The chemistry of copper is extremely rich because it can easily access Cu0, CuI, CuII, and CuIII oxidation states allowing it to act through one-electron or two-electron processes. As a result, both radical pathways and powerful two-electron bond forming pathways via organmetallic intermediates, similar to those of palladium, can occur. In addition, the different oxidation states of copper associate well with a large number of different functional groups via Lewis acid interactions or π-coordination. In total, these feature confer a remarkably broad range of activities allowing copper to catalyze the oxidation and oxidative union of many substrates.

Oxygen is a highly atom economical, environmentally benign, and abundant oxidant, which makes it ideal in many ways.1 The high activation energies in the reactions of oxygen require that catalysts be employed.2 In combination with molecular oxygen, the chemistry of copper catalysis increases exponentially since oxygen can act as either a sink for electrons (oxidase activity) and/or as a source of oxygen atoms that are incorporated into the product (oxygenase activity). The oxidation of copper with oxygen is a facile process allowing catalytic turnover in net oxidative processes and ready access to the higher CuIII oxidation state, which enables a range of powerful transformations including two-electron reductive elimination to CuI. Molecular oxygen is also not hampered by toxic byproducts, being either reduced to water, occasionally via H2O2 (oxidase activity) or incorporated into the target structure with high atom economy (oxygenase activity). Such oxidations using oxygen or air (21% oxygen) have been employed safely in numerous commodity chemical continuous and batch processes.3

However, batch reactors employing volatile hydrocarbon solvents require that oxygen concentrations be kept low in the head space (typically <5–11%) to avoid flammable mixtures, which can limit the oxygen concentration in the reaction mixture.4,5,6 A number of alternate approaches have been developed allowing oxidation chemistry to be used safely across a broader array of conditions. For example, use of carbon dioxide instead of nitrogen as a diluent leads to reduced flammability.5 Alternately, water can be added to moderate the flammability allowing even pure oxygen to be employed.6 New reactor designs also allow pure oxygen to be used instead of diluted oxygen by maintaining gas bubbles in the solvent, which greatly improves reaction rates and prevents the build up of higher concentrations of oxygen in the head space.4a,7 Supercritical carbon dioxide has been found to be advantageous as a solvent due its chemical inertness towards oxidizing agents and its complete miscibility with oxygen or air over a wide range of temperatures.8 An number of flow technologies9 including flow reactors,10 capillary flow reactors,11 microchannel/microstructure structure reactors,12 and membrane reactors13 limit the amount of or afford separation of hydrocarbon/oxygen vapor phase thereby reducing the potential for explosions.

Enzymatic oxidizing systems based upon copper that exploit the many advantages and unique aspects of copper as a catalyst and oxygen as an oxidant as described in the preceding paragraphs are well known. They represent a powerful set of catalysts able to direct beautiful redox chemistry in a highly site-selective and stereoselective manner on simple as well as highly functionalized molecules. This ability has inspired organic chemists to discover small molecule catalysts that can emulate such processes. In addition, copper has been recognized as a powerful catalyst in several industrial processes (e.g. phenol polymerization, Glaser-Hay alkyne coupling) stimulating the study of the fundamental reaction steps and the organometallic copper intermediates. These studies have inspiried the development of nonenzymatic copper catalysts. For these reasons, the study of copper catalysis using molecular oxygen has undergone explosive growth, from 30 citations per year in the 1980s to over 300 citations per year in the 2000s.

A number of elegant reviews on the subject of catalytic copper oxidation chemistry have appeared. Most recently, reviews provide selected coverage of copper catalysts14 or a discussion of their use in the aerobic functionalization of C–H bonds.15 Other recent reviews cover copper and other metal catalysts with a range of oxidants, including oxygen, but several reaction types are not covered.16 Several other works provide a valuable overview of earlier efforts in the field.17 This review comprehensively covers copper catalyzed oxidation chemistry using oxygen as the oxidant up through 2011. Stoichiometric reactions with copper are discussed, as necessary, to put the development of the catalytic processes in context. Mixed metal systems utilizing copper, such as palladium catalyzed Wacker processes, are not included here. Decomposition reactions involving copper/oxygen and model systems of copper enzymes are not discussed exhaustively. To facilitate analysis of the reactions under discussion, the current mechanistic hypothesis is provided for each reaction. As our understanding of the basic chemical steps involving copper improve, it is expected that many of these mechanisms will evolve accordingly.

