Stimuli-Responsive Pd2L4 Metallosupramolecular Cages - The Royal ...

Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2011

Supporting Information

Stimuli-Responsive Pd2L4 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.

*[email protected]

S1


Contents 1

2

3

4

5

Experimental Procedures ................................................................................................................ 3 1.1

General .................................................................................................................................... 3

1.2

Synthesis of 2(BF4)4 ................................................................................................................. 3

1.3

Synthesis of 2(SbF6)4 ............................................................................................................... 4

1.4

Synthesis of [Pd(DMAP)4](BF4)2 ............................................................................................... 5

1.5

Synthesis of [Pd2(S1)4](BF4)4 .................................................................................................... 7

1

H DOSY NMR Spectra ..................................................................................................................... 9

2.1

1

2.2

1

2.3

1

7

H DOSY NMR spectrum of 2(BF4)4 (CD3CN, 298 K) ............................................................... 10 H DOSY NMR spectrum of 2(SbF6)4 (CD3CN, 298 K) ............................................................. 11

Mass Spectra ................................................................................................................................. 12 3.1

Mass Spectra of 2(BF4)4 ......................................................................................................... 12

3.2

Mass Spectra of 2(SbF6)4 ....................................................................................................... 14

3.3

Mass Spectra of [2⊃(cisplatin)2](BF4)4 .................................................................................. 16

3.4

Mass Spectra of [Pd(DMAP)4](BF4)2 ...................................................................................... 18

1

H NMR Experiments..................................................................................................................... 20

4.1

2(BF4)4 + DMAP + Tosylic Acid (TsOH) ................................................................................... 21

4.2

2(BF4)4 + DMAP + Camphor-10-sulfonic acid (CSA). .............................................................. 23

4.3

2(BF4)4 + Bu4NCl + AgSbF6...................................................................................................... 24

4.4

2(BF4)4 + Cisplatin + Bu4NCl ................................................................................................... 25

Computer Modelling ..................................................................................................................... 26 5.1

6

H DOSY NMR spectrum of 1 (CD3CN, 298 K) .......................................................................... 9

SPARTAN Model of [2⊃(cisplatin)] ........................................................................................ 26

X-Ray Crystallographic Data .......................................................................................................... 27 6.1

X-ray data collection and refinement for 2(SbF6)4 ................................................................ 27

6.2

Table 1. Crystal data and structure refinement for 2(SbF6)4................................................ 29

6.3

X-ray data collection and refinement for [2⊃(cisplatin)2](BF4)4. .......................................... 30

6.4

Table 2. Crystal data and structure refinement for [2⊃(cisplatin)2](BF4)4. .......................... 32

6.5

Table 3. Squeeze results for [2⊃(cisplatin)2](BF4)4. ............................................................. 33

6.6

Space-filling representations of 2(SbF6)4 and [2⊃(cisplatin)2](BF4)4 ..................................... 34

References .................................................................................................................................... 34

S2


1 1.1

Experimental Procedures General

Unless otherwise stated, all reagents were purchased from commercial sources and used without further purification. 1H and 13C 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 (CDCl3: 1H δ 7.26 ppm, 13C δ 77.16 ppm; CD3CN: 1H δ 1.94, 13C δ 1.32, 118.26 ppm, d6-DMSO: 1H δ 2.50 ppm; 13C 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(BF4)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(CH3CN)4](BF4)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(BF4)4 as a tan solid. Yield 0.200 g (0.12 mmol, 95%). 1H NMR (400 MHz, d6-DMSO) δ: 9.54 (s, 2H, Ha), 9.38 (dd, J = 1.5, 5.9 Hz, 2H, Hb), 8.35 (dt, J = 1.5, 8.2 Hz, 2H, Hd), 8.01 (t, J = 7.5 Hz, 1H, Hf), 7.86 (dd, J = 5.9, 8.1 Hz, 2H, Hc), 7.79 (d, J = 7.8 Hz, 2H, He). 1H NMR (400 MHz, CD3CN) δ: 9.34 (d, J = 1.5 Hz, 2H, Ha), 9.08 (dd, J = 1.2, 5.8 Hz, 2H, Hb), 8.17 (dt, J = 1.4, 8.0 Hz, 2H, Hd), 7.87 (t, J = 7.8 Hz, 1H, Hf), 7.68 (d, J = 7.8 Hz, 2H, He), 7.66 (dd, J = 5.8, 8.0 S3


