B.R.S.M. When all you have is a hammer everything looks like a nail


I’ll see your Diels-Alder and raise you one 1,3-dipolar cycloaddition

On Monday, See Arr Oh over at Just Like Cooking posted on this non-obvious Diels-Alder reaction recently published by the Vanderwal group, suggesting that it'd make good problem session fodder. And I agree:

Fortunately, this tied in perfectly with my plans to run our group problem session next week on a pericyclic theme and so it was duly incorporated. If you're interested in what else featured, I also included a question on the origin of the metastability of Dewar Benzene (which I've blogged about before).

After a few easier questions I finished up by asking people to suggest a mechanism for this interesting sequence published a few years back.

Have a think and then read on for a possible answer!

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Woodward Wednesday 5: t-Butyllithium?!

Although it's been a while I do intend to do at least one full size Woodward Wednesday post this month. In the mean time here's a short (but important) synthesis that you may not know about.[1]

Who do you think was the first person to publish the preparation of tert-Butyllithium? Some big shot organometallic or inorganic chemist? Not so much. As far as I can tell it was none other than legendary organic chemist R. B. Woodward (J. Am. Chem. Soc., 1941, 63, 3229)![2] Many before tried and failed, and indeed Woodward noted that the the reaction between lithium and tert-butyl chloride was quite slow, although he discovered that it was efficiently catalysed by a few mole percent of magnesium. Eventually, the reaction could be performed using just lithium, providing it was finely enough divided. This so-called 'lithium sand' was prepared using a classic piece of kit invented by a fellow Harvard chemist: the Hershberg Wire Stirrer. This allowed molten lithium (in mineral oil at 250 degrees) to be whipped up into fine pieces. The mixture could then be cooled, the oil washed off and the lithium quickly used before it had a chance to react with the nitrogen atmosphere used to exclude air. You might ask why Woodward spent time fiddling around with such a dangerous reagent that appeared to defy all attempts to force it into existence. As best as I can tell, the answer was sheer curiosity; not so much regarding the substance itself, but to see if it could be used to prepare the elusive tri-tert-butyl carbinol. Alas, the only reaction observed with hexamethylacetone was reduction. Still, despite recent bad press, tert-BuLi remains a very useful reagent, and has helped me out of a tight synthetic spot on a few occasions.


1. I'll probably do reserpine next, but I'm not too sure what to do after that. Please leave suggestions in the comments!

2. Although, by Woodward's own admission, a couple of papers by the father of organometallic chemistry Henry Gilman from the previous year do imply that tert-BuLi was successfully prepared and used.

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An Uncommon Lab Reference

Last Monday I set my MSci student the task of preparing the above compound and sent him off to do some literature searching. He quickly found a mention of it in a J. Med. Chem. paper, although the authors didn't give any detail themselves on its preparation, instead claiming to have used the method of Shulgin and Shulgin, described in reference 17:

That's right: a reference to PIHKHAL in the primary chemical literature! When I got over my initial surprise I did track down a copy (the university library didn't have it) to look up the procedure. Indeed, a very detailed and reasonable sounding synthesis of the compound is described under the chapter on the synthesis of 2C-T-2 (along with an evocative description of just how high you can get on it).[1]

There's lots of detail and the whole thing is done on sufficient scale to produce 10 grams of the desired compound. Perhaps not too surprisingly, the route starts with chlorosulfonation of 1,4-dimethoxybenzene, followed up with reduction (Zn in HCl) to give the thiophenol which is then ethylated. Easy. We're going to try it this week, and I will enjoy seeing PIHKAL referenced in a lab notebook. It's funny, I've been aware of this book for probably ten years or more - heck, I even gave a talk last year entitled 'Quinones I Have Known And Loved' - but I never thought I'd be reading it at work. Steven Weinreb once  said of Russell Marker: "There are more stories told about [him] than any other chemist. Although perhaps many of these stories are apocryphal, they are so fascinating that more of us cannot bear to stop repeating them... they are the campfire stories that bind our profession together",[2] but I think that the same could also easily be said of Shulgin. I mean, along with Humphry Osmond the man actually coined the term 'psychedelic'.[3] I learned today that there's even a Shulgin Index, written in the style of the more common Merck index, describing the physical and pharmacological properties of some of the psychedelics he and others prepared over the years. I hope to one day have the chance to read a copy.



1. More in this vein can be enjoyed in the digitised versions of Shulgin's lab notebooks. Although his handwriting, combined with the quality lost from storage and scanning, can make them quite hard to read in places they seem to be quite interesting and frequently amusing and insightful. Although the first entry in the first book describes his experiences of taking 400 mgs of mescaline sulfate and the results (which, including hallucinations experienced with eyes open and shut were 'very pleasant'), there's also some real explorative medicinal chemistry documented there. They're actually much better kept than the lab books of many PhD chemists I have worked with, and it's easy to forget that this work was largely conducted in a shed in California. If it wasn't, you know, for all the drug taking.

