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The chiral Grignard

27 April 2011 - Orgo

The chiral Grignard  In 2000 Hoffmann et al demonstrated the synthesis and reactivity of a chiral Grignard reagent. These compounds can not ordinarily be made from the standard reaction of an (chiral) halide with magnesium metal because the stereogenic carbon atom next to magnesium at one point is a free radical with accompanying racemisation.

In the 2000 experiment the chiral Grignard was therefore prepared in a rather outlandisch reaction between a chiral sulfoxide (1) and three (!) equivalents of ethyl magnesiumchloride (2). The first one in an exchange reaction to intermediate 3, the second one in a substitution reaction to form the actual chiral Grignard 4 and the third one by necessity in a reaction with the sulfoxide byproduct 6 to ultimately form diethyl sulfoxide 7 and aryl magnesium chloride 8. Is there a better way?

Judging from a recent publication in Organic Letters, Chen/Fu and Xu think there is. They argue that an alternative pathway to didical formation exists by direct insertion of Mg into the halide C-X bond. In computer simulations (DFT) they reacted a hypothetical Mg4 cluster with methylbromide. Predictably the radical pathway has a much lower activation energy (with in the TS one radical delocalized over the entire Mg cluster) than any of the nonradical pathways.

But what will happen if the cluster size is increased?. Chen/Fu/Xu found that Mg9 has two nonequivalent types of Mg atoms A and B. In FMO analys the nonradical pathway proceeds by electron donation of a high energy MgA (3s) HOMO with the empty sigma orbital of the C-X halide lone pair LUMO (the halide is the electrophile). The MgA atoms are those exposed at corners or edges (defects) with lower coordination than the bulk Mg atoms. When the cluster size is increased the HOMO energy is raised favorably again as is evident from decreasing IP but the amount of defects decreases (The article only provides HOMO/LUMO data for Mg9 so direct comparison unfortunately is not possible). Regular bulk magnesium has even a much lower IP but no defects all so clearly a trade-off exists. The authors think the well-known Rieke magnesium should present the best of two worlds. Together with their choice of chlorine for the halide they feel a practical chiral Grignard is within reach. If only they could find someone to do the dirty laboratory bench work.......

DIY solvated electrons

22 April 2011 - Chemistry for poor people

Do read the Journal of Chemical Education for a wide range of practical advice on how to run an affordable laboratory if you represent a cash-strapped secondary school or if you are into clandestine chemistry. On offer this month: affordable solvated electrons for urgent Birch reductions. The official method requires liquid ammonia and sodium or potassium metal, very official-looking laboratory glassware and too many safety regulations.

The relaxed method favored by Ibanez et al. (DOI) requires household chemical ammonia solution in a babyfood glass container which is heated to 40°C together with hardware-store grade caustic soda. Evolving ammonia gas is passed through drinking straws (and cooled with computer-cleaning spray) to a U-shaped tube (PVC plumbling?) cooled in a styrofoam coffee cup containing a piece of alkali metal. But where to get the metal! In true MacGyver spirit the authors simply pry open a lithium battery and extract the lithium. One ammonia/metal solution coming up!

Second chance for Barton

16 April 2011 - Orgo

Barton decarboxylation chloroform Ko et al 2011  One of those things that make chemistry interesting: chemicals often come with a distinct smell, good or bad. In a recent Organic Letters publication ko, Savage, Williams and Tsanaktsidis (DOI) present the Barton decarboxylation as an organic reaction involving chemicals producing a particularly bad smell but fortunately for this reaction they have found a solution.

The decarboxylation reaction in general is based on the reaction of an acid chloride with 1-hydroxypyridine-2(1H)-thione to form a thiohydroxamic ester which on irradiation loses carbon dioxide generating two radical fragments. The carbon radical then grabs a proton or halogen atom from a suitable source and decarboxylation is a fact. A proton donor usually is tributyltin hydride which makes the reaction expensive and with a tin-sulfur spent reagent also smelly.

The authors make it very clear that their novel hydrogen donor replacement compound was stumbled upon by accident and not the result of any clever reasoning, computation modeling or sheer genius. They were in fact looking for ways to replace carbon tetrachloride as a chlorine donor by chloroform. To their surprise chloroform surrendered not chlorine but hydrogen.

In their new protocol chloroform is both solvent and reagent without the need of working up intermediates. Only drawback: the acid chloride has to be added slowly to the thione solution because chloroform is less efficient in hydrogen transfer than the tin hydride.

Cycloparaphenylene Part II

12 April 2011 - The Belt Wars

klik hier voor de afbeelding op ware grootteAs reported on in this blog back in 2009 cycloparaphenylenes have more than just one research group interested. In addition to the two groups and their efforts already mentioned (Bertozzi, Itami), a third group led by Yamago now holds the throne and the crown with an 8-cycloparaphenylene (DOI).

