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More abnormal NHC carbenes

23 June 2012 - Orgo

diaminocarbene pyramidalized bertrand 2012  The Bertrand lab continues to churn out carbenes by the dozens. In a latest variation a NHC carbene has its reactivity pattern tuned not only to behave as a nucleophile (the default behavior) but as an electrophile as well (DOI).
In a previous episode here one of the amino groups was replaced by a methylene group which enhances electrophilicity but also nucleophilicity. The new carbene has one of the amino groups pyramidalized which also increases electrophilicity (restricted N lone pair donation to carbene) but leaves nucleophilicity the way it was (no change in electronic contributions of the substituents).
Deprotonation of intermediate 2 turned out to be tricky: at -30°C carbene 3 attacks the base KHMDS by N-H insertion. Hence the -70°C. Nucleophilicity was then demonstrated by reaction with carbon dioxide and electrophilicity by reaction with cyclohexylisocyanide (otherwise an unknown reaction mode for NHC carbenes).

Chloroform chemical storage

18 June 2012 - Orgo

A new use for chloroform? We know it as a solvent, as a precursor to teflon and perhaps as precursor to dichlorocarbene. In Organic Letters Yuki Kuwahara and colleagues add a new use: that of cheap chemical storage vehicle for elemental chlorine, HCl and phosgene. DOI. How? Expose to oxygen and ultraviolet light. The photochemical decomposition of chloroform is complex but you end up first with HCl, Cl2 and ClCOCl and finally with carbon dioxide and carbon monoxide as well. Of course phosgene is very toxic and safe storage will always be an issue.
The photochemically enriched chloroform was successfully tested on several substrates (anisole, anthracene) in simple chlorination and then with phenol in esterfication to diphenylcarbonate. The last reaction did require an excess of triethylamine needed to remove the HCl.

The Michael addition Walker

15 June 2012 - Making It Move IX

molecular walker campana 2012  In a new episode of Making It Move we take a look at the Michael addition Molecular Walker as conceived by Araceli Campaña et al in Angewandte (DOI). Bioinspired by the motor proteins kinesin and dynein, this surprisingly simple two-legged creature is a-methylene-4-nitrostyrene and its platform a string of polyethyleneimine.
Walking is possible by virtue of a series of reversible intramolecular Michael and retro-Michael additions. The motion is not unidirectional: a bunch of walkers will continuously move around, each on its own track and when after some time chemical equilibrium sets in there is no longer any apparent change as monitored by proton NMR.
In DMSO the half-life for a single step is 1.5 hours. When walker-free amine is added, after 3 days only a fraction of walkers have detached from their own track as monitored by mass spectroscopy. When the central amine groups are replaced by methylene groups no walking takes place at all meaning that the walkers are unable to cheat by moving from start to finish in one go.
In one configuration, an anthracene unit was added to the opposite end of the walker, known to quench nitrostyrene fluorescence. Lo and behold, the fluorescence in DMSO decreased by 50% over a period of 5 hours.

Target: Artemether

08 June 2012 - The war on Malaria II

Artemether Stringham Taeger 2012  In a previous episode chemical company Sanofi was granted exclusive access to certain yeast cells that produce a precursor to anti-malarial drug artemisinin. One of the charities making this all possible is the Bill and Melinda Gates Foundation. Another charity that has apparently entered into the drug business is the Clinton Health Access Initiative. Bill together with Rodger Stringham and David Teager report on an improved process for the conversion of artemisinin to artemether in Organic Process Research & Development (DOI).
Does the Clinton Health Access Initiative have a pilot-plant facility or even an organic lab? Unless it is all cramped in suite 400 on Dorchester Avenue in Boston, the article is not very explicit. The acknowledgements mention Mangalam Drugs and Organics.
Case at hand: artemether has the carbonyl group replaced by a methoxy group in a two-step reduction - methylation. So far so good. The point is that principal supplier Novartis reports up to 68% overall yields but that many Indian and Chinese suppliers working with the procedure generously supplied by same Novartis, report considerably lower figures (58-62%). But Why? And how can the process be improved?
Any organic chemist knows reported yields in the literature should be considered with caution. Chemists tend to be over-optimistic / self-delusionional but this scenario was not considered. No bottlenecks were encountered in step 1, the reduction with sodium borohydride. Only the beta form was isolated due to its poor solubility in the quench. Drying the product without heat prevented formation of one byproduct. Moving on to step two, the methylation with HCl in methanol was more troublesome. The byproducts lurking around the corner are the anomer and the elimination product. Co-solvent (co-reagent?) trimethyl orthoformate made all the difference. The critical element in the workup was first adding more methanol before adding the base quench otherwise you end up with a nasty gum. The new record yield for the improved synthesis is 72%.
But what have all these suppliers been doing wrong with the existing Novartis procedure? The answer to that question, remains unclear. The Novartis yield for step two with co-solvent methylacetate (not the formate) was confirmed so no surprise there.

