Organic Letters. Synthesis of Oxygen-Free [2]Rotaxanes: Recognition of Diarylguanidinium Ions by Tetraazacyclophanes. and Sheng-Hsien Chiu*

Transcription

1 Organic Letters Synthesis of Oxygen-Free [2]Rotaxanes: Recognition of Diarylguanidinium Ions by Tetraazacyclophanes Yu-Hsuan Chang, Yong-Jay Lee, Chien-Chen Lai, Yi-Hung Liu, Shie-Ming Peng, and Sheng-Hsien Chiu* Supplementary Material Data Page Number Experimental procedures and characterization data for new compounds... S2 S10 1 H and 13 C NMR spectra of the cyclophane 1, 5, 10 and S11 S18 1 H and 13 C NMR spectra of the dibromide 6 and S19 S22 1 H and 13 C NMR spectra of the salt 9-, 16 and 22 TFPB... S23 S28 1 H and 13 C NMR spectra of the compound S1-S5... S29 S38 1 H and 13 C NMR spectra of the [2]rotaxane (18-21) TFPB... S39 S46 1 H and 13 C NMR spectra of the [2]rotaxane 23 TFPB and 24 TFPB... S47 S50 ITC titration isotherms and thermodynamic data for the complexation of 9 TFPB with the cyclophanes in CHCl 3... S51 S56 Dilution isotherm for the cyclophanes and 9 TFPB in CDCl3... S57 S58 Competition experiment of the cyclophane 1 and 5 with 9 TFPB in CDCl 3... S59 Competition experiment of the cyclophane 10 and 13 with 9 TFPB in CDCl 3... S60 1 H NMR spectra for assembly of [2]rotaxanes from 16 TFPB, cyclophane 1, and aldehyde S61 NOESY spectra for the equimolar mixtures of 9 TFPB and the cyclophanes (20 mm)... S62 S65 ESI-MS spectra of the [2]rotaxane TFPB and TFPB... S66 S71 S1

2 General All glassware, stirrer bars, syringes, and needles were either oven- or heat gun-dried prior to use. All reagents were obtained from commercial sources unless otherwise indicated. Reactions were conducted under Ar or N 2 atmospheres. Thin layer chromatography (TLC) was performed on Merck 0.25 mm silica gel (Merck Art. 5715). Column chromatography was performed using Kieselgel 60 (Merck, mesh) and Chromatorex NH series / DIOL series (Fuji Silysia, MB100-40/75). Melting points were determined by Fargo MP-2D melting point apparatus. For NMR spectroscopy, the deuterated solvent was used as the lock, and the solvent s residual protons were employed as the internal standard. Cyclophane 1: A CHCl 3 solution mixture (149 ml) of 1,3-phenylenedimethanamine (3) (406 mg, 395 μl, 2.98 mmol) and isophthalaldehyde (2) (400 mg, 2.98 mmol) was stirred at 50 C for 48 h and slowly added to a MeOH solution (298 ml) of NaBH 4 (4.51 g, 119 mmol). The organic solvents were evaporated under reduced pressure and the residue was partitioned between H 2 O (150 ml) and CH 2 Cl 2 (2 150 ml). The combined organic phases were dried (MgSO 4 ), concentrated and purified chromatographically (NH-silica gel; CH 2 Cl 2 /hexanes, 1:1) to afford cyclophane 1 as a white solid (432 mg, 61%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 3.78 (s, 16H), 7.19 (d, J = 8.0 Hz, 8H), (m, 10H); 13 C NMR (100 MHz, CDCl 3 ): δ = 53.6, 127.1, 127.8, 128.4, 140.3; HR-MS (ESI): calcd for [1 + Na] + C 32 H 36 N 4 Na + : m/z ; found Dibromide 6: NaH (60%; 1.45 g, 36.3 mmol) was added to a THF solution (72.4 ml) of 1,3-benzenedimethanol (8) (1 g, 7.24 mmol) and the solution mixture was stirred at room temperature for 30 min. The solution mixture was then added 1,3-bis(bromomethyl)benzene (7.64 g, 28.9 mmol) and heated to reflux for 16 h. After cooled to room temperature, the solution mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically (SiO 2 ; EtOAc/hexanes, 1:9) to afford dibromide 6 as a light brown oil (1.47 g, 40%).; 1 H NMR (400 MHz, CDCl 3 ): δ = 4.48 (s, 4H), 4.54 (s, 4H), 4.56 (s, 4H), (m, 8H), (m, 4H); 13 C NMR (100 MHz, CDCl 3 ): δ = 33.4, 71.8, 72.3, 127.2, 127.8, 128.3, 128.3, 128.6, 128.9, 138.0, 138.3, (one signal is missing, possibly because of signal overlap); HR-MS (ESI): calcd for [6 + Na] + C 24 H 24 Br 2 O 2 Na + : m/z ; found Cyclophane 5: A THF solution mixture (32.4 ml) of the dibromide 6 (816 mg, 1.62 mmol) and 1,3-benzenedimethanol (8) (224 mg, 1.62 mmol) was added to a S2

