The Periodic Table of Videos

I'd like to share this link with you: The Periodic Table of Videos (http://www.periodicvideos.com/).

A group of lecturers around Prof. Martyn Poliakoff from the University of Nottingham have compiled this "Periodic Table", which contains a video of a few minutes for every (!) known element. Sometimes it's an explosive experiment (e.g., Hydrogen), in other cases they simply show a sample, while giving some information about the element. I must say, I am impressed how they manage to come up with something for all the lanthanoids and actinoids. For Ytterbium, Yttrium, Terbium and Erbium, they even went on a trip to Ytterby (Sweden), the town these elements are named after. A great distraction for rainy days, and also a useful video collection for teaching!

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Hoveyda's Asymmetric Mo-Catalyzed Metathesis

I recently had the pleasure of listening to an excellent talk by Amir Hoveyda about his chiral-at-metal Mo catalysts for asymmetric metathesis. This kind of catalyst is based on the Schrock-type molybdenum catalysts. Most asymmetric catalysts nowadays employ bidentate ligands such as BINOL-type ligands that carry the stereochemical information. By chelating the metal centre, the fluxionality¹ is reduced, therefore ensuring a well-defined geometrical arrangement of the catalyst-substrate complex and good stereoselectivity. In addition, the loss of stereochemical integrity of the catalyst is suppressed. Hoveyda has used such complexes to achieve the formation of P-stereogenic phosphinates and phosphinoxides (where the phosphorus is a chiral centre) by desymmetrizing RCM of achiral precursors (ACIE: 10.1002/anie.200805066).

There is, however, a downside to reduced fluxionality. As Hoveyda points out, the Mo complex has to undergo a series of geometrical rearrangements during a catalytic cycle. If the complex is too rigid, these rearrangements are hindered. In other words, you may get high e.e.'s, but the catalytic activity will be low. This is where chiral-at-metal catalysts have a clear advantage: they only require monodentate ligands, which makes the complex more able to rearrange, and the reaction will be much faster.

The excellent stereocontrol is due to electronic effects rather than pure sterics. One of the ligands has to be an acceptor (the BINOL-type ligand) that ensures sufficient Lewis acidity of the metal centre. A donor ligand (the pyrrole) is also required because it distorts the complex geometrically in a way that facilitates the coordination of the alkene substrate. The use of this kind of asymmetric RCM is demonstrated in a total synthesis of (+)-quebrachamine, where they get a yield of 84% and an excellent 96% e.e. (Nature: 10.1038/nature07594).

I have only touched some of the most important points made in these papers. They are definitely worth reading!

¹ I wasn't familiar with the term "fluxionality". Apparently, it is often used in organometallic chemistry to indicate the possibility of interchanging between equivalent conformational arrangements. As a simple example, Wikipedia mentions the interchange of the two Me groups in dimethylformamide. A monodentate ligand in a metal complex is fluxional in the sense that it can rotate around the metal-ligand bond.

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Is Synthetic Organic Chemistry Dead?

Synthetic organic chemistry has come a long way in the course of the last century. At the beginning it was not much more than pure guesswork, mixing different things, heating and taking a guess what heteroaromatic might have formed. Nowadays, we have arrived at a point where it is possible to make almost any conceivable chemical structure by a rational approach, using the large toolbox of synthetic methods available today. Have we thus reached our goal? Is there nothing left to do in synthesis except improving the existing methodology?

Of course not. What we still need is a more profound understanding what is happening on the molecular level. Quite often we find ourselves faced with a synthetic problem where only one specific set of reaction conditions will work. Why this one? Nobody knows, and nobody can predict, so we have to try all possible conditions.

I would argue that the huge improvement in our understanding of reaction mechanisms and the complexity of chemical structures of today is largely related to the availability of more powerful analytical methods. A hundred years ago, melting points and elementary analysis were about the only ones, later on IR spectroscopy became available. But we all know that modern organic synthesis would be unthinkable without the help of NMR spectroscopy. Maybe a new method is just around the corner, waiting to be introduced. To gain more knowledge about mechanisms, we would need the ability to "look at" individual molecules, rather than ensembles of molecules as is the case today. A new method that could do this would definitely have a huge impact on organic synthesis.

While we observe billions of molecules at the same time with our analytics, in our mind we are still stuck with the single molecule that we draw on paper. In this way, we neglect all the interactions between molecules that can be very important for the outcome of a reaction. Take organolithium compounds as a simple example. We usually write "n-BuLi" as if it were an isolated species, although it is well-known that these compounds form clusters up to hexamers in solution, depending on the solvent and the concentration. From a theoretical point of view, it will be very important to devise models that take the interactions between molecules, molecule clusters and the solvent (more) into account.

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The One-Year-PhD Crisis

Who doesn't remember the time when you started your PhD. You were all enthusiastic about working on your own project, doing all kinds of new chemistry, and generally still believing in every far-flung idea your boss had.

One year later: frustration. Reality has caught up with you. This is like your thirtieth anniversary (so they say : you realize how much time has already passed, and how little you have achieved in that time. Suddenly you start feeling like you will be stuck with your current problems forever and that your PhD is likely to take ten years. Ok, so you needed some time to get used to working independently and for getting to know your project, but still, after one year you should have more results, right?

