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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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October 24, 2011

Tossing Out the 1920s Hydrogenators: Can It Be Done?

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Posted by Derek

We organic chemists have always liked the hydrogenation reaction. Take your compound up in a solvent, add a pinch of black catalyst powder, and put some hydrogen gas into the vessel. Come back a few hours later, filter off the catalyst, and there's your cleanly reduced compound, ready for the next step, often looking even better than it did before you ran the reaction.

For many decades, the standard ways to run these reactions have been to either take a balloon of hydrogen gas and attach it to the top of your round-bottom flask (as in this video clip), or run it on a "Parr shaker". That last piece of equipment has been with us, essentially unchanged, since the 1920s. It's simplicity itself: a thick-walled glass bottle for your reaction, a tube and stopper running into it (with a framework to hold it down under pressure), a hydrogen reservoir, and a motor to shake the bottle around. Its relentless dackadackadackadacka noise is one of the standard sounds of organic chemistry. These things are always off in separate hydrogenation rooms, and when you have several of them running in there at once the out-of-phase clatter makes sequential thought almost impossible. I wish that there were an audio file I could link to, but working organic chemists will all know the tune.

There are newer ways to run the reaction, and flow chemistry is the obvious choice. The "H-Cube" was an early entry into this space, and many of them are to be found around the chemistry world. Unfortunately, many of them are also found gathering dust. Uptake of the machine has been uneven, despite some obvious advantages. That's because the first-generation machine has some obvious disadvantages, too: you have to change the catalyst cartridge every time you want to try something different, because there's only one at a time. The cartridges themselves are not too large, so if your reaction isn't efficient enough, you can have a problem with not being able to run everything in one-time-through mode. And there's no liquid handling - you have to load your sample and collect it in whatever means you see fit. Various people have modified the machine over the years to get around these limitations, and the company now sells a machine incorporating many of these ideas. And there are competitors out there as well.

So here's my question for the chemical audience: has anyone had enough nerve to ditch the Parr shakers completely? I've heard of places that have done it, but when you inquire closely, you often find that there are still a couple around that do a disproportionate share of the hydrogenations. Are there any flow solutions that work well enough to get away with this? You'd think that there would be advantages to a walk-up instrument, if it were robust enough - put your starting solution in position A-3 on the rack, tell it what pressure and temperature you want, which catalyst to use, and add your run to the queue. Come back after lunch and there it is, eluted into another container, ready for you to pick up. NMR machines work this way, and so do microwave reactors. But do hydrogenators? Today, in the real world? Experiences with such things welcome in the comments. . .

Comments (36) + TrackBacks (0) | Category: Life in the Drug Labs


COMMENTS

1. Colm on October 24, 2011 8:11 AM writes...

So _that's_ what that noise the organic chemists two floors up are generating. It all makes sense now.

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2. David P on October 24, 2011 8:55 AM writes...

We demoed an H-Cube a while back. It was very neat. I don't understand the complaints about changing cartridges - how is that different from running a reaction in a Parr? Inf act that was the major benefit - you can handle reactive catalysts (Raney Nickel, 10% Pd/C) without actually handling them.

I can see the problem with having to run through a sample more than once, especially if you are unsure of the conditions to best get the reaction to work. But the over-riding downside to the instrument was the price. But we weren't big pharma, prepared to pay the big bucks for an occasionally used machine.

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3. processchemist on October 24, 2011 8:59 AM writes...

I have no simpathy for both parr shakers AND flow hydrogenations, for obvious reasons: like all eterogeneous reactions hydrogenation (2 or three phases) is heavily dependent on mass transfer (in some cases dramatically dependent: I remember a reductive amination where the formation of an unwanted side product was depending on stirring speed). Hard to devise something useful in the scale up from the results of a Parr shaker or a flow hydrogenator.

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4. milkshake on October 24, 2011 9:14 AM writes...