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Aerobic Copper-Catalyzed Organic Reactions

Copper-catalyzed C-H functionalization reactions: efficient synthesis of heterocycles.

Transformations of aromatic compounds into the corresponding amines, amides, and imides through carbon–hydrogen (C–H) bond functionalization represent one of the most step- and atom-economical methods for the synthesis of arylamine compounds. Because arylamines are privileged structures in materials- and biology-oriented functional molecules, the development of novel and efficient synthetic methods for aromatic C–H amination has received significant attention from a wide range of research fields including materials and pharmaceuticals. This review covers recent advances in catalytic aromatic C–H amination reactions. An array of recently developed new reactions are categorized by the nature of aromatic substrates: (1) 5-membered heteroarenes, (2) arenes having a nitrogen moiety in the molecule (intramolecular C–H amination), (3) arenes having a directing group, (4) simple arenes with excess amounts, and (5) simple arenes as the limiting reagents.

Catalytic Methods for Aromatic C–H Amination: An Ideal Strategy for Nitrogen-Based Functional Molecules

Cationic ruthenium(II) catalysts for oxidative C-H/N-H bond functionalizations of anilines with removable directing group: synthesis of indoles in water.

The selective functionalization of remote C–H bonds via intramolecular hydrogen atom transfer (HAT) is transformative for organic synthesis This radical-mediated strategy provides access to novel reactivity that is complementary to closed-shell pathways As modern methods for mild generation of radicals are continually developed, inherent selectivity paradigms of HAT mechanisms offer unparalleled opportunities for developing new strategies for C–H functionalization This review outlines the history, recent advances, and mechanistic underpinnings of intramolecular HAT as a guide to addressing ongoing challenges in this arena 1 	Introduction 2 	Nitrogen-Centered Radicals 21 	sp 3 N-Radical Initiation 22 	sp 2 N-Radical Initiation 3 	Oxygen-Centered Radicals 31 	Carbonyl Diradical Initiation 32 	Alkoxy Radical Initiation 33 	Non-alkoxy Radical Initiation 4 	Carbon-Centered Radicals 41 	sp 2 C-Radical Initiation 42 	sp 3 C-Radical Initiation 5 	Conclusion

Remote C-H Functionalization via Selective Hydrogen Atom Transfer.

Copper-catalyzed aliphatic C-H amination with an amidine moiety.

Copper-Catalyzed Aerobic Intramolecular Carbo- and Amino-Oxygenation of Alkynes for Synthesis of Azaheterocycles

Copper-catalyzed aminooxygenation of N-allylamidines with PhI(OAc)2.

Pd(II)-catalyzed synthesis of indoles from α-aryloxime O-pentafluorobenzoates via intramolecular aromatic C–H amination

A method for the synthesis of oxymethyl dihydropyrroles (pyrrolines) and dihydroimidazoles has been developed via Cu(II)-mediated intramolecular aminooxygenation of alkenylim­ines and alkenylamidines, respectively, with 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO).

Stephen Sanjaya

Papers

Copper-catalyzed aliphatic C-H amination with an amidine moiety.

Copper-Catalyzed Aerobic Intramolecular Carbo- and Amino-Oxygenation of Alkynes for Synthesis of Azaheterocycles

Copper-catalyzed aminooxygenation of N-allylamidines with PhI(OAc)2.

Pd(II)-catalyzed synthesis of indoles from α-aryloxime O-pentafluorobenzoates via intramolecular aromatic C–H amination

Cu(II)-mediated aminooxygenation of alkenylimines and alkenylamidines with TEMPO