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Gold Nanoparticle-supported Transition Metal Complexes as Hybrid Catalysts and MRI Contrast Agents : : 1

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2 Hydrogen Nuclei Alignment to the External Field Chem. Soc. Rev., 2012,41, 2575

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3 MRI Measurement Step 1: Place Subject in a Big Magnet When you put any material in an MRI scanner, the protons align with the direction of the magnetic field. Chem. Soc. Rev., 2012,41, 2575

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4 M xy = M * e -t/T2 M z = M * ( 1 - e -t/T1 ) T2 T1 Step 2: Apply Radio Waves Chem. Soc. Rev., 2012,41, 2575 recovers to 63% decays back to 37%

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5 Step 3: Measure Emitted Radio Waves T 1 = time constant of how quickly the Hs realign with the magnetic field T 2 = time constant of how quickly the Hs emit energy when recovering to equilibrium fat has high signal bright CSF has low signal dark T1-WEIGHTED ANATOMICAL IMAGET2-WEIGHTED ANATOMICAL IMAGE fat has low signal dark CSF has high signal bright CSF: Cerebrospinal fluid Med. Phys. 1984,11,425

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6 Contrast Agents for Clinical MRI (T 1 ) Invest. Radiol. 1993, 28, 521. T 1 contrast agents: Gd-DTPA, Gd-DOTA, Gd-oxalate increase signals by decreasing the T 1 of protons

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7 Contrast Agents for Clinical Animal MRI (T 2 ) T 2 contrast agents: Superparamagnetic Iron Oxide (SPIO) causing a shortening of T 2 and decreasing signal intensity on T 2 weight imaging J. Am. Chem. Soc. 2005, 127, 12387-12391 pre- injection immediate -post 1 hr4 hr12 hr top: grayscale map bottom: color map Fe 3 O 4 (9 nm)

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Dose DecreaseMetabolic Rate IncreaseBiocompatibilityContrast Enhancement Chelates Biovehicles ParamagnetismStructure Progress of MRI Contrast Agents 8

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9 Au NPs with controllable solubility soluble metal complex functional groups coordinating ligands space linker Contrast Agents Design Au nanoparticles ( Au NPs) have been known not only to possess solid surfaces resembling the (1 1 1) surface of bulk gold but also to behave like soluble molecules for their dissolvability, precipitability, and redissolvability. Lin, Y.-Y; Tsai, S.-C.; Yu, S. J. J. Org. Chem. 2008, 73, 4920-4928.

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Space Linker HS(CH 2 ) 11 N(H)P(O)(2-Py) 2 (L1) dissolved in organic solventsdissolved in water DO3A-SH (L2) Contrast Agents Design Ni complexes Mn complexes Gd complexes 10 L1 L2 M = Ni 2+ Mn 2+ M = Gd 3+

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Synthesis of L1 11 Lin, Y.-Y; Tsai, S.-C.; Yu, S. J. J. Org. Chem. 2008, 73, 4920-4928.

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12 Synthesis of RS-Au-L1-M n+ 3.77 nm 0.88 2.53 0.4 nm

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EPR Spectra of Mn Complexes [Mn(bpy)( -Cl) 2 ] n g - factor 2 Inorg. Chim. Acta, 2005, 358, 44594465 13 [CH 3 (CH 2 ) 3 N(H)P(O)(2-Py) 2 ]MnCl 2 (Mn4C)

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14 Mn 2+ 2p 3/2 = 639 eV Mn 2+ 2p 1/2 = 651 eV XPS Spectra of Mn Complexes satellite Physical Review B 1991, 43, 11971

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15 IR Spectra of Mn Complexes

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Hydrodynamic size (DLS) : 167 50 nm Au Mn TEM Images and EDS Spectrum of RS-Au-L1-MnCl 2 2.53 nm 0.4 16

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J. Polym. Sci., Part A: Polym. Chem. 2011, 49, 3464 Tetrahedron Lett. 2011, 52, 2058. Synthesis of L2 17

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Synthesis of L2 18 78 %

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Synthesis of RS-Au-DO3A-Gd 19 60 % 3.09 nm 0.52 2.99 nm 0.45

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20 1 H NMR Spectrum of Au-SR, DO3ASH and RS-Au-DO3A L2 RS-AuDO3A

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EPR Spectra of Gd Complexes GdDO3A 21 g factor = 1.998 J. Am. Chem. Soc. 2001, 123, 2637-2644 [Gd(H 2 O) 8 ] 3+