You can buy several different sizes of Ace pressure flasks with teflon inlet/fittings compatible with Parr hydrogenator. Since I needed to heat my asymmetric hydrogenations, I took the flask out of the cradle, put in a magnetic stirbar and placed it on oil bath behind a blast shield - and voila, experiments up to 7atm/80C worked fine and no dacka-dacka sounds of relentless copulation in the lab

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5. Industrialist on October 24, 2011 9:16 AM writes...

"Hard to devise something useful in the scale up from the results of a Parr shaker or a flow hydrogenator."

The majority of the non-pharma process chemical industry is heterogeneous. We fairly routinely scale from millilitres of catalyst to a few litres and then to tens or hundreds of cubic metres during process development. Mass transfer is just another optimisation variable.

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6. noshakeyshakey on October 24, 2011 9:16 AM writes...

H-Cubes come with various problems, all related to the complexity of the machine. Parr shakers are noisy, messy, and heavy handed chemists booger up the valves when they tighted them WAY too tight. My preference is a Fisher-Porter hydrogenation apparatus [and an Argon tank :)]

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7. MTK on October 24, 2011 9:24 AM writes...

@3,

I've scaled up several hydrogenations from Paar shakers to fixed equipment without a problem. It took longer than in the Paar shaker due to the mass transfer issue, but we had some engineers that knew the equipment and they were able to predict with a good degree of accuracy exactly how long the reaction would take.

I like the Paar shaker because I can easily calculate the volume of hydrogen that should be consumed at the end of the reaction. As long as you don't have any leaks, reaction monitoring is as easy. Read the pressure and see a) if hydrogen is still be consumed and b) how much has been consumed.

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8. processchemist on October 24, 2011 9:26 AM writes...

@milkshake

the exact tactic we're using at my shop. and Ace glass supplies pressure vessels with mechanical stirring up to 5 liters, much cheaper than a buchi autoclave

@industrialst

In the majority of non pharma chemical processes you don't have to care so much about impurities.

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9. KOH on October 24, 2011 9:26 AM writes...

We have both an X-cube (a multi-functional next-generation H-cube) and a Parr shaker in my lab. As exciting as the X-cube was at first, with all sorts of wonderful possibilities, it simply didn't work and we were reliant on what the company provided for catalysts. It turns out that not every Pd-catalyzed reaction translates well to flow chemistry. The Parr shaker only has half of its original parts, but it is still going strong while the X-cube essentially is a very expensive door stop. I agree with #6, though, that all of the valves and inlets for the Parr shaker must be cleaned out regularly and care must be taken to not be too aggressive.

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10. anchor on October 24, 2011 9:45 AM writes...

I can't forsake my shaker and the simple reason is economics. I have used both technology, but the high ended flow reactor can breakdown and waiting for the "plumber" to show up to fix the same is excruciatingly painful and not to mention the cost. The Parr shaker rarely breaks down, except for changing the worn out tubing and such. Besides, the flow reactor is priced high and not many academia can afford it.

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11. Ted on October 24, 2011 9:47 AM writes...

Around here the H-cube arrived with great fanfare and the hydrogenation room was scheduled to be decommissioned. But within a few months nobody was using the H-cube anymore and the chemists fought hard to block the impending loss of Paar shakers. The H-cubes simply had too many problems - clogging was the biggest complaint.

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12. sepisp on October 24, 2011 10:14 AM writes...

I've never seen a Parr shaker. Must be an American thing. Spinning basket is the modern method; it gives a higher shear. And who still uses a glass apparatus?

As for batch hydrogenation, the main problem with your analogy to GC/NMR robots is that a hydrogenation requires pressure-rated equipment. To start the run, you manually unscrew everything first, then assemble the thing again, do a leak test with nitrogen and hydrogen, and only then you can start running the actual reaction. After this, you need to disassemble the whole thing again. The first time a reactor would blow up the building because the robot failed in the pressure-proofing procedure would kill the whole industry with a massive product liability lawsuit.

And as #5 said, small batch reactors are the first step in scale-up. Most real-world chemistry is done in gas-phase high-pressure and temperature reactors, so it never ceases to amaze me how little university chemists know about it.