3 suspension of THF solution suspension (129.4 ml) of NaH (60%; 324 mg, 8.10 mmol) and the solution mixture was heated to reflux for 7 days. After cooled to room temperature, the solution mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically (SiO 2 ; EtOAc/hexanes, 1:9) to afford cyclophane 5 as a white solid (362 mg, 47%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 4.52 (s, 16H), (m, 16H); 13 C NMR (100 MHz, CDCl 3 ): δ = 72.1, 127.2, 127.4, 128.4, 138.4; HR-MS (ESI): calcd for [5 + Na] + C 32 H 32 NaO + 4 : m/z ; found Guanidinium Salt 9 TFPB: HCl (aq) (3N, 297 μl) was added to a CH 3 CN solution (17.8 ml) of 1,3-di-p-tolylguanidine [a] (213 mg, mmol) and the solution mixture was stirred at room temperature for 10 min before the addition of NaTFPB (789 mg, mmol). The solution mixture was stirred at room temperature for 10 min and the organic solvent was removed under reduced pressure. The residue was partitioned between DI water (30 ml) and CH 2 Cl 2 (2 30 ml) and the combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified chromatographically (SiO 2 gel; CH 2 Cl 2 ) and the product was precipitated from hexanes to afford guanidinium salt 9 TFPB as a pale yellow solid (879 mg, 89%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 2.33 (s, 6H), 5.44 (br, 2H), 7.02 (d, J = 7.8 Hz, 4H), 7.16 (br, 2H), 7.23 (d, J = 7.8 Hz, 4H), 7.49 (s, 4H), 7.68 (s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ =20.9, (m), (q, 1 J CF = 271 Hz), 126.3, 127.7, (m), 131.8, 134.8, 141.7, 155.1, (q, 1 J CB = 49 Hz); HR-MS (ESI): calcd for [9] + C 15 H 18 N + 3 : m/z ; found Cyclophane 10: A CH 2 Cl 2 solution mixture (242 ml) of 1,4-phenylenedimethanamine (11) (330 mg, 2.42 mmol) and isophthalaldehyde (2) (325 mg, 2.42 mmol) was stirred at 50 C for 4 d and cooled to 0 o C before the addition of a solution mixture of MeOH/THF/toluene (200 ml/30 ml/30 ml) and NaBH 4 (3.70 g, 97.8 mmol). The solution mixture was stirred at 0 o C for 1 h and the organic solvents were removed under reduced pressure. The residue was partitioned between H 2 O (250 ml) and CH 2 Cl 2 (2 250 ml) and the combined organic layers were dried (MgSO 4 ), concentrated, and purified chromatographically (NH-silica gel; CH 2 Cl 2 /hexanes, 1:1) to afford syslophane 10 as a white solid (301 mg, 52%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 3.77 (s, 8H), 3.80 (s, 8H), (m, 4H), (m, 2H), 7.32 (s, 8H), 7.44 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ = 52.3, 52.5, 126.9, 127.4, 128.3, 128.4, 139.0, 140.5; HR-MS (ESI): calcd for [10 + Na] + C 32 H 36 N 4 Na + : m/z ; found S3

4 Dibromide 15: NaH (60%; 1.45 g, 36.3 mmol) was added to a THF solution (72.4 ml) of 1,3-benzenedimethanol (8) (1 g, 7.24 mmol) and the solution mixture was stirred at room temperature for 30 min. The solution mixture was then added 1,4-bis(bromomethyl)benzene (7.64 g, 28.9 mmol) and heated to reflux for 16 h. After cooled to room temperature, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified chromatographically (SiO 2 ; EtOAc/hexanes, 1:15) to afford dibromide 15 as a light brown oil (1.75 g, 48%).; 1 H NMR (400 MHz, CDCl 3 ): δ = 4.48 (s, 4H), 4.53 (s, 4H), 4.55 (s, 4H), (m, 2H), (m, 5H), (m, 5H); 13 C NMR (100 MHz, CDCl 3 ): δ = 33.3, 71.7, 72.2, 127.0, 127.1, 128.1, 128.5, 129.1, 137.1, 138.4, 138.6; HR-MS (ESI): calcd for [15 + Na] + C 24 H 24 Br 2 NaO + 2 : m/z ; found Cyclophane 13: A THF solution (23.8 ml) of the dibromide 15 (600 mg, 1.19 mmol) and 1,3-benzenedimethanol (8) (164 mg, 1.19 mmol) was added to a THF solution suspension (95.2 ml) of NaH (60%; 240 mg, 6.00 mmol) and the solution mixture was heated to reflux for 7 days. After cooled to room temperature, the mixture was filtered through Celite and the filtrate was concentrated. The residue was purified chromatographically (SiO 2 ; EtOAc/hexanes, 1:5) to afford cyclophane 13 as a white solid (68 mg, 12%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 4.55 (s, 8H), 4.57 (s, 8H), 7.25 (d, J = 7.5 Hz, 4H), (m, 2H), 7.39 (s, 8H), 7.57 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ = 71.4, 71.5, 127.0, 127.0, 127.9, 128.3, 137.7, 138.6; HR-MS (ESI): calcd for [13 + Na] + C 32 H 32 NaO + 4 : m/z ; found S4