2. Chem. Eng. News, 1999, 77, 78; If you don't have access to that the article was also reprinted verbatim in The Journal of The Mexican Society the same year and can be enjoyed for free here.

3. It's interesting to note that this term come from the Greek for 'mind manifesting', which I think speaks of the pair's optimism for the curative power of such compounds. Hopefully I'll do another post on chemical etymology one day.





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Quality, not Quantity

Here’s another poser for you: what do the two molecules below have in common? Hint: in contrast to last week’s mechanistic question, this is more to do with their history.


The answer is... a few things. Firstly, they were both proposed incorrectly as structures for two very well known chemicals. On the left is the originally assigned structure for Meldrum’s acid, a useful reagent for acylations, generation of ketenes and Knoevenagel reactions. On the right is Dewar benzene, one of a number of different structures considered by James Dewar (of Dewar flask fame) for benzene.[1] When I look at these compounds, I’m shocked by the speed with which chemistry has moved forwards over the past hundred years. For example, although Kekulé proposed the correct structure of benzene sometime in the 1860’s it wasn’t actually confirmed until 1929 when Catherine Lonsdale, first female Fellow of the Royal Society, solved its structure using X-ray diffraction. That’s right: the structure of benzene wasn’t confirmed until four years after Sir Robert Robinson proposed the correct structure of morphine. And it only took another 30 years for the entire 64 kDa structure of haemoglobin to be solved! In fact, the size and complexity of molecules readily analysed with the kind of equipment found in any university chemistry department has leapt forward since 50 years ago. But we digress.

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A Funny Thing Happened on The Way To Hexaradialene

The last two weeks have seen me secure a postdoc in the US, pass my PhD viva and catch a nasty cold, leaving little time in my life for writing. Now that I've finally got a few spare hours I'm completely out of ideas for a post, so I'm just going to write about some nice oldschool mechanistic detective work from the 1970's that I came across recently. Enjoy!


Here's a tricky little problem that was set at the start of a postgraduate research symposium I attended back in July. It was printed on the programmes given out at the door with a deadline at the end of the two day conference and a cash prize up for grabs. So, all that was required for the glory and spoils was a mechanism that rationalised the following experimental outcome:

Once you've drawn a few things down, you'll quickly realise that the difficulty lies not in drawing a mechanism for formation of the product, but in getting those pesky labels in the right place.  Give it a go, and then read on for more information and the solution!

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And Another Thing…

While the recently misassigned structure of a certain binaphthyl compound has raised eyebrows here, and over at In The Pipeline, eliciting an entirely appropriate response from Chemjobber, I was reminded of an even sillier case of mistaken identity that was highlighted last year, but seems to have escaped comment on the blogosphere. The problem started back in 2007 when a paper was published in the Journal of Natural Products, where the authors claimed to have isolated a most improbable natural product from a fungus:

From J. Nat. Prod., 2007, 70, 989

Amazingly, nobody called bullshit on this until April 2011 despite the fact the paper was cited 32 times during that period. I mean, I still remember seeing the paper that blew away this structure, entitled "Is 2,3,4,5-Tetramethoxybenzoyl Chloride a Natural Product?", and just staring in wonder that such a question could be seriously posed in an ACS journal. Surely no one ever believed that is was?

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(+/-)-Echinopine B

Vanderwal (ˈvændəˌrwɑːl)

v. Vanderwalled, Vanderwalling, Vanderwals

v. tr. To complete an impossibly short, but racemic, synthesis of a popular target e.g.


A Synthesis of Echinopine B

Vanderwal et al., Angew. Chemie. Int. Ed., Early View [GROUP] [PDF] [SI]

DOI: 10.1002/anie.201203147

Since their isolation in 2008 the echinopine sesquiterpenes have proved quite popular targets for total synthesis, probably thanks to their unusual and compact molecular architectures. Johann Mulzer, one of my favourite living synthetic chemists, succeeded in a beautiful first total synthesis just a year after their isolation, asymmetrically synthesising both natural products (starting from cyclooctadiene!) and assigning their absolute configurations in an excellent paper that somehow ended up in Organic Letters. The year 2010 saw rather a lengthy synthesis by Nicolaou as well as a paper  by Chen outlining studies that developed into a total synthesis last year, which I commented on at the time.[1] Until a couple of weeks ago, Mulzer led the pack needing a mere 20 steps from commercial materials, with Chen a close second at 24, and KCN's ponderous 39 step route languishing at the back. At the time it came out, I didn’t think Mulzer was doing too badly, given the dearth of oxygen in the target and the lack of obvious disconnections. However, the synthetic bar has just been raised by Vanderwal and co-workers, who recently reported a nifty 12 step, albeit racemic, total synthesis that I think should stay at the top for a little while.

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Where Did It All Go Wrong?

