Control of stereogenic oxygen in a helically chiral oxonium ion
Chirality – when a molecule cannot be superimposed on its mirror image – is of fundamental importance in determining chemical interactions in the biological world. Researchers from Jonathan Burton and Martin Smith’s research groups, working alongside Robert Paton’s lab at Colorado State University (CSU), have synthesized the first example of a molecule where an oxygen atom is the only stereogenic centre (the focus of the molecule’s chirality).
Oxonium compounds, with an oxygen atom bound to three other atoms, are typically reactive and short-lived. Oxygen atoms in these molecules tend to quickly “flip” between mirror-image forms, a process known as racemization. Many oxonium ions are really reactive, so their synthesis and isolation can also be particularly challenging.
Using a combination of synthetic, analytical and computational studies, Owen Smith and Maddie Hindson (SBM CDT DPhil students in the Smith/Burton groups) and Mihai Popescu (postdoc in the Paton group, CSU) were able to establish new design rules to capture a stable, chiral oxygen atom. Their study, published today in Nature, describes how they designed, synthesised, and characterised a triaryl oxonium ion that could be isolated at room-temperature and was stable to racemization.
Using triaryl-substituted oxonium ions as starting points, they constructed organic scaffolds that hold the molecule together, slowing down racemization and enabling the room-temperature isolation of these chiral molecules.
The number of organic scaffolds that could be synthesized is, in principle, infinite, and making such molecules can be laborious and involves multiple synthetic and purification steps. So, the team used quantum mechanical calculations to narrow down their options, arriving at a final molecule that contains a central positively charged oxygen atom directly attached to three aromatic substituents. These additional ring systems gave the molecule a helical-like 3D structure that slows down racemization.
They were able to isolate enantioenriched oxonium ions and establish their absolute configuration by single crystal X-ray diffraction. Using HPLC and NMR spectroscopy, they were able to show that the 7-ring containing oxonium ion has a half-life to inversion of more than a month at room temperature – and as predicted, is indefinitely stable.
The discovery of a fundamentally new example of molecular chirality demonstrates our ability as chemists to design and synthesize new matter based on a computational blueprint. Given the fundamental importance of chirality in catalysis, medicine, and materials, it will be exciting to explore the properties of chiral oxygen-atom-containing compounds in future studies.