5 Thiourea S1: 1,3-di-tert-butyl-5-isothiocyanatobenzene (1.58 g, 6.39 mmol) and tert-butyl 4-aminobenzylcarbamate (945 mg, 4.25 mmol) were added to a 10 ml ball-mill jar and the solid mixture was ball-milled at room temperature for 24 h (a 30 min break was taken every 2 h to avoid overheating of the ball-miller). The solid mixture was purified chromatographically (SiO 2 ; CH 2 Cl 2 /hexanes, 2:8) to afford thiourea S1 as a brown oil (1.29 g, 65%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.30 (s, 18H), 1.43 (s, 9H), 4.28 (d, J = 4.6 Hz, 2H), 4.84 (br, 1H), 7.16 (s, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.34 (s, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.71 (s, 1H), 7.80 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ = 28.4, 31.3, 35.0, 44.1, 79.6, 119.6, 121.3, 125.1, 128.2, 136.0, 136.7, 137.4, 152.8, 155.9, ; HR-MS (ESI): calcd for [S1 + Na] + C 27 H 39 N 3 O 2 SNa + : m/z ; found Guanidine S2. A DMF solution (2.02 ml) of thiourea S1 (94.8 mg; mmol) was cooled to 0 o C and sequentially added NH 4 OH (aq) (35%; 40.4 mg, 45.9 μl, mmol), triethylamine (81.8 mg, 113 μl,0.808 mmol) and HgCl 2 (110 mg, mmol). The solution mixture was stirred virgrously at 0 o C. After the color turned black, the solution mixture was slowly warmed to room temperature and stirred for 1 h. The solution suspension was then added CH 2 Cl 2 (20 ml) and filtered through Celite. The filtrate was concentrated and the residue was partitioned between H 2 O (20 ml) and CH 2 Cl 2 (2 20 ml). The combined organic layers were dried (MgSO 4 ), concentrated, and purified chromatographically (NH-silica gel; EtOAc/hexanes, 4:6) to afford guanidine S2 as a pale yellow solid (68.1 mg, 75%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.24 (s, 18H), 1.44 (s, 9H), 4.22 (s, 2H), 4.92 (br, 1H), 5.03 (br, 2H), 6.93 (d, J = 1.5 Hz, 2H), 7.02 (d, J = 7.6 Hz, 2H),7.09 (s, 1H), 7.15 (d, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ = 28.4, 31.4, 34.8, 44.3, 79.4, 117.7, 117.9, 123.2, 133.0, 141.3, 144.8, 150.2, 152.0, 155.9; HR-MS (ESI): calcd for [S2 + H] + C 27 H 41 N 4 O + 2 : m/z ; found Guanidine S3. A THF solution (3.92 ml) of guanidine S2 (177 mg, mmol) was added HCl (12 N, 980 μl) and stirred for 2 h. The organic solvent was removed under reduced pressure and the residue was partitioned between NaOH (aq) (10%, 40 ml) and CH 2 Cl 2 (2 40 ml). The combined organic layers were dried (MgSO 4 ), concentrated and purified chromatographically (NH-silica gel; MeOH/CH 2 Cl 2, 4:96) to afford guanidine S3 as a pale yellow solid (128 mg, 93%).; M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.22 (s, 18H), 3.72 (s, 2H), 6.92 (s, 2H), (m, 3H), 7.14 (d, J = 8.1 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.3, 34.7, 45.9, 117.6, 117.7, 123.2, 128.0, 137.5, 141.9, 143.7, 150.5, 151.7; HR-MS (ESI): calcd for [S3 + H] + C 22 H 33 N + 4 : m/z ; found S5

