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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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April 20, 2006

Sulfurous Stenches: A Connisseur's Guide

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Posted by Derek

Inspired by Dylan Stiles' tribute to sodium ethanethiolate, I present Lowe's Guide to Sulfur Aromas:

Hydrogen sulfide: rotten eggs. No more, no less, and plenty of them. Rather more toxic than cyanide, but at least you can smell it coming more easily.

Dimethyl disulfide: not, as these things go, really all that bad. If you smelled it coming out of your refrigerator, you wouldn't be pleased. But compared to the others on the list, it's tolerable - perhaps the cleanest of the sulfur odors. And many organic chemists associate it with a successful Swern oxidation, which gives it some points.

Ethanethiol: the prototype of the class. All the basic sulfur-stink notes - skunky and intestinal. Very volatile, too, which really gives it a quick wallop, but at least it doesn't stay around forever. I had a grad school reaction that used this stuff neat as the solvent, so I know whereof I speak.

Cyclopropanethiol: not sure if you can buy this, but we made it in my lab a few years ago. Smells like a fire in a garlic warehouse - very sharp and penetrating. Notably different from its acyclic brethren.

Propanedithiol: two SH groups in one! Has the same general character as the other lower alkylthiols, but with a darker, more penetrating note. Lasts forever due to its high boiling point.

n-Butylthiol: since butyl groups reek in general, the butylthiol has a special kick all its own. Very rich and skunky indeed, and it sure does hang around.

t-Butylthiol: used as the odorant in natural gas lines, so you know it has something to recommend it. Nasty and overpowering at 100% concentration.

beta-Mercaptoethanol: rather similar to ethanethiol, but the extra OH group gives it some real staying power. Sort of the "sun and sport" version of the parent compound.

Mercaptoacetic acid: ugly, sharp, acrid reek, also with plenty of endurance. Nothing to recommend it.

Thiophenol: you've smelled it, if you've smelled burning rubber. But imagine the pure essence of burning rubber, distilled and bottle for your pleasure. Very long-lasting, too.

Mercaptopyridine: since pyridine reeks to the skies, and thiophenol is so awful, you'd expect the worst from this combination. But it has no smell whatsoever, by some trick of fate. Surely that's for the best.

Comments (41) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Novice Chemist on April 20, 2006 8:27 PM writes...

Is bleach kryptonite to all of these?

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2. UndergradChemist on April 20, 2006 8:53 PM writes...

I've learned that dimethyl sulfide is an excellent way to predict which column fractions my Swern-oxidized product is going to be in.

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3. Harry on April 20, 2006 8:54 PM writes...

Yeah, 1,3-Propanedithiol is pretty bad. I'd have to say 1,2-Ethanedithiol is slightly worse, but for my money, Crotyl Mercaptan is hands down the worst. It is concentrated essence of skunk (and in fact was sold as a cover scent for hunting)- believe me, it will cover practically anything (except, just possibly, Putrescine or Cadaverine- which smell EXACTLY as advertised).

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4. Ryan K. on April 20, 2006 9:26 PM writes...

I've used most all of these thiols at one point or another, and I even had to make a bunch of thiol ligands for the physical chemists doing gold surface chemistry. And all in all, I can't say that sulphur compounds really bother me all that bad. I mean, I wouldn't want to bathe in them or anything. I don't have any problem with amines either, I actually kind of enjoy the smell of many of them. Am I wierd???

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5. Paul on April 20, 2006 11:10 PM writes...

It's great fun to discreetly open a bottle of pyrrolidine next to someone and catch the look on his face as it changes from "where have I smelled that before?" to "damn...you are a sick bastard! now, let's go try it on _________."

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6. Brian on April 21, 2006 12:30 AM writes...

I don't think you're weird, Ryan, you're probably just desensitized. I recently found that after running a couple large scale Swern oxidations, I couldn't even detect the scent of dimethyl sulfide. Likewise, I got used to the smell of 1,3-propanedithiol after working with it for a while, although that took a bit longer.

