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

TPAP vs. PDC

After this rather interesting paper on the oxidation powers of sodium hydride (That has been slapped around by the blogging community in a big way) it seems appropriate with a post on reagents that actually are capable of performing oxidations.

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We all know pydridinium dichromate (PDC). It's one of these hopeless reagents that still gets taught on undergraduate chemistry courses despite the fact that A LOT has happened since 1979. I guess students should be aware of the existence of these reagents and maybe their use can be justified sometimes (Please let us know if you believe this to be the case). The "marvellous" thing about PDC is that it oxidises primary alcohols to aldehydes. And to be fair, when this was first discovered and described by Corey and Schmidt in 1979 it was probably an important contribution to synthetic organic chemistry (Click on image for enlargement).
The fun part with PDC is making it which is very simple and produces a beautiful bright orange/metallic crystalline substance (See picture).

However, this is where the fun stops. To oxidise a primary alcohol to an aldehyde we must expose it to stoichiometric (!!!) PDC. The reaction mixture is nasty (See picture of black suspension from hell).
Finally when the reaction is finished you have to get rid of a lot of chromium stuff. Filtration through a tightly packed silica plug is the way forward. However, due to the presence of pyridine the chromium junk will start moving and co-eluting even in straight hexane (See picture of horrible filtration).
There is a long, long list of old school reagents (e.g. Swern oxidation) and more modern ones (e.g. TPAP) that will carry this transformation out under much nicer conditions. TPAP (Tetra Propyl Ammonium Perruthanate) is a personal favourite that has worked wonders for me. TPAP is great for a number of reasons. Firstly, it is used in low catalyst loadings with the co-oxidant NMO (N-methylmorpholine N-oxide).

Secondly, the work-up is very simple normally just involving filtration through a plug of Celite followed by column chromatography. Some readers may have noticed that I on several occasions have mentioned some of Steven Ley's wonderful contributions to synthetic organic chemistry. Well TPAP is yet another of his little wonder reagents. The Ley group published a review on TPAP back in 1994 that illustrates its versatility. However, allow me to use one of my own examples where we compared PDC to TPAP. The oxidation of lactols to lactones can be tricky because of the equilibrium between open chain aldehyde and lactone, as illustrated.
However, both PDC and TPAP selectively oxidise to give the desired lactone. In this case PDC even when the rate enhancing additive pyridinium trifluoroacetate was added took 4 to 11 days to go to completion with 2 equivalents of oxidant. In the end high yields of clean material was obtained but as described above the work-up procedure is tedious. TPAP on the other hand provided the desired material overnight (In reality the reaction was probably done within an hour but I was at the pub at this point in time) followed by filtration and chromatography to give excellent yields of lactone. I should mention the major down side to TPAP. It is very expensive! However, due to low catalyst loadings, high yields, fast and simple purification I believe that the expense is easily justified for valuable starting materials. D!

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!