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.
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.
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!
References
Biogr. Mems Fell. R. Soc. 1971, 17, 399-429 (doi:10.1098/rsbm.1971.0015)
Chemistry World, 2010, April, 54-57
Two Reactions of Hydrazones
I thought I'd quickly share with you a couple of useful transformations involving hydrazones that I read about recently. The first one I found yesterday, reading George Majetich's perovskone full paper in Gilbert Stork's special issue of Tetrahedron. Although it's not the most atom economic thing ever, it struck me as quite a neat, if somewhat oldschool, way to transfer chirality. The second reaction is from Rawal's recent total synthesis of the weltwitindolinones, which I blogged about in detail here, and which I actually saw Rawal himself talk about on Tuesday at Bristol. The reason I've brought it up again is that when I wrote my last post commenter MadForIt asked about the mechanism of this transformation, which at the time I didn't know and didn't get round to looking up. By chance I found out the mechanism a few weeks later (completely by accident) but never got round to posting it up. Rawal's talk reminded me of this, but it didn't seem worth burying the answer in the archives so I thought I'd make a new post out of it here.
So, before I give you some possible answers, have a think about how you might do these and then read on for more information.
Woodward Wednesday 4: And All That Could Have Been
Woodward was a member of the highly elite few; organic chemists who won Nobel prizes not for a specific reaction, discovery, or work with a particular element but for simple mastery of organic chemistry - theory, synthesis, methodology, structural determination, biochemistry - the list goes on. The elegant citation for his prize summed this up nicely:
"Professor Woodward's research work covers vast and various fields in Organic Chemistry. A leading feature is that the problems have been extremely difficult and that they have been solved with brilliant mastery. He has attacked them with a maximum of theoretical knowledge, a never-failing practical judgement and, not least, a genial intuition. He has, in a conspicuous way, widened the limits for what is practically possible."
I'd be very surprised if we see a Nobel Prize award to a synthetic organic chemist any time soon. The total synthesis/general organic crowd never seem very high up Paul's lists. As we saw in the very first post in this series, Woodward interestingly didn't use the opportunity given him to lecture on the work that actually won him the prize, instead choosing to speak on his entirely new and unpublished work on cephalosporin C. I think Woodward entirely deserved his Nobel prize, which he gained through an unbelievable pertinacity where chemical problems and puzzles were concerned, as well as the willingness to take on daunting challenges. Woodward's chemical legacy was enviable and it's telling that no conversation or book on classic synthesis can fail to cover such masterpieces as his work on reserpine, strychnine, chlorophyll and B12. That aside, I've heard numerous chemists talk about his contributions to other Nobel Prize winning work, so I thought it might be interesting to write a post on this.
Unnatural Products 4: Tetrahedrane
“Why does the tetrahedrane molecule fascinate the organic chemist? Is it the aesthetic appeal of the topology of the tetrahedron or the hope that the unusual bonding properties of this molecule could lead to otherwise inaccessible knowledge of general importance, or is it indeed the synthetic challenge of the highly reactive - if at all capable of existence - tetrahedrane, together with the sporting ambition to reach the goal first?” – Maier, 1988
This bonus Unnatural Products post was written by guest blogger Ckellz from New Reactions, who has worked on far more strained systems than most of us ever will. If anyone else fancies writing a post, get in touch. Enjoy! --BRSM.
When I first found out that BRSM was doing a series on unusual and platonic hydrocarbons, I immediately became really excited and nostalgic. I spent a good part of my undergraduate research career working on strained systems (which culminated in the synthesis of a highly strained bicyclobutane bearing a CF3 group). During my time in Dr. Tilley's lab tetrahedrane 4 often came up as a topic of discussion (Dr. Tilley's goal is ultimately the synthesis of this elusive molecule) and how we thought it was a very interesting molecule that might actually be quite stable. So when I was reading the posts about cubane, I commented that I had a good deal of knowledge about its smaller C4 cousin. The next morning I received a very nice e-mail from BRSM asking me to do a guest post about tetrahedrane and I jumped at the opportunity!
