Department of Chemistry & Biochemistry Chung Cheng University Synthesis and Characterization of Au Nanoparticles-Supported N-Heterocyclic Carbene Copper(I) Complex. The Catalytic Application on Huisgen Cycloaddition Reactions 學生：莊雲婷 指導教授：于淑君　博士 2010 /07 / 30 Department of Chemistry & Biochemistry Chung Cheng University

Phosphine Ligand Phosphines are electronically and sterically tunable. Expensive. Air sensitive. P-C, P-OR cleavage under high temperature. Metal leaching. Chemical waste.

N-Heterocyclic Carbenes [M] NHCs are stronger σ-donor and weaker π-acceptor than the most electron rich phosphines. NHCs can be useful spectator ligands, because they are sterically and electronically tunable. NHCs can promote a wide series of catalytic reactions. NHCs have advantages over phosphines and offer catalysts with better air-stability.

N-Heterocyclic Carbenes as Ligands - In the early 90's NHC were found to have bonding properties similar to trialklyphosphanes and alkylphosphinates. - compatible with both high and low oxidation state metals - examples: - reaction employing NHC's as ligands: Herrmann, W. A.; Öfele, K; Elison, M.; Kühn, F. E.; Roesky, P. W. J. Organomet. Chem. 1994, 480, C7-C9. Herrmann, W. Angew. Chem. Int. Ed. 2002, 41, 1290-1309.

The Catalytic Applications of CuI O-arylation of Phenols Kharasch-Sosnovsky Reaction (Allylic Oxidations of Olefins) S-arylation of Thiols N-arylation of Amines (Buchwald-Hartwig Reaction) Hydrosilylation of Ketones Heck reaction Oxidation of Alcohols Carl Glaser. Berichte der deutschen chemischen Gesellschaft 1869. 2, 422–424. Sonogashira Reaction 1,3-dipolar cycloaddition Substitution Reaction Epoxidation Reaction Reductive Aldol Reaction

Drawbacks of Traditional Copper-Mediated Reactions insoluble in organic solvents - heterogeneous harsh reaction conditions - high temperatures around 200 °C - strong bases required - toxic solvent such as HMPA - long reaction times - the yields are often irreproducible structure not clear Girard, C. Org. Lett., 2006. 1689-1692

Catalyst Supported onto Au NPs Surface controllable solubility soluble metal complex Au NPs with controllable solubility 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. functional groups coordinationl ligands spacer linker Lin, Y.-Y; Tsai, S.-C.; Yu, S. J. J. Org. Chem. 2008, 73, 4920-4928.

Gold Nanoparticles Modified with Ionic Liquid Photographs of the obtained solutions of the 1-modified gold NPs after addition of (a) HCl (b) HBr (c) HBF4 (d) HI (e) HPF6. Chujo.Y. J. Am. Chem. Soc. 2004, 126, 3026-3027

Azide-Alkyne Huisgen Cycloaddition Rolf Huisgen was the first to understand this organic reaction at 1961. 1,3-Dipolar cycloaddition between azide and alkyne to give a 1,2,3-triazole K. Barry Sharpless and co-workers defined it as “a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries” Huisgen, R. .Angew. Chem. Int. Ed. 1961. 11. 633–645. Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004-2021 Anke Cwiklicki, A. Arch. Pharm. Pharm. Med. Chem. 2004, 337, 156−163

First Metal Catalyzed Azide-Alkyne Cycloaddition Copper (i) 2 eq 2-Azido-2-methylpropionic acid, 50 eq DIPEA, 2 eq CuI. (ii) 0.1 M NaOH (aq). Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057-3064 Ruthenium 2 mol % cat. Rt, 30 min Yield = 63-97 % Fokin, V. V.; Jia, G.; Lin, Z. J. Am. Chem. Soc. 2008. 130. 8923–8930

Reported CuI Catalyzed Azide-Alkyne Cycloaddition Reduction of CuII Salt Oxidation of Cu Metal Ligand Assisted CuI Salt Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596-2599 TOF= 2.3 h-1 Alonso, F. Eur. J. Org. Chem. 2010, 1875-1884. TOF= 59 h-1 Fokin, V. V.Org. Lett. 2004, 6, 2853-2855 TOF= 3.5 h-1

Reported CuI Catalyzed Azide-Alkyne Cycloaddition NHC-CuI Supported CuI Salt on Solid Phase Nolan, S. P. Chem. Eur. J. 2006, 12, 7558-7564. TOF= 368 h-1 Catalyst Cu loading (mol %) Temp. (oC) Time (hr) Yield (%) TOF (h-1) ref Cu(OH)x/TiO2 1.5 60 0.16 99a 396 Chem. Eur. J. 2009, 10464 CuNPs/AlO(OH) 3 rt 6 94b 5 J. Org. Lett. 2008. 497 CuI-Zeolite 10 15 83c 0.6 J. Org. Lett. 2007, 883 SiO2-NHC-CuI 1 0.5 93d 186 Tetrahedron, 2008, 10825

