About this Author
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: Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
Not Voodoo

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
Realizations in Biostatistics
ChemSpider Blog
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Eye on FDA
Chemical Forums
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa

Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
Gene Expression (I)
Gene Expression (II)
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net

Medical Blogs
DB's Medical Rants
Science-Based Medicine
Respectful Insolence
Diabetes Mine

Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem

Politics / Current Events
Virginia Postrel
Belmont Club
Mickey Kaus

Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Elements I Have Yet to Use | Main | You Mean You Don't Have to Buy Them? »

October 27, 2009

Reduce Your Number of Reductions, Why Don't You?

Email This Entry

Posted by Derek

I've been occupied all morning with voodoo. Well, the technical name for it is catalytic hydrogenation, but let's call it for what it is: witchcraft. It's a widely used reaction in organic chemistry, and you can use it to reduce all kinds of different functional groups on your molecules. But once you get off the well-traveled roads, it's all jungle drums at midnight.

One reason we chemists like this reaction so much is that it's simple. You add some dark insoluble powder to your compound - which is some metal like palladium, platinum, nickel or the like, adsorbed onto carbon black or another solid. Then you add solvent and put the whole thing under an atmosphere of hydrogen gas. That soaks into the metal particles, your compound sits on them and gets magically reduced, and after a while you filter everything off and there's your clean, transformed product.

Most of the time. You'll note that I've skipped over a lot of variables there. For one thing, there's the choice of metal catalysts. Pt and Pd get the most use, but they come on a variety of solid supports. Carbon, alumina, barium sulfate, calcium carbonate. . .they all act differently. And don't stop with those guys: nickel's not to be ignored, then rhodium's available, and even ruthenium if you want to crank up the pressure. The pressure of all that hydrogen, there's another variable. Just a balloon on top, atmospheric pressure? Or put in a thick glass bottle on a shaker and turn it up to 50 pounds per square inch? Higher, in a metal apparatus? And what temperature did you have in mind? Ambient, or would you like to heat things up? Remember, as the pressure goes up, so does the temperature you can run the solvents up to.

Ah yes, the solvents. A lot of the time you see this work done in methanol or ethanol, but the reactions will often go quite differently in ethyl acetate or even something less polar. I've even seen some done in dichloromethane, although that somehow just seems wrong. Acids often have a profound effect on things, particularly if there's a basic amine in your compound.

And I haven't mentioned poisoned catalysts yet, have I? A bit of lead, or the addition of (non-protonated) amines or sulfur-containing compounds can dial down the reactivity of a lot of these metals - often down to zero, but sometimes to a useful level that you can't reach any other way. And then there's transfer hydrogenation, where you don't use the gas itself, but let some other compound give up hydrogen inside the reaction and transfer it over to your substrate. Paraformaldehyde, formic acid, phosphites, cyclohexene - all of those will work, and they can all work differently.

So. . .how many variations are we up to? Do you want to use 5% palladium on carbon in methanol, room temperature at 50 psi? Or platinum oxide in acetic acid at 50 degrees? Rhodium on alumina, ethanol, 100 psi at 100 C? Or wet 10% platinum catalyst with formic acid? That should get you started on this simple, well-known reaction. I've run 22 of them in the last two days, with the assistance of the H-Cube reactor, and I have to say: I'm about hydrogenated out.

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


1. RB Woodweird on October 27, 2009 11:27 AM writes...

You have no idea. Try all of the above, except substitute carrier-free tritium gas for hydrogen. You will discover all sorts of strange and mysterious tricks that protons do that usually go unnoticed.

Not only do you get to see and use the usual reductive pathways, you can now observe how protons exchange for one another under catalysis and attempt to ride those mechanisms to success.

Permalink to Comment

2. Chemgeek on October 27, 2009 11:44 AM writes...

" I'm about hydrogenated out."

So you've become a solid at room temperature. Nice.

Permalink to Comment

3. Tok on October 27, 2009 11:46 AM writes...

Even if you're talking just Pd/C, there are hundreds of different variations that cause huge differences in reactivity. IE Degussa grade is good for hydrogenolysis. It's possible to get vastly different selectivities with different Pd/C catalysts.

