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Pyridine Doesn’t Do What You Think It Does

OK, this is not exactly a time-sensitive issue, but since I took a crack at one of the most prominent toxicology myths in the biology labs (ethidium bromide is not really all that bad, in case you missed it), I figured I should do the same for one of the persistent myths on the organic chemistry side. Most people in the field will have heard that pyridine is a male reproductive toxin – I can’t count the number of casual references (and jokes) I’ve heard to that effect. Can I resist quoting one? I cannot:

An organic chemist named Flynn / Was engaged in premarital sin / “Don’t worry, my dear”, he said with a leer / “The pyridine’s done it again!”

First heard that one about thirty years ago, so you get the idea. The problem is, there doesn’t really seem to be any evidence that pyridine causes infertility, temporary or permanent. In fact, this document from the CDC (dated 1992) says that “no studies were located” with data on reproductive toxicity by exposure to it via inhalation, dermal contact, oral ingestion (yikes) or injection. The summary states that “There is currently no information on the effects of pyridine on reproductive parameters in humans or animals via any route of exposure.” Believe me, people were making comments about pyridine’s effects well before then (as witness that limerick, for one thing), so the story was well-known with no evidence behind it.

Fine, then, but what about after 1992? I’ve searched around, but have been unable to find anything that modifies those conclusions in any way (and I would be glad to see any data if someone else has a reference). But so far, I have to conclude that the whole pyridine thing is a myth – there’s nothing behind it at all. Now, don’t get me wrong, here – I’m not advocating starting the morning off with a cold shot glass full of the stuff, although if you do that you can probably be sure that the worst part of your day has already occurred. Nor will dabbing some behind your ear improve your life in any way, unless you’re into people gasping in horror and disbelief behind your back as you walk past. (For the non-chemists in the crowd, pyridine’s smell is absolutely, immediately disgusting and sui generis; there’s nothing else quite like it, and I don’t even know what to compare it to). Pyridine exposure will not do you any good. But as far as anyone knows, it is no sort of reproductive toxin.

57 comments on “Pyridine Doesn’t Do What You Think It Does”

  1. Jon Watts says:

    Thanks Derek – this is a relief for many of us! But perhaps the smell is precisely the point – working with pyridine all day might just be its own, highly effective, form of birth control by inhibiting a much earlier stage of the reproductive process.

    1. Nick K says:

      The first time I smelled pyridine I nearly threw up. It was the worst smell I had ever encountered. Subsequently, and after working with the solvent, I became inured to its odour, and even began to like it a little(!). For my money, quinoline has a far worse smell, reminiscent of severe dental caries.

    2. navarro says:

      while i still had dreams of adding a chemistry minor to my double major in math and english i took some independent research hours in chemistry when i could fit them into my schedule. i spent about half of one semester’s independent project helping a grad student standardize an automated karl fischer titration device for use with pyridine. the grad student’s adviser was doing research that involved pyridine and he felt the repeated problems he was experiencing with his overall work was that the pyridine was being contaminated with too much water and so we had to find a way to get the machine to respond correctly to pyridine samples which had been dosed with varying known amounts of water. unfortunately for the professor, once we got everything to work we tested his stock of pyridine and discovered no unusual amounts of water in his pyridine. i’m not sure who he blamed for his crappy results after that because i leaped on a chance to create and characterize two types of uranium perovskites.

      there are many unique aromas to be found in a chemistry lab but pyridine is not one i would ever willingly revisit.

  2. Chemperor says:

    Interesting post. I’ve often wondered about the validity of such claims. The other common chemical that I’m skeptical about is HMPA. Many of my organic colleagues won’t even let it in the door, but it’s frequently used in the inorganic lab to solvate inorganics.

    1. A Nonny Mouse says:

      I used to be quite concerned about HMPA until I was informed about the studies that were conducted (this was when I was a post-doc at MIT in the early 1980s). HMPA was to be used for pulling polymers and so very large quantities were going to be used. For the toxicity studies, all the air that the rats were breathing was passed through HMPA in order to saturate the air. After several months this resulted in tumours in the nasal passage, as might be expected. I have certainly been less concerned since (the supervisor had been a consultant for DuPont at the time). This is why NMP is used for polymer pulling.

      As for pyridine, we one used it at school for tlc of amino acids and threw it down the drain on Friday evening after we had finished. School meals were abandoned on Monday as the lab drains ran into the kitchen drains and the kitchen staff refused to work due to the stench.

