Supporting Information Stimuli-Responsive Pd 2 L 4 Metallosupramolecular Cages: Towards Targeted Cisplatin Drug Delivery. James E. M. Lewis, a Emma L. Gavey, a Scott A. Cameron, a and James D. Crowley* a a Department of Chemistry, University of Otago, PO Box 56, Dunedin, New Zealand; Fax: +64 3 479 7906; Tel: +64 3 479 7731. *jcrowley@chemistry.otago.ac.nz S1
Contents 1 Experimental Procedures... 3 1.1 General... 3 1.2 Synthesis of 2(BF 4 ) 4... 3 1.3 Synthesis of 2(SbF 6 ) 4... 4 1.4 Synthesis of [Pd(DMAP) 4 ](BF 4 ) 2... 5 1.5 Synthesis of [Pd 2 (S1) 4 ](BF 4 ) 4... 7 2 1 H DOSY NMR Spectra... 9 2.1 2.2 2.3 1 H DOSY NMR spectrum of 1 (CD 3 CN, 298 K)... 9 1 H DOSY NMR spectrum of 2(BF 4 ) 4 (CD 3 CN, 298 K)... 10 1 H DOSY NMR spectrum of 2(SbF 6 ) 4 (CD 3 CN, 298 K)... 11 3 Mass Spectra... 12 3.1 Mass Spectra of 2(BF 4 ) 4... 12 3.2 Mass Spectra of 2(SbF 6 ) 4... 14 3.3 Mass Spectra of [2 (cisplatin) 2 ](BF 4 ) 4... 16 3.4 Mass Spectra of [Pd(DMAP) 4 ](BF 4 ) 2... 18 4 1 H NMR Experiments... 20 4.1 2(BF 4 ) 4 + DMAP + Tosylic Acid (TsOH)... 21 4.2 2(BF 4 ) 4 + DMAP + Camphor-10-sulfonic acid (CSA)... 23 4.3 2(BF 4 ) 4 + Bu 4 NCl + AgSbF 6... 24 4.4 2(BF 4 ) 4 + Cisplatin + Bu 4 NCl... 25 5 Computer Modelling... 26 5.1 SPARTAN Model of [2 (cisplatin)]... 26 6 X-Ray Crystallographic Data... 27 6.1 X-ray data collection and refinement for 2(SbF 6 ) 4... 27 6.2 Table 1. Crystal data and structure refinement for 2(SbF 6 ) 4... 29 6.3 X-ray data collection and refinement for [2 (cisplatin) 2 ](BF 4 ) 4.... 30 6.4 Table 2. Crystal data and structure refinement for [2 (cisplatin) 2 ](BF 4 ) 4.... 32 6.5 Table 3. Squeeze results for [2 (cisplatin) 2 ](BF 4 ) 4... 33 6.6 Space-filling representations of 2(SbF 6 ) 4 and [2 (cisplatin) 2 ](BF 4 ) 4... 34 7 References... 34 S2
1 Experimental Procedures 1.1 General Unless otherwise stated, all reagents were purchased from commercial sources and used without further purification. 1 H and 13 C NMR spectra were recorded on either a 400 MHz Varian 400 MR or Varian 500 MHz VNMRS spectrometer. Chemical shifts are reported in parts per million and referenced to residual solvent peaks (CDCl 3 : 1 H δ 7.26 ppm, 13 C δ 77.16 ppm; CD 3 CN: 1 H δ 1.94, 13 C δ 1.32, 118.26 ppm, d 6 -DMSO: 1 H δ 2.50 ppm; 13 C δ 39.52 ppm). Coupling constants (J) are reported in Hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: m = multiplet, q = quartet, t = triplet, dt = double triplet, d = doublet, dd = double doublet, s = singlet. IR spectra were recorded on a Bruker ALPHA FT-IR spectrometer with an attached ALPHA-P measurement module. Microanalyses were performed at the Campbell Microanalytical Laboratory at the University of Otago. Electrospray mass spectra (ESMS) were collected on a Bruker micro-tof-q spectrometer. UVvisible absorption spectra were acquired with a Perkin Elmer Lambda-950 spectrophotometer. Figure S1: Labelling scheme for 2(X) 4. 1.2 Synthesis of 2(BF 4 ) 4 To a stirring solution of 1 (0.141 g, 0.50 mmol, 2 eq.) in acetonitrile (10 ml) was added dropwise a solution of [Pd(CH 3 CN) 4 ](BF 4 ) 2 (0.111 g, 0.25 mmol, 1 eq.) in acetonitrile (5 ml). The resulting solution was stirred at room temperature for 1 hour before filtering through cotton wool and the product precipitated by vapour diffusion of diethyl ether over 36 hours. The supernatant was decanted off and the solid dried in vacuo to give 2(BF 4 ) 4 as a tan solid. Yield 0.200 g (0.12 mmol, 95%). 