Wrong. I have experienced this myself and seen it often with colleagues. This feeling of pointlessness usually occurs just before you make some serious progress or even a breakthrough. The feeling of "being stuck" appears to be a psychological phenomenon necessary for solving difficult problems. It's when your mind can take a broader perspective and start with lateral thinking. This is normally also a good time to take a holiday - it prevents you from becoming too focused to see an obvious solution.

You also tend to forget that it takes much longer to get "into" a project than it seems at first. The fact that you don't have to ask for advice every day does not mean that you are already familiar with all the details of your work. It usually takes about a year to get there, and that's when you start to see all the difficulties you are faced with. Don't worry, you can take it as a sign that you have become an expert on your topic!

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If you can read this, the world hasn't ended (yet)

About two hours ago, the Large Hadron Collider (LHC) at CERN, Geneva, has accelerated its first proton beam. This massive particle accelerator will hopefully be able to answer many questions about the beginning of the universe, and maybe be able to detect the Higgs boson, the so-called "God Particle" (cf. also here).

There has been much ado about the possibility that these collision experiments might create a black hole, which will grow in size and eventually destroy the earth. Although there is a consensus in the scientific field that there is no real threat, this topic is broadly discussed in the public media. Probably because this is about the only aspect of the LHC that a layman (such as me) can understand to an extent.

What I find very annoying is the religious people claiming that this kind of research is good for nothing, and that true answers to the fundamental questions can only be found in the Bible. Actually, calling the Higgs boson the "God Particle" is asking for trouble from that side. My theory is that the CERN is part of a plot of al-Quaida, who will probably wait until tomorrow (September 11th) to destroy the world.

Just another thought - could it be that all the other black holes we observe in the universe come from an alien civilization? That every intelligent species develops up to a point where they want to do experiments like at CERN and consequently destroy their planet? This could be a good science-fiction story...

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Halogen Bonding

Some of you may be familiar with the term "halogen bonding". In analogy to hydrogen bonding, this weak interaction occurs between an electron donor, such as nitrogen, and a halogen (Cl, Br, I). The halogen acts as an electrophile.

This is possible because the halogen has a region of positive partial charge at its tip, the so-called sigma-hole, as shown by calculations (doi:10.1007/s00894-006-0130-2). The group of Resnati and Metrangolo in Milan have used this interaction to construct a variety of polymeric chains and networks for crystal engineering. As they discuss in their current Science paper (doi:10.1126/science.1162215), it also plays an important role for drug design, which I am particularly interested in. Many drugs on the market are halogenated aromatics. The exact role of the halogen for binding is not always known, since often it was introduced in order to tune the hydrophobicity of the compound. I suspect that in many instances, halogen bonding to a backbone carbonyl oxygen could be of importance.

Clearly, more work is required to further investigate halogen bonding in a biological context. If people want to incorporate this kind of interaction into rational drug design or crystal engineering, good quantitative models will be needed.

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BOSS XI

Last week I had the opportunity to attend the Belgian Organic Synthesis Symposium (BOSS) in Ghent. This included 4-5 lectures a day, poster presentations and of course sightseeing! The speaker list comprised big names, such as Baran, Carreira, Denmark, Du Bois, Fürstner, Hartwig, Shibasaki and Trost. I'm not going into detail about the lectures, as this seems to be covered in Tot. Synth. You can see the full programme here.

I can say as much: the conference was really great, if you ever get a chance to go there, do so! Everything was well-organized, most of the lectures were highly interesting, and so were the posters. In addition, Ghent is a beautiful town that is well worth a visit.

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Scientific Misconduct

This nature article discusses the results of a survey about scientific misconduct, while an editorial makes some comments.

Quote: "The 2,212 researchers we surveyed observed 201 instances of likely misconduct over a threeyear period. That’s 3 incidents per 100 researchers per year. A conservative extrapolation from our findings to all DHHS-funded researchers predicts that more than 2,300 observations of potential misconduct are made every year." Almost 9% of the respondents had witnessed some sort of misconduct, and 37% of those incidents went unreported.

The authors conclude that, besides protecting the whistleblowers better, it is necessary "to create a zero-tolerance culture". The editor, however, holds the opinion that one also needs to take a look at "the environment that has allowed misconduct to flourish". In his opinion, there should be the possibility of finding a solution without ruining the career of a scientist, especially in mild cases.

I tend to follow the editor's reasoning. In my opinion, the zero-tolerance culture already exists to a certain extent, because a scientist convicted of, e.g. faking data, can forget about his career. But the result of such a policy is clear: no-one wants to blow the whistle on a colleague, because they don't want to end somebody else's career and because they will make themselves very unpopular. The real problem is the way misconduct is treated at the moment: we want to identify the guilty scientist, and punish him/her.

