1

Supplementary Materials

Design, synthesis and characterization of novel thiol-derivatized

ibuprofen monolayer protected gold clusters

Kuan-Han Lee, Yu-Sheng Lin, Po-Jui Huang

Table of Contents

Experimental Procedures S1-S12

1H NMR and 13C NMR spectra for compound 4 and 8 S13-S15

Experimental Procedures

N-Hydroxypentyl-2-(4-isobutylphenyl)propionamide (2a)

To a stirred solution of ibuprofen (1.00 g, 4.85 mmol) in dry THF (40 ml) and DMF

(10 ml) was added EDCI (0.90 g, 5.82 mmol) at 0oC. The solution was stirred at 0oC

for 10 min. Then 5-amino-1-pentanol (0.60g, 5.82 mmol) was added, and the solution

was stirred at rt for 24 h. The reaction mixture was poured into ice-water and

extracted with 50 ml ethyl acetate twice. The combined organic layer were extracted

with cold brine and dried over MgSO4. The solvent was removed under reduced

2

pressure to give a crude oil, which was purified by flash column chromatography with

dichloromethane-methanol (100 : 1) as eluant to afford compound 2 as yellow oil

(0.748 g, 53%). 1H NMR (CDCl3, 400 MHz) δ 7.187 (d, 2H, J = 4.0 Hz, ArH), δ

7.111 (d, 2H, J = 4.0 Hz, ArH), δ 5.587 (br, 1H, NH), δ 3.572 (t, 2H, J = 3.2 Hz, CH2),

δ 3.521 (q, 1H, J = 3.6 Hz, CH), δ 3.207~3.157 (m, 2H, CH2), δ 2.452 (d, 2H, J = 3.6

Hz, CH2), δ 2.215 (br, 1H, OH), δ 1.847 (m, 1H, J = 3.4 Hz, CH), δ 1.548~1.468 (m,

2H, CH2), δ 1.498 (d, 3H, J = 3.6 Hz, CH3), δ 1.449-1.395 (m, 2H, CH2), δ

1.317-1.238 (m, 2H, CH2), δ 0.897 (d, 6H, J = 3.4 Hz, (CH3)2). 13C NMR (CDCl3,

100 MHz) δ 174.672 (C=O), 140.637 (ArC), 138.514 (ArC), δ 129.516 (ArC), δ

127.216 (ArC), δ 62.355 (OCH2), δ 46.648 (CH2), δ 44.913 (NCH2), δ 39.326 (CH), δ

31.981 (CH2), δ 30.093 (CH2), δ 29.100 (CH2), δ 22.763 (CH2), δ 22.285 ((CH3)2), δ

18.359 (CH3). IR (νmax cm-1) 3299.9, 2930.5, 2359.5, 1648.9, 1547.2, 1457.2, 1368.2,

1235.8, 1061.0, 844.9, 784.6, 705.2, 564.2, 496.3. HRMS (ESI, m/z) C18H29NO2Na

calcd 314.2096, found 314.2093.

N-Hydroxyhexyl-2-(4-isobutylphenyl)propionamide (2b) 1H NMR (CDCl3, 400 MHz)

δ 7.188 (d, 2H, J = 4.0 Hz, ArH), δ 7.112 (d, 2H, J = 4.0 Hz, ArH), δ 5.515 (br, 1H,

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NH), δ 3.581 (t, 2H, J = 3.2 Hz, OCH2), δ 3.523 (q, 1H, J = 3.6 Hz, CH), δ 3.175 (m,

2H, J = 3.6 Hz, NCH2), δ 2.453 (d, 2H, J = 3.6 Hz, CH2), δ 2.149 (br, 1H, OH), δ

1.848 (m, 1H, J = 3.4 Hz, CH), δ 1.539~1.469 (m, 2H, CH2), δ 1.501 (d, 3H, J = 3.6

Hz, CH3), δ 1.443-1.371 (m, 2H, CH2), δ 1.356-1.282 (m, 2H, CH2), δ 1.254-1.191 (m,