6 Guanidinium Salt 16 TFPB: A CH 3 CN solution (8.00 ml) of guanidine S3 (141 mg, mmol) was added HCl (aq) (3N, 133 μl) and stirred at room temperature for 10 min. The solution mixture was then added NaTFPB (354 mg, mmol) and stirred for another 10 min. The organic solvent was removed under reduced pressure and the residue was partitioned between DI water (20 ml) and CH 2 Cl 2 (2 20 ml). The combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified chromatographically (Diol-silica gel, MeOH/CH 2 Cl 2, 1:99) to afford guanidinium salt 16 TFPB as a pale yellow solid (444 mg, 91%); M.p. = C; 1 H NMR (400 MHz, CD 2 Cl 2 ): δ = 1.32 (s, 18H), 3.79 (s, 2H), 7.06 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 1.6 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.58 (s, 4H), 7.60 (t, J = 1.6 Hz, 1H), 7.76 (t, J = 2.1 Hz, 8H); 13 C NMR (100 MHz, CD 2 Cl 2 ): δ = 31.4, 35.7, 45.6, (m), 121.4, 125.2, (q, 1 J CF = 271 Hz), 127.7, (m), 130.3, 132.0, 132.0, 135.6, 143.0, 155.3, 155.9, (q, 1 J CB = 50 Hz); HR-MS (ESI): calcd for [16 TFPB + H] + C 54 H 46 BF 24 N + 4 : m/z ; found [2]Rotaxane 18 TFPB: 1,3-di-tert-butylbenzaldehyde (9.11 mg, 41.7 μmol) was added to a CHCl 3 solution mixture (2.09 ml) of guanidinium salt 16 TFPB (50.7 mg, 41.7 μmol) and cyclophane 1 (19.9 mg, 41.7 μmol) and the solution mixture was stirred at 50 C for 16 h. The solution mixture was then slowly added to a MeOH solution (4.17 ml) of NaBH 4 (31.6 mg, 835 μmol) and the organic solvents were removed under reduced pressure. The residue was partitioned between DI water (10 ml) and CH 2 Cl 2 (2 10 ml) and the combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified chromatographically (Diol-silica gel; CH 2 Cl 2 /hexanes, 1:1) to afford [2]rotaxane 18 TFPB as a colorless oil (43.6 mg, 55%).; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.22 (s, 18H), 1.33 (s, 18H), (m, 20H), 6.45 (d, J = 8.0 Hz, 2H), 6.76 (s, 2H), 6.91 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 7.4 Hz, 8H), 7.17 (s, 2H), (m, 4H), 7.32 (s, 4H), 7.36 (s, 1H), 7.41 (s, 1H), 7.49 (s, 4H), 7.71 (s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.1, 31.5, 34.8, 35.0, 52.4, 54.2, 54.6, (m), 119.8, 121.4, 123.1, (q, 1 J CF = 271 Hz), 125.8, 128.1, 128.2, (m), 129.1, 129.4, 132.1, 133.1, 134.8, 138.7, 139.3, 140.9, 151.1, 153.9, 154.5, (q, 1 J CB = 50 Hz); HR-MS (ESI): calcd for [18] + C 69 H 91 N + 8 : m/z ; found [2]Rotaxane 19 TFPB: 1,3-di-tert-butylbenzaldehyde (2.05 mg, 9.39 μmol) was added to a CHCl 3 solution mixture (471 μl) of the threadlike salt 16 TFPB (11.4 mg, 9.37 μmol) and the cyclophane 5 (4.51 mg, 9.38 μmol) and the solution mixture was stirred at 50 C for 16 h. The solution mixture was then slowly added to a MeOH S6

