Coffee Break

I'm having coffee and missed having some some Curly Arrow links to fun stuff. So a list of links has been added (bottom right on the front page). Chemical Stick Figures and xkcd are personal favourites. Also Org Prep Daily has started posting again and so has been upgraded from a chemistry resource to a blog.
Have a nice weekend, 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!

A Cyclopropane Amino Acid Bites the Dust

"Ceterum autem censeo,

Carthaginem esse delendam"

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In recent years I have been getting somewhat annoyed with this fear of chirality that is quite widespread in industry and to some extent in academia. Stereogenic centers tend to make synthesis, purification and characterisation more complicated so I can see why it is convenient to avoid it all together and just Sonogashira yourself to death? The compounds that come out of all this tend to be very flat and aromatic and yet industry is puzzled why they aren't getting more new drugs to market. I strongly suspect that there is a very finite number of potential drugs in the flat aromatic category and that we may be getting to the end of the line.

Nature is asymmetric and three-dimensional (nucleosides, amino acids, carbohydrates...etc.) so why are we not devoting more energy to chiral molecules in drug discovery? By now there are many robust and general asymmetric processes and there is the chiral pool (more like a chiral ocean really) so getting into some exciting chiral medchem isn't really that difficult.

Anyway, the reason for this tantrum is the sad news that  Eli Lilly's very cool cyclopropane glutamate analogue LY2140023 has failed phase II trials. This class of compounds has been under way for a long time against a very difficult target and the culmination at Lilly is a densely functionalised beast with 4 contiguous stereocenters. Well CNS is a horrible area to do drug discovery. First time around the drug did really well but this time around placebo was more effective than LY2140023! Hence, Lilly is giving it another shot in clinical trials. Hopefully they will get this sucker back on track. I'd love to see something like this make it all the way. D!

How to make dry HCl gas

Dry HCl gas is essential for certain reaction types and can come in handy for making various saturated HCl solutions. The easy solution to this problem is to have an HCl cylinder handy. However, I’m sure that some of you have experienced (or have heard of) the horrors of the corroded gas regulator on an HCl cylinder. Regulators on HCl cylinders have a very bad habit off snapping off! One of my good friends had a very close call with a big HCl cylinder. Luckily he was standing right next to the door so the only thing that needed to be replaced was that particular lab. If you must have an HCl cylinder standing around I’d recommend a lecture bottle (see photo). These are (in theory) less likely to go off since they have a relatively short life time and if they go off they are likely to kill fewer chemists. Nonetheless, this particular HCl lecture bottle in my current lab has decided to corrode/fuse. A tech-guy has been by three times over the last 6 months trying to get the regulator off. I just wish he would take the damn thing with him and not store it in the hood next to me. A safer, relatively simple, cheap and convenient way to get hold of some dry HCl gas is to make it yourself. The standard approach that I’m guessing most chemists still use is to add conc. sulfuric acid to sodium chloride or conc. HCl. However, avoiding the use of conc. sulfuric is desirable because it’s nasty and you’ll have to clean up afterwards. So in the interest of safety I would recommend the addition of conc. HCl to calcium chlorid. It’s cheap, the HCl gas that you generate is completely dry, it’s relatively easy to clean things up and the reaction is very easy to control. Here’s the original reference:

A Convenient Way to Generate Hydrogen Chloride in the Freshman Lab, Francisco J. Arnáiz, Journal of Chemical Education, 1995, 72 (16), 1139.

On the photo you can see one of my recent set-ups. Here I am adding conc. HCl to calcium chloride with a pressure equalising addition funnel and bubbling the HCl directly into my reaction flask. Please note the use of a Pasteur pipette for bubbling the gas into the reaction flask. Do not get tempted to use a metal needle. Also I often add a wash bottle between the reaction flask and the gas source in case of unexpected suck backs. D!

Evil Molecules Part 1 - Explosive Azides, Diazidomethane

Say hello to diazidomethane. Is it time for a change of underwear yet? I work with azides on a daily basis and I even determine the melting point of my azides. My azides are nice a stable because they all adhere to the 6 heavy atoms (carbon or heavier) per azido-group rule of thumb. However, if you stray from the 6 heavy atom path you are looking for trouble and if you decide to do 1/2 a carbon per azide as we have in this case you will be looking for a new chemistry department.

In this really interesting paper from Alcon Research Ltd. they unintentionally made a fair bit of diazidomethane when performing the synthetic sequence shown in the scheme below. To remove residual dichloromethan after the first step the chemists at Alcon redissolved the crude product in DMF and concentrated it to dryness. To my (and theirs I'm sure) surprise this doesn't remove all dichloromethane despite a huge difference in boiling point. After performing the second step, they worked the reaction up and concentrated it on a rotary evaporator.

 This is what they observed when they came back the next morning:

“... it was noted that about 30 mL of a twophase liquid had collected in the glass crosspiece at the bottom of the condenser assembly.”

When they attempted draining the stuff it decided to go nuts. All I’ll say is that nobody died but you’ll have to dig the paper out yourself if you want the full story.

Remember, halogenated solvents (dichoromethan, chloroform, 1,2-dichloroethane...) and azide ions are bad news. Don’t do it!

Diazidomethane explosion, R. E. Conrow and W. D. Dean, Org. Proc. Res. Dev., 2008, 12 (6), pp. 1285-1286. D!