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7. Anonymous on April 21, 2006 12:41 AM writes...

If you want some really good metaphors and similies for smells, you should take a look at this book. According to the narrative, humans are controlled by smell. So yes, if you don't find anything wrong with these sulphur compounds, you may be weird.

Perfume : The Story of a Murderer
by Patrick Sueskind (who's going to win the Nobel Prize in literature if he keeps going in similar fashion)

http://www.amazon.com/gp/product/0375725849/103-1997417-0632644?v=glance&n=283155

(Also, on the off chance that you do glance at the book, unlike what a lot of people say about wanting to read it in German, it's not any better in the original. The translation is good.)

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8. Jan on April 21, 2006 2:32 AM writes...

Larger thiol-containing molecules are not that bad smelling. For me it is always the smell for success. But on the way to this thiols we use a lot of ugly stuff like thiopivalic acid the big brother of mercaptoacetic acid. After some photochemistry there are even worse degredation products coming out of the flask...and no, our neighbours don't like us.

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9. Demosthenes by day on April 21, 2006 6:03 AM writes...

You forgot to mention which one you serve with fish and which one with red meat.
I felt like I was reading the Wine Spectator of thiols.

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10. Thomas E. McEntee on April 21, 2006 6:53 AM writes...

I found the 1,3-propanedithiols, circa the late 1960s, to be almost pleasant after a while; I preferred them to the bottles of 1,2-ethanedithiol...we used both in our synthetic endeavors. However, it was an ancient sealed glass ampoule containing 250 grams of t-butylmercaptan that gained the most notoriety. The ampoule bore an ancient label bearing the name of a pre-WWII German chemical company and in flowing handwritten script the term 'tert-Butylmercaptan'. It had sat silently in the storeroom for decades until 1967 before being retrieved and brought to a colleague's lab. One day, a friend in that research group accidentally knocked the ampoule off the shelf and onto the floor. People scrambled and got out of the lab and closed the door...and waited for the smell to clear. In those days, the hoods vented directly out above the chemistry building and it wasn't long before fire engine sirens could be heard screaming through the area in Boulder known as "The Hill" that adjoined the university, in response to a "massive gas leak". Somehow, someone in his group had the presence of mind to call the authorities and explain the properties and uses of t-butylmercaptan. As I recall, the gas company had to be called in to verify that these grad students actually knew what they were talking about.

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11. MolecularGeek on April 21, 2006 8:40 AM writes...

Oh boy, the memories. I remember a project I worked on a LONG time ago involving making thiohydantoins of amino acids for GC analysis. The reaction required phenylisothiocyanide in pyridine. I can still feel the bitter receptors on my tongue flashing in pain when I got a whiff of the vapors as I transfered it between hoods. And they wonder why I stick to modeling now.

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12. tom bartlett on April 21, 2006 8:45 AM writes...

I'll take dimethyl sulfide over indole or diphenylphosphine any day.

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13. kumar on April 21, 2006 9:35 AM writes...

Similar situation as described by McEntee, the details escape me, somebody in the neighbouring lab was trying to synthesize or generate (Me3Si)2S under the hood. we had a fire alarm, building evacuated and fire fighters come over.
Other than thio compounds, cyclooctadiene was a big stinker. wonder which other non-thio and non-N compounds stink as much.

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14. Giagan on April 21, 2006 11:01 AM writes...

I find that tetrahydrofurfuryl alcohol smells like either bacon or those salty, smoked almonds.

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15. Sigivald on April 21, 2006 11:54 AM writes...

Around here, because of the paper mills, (some) people refer to hydrogen sulfide as "the smell of money".

Stinky, though.

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16. Harry on April 21, 2006 12:00 PM writes...

Re # 13 Kumar: Well, Butryic Acid is pretty nauseating- with the gentle fragrance of sour milk. Also a few diones I've worked with have pretty overpowering odors- not in the thiol/selenol/diamine class though.

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17. Thomas E. McEntee on April 21, 2006 12:34 PM writes...

