Wednesday, March 31, 2010

Catalytic Hydrogenation Part III - More Tips and Tricks

I do apologies for the very infrequent posting. I seem to have developed a life with other areas of interest than chemistry. However, due to the many old posts that people find useful the blog gets around 150 unique visitors every day (Including Nobel Laureates!!! Can you guess who?) so I'll keep Curly Arrow running at a gentle simmer.
Returning to catalytic hydrogenation, as promised:
Mechanistic considerations: What is the mechanism for catalytic hydrogenation. I am really not up to date on what people have figured out but about 15 years ago no one was really sure. There is good evidence that the reaction proceeds by a stepwise radical mechanism. So if you are reducing a double bond you add a H-dot and end up with an adjacent radical. This can be helpful since the dot could be ending up at a carbon where it is "stabilised". As a result you may have rotation around bonds before the next H-dot makes an appearance. Also you could end up with selectivity issues that are worth considering. For example, when I try to peel a benzyl group of an alcohol will it come off as toluene (good) or benzyl alcohol (bad)?
I recently, suppressed an unwanted side reaction by selecting hydrogenation condition that would suppress formation of an unwanted radical and promote the debenzylation of an alcohol that I was interested in so these things are (of course) worth thinking about.
How do I work a catalytic hydrogenation up?
Activated charcoal sticks to all surfaces. Your stir bar is a mess, the flask is a mess etc. To minimise the problem tip some Celite into the reaction and leave it to stir. This rather effectively mops up almost all the catalyst. Meanwhile pack a sintered funnel with a firm pad of Celite. Put a filter paper on top and suck some solvent through to check that it is packed properly. You do not want catalyst in your sinter! It will go black and nasty and stay that way. Pour the reaction mixture on top of the celite pad and suck the solvent through the Celite. Wash a couple of times with a polar solvent (and ideally hot). Compounds tend to stick to the catalyst so this is an attempt at getting it all off.
Concentrate your solvent in vacuo and check how much you have before binning the catalyst. I have done fairly large scale reductions and ended up with nothing after filtering because my product wouldn't let go of the catalyst. In one case I had to reflux the catalyst in DMF and filter the boiling solution to get my compound.
Finally, when you do have your product don't just throw the catalyst waste in the bin. The stuff tends to get really hot and catch fire. In the perfect lab you have a plastic bin only for your used hydrogenation catalyst where you keep all the waste nicely soaked in water to prevent it going off.
A note on Celite. As some of you may have noticed Celite comes in many, many different varieties. Catalytic hydrogenation is potentially an extremely clean process. I have used this as the very last step in the synthesis of unnatural amino acids and after filtration the product really is completely pure as it is. This is handy since it is incredibly polar at this stage and I really don't enjoy preparative RP HPLC. However, be careful with Celite. Make sure you get some good quality stuff that doesn't partly dissolve in organic solvents. I used some stuff in Australia that was slightly soluble in methanol. Moreover, I recently discovered that Aldrich Celite 545 is weakly basic and will dissolve in acetic acid giving you a ridiculous crude yield after filtering and concentrating. A student of mine even managed to isolate a metal salt of her carboxylic acid product because she concentrated it on Celite 545 prior to running a column. So check the specs for your Celite before you tip it into your valuable product.
Catalysts - what is available and what should I use? Books have been written about this so I regret promising to comment on the topic. However, it is worth remembering that a huge variety of catalysts are available that may save the day. Poisoned catalyst are worthy of mention. For example, you can get sulfided Pd-black. This stuff is sometimes useful when working with sulfur containing compounds that poison the regular of the shelf catalysts. Also there is classic stuff such as Lindlar's catalyst. Lindlar's catalyst is Pd poisoned with lead, for example, allowing the reduction of alkynes to cis-alkenes.
Deuterium! Finally, I should remind you that you can get deuterium (and tritium) gas. Deuterium of high purity is reasonably affordable giving you a simple way to isotope label compounds often using exactly the same reaction conditions as employed for hydrogenation. However, where possible I would recommend using aprotic solvents. We have observed some hydrogen-scrambling when performing deuteration in methanol and ethanol. D!


Asia said...

"I seem to have developed a life with other areas of interest than chemistry" - this was pretty awesome :)
Your posts are so useful and funny (just opposite to everything I learnt during my studies), please don't stop updating your blog!

Unknown said...

Celite 545 will dissolve in acetic acid! then what should you do if your reaction is in acetic acid? Well at least this explains my ridiculous crude yield currently! Keep up the good work with the blog, very informative!

milkshake said...

I think the mysterious nobelist that is visiting you is Obama, because your site has successfully avoided having too mcuh recent activity and therefore it became a very peaceful place to visit.

