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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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May 23, 2006

Can't Buy These Thrills

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Posted by Derek

There are a number of reagents that you used to be able to buy which are no longer around. Some of these have just fallen out of favor, but a compound has to go pretty far down the list before no one sees any profit in selling it. The more common reasons for the disappearance are a bit more dramatic.

A notorious example is "Magic Methyl" (methyl fluorosulfonate). Flurosulfonate is about as good a covalent leaving group as nature provides, and Magic Methyl was accordingly one heck of a way to methylate anions that turned up their noses at anything difficult. Problem was, though, that it also tended to methylate the user. There was at least one fatality in the 1970s from a not-very-large spill of the stuff, and by the time I got to grad school it had been pulled from commercial supply. It's never coming back, either. You can still make the stuff and use it yourself, and people do once in a while (not to mention things that are even more reactive, although that one's not volatile, at least). But there are research organizations that forbid even that.

There are substitutes, but nothing's quite in the same league. Methyl triflate is the closest thing going, as far as I know. It's an open question as to how much less nasty that one is - you can still buy it by the gallon. No one's been killed by it, but if someone dropped a bottle near me I'd still hold my breath and dive out the door.

Dess-Martin reagent is one that's appeared and disappeared over the years. It's a useful oxidizing reagent, which tends to react very cleanly and on some substrates that are hard to work with otherwise. Making it has always been a nerve-wracking process, though. The reagent itself shouldn't be heated, but is reasonably well-behaved. But the intermediate compound in the synthesis (IBX) has been known for some time to be erratically explosive, especially if it's allowed to dry out. It's sensitive to impact, which always made for a good time when it was time to get it out of the funnel after filtering it.

The fun didn't stop there. The last step in the synthesis, right after the IBX formation, was famously wonky, and has only been ironed out in recent years. Or so I'm told - I made a couple of hundred-gram batchs of the stuff, fifteen years ago, going two for three in attempts on the last step, and do not plan to do so again. You can buy the reagent at the moment, but it's been dropped from catalogs before (as Aldrich did during the 1990s).

Comments (14) + TrackBacks (0) | Category: Things I Won't Work With


1. Squin on May 23, 2006 9:42 PM writes...

There are some fantastic reagents out there, some scare the hell out of me, others are scary and cool at the same time. I once made about 20g of solid vinyl-lithium (very flammable in air), that was a lot of fun but I did not for one second lose my respect for it

There was a accident in my lab recently caused by someone who used a procedure that they hadn't been taught. It could've been very seriously (ie. death) but they got away with minor cuts.
It got me thinking about not only reagents but also procedures which can be more dangerous than their individual components.
I was wondering if anyone knows any good websites that contains real world information on how to use dangerous reagents and teaching for procedures.
Dylan's tenderbutton blog has listed some great procedures (ie. the large scale LiAlH4 rxn) but there should be some others.

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2. secret milkshake on May 23, 2006 9:59 PM writes...

Many things become unavailable because of the transport regulations - recently, it was Diazald, the reagent Aldrich started with and made safely tonns of it. But it has a decomposition exotherm abouve certain temperature so it cannot be trucked in these days any more. The same problem was recently with DEAD, now they started selling it again as a solution in toluene.

IBX explosivity is related to impurities, iodoso benzoic acid and bromate/sulfuric acid (used in the old prep) I think the current oxone oxidation does not suffer from this problem - pure IBX is about as sensitive to heat/shock as TNT.
For acetylating IBX to periodnane, the Ireland prep works very nice (catalysing the acetylation with TsOH). I have done it many times on 50G+ scale, always very reproducible results and good yields.

Magic methyl: FSO2Me is awfuly volatile, so it is easy to poison yourself. (People fatally poisoned themselves even with dimethyl sulfate, the stuff apparently does not smell)
Me-triflate is more powerfull than magic methyl. My favorites are Me3O+ SbF6- or BF4- : These are stable crystalline solids that store resonable well. Once I made a 200G batch of Et3O+ BF4-, by the classical Merwein prep.

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3. eugene on May 23, 2006 11:23 PM writes...

Dimethyl sulfate is fatal? I guess I have to be careful around it. Not that I breathe it on on purpose anyways...

Speaking of things you can't get, whatever happened to tetrachloromethane? That was such a great solvent. Perfect for all your radical bromination reactions and work-ups. I know, I know, it'll give me cancer. Still, it's a shame it's gone (or at least a lot more expensive!). Apparently benzene is being hounded too these days. Then I'll really be in trouble: I might have to fix the rotovap if I ever expect to get the toluene off.

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4. Thomas McEntee on May 24, 2006 6:40 AM writes...

Back in the 1960-70s when I was a young chemist in the lab, the oldtimers bemoaned the increasing emphasis on lab safety and all these worries about carcinogens etc. Mind you, being still young and immortal, we were still able to be standing at the hood with a burning cigarette hanging from our lips and shaking the sep funnel while we did the ether extractions. Carbon tet or benzene?...available in half-gallon glass bottles in every lab.