Ahh, butyric acid...this is the last story on this topic I promise...it's 1962 in the sophomore college dorm and one big, drunk defensive tackle has terrorized a dorky chemistry major...not me...a couple of months into organic chemistry. Somehow, the chem dork has obtained a master key that will unlock any lock in both the chem building and the dorm. and armed with a half-gallon of butyric acid obtained in a midnight mission to the stockroom, has doused the lineman's dorm room and furniture....

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18. Tot. Syn. on April 21, 2006 1:31 PM writes...

Mercaptopyridine - as you said, it doesn't smell, and bizarrely, it's also relatively safe - only an irritant according to Aldrich. Which begs the statement that your nose knows more about chemical safety than your brain. If it smells bad, leave it in the cupboard, find another prep, and go for coffee.

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19. Harry on April 21, 2006 7:46 PM writes...

My all time maximum stench story involves a 500 gallon tank, half full of liquified Methyl Mercaptan, a hot (105F) summer's day and an unarmored gauge glass. Oh yes- it also involved two shut-off valves permanently rusted into the open position.

Suffice it to say that much fun was had by all involved, including my having the dubious honor of addressing the media after the incident.

I found out later that the emergency dispatch centers as far as 20 miles away were flooded with gas leak calls.

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20. SRC on April 21, 2006 8:10 PM writes...

Mine involves 2-mercaptomethylethanethiol. Volatile, but persistent, and oh so funky.

I returned from a series of seminars to find _______ university shut down while the gas company checked everywhere for leaks. Nice still day, heavier than air compound, fume stacks next to the library, embarrassed (but blameless) grad student, fill in the blanks...

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21. Pete on April 21, 2006 8:59 PM writes...

A year or so ago I at last had resorted to using a thioketal in a synthesis and so ordered a nice new bottle of 1,2-ethanedithiol. I expected the stench of course, but figured I'd keep it in the hood and no worries (our HVAC system had been recently renovated and was working very well in my estimation) Well, the guys from down the hall came calling (one strangely thought it smelled like wild mushrooms although he was the only one). I closed all the doors I could convinced I could contain it when I scaled up the reaction a few days later... People from two floors above and below came this time. This is when I was introduced/banished to the penthouse (we had a penthouse in the chem building?) where there was a single hood, on it's own ventilation system and not a soul around. Needless to say I'm glad that chemistry was abandoned within a week or two.

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22. Chris C on April 21, 2006 9:39 PM writes...

I had a nasty sulfur smell coming from some cleared bacterial lysate. I resuspended my E. coli in a lysis buffer, freeze-thawed the cells in liquid nitrogen and sonicated for 15 minutes. The lysate gave off such a stench that it gagged me. The whole lab stank.

What could this be from? Can this be produced by the degradation of proteins?

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23. c chad warford on April 21, 2006 9:50 PM writes...

straw poll, while we're on the subject of sulfur and smells: how about carbon disulfide (CS2)? i've used it as solvent and thought it to be quite nice, like pumpkins or some other gourd. others in my lab thought me crazy, and not just because its supposedly toxic (but then again, what isn't?)

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24. BCP on April 21, 2006 10:26 PM writes...

I'm with Harry and Thomas - for me the most evil smelling reaction I ever did on a routine basis was a simple amide formation on a heterocyclic amine using isovaleric acid, di-isopropylcarbodiimide in pyridine at 80C (seriously) - now there was a stomach churning combination - worse than most sulfur chemistry I've done. The thing that gets me about some of these smaller aliphatic acids is that they seem surprisingly difficult to get rid of to below nasal LOD levels - at least with thiols you have bleach. God help you if you contaminate a surface outside of your hood - it'll be with you a while.

As for the mercacptopyridine comment - I've always rationalized this as being due to these guys existing predominantly in the thiopyridone rather than thiopyridine tautomer, which is a very different beast. Maybe there's a correlation between stench power and how enolizabe a C=S bond is.

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25. GC on April 21, 2006 10:41 PM writes...

