Catalytic Hydrogenation - A Farewell to Alcohol(s)

We have a project in my group on bitopic ligands targeting the adrenergic receptors. We recently published a perspective paper on the topic that you can check out here. Anyway, today we had a project meeting regarding the synthesis of bitopic salbutamol analogues.

To this end, one of the guys wanted to synthesise an epoxide as outlined above. However, to his (and everyone else surprise) even under mild conditions he managed to loose both of his benzylic alcohols in the process. The crude product is of excellent purity and he isolated the over-reduced phenol in >90% yield.

This is a common problem but it really is trial and error. I would say that the case above is the most extreme example I have seen considering that it was run at atmospheric pressure and room temperature. It brought memories back from when I was a PhD student. The very last reaction I did in the lab was an attempt to reduce an alkene, however, as you can probably guess what I got out as the major product was the deoxygentaed molecule. However, this reaction was somewhat more messy than that above and the desired molecule may have been hiding in the mixture as well. D!

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.

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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.
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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.
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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.
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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.
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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!

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.
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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.
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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

How to Turn an Amine Into a Leaving Group

Leaving group activation of alcohols followed by nucleophilic substitution is routine stuff for the synthetic organic chemist. Just make the tosylate, nosylate, mesylate, triflate.... and things generally go according to plan. However, what if you are stuck with an amine and want to substitute it with a nucleophile. There are a number of ways to do this but it's not just a walk in the park. Until recently I had never had to do this but then one fine morning I wanted to do the reaction above. How does one go about doing this? Is there a simple method by which I could activate the amine and displace it with the anion of 2-nitropropane, followed by a simple reduction to get the amine I wanted? Well, as it turns out Katritzky and co-workers published a paper in 1979 introducing triphenylpyrylium salts that can convert amines to leaving groups. Granted, the atom economy in this process is (to say the least) poor. However, the required pyrylium salt is commertcially available at a resonable price. All you do is stir it up with the amine. Prior to adding the amine the suspension is pale yellow and then when you toss the amine in it becomes a deep red slurry. In the photo the amine has just been added. It's always exciting with a bit of colour if your an organic chemist. The product is isolated by filtration. In this case the pyridinium salt was isolated as a light brown solid in 63% yield, perfectly clean by NMR. Next the pyridinium salt was treated with deprotonated 2-nitropropane in hot DMSO to give the nitro compound that was reduced using old school conditions. Interestingly, we could not get any reduction AT ALL of the nitro compound by catalytic hydrogentaion (at atmospheric pressure). Very odd! I would have expected to see at least a few percent of the reduced stuff. Any ideas out there? Anyway, the amine was isolated in good yield over two steps after a short (2 cm tall) DCVC column. Yes a wastefull method but it is simple and fast. D!

Lithium Aluminium Hydride Reductions - Rochelle's Salt

Haha I'm still (barely) alive. Thanks for sticking around. Been busier than usual sorting my private and professional life out. Wrote a ton of grant proposals, published some papers (here, here, here and here), writing a book chapter, trying to be productive in the lab (fat chance) as well as having a life after work and some time off. So Curly Arrow got down prioritised for a while. Hopefully that is changing now.

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Last week I did a lithium aluminium hydride reduction on large scale (see picture). This reminded me of the first time I had to work a reaction of this type up. My first experience (sometime last century) was a DIBAL reduction and if you haven't tried this stuff yet I can tell you that all these aluminium hydride reagents end up forming massive aluminium emulsions that are impossible to work with. The first time round I ended up making an utter mess and getting a very low yield. Realising that I couldn't possibly be the first chemist to encounter this problem I looked into things. The trick is obviously to break the emulsion up. There is a number of ways to do this. My favourite method is to use a saturated aqueous solution of Rochelle's salt (sodium potassium tartrate). Rochelle's salt is an excellent ligand for aluminium and breaks the aluminium emulsion. The procedure is simple. Cool your finished reduction down to 0 degrees C, or lower depending on the situation (For my large scale reduction I cooled it with acetone/dry ice) and quench excess reducing agent with something non-protic. For example ethyl acetate or acetone works well. Just remember to use something you can easily evaporate off when things are done. Don't be impatient and add it dropwise with vigorous stirring. Use a addition funnel for larger scale reactions. When the quench is complete remove the cooling bath.

I find it convenient to have a saturated aqueous solution of Rochelle's salt standing around. Please note that Rochelle's salt has a ridiculously high solubility in water so when preparing the aqueous solution go easy on the water and pick a small flask. When my reaction is quenched and everything looks like jelly I add some Rochelle's salt solution. Often I'll add it as a half saturated (or even more dilute) solution (a larger aqueous layer sometimes makes separation of the phases at the end easier). After pouring Rochelle's into your flask get the mixture stirring vigorously, have a cup of coffee and check your email. The better stirring and the more Rochelle's you use the faster it'll break up the emulsion. Ultimately you end up with two nice and clear phases that are simple to separate in a separatory funnel. D!