The dangers of dimethyl sulfate were known, fortunately, although this didn't stop me from using bottles of it although always in the hood and with gloves on my hands. Speaking of alkylating agents, one of my favorites was triethyloxonium tetrafluoroborate (one of the Meerwein salts), made by the reaction of (gasp!) epichlorohydrin, ether, and BF3 etherate in a nice dry glove bag (see for details). Unrelated, but one that still causes me to think about its effects on my body, was all the work I did making and using chromyl chloride.

All of the lab exposure we had pales by comparison with the dangers that many plant workers in the chemical process industry were exposed to.

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5. Bitter Pill on May 25, 2006 6:16 PM writes...

I heard that explosion potential is why HOAT is off the market. That put a cramp in a number of colleagues reactions.

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6. Anniechem on May 25, 2006 7:01 PM writes...

My former supervisor told me about one time when she was on sabbatical, doing some work at a nearby university, she opened up a drawer and there laid a bottle of Magic Methyl! She knew exactly how dangerous it was, backed away slowly, and asked the people in that lab why they had it in a drawer not designed for chemicals. They didn't even know what Magic Methyl was or that it was the least bit dangerous....scary!

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7. Hap on May 25, 2006 7:01 PM writes...

the 11th Merck Index (entry 3244) calls dimethyl sulfate "hazardous" with "no warning characteristics (odor, irritation)" - it can either be absorbed through the skin or by breathing, with symptoms (including the time delay) similar to those of phosgene. Not coincidentally, Merck lists one of its uses as a "war gas". It sounds like Magic Methyl Lite.

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8. josef on May 26, 2006 4:57 AM writes...

Can you discuss the problems while preparing Dess-Martin periodinane in more detail? Personally, I have no experience with the procedure, but on the paper it looks rather simple. why is it so tedious? thanks

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9. secret milkshake on May 27, 2006 5:50 PM writes...

HOAt is back, sold by Aldrich as a solution. The stuff is pretty dear, even more than HATU. (Carpino sold his patents to these reagents to a company that is now a part of Celera; they have monopoly on these reagents.)

Magic methyl gives you lung edema, like phosgene, like dimethyl sulfate. The problem is that the reagent has only faint smell, it does not feel irritating, initially. By the time you start coughing the damage is done. That could mean some weeks on a respirator, intense course with diuretics, needle between your ribs to periodicaly suck the water from your lungs, etc, if you survive. Cancer is definitely a possibility (especialy with hard electrophiles: O-alkylated nucleic bases are mutagenic, N-methylated are not) but it usualy takes many years to develop.

Dess-Martin is easy & high-yielding - you just have to use a more recent prep. (Oxone oxidation, then TsOH-catalysed acetylation)

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10. scott on June 5, 2006 8:46 PM writes...

josef: The dangerous step in the preparation of Dess-Martin is the acylation step. Making IBX is super easy and safe using the oxone prep.

Solid IBX decomposes violently when heated, so when doing this reaction on a reasonable scale, make sure your stirring is really efficient (mechanical if need be), and carefully monitor the reaction temperature. Of course, make sure there's a shield between you and the reaction.

There's nothing tedious about any of it... it just poses a very substantial safety risk.

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11. NitricAcid on March 3, 2010 3:53 PM writes...

I used to work with a lot of methyl triflate. At one time, we had a new graduate student join us from, and she was warned about the dangers of methyl triflate.

Now, we kept our methyl triflate in one of those Schlenk-like tubes with teflon stoppers (I forget what they're called), and the teflon would eventually deteriorate. So, one fine day, this girl (I'll call her Mary) took off the old stopper, put a new one one, and proceeded to toss the old on in the garbage can next to my desk. Not leaving it in the fume hood to air out, not washing it at all, just tossing it.

When I let her know that this was no way to treat anything contaminated with methyl triflate, she picked it up, held it to her nose, sniffed, and declared, "But it doesn't smell!!" and tossed it back.

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12. ke on August 10, 2013 9:45 AM writes...

"triethyloxonium tetrafluoroborate" is safer because it is non-volitile. Also, as soon as it hits water, if becomes diethyl ether, ethanol, and tetrafluoroboric acid. Although you get a strong acid, dilute a strong acid to ~1% and it is no longer dangerous. Dilute "magic Methyl" to ~1% and now you have large volume of still toxic material to deal with.

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13. peter on June 23, 2015 5:54 PM writes...

FWIW, 10 years later, Aldrich has been making and selling methyl triflate for years and still is.®ion=US

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14. Derek Lowe on June 23, 2015 6:50 PM writes...

#13 Peter - right you are (and in fact, the post mentions that you can buy it by the gallon). But methyl fluorosulfonate is another matter.

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