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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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November 26, 2007

Still and All

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Posted by Derek

I did something today that I haven’t done in several years: a vacuum distillation. That used to be a larger part of every chemist’s life, but advances in chromatography have eaten into a lot of the older techniques for purifying compounds. Recrystallization is another obvious example of a lost art, one that I’ve steadily heard characterized as such for the last twenty years. Well back before my time, people purified their liquids through distillation and their solids by recrystallizing them, and that was that.

Both of those can still be the best way to go, depending on your compounds. When you come across these methods in the older literature, you always have to ask yourself if you should stick with them, or if a chromatography would do the job more easily. Today, though, it was a modern procedure I was following, so distillation it was.

still%20head.jpgFor the non-chemists in the audience, here's how you do it. You rig a glass apparatus onto the top of your round-bottom flask of gunk - there's one at the left. This "still head" has a short neck coming up, a bend that accommodates a thermometer, then a cold-water circulating condenser built in right before a tube to deliver the drops of distilled product. Along that region there's another fitting to hook the vacuum pump up.

Pulling a vacuum on the system lowers the boiling point of the liquids inside it - one of the reasons you have to adjust recipes at high altitude, actually. (If you lower the pressure enough, you can get water to boil at room temperature). Without that lowering, many compounds would have to be heated up so much to distill them that they'd start to decompose. Heating things to that point isn't much fun, in any case. Far better to pump things down and take them over at a more reasonable temperature.

The usual technique is to pump things down first, just to get any bumping and bubbling out of the way as leftover low-boiling solvents and dissolved gases clear out. Then you gradually increase the temperature on the distillation pot until things start to boil. You can see the condensation form on the inside of the still head as things get going, then drops start to condense and drip off the end of the thermometer back into the pot. A bit more heating and things make it over to the condenser, roll down the collection tube, and into the receiver flask.

cow.jpg
Of course, you may have more than one thing in that pot. The stuff that's boiling out will eventually all come over, and as you heat things up some more the next higher-boiling component will then start to boil and the process repeats. That's why they make adapters that can fit several receiver flasks - these things will turn to accomodate different fractions, one after the other. The common lab name for these is a "cow" (Germans call them "spiders").

When you're finished, you generally have one or more flasks full of clear liquid on the far end of things, and the distillation pot generally looks just awful. All the high-boiling impurities have concentrated, and the resulting mix has been thoroughly cooked. It's a dramatic illustration of what you've accomplished - dark brown sludge separated out from pure product. Distillation makes you feel as if you've earned your lunch break.

Comments (22) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. psi*psi on November 26, 2007 10:59 PM writes...

recrystallization is no lost art! it is one of the reasons i've run...4? flash columns in the past year
plus it ends with something sparkly :)

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2. eugene on November 27, 2007 1:27 AM writes...

Some of the compounds I distill, have freezing points just above room temperature and come out as supercooled liquids once you disconnect the vacuum. I always enjoy getting that clear liquid in the receiving flask, and then dropping in a seed crystal and watching it grow bigger and bigger (with differing speeds).

One particular compound I've distilled so many times, that it now just crystallizes in the condenser instead of requiring a seed crystal (not fun at all as it clogs the entire apparatus) due to, what I assume, small micro-crystals of it flying all over the fume hood and settling on all the glassware.

Sometimes I save a distillation product for my lab mates and make them gather around while I drop in the seed crystal. Very impressive, but I think I enjoy it the most.

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3. ..... on November 27, 2007 2:01 AM writes...

I work in an (academic) lab and we run this type of distillation near daily. Rarely for product isolation but almost always to purify reagents.
Even reagents fresh out of a new Aldrich bottle often have gunk/water.

Standard dialogue with boss:

Me: My reaction failed
Boss: Did you distill reagents X, Y and Z?
Me: Um.....no, not reagent Y.
Boss: Try again. Distill Y.

Can't wait for industry where yield apparently doesn't matter.

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4. Ed on November 27, 2007 3:15 AM writes...

In the UK, the "cow" is called a pig!

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5. Petros on November 27, 2007 3:26 AM writes...