Reported Mechanism for CuI-Catalyzed Azide-Alkyne Cycloaddition 機制 Nolan, S. P. Angew. Chem. Int. Ed. 2008, 47, 8881 –8884

Motivation Using NHCs to replace phosphines in organomatallic catalysis. Base on economic standpoint, copper metal is much more Inexpensive than palladium catalyst . - PdCl2 $4805.00(150g) ReagentPlus® (Aldrich) - CuCl $206.00(100g) ReagentPlus® (Aldrich) Synthesis of NHC-Cu(I) complexes with well-defined structures. Greener catalysis – microwave and solventless conditions. To design an easily recovered and effectively recycled Au NPs supported copper(I) complex catalyst.

Preparation of CuI Complex Catalyst Preparation of (HS-hmim)HPF6 hmim = 1-hexyl-3-methylimidazolium Preparation of (HS-hmim)HPF6

Synthesis of Octanethiol Protected Au NPs TOAB = tetra-octyl ammonium bromide SR = Octane thiol Au(SR) size : 2.4  0.39 nm

Synthesis of Au NPs Modified with Ionic Liquid IL = (S-hmim)(HPF6) Au(SR)(IL) size : 2.04  0.7 nm

-CH3 HS-CH2- CHCl3 -CH3 CHCl3 HS-CH2- DMSO DMSO -CH3

Design of Au(SR)(IL)(ILCu) (6)

Synthesis of Au NPs Supported NHC-CuI Complex ILCu = S-hmim-CuCl Au(SR)(IL)(ILCu) size : 1.63  0.32 nm

1H NMR Spectra of (hmim)HBr (1) & CuI(hmim) (2) -CH2- Hb Ha -CH3 * # H2O DMSO

1H NMR Spectra of Au(SR)(IL) (5) & Au(SR)(IL)(ILCuCl) (6) *d-DMSO #H2O Hb Ha -CH2- -CH3

13C NMR Spectra of Au(SR)(IL) (5) & Au(SR)(IL)(ILCuCl) (6) 136.3 ppm 182.6 ppm *DMSO 123.3 ppm 121.9 ppm 123.6 ppm 122.1 ppm

IR Spectra of Ligand and NHC-CuI Series (S-hmim)HPF6 (3) 2589 Au(SR)(IL) (5) Au(SR)(IL)(ILCu) (6) 1573 1167 1636 1229 (hmim)HBr (1) 1575 CuI(hmim) (2) 1169 1677 1218

EDS of Au(SR)(IL)(ILCuCl) (6) Element Weight% Atomic% C 25.56 72.89 Ni 25.13 14.67 Cu 10.60 5.71 Au 38.71 6.73

XPS of Au(SR)(IL)(ILCuCl) (6) 87.5 eV 4f5/2 4f7/2 83.7 eV Au 83.8 eV 87.5 eV Brust, M. J. Chem. Soc. Chem. Commun. 1994, 801-802.

XPS of Au(SR)(IL)(ILCuCl) (6) 952.6 2p3/2 2p1/2 Cu 932.8 Binding Energy Cu(2p1/2) Cu(2p3/2) CuClPPh3 953.2 eV 933.5 eV CuCl(PPh2H)3 953.3 eV 933.4 eV CuCl(PPh3)(o-phen) 952.4 eV 932.4 eV Frost, D. C. Mol. Phys, 1972. 24. 861-877.

CuI(hmim) (2) Catalyzed Huisgen Cycloaddition – Solvent Effect Condition: Benzyl azide = 1 mmol, phenyl acetylene = 1.2 mmol. solvent = 0.25 mL, rt, 1 mol% (hmim)CuI. The conversion were determined by 1H NMR

CuI(hmim) (2) Catalyzed Huisgen Cycloaddition 27 % Condition: Benzyl azide = 1 mmol, phenyl acetylene = 1.2 mmol. solvent = 0.25 mL, rt, 0.05 mol% (hmim)CuI. The conversion were determined by 1H NMR TOF (h-1) 333 2225 5062 Nolan, S. P. Angew. Chem. Int. Ed. 2008, 47, 8881 –8884

CuI(hmim) (2) Catalyzed Huisgen Cycloaddition Condition: azide = 1 mmol, phenyl acetylene = 1.2 mmol. neat, rt, 1 mol% (hmim)CuI. The conversion were determined by 1H NMR

CuI(hmim) (2) Catalyzed Huisgen Cycloaddition Condition: azide = 1 mmol, 1-nonyne = 1.2 mmol. neat, rt, 1 mol% (hmim)CuI. The conversion were determined by 1H NMR

