Monday, January 25, 2010

Catalytic Hydrogenation Part II - Tips and Tricks

Well since I appear to be suffering from insomnia I may as well blog a bit. It's about time anyway.
All synthetic organic chemists will eventually be facing a catalytic hydrogenation. Catalytic hydrogenations are great because they are easy to perform, generally work well and it allows you to do a fair bit of rather useful chemistry. But remember not to set them on fire.
I have helped many chemists trouble shoot their hydrogenations so a post on the subject seems appropriate. I am by all means not an expert on this stuff but here are some things you may find useful.
Which and how much catalyst should I use, what solvent is good?
For your basic reduction, e.g. debenzylation or reducing an olefin Pd on activated charcoal should be your first stop. Polar solvents such as methanol and ethanol are good. Even water is fine if your compound dissolves. But in reality anything that doesn't kill off your catalyst will work. I can recall using MeOH, EtOH, EtOAc, acetone, THF, DMF, AcOH. Sometimes I've even used mixtures for solubility reasons. I generally aim for a 10% (w/w) catalyst loading to start with.
Remember to have a large solvent surface area in your flask and stir it vigorously to allow the H2-atmosphere to get in there.
What do I do when the standard condition don't work?
This is the tricky bit. There can be many reasons why it isn't going.
  • Your catalyst could be old and inactive. Try a fresh pot.
  • If your are trying to remove a protection group such as benzyl or Cbz from an alcohol or an amine try using acetic acid as the solvent. Protonating the heteroatom facilitates the reaction.
  • Try using Pearlmann's catalyst Pd(OH)2 on activated charcoal which in my experience is a more active catalyst.
  • Try heating the reaction.
  • Try combinations of the above. E.g. heat the sucker using Pearlmann's catalyst in acetic acid.
  • Your product or an impurity in your product may be poisoning the catalyst. This could mean that it just isn't going to work unless you remove the impurities that are giving you trouble or alternatively use a hydrogenator that allows high pressure and temperature. The classic piece of kit for this is the Parr shaker (see picture above) which looks like a steam train and makes the entire floor vibrate. Alternatively a more modern alternative such as a Parr series 5500 model could be used.
However, sometimes regardless of what you do the stuff just cannot be reduced. I personally tried this once and believe me I tried a lot of conditions. I could just about break any bond in my molecule except the one I wanted to get rid off. In the end I had to start over introducing a different protection group. The problem in this case was probably the positioning of a sulfur atom right next to the benzyl group I was trying to remove. In the final paper weeks of debenzylation attempts were summed up in one sentence, depressing. Some of the stuff I tried can be seen in the scheme. Four slightly different starting materials were tested. The most exciting result was decomposition.
In the next post we'll have a look at how to work the reaction up and have a quick glance at different catalyst systems and touch upon the mechanism. D


OrganicOverdose said...

Nice mate, good to see you're back at it. I personally haven't done any hydrogenation mostly because it would kill my compound but from what I have seen it seems much more scary (H2 + Pd in sealed vessel) than it really is.

Labchimp said...

I think you will run into some serious troubles trying to hydrogenate something with a sulfide in the molecule, which will potentially poison the Pd.

I don't suppose you have tried Na or Li in liquid NH3(l)? You only need a few minutes to remove a benzyl ether. Also hydrogenations in methanol with ammonia should circumvent the problems associated with poisoning by sulfur, if this is the case here.

milkshake said...

A student in Prague once synthesized some sort of L-aminosugar fairly laboriously, and at the end of the synthesis he hydrogenated the whole batch - to bring about the final debenzylation (which was supposed to be the least problematic step of the scheme). But the debenzylation was very slow and he was adding more and more catalyst, and was heating it, and still no luck so eventually he had a brilliant idea of using a more active catalyst. He used Adams catalyst on heating bath without bothering to learn the differences between Pd and Pt. He ended up with tris(cyclohexylmethyl)-substituted product, nice and clean - and perfectly useless.

Anonymous said...

I love using hydrogenation. I have used it several times and have had great success. The reaction always seems so clean and neat compared to what I normally do in the lab!

Med Chem said...

thanks for the nice information.
For deprotection of Cbz/benzoyl use of EtOAc as solvent and hydrogen balloon works fine.

krest17 said...

Cool, waiting for 2nd part

Anonymous said...

A little-known catalyst for hydrogenation that cannot be poisoned by sulfur is ReS2. I know of only one ref. (Cotton & Wilkinson, Adv. Inorg. Chem., , 5th Ed., NY: J. Wiley & Sons, 1988., p. 852.). You can start with ReO3 or ReO2 or probably Re2O7, HReO4 or NH4ReO4 (arguably the most economical Re source). Re(IV,V,IV,VII) should all reduce to Re metal in H2/solvent. Any sulfur picked up along the way should be no problem. Persevere!

Daniel Sejer said...

@anonymous, Does the Re-catalyst work at ambient temperature and atmospheric pressure and are there any special solvent considerations? D!

Anonymous said...

Nice discussion about hydrogenation. How to get rid of dissolved celite if it comes with polar compound during hydrogenation.

Anonymous said...

Your blog has provided some very helpful tips! You mention types of solvents, but what concentration should they be relative to your reactant--I've heard 1g sample/mL solvent, but is there any problem with going more dilute? or more concentrated? -Heather

Eric said...

Does anyone know of a homogeneous hydrogenation catalyst for O-debenzylation. I am trying to remove benzyl ethers from a polymer. I'm also looking at using eggshell type Pd/C to increase the available surface sites.

Unknown said...

In the case of Sulfur containing sugars, catalytic hydrogenation for debenzylation does not work due to catalyst poisoning. The possible method can be used is Birch reduction but problem arises with purification. Treatment with H+ resin somehow not able to remove the impurities (Na, NaOH).