Printer vriendelijke versie

Nobel Prize in Chemistry 2011 predictions

28 September 2011 - The crystal ball

October 5 is drawing near with another edition of NPIC day. See this blog's 2008, 2009 and 2010 coverage here. The contestants are basically the same as last year. In terms of clusters they are: Jacqueline Barton Bernd Giese & Gary Schuster (DNA electron transfer), Charles Lieber/George M. Whitesides/James Fraser Stoddart (nanotech advance) and Martin Karplus/Ad Bax (biomolecular structure elucidation).

Thomson's shortlist for 2011 (here) now includes Fritz Vögtle, Donald Tomalia and Jean Fréchet for their work on dendrimers which may problematic as there are other pioneers in this field alive and well. One other name in this list Allen J. Bard is equally problematic because as far as the Wikipedia community is concerned his contribution to science - scanning electrochemical microscopy - is irrelevant. Sure, there is a biopage but no page on this type of microscopy or even a single Bard citation on any page.

If it is up to Chembark the prize belongs to Richard Zare and W. E. Moerner for their work on lasers. Moerner gets a mention on the Single-molecule experiment page. Zare (again in the Wikipedia universe) is notable only for his involvement in the controversial Allan Hills 84001 life-from-Mars claim. Does he still stand by that article?

Predictions aside, it will be equally interesting to see how the media will eventually handle the winning science. Science journalists must occasionally be lost for words. How to sell the prize to the general public! In 2005 when the prize was in the field of olefin metathesis it was described as an innovative way to reduce chemical waste by the leading TV news bulletin in the Netherlands which may be true but is beside the point. Last year when the prize was all about coupling reactions the same bulletin skipped to item all together.

This blog by the way as last year is supporting Whitesides. For a virtual tour of his lab see the latest episode of Meanwhile in the Whitesides lab

Meanwhile in the Whitesides lab

24 September 2011 - Part II

Whitesides science 2011.gifAfter our virtual visit to the Whitesides lab in 2010 here let's find out what is new from Harvard in 2011.
Take a piece of transparent and grated polyester film, apply a platinum coating on top and stick double-sided tape on the bottom. Then render the top layer hydrophilic by a 3-mercapto-1-propanesulfonic acid coat and the bottom hydrophobic with teflon. Apply iron powder to the bottom using the double-sided tape. Cut up the film into tiny squares (2x2 mm) and set them afloat in a petri dish filled with perfluoro-1-methyldecalin and water. What do you get? Tang et al. (DOI) used this recipe and in their petri dish the floating tiles behaving as reflective Diffraction grating elements, all lit up, each with a different color. In addition to that, due to the iron cargo, the tiles could be steered using an magnetic field. When water was replaced by an agarose solution, a specific tile configuration could be preserved by gel formation. PDMS was then pored over the surface and the agarose removed by melting. What do you then get? A fancy bracelet!.

And what about biomimetic hair? In deep reactive-ion etching the combination of sulfur hexafluoride and a plasma results in a directed beam of radicals that can eat away the surface of a silicon wafer not protected by a resist. In this way you can punch nanometer-size holes or trenches into the silicon. To prevent wall collapse etching is periodically replaced with passification: adding a teflon layer by introducing gaseous octafluorocyclobutane. This protects the walls more than the bottom of the hole resulting in deeper trenches. Kim et al. (DOI) used such a wafer or rather its mirror image made from a UV-epoxy resin cast. In SEM images the surface of this epoxy resin is covered with a forest of coin stacks or hairs. These hairs were then covered in a layer of platinum (sputtering) and then in a layer of polypyrrole by pyrrole electrodeposition: STEPS or structural transformation by electrodeposition on patterned substrates. And what to do with this kind of devices? In one demonstration a distance gradient was engineered between the pillars and then bacteria were set loose on the surface. The way they deal with available surface space will determine where they congregate.

The Whitesides group has a continuing interest in Magnetic levitation. Latest innovation: component assembly in 3D that does not require mechanical contact. ( Mirica et al. DOI). Various objects are suspended simultaneously between two magnets. The relative horizontal position can be manipulated by the density of each object, the strength of the magnetic field and the density of the liquid medium. One demonstration concerned a suspended optical table. Sounds like a solution of the age-old thread-in-needle problem is just around the corner.

And on an entirely different topic. Do thunderstorms trigger the nucleation of ice? only one way to find out. Stan et al. (DOI) built themselves a tabletop contraption allowing water droplets traverse a microchannel in a complex carrier gas while cooling and at the same time being exposed to an electric field. Visually observed (video) darkening of the droplets signalled the onset of freezing. A strong enough field the researchers say should be able to align the water molecules in a way that triggers freezing but after much experimenting the inevitable conclusion was a negative one.

By the way, back in January Whitesides (together with John Deutch) had thing to say about the future of chemistry in an open comment to Nature. The message: do away with the traditional scientific disciplines and get serious about integrated research. Here is a reminder of some interesting quotes: academic chemistry is overpopulated (...) and produced too few new ideas and too many average scientists (...) or jobs and Many subdisciplines of chemistry still use an apprenticeship model in which a professor conceives the problem and strategy, and graduate students execute the bench work. It is hard to imagine a worse way to prepare tomorrows chemists to work at the integration of many disciplines

Lazy chemistry

14 September 2011 - Orgo

Here is an ongoing trend in organic chemistry: how to make as much compounds as possible or try out as much reactions as possible with the least possible effort, preferably automated. Makes sense of course. Organic synthesis is time consuming and the more compounds available for lets say drug screening the better.