Hz, 2H, Hc). 13C NMR (500 MHz, d6-DMSO) δ: 153.3 (Ca), 151.1(Cb), 143.5 (Cd), 141.8, 138.3 (Cf), 128.6 (Ce), 127.4 (Cc), 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 (CH3CN): m/z = 1598.1482 [Pd2(C19H11N3)4(BF4)3]+ calc. 1598.2022; 756.0795 [Pd2(C19H11N3)4(BF4)2]2+ calc. 756.0989. UV-Vis (DMSO, ε [M-1.cm-1]): λmax nm = 314 (1.02 × 105), 268 (1.20 × 105). Anal. Calc for 2(BF4)4.(CH3CN)3(H2O)3: C, 52.88; H, 3.19; N, 11.28%. Found: C, 52.67; H, 3.02; N, 11.40%.

Figure S2: 1H NMR (400 MHz, d6-DMSO) spectrum for 2(BF4)4.

Figure S3: 13C NMR (500 MHz, d6-DMSO) spectrum for 2(BF4)4.

1.3

Synthesis of 2(SbF6)4

AgSbF6 (0.172 g, 0.50 mmol, 2 eq.) and Pd(CH3CN)2Cl2 (0.065 g, 0.25 mmol, 1 eq.) were stirred in acetone (dry, 10 mL) under N2 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(SbF6)4 as a tan solid. Yield 0.225 g (0.10 mmol, 79%). 1H NMR (400 MHz, CD3CN) δ: 9.27 (s, 2H, Ha), 9.00 (dd, J = 1.1, 5.9 Hz, 2H, Hb), 8.17 (dt, J = 1.5, 8.1 Hz, 2H, Hd), 7.87 (t, J = 8.2 Hz, 1H, Hf), 7.68 (d, J = 7.8 Hz, 2H, He), 7.66 (dd, J = 5.8, 7.6 Hz, 2H, Hc). 13C NMR (400 MHz, CD3CN) δ: 154.5 (Ca), 151.4 (Cb), 144.5 (Cd), 143.3, 138.7 (Cf), 129.4 (Ce), 128.5 (Cc), 124.1, 94.6, 83.5. IR (ATR): υ (cm-1) 3069, 1579, 1557, 1482, 1448, 1417, 1239, 811, 696. HRESI-MS (CH3CN/CH3OH): m/z = 2044.8478 [Pd2(C19H11N3)4(SbF6)3]+ calc. 2044.8741; 904.9749 [Pd2(C19H11N3)4(SbF6)2]2+ calc. 904.9897. UV-Vis (DMSO, ε [M-1.cm-1]): λmax nm = 317 (9.10 × 104), 270 (1.05 × 105). Anal. Calc for 2(SbF6)4.(CH3COCH3)5: C, 42.50; H, 2.90; N, 6.54%. Found: C, 42.70; H, 3.11; N, 6.40%. S4


Figure S4: 1H NMR (400 MHz, CD3CN) spectrum for 2(SbF6)4.

Figure S5: 13C NMR (400 MHz, CD3CN) spectrum for 2(SbF6)4.

1.4

Synthesis of [Pd(DMAP)4](BF4)2

Figure S6: Labelling scheme for [Pd(DMAP)4](BF4)2. [Pd(CH3CN)4](BF4)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%). 1H NMR (400 MHz, d6-DMSO) δ: 8.22 (d, J = 7.1 Hz, 2H, Ha), 6.71 (d, J = 7.3 Hz, 2H, Hb), 2.96 (s, 6H, Hd). 1H NMR (400 MHz, CD3CN) δ: 7.97 (d, J = 7.4 Hz, 2H, Ha), 6.55 (d, J = 7.4 Hz, 2H, Hb), 2.98 (s, 6H, Hd). 13C NMR (400 MHz, CD3CN) δ: 156.1 (Ca), 150.0 (Cb), 109.2 (Cc), 39.59 (Cd). 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(C7H10N2)4(BF4)]+ calc. 681.2449; 297.1205 [Pd(C7H10N2)4]2+ calc. 297.1196. Anal. Calc for C28H40B2F8Pd: C, 43.75; H, 5.24; N, 14.58%. Found: C, 44.05; H, 5.36; N, 14.67%.