7 solution (941 μl) of NaBH 4 (7.12 mg, 188 μmol) and the organic solvents were removed under reduced pressure. The residue was partitioned between DI water (10 ml) and CH 2 Cl 2 (2 10 ml) and the combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified chromatographically (Diol-silica gel; CH 2 Cl 2 /hexanes, 3:7) to afford [2]rotaxane 19 TFPB as a colorless oil (7.7 mg, 43%).; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.23 (s, 18H), 1.33 (s, 18H), 3.81 (s, 4H), 4.43 (d, J = 10.6 Hz, 8H), 4.46 (d, J = 10.6 Hz, 8H), 6.31 (s, 2H), 6.46 (d, J = 7.8 Hz, 2H), 6.68 (s, 1H), (m, 12H), (m, 9H), 7.34 (s, 1H), 7.36 (s, 1H), 7.49 (s, 4H), 7.70 (s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.2, 31.5, 34.8, 35.0, 52.5, 54.1, 73.9, (m), 119.6, 121.3, 122.1, 123.0, (q, 1 J CF = 271 Hz), 125.8, 128.5, 128.8, 128.9, (m), 129.4, 130.5, 131.3, 134.8, 137.3, 138.9, 141.6, 151.0, 152.4, 153.2, (q, 1 J CB = 50 Hz); HR-MS (ESI): calcd for [19] + C 69 H 87 N 4 O + 4 : m/z ; found [2]Rotaxane 20 TFPB: 1,3-di-tert-butylbenzaldehyde (79.1 mg, mmol) was added to a CH 2 Cl 2 solution mixture (18.1 ml) of the guanidinium salt 16 TFPB (441 mg, mmol) and cyclophane 10 (173 mg, mmol) and the solution mixture was stirred at 50 C for 6 h. The solution mixture was then slowly added to a MeOH solution (36.2 ml) of NaBH 4 (274 mg, 7.24 mmol) and the organic solvents were evaporated under reduced pressure. The residue was partitioned between DI water (20 ml) and CH 2 Cl 2 (2 20 ml) and the combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified chromatographically (Diol-silica gel; CH 2 Cl 2 /hexanes, 7:3) to afford [2]rotaxane 20 TFPB as a colorless oil (60 mg, 9%).; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.34 (s, 36H), 3.61 (s, 2H), 3.65 (s, 8H), (m, 6H), 3.77(d, J = 12.7 Hz, 4H), 6.14 (d, J = 8.1 Hz, 2H), (br, 2H), 6.80 (s, 2H), 7.05 (m, 10H), 7.14 (d, J = 7.7 Hz, 4H), 7.17 (s, 2H), (m, 2H), 7.37 (s, 1H), 7.47 (s, 1H), 7.49 (s, 4H), 7.69 (s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.2, 31.5, 34.9, 35.2, 52.3, 53.4, 53.7, 54.1, (m), 119.4, 121.7, 122.2, 122.3, 123.1, (q, 1 J CF = 271 Hz), 124.6, 127.7, 128.1, 128.8, (m), 129.0, 129.1, 132.0, 133.0, 134.8, 138.4, 139.3, 151.2, 153.4, 154.2, (q, 1 J CB = 50 Hz) (one signal was missing, possibly because of signal overlap); HR-MS (ESI): calcd for [20] + C 69 H 91 N + 8 : m/z ; found [2]Rotaxane 21 TFPB: 1,3-di-tert-butylbenzaldehyde (17.1 mg, 78.3 μmol) was added to a CHCl 3 solution mixture (3.92 ml) of the guanidinium salt 16 TFPB (95.4 mg, 78.4 μmol) and cyclophane 13 (37.7 mg, 78.4 μmol) and the solution mixture was stirred at 50 C for 16 h. The solution mixture was then slowly added to a MeOH solution (7.85 ml) of NaBH 4 (59.4 mg, 1.57 mmol) and the organic solvents were S7

8 removed under reduced pressure. The residue was partitioned between DI water (10 ml) and CH 2 Cl 2 (2 10 ml) and the combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified chromatographically (Diol-silica gel; CH 2 Cl 2 /hexanes, 6:4) to afford [2]rotaxane 21 TFPB as a colorless oil (20.1 mg, 13%).; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.27 (s, 18H), 1.32 (s, 18H), 3.84 (s, 2H), 3.86 (s, 2H), 4.00 (br, 2H), 4.39 (d, J = 10.1 Hz, 4H), 4.44 (d, J = 10.1 Hz, 4H), 4.48 (d, J = 10.6 Hz, 4H), 4.53 (d, J = 10.6 Hz, 4H), 6.38 (s, 2H), 6.44 (br, 2H), 6.49 (d, J = 7.9 Hz, 2H), 6.89 (s, 8H), (m, 11H), 7.36 (s, 1H), 7.39 (s, 1H), 7.48 (s, 4H), 7.69 (s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.2, 31.5, 34.8, 35.1, 52.6, 54.2, 54.1, 73.5, (m), 119.6, 121.3, 122.2, 123.3, (q, 1 J CF = 271 Hz), 124.8, 127.5, 128.4, (m), 129.0, 129.2, 129.7, 130.5, 131.3, 134.8, 137.3, 137.9, 138.9, 141.6, 151.1, 152.1, 153.8, (q, 1 J CB = 50 Hz); HR-MS (ESI): calcd for [21] + C 69 H 87 N 4 O + 4 : m/z ; found Thiourea S4: 1,3-di-tert-butyl-5-isothiocyanatobenzene (50.2 mg, mmol) was added to a THF solution (2.01 ml) of 3,5-di-tert-butylbenzylaniline (41.3 mg, mmol) and the solution mixture was heated at 50 o C for 16 h. The organic solvent was removed under reduced pressure and the residue was purified chromatographically (SiO 2 ; CH 2 Cl 2 /hexanes, 4:6) to afford thiourea S4 as a pale yellow solid (55.0 mg, 60%).; M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.30 (s, 36H), 7.22 (s, 4H), 7.29 (s, 2H), 7.91 (br, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.3, 35.0, 119.0, 120.7, 136.5, 152.3, 179.1; HR-MS (ESI): calcd for [S4 + H] + C 29 H 45 N 2 S + : m/z ; found Guanidine S5: A DMF solution (6.41 ml) of thiourea S4 (301 mg; mmol) was cooled to 0 o C and sequentially added (35%; 133 mg, 151 μl, 1.33 mmol), triethylamine (269 mg, 371 μl,2.66 mmol), and HgCl 2 (361 mg, 1.33 mmol). The solution mixture was stirred virgrously at 0 o C. After the color turned black, the S8

