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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 14, 2008

A Meditation on Solvents

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Posted by Derek

Hexane (or its cheaper, less well-defined cousin, petroleum ether) is the proto-solvent. Light and thin, it’s the weakest at actually dissolving anything, so it’s the background to most stronger mixtures in a purification. Like most other solvents, though, it’ll strip the oils right off your skin, leaving you spiderwebbed with white lines across your fingers and in need of some lotion. Its smell isn’t pleasant, but it doesn’t really stink, either. A nonchemist would easily place it in the oil / kerosene / gasoline end of things, which is exactly where it belongs.

When I first encountered ethyl acetate back in college, little did I realize that I was picking up the scent of the rest of my life. I've been in the lab ever since, and so has it. Pleasant, unspecifically fruity, vaguely bubblegum-like, the smell of that solvent is a daily companion to almost every synthetic organic chemist in the world. Mixed with hexane in different proportions according to your needs, it runs the majority of chromatographies in the world. Squirt bottles of it sit around on benches. By now, it’s an old, old friend, and the smell of it says that I’m actually getting something done.

Ether (the real ether, diethyl ether) seems like it’s close to not being there at all. No long for this world, it’s supremely light, and evaporates so quickly, that it just barely holds on to the liquid state. It has a slightly dangerous overtone to it, since it can ignite so easily and forms explosive peroxides if it’s left sitting around. The somewhat smothering smell can’t quite be described, but is instantly recognizable. Its oxygen atom gives it more dissolving power, so ether/hexane mixtures are good for delicate separations, although often impractical on a larger scale. To me, ether is sort of a lighter, stronger hexane, in the relationship that titanium has to steel.

Methanol, on the other hand, has no smell – no smell whatsoever to me, at any rate, despite what that Wikipedia link says, although I think I can tell it from air. Pure lab ethanol smells great, but methanol is a blank to me. It’s the most watery of the common solvents – it’s lighter, but that OH group gives it some surface tension, which (along with its bizarre weight) is one of water’s defining characteristics. You notice the difference, compared to thin, slippery hexane or ether – methanol is a solvent with some body to it. It’s powerful stuff in chromatography, too – one per cent added to a weaker solvent will totally change things.

Do you call it dichloromethane or methylene chloride? The latter probably gets more use, and rolls off the tongue a bit more easily. This stuff is like the demon form of hexane – it has no oxygen atoms like ether or ethyl acetate, but is a pretty strong solvent, in what always seems a mysterious way. With another immediately recognizable but hard to describe smell, its odor is the prototype of “chlorinated”. But the thing that stands out the most is its weight. This is the only common solvent that’s heavier than water, and you can build up your arms doing curls with jugs of the stuff. We don’t use its even denser cousin chloroform all that much; it would be even better bodybuilding material.

Acetone is one of the solvents familiar both in and out of the lab: nail polish remover, without the added scents. You hardly ever run an actual reaction in the stuff, though, and when you do it feels a bit odd. That’s because acetone has become the default flask-rinsing solvent of the chemistry world. I’m not sure when that was settled, but it was decades ago: a perfectly respectable solvent, stuck in the role of janitor to all that brown, red, and yellow stuff stuck to the inside of a million round-bottom flasks.

Comments (34) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Petros on April 14, 2008 9:28 AM writes...

I reckon that methanol does have a smell, less pleasant than ethanol and fainter.

If using ether in combination I aways found a mixture with pentane better than hexane.

Chloorform has a distnctive, sickly, smell. I remember feeling nauseous aafter an afternoon of chloroform extractions in the pre fume-hood days.

And you didn't mention the arome of the aromatics.
Benzne is quite pleasant, and a suprisingly good solvent. I always liked to use it to disolve solids for applying to the top of a silcia column.

Toluene is harsher, and less effective as a general solvent.

And then theer is pyridine, with its distinctive aroma,, although its basicity makes it unsuitable as a genral solvent.

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2. mersault on April 14, 2008 9:35 AM writes...

What about THF? Surely the best smelling solvent there is. Versatile and surprisingly high up the ladder of dissolvability...

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3. Dave H on April 14, 2008 9:54 AM writes...

Funny

I have a great nose for methanol, but can't smell methylene chloride.