1 H NMR (400 MHz, d 6 -DMSO) δ: 9.54 (s, 2H, H a ), 9.38 (dd, J = 1.5, 5.9 Hz, 2H, H b ), 8.35 (dt, J = 1.5, 8.2 Hz, 2H, H d ), 8.01 (t, J = 7.5 Hz, 1H, H f ), 7.86 (dd, J = 5.9, 8.1 Hz, 2H, H c ), 7.79 (d, J = 7.8 Hz, 2H, H e ). 1 H NMR (400 MHz, CD 3 CN) δ: 9.34 (d, J = 1.5 Hz, 2H, H a ), 9.08 (dd, J = 1.2, 5.8 Hz, 2H, H b ), 8.17 (dt, J = 1.4, 8.0 Hz, 2H, H d ), 7.87 (t, J = 7.8 Hz, 1H, H f ), 7.68 (d, J = 7.8 Hz, 2H, H e ), 7.66 (dd, J = 5.8, 8.0 S3
Hz, 2H, H c ). 13 C NMR (500 MHz, d 6 -DMSO) δ: 153.3 (C a ), 151.1(C b ), 143.5 (C d ), 141.8, 138.3 (C f ), 128.6 (C e ), 127.4 (C c ), 121.5, 93.3, 83.6. IR (ATR): υ (cm -1 ) 3087, 1575, 1558, 1483, 1444, 1420, 1199, 1046, 803, 727, 690, 572, 558, 520. HRESI-MS (CH 3 CN): m/z = 1598.1482 [Pd 2 (C 19 H 11 N 3 ) 4 (BF 4 ) 3 ] + calc. 1598.2022; 756.0795 [Pd 2 (C 19 H 11 N 3 ) 4 (BF 4 ) 2 ] 2+ calc. 756.0989. UV-Vis (DMSO, ε [M -1. cm -1 ]): λ max nm = 314 (1.02 10 5 ), 268 (1.20 10 5 ). Anal. Calc for 2(BF 4 ) 4.(CH 3 CN) 3 (H 2 O) 3 : C, 52.88; H, 3.19; N, 11.28%. Found: C, 52.67; H, 3.02; N, 11.40%. Figure S2: 1 H NMR (400 MHz, d 6 -DMSO) spectrum for 2(BF 4 ) 4. Figure S3: 13 C NMR (500 MHz, d 6 -DMSO) spectrum for 2(BF 4 ) 4. 1.3 Synthesis of 2(SbF 6 ) 4 AgSbF 6 (0.172 g, 0.50 mmol, 2 eq.) and Pd(CH 3 CN) 2 Cl 2 (0.065 g, 0.25 mmol, 1 eq.) were stirred in acetone (dry, 10 ml) under N 2 in the dark for 30 minutes. The reaction was filtered through celite (dried in oven) to give a red solution that was added dropwise to a stirring solution of 1 (0.141 g, 0.50 mmol, 2 eq.) in acetone (dry, 10 ml). After stirring for 1 hour the reaction solution was filtered through cotton wool and the product precipitated by vapour diffusion of diethyl ether over 48 hours. The supernatant was decanted off and the solid dried in vacuo to give 2(SbF 6 ) 4 as a tan solid. Yield 0.225 g (0.10 mmol, 79%). 1 H NMR (400 MHz, CD 3 CN) δ: 9.27 (s, 2H, H a ), 9.00 (dd, J = 1.1, 5.9 Hz, 2H, H b ), 8.17 (dt, J = 1.5, 8.1 Hz, 2H, H d ), 7.87 (t, J = 8.2 Hz, 1H, H f ), 7.68 (d, J = 7.8 Hz, 2H, H e ), 7.66 (dd, J = 5.8, 7.6 Hz, 2H, H c ). 13 C NMR (400 MHz, CD 3 CN) δ: 154.5 (C a ), 151.4 (C b ), 144.5 (C d ), 143.3, 138.7 (C f ), 129.4 (C e ), 128.5 (C c ), 124.1, 94.6, 83.5. IR (ATR): υ (cm -1 ) 3069, 1579, 1557, 1482, 1448, 1417, 1239, 811, 696. HRESI-MS (CH 3 CN/CH 3 OH): m/z = 2044.8478 [Pd 2 (C 19 H 11 N 3 ) 4 (SbF 6 ) 3 ] + calc. 2044.8741; 904.9749 [Pd 2 (C 19 H 11 N 3 ) 4 (SbF 6 ) 2 ] 2+ calc. 904.9897. UV-Vis (DMSO, ε [M -1. cm -1 ]): λ max nm = 317 (9.10 10 4 ), 270 (1.05 10 5 ). Anal. Calc for 2(SbF 6 ) 4.(CH 3 COCH 3 ) 5 : C, 42.50; H, 2.90; N, 6.54%. Found: C, 42.70; H, 3.11; N, 6.40%. S4
Figure S4: 1 H NMR (400 MHz, CD 3 CN) spectrum for 2(SbF 6 ) 4. Figure S5: 13 C NMR (400 MHz, CD 3 CN) spectrum for 2(SbF 6 ) 4. 1.4 Synthesis of [Pd(DMAP) 4 ](BF 4 ) 2 Figure S6: Labelling scheme for [Pd(DMAP) 4 ](BF 4 ) 2. [Pd(CH 3 CN) 4 ](BF 4 ) 2 (0.022 g, 0.05 mmol, 1 eq.) and 4-dimethylaminopyridine (0.024 g, 0.2 mmol, 4 eq.) were stirred in acetonitrile (2.5 ml) for 30 minutes. The product was precipitated as a light yellow crystalline solid by vapour diffusion of diethyl ether over a period of 24 hours. Yield 0.032 g (0.04 mmol, 84%). 1 H NMR (400 MHz, d 6 -DMSO) δ: 8.22 (d, J = 7.1 Hz, 2H, H a ), 6.71 (d, J = 7.3 Hz, 2H, H b ), 2.96 (s, 6H, H d ). 1 H NMR (400 MHz, CD 3 CN) δ: 7.97 (d, J = 7.4 Hz, 2H, H a ), 6.55 (d, J = 7.4 Hz, 2H, H b ), 2.98 (s, 6H, H d ). 13 C NMR (400 MHz, CD 3 CN) δ: 156.1 (C a ), 150.0 (C b ), 109.2 (C c ), 39.59 (C d ). IR (ATR): υ (cm -1 ) 1617, 1544, 1444, 1392, 1351, 1224, 1049, 1017, 944, 806, 520. HRESI-MS (MeCN): S5
