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Hexacyclohexylcyclohexane

27 July 2020 - Chemical Zoo

Dillenburger et al. report the chemical anaysis of hexacyclohexylcyclohexane which is cyclohexane with on every carbon atom a cyclohexyl unit (DOI). To arrive at this result hexaphenylbenzene was hydrogenated in an autoclave with hydrogen and palladium on carbon at 250 bar and 150 degrees for four days. A seemingly simple reaction but the authors noted that while the starting compound had disappeared after 1 day, from then on product increase was only marginal. It also did not help that in MS-APCI a compound may partially dehydrogenate again. The final reaction product (76% yield) did contain two compounds, the sought-after and fully hydrogenated one and hexahexylbenzene which is an intermediate. Although both compounds were well resolved in HPLC it was not possible to separate them with a regular silica column. In one recrystallisation method it was however possible to separate the two compounds as individual crystals. From X-ray crystallography it was then found that the central cyclohexyl chain in one isomer forms a chair configuration and in another isomer a twisted boat. All cyclohexyl substituents are chairs.
Not sure what to make of it. The authors do not mention synthesis because the desired compound was not isolated. But with an additional effort? The reaction was not repeated with a reaction time of just one day. If compounds resolve in HPLC, preparative HPLC must be in reach. Hexaphenylbenzene costs just 115 euro per gram and will not blow the research budget. Do people still do melting points? Vacuum sublimation?

A case of contaminated paracetamol

10 July 2020 - Pharma

News item in the Netherlands: newspaper NRC and investigative TV program Zembla have uncovered contaminated paracetamol for sale to consumers (NRC piece). The contaminant is 4-chloroaniline, a compound that is listed at the European Food Safety Authority (EFSA) as a genotoxic carcinogen. The levels found (6 mg per kilo) are 18 times the level considered safe. Other national health authorities interviewed for the news report were less alarmed. They do not see a need for a product recall.
The paracetamol raw material was produced in China and currently in high demand due to the corona pandemic. The synthesis method is not one listed on the Wikipedia page but a method starting from chlorobenzene. It is permitted to use this method since 2002, widely used in the world not just China and considered a cheaper production method. Drug manufacturers in Europe are not always required to disclose their raw-material producers, in the Netherlands it is a trade secret but in Italy it is public information.

But what is the synthesis method of not one of the classics? A Quora page has one answer: chlorobenzene is nitrated to 4-nitrochlorobenzene, then nucleophilic aromatic substitution with sodium hydroxide and HCl workup gives 4-nitrophenol, reduction with hydrogen and platinum gives 4-aminophenol and finally acylation with acetic acid gives the paracetamol (N-(4-hydroxyphenyl)acetamide). Still does not explain the chloroaniline. My best guess is incomplete removal of 4-nitrochlorobenzene starting material in the 4-nitrophenol synthesis. Preventable because the solubility of reactant and product are very dissimilar.

But is there reason for concern? It does not help that the European ESFA has way lower safety limits than national authorities, companies conduct their own quality checks on Chinese imports, establish that raw paracetamol meets expectations then proceed to formulate and sell. NRC news does not have a scoop.

The robotic chemist

10 July 2020 - Automation

The University of Liverpool has introduced a mobile robotic chemist. The features of this oversized suitcase on wheels with an industrial robot arm on top are described by Burger et al. in the journal Nature (DOI). They are impressive. It navigates through a regular laboratory with a combination of lidar (same as in cars) and touch-feedback with an accuracy of 0.12 mm that it allows humans to work in the same space (lots of industrial robots are lethal and therefore live in cages). The only thing that stops the robot from working is a battery recharge time of three hours but can be easily remedied. Having the same dexterity and mobility as a human the robot can do a lot of mundane things working with ordinary lab equipment like filling vials, capping ,sonicating and operating a GC.

The robot was put to work in water splitting research. The number of variables in the design (photocatalyst type, pH, ionic strength, surfactant yes/no, scavenger yes/no) would result in nearly 100 million individual experiments. Not that the robot or an army of robots would mind but fortunately Bayesian optimization helped to reduce the number to 700 (clocking 2.7 km in 8 days) required to find a promising condition for hydrogen evolution.

But why is building the robot part academic research? This type of robot should be highly attractive to a lot of large commercial analytical laboratories which should be willing to throw a lot of resources into their development, out-competing universities. After all, the Tesla car is being developed in industry and not in academia. In corona times there is an especially urgent need for analytical laboratories running on a massive scale, our lives depend on it. Not mentioned in the article but robots do not shed DNA - is DNA contamination still an issue in PCR? The acknowledgements make clear the robot arm supplier did help in parts of the design and one commercial company called CSols Inc. (a laboratory informatics company) funded part of the research.

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