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.

/pdf/aerobic-copper-catalyzed-organic-reactions-3ctljpvivz.pdf

Aerobic Copper-Catalyzed Organic Reactions

Based on the principles and metrics of green chemistry and sustainable development, biocatalysis is both a green and sustainable technology. This is largely a result of the spectacular advances in molecular biology and biotechnology achieved in the past two decades. Protein engineering has enabled the optimization of existing enzymes and the invention of entirely new biocatalytic reactions that were previously unknown in Nature. It is now eminently feasible to develop enzymatic transformations to fit predefined parameters, resulting in processes that are truly sustainable by design. This approach has successfully been applied, for example, in the industrial synthesis of active pharmaceutical ingredients. In addition to the use of protein engineering, other aspects of biocatalysis engineering, such as substrate, medium, and reactor engineering, can be utilized to improve the efficiency and cost-effectiveness and, hence, the sustainability of biocatalytic reactions. Furthermore, immobilization of an enzyme ...

/pdf/role-of-biocatalysis-in-sustainable-chemistry-5b3e0qe0ep.pdf

Role of Biocatalysis in Sustainable Chemistry

The successes and failures of past research in the development of microfluidic reactors for chemical synthesis are highlighted. Current roadblocks are assessed and a series of challenges for the future of this area are identified.

/pdf/the-past-present-and-potential-for-microfluidic-reactor-30n6i6acaz.pdf

The past, present and potential for microfluidic reactor technology in chemical synthesis

The fine chemicals and pharmaceutical industries are transforming how their products are manufactured, where economically favorable, from traditional batchwise processes to continuous flow. This evolution is impacting synthetic chemistry on all scales-from the laboratory to full production. This Review discusses the relative merits of batch and micro flow reactors for performing synthetic chemistry in the laboratory.

Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis.

Using continuous flow techniques for multi-step synthesis enables multiple reaction steps to be combined into a single continuous operation. In this mini-review we discuss the current state of the art in this field and highlight recent progress and current challenges facing this emerging area.

/pdf/continuous-flow-multi-step-organic-synthesis-2p7n5fghtp.pdf

Continuous flow multi-step organic synthesis

Microreactor Technology and Continuous Processes in the Fine Chemical and Pharmaceutical Industry: Is the Revolution Underway?

A method for preventing plugging of a continuous-reaction channel-system caused by a by-product of a continuous-reaction being carried out in said channel-system comprises the step of generating at least one ultrasonic wave travelling through said channel-system by coupling in a flow direction of at least one process fluid of a plurality of process fluids said at least one ultrasonic wave into said at least one process fluid.

Method for preventing plugging of a continuous-reaction channel-system and micro-reactor for carrying out the method

The present invention relates to a process for the preparation of organic nitrates having at least one nitryloxy and at least one hydroxy group, wherein the at least one hydroxy group may be present in form of an esterified hydroxy residue, the latter being esterified with an acid other than nitric acid.

Method for the preparation of organic nitrates

The present invention relates to a process for lithium exchange reactions comprising mixing at least two fluids in a microreactor having at least two injection points.

Fabio Rainone

Papers

Microreactor Technology and Continuous Processes in the Fine Chemical and Pharmaceutical Industry: Is the Revolution Underway?

Method for preventing plugging of a continuous-reaction channel-system and micro-reactor for carrying out the method

Method for the preparation of organic nitrates

Method for lithium exchange reactions