Re: Chris C's cell workup. Does anyone else HATE the smell of media? I've worked with some low to medium-nasty stuff (various indoles where the degree of substitution was low enough to keep it volatile enough to stink like hell, plenty of pyridine, propanedithiol, mercaptoethanol, cyanoborohydride, various low MW alkylamines, hot DMSO...the list goes on...) and they are all kind of nasty but usually warrant not much more than a shrug. However, I want to vomit every time I work up cells or walk by the autoclave when there's broth in it. This has not abated over time, despite developing a sort of fondness for stuff like HOCH2CH2SH.

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26. secret milkshake on April 21, 2006 10:43 PM writes...

Isovaleric has a nice wet-hobo-like note to it. (Lot like butyric, but better.) Cyhex-carboxylic is also memorable. What amazes me that in concentrated state these acids smell sweaty-goaty but they get more horrible greasemonkey-ass-like as you dilute...You will probably stop smelling them at the point - and you will have whole subway bench for yourself. Phenylacetic acid is also good - concentrated smells like nasty artificial honey flavor but it is diluted, it is like old dried urine - just like elderly leaky folks that never wash their pants.

One of the favorite jokes is to get freshman to put a little ethyl or methyl isovalerate on themselves like perfume. These ester have a wonderful fruity odor, before they start hydrolyzing on the skin. Then it is like durian.

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27. Derek Lowe on April 22, 2006 12:48 PM writes...

C Chad, if you think that people complain about carbon disulfide, read the entry on the diselenide over in the "Things I Won't Work With" category. That one's a legend.

As for the bacterial lysate that Chris C mentioned, there sure could be some nasty thiols in there, various cysteine- and methionine-derived stuff, I'd guess. Mix that was a background of low-MW amines and you have quite a brew.

I think that BCP is right about the tautomers of mercaptopyridine, but there may be more to it. That breaks up the pyridine, and thioamides aren't particularly smelly, true. But CS double bonds can still reek. Thioketones, much less well known, are supposed to be horrible. Thioacetone has been recommended to me as a contender for the worst smell ever, not that I'm going to go make some to find out. I wonder if the smell is partly due to some of the hemithioacetals and so on, perhaps forming once the compound is inhaled?

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28. John S. Roberts on April 22, 2006 2:20 PM writes...

I find it interesting that no one mentioned selenium compounds. Those are much worse than the sulfur compounds. Also, it should be noted that dimethyl sulfide is the most common naturally produced organic sulfur compound, being produced by bacterial action in maritime environments.

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29. Kevin on April 22, 2006 3:36 PM writes...

What, no mention yet of thioethers? I find them
to be (if such a thing is possible) even fouler than
thiols.

Oh, by the way, the NMR spectrum of
2-mercaptopyridine lacks a peak for a thiol, so
I think the people who say that it's a pyridinthione
are on the right track. Still peculiar - thiones
aren't reputed to smell any too sweet, either.
Perhaps equal and opposite stenches cancel out?

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30. Cryptic Ned on April 23, 2006 1:09 PM writes...

As a virology student I don't do much with concentrated chemicals, but in my two years in the lab there are two compounds I've managed to spill all over the floor: butyric acid and glacial acetic acid. By far the two worst-smelling things we have in the building, most likely.

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31. robopox on April 23, 2006 7:07 PM writes...

GC:
Media? you're ragging on fresh media?

Now, after my students have isolated their Staphylococcus
from every ....er....orifice, and grown the cultures, I get
to kill the cultures in the autoclave.

Rotted media, a boatload of propionate, butyrate, sulfides, spermidine, spermine, cadaverine, putrescine,
and melted plastic.

at 250 F.

skunks vomit.
maggots gag.
road kill crawls away.
cadavers in anatomy puke formaldehyde.

I love the smell of media. It smells like.....victory.

sissy.chemists.don't.know.stink

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32. Ryan K. on April 23, 2006 10:11 PM writes...

Man, I never thought that anyone would characterize Glacial Acetic Acid as one of the most foul smelling things. I actually like the smell of acetic acid, and it just confirms something that I have long known. Biologists are wussies.

