If not wikipedia then what

31 July 2008 - the online encyclopedia spectrum

The importance of publicly and freely accessible chemical information is bigger than ever. Twenty years ago the chemical enthusiast could wander into a university library and physically pick up a book or a journal but with electronic publishing and all, login accounts bar access to a library computer or e-library. Subscription fees for scientific journals including those chemical go through the roof and even simple college textbooks become hugely expensive. The New York Times last week reported on a new (free and therefore illegal) file sharing initiative called pirate bay with on offer John E. McMurry’s Organic Chemistry that in a shop costs over 200 dollars.

So what is out there on the Internet for those without library access and/or monetary resources.

Of course Wikipedia should be the answer to everything but the chemistry desk seems to be in a bit of a crisis. There is hardly any growth in chemistry content (except for the talk pages) and in fact content gets deleted one sentence at the time (wikipedia is shrinking). What appears as new content often turns out to be a copy from another part of wikipedia and many additions are in fact invitations to read content somewhere else (those same journals you do not have access to!). Wikipedia really needs to reconsider some policies such as original research and merging and should provide some guidance with respect to those pesky single-issue editors.

So if not wikipedia then what?

There is of course citizendium created by wikipedia co-founder Larry Sanger in 2007. This encyclopedia is invitation only and specialist editors should offer better quality than volunteer-run wikipedia. The interesting observation however is that the specialists on citizendium and the volunteers on wikipedia are preoccupied with identical tasks: categorize articles, add links, formatting and spending a lot of time on the talk pages. So no new content there.

Move over to scholarpedia. This initiative invites active researchers to write an article about their specialization with impressive results. Unfortunately for us chemists it is heavily focused on topics in dynamic systems, artificial intelligence and neuroscience. In fact there there is just one chemistry article: Belousov-Zhabotinsky reaction

Next up: h2g2 stands for Hitchhikers Guide to the Galaxy and is a volunteer driven content generator run the the BBC. Be prepared for articles on The Mole, The Chemistry Of Vampire Slaying and Acidity and Basicity. Lets say quality varies over a very wide range.

And there is of course the new encyclopedia on the block, presented by -resistance is futile- Google and christened Knol as a Unit of knowledge. In the Knol model editing is available to anyone (identity checked through creditcard info), it is not possible to co-author and several articles may exist for the same topic. Only one chemistry article thus far, organic chemistry.

Organocatalytic domino

29 july 2008 - Catalysis

Combine the fields of organocatalysis with that of domino reactions and you have created the brand new field of organocatalytic domino reactions. This science is of some importance because it is as close to biomimetic synthesis as you can get. The basic idea is to synthesise complex molecules from a mix of several simple molecules and a simple organocatalyst. With a chiral catalyst as an added bonus, the reaction is also asymmetric. Advantages in general: no metal catalyst therefore potentially environmentally friendly, avoids use of protective groups. Many handles exist for this particular field, to name just a few: organocatalytic cascade, domino, tandem, multicomponent, assembly, organoclick or variations on catalytic organocascades.

Here is what happened thus far.

The first relevant work (the classic 1917 tropinone synthesis aside) appears to be produced by the laboratory of Carlos Barbas in 2002 concerning Hajos-Parrish chemistry joining three molecules of acetaldehyde together to a complex hydroxyhexanal (DOI) and in another exploit a pyranose forms from propionaldehyde (DOI).

In a 2004 paper Barbas et al. are making a case for (DOI) so-called organo-click chemistry based on organocatalytic multicomponent reactions with reference to click chemistry (invention of Cripps buddy Sharpless), for instance with a Domino aldol/Knoevenagel/Diels–Alder reaction. Typical reagent set: Meldrum's acid, 4-nitro substituted benzaldehyde and acetone with pyrrolidone catalyst in an ionic liquid.

In 2005 three big guns in organic chemistry set their sights on organocatalytic cascades with three JACS publications separated by just 13 days : List et al. (DOI), MacMillan et al. (DOI) and Jorgensen et al. ( DOI).

The first system combines organocatalytic transfer hydrogenation with an Hantzsch ester and Michael cyclization using a McMillan catalyst.

The second system is sequential nucleophilic attack (a furan) and electrophilic attack (a chlorine donor) on crotonaldehyde using the same chiral catalyst for step one.

The third system is almost identical to the second based on iminium / enamine activation. This time the nucleophilic partner is a mercaptane and DEAD is starring as the electrophile.

What these three systems have in common is sequential iminium catalysis (electrophilic) and enamine catalysis (nucleophilic).

This order is reversed in a report by Enders et al. in 2006 (DOI) creating a cyclohexene carbaldehyde with 4 new stereocenters from propionaldehyde, a nitro alkene and an enal.

Two recent 2008 contributions: Jorgenson (DOI) adopting the Enders protocol claims bragging rights for controlling the formation of 1 out of 64 possible stereoisomers in a single organocatalytic cascade


and Penon (DOI), again inspired by Enders, demonstrates another cascade, forming 5 stereocenters in one go one of which qauternary and listing cyanoacrylate as an unlikely reagent (the authors haste to note that this compound can be found in superglue).