BASF on sustainable chemistry

05 June 2012 - Marketing

BASF promo.gifCheck out this BASF promo on youtube. The video warns that pretty soon in 2050 we share the world with 9 billion people who want a "livable environment", a "stable climate", "clean water" and most of all a "sustainable future". BASF creates chemistry! All nice and well. But what are the labcoat-wearing individuals admiring right in the middle of the clip? n-octane? What kind of message is that? In 2050 we will still rely on gasoline? Octane's only claim to fame is its presence in gasoline. And BASF does not have to create it, just distill it. Okay it could be perfluorooctane but here Wikipedia does not list any cool sustainable applications either.
What more appropriate molecules could BASF have showcased? They make a lot of pesticides like Fipronil. In the promo the company mentions it is dedicated to increasing crop yields and pesticides are one way to accomplish that. BASF also makes a lot of polyurethanes that help reduce the weight of any transporter. It also sells isometheptene. With 9 billion fellow humans you may need that occasionally.

Also see ExxonMobil on fuel

The future of DOI is ORCID

02 June 2012 - Information science

We are used to DOI's now for over 10 years. If a DOI is known for an scientific article, simply punching in the url http://dx.doi.org/xxxxxx will get you to its location and eventually access. All scientific publishers today support DOI's although implementation is not flawless. Articles from before the DOI era have a DOI added but retroactively including this DOI to the actual pdf of that article while technically trivial, for publishers is a major challenge. Any scientific article concludes its business with a list of citations and what would be more convenient if all citations would be accompanied with a clickable DOI? Wiley agrees but ACS publications and many more publishers do not. And why do all links in these pdf files target SELF and not BLANK? Scientific publishers deserve more competent IT managers!. At least Wikipedia has fully adopted it and to satisfaction.
And getting to the actual topic of this blog, why is it not possible to attach a similar identifier to a scientist? A good question and addressed in a Science News item by Declan Butler that sadly does NOT have a DOI. Butler introduces us to a certain Y. Wang who apparently publishes 10 articles per day and is the most productive scientist on the planet. Of course many different Wangs exist and if only it was possible to distinguish between all these Wangs. Via a unique identifier called a ORCID (Open Researcher and Contributor ID) !!.
Pretty straightforward, but why is this identifier still discussed and not implemented even in 2012? One obvious reason could be that fat commercial players are trying to get an exclusive hold on the game, for example fat cats like Thomson Reuters with their ResearcherID. Implementing an identifier on a non-profit basis really should not be that costly: Crossref charges one dollar for a DOI (here) although we should be aware that even non-profits can get tremendously wealthy by overcharging (hi ACS!).
The major challenge in the proposed scheme of course is assigning authors to articles. According to the ORCID website individuals alive today can create a orcid just like that. But who is going to link http://dx.doi.org/10.1021/ja01201a526 to Robert Burns Woodward? It should not be linked to Bob Woodward or Robert Woodward or even Mr. Burns. This blog is going into ponder-mode........

Water clusters exposed

02 June 2012 - Chemical physics

Another one of those unsolved problems in chemistry solved! At least according to Pérez et al. who have news to report regarding water clusters (DOI). Simple water is not just a collection of water molecules: due to hydrogen bonding water molecules tend to cluster into larger assemblies but what do these assemblies exactly look like? The proposals vary from dimers to (H2O)100 networks but tetramers, pentamers and hexamers take prominent positions. Pérez has been looking at hexamers only and more specifically the hexamer isomers. The weapon of choice: rotational spectroscopy or more precisely a chirped-pulsed Fourier transform microwave (CP-FTMW) spectrometer. Rotational spectroscopy can only be applied to gas phase molecules which makes you wonder how it can be used in a typical bulk property. Experimental details are scarce but probably the method works by ejecting liquid water into a vacuum and then the clusters are analysed as they break up? A carrier gas is also involved. Somehow. The working temperature is not mentioned anywhere. Out comes a complex spectrum but based on computational modelling all peaks can be assigned to the heptamer and three hexamer isomers: a cage, a prism and a book with population ratio 1:1:0.25. Rest assured, there are complications: the ratio depends on the type of carrier gas and peaks multiply by using oxygen-18 enriched water.
The presence of a book geometry is counter-intuitive and instantly this blogs favorite. With 5 idle hydrogen atoms, this isomer should convert to the prism (three idle hydrogen atoms) with ease but does not. And what about a (H2O)6n ladderane?
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