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Endo or exo? Balancing bulkyness

28 February 2011 - OrgChem

Norcamphor reduction Upadhyay 2011  Combine the ketone norcamphor, the reducing agent samarium iodide, the proton donor methanol and the solvent THF in a test tube and the scientific paper will write itself. Because how do you make sure only the endo or exo alcohol is formed in this organic reduction?. In general, the exo product is formed by unhindered endo-attack from a relative large substrates. For smaller substrates the more hindered exo attack is also an option. In a recent paper Upadhyay & Hoz establish that proton donors such as ethanol, trifluoroethanol (TFE) and ethylene glycol (EG) stick to the plot because increasing the concentration of the alcohol increases the concentration of the relatively large SmI2.ROH adduct as substrate and hence the endo/exo ratio. Methanol and water on the other hand appear to be behaving oddly because on increasing their concentration the endo concentration first decreases before it increases.

So what sets these two groups of proton donors apart? According to Upadhyay & Hoz it is not polarity or acidity but their ability to form a complex with samarium ions. The reaction product of the first electron transfer is a radical anion (1) with a bulky -O-Sm(III) substituent. At low concentrations, water and methanol can join up with two Sm ions forming an even bulkier Sm-O(R)-Sm dimer. The dominant orientation for the substituent group after the second electron transfer and final protonation is therefore endo. When the proton donor concentration increases less dimer is present. When the substituent and electron donor are about equal size endo and exo product are expect in equal amounts. With even higher proton donor concentration protonaton takes place before the second electron transfer forming intermediate 2. Now the electron donor is again much larger the the oxo substituent and endo-formation prevails again. Convincing theory? Not all the data collected in the paper are helpful. Comparing the high-methanol reaction with the low methanol reaction is chemical yield is cut in half at a tenth of the reaction time which is odd. The TFE and EG plots do not rule out an actual U shape, it would be a matter of longer measurements at lower concentrations.

New descriptor for molecular stability

23 February 2011 - Computational chemistry

Andrej Krzan and Janez Mavri have been wondering about the occasional thin line between stable molecules and unstable molecules (DOI). Take for instance stable oxalic acid (HOC(O)(O)COH) and the non-existent carbonic acid dimer HOC(O)O(O)COH or the biodegradable biopolymer poly(glycolic acid) and the non-existent polycarbonic acid. When too many electron-withdrawing groups make a demand on carbon so it seems the molecule starts falling apart. But how to quantify stability?
An Atoms in Molecules sweep among a range of molecules related to oxalic acid did not yield a trend in the critical bond point (BCP) position. On the other hand a strong correlation was found between atomic charge and atomic volume. In one extreme the central carbon atom in the very stable isobutylene has no net charge and a large atomic volume of 70 cubic Bohr units. In the other extreme the central carbon atom in the hypothetical carbonic acid has a charge of +2.7 and an atomic volume approaching 10. Two molecules dodge the trend. Carbon dioxide and formic acid have higher volumes than predicted from atom charge and this makes Krzan and Mavri believe that volume (anything higher than 20) is the new stability decider.

The art of lifting an egg

19 February 2011 - Soft robotics

soft robots Ilievski 2011.gifGeorge Whitesides and DARPA have joined forces to bring you another innovation in robotics. Problem: regular robots are clumsy when it comes to handling soft materials when the robot shell is a hard material. A robot picking up a raw egg must have a good sense of the amount of force it can apply if it want to avoid disaster. Solution: fit the robot with a soft shell as well. In the accompanying pic a plastic gripper is lowered, an egg is grabbed and then successfully lifted (Ilievski et al. DOI). This gripper is made up of a core of starfish-shaped polydimethylsiloxane. This section has channels in it that allows pressurized air to enter and exit the arms. It is cast from a mold based on ABS produced in a 3D printer. The core is flanked by two layers of another silicone elastomer, grooved for extra grip. When air is introduced in the channels the central section will expand but as the outer layers resist the expansion the nett result is bending of the arms and a gripping motion. The lifting action is not limited to eggs: for some reason anesthetized mice were included in the research. The Whitesides lab assures us no animals were hurt in the making of the gripper.

* Also see: egg grabbing footage here (.mwv file)
* Also see: Meanwhile in the Whitesides lab

From hexane to benzene

12 February 2011 - Catalysis

dehydroaromatization Ahuja 2011  After reading this blog you will have learned how to synthesis benzene from n-hexane. Now you say hexane is at the most a solvent but not a reagent but then you have underestimated the power of catalysis. Ahuja et al. (DOI) claim to be first to use homogeneous catalysis with reasonable temperatures in the dehydroaromatization of linear alkanes. The technique is transfer hydrogenation with either t-butylethylene (TBE) or propene and the catalyst one based on iridium with a phosphine pincer ligand. Sure enough 165°C and 120 hours into the reaction benzene is formed at 44% conversion.
The real prize though is synthesis of alkylated arenes that are currently produced industrially from aromatics with Friedel-Crafts acylation and Clemmensen reduction. These aromatics are petroleum-based of which supply is dwindling whereas n-alkanes can be produced in the Fischer-Tropsch process from carbon monoxide and hydrogen gas.
The conversion of n-dodecane with 4 equivalents of TBE is believed to proceed by a triple dehydrogenation, followed by electrocyclization and another dehydrogenation. The yield of the actual objective - n-hexylbenzene - is meager (1%) but the total aromatics count is 52%. The authors also present a riddle: what is benzene (17%) doing in the mix? Somehow a carbon - carbon bond gets cleaved but n-hexylbenzene itself or hexylcyclohexane are resistant to cleavage when exposed to the reaction conditions and catalyst.

Pfizer on Eletriptan

05 February 2011 - Pharma research

eletriphan synthesis Ashcroft 2011  Oops, there the European Union drains another 2300 chemistry jobs as Pfizer announces job cuts in Sandwich UK. Too bad because this blog just came across some recent&decent research by Ashcroft et al. (DOI) originating from just this facility. The topic is eletriptan and novel way to synthesise it. The compound commercially known as Relpax and supposed to treat migraine is horribly expensive. A quick internet search gives a ballpark value of 15 US dollars for a single 20 mg tablet and finding an alternative synthetic approach therefore makes a lot of sense.

Synthesis of chunk 1 started off from the dimethyl acetal of bromo acetaldehyde 1 which was converted to dioxane 2. After conversion to Grignard reagent 3 it was reacted with Weinreb amide 4 (derived from 4-methylaminobutyric acid and carboxybenzyl protected) to ketone 5 (THF, 60°C). Deprotection , cyclization and imine reduction (H2, Pd/C MeOH) then yielded racemic pyrrolidine 6 isolated as its fumarate salt. Although asymmetric synthesis has been around for 40 years, industry still relies on good old chiral resolution: chiral (R)-7 was isolated from the diastereomeric salt with the dibenzoyl ester of tartaric acid. The authors also add this route was not their favorite for other reasons: the intermediates are all clumsy oils and functional group protection is something you want to avoid.

Chunk 2 was prepared from 4-nitrophenethyl bromide 8 . Reaction with sodium benzenesulfinate (2-propanol/water) gave sulfone 9 and without workup hydrogenation (Pd/C) produced aniline 10. Oxidation with sodium nitrite gave the diazonium salt 11 which was isolated as the oxalyl hydrazine 12 by reaction with ascorbic acid. In the final step the free hydrazine was liberated from its calcium salt by adding sulfuric acid and joined with 7 in a Fischer indole synthesis to target eletriptan 13.