Permalink to Comment

4. Philip on October 27, 2009 11:51 AM writes...

Just to illuminate a small bit of the black art of hydrogenation - It's almost never a good idea to use methanol as a solvent for hydrogenations. All those catalysts that can add hydrogens can also take them away and sometimes do. That gives you a little formaldehyde which can react and then you get to give it back some hydrogens and all of a sudden you've lost a bit of product to methylation that you probably won't be able to get rid of easily. I've done it. Actually, most of time you probably don't even notice. It doesn't seem to happen (i.e. much slower) with ethanol.

Just to illuminate a small bit of the black art of hydrogenation.

Permalink to Comment

5. RTW on October 27, 2009 12:10 PM writes...

Well - I am glad we had a group to do these for us. They collectively had probably well over 60 years experience, and probably somewhere in the area of 100K or more such reactions run to draw information from. So - Generally we specified what we wanted done and let them actually select the conditions. This is not to say it always worked the first time but thanks to their collective wisdom much more success than failure.

Permalink to Comment

6. Jim T on October 27, 2009 12:33 PM writes...

I'd also mention one point about methanol... In addition to it's propensity to methylate nitrogens (in particular), it also has a nasty habit of going up in flames. Such that we've basically disavowed using methanol in hydrogenation.

Permalink to Comment

7. DC on October 27, 2009 12:35 PM writes...

Echoing the above. Ethanol is a safer choice.

Permalink to Comment

8. nitrosonium on October 27, 2009 12:39 PM writes...

#3. Amen to that. I know there are a million different examples of this but here's my most recent experience with the subtle differences in Pd catalyst and selectivities.
just had the occasion to prepare (Boc)2NOH on 100g scale (a little on the big size for our small CRO) The last step is hydrogenolysis of (Boc)2NOBn. If you use Pd/C you get an 85:15 mixture of the desired product:N-O reduction product (the imide). then you have to run a column. If you use Pd/BaSO4, you get 100% debenzylation. filtration through celite followed by rotovap gives quant. (crystalline) product!

Permalink to Comment

9. Vader on October 27, 2009 1:12 PM writes...

"I'm about hydrogenated out."

I recommend a diet rich in canola oil.

Permalink to Comment

10. partial agonist on October 27, 2009 2:07 PM writes...

more on safety issues:

I've seen more fires due to hydrogenation workup than anything else.

Somebody mentioned methanol- good point.

Also 10% Pd on C retains a lot of the hydrogen rather fiercely and can ignite when filtered to dryness. 5% is milder in that regard. But with either one, when filtering off the catatlyst I always tell people to wash with nonflammables (like methylene chloride) then make sure that the spend catalyst gets wetted quickly.

Raney Nickel can be a flammability pain even to a greater extent.

Permalink to Comment

11. candescent undergrad on October 27, 2009 2:40 PM writes...

There's been some mention of accidental dehydrogenation of methanol when it's used as a solvent; has anyone noticed particular conditions where this has happened at good clip without igniting? I've actually been playing around with doing this on purpose, with mixed success, to produce some cheap 13C formaldehyde, but I've had trouble balancing a decent reaction rate with not setting my hand on fire (though that did liven up my day).

Permalink to Comment

12. CMCguy on October 27, 2009 2:43 PM writes...

You obviously do not have ready access to someone trained in the "dark arts" of hydrogenation reactions: Such a person can tell one based on looking at a structure what catalyst, solvent, and pressures to try first (and on target 95% on time). Also they provide hints of preactivation by heptane reflux or a drop of acid "trick". If one is deemed worthy enough they may even allow use of their "magic" ingredient from a particular lot of catalyst keep locked away because it works when all conventional sourced reagent falls short. I have known a couple such Masters and both approached the archetypical mad scientist model because their labs were isolated bunkers scattered with odd mechanical beasts. I also wonder if they were actually driven mad from reverberated of the cyclic thumping or one or more Parr shakers, which after a single day would give me a headache that lasted a week.

Permalink to Comment

13. anchor on October 27, 2009 2:59 PM writes...

#6 and #7 are both correct. If MeOH is the only option, I found that blanketing with nitrogen prior to the addition of catalyst helps.

Permalink to Comment

14. barry on October 27, 2009 3:07 PM writes...

