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

The History of Curly Arrows

Christmas is approaching rapidly and I am off from work until 4th January. I will try my very, very best to do nothing work related for the next 2 weeks (Could be tricky. Fingers crossed)
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This years Christmas post is a tribute to Robert Robinson for inventing the curly arrow. It really is fascinating to think how recently we have have come to think about molecules the way we do now. The whole idea of bonds between atoms and sharing of electrons to make up covalent bonds really isn't as old as one would think. So hats off to Robinson who published some fantastic papers back in the 1920s where he introduced the concept. Back in the 20s Robinson was the first to draw stuff that we would recognise as curly arrows today using curly arrows to explain (and successfully predict) the outcome of reactions. Ingold was another champion in this area of chemistry who embraced the ideas put forth by Robinson (but apparently forgot to credit him for it!) and expanded it to include resonance effects and introduced stuff such as SN1, SN2, E1, E2 etc.
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Merry Christmas and Happy New Year to all the Curly Arrow readers and to Robinson and Ingold for being on top of things. See you all again in 2010. D!

The Colour of Chemistry Part II

Yesterday one of the PhD students was having a bit of fun iodinating with Iodine monochloride. D!

The Colour of Organic Chemistry

As a synthetic organic chemist what I would like at the end of the day are some white or colourless crystals. However, off-white, tan or yellow amorphous solid is more or less what you expect to end up with. But when I get bright pink, purple and green stuff I really don't know what to make of it. D!

Butt-in-diol?

Old school 1,4-butynediol. A wondeful and cheap building block. D!

Curly Arrow - Established 18th October 2006

Three years later. I'm surprised that I still manage to keep Curly Arrow alive. The reason that things are still happening is you guys that read my stuff and send me some very positive and enthusiastic emails. I'm getting a lot of hits from Google and the blog appears to have a tremendous impact. For example if you do a Google search on Click Chemistry you'll see the Wikipedia entry as the top hit followed by Curly Arrow. Curly Arrow has a higher rating than the original literature on Click Chemistry! So I guess I'll just keep at it and see what happens. I have listed the stats for the past year below. Numbers are up but the top 10 visitors (that I can identify) haven't changed much. The major difference is that the only company (GSK) is out and that Japan has made an entry. I can see a whole bunch of european networks that I get a ton of hits from and I suspect that certain German Universities should be on the list. As a consequence this year I have also included top 10 contries that visit the blog. D!
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From 18th October 2008 to 18th October 2009
Absolute unique visitors: 28,799 (previous year 21,250)
Total visits: 50,230 (138 Visits/Day) [previous year 37,513 (103 Visits/Day)]
Average time on site: 1:45 minute (previous year 1:28 minute)
The 10 most frequent visitors identifiable:
(1) Princeton University (last year: Princeton University)
(2) Scripps Research Institute (last year: Scripps Research Institute)
(3) Oxford University (last year: Oxford University)
(4) Ohio State University (last year: University of Cambridge)
(5) Kyoto University (last year: Flinders University)
(6) State University of New York at Buffalo (last year: State University of New York at Buffalo)
(7) Massachusetts Institute of Technology (last year: Carleton University)
(8) University of Cambridge (last year: GlaxoSmithKline)
(9) University of Melbourne (last year: University of California Santa Barbara)

(10) University of California Irvine (last year: University of California Irvine)
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Top 10 countries that visit the blog:
(1) United States (18,651 visits)
(2) United Kingdom (5,076 visits)
(3) Germany (3,109 visits)
(4) Canada (2,648 visits)
(5) Australia (2,588 visits)
(6) Denmark (2,414 visits)
(7) India (1,856 visits)
(8) Japan (1,081 visits)
(9) Sweden (932 visits)
(10) New Zealand (926 visits)

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!

Stereogenofobia and Electra's Art

I have previosuly been moaning about the fear of stereogenic centers that industry seems to suffer from here. So it was with great pleasure that I read Derek Lowe's latest contribution to Chemistry World were he appears to share some of my views.

Derek Lowe is a medicinal chemist running the hugely succesfull blog In the Pipeline. If you don't already frequent this blog you should get started. He shares interesting stuff about all aspects from synthetic organic chemistry, science and society, what's going on in industry etc.
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On a completely different note, I have added a new link to the Coffee Break section (Bottom right of the page) called Electra Lady Land. A friend of mine is an artist and I am a great fan of her work so I have decided to promovate her stuff here. Go have a look at her paintings. D!

Making the cut

I keep thinking that I'm all done paper pushing and then somehow magically I'm back at it full force. So recently I've submitted four grant proposals, written a chapter for a book, started teaching again and in parallel I'm doing a half hearted attempt at some lab work. So the last thing I needed to see was this paper Don't read that paper if you are a suicidal post doc.
I guess it's the life I've picked but it sure is tempting to bail out and get a "real job" as my mum calls it. Anyway, posting is about to resume with some exciting stuff on how to turn a primary amine into a leaving group. Sigh, D