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13. Walter White on October 24, 2011 10:20 AM writes...

Like all these "open access" new instruments they tend to be poorly used unless there is someone assigned to be the dedicated expert and walk the sceptics through the process.

Chemists dont like change and they like equipment that loses their compounds even less, so form past experience if you want to get an H-cube site it next to someone who likes helping others.

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14. Rock on October 24, 2011 10:28 AM writes...

I have mainly used Parr shakers since balloon hydrogenations were outlawed at my old company. I didn't mind them much although I found them to be way over-engineered. How large a motor do you need to mix 200-500 mL of solvent? The larger 2L ones were even worse, almost shaking off the bench. I have spoken to an instrument company once about re-designing a unit. Much smaller footprint, vertical hydrogen tank and vortex shaker.

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15. JH on October 24, 2011 11:08 AM writes...

Here's an interesting piece on H-cube.

Evaluation of a commercial packed bed flow hydrogenator for reaction screening, optimization, and synthesis

doi:10.3762/bjoc.7.132

Permalink to Comment

16. JH on October 24, 2011 11:24 AM writes...

Ok, let's add an actual link: http://dx.doi.org/10.3762/bjoc.7.132

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17. Liz on October 24, 2011 11:49 AM writes...

We’ve invested a considerable amount of work trying to increase useage of the H-Cube in our labs, due in part to our management’s desire for a safer alternative to traditional hydrogenation apparatus. Many people who have used the H-Cube can attest to the fact that the reactor can seem “finicky”, performance can be frustratingly variable, but when the stars align and it’s working well you can get some terrific results. We have liquid handling and the new timer option to reduce down-time due to loss of prime and have written an in-house user’s manual that covers a lot of the problems. The most important thing we have is a dedicated power-user to keep the things running optimally. With a lot of attention paid to it, we’ve learned many of the things that make it “finicky” but are still sometimes taken by surprise. Also, the commercial cartridges can vary widely in performance so until this is addressed by themanufacturer (wake up and listen to your customers, guys!) you’re better off packing your own.
Readers of this blog should understand that flow hydrogenation is not a replacement for batch hydrogenation (Parr, balloon, or otherwise). It is a fundamentally different process that can give unique results due to the fact that substrate is exposed to large excesses of catalyst and product is continually removed by the flowing stream. It is not always bettter than batch, over-reduction can be a problem, but it is certainly safer. In addition, not all heterogeneous flow reactors are alike! The H-Cube “bubble flow” system works very differently than the HEL trickle bed, for example, and it’s no trivial matter to translate a reaction from one to the other.
I’m a firm believer that one day, hopefully in the near future, when the flow hydrogenator makers “get it right” then these machines will take off like the microwave. The manufacturers need to listen to their customers, especially now that they have saturated the market with reactors that are being used as door stops (BTW – we gave up on our X-Cube and donated it). Best of luck to ThalesNano and HEL! Keep at it guys!

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18. Jon on October 24, 2011 11:49 AM writes...

I mostly use stainless steel autoclaves from Parr. Sure, it has its problems, but it scales up better.

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19. A Nonny Mouse on October 24, 2011 11:53 AM writes...

Been using a Buchi mini-clave for the last 12 years which works to 12 bar with glass. I have worked with larger scale ones up to 60 bar with a stainless jacket.

The glass blower also made a piece of kit using a parr bottle with a rodavis top + Youngs valve + side arm for a pressure gauge. About 2 litre capacity and 3 bar. With a magnetic stirrer it has done 200g batches at a time. I suppose it's like the Ace set-up described above

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20. Iridium on October 24, 2011 12:04 PM writes...

H-cube is the best when you are working in small scale: 5 to 50mg.
If you want to use it to hydrogenate >1g make sure substrate is pure to avoid poisoning the catalyst.

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21. MTK on October 24, 2011 12:15 PM writes...