At least the Itami group can now boast a crystal structure for the less impressive 12-cycloparaphenylene molecule in a new publication (Segawa et al. DOI). The synthesis has also been improved and according to note 10 Itami's method is now also the more affordable: in terms of metal catalyst costs only 6000 dollars per mole of belt (catalysis by cheap nickel) versus the 40,000 dollar per mole belt in the Yamago method (stochiometric palladium).

In the new crystal structure the rings are 150 picometer across with D3d symmetry and aligned in a herringbone pattern. The molecules are also aligned in a way that they form tubes which makes the researchers speculate host-guest chemistry opportunities or even chemically linking the hoops together in a bottom-up nanotube synthetic scheme.

Fingerprinting latest

08 April 2011 - CSI Sydney

fingerprint enhancement spindler 2011.gifNews from the department of forensic fingerprinting. Scientists venture beyond the mere identification of a person from the unique fingerprint pattern left on an object and move towards identifying the person by the chemistry of the patterns themselves.

After all, what can be observed as a print basically is sweat deposited by the owner and chemicals detected in it can reveal the owners lifestyle. In 2007 Russel (Leggett et al. DOI) devised a method to detect the nicotine metabolite cotinine in a fingerprint. In this way if the fingerprint does not match with a known individual at least you can be certain it is a smoker.

The method used hinges on gold nanoparticles which are coated first with a certain protein and then with a anti-cotinine antibody. A glass slide with a fingerprint on it is then immersed in a solution of these nanoparticles, the slide is then rinsed to wash of unreacted solution , then a second solution is added containing an antibody with a fluorescent dye attached. In the Russel experiment only fingerprints from a smoker yielded fluorescent images.

In a new adaptation Spindler et al. (2011, DOI) target L-amino acids. Main objective: visually enhance fingerprint traces. Rationale: amino acids are always present in fingerprints while existing methods rely on chemicals not always present. Opportunity: co-author Hofstetter in 1998 invented the required antibodies (DOI). Results: conventional methods do a better job with fresh fingerprints but the new method has merit when it comes to aged fingerprints. As a by-catch the method turns out to be selective for test subjects with a phenylalanine-sweetened chewing gum habit.

Artificial leaf chemistry

04 April 2011 - Catalysis

artificial leaf Richardson 2011  In photosynthesis water and carbon dioxide in the presence of light react together to form carbohydrates and oxygen. In artificial photosynthesis this process is recreated in the laboratory. In a recent venture Barry Carpenter has plotted the next step in photosynthesis based on a certain carbon dioxide reduction using amines (Richardson et al. 2011 DOI). In this system CO2 is reduced by a metal porphyrin or metal corrole with p-terphenyl (PTP) as photosensitiser. The metal is reactivated by an tertiary amine as sacrifical catalyst (a.k.a. reductive quencher) This reaction is well known but thus far not very practical because it has not been possible yet to generate the amine.
In Carpenter's novel system the amine is regenerated in a kind of internal transfer hydrogenation. The catalyst (1) reacts with CO2 to form a radical cation 2 and a CO2 radical anion. A proton is then transfered to nitrogen from the neighboring bridge and the molecules cage structure makes sure this is an efficient step. The CO2 radical anion collects two protons first from the amino group and then from the alkyl bridge in a Hofmann elimination.
The spent amino catalyst 5 now has an alkene group. In the grand scheme yet to be worked out CO2 reduction is coupled with photochemical water oxidation forming oxygen and hydrogen. Hydrogen then regenerates the catalyst. For now the Carpenter group made sure formic acid was formed and that the proposed structure for 5 was correct. Not all went according to plan: hydrogenation of 5 back to 1 with H2/Pd/C was possible in ethyl acetate but not in ethanol. The formation of 6 (after chloroform quench) is unexplained but amines are well known to behave oddly.

Total synthesis highlights

01 April 2011 - Wikibook chemistry curation project Part V

In the fifth part of our wikibook chemistry curation project again dozens of Wikipedia editors have contributed to bring you the ultimate wikibook this time on total synthesis with classics on cholesterol, vitamin B12, quinine and taxol. And why is it again that molecules have to be recreated in the lab that exist in abundance in nature? Good question!

Open here: Wikibooks/Isomerism.pdf (8.5 MB, 120 pages)
Open here: Wikibooks/Organic_Reactions.pdf (10 MB, 184 pages)
Open here: Wikibooks/Functional_groups.pdf (12 MB, 167 pages)
Open here: Wikibooks/chemical_bonds_to_carbon.pdf (6 MB, 143 pages)
Open here Wikipedia_total_synthesis.pdf (8 MB, 104 pages)