Figure S7: 1H NMR (400 MHz, CD3CN) spectrum for [Pd(DMAP)4](BF4)2.

Figure S8: 13C NMR (400 MHz, CD3CN) spectrum for [Pd(DMAP)4](BF4)2.

S6


1.5

Synthesis of [Pd2(S1)4](BF4)4

Figure S9: Self-assembly of cage complex S2 from ligand S1. To a stirring solution of [Pd(CH3CN)4](BF4)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%). 1H NMR (400 MHz, d6-DMSO) δ: 9.60 (s, 2H, Ha), 9.36 (d, J = 5.0 Hz, 2H, Hb), 8.28 (d, J = 8.0 Hz, 2H, Hd), 7.95 (s, 2H, Hg), 7.82 (dd, J = 5.9, 7.9 Hz, 2H, Hc), 7.73 (dd, J = 1.4, 7.9 Hz, 2H, He), 7.58 (t, J = 7.8, 1H, Hf). 13C NMR (400 MHz, d6-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 (CH3CN/CH3OH): m/z = 1594.2218 [Pd2(C20H12N2)4(BF4)3]+ calc. 1594.2213; 754.1044 [Pd2(C20H12N2)4(BF4)2]2+ calc. 754.1085; 333.5552 [Pd2(C20H12N2)4]4+ calc. 333.5521. UV-Vis (DMSO, ε [M-1.cm-1]): λmax nm = 286 (1.75 × 105). Anal. Calc for C80H48N8B4F16Pd: C, 61.01; H, 3.03; N, 7.11%. Found: C, 53.45; H, 3.03; N, 6.18%.

Figure S10: 1H NMR (400 MHz, d6-DMSO) spectrum for S2.

S7


Figure S11: 13C NMR (400 MHz, d6-DMSO) spectrum for S2.

S8


2 2.1

1

H DOSY NMR Spectra 1

H DOSY NMR spectrum of 1 (CD3CN, 298 K)

S9


2.2

1

H DOSY NMR spectrum of 2(BF4)4 (CD3CN, 298 K)

S10


2.3

1

H DOSY NMR spectrum of 2(SbF6)4 (CD3CN, 298 K)

S11


3

Mass Spectra

3.1

Mass Spectra of 2(BF4)4

Intens. x105

+MS, 0.2-1.0min #(10-59) 547.5397

2.0

1.5

1.0

385.9911

300.0890

0.5

687.0769

1599.1474

1006.4563 0.0 500

1000

1500

2000

2500

m/z

+

Figure S12: HR-ESI Mass Spectrum (+ve ion, MeCN) of 2(BF4)4. m/z = 1598.1482 [Pd2(1)4(BF4)3] ; 756.0795 [Pd2(1)4(BF4)2]2+.

S12


Intens. x104

+MS, 0.1-0.9min #(6-54) 756.0794 755.0793

755.5801

1.5 754.5787 756.5807 757.0784 754.0790 1.0

757.5808

758.0803

753.5755

0.5

758.5798 753.0733

759.0916

752.0030 752.5327 751.0019 751.4981

759.5795

0.0

(C19H11N3)4Pd2(BF4)2, M ,1510.19

2000

755.5990 756.0989 755.0988

1500 754.5988

756.5994 757.0991

754.0987

1000

757.5997 753.5989

500

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 [Pd2(1)4(BF4)3] . Intens.