I’m sure life as an isolation chemist is hard. First of all, you have to actually find a source of interesting molecules, and while this sometimes involves diving in spectacular locations, or trekking through unspoiled rainforest to pick rare fruit, I’m sure it more often involves literally HPLCing shit or eviscerating four tons of eels. Furthermore, when you’ve actually got the compound, that’s only half the battle, as Nature is unbelievably creative at devising unique and surprising architectures to baffle the unwary. Synthetic chemists spend large amounts of time bewildered by NMR, and we get some pretty big clues from what we actually put in the flask to start with. Starting from scratch is even harder, even with the modern array of analytical equipment. Even the gold standard technique of X-ray crystallography isn’t perfect, and there have been some very famous natural products misassigned even with the aid of this breathtakingly powerful tool, including competition molecule diazonamide A, and kinamycin C.[1] Having said all that, looking at this recent example of a proposed natural product structure that was revised by synthesis, I have to say that I think I could have done a better job myself. Drunk.

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Chemical Etymology 1: Introduction

Credit: xkcd (http://xkcd.com/1012/)


I still find myself encountering unfamiliar terms in the literature all the time. Sometimes in my favourite organic chemistry journals, but especially when I stray further away from ‘pure organic’ into biochemistry, pharmacology, physical organic chemistry and other areas I know much less about. Before (or after) resorting to looking up new words, I really enjoy taking a guess at what they mean based on the smattering of Latin and Ancient Greek I learned at school and picked up over the last few years as a scientist. Strangely, I also find that knowing where words come from really helps me remember them, and I’m much more likely to know what they mean when I see them again. I’m not a linguist, but it seems to me that actually just a few root words seem to crop up rather a lot, and I’ve found that being familiar with a handful can be pretty useful. The aim of this post, and probably a couple more over the next month is to try and teach people who have never considered the origins of chemical terms something new.

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So You Think You’re Having A Bad Day?

Another quick update! Still busy!

From Biogr. Mems Fell. R. Soc. 1971, 17, 399-429 (doi:10.1098/rsbm.1971.0015)

Next week I'm starting a new total synthesis project with alkaloids. This is pretty exciting, as some incredibly famous (historic and modern) targets belong to this class, and, well, it's always fun to learn new things. Most of the compounds I've made in the past three years have been bright orange, which has made chromatography a bit of a breeze, and I'll miss that, but it's time to move on. While doing some literature searching and background reading for my new project I noticed the name William Kermack on quite a lot of papers. I knew I'd heard it before, but I struggled to remember where for a while. Eventually I remembered: he was mentioned in a footnote to an article on Sir Robert Robinson and the curly arrow in Chemistry World in 2010. You can read it for free, courtesy of the University of Saint Andrews here.

Born in the small town of Kirriemuir at the end of the 19th century, Kermack studied maths, natural philosophy, and chemistry at the University of Aberdeen, where he enrolled as a student at the age of 16, before heading south to work with William Perkin junior and Sir Robert at the legendary Dyson Perrins laboratoryof the University of Oxford (as a member of the British Dyestuffs Corporation contingent there). Two years later, in 1921, he returned to Scotland to take charge of the Chemical Section of the Royal College of Physicians in Edinburgh where he continued the work on alkaloids he began in Oxford as well collaborating with the medical researchers there. Tragically, his career as a bench chemist came to a violent end one fateful monday evening in 1924, when, while working alone in the lab, a flask exploded showering him in caustic reaction mixture. After two months in hospital he was discharged completely blind at the age of just 26.

Remarkably, this didn't particularly affect his career as chemist. He continued to collaborate and supervise PhD students, and still made he way to the lab each day by public transport. A year later he got married. He continued to research alkaloids, and became interested in carbohydrate chemistry, statistics and epidemiology as well. He obtained a D.Sc. from his alma mater, Aberdeen, for work on carbolines and was elected a Fellow of the Royal Society. Some 25 years after his accident he was appointed the first Professor of Biochemistry at the University of Aberdeen, which surprised many as he was, by training, an organic chemist whose major interest at the time was statistics, and he lacked experience in teaching and administration. An editorial in Nature remarked that ‘to proceed with such an appointment in a laboratory subject has something in it of an act of faith, based not alone on the high scientific attainments but also on the rich mental endowments and sterling qualities of the new professor’

Before accepting the new position, while still in Edinburgh, he commissioned a Plasticine model of his new department to enable him to familiarise himself with its layout, and was indeed able to find his way around without any problems. He lectured, oversaw the expansion of his own department (and others), translated works from German to English, wrote books, worked for the Chemical Abstracts service, collaborated and researched, aided by his students and his remarkable memory, and eventually became Dean of the Faculty of Science. He continued to work until his death at the age of 72, at his desk, while at work on another book on biochemistry. Kermack lead a remarkable life, rising to become a respected and popular academic, in spite of his disability, in an era when few technological aids existed to help the blind. So, next time you have a bad day in the lab, remember that things could be worse, and that Kermack himself only referred to his accident as a minor setback!



Biogr. Mems Fell. R. Soc. 1971, 17, 399-429 (doi:10.1098/rsbm.1971.0015)

Chemistry World, 2010, April, 54-57

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