2H, CH2), δ 0.897 (d, 6H, J = 3.4 Hz, (CH3)2). 13C NMR (CDCl3, 100 MHz) δ

174.566 (C=O), 140.614 (ArC), 138.529 (ArC), δ 129.509 (ArC), δ 127.273 (ArC), δ

62.416 (OCH2), δ 46.656 (CH), δ 44.905 (NCH2), δ 39.235 (CH2), δ 32.375 (CH2), δ

30.101 (CH), δ 29.312 (CH2), δ 26.174 (CH2), δ 25.067 (CH2), δ 22.285 ((CH3)2), δ

18.359 (CH3). IR (νmax cm-1) 3294.5, 3081.7, 2926.1, 1903.1, 1644.8, 1543.6, 1456.0,

1368.4, 1235.5, 1059.3, 921.8, 844.8, 797.3, 703.6, 592.1, 506.2, 484.6. HRMS (ESI,

m/z) C19H31NO2Na calcd 328.2252, found 328.2249.

2-(4-Isobutylphenyl)propanamido)pentyl-4-methylbenznesulfonate (3a)

To the solution of compound 2a (1.00 g, 3.43 mmol) in 30 ml CH2Cl2 was added

triethylamine (2.43 g, 24.01 mmol) and the mixture was stirred at 0oC for 5 min. Then

p-toluenesulfonyl chloride (1.96 g, 10.29 mmol) and 4-dimethylaminopyridine (0.50 g,

4.12 mmol) were added. The reaction mixture was stirred at rt for 4h and the solvent

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was removed under reduced pressure. The residue obtained was subjected to silica gel

column chromatography using CH2Cl2 as eluant to afford compound 3a as yellow oil

(43%). 1H NMR (CDCl3, 400 MHz) δ 7.768 (d, 2H, J = 4.0 Hz, ArH), δ 7.341 (d, 2H,

J = 4.0 Hz, ArH), δ 7.176 (d, 2H, J = 4.0 Hz, ArH), δ 7.108 (d, 2H, J = 4.0 Hz, ArH),

δ 5.385 (br, 1H, NH), δ 3.967 (t, 2H, J = 3.2 Hz, OCH2), δ 3.495 (m, 1H, J = 3.6 Hz,

CH), δ 3.127 (m, 2H, J = 3.4 Hz, CH2), δ 2.451 (d, 2H, J = 3.6 Hz, CH2), δ 2.448 (s,

3H, CH3), δ 1.846 (m, 1H, J = 3.4 Hz, CH), δ 1.629~1.560 (m, 2H, CH2), δ 1.493 (d,

3H, J = 3.6 Hz, CH3), δ 1.356 (m, 2H, J = 3.6 Hz, CH2), δ 1.270-1.211 (m, 2H, CH2),

δ 0.895 (d, 6H, J = 3.2 Hz, (CH3)2). 13C NMR (CDCl3, 100 MHz) δ 174.452 (C=O),

144.715 (ArC), 140.682 (ArC), 138.537 (ArC), 133.041 (ArC), δ 129.812 (ArC), δ

129.585 (ArC), δ 127.803 (ArC), δ 127.280 (ArC), δ 70.231 (OCH2), δ 46.694 (CH),

δ 44.935 (NCH2), δ 39.114 (CH2), δ 30.116 (CH), δ 28.744 (CH2), δ 28.327 (CH2), δ

22.520 (CH2), δ 22.323 ((CH3)2), δ 21.596 (CH3), δ 18.389 (CH3). IR (νmax cm-1)

3711.9, 3298.4, 2953.2, 2867.9, 2373.0, 1869.7, 1648.2, 1543.2, 1459.8, 1359.7,

1231.2, 1176.4, 1017.9, 958.8, 920.3, 811.0, 793.4, 773.1. HRMS (ESI, m/z)

C25H35NO4SNa calcd 468.2184, found 468.2181.