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4. Yttrai on April 14, 2008 10:17 AM writes...

Ethyl acetate is the foulest smelling solvent on earth. IMHO of course ;)

THF is quite pleasant, when you're not in charge of the still in grad school. Then, it can get nasty very quickly. Same with TEA - not terrible in small doses, but saturation comes quickly and abates slowly.

Toluene is great but ill advised. As per Dylan Stiles it is in fact the best solvent for moist loading compound on columns,with the aid of Celite.

Also, Methanol does have an odor to some of us,and like Ethanol and i-Propanol it's quite nice. Acetonitrile on the other hand, has no odor to me.

And honestly: i love the odor of n-Butanol. I know i'm the only person in the world who does, but man do i love that stuff.

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5. Propter Doc on April 14, 2008 10:25 AM writes...

THF has the most evil smell of all solvents. It drives me insane and I will go to great lengths to avoid using it. Ethyl acetate is also familiar to people who nail varnish as it is the solvent of choice for the so-called 'solvent-free' or 'acetone-free' nail varnish removers (at least here in the UK).
I understand that we're all supposed to be using pentane these days to avoid hexane's toxicity. Dichloromethane or 'dee cee em' is the name I've always known - perhaps a British English thing?
Methanol is never so much a smell as a presence to me. I can detect it but it doesn't really register as a smell.

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6. rhodium on April 14, 2008 10:39 AM writes...

I have an unusual fondness for pentane. It seems to leave less residue than hexane (unless you really pay for the top grade), it is so easy to get rid of and it seems to me to smell differently from hexane. Also, what of the glymes? DME is under-appreciated (and you have to like such a non-conformist with a gauche ground state) and diglyme lets you heat the crap out of your reactions.

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7. Tot. Syn. on April 14, 2008 10:42 AM writes...

A few comments from my experience...
Hexane does nasty things to ones DNA, so it's use is dropping fast in many labs in the UK, to be replaced with pentane, isohexane or cyclohexane. All are more expensive, so sometimes the cheap and nasty 40-60 petroleum ether will do. Cyclohexane has another useful property - even less polar than hexane, and forms an azeotrope with water.
Methanol is a favourite lab smell for me, but DCM (or dike as my PhD supervisor calls it) make me feel ill. Ether smells fantantic, as does chloroform, but maybe it's the giddy feeling I enjoy!

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8. Jose on April 14, 2008 10:50 AM writes...

THF smells delish. And MTBE is not too far off... but pyridine makes me want to vomit, even in tiny doses.

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9. eugene on April 14, 2008 11:37 AM writes...

I've been hearing about that 'hexane is toxic' stuff for a while now. First of all, it can't be that toxic, but I agree it could be bad for you because of some strange reason. It's the solvent I use most, outside of ether, so I would like to see some first hand sources on the toxicity front. I'm not buying it. Everyone who's told me this, has been unable to provide sources and it's not an established thing like with benzene and such.

Why would hexane be more toxic than pentane? If forced to though, I imagine I'd switch to heptane rather than pentane or even cyclohexane. Pentane is too volatile, and I don't need a frozen solid developing in my flask when I try to get rid of cyclohexane under high vacuum.

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10. psi*psi on April 14, 2008 11:47 AM writes...

Pentane smells nice, but catches fire easily. I loathe THF. Toluene often gives killer separation for large aromatics.

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11. Anonymous on April 14, 2008 12:00 PM writes...

I always liked the smell of MTBE and could def smell MeOH. I am not in the lab anymore but I swear this dry erase marker had butanol in it at time (and it has oxidized..phew!)

We used to run our Finkelstein's (Cl to Br) in acetone (dried via distillation over drierite)

Really didnt care for the aroma of MeCN---most all of the analytical folks out there have made this one *their* old fried


hate toluene, but dont despise pyridine like most folks do

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12. anon on April 14, 2008 12:01 PM writes...

"I've been hearing about that 'hexane is toxic' stuff for a while now. First of all, it can't be that toxic, but I agree it could be bad for you because of some strange reason."

I think it is alleged to metabolize to the 2,5-dione and then form pyrroles with bioamines. Probably BS. The safety guys say EVERYTHING'S toxic.

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13. Anonymous on April 14, 2008 12:09 PM writes...