        1. Anonymous says:

          That older post mentions smoking in the lab, even during ether extractions (just turn your head when venting). As the story goes … Robert B Woodward was a chain smoker and had a habit of flicking his butts into the waste can (using his thumb to tension his middle finger and then – boing! – let it fly.) As a prank, some of the guys in the lab, laid down some ether in the waste can. RBW came in to chat and, after a bit, flicked a smoldering butt into the can: whoosh! Good times.

          As another story goes, a safety officer came into the lab and noticed the grad student smoking and starting her safety spiel. The grad student took a can of ether, poured some out on his bench, took his cigarette and snuffed it out in the ether. Take THAT! The safety officer, turned on her heels and left the lab in a huff (of ether?).

          Rather than make a separate post under the main heading, I’ll mention Magic Methyl = methyl fluorosulfonate = MeO-SO2-F . Companies stopped making and selling it after some deaths following accidental exposures. As I recall, one case involved a researcher spilling a large amount of MM onto their clothing, ignoring or dismissing it for a long while and going home with MM soaked through to their skin, Later that night, complications set in (edema of the lungs, impaired breathing) and death soon after. I think that there was a second similar incident. (Removing the clothing and hitting the safety shower probably would have saved their lives.) Profs and others essentially banned MM because of those accidents. However, Magic Methyl is about as reactive (I want to say “toxic”) as Methyl Triflate MeO-SO2-CF3 which is still available for use.
          The Magic Methyl (banned) vs MeOTf, MeI, MeO-SO2-OMe which are not banned example was just to show that there is another side to regulations and practices. The Murderous Demon Chemical had to be removed from inventory. Chemicals not yet associated with a newsworthy accidental death are not.

      1. Mike says:

        Similar issue with DMF. I think it causes testicular cancer, but if you look at the studies it was based on workers in tanning factors that were spraying hundreds of gallons of it each day and literally get soaked in it. Pretty sure handling milliliters in the lab is pretty safe.

    2. loupgarous says:

      I wikied HMPA and winced. The structural formula drawing looks like an ingredient of something born to phosphorylate acetylcholinesterase.

  3. Tim says:

    What about the one that pyridine exposure causes male chemists to only have daughters? Thinking of all my chemistry colleagues, 90% have daughters, only a few examples of sons. It’s commonly a joke that those guys didn’t spend enough time in lab. Anybody notice this or heard a reason? I’ve heard the handwaving ‘pyridine’ defense there too.

    1. John Wayne says:

      I have a son, and I’m offended by the accusation (jk)!

      I’ve heard this one too

    2. David Borhani says:

      I guess I spent enough time in the lab: 3 daughters, 0 sons!

    3. anon the II says:

      I first heard this thing about pyridine and only having girls over 40 years ago when I started working in a lab doing undergrad research. Maybe it’s a Pavlovian response but when I smell pyridine, I feel it in my nether regions.

      Oh yeah, I have one of each. Maybe that’s because I’ve avoided it. DMAP is my friend.

    4. Schimmel says:

      I have been a medicinal chemist for 15 years. I have 4 boys and 0 daughters. Apparently I would be one of the outliers for both myths.

    5. Anonalso says:

      Our old group saying in grad school was:

      Pyridine gives you girls
      Piperdine gives you boys

  4. schinderhannes says:

    I always thought it is even worse and pyridine is causing
    impotentia coeundi not only impotentia generandi!
    That´s what we get thought in Germany, but your limerick implies that it is seen differently in English speaking countries 🙂

  5. GladToMoveToProcess says:

    Re the odor of pyridine: many years ago someone told me that there are two kinds of people – pyridine people and 1-butanol people. One group likes the smell of pyridine and hates butanol, vice versa for the other group. I’m definitely a pyridine person, liking the odor and getting nearly sickened by the odor of 1-butanol. Tert-butanol isn’t a problem. Anyone else in my camp?

    1. Me says:

      Not sure I know 1-butanol (butyl acetate though…mmmmmm 🙂 ), but pyridine made me nauseous on many levels.

      1. Chemperor says:

        I’ve been working with t-butyl isocyanide for the last two weeks. We keep an open bottle of pyridine in the lab as an air freshener. 🙂

    2. Derek Lowe says:

      Never have I heard of anyone who likes the odor of pyridine. A first! FWIW, I think that butanol is foul, too.

      1. Isidore says:

        I don’t mind n-butanol although I prefer n-propanol or isopropanol. Pyridine makes me nauseous also. And FYI, I am a chemist and I have a son and a daughter.

      2. SuperScienceGrl says:

        Never met a small alcohol I didn’t like the smell of. You’re right though; pyridine odour has a certain je ne sais quoi about it. A totally disgusting je ne sais quoi.

