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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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July 25, 2005

Hydrogenation Made Easy?

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Posted by Derek

I recently saw a demonstration of a gizmothat promises to make catalytic hydrogenation easier. If it works, it's about time. This is an ancient reaction (the standard apparatus is pretty much unchanged since the 1920s), but it's still extremely useful. But nobody likes to run the darn things.

For the non-chemists in the crowd, the idea is that hydrogen gets added to a bond (or bonds) in your molecule. So a carbon-carbon double bond gets reduced to a single bond, for example, or a triple bond to a double. (Unless you're careful, though, that triple bond is going to go all the way down without stopping.) You can even reduce aromatic rings down to their saturated counterparts, which was the very reaction I was speaking about the other day (taken a hexagon-with-a-circle drawing down to a plain hexagon.)

And it doesn't have to be C-C bonds that you reduce. N-O bonds are particularly labile to the reaction, so nitro groups get turned into amines, among other things. And some single bonds, especially those near aromatic rings, can just get completely cleaved, which is the basis for a lot of protecting group chemistry that people use to tape down reactive parts of their molecules for a while.

To do all these neat things, you need a metal catalyst, whose efficacy correlates nicely with their cost. Platinum, for example, is a fine one. Palladium, its blood relation, is very widely used. Nickel, rhodium, and iridium have their uses, and from there you go off into some real esoterica. These things are sometimes used just as fine metal powders, but often they're furnished as a fine dispersion on some sort of solid support - powdered charcoal or alumina, for example. Good ol' 5 per cent palladium on carbon is probably the most often used hydrogenation catalyst in organic chemistry.

You might get the impression from all these variations that the field is lacking in rigor. You would be very correct indeed. Tom Goodwin, my undergraduate organic chemistry professor, accurately described it as "witchcraft." The real atom-by-atom mechanism of the reaction is known in broad detail, but many key things are still obscure. Hydrogenations can vary not only according to the substrate molecule and the metal, but according to its solid support (and its loading on it), the solvent used in the reaction, the temperature, the pressure of the hydrogen gas in the vessel, and the source of the hydrogen itself.

It's that hydrogen gas that causes the uneasy feelings about the reaction. Hydrognations have been responsible for untold minor fires in labs all over the world, and once in a while a major one. Hydrogen is famously flammable itself, but there are other problems. Once the metal catalysts are saturated with the gas, they often glow red-hot on exposure to air, which is not so good when you have lots of organic solvent around. The "Raney nickel" catalyst comes already soaking in hydrogen, and a classic way of seeing if it's still good is to wipe some of the wet powder on a paper towel. If it bursts into flame when it dries, it's fine.

I've instantly singed the hair from the upper joints of my fingers through misjudgment of these little details. (Another hard-to-forget experience with hydrogenation apparatus is here. If this contraption works as advertised, perhaps my nerves will have one less thing to jangle them.

Comments (2) + TrackBacks (0) | Category: Life in the Drug Labs


1. Philip on July 26, 2005 10:40 PM writes...

Interesting comments. I kind of like to run hydrogenations, at least the balloon kind. They usually work. They're easy to set up if you have the right valves in your hood. They're safe if you have a paranoid respect for the danger (ie do copious vac/N2 purges between air and hydrogen among other things) and compounds almost always come out cleaner due to the cleansing effect of the carbon.

What I don't care for is other people around me running hydrogenations. It's downright terrifying.

I don't think that gizmo will ever gain much traction. They'll sell a lot of them and then they'll get used a couple of times and then they'll go into storage along side all the combi-chem equipment that was a little more complicated than ever made any sense.

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2. Dr Snowboard on July 27, 2005 3:16 AM writes...

I think the main selling point of this apparatus will be the ability to run at pressure. We run hydrogenations with a H2 generator running into a gas burette to avoid the need for a cylinder strapped to the bench and it works pretty well, but there's always a couple of reactions a year we'd really like to crank up the pressure on.. I've seen much bigger white elephants bought in the past.

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