Novel Imatinib base synthesis

19 Juli 2008 - Industrial organic chemistry

A new imatinib synthesis is presented as an alternative for the existing industrial method. But is it really an improvement and one suitable for industry?

Organic Process Research & Development (Link) is a scientific journal (ACS) dedicated to industrially relevant organic synthesis which is very different from regular academic laboratory synthesis. In industry and especially in pharma, reagents have to cheap, safe to handle and non-toxic, the reaction has to be reproducible and should be scalable. Side products and waste products have to be precisely known.

Hundreds of synthetic protocols are known en new ones invented every year for one and the same chemical transformation. Only those that have proven to be reliable will find their way into disciplines such as total synthesis (after all, why risk all yield with a fancy new reagent in step 25 of your synthesis) and even fewer end up in a chemical plant. This is why reading up on industrial synthesis is worthwhile if you want to filter out the relevant reactions from the wannabees.

As an example of research aimed at industrial production one involving imatinib. This cancer drug was one of the first offspring of rational drug design and if you believe the Wikipedia page hugely expensive despite its simple appearance (no stereocenters!). A group of Northwest University researchers set out to improve the existing Novartis procedure DOI and here is how they did it.

2-acetylpyridine (1) was alkylated with the acetal of N,N-dimethylformamide 2 to enamine 3. A pyrimidine ring in 5 was formed with base and reagent guanidine nitrate 4 and nitrotoluene fragment 6 was added in a Ullmann-type reaction with CuI generating secondary amine 7. The nitro group was reduced by hydrazine / FeCl3/C to the amine which was then converted to amide 8 with acid chloride 9. The final step is addition of piperazine 10 to form imatinib 11.

So is this procedure an improvement on the existing method and ready-made for industrial implementation? Surely they have eradicated the use of toxic cyanamide, cumbersome sodium metal and expensive palladium but they have also introduced equally toxic hydrazine and the harmful and explosive guanidine nitrate. As a further point of criticism the final step is demonstrated on a 0.5 gram scale. If the journal Organic Process Research & Development would live up to its standards the scale would at least be a kilogram.

Liu, Y., Wang, C., Bai, Y., Han, N., Jiao, J., Qi, X. (2008). A Facile Total Synthesis of Imatinib Base and Its Analogues. Organic Process Research & Development, 12(3), 490-495. DOI: 10.1021/op700270n

Frustrated Lewis pair briefing

17 July 2008 Updated 11 September

One of these 2008 buzzwords: Frustrated Lewis pair (FLP). This is a Lewis acid - base pair in which steric hindrance precludes regular Lewis acid–base adduct formation - as in for instance ammonia borane - through a coordinate covalent bond. Justly frustrated , these reactive groups turn to other molecules hanging around with unexpected reactivity. The first Lewis pairs to be investigated were based on boron and phosphorus, largely as a result of work by the group of Douglas W. Stephan of the University of Windsor (Latest review Stephan 2008 DOI).

Ever since his pioneering 2006 article on metal-free hydrogenation with a frustrated phosphonium borate (DOI) (48 citations to date) Stephan explained how the catalyst was made in the first place - by thermal rearrangement of phosphine / tris(pentafluorophenyl)boron Adducts (DOI) - and how its Lewis acidity can be tuned (DOI).

That phosphine-borane complexes can expulse hydrogen to form phosphinoborines is known since 1953 (Burg & Wagner DOI). Reversible hydrogen uptake and delivery surely was a surprise.

Stephan then demonstrated the reaction of sterically hindered phosphines and boranes in tricomponent reactions with hydrogen (cleavage!) ( DOI) and with olefines (to zwitterionic phosphonium borates) (DOI) and with nitriles (reduction!) ( DOI)

The tricomponent olefin reaction is unusual because phosphines or boranes are unable to react to the olefin on their own. Therefore a special reaction mechanism must be at work.



In a recent in silico contribution Stirling et al (DOI) shed some light. The reaction is described as truly trimolecular with a single (early) transition state, slightly asynchronous with B-C bond formation preceding P-C bond formation. Further computed characteristics: reaction is strongly exothermic and irreversible and the molecules preorganise themselves for reaction based on a mixture of van der Waals force interactions, weak interactions between hydrogen and fluorine and weak boron - ethylene interactions. A charge transfer complex as postulated by Stephan is not observed.

Another computational study (DOI) also arrives at a concerted reaction mechanism in which ethylene seems to act as a bridge for electron transfer from the Lewis base center P to the Lewis acid center B

In another development, Bertrand et al have demonstrated hydrogen and ammonia cleavage with certain carbenes (DOI).