Hexane ( mainly its in vivo omega-oxidized metabolite), has some slow toxical effects on myelin sheath (that's what surrounds your neurons).

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14. Doh! on April 14, 2008 12:45 PM writes...

Hexane is toxic!? Great. I always used to think, "With the way I use hexane (sloshing all about, rarely with gloves), I hope they never find out it's toxic like benzene." I always used to hear about the old-school chemists washing their hands in benzene. Now I guess I'm old school, since I always wash my hands with hexane (in the event of a spill, of course).

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15. CMC guy on April 14, 2008 1:15 PM writes...

Heptane is the typical replacement for hexanes or pentane in scale-up, although had less liking for the odor. Personally never liked smell of cyclohexane (some people found pleasant) but on occasion found it provided substantial differences in crystallizations vs other hydrocarbons.

Do people still use much Pet Ether (or Ligroin or Naptha variants) these days? Used to be cheaply available as a side fraction from oil refining but with cost of gasoline wonder if now economical (considering catalog prices may not be consideration in most labs).

I can't say if able to detect a DMSO smell but have experienced the metallic/garlic taste when gotten on skin. Vinegar can turn my stomach but glacial AcOH never bothered me so perhaps dilution enhances volatility.

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16. Chris Byrne on April 14, 2008 2:33 PM writes...

Unfortunately, I have a lot of experience with methylene chloride.

My first job as a teenager was as a furniture restorer and refinisher in my uncles shop, and methylene chloride is (or at least was) one of the most common paint and varnish strippers for professional industrial use.

I would spend several hours at a time standing in a stainless steel tank, with standard cotton overalls (methylene chloride melts many synthetic fabrics) and chemical resistant gloves, apron, and boots; stripping furniture with a flow over system (essentially a hose pumping the solvent out through a scrub brush)some wire brushes and putty knives.

I would have to get most of my body fully into pieces of furniture that had this solvent all over it, splashing all over, etc...

We kept large amounts of mineral spirits and distilled water on hand, because the stuff burns like a sunofabitch on your skin, and it doesn't rinse off with water. You have to rinse it off and neutralize some of the burn with the mineral spirits first, then rinse that off with the water.

Several times a day I'd get large portions of my body covered by this stuff; and I discovered one of its secondary effects.

It's a remarkably effective depilatory.


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17. MTK on April 14, 2008 2:37 PM writes...

I can smell all of the ones mentioned, although in some cases I bet it's not the solvent itself, but something in the solvent. MTBE is my favorite solvent for a lot of reasons including scent. I'm not a fan of the smell of THF.

Unfortunately, most of things are not too good for you. Toluene and acetonitrile, for example, have a lot lower tox levels than one might think.

Derek, you do still use chloroform in it's deuterated state, don't you?

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18. ZAL on April 14, 2008 3:17 PM writes...

I love the smell of MTBE (which BTW is a great choice for recrystallizations) and EtOH, I can tolerate DCM (I call it like that or Dee-Cee-Eem, but I'm not british!) and THF, but I really can't stand pyridine (who does?).
You forgot to mention DMF, the best friend of your nucleophilic substitutions...after having used it a few times I realized it's not as bad as they say, you just need a lot of water to get rid of it!

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19. phlogiston on April 14, 2008 4:18 PM writes...

At scale, you end up using heptane to replace hexanes (due to lower vp, hence safer to chance spark) and IPAc to replace EtOAc for the same reason. I like the slightly floral smell of IPAc. Other popular solvents are MTBE, acetonitrile, and EtOH. Given oil prices, renewable feedstock solvents such as 2-MeTHF (magical for lots of reactions) and cyclopentyl methyl ether are very popular. Dioxane is one of my least favorite both smell wise and its a pain to vap off. DME is a good choice instead. I avoid ether like the plague due to all the safety concerns and DEA paperwork.

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20. Don B. on April 14, 2008 4:56 PM writes...

Personnally, I like the smell of diethyl ether.

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21. milkshake on April 14, 2008 5:49 PM writes...

Neurotoxic cummulative effects of hexane first showed up in vegetable oil plant workers who have been extracting edible oils with ton quantities of hexanes. Pentane or heptane do not produce this kind of toxicity on chronic exposure - and since 2-hexanone and 2,5-hexanedione are even more neurotoxic, it is a reasonable guess that these two are among the hexane metabolites.

