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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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May 19, 2009

TMS Reagents: Handle With Care!

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Posted by Derek

Some emails and discussions with colleagues have raised an important point to be learned from the recent TMS-diazomethane tragedies. Many people are probably taking some of these reagents less seriously than they should.

As organic chemists know, the trimethylsilyl group is a strange beast, and can often substitute for a proton in small reagents. That often gives such compounds new and useful properties along the way – for example, hydrazoic acid (hydrogen azide) is an extremely dangerous substance because of its unpredictable explosive qualities. It should never be generated except in very dilute solution (that is, unless you’re prepared at every moment for a serious detonation, and not many people are). But the corresponding trimethylsilyl azide is an article of commerce – you can pick up the phone and order a bottle. No one in the history of the fine chemical industry, as far as I know, has been crazed enough to offer hydrazoic acid for sale. How could it be delivered - by trained hummingbirds?

But the two reagents can do many of the same transformations, since the TMS group is often just about as easy to lose at the end of the reaction as a proton is. The exact same situation obtains with trimethylsilyldiazomethane: no one’s ever tried to sell or ship the parent compound, but solutions of the TMS derivative are ready to be ordered at your convenience.

But that's only because they're less explosive. All the TMS reagents are just as poisonous as their proton counterparts. And that's where I think some chemists aren't making the connection. We treat diazomethane gingerly because we don't want it to explode, but we should also be handling it like the volatile toxin it is. The same goes for hydrazoic acid. If you have to deal with the stuff, you're mostly thinking every second about how it could go off on you. But you should also be thinking about how it's a potent, poisonous vasodilator. It doesn't have to blow up: a good deep gust of it will relax your arterial walls permanently by killing you, and TMS azide will do the exact same thing.

These compounds are intrinsically toxic, and they're also toxic because they'll hydrolyze back to the parent compounds in a warm, wet environment - like the inside of your lungs. I think that people treat another one of the series, trimethylsilyl cyanide, with more respect. That's because HCN gets a lot of respect for its inhalation toxicity (and with damned good reason), and opening an ampoule of TMS-CN is (or should be) a reminder that it's just as nasty. And since it doesn't explode, that's the main thing that you think about.

So spread the word: these reagents, though extremely useful, are not to be handled lightly. They're volatile and they're just as poisonous as their parents. The ease of ordering and handling them, in fact, may make them even more of a potential hazard. Treat 'em with respect.

Note: for those looking for a thorough reference work on the subject, this seems like an up-to-date choice.

Comments (15) + TrackBacks (0) | Category: Safety Warnings


COMMENTS

1. Muruga on May 19, 2009 11:31 AM writes...

The recent fatal accidents are the eye-openers for the organic chemists. The aforesaid TMS-derived reagents are said to be "relatively less-hazardous" (explosive/health), which means that they are still hazardous. Thank Derek for this alert.

Permalink to Comment

2. Hap on May 19, 2009 11:58 AM writes...

1) Whee! More drug spammers (see 1).

2) Would the mol. wt. of the TMS group help to limit the volatility of the corresponding compound? It doesn't help if you spill it or if the TMS group comes off rapidly, but it might help decrease the exposure in some cases, if not the toxicity (though apparently not enough, based on the mode of administration of the recent TMSCHN2 death).

3) The warnings are useful - if I knew there was a hazard, I had an idea how carefully I had to treat something, while with unknown hazards it seems to be difficult to treat them with a high level of alert every time, even though assuming that unknowns are hazardous until shown otherwise is probably appropriate. The lack of information on TMSdiazomethane before these accidents is at least part of the problem - if you have to depend on what assumptions people make or don't make about the toxicity of a compound, there will be problems somewhere. (In addition, if management or nonchemists running things have no data on the hazards of particular compounds, they may make rules that are hazardous to people likely to work with them or they may simply not be aware of hazardous behaviors involving the chemicals and so be unable to deal with potential hazards effectively.)

I'd still like to know if and why someone thought it would be safe to do wet chemistry (let alone scaleup chemistry) with the hoods disabled.

Permalink to Comment

3. andrew on May 19, 2009 1:06 PM writes...

Anyone read the MSDS for TMS-diazomethane? I'm using it, and I've read the Alfa MSDS. Doesn't seem to spectacular. It's only the recent accidents that have made me sit up and pay more attention.

Permalink to Comment

4. Hap on May 19, 2009 1:16 PM writes...

1) used to be 1. Bye, bye, spammer!