9 solution mixture was slowly warmed to room temperature and stirred for 1 h. The solution suspension was then added CH 2 Cl 2 (40 ml) and filtered through Celite. The filtrate was concentrated and the residue was partitioned between H 2 O (40 ml) and CH 2 Cl 2 (2 40 ml). The combined organic layers were dried (MgSO 4 ), concentrated, and purified chromatographically (NH-silica gel; EtOAc/hexanes, 2:8) to afford guanidine S5 as a white solid (222 mg, 77%).; M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.27 (s, 36H), 6.94 (d, J = 1.5 Hz, 4H), 7.10 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.4, 34.8, 117.4, 118.0, 143.1, 150.4, 151.8; HR-MS (ESI): calcd for [S5 + H] + C 29 H 46 N + 3 : m/z ; found Guanidinium Salt 22 TFPB: A CH 3 CN solution (8.00 ml) of guanidine S5 (118 mg, mmol) was added HCl (aq) (3N, 90.3 μl) and stirred at room temperature for 10 min. The solution mixture was then added NaTFPB (240 mg, mmol) and stirred for another 10 min. The organic solvent was removed under reduced pressure and the residue was partitioned between DI water (20 ml) and CH 2 Cl 2 (2 20 ml). The combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified chromatographically (SiO 2, CH 2 Cl 2 /hexanes, 1:1) and the product was precipitated in hexanes to afford guanidinium salt 22 TFPB as a pale yellow solid (302 mg, 86%); M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.31 (s, 36H), 5.56 (br, 2H), 7.13 (s, 4H), 7.29 (br, 2H), 7.56 (s, 4H) 7.61 (s, 2H), 7.76 (s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.0, 35.1, (m), 120.5, (q, 1 J CF = 271 Hz), 124.9, (m), 130.5, 134.8, 155.0, 155.2, (q, 1 J CB = 50 Hz); HR-MS (ESI): calcd for [22] + C 29 H 46 N + 3 : m/z ; found [2]Rotaxane 23 TFPB: A CHCl 3 solution mixture (442 μl) of the dumbbell-shaped salt 22 TFPB (11.5 mg, 8.85 μmol), 1,3-phenylenedimethanamine (3) (2.41 mg, 2.34 μl, 17.7 μmol) and isophthalaldehyde (2) (2.37 mg, 17.7 μmol) was stirred at 50 C for 10 d and the solution mixture was slowly added to a MeOH solution (1.77 ml) of NaBH 4 (13.4 mg, 354 μmol). The organic solvents were removed under reduced pressure and the residue was partitioned between DI water (10 ml) and CH 2 Cl 2 (2 10 ml). The combined organic layers were dried (MgSO 4 ), concentrated, and purified chromatographically (SiO 2 gel; CH 2 Cl 2 /hexanes, 7:3) to afford [2]rotaxane 23 TFPB as a white solid (12.6 mg, 80%).; M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.15 (s, 36H), 3.72 (s, 16H), 6.69 (s, 4H), 7.14 (d, J = 7.1 Hz, 8H), (m, 4H), 7.36 (s, 2H), 7.38 (s, 4H), 7.50 (s, 4H), 7.72 (s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.1, 35.0, 54.5, (m), 119.4, 122.8, (q, 1 J CF = 271 Hz), 128.1, 128.1, (m), 129.2, 133.3, 134.8, 139.3, 153.6, 154.1, (q, 1 J CB = 50 Hz); HR-MS (ESI): calcd for [23] + C 61 H 82 N + 7 : m/z ; S9

