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Novel ammonia chemistry

25 June 2008 - updated 15 November

The lab of carbene pioneer Guy Bertrand recently unveiled a novel homogeneous hydroamination involving ammonia (Lavallo et al. DOI). Cheap ammonia is a common reagent in organic chemistry (take nucleophilic substitution of alkyl halides) and the first reported heterogeneous (not homogeneous) hydroamination (reaction of ethylene with ammonia and sodium metal) dates back to 1954 (Howk et al. DOI), patents not included.

Homogeneous reactions but not hydroaminations have been reported by Hartwig in 2006 (Shen et al. DOI) and by Buchwald (Surry et al. DOI) in 2007 as extensions of the Buchwald-Hartwig reaction.

In the novel system the substrate is an alkyne such as 3-hexyne and the complex catalyst is based on a N-heterocyclic carbene called CAAC (cyclic alkyl amino carbene) coordinated to gold(I) with a toluene ligand and tetraphenylborate counterion. The reaction product is the corresponding imine.

Update November 2008: More ammonia chemistry with a novel conversion of benzyl alcohol to benzylamine in a single step using a ruthenium hydride as reported by Gunanathan and Milstein (DOI).

The reaction mechanism involves oxidation of the alcohol to the aldehyde followed by imine formation and subsequent hydrogenation (transfer hydrogenation). With water insoluble alcohols the reaction takes place on-water
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20 June 2008 - reactive intermediates

A German/American/Hungarian team has recently isolated hydroxymethylene (HOCH), a singlet carbene and formaldehyde tautomer, although only in an argon matrix at 11 K (Schreiner et al. DOI). Ordinarily carbenes are too energetic for isolation but in this particular case the oxygen lone pair is able to provide stabilization just as in a N-heterocyclic carbene.

The compound was prepared by flash pyrolysis at 1000 °C of glycolic acid with extrusion of carbon dioxide, trapped at 11 K and analysed by infrared spectroscopy and UV/VIS spectroscopy. A big surprise came when hydroxymethylene was found to convert to formaldehyde. Surprisingly because the conversion rate appears to be independent of temperature, the activation energy is supposed to be very high (in silico) and because the deuterated compound (HCOD) does not rearrange at all. The effect is attributed to a tunneling effect similar to the one observed in the kinetic isotope effect.

The researchers state that their findings are bad news for astronomers who have claimed to have spotted hydroxymethylene through their telescopes: the molecule is just too unstable.

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Murchison: uracil is extraterrestrial

19 June 2008 - Space invasion

The Murchison meteorite is making headlines ever since it plummeted to earth on 28 September 1969. A whole host of organic compounds (alkanes, amino acids, carboxylic acids ) have been identified in its interior which supports the theory that the building blocks of life arrived from outer space. In one estimate infant Earth was bombarded with an annual 109 Kg of organic matter.

Detecting organic matter in meteorites is difficult because it is present in trace amounts and because either the meteor itself is contaminated or contamination sets in as a result of chemical processing. An infamous example is the Orgueil meteorite.

Novel research from no less than 7 research centers sets the record straight for the Murchison meteorite with respect to uracil, one of the building blocks for RNA. A study (Martins et al. 2008 DOI) looks specifically at uracil's content of Carbon-13. This isotope makes up 1.1% of carbon on Earth but in space this concentration is much higher due to constant cosmic bombardment (compare to carbon dating).

The researchers were able to lay their hands on 15 grams of the meteorite and in order to rule out contamination they cleverly collected a soil sample from the original Murchison location. The analytical process is extremely complicated and involves multiple rounds of extraction, a hydrolysis step (not even included in the experimental procedure), chemical derivatization and ultimately a combination of gas chromatography which isolates the uracil and then isotope ratio mass spectrometry which separates 13CO2 and 12CO2 after oxidation of the uracil.

The publication is hopelessly fuzzy about its definition of carbon-13 enrichment but lets say uracil in the meteorite is 44 promille up while that in the soil sample is 10 promille down compared to a reference sample. The researchers are thus confident that the Murchison uracil payload is indeed extraterrestrial and this concurs nicely with earlier similar research on the amino acid content.

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Oseltamivir total synthesis number 7

16 June 2008 - Oseltamivir part II

It is Oseltamivir total synthesis rush-hour this year with rendition number 7 (see earlier post on number 6) this time from the people responsible for the commercial production of the compound: Hoffmann-La Roche (Zutter et al. 2008 DOI).

Starting material: cheap 2,6-dimethoxyphenol. Novelty: stereoselectivity introduced by asymmetric biocatalysis. Disappointment: method involves azides.