While this makes sense for the worst cases of fraud, in milder cases one should try and ask the question *why* the misdeed was done. Take, for example, the way hospitals treat mistakes nowadays: they try to find out how it could happen, and how it can be avoided in the future. This is very sensible, because it treats the problem in a proactive way: instead of reacting to the incident by punishing somebody, future incidents are reduced by tackling the things that cause them in the first place.

If there is a lot of pressure to produce as much data as possible in a research group, it is tempting to cut a corner once in a while. Can this not partly be considered the prof's fault? In a similar way, one should address the working atmosphere in the group in question. The problem with the academic system is that there is no informal institution to turn to, besides your boss, if you are to witness a case of scientific misconduct. So we fall back to the old issue: the only person you can contact in case of problems has all the power over you.

At the University of Toronto, a "Graduate Student Oath", similar to the Hippocratic Oath, has been tried as a means to strengthen scientific ethics (Science). Although this is an interesting idea, I doubt it will change the behaviour of people very much.

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Danishefsky + Rebek = ?

I recently wrote about the reaction of isonitriles with carboxylic acids under microwave irradiation, as reported by Danishefsky. Rebek's group took up this idea and tried the reaction inside capsules formed by two cavitands (DOI:10.1021/ja802288k).

In the presence of the capsule, acid 1 and isonitrile 2 react at room temperature to give the intermediate 3. However, the n-butyl intermediate 3a is not detected and immediately rearranges to the product 4a, still trapped inside the capsule. Release of the intermediate and reaction with 1 in the bulk solution gives a small amount of 5a (this side product gets trapped in a capsule again).

In the case of isopropyl substitution, intermediate 3b is actually seen by NMR. It cannot rearrange to product 4b, but is released from the capsule instead and reacts with 1 to give formamide 5b. The authors explain this with the steric bulk of the isopropyl group that prevents the rearrangement inside the capsule.

As far as I know, this is the first experimental evidence for intermediates of the type of 3, which take part in the reaction mechanism suggested by Danishefsky. In addition, it also shows that the carboxylic acid - isonitrile reaction can be "catalyzed" by cavitands without the need for microwave irradiation.

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News from the NanoPutians

Besides having a strange taste in humour, we wacky Europeans are also a bit crazy. Soccer-crazy.

In less than two weeks, the European Football Championship is starting. On this occasion, I would like to present the first bis(alkinylplatinum(II))-based fullerene receptor (1). A fullerene, such as C₆₀ (2) is readily recognised by this box-shaped metal complex. The association reaction can be accelerated by arylacetylene 3, which contains two hydroxylamine functionalities that serve as a catalytic dyad.

(I know this is silly, but I rather like to draw nanoputians...)

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Carbon NMR Fail

You need to measure a ¹³C-NMR for all new compounds, that's a golden rule. But what do you do when you can't dissolve more than, say, 5 mg, of your stuff? Either you can't afford to dump more of it in DMSO, never to be seen again^*, or it just isn't soluble enough.

In that case you simply try anyway, run an overnight experiment on a 400 MHz machine, and hope for the best. Sometimes it will work, sometimes it won't.

What you always get is the massive solvent signal. On the left, there are some tiny bumps in the background noise, mocking me, that might just be the beginnings of real peaks. Of course there should be many more peaks than the three you can hardly see.

What now? I can hand this over to the NMR service. The first thing they will ask is: "Why don't you give us a more concentrated sample?" In the past, I even had to redo a synthesis in order to get enough material for a missing carbon spec. Naturally, I should have started the synthesis on a larger scale, but somehow I always end up with those ominous 10 mg of end product. I hate sacrificing so much precious product to the DMSO god!

^* I know it is possible to evaporate DMSO, but it takes forever. Also, the material I get out of it is usually an ugly, sticky oil instead of the nice solid I started with.

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"Danishefsky 2-component reaction"

This JACS communication by Danishefsky's group is inspired by the well-known Passerini 3-component (isonitrile + aldehyde + acid) and Ugi 4-component (isonitrile + aldehyde + amine + acid) reactions. They ask the question if isonitriles 1 react with carboxylic acids 2. At room temperature, they do not, but under microwave irradiation they furnish N-formyl amides 3 in good yields. The authors go on to propose the mechanism shown, which could probably be further supported by isotope labeling.

They wanted to apply this new kind of reaction to the synthesis of asparagine-linked glycopeptides. Therefore glycosylisonitrile 4 was reacted with aspartate 5. Instead of the expected product, ester 6 was formed. In the paper, the formation of a "β-GlcNAc donor" by participation of the NAc group is assumed. Its structure is not specified, but I suppose it could be something like 7.

To get around this problem, non-participating neighboring groups like OBn and N₃ were used (8). Now, reaction under the same conditions furnished the expected glycosyl amino acids 9. Even better, the reaction was anomerically specific; that is, β-isonitrile 8 gave exclusively the β-linked product 9, while α-isonitrile 10 yielded only 11.

The formyl group could also be converted into methyl or completely removed, which sets the stage for building up a peptide chain. What is really striking about this new type of reaction is its simplicity. To quote the paper: "[The results described herein]... might well have been discovered a century ago." Why has nobody ever tried this before? Is it because of the bad smell of isonitriles?

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