Hydrogen activation by a singlet carbene is very similar to that of a transition metal as both have a filled orbital and a vacant nonbonding orbital. Unable to interact with each other (or dimerize to an alkene) carbenes too can be considered frustrated Lewis pairs. In this reaction the carbene reacts as a nucleophile, creating a transient hydride which recombines with the positively polarized carbon.

The definition of FLP gets a bit stretched in the Bertrand report (in it FLP does not get a mention but others have made the connection) but a true carbene - borane system was reported in 2008 By Stephan et al. (DOI) and (identical system only 5 days later) by Holschumacher et al. (DOI):

In absence of hydrogen carbene and borane will slowly form an insoluble and unreactive adduct, the reaction of carbene with hydrogen alone was not investigated.

Most recently, the frustrated Lewis pair family was extended to combinations of amines and boranes by Sumerin et al. (DOI). TMP was reacted to B(C6F5)3 in presence of hydrogen gas to form a adduct capable of reducing benzaldehyde:


A B/P system with an ethylene or alkene bridge and capable of simple reductions has been developed by Spies et al (DOI (DOI).

European Chemistry vacation

14 July 2008 - Holiday

It is the holiday season in Europe and of course you could visit the Eiffel tower, the Acropolis or one of many Mediterranean beaches. But if all that sounds dull & boring to you (please say yes) why not do a historical chemistry tour!.

Start of the tour: Leiden (The Netherlands, North Sea coast) at the Boerhaave Museum (a science museum) which commemorates with a special exhibition, the liquefaction of helium exactly 100 years ago by Heike Kamerlingh Onnes. They have all his equipment on display (!) .

Next stop: Teylers Museum (80 km northbound) opened its doors in 1784 as a curiosity cabinet. Among its inventory uranium glass and a 1790 device for reacting hydrogen with oxygen.

Fortress Sonnenborgh (website) in downtown Utrecht (go east, we are still in the Netherlands) houses remnants of a chemical laboratory used by University of Utrecht professor Barchusen between 1702 and 1723.

Leaving the Netherlands behind we move into Germany heading for Bad Münstereifel and the Iversheim lime kiln (in full working order) proudly owned by the guys of the 30th legion of the Roman Army between 150 and 300 AD. And don't say that's not chemistry. Local Dolomite rock (CaMg(CO3)2) is heated to 1000°C expulsing carbon dioxide and forming a variety of quicklime (CaMgO). At the construction site water is added to form the hydrate CaMg(OH)4 and when mixed with sand it can can be processed into any shape. The hardening process is a chemical reaction with (surprisingly) carbon dioxide reforming the dolomite and expulsing water (see a 2008 Chemie in unserer Zeit feature DOI).

Moving even further east Weikersheim Castle holds remnants of an alchemical laboratory built and occupied by Graf Wolfgang II. von Hohenlohe around the year 1600 and an exhibition dedicated to it ( DOI). The poor Graf was almost swindled by master alchemist / con artist Michael Polhaimer with a promise of gold by transmutation of lead. Polhaimer was caught and spent two years in the castle's jail rather than in the laboratory.

Final stop Chemie-Museum Merseburg, near Leuna right in the heart of German chemical industry during both World Wars (ammonia, synthetic rubber, synthetic oil) and one of the biggest chemical plants of the DDR. This chemical science park contains a Haber-Bosch ammonia plant, a plant for the production of syngas and much more ( DOI).

I wonder what they sell in the gift shop.

Uranyl chemistry riot

12 july 2008 - Organometallics

Uranyls are hexavalent compounds of uranium of the type UO22+ with a O-U-O bond angle of 180° (trans) that is taken for granted. A cis-uranyl therefore was a surprising find as reported by Paul B. Duval et al. of the University of Missouri-Columbia in an Angewandte Chemie (VIP) article in 2007(DOI).

However Michel Ephritikhine et al. of CEA Saclay (the French Atomic Energy Commission) now allege in the same journal that news was too good to be true (DOI).

In a very simple reaction the Missouri people added uranyl acetate to a stirred suspension of monocarboxylated ferrocene (fcc) in dichloromethane (Note added: as to the why of this combination the article is not specific) and after evaporation reddish-orange crystals appeared in a 83% chemical yield.

The reaction product was identified as a coordination polymer of alternating ferrocene units connected to uranyl group through the carbocylic acid group and connected to the next unit via a newly formed carbon-carbon bond. X-ray crystallography revealed the cis-uranyl configuration and as another novelty the reaction was found to reversible simply by adding glacial acetic acid.

The CEA people on the other hand, repeating the procedure only found some red crystals among an orange powder and dark materials but ultimately isolated what they believe is (UO2(fcc)2(L)2)·L with L solvent pyridine or methanol in about 80% yield which is basically uranyl acetate with the acetate groups replaced by ffc and water by solvent. Nothing remarkable really, no bent O-U-O bonds and no reversible CC bond formation.

The reaction is seemingly simple but the findings of both groups are miles apart and they cannot be both a little bit right. The Angewandte post office should expect Missouri mail right about.....now!