Mechanistic Insights into Copper(I)-Catalyzed Azide-Alkyne Cycloadditions using Continuous Flow Conditions

The copper-catalyzed azide-alkyne cycloaddition (CuAAC, "click chemistry") was studied employing copper-in-charcoal (Cu/C) and a variety of copper metal sources as "heterogeneous" catalysts. The type and pretreatment conditions of the different copper sources on the CuAAC were investigated. In addition, the effect of copper leaching from the catalyst over time and in dependence on the reaction mixture composition was studied by ICP-MS analysis in the continuous flow mode. These investigations confirm a "homogeneous" mechanism and suggest surface layer copper(I) oxide as the catalytically active species in CuAAC chemistry involving zerovalent copper metal.

[1]  D. Lastécouères,et al.  A highly active and reusable copper(I)-tren catalyst for the "click" 1,3-dipolar cycloaddition of azides and alkynes. , 2008, Chemical communications.

[2]  Paul Watts,et al.  Continuous flow reactors for drug discovery. , 2003, Drug discovery today.

[3]  Andrew R. Bogdan,et al.  The Use of Copper Flow Reactor Technology for the Continuous Synthesis of 1,4‐Disubstituted 1,2,3‐Triazoles , 2009 .

[4]  T. Wirth,et al.  Advanced organic synthesis using microreactor technology. , 2007, Organic & biomolecular chemistry.

[5]  Morten Meldal,et al.  Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. , 2002, The Journal of organic chemistry.

[6]  J. Boggio.  The room temperature oxidation of Cu (111): Pressure effects , 1979 .

[7]  Andreas Kirschning,et al.  Combining enabling techniques in organic synthesis: continuous flow processes with heterogenized catalysts. , 2006, Chemistry.

[8]  Steven V Ley,et al.  [3 + 2] Cycloaddition of acetylenes with azides to give 1,4-disubstituted 1,2,3-triazoles in a modular flow reactor. , 2007, Organic & biomolecular chemistry.

[9]  M. Villa,et al.  Oxidative DNA damage of mixed copper(II) complexes with sulfonamides and 1,10-phenanthroline. Crystal structure of [Cu(N-quinolin-8-yl-p-toluenesulfonamidate)2(1,10-phenanthroline)]. , 2003, Journal of inorganic biochemistry.

[10]  Morten Meldal,et al.  Cu-catalyzed azide-alkyne cycloaddition. , 2008, Chemical reviews.

[11]  Yegao Yin,et al.  Cu(II)-assisted oxidation of quinoline-2-carbaldehyde hydrazone to give [1,2,3]triazolo[1,5-α]quinoline: The first example of Cu(I) complex containing [1,2,3]triazolo-ligand , 2007 .

[12]  Übergangsmetallkomplexe mit Organoazidliganden: Synthese, Strukturchemie und Reaktivität , 1998 .

[13]  W. Thiel,et al.  Transition Metal Complexes with Organoazide Ligands: Synthesis, Structural Chemistry, and Reactivity. , 1998, Angewandte Chemie.

[14]  K. Kacprzak.  Efficient one-pot synthesis of 1,2,3-triazoles from benzyl and alkyl halides , 2005 .

[15]  C. Oliver Kappe,et al.  Microwave-assisted cross-coupling and hydrogenation chemistry by using heterogeneous transition-metal catalysts: an evaluation of the role of selective catalyst heating. , 2009, Chemistry.

[16]  M. H. Torre,et al.  Synthesis and Characterization of EDTA Complexes Useful for Trace Elements Supplementation , 2002 .

[17]  S. Ley,et al.  Tagged phosphine reagents to assist reaction work-up by phase-switched scavenging using a modular flow reactor. , 2007, Organic & biomolecular chemistry.

[18]  Yanju Wang,et al.  An integrated microfluidic device for large-scale in situ click chemistry screening. , 2009, Lab on a chip.

[19]  J. Moses,et al.  The growing applications of click chemistry. , 2007, Chemical Society reviews.

[20]  K. Sharpless,et al.  Polytriazoles as copper(I)-stabilizing ligands in catalysis. , 2004, Organic letters.

[21]  K. Sharpless,et al.  Click-Chemie: diverse chemische Funktionalität mit einer Handvoll guter Reaktionen , 2001 .

[22]  Fahmi Himo,et al.  Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. , 2005, Journal of the American Chemical Society.

[23]  Shigeru Suzuki,et al.  Native oxidation of ultra high purity Cu bulk and thin films , 2006 .

[24]  Ling Wang,et al.  Effect of Hydrogen Peroxide on Oxidation of Copper in CMP Slurries Containing Glycine , 2003 .