A succesful vacuum distillation was always a pleasure to run. And I remember some where it was not necessary to seed the collecting falsk, simple moving it could induce solidification

I'm shocked to hear that recystallization is becoming less popular although conversation at the Cambridge Med Chem confrence led me to understand that many common solvents are now supposed to be avoided on safety grounds.

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6. bcpmoon on November 27, 2007 5:23 AM writes...

Mind the gap: In process, chromatography is to be avoided, crystallization is the easiest, best, cleanest, most efficient and greenest way to go. I bet that medchem would crystallize all day if the amounts they handle were larger.

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7. milo on November 27, 2007 6:50 AM writes...

In my industry, distillation is the only way things are purified (aside for the odd crystallization), even on a lab scale. In the lab, I will routinely separate 3-4 compounds out of a 2 kg mixture using a fractionating column. Once you do it a few times, you realize what a simple and powerful isolation method it is. For even better separations, I'll break out the spinning band....

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8. Rich Apodaca on November 27, 2007 9:54 AM writes...

For working on scale, I'd take a recrystallization or vacuum distillation any day over a column chromatography.

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9. Kevin on November 27, 2007 10:33 AM writes...

Ed: I was under the impression that a pig was the three-legged variety with the vacuum hose barb as the curly tail, and a cow was the four-uddered version with no vacuum hose barb.

I did some low M.W. thiol chemistry for my PhD, so I am betrothed to the Kugelrhor.

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10. Green Koala on November 27, 2007 10:37 AM writes...

milo,

A spinning band distillation; really!? Wow, thought those were all still sitting in the dusty corners of old academic chemistry lab basements. Fantastic gadget in theory - does it work as well as one would like?

I guess there's a lot of practical stuff out there in other industries that we in our own little specialty niches never get exposed to.

GK

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11. Tom on November 27, 2007 11:58 AM writes...

Ah... I love to do vacuum distillations. Turning a dark yellow oil into several mls of crystal clear oil is quite satisfying. It is kind of like the feeling you get after mowing the grass.

Don't get me wrong.. I love the biotage, but there is something great about a good old fashion distillation.

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12. Moebius on November 27, 2007 5:01 PM writes...

My master's adviser had us use a Chromatotron. We were skeptical at first, but once you get the hang of it, it is pretty cool. I am now in the industry and use Biotage most of the time and our director likes to use the Chromatotron. He is the only one using it. I run prep TLCs once in a while, but I have never seen anyone in my lab use them.

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13. milkshake on November 27, 2007 5:28 PM writes...

When I feel frustrated with my project and inadequate, I make a 50g batch of nitropyrazole building block. We always have use for the stuff, the preparation is extremely simple and recrystallisation yields gorgeous plates.

As for the distillation, the annoying part is that you have to have at least 1 g of material, to not lose it byo spreading it all over the glasware (10g is better stil) but the beauty is that all solvents, moisture and dark impurities are out. Kugelrohr is underused - I like it for crude distillation of high-boiling stuff, to get out salts, tars and solvents. In one of the previous companies I was cranking out solubilizing sidechains for a kinase project - and by their nature these diamines vere very water soluble and polar so aqueous workup was out. One alternative for purification was a big silica column in chloroform-methanol-ammonia system, but Kugelrohr was much more satisfying solution most og the time.

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14. anon on November 28, 2007 5:42 AM writes...

I used to use a pig but then I discovered Perkin's triangle: wouldn't use anything else.

(Except on a larger scale where a wiped film still is the kit of choice).

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15. KB on November 28, 2007 8:08 AM writes...

Hmmmm. Recrys of NBS from boiling water. Lovely, white fluffy crystals. Never brominate without it! And, it's possibly the easiest recrys known to man. Makes you realise how duff the stuff Aldrich et all is!

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16. Loon E Toon on November 28, 2007 8:17 AM writes...

Recrystallization works wonderfully when it works, but finding the right conditions is not always trivial. I once spent weeks trying to come up with the proper conditions to separate some isomers from a reaction; not volatile enough for vacuum distillation, gave poor resolution on silica, never came off alumina, didn't have prep scale HPLC (this was grad school with a cheap advisor after all), couldn't convince my boss to spring for the money to derivatize it because I couldn't guarantee it would work. Eventually found a 3 component system that worked (sort of). Later found a 1930s era paper from a group using related compounds; they mentioned that they had tried over 2000 solvent mixtures before finding one that worked.

