2.0 µm, black) and the mixture of basket 1 (2.0 µm) and guest 6 (30.0 µm) in water at 298 K; note that a solution of guest 6 (30.0 µm) was placed in the reference cell. S9

11 Figure S9. 1 H NMR spectra (600 MHz, K) of a solution of guest 6 (0.25 mm in D 2 O) obtained upon an incremental addition of dual-cavity basket 1 ( molar eq., 4.0 mm) in D 2 O. S10

12 Crystallographic details for dual-cavity basket 3 Formula C72 H54 O24, 6.45 (CH3OH) Formula weight Temperature 150(2) K Wavelength Å Crystal system Orthorhombic Space group P Unit cell dimensions a = (4) Å b = (4) Å c = (7) Å Volume (5) Å 3 Z 8 Density (calculated) Mg/m 3 Absorption coefficient mm -1 F(000) 6353 Crystal size 0.15 x 0.27 x 0.27 mm 3 Theta range for data collection to Index ranges -20<=h<=20, -21<=k<=21, -43<=l<=43 Reflections collected Independent reflections [R(int) = 0.073] Completeness to theta = % Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters / 180 / 1005 Goodness-of-fit on F Final R indices [I>2sigma(I)] R1 = , wr2 = R indices (all data) R1 = , wr2 = Largest diff. peak and hole and e/å 3 S11

13 (A) (B) (C) Figure S10. All plots are drawn with 30% probability ellipsoids, with hydrogen atoms and methanol molecules omitted. The plots show: (A) molecule B (B) molecule A and (C) the asymmetric unit containing both molecules A and B. S12

14 Electronic Structure Calculations All electronic structure calculations were performed using Gaussian Ground-state geometry optimizations of 5 were carried out using the B3LYP exchange correlation functional and the 6-31G* basis set. 2 4 The modredundant keyword in Gaussian 09 was used to freeze the dihedral angle of interest in 2 increments while all other atoms were optimized using the parameters described above. The results are listed below in Table S1. The M06-2X exchange correlation functional and the 6-31G* basis set were used to study the intermolecular interactions between guests 4/6 and dual-cavity basket 5. 5 Solvent effects were modeled using the polarizable continuum model (PCM), with water as solvent. 6 Co-conformations of [5 4], 5 6] and [5 6 2 ] (i.e. guest is positioned differently inside the host) were generated manually in order to sample conformational space and all structures were optimized using described parameters. The relative energies of [5 4], [5 4 2 ], [5 6] and [5 6 2 ] complexes are summarized in Table S2. Average Average Relative Energy Fixed Free (kcal/mol) Torsion Torsion Table S1: Results of the dihedral angle study of dual-cavity 5. S13

15 [5 4] [5 4 2 ] [5 6] [5 6 2 ] Relative Relative Relative Relative Conf # Energy (Kcal/mol) Conf # Energy (Kcal/mol) Conf # Energy (Kcal/mol) Conf # Energy (Kcal/mol) Table S2: Relative energies of [5 4], [5 4 2 ], [5 6] and [5 6 2 ] complexes, each having the guest molecule positioned differently inside the host. Binding Energies in Kcal/mol Complex ΔE ΔH ΔG [5 4] [5 4 2 ] [5 6] Table S3: Binding energies of [5 4], [5 4 2 ], and [5 6] complexes, each having the guest molecule positioned differently inside the host. S14

16 9.4 A 9.1 A [5 4 2 ] Figure S11. A stick representation of energy-minimized [5 4 2 ] (DFT, M06-2X/6-31G*) in water showing two guests forming C H---π contacts with the host's one cavities to alter their size. S15

17 Dihedral Angle Study Coordinates: DC-0 C C C C C C C C C C C C C C C C C C H H H H H H H H H C C C C C C C C C C H C C H S16