[25]  W. Dehaen,et al.  A microwave-assisted click chemistry synthesis of 1,4-disubstituted 1,2,3-triazoles via a copper(I)-catalyzed three-component reaction. , 2004, Organic letters.

[26]  H. V. Rasika Dias,et al.  Copper and silver complexes containing organic azide ligands: syntheses, structures, and theoretical investigation of [HB(3,5-(CF3)2Pz)3]CuNNN(1-Ad) and [HB(3,5-(CF3)2Pz)3]AgN(1-Ad)NN (where Pz = pyrazolyl and 1-Ad = 1-adamantyl). , 2000, Inorganic chemistry.

[27]  S. Neubacher,et al.  Short and Efficient Synthesis of Alkyne‐Modified Amino Glycoside Building Blocks , 2009 .

[28]  Chuan Seng Tan,et al.  Abnormal contact resistance reduction of bonded copper interconnects in three-dimensional integration during current stressing , 2005 .

[29]  B. König,et al.  Synthesis, Characterisation and Ligand Properties of Novel Bi-1,2,3-triazole Ligands , 2007 .

[30]  R. Hilfiker,et al.  Polymorphism, salts, and crystallization : The relevance of solid-state development , 2006 .

[31]  B. Lipshutz,et al.  Copper-in-charcoal (Cu/C) promoted diaryl ether formation. , 2007, Organic letters.

[32]  H. Hiemstra,et al.  CuI‐Catalyzed Alkyne–Azide “Click” Cycloadditions from a Mechanistic and Synthetic Perspective , 2005 .

[33]  C. Jimeno,et al.  A highly active catalyst for Huisgen 1,3-dipolar cycloadditions based on the tris(triazolyl)methanol-Cu(I) structure. , 2009, Organic letters.

[34]  B. Lipshutz,et al.  Heterogeneous copper-in-charcoal-catalyzed click chemistry. , 2006, Angewandte Chemie.

[35]  Henning S. g. Beckmann,et al.  One-pot procedure for diazo transfer and azide-alkyne cycloaddition: triazole linkages from amines. , 2007, Organic letters.

[36]  M. R. Pitts,et al.  QuadraPure Cartridges for Removal of Trace Metal from Reaction Mixtures in Flow , 2007 .

[37]  Michael E Phelps,et al.  Integrated microfluidics for parallel screening of an in situ click chemistry library. , 2006, Angewandte Chemie.

[38]  C. Kappe,et al.  Heterogeneous versus homogeneous palladium catalysts for ligandless mizoroki-heck reactions: a comparison of batch/microwave and continuous-flow processing. , 2009, Chemistry.

[39]  Steven V Ley,et al.  Multistep synthesis using modular flow reactors: Bestmann-Ohira reagent for the formation of alkynes and triazoles. , 2009, Angewandte Chemie.

[40]  Luke G Green,et al.  A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes. , 2002, Angewandte Chemie.

[41]  P. Nielsen,et al.  Synthesis of 5‐(1,2,3‐Triazol‐4‐yl)‐2′‐deoxyuridines by a Click Chemistry Approach: Stacking of Triazoles in the Major Groove Gives Increased Nucleic Acid Duplex Stability , 2007, Chembiochem : a European journal of chemical biology.

[42]  R. Wu,et al.  Hydrothermal syntheses and structural characterization of four complexes with in situ formation of 1,2,3-triazole-4-carboxylate ligand , 2009 .

[43]  Andreas Kirschning,et al.  Continuous flow techniques in organic synthesis. , 2003, Chemistry.

[44]  M. Finn,et al.  Cu(II)-aza(bisoxazoline)-catalyzed asymmetric benzoylations. , 2005, Organic letters.

[45]  Paul Watts,et al.  Continuous Flow Reactors, a Tool for the Modern Synthetic Chemist , 2008 .

[46]  M. Bradley,et al.  Tools for efficient high-throughput synthesis. , 2007, Drug discovery today.

[47]  Y. Waseda,et al.  Native Oxide Layers Formed on the Surface of Ultra High-Purity Iron and Copper Investigated by Angle Resolved XPS , 1997 .

[48]  M. G. Finn,et al.  Click Chemistry: Diverse Chemical Function from a Few Good Reactions. , 2001, Angewandte Chemie.

[49]  Peng Wu,et al.  Catalytic Azide—Alkyne Cycloaddition: Reactivity and Applications , 2007 .

[50]  Bernhard Gutmann,et al.  Microwave chemistry in silicon carbide reaction vials: separating thermal from nonthermal effects. , 2009, Angewandte Chemie.