Methanol, acetonitrile and nitromethane have a rather faint smell - but I could recognize them reliably. Methanol has alcohol-like cooling smell, acetonitrile and nitromethane if pure have a faint cyanide-like smell with a greasy-DMF-like undertone. Acetonitrile contaminated with acetamide has a mouse piss-like finish (acetamide is very smelly). You can also smell peroxides in ether and THF in quite small concentrations, they have very unpleasant acrid-sour-like iritating smell and concentrate in the evaporation residue.

I am not fond of THF smell: to me it smells like horse stable and manure - and it gives me headache. But I love MTBE and ether.

I also like benzene and cyclohexane for re-crystalizations. For recrystallizing some very polar or very non-polar stuff, acetonitrile can be magic also.

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22. Sili on April 14, 2008 8:04 PM writes...

Don't have much to say apart from how this little piece reminded me of Primo Levi.

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23. Freedom Like A Shopping Cart on April 14, 2008 10:27 PM writes...

Acetone is a great solvent for a lot of reactions
If I get something to work in DMF, I'll always try it in acetone, just because it's so much easier to work with. A lot of simple alkylations work well in it, because of it's high on the "polar, aprotic" list.

Does anyone else smell slightly burnt popcorn whenever using acetonitrile?

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24. temple on April 14, 2008 11:45 PM writes...

And I thought I was the only one reminded of Levi's book. Good stuff.

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25. processchemist on April 15, 2008 1:59 AM writes...

MTBE! the fine scent of a well fixed crystallization. I must admit that diisopropyl ether has a better scent, but, like ether, it's the kind of scent that makes me a bit paranoid. Scents are among the finest security indicators in a kilolab or on a pilot plant.

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26. Brooks Moses on April 15, 2008 2:30 AM writes...

Acetone, to me, doesn't smell like nail-polish remover. It smells like the Celanese plant that makes cellulose acetate, about 20 miles from where I grew up. Wedged into a narrow valley with just enough room left over for a small river, some train tracks, and a highway, and making enough cellulose acetate fiber for devil-knows-how-many cigarette filters, you couldn't possibly miss it on a good day with a strong wind. And on bad days when the air was stangnant....

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27. eugene on April 16, 2008 9:54 AM writes...

"Neurotoxic cummulative effects of hexane first showed up in vegetable oil plant workers who have been extracting edible oils with ton quantities of hexanes. Pentane or heptane do not produce this kind of toxicity on chronic exposure - and since 2-hexanone and 2,5-hexanedione are even more neurotoxic, it is a reasonable guess that these two are among the hexane metabolites."

Milkshake, after thinking about this, I'm still going to call bullshit on 'hexane is toxic' stuff. The plant workers could have been using old hexane that was sitting out in metal drums under the sun. Easy to make the 'toxic metabolites' there with some metal and oxygen after about a year. There is still no evidence that chronic exposure to hexane (pure hexanes) causes long term damage. What I really want to see is a controlled animal study of some sort.

A lab chemist wouldn't have to worry in the case I'm right. We usually buy hexane in glass bottles and use it up fast enough. I bet our hexane is more pure as well.

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28. Jose on April 17, 2008 5:20 PM writes...

Also wanted to add Skelly-Solv and Stoddard solvent to this list, both of which only seem to appear in British papers from the '50s...

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29. Anonymous on April 18, 2008 12:19 PM writes...

I couldn't swear to this, but I think the 2,5-hexanedione was suggested to be a problematic metabolite, not an impurity. Nevertheless, that's why we use fume hoods and practice good chemical hygiene, because you should assume EVRYTHING may have undocumented longterm effects and the less exposure the better (Preaching to the choir here, I know (I hope), but this seemed to be trending toward a 'I only get a lttle, so I'll be ok' argument - always bothers me.)

That said, in our industrial medchem labs, we stopped using hexane because it is apparently particularly bad at building up static charge, in things like ungrounded chromatography setups.(read: any flash setup I ever saw before we had an incident). We use heptane instead.

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30. pharma giles on April 19, 2008 6:19 AM writes...