10 found [2]Rotaxane 24 TFPB: A CHCl 3 solution mixture (2.80 ml) of the dumbbell-shaped salt 22 TFPB (35.8 mg, mmol), 1,4-phenylenedimethanamine (11) (7.50 mg, mmol) and isophthalaldehyde (2) (7.39 mg, mmol) was stirred at 50 C for 72 h and then slowly added to a MeOH solution (11.0 ml) of NaBH 4 (83.3 mg, 2.20 mmol). The organic solvents were removed under reduced pressure and the residue was partitioned between DI water (20 ml) and CH 2 Cl 2 (2 20 ml). The combined organic layers were dried (MgSO 4 ), concentrated and purified chromatographically (SiO 2 gel; CH 2 Cl 2 /hexanes, 8:2) to afford [2]rotaxane 24 TFPB as a white solid (27.6 mg, 56%).; M.p. = C; 1 H NMR (400 MHz, CDCl 3 ): δ = 1.26 (s, 36H), 3.65 (s, 8H), 3.73 (s, 8H), 6.49 (d, J = 1.3 Hz, 4H), 6.97 (s, 8H), 7.14 (s, 2H), 7.22 (d, J = 7.3 Hz, 4H), (m, 3H), 7.41 (s, 2H), 7.50 (s, 4H), 7.70(s, 8H); 13 C NMR (100 MHz, CDCl 3 ): δ = 31.2, 35.1, 53.3, 53.6, (m), 118.2, 122.7, (q, 1 J CF = 271 Hz), 127.8, 127.9, (m), 128.9, 129.1, 132.6, 134.8, 139.1, 139.5, 152.9, 153.8, (q, 1 J CB = 49 Hz); HR-MS (ESI): calcd for [24] + C 61 H 82 N + 7 : m/z ; found Reference: [a] Xing, H.; Zhang, Y.; Lai, Y.; Jiang, Y.; Ma, D. J. Org. Chem., 2012, 77, S10

11 ppm S

12 ppm S12

13 ppm S13

14 ppm S14

15 ppm S15

16 ppm S16

17 ppm S17

18 ppm S18

19 ppm S19

20 ppm S20

21 ppm S21

22 ppm S22

23 ppm S23

24 ppm ppm S24

25 ppm S25

26 ppm ppm S26

27 ppm S27

28 ppm ppm S28

29 ppm S29

30 ppm S30

31 ppm S31

32 ppm S32

33 ppm S

34 ppm S34

35 ppm S35

36 ppm S36

37 ppm S37

38 ppm ppm S38

39 ppm S39

40 ppm ppm S40

41 ppm S41

42 ppm ppm S42

43 ppm S43

44 ppm ppm S44

45 ppm S45

46 ppm ppm S46

47 ppm S47

48 ppm ppm S48

49 ppm S

50 ppm ppm S50

51 ITC measurements were performed using a MicroCal MCS calorimeter interfaced with a microcomputer. All sample solutions were carefully degassed prior to titration using the equipment provided with the instrument. A solution of the cyclophane 1 or 5 (CHCl3) was titrated into a solution of the threadlike salt 9 TFPB (CHCl3) using a 280-μL syringe. Each titration consisted of a preliminary 10-μL injection followed by 27 subsequent additions of 10 μl. The entropy (ΔS o ) of the complexation was determined by subtracting the heat of dilution of each titration from the enthalpy (ΔH o ) of the titration. All the experiments were performed at 298 K. MicroCal LLC software was used to compute the thermodynamic parameters of the titration based on the one-site binding model. The Gibbs free energy (ΔG o ) was calculated from the binding constant using R = cal*k -1 *mol -1. Aliquouts (10 μl, 10 mm) of CHCl3 solution of the macrocycle 1 were titrated into stirring CHCl3 solution of the 9 TFPB (1 mm) at 298 K. Host M + Entry N K (M -1 ) ΔH o (cal*mol -1 ) ΔS o (cal*k -1 *mol -1 ) ΔG o (kcal*mol -1 ) ± E4 ± 6.13E ± ± 0.03 Threadlike Cyclophane ± E3 ± 5.43E ± ± 0.04 Salt ± E4 ± 4.05E ± ± TFPB Average ± E4 ± 5.27E ± ± ± 0.03 Aliquouts (10 μl, 20 mm) of CHCl3 solution of the cyclophane 5 were titrated into stirring CHCl3 solution of the 9 TFPB (2 mm) at 298 K. Host M + Entry N K (M -1 ) ΔH o (cal*mol -1 ) ΔS o (cal*k -1 *mol -1 ) ΔG o (kcal*mol -1 ) ± E3 ± 2.40E ± ± 0.06 Threadlike Cyclophane ± E3 ± 3.67E ± ± 0.07 Salt ± E3 ± 1.02E ± ± TFPB Average ± E3 ± 2.60E ± ± ± 0.06 S51

