Counting on copper.

At the end of the Finnish epic Kalevala, the hero Väinämöinen sets sail into the heavens, leaving behind the mortal realm in a copper boat. Modern engineers seem to have taken this to heart: ships’ hulls are lined with materials based on copper, which inhibits the growth of bacteria, barnacles and other unwanted passengers. Väinämöinen’s vessel is just one example of how the reddish-brown lustre of copper has spurred human imagination throughout history. To the ancient Romans, copper was known as cuprum, in reference to the island Cyprus, where much of their copper was mined. Nowadays the word copper typically conjures visions of pennies, electrical wiring or perhaps the Statue of Liberty, who owes her green complexion to copper(ii) carbonate. But despite its seemingly unremarkable presence in everyday life, copper continuously plays an active role in science for its essential, lifesaving biological functions and its diverse chemical properties. Much of copper’s versatility arises from its ability to carry out three different chemical processes: Lewis acid catalysis, single-electron-transfer processes and two-electron-transfer reactions. In Lewis acid catalysis, Cu+ or Cu2+ ions bring together different molecules and facilitate a chemical reaction between them. A famous example is the copper-catalysed azide–alkyne cycloaddition, known as click chemistry. In this reaction, one of the starting materials is tagged with an azide moiety whereas the other bears an alkyne group; the two first coordinate to copper, then covalently bind to each other to form a triazole ring1. No transition metal is as effective a catalyst as copper for this step. Owing to its reliability and high selectivity, this click reaction is widely used, from the total synthesis of natural products and their derivatives to the preparation and modification of polymers. Another example of Lewis acid catalysis mediated by copper ions is the synthesis of cyclic peptides — a class of compounds with numerous biological applications. Cyclosporin A and gramicidin S, for example, are antibiotics; octreotide and calcitonin act on the endocrine system; and eptifibatide helps prevent clot formation and strokes. Owing to its positive charge, Cu2+ (along with other ions) is able to bind to electron pairs of the oxygen, nitrogen and sulfur atoms of the linear peptide precursors, thereby bending them into curved shapes that can more easily form closed ring structures2. Mechanistically more complex than Lewis acid catalysis, single-electron-transfer processes carried out by copper — alternating between its Cu+ and Cu2+ forms — are indispensable in biology. Cellular respiration in which an organism extracts energy from glucose involves the copper-containing enzymes of the mitochondrial membrane. These enzymes oxidize glucose and reduce oxygen through stepwise single-electron transfers, also forming water in the process. Other enzymes that carry out coppermediated single-electron transfers include the somewhat lesser known, yet also important, superoxide dismutase and tyrosinase3. The copper–zinc-based superoxide dismutase protects cells from reactive oxygen species by converting those into the less toxic hydrogen peroxide molecule, itself subsequently transformed into oxygen and water. Copper-containing tyrosinase converts tyrosine into l-dopa, a precursor to the hormone adrenaline, which mediates ‘fight-or-flight’ responses under acute stress. l-dopa is also used to treat Parkinson’s disease; it is metabolized to dopamine, which mediates communication between brain nerve cells. The last type of common copper catalysis are two-electron-transfer reactions — also called coupling reactions — which take place in three steps: oxidative addition, trans-metallation and reductive elimination. First, Cu(0) breaks a carbon–halogen bond to form a carbon–copper bond and a copper–halogen one, while being oxidized to Cu2+. Next, the halide ion is displaced from the copper metal centre by a nucleophile or another entering group. Finally, the carbon–copper and copper– nucleophile bonds are both cleaved to yield a carbon–nucleophile bond and the Cu(0) catalyst is regenerated. Coupling reactions were first popularized with palladium catalysts, and earned Heck, Negishi and Suzuki the 2010 Nobel Prize in Chemistry. These reactions now find widespread use in drug synthesis and will most likely only continue to attract attention. As a catalyst, copper produces efficient yields under mild reaction conditions and is relatively resistant to poisons that would disrupt other catalysts, making it a desirable alternative to palladium. From the synthesis of pharmaceuticals to the design of new structures in nanotechnology5, copper is continually being rediscovered as catalyst and a versatile building block. This trend shows no sign of abating, perhaps suggesting that the use of copper may only be limited by one’s imagination. ❐