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Compound 3b was prepared from 2b following the procedure described for 3a as

yellow oil (47%). 1H NMR (CDCl3, 400 MHz) δ 7.777 (d, 2H, J = 4.2 Hz, ArH), δ

7.345 (d, 2H, J = 4.2 Hz, ArH), δ 7.172 (d, 2H, J = 1.8 Hz, ArH), δ 7.124 (d, 2H, J =

1.8 Hz, ArH), δ 5.346 (br, 1H, NH), δ 3.979 (t, 2H, J = 3.2 Hz, OCH2), δ 3.518-3.469

(m, 2H, NCH2), δ 3.131 (q, 1H, J = 3.4 Hz, CH), δ 2.452 (d, 2H, J = 3.4 Hz, CH2), δ

2.449 (s, 3H, CH3), δ 1.846 (m, 1H, J = 3.2Hz, J = 3.4 Hz, CH), δ 1.617~1.547 (m,

2H, J = 3.4 Hz, CH2), δ 1.499 (d, 3H, J = 3.4 Hz, CH3), δ 1.389-1.313 (m, 2H, CH2),

δ 1.281-1.206 (m, 2H, CH2), δ 1.183-1.120 (m, 2H, CH2), δ 0.895 (d, 6H, J = 3.2 Hz,

(CH3)2). 13C NMR (CDCl3, 100 MHz) δ 174.437 (C=O), 144.692 (ArC), 140.690

(ArC), 138.575 (ArC), 133.080 (ArC), δ 129.804 (ArC), δ 129.577 (ArC), δ 127.818

(ArC), δ 127.303 (ArC), δ 70.375 (OCH2), δ 46.717 (CH), δ 44.950 (NCH2), δ 39.258

(CH2), δ 30.139 (CH), δ 29.199 (CH2), δ 28.623 (CH2), δ 25.962 (CH2), δ 24.901

(CH2), δ 22.323 ((CH3)2), δ 21.596 (CH3), δ 18.382 (CH3). IR (νmax cm-1) 3321.9,

3051.8, 2928.8, 2865.5, 1730.8, 1658.6, 1514.4, 1461.6, 1358.5, 1265.8, 1175.6,

1097.8, 962.1, 932.5, 816.2, 768.0, 694.5, 631.5, 518.7, 503.4. HRMS (ESI, m/z)

C26H37NO4SNa calcd. 482.2341, found 482.2342.

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2-(4-Isobutylphenyl)-N-meracptopentylpropionamide (4a)

To the solution of Compound 3a (1.00 g, 2.25 mmol) in 50 ml MeOH, NaSH (0.50 g,

8.98 mmol) in 10 ml H2O was added dropwise and the mixture was stirred at rt for

24h. The solution was concentrated and extracted with EtOAc (2 x 20 ml). The

organic layers were combined and evaporated. The resulting residue was subjected to

flash column chromatography using CH2Cl2-MeOH (10 : 1) as eluant to afford 4a

(38% yield) as white solid (m.p. 153-154 oC). 1H NMR (CD3OD, 400 MHz) δ 7.236

(d, 2H, J = 4.0 Hz, ArH), δ 7.087 (d, 2H, J = 4.0 Hz, ArH), δ 4.616 (br, 1H, NH), δ

3.593 (q, 1H, J = 3.6 Hz, CH), δ 3.192-3.116 (m, 2H, CH2), δ 3.016 (t, 2H, J = 3.6 Hz,

NCH2), δ 2.440 (d, 2H, J = 3.6 Hz, CH2), δ 1.831 (m, 1H, J = 3.4 Hz, CH), δ 1.732 (m,

2H, J = 3.6 Hz, CH2), δ 1.487 (m, 2H, J = 3.4 Hz, J = 3.6 Hz, CH2), δ 1.418 (d, 3H,