52 S52

53 S53

54 ITC measurements were performed using a MicroCal MCS calorimeter interfaced with a microcomputer. All sample solutions were carefully degassed prior to titration using the equipment provided with the instrument. A solution of the cyclophane 10 or 13 (CHCl3) was titrated into a solution of the threadlike salt 9 TFPB (CHCl3) using a 280-μL syringe. Each titration consisted of a preliminary 10-μL injection followed by 27 subsequent additions of 10 μl. The entropy (ΔS o ) of the complexation was determined by subtracting the heat of dilution of each titration from the enthalpy (ΔH o ) of the titration. All the experiments were performed at 298 K. MicroCal LLC software was used to compute the thermodynamic parameters of the titration based on the one-site binding model. The Gibbs free energy (ΔG o ) was calculated from the binding constant using R = cal*k -1 *mol -1. Aliquouts (10 μl, 12 mm) of CHCl3 solution of the cyclophane 10 were titrated into stirring CHCl3 solution of the 9 TFPB (0.8 mm) at 298 K. Host M + Entry N K (M -1 ) ΔH o (cal*mol -1 ) ΔS o (cal*k -1 *mol -1 ) ΔG o (kcal*mol -1 ) ± E3 ± 1.64E ± ± 0.08 Threadlike Cyclophane ± E3 ± 1.17E ± ± 0.05 Salt ± E3 ± 2.19E ± ± TFPB Average ± E3 ± 1.72E ± ± ± 0.08 Aliquouts (10 μl, 18 mm) of CHCl3 solution of the cyclophane 13 were titrated into stirring CHCl3 solution of the 9 TFPB (1.2 mm) at 298 K. Host M + Entry N K (M -1 ) ΔH o (cal*mol -1 ) ΔS o (cal*k -1 *mol -1 ) ΔG o (kcal*mol -1 ) ± E2 ± 1.4E ± ± 0.12 Threadlike Cyclophane ± E2 ± 1.25E ± ± 0.14 Salt ± E2 ± 9.85E ± ± TFPB Average ± E2 ± 1.22E ± ± ± 0.11 S54

55 S55

56 S56

57 S57

58 S58

59 Competition experiment for the cyclophane 1 and 5 with threadlike salt 9 TFPB a) b) c) 1 H NMR spectra (400 MHz, CDCl 3, 298 K) of a) an equimolar mixture (10 mm) of 1 and 9 TFPB, b) an equimolar mixture of 1, 5, and 9 TFPB, c) an equimolar mixture of 5 and 9 TFPB Complexation ratio for b) Tetraaza-cyclophane 1: δ δ(free) δ(shift) = = = 76% δ(max) D Tetraoxo-cyclophane 5: δ δ(free) δ(shift) = = = 23% δ(max) D S59

60 Competition experiment for the cyclophane 10 and 13 with threadlike salt 9 TFPB a) b) c) 1 H NMR spectra (400 MHz, CDCl 3, 298 K) of a) an equimolar mixture (10 mm) of 10 and 9 TFPB, b) an equimolar mixture of 10, 13, and 9 TFPB, c) an equimolar mixture of 10 and 9 TFPB Complexation ratio for b) Tetraaza-cyclophane 10: δ δ(free) δ(shift) = = = 62% δ(max) D Tetraoxo-cyclophane 13: δ δ(free) δ(shift) = = = 37% δ(max) D S60

61 (a) O H (b) N Ar H Ar N H (c) D R D R (d) D R N R H H N D R (e) R N H Ar-CH 2 -N H NMR spectra (400 MHz, CDCl 3, 298 K) of an equimolar mixture of the threadlike salt 16-TFPB, the tetraaza-cyclophane 1, and the aldehyde 17 that had been heated at 323 K for (a) 0, (b) 10, (c) 30, (d) 90, and (e) 540 min. D and R denote signals representing the dumbbell-shaped salt and the [2]rotaxane, respectively. S61

62 S62

63 S63

64 S64

65 S65

66 [18] + = C 69 H 91 N 8 + = S66

67 +TOF MS: 9 MCA scans from Sample 1 of chiu-YHC-Rtx233-3.wiff a= e-004, t0= e+001 R; (Nanospray) Max. 2.5e4 counts. I n t e n s i t y, c o u n t s 2.4e4 2.2e4 2.0e4 1.8e4 1.6e4 1.4e4 1.2e4 1.0e [19] + = C 69 H 87 N 4 O 4 + = m/z, Da S67

68 +TOF MS: 12 MCA scans from Sample 1 of chiu-YHC-pNrtx-3.wiff a= e-004, t0= e+001 R; (Nanospray) Max. 2.3e4 counts. In te n s ity, c o u n ts 2.3e4 2.2e4 2.1e4 2.0e4 1.9e4 1.8e4 1.7e4 1.6e4 1.5e4 1.4e4 1.3e4 1.2e4 1.1e4 1.0e [20] + = C 69 H 91 N 8 + = m/z, Da S68

69 +TOF MS: 13 MCA scans from Sample 1 of chiu-YJL threasing-p-O-rtx-3.wiff a= e-004, t0= e+001 (Nanospray) Max. 1.4e4 counts. I n t e n s i t y, c o u n t s 1.4e4 1.3e4 1.2e4 1.1e4 1.0e [21] + = C 69 H 87 N 4 O 4 + = m/z, Da S69

70 [23] + = C 61 H 82 N 7 + = S70

71 [24] + = C 61 H 82 N 7 + = S71