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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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June 15, 2011

High Pressure - The Good Kind

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Posted by Derek

I was talking with some colleagues about underused synthetic chemistry technologies the other day, and one that came up was high pressure. Here's a new paper from JACS looking at pressure effects on a common reaction (Michael addition), and there are quite a few others like it scattered around the literature. In general, reactions that have a lot of steric congestion, or whose transition state occupies less volume than the starting complex, will show some effects as you go to higher pressure.

But no one ever does it. Well, not quite "no one", but pretty damned few people do. I think the problem is that you need special equipment, for the most part, and you also need to have the idea of using high pressure. Both of those are in short supply. But I wonder if someone were to make a lab-friendly high pressure reactor, if it might get taken up a bit more. (Note to equipment manufacturers: I am not promising to buy the thing if you make it. But it's a thought).

Comments (32) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Kevin on June 15, 2011 2:16 PM writes...

Wasn't this the kind of thing that people tested out first in sonication baths? If you were able to get product there, then that was justification to go out and buy high-pressure equipment.

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2. opsomath on June 15, 2011 2:53 PM writes...

I always wanted to try using thiophene as a Diels-Alder diene, like you can do with furan. The trouble is that thiophene is way more aromatic. You can do the reaction with awesome yields - if you have a truly impressive pressure vessel. (http://dx.doi.org/10.1002/anie.200353487) A lab buddy and I discussed kludging together a flow process using an old HPLC column and pump - HPLC pressures are reasonably close to the pressures in the paper - but it was just a side project and not a very important one. Anyone ever done this?

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3. anon th II on June 15, 2011 2:56 PM writes...

I remember when I was in graduate school, Bill Dauben, at Berkeley, was promoting the use of high pressure to do reactions. If I remember correctly (and I'm not going to look it up), he was able to make cantharidin, better known as Spanish Fly, using a Diels-Alder reaction because the preferred facial selectivity switched to correct one at some outrageously high pressure (54 Tbar?). Unfortunately, the low volumes (safety?) and high pressures needed to take advantage of small "volume of activation" made it rarely worth the effort and few followed in Dauben's path. Until today!!

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4. Brute Force Chemistry on June 15, 2011 3:05 PM writes...

Not an advertisement, mind you, but something a colleague showed me recently.

http://www.supercriticalfluids.com/hprseries.htm

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5. You're Pfizered on June 15, 2011 3:23 PM writes...

Part of the reason that this probably isn't done more has to do with Safety Departments in industry frowning on chemistry that has the potential to take out large pieces of hoods/people if something bad happens. Hell, we're only allowed to use a maximum of 100mg of 10% Pd/C in a balloon hydrogenation...

We have a lab specifically for any high pressure type chemistry as well as larger scale hydrogenations, which is actually fine by me.

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6. biotechchem on June 15, 2011 3:27 PM writes...

Thales Nano of H-cube fame has a high-pressure high-temperature flow system called X-cube. I don't know anyone who has used it, though.

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7. Anonymous on June 15, 2011 4:00 PM writes...

What ever happened to the good old days of using Monel bombs?

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8. Fellow Old Tomer on June 15, 2011 4:19 PM writes...

Anon the II, your recollection is correct. Todd Brookhart, a Dauben postdoc synthezised Cantharidin at high pressure; the reference is Tetrahedron Letters Volume 21 Page 1815 (1980). The apparatus used was a diamond anvil; the diamonds were from seizures via US Customs. Not much used in process development, which is a shame because the reaction can followed by IR.

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9. Martin on June 15, 2011 4:56 PM writes...

I used to use one of the 10kbar reactors a bit during my German postdoc year, and it was an impressive piece of kit. Basically you put your reactants in a teflon vial and placed it in a bore in the middle of a massive steel block, filled the rest of the bore with heptane and pushed the plunger into so that a ~10 cm of heptane liquid was compressed to ~1 cm. Got seriously hot as well while being compressed so you had to go slow if temp was an issue. I was doing Diels-Alders so it wasn't for me. Can't remember who made it, I think it was Hungarian. It was most definitely not a benchtop device. Sat in the "bomb room" in the basement of the building. Great scary room to visit actually, all the mini-bunkers which looked like shower cublcles against one wall (the outer wall of the building IIRC)

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10. not bob on June 15, 2011 5:24 PM writes...

