"Cool" combination produces easier carbon bonds

[Plazma Inferno!]

Almost 90 percent of known active pharmaceutical ingredients contain one or more ‘heterocyclic aromatic rings’, structures that contain atoms of at least two different elements . Most of these rings contain carbon and nitrogen atoms. ‘Connecting two carbon atoms is a crucial step in synthesizing heterocycle-containing molecules’, explains University of Groningen Associate Professor of Synthetic Organic Chemistry Syuzanna Harutyunyan.
But carbon-carbon bonds are notoriously difficult to make. An intermediary step is often required, but this makes the synthetic process longer and thus less efficient. Furthermore, many pharmaceutically relevant heterocyclic molecules are chiral, which means they are present in two mirror-image versions. These versions often exhibit different biological activities. ‘So we need a way to create the right chiral version as well’, says Harutyunyan.
In the Science paper, Harutyunyan and her team describe just that: the efficient creation of carbon-carbon bonds with a high chiral selectivity for a wide range of nitrogen-containing heterocyclic molecules. For this breakthrough, Harutyunyan reverted to methods from the early twentieth century. Grignard reagents, originally developed by Victor Grignard, the first laureate of the Nobel Prize for Chemistry in 1912, are still an important tool in creating carbon-carbon bonds.

http://www.rug.nl/news/2016/04/_cool_-combination-produces-easier-carbon-bonds?lang=en

Paper: http://science.sciencemag.org/content/352/6284/433

 

[exchemist]

Almost 90 percent of known active pharmaceutical ingredients contain one or more ‘heterocyclic aromatic rings’, structures that contain atoms of at least two different elements . Most of these rings contain carbon and nitrogen atoms. ‘Connecting two carbon atoms is a crucial step in synthesizing heterocycle-containing molecules’, explains University of Groningen Associate Professor of Synthetic Organic Chemistry Syuzanna Harutyunyan.
But carbon-carbon bonds are notoriously difficult to make. An intermediary step is often required, but this makes the synthetic process longer and thus less efficient. Furthermore, many pharmaceutically relevant heterocyclic molecules are chiral, which means they are present in two mirror-image versions. These versions often exhibit different biological activities. ‘So we need a way to create the right chiral version as well’, says Harutyunyan.
In the Science paper, Harutyunyan and her team describe just that: the efficient creation of carbon-carbon bonds with a high chiral selectivity for a wide range of nitrogen-containing heterocyclic molecules. For this breakthrough, Harutyunyan reverted to methods from the early twentieth century. Grignard reagents, originally developed by Victor Grignard, the first laureate of the Nobel Prize for Chemistry in 1912, are still an important tool in creating carbon-carbon bonds.

http://www.rug.nl/news/2016/04/_cool_-combination-produces-easier-carbon-bonds?lang=en

Paper: http://science.sciencemag.org/content/352/6284/433

Finally I have got round to revising a bit about Grignard reagents and the Grignard reaction, in order to understand this. Ingenious idea to try very low temperature, to stop the Grignard reagent reacting with the Lewis acid. But -78C is pretty damn cold for chemical reactions of any sort: I'm surprised it goes at any rate at such temperatures, but clearly it does.

I always found the Grignard reagent rather exotic - the idea of magnesium forming a (largely) covalent bond with carbon. But then, magnesium is fairly close to the metal/non-metal diagonal, has an atomic radius only about double that of carbon (so orbital overlap can be reasonable), and the electronegativity difference between magnesium and carbon is quite a bit less than between magnesium and the typical anions found in its ionic salts.

Clever chap, Grignard......