+MS, 0.1-0.9min #(6-54)

8000

1598.14811599.1472 1597.1454

1600.1482 1596.1460

6000

1601.1506 1595.1460 4000 1602.1534 1594.1476 1603.1515 2000 1593.1497

1604.1529 1605.1520

1592.1484

1606.1410

0

(C19H11N3)4Pd2(BF4)3, M ,1597.20 1598.2022

2000

1597.2019

1599.2021

1596.2018 1600.2028 1500 1595.2017

1601.2023

1000 1602.2033 1594.2023

1603.2031 500 1593.2030

1604.2042 1605.2047

1592.2039

1606.2059

0 1590.0

1592.5

1595.0

1597.5

1600.0

1602.5

1605.0

1607.5

1610.0

2+

Figure S14: Experimental (top) and theoretical (bottom) isotope patterns for [Pd2(1)4(BF4)2] . S13

m/z


3.2

Mass Spectra of 2(SbF6)4

Intens. x106

+MS, 11.5-15.7min #(683-937) 282.1049

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(SbF6)4. m/z = 2044.8478 [Pd2(1)4(SbF6)3] ; 904.9749 [Pd2(1)4(SbF6)2]2+.

S14


Intens.

+MS, 11.5-15.7min #(683-937) 2044.8478 2043.8408

500

2042.8628

2045.8551 2046.8338

2047.8415

400 2041.8562 2040.8500

2048.8495 300 2039.8439 2049.8578

200 2038.8382

2050.8375

2037.8326

2051.8462

100

0

(C19H11N3)4Pd2(SbF6)3, M ,2040.87 2044.8741

2000

2046.8746

2043.8745 2042.8736 1500

2047.8760

2041.8739

2048.8753 1000 2040.8731 2049.8767 2050.8763

2039.8735

500

2051.8776

2038.8726

2052.8777 2053.8788

2037.8735 0 2035

2040

2045

2050

2055

m/z

+

Figure S16: Experimental (top) and theoretical (bottom) isotope patterns for [Pd2(1)4(SbF6)3] . Intens. x104

+MS, 11.5-15.7min #(683-937) 904.9749

902.9718

1.25

903.9749

1.00 905.9763

901.9693

906.9749

0.75 900.9647

904.4837 903.4837

905.4844

899.9645

0.50

902.4829

898.9632

907.9752

906.4849

908.9731

0.25 907.4850

897.9633

0.00

Pd2(C19H11N3)4(SbF6)2, M ,1805.98 904.9897

2000 903.9894

903.4896

1500

905.4903

902.9892

906.4907

1000

906.9904

902.4893

500

907.4911

901.9889

907.9911 901.4893

908.4917 908.9921

900.9890 0 896

898

900

902

904

906

908

910

912

914 m/z

2+

Figure S17: Experimental (top) and theoretical (bottom) isotope patterns for [Pd2(1)4(SbF6)2] . S15


3.3

Mass Spectra of [2⊃(cisplatin)2](BF4)4

Intens.

+MS, 0.5-1.5min #(27-88)

2198.1578 2199.1594

2000 2196.1619

2200.1607 2201.1643

2195.1640 2202.1625

1500

2194.1608 2203.1591 2193.1593

1000

2204.1663 2192.1637

2205.1698 2206.1796 2207.1759

2191.1793

2183.2888 500

(C19H11N3)4Pd2(BF4)3(PtN2H6Cl2)2, M ,2195.11 2000

2198.1093

1500

2200.1093

2196.1094

2201.1093

2195.1095 1000

2202.1094 2194.1096 2203.1095 2193.1098 2204.1096

500 2192.1100

2205.1097 2206.1099

2191.1102

2207.1100

2190.1105 0 2180

2185

2190

2195

2200

2205

2210

2215

m/z

Figure S18: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF4)3⊃2[Pt(NH3)2Cl2]}+. Intens.

+MS, 0.5-1.5min #(27-88)

1055.5713 6000

1056.5710

1054.5700

1057.0710 1054.0693

5000

1057.5709 4000

1053.5679

3000

1058.0707

1053.0650

1058.5690 1059.0682

1052.5600

2000 1049.5346

1052.0549

1059.5651

1051.5456

1060.0615 1060.5532

1000

0

(C19H11N3)4Pd2(BF4)2(PtN2H6Cl2)2, M ,2108.11

2500

2000 1055.5526

1056.5526 1054.5526

1500

1057.0526

1054.0526 1057.5527 1000

1053.5526

1058.0527 1058.5528

1053.0527 500

1059.0528 1052.5528

1059.5530

1052.0528

1060.0530

1051.5529 0 1048

1050

1052

1054

1056

1058

1060

1062

1064

Figure S19: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF4)2⊃2[Pt(NH3)2Cl2]}2+.

