Chemists have synthesized the first stable molecule whose chirality is solely attributed to a stereogenic oxygen, according to a new study (Nature 2023, DOI: 10.1038/s41586-023-05719-z).
Though carbon is famous for its chiral capabilities, other atoms such as phosphorus, sulfur, and nitrogen can also serve as stereogenic centers in organic molecules. Oxygen has been less cooperative. Oxonium ions—compounds that contain a positively charged oxygen bonded to three substituents—have the potential to be chiral, but they are notoriously reactive, say Jonathan W. Burton and Martin D. Smith, synthetic organic chemists at the University of Oxford. Further, the lone pair of electrons on the oxygen within the oxonium ion can invert the molecule’s geometry, creating a mixture of two chiral forms. The few previous examples of chiral oxonium ions are too unstable to be isolated, or contain other stereogenic centers in addition to the chiral oxygen; so the search for chiral oxonium ions languished in the literature, they say. Burton, Smith, and their colleague Robert S. Paton, a computational chemist at Colorado State University, realized they had an opportunity to try their hand at solving this stereochemical puzzle.
These researchers reasoned they could lock the lone pair in place by encircling the oxygen with a bulky ligand that would prevent the molecule from inverting between chiral geometries. So they synthesized a series of oxonium ions in which the stereogenic oxygen is bonded to various fused triaryl ring systems. The team analyzed the structure and stability of this first set of triaryloxonium ions in the lab, then used computational simulations to rationalize their chiral properties. These simulations also enabled the team to predict how best to tweak the ring system to increase the stability of their next chiral compound. The team went back to the lab to synthesize this proposed molecule, which they isolated as an unexpectedly shelf-stable crystalline salt.
“I was really surprised at how tractable the synthesis was,” says Smith. Despite popular convictions, this oxonium ion is “much easier to handle and to make than you would think,” he adds. The team says the success of this work demonstrates the growing predictive power of computer simulations in chemistry. “We’re moving towards the point where we can usefully use computation to help select what you’re actually going to the lab to synthesize,” Paton says.
Jonathan Clayden, an organic chemist at the University of Bristol who was not involved in the study, says it’s striking that chemists have known a molecule like this was possible in principle, but no one had managed to make it before now. He says this research is “a lovely piece of work” that demonstrates a productive interplay between computational and empirical methods.
Clayden and the researchers suggest that chiral oxonium ions might someday have applications as a new class of chiral counterions, which are specialized reagents used in the synthesis of complex organic compounds. For now though, Burton, Paton, and Smith are excited to introduce a “cool and unusual molecule” to the stereochemical catalog. “It’s nice to do something just very fundamental,” Smith says.
This story was updated on March 24, 2023, to include additional statements from Martin Smith and Robert S. Paton and to clarify the means by which computational simulations advanced the work. An illustration showing the crystal structure of the chiral triaryloxonium ion was also added.