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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: derekb.lowe@gmail.com Twitter: Dereklowe

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September 6, 2007

Aromatherapy

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Posted by Derek

I was talking about reactive compounds the other day, but I should note that some of the reactive ones can still linger around in a peculiar manner. Acid chlorides are a good example, from both carboxylic and sulfonic acids. They’re reactive, all right – just pitch one into a bunch of amine and find out. So you’d think that if you spilled some, that their admittedly nasty aromas would be a problem that solves itself, right? They won’t last long outside the bottle; they’ll react with water and such in the air and stop stinking the place up – right?

Wrong. Some of these guys can hang around for abominable lengths of time if you don’t actively clean them up. The problem is, I think, that while they do react with water, it’s only a fast reaction under stirring conditions. In the bulk phase, the liquid acid chlorides tend to be rather thick and oily. My guess is that the outer layer does react with water (at its own pace), but that diffusion is slowly bringing more unchanged acid chloride to the surface. Where it reeks.

The sulfonyl chlorides tend to be solids, which makes the problem that much worse. The crystals don’t do the stainless-steel thing and form a reacted skin around them that seals up the inside. No, for all I can tell, tosyl chloride (the prototype sulfonyl chloride, found in organic labs around the world) will stink indefinitely. I’ve no idea of what its nose-wrinkling, headache-inducing half-life is, just that it’s very long indeed.

At least its hydrolysis product, toluenesulfonic acid, doesn’t smell. It won’t improve whatever its standing on, true, but at least you won’t know it’s there from across the room. But those oily liquid carboxylic acid chlorides stink horribly as their free acids, too, so over time, if you’re so inclined, you can note the changeover from the musty, acrid smell of the chloride to the rancid, goaty stench of the parent acid. The midpoint of the process is a treat.

So, you lazy chemists, break down and clean the stuff up. It’s not going to get any better unless you put some energy into the system (in the form of hands, elbows, and paper towels). All of our problems should clean up so well.

Comments (11) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Anonymous on September 6, 2007 10:08 PM writes...

Once I needed a reference sample of allyl alcohol, but I couldn't find a bottle around. So I figured I would take some allyl chloroformate and let it react with water. I mixed the two together and allowed to stir for 30 minutes -- no reaction. Taught me a lesson about the robustitude of such reagents.

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2. Andy on September 7, 2007 3:07 AM writes...

Aryl sulfonyl chlorides are often prepared from chlorosulfonic acid and isolated by adding to ice whereupon the product precipitates. I always assumed that the reaction of acid chlorides and sulfonyl chlorides with water was pH dependent not stirring rate dependent, and didn't react quickly at pH 7.
Whatever, mess should be cleared up smelly or not.

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3. Keith on September 7, 2007 7:09 AM writes...

Remember the Shotten-Baumann acylation of phenols with benzoyl chloride? Done in 2M aqueous sodium hydroxide .......... and you get the ester.

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4. ORK on September 7, 2007 7:34 AM writes...

The worst smelling acid chloride in my opinion is crotonyl chloride, at first wiff you get a kind of vomit like smell and in the end as a added bonus you get the lachrymator that most all crotonyl agent are.

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5. Karl Hungus on September 7, 2007 8:54 AM writes...

Ethylene dithiol is the worst stuff I've worked with. I wasn't super careful the first time, and I stunk up the labs with the smell of the worst egg farts you can imagine. I was persona non grata for some time after that, and quickly learned how to work with it (if you spill it, even the smallest drop will stink to high heavens, wash it up with dilute NaOH).

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6. .... on September 7, 2007 9:03 AM writes...

I cannot tolerate CbzCl anymore following my brilliant decision to run a large scale Cbz protection of serine outside of the hood (we had a nifty pH titrator set up on the bench that was the bees-knees for these types of reactions). The smell was so overwhelming and coated the hairs inside my nose so I could smell it everywhere I went. I had a headache for several days and now have terrible memories any time I catch a faint whiff of the stuff.

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7. milkshake on September 7, 2007 11:04 AM writes...

Use the CbzOSu, the hydroxysuccinimide version of the reagent. White crystals, no smell, no benzyl chloride in the crude producr, easy to work-up.

A colleague in the lab just few days ago had a mishap - he opened an over-pressurized big bottle of Cbz-Cl that was stored at room temp (so lots of CO2 build up in there) and a fountain of neat Cbz chloride erupted into his face. He had goggles so he kept his sight but the skin irritation and the smell must have been quite bad - and the lab stunk even the next day.

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8. MikeS on September 7, 2007 11:42 AM writes...

I had a similar accident with CBZ-Cl. It was stored in a Aldrich bottle with a regular non-vented sure-seal cap, which was poor form on Aldrich's part.

Fortunately, since I was aware of the possibility of pressure build-up and because the bottle looked pretty old, when I went to withdraw some with a syringe I made sure to pull the hood sash down and point the bottle away from me.

When I pierced the septum, the pressure in the syringe was great enough to overpower my thumb and the syringe plunger loudly popped out and ricocheted around the hood a couple of times, and about 100ml of the stuff was dispersed in a fine mist that coated the inside of my hood.

As I was wearing gloves and a labcoat, and the hood sash was down, I hardly got any on myself, but the little bit that shot through the gap under the sash and soaked through my labcoat into my shirt smelled bad enough to send me home for a shower and a new change of clothes.


As for the aqueous stability of acid and sulfonyl chlorides, stirring them with NaOH and Na2CO3 will usually hydrolyze them reasonably quickly, but they are quite stable when exposed to neutral or acidic water. The reason that Shotten-Baumann conditions work is that because the deprotonated phenol is a far superior nucleophile and has much greater solubility in the organic phase than hydroxide.

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9. Jason on September 7, 2007 1:18 PM writes...

There was a paper published a few years ago (Org Let, perhaps) showing the stability of aliphatic acyl chlorides with over four or five carbons in water as solvent. Their hydrophobicity was such that they were virtually inert to conditions that rapidly hydrolized acetyl chloride, and they were amenable to esterification reactions in water in high yields.

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10. Dennis on September 7, 2007 4:56 PM writes...

I have never smelled a goat before. Has every other organic chemist in the world though? Or are we just imagining that they smell like those nasty acids?

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11. Curious Wavefunction on September 9, 2007 8:32 PM writes...

Goats smell like goat cheese

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