I'd like to ask a question regarding Paar apparatus safety. I've used them a lot in a number of labs and I've never had nor heard of a safety incident using them.

I can certainly imagine how an accident could happen, either through equipment failure or operator error, but have never actually had one happen.

Can someone relay to me what incidents have happened. I'd like to know to prevent it from happening.

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22. A Nonny Mouse on October 24, 2011 12:19 PM writes...

Forgot to mention that my colleague, who worked at JM for quite a few years, used to use HEL systems for doing parallel reactions to optimise the hydrog conditions.

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23. Design Monkey on October 24, 2011 12:35 PM writes...

Never really had classic Parr shakers (must be USA thing).

We do have reasonably often used teflon and steel pressure reactors with stirrers. And also a dusty H-cube, which run into technical troubles and is not exactly usable due to that.

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24. molecular architect on October 24, 2011 1:46 PM writes...

Maybe I'm old-fashioned but I like the simplicity of the Parr apparatus when hydrogenation needs to be run at elevated pressure. It can easily be adapted to very small scales by pouring a small amount of melted paraffin wax in a Parr bottle and placing a test tube in until the wax hardens. Add/remove reagents via a pipet.

For room pressure hydrogenations, I used to use the Brown Gasimeter (which sadly is no longer manufactured by Ace Glass). Invented in HC's labs it turned hydrogenation into a simple titration. Hydrogen was generated by adding an aqueous solution of sodium borohydride to a solution of aq. HCl. You could measure the progress of the reaction by the amount of borohydride solution consumed. In grad school, we had one of these set up all the time. It was convenient and fast. The apparatus could also be used to generate a variety of other gases although I never used it for anything else.

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25. German Chem on October 24, 2011 1:47 PM writes...

Our Parr shaker gets dusty somewhere in our lab. I enjoy the good old water column filled with atmospheric hydrogen pressure out of an H2 bomb (ca. 1l volume). Works well up to a 6l flask. Although the refill of hydrogen is a bit annoying (sometimes more than 50 liters...).

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26. CMCguy on October 24, 2011 2:30 PM writes...

I definitely recall the "tune" and appreciate the comment about "when you have several of them running in there at once the out-of-phase clatter makes sequential thought almost impossible" is so true as used to have a couple just around the corner from my desk. While I could block out one running if both in use at one time I would head to the library to catch up on literature.

#21 Only accidents seen involving Parr shakers have been a few events when person dropped the bottle, invariably after the reaction run and not before opf course, either just spilling some product out on bench or once shattering on the floor (CO2 extinguisher handy). Of course don't count the sparks and outright flames that often ensued when filtering off Pd or other catalyst. Such was normal lab entertainment in grad school but had learn to avoid once in industry lab.

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27. Anonymous on October 24, 2011 2:45 PM writes...

Our company also tried hard to get everybody to switch from Parr shakers to H-cubes, and it didn't take long for a storm of protest to gather. The H-cubes were too finicky for open-access use, and a problem with the plumbing system lost your product. Also, we ran into major problems with catalyst cartridges - very few were available, consistency from lot to lot was very poor, and although we tried several times to find a solution involving packing our own or having them packed, that turned out to be foreclosed by the patent positions involved.

The one advantage the H-cube had was handling very small quantities of material. If you weren't using at least 15 mL of solvent in a 125-mL parr shaker, the reactions weren't very consistent. From 5-50 mg of material, it was worth taking a chance that the H-cube might actually work this time.

@21. MTK - in the 20 years I worked there, we never had a single problem with a Parr shaker in use, and at one time we must have had over 50 of them. However, there were relatively frequent issues with poor technique in filtering catalysts. Every lab fire I remember hearing about while I was there had improperly stored waste catalyst involved somewhere.

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28. GladToMoveToProcess on October 24, 2011 3:33 PM writes...

#21: I've never had a problem, but one of my bosses told me of a large hydrogenation (might have been a lot of a nitroaromatic) that was exothermic enough to run away; exploded the (2 L) bottle, peeled back the shield, the spray then caught fire.