        1. Derek Lowe says:

          For me, methanol has no smell to speak of, but pure ethanol smells great. Propanol is a bit too much, and butanol, definitely.

          1. loupgarous says:

            My first time smelling methanol was in junior high, when A.C. Gilbert was still putting it in chemistry sets (as a fuel for the little wick burner the set came with). It smelled like green wood, but sharper.

  6. oldnuke says:

    When I was in high school, I got some butyric acid on my hand. Whew!

    Mom made me stay outdoors (it was a cold winter day) until I decontaminated myself with some dilute NaOH.

    1. Druid says:

      Bacteria in the large intestine of animals (and people) convert a lot of dietary fiber into short-chain fatty acids (mainly acetate, propionate and butyrate), and give some animal feces their distinctive smell. The animals get a lot of calories from this source and so can live on grass. In the right place, they’re good for you!
      But like another contributor, I much prefer the smell of benzene to the smell of pyridine. I remember Richard Cookson giving an audience demonstration of the identical smells of pyridine and d5-pyridine (to disprove the microwave theory of smell). I have never seen strips of filter paper move round an auditorium so fast, mainly because we all believed the sterility story which we taught at school in the ’60s!

    2. Ursa Major says:

      Whenever I read the name of butanoic acid or look at the structure, my mind inserts what we called it in high school: puke-anoic acid.

  7. Curt F. says:

    Why we’re on the topic of solvents, what do people think of tetramethylsilane (TMS)? The other day I was curious if anyone uses it as a solvent, because it seems like it has decent properties as a non-polar aprotic sovlent, but I couldn’t find anything because every Google and Google Scholar result is about NMR. Maybe it smells bad too? Or is it highly toxic? (I’m not an NMR person.)

    1. MTK says:

      I’ve never heard of anyone using TMS as a reaction solvent.

      One problem is that it can be deprotonated by BuLi and I’d assume that reactivity at silicon with alkoxides might be problematic.

    2. b says:

      The problem with TMS as a solvent is that its boiling point is barely above RT and it has a high vapor pressure. If you don’t store it in the fridge, it’ll disappear from the bottle rather quickly.

    3. Phil says:

      There are plenty of nonpolar aprotic solvents that are a lot cheaper (heptanes?), but if you really wanted to try it out, tetraethylsilane boils at 150C, probably more suitable.

  8. Barry says:

    tetramethylsilane smells distinctly sweet, without evoking any food- floral-odor in my repertoire.

  9. Watson says:

    Heptafluorobutyric acid is one of the worst I’ve worked with. It sticks to your nose hairs so you can’t get away from it.

  10. tlp says:

    Never heard of this myth, but I have excuse to be born about time when you’ve heard the limerick for the first time. I wonder why did people pick pyridine and not piperidine? The smell of the latter brings about certain associations much more readily than pyridine’s.

    1. WhoAmI says:

      If it smells like semen it can only be good for semen ! (what some chinese fertility seller with two barrels of the stuff on their arms probably said on alibaba at some point)

  11. Phil says:

    One step in the (never completed) total synthesis I worked on in my Ph D was a Tebbe methylenation that called for dry pyridine. The stuff from our purification system was not good enough, so I distilled it myself on regular occasion. One late evening, I made a bonehead mistake and ended up exposing myself to quite a bit of hot pyridine by inhalation. I can verify firsthand the following effects described in Patty’s Industrial Hygiene and Toxicology:

    “Clinical symptoms and signs of intoxication include gastrointestinal disturbance with diarrhea, abdominal pain, nausea…”

    It was a rough night.

  12. Will says:

    Apparently the National Toxicology Program put out a report in 1997 where pyridine was tested in rats. While it did not affect the female estrus cycle, it does show a slight but statistically significant decrease in spermatozoal motility. https://ntp.niehs.nih.gov/ntp/htdocs/lt_rpts/tr470.pdf

    1. JimM says:

      Apparently the National Toxicology Program put out a report in 1997 where pyridine was tested in rats. While it did not affect the female estrus cycle, it does show a slight but statistically significant decrease in spermatozoal motility.

      This is exactly what I was guessing from the reports it’s associated w/daughters, because Y-bearing sperm swim faster because the Y chromosome is less massive than the X.

      1. Dr CNS says:

        Has this gender preference been shown in rats?