While methanol is notorious for participating in hydrogenations, it's not alone. A process group was bedeviled at one point by a contaminant that turned out to be N-isopropylation of an indole, coming from the isopropyl alcohol in which they were doing a hydrogenolysis. Until you replace the H2 with D2 or tritium, you're cheerfully blind to most of what happens in that reaction.

Permalink to Comment

15. Martin on October 27, 2009 6:59 PM writes...

5% formic in methanol is the one that usually goes bang on me when doing transfer hydrogenations. Usually just as I spoon in a bit of catalyst. Interestingly when this catches fire and you extinguish it with the quick "cover with a bung" method, the reaction is completely poisoned in my experience (formaldehyde? from partial combustion?), necessitating filtration evaporation, starting again if the substrate was pre-dissolved in the methanol/formic.

Seems to be safer to add a slurry of the catalyst pre-wetted to the mix and then go.

Permalink to Comment

16. cliffintokyo on October 27, 2009 8:13 PM writes...

It was the eezi-blow window (or was it wall?) in the hydrogenation suite that always caused me to approach performing any hydrogenation (or ozonolysis) reactions with due care and respect.
A subliminal additional safety precaution perhaps?
(And they dare to pretend that real chemists in industry don't earn their bread?!)

Permalink to Comment

17. andrew on October 28, 2009 3:16 AM writes...

Where is Milkshake when you need him?

Permalink to Comment

18. milkshake on October 28, 2009 3:30 AM writes...

here and awake, running hydrogenations

By the way, it is better to use 96% ethanol for nitro and azide hydrogenations (or Cbz-deprotection of amines) instead of the anhydrous grade - the absolute stuff has more of acetaldehyde hence the problem with N-ethylation.

I have recently run a wonderful lit procedure: a hydrogenolysis of benzylic Cl in the presence of 2-bromoethyl group in the molecule which survived unmolested. It was H-transfer with Pd/C in EtOAc at reflux with aqueous NaH2PO2 as a hydrogen source. Don't even ask how and why, some wacky process group came up with this concoction.

Permalink to Comment

19. JH on October 28, 2009 4:56 AM writes...

Being blind to much of what goes on in a reaction is quite commonplace I think. Proton exchange to deuterium with deuterated acids is a mechanistically different version of the same theme. It's just the changes that are permanent or easy to notice we usually tend to think about.

Permalink to Comment

20. eugene on October 28, 2009 5:01 AM writes...

22 hydrogenations in one day! I wish I had that H-cube thingy... The most tricky ones for me involved poisoning the Raney Nickel catalyst just enough so that alkynes are gently reduced to Z double bonds without any starting material being left and just a little bit of the over hydrogenated alkane product being formed so that column separation would not be too tricky. Definitely took me until the end of a day for all of that one reaction plus column though.

Permalink to Comment

21. Vasili on October 28, 2009 6:46 AM writes...

Safe hydrogenation:

1.use wet Pd/C.
2.Add catalyst to the flask FIRST, then a bit of EtOAc to soak it and then the preferred solvent touching the flask walls.

No fires.

Permalink to Comment

22. Sili on October 28, 2009 8:08 AM writes...

Never had to try these reactions, myself (never had to do all that much, really), but I had considered them when doing some literature search.

I'd hoped to find some alternative to (AcO)3BH, but I never got the reductive amination to work in the first place. Too lazy or stupid - I'm not sure.

Permalink to Comment

23. David P on October 28, 2009 8:36 AM writes...

Backing up Vasili here: it is safest to add the catalyst to the flask first, under a blanket of nitrogen or argon.

This is definitely one of those reactions where bad habits creep in, because you can get away with it when you only use a few mgs of catalyst, but then rapidly get into trouble when you have to scale up.

My old company stopped us using 10% Pd/C and also strongly discouraged us from using methanol. IIRC it doesn't even dissolve hydrogen very well - ethanol is much better.

Permalink to Comment

24. Pats on October 28, 2009 7:18 PM writes...

EtOAc is a good alternative. If you have to specifically use methanol, then tilt the Parr shaker bottle (45 deg) cotaining the compound in solvent, place the catalyst on the side little above the reaction mass and slowly move the solution to wet the catalyst. This slow wetting and taking the catalyst into reaction mixture generally avoids fire hazard.