S16

1066

m/z


Intens.

+MS, 0.5-1.5min #(27-88)

1898.1980 1899.1978 1897.1974

4000

1900.1982

1896.1983

1901.1982 1895.1988 3000 1902.2003 1894.2003 1903.2013 2000 1904.2021

1893.1978

1905.2041 1892.2041

1000

1906.2100 1907.2170

1891.2056

1880.2052

1912.2236

1916.2346

1918.2385

(C19H11N3)4Pd2(BF4)3(PtN2H6Cl2), M ,1896.15 2000

1898.1559

1500 1896.1558

1900.1560

1901.1560

1895.1558 1000

1902.1563 1894.1560 1903.1563 500

1893.1562 1904.1568 1905.1568

1892.1566

1906.1574

1891.1571 0 1880

1885

1890

1895

1900

1905

1910

1915

m/z

Figure S20: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF4)3⊃[Pt(NH3)2Cl2]}+.

Intens. x104

+MS, 0.5-1.5min #(27-88) 905.5928 905.0923

1.0

906.5933 904.5934 0.8

907.0926

904.0922 0.6

907.5922

903.5924

908.0922

0.4 903.0916

908.5935 909.0905

0.2 902.5922

898.1528 900.0044

900.9962

909.5919 910.0830

902.0838

0.0

(C19H11N3)4Pd2(BF4)2(PtN2H6Cl2), M ,1809.15

2000

905.5758

1500

906.5760

904.5758

907.0759 904.0757 907.5761

1000 903.5758

500

908.0761

908.5764

903.0758

909.0764 902.5760

909.5767

902.0762 0 898

900

902

904

906

908

910

912

Figure S21: Experimental (top) and theoretical (bottom) isotope patterns for {2(BF4)2⊃[Pt(NH3)2Cl2]}2+. S17

914

m/z


3.4

Mass Spectra of [Pd(DMAP)4](BF4)2

Intens. x104

+MS, 0.1-2.8min #(8-168) 350.0720

8

491.1532

6

4

297.1196

395.0664

2

681.2381

0 400

600

800

1000

1200

1400

1600

1800

2000

Figure S22: HR-ESI Mass Spectrum (+ve ion, MeCN) of [Pd(DMAP)4](BF4)2. m/z = 681.2381 [Pd(C7H10N2)4(BF4)]+; 297.1205 [Pd(C7H10N2)4]2+.

S18

2200 m/z


Intens.

+MS, 0.2-2.8min #(9-166) 681.2381 680.2392

683.2376

6000

4000 679.2390

682.2399 685.2390 684.2399

2000

686.2415 678.2416 0

(C7H10N2)4Pd(BF4), M ,681.24

2000

681.2449

1500

680.2452 683.2440

1000

679.2442

682.2468 685.2452 684.2472

500

686.2485

678.2476 677.2456 0 670

675

680

685

690

695

m/z

+

Figure S23: Experimental (top) and theoretical (bottom) isotope patterns for [Pd(DMAP)4](BF4) . Intens. x104

+MS, 0.2-2.8min #(9-166) 297.1196

3.0

298.1191

2.5 296.6197 2.0

1.5 299.1194

1.0

297.6199

296.1187

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 296.1203

500

297.6217

298.6219

299.6225 295.1211 0 292

294

296

298

300

302

304

2+

Figure S24: Experimental (top) and theoretical (bottom) isotope patterns for [Pd(DMAP)4] . S19

m/z


4

1

H NMR Experiments

Figure S25: Reaction scheme for 1H NMR disassembly/reassembly experiments.

S20


4.1

2(BF4)4 + DMAP + Tosylic Acid (TsOH)

To a 17 mM solution of 2(BF4)4 in d6-DMSO (0.75 mL) was added DMAP (0.012 g, 0.1 mmol). After stirring for 5 minutes a 1H NMR spectrum was obtained showing disassembly of the cage complex and formation of [Pd(DMAP)4](BF4)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 1H NMR spectrum was obtained revealing protonation of DMAP and reassembly of 2.