The Skraup Reaction - How to Make a Quinoline

Recently, Derek Lowe was discussing reactions he hadn't done at his blog In the Pipeline. Among these were, in his own words "the widely disliked Skraup cyclization for quinolines". This was somewhat surprising to me. I have very limited experience with the Skraup reaction but it has worked for me and one of my former colleagues said it had always been a great reaction in his hands. Personally I was surprised how well it worked considering the reaction conditions. This is what I did: 

Easily the most extreme reaction conditions I have employed. Hardly surprising this is a lively reaction. Adding acrolein (boiling point of 53 oC) to a 70% sulfuric acid cocktail at 110 oC is rather exciting. Things are vaporising, spraying, hissing and instantly turns into jet black tarry goo. After 45 minutes the reaction is allowed to cool and then you attempt to work the black polymeric goo up with 25% aq. NaOH, brine and ethyl acetate. I suspect that the modest yield is due to loss of material during this annoying work-up. Scaling the reaction up is likely to improve the yield. The Skarup reaction is indeed performed on ridiculous industrial scale so it can't be all that bad. My system was rather elaborate containing two phenolic ethers and still I managed to pull out 47% and it was reproducible. Unfortunately, I cannot give full structural details as this was done in industry and I seem to recall some papers I signed explaining my life would end if I ever mentioned any of that stuff.

I should mention that it is rather important that you don't use too much acrolein as this will turn the whole thing into a rubbery solid (as I discovered) that is impossible to work with.

Anyway, the conditions I employed here a slightly different from the standard method so it may be worth giving a go if you are into quinolines. The full experimental details can be found here: C. O'Murcho, Synthesis, 1989, 880-882. By the way that's Zdenko Hans Skraup himself on the photo above. D!

Whatman Phase Separators

I hope everyone had a merry Christmas and I wish you all a happy and prosperous New Year. Time for the first post of 2009.
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A former colleague of mine introduced me to the ingenious invention: Phase Separators. This is a big help in the lab and really saves me a lot of time, particularly with qualitative work. A Phase Separator is essentially a piece of filter paper that has been treated with silicone. If you fold it up and stick it in a funnel and pour a mix of organic solvent and water on it it will only let the organic solvent pour through. It only works well with solvents more dense than water, typically dichloromethane or chloroform. They are best employed for qualitative work where all that's required is a quick NMR to determine a ratio between isomers, whether a reaction is finished etc. For this type of work I basically transfer my reaction to a separation funnel with dichloromethane and wash it with appropriate aqueous phases. After the final wash the whole thing is poured directly into a Phase Separator, the organic phase is collected in a round bottom flask and concentrated in vacuo. I never observe any residual water in my NMR spectra so drying the organic solvent is unnecessary. D!

Career plans

Not surprisingly, most of Curly Arrows readers are early career chemists, predominantly PhD students and Post Docs. So although subjects such as publications, H index, impact factors etc. have been beaten to death elsewhere I thought I'd do a brief post on the topic here because it is very important for your career prospects that you start thinking of these things early on. When in the past I have been presented with a pile of job applications the first things I (and others) look at are:
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a) Name of applicant and of recent supervisors (to see if I know any of them)

b) Publication list
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So since 95% of the time I don't know the people the applications fate is determined in the course of 1 minute based on your publication list.

It sounds unreasonable but this is how you quickly eliminate 75% of the applicants. If you make it through the first screen then people actually sit down and read your application in detail, request references etc.

So if you want to get the dream job work hard and publish lots of papers. It doesn't have to be Nature papers the main thing is that your look productive (journals with impact factor >2 are fine for a synthetic organic chemist).

Unfortunately, too many supervisors will give you dead end piece of shite projects that are destined for the bin. Check your prospective boss out. How much does he publish, in what journals, talk to former and current students in the group etc. Also worth considering is whether the group publish papers with alphabetical author lists or not. The alphabetical approach can really screw your career in a fair few countries. When you apply for grants in Denmark they generally look for first and last authorship to determine your project input but also at which journals you published in to estimate the quality/impact of the work.

Having a decent track record and publication list is going to get you through the first screening round. However, to make it to the interview good references and relevant skills will obviously be very important. So think about it and start planning your career early on. D!

NMR Tube Cleaner Part 2

Some time ago I had a post about the amazing NMR tube cleaner. I love this piece of equipment and use it regularly. However, as some readers pointed out some people are remarkably good at breaking these things (repeatedly!). Where I work now we have a workshop and the guys there create the most amazing gear for us including an almost unbreakable NMR tube cleaner. It's made from hard plastic and metal and isn't affected by organic solvents. So if you are fortunate enough to also have access to a workshop you may consider ordering one of these beauties. D!

What is a liquid?

I recently had dinner with some chemists and after a bit of red wine the question "What is a liquid?" popped up. The reason the question popped up is the gas sulfur hexaflouride. I had never heard of this stuff before but allegedly you can float solid objects on top of it. Intuitively, I would say that if a ship can sail in it it's a liquid but things clearly aren't that simple. There's quite a few videos with this stuff on the web. In this particular video they float an object on some SF6 in a fish tank (I'm assuming the video is not a hoax). So what is the definition of a gas/liquid? Obviously it' a density thing. Did anyone out there pay attention when they had physical chemistry and would they care to explain it to a simple preparative chemist? Also what is the least dense liquid out there? Besides pentane (0.626 g/cm3) I can't come up with much that has a density below 0.7. D!