m/z = 681.2381 [Pd(C 7 H 10 N 2 ) 4 (BF 4 )] + calc. 681.2449; 297.1205 [Pd(C 7 H 10 N 2 )4] 2+ calc. 297.1196. Anal. Calc for C 28 H 40 B 2 F 8 Pd: C, 43.75; H, 5.24; N, 14.58%. Found: C, 44.05; H, 5.36; N, 14.67%. Figure S7: 1 H NMR (400 MHz, CD 3 CN) spectrum for [Pd(DMAP) 4 ](BF 4 ) 2. Figure S8: 13 C NMR (400 MHz, CD 3 CN) spectrum for [Pd(DMAP) 4 ](BF 4 ) 2. S6
1.5 Synthesis of [Pd 2 (S1) 4 ](BF 4 ) 4 Figure S9: Self-assembly of cage complex S2 from ligand S1. To a stirring solution of [Pd(CH 3 CN) 4 ](BF 4 ) 2 (0.66 g, 1.49 mmol, 1 eq.) in acetonitrile (dry, 5 ml) was added S1 (0.833 g, 2.97 mmol, 2 eq.). The reaction mixture was heated at 50 C for 30 minutes. The product was precipitated as a pale yellow solid by vapour diffusion of diethyl ether into the cooled reaction mixture. Yield 0.98 g (0.58 mmol, 78%). 1 H NMR (400 MHz, d 6 -DMSO) δ: 9.60 (s, 2H, H a ), 9.36 (d, J = 5.0 Hz, 2H, H b ), 8.28 (d, J = 8.0 Hz, 2H, H d ), 7.95 (s, 2H, H g ), 7.82 (dd, J = 5.9, 7.9 Hz, 2H, H c ), 7.73 (dd, J = 1.4, 7.9 Hz, 2H, H e ), 7.58 (t, J = 7.8, 1H, H f ). 13 C NMR (400 MHz, d 6 -DMSO) δ: 153.2, 151.1, 143.5, 141.8, 138.3, 128.6, 127.4, 121.6, 109.6, 93.3, 83.6. IR (ATR): υ (cm -1 ) 3566, 3210, 1718, 1600, 1562, 1488, 1413, 1295, 1198, 1163, 1050, 809, 796, 680, 520, 418. HRESI-MS (CH 3 CN/CH 3 OH): m/z = 1594.2218 [Pd 2 (C 20 H 12 N 2 ) 4 (BF 4 ) 3 ] + calc. 1594.2213; 754.1044 [Pd 2 (C 20 H 12 N 2 ) 4 (BF 4 ) 2 ] 2+ calc. 754.1085; 333.5552 [Pd 2 (C 20 H 12 N 2 ) 4 ] 4+ calc. 333.5521. UV-Vis (DMSO, ε [M -1. cm -1 ]): λ max nm = 286 (1.75 10 5 ). Anal. Calc for C 80 H 48 N 8 B 4 F 16 Pd: C, 61.01; H, 3.03; N, 7.11%. Found: C, 53.45; H, 3.03; N, 6.18%. Figure S10: 1 H NMR (400 MHz, d 6 -DMSO) spectrum for S2. S7
Figure S11: 13 C NMR (400 MHz, d 6 -DMSO) spectrum for S2. S8
2 2.1 1 H DOSY NMR Spectra 1 H DOSY NMR spectrum of 1 (CD 3 CN, 298 K) S9
2.2 1 H DOSY NMR spectrum of 2(BF 4 ) 4 (CD 3 CN, 298 K) S10
2.3 1 H DOSY NMR spectrum of 2(SbF 6 ) 4 (CD 3 CN, 298 K) S11
3 Mass Spectra 3.1 Mass Spectra of 2(BF 4 ) 4 Intens. x10 5 2.0 547.5397 +MS, 0.2-1.0min #(10-59) 1.5 1.0 385.9911 300.0890 0.5 687.0769 1006.4563 1599.1474 0.0 500 1000 1500 2000 2500 m/z Figure S12: HR-ESI Mass Spectrum (+ve ion, MeCN) of 2(BF 4 ) 4. m/z = 1598.1482 [Pd 2 (1) 4 (BF 4 ) 3 ] + ; 756.0795 [Pd 2 (1) 4 (BF 4 ) 2 ] 2+. S12
Intens. x10 4 1.5 755.0793 755.5801 756.0794 +MS, 0.1-0.9min #(6-54) 754.5787 756.5807 757.0784 1.0 754.0790 757.5808 0.5 753.5755 758.0803 758.5798 753.0733 759.0916 0.0 751.0019 751.4981 752.0030 752.5327 759.5795 (C19H11N3)4Pd2(BF4)2, M,1510.19 2000 1500 755.0988 755.5990 756.0989 754.5988 756.5994 757.0991 1000 754.0987 757.5997 500 753.5989 758.0995 758.6001 753.0992 759.1004 752.5996 759.6010 0 752 754 756 758 760 m/z Figure S13: Experimental (top) and theoretical (bottom) isotope patterns for [Pd 2 (1) 4 (BF 4 ) 3 ] +. Intens. 8000 1597.1454 1598.14811599.1472 +MS, 0.1-0.9min #(6-54) 1600.1482 6000 1596.1460 1595.1460 1601.1506 4000 1602.1534 1594.1476 2000 1603.1515 1593.1497 1604.1529 1592.1484 1605.1520 1606.1410 0 (C19H11N3)4Pd2(BF4)3, M,1597.20 2000 1597.2019 1598.2022 1599.2021 1596.2018 1600.2028 1500 1595.2017 1601.2023 1000 1594.2023 1602.2033 1603.2031 500 1593.2030 1604.2042 1592.2039 1605.2047 1606.2059 0 1590.0 1592.5 1595.0 1597.5 1600.0 1602.5 1605.0 1607.5 1610.0 m/z Figure S14: Experimental (top) and theoretical (bottom) isotope patterns for [Pd 2 (1) 4 (BF 4 ) 2 ] 2+. S13
