B.R.S.M. Help! I'm trapped in a molecule factory!


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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Superlatives 2: The Gassiest Reaction of Them All?

Perhaps Organic and Biomolecular Chemistry isn't a journal well known for its reviews, however I recently enjoyed reading this rather unusual perspective by Jason Chen on "Gas Extrusion in Natural Products Total Synthesis". All the classics are there: the retro [4 + 1] cycloaddition of sulfolanes to generate dienes (and the related Ramberg–Bäcklund reaction), the Boger-style 1,2,4,5-tetrazine [4 + 2]-retro-[4 + 2] method for the synthesis of aromatic rings and many more unusual ways to lose nitrogen besides. There are also some much rarer reactions, including an example from Padwa's synthesis of stempeliopine where addition of carbon suboxide (O=C=C=C=O) to a thioamide is followed by a cascade that eventually spits out carbonyl sulfide (OCS). I bet that's a synthesis that makes you unpopular in the lab[1]

Probably the winner for the gassiest sequence described is from a Movassaghi paper that I remember from last year. Although the reaction hasn't actually been used to make a natural product yet, it looks like a useful way to access  hetero cyclotryptamine natural products, of which there are many. The idea is to synthesise an unsymmetrical sulfamide, where the two amines are connected to the two units to be linked. Oxidation of this with NCS then generated a thiadiaziridine dioxide in some bizarre Aza-Myers-Ramberg-Bäcklund-type reaction. This then lost sulfur dioxide as expected to give a diazene that was decomposed photolytically with loss of nitrogen to give a pair of radicals that recombined quickly. Amazingly this recombination occurred sufficiently to prevent the formation of homodimeric products. Neat reaction - I love the fact that the linker is completely traceless!

Gas extruding reactions are more important that might be imagined at first (especially for the construction of strained systems), and it's nice to see a review dedicated to them.



1. Carbon suboxide apparently smells (surprisingly?) awful . From an early review on its chemistry:

"The physical properties of carbon suboxide are of considerable interest.  It is a  gas  under ordinary conditions,  having  an unbearable odor like acrolein and mustard oil.  In  small amounts  it  acts as  a  lachrymator; in  high concentrations it attacks the eyes, nose  and breathing  organs, giving a  feeling of suffocation."

There are lots of ways to make it, some of which are more appealing than others. Padwa generates it from dibromomalonoyl dichloride and zinc in ether at room temperature, which sounds quite sensible. Unfortunately, the OCS by-product also smells pretty bad. It's a little known fact that pure carbon disulfide has a pleasant smell redolent of diethyl ether (according to the Merck index; I used to have a CS2 still and I never experienced this). The reason it's so unpleasant to work with are traces of OCS (and thiols) from its manufacture. According to Wolf and Amarego these can be removed by washing with aqueous KMnO4 solution, followed by mercury. Or not.


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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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Selenium: Include Me Out

No, thanks.

This week I noticed that J. Derek Woollins, head of Chemistry at the University of Saint Andrews and legendary selenium chemist, recently published a review of the research leading to the discovery of his eponymous reagent in Synlett. Although, for reasons of self preservation, I tend to lose interest in the chalcogens after the first row or two, I quite like personal accounts of research so I thought I’d give it a try. Unfortunately, being an organic chemist, I couldn't follow a lot of the inorganic chemistry but I did enjoy some of the stories of things going wrong:

“Paul Kelly also later extended this work by making M–Se–N complexes using tetraselenium tetranitride (Se4N4) as the starting material. This is a very sensitive material. Indeed the first time we prepared it (from a reaction in liquid ammonia), whilst washing the red solid with a solution of potassium cyanide, nitrogen was let into the flask fairly briskly. The resulting turbulence caused an explosion, which destroyed the flask embedding pieces of red selenium into the white shirt Paul was wearing; from a distance this looked like major bleeding. Bravery was not lacking in the group during that era, and Paul Kelly also carried out what remains as the only published reaction of (extraordinarily explosive) pentasulfur hexanitride (S5N6) to give a complex containing the [S2N3]– ligand.”

Ah, wacky fun! I’m quite sure that S5N6 falls into the category of things that shouldn’t really exist, and trying to force them to do so isn’t good for anyone’s nerves.[1] Actually, the group engaged in quite a lot of this kind of lunatic chemistry. Another great example:

“Leaning on our previous work on reactions in liquid ammonia, we prepared sodium selenide (Na2Se) by the simple reduction of selenium with sodium in liquid ammonia. The resulting material is much more soluble than that prepared by the solid state route, though it is worth noting that this wonderfully finely divided solid is also very pyrophoric – on one occasion, around 75 grams caught fire in the port of our glove box with rather unpleasant consequences.