CuI(hmim) (2) Catalyzed Huisgen Cycloaddition

Cycloaddition Reactivity of Various Substrates Alkyne: Azide: > pKa = 19 pKa = 25 ≅ > > > > >

CuI Contents of Au(SR)x(LR)y(ILCu)z (6) Determined by NMR Spectroscopy 2H 2H 2H 3H ILCu : iodoanisole = (1-0.1648) : 0.1648 = ILCu : 2.245 x 10-6 ILCu = 1.137 x 10-5 mol ILCu : SR = (1-0.1648) : 0.1080 = 1:0.13 Au(SR)x(LR)y(ILCu)z = AuSR0.13LR0Cu1 d6-DMSO 4-iodoanisole : 2.245 x 10-6 mol Au(SR)(ILCu) : 8 mg

AuILCuCl (6) Catalyzed Huisgen Cycloaddition Conversion were determined by 1H NMR. Reaction condition : 10 mg AuSR0.38LR0Cu1. benzyl azide = 1.8 mmol. phenyl acetylene = 2.15 mmol. solvent = 0.4 mL

AuILCuCl (6) Catalyzed Huisgen Cycloaddition Conversion were determined by 1H NMR.

Various Copper Salts and Their Cycloaddition Reactivities Conversion were determined by 1H NMR. Reaction condition : benzyl azide = 2.8 mmol. phenyl acetylene = 3.4 mmol. solvent = 0.75 mL. a.1,4-product and 1,5-product is mixed. Reactivity : NHC-CuI > NHC-CuCl

Competative Substrate Binding on Au Surface v.s. Thiol Poisoning Conversion were determined by 1H NMR. Reaction condition : 10 mg CuCl(hmim), benzyl azide = 2.8 mmol. phenyl acetylene = 3.4 mmol. CHCl3= 2 mL. (4) = 2.33x10-6 mol octanethiol / mg Decrease reactivity : free octanethiol > Au NPs supported-octanethiol

The Surface Thiol Ratio on AuILCuCl v.s. Catalytic Reactivity Au(SR)x(LR)y(Cu)z Conversion were determined by 1H NMR. Reaction condition : 1 mol% Cu of (6). benzyl azide = 1 eq. phenyl acetylene = 1.2 eq. solvent = 0.25 mL. Increase (x+y)/z , decrease reactivity

Saturation of Au Surface with Alkyne CuCl Au

Microwave-Assisted (6) Catalyzed Huisgen Cycloaddition thermal Solvent Time (min) Conversion (%) [Bmim][Br] 0.5 65 DMSO 1.5 4 2 24 3 99 CH3CN 8 1 54 Conditions: Benzyl azide (0.8 mmol), alkyne (0.96 mmol), Solvent = 0.15 mL. Conversion detected by 1H NMR Kappe, C. O. Angew. Chem. Int. Ed. 2004, 43, 6250-6284.

Microwave-Assisted (6) Catalyzed Huisgen Cycloaddition Conversion were determined by 1H NMR. Reaction condition : cat.(6) = 10 mg, azide = 1 eq. phenyl acetylene = 1.2 eq. solvent = 2 drop [Bmim][PF6].

Conclusions We have successful synthesized Au NPs- supported NHC-CuI complex (6) and characterized it by using 1H- and 13C-NMR, TEM, IR, EDS and XPS. We have successfully demonstrated the catalytic activity of the CuI complex in both the molecular and supported forms for the Huisgen cycloaddition. Further acceleration on the rate of the CuI catalyzed Huisgen cycloaddition was achieved under microwave irradiation conditions.

Mechanism for Ru Catalyzed Click Reaction 2 mol % cat. Rt, 30 min 80 % Fokin, V. V.; Jia, G.; Lin, Z. J. Am. Chem. Soc. 2008. 130. 8923–8930

Yamamoto, Y. Tetrahedron. Letters. 2008, 49, 2824-2827

Yamamoto, Y. Tetrahedron. Letters. 2008, 49, 2824-2827

DFT calculated barrier of Step A) 23.7 kcal/mol Step B) 0.7 kcal/mol Step C) 14.9 kcal/mol Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210-216

NMR Characterization of Octanethiol-Protected Au NPs The 1H-NMR spectra of (a) free octanethiol, (b) Au:C8=1:5,(c) Au:C8=2:1, and (d) Au:C8=5:1. The 13C-NMR spectra of (a) free octanethiol, (b) Au:C8=1:5,(c) Au:C8=2:1, and (d) Au:C8=5:1. G.C. Lica et al. Journal of Electroanalytical Chemistry. 2003. 127-132

(CO) of LNi(CO)3 Corn angle ()