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November 16, 2012
Sulfolane
Posted by Derek
Here's a paper that I missed in Organic Process Research and Development earlier this year, extolling the virtues of sulfolane as a high-temperature polar solvent. I have to say, I've never used it, although I hear of it being used once in a while, mainly by people who are really having to crank the temperature on some poor reaction.
The only bad thing I've heard about it is its difficulty of removal. That high-boiling polar aprotic group all has this problem, of course (DMSO is no treat to get out of your sample sometimes, either, although it's so water-soluble that you always have sheer extraction on your side). But sulfolane is higher-boiling than all the rest (287C!), and it also freezes at about 28C, which could be a problem, too. (The paper notes that small amounts of water lower the freezing temperature substantially, and that 97/3 sulfolane/water is an article of commerce itself, probably for that reason). It has an unusual advantage, though, from a safety standpoint: it stands out from all the other polar aprotics as having remarkably poor skin penetration (as contrasted very much with DMSO, for example). It's more toxic than the others, but the skin penetration makes up for that, as long as you're not ingesting it some other way, which is Not Advised.
The paper gives a number of examples where this solvent proved to be just the thing, so I'll have to keep it in mind. Anyone out there care to share any hands-on experiences?
Comments (15)
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1. Triazine on November 16, 2012 2:04 PM writes...
287 C sure is high, but at least it is soluble in water. If I never have to run another Friedel–Crafts reaction in nitro-benzene I'll be a happy man.
Permalink to Comment2. Derek Lowe on November 16, 2012 2:20 PM writes...
Yeah, nitrobenzene is no fun. I used to use benzonitrile as a solvent for Claisen rearrangements, and there was no good way to get rid of that one short of a column, either. . .
Permalink to Comment3. andreew on November 16, 2012 2:53 PM writes...
Did you notice?
http://en.wikipedia.org/w/index.php?title=Sulfolane&oldid=127449045 (dated 1 May 2007)
"Shortly thereafter, it was discovered that both the product yield and the lifetime of the catalyst could be improved by adding hydrogen peroxide and then neutralizing to a pH of roughly 5-8 before hydrogenation."
http://pubs.acs.org/doi/full/10.1021/op300108w (dated 2012)
"Shortly thereafter, it was discovered that both the product yield and the lifetime of the catalyst could be improved by adding hydrogen peroxide and then neutralizing the reaction mixture to a pH of roughly 5–8 before hydrogenation.(2)"
It's a minor point, but still!
Permalink to Comment4. Toad on November 16, 2012 3:04 PM writes...
I can see the advantage of sulfolane in process environments. Keep in mind that process chemists are much better than us med chemists in finding the right conditions for such, especially on scale. Imagine just adding water or something similar to precipitate your compound or intermediate, filter, and voila, you can even distill the filtrate to recover solvent. This just wouldn't be practical for mg scale reactions we tend to focus on.
Permalink to Comment5. NUchemist on November 16, 2012 4:30 PM writes...
Beats diphenyl ether as a high-temp reaction solvent.
Permalink to Comment6. vanad on November 16, 2012 6:40 PM writes...
Hi, andreew #3, what's your point caller?
what does reference 2 in that ACS paper refer to? what does the wikipedia article cite as its source? please give us more information. Thanks.
Permalink to Comment7. dylan on November 16, 2012 7:13 PM writes...
I've used sulfolane on exactly one occasion and found it to be perfectly OK. The high freezing poing makes the logistics of handling pretty similar to that of t-butanol: place the bottle on top of an oven to get it nice and liquified before attempting transfer. Workup was very much the same as reactions I've done in DMSO or DMF: dilute extensively with water and extract with ether, and chromatography should remove the last bits.
Permalink to Comment8. Martin on November 17, 2012 12:20 AM writes...
I've been doing a fair bit of small scale work in NMP, and am finding the simplest workup involves Kugelrohr distillation at high vac. and moderate T. Sulfolane is readily removed that way as well but you need to strike a happy medium of vacuum and receiver bulb temperature. Not too cold that it solidifies and gums up the short path, and not too warm that it flies up your vacuum line into your liquid N2 trap. Note the smell is actually not very nice either so dismantle the Kugelrohr pieces and wash in the 'hood.
Permalink to Comment9. processchemist on November 17, 2012 4:39 AM writes...
I used sulpholane only once, years and years ago, during a the first scale up of a medchem synthesis, and hated it. It was used after a fisher indole sysnthesis (not funny at all) and an N-methylation with/in IMe (violent discussion about the acceptable residual pression of methyl iodide exhausted from the vacuum system during distillation) for some nucleophilic substitution. Really hard to get rid of it in order to obtain a proper crystallization of the intermediate. And I changed two steps of the route, eliminating sulpholane and all the related problems.
Permalink to CommentBut maybe in some cases it can do the trick. I don't exclude anything, after I saw the final crystallization of an investigational API with DMSO/MTBE (and it was working fine).
10. Harry on November 17, 2012 8:57 AM writes...
I used it many years ago when we were researching converting a halogen exchange (Chlorine to Fluorine)from a pressure reaction to atmospheric.
We tried a number of aprotic solvents (mostly higher boiling amides) as well as sulpholane.
It actually worked pretty well, and workup wasn't a big problem as we just distilled the product out of the reaction vessel, and filtered the residues before reuse. We could get several runs out of it before we had to worry about it getting too nasty.
We finally settled on Acetamide as the solvent, since it was considerable cheaper, and gave slightly better results.
Of course by that time, the whole project was scrubbed.
Permalink to Comment11. kilomentor on November 18, 2012 10:33 PM writes...
I think the most interesting fact in the paper is that the author reports that sulfolane is immiscible with tert-butyl methyl ether (MTBE). This will make many workups much easier by extraction into MTBE and subsequent washing of the MTBE with water.
Permalink to Comment12. jvon on November 19, 2012 8:08 AM writes...
Sulfolane is used in fractionate distillation of petroleum, which is, as noted, carried out at high temperatures and large scales.
Permalink to CommentAs for ingesting sulfolane Some Other Way, watch out for those refineries and their process control technicians, because once the stuff hits the ground it tends to kind of move, and cleaning it from a water supply can be a bit of an expensive hobby. http://dec.alaska.gov/spar/csp/sites/north-pole-refinery/health.htm
13. anchor on November 19, 2012 8:36 AM writes...
Derek: Given its aprotic and dipolar nature can it function as a good solvent for microwave reaction? My concern was retro-chelotropic reaction under high temperature microwave conditions.
Permalink to Comment14. Ulf on November 20, 2012 5:46 PM writes...
Hi,
for those products that are redily soluble in MTBE sulfolane is the solvent of choice for as an example the Fisher indole synthesis as sulfolane is not miscible with MTBE so it remains even better than DMSO in the aqueous phase. You can remove the water from the combined aqueous phase and as you will end-up with a salt sulfolane mixture you only need to add toluene to be able to remove all of the salts. After removal of the touene you will have pure sulfolane again.It is very stable against very harsh conditions as strongly acidic at high temperatures.
Permalink to CommentWhy do you use Wikipedia when you have the original peer-reviewed article? I have read the article with ref number 2.
15. lelldar on November 22, 2012 12:43 PM writes...
I think andreew means that the authors (possibly?) copied the part from Wikipedia. The sentence was in wikipedia as of 2007 and was cited in the article in 2012.
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