#9 - Yeah, our lab had one of these too, except it wasn't in any bunker - just sitting in the middle of the lab. I saw it used maybe 20-30 times over the course of my time there and used it maybe 5 or 6 times myself. It never really helped anyone as far as I recall...

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11. the cat on June 15, 2011 5:53 PM writes...

The synthesis of cantharidin has been performed efficiently at atmospheric pressure in a solvent system of 5 M lithium perchlorate-diethyl ether.
See: JACS 1990, 112(11), 4595-4596

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12. susurrus on June 15, 2011 8:19 PM writes...

Part of my grad work was a 12KBar Diels-Alder reaction to construct a decalin system for a natural product. Every day I ran a gram of s.m. through that miserable POS apparatus. Plus, once a week I had to go buy all the castor oil that Rite-Aid had on it's shelves to re-fill the pressure chamber. The clerks must have thought I had severe G.I. problems.

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13. WB on June 15, 2011 8:42 PM writes...

A colleague of mine has an entire single-story building for high pressure reactions in Singapore. The place has thick bunker walls, so my guess is if anything blows up it's mostly the roof that gets damaged.

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14. PorkPieHat on June 15, 2011 9:51 PM writes...

It looks like there were only a handful of these in academic labs since they were introduced. They are surprisingly safe to operate. When they blow, what you observe is a piss & spray of castor oil (or whatever else oil you use) from the pressure release cap. That they explode in catastrophic fashion is something I've never heard of or experienced.

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15. Curryworks on June 15, 2011 10:28 PM writes...

High pressure is a very useful tool for conducting vessels radical polymerizations to make ultra high MW polymers. Due to the major decrease in termination events while not harming propagation.

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16. gippgig on June 15, 2011 11:24 PM writes...

#8 - that synthesis actually made mainstream news - the Washington Post newspaper ran an article about it ("Famed Spanish Fly, Stuff of Fantasies, Synthesized in Lab", July 10, 1981). The article mentioned "a new technique that uses high pressure to facilitate chemical reactions."

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17. sepisp on June 16, 2011 2:40 AM writes...

The lack of high-pressure experience is another example of the gap between the industry and academia. I'd understand this if this blog was only about total synthesis or something, but the fact that industry workers have similar opinions is beyond me. If you think of petrochemical reactors, most of those are pressurized and often operate in the gas phase.

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18. processchemist on June 16, 2011 3:14 AM writes...

@sepsip

The fact is that API/fine chemicals manufacturing is a different world from commodities/petrochemical production: relatively small volumes of a range of high added value products usually don't justify the investment for dedicated high pressure or continuous production equipment (so the emphasis on the microreactor technology - "don't scale up, number up" transmits the idea of flexibility and "low" initial investment). High pressure industrial hydrogenators (up to 100 bar) are not exactly the most common piece of equipment in the standard API manufacturing unit, in these days (some plants have one, many others don't, and in my country the last one I heard about was installed in the mid 90's ). And safety is another significative cost, talking about high pressure on industrial scale.

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19. andrewD on June 16, 2011 3:54 AM writes...

Well Derek, it all depends on what you call high pressure. I have used Hydrogen Sulphide/Ammonia at 5 bar and 80 deg in a glass Buchi pressure reactor as well as in a glass line Pfudler (the latter using 500kg of Hydrogen Sulphide). I have used hydrogen in similar systems to 4bar/70 deg both in the Lab and on plant. I am/was a Process Development chemist in the Fine Chemical sector.
Buchi do lab pressure reactors in glass and metal, there is no reason for not using pressure reactions other than unfamiliarity and inertia.

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20. MTK on June 16, 2011 8:11 AM writes...

The design of a high-pressure or hydrogenation facility is actually pretty neat, if you've never seen one before. generally the room with the reactors has got three sturdy walls including the one everyone hides behind where all the controls are, then you've got one significantly weaker wall, the back wall usually, which is designed to be the blow-out wall should something happen. Outside of that wall there's usually a bern, hill, or something similar to catch all the debris from said blow-out.