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Gd 3+ 3d 3/2 = 1220 eV Gd 3+ 3d 5/2 = 1185 eV satellite XPS and IR Spectra of Gd Complexes 22

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2.99 nm 0.4 Au Gd TEM Images and EDS Spectrum of RS-Au-DO3A-Gd 23

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24 Quantification of Paramagnetic Metal Complexes Flame atomic absorption spectrometry, FLAA ) Inductively coupled argon plasma optical emission spectrometry ICP-OES ) ( Graphite-furnace atomic absorption spectrometry, GFAA ) ( Inductively coupled plasma mass spectrometry, ICP-MS ) RS-Au-L-MnCl 2 1.42 10 -6 mol Mn 1 ppm 0.32 mg RS-Au-L-MnCl 2 in 25 mL solvent RS-Au-DO3A-Gd 3.5 10 -7 mol Gd 380 ppm 172 mg RS-Au-DO3A-Gd in 25 mL solvent

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25 Dynamic Motion between Solvent and Paramagnetic Metal Complexes Chem. Soc. Rev., 2010, 39, 51-60

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Concentration Dependent T 1 and R 1 Influenced by Ni 2+ Complexes 26 Ni11C Au@Ni Ni4C r 1 = relaxivity P M : q: 1M : M : (exchange time) R1R1

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The Hydroxyl Proton Relaxation Rates Influenced by Ni 2+ Complexes 27 [Ni 2+ ] (mM)T 1 (s)T 1 error (s)R 1 (s -1 ) 100.1350.0047.401 50.2420.0064.132 30.4190.0042.386 1.50.7390.0171.353 0.91.0860.0350.920 0.51.5210.0500.657 [Ni 2+ ] (mM)T 1 (s)T 1 error (s)R 1 (s -1 ) 100.1480.0086.756 50.3340.0102.994 30.4670.0182.141 1.51.0080.0560.992 0.91.3620.0480.733 0.51.9070.0570.524 Au@Ni r 1 (s -1 mM -1 ) = 0.933 Ni11C r 1 (s -1 mM -1 ) = 0.752 [Ni 2+ ] (mM)T 1 (s)T 1 error (s)R 1 (s -1 ) 100.1890.0065.291 50.3360.0102.976 30.5140.0131.946 1.50.8790.0171.138 0.91.1680.0220.856 0.51.6760.0360.597 Ni4C r 1 (s -1 mM -1 ) = 0.779 The relaxation rate of Ni 2+ is slightly enhanced upon immobilization onto AuNPs. Methanol T 1MeOH = 6.622 s R 1 = 0.151 s -1 r 1 = 3.87 *10 -3 s -1 mM -1

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Sample r 1OH (s -1 mM -1 )r 1CH3 (s -1 mM -1 ) MnCl 2 19.85 0.865.10 0.20 Mn4C16.58 0.573.99 0.08 Mn11C18.23 0.634.61 0.23 MnCl 2 Mn4C Mn11C Relaxivity of Molecular Mn Complexes at 298K 298K Bulk methanol Chemical exchange Bound methanol 28

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Sample Mn 2+ loading (ppm/mg) r 1OH (s -1 mM -1 )r 1CH3 (s -1 mM -1 ) Au@Mn-5v11.8218.30 0.595.20 0.04 Au@Mn-5v22.5719.81 0.315.04 0.05 Au@Mn-5v43.2620.95 0.185.73 0.01 Au@Mn-5v64.6921.66 0.385.42 0.10 Relaxivity of Au-L1-Mn Complexes at 298K 29 Weight ratio Au : L = 5:1 (Au@Mn-5v1) Au : L = 5:2 (Au@Mn-5v2) Au : L = 5:4 (Au@Mn-5v4) Au : L = 5:6 (Au@Mn-5v6)

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Relaxivity of Mn 2+ in Various Forms at 298K 30

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31 MRI of Mn Complexes in MeOH Background tau 400 ms500 ms600 ms700 ms 800 ms900 ms1 s FOV : 3.6 x 3.6 x 0.1 cm MeOH Mn4C MnCl 2 RS-Au-L-MnCl 2 (inversion recovery)

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Temperature : 228 K ~ 308 K Temperature Dependent Relaxivity of Mn Complexes 32 T 1MeOH = 6.622 s T 1Mncl2 = 0.037 s (r 1 : 26.81 mM -1 s -1 ) Au@Mn-5v4: 0.035 s (r 1 : 28.49 mM -1 s -1 ) Au@Mn 5v1: 0.044 s (r 1 : 22.65 mM -1 s -1 )

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33 Nuclear Magnetic Relaxation Dispersion (NMRD) profile of Gd complexes under Difference Temperature Dalton Transactions 2012, 41, 5472. 25 C (), and 37 C ( ).