Take Robbins and Hartwig. In a recent publication they admit that many new reactions are stumbled upon rather than cleverly designed and in an ambitious screening program they demonstrate how to maximize the number of reactions a human can reasonably do without investing any time in reasoning how reaction can come about (DOI).

First they mixed together 17 organic compounds that each contain one functional group, among them 2-cyanonaphthalene, diphenylacetylene and dodecane. This mixture was distributed over 384 positions of a microtiter plate. Then to each of 16 horizontal rows was added an excess of a metal compound (among them CuCl, FeCl3 and MoCl5, one blank) and to each of 24 vertical rows was added a ligand, for example triphenylphosphine, cyclooctadiene and diaminocyclohexane (and a blank). After a given reaction time the content of each well was analyzed by GC-MS with each potential product identified by the molecular ion peak. The number of potential reactions uncovered this way (also allowing for homocoupling) is 16 x 24 x 17 x 17 / 2 = 55,488.

The Robbins / Hartwig paper does not actually reveal the number of reactions discovered but highlights a few. One of them is the coupling of 1-dodecyne with 4-butylaniline catalyzed by copper chloride and not even demanding a ligand at all (sobering result). The added bonus of this high-throughput method is an estimate of functional group tolerance with all these other 15 compounds are just hanging around.

More lazy chemistry is reported by Osowska and Miljanic (DOI). Their target is the synthesis of new imines and they do this with a seemingly shotgun approach. In it 5 aldehydes and 5 anilines were dissolved in toluene in a single vessel and refluxed for 72 hours. In ordinary circumstances the reaction product would be a hopeless mix of 25 different imines impossible to separate but there is a twist. The reaction product, described here as an orange sticky solid was subjected to distillation in vacuo and after 4 days (mind you, this is proof of concept chemistry, not industrial-grade chemistry) a first fraction could be scraped off from the condenser which turned out to be surprisingly just one of 25 imines in 77% yield with 96% purity. Five days later the second fraction contained a second pure imine and many days later with increasing the temperature to 240°C the final 5th imine rested on the bottom of the flask resisting any further distillation.

The trick is that the most stable and lowest boiling imine will distill first. All the other imine forming reactions are reversible and in the spirit of Le Chatelier's principle the most stable imine will continue to be generated at the expense of the other imines. this is called self-sorting (see: dynamic covalent chemistry). When the two imine reactants are depleted, the next stable imine gets a go. In this system equilibration is based on thermodynamic reaction control and removal from the system based on kinetic control.

Ataluren trial success: trial aborted.

07 September 2011 - Pharma

Ataluren synthesis  Last week the newspaper NRC Handelsblad reported on a court case in which the parents of two young boys sued a pharmaceutical company over access to one of their developmental drugs. The drug in question was Ataluren, the pharmaceutical company PTC Therapeutics. The boys suffer from Duchenne muscular dystrophy and had taken part in a clinical trial. Whereas the results of this trial on the whole were inconclusive the boys did seriously benefit from the drug. Hardly any wonder the parents took action when the whole development program was canceled.

And the judge? He threw the case out arguing that doctors do not make the compound themselves and arguing that the compound is not commercially available. Are these arguments valid? and do the boys have options?

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).

Except for the fluorine atom in it the compound is unremarkable. If you have to believe the Internet many Chinese companies produce and sell it. Ataluren is also still in the running as a potential treatment for some other diseases. So if need be the compound will be around for some time to come.

Microwaving a Grignard

02 September 2011 - Microreview

What happens when you microwave a piece of metal? Investigations as reported on youtube (here, here or here) are inconclusive. A fork does nothing, a spoon will spark somewhat and microwaving a ball of aluminum foil involves a lot of violent arcing.
What happens when you microwave a Grignard reaction?. Microwave chemistry holds the promise of faster reactions with higher yields due to efficient energy transfer but the presence of magnesium scrap makes any outcome uncertain. As Grignards are notoriously difficult to get started as a result of Mg surface passivation an investigation makes sense.

An early adaptor is Grunenthal GmbH from Aachen Germany which holds a patent on Grignard microwaving since 2004 (Link). The first to microwave a Grignard in academia were Nilsson et al. (DOI) and Suna et al. (DOI), both a year later in 2005 and both reporting success. More success stories followed: Scammells (2007) (DOI) and Hulshof (2010) (DOI).

From the Hulshof research the following observations emerged: much arcing between the Mg turnings resulted in microcavities and formation of spherical Mg particles from Mg melting, all of this resulting in high Mg surface to volume ratio and hence reduced reaction initiation time. In the reaction of bromothiophene and carbon dioxide initiation time was reduced 20-fold. The Grignard of 2-chloropyridine formed twice as fast but its instability and polymerisation prevented CO2 quenching. Bromobenzene in the same reaction was not impressed and no differences were reported.

In a very recent contribution 2011 Kappe et al. reinvestigated the microwave assisted Grignard formation of 2-chloropyridine (DOI). This time using a methanol quench they too reported initiation rate acceleration.They also discovered what happens when you turn up the microwave power to the limit: the reaction will stop. This is not an instance of the fabled and controversial microwave effect. It is simply the THF solvent that starts to decompose and spoil the Mg surface.