3.2 Mass Spectra of 2(SbF 6 ) 4 Intens. x10 6 282.1049 +MS, 11.5-15.7min #(683-937) 1.0 387.9998 0.8 0.6 0.4 671.0928 0.2 563.5140 444.0296 0.0 200 400 600 800 1000 1200 1400 m/z Figure S15: HR-ESI Mass Spectrum (+ve ion, MeCN) of 2(SbF 6 ) 4. m/z = 2044.8478 [Pd 2 (1) 4 (SbF 6 ) 3 ] + ; 904.9749 [Pd 2 (1) 4 (SbF 6 ) 2 ] 2+. S14
Intens. +MS, 11.5-15.7min #(683-937) 500 2044.8478 2043.8408 2042.8628 2045.8551 2046.8338 400 2041.8562 2047.8415 300 2040.8500 2048.8495 200 2038.8382 2039.8439 2049.8578 2050.8375 100 2037.8326 2051.8462 0 (C19H11N3)4Pd2(SbF6)3, M,2040.87 2000 2044.8741 2043.8745 2046.8746 2042.8736 1500 2041.8739 2047.8760 2048.8753 1000 2040.8731 2049.8767 500 2039.8735 2050.8763 2037.8735 2038.8726 2051.8776 2052.8777 2053.8788 0 2035 2040 2045 2050 2055 m/z Figure S16: Experimental (top) and theoretical (bottom) isotope patterns for [Pd 2 (1) 4 (SbF 6 ) 3 ] +. Intens. x10 4 904.9749 +MS, 11.5-15.7min #(683-937) 1.25 902.9718 903.9749 1.00 901.9693 905.9763 906.9749 0.75 900.9647 904.4837 903.4837 905.4844 0.50 899.9645 898.9632 902.4829 906.4849 907.9752 908.9731 0.25 897.9633 907.4850 0.00 2000 904.9897 Pd2(C19H11N3)4(SbF6)2, M,1805.98 903.9894 1500 903.4896 905.4903 902.9892 1000 906.4907 902.4893 906.9904 500 901.9889 907.4911 907.9911 0 901.4893 908.4917 900.9890 908.9921 896 898 900 902 904 906 908 910 912 914 m/z Figure S17: Experimental (top) and theoretical (bottom) isotope patterns for [Pd 2 (1) 4 (SbF 6 ) 2 ] 2+. S15
3.3 Mass Spectra of [2 (cisplatin) 2 ](BF 4 ) 4 Intens. 2198.1578 +MS, 0.5-1.5min #(27-88) 2000 2199.1594 2196.1619 2200.1607 2201.1643 2195.1640 1500 2202.1625 2194.1608 2203.1591 1000 2193.1593 2204.1663 500 2183.2888 2191.1793 2192.1637 2205.1698 2206.1796 2207.1759 (C19H11N3)4Pd2(BF4)3(PtN2H6Cl2)2, M,2195.11 2000 1500 2198.1093 2196.1094 2200.1093 1000 2194.1096 2195.1095 2201.1093 2202.1094 2203.1095 500 2193.1098 2192.1100 2191.1102 2190.1105 2204.1096 2205.1097 2206.1099 2207.1100 0 2180 2185 2190 2195 2200 2205 2210 2215 m/z Figure S18: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF 4 ) 3 2[Pt(NH 3 ) 2 Cl 2 ]} +. Intens. 1055.5713 +MS, 0.5-1.5min #(27-88) 6000 1054.5700 1056.5710 5000 1054.0693 1057.0710 1057.5709 4000 1053.5679 1058.0707 3000 1053.0650 1058.5690 2000 1000 1049.5346 1051.5456 1052.0549 1052.5600 1059.0682 1059.5651 1060.0615 1060.5532 0 2500 (C19H11N3)4Pd2(BF4)2(PtN2H6Cl2)2, M,2108.11 2000 1055.5526 1500 1054.5526 1056.5526 1057.0526 1054.0526 1057.5527 1000 1053.5526 1058.0527 1053.0527 1058.5528 500 0 1059.0528 1052.5528 1059.5530 1052.0528 1060.0530 1051.5529 1048 1050 1052 1054 1056 1058 1060 1062 1064 1066 m/z Figure S19: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF 4 ) 2 2[Pt(NH 3 ) 2 Cl 2 ]} 2+. S16