Permalink to Comment

25. cliffintokyo on October 28, 2009 8:44 PM writes...


Your enthusiasm puts me to shame.
However, I hope that you are not literally running reactions at 03:30.
It is against safety policy to work alone in the lab, even to prepare saturated brine, e.g. because of the risk that someone else's overnight reaction might 'take off'.....unless your company works round-the-clock shifts, that is.

Permalink to Comment

26. milkshake on October 29, 2009 1:33 AM writes...

Its against your safety policy, officer. Now go get some donuts.

Night time is the best time to run dangerous experiments because it is easier to put out the fires, cover up the explosions and wipe out the blood stains when no-one is watching.

Permalink to Comment

27. Jose on October 29, 2009 3:02 AM writes...

Unless you're in grad school: then you should be drinking beer while finishing a workup and collecting column fractions (by hand, of course) at 1 am with something highly abrasive on at 90 dB or so.

Permalink to Comment

28. cliffintokyo on October 29, 2009 5:08 AM writes...

That's the spirit!

PS: I prefer pistacchios with my late-nite frosties.
PPS: Does TA culture still exist? I mean, do your (preferably more gorgeous) tutorial students still drop in the lab to hang-out after hours (and maybe pick up some advice about the problems you set)?
PPPS: Am I getting too far off topic here?

Permalink to Comment

29. Sili on October 29, 2009 5:10 AM writes...

Problem is when someone leaves the blood stains all over the floors and doesn't clean up after themselves - ruins it for the rest of us.

As if I wasn't unproductive enough before the clamp-down.

Permalink to Comment

30. milkshake on October 29, 2009 6:38 AM writes...

Even a totally inconsiderate person like that can do it only once

Permalink to Comment

31. Little Miss Process on October 29, 2009 10:51 AM writes...

Aww, Milkshake, we're not wacky... just a little misunderstood dB-) (Yes that's a smilie in a hardhat and safety specs).

These days the old guys with the experience of the black arts are all retiring, and we're making do with PCA modelling and statistical experiment design instead. It's a bit of a black art in itself, but when presented with variable sets that run to the millions, it's a great way to home in on a set of conditions that works with a minimum of reactions.

And don't be afraid to Step Away From The H-Cube. Yes, it's terribly useful, but you're limited to what they provide in the capsule whatchamajiggies. (AFAIK. I don't use one :-P)


Permalink to Comment

32. Valli on November 6, 2009 12:15 PM writes...

backing up comments #21 and #23. I had the same experience that on small scale (mg scale), no problem of fire. On bigger scale (grams scale), there was fire two times. Even weighing Pd/C directly in a beaker containing MeOH, catches fire. Best way in big scale is to inertise the flask, weigh first Pd/C, then wet it with solvent like EtOAc. Also, i had found whenever the Pd/C is fresh, the chances of fire is more. On prolonged storage, it probably becomes wetter and so no problem of fire.

Permalink to Comment

33. Valli on November 6, 2009 12:27 PM writes...

One more experience i would like to add. Since my starting material (nitro aromatic compound) for Pd/C hydrogenation was soluble in DCM, i used to take mixture of solvents DCM and MeOH for reaction, which worked very well with almost quantitative yield.But,when i did the same reduction of nitro to amino, in solvent mixture of CHCl3 and MeOH, i had very less product and more impurities(4 close TLC sopts besides the product). I had experienced this poor yield/side reactions three times (using different starting materials, but always a nitro aromatic compound). I could not figure out what could be the side reaction. Can any one suggest?

Permalink to Comment

34. Anonymous on December 6, 2011 8:50 AM writes...

I am use 5% platinum carbon in hydrogenation reaction with 5 to10lit water for slurry prepration. but i use methanol for slurry prepration its ok or not. my reation mass is acidic before hydrogenation reaction give suggestion. after reation my reaction mass ph is 6.8 to 7.1 why?

Permalink to Comment


Remember Me?


Email this entry to:

Your email address:

Message (optional):

The Last Post
The GSK Layoffs Continue, By Proxy
The Move is Nigh
Another Alzheimer's IPO
Cutbacks at C&E News
Sanofi Pays to Get Back Into Oncology
An Irresponsible Statement About Curing Cancer
Oliver Sacks on Turning Back to Chemistry