18 H H C C H C C C C H H H H C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C S17

19 C O N O C C C C O N O C H H H C H H H C H H H C H H H C H H H C H H H DC-2 C C C C C C C S18

20 C C C C C C C C C C C H H H H H H H H H C C C C C C C C C C H C C H H H C C H C C C C H S19

21 H H H C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N S20

22 O C H H H C H H H C H H H C H H H C H H H C H H H DC+2 C C C C C C C C C C C C C C C C C S21

23 C H H H H H H H H H C C C C C C C C C C H C C H H H C C H C C C C H H H H C C C C O N O S22

24 C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C H H H C H H H C S23

25 H H H C H H H C H H H C H H H DC-4 C C C C C C C C C C C C C C C C C C H H H H H H H H H S24

26 C C C C C C C C C C H C C H H H C C H C C C C H H H H C C C C O N O C C C C O N O C C C S25

27 C O N O C C C C O N O C C C C O N O C C C C O N O C H H H C H H H C H H H C H H H C H H S26

28 H C H H H DC+4 C C C C C C C C C C C C C C C C C C H H H H H H H H H C C C C C C C C C C S27

29 H C C H H H C C H C C C C H H H H C C C C O N O C C C C O N O C C C C O N O C C C C O N S28

30 O C C C C O N O C C C C O N O C H H H C H H H C H H H C H H H C H H H C H H H DC-6 C C C S29

31 C C C C C C C C C C C C C C C H H H H H H H H H C C C C C C C C C C H C C H H H C C H C S30

32 C C C H H H H C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C S31

33 C C O N O C H H H C H H H C H H H C H H H C H H H C H H H DC+6 C C C C C C C C C C C C C S32

34 C C C C C H H H H H H H H H C C C C C C C C C C H C C H H H C C H C C C C H H H H C C C S33

35 C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C H H H C S34

36 H H H C H H H C H H H C H H H C H H H DC-8 C C C C C C C C C C C C C C C C C C H H H H H S35

37 H H H H C C C C C C C C C C H C C H H H C C H C C C C H H H H C C C C O N O C C C C O N S36

38 O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C H H H C H H H C H H H C H H S37

39 H C H H H C H H H DC+8 C C C C C C C C C C C C C C C C C C H H H H H H H H H C C C C C C S38

40 C C C C H C C H H H C C H C C C C H H H H C C C C O N O C C C C O N O C C C C O N O C C S39

41 C C O N O C C C C O N O C C C C O N O C H H H C H H H C H H H C H H H C H H H C H H H S40

42 DC-10 C C C C C C C C C C C C C C C C C C H H H H H H H H H C C C C C C C C C C H C C H H H S41

43 C C H C C C C H H H H C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O S42

44 N O C C C C O N O C H H H C H H H C H H H C H H H C H H H C H H H DC+10 C C C C C C C C C S43

45 C C C C C C C C C H H H H H H H H H C C C C C C C C C C H C C H H H C C H C C C C H H H S44

46 H C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C S45

47 H H H C H H H C H H H C H H H C H H H C H H H Host:Guest Coordinates: DC-1adam-1 C C C C C C C C C C C C C C C S46

48 C C C H H H H H H H H H C C C C C C C C C C H C C H H H C C H C C C C H H H H C C C C O S47

49 N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C C C C O N O C H C H C H C S48

50 H C H C H H H H H H H H H H H H H C H H C H C C H H C H H C H C H H C H H C H H C H N C S49

51 C C H C H C H H H DC-1adam-2 C C C C C C C C C C C C C C C C C C H H H H H H H H H C C C C C C S50

52 C C C C H C C H H H C C H C C C C H H H H C C C C O N O C C C C O N O C C C C O N O C C S51

Supplementary Figure S1. 19 F NMR spectra of the reaction of 5e with XeF 2 in toluene-d 8.

Supplementary Figure S1. 19 F NMR spectra of the reaction of 5e with XeF 2 in toluene-d 8. Supplementary Figure S2. 31 P NMR spectra of 5e and the reaction of 5e with XeF 2 in toluene-d 8. Supplementary