Intens. 1898.1980 1899.1978 +MS, 0.5-1.5min #(27-88) 1897.1974 1900.1982 4000 1896.1983 1901.1982 1895.1988 3000 1902.2003 1894.2003 1903.2013 2000 1893.1978 1904.2021 1905.2041 1000 1880.2052 1891.2056 1892.2041 1906.2100 1907.2170 1912.2236 1916.2346 1918.2385 (C19H11N3)4Pd2(BF4)3(PtN2H6Cl2), M,1896.15 2000 1500 1898.1559 1896.1558 1900.1560 1895.1558 1901.1560 1000 1894.1560 1902.1563 1903.1563 500 1893.1562 1904.1568 1892.1566 1905.1568 1891.1571 1906.1574 0 1880 1885 1890 1895 1900 1905 1910 1915 m/z Figure S20: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF 4 ) 3 [Pt(NH 3 ) 2 Cl 2 ]} +. Intens. x10 4 1.0 905.5928 905.0923 +MS, 0.5-1.5min #(27-88) 906.5933 904.5934 0.8 907.0926 904.0922 0.6 907.5922 903.5924 908.0922 0.4 903.0916 908.5935 0.2 898.1528 900.0044 900.9962 902.0838 902.5922 909.0905 909.5919 910.0830 0.0 (C19H11N3)4Pd2(BF4)2(PtN2H6Cl2), M,1809.15 2000 905.5758 1500 904.5758 906.5760 1000 904.0757 907.0759 907.5761 903.5758 908.0761 500 903.0758 908.5764 0 909.0764 902.5760 909.5767 902.0762 898 900 902 904 906 908 910 912 914 m/z Figure S21: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF 4 ) 2 [Pt(NH 3 ) 2 Cl 2 ]} 2+. S17
3.4 Mass Spectra of [Pd(DMAP) 4 ](BF 4 ) 2 Intens. x10 4 8 350.0720 +MS, 0.1-2.8min #(8-168) 491.1532 6 4 297.1196 395.0664 2 681.2381 0 400 600 800 1000 1200 1400 1600 1800 2000 2200 m/z Figure S22: HR-ESI Mass Spectrum (+ve ion, MeCN) of [Pd(DMAP) 4 ](BF 4 ) 2. m/z = 681.2381 [Pd(C 7 H 10 N 2 ) 4 (BF 4 )] + ; 297.1205 [Pd(C 7 H 10 N 2 ) 4 ] 2+. S18
Intens. +MS, 0.2-2.8min #(9-166) 681.2381 680.2392 6000 683.2376 4000 679.2390 682.2399 684.2399 685.2390 2000 678.2416 686.2415 0 (C7H10N2)4Pd(BF4), M,681.24 2000 1500 680.2452 681.2449 683.2440 1000 679.2442 682.2468 500 684.2472 685.2452 0 686.2485 678.2476 677.2456 670 675 680 685 690 695 m/z Figure S23: Experimental (top) and theoretical (bottom) isotope patterns for [Pd(DMAP) 4 ](BF 4 ) +. Intens. x10 4 3.0 297.1196 +MS, 0.2-2.8min #(9-166) 2.5 298.1191 296.6197 2.0 1.5 299.1194 1.0 296.1187 297.6199 298.6201 0.5 299.6208 295.1187 300.1221 0.0 (C7H10N2)4Pd(BF4)0, M,594.24 2000 297.1205 1500 298.1202 296.6208 1000 299.1208 500 296.1203 297.6217 298.6219 299.6225 0 295.1211 292 294 296 298 300 302 304 m/z Figure S24: Experimental (top) and theoretical (bottom) isotope patterns for [Pd(DMAP) 4 ] 2+. S19
4 1 H NMR Experiments Figure S25: Reaction scheme for 1 H NMR disassembly/reassembly experiments. S20
4.1 2(BF 4 ) 4 + DMAP + Tosylic Acid (TsOH) To a 17 mm solution of 2(BF 4 ) 4 in d 6 -DMSO (0.75 ml) was added DMAP (0.012 g, 0.1 mmol). After stirring for 5 minutes a 1 H NMR spectrum was obtained showing disassembly of the cage complex and formation of [Pd(DMAP) 4 ](BF 4 ) 2. The formation of Pd(DMAP) 4 and the presence of free ligand was confirmed by ESI-MS (Fig. S27). TsOH (0.017 g, 0.1 mmol) was added and the suspension gently heated until all solids were dissolved. A further 1 H NMR spectrum was obtained revealing protonation of DMAP and reassembly of 2. Figure S26: Stacked 1 H NMR (500 MHz, d 6 -DMSO) spectra of a) 1, b) 2(BF 4 ) 4, c) 2(BF 4 ) 4 plus DMAP (8 eq.), and d) 2(BF 4 ) 4 plus DMAP plus TsOH (8 eq.). N.B. the signals for the reassembled cage differ slightly from the original due to interactions between the palladium cations and the sulfonate anions. This type of interaction has been studied and exploited extensively by Shionoya and coworkers. 1-3 S21