Step 1 converts phenol 1 to triether 3 with the mesilate of 3-pentanol and a strong base. Bromination with NBS gives dibromide 4, and subsequent ethoxycarbonylation with CO, palladium acetate and dppp the diester 5. The next step is a all-cis hydrogenation, tagged "quite remarkable" as only one compound (6) out of 10 possible diastereomers is formed.

Alcohol deprotection (TMS-I) gives meso diol 7. Desymmetrization of this compound to chiral 8 with just one of the ester groups converted to a carboxylic acid group is performed by a pig liver esterase which again "quite remarkably" is able to endure 10% substrate loading. Next up is a Curtius degradation to 9 with capture of the intermediate isocyanate by the alcohol group.

The amine group is protected as a BOC amine and elimination of the alcohol group with sodium hydride is accompanied by a ("unique") decarboxylation to 10.

An azide group is introduced in 12 through triflate 11 (inversion of stereochemistry). In the final steps the azide is reduced to the amine 13, acylated to 14 and deprotected (HBr) to 15 as the phosphoric acid salt.

All other groups involved in this field to date advertise that their method is azide-free (dangerous!) and even the current commercial production method does not use azides. In this regard its back to square one for Roche.

Venlafaxine via hetero-Diels-Alder

15 June 2008 - OrgChem

Mauro Panunzio is showcasing his azadiene hetero-Diels-Alder protocol with the synthesis of antidepressant Venlafaxine (DOI). Earlier in 2006 he target-practised on Prozac and duloxetine ( DOI). Here is how it is done.

Benzaldehyde (1) is added to LiHMDS to imine (2) which reacts as a nucleophile with acid chloride (3) in a nucleophilic acyl substitution to azadiene (4). HDA reaction of this intermediate with cyclohexanone is mediated by Lewis acid Eufod and microwave irradiation to lactam (5). Formaldehyde adds a hydroxymethyl group and the phenyl group is removed in (6) with formic acid in a transketalization again using a microwave. In the final step Lithium aluminium hydride opens both hemiaminal groups to Venlafaxine (7).

Novelty molecular brake

12 June 2008 - Molecular Engineering

Taiwanese researchers have demonstrated a novel synthetic molecular brake , one of the components in the arsenal of molecular machines (Jye-Shane Yang et al. 2008 DOI), also see the earlier post on molecular hinges .

The earliest such system (Kelly et al. 1994 DOI, article aptly called a molecular break) is based on a trypticene rotator and a bipyridine brake which can reversibly lock and unlock by a complexation process with lead ions.

In another system (Feringa et al. 1997 (DOI)) free rotation in a biphenyl group is found to be more difficult for the cis-isomer than for the trans isomer which gives a potential for photochemical switching.

Both researchers, Kelly and Feringa, would a few years later also go head to head in the development of synthetic molecular motors.

Other systems of later date are based on a sulfide-sulfoxide redox cycle (Jog et al. 2003 DOI) and a solvent-mediated system interrupting hydrogen bonding (Alfonso et al. 2006 DOI)

In the novel Taiwanese system a three-bladed trypticene (Diels-Alder reaction product of anthracene and an aryne) is replaced by four-bladed pentiptycene molecule (same reaction but with a diaryne synthon).

To the pentiptycene scaffold is attached a stilbene unit at the central benzene ring. Free rotation around the aryne carbon and alkene bond is very easy with 109 revolutions per second (room temperature). Photochemical trans-cis isomerization generates the the cis-isomer, forcing the benzene ring in between the blades. This is effectively a break with the number of revolutions per second reduced to just 3 (based on NMR spectroscopy). The process is reversible by selecting a different wavelength.

A big difference with the molecular motors is that motion is not unidirectional , that is the propelling motion goes back and forth. In this sense an enthusiastic YouTube cartoon related to this particular research is misleading.

New avenue for phosphorous hydrolysis

11 June 2008 - InorgChem

White phosphorous (P4) is a very reactive and pyrophoric chemical. To shield it from oxygen it is stored in water. This does not mean phosphorous does not react with water. Alkaline hydrolysis yields sodium hypophosphite, sodium phosphite and phosphine. Acid hydrolysis gives phosphoric acid (H3PO4) and phosphine.

Novel research by Barbaro et al. (DOI) has revealed an alternative hydrolysis route when the P4 reactivity is tuned by coordination with the organometallic complex CpRu(PPh3)2Cl, a member of the ruthenocene family. The resulting compound is found to react with water to form phosphorous acid H3PO3 and a novel air-stable phosphane complex which itself no longer reacts with water. The researchers hope this finding may lead to new chemical reagents. Hype word-count for this article: 4 (breakthrough, peculiar, spectactularly, surprisingly).