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21. anchor on June 16, 2011 8:32 AM writes...

Derek : A nice paper, but for your information the paper appears in organic letters and not JACS. Though OL is ACS publication.

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22. anchor on June 16, 2011 8:33 AM writes...

Derek : A nice paper, but for your information the paper appears in organic letters and not JACS. Though OL is ACS publication.

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23. simpl on June 16, 2011 8:35 AM writes...

@sepsip
I gave up comparing petrochemicals to pharma ages ago: its too depressing.
@processchemist
In our plants, to my knowledge, hydrogenation is the only standard reaction done at high pressure. The other stuff is farmed out to BASF or special use.

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24. GladToMoveToProcess on June 16, 2011 1:02 PM writes...

Re andrewD @19: Similarly not high pressure by any means, but I recently did a recrystallization from MeOH in a sealed tube (Ace Glass, with a screw-in Teflon plug and o-ring) at 115 deg C. The vapor pressure of MeOH at that temp is something like 5 bar; the tube is rated for 10, but it was still scary enough. Haven't figured how to scale this one, as the academic lab I'm in now doesn't have the Parr or Buchi equipment we had in industry. Again, not truly high pressure, but still enough to raise the blood pressure!

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25. canchem on June 16, 2011 3:21 PM writes...

@19/24: Last place I was at had me running reactions in DCM in a bath set to 110 deg C - forget what the glassware was to get that high, but the bloody stuff weighed a ton. Sure made the SnAr easy to clean up though - much nicer than playing in DMF.

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26. PMP on June 16, 2011 3:51 PM writes...

The use of high pressure in enantioselective catalysis appears to be a Polish specialty. I remember Janusz Jurczak promoting the technique by saying that they started doing this in Warsaw because he is a heavy man and could produce the pressure himself... Nevertheless I think this is potentially a very useful method and produces the quaternary centers with very simple starting materials.

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27. PMP on June 16, 2011 3:51 PM writes...

The use of high pressure in enantioselective catalysis appears to be a Polish specialty. I remember Janusz Jurczak promoting the technique by saying that they started doing this in Warsaw because he is a heavy man and could produce the pressure himself... Nevertheless I think this is potentially a very useful method and produces the quaternary centers with very simple starting materials.

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28. PMP on June 16, 2011 3:54 PM writes...

The use of high pressure in enantioselective catalysis appears to be a Polish specialty. I remember Janusz Jurczak promoting the technique by saying that they started doing this in Warsaw because he is a heavy man and could produce the pressure himself... Nevertheless I think this is potentially a very useful method, and I also wonder why it is not used more often. Other "neglected" methodologies are the use of cathodic/anodic redox reactions and the use of solid-state reactions.

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29. pitkäsiima on June 18, 2011 4:42 PM writes...

#18: Sounds like a good market for some custom manufacturer to me. I wonder why so many companies or other organizations are so content in not being able to wipe their own ass in matters that are their core competency. It's like someone started a taxi company except for outsourcing the driving to someone else.

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30. Duncan on June 21, 2011 6:35 AM writes...

I would argue accessible high pressure reactors already exist in the form of microwave and flow reactors. Beyond the limits of these systems, safety is a concern and specialist pressure reactors are probably the best way to go.

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31. Secondaire on June 21, 2011 8:25 PM writes...

We have a bomb reactor that goes up to maybe 3,000 PSI or something, but I've never seen anyone ever use it...

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32. Martin on June 22, 2011 6:35 PM writes...

#30 - I can't vouch for your microwave reactor but our Biotage is only rated to 20 bar,* and we're talking about reactions on the kilobar range here. The one I used in .de was a 10 kbar unit.

*Before it cuts out heating. I had a reaction overpressure to something off the scale, and it never came down even when temp had returned to 25C. On the Biotage units this necessitates opening a safety grub screw and piercing the reaction vessels septum with a needle. Never did find out what the gas was that came out but it quite a big whoosh into the hood.

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