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Long Live the Intermediate!

What’s in between in a reaction matters just as much as what sets it off

Roald Hoffmann

A Coin Has Two Sides

The catalyst, however, is hardly all there is to the story. As the reaction mechanism above mandates, the catalyst has a partner, often unseen. This elusive entity is the reaction intermediate Cat•A. Actually, “partner” is the wrong word; you can’t have one without the other. While the catalyst gets involved and is regenerated, the reaction intermediate does the reverse. It was not there when the reaction began. It is generated and then disappears, to reappear again in the next cycle.

2012-03MargHoffmannFB.jpgClick to Enlarge ImageThis pairing of catalyst and intermediate is a feature of all catalytic cycles, from the simple example on the previous page to the more complicated real-world reactions. There’s nothing weird in these fleeting transformations—no philosopher’s stone, no action at a distance—just plain, good old chemistry. The figure at right, for example, shows a very useful reaction that builds carbon-carbon bonds in complex organic molecules, such as one might need to make a pharmaceutical. The reaction is known as the Stille coupling, named for its originator, the late John Stille. Molecule 1 is the catalyst here, a compound that consists of palladium (Pd) in its reactive, zero-oxidation state, with ligands (L) attached. Molecule 2 is the reagent, RX, where R is an organic group such as CH3 or C6H5, and X is a halogen atom such as fluorine. This reagent adds to the catalyst in a reaction called an oxidative addition, in which Pd donates two electrons to form bonds with both R and X. Thus is generated 3, an intermediate, actually the first of two in this cycle.

The intermediate, in turn, reacts with 4, a compound composed of tin (Sn), three butyl groups (Bu) and another organic group (R’). In this reaction, the X on Pd is traded for R’, generating two products. One is 5, in a sense a by-product. The other is 6, a second intermediate that has both R and R’ attached to the Pd. It expels the twain in a reaction called a reductive elimination. The net result is that the two organic groups, R and R’, are linked together by a new carbon-carbon bond, 7. That is the aim of the reaction, the thing that makes it useful. At the same time, the catalyst is regenerated. Reactions quite similar to this were rewarded with the 2010 Nobel Prize in Chemistry.

The Stille coupling is an example of homogeneous catalysis: All reactions take place in a solution. The pairing of catalyst and intermediate also happens in heterogeneous catalysis, in which reactions take place on metal particles or on reactive centers bound to solid grains. For example, metal surfaces that break apart hydrogen and nitrogen molecules (H2 and N2) and bind the separated atoms to the surface are the intermediates in what is perhaps the single most important catalytic industrial process of our world, the Haber-Bosch process. That reaction, illustrated at the bottom of the following page, is responsible for combining hydrogen gas and abundant atmospheric nitrogen into a biologically and chemically useful molecule, ammonia (NH3). Half of the many nitrogen atoms in your body have seen the inside of a factory, have visited the small metal particles that catalyze this incredibly successful reaction.

Intermediates are just as ubiquitous in our bodies, in the still more successful biochemical reactions crafted by evolution. Here, the catalysts are enzymes—the ever-so-efficient molecules (proteins themselves) that facilitate, for example, the removal of amino acids, one by one, from ingested proteins. During each step, the enzyme’s active site binds the substrate, temporarily forming an intermediate.

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