  13. Terry says:

    My late father was an analytical chemist, and like many he always had magnetic stir bars in his pants pockets. He was an expert in non-aqueous titration methods, and it wasn’t until high school chemistry did I realize that stir bars had no natural odor of their own–my dad’s pocket stir bars always stank of what I now know is pyridine, which still seems a nostalgic aroma even today.
    We even lit our grill (and burnt paper trash) using benzene as an igniter that you could buy by the gallon at the hardware store (shudder). So much for growing up in New Jersey!

  14. Christophe Verlinde says:

    Here is a more recent study:
    Natl Toxicol Program Tech Rep Ser. 2000 Mar;470:1-330.
    NTP Toxicology and Carcinogenesis Studies of Pyridine (CAS No. 110-86-1) in F344/N Rats, Wistar Rats, and B6C3F1 Mice (Drinking Water Studies).

    “…Sperm motirm motility in exposed male mice was significantly decreased relative to controls. Liver weights were significantly increased relative to controls in males exposed to 100 ppm or greater and in 250 and 500 ppm females. …”

  15. Li Zhi says:

    My mind instantly went to cyclohexylamine. I wonder if someone confused the two – granted you’d have to be more than a bit confused to do that, but still. Back in the 70’s, the MSDS for cyclohexylamine said it caused testicular atrophy. I just checked a couple, and any similar claims are absent. I see no obvious reason cha would be a contaminant in pyridine… but, I ain’t no organic chemist. I worked in a paint QC lab in the early 70’s. We used benzene (in a 5 gallon pail) to wash our hands with, as well as clean test equipment. I can’t recall if there was any ventilation – at most an ‘elephant trunk’ hanging over the red ‘safety’ container with the pop open lid we kept the pail in. As far as stinks go, I’ve never had the experience of encountering thioacetone, but way back then the story (myth?) goes that one guy cracked open a 30ml bottle of it (carefully, in a fume hood), just to inspect it, and then closed it up. They had to evacuate the building downwind of the building the chemist was in, because the exhaust on the roof blew towards the other building’s fresh air intakes. The guy didn’t even spill any, supposedly.

    1. KazooChemist says:

      Another urban myth. Derek has commented on thioacetone before. There is no such thing as a 30 ml bottle of the stuff.

      http://blogs.sciencemag.org/pipeline/archives/2009/06/11/things_i_wont_work_with_thioacetone

    2. Anonymous says:

      This caught my eye: “We used benzene (in a 5 gallon pail) to wash our hands” and reminded me a major study reported in C&EN many years ago (80s? 90s?). Maybe title this “Benzene doesn’t do what you think it does.”

      It was a multi-year study of factory workers exposed to benzene (in measurable, work-place monitored non-zero concentrations) and a matched cohort that was not exposed to benzene in their normal lives. The factory workers lived longer and with fewer health problems than the cohort yet the study concluded that benzene is highly toxic and will kill you.

      This was in the days of usenet newgroups and sci.chem. (Anybody else remember sci.chem? We should hold a reunion!) One of the regular participants was known for his knowledge, sarcasm, subtlety and bluntness, vitriol and humor. I believe it was he posted about the benzene exposure study:

      “The study proves that benzene will kill you. It kills you by making you live longer.”

      Now that I think about it, that usenet contributor (Stanford trained organic chemist) had a science and chemistry focused web blog that predates In The Pipeline by many years. His blog was not exclusively chemistry. I occasionally notice his signed comments on sciencemag.org articles. (No, I am not referring to Archimedes Plutonium, also a contributor to sci.chem.)

      1. Derek Lowe says:

        I would be very glad to hear about a chemistry blog that predates mine by many years – details? FWIW, I was on Usenet in the 1990s myself; I well recall Archimedes Plutonium, Nancy Leider, “Serdar Argic” and many of the other loons of that era.

  16. Cringing says:

    The heterocyclic chemistry course I took as an undergrad had a wonderfully erudite lecturer who began his lecture on pyridine synthesis by informing us that pyridines cause testicular atrophy, which he kindly translated for us as “it makes your balls shrink”. Thus began a 5 minute anecdote about medical jargon, ending in the sad tale of a chap suffering all sorts of problems with his, ah, reproductive health, resulting in a note in his file reading “his necrotic member auto-amputated”. The lecturer asked why they couldn’t just translate it as “it fell off”.

  17. Mark S. says:

    Ref Sons v Daughters …
    IANA Chemist. But, like chemists, my line of work is overwhelmingly male, with a slightly-nerdly streak of macho running through it.

    Everybody in our industry just *knows* that we mostly have daughters, not sons. Due of course to occupational exposure to, well, a long list of insults ranging from contaminated air to bad lifestyle to shift work to micro-dose ionizing radiation. Which factor matters depends on who’s telling the tale.