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33. Mark on April 24, 2006 10:31 AM writes...

I love where all of this is going.

As a synthetic chemist who has worked with and smelled all of the chemicals and mentioned, AND who also served a summer sentence killing microbes for a University Immunology lab, by far the worst "vertiginous wretching horror" [not my words, but those of William S Burroughs] was the reek of autoclaved bacteria, molds and the like.

I will take the chemicals over the microbes any day

PS I once made something in the lab that was far fouler than any of these chemicals: it was a bromoacetylene with a furyl group on the other end of the triple bond

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34. Denni on April 24, 2006 11:49 AM writes...

Perhaps you're right that biologists are wussies...

I only spilled ten mL of mercaptoethanol and they evacuated the entire lab ;)

(That was a few years ago)

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35. Cryptic Ned on April 24, 2006 9:34 PM writes...

Biologists are wussies.

Well, I can't think of very many chemicals we deal with that have any smell at all.

Here's what I've come up with:

A) Butyric acid - smells horrible.
B) Glacial acetic acid - very strong annoying smell.
C) Bleach - very strong annoying smell.
D) LB medium - nice smell.
E) LB medium with bacteria in it - not as nice.
F) Agarose being burned in the microwave - smells pretty bad.
G) Ethanol - vodka.
H) Isopropanol - vodka.
I) DMSO - people say this smells like something, but I've never noticed it.
J) Paraformaldehyde - see DMSO.

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36. MORVAN on October 10, 2006 9:25 AM writes...

Dear friends,
if you need to use thiopivalic acid, we developed a odourless derivative per grams to kilos.
Bernard

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37. Blazing Dragon on December 16, 2006 11:28 PM writes...

Has anyone here ever worked with isocyanides (isonitriles)? Some of the vilest compounds I've ever smelled, seem to get into your nose and hang around for minutes after one single sniff, most of them have a stench that is characteristic (kinda stinky like sulfur compounds, but very distinct) (no pun intended). Cyclopentyl isonitrile is a truly vile compound.

Saw a post in JACS (I think) recently where a chemist combined isonitrile functional groups with ester functional groups in the same molecules (for the most part, the ester functionality won and the molecules didn't smell bad).

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38. Rich on July 1, 2007 9:02 AM writes...

Biologists ain't wusses! I work on the bacterial metabolism of these lovely stinky sulfur compounds - my personal favourites is allylmethylsulfide, which smells very nice. Dimethylsulfide, methanethiol etc, I can no longer smell as I work with them so much I seem to be desensitised. Do like crotylsulfide and the propylsulfides for their ability to empty the lab though...
~Rich

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39. Soylent on August 19, 2009 4:02 AM writes...

Here in Sweden we have a delicacy called surströmming("sour herring"). True to its name it is fermented herring with a wide array of foul smelling compounds(e.g. hydrogen disulfide, butyric acid, propionic acid, a touch of cadaverine and putrescine, methanethiol and ammonia).

If you get a nice, slightly swollen tin can of fermented herring and you ignore the advice of opening the can submerged in water you're in for quite a treat.

The people who can stomach this stuff say it's quite nice once you get passed the noxious smell.

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40. Karlene Barras on February 11, 2013 1:35 PM writes...

I like this site very much so much good information.

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41. martin on March 11, 2013 10:33 AM writes...

I have worked with a couple of thiols myself and my least favorite was 1,3-propanedithiol which smells like a lebanese garlic sauce overdose and stays on you forever. I actually spilled ONE drop from a pipet on my clothes and I had to throw it away in the garbage can. Terrible smell. Ethanedithiol and thioethanol are bad too.

As for the worst smelling chemical I have smelled, it is skatole (3-methylindole) which smells exactly like a fresh dump in you face. Someone spilled a chromato fraction on the floor and it smelled for days. I was inches away from being sick. Funny enough, everybody had a different interpretation of the smell. Sweet, pyridine, amines. In my case, it just smell like poop (bad one)

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