282.1005 304.0769 681.2306 683.2281 283.1005 685.2295 305.0747 306.0267 280.0817 284.1026 304.0845 282.1026 681.2449 683.2440 685.2452 305.0878 283.1059 280 285 304 306 Figure S27: Experimental (top) and theoretical (bottom) isotope patterns for [1H] +, [1Na] +, and [Pd(DMAP) 4 ](BF 4 ) + (left to right respectively). 306.0912 680 685 S22
4.2 2(BF 4 ) 4 + DMAP + Camphor-10-sulfonic acid (CSA). To a 4 mm solution of 2(BF 4 ) 4 in CD 3 CN (0.75 ml) was added DMAP (0.003 g, 0.02 mmol). After stirring for 5 minutes a 1 H NMR spectrum was obtained showing disassembly of the cage complex and formation of [Pd(DMAP) 4 ](BF 4 ) 2. CSA (0.006 g, 0.02 mmol) was added and the solution stirred for 5 minutes. A further 1 H NMR spectrum was obtained revealing protonation of DMAP. After 17 hours complete reassembly of 2 was observed. Figure S28: Stacked 1 H NMR (400 MHz, CD 3 CN) spectra of a) 1, b) 2(BF 4 ) 4, c) 2(BF 4 ) 4 plus DMAP (8 eq.), and d) 2(BF 4 ) 4 plus DMAP plus CSA (8 eq.). N.B. the signals for the reassembled cage differ slightly from the original due to interactions between the palladium cations and the sulfonate anions. This type of interaction has been studied and exploited extensively by Shionoya and coworkers. 1-3 S23
4.3 2(BF 4 ) 4 + Bu 4 NCl + AgSbF 6 To a 4 mm solution of 2(BF 4 ) 4 in d 6 -DMSO (0.75 ml) was added Bu 4 NCl (0.007 g, 0.02 mmol). A precipitate was observed to form. A 1 H NMR spectrum was obtained showing disassembly of the cage complex. Upon addition of AgSbF 6 (0.008 g, 0.02 mmol) no change in the 1 H NMR spectrum was observed. Subsequent addition of further AgSbF 6 (0.020 g, 0.06 mmol) resulted in the reassembly of the cage complex. Figure S29: Stacked 1 H NMR spectra (400 MHz, d 6 -DMSO) of a) 1, b) 2(BF 4 ) 4, c) plus Bu 4 NCl (8 eq.), d) plus AgSbF 6 (8 eq.), and e) plus further AgSbF 6 (20 eq.). S24
4.4 2(BF 4 ) 4 + Cisplatin + Bu 4 NCl To a 4 mm solution of 2(BF 4 ) 4 in CD 3 CN (0.75 ml) was added cisplatin (0.002 g, 0.005 mmol) and the mixture sonicated for 10 minutes. A downfield shift and broadening of the H a and H b signals was observed in the 1 H NMR spectrum, indicative of encapsulation of cisplatin within 2. Bu 4 NCl (0.007 g, 0.02 mmol) was added to the reaction mixture. A precipitate was observed to form. A 1 H NMR spectrum was obtained showing disassembly of the host-guest complex. Figure S30: Stacked 1 H NMR spectra (400 MHz, CD 3 CN) of a) 1, b) 2(BF 4 ) 4, c) host-guest adduct [2 (cisplatin) 2 ](BF 4 ) 4, and d) plus Bu 4 NCl (8 eq.). S25
5 Computer Modelling 5.1 SPARTAN Model of [2 (cisplatin)] Figure S31: MMFF force field energy minimised SPARTAN model of [2 (cisplatin)]. Ball-and-stick representations viewed from a) the side, and b) the top; space-fill representations viewed from c) the side, and b) the top. S26
6 X-Ray Crystallographic Data 6.1 X-ray data collection and refinement for 2(SbF 6 ) 4 X-ray data for 2(SbF 6 ) 4 were collected at 89 K on a Bruker Kappa Apex II area detector diffractometer using monochromated Mo Kα radiation. The structure was solved by direct methods and refined against F 2 using anisotropic thermal displacement parameters for all non-hydrogen atoms (except where noted below) using APEX II software. Hydrogen atoms were placed in calculated positions and refined using a riding model. The structure was solved in the primitive triclinic space group P 1 and refined