    My view of the controversy: Manly Men who work with other manly men expect to create all little manly men to carry on the tradition. Anything else must be an aberration. Jus’ ’tain’t right havin’ girls.

    Or so they say.

  18. Kent G. Budge says:

    Since you quote a limerick, I cannot resist sharing Sir Martyn Poliakoff’s favorite (favourite?) in case anyone has managed not to hear it yet:

    A mosquito was heard to complain
    That chemists had poisoned her brain.
    The cause of her sorrow
    Was paradichloro-
    Diphenyltrichloroethane.

    And, yes, I realize the descriptive name is a bit off and out of date.

    And one of my own favorites, which I picked up heaven knows where:

    A clever young lawyer named Rex
    Had diminutive organs of sex.
    Arraigned for exposure,
    He pled, with composure,
    De minimis non curat lex.

    1. Derek Lowe says:

      Oh, here we go. Before you know it, I’ll be quoting Robert Conquest’s limerick ouevre, which he mostly didn’t sign his name to!

  19. 1boy1girl says:

    Derek please do an investigation on chemists having more boys or girls

  20. Nitin Chawla says:

    Thanks Derek.

    Though I deal with Pyridines, but I wasn’t even aware if there are any studies claiming that Pyridine causes infertility.

  21. Baltic says:

    When I was a kid, I once drank an entire bottle of cheap ketchup. It was supposedly “chilli-flavoured”, or so it said on the bottle. One of the cheap brands, the taste reflecting the quality, both being a direct representation of the price. Still, I downed it all. I can’t remember why, since I can’t walk past the bottles on the supermarket shelves (yes, they still produce the stuff, some 25 years later) without a slight shuddering. Maybe I lost a bet or something. Can’t remember. What I can remember, is how sick I felt. I threw up repeatedly, each time producing a mix of stomach acid and what was left of the constituents of ketchup. I don’t think I will ever forget the disgusting oily, remotely chilli-like, yet somehow sweeter, notes that were added to that “classic” taste of your own puke.

    The reason I’m sharing this childhood memory is, I was instantly reminded of it when I, years later, in undergrad lab assignment had to open my first bottle of pyridine. The same cocktail of flavours, only this time it was in my nose, not in my mouth. Colourful, to say the least. Ugh.

    I had heard the stories about it impairing fertility, too. However, since I don’t plan on having children anytime soon, and once that passes, might be too old to procreate (from moral, not physical point of view), my thoughts on the matter were never too close to “oh no, my lineage!”, they were somewhat closer to “yay, free contraceptive!”. And since I didn’t rely on this, ahem, option entirely in the latter case, I never did bother to check whether pyridine was as dangerous for the particular function as reputed.

  22. per says:

    on the echa website (https://echa.europa.eu/), there is data for pyridine. Looks to kill offspring in an OECD 421 study.

  23. Scott says:

    “(For the non-chemists in the crowd, pyridine’s smell is absolutely, immediately disgusting and sui generis; there’s nothing else quite like it, and I don’t even know what to compare it to).”

    Oh, come on, Derek, pull the other one. I’ve seen you write about horrors like selenophenol. I’m sure you can find *something* to compare the smell of pyridine to. Godzilla’s high school gym clothes, maybe?

    As for the [career field] produces girls/boys tales, I’ve noticed that US Navy submariners tend towards girls in general, and particularly during their sea tours. Seems that the only time you see a submariner with a boy, said male spawn was conceived during a shore tour (Sailors alternate between sea and shore tours, roughly 3-4 years at sea, then 3-4 years on shore, then 3-4 years at sea again). I’m not sure I even *want* to know about all the atmospheric contaminants we breathed in, the chronic offender of “eau du boat” is monoethyl amine (which we used for clearing carbon dioxide out of the atmosphere).

  24. Wally Fu says:

    Back in the early 1980s I developed a process to make Larvin insecticide at Union Carbide. The original process of using pyridine base and methylene chloride solvent for reaction, toluene for precipitation and methanol for isolation was replaced with pyridine (base as well as solvent) for reaction. The process was unconventional, it gave much higher yield, product stability (pyridine removed the trace transition metals in the raw materials) and easy of operation. I spent many months at the Woodbine, Georgia plant scaling this up and was exposed to pyridine many times. The myth was busted when my fourth child was born in 1983.

    1. Anonymous says:

      Boy or girl?

  25. BK says:

    Damn, now I need to get a vasectomy…

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