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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

Privileging the Intermediate

Perhaps we value the catalyst because it comes first: Could it be that you can’t have a reaction intermediate without first having a catalyst? I don’t think so. In fact, the clue that catalysis is at work is often simply the rate of reaction. A transformation that we thought would be slow in fact goes like a shot. In such reactions one looks as often for the reaction intermediate as for the catalyst.

The intellectual bonus of finding a reaction intermediate is that it immediately suggests what the catalyst is, and may, in fact, give you the reaction mechanism in one fell swoop. If you find a catalyst, as valuable as that discovery may be, it does not give you the mechanism. It only provides you with the impetus to write down alternative mechanisms for the way the catalyst might tangle with the reactant.

In recent times, people have found new ways to look for catalysts, ways that focus on the intermediates. One such approach is the de novo design of enzymes: Pick a reaction you want to have happen, sculpt the essentials of the active site (which, together with the substrate, forms the intermediate) and fine-tune the rest of the protein. Another approach is directed evolution, in which libraries of potential catalysts (not only enzymes) are generated and tested for their ability to catalyze a reaction. Their ability to destabilize reaction intermediates—a way to higher turnover numbers—can be probed, remarkably, by mass spectrometry. Only the most effective versions are selected for further refinement.

Each of these approaches—and there are many, for the field is supremely active—deserves an essay on its own. Here, let me provide two older examples, to which I was guided by two of my colleagues, Brian Crane and Geoff Coates, both great hunters of catalysts.

An intermediate found first. It’s hard to turn back the clock in a field as dynamic as molecular biology. But in the mid-1950s the ribosome was just beginning to be seen, and the details of protein synthesis were unknown. In a critical experiment, biochemists Mahlon Hoagland and Paul Zamecnik discovered a reaction intermediate involved in protein synthesis: the aminoacyl adenylates, amino acids that have been “activated” in a reaction with adenosine triphosphate (ATP). Within a year of the discovery, multiple research groups had begun to describe the enzymes responsible for that activation.

The same enzymes turn out to catalyze a second reaction, too: the addition of the activated amino acid to a transfer RNA (tRNA). The latter compound shuttles its specific amino acid component to the ribosome, where it is added to a growing chain of amino acids during protein synthesis. The enzymes in question are now well known as aminoacyl tRNA synthetases. They were discovered because the relevant intermediates in the activation of amino acids were found first. Indeed, aminoacyl adenylate intermediates are so unstable, so easily added to tRNAs, that they are difficult to isolate in the presence of tRNA.

An intermediate that became a catalyst. Like all real stories, that of Karl Ziegler’s remarkable development of ethylene polymerization catalysts is not a simple one. Ziegler and his coworkers were studying the reaction of lithium aluminum hydride (LiAlH4) with ethylene, a two-carbon compound. Their products were longer-chain hydrocarbons, 4 to 12 carbons long. From the LiAlH4 reagent they moved to aluminum hydride (AlH3), which also catalyzed the reaction. But then Ziegler discovered that a reaction intermediate in the AlH3 reaction was triethylaluminum, Al(CH2CH3)3. This compound, which could be made independently, was an even better catalyst for polymerizing ethylene. Substantial pressure was still required to make the polymerization go; the process was much improved by the participation of titanium chloride (TiCl4). To this day, small mysteries remain in the details of this reaction, but a world without polyethylene plastics is hard to imagine.

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