CH3), δ 1.396-1.336 (m, 2H, CH2), δ 0.835 (d, 6H, J = 3.4 Hz, (CH3)2). 13C NMR

(CD3OD, 100 MHz) δ 177.283 (C=O), 141.433 (ArC), 140.455 (ArC), δ 130.241

(ArC), δ 128.111 (ArC), δ 47.174 (CH), δ 46.017 (CH2), δ 40.157 (NCH2), δ 35.784

(CH2), δ 31.465 (CH), δ 30.124 (CH2), δ 29.677 (CH2), δ 26.835 (CH2), δ 22.713

((CH3)2), δ 18.727 (CH3). IR (νmax cm-1) 3326.9, 2925.1, 2856.0, 2359.5, 1643.1,

1536.1, 1426.6, 1369.7, 1222.9, 1188.9, 1036.4, 847.2, 777.4, 665.3, 523.1. HRMS

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(ESI, m/z) C18H29NOSNa calcd 330.1867, found 330.1870.

Compound 4b was prepared from 3b as white solid (m.p. 148-149 oC) in 45% yield.

1H NMR (CD3OD, 400 MHz) δ 7.232 (d, 2H, J = 4.0 Hz, ArH), δ 7.085 (d, 2H, J =

4.0 Hz, ArH), δ 4.618 (br, 1H, NH), δ 3.588 (q, 1H, J = 3.6 Hz, CH), δ 3.187-3.079

(m, 2H, NCH2), δ 3.024 (t, 2H, J = 3.6 Hz, SCH2), δ 2.444 (d, 2H, J = 3.6 Hz, CH2), δ

1.832 (m, 1H, J = 3.4 Hz, CH), δ 1.747~1.673 (m, 2H, J = 3.6 Hz, J = 3.8 Hz, CH2), δ

1.497-1.331 (m, 4H, J = 3.4 Hz, J = 3.6 Hz, CH2CH2), δ 1.413 (d, 3H, J = 3.6 Hz,

CH3), δ 1.286-1.227 (m, 2H, CH2), δ 0.885 (d, 6H, J = 3.2 Hz, (CH3)2). 13C NMR

(CD3OD, 100 MHz) δ 177.235 (C=O), 141.440 (ArC), 140.501 (ArC), 130.241 (ArC),

δ 128.104 (ArC), δ 47.174 (CH), δ 46.022 (NCH2), δ 40.278 (CH2), δ 35.777 (CH2), δ

31.473 (CH), δ 30.442 (CH2), δ 30.094 (CH2), δ 29.396 (CH2), δ 27.282 (CH2), δ

22.713 ((CH3)2), δ 18.735 (CH3). IR (νmax cm-1) 3494.5, 3330.9, 2923.6, 2854.3,

1646.3, 1538.3, 1461.0, 1365.1, 1222.0, 1173.9, 1035.8, 807.7, 729.4, 639.1, 613.9,

526.1, 409.5. HRMS (ESI, m/z) C19H31NOSNa calcd 344.2024, found 344.2024.

N-(4-Hydroxyphenyl)-2-(4-isobutylphenyl)proionamide (6)

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Compound 6 was prepared from ibuprofen (1.00 g, 4.85 mmol) and 4-hydroxyaniline

(0.53 g, 4.85 mmol) following the similar procedure described for 2a in 83.3% yield.

M.p. 135-136 oC. 1H NMR (CDCl3, 400 MHz) δ 7.240 (d, 2H, J = 4.0 Hz, ArH), δ

7.183 (br, 1H, NH), δ 7.131 (d, 2H, J = 4.0 Hz, ArH), δ 7.109 (d, 2H, J = 4.4 Hz,

ArH), δ 6.675 (d, 2H, J = 4.4 Hz, ArH), δ 3.692 (q, 1H , J = 3.6 Hz, CH), δ 2.454 (d,

2H, J = 3.6 Hz, CH2), δ 1.848 (m, 1H, J = 3.6 Hz, CH), δ 1.563 (d, 3H, J = 3.6 Hz,