to an R 1 value of 5.2%. Present in the asymmetric unit were two ligands bound orthogonally to a single Pd(II) atom, two hexafluoroantimonate counteranions (one of which is rotationally disordered), and multiple disordered solvent molecules (H 2 O, acetone and MeOH). The rotationally disordered hexafluoroantimonate counteranion was disordered over two sites with occupancies of 75% (F3 through F6) and 25% (F7 through F10). Sb1, F1 and F2 were all full occupancy. FLAT command was used to restrain F3 through F10 in the same plane. The quarter occupancy fluorine atoms did not behave well when refined anisotropically, thus were made isotropic. Figure S32: Ball-and-stick model of the rotationally disordered hexafluoroantimonate counteranion. Inside the cage cavity were present four water and one methanol molecules. All were refined as full occupancy. Outside the cage were present three partial occupancy methanol molecules, a full occupancy methanol molecule disordered over three sites, and a full occupancy acetone molecule. S27
Figure S33: Ball-and-stick representation of the crystal structure of 2(SbF 6 ) 4 showing disordered solvent molecules. SbF 6 counteranions and non-solvent hydrogen atoms have been removed for clarity. Figure S34: Ball-and-stick representation of the crystal structure of 2(SbF 6 ) 4 showing disordered solvent molecules within the internal cavity of the cage complex. SbF 6 counteranions, external solvent molecules and non-solvent hydrogen atoms have been removed for clarity. S28
6.2 Table 1. Crystal data and structure refinement for 2(SbF 6 ) 4. Identification code eg273 Empirical formula C 44.10 H 48.40 F 12 N 6 O 8.10 Pd Sb 2 Formula weight 1369.99 Temperature 293(2) K Wavelength 0.71069 Å Crystal system Triclinic Space group P 1 Unit cell dimensions a = 12.850(5) Å α= 66.868(5). b = 15.422(5) Å β= 88.549(5). c = 16.768(5) Å γ = 80.667(5). Volume 3012.7(18) Å 3 Z 2 Density (calculated) 1.510 Mg/m 3 Absorption coefficient 1.270 mm -1 F(000) 1352 Crystal size 0.45 x 0.13 x 0.12 mm 3 Theta range for data collection 1.46 to 20.68. Index ranges -12<=h<=12, -15<=k<=15, -16<=l<=16 Reflections collected 55742 Independent reflections 6112 [R(int) = 0.0854] Completeness to theta = 20.68 98.6 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7445 and 0.6373 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 6112 / 17 / 695 Goodness-of-fit on F 2 1.096 Final R indices [I>2sigma(I)] R 1 = 0.0517, wr 2 = 0.1386 R indices (all data) R 1 = 0.0670, wr 2 = 0.1498 Largest diff. peak and hole 1.145 and -0.684 e.å -3 S29
6.3 X-ray data collection and refinement for [2 (cisplatin) 2 ](BF 4 ) 4. X-ray data for [2 (cisplatin) 2 ](BF 4 ) 4 were collected at 89 K on a Bruker Kappa Apex II area detector diffractometer using monochromated Mo Kα radiation. The structure was solved by direct methods and refined against F 2 using anisotropic thermal displacement parameters for all non-hydrogen atoms using APEX II software. Hydrogen atoms were placed in calculated positions and refined using a riding model. The structure was solved in the primitive triclinic space group P 1 and refined to an R 1 value of 7.5%. One molecule of the host-guest adduct is present in the unit cell. ISOR command was used for atoms C1, C2 and C3. The tetrafluoroborate counteranions and solvent of crystallisation molecules