Named Reactions 2: Break It Down Now
Physics Nobel Laureate, legendary teacher and all-round cool guy Richard Feynman once said: “[There’s a] difference between knowing the name of something and knowing something”. This is true in a whole range of fields, and we’ve probably all seen enough students confidently assert that a particular step is “just a simple named reaction”, only to completely crumble when asked the mechanism or conditions. Still, I think named reactions are a great way of learning some really important chemistry that can then be applied to many other things. A chemist who knows, say, the fifty most common named reactions and a decent chunk of basic theory will be in a good position to take a guess at the mechanism of most things they encounter. They're also a useful conversational shorthand if you want to convey how something works without reaching for a pen and paper. Very few reactions are so obscure and ‘out there’ that they’re not at least conceptually related to things we all know well. For example, I set this as part of a group problem session I ran last week:[1]
Unnatural Products 3: Pentaprismane
For the last planned post in my Unnatural Products series, I’m going to write about Eaton’s 1981 synthesis of pentaprismane.[1] At the time, unnatural hydrocarbons were hot targets, and as the next largest prismane on the list this target was the subject of much research by groups around the world. Perhaps Eaton's biggest rivals were the groups of Paquette and Petit, and in fact all three had, at various times, synthesised hypostrophene as an intended precursor to the target.
Unfortunately, the ‘obvious’ [2 + 2] disconnection from pentaprismane turned out to be a dead end and the photochemical ring closure was unsuccessful. The 1970s and early 1980s saw the publication of a number of other similarly creative, but sadly ill-fated, approaches based on various ring contractions, and the compound gained a well-earned reputation for extraordinary synthetic inaccessibility.
Unnatural Products 2: Dodecahedrane
Second in my somewhat badly thought out Unnatural Products series is dodecahedrane. To be honest, this compound is actually pretty much the main reason for this series. I only found out it had been made at the start of the year (even though Paquette did it way back in 1983),[1] and it blew my mind. I mean look at it – where do you even start? It took me a full hour to draw the damn thing in Chemdraw, and I still can't get it to look right on paper. As Paquette himself said in an abstract ‘the aesthetically pleasing symmetry of the dodecahedral framework was clearly apparent’. In common with the syntheses of the other two compounds above the route involved both Diels-Alder reactions and lots of photochemistry. Let’s take a look.
Unnatural Products 1: Cubane (again)
The two rather tasty Ripostatin B syntheses simultaneously in Angewandte on Thursday notwithstanding, here’s some much older chemistry I’ve been wanting to do a post about for a while.
There are exactly five regular polyhedrons that can be made, and as they were first discussed in detail by Plato, they’re sometimes known as the platonic solids.[1] Now, you might not have heard of them under that name, but I’m pretty sure most of them are familiar to chemists. In order of increasing size, the series starts with the tetrahedron, the shape of stereogenic centres at carbon, and the source of asymmetry in life. In fact, Jacobus Henricus van 't Hoff won the very first Nobel prize in chemistry ever back in 1901 for being one of the first to notice this. Although the parent hydrocarbon has yet to be synthesised, a number of tetrahedrane derivatives have been reported. Next comes the cube, the corresponding hydrocarbon of which, cubane, was famously first synthesised by Eaton back in 1964. Third up is the octahedron, more of an inorganic chemist's shape and rather unlikely to ever exist with a carbon skeleton due to the crazy C-C bond angles required. Fourth, the dodecahedron, has actually been better studied by organic chemists than most people realise and, after much competition, Leo Paquette was the first to synthesise the corresponding hydrocarbon in 1983. Last and largest in the series is the icosahedron, which I can’t think of a way to link to chemistry, but we’re certainly unlikely to ever see a carbon based version as all the atoms in the skeleton need to have five bonds.
Credit: Wikipedia.org
In this post and the next two I’m going to discuss three syntheses; those of the two platonic solids made to date (cubane and dodecahedrane), and that of the non-regular polyhedron pentaprismane, because it’s also pretty cool. Why do this? Well, when if you consider, say, dodecahedrane in a retrosynthetic sense then unless you lived through the era when these compounds were fashionable targets, have studied them, or are a bit of a genius then it's not obvious where to start so hopefully we can learn a bit of chemistry. I also enjoy a bit of chemical history and some of the methods used were pretty neat as we'll see.