CH3), δ 0.896 (d, 6H, J = 3.4 Hz, (CH3)2). 13C NMR (CDCl3, 100 MHz) δ 173.505

(C=O), 153.531 (ArC), 141.069 (ArC), 137.870 (ArC), 129.812 (ArC), δ 129.660

(ArC), δ 127.401 (ArC), δ 122.717 (ArC) , δ 115.728 (ArC), δ 47.293 (CH), δ 44.958

(CH2), δ 30.123 (CH), δ 22.346 (CH3)2), δ 18.374 (CH3). IR (νmax cm-1) 3300.1,

2952.4, 2361.9, 1719.4, 1653.6, 1612.6, 1537.7, 1510.3, 1452.1, 1377.7, 1231.2,

1167.4, 1065.5, 1000.9, 936.4, 828.0, 777.0, 667.6. HRMS (ESI, m/z) C19H23NO2Na

calcd. 320.1626, found 320.1624.

N-[4-(4-Bromobut-2-enyloxy)phenyl]-2-(4-isobutylphenyl) propionamide (7)

Compound 6 (1.00 g, 3.37 mmol) and K2CO3 (0.93 g, 6.73 mmol) in 40 ml butanone

was stirred at rt, then 4-bromo-2-buten-1-ol (2.03 g, 13.48 mmol) was added. The

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resulting mixture was heated to reflux for 3 h. The solvent was evaporated under

reduced pressure, then the resulting mixture was extracted with EtOAc (20 ml x 2).

The combined organic layers were removed and the residue was subjected to flash

column chromatography by using n-hexane-EtOAc (10 : 1) as eluant to afford 7 as

white solid (72%). M.p. 112-113 oC. 1H NMR (CDCl3, 400 MHz) δ 7.306 (d, 2H, J =

4.4 Hz, ArH), δ 7.258 (d, 2H, J = 4.0 Hz, ArH), δ 7.155 (d, 2H, J = 4.0 Hz, ArH), δ

6.902 (br, 1H, NH), δ 6.804 (d, 2H, J = 4.4 Hz, ArH), 6.087-6.012 (m, 1H, CH),

5.986-5.923 (m, 1H, CH), δ 5.503 (d, 2H, J = 4.6 Hz, OCH2), δ 3.973 (d, 2H, J = 3.6

Hz, CH2Br), δ 3.674 (q, 1H , J = 3.6 Hz, CH), δ 2.472 (d, 2H, J = 3.6 Hz, CH2), δ

1.864 (m, 1H, J = 3.4 Hz, CH), δ 1.588 (d, 3H, J = 3.6 Hz, CH3), δ 0.909 (d, 6H, J =

3.4 Hz, (CH3)2). 13C NMR (CDCl3, 100 MHz) δ 174.589 (C=O), 156.375 (ArC), δ

141.261 (ArC), δ 140.873 (ArC), δ 133.624 (ArC), δ 130.103 (ArC), δ 129.899 (CH),

δ 129.697 (ArC), δ 128.496 (CH), δ 123.013 (ArC), δ 115.157 (ArC), δ 67.235

(OCH2), δ 48.156 (CH), δ 46.318 (CH2), δ 39.824 (CH2), δ 31.253 (CH2), δ 22.766

(CH3)2), δ 18.973 (CH3). IR (νmax cm-1) 3293.9, 2951.0, 2361.3, 1656.0, 1600.5,

1539.6, 1508.7, 1457.4, 1411.8, 1379.6, 1292.9, 1229.7, 1175.0, 1017.4, 974.8, 832.7.

HRMS (ESI, m/z) C23H28BrNO2Na calcd 452.1201, found 452.1203.