I've also used the Parr for reactions that generated a reactive gas, e.g. cyanic acid, that proceeded to react with a substrate. Add all the reactants save one, mix them well, add the gas-generating one, slam on the stopper (valves to the tanks closed!) and start shaking. Pretty exciting to watch the pressure rise, but never had an incident.

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29. DrSnowboard on October 25, 2011 1:46 AM writes...

We assumed the main risk of hydrogenation was use of a cylinder of H2, so replaced that with a benchtop hydrogen generator and used a simple glass gas burette or supply on demand. We used an H-cube for pressure and more exotic reactions as we had no room to put a Parr in, plus we didn't manage to scrounge one in time from the various closedowns that initially kitted out the lab...

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30. Anonymous on October 25, 2011 9:52 AM writes...

Limited mass transfer is an issue with both the Parr shakers and many flow systems. The reaction is limited by the reactor and not the chemistry. Using flow in the trickle bed regime, where essentially you are passing liquids through a flow of gas, allows for gas to be reabsorbed as it is consumed. This enables process conc solutions to be fully converted in one pass. The HEL FlowCAT is being used for reactions from 1g to 1kg.

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31. Liz on October 25, 2011 12:07 PM writes...

#29 People in our organization also assume the tanks are dangerous, but I don't know that this is true. Seems to me the danger is ignition at the interface between solvent vapor, air, and hydrogen. Therefore it doesn't really matter where the hydrogen comes from, right? If buses fueled by hydrogen tanks are driving around big cities in the US, why do we feel uncomfortable with a tank with properly strapped to our lab bench? Any thoughts on this from readers?
TN makes a lot of hay out of their miniaturized hydrogen generator technology (H-Cube), but in the end those generators wear out pretty quickly and don't put out enough H2. FlowCat is a great tool, robust, well-engineered, but doesn't scale down well (not suited for small-scale reaction screening).

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32. Nick K on October 25, 2011 1:44 PM writes...

Parr hydrogenators are (almost) bulletproof, but take care to lubricate the bearings regularly. Recently I knackered my poor old Parr shaker (constructed in 1973!) by neglecting to do this. Fortunately, it is still usable. I simply put a magnetic stirrer bar in the bottle and place the cage on a stirrer hotplate. The rate of hydrogenation is only slightly less than with shaking, but OTOH it's silent. Magnetic stirring works even with Raney nickel. In response to #28, I've found large-scale reductions of nitroaromatics in a Parr can be alarming due to the exotherm and potential for a runaway. It might be better to run such reactions at 1 atm, even if it means having to refill the reservoir more frequently.

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33. Paul on October 25, 2011 11:40 PM writes...

If buses fueled by hydrogen tanks are driving around big cities in the US

There are plenty of buses fueled by compressed natural gas, but why would anyone use hydrogen? It's more expensive than natural gas, has lower energy density, is less available, and it's more dangerous.

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34. processchemist on October 26, 2011 2:49 AM writes...

@32

Yes, large scale reduction of nitroaromatics can be alarming. I performed one on a 5 liters scale years ago, and the only way to contain the exotherm was to lower the hydrogen pressure (cooling only was not enough). It's a quite obvious solution: we all usually control an exothermic reaction with the feed rate of one of the reactants.

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35. N on October 26, 2011 10:01 AM writes...

I recently used a H-cube, and the things that can be done with it are really quite astonishing - for example, taking a 5g-scale reaction up to 100 bar and leaving it on overnight. In terms of wide utility though, I can see that it mightn't live up to its hype. On the other hand, we did some useful chemistry on it, in part because of the silly pressures.

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36. Anonymous on October 27, 2011 2:54 AM writes...

DrSnowboard: the main risk is not the cylinder, it's handling self-heating compounds like activated hydrogenation catalysts in an explosive atmosphere like that produced by volatile flammable solvents. That, and that hydrogen doesn't burn nicely likely other gases, it explodes.

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