2) Jose had a comment (37) to the previous TMSCHN2 post with the message that MSDS are written for the legal protection of employers and purchasers and not for the people actually using the chemicals (the severity of the warnings don't correlate with the severities of the hazards, for example). I also linked to the MSDS in an earlier comment in the same thread.

There is the less cynical possibility that the people who wrote the MSDS had no actual data as to the hazards of TMSCHN2 - they wrote about what they knew (hexane) and didn't say anything about what hazards they knew not. Alas, the absence of a known hazard with a chemical doesn't mean there isn't one - we may just not know about it or have a good data to substantiate the hazard. Beyond chemical intuition (which isn't always helpful, unless you have lots of other intuition and experience), there isn't much way to know a hazard in the absence of data, and so one has to assume that compounds may be hazardous if you don't know otherwise.

Permalink to Comment

5. milkshake on May 19, 2009 2:27 PM writes...

TMS-diazomethane keeps good in the fridge almost indefinitely whereas freshly-made diazomethane solution bleaches out within few days. Re-making diazomethane is not great fun:

NMMG and NMU are known contact explosives and strong experimental carcinogens (used also to induce tumors in animals). They are becoming increasingly expensive and difficult to buy and the diazomethane generated from them is always contaminated with traces of methylamine.

The Diazald is nicer but the mix requires distillation of the resulting diazomethane solution, in a special apparatus devoid of ground joints. If the chemist is forgetful, walks out and drinks coffee and accidentally lets the mix to distill to a small volume the whole setup likes to go kaboom.


Permalink to Comment

6. Jose on May 19, 2009 3:42 PM writes...

I do not believe data is ever not disclosed by design. More precisely, the litigation angle means that MSDS sheets are written so that *all possible* hazards and exposures are explicit, which means it becomes impossible to know what the true and likely hazards are. Fear of lawsuits = blanket MSDS sheets = worthless for real life exposures.

Permalink to Comment

7. Hap on May 19, 2009 4:38 PM writes...

I didn't mean to imply that people would hide risks of which they had information. I wonder, though, under what conditions companies would voluntarily reveal risks without the fear of lawyers falling on them from the sky if they didn't. What fields work in this way?

Permalink to Comment

8. Stephanie Siddell on May 19, 2009 8:47 PM writes...

Thank you Derek, Michael Tutton, and ladies and gentlemen chemists. It is through you that Roland Daigle's family and my family are able to take the first step towards insuring the health and safety of other chemists (Andrew, #3 above). Right up to the end, I don't think my son made any association between the compound he was working with that day and what was happening to him physically. It took a good 8 hours after the incident until he even started feeling the ill effects. He was a young chemist, in the field just shy of 18 months. Knowing my son, I don't believe that he was complacent, I believe that he truly did not know the hazards, much like Andrew and Roland, and I'm sure others. Again, thank you and be safe.

Permalink to Comment

9. Richard on May 19, 2009 9:01 PM writes...

I hate that these materials comes in packaging that is not even easy to handle and that these materials are sold in such bigger than necessary volumes (I'd pay for the smaller bottle if it doesn't have to sit in the lab for another year.)

Puryevors of chemicals should make packaging that makes it easier to transfer 1 mmol of reagent in a flask.

I mean--that's whole "sure-seal" and transfer by cannula? Never works as cleanly as it should.

I think this is an issue that ACS should investigate for the safety for everyone.

Permalink to Comment

10. Stephanie Siddell on May 19, 2009 9:03 PM writes...

Oh, and thank you to InfMP (12) of the previous TMSCHN2 post. It was because of you adding your paragraph to Wiki that we were able to find Mike Tutton's article about Roland Daigle. Prior to that, my family and I were simply bewildered. We and Roland's family have talked many times, and hope to meet one day soon. We did wonder who added that paragraph to Wiki. Thank you and please keep up the fine work...you never know who is in need of your knowledge.

Permalink to Comment

11. Chemjobber on May 19, 2009 9:51 PM writes...

Mrs. Siddell: are you willing to speak with me about your son? If so, please e-mail me at chemjobber@gmail.com

Permalink to Comment

12. InfMP on May 21, 2009 9:50 PM writes...

no problem.

Permalink to Comment

13. james little on August 20, 2009 6:13 PM writes...

i've got a description on how to make small amounts of diazomethane for analytical purposes without distillation on my website..

Permalink to Comment

14. Andrew on June 3, 2014 12:35 PM writes...

Thanks for your advice!

Permalink to Comment

15. Andrew on June 3, 2014 12:35 PM writes...

Thanks for your advice!

Permalink to Comment

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