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2-(4-Isobutylphenyl)-N-[4-(4-mercaptobut-2-enyloxy)phenyl] propionamide (8)

Compound 8 was prepared from 7 following the similar procedure described for 4a.

in 56% yield. M.p. 143-143.8 oC. 1H NMR (CD3OD, 400 MHz) δ 7.391 (d, 2H, J =

4.4 Hz, ArH), δ 7.297 (d, 2H, J = 4.0 Hz, ArH), δ 7.106 (d, 2H, J = 4.0 Hz, ArH), δ

6.852 (d, 2H, J = 4.4 Hz, ArH), δ 6.074-5.993 (m, 1H, CH), δ 5.923-5.855 (m, 1H,

CH), δ 4.480 (d, 2H, CH2), δ 3.756 (m, 3H, CH+CH2), δ 2.444 (d, 2H, J = 3.6 Hz,

CH2), δ 1.836 (m, 1H, J = 3.4 Hz, CH), δ 1.482 (d, 3H, J = 3.6 Hz, CH3), 0.887 (d, 6H,

J = 3.4 Hz, (CH3)2). 13C NMR (CD3OD, 100 MHz) δ 175.366 (C=O), 156.785 (ArC),

141.516 (ArC), 140.334 (ArC), 132.999 (ArC), δ 130.301 (ArC), δ 129.998 (CH), δ

129.778 (CH), δ 128.111 (ArC), δ 123.095 (ArC), δ 115.851 (ArC), δ 69.164 (OCH2),

δ 47.651 (CH), δ 46.030 (NCH2), δ 37.482 (SCH2), δ 31.450 (CH), δ 22.705 (CH3)2),

δ 19.114 (CH3). IR (νmax cm-1) 3434.1, 3296.4, 2952.3, 2910.4, 2858.2, 2361.2,

1719.4, 1653.0, 1601.7, 1514.2, 1459.6, 1412.2, 1381.8, 1291.4, 1235.4, 1052.0,

1010.2, 963.6, 825.0, 775.7, 666.4, 528.8. HRMS (ESI, m/z) C23H29NO2S calcd

406.1817, found 406.1814.

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Thiol-derivatived Monolayer Protected Gold Clusters (MPCs) 5 and 9.

Tetrachloroauric acid (HAuCl4) (0.24 g, 0.71 mmol) in 25 ml de-ionized H2O was

added tetraoctylammonium bromide (TOAB) (1.29 g, 2.36 mmol) in 25 ml toluene.

The two-phase mixture was stirred vigorously for 90 min until all the HAuCl4 was

transferred into the organic layer and the 1-octanethiol (0.32 g, 2.15 mmol) was then

added to the organic phase. The resulting mixture was stirred for additional 30 min. A

freshly prepared aqueous solution of NaBH4 (0.30 g, 7.93 mmol) was added slowly

(ca. 1drop/sec.) with vigorously stirring. After further stirring for 4 h the organic

phase was separated, evaporated to 5 ml under reduced pressure and mixed with 200

ml EtOH to remove excess thiol. The mixture was kept for 4 h at 0oC and the dark

brown precipitate was collected by filtration. The crude product was dissolved in 5 ml

toluene and precipitated with 150 ml EtOH to give octanethiolate MPCs in 90% yield.

The octanethiolate MPCs and 0.2 g TOAB were added into a 2 ml solution of

toluene, and then heated in oil bath at 190 oC for 30 min until the brown color turned

into dark red color. The temperature was cooled to 110oC for 5 h then cooled to 40 oC.

The toluene was removed and washed with EtOH and acetone to afford the

homogenized MPCs.

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Compound 4a (0.12 mmol) and 0.03 g homogenized octanethiolate MPCs were

dissolved in 3ml toluene and stirred vigorously at rt for 48 h. The toluene was

removed and washed with EtOH and acetone to give 5a.

Compound 5b and 9 were prepared from 4b and 8 followed the procedure

described for 5a.

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1H and 13C NMR spectra of 2-(4-isobutylphenyl)-N-meracptopentylpropionamide

(4a)

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1H and 13C NMR spectra of 2-(4-isobutylphenyl)-N-meracptohexylpropionamide

(4b)

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1H and 13C NMR spectra of

2-(4-isobutylphenyl)-N-[4-(4-mercaptobut-2-enyloxy)phenyl] propionamide (8)