(By the way, if you write your personal web content never ever apologize to your readers for lack of recent postings. They are bunch of freeloaders and therefore not entitled to get frequent updates)

Getting stuff that is stuck on charcoal off the catalyst: Charcoal acts like reverse phase with preference for polyaromatic big and greasy things. You deactiate the grease-binding properties best by using nonpolar solvent like toluene. Since many medchem-useful things do not dissolve as great in toluene, washing your catalyst in the end with ethyl acetate or dichloroethane may the best option.

Celite workup: I don't like it, the fine particulates can pass through the frit just as easily as the catalyst but are hard to see in the filtrate and in the frit. Instead, I would reserve few medium-fine porosity filtration funnels for the catalyst work and live with the fact that they are black, and I use them only for filtering the hydrog catalyst.

Occasionally when some Pd or Pt colloid still makes it through, i would evaporate the filtrate to dryness and re-dissolve it a solvent with opposing polarity (non-polar after polar, or vice versa, sometimes with gentle heating on heatgun) and filter it again. The colloids tend to coagulate when you change the solvent polarity.

getting rid of old catalyst: its best to make it wet with water and then dump the slurry onto old spent silica in a bucket, 9spent silica waste which has the solvents already dried out). Small amount of spent catalyst can be even flushed down the sink, Pd and Pt in elementary form is nontoxic. recycling your spent catalyst is only worth for large-scale processes.

Daniel Sejer said...

@Milkshake, as my old boss used to say if you deliver clean compounds on tme I don't care how you make them. As I have indicated I'm a Celte fan. However, you are correct about the fine particles that may pass through. This is exactly why selecting a good Celte is important. I think I forgot to mention that I always pre-wash the Celite with an approprate organic solvent after packing to check that it is properly packed and to ensure that any fne particles are elemnated prior to the important stuff gong through. I orginally started using Celite because I found that the Charcoal would pass though the standard pore 3 sinters.
Also regarding charcoal what you write is correct but things appear to be more complex than that in my experience. I have occasionally had problems with very polar non-aromatic compounds not wantng to let go of the charcoal. In one case I had a thioether in my molecule that may account for the stickness but I have also observed it in situations were it makes less sense. D!

Anonymous said...

Actually, the mechanisms by which deuterium (and tritium) are diluted by hydrogen in a catalytic reduction are not bypassed by merely using a nonprotic solvent. Often a protic solvent will minimize exchange. If you stir ethyl acetate over a catalyst with an atmosphere of isotopic hydrogen, the ethyl acetate will be labeled. This dilutes the isotopic hydrogen with 1H. The maximum incorporation of isotopic hydrogen usually happens when you choose the solvent in which the reaction you are trying to accomplish happens as rapidly as possible.

Unknown said...

Silly question, how much catalyst typically used for debenzylation? (mol equivalent to substrate)...thanks!

milkshake said...

I would use 0.5g-1g of 10% Pd-C (or a Pearlmann cat) for 5 g of starting material.

If the hydrogenation does not proceed fast enough, rather than adding more catalyst it is better to increase the temperature, for example to continue under H2 baloon ontop of a reflux condenser. You can do fast benzylamine debenzylations in diluted aqueous HCl as a solvent at 80-100C under H2 baloon, and the advantage is that water is nonflammable.

When hydrogenation does not proceed the best thing is to filter the catalyst off, add a fresh catalyst, and do the hydrogenation under acidic conditions, with an equivalent of some strong acid added, or in AcOH. Or you can add some TMS-Cl, it produces an equivalent of HCl in situ. (Some people even add dichloromethane, also to generate HCl). Turns out amines are very fond of shuting down Pd for debenzylation (Pd with an amine then becomes more selective towards C=C saturation)_ and acidifying the mix takes care of the amine impurities. Also you need to be sure there are no thiols (I knew a guy who wasted two months on trying to make Fukuyama reduction to work before he found out that somethink like 0.5% of thiophenol in his thiophenyl ester substrate has been ruining his catalyst.)

Daniel said...

Thank you Milkshake, most appreciated!

Anonymous said...

One way to filter off your catalyst without using celite is through a PTFE membrane filter (like from Millipore 0.2um) over a glass frit sealed with clamp. The setup is sold through VWR (26316-690) and you just attach it over a vacuum adapter and filter directly into a round bottom. You're left with a neat little round pile of catalyst on the membrane and there's less metal waste to throw out.

Anonymous said...

another good way to work up a catalytic hydrogenation is via centrifugation. pour the reaction mixture into a falcon and centrifuge at 2000 rpm. The resulting supernatant can be filtered throgh a PTFE more smoothly.