I imagine that ‘rather unpleasant’ probably doesn’t cover it. I can think of few things that would evacuate a building faster than screaming the words ‘selenium fire!’.[2] Fortunately, my own experience of selenium is a lot less exciting - I used phenylselenyl bromide a bit during my Masters to make enones, and aside from a marked decrease in affection from my girlfriend at the time, I suffered few ill effects. In fact, I suspect that beyond the old trick for forming enones (and the related Grieco olefination), many organic chemists would struggle to even think of uses for selenium in the lab. I am aware of one more reaction you can do with it, though, and I'll quickly explain why you shouldn't bother.

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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.

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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]

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‘No Added Metals’ Is The New ‘Metal Free’

Base image from http://mrsec.wisc.edu/Edetc/nanolab/photonic/index.html

Did anyone else see that paper on Thursday in Chem. Comm. titled "Use of Dimethyl Carbonate as a Solvent Greatly Enhances the Biaryl Coupling of Aryl Iodides and Organoboron Reagents without Adding Any Transition Metal Catalysts", and think "here we go again"?[1] I immediately though it kind of appropriate that Chem. Soc. Rev. very recently published a history of transition metal contaminants in catalysis (DOI: 10.1039/C2CS15249E). However, on reading the Chem. Comm. paper, it seems the authors were very careful both to check all their reagents, and not make any grand claims. Not surprising, really, given the numerous examples of misunderstanding of such results in the literature. Even the title is cautious, saying 'without adding any transition metal catalysts', quite a step down from the bold claims of 'transition metal free' reactions seen in the literature of a decade or so ago.


And Now For Something Completely Different 2: Five Uses For Wax In The Lab

Note: In my opinion, it would be fairly ill advised to attempt any of these.

So, wax. According to wikipedia, a wax is just a plastic/malleable compound that melts slightly above room temperature to give a non viscous liquid. As this definition doesn't stipulate any chemical properties, there's a pretty large number of compounds which fall into this bracket, and so waxes from different sources can have very different chemical compositions. Wax from natural sources such as insects and animals tends to be composed of the esters of various fatty acids with long chain alcohols, whereas synthetic waxes tend to be simple mixtures of various long chain hydrocarbons. Earwax is different again.[1] Regardless of its provenance, wax can be a pretty useful substance, with myriad uses around the lab. Here are the first five I can think of;  no doubt there are others!

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Black dot… I mean Linstead notation.

Anyone who's read some of the older chemical literature (or even recent papers by old school chemists) has probably noticed the 'black dot' notation used to depict stereochemistry at ring junctions, particularly by chemists in the US and Canada. Here's a recent example, so you'll know what I'm on about if you don't already.


From Angew. Chem. Int. Ed., 2010, 49, 4864 – 487.[1]

I don't know how things are in the US, but at no point during my chemical education do I ever remember having this notation explained to me. I recall encountering it for the first time at the start of my PhD, asking around a bit, and then just working it out for myself. Turns out it's actually really simple - a black dot at a ring junction just means that the hydrogen there is on the β-face, i.e. above the plane of the paper. To this day I've never seen this explained in a textbook, and have wondered from time to time where the heck it came from. As named reactions become canonised, the references the seminal papers slowly disappear, and clearly the same thing has happened here, as with many other conventions and nomenclatures. However, not having a name for this notation I'd never been able to trace where it started. Until now.

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Cycloadditions are great

This is my attempt at answering Rachel Pepling’s call for posts for her blog carnival over at CENtral Science. The theme is 'Your favourite chemical reaction'.

Update: 23/09/11 - removed some of the more egregious grammatical errors.

It only took me a few seconds of thought to answer the question 'What's your favourite chemical reaction', far less than if I'd been asked about my favourite book, meal or album. It's the Diels-Alder cycloaddition, obviously. I reckon I've done well over a hundred of these by now (including three today), and those two names will certainly appear in the title of my PhD thesis. On social media websites I usually list my interests as rock climbing, mountain biking and cycloadditions.[1]

I guess what I like about this reaction, and why it's a mainstay of total synthesis, is that it's a fantastic way to generate stuctural complexity blindingly fast. It can set up to four stereocenters, and you can even take simple achiral precursors and introduce asymmetry catalytically. But, unlike a lot of reactions which are capable of such synthetic leaps forward, it's also generally very  predictable. One of my favourite parts of the history of this reaction is this quote from the seminal paper by Diels and Alder:

"We explicitly reserve for ourselves the application of the reaction developed by us to [natural products synthesis]"[2]

Nice try guys, but the 1300+ papers published in 2010 on this transformation seem to indicate that this request has been largely ignored by the synthetic community. And why not - it's an all round great reaction, probably the hammer and/or duct tape of the total synthesis toolbox. It's also nice that it's named for an advisor and his PhD student, because the people who actually do the chemistry often don't get the credit they deserve. However, despite all of these things I'm not actually going to write about the Diels-Alder reaction here. The reason is that it's just too well known - we even teach it to first year undergraduates. Everyone knows what it is, and how good it is, and I think this carnival is a great opportunity to dredge up some lesser known reactions and hopefully get people thinking about some chemistry that's new to them.

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