were deemed too disordered to model. SQUEEZE was used to remove the aforementioned disorder, resulting in a void electron count of 374. With four tetrafluoroborate counteranions present totalling 168 electrons, the remaining 206 electrons can be accounted for by a variety of solvent molecule combinations from those solvents present, i.e. MeCN, DMF, Et 2 O and H 2 O (e.g. (MeCN) 2 (DMF) 3 (Et 2 O); (MeCN) 8 (H 2 O) 3 ). In the asymmetric unit two ligands are bound orthogonally to a single Pd(II) atom and one cisplatin molecule is present. In the crystal lattice the molecules are arranged in an interlocking fashion with a centroid-centroid distance between the central pyridine moieties of 4.67 Å. Figure S35: Ball-and-stick representation of the asymmetric unit cell of [2 (cisplatin) 2 ](BF 4 ). S30
Figure S36: Capped-stick representation of interlocking between adjacent host-guest molecules in the crystal lattice of [2 (cisplatin) 2 ](BF 4 ) 4. Hydrogen atoms have been removed for clarity. Figure S37: Space-fill representation of interlocking between adjacent host-guest molecules in the crystal lattice of [2 (cisplatin) 2 ](BF 4 ) 4. Hydrogen atoms have been removed for clarity. S31
6.4 Table 2. Crystal data and structure refinement for [2 (cisplatin) 2 ](BF 4 ) 4. Identification code jl_merged Empirical formula C 76 H 56 C l4 N 16 Pd 2 Pt 2 Formula weight 1938.15 Temperature 89(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P 1 Unit cell dimensions a = 11.9663(19) Å α= 76.455(9). b = 12.3450(19) Å β= 83.846(10). c = 17.495(3) Å γ = 85.135(10). Volume 2493.3(7) Å 3 Z 1 Density (calculated) 1.291 Mg/m 3 Absorption coefficient 3.299 mm -1 F(000) 940 Crystal size 0.32 x 0.32 x 0.31 mm 3 Theta range for data collection 1.20 to 26.47. Index ranges -14<=h<=14, -15<=k<=15, -21<=l<=21 Reflections collected 53506 Independent reflections 10143 [R(int) = 0.0729] Completeness to theta = 26.47 98.4 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.4278 and 0.4183 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 10143 / 18 / 454 Goodness-of-fit on F 2 1.093 Final R indices [I>2sigma(I)] R 1 = 0.0748, wr 2 = 0.2226 R indices (all data) R 1 = 0.0965, wr 2 = 0.2379 Largest diff. peak and hole 4.948 and -1.483 e.å -3 S32
6.5 Table 3. Squeeze results for [2 (cisplatin) 2 ](BF 4 ) 4. Platon squeeze void nr 1 Platon squeeze void average x 0.500 Platon squeeze void average y 0.238 Platon squeeze void average z 0.923 Platon squeeze void volume 908 Platon squeeze void count electrons 374 Platon squeeze void content Highly disordered BF 4 anions and solvent. The number of electrons is consistent with a number of combinations of solvent (H 2 O, DMF, Et 2 O and/or MeCN). S33
Electronic Supplementary Material (ESI) for Chemical Science 6.6 Space-filling representations of 2(SbF6)4 and [2 (cisplatin)2](bf4)4 Figure S38: Space-filling representations of the crystal structures of 2(SbF6)4 viewed from a) the side, and b) the top, and of [2 (cisplatin)2](bf4)4 viewed from c) the side, and d) the top. Counterions and solvent molecules had been removed for clarity. 7 References (1) (2) (3) Clever, G. H.; Tashiro, S.; Shionoya, M. Angew. Chem. Int. ed. 2009, 48, 7010. Sakata, Y.; Hiraoka, S.; Shionoya, M. Chem. Eur. J. 2010, 16, 3318. Clever, G. H.; Tashiro, S.; Shionoya, M. J. Am. Chem. Soc. 2010, 132, 9973. S34