Figure S26: Stacked 1H NMR (500 MHz, d6-DMSO) spectra of a) 1, b) 2(BF4)4, c) 2(BF4)4 plus DMAP (8 eq.), and d) 2(BF4)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

681.2306

304.0769

683.2281

685.2295

283.1005

305.0747

306.0267 284.1026

280.0817

304.0845

282.1026

681.2449

683.2440

685.2452 305.0878 283.1059

306.0912 280

285

304

306

680

685

Figure S27: Experimental (top) and theoretical (bottom) isotope patterns for [1H]+, [1Na]+, and [Pd(DMAP)4](BF4) + (left to right respectively).

S22


4.2

2(BF4)4 + DMAP + Camphor-10-sulfonic acid (CSA).

To a 4 mM solution of 2(BF4)4 in CD3CN (0.75 mL) was added DMAP (0.003 g, 0.02 mmol). After stirring for 5 minutes a 1H NMR spectrum was obtained showing disassembly of the cage complex and formation of [Pd(DMAP)4](BF4)2. CSA (0.006 g, 0.02 mmol) was added and the solution stirred for 5 minutes. A further 1H NMR spectrum was obtained revealing protonation of DMAP. After 17 hours complete reassembly of 2 was observed.

Figure S28: Stacked 1H NMR (400 MHz, CD3CN) spectra of a) 1, b) 2(BF4)4, c) 2(BF4)4 plus DMAP (8 eq.), and d) 2(BF4)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(BF4)4 + Bu4NCl + AgSbF6

To a 4 mM solution of 2(BF4)4 in d6-DMSO (0.75 mL) was added Bu4NCl (0.007 g, 0.02 mmol). A precipitate was observed to form. A 1H NMR spectrum was obtained showing disassembly of the cage complex. Upon addition of AgSbF6 (0.008 g, 0.02 mmol) no change in the 1H NMR spectrum was observed. Subsequent addition of further AgSbF6 (0.020 g, 0.06 mmol) resulted in the reassembly of the cage complex.

Figure S29: Stacked 1H NMR spectra (400 MHz, d6-DMSO) of a) 1, b) 2(BF4)4, c) plus Bu4NCl (8 eq.), d) plus AgSbF6 (8 eq.), and e) plus further AgSbF6 (20 eq.).

S24


4.4

2(BF4)4 + Cisplatin + Bu4NCl

To a 4 mM solution of 2(BF4)4 in CD3CN (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 Ha and Hb signals was observed in the 1H NMR spectrum, indicative of encapsulation of cisplatin within 2. Bu4NCl (0.007 g, 0.02 mmol) was added to the reaction mixture. A precipitate was observed to form. A 1H NMR spectrum was obtained showing disassembly of the host-guest complex.

Figure S30: Stacked 1H NMR spectra (400 MHz, CD3CN) of a) 1, b) 2(BF4)4, c) host-guest adduct [2⊃(cisplatin)2](BF4)4, and d) plus Bu4NCl (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 6.1

X-Ray Crystallographic Data X-ray data collection and refinement for 2(SbF6)4

X-ray data for 2(SbF6)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 F2 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 R1 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 (H2O, 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(SbF6)4 showing disordered solvent molecules. SbF6 counteranions and non-solvent hydrogen atoms have been removed for clarity.

Figure S34: Ball-and-stick representation of the crystal structure of 2(SbF6)4 showing disordered solvent molecules within the internal cavity of the cage complex. SbF6 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(SbF6)4.

Identification code

eg273

Empirical formula

C44.10 H48.40 F12 N6 O8.10 Pd Sb2

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)°.

Å3

Volume

3012.7(18)

Z

2

Density (calculated)

1.510 Mg/m3

Absorption coefficient

1.270 mm-1

F(000)

1352

Crystal size

0.45 x 0.13 x 0.12 mm3

Theta range for data collection

1.46 to 20.68°.

Index ranges

-12