Makes tweaking the silica column with a touch of HCl seem trivial.


Permalink to Comment

17. MTK on November 28, 2007 8:47 AM writes...

Spot on, bcpmoon, with respect to process chem.

I once went at least 5 years without running a single column. Recrystallizations all the way. Literally, I wouldn't have known where in the lab the lab to even find a column.

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18. Dustin James on November 28, 2007 1:47 PM writes...

At my former job we distilled 2 to 3 kg of hydrocarbon mixtures--usually mono-, di- and trialkylated biphenyl or naphthalene. After doing this a couple of hundred times, I mastered the art of wrapping the still head with heat tape to prevent crystallization of the unreacted biphenyl or naphthalene as the distillation started. We used a large vacuum jacketed column packed with glass helices and a still head with a magnet-actuated splitter. Split ratio was 3:1 to 10:1 as I recall. We generally collected equal fractions of 100 g each, then analyzed (by GC) and blended fractions to get the product we wanted. The use of an Excel spreadsheet to calculate blending recipes was mandatory. In our business, the idea was not to make the purest single component product, but to get the highest yield of product with the desired physical properties (viscosity, dye solubility, etc.). We blended mono-, di- and sometimes trialkylated products. Some of the alkylated isomers were solids at room temperature if pure, so we had to blend in enough other stuff to make sure that the product stayed liquid. We would never do chromatography to isolate a product unless it was on the 1 g scale or so.

We also did melt recrystallization in the plant. The idea was to pump your liquid impure material, like durene (1,2,4,5-tetramethylbenzene), through a long pipe that was cooled below the melting point of the product. The pure product would crystallize on the walls of the pipe while the impurities would continue to flow through the middle of the pipe. Then the pipe would be heated to melt the purified product and pump it to the next section. This could be done in a continuous or semi-continuous process using several sections of pipe.

I think that today's chemists are woefully unprepared for doing continuous chemical processes. They are all trained for batch processes. But continuous processes can be high yielding and less costly.

My 2 cents.
Dustin

Permalink to Comment

19. andrew on December 8, 2007 11:24 PM writes...

In response to ....., while preparing for an NMR tube experiment, I ran a sample from a Sigma-Aldrich bottle of aldehyde. By integration, only 20 % aldehyde. On distillation, lo and behold, 100 mL of brown stuff gave ~ 20 mL of clear colorless liquid, with the remainder being black tar.

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20. GG on December 18, 2007 6:41 AM writes...

People in my lab use exactly the same distillation apparatus every 2-3 months, to purify the reagents for surface reaction...
The compound is distilling with drying agent, then pump and heat, and the clear liquid condenses into molecular sieves-filled flask to keep it dry.

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21. QG on February 24, 2008 10:47 PM writes...

1) Do yourself a really big favour, don't use the short path distillation apparatus as shown above. There is a far better design out there, one with a vertical cold finger. This reduces the distillation path length greatly from about 20 cm (as shown above) to just about 2-5 cm. This means you can distil small amounts of compound with losing lots of it on the walls of the apparatus.
see: http://en.wikipedia.org/wiki/Image:Short_path_distillation_apparatus.png

2) Also the Perkin triangle is the king of large scale vacuum distillation, no need for pigs, cows or any other farmyard animal, set to heat and collect fractions as they come off. Also not a bad way to dry solvents either, set to reflux and just collect when ready.
see: http://en.wikipedia.org/wiki/Perkin_triangle

3) As for crystallisation you could do worse than to see: http://en.wikipedia.org/wiki/Image:Short_path_distillation_apparatus.png

4) Finally, what is the best way to get rid of a trace amounts of a high boiling solvent ~~~ often columning, not hours on the high vacc!!! Add your compound to column. Wash column with hexane, to wash off the high boiling solvent off the column. Then wash the desired compound off the column with DCM/EtOAc. Obviously this wont work if you have a compound that runs really fast in a non-polar solvent like hexane!

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22. QG on February 25, 2008 7:54 PM writes...

I made an error above, the third links should be: http://en.wikipedia.org/wiki/Recrystallization

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