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34 Pure water at 1.5 T : 3 s GdCl 3 at 82 MHz: 0.09 s (r 1 : 10.51 mM -1 s -1 ) GdDO3A: 0.10 s (r 1 :9.60 mM -1 s -1 ) RS-Au-DO3A-Gd: 0.09s (r 1 :11.01 mM -1 s -1 ) Gd-DTPA: 0.2s (r 1 :5.01 mM -1 s -1 ) Nuclear Magnetic Relaxation Dispersion (NMRD) profile of Gd complexes GdDO3A

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35 Hydrodynamic size (DLS) : 167 50 nm

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36 Proposed Mechanism for RS-Au-DO3A Gd Aggregation P M : q: 1M : M : (exchange time) R1R1 Hydrodynamic size (DLS) : 161 nm 73

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Acetylation of Alcohol Application : 1. protective agent 2. medicine synthesis, ex: aspirin 3. protein acetylation 37

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38 Acetylation of Alcohol Tetrahedron Lett. 2008, 49, 3165

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39 Substrates of Acetylation GdDO3A (Cat. 1) RS-Au-DO3A-Gd (Cat. 2)

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40 Cat. 1 Catalyzed Acetylation Reactions of ROH with Acetic Anhydride

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41 Cat. 1 Catalyzed Acetylation Reactions of ROH with Acetic Anhydride

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42 Cat.1 and Cat.2 Catalyzed Acetylation Reactions of ROH with Acetic Anhydride under MW Irradiation

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43 Cat.1 and Cat.2 Catalyzed Acetylation Reactions of ROH with Acetic Anhydride under MW Irradiation

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44 Recycling of Cat. 2 in Acetylation Reactions of Phenol with Acetic Anhydride

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45 Proposed Mechanism for Acetylation of Alcohols Org. Lett.1999, 1, 1985.

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46 Conclusions 1.We have developed a methodology to successfully immobilize molecular Mn(II) and Gd(III) complexes onto surfaces of Au NPs. Their structures were characterized by using 1 H NMR, IR, TEM, AAS, ICP-AES, EPR and XPS spectroscopy. 2.The relaxivity of RS-Au-L-M + NPs (M = Ni 2+, Mn 2+ ) in methanol is as expected to be greater than that of the molecular complexes. 3. We have synthesized water soluble RS-Au-DO3A-Gd NPs. These NPs were found to exhibit excellent T 1 -shortening effect in MRI. 4.We have successfully demonstrated the catalytic activity of the Gd(III) complexes for acetylation of alcohol with acetic anhydride 5. Further acceleration on the rate of the Gd (III) complexescatalyzed acetylation of alcohols can be achieved under microwave irradiation conditions. 6. The RS-Au-DO3A-Gd NPs can be effectively recycled throughout eight cycle under microwave irradiation

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47 Acknowledge : : :

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48 Acknowledge

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49 Acknowledge

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50 10~50 nm 100~200 nm

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51 Integration of the 1 H NMR signals of phenyl acetate (iodoanisole as internal standard) gave 97.9% NMR yields (0.538 mmol), while GC analysis on the same sample gave 99% GC yields (0.544 mmol).

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52 1 mM Mn 2+ : RS-Au-L-MnCl 2 1.42 10 -6 mol Mn 25 mL solvent, 17.6 mg RS-Au-L-MnCl 2 1 mM Gd 3+ : RS-Au-DO3A-Gd 3.5 10 -7 mol Gd 25 mL solvent, 71.4 mg RS-Au-DO3A-Gd

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53 S1 Gd1 : 1.238 nm S1 C15 : 0.961 nm

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54 C14 Mn2 : 0.89 nm N3 Mn2 : 0.45 nm

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55 ICP-OES: ICP-Mass: , HR-ICP-Mass:

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56 90 degree RF Relaxation Z-axis , Z , , (phase), , dephase Z-axis x-axis