B.R.S.M. The road to Tet. Lett. Is paved with good intentions


Chem Coach Carnival: I’m A Postdoc and I Love It

Hi all, we* interrupt our* scheduled** programming to bring you an exciting** Chemistry Carnival entry! See Arr Oh recently had the brilliant idea of a Chem Coach Carnival, where people in different chemical careers describe their working lives to give others an idea of what it's like to be in their shoes. Here's my entry, which unfortunately seems to have turned out a bit too long:

What do you do?
As you might have guessed, I'm currently a 'postdoc' or post-doctoral research associate at a UK university. If you're not familiar with the academic hierarchy you can see where this fits in the academic food chain here, thanks to Karl Collins.

What does a typical day involve?
I'm one of three postdocs in a research group of around twenty people engaged in diverse projects across the spectrum of organic chemistry. When I was at school The RSC ran a campaign to tell people that 'not all chemists wear white coats', but I'm proud to do so for 90% of a normal day. At the moment I'm mostly working on a short-ish biomimetic alkaloid synthesis but in addition to my own project(s), I also get to field questions from PhD and MSci students, show people how to do stuff in the lab, write papers, work on my own crazy ideas, manage an MSci student and worry about what I'm doing with my life. I also do some teaching in the form of undergraduate tutorials, which is great fun. My job is essentially to solve an increasingly varied and intricate series of puzzles, and it's good.

How did you get where you are?
It sometimes feels like I've spent my whole life in full time education as I started university straight after school and my PhD a few months after I finished my undergrad. As it happens, I'm currently still at the same institution from which I obtained my PhD a few months back. Staying in one place like this is usually inadvisable, but it's not a bad university, there's a good climbing wall nearby, and my current position is really just a short term filler until I move to the US next year for a 'real' postdoc. Goodness knows what I'll do after that. Fortunately, thanks to the shorter British PhD, I've only just turned 26.

How does chemistry inform what you do?
I really can't know enough chemistry as it pervades everything I do at work. The deeper my knowledge, the better I'll be at my current job, and the greater the chance I'll have of getting another.

Pros and Cons?
It seems that this job combines most of the good bits of being an academic and a PhD student; on the one hand I get almost total freedom to do what I like, I still spend most of my time in the lab, I get to teach and I get to be familiar with all the stuff that other people in the group work on but I don't have to write grant proposals or a thesis, take exams, or attend many meetings. It's pretty much how I think being a chemist should be. The main problems with the job are that it doesn't pay that well; although money is rarely a problem for me, I couldn't start a family or buy a house; the hours are pretty long, and are only going to get worse when I cross the Atlantic; and it isn't a long term career, as doing more than a couple of one or two year postdocs is widely considered a bad idea. It can also be stressful and frustrating.

A funny story?
Reading through what I've just written I guess I come across as pretty keen on chemistry, but it hasn't been a lifelong interest of mine. I wanted to study physics at university but sucked at math so I ended up studying materials science. That turned out to be a little too last-but-one century for me; the amount of time we spent learning about steel and concrete really put me off. After a year I switched to chemistry, but was a mediocre undergrad as I spent most of my time running the university mountaineering club and planned to get a job in the outdoor industry when I graduated. It wasn't until my final year masters project that things changed for me. Although I usually did much better in inorganic chemistry, I chose to join an organic research group that looked interesting on paper, but to my surprise it turned out to consist only of one mostly retired emeritus professor and a young - but extremely talented - postdoc. To hear those two talk about chemistry was amazing; it was like listening to a conversation in another language, and as they swapped stories about this academic or that, discussed the latest Nicolaou paper or just stood around cracking jokes I realised that the world of organic chemistry was much more interesting than I'd ever realised. I loved the history, the in-jokes and the community. I wasn't a great masters student, but I doubt anyone else in my year learned as much as I did during their project. Four years later I'm still a chemist. And I'm not ready to stop learning yet.


*Majestic plural.

** This is not true.

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Drugs I Shan’t Be Taking This Week 1: 2,4-Dinitrophenol

I was saddened and surprised today to read this story on the BBC News website about a young man who died by overdosing on 2,4-dinitrophenol. Huh? Now, perhaps on account of my long hair and somewhat dishevelled appearance, I get offered a lot of drugs, but this isn't something I've ever heard hawked on street corners. It turns out that despite previous uses as a detonator and pesticide it's apparently quite popular among bodybuilders as a weight loss drug, something the FDA found it to be unsafe for back in 1938. Which is really something as 'safe' had a whole different meaning back then; hell, the 1948 the Nobel Prize for Medicine was awarded to Paul Müller for his discovery of 'wonder' pesticide DDT. But how does 2,4-dinitrophenol work? Well, here's a mechanism of action I wouldn't have guessed:

"DNP acts as a protonophore, allowing protons to leak across the inner mitochondrial membrane and thus bypass ATP synthase. This makes ATP energy production less efficient. In effect, part of the energy that is normally produced from cellular respiration is wasted as heat. The inefficiency is proportional to the dose of DNP that is taken. As the dose increases and energy production is made more inefficient, metabolic rate increases (and more fat is burned) in order to compensate for the inefficiency and meet energy demands. DNP is probably the best known agent for uncoupling oxidative phosphorylation."

Well, that sounds tempting! So, for a slightly higher basal metabolism you get a permanent fever, sweats and insomnia! Surprisingly, to me at least, mitochondrial uncoupling appears to be considered a valid approach for the development of anti-obesity drugs, despite these unavoidable side effects. The problem with using 2,4-dinitrophenol for this purpose is that the therapeutic index is very small, and overheating is quite easy even using a 'safe' dose, causing all kinds of problems. I read a few accounts of people's experiences with the drug online, and most of them concluded that taking 2,4-DNP was far more unpleasant than good old fashioned dieting. As Samuel Goldwyn once said, "gentlemen, include me out".



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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!

Filed under: Ask the audience, Literature, Named reactions, Serious | 15,270 views | 2 comments Continue reading

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.

Filed under: Literature, Woodward Wednesdays | 43,223 views | 4 comments 4 Comments

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.





Filed under: Fun, Literature, Serious | 16,306 views | 2 comments 2 Comments