New options with nitrogen

HOUSTON—Ketones are natural carbon-based compounds that are a regular building block for chemical engineering, and the primary amino group (NH2)—which contains one nitrogen atom and two hydrogen atoms—is a functional group found in a variety of chemical products. When ketones are functionalized with a primary amino group at the alpha carbon, it forms a primary alpha-aminoketone.

These compounds are important base constructs for creating pharmacologic products, as well as those for other applications such as farming fertilizers and pesticides. In research that will shorten the development steps necessary for such compounds, a team from Rice University shared news in February that they had engineered a one-step method for adding nitrogen to alpha-aminoketones. The work, reported in a paper entitled “Aza-Rubottom Oxidation: Synthetic Access to Primary α-Aminoketones,” was published last month in the Journal of the American Chemical Society.

“It’s a good precursor, because there’s no extra functionalization, like an acyl group, on the NH2 and it can then be converted to whatever you want,” explained László Kürti, an associate professor of chemistry and synthetic organic chemist at Rice University. “Previously, this was the issue: people would put nitrogen in there with extra functionality, but the further processing necessary to get to a free NH2 was complicated.”

“Oxygen is routinely put into the alpha position,” he said. “But nitrogen, no. We are the first to show this is possible in a large number of substrates, and it’s simple. It turns out that the solvent itself catalyzes the reaction.”

This new approach was discovered by postdoctoral researcher Zhe Zhou when he combined a silyl enol ether and a nitrogen source in hexafluoroisopropanol at room temperature. The resulting mixture was similar to Rubottom oxidation, a technique by which to oxidize enol ethers. Zhou and Qing-Qing Cheng, another postdoctoral researcher and co-author on the paper, refined this method and tested it further by creating 19 aminoketones, three of which were synthetic amino acid precursors. Kürti called the latter “significant for drug design,” adding that “The enzymatic processes in living organisms are not going to attack them, because they don’t fit in the enzymes’ pockets.”

“Our amination method promises to replace a common three-step process to make alpha-aminoketones, and the yield, comparably, is very good,” Zhou said. “In the standard process, each step cuts the yield, so one-step process is still superior even if the yields are identical, because it takes less time and there’s less risk of something going wrong. The last thing you want is to get eight steps from the beginning and then ruin it on the ninth because the conditions are not selective enough. Cutting steps is always beneficial in organic synthesis.”

In other molecular news out of the University recently, a team comprised of international researchers, including Rice materials scientist Edwin Thomas, made a new discovery regarding the formation of block copolymers. They learned that the left or right “chirality”—a property of asymmetry in which a molecule can’t be superposed on its mirror image, similar to the difference between your left and right hand—of a molecule is determined by the initial monomers of a polymer. Per the Rice press release, a “left-handed” molecule could be promising in drug development, while its chiral counterpart, the “right-handed” version, is toxic. In their work, the chirality of the copolymers “replicated itself as the microscopic material came together to form larger scale spiraling structures akin to those commonly found in nature,” as noted in a press release. The research appeared in the Proceedings of the National Academy of Sciences.

“From a properties standpoint, chirality is pretty big for optics,” Thomas said of their work. “The hope is that we can control self-assembly of chiral entities to make super-chiral entities 10 or 100 times bigger so that they are able to interact with visible or even infrared light.” He added that the resultant polymers are elastic, and could potentially be engineered to react to certain wavelengths of light.

“We could make photonic crystals that reflect right-handed light and transmit left-handed light,” Thomas explained. “With circularly polarized light, it could transmit for one handedness and reflect for the other handedness. It would be a mirror for right and perfectly transparent for left.”