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Chemical reaction database update

22 October 2013 - Cheminformatics

There are some new initiatives to report on the topic of open-access chemical reaction databases, all sparked by a single email to the Openbabel discussion list. Here is a quick summary of some of the responses. Chemspider is serious about setting up a database, see slideshare presentation here. Not exactly open-source but at least a free resource (open-access). The database resides here and one test with NC1=C(C=O)C=C(C=C1)Br has 8 (!) immediate hits. Chemaxon lists 241 organic reactions with open-access but no download button here either. From inChi it is a small step to RInChI! The website is here. Describing a chemical reaction in a single string is certainly intriguing. A small sample set is included.

In the meanwhile progress on our own CRD database is slow. The number of reactions is a lousy 149. No matter what level of job automation, it still takes too much time to process just one reaction, the Openbabel discussion has some complaints about patent literature as too difficult. In my experience patents work very well, partly because patents are more careful about identifying chemicals by the correct name. One more initiative worthwhile to mention: OSRA promises that it can scan any pdf document and extract the SMILES code of each and every chemical depicted. Now that would bring complete job automation within reach and make commercial chemical database bosses nervous. I am going to try it out for myself.

Not yet open-access (no website) but at least the raw data are available for free here (.sql file, 4 MB) for the CRD. Reaction number 149 is depicted below.
CRD149.PNG

Diversity is Good

17 October 2013 - Strategies

Beckmann 2013 structural diversity in drug targets.PNGHow diverse are our drugs anyway? Assuming that molecular shape is dominant in pharmaceutical effectiveness, you would expect our drugs to come in all sorts of shapes otherwise they would all compete for the same biochemical spot. An intriguing plot presented by Beckmann et al. here reveals that is not the case and in the big triangle between disk (benzene), rod (acetylene) and sphere (adamantane) most drugs huddle together between rod and disk and few venture into sphere territory. But Beckmann et al. are doing something about that: producing more sphere-shaped molecules. The keywords are diversity-oriented synthesis , a build/couple/pair (B/C/P) strategy, fluorous chemistry and macrocycles.

Starting point in the Beckmann research research is a propargylic amine, the amine end of which is fitted with a detachable organofluorine segment for easy of separation later on, and with an azide carrying group. This is the build phase. In the couple phase the the azide is then converted to an aza-ylide which is then reaction with a number of electrophiles. In the third step, the pairing, the linear molecules are coupled end-to-end to macrocycles using a number of techniques such as click chemistry and enyne metathesis. In the final step in creation of diversity the fluorous tag was cleaved and replaced by a number of ester residues. In all, 59 compounds were created in 5 steps from a single precursor.

The sphere concept is here to stay? Not related in any way to the Backmann research it must explain the sudden interest in the otherwise totally obscure cavicularin as a target in total synthesis.

The sodium borohydride - nitroform adduct

14 October 2013 - Chemical Zoo

The combined US navy, US Air Force and the US Defense Threat Reduction Agency were more than happy to fund research into the adduct of sodium borohydride and nitroform as a new high-energy density material aka explosive. The report is titled "BH3C(NO2)3: The First Room-Temperature Stable
(Trinitromethyl)borate" and principal author Bélanger-Chabot points out that the compound is not only explosive but also green because the boron employed is non-toxic (DOI). As if greenness is relevant in warfare. Additional and more sensible rationale, a stable B-C bond in this compound is certain to stabilise an otherwise unstable nitroformate anion. In the meanwhile the initial recipe is dead-simple , mix nitroform and sodium borohydride in glyme and after effervescence the yellow solution contains a quantitative amount of BH3C(NO2)3. The work-up is tricky : The solvent was removed under vacuum between -40 and -8°C over the course of several days. The compound exists thanks to the glyme, remove it by a vacuum and you end up with sodium nitroformate. Even with glyme decomposition takes place within a week at RT.

So the compound is less stable than expected, and the authors suggest that the strong B-C bond is partially offset by reorganisations from planar to tetrahedral on dissociation of the two ionic fragments.

Questions: why is the adduct called a borate when no oxygen is in sight? With respect to the opening line : "Ever since the first report on the nitroformate anion (...) trinitromethyl derivatives have been a subject of significant interest" what is the meaning of "signification interest" given that this first report dates back to 1899, more than a century ago. I guess interest in the electron or radioactivity can be considered "significant" in this timespan but the nitroformate anion?

Meanwhile in the Whitesides lab (IV)

08 October 2013 - Nobel Time

Nobel time is near so let's have a quick look at what George M. Whitesides (99:1 on Chembark) is up to in his laboratory, also see previous episodes from 2012 , 2011 and 2010. We are detecting some themes here, for example soft materials like the (The Jumping Soft Robot) from an earlier blog , the lab-on-a-chip here and premeditated torture of little worms here, this time by starvation.

A very recent contribution is what looks like research on 3D-tumor models DOI for drug evaluation involving no doubt a lot of chemical engineering. Another report is about stretchable transparent conductive films (DOI) en route to transparent loudspeaker systems (that would be cool) . Whitesides also has an interest in the binding of ligands to proteins and the role water plays in it, as recently summarised In the Pipeline.

And what is this? In the brand new field of infochemistry you can create a devise that can burn up to three alkali metal salts on a piece of cotton, creating 19 unique signals and then record the signal using a telescope from a kilometer away (DOI). What for? Search and rescue of course!