Anyone remember carbon tetrachloride? For TLC or column chromatography (pre Biotage days, of course), carbon tet/chloroform mixtures often gave good separations when ethyl acetate/hexane failed.

And it was THE perfect solvent for radical brominations with NBS. The succinamide by-product used to float and you could just decant your product solution and strip it down.

Ozone unfriendliness and toxicity issues have rendered it virtually unavailable, certainly in largish quantities.

Happy days. The days when you weren't a "proper" chemist until you had blown at least one bromination up the back of your fume cupboard have long gone...

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31. eugene on April 19, 2008 12:57 PM writes...

"but this seemed to be trending toward a 'I only get a lttle, so I'll be ok' argument - always bothers me."

No, it's trending towards asking for facts instead of hearsay. Your post only offers more hearsay however. I would assume that as scientists, we shouldn't take hearsay seriously. You have yet to convince me that hexanes are dangerous.

Full disclosure:

I use hexanes, and I spilled a little on my hand before. I inhaled hexanes vapor from columns and I sometimes wash off grease with hexanes from a wash bottle and get some hexanes on me. I also don't let the hexanes get too old and they are stored in a cool, dark place in a brown glass bottle. From my own chemistry, I only know too well how (mostly radical) auto-oxidation of hydrocarbons can result in a large number of alcohols and ketones in a short time, especially if you throw in a competent metal catalyst.

I am responsible for common solvents in my group and even though I still think this "hexane is toxic" thing is bullshit and I'm calling you out on it, I'm ordering heptanes to keep other members of the group safe just in case. It's not that much of a bother for me to switch. However, I would appreciate facts instead of fearful murmurings in the dark. This isn't how the EPA or the FDA works, otherwise we'd have banned everything by now.

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32. Anonymous on April 19, 2008 7:26 PM writes...

Well, there's this:

http://www.atsdr.cdc.gov/toxprofiles/phs113.html

The point of my rather cavalier comment above was that we work with many things for which we may not know the long term affects of exposure, and therefore we would be wise to avoid unnecessary exposure, even if it is unlikely that small incidently exposure won't have an adverse effect. Conversely, I suppose that many of the readers of this forum regularly work with things that we know are hazardous (I do), but are able to do so safely because they are properly trained and use appropriate practices.

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33. eugene on April 20, 2008 12:08 PM writes...

Thanks, that was something that I was looking for.

A few thoughts: The only neurotoxicity cases are from the 60s and 70s. Chemists continued to take hexane baths many years since then. The cases were in poorly ventilated shoe factories. Complete recovery occurred in all cases, although the most extreme, which was complete paralysis of a leg, took about 1-2 years to recover. The less extreme cases were numbness in joints and took 6 months to go away.

No one did any studies if n-hexane is absorbed through the skin. Exposure of rats causes damage to the reproductive system if you make them breathe air impregnated with a humongous amount of hexane. Other animals have different symptoms including lung damage. No human is going to be exposed to this much hexane.

There is no evidence of hexane causing cancer (including my own anecdotal evidence of observing people who take hexanes baths). The neurotoxicity due to ungodly levels of exposure is temporary and only means numbness in the legs.

Conclusion: Keep on buying hexanes for the lab if they are cheaper than heptanes.

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34. Norepi on April 25, 2008 12:23 PM writes...

Yeah, I dunno about the hexane being toxic thing. It seems people have been obsessing about it forever; I remember in grade school they tried to get rubber cement banned because of the hexane in it; that's the smell I always associate hexane with; years and years of grade school art projects. :P

As far as what's toxic about it, I remember hearing something a few years ago something along the lines of "biochemistry is done in two-carbon units"; "you can do that with hexane but not with pentane."

I cannot smell methanol. I can't especially smell acetonitrile either, and it seems only poorer-quality DMSO smells garlicky due to residual Me2S. I hate the smell of THF and almost never use it (I work with big greaseball molecules that literally don't dissolve in the stuff.) So I work with a lot of halogenated solvents: DCM, DCE, and chloroform, all of which really mess up one's sense of smell after about six months.

I'm actually running a reaction in refluxing cyclohexanol as I type. Now there's the oddest solvent ever. You have to defrost it to be able to use it, and it has a really sick sort of smell to it that really hangs around for a while.

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