PhD in Medicinal Chemistry

Design and synthesis of the first selective ligands for the GPRC6A receptor – a novel human G-protein coupled receptor with unknown physiological function

More info at this web site.

DO NOT email us but please follow the application procedure at the bottom of this web page.

There are links to all necessary information on the same web page.

D!

Green

This is what 40 g of the depicted indole looks like after one recrystallisation. It really shouldn't be green but it is very pretty and even better it's analytically pure. D!
Okay, okay people. Is the photo more to your satisfaction? D!

100th Anniversary

Wow, I just realised that I've passed the 100 posts mark a while back.

-
The Coffee Break section has been updated with a new comic website called The Perry Bible Fellowship. Fantastic stuff that you really should check out. Also there's been a fair bit of activity at Electra Lady Land so that's worth a visit if your into the arty stuff. D!

Anhydrous Solvents Part 3: Acetone and Molecular Sieves - Bad idea!

I have discussed anhydrous solvents a couple of times and have been advertising the use of molecular sieves (MS) quite strongly. During my MS crusade I have pointed out that MS are no good for drying THF but that pretty much all other standard solvents work well with sieves. As it turns out this is incorrect and I have received a terrible punishment from the MS God. It's all rather embarrassing as a PhD student in the lab was fully aware of the particular problem I'm getting to shortly. The deal with MS is that they are weakly basic. I take advantage of this by always adding some MS to my CDCl3 which keeps it dry and mops up any HCl formed by the slow decomposition of CDCl3. The other day I was running some of 1H NMR and to my great pleasure I had finally (after months of struggling) made a very important target molecule. I had split the fractions from a column up in three batches to be on the safe side. All three 1H NMR spectra were great so I decided to combine them in one flask. I was running NMR in acetone-d6 and decided to use some acetone for the transfer. I couldn't find the HPLC acetone we normally have standing around and was getting a bit frustrated when I remembered that about a year ago I had made a bottle of acetone over MS (This is were all the alarm bells go of with the experienced chemist). I managed to find the bottle and proceeded to transfer all my stuff into a new flask. However to my utter surprise I was unable to remove the solvent on the rotary evaporator. On the high vacuum pump with a fair bit of heating most of it came off but by TLC there was a new UV acitve (and quite polar) compound. I had to re-column my product but it still wasn't pure! Currently I am attempting to crystallise it from the impurities. A fair bit of yelling and acussing people of sabotage took place. Fortunately it was late and there was only one other person in the lab.

Before I proceeded to clean up my compound I decided to figure out what the source of the problem was and I quickly discovered that the acetone smelt funny. Initially, I thought it was contaminated with benzaldehyde but when more dilute it had a floral/perfume scent that reminded me of ketones/esters. At some point the PhD student in the lab realised that I had been adding MS to acetone and mentioned that as far as he knew that was a no go because it goes Aldol in the presence of the weakly basic MS. I cannot believe that this hadn't occurred to me. As it turns out it is well known that ketones go Aldol when exposed to MS and many different compounds are formed. A selection of possible products from acetone are shown in the Scheme above. The polar compound I removed by chromatography is the acetone trimer with one hydroxy group.
In my defence I'll say that acetone can be dried with MS provided you use the acetone within a few days. I successfully used the anhydrous acetone during a week of experiments back in July 2009. The take home message is to bin it after a week and not use it a year later as I did. In fact just don't add MS to acetone but instead dry it with MgSO4 as described here. D!

Hard Science

There's some seriously hard science in the latest issue of ChemComm. 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.

---
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!

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

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)
---
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.
---
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!